SA Guide

GUIDELINES FOR THE
REGISTRATION OF
MEDICINES IN
SOUTH AFRICA

Version 6

2
GUIDELINES FOR THE REGISTRATION OF MEDICINES.

INDEX:

1. INTRODUCTION ......................................................................................P007

2. GENERAL .................................................................................................P008
2.1 HOW TO APPLY ...............................................................................P008
2.2 ELIGIBILITY......................................................................................P009
2.3 LANGUAGE ......................................................................................P009
2.4 WHERE TO SEND APPLICATIONS..................................................P009
2.5 TRANSITIONAL CONVERSION TABLE...........................................P009

3. WHEN IS A PRODUCT REGARDED A MEDICINE ...................................P010

4. PREPARING AND SUBMITTING AN APPLICATION FOR
REGISTRATION OF A NEW MEDICINE....................................................P011
4.1 CONFIDENTIALITY...........................................................................P011
4.2 TYPES OF APPLICATIONS..............................................................P011
4.3 GUIDELINES ON SAME/SEPARATE APPLICATIONS....................P012
4.4 FORM AND FORMAT OF AN APPLICATION FOR .........................P013
REGISTRATION
4.4.1 General ..................................................................................P013
4.4.2 Presentation of copies and number of copies required ....P014
4.5 FEES .................................................................................................P015
4.6 REQUIREMENTS FOR COMPLETION OF AN .................................P016
APPLICATION FOR REGISTRATION DOSSIER
4.6.1 Administration Data (front page) .........................................P016
4.6.2 Part 1 A - Professional Package Insert................................P017
4.6.3 Part 1 B - Patient Information Leaflet ..................................P022
4.6.4 Part 1 C - An example or facsimile of the label ...................P023
4.6.5 Part 1 D - Foreign registration .............................................P024
4.6.6 Part 1 E - Pre-clinical studies...............................................P024
4.6.7 Part 1 F - Clinical studies .....................................................P026
4.6.8 Part 2: Pharmaceutical and Anal ytical ...............................P029
Requirements
4.6.8.1 Part 2A -The active raw material (Development ...P030
Chemistry and characterisation)
4.6.8.2 Part 2B - Formulation.............................................P032
4.6.8.3 Part 2C - Raw material specifications and raw.....P033
control procedures
4.6.8.4 Part 2D - Containers and packaging materials.....P035
4.6.8.5 Part 2E - The manufacturing procedures .............P036
4.6.8.6 Part 2F - The finished product...............................P036
4.6.8.7 Part 2G - Stability ...................................................P037
4.6.8.8 Part 2H - Pharmaceutical development ................P038
4.6.8.9 Part 3 - In vivo and/or in vitro equivalence...........P039
studies as proof of efficacy
4.6.8.10 Part 4 - Details relating to the premises on ..........P041
which primary production is undertaken and to
the staff involved in production and testing
of a biological medicine

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ADDENDA TO 4.6
Addendum A - Guideline for stability testing ................................P042
Addendum B - Submission of Validation protocols and ..............P068
Validation reports
Addendum C - Exemption from re-identification and ...................P073
Re-assay of imported medicines
Addendum D - (1) Manufacturing process flow diagram..............P075
Addendum E - Al cohol content of medicines for oral ..................P077
Ingestion

4.7 CRITERIA FOR FAST-TRACK ASSESSMENT.................................P079
4.7.1 Types of products that will be considered for an...............P079
expedited review
4.7.2 Criteria and other factors that will be examined ................P079
in making a decision for fast-tracking

4.8 PROPRIETARY NAME POLICY........................................................P079

4.9 STANDARD PACKAGE INSERT INFORMATION FOR....................P082
CERTAIN CATEGORIES/INGREDIENTS
4.9.1 General drowsiness warning for Antihistamines ...............P082
(Old Generation)
4.9.2 General drowsiness warning for Antihistamines ...............P082
(New Generation)
4.9.3 Non-content claim: " Contains no Aspirin" .........................P083
4.9.4 Dependence producing potential of medicines..................P083
4.9.5 Important patient information to be included in all ............P083
package inserts of medicines intended for Malaria
Prophylaxis
4.9.6 Use of medicines during pregnancy and lactation.............P083
4.9.7 Package inserts/slogans ......................................................P083
4.9.8 Package insert requirements: Water for Injection..............P084
4.9.9 Products containing Ace-inhibitors ....................................P084
4.9.10 Antibiotics indicated for the treatment of ...........................P084
Beta-Haemolytic Streptococcal infections
4.9.11 Reye's Syndrome warning for medicines containing ........P084
Aspirin
4.9.12 Benzalkonium Chloride-preserved Ophthalmological .......P084
preparations
4.9.13 Package inserts for Benzodiazepine...................................P085
4.9.14 Benzodiazepine or Benzodiazepine-like .............................P086
4.9.15 Beta-2 Agonists ....................................................................P087
4.9.16 Standardized package inserts for Beta-Blocking agents...P087
4.9.17 Warning for inclusion in Beta-Blocker and Clonidine........P089
package inserts
4.9.18 Beta-Lactam Antibiotics.......................................................P089
4.9.19 Bismuth containing medicines............................................P089
4.9.20 Package inserts for Clofibrate containing medicines ........P089
4.9.21 Contrast Media - Water Soluble - Boxed Warning ..............P090
4.9.22 Exemption from package insert requirements in ...............P090
respect of contact lens solutions

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4.9.23 Warning for inclusion in Potent Topical Corticosteroid ....P091
package inserts
4.9.24 Products for topical use containing Corticosteroids.........P091
4.9.25 Co-Trimoxazole.....................................................................P091
4.9.26 Dicyclomine in infants..........................................................P091
4.9.27 Package inserts for Disopyramide preparations ................P091
4.9.28 Fluoroquinolone Antibiotics ................................................P091
4.9.29 Boxed warning for Glibenclamide & Gliclazide..................P092
4.9.30 Iodine and Iodine containing medicines .............................P092
4.9.31 Package inserts for Metoclopramide preparations ............P092
4.9.32 Warning to be included in the package inserts for all .......P092
products containing Metronidazole
4.9.33 Non Steroidal Anti-Inflammatory Agents ............................P092
4.9.34 Package insert warning for Oestrogen-containing ............P092
Products
4.9.35 Phenylbutazone & Oxyphenbutazone.................................P093
4.9.36 Potassium Supplementation................................................P093
4.9.37 Long-acting Sulphonamides................................................P094
4.9.38 Tamoxifen .............................................................................P094
4.9.39 Tartrazine (FD & C Yellow No 5) Warning ...........................P094
4.9.40 Topical Tretinoins - statement of Pregnancy and ..............P094
Lactation
4.9.41 Tricyclic Antidepressants ....................................................P095
4.9.42 Statement on Eosinophilia Myalgia Syndrome to be .........P096
included in package inserts of L-Tryptophan
containing products
4.9.43 Codeine Warning ..................................................................P097

4.10 PROOF OF EFFICACY......................................................................P097
4.10.1 General ..................................................................................P097
4.10.2 Bioavailability and Bio-equivalence....................................P100
4.10.2.1 Introduction ............................................................P100
4.10.2.2 Definitions ..............................................................P100
4.10.3 Preliminary considerations for a generic or new ...............P101
formulation registration application
4.10.3.1 Registration dossier...............................................P101
4.10.3.2 Standards of active ingredient(s)..........................P101
4.10.3.3 Criteria for waiver of in vivo bioequivalence........P102
testing
4.10.3.4 Interspecies extrapolation.....................................P102
4.10.3.5 Selection of reference product ..............................P102

4.10.4 In Vivo Bioequivalence Testing ...........................................P103
4.10.4.1 Comparative bioavailability studies......................P103
4.10.4.1.1 Type of design ......................................P103
4.10.4.1.2 Treatment and dose selection..............P104
4.10.4.1.3 Trial subjects and number ...................P104
4.10.4.1.4 Sample collection .................................P105
4.10.4.1.5 Drug analysis ........................................P106
4.10.4.1.6 Pharmacokinetics analysis ..................P106
4.10.4.1.7 Statistical analysis................................P107
4.10.4.1.8 Trial reporting .......................................P109

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4.10.4.2 Pharmacodynamic (Pharmacological ...................P109
end-point) studies
4.10.4.3 Clinical end-point (efficacy) studies .....................P109
4.10.5 Trial Protocol Requirements................................................P110
4.10.6 Dissolution............................................................................P110
4.10.7 Other......................................................................................P112
4.10.7.1 Disintegration.........................................................P112
4.10.7.2 Acid-neutralising capacity.....................................P112
4.10.7.3 Microbial growth inhibition zones.........................P113
4.10.7.4 Proof of release by membrane diffusion ..............P113
4.10.7.5 Particle size distribution........................................P113
4.10.7.6 Blanching test ........................................................P113
4.10.7.7 Any other method ..................................................P113
4.10.8 Definitions.............................................................................P113
4.10.8.1 Pharmaceutical equivalents ..................................P113
4.10.8.2 Therapeutic equivalent ..........................................P113
4.10.9 Application Control Document for Bioequivalence............P117
Studies

5. APPLICATION FOR THE AMENDMENT TO A REGISTRATION..............P120
DOSSIER FOR A MEDICINE
5.1 General information applicable to all applications for ..................P120
amendments
5.2 Application to amend the particulars regarding proprietary.........P121
name, applicant, manufacturer, packer, final product release
control and final product release responsibility
5.2.1 General information..............................................................P121
5.2.2 Change of proprietary name................................................P122
5.2.3 Change of applicant .............................................................P122
5.2.4 Change of/additional: Manufacturer,...................................P124
Packer/FPRC/FPRR
5.2.5 Change of name of applicant only.......................................P126
5.2.6 Change of address of applicant...........................................P126
5.2.7 Change of address of applicant / manufacturer / ...............P127
packer / laboratory

Appendix A1.....................................................................................P128
Appendix A2.....................................................................................P129

5.3 Application for the amendment to a Package Insert......................P131
5.4 Guidelines for amendment of registration dossier already...........P131
lodged with MCC, pertaining to Parts 2A, 2B, 2C, 2D, 2E, 2F,
2G and 2H of the application registration dossier
5.4.1 General ..................................................................................P131
5.4.1.1 Format of submission of Amendments to............P132
MRF 1.0 Parts 2 A-H or
MBR1 Annexures 2 to 11, 13 and 16
5.4.2 Permitted amendments pertaining to Parts 2A-H...............P135
of the application registration dossier
5.4.2.1 Permitted amendments..........................................P136

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5. FORMS
MRF 1.0......................................................................................................P139

PART 1 A SCIENTIFIC PACKAGE INSERT........................................P141
PART 1 B PATIENT INFORMATION LEAFLET ..................................P142
PART 1 C FACSIMILE OR SPECIMEN OF THE LABEL.....................P143
PART 1 D FOREIGN REGISTRATION ................................................P144
PART 1 E PRE-CLINICAL STUDIES...................................................P145
PART 1 F CLINICAL STUDIES ...........................................................P146
PART 2 A (i) MEDICINES OTHER THAN BIOLOGICALS.......................P147
ACTIVE RAW MATERIAL (DEVELOPMENT CHEMISTRY
AND CHARACTERISATION)
PART 2 A (ii) PRIMARY PRODUCTION LOT (BIOLOGICAL ...................P148
MEDICINES)
PART 2 B (i) FORMULATION..................................................................P149
PART 2 B (ii) FORMULATION OF THE RECONSTITUTING LIQUID.......P150
FOR THE FINAL FILLING LOT FOR BIOLOGICAL
MEDICINES
PART 2 C SPECIFICATIONS AND CONTROL PROCEDURES..........P151
FOR RAW MATERIALS USED IN THE MANUFACTURE
OF THE FINAL PRODUCT (MEDICINES) OR FINAL
FILLING LOT AND DILUENT (BIOLOGICALS)
PART 2 D CONTAINER AND PACKAGING MATERIAL.....................P152
PART 2 E MANUFACTURING PROCEDURES...................................P153
PART 2 F FINISHED PRODUCT - FINAL FILLING LOT & .................P154
DILUENT (BIOLOGICALS)
PART 2 G STABILITY DATA - THE FINISHED PRODUCT.................P155
PART 2 H PHARMACEUTICAL DEVELOPMENT...............................P156
PART 2 I EXPERTISE AND PREMISES USED FOR.........................P157
MANUFACTURING OF BIOLOGICAL MEDICINES
PART 3 IN VIVO AND/OR IN VITRO EQUIVALENCE STUDIES .....P158
AS PROOF OF EFFICACY

MRF 2.0 MCC SCREENING FORM FOR APPLICATIONS FOR ......P159
REGISTRATION OF MEDICINES
MRF 3A.0 MCC - AMENDMENT APPLICATION.................................P163
MRF 3B.0 MCC - AMENDMENT APPLICATION FORM......................P166
MRF 3C.0 MCC - APPLICATION FORM FOR THE AMENDMENT .....P169
TO A PACKAGE INSERT

7
MCC

GUIDELINES FOR THE REGISTRATION OF MEDICINES.

NOTE: These guidelines outline the format and data requirements for preparation
and submission of an application for registration of medicines, and should be read in
conjunction with Medicines and Related Substances Control Act 101 of 1965, and
the regulations to this Act.

1. INTRODUCTION

The registration of medicines in South Africa is governed by the provisions and
requirements of the Medicines and Related Substances Act 101 of 1965, and the
Regulations and Guidelines published in terms thereof.

These Guidelines describe the information required with the application form for
registration of medicines. The information submitted will be evaluated by the
Medicine Registration Section of the Medicines Control Council in terms of Section
.

The aim of these Guidelines is to assist applicants in the preparation of
documentation for the registration of a new medicine (for a new chemical entity or for
a multi source interchangeable product), an old medicine, or for an amendment of an
existing medicine registration or old medicine application.

It is a legal requirement that data submitted for evaluation must satisfactorily
substantiate the quality, safety and efficacy of the product for the purposes for
which it is intended. The Guidelines are meant to assist the applicant in meeting the
requirements of the Act. It is acknowledged that in some instances scientific
developments may dictate alternative approaches. Hence, where the applicant
chooses to deviate from a guideline, the decision must be fully explained, motivated
and justified in the expert reports submitted with the application.

Whenever there is doubt, applicants are advised to consult the Medicines Control
Council for confirmation and clarification before completing the application form.
Applicants must always refer to the current version of the relevant Guidelines for
the registration of Medicines in South Africa before completing the application
form.

Guidelines are constantly evolving as a result of scientific developments and harmonisation
of the requirements of the major overseas regulatory authorities. MCC endeavours to keep
abreast of such developments and keep its application requirements and evaluation policies
in line with best international practice.

8

2. GENERAL

2.1 HOW TO APPLY

The Medicines Control Council requires that an application be submitted for
authorisation to market a medicine, veterinary medicine, complementary medicine
and a medical device in South Africa.

These guidelines are relevant only to medicines.

2.1.1 General Information

2.1.1.1 The administrative processing of the application cannot proceed unless the basic
requirements that are checked for during the screening process, outlined in the
regulations, are complied with.

2.1.1.2 The application will be considered complete only if the submission is in the proper
format, with the required data packages, the correct number of copies and the
appropriate prescribed application fee.

2.1.1.3 All applications must be accompanied by a duly completed screening form that
should be used by the applicant as a checklist for completeness before submitting
an application.

2.1.1.4 Applicants should ensure that only the required and relevant information is included
in all submissions. (No raw data i.e. individual patient data are to be included
unless considered necessary)

2.1.1.5 The application will not be allocated an application number until such time that it
has been successfully screened and the non-refundable screening fee paid in full.

2.1.1.6 Once the application has been accepted, it will be logged in, acknowledged, and
processed for evaluation. At this point, time lines will be allocated for the
evaluation, and this will be communicated to the applicant.

2.1.1.7 All applications will be subjected to an in-house pre-evaluation process, from which
the application will be forwarded to an in-house or external evaluator depending on
the nature of the application. Once the evaluation is in progress, the applicant will
be informed on when the report will be presented to the Standing Committee.
If any additional information is required for completion of the evaluation of the
application, this will be communicated to the applicant, with time lines within which
to respond.

2.1.1.8 At no stage will the applicant be permitted to communicate directly with the
evaluator. All queries and concerns must be communicated through the regulatory
authority so that they can be logged in and processed.

9
2.2 ELIGIBILITY

An application must be made by a person resident in South Africa, a closed
corporation incorporated in South Africa or a company with at least a responsible
delegated person residing in South Africa. An Applicant Master File must have been
submitted to MCC and a satisfactory Applicant Inspection performed (incorporate
relevant circular). The Managing Director or designated pharmacists are eligible to
sign the applicant form.

2.3 LANGUAGE

All applications and supporting data submitted to the Medicines Control Council must
be presented in English. Any documents in languages other than English must be
accompanied by a translation into English.

2.4 WHERE TO SEND APPLICATIONS

Applications should be posted to Private Bag X 828, Pretoria 0001 or delivered to
Room 1133, Hallmark Building, 237 Proes Street, Pretoria, where they will be logged
and acknowledged. All correspondence should be addressed to the Registrar of
Medicines. Applications received in any other manner other than as stated above will
not be considered for processing.

2.5 TRANSITIONAL CONVERSION TABLE

For application for registration of medicines the old MBR1 form for application for
registration prescribed by Act 101 of 1965 is now replaced by the Medicines
Registration Form (MRF) 1.O. There will no longer be a separate form for biological
medicines.

Circulars issued before and during the transformation process referred to the
Annexures of the previous MBR1 application form. In the transitional period the
circulars will still be applicable. These Guidelines will be continuously updated to
reflect policies developed by the Medicines Control Council.

10
For ease of reference the following conversion table is included.

MBR1 FORM MEDICINES
REGISTRATION
FORM 1.O
SUBJECT
Annexure 1 Part A, B, C PI / PIL / Label
Annexure 2 Part 2B Formulation
Annexure 3 Part 2A Active raw material
Annexure 4 Part 2C Raw materials
Annexure 7 Part 2F Finished product
Annexure 8 Part 2D Container and packaging
material
Annexure 9A Part 2F Finished product
Annexure 9B Part 2D Container and packaging
material
Annexure 10 Part 2G Stability data
Annexure 11 Part 2E Manufacturing
procedures
Annexure 12 Part 1D Foreign registration
Annexure 13 Part 3 Part 3
Annexure 14 Part 1E Pre-clinical studies
Annexure 15 Part 1F Clinical studies
Annexure 16 Part 2H Pharmaceutical
development

3. WHEN IS A PRODUCT REGARDED A MEDICINE

A product is liable for registration with the Medicines Control Council if:

a. Any of the ingredients of a product is listed in one of the Schedules to the Act

b. The product is a medicine by virtue of the definition of a medicine. The
Medicines and Related Substances Control Act, 1965 (Act 101 of 1965) defines a
medicine as:

"any substance or mixture of substances used or purported to be suitable for use or
manufactured or sold for use in:

(1) the diagnosis, treatment, mitigation or prevention of disease, abnormal physical
or mental state or the symptoms thereof in man; or
(2) restoring, correcting or modifying any somatic or psychic function in man;
and includes any veterinary medicine.

c. If the product falls under any of the pharmacological classifications as specified
in Regulation 4 & 5 of the Regulations to Act 101 of 1965.

11
d. In addition, the intended use of a product, even if no claims are reflected on the
label, may still render a product registerable. If a substance is not ordinarily
eaten or drunk by man, it cannot be considered a foodstuff only because there
are no apparent claims. Legislation requires that every medicine shall be
registered by the Council before it may be sold/marketed.

Note: Unregistered medicines in terms of the Act are also included and will required
to be registered.

4. PREPARING AND SUBMITTING AN APPLICATION FOR REGISTRATION OF A
NEW MEDICINE:

4.1 CONFIDENTIALITY
The confidentiality of information submitted to the Medicines Control Council is
preserved by the Act. The MCC, Committee member or staff member may disclose
to any person any information in relation to the acquisition, supply, marketing,
importation, export, development, manufacture or research in connection with any
medicine, complementary medicine, veterinary medicine or medical device or any
other matter related thereto. Information may only be divulged following an order
issued by a court of competent jurisdiction. The MCC may insist on written
confirmation of the identification and affiliation of an individual inquiring telephonically
or in person about a product.

4.2 TYPES OF APPLICATIONS
Medicines are divided into the following classification for purposes of evaluation and
determining of application fees:

4.2.1 New chemical entities

4.2.2. Multi-source / generic applications (e.g. line extensions) where clinical information is
presented to support:

efficacy [and safety] of the formulation
safety and efficacy of a new indication

4.2.3 multi-source / generic applications with:

dissolution studies as evidence in support of comparative efficacy
bio-availability studies as evidence in support of comparative efficacy
other availability data as evidence in support of comparative efficacy

4.2.4 Other multi-source generic applications e.g. liquids/solutions not mentioned under
4.2.3 above.

4.2.4 Biological medicines

4.2.5 Vaccines

4.2.6 Biotechnological products

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4.3 GUIDELINES ON SAME/SEPARATE APPLICATIONS

For the purpose of registration:

Type of applications Same
applica-
tion
Separate
applica-tion
required
Each individual dosage form of a particular medicine

X
Deviations or variances of the active ingredient of a product

X
Tablets/Capsules/Suppositories/Lozenges
1. Different pack-sizes of exactly the same strength and formulation
2. Different strengths and formulations
3. Uncoated and coated tablets of the same strength and formulation

X

X
X
Syrups/Liquids/Solutions(excluding parenterals) /Creams/Ointments
1. Different container sizes of the same strength and formulation
2. The same container size of different strengths and formulations

X

X
Ampoules and Vials and Large Volume Parenterals
1. Ampoules containing identical solutions of the same strength (provided the dose remains
constant) but of different volumes
2. Ampoules containing solutions of different strengths
3. Ampoules, single dose vials containing masses of dry powder, crystals etc. of different mass
4. Ampoules, single dose vials containing the same respective masses of dry powder, crystals etc.
5. Ampoules, single dose vials, as well as pre-filled disposable syringes and cartridges containing
identical solutions of the same strength and same volume of liquid
6. Dental cartridges containing fluids of the same strength (provided the dose remains constant)
but different volumes
7. Ampoules containing water for injection, but of different volume
8. Special ampoules of dry powder and water for injections contained in the same unit, but
intended for mixing at the time of injection
9. Ampoules containing identical solutions of different volumes used only as a diluent in the
reconstitution of a preparation for parenteral use
10. Multi-dose vials of the same strength and formulation in different volumes
11. Multi-dose vials and a single dose ampoule of the same formulation if the single-dose ampoule
corresponds to the dose indicated for the multi-dose vial;
12. Multi-dose vials containing dry powder of different mass and the same formulation, and having
the same concentration when reconstituted
13. An ampoule of diluent packed together with any preparation including biological medicines
14. Infusion solutions of the same or different volumes and of the same formulation which are
packed in containers of exactly the same type of material depending on the relevant information
submitted
15. Infusion solutions of the same or different volumes and of the same formulation which are
packed in containers made of different types of materials
16. A preparation, packed in plastic containers, intended to be marketed in glass containers
containing the same volume and the same formulation provided the following data are
submitted:-
- characteristics of the rubber stopper;
- specifications for the glass;
- a comprehensive manufacturing process with particular reference to the
washing and sterilising cycles and apparatus
used;
- data on particulate matter (contamination);
- stability data with reference to the effect of the pH of the solution.

X

X

X

X
X

X

X
X

X

X

X

X

X

X
X

X

Products with the same strength and formulation but with different colours and/or flavours

X
Applications containing the same active ingredient(s), and where additional indications are sought,
where such new indications render the product in a different scheduling status, or different
pharmacological classification or have any other restrictions imposed other than the original
application

X

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4.4 FORM AND FORMAT OF AN APPLICATION FOR REGISTRATION

4.4.1 General

4.4.1.1 Application for registration of a medicine must be submitted on the MEDICINE
REGISTRATION FORM (MRF) - Form 1 O

4.4.1.2 Each page of the application must be numbered and the printing must be clearly
legible. Paginate all pages and index according to the FORM 1.O PART e.g.
2.B1 (referring to PART 2 B, first page). Double-sided copies are allowed except for
package inserts.

4.4.1.3 The requirements with regard to metrication in accordance with the Trade
Metrology Act must be applied.

4.4.1.4 The application for registration dossier must be properly indexed by the use of
clearly labelled tabs to indicate each SECTION of the dossier

4.4.1.5 Each PART must contain a complete index to that specific PART.

4.4.1.6 The application for registration must be properly bound on the left side as this
allows for easy update/addition of pages. Binding is left to the discretion of the
applicant; however, the use of lever-arch files is not accepted.

4.4.1.7 The correct number of copies of applications and additional documents required for
processing of the application must be submitted in the format detailed below.

4.4.1.8 The accompanying covering letter must be bound into each application dossier.

4.4.1.9 All applications must be accompanied by a duly completed Pharmaceutical
Evaluation report that must reflect the page number of the dossier where the
specific information is contained. A copy of this must be bound in each copy of the
application for registration dossier.

4.4.1.10 Each pre-screening application must be accompanied by a completed pre-
screening form, Form 2.O, and a non-refundable pre-screening fee.

4.4.1.11 After completing the pre-screening process successfully, each application must be
accompanied by the appropriate application fee.

4.4.1.12 The containers/boxes in which documentation is submitted to the MCC must be
clearly labelled. The following details should appear clearly on each box:

the contents of the container e.g. Parts, samples, cover letters etc.
product identification code for each application
applicant name
number of boxes e.g. 1 of 10
type of application e.g. fast-track, AMRP

14
4.4.2 Presentation of copies and number of copies required

4.4.2.1 Presentation of copies

In order to facilitate processing of the application for registration it is required that
certain Parts of the application for registration be duplicated and submitted as
prescribed in the pre-screening approval letter together with the application fee. All
documentation must be in English or the original document must be accompanied
by a translation into English.
No additional documentation other than that which has been clearly stipulated
below may be bound in any of the files identified below.

(i) File 1 (With original submission for screening)
Copy of the latest Inspection Report (not older than 4 years) from the Medicines
Control Council for the manufacturer of imported products
Inspection flow diagram
WHO certificate
Certificate of analysis for the sample submitted
Batch manufacturing documents for the sample submitted

(ii) File 2
Covering letter
Pharmaceutical evaluation report
Parts 1 A, 1C, 1D, 2A, 2B, 2C, 2D, 2E, 2F, 2G and 2H

(iii) File 3
Covering letter
Application for registration front page
Parts 1A, 1C, and 2B

(iv) File 4
Covering letter
Parts 1A, 1C, 2B, 2E, and 2F

(v) File 5
Covering letter
PART 2A

(vi) File 6
Covering letter
SBRA, if applicable

(vii)File 7
Covering letter
Parts 1 A, 1C, and 1D.
Approved foreign package insert/s
Clinical and Toxicological Expert reports

15

(viii) File 8
Covering letter
Pharmaceutical evaluation report
Parts 1A, 1C, 1D, 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H, Pharmaceutical Expert
report

4.4.2.2 SBRA (Summary Basis of Registration Application)

a) General
To expedite the review process of the safety and efficacy of medicines it is
required that an Summary Basis for Registration Application (SBRA)
accompany each application for registration where a clinical/ toxicological
expert report is not presented and clinical/ pre-clinical data is submitted in
support of the application.

The SBRA is intended to be a very brief and concise document containing
the core data on the basis of which the applicant intends to obtain registration
for the product. It is to be presented as a summary only: therefore no articles,
reports etc. are to be incorporated into the SBRA nor should such papers be
attached to it either, as these belong with the full submission.

Adaptation to the format prescribed in b) below, to suit each individual
product/dosage form at the discretion of the applicant, where specific items
are not applicable, may be necessary. Applicants are kindly requested to
leave a wide left-hand margin (of at least 5 cm), for office use.

b) SBRA format
Refer to Form xxxx for details and a completed hypothetical example.

4.5 FEES.

For medicine registration the following fees are relevant:

i) A pre-screening fee
ii) An application fee, accompanying the application for registration;
iii) A registration fee, payable when the application complies to all requirements
for registration, and is payable before a registration certificate is issued;
iv) An annual retention fee to maintain registration.
v) A fee to cover any amendments to the dossier or certificate.

The fees are determined according to the type of application and will be published in
the Government Gazette.

16
4.6 REQUIREMENTS FOR COMPLETION OF AN APPLICATION FOR
REGISTRATION DOSSIER.

4.6.1 Administrative Data (front page)

Details as per application form must be completed.
i) Business address in relation to a business that is carried on in the Republic of
South Africa, means the full physical address of the premises where such business
is conducted.

ii) Proprietary name means the name which is unique to a particular medicine and
by which it is generally identified and which, in the case of a registered medicine, is
the name approved in terms of section 24 (8) in respect of such medicine. (Refer to
section 4.8 of these guidelines.) It should be noted that medicines which are not
identical in composition or strength are not regarded as the same medicine

iii) Dosage form: Select the most appropriate dosage form from this list, when
completing the administrative data. This dosage form will also be reflected on the
registration certificate. For the purpose of the package insert application may be
made to give more detailed description of the dosage form e.g. chew tablet, slow
release tablet etc.

Blood bag Globule Pessaries
Bone cement Granules Plaster
Beads Gum Pods
Capsules Implant Powder
Cleansing bar Infusion (parenteral) Shampoo
Combination of dosage forms Inhaler Soap
Condom Injection Solution
Cone Insert Sponge
Cord Intra-uterine device Spray
Cream J am Stick
Cardioplegic solution Leaves Suppository
Chip (dental) Liquid Suspension
Decoction Lotion Swab
Dialysate Lozenge Syrup
Diluent for injection Lump Tablet
Dental material Medical device Tampon
Dressing Mouthwash Test kit
Drops Nasal inhaler Tincture
Elixir Nasal spray Toothpaste
Emulsion Oil Towelette
Enema Ointment Transdermal therapeutic system
Foam Ovule Vaginal ring
Gas Paste Wafer
Gel Pellet

17

iv) Descriptive name of biological medicine e.g. viral vaccine, viral antiserum,
bacterial vaccine, bacterial antiserum, allergen, immunoglobulin or blood
product, as given in a recognised pharmacopoeia or where such name does
not exist, a name determined by the MCC
v) The name and full physical address, including the country, of the
manufacturer/s, packer/s, final product testing laboratory/ies (FPRC) and
final product release responsibility (FPRR).
The Administrative data of the Registration dossier must be correlated with
the data reflected in the relevant Parts/Annexures as follows:

Manufacturer

PART 2 E (Annexure 11)

Packer

PART D & E (Annexures 9B and 11)

Testing laboratory/ies (FPRC)

PART 2 F (Annexure 9A) (It is proposed
that this is stated in full on the front page
only, and referred to only as FPRC in
Annexure 9A)

Final product release responsibility
(FPRR)

PART 2 F (Annexure 9A) It is proposed
that this is stated in full on the front page
only, and referred to only as FPRR in
Annexure 9A)

vi) Pharmacological classification. Refer to regulations ........
vii) Particulars with regard to Section C of the front page of the MRF must be
supplied by the applicant in cases where an application for registration of a
medicine has already been submitted
viii) The responsible person filling in the form should provide his e-mail address.

4.6.2 PART 1 A -PROFESSIONAL PACKAGE INSERT

The professional package insert is regarded as the document that ensures the safe
and effective use of the medicine under most circumstances. It presents a scientific,
objective account of the medicines uses and limitation as established by the
supporting evidence. Ensure that all statements are adequately cross-referenced. No
promotional material may be included. Promotional statements and comparisons to
other agents, indicative of any potential advantage over competitors will not be
allowed.

After registration, the professional package insert may not be altered without the
approval of the Medicines Control Council. In the case of safety-related matters the
Council should be informed immediately, with submission of an approved professional
package insert, a proposed amended package insert and the evidence/motivation for
the change. (refer to Section 5.3 Application for the Amendment to a package insert).

18
The professional package insert must contain the required information under the
headings as prescribed in the Regulations:

1. Scheduling status.
The scheduling status as prescribed in the Regulations to Act 101 should be
included here.

2. Proprietary name
That is the trade name of the medicine as approved by the Medicines Control
Council as stipulated in the Act. Such proprietary name shall be unique to a
particular medicine. It should further comply with the guidelines to proprietary
names as detailed in this document

3. Dosage form
The dosage form should be chosen from one of the following: (Refer 4.6.1 (iii)
of Administrative data dosage forms)

4. Composition.
The following information is required under this heading:
(i) the approved name of each active ingredient and the quantity thereof
contained in a dosage unit or per suitable mass or volume or unit of the
medicine;
(ii) the approved name and percentage of any bactericidal or bacteriostatic
agent which has been added to the medicine as a preservative;
(iii) the approved name of any anti-oxidant contained in the medicine;
(iv) the quantity of ethyl alcohol contained in the medicine if intended for oral
or parenteral administration to humans as given in PART 2 B of the
application for registration form;
(v) the warning in block letters 'CONTAINS TARTRAZINE' if the medicine
contains tartrazine and if intended for administration to humans;
(vi) the approved name of any other inactive ingredients contained in the
formulation;
The "approved name" is defined in the Act, and in relation to a medicine it
means the internationally recognised name of such substance, or such other
name as the Medicines Control Council may determine, which is not a brand
name or trade name registered in terms of the Trade Marks Act, 1993 (Act 194
of 1993)

5. Pharmacological classification.
The category as well as the description of the classification as required by
Regulation needs to be reflected here.

19
6. Pharmacological action.
A description of the pharmacological action of the medicine, especially in
humans is required. The pharmacokinetic properties of the medicine shall be
described, where applicable under a subheading: Pharmacokinetics. All
statements in the submitted draft of the professional package insert shall be
cross-referenced to the actual pages of the documents attached to PART 1F &
and PART 3 of the application form and/or to the standard books of reference.
The standard books to be referred to are the latest edition of Goodman &
Gilmans: The Pharmacological Basis of Therapeutics and the United States
Pharmacopoeia Drug Index.

7. Indications.
The indications shall be clearly stated to avoid confusion. It should be stated
whether the treatment is curative, palliative or adjunctive and should include
any statement imposed by the Medicines Control Council.
All claims in the submitted draft of the package insert shall be cross-referenced
to the actual pages of the documents attached to PART 1F & and PART 3 of
the application form and/or to the standard books of reference. The standard
books of reference referred to are the latest edition of Goodman & Gilmans:
The Pharmacological Basis of Therapeutics and the United States
Pharmacopoeia Drug Index

8. Contra-indications.
This should state situations where patients should never or generally not be
treated with the agent. Cases where patients should never be treated should be
specifically outlined.
All safety aspects in the submitted draft of the package insert shall be cross-
referenced to the actual pages of the documents attached to PART 1F & and
PART 3 of the application form and/or to the standard books of reference. The
standard books of reference referred to are the latest edition of Martindale: The
Complete Drug Reference and the United States Pharmacopoeia Drug Index.

9. Warnings.
This section should be reserved for pertinent safety issues or any precautions
that need the specific attention of the prescriber or the user. Information under
this heading shall be cross-referenced to the actual pages of the documents
attached to PART 1F & and PART 3 of the application form and/or to the
standard books of reference. The standard books of reference referred to are
the latest edition of Martindale: The Complete Drug Reference and the United
States Pharmacopoeia Drug Index.

10. Pregnancy and Lactation:
It should be clearly indicated whether pregnancy and lactation are contra-
indicated or whether limited or no information in pregnancy and lactation is
available.

20
In the case of a medicine where the safety of a medicine with regard to its use
in pregnancy has not been established, the following statement must be
included: The safety of this medicine in pregnant and lactating woman has not
been established. While applicants may reformulate this statement to suit their
own style, deviation of the essentials of this message will not be acceptable.

11. Dosage and directions for use.
The dosage and dosage interval should be clearly described. The maximum
dosages should be clearly stated where relevant. Any recommended children's
dosage shall be indicated where applicable. When relevant, the dosages and
warnings for special population groups should also be clearly addressed, e.g.
the elderly or population groups such as the renally impaired etc. Directions for
reconstitution/dilution must be clearly indicated where relevant including the
time period and conditions for storage after reconstitution/dilution. Suitable
diluents must be indicated
Proposed dosages in the submitted draft of the package insert shall be cross-
standard books of reference being referred to are the latest edition of Goodman
& Gilmans: The Pharmacological Basis of Therapeutics, Martindale: The
Stability claims on reconstituted/diluted products and storage thereof must be
supported by data in PART 2G .

12. Side-effects and special precautions
An indication of the severity, clinical importance and frequency should be given.
Frequency should be reflected as frequently and less frequently. Alternatively,
the definitions according to the CIOMS classification may be used. (reference
document required for CIOMS listing)
All the side-effects which are likely to occur for each of the active in the dosage
form shall be described, unless the Medicines Control Council decides
otherwise.
Include known clinically relevant interactions and other potentially serious
interactions based on the pharmacology of the medicine. It is useful to group
interactions according to outcome e.g. potentiation or reduction in effect and to
explain the mechanism of the interaction if it is known. All safety aspects in the
submitted draft of the package insert shall be cross-referenced to the actual
pages of the documents attached to PART 1E, 1F and PART 3 of the
application form and/or to the standard books of reference. The standard books
of reference referred to are the latest edition of , Martindale: The Complete
Drug Reference and the United States Pharmacopoeia Drug Index.

13. Known symptoms of overdosage and Particulars of its treatment.
The symptoms and signs of overdosage should be stated including specific
recommendations for treatment, when such treatment is accepted practice. All
safety aspects in the submitted draft of the package insert shall be cross-

21
standard books of reference referred to are the latest edition of Martindale: The

14. Identification.
A complete description of the medicines physical appearance. This should
correspond to the specifications of the final product.

15. Presentation.
The quantity, volume or mass per package as well as colour and type of
packing material e.g. amber glass bottle/ blister;

16. Storage instructions.
The storage instructions should be practically formulated and should quote
storage temperatures and other relevant storage conditions e.g. .Keep
container well closed, do not discard drying agent for hygroscopic products,
or Do not remove from container. for light sensitive products
Protection that may be offered by a Particular container shall not be regarded
as a reason for omitting certain storage instructions.
In-use storage instructions must be stated, where relevant.

The words 'Keep out of reach of children' must be included in all package
inserts

17. Registration number (or reference number).
The number as allocated by the Medicines Control Council.

18. Name and Business address of the Applicant.
The physical address of the Applicant is required. Business address should be
defined as stated above.

19. Date of notification of approval of the professional package insert.
This date refers to the date on which the package insert was approved by the
Medicines Control Council. Subsequent printing dates should only be used when the
Medicines Control Council has approved changes.
The professional package inserts of multi-source equivalent products shall be
essentially similar to the innovators package insert, a recently approved package
insert of the same active ingredient(s), the standard books of reference and /or a
monograph, when relevant, for that category of medicines.

Note: Any deviations from the requirements as described in these guidelines will
require approval by the Council prior to implementation.

22
4.6.3 PART 1 B -PATIENT INFORMATION LEAFLET
The patient information leaflet must be written in easily understandable English, be
consistent with the professional package insert and in accordance with the regulations,
in terms of the legibility, language and format. (refer to Addedum for lay terms).

Each immediate contained should have a patient information leaflet and should reflect
the following:

(a) Scheduling status

That is the scheduling status of the medicine as determined from time to time by the
regulation;

(b) Proprietary name and dosage form of the medicine;
When umbrella / brand names are used, the applicants would be responsible
to include precautionary statements of usage of these products simultaneously
so as to inform patients of the correct usage and potential safety concerns.
Example, if a range of products under the same umbrella name contains
paracetamol, it should not be used in conjunction with another products in the
range also containing paracetamol.

(b) What this medicine contains

The composition of the medicine, that is -

(i) the approved name of each active ingredient and the quantity thereof contained
in a dosage unit or per suitable mass or volume or unit of the medicine;
(ii) all inactive ingredients must be listed qualitatively;

(c) What this medicine is used for

The registered indications for use of the medicine as accepted by the Council in the
professional package insert;

(e) Before taking this medicine the following information should be included

contra-indications
precautions
warnings eg warnings concerning sedative properties of the medicine, warnings
concerning the risks involved with sudden withdrawal of the medicine etc must be
included here
interactions
General statement must be included in this section:
If you are taking medicines on a regular basis, concomitant use of the medicine
may cause undesirable interactions. Please consult your doctor, pharmacist or
other health care professional for advice.
If you are pregnant or breast feeding your baby while taking this medicine please
consult your doctor, pharmacist or other health care professional for advice.

(f) How to take this medicine

The recommended dosage must be included here. (Any special information which the
patient may require for the proper and safe use of the medicine should be provided)

23
Information on what to do in specific circumstances, for example in the case of a
missed dose, an unexpected reaction or in the case of an overdose should be included.
Do not share medicines prescribed for you with others. must be stated. In the event
of overdosage, consult your doctor or pharmacist. If neither is available, rush the
patient to the nearest hospital or poison control centre:

(g) Side-effects

This section should be in laymans terms for the consumer to understand -

(i) the side-effects associated with the use of the particular medicine listing the
more frequently side-effects firstly.
(ii) those side-effects which can be easily recognised by the patient;
(iii) the following general statement: Not all side-effects reported for this medicine
are included in this leaflet. Should your general health worsens while taking
this medicine, please consult your doctor, pharmacist or other health care
professional for advice.

(h) Storage and disposal information -

Should contain information on how to store the medicine properly and how to dispose of
unused medicine. The statement Store all medicines out of reach of children. must be
stated.

(i) Presentation

The number, volume or mass per package unit must be mentioned. A description of
the packaging material (i.e. bottle, blister, etc.) should be included.

(j) Identification of the medicine

A complete description of its physical appearance of the medicine.

(k) Registration number

The number allocated to the medicine;

(l) The name, business address and telephone number of the applicant

(m) The date of publishing the patient information leaflet

Note:
The responsibility for ensuring that the patient information leaflet is in line with the
regulations, including assurance that the patient information leaflet corresponds with
the information in the professional package insert will essentially rest with the
applicant. Any deviations from the requirements as described in these guidelines will
require approval by the Council prior to implementation.

4.6.4 PART 1 C- AN EXAMPLE OR FACSIMILE OF THE LABEL
An example of the facsimile of the label must be included here. Requirements eg font
size as stipulated in the Regulations should be adhered to.
The following inclusions are permitted:
For state use only Not for sale for tender items
Professional sample samples for professionals

24
Note: Any deviations from the requirements as described in these guidelines will
require approval by the Council in terms of Section 36 of the Act, prior to
implementation.

4.6.5 PART 1 D - FOREIGN REGISTRATION

4.6.5.1 A list of countries in which an application has been lodged and the status of such
applications shall be furnished. Countries that are members of the PER Scheme,
other EU countries and the USA should specifically be identified. Approvals (with
indications), deferrals, withdrawals and rejections should be stated. If the medicine
has already been registered in any of the countries mentioned above, a copy of the
registration certificate and the approved package insert (data sheet) as well as the
conditions of registration, should be provided.

4.6.5.2. It should be stated whether data packages submitted in the countries in 4.6.5.1 are
essentially similar to those submitted to the Medicines Control Council, including the
proposed indications.

4.6.5.3. The Medicines Control Council should also be notified of any rejections, withdrawals
or approvals of applications in the EU commission (mutual recognition process),
Australia Canada, the Netherlands, Sweden, UK and USA during the evaluation
period. Where the rejections or withdrawals relate to safety matters details in each
case should be provided.

4.6.6 PART 1 E - PRE-CLINICAL STUDIES

4.6.6.1 Guidelines are constantly evolving as a result of scientific developments and
harmonisation of the requirements of the major overseas regulatory authorities. The
Medicines Control Council endeavors to keep abreast of such developments and
keep its application requirements and evaluation policies in line with best
international practice.

4.6.6.2. Legislation to be read in conjunction with these guidelines is:
The Act
Application form - PART 1E
Regulations

4.6.6.3 For Biological Medicines the applicant must include details (published or
unpublished) of the results of any trials or experiments carried out in man or in the
animal target species, or carried out in other animals, that establish and confirm the
safety of the medicine, with particular reference to the dosage and directions for use.

4.6.6.4 For medicines other than biological medicines
In PART 1 E the applicant needs to address the Pharmacology and Toxicology of the
medicine;

25

4.6.6.4.1 Pharmacology:

4.6.6.4.1.1 Pharmacodynamics:
i) The primary effects of the medicine, with results in different animal species
(ED
50
values if possible) must be addressed.
ii) Comparison of the effects of the product with that of reference products is
valuable information.
iii) Where relevant, the pharmacology of significant metabolites must be
investigated.
iv) Other pharmacodynamic effects, especially those that might be of
significance for adverse effects of the medicine, should be studied and
described.
v) Interaction studies, where relevant, should be included.

4.6.6.4.1.2 Pharmacokinetics:
i) To assist in the interpretation of toxicological studies, it is important to
compare the exposure of the animals used in the toxicity testing with that
anticipated in patients given the proposed therapeutic dose regimen.
ii) PART 1E should, therefore, include comparative pharmacokinetics data,
which includes C
max
(after a single dose and at steady state) and AUC data
for the parent drug and major/active metabolite(s), where relevant, in
human and all species used in the toxicity, carcinogenicity and reproduction
studies.
iii) These data should preferably be obtained from the toxicity studies.
iv) Other information (for example, t
and clearance), may be of value where

important differences have been shown between animals and man.

4.6.6.4.2 Toxicology:
i) A summary or expert report must be submitted for each animal species
studied, including sex, number of animals, dosage, route of administration,
duration of study and toxic manifestations.
ii) Important points pertaining to preclinical toxicity to consider and address
are:
Dose-response relationship
Time-response relationship
Species specificity
Target organ specificity
Reversibility / irreversibility of toxic effects.
iii) Medicines that show specific toxicological effects, such as immunotoxicity,
hepatotoxicity or neurotoxicity, should be investigated further, taking into
account the points under ii)
iv) New medicines which belong to classes that are known to produce a
particular toxic effect, should be tested appropriately.

26
v) The possible mechanism(s) underlying the changes observed in toxicity
studies need to be investigated and addressed.
vi) Due to the local climatic conditions the phototoxic potential of a medicine
should be considered.
vii) The points to address in the reproduction studies are: fertility, embryonal
toxicity, teratogenicity, peri- and postnatal effects.

4.6.6.5 The details of results from tests shall depend on the state of scientific knowledge at
the time when the application is lodged. Any interim and final results of ongoing
studies must be submitted as soon as these data become available.

4.6.6.6. A new route of administration or an increased daily dose of known excipients may
result in the need for additional pharmaco-toxicological data.

4.6.7 PART 1 F - CLINICAL STUDIES

4.6.7.1 Guidelines are constantly evolving as a result of scientific developments and
harmonisation of the requirements of the major overseas regulatory authorities
(USA, UK, Sweden, EU, Canada, Netherlands, Australia). The Medicines Control
Council endeavors to keep abreast of such developments and keep its application
requirements and evaluation policies in line with best international practice as per
introduction. Please refer the Medicines Control Council Clinical trials guidelines.

4.6.7.2 Legislation to be read in conjunction with these guidelines are:
Act
Application form - PART 1 F.
Regulation.

4.6.7.3 A medicine cannot be marketed in South Africa without being registered by the
Medicines Control Council. Data that satisfactorily establish the quality, safety and
efficacy of the medicine, for the purposes for which it is to be used, must be
submitted for evaluation by the Medicines Control Council before consent can be
granted.

Note: Old medicines that have been lodged with MCC and allocated a reference
number are allowed to be marketed.

4.6.7.4 All applications and amendments must be accompanied by a covering letter. The
letter should briefly and succinctly state the purpose of the application.

4.6.7.5 All data must be submitted on A4 sized paper in compliance with the regulations
and each PART of the application should contain a detailed index. The data must
be presented in such manner that allows for easy cross-referencing to the index,
other studies and the professional package insert. [Applicants wishing to submit

27
data in electronic form should discuss the requirements with the Registrar of the
Medicines Control Council].

4.6.7.6 Data presented in support of the safety and efficacy of the medicine must be
derived from clinical trials conducted in compliance with internationally accepted
GCP guidelines. The studies must be properly designed and conducted and must
be of acceptable statistical power. Where relevant, results published in peer
reviewed scientific journals should be submitted.

4.6.7.7 Clinical trials should be conducted with the formula as applied for. Where studies
have been conducted with different formulations, comparative equivalence studies
need to be submitted to enable extrapolation to the formula intended for the
market.

4.6.7.8 Normally individual patient data from clinical trials need not be included in an
application dossier (except in the case of bioequivalence studies where the
individual plasma/serum concentrations and derived pharmacokinetic data are to
be supplied). Tabulated individual patient data may be included in the application if
the applicant considers it appropriate.

4.6.7.9 Studies designed to demonstrate the pharmacodynamics of a medicine should
address the effect of the medicine, duration of effect, dose-response and tolerance.
Additional action on the central nervous system, respiration, circulation, blood
chemistry, liver and kidney function, etc., should be considered at the proposed
therapeutic dose(s).

4.6.7.10 Pharmacokinetics studies should be conducted with the formula as applied for. All
relevant pharmacokinetics data shall be given, such as amount and rate of
absorption after various routes of administration, plasma concentration, half-lives,
drug clearance, drug metabolism as well as the routes and rates of excretion.
The pharmacokinetics studies are to be carried out with both single dose and
multiple doses to steady state within the recommended dosage range.
Where applicable the plasma concentration(s) producing pharmacological and/or
therapeutic effects, as well as adverse effects should be presented.
Possible dose-dependent pharmacokinetics needs to be addressed.

4.6.7.11 The trial design of the relevant clinical studies should be such that the safety and
efficacy of the medicine can be established in comparison to either placebo and/or
a registered medicine in UK, USA, Sweden. Netherlands, Canada, Australia and
EU. The description of the studies must include patient population size and
diagnosis, in- and exclusion criteria, test and comparator drug dosage regimens
and duration of therapy, parameters assessed for efficacy and safety, including
results of special investigations. Detailed statistical results must be presented. It
should be noted that the randomised, double-blind, placebo and/or active controlled
trial design remains the gold standard for establishing the efficacy and safety of
medicines.

28
4.6.7.12 The dosage of the active comparator (refer to Section 4.10 Bio-equivalence of a
new multi-source medicines) must be in line with that approved for the specific
indication.

4.6.7.13 The patient drop-outs must be addressed, including the time of and reason(s) for
withdrawal.

4.6.7.14 To enable evaluation of safety of the medicine it should be noted that the long-term
safety, particularly for medicines proposed for chronic use, needs to be addressed.

4.6.7.15 While a product is being evaluated, applicants should notify MCC of:
i) any approvals, rejections or withdrawals of applications in other countries and
ii) any serious adverse effects observed for the first time, or at a frequency which
has become a concern.

4.6.7.16 During the evaluation period, if new significant data becomes available that is
contrary to the use of the medicines, applicants must notify Council. With this
notification the applicant should state its intention.

4.6.7.17 An application also needs to be submitted in the same format as outlined in PART
1F form as well as the relevant regulations and guidelines for a registered
medicine, when the following amendments are requested:
i) Deletion of contra-indication.
ii) Addition of or amendment(s) to indication(s).
iii) Dosage amendments.
iv) Deletion of safety related information, i.e. warnings and precautions.

29
4.6.8 PART 2: PHARMACEUTICAL AND ANALYTICAL REQUIREMENTS
The technical requirements for pharmaceutical and analytical information are divided into
several parts in the application form as follows:

PARTS

TITLE

CONTENTS

2A

ACTIVE INGREDIENT(S)

(1) CHEMICAL
(2) SOURCE (Name & address)
(3) ACTIVE INGREDIENT
FILE (AIF)
(4) CERTIFICATE OF
ANALYSIS (COA)
(5) PROOF OF CHEMICAL
AND PHYSICAL
EQUIVALENCE

2B

FORMULATION

(1) UNIT FORMULA

2C

RAW MATERIALS
(1) SPECIFICATIONS
(2) CONTROL PROCEDURES

2D

CONTAINER & PACKAGING
MATERIAL

(1) SPECIFICATIONS

2E

MANUFACTURING
PROCEDURE
(1) MANUFACTURING
(2) PACKAGING
(3) VALIDATION PROTOCOL
(4) INSPECTION FLOW
DIAGRAM
2F

FINISHED PRODUCT

(1) SPECIFICATIONS & LIMITS
(3) CERTIFICATE OF
ANALYSIS (CoA)
(4) VALIDATION

2G

STABILITY

(1) PROGRAM
(2) DATA
(3) SHELF-LIFE

2H

PHARMACEUTICAL
DEVELOPMENT

(1) FORMULATIONS
2) PHARMACEUTICAL
EXPERT REPORT

3

IN VIVO AND/OR IN VITRO
EQUIVALENCE STUDIES AS
PROOF OF EFFICACY

(1) PURPOSE OF STUDY
(2) REFERENCE PRODUCT
(3) METHOD
(4) DATA
(5) DISCUSSION

30

4.6.8.1 PART 2A - THE ACTIVE RAW MATERIAL (DEVELOPMENT CHEMISTRY AND
CHARACTERIZATION)

4.6.8.1.1 The approved name (INN) or chemical description of the active ingredient(s) must
be stated including the structural formula, the empirical formula and the molecular
mass.
4.6.8.1.2 The solubility of each active ingredient must be stated in terms of a unit part of the
substance per number of parts of the solvent, or in unit mass of substance in a
given volume of solvent, at a specific temperature. The solvents must include water
and the solvent(s) relevant to the formulation. Storage requirements of the raw
material and retesting period must be stated
4.6.8.1.3 The name and physical address of each manufacturer being applied for must be
stated. If one or more brokers are utilised, the name and physical address of each
broker must be stated. Brokers must be clearly differentiated from manufacturers
of raw materials. No active ingredient from any source other than the approved
source(s) may be used.
4.6.8.1.4 A Ph. Eur. Certificate of Suitability or Active Ingredient File (AIF) including the
following information must be submitted:
The name and physical address of the manufacturer
History of the manufacturer (how long in existence, activities, types of
materials/products manufactured etc.)
The approved name of the relevant active
The chemical name and chemical structure
A description of the pathway of synthesis using a flow chart which includes the
starting materials, reagents, solvents, conditions, processes, duration of
treatments, intermediates formed and any other relevant aspects. Note that
specifications and control procedures for substances used in this process are
not required.
Occurrence of isomers and polymorphism.
A description of impurities. Distinguish between actual and possible impurities
A description of possible degradation products
The physical and chemical properties of the active raw material
The detailed methods used for identification and assay, including
chromatograms wherever relevant
CoA results of at least two production batches
Results of stability studies performed on the raw material obtained by the above
method of synthesis. The conditions under which degradation products are
formed must be included. A stability-indicating assay must be used in these
studies, must be described in full and supporting chromatograms including
wherever relevant.
Stability data on new chemical entity raw materials generated according to the ICH
guidelines (see Addendum A) Stability data derived from at least two production

31
batches of well-known actives(generic), stored at accelerated conditions for at least
6 months and for at least twelve months stored at the maximum recommended
storage.

4.6.8.1.5 Certificates of analyses (CoA)
A CoA (a), which accompanied a batch of active raw material, received by the
manufacturer of the final product must be submitted. Additionally, a CoA or
analytical report, reporting on the statutory identification and assay and any other
test which is specified in Annexure 4, but is not reported on in (a), issued by or on
behalf of the manufacturer of the final product, must be submitted.

4.6.8.1.6 Equivalence of active raw materials obtained from different manufacturers or by
different methods of synthesis.
When more than one manufacturer is being applied for or when an additional or
change in manufacturer is applied for, the following must be submitted in lieu of
each manufacturer:

A. An AIF or Ph. Eur. Certificate of Suitability.
Note that if the identical method of synthesis is used by each manufacturer
(or the same parent company) or at different sites of the same manufacturer, a
statement to this effect will suffice.
B. A communication pointing out the differences in the methods used, and the
differences with regard to the impurity profiles.
C. CoA's issued by each manufacturer (approved source and additional source)
and the analytical reports issued by the laboratory of the manufacturer of the
final product.
D. Critical tests e.g. identification, assay, particle size, optical rotation, residual
solvents, etc performed on samples from each source to demonstrate physical
and chemical equivalence, must be performed by a laboratory (either the
laboratory of the manufacturer to an independent laboratory, for example). The
same analytical methods must be used for these tests.

4.6.8.1.7 For biological medicines, specifications of raw material used in the primary
production lot are required:
a) In the case of a biological medicine of microbial origin, history and preparation
of the seed lot must be described with specific reference to the tests that are
carried out on such a seed to lot establish and maintain the integrity thereof.
b) Particulars of the composition of all culture media used in the preparation and
testing of a biological medicine must be given.
c) Particulars must be given of the other biological source material from which a
biological medicine (e.g. blood fractions) is extracted, including origin of culture
or blood.
d) Specifications must be at the level of the latest editions of recognised
pharmacopoeial reference books and any deviations must be fully
substantiated.

32
e) Reference only to the recognised pharmacopoeial reference books shall be
acceptable where the specifications correspond to the reference.

4.6.8.1.8 For biological medicines full details of tests carried out on the raw materials must
be provided.( Refer to WHO guidelines on Biologicals)

4.6.8.2 PART 2B - FORMULATION

4.6.8.2.1 The formula must show the approved names (INN) or chemical names of all active
raw materials and excipients (inactive ingredients) including those that do not
necessarily remain in the final product after manufacturing, such as granulating
agents and gases used for flushing, etc. For excipients that do not appear in the
final product, this must be so indicated. Each raw material must be listed together
with its quantity per dosage unit. This would include the vehicle(s), solvent(s) or
base(s). In the absence of an approved name (INN) or chemical name, a
chemical description or characterisation of the substance must be given. Special
technical characteristics of the excipient, where applicable, must be indicated such
as lyophilised, micronised, solubilised, emulsified, etc.
Some excipients are single chemical entities while others are combinations. Some
are chemically transformed, e.g. modified starch. For excipients that are mixtures of
chemically related or unrelated components, e.g. polyol esters (mixture of mono-,
di- and triesters), direct compression excipients or film coating material, or
excipients that are chemically modified, the dossier must specify the nature and
quantity of each component.

4.6.8.2.2 A product may contain more than one active ingredient provided that
i) each active ingredient makes a contribution to the claimed indications;
ii) the effect of combining the active ingredients in one product does not decrease
the safety, stability or efficacy of the product; and
iii) the product provides rational concurrent therapy for a significant proportion of
the target population. e.g. tuberculostatic combinations

4.6.8.2.3 The purpose of each inactive raw material must be stated briefly. If the excipient is
used for multiple purposes in the formulation, each purpose must be mentioned.

4.6.8.2.4 Any overages for the active ingredient must be stated separately and the reasons
for it must be given. The label claim quantity must be stated and the excess
quantity indicated as the actual amount or as a percentage. For example, 500 mg +
5 mg (=1%) overage* .
*Use the asterisk to explain the purpose of the overage.

4.6.8.2.5 Where a potency adjustment for the active ingredient has to be made, a statement
to the effect that the actual quantity of the active will depend on the potency, and
the excipient(s) that will be used to adjust the bulk quantity must be mentioned, as
well as the manner in which the adjustment will be made. Potency calculations,
where applicable, must be shown in PART 2E (Manufacturing Procedures).

33

4.6.8.2.6 Flavouring and colouring agents, because of their complexity in many instances,
may be described in terms of their main constituents only, provided that appropriate
chemical identification and characterisation for them is given in the relevant
section. The Index Numbers of colourants must be included in the formula. The use
of dyes, printing ink, coating materials, flavourants and organic solvents is subject
to the same safety and quality requirements that apply to medicinal substances.

4.6.8.2.7 The content of alcohol, if included, for oral and intravenous medicines must not
exceed the following maximum concentrations:
i) 0,5% (v/v) ethyl alcohol for children under 6 years of age;
ii) 5,0% (v/v) ethyl alcohol for children of 6 to 12 years of age; and
iii) 10% (v/v ethyl alcohol for adults and adolescents over 12 years of age.

The presence of alcohol in the product must be declared, and the concentration
stated, on the label, the package insert and in the patient information leaflet. (Refer
to Addendum F)
Products where higher concentrations of alcohol are required for specific purposes
(e.g. plant extracts or where solubility or preservation might be problematic) may be
exempted from the above alcohol concentration limits provided that justification and
motivation for it is submitted together with proof that the dosage will not result in
blood alcohol levels of 25 mg/dl (milligram per decilitre) or higher.

4.6.8.2.8 Where the vehicle is added up to the required volume or mass of the product, the
actual or estimate quantity of that vehicle may be stated. However, expressions
such as add up to and q.s. are acceptable. Solutions added to adjust the pH
must be described in terms of composition and strength (normality, molarity, etc.),
but it is not necessary to state the actual quantity added as none may be added or
only minute quantities may be needed.

4.6.8.2.9 For biological medicines the details of any solution supplied by the manufacturer for
the reconstitution before use of a dried biological medicine that is offered for sale in
a dried form shall be supplied.

4.6.8.3 PART 2C - RAW MATERIAL SPECIFICATIONS AND RAW MATERIAL
CONTROL PROCEDURES

4.6.8.3.1 Specifications and the limits of all raw materials, including the active ingredient(s)
must be listed and must at least be at the level of the latest editions of recognised
pharmacopoeial reference books, (BP, USP, EP) Any deviation from such
specifications and limits must be fully substantiated. More than one pharmacopoeia
may be used for the raw materials provided that the reference is used fully and not
partially or selectively. For example, USP may be used for starch, and BP for
lactose, etc.
One ingredient may be tested in accordance with alternative pharmacopoeias,
depending on the site of manufacture.

34

4.6.8.3.2 In-house specifications must at least be at the level of an approved
pharmacopoeia. Any in-house specifications that are at a lower level than those of
an approved pharmacopoeia must be fully motivated, subject to approval by the
Council.(Cross reference to a Pharmacopoeia is necessary)

4.6.8.3.3 Additional specification parameters, over and above those stipulated in the official
compendia, such as a very accurate description of isomers, polymorphs, etc., must
be submitted for all active ingredient(s) where required by the Council.

4.6.8.3.4 Control procedures for all raw material specifications shall be fully described,
unless a complete monograph appears in an approved pharmacopoeia. In the latter
instance, reference to the pharmacopoeia must be made as indicated in 1 above.

4.6.8.3.5 Specification limits and the control procedures for particle size of active ingredients
which have a solubility of less than 1 part in 200 parts water and for those which
the Council may publish by notice, must be submitted. Particle size must be stated
in SI units (m) where the particle size is stated in sieve sizes, the corresponding
size in SI units should be included. Exemption from this requirement may be
granted if the active ingredient is reconstituted into, or is administered as, a
solution, or for any reason determined by the Council.

4.6.8.3.6 Colourants and flavourants must comply with either one of the following:

i) at least a specification limit and control procedure regarding chemical
identification and a statement that the flavourants comply with the general
requirements and that the colourants comply with the purity criteria of Act 54 of
1972 (The Foodstuffs, Cosmetics and Disinfectants Act, Act 54 of 1972).
ii) at least a specification limit and control procedure regarding chemical
Identification and a statement that it complies with the directives of the EU or
the register of the FDA.

4.6.8.3.7 The following minimum requirement must be complied with by the applicant and a
confirmation given that:

i) Identification and assay of the active raw material will be performed irrespective
of the possession of a certificate of analysis from the supplier;
ii) Identification of the inactive raw material will be performed irrespective of the
possession of a certificate of analysis from the supplier; and that
iii) Any tests not included in a valid* certificate of analysis will be performed.
*valid as defined by c GMP

35
4.6.8.3.8 For those inactive ingredients for which a conclusive identification test is not
included, all those parameters which are specific to the identification of that raw
material must be performed irrespective of the possession of a Certificate of
Analysis from the supplier.

4.6.8.3.9 For all raw materials of organic origin, microbial limits and test procedures must be
included.

4.6.8.3.10 Frequency of testing of water and microbiological testing of water must be stated.
Water must be tested at least once a week for microbiological contaminants, and
daily or just before use for conductivity and pH.

4.6.8.3.11 For a biological medicines:
a) Specifications for the primary production lot used in the manufacture of the final
filling lot of a biological medicine and specifications for all raw materials for the
diluent must be listed.
b) Tests of a biological source material must include tests to confirm the
identification, safety and potency of the primary production or bulk lot used in
the manufacture of the final filling lot.
c) Parameters and criteria of acceptance to confirm the identification, safety and
potency of the product must be provided.

4.6.8.4 PART 2D - CONTAINERS AND PACKAGING MATERIALS

4.6.8.4.1 Full details of the immediate container specifications and limits, including
dimensions and sketches where applicable, as well as those of applicators and
administration sets, the closure system wadding and any other component in direct
contact with the product, where applicable, and the control procedures thereof must
be supplied.

4.6.8.4.2 A brief description of the outer container, if any, must also be given. At least the
nature of the material must be mentioned. e.g. Outer cardboard carton.

4.6.8.4.3 The type of container described here must correspond to that described in the
package insert under Presentation and in the stability studies.

4.6.8.4.4 In cases where an equivalent or better immediate container packaging material is
requested, data to substantiate this claim must be submitted, i.e. USP Permeation
test. Refer to Addendum G on minor and major amendments for stability testing
requirements.

36
4.6.8.5 PART 2E - THE MANUFACTURING PROCEDURES

4.6.8.5.1 The batch manufacturing formula and the batch size(s) must be included. Where
more than one batch size is indicated, the batch formula of the smallest batch size
only may be given.

4.6.8.5.2 A copy of the Master Manufacturing document or a comprehensive flow diagram or
a description of the manufacturing procedures detailing the various stages of
manufacturing, packaging and labelling, including the type of equipment (including
sieve sizes), duration of treatment, temperature, light and humidity conditions, as
well as machine settings (e.g. rotation speed or rpm), must be submitted. All in-
process controls (analytical, microbiological, and physical) must also be shown in
the flow diagram.

4.6.8.5.3 The Inspection Flow Diagram must be included.

4.6.8.5.4 A process Validation programme or process validation report (as per requirements
stipulated in Addendum B) must be submitted.

4.6.8.6 PART 2F - THE FINISHED PRODUCT

4.6.8.6.1 The name of each final product specification and the limits must be listed for in-
process controls, final product controls, stability studies and manipulated final
product (if applicable).

4.6.8.6.2 All control procedures must be described in full.

4.6.8.6.3 The validation data of the assay method of the active ingredient must be submitted.
It must be demonstrated that the assay method is stability indicating, i.e. will
distinguish between the active ingredient and the degradation product.(s) If the
assay method is not stability indicating the validation data of the procedures used
to determine the assay and that used to determine the degradation product must
be submitted. Chromatograms confirming the separation of the active from the
degradation products, if relevant, must be included (See Addendum A).

4.6.8.6.4 All other quantitative methods must be validated and the validation data included.

4.6.8.6.5 A complete analysis report or certificate of analysis for one batch (pilot- or
production) of the finished product must be submitted with the application.

4.6.8.6.6 The final release criteria must include the checking of certificate of analysis,
appearance of the dosage form, the container, the package insert, the label, the
batch number, and the expiry date of the product (FPRR functions).

37
4.6.8.6.7 Content uniformity must be specified and a control procedure must be submitted if
the quantity of the active ingredient is less than 2 mg or less than 2% mass per
mass of the total mass of the dosage unit (e.g. tablet, capsule, etc.). The assay
need not be performed in the case where Uniformity of Content has already been
performed for batch release purposes.

4.6.8.6.8 For quality control and batch release purposes, final product specifications for all
oral tablets and capsules (conventional oral dosage forms), shall include a
requirement for dissolution rate of active ingredient unless otherwise determined by
the Council. Dissolution rate of at least the least water-soluble active ingredient in a
combination product should be tested as a release requirement.

4.6.8.6.9 Disintegration time, where relevant, for example for chew tablets, matrix tablets and
soft gelatine capsules will be determined as a lot release requirement on all
batches on which dissolution rate is not determined as a criterion for lot release.
Disintegration time can be used as a lot release requirement for multivitamins and
mineral preparation, unless a dissolution requirement for a specific product is
included in the USP, in which case dissolution must be done as a lot release
requirement.

4.6.8.6.10 For a product from a non-biological origin which has endotoxin levels the validation
data as required by the USP / BP/ EP must be submitted to the Council. The
applicant may thus employ the LAL method after informing the Council of their
intentions.

4.6.8.6.11 For products with a biological origin or any other products for which no endotoxin
levels have been specified in a pharmacopoeia, the validation data must be
submitted for evaluation. This must have been approved and accepted by the
Council before the LAL test may be utilised. This information must include the initial
quality control data, inhibition/enhancement data and the endotoxin limit for the
product.

4.6.8.6.12 For imported products at least the identification, assay of the active ingredient must
be performed after importation. This is intended to verify that the product has not
been affected adversely during the transfer process. Exemption may be granted for
an applicant not to re-identify and re-assay imported products provided that the
requirements of Addendum C are adhered to.

4.6.8.6.13 See Addendum A on stability for suggested parameters for each dosage form.

4.6.8.7 PART 2G - STABILITY

4.6.8.7.1 All applications for registration of a medicine must be submitted with stability data
in accordance with the minimum requirements stated in the Guidelines for
Stability (Addendum A). Note, at least data for 3 months (at time of submission)
and 9 months (before registration) at the recommended storage conditions for
products containing well known chemical entities (e.g. line Extensions and generic

38
products.) and 3 months under accelerated conditions for generic products; and 12
months at the recommended storage conditions plus 6 months under accelerated
conditions for new chemical entities must be submitted (See Addendum A).

4.6.8.7.2 The stability program must be described in detail and must include the following
information:

(i) Conditions (temperature, humidity)
(ii) Time points for testing e.g. months, 6 months etc.
(iii) Specifications to be determined
(iv) How often will stability testing be performed on future batches (should be in
accordance with c GMP guidelines.)

4.6.8.7.3 Information pertaining to the batch for which stability data is submitted must include
the following:

(i) Batch No. (Confirm that the formula is the same as the one applied for)
(ii) Date of manufacture.
(iii) Name of manufacturer.
(iv) Source of active raw material (manufacturer not the supplier).
(v) Indicate whether production/pilot/experimental batch.
(vi) Container (Confirm that the container is the same as the one applied for).
(vii) Storage conditions (must be controlled according to guidelines).
(viii) Specifications and limits.
(ix) Stability results.

4.6.8.7.4 Discussion and conclusion of shelf life for each type of container must be provided.

4.6.8.8 PART 2H - PHARMACEUTICAL DEVELOPMENT

4.6.8.8.1 Any change or differences in the formulation during the development history must
be indicated clearly.

4.6.8.8.2 A separate Expert Report must be included with each application to include at least
the following:

4.6.8.8.2.1 Active Ingredient(s):
(a) Comment on the synthesis of the active ingredient(s);
(b) Discuss all physico-chemical properties, e.g. solubility, water content,
particle size, crystal properties, polymorphs, chirality, etc. Reference may
be made to the AIF;

39

4.6.8.8.2.2 Formulation:
(a) Motivate and explain the function of the inactive ingredients;
(b) Indicate the safety/toxicity profile of the inactive ingredients;
(c) State any interactions likely to occur or that may occur under given
circumstances;
(d) Motivate/explain all overages;
(e) Discuss relevant physico-chemical parameters separately, e.g., dissolution
and choice of medium, pH, etc.
(f) Include pre-formulation studies and motivate.
(g) Novel formulations and excipients must be discussed /explained.

4.6.8.8.2.3 Production/Manufacture:
(a) Describe how the manufacturing method was derived;
(b) Describe how in-process controls and validation plans were developed.

4.6.8.8.2.4 Stability:
(a) Discuss the stability of the final product formulation and the parameters
used during stability and to confirm quality for lot release;
(b) Discuss the containers used during stability studies;
(c) Discuss dissolution;
(d) Conclusion on stability;

4.6.8.8.2.5 Conclusion in Expert Report

4.6.8.8.2.6 Name Date and Signature of responsible person.

4.6.8.8.2.7 A reference list used in the compilation of the report.

4.6.8.8.2.8 No more that 25 pages of A4 paper.

4.6.8.9 PART 3 - IN VIVO AND/OR IN VITRO EQUIVALENCE STUDIES AS PROOF
OF EFFICACY

4.6.8.9.1 The applicant may request partial or total exemption from these requirements if
efficacy and safety are intended to be established by means of clinical data (or for
other reasons determined by the Council): Provided that clinical trials have been
conducted with the same formulation as the one being applied for.

40

4.6.8.9.2 Where clinical evidence in support of efficacy has not been submitted, studies and
data to demonstrate the pharmaceutical and/or biological availability of the product
must be included. Refer also to 4.10 BIO-EQUIVALENCE OF A NEW MULTI-
SOURCE MEDICINE

4.6.8.9.3 The purpose of the study must be stated.

4.6.8.9.4 Full details of the reference products used as the standard for reference purposes
(including the applicant, proprietary name, lot number, expiry date, etc.), must be
supplied. The reference products used must be motivated and will be subject to
approval by the Council.

4.6.8.9.5 Details of the method used must be given.

4.6.8.9.6 Full data must be submitted. (including all raw data)

4.6.8.9.7 A discussion and the conclusion drawn from the data must be submitted

4.6.8.9.8 If pharmaceutical availability or equivalence data is submitted, the studies must be
carried out according to the guidelines determined by the Council, and the data
must be submitted in the prescribed format.

4.6.8.9.9 The applicant must state whether there are any in vivo-in vitro correlation from the
data obtained by the method used.

4.6.8.9.10 The applicant must confirm that the data submitted have been obtained with the
formulation being applied for.

4.6.8.9.11 Bioequivalence studies for all antibiotics and bioavailability for antimicrobial
preparations (such as for tuberculosis) must be carried out, unless otherwise
determined by the Council. (See Addendum D).

4.6.8.9.12 The applicant must motivate and justify why the study and the results obtained
should be acceptable.

4.6.8.9.13 When bio-equivalence studies are submitted in support of efficacy of the
formulation, the Application control document for bioequivalence studies included
under FORMS must accompany the data.

41
4.6.8.10 PART 4 - DETAILS RELATING TO THE PREMISES ON WHICH PRIMARY
PRODUCTION IS UNDERTAKEN AND TO THE STAFF INVOLVED IN
PRODUCTION AND TESTING OF A BIOLOGICAL MEDICINE.

4.6.8.10.1 A description of the premises where preparation of the primary production or bulk
batch are carried out, names, qualifications, field and experience of the persons
involved in preparation of the primary production and the final lot and details of
the facility where the imported final filling lot is stored must be recorded.

i) A floor plan of the premises must be included.
ii) If the premises are used for other purposes such details must be supplied.
ii) Conditions under which the product is stored must be described.

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ADDENDUM A

GUIDELINE FOR STABILITY TESTING

The Tripartite guideline which has been developed within the Expert Working Group
(Quality)of the International Conference on Harmonization provides a general indication on the
requirements for stability testing. It primarily addresses the information required in applications
for registration for new chemical entities and associated medicinal products.

The Council has decided to adopt this guideline with only minor modifications.

Salient aspects relating to testing conditions, numbers of batches to be tested and the
requirements regarding follow-up stability data previously conveyed to applicants have
changed and applicants are advised to study these guidelines carefully.

Applicants are reminded that these guidelines are based on the Tripartite guideline has now
been included in the USP23 (<1196>). Or the latest edition where applicable.

It should be noted that the conditions for light stability testing of active substances and dosage
forms have not yet been finalised by the Expert Working Group.

Appendices 1 and 2 attached to this Guideline comprise -

APPENDIX 1 - GLOSSARY AND INFORMATION
APPENDIX 2 - APPROPRIATE TESTS

The Councils policy on testing conditions, numbers of batches to be tested and
the requirements regarding follow-up stability in respect of generic products
has also been revised, and is included in this Guideline.

43
INDEX TO STABILITY GUIDELINE

Preamble

1 STABILITY TRIAL DESIGN --------------------------------------------------------------- p45

1.1 ACTIVE SUBSTANCE ---------------------------------------------------------------------- p45
1.1.1 NEW CHEMICAL ENTITY------------------------------------------------------------------ p45
1.1.1.i General------------------------------------------------------------------------------------- p45
1.1.1.ii Stress testing ----------------------------------------------------------------------------- p45
1.1.1.iii Formal studies---------------------------------------------------------------------------- p45
1.1.1.iv Selection of batches--------------------------------------------------------------------- p45
1.1.1.v Test procedures and test criteria----------------------------------------------------- p46
1.1.1.vi Specifications ----------------------------------------------------------------------------- p46
1.1.1.vii Storage conditions----------------------------------------------------------------------- p46
1.1.1.viii Testing frequency------------------------------------------------------------------------ p47
1.1.1.ix Packaging/Containers ------------------------------------------------------------------ p47
1.1.1.x Evaluation---------------------------------------------------------------------------------- p47
1.1.1.xi Statements/Labeling -------------------------------------------------------------------- p48

1.1.2. WELL-KNOWN CHEMICAL ENTITY---------------------------------------------------- p49

1.2 DOSAGE FORM------------------------------------------------------------------------------ p49
1.2.1 PRODUCTS CONTAINING NEW CHEMICAL ENTITIES-------------------------- p49
1.2.1.i General------------------------------------------------------------------------------------- p49
1.2.1.ii Selection of batches--------------------------------------------------------------------- p49
1.2.1.iii Test procedures and test criteria----------------------------------------------------- p50
1.2.1.iv Specifications ----------------------------------------------------------------------------- p50
1.2.1.v Storage test conditions ----------------------------------------------------------------- p51
1.2.1.vi Testing frequency------------------------------------------------------------------------ p52
1.2.1.vii Packaging material ---------------------------------------------------------------------- p52
1.2.1.viii Evaluation---------------------------------------------------------------------------------- p53
1.2.1.ix Statements/Labeling -------------------------------------------------------------------- p54

1.2.2 PRODUCTS CONTAINING WELL-KNOWN CHEMICAL ENTITIES------------ p54
1.2.2.i Selection of batches--------------------------------------------------------------------- p54
1.2.2.ii Storage test conditions ----------------------------------------------------------------- p55

2 PRESENTATION OF STABILITY DATA----------------------------------------------- p55

3 PREDICTION OF SHELF-LIFE----------------------------------------------------------- p56

4 FOLLOW-UP STABILITY DATA --------------------------------------------------------- p57

5 SUPPLEMENTS TO PRODUCT APPLICATION------------------------------------- p57
5.1 Manufacturing, formulation and control changes (general)
5.2 Change in formulation
5.3 Change in packaging

6 CALCULATION OF EXPIRY DATE ----------------------------------------------------- p57

7 STORAGE IN BULK------------------------------------------------------------------------- p57

44
8 EXTENSION OF SHELF-LIFE ------------------------------------------------------------ p58

9 IMPLEMENTATION-------------------------------------------------------------------------- p58

APPENDIX 1 -------------------------------------------------------------------------------------------- p59

APPENDIX 2 -------------------------------------------------------------------------------------------- p64

45
1. STABILITY TRIAL DESIGN

There shall be a written testing program designed to assess stability characteristics of
dosage forms. The results of such stability testing shall be used in determining
appropriate storage conditions and expiry dates.

The design of the study should consider the methodology for determining the stability
of the active substance and dosage forms. The following factors must be considered in
designing a stability trial:

1.1 ACTIVE SUBSTANCE

1.1.1 New Chemical Entity

1.1.1.i General
Information on the stability of the active substance is an integral part of the
systematic approach to stability evaluation.

The actual studies to be carried out will depend on the nature of the active
substance, but may include the effect of elevated or low temperatures,
susceptibility to moisture, oxidation and the effect of light. The effect of pH and high
oxygen atmosphere may be important for aqueous solutions or suspensions of the
active substance.

1.1.1.ii Stress Testing
Stress testing helps to determine the intrinsic stability of the molecule by
establishing degradation pathways in order to identify the likely degradation
products, and to validate the stability indicating power of the analytical procedures
used.

1.1.1.iii Formal Studies
Primary stability studies are intended to show that the active substance will remain
within specification during the retest period if stored under recommended storage
conditions.

1.1.1.iv Selection of Batches
Stability information from accelerated and long-term testing is to be provided on at
least three batches. The long-term testing should cover a minimum of 12 months
duration on at least three batches at the time of submission of the application for
registration.

The batches manufactured to a minimum of pilot plant scale should be by the same
synthetic route and use a method of manufacture and procedure that simulates the
final process to be used on a manufacturing scale.

The overall quality of the batches of active substance placed on stability should be
representative of both the quality of the material used in pre-clinical and clinical
studies, and the quality of material to be made on a manufacturing scale.

In the event of more than one manufacturer being used, it must be confirmed that
the same method of synthesis is used, or extensive comparative data be submitted
including all aspects of quality, safety and efficacy.

46

Supporting information may be provided using stability data on batches of active
substance made on a laboratory scale.

The first three production batches of active substance manufactured post approval,
if not submitted in the original application for registration, should be placed on long-
term stability studies using the same stability protocol as in the approved
application for registration.

1.1.1.v Test Procedure and Test Criteria
The testing should cover those features susceptible to change during storage and
likely to influence quality, safety and/or efficacy. Stability information should cover
as necessary the physical, chemical and microbiological test characteristics.
Validated stability-indicating testing methods must be applied. The need for the
extent of replication will depend on the results of validation studies.

1.1.1.vi Specifications
Limits of acceptability should be derived from the profile of the material as used in
the preclinical and clinical batches. It will need to include individual and total upper
limits for impurities and degradation products, the justification for which should be
influenced by the levels observed in material used in preclinical studies and clinical
trials.

1.1.1.vii Storage Conditions
The length of the studies and the storage conditions should be sufficient to cover
storage, shipment and subsequent use. Application of the same storage conditions
as applied to the drug product will facilitate comparative review and assessment.
Other storage conditions are allowable if justified. In particular, temperature
sensitive active substances should be stored at an alternative, lower temperature
condition, which will then become the designated long-term testing storage
temperature. The six months accelerated testing should then be carried out at a
temperature at least 15
o
C above this designated long-term storage temperature
(together with appropriate relative humidity conditions for that temperature). The
designated long-term testing conditions will be reflected in the labelling and retest
date.

Conditions Minimum time period at
Submission

Long-term testing 25 2
o
C/60 5%RH 12 months

Accelerated 40 2
o
C/75 5%RH 6 months

Where "significant change" occurs during six months storage under conditions of
accelerated testing at
40
o
C 2
o
C/75% RH 5%, additional testing at an intermediate condition (such as
30
o
C 2
o
C/60% RH5%) should be conducted for active substances to be used in
dosage forms tested long-term at 25
o
C/60% RH and this information included in
the application for registration. The initial application should include minimum of 6
months' data from a 12 month study.

47
"Significant change" at 40
o
C/75% RH or 30
o
C/60% RH. is defined as failure to
meet the specification.

The long-term testing will be continued for a sufficient period of time beyond 12
months to cover all appropriate retest periods, and the further accumulated data
may be submitted to the Council during the assessment period of the application.
The data (from accelerated testing or from testing under an intermediate
condition(s) may be used to evaluate the impact of short-term excursions outside
the label storage conditions such as may occur during shipping.

1.1.1.viii Testing Frequency
Frequency of testing should be sufficient to establish the stability characteristics of
the active substance. Testing under the defined long-term conditions will normally
be carried out every three months over the first year, every six months over the
second year and then annually.

1.1.1.ix Packaging/Containers
The containers to be used in the long-term, real-time stability evaluation should be
the same as or simulate the actual packaging used for storage and distribution.

1.1.1.x Evaluation
The design of the stability study is to establish, based on testing a minimum of
three batches of the active substance and evaluating the stability information,
(covering as necessary the physical, chemical, and microbiological test
characteristics), a retest period applicable to all future batches of the bulk active
substance manufactured under similar circumstances. The degree of variability of
individual batches affects the confidence that a future production batch will remain
within specification until the retest date.

An acceptable approach for quantitative characteristics that are expected to
decrease with time is to determine the time at which the 95% one-sided confidence
limit for the mean degradation curve intersects the acceptable lower specification
limit. If analysis shows that the batch-to-batch variability is small, it is advantageous
to combine the data into one overall estimate, and this can be done by first
applying appropriate statistical tests (for example, p values for level of significance
of rejection of more than 0,25) to the slopes of the regression lines and zero time
intercepts for the individual batches. If it is inappropriate to combine data from
several batches, the overall retest period may depend on the minimum time a batch
may be expected to remain within acceptable and justified limits.

The nature of any degradation relationship will determine the need for
transformation of the data for linear regression analysis. Usually the relationship
may be represented by a linear, quadratic, or cubic function on an arithmetic or
logarithmic scale. Statistical methods should be employed to test the goodness of
fit of the data on all batches and combined batches (where appropriate) to the
assumed degradation line or curve.

The data may show so little degradation and so little variability that it is apparent
from looking at the data that the requested retest period will be granted. Under the
circumstances, it is normally unnecessary to go through the formal statistical
analysis but merely to provide a full justification for the omission.

48
Limited extrapolation of the real time data beyond the observed range to extend
expiration dating at approval time, particularly where the accelerated data supports
this, may be undertaken. However, this assumes that the same degradation
relationship will continue to apply beyond the observed data, and hence the use of
extrapolation must be justified in each application in terms of what is known about
the mechanism of degradation, the goodness of fit of any mathematical model,
batch size, existence of supportive data, etc.

Any evaluation should cover not only the assay, but also the levels of degradation
products and other appropriate attributes.

When degradation products are identified in significant amounts or suspected of
toxicity, a concerted effort has to be made to collect the following additional
information about the substance concerned:

chemical structure
cross-reference to any available information about biological effect and
significance at the concentrations likely to be encountered
procedure for isolation and purification
mechanism of formation, including order of reaction
physical and chemical properties
specifications and directions for testing their presence at the levels of
concentrations expected to be present, and
indication of pharmacological activity, or inactivity or toxicity profile.

Where the route of degradation is not known, suitable screening chromatographic
or other tests may be required.

Official compendia or other tests designed to identify impurities in the active
substance used in the formulation may not necessarily be suitable for investigation
into degradation products.

When it has been considered necessary to perform toxicity studies, these results
should be presented.

Consideration should be given to the stereo-chemical and polymorphic integrity of
active substances.

Stability information gained should enable the applicant to institute a routine system
whereby re-analysis to validate the conformance to specification of the active
substance is done, in order that the stability of the dosage form concerned is
assured.

1.1.1.xi Statements/Labelling
A storage temperature should be based on the stability evaluation of the active
substance. Where applicable, specific requirements should be stated, particularly
for active substances that cannot tolerate freezing. The use of terms such as
"ambient conditions" or "room temperature" is unacceptable.
A retest period should be derived from the stability information.

49
1.1.2 Well-known Chemical Entities (established active substances)
Annexure 10(a) must be completed.

Literature data on decomposition process and degradability are generally available
and must be included in the submission.

If degradation pathways/products are unknown, references to support such
conclusions must be included or experimental data submitted.

Reference to pharmacopoeias does not satisfy the requirements of Annexure
10(a)(i) and (ii).

1.2 DOSAGE FORMS

1.2.1 Products containing new chemical entities

1.2.1.i General
The design of the stability program for the finished product should be based on the
knowledge of the behaviour and properties of the active substance and the
experience gained from clinical trial formulation studies and from stability studies
on the active substance. The likely changes on storage and the rationale for the
selection of product variables to be included in the testing program should be
stated.

1.2.1.ii Selection of Batches
Stability information from accelerated and long-term testing is to be provided on
three batches of the same formulation and dosage form in the containers and
closure proposed for marketing. Two of the three batches should be at least pilot
scale. The third batch may be smaller (e.g.25 000 to 50 000 tablets or capsules for
solid oral dosage forms).

The long-term testing should cover at least 12 months duration at the time of
submission. The manufacturing process to be used should meaningfully simulate
that which would be applied to large scale batches for marketing. The process
should provide product of the same quality intended for marketing, and meeting the
same quality specification as to be applied to release of material. Where possible,
batches of the finished product should be manufactured using identifiably different
batches of active substance.

Where an application includes different sources of active substances that are not
physically and/or chemically equivalent, and/or where the difference in physical
and/or chemical specifications may adversely affect the stability of the product,
stability studies should be performed on the final product manufactured from each
active substance.

Data on laboratory scale batches is not acceptable as primary stability information.
Data on associated formulations or packaging may be submitted as supportive
information, provided that the difference in the formulations is clearly stated. The
first three production batches manufactured post approval, if not submitted in the
original application for registration, should be placed on accelerated and long-term
stability studies using the same stability protocols as in the approved application for
registration.

50

1.2.1.iii Test Procedures and Test Criteria
The testing should cover those features susceptible to change during storage and
likely to influence quality, safety and/or efficacy. Analytical test procedures should
be fully validated, and assays should be stability-indicating i.e., they must be
capable of separating and detecting compounds which are likely to be present as
impurities or which may arise via established degradation pathways.

The need for the extent of replication will depend on the results of validation
studies.

Where the "in-use" form of the product differs markedly from the manufactured and
packaged form (e.g. where the product is required to be reconstituted, diluted or
mixed prior to use), data to establish the stability of the "in-use" form of the product
should be supplied.

Where the manufacturer claims the product may be diluted with a range of
solutions prior to use, e.g., products that require dilution prior to parenteral infusion,
stability data to establish compatibility with and stability in each solution should be
submitted. Data on compatibility with the range of materials, such as are used for
the intravenous infusion containers and the administration sets recommended for
use should be submitted.

Where the dosage form is to be reconstituted at the time of dispensing, the
labelling should bear supportive expiration information and storage conditions for
both the reconstituted and unreconstituted dosage forms.

The range of testing should cover not only chemical and biological stability but also
loss of preservative (where relevant), physical properties and characteristics,
organoleptic properties and, where required, microbiological attributes.

Preservative efficacy testing and assays on stored samples should be carried out
to determine the content and efficacy of antimicrobial preservatives.

Stability should be established for the whole period of intended use under the
conditions reflected in the printed packaging components (SECTION 1 A ,B and C).

1.2.1.iv Specifications
Limits of acceptance should relate to the release limits (where applicable) and be
derived from consideration of all the available stability information. The shelf life
specification could allow acceptable and justifiable deviations from the release
specification based, on the stability evaluation and the changes observed on
storage. It will need to include specific upper limits for degradation products, the
justification for which should be influenced by the levels observed in material used
in pre-clinical studies and clinical trials. The justification for limits proposed for
certain other tests such as particle size and/or dissolution rate will require inference
to the results observed for batch(es) used in bioavailability and/or clinical studies.
Preservative efficacy testing should support any differences between the release
and shelf life specifications for antimicrobial preservatives.

51
1.2.1.v Storage Test Conditions
The length of the studies and the storage conditions should be sufficient to cover
storage, shipment, and subsequent use (e.g. reconstitution or dilution as
recommended in the labelling).

See table below for accelerated and long-term storage conditions and minimum
times. An assurance that long-term testing will continue to cover the expected
shelf-life should be provided. Other storage conditions are allowable if justified.
Heat-sensitive drug products should be stored under an alternative lower
temperature condition which will eventually become the designated long-term
storage temperature. Special consideration may have to be given to products that
change physically or even chemically at lower storage conditions, e.g. suspensions
or emulsions, which may sediment, or cream, oils and semi-solid preparations
which may show an increased viscosity.

The clarity of solutions and the physical stability of semi-solid preparations and
emulsions should be determined over a wide temperature range. Where a lower
temperature condition is used, the six months accelerated testing should be carried
out at a temperature at least 15
o
C above its designated storage temperature
(together with appropriate relative humidity conditions for that temperature). For
example, for a product to be stored long term under refrigerated conditions,
accelerated testing should be conducted at 25 2
o
C/60% 5%RH. The designated
long-term testing conditions will be reflected in the labelling and expiration date.

Storage under conditions of high relative humidities applies particularly to solid
dosage forms. For products such as solutions, suspensions, etc., contained in
packs designed to provide a permanent barrier to water loss, specific storage under
conditions of high relative humidity is not necessary, but the same range of
temperatures should be applied. Low relative humidity (e.g. 10 - 20% RH) can
adversely affect products packed in semi-permeable containers (e.g. solutions in
plastic bags, nose drops in small plastic containers, etc.) and consideration should
be given to appropriate testing under such conditions.

For solutions with a high sugar content (greater than 60 %), or where the solubility
of the active is low (less than 5 mg per 100 ml) or its content close to saturation,
stability data at low temperatures (2 to 8
o
C) must be conducted for at least 14
days.

Conditions Minimum time period
At submission

Long-term testing 25 2
o
C / 60 5% RH 12 months

Accelerated 40 2
o
C / 75 5% RH 6 months

Where "significant change" occurs due to accelerated testing additional testing at
an intermediate condition, e.g., 30 2
o
C / 60%RH 5% RH should be conducted.
"Significant change" at accelerated condition is defined as:

A 5% potency loss from the initial assay value of a batch;
Any specified degradant exceeding its specification limit;
The product exceeding its pH limits;
Dissolution exceeding the specification limits for 12 capsules or tablets;

52
Failure to meet specifications for appearance and physical properties, e.g.
colour, phase separation, resuspendability, delivery per actuation, caking,
hardness, etc.

Should significant change occur at 40
o
C/75%RH then the initial application for
registration should include a minimum of 6 months' data from an ongoing one-year
study at 30
o
C/60%RH, the same significant change criteria shall apply.

The long-term testing will be continued for a sufficient time beyond 12 months to
cover shelf-life at appropriate test periods.

The first three production batches manufactured post-approval, if not submitted in
the original application for registration application, should be placed on accelerated
and long-term stability studies using the same stability protocol as in the approved
drug application.

1.2.1.vi Testing Frequency
Frequency of testing should be sufficient to establish the stability characteristics of
the drug product. Testing will normally be every three months over the first year,
every six months over the second year, and then annually.

The use of matrixing or bracketing may be applied if justified (See Glossary).

1.2.1.vii Packaging Material
The testing should be carried out in the final packaging proposed for marketing.
Additional testing of unprotected drug product forms a useful part of the stress
testing and pack evaluation, as do studies carried out in other related packaging
materials in supporting the definitive packs.

Where package container sealant integrity is to be assessed, more than 75%
relative humidity may be appropriate to stress its adhesive properties at 30 to 40
o
C
e.g., blister units and strip packages. Alternatively, sealant integrity may be
performed through physical testing of the pack itself.

The loss of moisture can be important for liquid formulations, semisolid and certain
solid dosage forms packed in moisture permeable containers and studies at low
relative humidity and high temperature for a limited period of time may be
appropriate for these products.

For most dosage forms stability data need only be obtained for the container-
closure system to be marketed, provided that all container-closure systems are of
identical composition and seal integrity, and a brief justification is included stating
the reasons for the container size chosen, e.g. larger air volume, largest surface
contact etc.

If the product is to be marketed in more than one type of container and the
applicant proves that resistance to variables such as moisture permeation, oxygen
permeation, light diffusion etc., is demonstrated to be equal to or better than
existing container closure systems, additional stability testing would usually not be
required for solid dosage forms before such changes in packaging can be
supplemented.

53
Physicians samples should be included in the stability studies if their container-
closure system is different from the marketing container unless equivalence or
superiority of the packaging material is demonstrated.

In instances where the product will be marketed packaged in a "moisture
permeable" material (e.g. polyethylene, polypropylene, polyvinyl chloride, etc.), the
stability of the product should be determined under conditions of high humidity and
elevated temperature Stability may be conducted in the least protective container-
closure system if the superiority of the other containers can be proven. These data
must be included in PART 2G.

The time during which the product is stored in the bulk container, prior to packing
into the final immediate container, constitutes part of the approved shelf-life, i.e.,
the date of expiry remains a function of the date of manufacture, not the date of
packaging. Bulk products, which are stored for a period of time prior to packaging
into the final immediate containers for 25% or more of the approved shelf life,
should be tested, with stability indicating methods, prior to packaging.

1.2.1.viii Evaluation
A systematic approach should be adopted in the presentation and evaluation of the
stability information, which should cover as necessary physical, chemical, biological
and microbiological quality characteristics, including particular properties of the
dosage form (for example dissolution rate for oral solid dosage forms).

The design of the stability study is to establish shelf-life and label storage
instructions applicable to all future batches of the dosage form manufactured and
packed under similar circumstances, based on testing a minimum of three batches
of the drug product. The degree of variability of individual batches affects the
confidence that a future production batch will remain within specification, until the
expiration date.

An acceptable approach for quantitative characteristics that are expected to
decrease with time, is to determine the time at which the 95% one-sided
confidence limit for the mean degradation curve intersects the acceptable lower
specification limit. If analysis shows that the batch-to-batch variability is small, it is
advantageous to combine the data into one overall estimate, and this can be done
by first applying appropriate statistical tests (e.g. p values for level of significance of
rejection of more than 0,25) to the slopes of the regression lines and zero time
intercepts for the individual batches. If it is inappropriate to combine data from
several batches, the overall shelf-life may depend on the minimum time a batch is
expected to remain within acceptable and justified limits.

The nature of the degradation relationship will determine the need for
transformation of the data for linear regression analysis. Usually the relationship
can be represented by a linear, quadratic, or cubic function on an arithmetic or
logarithmic scale. Statistical methods should be employed to test the goodness of
fit on all batches and combined batches (where appropriate) to the assumed
degradation line or curve.

Where the data shows so little degradation and variability that it is apparent from
looking at the data that the requested shelf-life will be granted, it is normally
unnecessary to go through the formal statistical analysis. Only a justification for the
omission needs to be provided.

54
Limited extrapolation of the real time data beyond the observed range to extend
expiration dating at approval time, particularly where the accelerated data supports
this, may be undertaken. However, this assumes that the same degradation
relationship will continue to apply beyond the observed data, hence the use of
extrapolation must be justified, in each application, in terms of what is known about
the mechanisms of degradation, the goodness of fit of any mathematical model,
batch size, existence of supportive data, etc.

Any evaluation should consider not only the assay, but the levels of degradation
products and appropriate attributes. Where appropriate, attention should be paid to
reviewing the adequacy of the mass balance, different stability, and degradation
performance.

The stability of the drug products after reconstitution or dilution according to
labelling, should be addressed to provide appropriate and supportive information.

In the case of reconstituted products for oral use, the reconstituted product must be
tested for at least the recommended storage period at 25
o
C even if the
recommended storage temperature is 2-8
o
C.

1.2.1.ix Statements/Labelling
The storage temperature should be based on the stability evaluation of the drug
product. Where applicable, specific requirements should be stated particularly for
drug products that cannot tolerate freezing.

The use of terms such as "ambient conditions" or "room temperature" is
unacceptable.

There should be a direct linkage between the label statement and the
demonstrated stability characteristics of the drug product.

The use of a temperature range, for example 15 - 25
o
C, is not acceptable, unless
adequate motivation for the lower temperature is submitted. The recommendation,
"Store below 25
o
C. Do not refrigerate" could be considered.

1.2.2 Products containing well-known chemical entities (Generics) and line extensions
such as new dosage forms or additional strengths.

1.2.2.i Selection of Batches
Stability information from accelerated and long-term testing is to be provided on at
least two batches of the same formulation and dosage form in the containers and
closure proposed for marketing. One of the two batches should be at least pilot
scale. The second batch may be smaller (e.g.25 000 to 50 000 tablets or capsules
for solid oral dosage forms). The long-term and accelerated testing should cover at
least 3 months duration at the time of submission. The manufacturing process to be
used should meaningfully simulate that which would be applied to large scale
batches for marketing. The process should provide a product of the same quality
intended for marketing, meeting the same quality specifications as that applied to
release of product.

55
1.2.2.ii Storage Test Conditions

Conditions Minimum time period at
submission
Long term testing 25 2C / 60 5% RH 3 months
Accelerated 40 2C / 75 5% RH 3 months

The long-term testing will be continued for a sufficient time to cover
shelf-life, at appropriate test periods.
The first two production batches manufactured post-approval, if not submitted in
the original application for registration, should be placed on long-term stability using
the same stability protocols as in the approved application for registration.

If the accelerated data submitted in the original application is derived from batches
other than production batches, accelerated data on at least one production batch
must be generated.

Heat-sensitive drug products should be stored under an alternative lower
temperature condition which will eventually become the designated long-term
storage temperature. Where a lower temperature condition is used, the 3 months
accelerated testing should be carried out at a temperature at least 15
o
C above its
designated long-term storage temperature (together with appropriate relative
humidity conditions for that temperature).

Note:

Other general points discussed under "Products containing new chemical entities" are
also relevant to generics.

2 PRESENTATION OF STABILITY DATA

a The criteria for acceptance of each parameter (minimum and maximum values)
relating to stability must be stated.

b Overages in the formulation of batches included in the stability investigation
should be clearly stated.

c The actual analytical results obtained at the commencement (zero time) and at
nominated time intervals throughout the trial (for example 0, 3, 6, 9, 12, 18, 24,
30, 36 months which can if necessary be adapted to suit the product) must be
provided in a tabulated form. For products predicted to degrade rapidly, more
frequent sampling is necessary.

d. The container-closure system used must be clearly indicated, e.g. the type,
nature, grade and colour of the material of the container and closure, composition
of strip packaging, blister packaging and liners and size of the container(s) or
pack-size must be clearly stated.

e Storage conditions must be clearly defined with respect to temperature, light,
humidity, opening and closing of container, whether stored upright or inverted,

56
whether a desiccant is included in the container and presence of foam/cotton
wool.

f The name and strength of product, dosage form, batch size, and type of batch
(eg pilot, production or experimental) batch number, name of manufacturer,
source of active substance, dates of manufacture and initial testing must be
stated.

g If more than one assay result is available for any particular time interval, all
results should be quoted including the Mean and Standard Deviation (where
possible).

h The actual result obtained for an assay at the beginning of the stability trial
should be recorded and compared with subsequent values.

i Initial assay results should be expressed as the quantity of active substance per
unit dosage form in terms of micrograms, milligrams or grams. Assay results for
subsequent checkpoints should be given in the same way and in terms of
percentage of initial assay.

j Quantitative results must be reflected wherever relevant. The expression
"complies" does not suffice.

k All results obtained should be discussed and conclusions drawn from the stability
studies be given. A shelf life must be concluded from the results. Explanations
should be given where necessary e.g. anomalous or unusual results, change in
assay method. Results should be processed utilizing current statistical methods
and any assumption made should be statistically tested at the 90 - 95 %
confidence level.

l Stability-indicating method PART 2G: The statement "Reference to PART 2F may
be made, included under the requirements for PART 2G, refers to the specific
analytical method and does not absolve the applicant from submitting reasons
why the assay methods are assumed to be stability-indicating.

m An assurance that long-term testing will continue to cover the shelf-life period
must be given in PART 2 G (written undertaking at the time of submission of the
application). Applicants are reminded of the recommendation under testing
frequency that products should be tested at least annually after the second year.

3 PREDICTION OF SHELF-LIFE FROM STABILITY DATA

a At least nine months' data derived from the product stored at the maximum
recommended storage conditions and three months under conditions of stress
for generic products must be available at the time of registration, for
consideration of a tentative shelf-life of 24 months. For products containing new
entities, the data accumulated over a sufficient period of time, beyond the initial
12 months, to cover appropriate retest periods must be available.

b Generally a tentative shelf-life is only assigned provided that the stability
investigation of the product as above has been satisfactorily completed.

57
c Applicants are reminded that a tentative shelf-life is often established on
condition that the applicant has committed himself by an undertaking [in PART 2
G] to continue and complete the required on-going studies and to submit the
results as they become available.

4 FOLLOW-UP STABILITY DATA

a The tentative shelf-life must be substantiated by stability data derived from at
least two production batches, stored at the maximum recommended storage
conditions for the full period of shelf-life for generics. If the accelerated data
submitted previously were derived from batches other than production batches,
three months' accelerated data on at least one of the production batches are
required.

b For products containing new entities, the tentative shelf-life must be substantiated
by stability data derived from at least three production batches. If the accelerated
data submitted previously were derived from batches other than production
batches, six months' accelerated data on the three production batches are
required.

c The maximum recommended storage conditions, integrity of container used and
formulation will determine the temperatures and humidity conditions to be
included in the stress-testing program.

d Stability trials involving the product stored at the maximum recommended
temperature must be continued for the full period to validate the tentative shelf-
life.

e An approved shelf-life may be extended through submission of additional data
accumulated on production batches covering the full period applied for..(Refer to
Addendum G)

5. SUPPLEMENTS TO PRODUCT APPLICATION
(Refer to ADDENDUM G for stability requirements for major and minor
amendments)

6 CALCULATION OF EXPIRY DATE

The expiry date of the finished product is calculated from the date of manufacture i.e.
date of first weighing off of raw materials for manufacturing. If the production batch
contains reprocessed material the expiry date is calculated from the date of
manufacture of the oldest reprocessed batch and it should be verified that the batch
will meet the final product specification for the full period of the shelf-life allocated.

7. STORAGE IN BULK

The applicant must consider the suitability of the container used for in-process storage
and transportation of bulk product in terms of compatibility, moisture permeation and
closure sealability.

58
8. EXTENSION OF SHELF-LIFE

For an extension of shelf-life real time data obtained according to the program included
in PART 2 G on at least two production batches for the full period required must be
submitted for generics and on at least three batches for new chemical entities.

Note:
In order to facilitate evaluation, the application for an extension of shelf-life should
include all the stability data in support of the shelf-life extension (including previously
submitted data for the relevant batches).
Reference only to previously submitted data is not acceptable.

9 IMPLEMENTATION

Applicants are reminded that this guideline provides a general indication on
requirements for stability testing and the Council agrees with the preamble included in
the USP and concedes that there are scientifically justifiable reasons for using
alternative approaches. Furthermore, it remains the prerogative of the Council to
request any additional studies which it may deem necessary.

59
APPENDIX 1

GLOSSARY AND INFORMATION
The following terms have been in general use, and the following definitions are provided to
facilitate interpretation of the guideline.

Accelerated testing
Studies designed to increase the rate of chemical degradation or physical change of an
active substance or product by using exaggerated storage conditions as part of the formal,
definitive, storage program. These data, in addition to long-term stability studies, may also
be used to assess longer term chemical effects at non-accelerated conditions and to
evaluate the impact of short-term excursions outside the label storage conditions such as
might occur during shipping. Results from accelerated testing studies are not always
predictive of physical changes.

Active substance; Active Ingredient; Drug Substance; Medicinal Substance
The unformulated active substance which may be subsequently formulated with excipients to
produce the product.

Bracketing
The design of a stability schedule so that at any time point only the samples on the
extremes, e.g. example of container size and/or dosage strengths, are tested. The design
assumes that the stability of the intermediate condition samples are represented by those at
the extremes. Where a range of dosage strengths is to be tested, bracketing designs may be
particularly applicable if the strengths are very closely related in composition (e.g. for a tablet
range made with different compression weights of a similar basic granulation, or a capsule
range made by filling different plug fill weights of the same basic composition into different
size capsule shells). Where a range of sizes of immediate containers is to be evaluated,
bracketing designs may be applicable if the material of composition of the container and the
type of closure are the same throughout the range.

Climatic Zones
The concept of dividing the world into four zones based on defining the prevalent annual
climatic conditions. Fluctuations in climatic conditions throughout South Africa prohibit the
characterization of this country by any one of the four identified zones and the conditions of
storage likely to be encountered in South Africa must be considered in designing the stability
trial.

Dosage Form; Preparation
A pharmaceutical product type, e.g. tablet, capsule, solution, cream, etc. that contains an
active ingredient generally, but not necessarily, in association with excipients.

Product; Finished Product
The dosage form in the final immediate packaging intended for marketing.

Excipient
Anything other than the active substance in the dosage form.

Expiry/Expiration Date
The date placed on the container/labels of a product designating the time during which a
batch of the product is expected to remain within the approved shelf life specification if
stored under defined conditions, and after which it must not be used.

60
Formal (Systematic) Studies
Formal studies are those undertaken to a pre-approval stability protocol, which embraces the
principles of these guidelines.

Long-Term (Real Time) Testing
Stability evaluation of the physical, chemical, biological, and microbiological characteristics
of a product and an active substance, covering the expected duration of the shelf life and
retest period, which are claimed in the application for registration and will appear on the
labelling.

Mass Balance; Material Balance
The process of adding together the assay value and levels of degradation products to see
how closely these add up to 100 per cent of the initial value, with due consideration of the
margin of analytical precision. This concept is a useful scientific guide for evaluating data,
but it is not achievable in all circumstances. The focus may instead be on assuring the
specificity of the assay, the completeness of the investigation of routes of degradation, and
the use, if necessary, of identified degradants as indicators of the extent of degradation via
particular mechanisms.

Matrixing
The statistical design of stability schedule so that only a fraction of the total number of
samples is tested at any specified sampling point. At a subsequent sampling point, different
sets of samples of the total number would be tested. The design assumes that the stability of
the samples tested represents the stability of all samples. The differences in the samples for
the same product should be identified as, for example, covering different batches, different
strengths, and different sizes of the same container and closure and, possibly in some
cases, different container/closure systems.

Matrixing can cover reduced testing when more than one variable is being evaluated. Thus
the design of the matrix will be dictated by the factors needing to be covered and evaluated.
This potential complexity precludes inclusion of specific details and examples, and it may be
desirable to discuss design in advance with the Council, where it is possible. In every case it
is essential that all batches are tested initially and at the end of the long-term testing.

Mean Kinetic Temperature
When establishing the mean value of the temperature, the formula of J D Haynes* can be
used to calculate the mean kinetic temperature. It is higher than the arithmetic mean
temperature and takes into account the Arrhenius equation from which Haynes* derived his
formula. *. Pharm. Sci. J 60, 927-929, 1971.

New Chemical Entity; New Molecular Entity; New Active Substance
A substance which has not previously been registered as a new active substance with the
Council.

Pilot Plant Scale
The manufacture of either active substance or product by a procedure fully representative of
and simulating that to be used on a full manufacturing scale. For oral solid dosage forms this
is generally taken to be at a minimum scale of one-tenth that of full production or 100 000
tablets or capsules, whichever is the larger.

61
Primary Stability Data
Data on the active substance stored in the proposed packaging under storage conditions
that support the proposed retest date. Data on the product stored in the proposed container-
closure for marketing under storage conditions that support the proposed shelf-life.

Random Sample
The sampling procedure should fulfill the condition that analysis (with the required accuracy)
of the sample shows no difference in object quality compared to the object itself.

Retest Date
The date when samples of the active substance should be re-examined to ensure that
material is still suitable for use.

Retest Period
The period of time during which the active substance can be considered to remain within the
specification and therefore acceptable for use in the manufacture of a given drug product,
provided that it has been stored under the defined conditions. After this period, the batch
should be retested for compliance to its specification and then used immediately.

Shelf-life; Expiration Dating Period
The time interval that a product is expected to remain within the approved shelf-life
specifications provided that it is stored under the conditions defined on the label in the
proposed containers and closure.

The shelf-life is used to establish the expiry date of individual batches. It is the length of time
required for:

a The least stable active ingredient to degrade to the specified, motivated and
approved or proposed fraction of the labelled quantity
b some element of pharmaceutical elegance to drop to an unacceptable level, or
c an arbitrary minimum of 2 years, unless otherwise determined by the Council.

The shelf life could also reflect the length of time required for:

d a measurable increase in toxicity as shown by either animal experiments or clinical
adverse reaction reports, or,
e a measurable loss in reported clinical effectiveness(even though analytical methods
show little or no reduction in apparent concentration).

Specification - Release
The combination of physical, chemical, biological, and microbiological test requirements that
determine a product is suitable for release at the time of its manufacture.

Specification - Check/Shelf Life
The combination of physical, chemical, biological and microbiological test requirements that
a active substance must meet at its retest date or a product must meet throughout its shelf
life.

Stability-Indicating Methodology
Analytical methods that will quantitatively differentiate between the active ingredient and all
known breakdown products or impurities.

62
Stability
The capacity of an active ingredient or dosage form to remain within specifications
established to assure its identity, purity, strength and critical physico-chemical
characteristics.

Storage Conditions
An acceptable variation in temperature and relative humidity of storage facilities. The
equipment must be capable of controlling temperature to a range of +- 2
o
C and Relative
Humidity to +- 5% RH. The real temperatures and humidities should be monitored during
stability storage. Short-term spikes due to opening of doors of the storage facility are
accepted as unavoidable.

The effect of variations during equipment failure should be addressed by the applicant and
reported if judged to impact stability results. Exceptions that exceed these ranges (i.e., 2
o
C
and/or 5% RH) for more than 24 hours should be described in the study report and their
impact assessed.

Strength
A quantitative measure of active ingredient, as well as other ingredients requiring
quantification.

Stress Testing (Active Substance)
These studies are undertaken to elucidate intrinsic stability characteristics. Such testing is
part of the development strategy, which is normally carried out under more severe conditions
than that used for accelerated tests. Stress testing is conducted to provide data on forced
decomposition products and decomposition mechanisms for the active substance. The
severe conditions that may be encountered during distribution can be covered by stress
testing of definitive batches of the active substance. These studies should establish the
inherent stability characteristics of the molecule, such as the degradation pathways, and
lead to identification of degradation products and hence support the suitability of the
proposed analytical procedures. The detailed nature of the studies will depend on the
individual active substance and type of drug product.

This testing is likely to be carried out on a single batch of material and to include the effect of
temperature in 10C increments above the accelerated temperature test condition (e.g., 50

o
C, 60
o
C, etc.) humidity where appropriate (e.g., 75% or greater); oxidation and photolysis
on the active substance plus its susceptibility to hydrolysis across a wide range of pH values
when in solution and suspension. Results from these studies will form an integral part of the
information provided to the Council.

Light testing should be an integral part of stress testing. [The standard conditions for light
testing are still under discussion and will be conveyed to applicants in a separate Guideline].

It is recognized that some degradation pathways can be complex and that under forcing
conditions decomposition products may be observed which are unlikely to be formed under
accelerated or long-term testing. This information may be useful in developing and validating
suitable analytical methods, but it may not always be necessary to examine specifically for
all degradation products, if it has been demonstrated that in practice these are not formed.

63
Stress Testing (Drug Product)
Light testing should be an integral part of stress testing (see above).
Special test conditions for specific products (e.g. metered dose inhalations and creams and
emulsions) may require additional stress studies.

Supporting Stability Data
Data other that primary stability data, such as stability data on early synthetic route batches
of active substance, small scale batches of materials, investigational formulations not
proposed for marketing, related formulations, product presented in containers and/or
closures other than those proposed for marketing, information regarding test results on
containers, and other scientific rationale that support the analytical procedures, the proposed
retest period or shelf-life and storage conditions.

Tentative Shelf-life
A provisional shelf-life determined by projecting results from less than full term data (such as
"accelerated studies") and storage under maximum recommended conditions for a period
motivated by the applicant using the dosage form to be marketed in the proposed container-
closure system.

64
APPENDIX 2

APPROPRIATE TESTS

Both physical and chemical characteristics of the product should be monitored during
storage. The possibility of interaction between the components of a fixed-combination
product should be considered. Where a pharmaceutical interaction appears possible, the
applicant should either submit data to establish that an interaction does not occur, or that it
is clearly recognized and defined. Where significant interaction with the pack is likely, the
effects on the product and on the pack should be evaluated, (e.g., due to leaching of
extractables, or due to absorption of constituents) and the results reported. The following
tests must always be included for all dosage forms:

Appearance
Assay of all actives
Degradation, if relevant

Assay
Detailed records of all analytical methods used in the stability studies should be kept along
with validation data.

Published methods of analysis for which validations are also published as well as
compendial methods of analysis should be kept, with partial validation data only
demonstrating suitability of the in-house equipment and personnel. If a change in procedure
is necessary during the stability trial, data should be generated and kept and processed in
such a way as to prove that no statistically significant difference exists between the results of
the older method versus the newer method.

The stability-indicating methodology should be validated by the applicant (and the accuracy,
precision and reproducibility established) and analytical procedures described in sufficient
detail to permit validation.

Degradation products
Chromatographic or other analytical methods designed to determine the content of
degradation products should be submitted with the assay results, even where an assay
procedure specific to the active ingredient has been used.

Physical properties
In addition to assay for content of active ingredient and degradation products, it is necessary
to ensure that physical properties of the product are unimpaired after storage. Consideration
should be given to the stereo-chemical integrity of the product. The additional tests will vary
with the formulation in question, but important attributes of various dosage forms may
include the following:

Tablets
Disintegration time, multi-point profile of dissolution rate for each active (if it is a multi
component product), moisture content, appearance, hardness, friability, colour and
odour.

Solubility time and appearance of solution for soluble tablets, dispersion time and
fineness of dispersion as well as multi-point profile of dissolution rate for dispersible
tablets, unless the active ingredient is in solution after dispersion.

65
Capsules
Moisture content, colour and appearance (capsule shell and contents), brittleness,
disintegration time (when dissolution rate is not applicable) and dissolution rate
(multipoint profile).
In conducting stability trials for solid dosage forms and other products with compendial
dissolution requirements, and which have a history of bioavailability problems,
dissolution rates could be determined and multi-point profiles presented in tabulated form
as a function of percentage of labelled claim dissolved to time.

Emulsions and suspensions
Appearance (such as colour and phase separation), odour, pH and viscosity,
resuspendability, particle size, sterility for ophthalmic preparations, preserving ability,
preservative content.

Solutions
pH, viscosity, (where relevant), solubility time (reconstitution time and appearance
thereof), sterility for ophthalmic preparations, preserving ability, preservative content.

Tests should be performed to ensure compatibility between the container-closure system
and the product and the results included in the submission.

Test methods to determine particle size should not employ extensive dilution of particles
or any other manipulation, which could affect the real particle size existing in the dosage
form. The applicability of the particle size dependent variable, such as sedimentation,
should also be considered.

After storage, samples of suspensions should be prepared for assay in accordance with
the recommended labelling under "Directions for use".

Powders, granules (including those for reconstitution)
Moisture, resuspendability/reconstitution time and appearance of reconstituted product,
microbial limits. The reconstituted product must be tested according to the requirements
for a solution or suspension.

Metered Dose Inhalation aerosols
Uniformity of delivered dose, number of metered doses, particle size (suspensions),
spray pattern, microbial limits, deposition of emitted dose.

Because the container contents are under pressure, filled containers must be checked
for loss in mass over the expiration-dating period. For suspensions, aggregate (or
solvate) formation may lead to clogged valves, or the delivery of a pharmacologically
inactive dose. Corrosion of the metering valve or deterioration may adversely affect the
delivery of the correct amount of active ingredient.

Ointments and creams
Homogeneity, pH, rheological properties, particle size and mass loss (plastic containers).
Preserving ability if preservative present. Preserving ability for all topical preparations
containing corticosteroids.

Parenterals
Small volume parenterals include an extremely wide range of preparations and
container-closure types. Each should be included in the stability study. Evaluation of
these products should include at least the following: pH, particulate matter, pyrogens and

66
/ or endotoxin testing (containers larger than 15 ml), syringeability of non-aqueous
products.

If a validated system exists, sterility is generally not required to be included in the
stability program. Initial sterility should be recorded on stability reports.
Tests should be performed to ensure the compatibility between the container-closure
and the product and the results submitted. Aspects to be investigated on the closure
include possible pigmentation, resealing following multiple penetration and force required
for needle to penetrate.

For Large Volume Parenterals the smallest container-closure size should be studied,
provided that all container-closure systems are identical in composition and seal
integrity.

A brief justification should be included stating the reasons for the container size chosen
e.g. largest air volume or largest surface contact etc. Additional tests - globule size
(where applicable), volume (plastic containers), moisture permeability (where applicable)
and extractables (plastic containers). Tests should be performed to ensure the
compatibility between the container-closure and the product. These data must be
submitted.

Suppositories
Melting range point, breaking strength and disintegration. The effect of aging may also
be observed from hardening of the suppository base; therefore control and stability
testing should include disintegration time at 37 C. Accelerated studies should be
conducted at 2 - 3 C below the melting point of the suppositories.

Admixtures
For any product intended for use as an additive to another product, the possibility of
incompatibility exists.

A suggested protocol should provide for tests to be conducted at zero-, 6-, 8-, and 24-
hour intervals. These should include:

Assay of active ingredient and any other ingredient for which a limit is set in the final
product specification;
pH (especially for unbuffered LVPs), colour, clarity (particulate matter);
interaction with the container;
identification of precipitation/sediment (although the presence of any precipitation is
already non-conforming).

Intra-Uterine Devices (IUD)
Tensile strength of the withdrawal string and integrity of the package, i.e. seal strength of
the pouch, sterility of the device. If the device contains a reservoir from which active
ingredient diffuses through a controlled release membrane, it should be tested for total
active content, degradation products and in-vitro release rate of the active ingredient in
addition to the above tests. Vaginal devices such as doughnut shaped plastic or other
polymeric matrix containing an active ingredient uniformly dispersed throughout the
matrix must be checked for in vitro release rate of the active ingredient and extraneous
extractable substances to establish stability and compatibility of the active with the
matrix.

67
Transdermal patches
Release rate, seal integrity, mass variation, adhesive properties.

Content of Antimicrobial preservatives
Dosage forms containing preservatives to control microbial contamination should have
the preservative content monitored initially (zero time) and at reasonable intervals
throughout the projected expiration dating period of the product. This may be
accomplished by performing microbial challenge tests (e.g., Antimicrobial preservative
effectiveness test of the USP or BP which is applicable to unopened containers) and by
performing chemical assays for the preservative. When the minimum quantity of
preservative to achieve effective microbial control has been determined for solutions,
chemical assays for the full period of the shelf-life may be adequate, provided that the
results of tests demonstrating the preservative effectiveness are submitted for
evaluation. It is particularly important to consider the adequacy of the preservative
system under conditions of use for multi-dose vials. When less than full-term data are
submitted for registration purposes, or for a major change in formulation, preliminary
results for preservative effectiveness for a minimum storage period of nine months
should be included for those products for which the effect of ageing on preservative
effectiveness needs to be demonstrated e.g., suspensions, creams etc.

Those products requiring control of the microbial quality that do not contain
preservative/s, should be tested initially (at zero time) and at the termination of study or
at the end of the projected expiration dating period according to the final product
specification (SECTION 2F), for bioburden
(e.g. Microbial limits tests of the USP or BP, which include a limit for total microbial count
and for absence of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa
and Salmonella species. In addition, it is recommended that topical preparations be
controlled for the absence of
Pseudomonas cepacia, Aspergillus niger and Candida albicans, as well as any other
topical pathogens that may be identified as potentially harmful. Simulated use tests on
topical preparations packed in jars and on ophthalmics are desirable.

Effects of Opening and Closing Containers
Investigation into "in-use" stability may be important for certain sensitive products. Where
applicable, the opening and closing of containers may follow a recommended dosage
direction included in Annexure 1 to the MBRI application form.

Desiccants
Duration of satisfactory performance of desiccants should be related to the shelf-life/expiry
date.

68
ADDENDUM B
SUBMISSION OF VALIDATION PROTOCOLS AND VALIDATION REPORTS

This document intends to communicate to the pharmaceutical industry, the policy and
requirements in respect of validation protocols and validation reports to be submitted to the
Council.

1. Important References:

Chapter 9 of the SA Guide to Good Manufacturing Practice (1996 edition)
United States Pharmacopoeia (USP)
British Pharmaceutical Codex (BPC)
FDA Guidelines on Validation

2. Council resolution:

2.1 The standard to be used to assess compliance with current Good Manufacturing
Practice, will be the South African Guide to Good Manufacturing Practice (latest
edition).

The Medicines Control Council resolved, during the meeting of 13 October
1994,
"that the Guide to Good Pharmaceutical Manufacturing Practice as amended, which
was prepared jointly by the secretariat and the PMA, be considered as the standard
determined by Council as referred to in the specific condition for registration of a
medicine, namely that the applicant shall ensure that the medicine is manufactured
and controlled in accordance with Good Manufacturing Practice as determined by
Council."

3. What is validation:

3.1 The SA Guide to GMP defines "validate" as follows:

" VALIDATE
To provide documented evidence that an item of equipment, process, system or
method is in a state of control (i.e. that all assignable causes of variation have been
eliminated) and is able to consistently deliver specified results."

3.2 Validation is an integral part of current good manufacturing practice; it is, therefore,
also an element of the quality assurance programme associated with a particular
product or process.

3.3 There should be levels where validation and qualification should be performed, and
the level should determine the intensity of validation of products. It should be least
for liquid preparations (solutions) and most for parenteral medicines, and for solid
dosage forms it should depend on the criticality of the product as far as the patient
is concerned.

69
4. When should validation be done:

4.1 Validation should be considered in the following situations:

* totally new processes
* new equipment processes and equipment which have been altered to suit
changing priorities
* processes where the end product test is poor and an unreliable indicator of
product quality

4.2 When any new manufacturing formula or method of preparation is adopted, steps
should be taken to demonstrate its suitability for routine processing. The defined
process, using the materials and equipment specified, should be shown to yield a
product consistently of the required quality.

4.3 In this phase the extent to which deviations from the chosen processing
parameters can influence product quality should also be evaluated. In general the
final batch size should not be more than ten times the batch size of the
representative development batches.

4.4 The validation in the production unit mainly comprises the determination and
evaluation of the process parameters of the facilities applied for the scale-up to
final batch size. The control of all critical process parameters, the results of the in-
process controls, final controls and stability tests should prove the suitability of the
important individual steps of a procedure.

4.5 At least three batches (including at least two production batches in the final batch
size) should be validated to show consistency. Worst case situations should be
considered.

4.6 When certain processes or products have been validated during the development
stage, it is not always necessary to re-validate the whole process or product if
similar equipment is used or similar products have been produced, provided that
the final product conforms to the in-process control and final product specifications.

4.7 There should be a clear distinction between in-process controls and validation. In-
process tests are performed each time on a batch-to-batch basis using
specifications and methods devised during the development phase. The objective
is to monitor the process continuously.

5. What does validation involve:

5.1 Validation involves the accumulation of documentary evidence relating to a
process, item of equipment, or facility. This is achieved by means of a validation
protocol which should exist for every product and which details the tests to be
carried out, the frequency of testing, and the results anticipated (acceptance
criteria).

70
6. The Validation Protocol (VP)

6.1 The Validation protocol should clearly describe the procedure to be followed for
performing validation. The protocol should include at least:
the objectives of validation and qualification study,
site of the study,
the responsible personnel,
description of equipment to be used (including calibration before and after
validation),
SOPs to be followed,
standards and criteria for the relevant products and processes,
the type of validation,
time/frequency should be stipulated,
processes and/or parameters to be validated (e.g. mixing times, drying
temperatures, particle size, drying times, physical characteristics, content
uniformity etc.) should be clearly identified.

7. The Validation Report (VR)

7.1. A written report should be available after completion of the validation. The results
should be evaluated, analysed and compared with acceptance criteria. All results
should meet the criteria of acceptance and satisfy the stated objective. If
necessary, further studies should be performed. If found acceptable, the report
should be approved and authorised (signed and dated).

7.2. The report should include at least:
the title and objective of the study,
reference to the protocol,
detail of material,
equipment,
programmes and cycles used,
details of procedures and test methods,
results (compared with the acceptance criteria) and
recommendations on the limits and criteria to be applied to all future production
batches (which could form part of the basis of a batch manufacturing
document).

8. Re-validation:

8.1. As a rule re-validation is required under the following circumstances:
change of formulae, procedures or quality of raw materials change, change of
equipment, installation of new equipment, major revisions to machinery or
apparatus and if breakdowns have occurred
major changes to process parameters
changes to facilities and installations which influence the process
on appearance of negative quality trends
on appearance of new findings based on current knowledge, e.g. sterilisation
where the frequency of checking is dependent on sophistication of in-process
methodology

NOTE: The extent of re-validation will depend on the nature and significance of the
changes.

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9. GENERAL NOTES

9.1 The following aspects could be considered during the validation of specific dosage
forms.
9.2 Validation of tableting: In the case of an oral tablet manufactured by granulation
and compression, the critical process parameters may include (but not be limited
to):

particle size distribution of the active
blending time for the powder
granulating time and speed
amount of granulating fluid-binder concentration
drying time
final moisture content
granule particle size distribution
granule active content and homogeneity
blending time of external phase
tablet hardness with respect to water content, friability, disintegration, and
dissolution
lubrication level with respect to tablet hardness, disintegration, dissolution and
die-ejection force
tablet weight and thickness control
uniformity of content

If the tablet is film coated, the following additional parameters may require
validation:

spray rate of coating solution
inlet and outlet air temperatures
coating weight of polymer with respect to table appearance, friability,
disintegration, and dissolution

10. REQUIREMENTS:

10.1 Each applicant should have a Validation Master Plan (VMP) (See SA Guide to
GMP, Chapter 9)

10.2 Each product must have a Validation Protocol (VP), (where validation is
required, i.e. for inter alia solid dosage forms, certain suspensions, sterile
products etc. or where major changes in formulation or manufacturing method
is envisaged).

10.3 There should be a Validation Report (VR) following the completed validation.

10.4 Validation Protocols and Validation Reports should be available for inspection
purposes by the Inspectorate. The following is applicable:

A New Applications for registration:
A VP must be included in SECTION 2 E. (The VR should only be
submitted when requested by the Inspectorate).

B Applications for change in applicant/manufacturer/packer/laboratory

72
A VP must be submitted with each application for a change in
manufacturer or laboratory, or change in applicant where it also involves
a change in manufacturer.

[If the validation had already been done, this should be indicated in the
application. A VR should only be submitted when requested by the
Inspectorate.]

10.5. Applications will not be accepted if the Validation Protocol is found to be
incomplete.

10.6. Applicants should note that the submission of the VP or VR does not imply that
the VP or VR had been approved by the Council.

Should applicants have any queries, please do not hesitate to contact the Council.

73
ADDENDUM C

EXEMPTION FROM RE-IDENTIFICATION AND RE-ASSAY OF IMPORTED MEDICINES

Imported medicines must be identified, assayed and other relevant tests conducted after
importation, to prove that the product integrity has not been prejudiced during transport from
sources in other countries

A Exemption from these requirements will be considered in the following circumstances:

1) When very small quantities are used for selected patients, or groups of patients.
2) If the identification and assay cannot be performed in South Africa. (Applicants must
note that the return of samples to overseas manufacturers is strongly discouraged
unless the required tests cannot be performed locally)
3) Any other reason deemed by the applicant as being of such nature as to qualify for
consideration for this exemption

B When requesting exemption the following must be submitted:

1) A suitable motivation for the request, that is a suitable projection as to the annual usage
of the relevant project, and or detail of the identification and assay method which
cannot be performed locally
2) Evidence that the conditions during transport are continuously monitored. A tabulated
summary indicating the method of transport utilised and the conditions during transport
as indicated below. A minimum of five printouts are required, giving an account of the
same product, or of five different products, provided that the products require the same
storage conditions, and provided that the products are dispatched from the same site,
but by different shipments

NAME OF PRODUCT FOR WHICH EXEMPTION IS REQUESTED:
REGISTRATION NUMBER OR REFERENCE NUMBER:
DOSAGE FORM:
CONDITIONS DURING TRANSPORT

Name of
Product

Batch
Number

Minimum and
maximum
temperature
recorded

Maximum
humidity
recorded
(where relevant)

Duration of
transport (Date
commenced and
date terminated)

Mode of
Transport

Signature of
MD/
responsible
pharmacist
who verified
the printouts

3) A copy of the accelerated stability data of the formulation being applied for, packed in
the final container as in Annexure 8, (to determine if the humidity must be monitored)
4) A copy of Annexure 2 as per the MBR 1 document
5) An indication as to whether the request is for bulk products or for the product packed in
the final container
6) A certificate of GMP compliance, not older than 2 years issued by either: a competent
regulatory Council or in terms of the WHO certification scheme,

74

7) A copy of the proposed master release document in accordance with Annexure 9A,
reflecting the specifications pertaining to the product in question (example as attached),

(a) the type of recorder used in transit
(b) specify that the received certificate of analysis: is valid, is complete ( reflects the
actual results of the tests performed) and reflects compliance with the registration
dossier
(c) a visual identification of the product and dosage form
(d) a consignment reference e.g. GRN (goods received notice ) or invoice, etc.(
Batch numbers on the invoice must concur with the batch numbers of the
products).
(e) confirmation of the integrity of the containers, seals, and labels. Each aspect
must be specified and controlled to ensure that no damaged articles are
accepted.

C Furthermore, it must be confirmed that the following are in place:

1) The record of the transport conditions (temperature and humidity where relevant) by
suitable devices which provide a printout of the conditions during each transport period,
which is filed with the batch release documents that will form a permanent record of the
specific consignment and which is filed with the batch release documents
2) A SOP specifying the details of inclusion of the recorders and which is available for
inspection. The procedure must include amongst others, the number of recorders,
position of placement, date of activation and inactivation ( on leaving the place of
dispatch i.e. factory, and on receipt by the applicant i.e. warehouse) and evaluation of
the printout with the reference to the stability data.
3) Validation of monitors, the results of which are available for inspection.

75
ADDENDUM D
(1) MANUFACTURING PROCESS FLOW DIAGRAM

NB. This is only an example, applicants are required to make the flow diagram as
comprehensive as possible

PRODUCT NAME: ALLOPURINOL TABLETS (EXAMPLE)

Allopurinol
Powder

MILLING

MIXING

Dicalcium hydrogen
Phosphate

MILLING

SCREENING

MILLING

Dicalcium hydrogen
Phosphate

Dicalcium hydrogen
phosphate

MIXING/BLENDING

Hydrolysed
starch

Spray-dried lactose

Croscarmellose sodium

MIXING/BLENDING

Socium lauryl sulphate

Purified Talc

SIEVING

BLENDING

TABLET
COMPRESSION

IN-PROCESS TESTING

TO PACKAGING

QC TESTING AND
RELEASE

76
b) PACKAGING PROCESS FLOW DIAGRAM

LINE OPENING

LABEL CHECKS

LABEL COUNT

BATCH ENCODING

EXPIRY DATING

UNSCRAMBLING

VACUUM/AIR CLEANING

FILLING

Fill Check

CAPPING

LABELLING

OVER-WRAPPING

PACKING/BOXING

Reconciliation

DISTRIBUTION STORE

NB- Details of equipment and process conditions may be added in or next to each
stage (box) or separately in an itemised paragraph.

77
ADDENDUM E

ALCOHOL CONTENT OF MEDICINES FOR ORAL INGESTION

The following policy with regard to the alcohol content of medicines for oral ingestion shall
apply:

1. POLICY ON ALCOHOL CONTENT OF MEDICINES FOR ORAL INGESTION:

1.1 The following maximum concentration limits will be allowed for ethyl alcohol as
inactive ingredient in products intended for oral ingestion:

0,5 % v/v ethyl alcohol for children under 6 years of age
5,0 % v/v ethyl alcohol for children 6-12 years of age
10,0 % v/v ethyl alcohol for adults and adolescents over 12 years of age.

1.2 Minute dose preparations are exempted from this requirement.

2. For products where higher concentration of alcohol are required, (e.g. plant extracts
or where solubility or preservation might be problematic), exemption from ethanol
concentration limits will be considered individually, provided that justification and
motivation is submitted together with proof that the proposed dosage will not result in
blood alcohol levels of 25 mg/dl or higher. (Table 1 is attached for reference
purposes only).

3. In all instances the alcohol content of a mixture must be stated prominently on the
immediate container label, the outer label (carton), as well as in the package insert.

4 All medicines (registered products, "Old medicines" and new applications) must
comply with the alcohol levels stated in the policy.

78

TABLE 1.#
Volume (Millimetres) of Ethanol Preparation Predicted to Produce a Blood Ethanol Concentration of
25mg/100ml* (100ml=1dl)

% Ethanol (v/v) in Age
Product (Weight)

2yr 4yr 6yr 8yr 10yr 12yr
(12kg) (16kg) (21kg) (27kg) (32kg) (38kg)

2,5 91 122 160 205 243 289

5,0 46 61 80 103 122 144

7,5 30 41 53 68 81 96

1,.0 23 30 40 51 61 72

12,5 18 24 32 41 49 58

20,0 11 15 20 26 30 36

25,0 9 12 16 21 24 29ml

* Values were calculated from data contained in McCoy et al, by use of the formula: dose (in
milligrams) =plasma concentration (Cp) x volume distributed (Vd) and assuming that absorption is
complete. For example, the calculation to obtain the value of 40 ml for a 6-year-old ingesting a
product containing 10% alcohol would be made as follows: Cp =250 mg/L and Vd =0.6 L/kg x 21
kg; therefore, dose =250 mg/L x (0.6L/kg x 21kg) =3.150 mg. Because for absolute ethanol (specific
gravity 0.789), 1 g =1.27 ml, 31.5 g =4 ml; thus, for 10% ethanol, the calculated volume is 40 ml.
_______________________________________________________
#TABLE 1 is an abstract from an article on "Ethanol in Liquid preparations intended for Children", by
the American Academy of Pediatrics, published in PEDIATRICS, Vol. 73 no.3 March 1984, page
406.

79
4.7 CRITERIA FOR FAST-TRACK ASSESSMENT

4.7.1 Types of products that will be considered for an expedited review:

New Chemical Entities which can be regarded as a major therapeutic advance, i.e.
the treatment of a life threatening or a severely debilitating disease where there is
currently inadequate or no treatment.

All medicines on the Essential Drugs List where four separate companies have not
registered and marketed the specific dosage form and dosage strength.

All medicines that require rapid registration by virtue of the tendering process, where
the State may deem it necessary and where at the request of the Director General a
rapid registration process is required.

All medicines required by the State for specific National Health Programmes e.g.
specific TB combinations, vaccines etc. on request by the Director General.

4.7.2 Criteria and other factors that will be examined in making a decision for fast-
tracking.

4.7.2.1 New Chemical Entities:
A written motivation will be required from the applicant why the product should be
regarded as a major therapeutic advance.

4.7.2.2 Medicines on the EDL:
A written request for fast-tracking with reference to the relevant pages of the EDL
and the number of registered and marketed generic products will be required from
the applicant.

4.7.2.3 International tendering process:
A written motivation for fast-tracking of a product for purposes of international
tendering process will be required from the Director General or an appropriately
authorised delegate.

4.7.2.4 Urgent medicines required by the State:
These will be medicines that are considered by the State to be in the National
interest and will be on written motivation from the Director General or an
appropriately authorised delegate.

4.8 PROPRIETARY NAME POLICY.

"PROPRIETARY NAME" is defined in the Regulations pertaining to The Medicines
and Related Substances Control Act, 1965 as follows-

"PROPRIETARY NAME, in relation to a medicine, veterinary or complementary
medicine and medical device, means a name -

a) which is unique to a particular medicine, veterinary, or complementary medicine
and medical device;

80
b) which is generally identifiable ; and approved in respect of that specific medicine,
veterinary, or complementary medicine and medical device in terms of the Act.
The Act states that a medicine, complementary medicine, veterinary medicine or
device must be registered under such name as the Council may approve.

In assessing the merits of a proposed proprietary name, the first and foremost
question is that of patient safety.

The Medicines Control Council subscribes to the WHO guideline in respect of the
protection of INN-stems and encourages the pharmaceutical industry to be
continually aware of this issue. (Resolution WHA46.19 adopted by the World Health
Assembly in May 1993 on non-proprietary names for pharmaceutical substances).

To assist applicants in the choice of suitable proprietary names for medicines,
various matters which are taken into consideration when evaluating names submitted
by applicants are outlined below.

4.8.1 A proprietary name should not contain an INN-stem (as published by the WHO).
A communication from the World Health Organisation stresses the importance of
the need to protect INN-stems. The relationship of pharmacologically related
substances is indicated by using a common stem, which in turn forms part of the
International Non-proprietary Name. The orderly development of generic
nomenclature could be hindered if these stems are not protected. The sentiments
of the WHO in this regard are shared by MCC, and are taken into consideration
when considering proprietary names.

For example, "-ac" is an INN-stem for anti-inflammatory agents of the ibufenac
group, and a proprietary name ending with " ac" would not be acceptable
regardless of the active ingredient, which it contains. The reasons are protection of
the stem and confusion, which could arise if the product does not contain an anti-
inflammatory agent of the ibufenac group. Similarly a proprietary name with the
term vir anywhere in the name would be unacceptable as the INN-stem is quoted
as -vir-.

A proprietary name commencing with, or containing "ac" in another position within
the name could, however, be considered.

4.8.2 The derivation of proprietary names from International Non-proprietary Names that
is, generic names is discouraged, as this practice could lead to confusion. For
example, the choice of the name Metaperamide for a product containing
loperamide, could induce health professionals to think that the product contains
another loperamide-type compound.

4.8.3 If a proprietary name is derived from a generic name, it should not be similar to the
generic name, thereby leading to confusion. For example, the name trimazole
could be interpreted as being an antiprotozoal of the metronidazole group, an
antifungal of the miconazole group or a brand of co-trimoxazole even though the
name does not contain an INN-stem for any of these groups.

4.8.4 In the case of single component generic medicines, applicants are encouraged to
market their products under the complete generic name followed or preceded by
their company name, acronym or other distinguishing feature.

81
4.8.5 Legislation determines that the name under which a medicine is registered shall be
unique. The importance of this requirement cannot be over-emphasised,
particularly when developing a range of products. Each strength and/or dosage
form requires a unique name. Applicants should examine all available resources to
establish that names are unique. Motivations should accompany applications
where relevant e.g. to justify the use of an identical or very similar name which
appears in Martindale/other reference book for a product not containing the same
ingredient(s) and which may be on the market elsewhere.

4.8.6 Names which are identical to or which are similar to the names of products
previously marketed will not generally be favourably considered regardless of
whether such products are dormant or not.

4.8.7 The use of "umbrella/brand types" of names across products in associated
therapeutic categories generally does not pose a problem, however, when these
names are used for products in different commodity categories, the
misrepresentation of non-medicines as medicines and vice versa could occur.
Applicants would be responsible to include precautionary statements of usage of
these brands simultaneously so as to inform patients of the correct usage.

4.8.8 A name must be distinctive in sound (spoken) and when written and not likely to be
confused with the name of another product. The concern about such names is
primarily one of safety, e.g., the names Amytal (barbiturate) and Amitol
(multivitamin) could result in a situation in which safety is compromised if the one
containing a barbiturate is supplied to a patient instead of the one containing a
vitamin.

4.8.9 The name must not be misleading e.g., the use of the name Sedinax for a product
containing only an analgesic or the name Painkid for a product not indicated for
paediatric use.

4.8.10 Any phrase that implies superiority, including use of animal species associated with
speed or strength, or implies superiority over other products is not allowed.

4.8.11 The meaning of abbreviations, symbols, numerals and names, which are in a
language other than English must be explained in the covering letter accompanying
an application. With regard to phrases which occur in the proprietary names of
products, and which are not English, applicants are requested to submit to the
Medicines Control Council, reputable interpretations/translations/explanations of
the phrases in question, in relation to the claims made for the product; i.e. the
intended use thereof.

4.8.12 A proprietary name may include a pharmacological/therapeutic connotation,
provided that it is in line with the indications in the package insert; however, each
application will be evaluated on merit.

4.8.13 It is important to bear in mind the claims made in the package insert in relation to
the proposed name of the product, when considering the acceptability of names,
hence the requirement of submission of package inserts in all instances.

4.8.14 When the name being applied for is identical/too similar to a name already
approved for another product, applicants will be advised that the proposed name is
too close to an existing name. Only if the existing product is registered will the

82
name be disclosed. Disputes regarding similarity of names not identified by the
Medicines Control Council at the time of registration/ change are the concern of
applicants, not the Medicines Control Council. If however, valid safety concerns are
identified, the applicant will be advised accordingly.

4.8.15 Trademark infringements are the concern of applicants, not the Medicines Control
Council

4.8.16 Proprietary names will only be evaluated as part of a new application for
registration or application for change. Request for evaluation of acceptability of
possible proprietary names prior to submitting a formal application will not be
processed.

4.8.17 Proprietary names can not be reserved for applications that have not yet been
submitted.

4.8.19 Current policy will not be applicable to line extensions of older products unless a
valid safety aspect has come to the fore, in which case the applicant will be advised
accordingly.

4.8.20 A list of names that are regarded as potentially misleading is available on request.
Names which may lead to self-diagnosis in conditions requiring professional
diagnosis or names implying efficacy that cannot be substantiated for the active
ingredient(s) are included on this list

As with all registration matters, applicants always have the opportunity to submit comments
in the event of a difference in opinion. Such comment will be forwarded to Council for
consideration.

4.9 STANDARD PACKAGE INSERT INFORMATION FOR CERTAIN CATEGORIES
/INGREDIENTS:

Unless the applicant can provide convincing evidence to the contrary, package
inserts should contain the following, although the wording need not be identical:
Standard information to be included in the professional package insert.

4.9.1. GENERAL DROWSINESS WARNING FOR ANTIHISTAMINES (OLD
GENERATION)

This medicine may lead to drowsiness and impaired concentration that may be
aggravated by simultaneous intake of alcohol or other central nervous system
depressants. Patients should be warned against taking care of vehicles or
machinery or performing potentially hazardous tasks where loss of concentration
may lead to accidents.

4.9.2 GENERAL DROWSINESS WARNING FOR ANTIHISTAMINES (NEW
GENERATION)
This medicine lacks significant sedative effects.

83
4.9.3 NON-CONTENT CLAIM : " CONTAINS NO ASPIRIN"

The use of the words "contains no Aspirin" may not appear on the package insert
or in the advertising of non-aspirin containing medicines. In terms of regulation
9(3) the wording may still appear on the immediate label of the medicine provided
that the type size is not bigger than the type size in which the active ingredients
appear.

4.9.4 DEPENDENCE PRODUCING POTENTIAL OF MEDICINES

Warnings concerning the dependence-producing potential of certain substances
may be made known of the professionals.

4.9.5 IMPORTANT PATIENT INFORMATION TO BE INCLUDED IN ALL PACKAGE
INSERTS OF MEDICINES INTENDED FOR MALARIA PROPHYLAXIS

The following patient warnings must be included in all package inserts of products
intended for malaria prophylaxis:

Because no form of prophylaxis is fully effective, the prevention of mosquito bites
should form the mainstay of malaria prophylaxis. The following preventative
measures to prevent mosquito bites should be taken:

i) endemic areas should preferably be visited during the dry season or in years
when rainfall is low;
ii) high risk patients should avoid malaria areas altogether.
High risk persons include:
babies and young children less than 5 years of age;
pregnant women;
immunocompromised individuals such as those on long-term steroids,
cancer patients and those on chemotherapy, AIDS patients and those
who have had their spleens removed;
iii) not going outside between dusk and dawn, when mosquitoes are most active;
iv) applying insect repellant to exposed skin and clothing;
v) wearing long sleeves and trousers at night;
vi) using mosquito nets, screens, coils or pads

A warning that should flu-like symptoms appear the patient must inform the doctor
that he has been to a malarious area.

4.9.6 USE OF MEDICINES DURING PREGNANCY AND LACTATION

In cases where the safety of a medicine with regard to its use in pregnancy and
lactation has not been established, the following warning must be included in the
package inserts for those medicines.
"The safety of this preparation in pregnant women and or lactating has not been
established."

4.9.7 PACKAGE INSERTS / SLOGANS

Advertising (slogans) in package inserts is not permissible.

84
4.9.8 PACKAGE INSERT REQUIREMENTS: WATER FOR INJECTION
General exemption from package insert requirements in respect of sales packs of
water for injection has been granted provided that the following warning appears on
at least the outer label in prominent type: "Water for injection must not be
administered alone".

4.9.9. PRODUCTS CONTAINING ACE-INHIBITORS

The following boxed warnings must be included:

"Should a woman become pregnant while receiving an ACE-inhibitor, the
treatment must be stopped promptly and switched to a different medicine."
"Should a woman contemplate pregnancy, the doctor should consider
alternative medication."
The following warnings must be included:
"ACE-inhibitors pass through the placenta and can be presumed to cause
disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios
as well as hypotension, oliguria and anuria in newborns have been reported
after administration of ACE-inhibitors in the second and third trimester. Cases
of defective skull ossification have been observed. Prematurity and low birth
mass can occur."

4.9.10 ANTIBIOTICS INDICATED FOR THE TREATMENT OF BETA-HAEMOLYTIC
STREPTOCOCCAL INFECTIONS

The following statement must be included under the heading DOSAGE AND
DIRECTIONS FOR USE:

"In the treatment of beta-haemolytic streptococcal infections, a therapeutic dose
must be administered for at least 10 days".

4.9.11 REYE'S SYNDROME WARNING FOR MEDICINES CONTAINING ASPIRIN

The following warning be included in all package inserts for aspirin containing
products:

"WARNING: ASPIRIN HAS BEEN IMPLICATED IN REYE'S SYNDROME, A RARE
BUT SERIOUS ILLNESS, IN CHILDREN AND TEENAGERS WITH CHICKENPOX
AND INFLUENZA. A DOCTOR SHOULD BE CONSULTED BEFORE ASPIRIN IS
USED IN SUCH PATIENTS."

4.9.12 BENZALKONIUM CHLORIDE-PRESERVED OPHTHALMOLOGICAL
PREPARATIONS:

The concentration of benzalkonium chloride should not exceed 0,01% and should
not be used in preparations intended for soft contact lens solutions.

The following warnings should be included in the package insert:
As the possibility of adverse effects on the corneal permeability and the danger of
disruption op the corneal epithelium with prolonged or repeated usage of
benzalkonium chloride preserved ophthalmological preparations cannot be
excluded, regular ophthalmological examination is required.

85
Caution should be exercised in the use of benzalkonium chloride preserved topical
medication over an extended period in patients with extensive ocular surface
disease.

4.9.13 PACKAGE INSERTS FOR BENZODIAZEPINE

Unless the applicant can provide convincing evidence to the contrary package
inserts for benzodiazepine should contain the following, although the wording need
not be identical:

Under " Side-effects and special precautions"

The side-effects most commonly encountered are drowsiness and over
sedation. Drowsiness is more common in elderly and debilitated patients and
in patients receiving high doses. Less common are depression of mood and
affect, disorientation or confusion, lethargy and ataxia.
Paradoxical reactions such as acute hyper excitable states with rage may
occur. If these occur, the medicine should be discontinued.
There is a potential for abuse. Withdrawal symptoms (including convulsions)
have occurred following abrupt cessation especially in patients receiving large
doses for prolonged periods.

Injections:
Respiratory depression due to a depressant effect on the respiratory centre
and cardiovascular collapse may occur following intravenous and
intramuscular administration.

Special Precautions:
Particular caution should be exercised with the elderly and debilitated - who
are at particular risk of over sedation respiratory depression and ataxia. (The
initial oral dosage should be reduced in these patients);

patients with pulmonary disease and limited pulmonary reserve;
patients suffering from impairment or renal or hepatic function;
patients suffering from anxiety accompanied by an underlying depressive
disorder;
patients receiving barbiturates or other central nervous system
depressants. There is an additive risk of central nervous system
depression when these medicines are taken together;
patients should be cautioned regarding the additive effect of alcohol;

the medicine should be used judiciously during pregnancy and preferably
avoided. Given during labour it crosses the placenta and may cause the
floppy-infant syndrome characterised by central respiratory depression,
hypothermia and poor sucking. It should not be administered to lactating
mothers.

Patients should be advised, particularly at the initiation of therapy, not to drive a
motor vehicle, climb dangerous heights or operate dangerous machinery. In these
situations, impaired decision making could lead to accidents.

86
Overdosage:
Manifestations of overdosage include somnolence, confusion, coma, respiratory
and cardiovascular depression and hypotension.

4.9.14 BENZODIAZEPINE OR BENZODIAZEPINE-LIKE

Product name to be inserted in [ ]
INDICATIONS
[ ] is only indicated when the disorder is severe, disabling or subjecting the
individual to extreme stress.

DOSAGE AND DIRECTIONS FOR USE:
Treatment should be started with the lowest recommended dose. The maximum
dose should not be exceeded.

For products with anxiety approved as indication:
Treatment should be as short as possible. The patient should be reassessed
regularly and the need for continued treatment should be evaluated, especially in
case the patient is symptom-free. The overall duration of treatment generally
should not be more than 8-12 weeks, including a tapering off process. In certain
cases extension beyond the maximum treatment period may be necessary; if so, it
should not take place without re-evaluation of the patient's status.

For products with insomnia approved as an indication:
Treatment should be as short as possible. Generally the duration of treatment
varies from a few days to two weeks, with a maximum, of four weeks including the
tapering-off process. In certain cases extension beyond the maximum treatment
period may be necessary; if so, it should not take place without re-evaluation of the
patient's status.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:

[ ] is not recommended for the primary treatment of psychotic illness. [ ] should
not be used alone to treat depression or anxiety with depression as suicide may be
precipitated in such patients. [ ] should be used with extreme caution in patients
with a history of alcohol or drug abuse.

Dependence
There is a potential for abuse and the development of physical and psychological
dependence, especially with prolonged use and high doses. The risk of
dependence is also greater in patients with a history of alcohol or drug abuse.
Once physical dependence has developed, abrupt termination of treatment will be
accompanied by withdrawal symptoms. These may consist of headaches, muscle
pain, extreme anxiety, tension, restlessness, confusion and irritability.
In severe cases the following symptoms may occur: de-realisation,
depersonalisation, hyperacusis, numbness and tingling of extremities,
hypersensitivity to light, noise and physical contact, hallucinations or epileptic
seizures.

Rebound effects
A transient syndrome whereby the symptoms that led to treatment with [ ] recur in
an enhanced form may occur on withdrawal of treatment. It may be accompanied
by other reactions including mood changes, anxiety and restlessness. Since the

87
risk of withdrawal phenomena/rebound phenomena is greater after abrupt
discontinuation of treatment, it is recommended that the dosage is decreased
gradually.

Duration of treatment
The duration of treatment should be as short as possible (see Dosage), but should
not exceed 4 weeks for insomnia and eight to twelve weeks in case of anxiety, (**)
including the tapering-off process. Extension beyond these periods should not take
place without reevaluation of the situation. It may be useful to inform the patient
when treatment is started that it will be of limited duration, and to explain precisely
how the dosage will be progressively decreased. Moreover, it is important that the
patient be aware of the possibility of rebound phenomena, thereby minimising
anxiety over such symptoms should they occur while the product is being
discontinued.

(**) Note that the duration be adapted according to approved indications for each
individual product.

4.9.15 BETA-2 AGONISTS

INDICATION
Treatment of reversible airway obstruction in asthma, chronic bronchitis and
emphysema and prevention of bronchospasm in exercised-induced asthma.

Under "SIDE EFFECTS AND SPECIAL PRECAUTIONS"
Hypokalaemia may occur.
Overdosage may cause cardiac effects.
High dosages may increase the risk of serious side-effects, including cardiac
dysrhythmias. This risk is further aggravated if administered concomitantly
with other medicines that cause hypokalaemia and cardiac dysrhythmias or in
the presence of hypoxia and acidosis.
The maximum dose should not be exceeded.

Under "DOSAGE AND DIRECTIONS FOR USE":
Do not exceed the recommended dose.

4.9.16 STANDARDIZED PACKAGE INSERTS FOR BETA-BLOCKING AGENTS

inserts for beta-blocking agents should contain the following, although the wording
need not be identical:

Under "Side-effects and special precautions"
a) Bronchoconstriction may occur in patients suffering from asthma,
bronchitis and other chronic pulmonary diseases
b) Congestive cardiac failure and marked bradycardia may occur
c) A variety of neuropsychiatric disorders may occur, ranging from vague
fatigue and nightmares to overt psychosis
d) the following may occur: exacerbation of peripheral vascular disease, or the
development of Raynaud's phenomenon (due to unopposed arteriolar alpha-
sympathetic activation), sexual impotence, hypoglycaemia, skeletal muscle
weakness and gastrio-intestinal disturbances. Severe peripheral vascular
disease and even peripheral gangrene may be precipitated.

88
e) Adverse reactions are more common in patients with renal
decompensation, and in patients who receive the drug intravenously.
f) It is dangerous to administer this medicine concomitantly with the
following medicines: hypoglycaemic agents, phenothiazines and various
antiarrhythmic agents.
NB:- Such drug-drug interactions can have life-threatening
consequences.

SPECIAL NOTE:- digitalisation of patients receiving long-term beta-
blocker therapy may be necessary if congestive cardiac failure is likely to
develop. This combination can be considered despite the potentiation of
negative chronotropic effect of the two medicines. Careful control of
dosages and of the individual patient's response (and notably pulse rate)
is essential in this situation.
g) Abrupt discontinuation of therapy may cause exacerbation of angina
pectoris in patients suffering from ischaemic heart disease.
Discontinuation of therapy should be gradual, and patients should be
advised to limit the extent of their physical activity during the period that
the medicine is being discontinued.
h) Administration to pregnant mothers shortly before giving birth, or during
labour may result in the newborn infants being born hypotonic, collapsed
and hypoglycaemic.
i) Patients with phaeochromocytoma usually require treatment with an
alpha-adrenergic blocker.

Under "Contra-Indications":
a) Particular caution should be exercised with patients suffering from the
following: asthma, bronchitis, chronic respiratory diseases, second and
third-degree heart block and bradycardia (less than 50 beats per minute),
peripheral vascular diseases and Raynaud's phenomenon.
b) The normal dose should be reduced in elderly patients, or in patients
suffering from renal dysfunction.
c) In the perioperative period it is generally unwise to reduce the dosage to
which the patient is accustomed, as there may be danger of aggravation
of angina pectoris or hypertension. A patient's normal tachycardic
response to hypovolaemia or blood loss may be obscured during or after
surgery. Particular caution should be taken in this regard.

Under "Known symptoms of overdosage and particulars of its treatment"
Overdosage may produce bradycardia and severe hypotension.
Bronchospasm and heart failure may be produced in certain individuals.

Cases of mild overdose should be observed for at least 4 hours, as apnoea
and cardiovascular collapse may appear suddenly.

Gastric lavage should be performed within 4 hours of suspected overdose.
Repeated activated charcoal is necessary in severe overdose.

Atropine may be used to treat severe bradycardia. If the response is
inadequate, glucagon may be give intravenously. Alternatively, dobutamine or
isoprenaline may be required to reverse beta-blockade. Intravenous cardiac
pacing may be required for severe bradycardia. Bronchospasm should be
treated with IV aminophylline or inhaled or IV beta-agonist e..g. salbutamol.

89

4.9.17 WARNINGS FOR INCLUSION IN BETA-BLOCKER AND CLONIDINE PACKAGE
INSERTS

The following warnings must be included in all beta-blocker and clonidine package
inserts.

"Caution should be exercised when transferring a patient from clonidine. The
withdrawal of clonidine may result in the release of large amounts of
catecholamines which may give rise to a hypertensive crisis. If beta-blockers
are administered in these circumstances, the unopposed alpha receptor
stimulation may potentiate this effect";

"If a beta-blocker and clonidine are given concurrently, the clonidine should
not be discontinued until several days after the withdrawal of the beta-blocker
as severe rebound hypertension may occur".

4.9.18 BETA-LACTAM ANTIBIOTICS

The following statement must be included in the package inserts of all beta-lactam
and fluoroquinolone antibiotics containing an indication or claim for Pseudomonas
aeruginosa under the heading

INDICATIONS:
"In the treatment of infections caused by Pseudomonas aeruginosa, an
aminoglycoside must be administered concomitantly".

4.9.19 BISMUTH CONTAINING MEDICINES

The package inserts for bismuth containing preparations must include a warning
regarding the possibility of neurotoxicity with prolonged or excessive use.

4.9.20 PACKAGE INSERTS FOR CLOFIBRATE CONTAINING

Package inserts for all clofibrate-containing medicines must reflect:

Under "Indications"
Before starting treatment with clofibrate, attempts should be made to control
serum lipids with appropriate dietary regimens, weight loss in obese patients,
control over diabetes mellitus, etc.

If after considering the possible benefits in relation to the risks, it is decided to
use clofibrate it is indicated in types II(B), III, IV and V hyperlipoproteinaemias
(Frederickson and Levy Classification)

90
FREDERICKSON LIPOPROTEIN MAJ OR LIPID
TYPE ELEVATION ELEVATION
-------------------------------------------------------------------------------------
I (very rare) chylomicra Triglycerides
------------------------------------------------------------------------------------
II (a) (LDL) Cholesterol
-----------------------------------------------------------------------------------
II (b) pre - + Cholesterol +
(VLDL +RDL) Triglycerides
----------------------------------------------------------------------------------
III (rare) abnormal (LDL) Cholesterol +
Triglycerides
---------------------------------------------------------------------------------
IV pre (VLDL) Triglycerides
---------------------------------------------------------------------------------
V (rare) chylomicra + Triglycerides +
pre (VLDL) cholesterol
--------------------------------------------------------------------------------

It has not been established whether the medicine-induced lowering of serum
cholesterol or lipid levels has detrimental, beneficial or no effects on
morbidity or mortality due to atherosclerosis or coronary heart disease.

Clofibrate therapy should be discontinued if a significant lowering in serum
lipids is not obtained.

Due to its action on cholesterol metabolism, clofibrate may increase the
lithogenicity of bile and there is an increased frequency of gallstones.

A possible association between treatment with clofibrate and gastro-intestinal
malignancies exists.

4.9.21 CONTRAST MEDIA - WATER SOLUBLE - BOXED WARNING

Fatal reactions have been associated with the administration of water-soluble
contrast media. It is therefore of utmost importance that a course of action be
carefully planned in advance for the immediate treatment of serious reactions, and
that adequate and appropriate facilities and personnel be readily available in case
of a severe reaction. Patients should be observed for a possible severe reaction
during and for at least 30 - 60 minutes after administration of [proprietary name].
Patients with known or suspected hypersensitivity to iodated contrast media must
be closely observed.

4.9.22 EXEMPTION FROM PACKAGE INSERT REQUIREMENTS IN RESPECT OF
CONTACT LENS SOLUTIONS.
THIS EXEMPTION SPECIFICALLY DOES NOT APPLY TO ARTIFICIAL TEAR
SOLUTION.

Contact lens solutions are exempted from package insert requirements in respect
of contact lens solutions provided that: -
i) the relevant immediate container labels and cartons (if any) contain the
necessary information that would normally be required on the package insert;

91
ii) such labels are fully bilingual;
iii) no advertising matter of reference to other products be included on such
labels; and
iv) the draft labels be submitted to this office for prior approval.

4.9.23 WARNING FOR INCLUSION IN POTENT TOPICAL CORTICOSTEROID
PACKAGE INSERTS

The following warning must be included in all potent topical corticosteroid package
inserts:
"Potent topical corticosteroid preparations (name) should not be applied to
any skin crease areas"

4.9.24 PRODUCTS FOR TOPICAL USE CONTAINING CORTICOSTEROIDS

Package insert for all topical corticosteroid must reflect the following:

Under "CONTRA-INDICATIONS":
"Corticosteroids have been shown to be teratogenic in animals following
dermal application. As these agents are absorbed percutaneously,
teratogenicity following topical application cannot be excluded. Therefore
(name of product) should not be used during pregnancy."

4.9.25 CO-TRIMOXAZOLE
All package inserts of products containing co-trimoxazole or long-acting
sulphonamides must include a warning with regard to the occurrence of erythema
multiforme, toxic dermal necrolysis and allergic vasculitis.

4.9.26 DICYCLOMINE IN INFANTS

The indication "infantile colic" and dosage schedule for children under six months
of age be not included and a warning against its use in "infantile colic" be included;

Applicants submit evidence of, as well as a motivation for the dosage, dosage
intervals, efficacy and safety of the administration to children older than six months
and;

4.9.27 PACKAGE INSERTS FOR DISOPYRAMIDE PREPARATIONS

Under "Side-effects and Special Precautions"
The administrations of disopyramide may precipitate cardiac failure when
administered to patients with congestive failure who have been stabilised.

Under "Contra-indications"
The administration of disopyramide is contra-indicated in patients with
congestive cardiac failure, irrespective of whether the patient is digitalised or
not

4.9.28 FLUOROQUINOLONE ANTIBIOTICS

Refer to Beta-lactam antibiotics

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4.9.29 BOXED WARNING FOR GLIBENCLAMIDE & GLICLAZIDE

A reduction in dosage may be necessary in patients with renal dysfunction.

4.9.30 IODINE AND IODIDE CONTAINING MEDICINES

Synthetic thyroid hormone preparations are exempted from the following
requirements.
On the LABELS as well as the package inserts of all medicines containing more
than 0,60 mg iodine/ionic iodide per daily dose, the following warning must appear:
"NOT TO BE USED DURING PREGNANCY OR BY LACTATING
MOTHERS"

On the package inserts of ALL iodine containing preparations, there must be a
warning:
" NOT TO BE USED BY PERSONS WHO ARE ALLERGIC TO IODINE"

4.9.31 PACKAGE INSERTS FOR METOCLOPRAMIDE PREPARATIONS

Kindly note that this warning must appear on ALL package inserts
"WARNING
The use of metoclopramide throughout the duration of pregnancy is
considered unsafe as teratogenicity has been demonstrated in animal
studies."

4.9.32 WARNING TO BE INCLUDED IN THE PACKAGE INSERTS OF ALL PRODUCTS
CONTAINING METRONIDAZOLE
The following warning must be included in the package inserts of all products
containing metronidazole:
"Pseudomembranous colitis has been reported following the use of
metronidazole".

4.9.33 NON STEROIDAL ANTI-INFLAMMATORY AGENTS

The following warning regarding the use of non-steroidal anti-inflammatory agents
in pregnancy must be included in all package inserts of non-steroidal anti-
inflammatory agents:
Regular use of NSAIDs during the third trimester of pregnancy may result in
premature closure of the foetal ductus arteriosus in utero and possibly in
persistent pulmonary hypertension of the newborn. The onset of labour may
be delayed and its duration increased.

In addition to the above, the following special precaution should be included:
In view of the products inherent potential to cause fluid retention, heart
failure may be precipitated in some compromised patients.

4.9.34 PACKAGE INSERT WARNING FOR OESTROGEN-CONTAINING PRODUCTS

With the exclusion of oestrogen-containing oral contraceptives, all other oestrogen-
containing medicines shall have package inserts bearing the following warnings:
"Not for use during pregnancy. Vaginal adenosis and vaginal and cervical
adenocarcinoma has been noted in post pubertal girls whose mothers were

93
treated for threatened abortion with large doses of stilboestrol or related
oestrogenic substances during their pregnancies."

"An increased incidence of endometrial uterine carcinoma, related to the
continuous use of oestrogens in the post menopausal period, has been
reported."

Products intended solely for post-menopausal use may have in their package
inserts, instead of the aforementioned warning, the warning:
"NOT FOR USE DURING PREGNANCY"

All combination oral contraceptive products containing oestrogen shall have
package inserts reflecting:
Under "SIDE EFFECTS AND SPECIAL PRECAUTIONS":
Oral contraceptive failure may occur with concomitant antibiotic therapy. For
maximal protection, additional non-hormonal contraception is recommended
for the duration of antibiotic therapy and for seven days afterwards. Those on
long-term antibiotic therapy need only take extra precautions for the first two
weeks of antibiotic therapy.

Spotting and breakthrough bleeding are possible signs of diminished
contraceptive effectiveness.

4.9.35 PHENYLBUTAZONE & OXYPHENBUTAZONE

The indications and period of use for phenylbutazone and oxyphenbutazone
preparations must be restricted to "acute exacerbations of ankylosing spondylitis"
and a maximum period of use of 7 days;

Warnings (to be in prominent type and boxed) - the following must be included:
Because of potentially serious and occasionally fatal adverse effects, use
should be restricted to a maximum of 7 days and the maximum
recommended dosage should not be exceeded".

"Caution against repeated short-term use is advised, due to the possible
danger of sensitisation";

"Haematological disorders are potentially fatal";

For parenteral dosage forms the dosage be limited to a maximum 600 mg per day;
Combination products containing phenylbutazone and oxyphenbutazone is
not allowed

4.9.36 POTASSIUM SUPPLEMENTATION

The following statement must be included in package inserts of medicines
containing potassium for the purpose of potassium supplementation (under the
heading pharmacological Action):
"This medicine contains potassium ..... (salt to be named). It has not been
proven that this dosage will necessarily prevent a significant potassium loss
or correct an existing deficiency of potassium".

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4.9.37 LONG-ACTING SULPHONAMIDES

Refer to co-trimoxazole

4.9.38 TAMOXIFEN

The following safety information must be included in the package inserts of all
tamoxifen containing products:

WARNINGS:
"Endometrial changes
An increased incidence of endometrial changes, including hyperplasia, polyps
and cancer has been reported in association with tamoxifen treatment. Any
patients receiving or having previously received tamoxifen, who report vaginal
bleeding should be promptly investigated".

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
"Tamoxifen was shown to be genotoxic in some in-vivo genotoxicity tests in
rodents. Gonadal tumours in mice, and liver tumours in rats receiving
tamoxifen were reported in long-term studies. The clinical relevance of these
findings has not been established.

4.9.39 TARTRAZINE (FD & C YELLOW NO 5) - WARNING - PACKAGE INSERT

It is required that the following warning be included under the heading of
"WARNING" in the package insert of medicines which contain "Tartrazine" -
"This product contains FD & C Yellow No 5 (Tartrazine) which may cause
allergic-type reactions (including bronchial asthma) in certain susceptible
individuals. Although the overall incidence of tartrazine sensitivity in the
general population is currently thought to be low it is frequently seen in
patients who also have aspirin sensitivity."

4.9.40 TOPICAL TRETINOINS - STATEMENT ON PREGNANCY AND LACTATION.

Oral tretinoin has been shown to be teratogenic in a wide variety of animals.

Limited animal data urge caution in the use of preparations containing tretinoin
during the first trimester of pregnancy.

In the case of eventual pregnancy the patient should inform her doctor.
Therefore, it may be concluded that cutaneous administration of tretinoin to
pregnant women should not pose a significant hazard, although, as with all
medicines, its use should be avoided during pregnancy unless the benefits
outweigh any potential risk to the foetus.

It is not known whether tretinoin is excreted in animal or human milk. Because
many medicines are excreted in human milk, caution should be exercised when
applying topical tretinoin to nursing women. In this event the product should not be
used on the chest.

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4.9.41 TRICYCLIC ANTIDEPRESSANTS:

ACCEPTABLE CLAIMS
Serious depressive conditions such as major depressive illness, reactive
depression and secondary depression. The following reflects what is defined under
the various disorders:
Major depressive illness:
endogenous depression, unipolar depression, bipolar depression
(manic-depressive psychosis), masked depression;
Reactive depression:
neurotic depression;
Secondary depression:
depression associated with alcoholism, schizophrenia, and
Parkinsonism, depression associated with personality disorder,
depression caused by medicines and senility with depression.
The claims for enuresis and other states which may benefit from the administration
of tricyclic antidepressants such as phobic anxiety disturbances, obsessive
compulsive disturbances and chronic pain, may be considered but will require the
submission of substantiating data.

STANDARDIZED PACKAGE INSERTS FOR TRICYCLIC ANTIDEPRESSANTS
inserts for tricyclic antidepressants should contain the following, although the
wording need not be identical:

Peripheral anticholinergic side effects: notably dry mouth, constipation,
urinary retention and pupillary dilatation with blurred vision and changes in
visual accommodation. When anticholinergic effects are severe, the medicine
should be discontinued or reduced.

Drowsiness or excessive sedation in certain patients. On the other hand
disorientation and agitation, insomnia and restlessness can also occur with
normal doses. The risks of central nervous system depression are greater
when administered together with other central nervous system depressants,
e.g. alcohol, barbiturates.

NOTE: Elderly patients are more prone to all these effects, and therapy should be
initiated at lower than standard doses in the elderly.

Special Precautions:
a) At the time of initiation of therapy, patients should be advised not to drive
a motor vehicle, climb dangerous heights or operate dangerous
machinery, for at least several days. In these situations impaired decision
making could lead to accidents.

b) Caution should be observed with patients suffering from a depressive
phase of manic depressive psychosis, as occasionally hypomania or
mania can be precipitated in such patients. Withdraw the drug if the
depression turns into a manic phase.

c) In elderly male patients suffering from prostatism urinary retention may be
precipitated.

96

d) In patients suffering from cardiac disease, special caution should be
observed because of the occasional problems of tachycardia,
dysrhythmias orthostatic hypotension and other unwanted effects on
blood pressure, aggravation of conduction disturbances and
electrocardiographic abnormalities. Regular cardiological and
electrocardiagraphic examination is advised.

e) Epilepsy may be aggravated.

f) The medicine should not usually be given to patients receiving other
central nervous system depressants, e.g. barbiturates, and to patients
receiving monoamine oxidase inhibitors only after a suitable interval (the
drugs may be given together if the dosages are carefully controlled,
preferably in hospital). The pressor effects of the direct- acting
sympathomimetic agents, adrenaline and noradrenaline, are enhanced,
and the use of local anaesthetics containing these vasoconstrictors
should be avoided as hypertensive reactions may occur. The
simultaneous administration of anticholinergic agents may be dangerous.
The hypotensive effect of certain antihypertensive agents may be
reduced.

g) Narrow-angle glaucoma may be aggravated.

h) Withdraw the drug if allergic skin reactions appear.

Under "Contra-Indications":
The acute phase of myocardial infarction. Administration is not advised
during the first trimester of pregnancy, unless there are compelling reasons
for its use.

Under "Overdosage":
Overdosage and poisoning may be characterised by central nervous system
depression or excitation, severe anticholinergic effects and cardiotoxicity.
The following symptoms and signs are characteristic of acute overdosage:
drowsiness, restlessness, ataxia, stupor, coma, pyrexia, palpitations,
tachycardia, cardiac arrhythmias, hypotension and in severe cases,
respiratory depression. Epileptiform seizures may occur. Mixed poisoning
with other central nervous system depressants is not uncommon.

Special warning:
This medicine should at all times be kept out of the reach of children, as even
small doses may be fatal to them.

4.9.42 STATEMENT ON EOSINOPHILIA MYALGIA SYNDROME TO BE INCLUDED IN
PACKAGE INSERTS OF L-TRYPTOPHAN CONTAINING PRODUCTS

The following statement must be included under the heading "WARNINGS" in the
package inserts of the products containing L-Tryptophan.
"In the USA the Eosinophilia Myalgia Syndrome has been associated with the
intake of L-Tryptophan."

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4.9.43 CODEINE WARNING

The following warning must appear on the immediate container label, the outer
label (if applicable) and the package insert of all CODEINE-containing products:
Exceeding the prescribed dose, together with prolonged and continuous use
of this medication may lead to dependency and addiction.

4.10 PROOF OF EFFICACY

4.10.1 GENERAL

The following information must be included in section 3 of the medicine
registration form

1.1 The applicant may request partial or total exemption from these requirements
if efficacy and safety are intended to be established by means of clinical data
(or for other reasons determined by the Council), provided that clinical trials
have been conducted with the same formulation as the one being applied for.
1.2 Where clinical evidence in support of efficacy has not been submitted, studies
and data to demonstrate the pharmaceutical and/or biological availability of
the product must be included.
1.3 Proof of efficacy/equivalence is required in the following instances:

1.3.1 Generic product registration applications.
1.3.2 Products where the formulation intended to be marketed differs from
that used in the clinical trial(s).
1.3.3 Products with major changes according to the Guidelines for
Amendments of the Registration Dossier.
1.3.4 All dosage forms not included in 1.7

1.4 Proof of efficacy/equivalence (pharmaceutical in vivo /in vitro/bioequivalence
evaluation) does not apply to generic biological substances.
1.5 The type of the study must be stated.
1.6 Reference product:

The products of the innovators registered by the South African Council (MCC)
and USA (FDA), UK (MCA), EC (CPMP), Sweden (MPA), Australia (TGA)
and Canada (CDD), will be accepted as reference standards in comparative
bioavailability studies and comparative pharmaceutical availability studies

The South African innovator's product will be the only standard
against which pharmaceutical availability and bioavailability
studies shall be measured, whether the innovator's product is
registered or not (e.g. Old medicines), the only exception being
multivitamin and vitamin and mineral combinations

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Details of the reference product used as the standard for reference purposes
(including the applicant, proprietary name, lot number, expiry date, etc.), must
be supplied. The reference product used must be motivated and will be
subject to approval by the Council.
Data submitted must always be comparative. Certificate of Analysis of both
products used, must be submitted. The certificate of analysis is available for
the test product, an analysis is available for the reference product (if the
applicant is not the manufacturer of the reference product).

1.6.1 Generic product: the product must be compared to a well-established
innovator product (reference product) the choice of which must be
justified by the applicant.
1.6.2 Different formulations: the product must be compared with the product
used in the clinical trial(s) if the formulations differ.

1.6.3 Major changes: the product on the market prior to the change must be
used as the reference product.

1.7 The requirement for proof of efficacy/equivalence may be waived for certain
categories of substances. In the following cases efficacy may be assumed
and proof of efficacy may not be required:

1.7.1 The Council may, at its discretion, rule that liquid oral preparations
with single active ingredients and combinations of two or more well
known ingredients, having the same active ingredients as a product
already registered by the Council, excluding suspensions, generally
be regarded as being pharmaceutically available and thus,
biologically.
1.7.2 The efficacy of the following is generally assumed:
i) Parentally administered products in aqueous solutions, unless
compromised by other factors such as pH, isotonicity, etc
ii) Aqueous oral solutions.
iii) Powders which are dissolved in a diluent prior to parenteral
administration.
iv) Powders and granules which are reconstituted prior to oral
administration, provided that it can be confirmed that the active
ingredients are in solution in the constituted product.
1.7.3 Powders for reconstitution if the reconstituted product is an aqueous
solution (proof of this may be required).
1.7.4 Effervescent tablets resulting in a clear solution after effervescence

1.8 Proof of efficacy may be submitted by using one of the following methods,
depending on the relevance:

1.8.1 Bioavailability
1.8.2 Dissolution
1.8.3 Disintegration
1.8.4 Acid neutralising capacity
1.8.5 Microbial growth-inhibition zones
1.8.6 Proof of release by membrane diffusion
1.8.7 Particle size distribution
1.8.8 Blanching test

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1.8.9 Any other method an applicant wishes to submit, provided the
rationale for submitting the particular method is included.

1.8.1 Bioavailability

Bioavailability as proof of efficacy may be used in any instance as
proof of efficacy, but must be used in the following cases:
a) modified release tablets or capsule dosage forms e.g. slow
release or sustained release.
b) When a monograph in the USP for an active ingredient does
not include a method for dissolution.
c) When the active ingredient is mentioned in the attached list A,
irrespective of a monograph being available in the USP.
d) Suspensions, except when a monograph for dissolution is
available in the USP for the active in suspension.
e) Bioequivalence studies for all antibiotics and bioavailability for
antimicrobial preparations (such as for tuberculosis) must be
carried out, unless otherwise determined by the Council.
f) Antibiotics and antibiotic combinations.

Comparative bioavailability data will generally be required
for the assessment of efficacy of tablets, capsules,
suppositories and suspensions.
Pharmaceutical availability data may be acceptable for
efficacy assessment of certain tetracycline-type and certain
penicillin-type medicines (except those specifically
excluded by the Council) and chloramphenicol, where the
current USP includes a dissolution requirement for the
particular dosage form being applied for.

1.9 A discussion and the conclusion drawn from the data must be submitted
1.10 The applicant must state whether there are any in vivo-in vitro correlation
from the data obtained by the method used.
1.11 The applicant must confirm that the data submitted have been obtained with
the formulation being applied for
1.12 The applicant must motivate and justify why the study and the results
obtained should be acceptable.
1.13 When bio-equivalence studies are submitted in support of efficacy of the
formulation, the Application control document for bioequivalence studies
included under FORMS must accompany the data.
1.14 When proof of efficacy studies presented for registration purposes were
derived from pilot batches, acceptable data derived from production batches
must be submitted before distribution of the production batches can take
place.

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4.10.2 BIOAVAILABILITY AND BIO-EQUIVALENCE

4.10.2.1 INTRODUCTION

A drug is rarely administered as a single chemical entity. It is more frequently
combined in the finished dosage form (tablet, capsule, solution or suspension)
with a variety of different substances (e.g. fillers, binders, lubricants, surfactants,
preservatives etc.), added to achieve desirable formulation characteristics.
Although these substances are often considered inert, they may affect drug
availability by complexing with the active ingredient, altering its stability or
release, or other actions. Thus different formulations containing the same
amount of active ingredient may have different bioavailability characteristics,
giving rise to concern about potential differences in therapeutic performance and
safety between different formulations, as well as between generic products and a
registered established product.

The extent to which these differences in bioavailability might affect the
therapeutic performance of a product depends on many factors, including the
pharmacokinetic profile of the drug, the clinical situations in which it is used, its
efficacy and safety and the intended dosage regimen. Indications for formulation-
related differences in bioavailability appear to be common and include a variety
of different drugs.

Bioequivalence testing is designed to set standards whereby formulation-related
differences in bioavailability could be evaluated. An abbreviated registration
application submission for generic medicines and veterinary medicines based on
acceptable bioequivalence tests is permitted. These tests may also be used for
supplemental applications for approval of a new dosage form, evaluation of
equivalence of different dosage regimens, or as bridging trials to correlate
information of different formulations used in the development of a new drug
entity. The guidelines are suggested as an aid in determining the type of
registration application data required and to establish the appropriate study
design, data collection, analysis, evaluation and reporting. It is not intended to
cover all aspects of bioequivalence evaluation, but only to define the general
requirements and considerations associated with such studies. All
bioequivalence studies (comparative bioavailability, pharmacological end-point
and clinical end-point studies), tissue residue studies, must be conducted in
compliance with good laboratory and clinical practice standards.

Guidelines regarding the pharmacological and statistical analysis of
bioequivalence trials are described. The basis of bioequivalence evaluation for
conferring therapeutic equivalence of a generic product relative to the original or
proprietary product is that clinical equivalence has been shown.

4.10.2.2 DEFINITIONS

A) Bioavailability
The bioavailability of a medicine refers to the rate and extent that the active
ingredient(s) passes into the systemic circulation and/or reaches the site(s) of
action. Absolute bioavailability is measured relative to intravenous
administration, where as relative bioavailability compares the bioavailability of

101
different dosage forms administered by the same route, or two routes of
administration of the same active ingredient(s), excluding intravenous
administration.

B) Bioequivalence
Pharmaceutically equivalent or pharmacologically alternative formulations are
considered to be equivalent when the bioavailabilty differs only within certain
limits under identical experimental conditions and when administered at the
same molar dose(s).

C) Pharmaceutical equivalent(s)
Pharmaceutical or chemical equivalents are products that contain the same
amount of active drug (i.e. the same salt, or ester or chemical form), but not
necessarily the same inactive ingredients in the same (or comparable)
dosage form.

D) Pharmaceutical alternative(s)
A pharmaceutical alternative contains the same therapeutic moiety, but may
differ in its salt, ester, dosage form and strength.

E) Therapeutic equivalence
Products that contain the same active ingredient(s) or therapeutic
ingredient(s) are therapeutically equivalent when they exhibit similar efficacy
and safety profiles. Although therapeutic equivalence may clinically imply
similar therapeutic effect, irrespective of the type of agent used (e.g.
paracetamol or aspirin for analgesia) or the dosage regimen, it is only
applicable to products containing the same active or therapeutic ingredient(s).
Bioequivalent products are likely to exhibit therapeutic equivalence.

F) Identical formulations
Identical formulations have identical active and inactive ingredients, as well as
physico-chemical characteristics (e.g. identification, concentration, particle
size, dissolution rate, crystalline form and dosage form).

4.10.3 PRELIMINARY CONSIDERATIONS FOR A GENERIC OR NEW FORMULATION
REGISTRATION APPLICATION

4.10.3.1 Registration dossier
An abbreviated registration application submission for generic medicines or for a
new formulation of a registered product is permitted. However, such an
application should be supported by the normal chemical, formulation,
manufacture, quality control and stability data that is required for any new
application. This includes full details for SECTIONS 1&2 of the application for
registration. Except for bioequivalence data and any other supportive data that
may be required as outlined in this guideline, no other detailed efficacy and safety
data will be required, unless a new claim/indication is being applied for.

4.10.3.2 Standards of active ingredient(s)
The basic premise for any generic registration and bioequivalence evaluation is
that the test and reference products are chemically equivalent. Supportive
evidence must be supplied of the purity, chemical form and pharmacopoeial
standards of the active ingredient(s) of the generic product.

102
4.10.3.3 Criteria for waiver of in vivo bioequivalence testing
Formulation-related problems with bioavailability are expected in products with
particularly non-linear pharmacokinetics (e.g. because of a pronounced first pass
effect), when absorption takes place only in restricted sections of the intestine, or
when degradation of the active ingredient occurs in the gastro-intestinal tract.
Problems with efficacy and safety are expected with products having a low
therapeutic index (e.g. cardiac glycosides) or a steep dose-response relationship
(e.g. cytotoxic drugs). Therefore bioequivalence testing becomes essential in the
case of products having life-threatening indications, a steep dose-response curve
and low therapeutic index and is relevant in cases of products which have non-
linear pharmacokinetics, poor solubility and where absorption occurs only in a
localised part of the gastro-intestinal tract.

The requirement for in vivo tests may be waived for certain generic products in
which bioavailability is known not to be influenced by the formulation. Example of
categories of products which may be eligible for waivers include:

(a) Parenteral solutions intended for injection by intravenous, subcutaneous or
intramuscular routes of administration.
(b) Oral solutions or other solubilized forms.
(c) Topically applied solutions intended for local therapeutic effects.
(d) Inhalant volatile anaesthetic solutions.

In general, the generic product being considered for a waiver contains the same
active ingredient(s), in the same concentration as the product already registered
(an approved) medicine.

4.10.3.4 Interspecies extrapolation
In general no extrapolation of bioequivalence studies performed in animals to
humans is accepted.

4.10.3.5 Selection of reference product
As a general rule, the proposed generic product or new formulation should be
tested against the original innovator product or existing formulation respectively.
If the innovator product is not marketed in South Africa, then any generic product
that has been approved as a complete new medicine application, i.e. application
approval based on submission of clinical efficacy and safety data, could be used
as a reference product.

Foreign reference products of products registered in South Africa will be
accepted from regulatory authorities approved by the Council provided it can be
confirmed that the formulation of the foreign product is identical to the product
available in South Africa. Alternatively a comparative dissolution profile must be
shown between the reference product used and the equivalent product registered
in South Africa.

Where more than one new medicine application exists for the same product and
each approved product is labelled differently, e.g. in the case of medicines
registered for different claims, the applicant of the proposed new generic product
must clearly identify which product they intend to copy.

103
The use of a generic product registered in South Africa or elsewhere on the basis
of bioequivalence testing, as a reference product for a subsequent new generic
product will not be permitted.

4.10.4 IN VIVO BIOEQUIVALENCE TESTING
In vivo bioequivalence testing includes: comparative bioavailability or blood level
studies; pharmacodynamic (or pharmacological end-point) studies and clinical end-
point (or chemotherapeutic efficacy) studies. The bioequivalence test necessary
will depend upon the type of product, pharmacokinetic characteristics of the
product, correlation between indirect and direct test methods and analytical
method available. Bioequivalence testing should be conducted using the most
appropriate method available for the specific use of the product.

4.10.4.1 Comparative bioavailability studies
Comparative bioavailability or blood level studies compare a test (generic)
product to a reference (innovator/approved) product using bioavailability
parameters derived from the concentrations of the drug moiety and/or its
metabolites, as a function of time, in whole blood, plasma, serum or in any other
appropriate biological fluid or tissues. This approach is particularly applicable to
dosage forms intended to deliver the active drug ingredient(s) to the systemic
circulation (e.g. injectable drugs and most oral dosage forms).

Comparative bioavailability studies are the preferred method for bioequivalence
testing. When absorption of the product is sufficient to measure drug
concentration directly in the blood or other biological fluid or tissues then a blood
or other biological fluid or tissue level bioequivalence study should be performed.
It is an indirect test which assumes that drug levels measured in the blood or
other biological fluid or tissues is correlated with drug levels present at the
biophase or site of drug action. Once the active ingredient is absorbed, the
principle underlying any comparison is that the active ingredient(s) of two
products that give rise to essentially equivalent concentrations of the parent drug
(or an active metabolite, or both) in the circulating blood or other biological fluid
or tissue, viewed as a concentration-time curve, will elicit equivalent therapeutic
effects. The basis of the test is therefore that a correlation has been established
between drug effect and drug concentration in blood or other biological fluid or
tissues.

General considerations associated with the design of blood level bioequivalence
studies are discussed hereafter.

4.10.4.1.1 Type of design
The experimental design of a bioequivalence study may either comprise
parallel groups in which the study population in each treatment group receives
only one of the products, or a cross-over design in which each trial subject
receives each product one or more times.

A balanced, randomized, two-phase, cross-over design is generally
recommended. Cross-over designs allow the inter-trial subject variation to be
removed from the error term which leads to a more sensitive statistical test.
With a standard two-phase (two products) cross-over design, each trial subject
receives the two products at different times. For the design to be balanced, trial
subjects are randomly assigned to either the first or second sequence with the
restriction that equal numbers of trial subjects are initially assigned to each

104
sequence. The assumption of a balanced design is that equal residual effects
occur for both test and reference products.

Other designs such as a two-phase design with four treatment sequences
(Test/Test, Reference/Reference, Test/Reference and Reference/Test) or the
extended period design may be appropriate depending on the circumstances.

When a cross-over or extended period design is used, a suitable washout
period should be allowed between the dosing of the subjects in one sequence
and the next. The washout period should extend until a baseline concentration
of zero, in terms of the analytical test, is attained. This may be accomplished by
allowing at least 4-5 half-lives between treatment phases. The maximum half-
life should be used and not the mean in a sample of subjects. Additional time
may be required for the disappearance of any pharmacological effects that
persist after total clearance of the drug (e.g. liver microsomal enzyme induction,
electrolyte imbalance).

For drugs with an extremely long half-life it may be necessary to use a parallel
group design. Long washout periods increase the probability of dropouts in a
trial.

4.10.4.1.2 Treatment and dose selection
Typically only two treatment groups viz., the test (generic/new formulation) and
the reference (innovator/approved) products are used. A single dose study will
in most cases be adequate for the demonstration of bioequivalence. However,
a multiple dose study is required for products containing substances with
known non-linear kinetics, for products with a narrow therapeutic index, and for
most modified release products. Exemption will be considered for products with
short half-lives, where steady-state is not readily achieved. The highest
approved dose for a product should be used in all comparative bioavailability
studies.

For certain products it is desirable to test bioequivalence under fasting
conditions in order to enhance absorption rates and to reduce variability of
blood levels. Fasting condition, if used, should be fully described giving careful
consideration to the pharmacokinetics of the product.

4.10.4.1.3 Trial subjects and number

The number of subjects required in a comparative bioavailability study is
determined by a detailed knowledge of the specific product and the statistical
design. Generally a minimum of 12 subjects for immediate release products
and 20 subjects for controlled release products, using a cross-over design for
medicines, respectively are required. For parallel-designed trials more subjects
are generally required. To ensure that an adequate number of trial subjects are
used to obtain conclusive results, appropriate statistical procedures should be
employed.

Generally speaking 12 subjects in a cross-over study for immediate release
tablets or capsules and 20 subjects for modified release tablets or capsules,
should complete the study. However, the exact number of subjects will be
determined by the more detailed knowledge of the specific product known to
the applicant and the statistical design of the study

105

Bioequivalence trials are conducted with healthy subjects. In veterinary
medicines animals of the same breed and approximately of the same age, from
the target species for which the product is indicated are preferably required. A
single sex or equal numbers of either sex may be used.

The health status of the trial subjects must be confirmed by performing a
complete physical examination and by appropriate haematological and blood
chemistry evaluation of each individual before each treatment. Subjects should
not receive any medication prior to testing for a period of at least two weeks,
depending on the biological half-life of the medicated product.

4.10.4.1.4 Sample collection
A blood sample should be collected from each subject immediately prior to the
administration of the first dose in both single and multiple dose studies. The
interval between serial blood samples and number of blood samples to be
taken post treatment will depend on the nature of the drug, its route of
administration and the pharmacokinetic parameters of major interest. A pilot
study is generally recommended to determine the interval and number of blood
samples needed.

In a single dose study, at least 12 samples need to be collected over the entire
extent of the drug blood-concentration-time (C-T) curve, for at least 4-5 plasma
half-lives of the product beyond the maximum blood drug concentration (Cmax).
Sampling times should also be selected to adequately determine Cmax, the
time at which Cmax occurs (Tmax) and the area under the drug blood C-T
curve (AUC). It is recommended that in single dose bioavailability trials for
determination of the correct pharmacokinetic parameters there should be at
least 3 blood drug concentration points during the absorptive phase, about 3 in
the region of the peak, at least 3 during the distributive phase and at least 3
during the elimination phase. If a certain parameter is of major interest, the
blood sampling may be adjusted to increase the accuracy of such a parameter.
For example if the peak drug concentration is of major importance due to
possible side effects of the product, more blood samples should be taken in the
region where the peak concentration is expected.
In multiple dose studies, dosing should take place for at least 5 elimination half-
lives of the parent compound or active metabolites before the blood C-T curve
are studied. Blood samples should be collected at 3 trough concentrations
(Cmin) over a period equal, to or greater than 2 times the elimination half-life to
ascertain that steady state has been reached.

For veterinary medicines to adequately describe the depletion phase of the
blood drug C-T curve in food producing animals, following either single or
multiple treatment, samples should be collected to the limit of detection of the
product in blood, which generally will not be more than 1/10 of the tolerance
concentration in the target tissue, as defined for the innovator product. When
tolerance concentrations have been established for multiple tissues for the
innovator's product, the limit of detection will be not more than 1/10 of the
lowest tolerance drug concentration. If tolerance concentrations have not been
established, an acceptable method capable of detecting the drug in blood for at
least four to five half-lives beyond Tmax should be used.

106
Blood sampled may either be collected in an anticoagulant e.g. heparin, or
EDTA or without any anticoagulant, depending on the analytical method and
type of product.

4.10.4.1.5 Drug analysis
Precise and accurate estimation of pharmacokinetic parameters, including
bioavailability, depends critically on reliable determination of drug and
metabolite concentrations in physiological fluids such as plasma, serum and
urine. It is essential that all assay methodology be properly validated and the
results reported in the registration application. While validation of each method
will stand on its own, comparison of the methods will be necessary e.g. where
more than one method has been employed in a long-term study. When sample
analysis is conducted at more than one site, it is necessary to validate the
analytical method(s) at each site and provide appropriate validation information
for different sites to establish interlaboratory reliability.

Method validation includes all procedures required to demonstrate that a
particular method for quantitative demonstration of an analyte (or series of
analytes) in a particular biological matrix is reliable for the intended application.
The parameters to ensure the acceptability of the performance of an analytical
method are stability of the drug in the matrix under study storage conditions,
accuracy, precision, sensitivity, specificity (selectivity), response function,
extraction recovery and reproducibility.

The need for stereo-selective determination of racemic mixtures in
bioavailability/bioequivalence trials have been reported. Enantiomers may
have entirely different pharmacological and toxicological properties and may
undergo stereo-selective metabolism and/or elimination. General stereo-
selective determination of racemic mixtures is currently not required for a
registration application of generic products. However, if the activity of a
racemate mixture resides in only one enantiomer; the presence of one
enantiomer, affects the kinetics or dynamics of other(s), and if an inactive
enantiomer inverts to active, then individual enantiomer analysis may be
required. Stereo-selective determination is not required if chiral enantiomers
are equipotent or if the relative concentration of enantiomers remains constant
over time.

4.10.4.1.6 Pharmacokinetics analysis
Measurement of the extent and rate of absorption is needed in order to
evaluate equivalence in comparative bioavailability trials. In single dose
studies, AUC, Cmax and Tmax are the most important parameters currently
required. AUC is used as a measure of the extent of absorption, whereas
Cmax and Tmax are measures of rate. However, both Cmax and Tmax are
subject to large variations, particularly with controlled/modified release
formulations, and therefore additional pharmacokinetic parameters are
recommended to evaluate the rate of absorption. Since Cmax may also reflect
extent of absorption, the ratio Cmax/AUC is suggested to compensate for this
problem. The ratio is independent of both intra-subject variations and possible
differences in the extent of absorption. Mean residence time (MRT) is another
measure of the rate of absorption that can be used in products which have a
short terminal half-life. For drugs which have a long elimination half-life the
MRT is less suitable.

107
In multidose studies the normal bioequivalence parameters AUC, Cmax and
Tmax are also required. In addition the percentage peak-trough fluctuation
(PTF), Cmin and average steady state concentration (Cmax) will also be
required to characterise the rate of absorption during steady state. For
modified/controlled release formulations the plateau time of one dosing interval
or dosing cycle which exceeds 50 % (T50 % Cmax) and 75 % (T75 % Cmax) of
the maximum concentration are also useful parameters to use.

Cumulative urinary excretion data of drugs which are mainly excreted via the
kidneys (60 % of the administered dose) is a parameter which may be useful.
The biological terminal half-life is a parameter often included in the evaluation
of bioequivalence.

The parameters should be tabulated and compared to published data. For this
purpose, total clearance and volume of distribution are convenient parameters,
since they are dose-independent and facilitate the comparison of the results
from different studies.

The AUC is calculated using the linear trapezoidal rule between the first and
the last measured time points. This area must then be extrapolated to infinity.
The portion of the AUC when extrapolated to infinity should not exceed 20 % of
the total AUC in each of the subjects. If the extrapolated portion of the area
under the curve is a large percentage of the total AUC (20 % or more), the
study was not designed properly and further blood samples should have been
drawn. In some cases it may be impractical (or even impossible) to extrapolate
the AUC to infinity and in such cases, the AUC over the blood sampling period
should be used, and the reasons for not extrapolating specified.

The maximum concentration (Cmax) and the time to the maximum
concentration (Tmax) can be obtained directly from the data by inspection.

An approach that is sometimes used is that of fitting a complete compartmental
model to the data. The AUC(0-inf) is then estimated from the integral of this
multi-exponential function, while Cmax and Tmax can also be estimated from
this function. However, it is not always possible to obtain an adequate fit of a
compartmental model to the data, resulting in poor estimates of the parameters.
Since the parameters are not obtained directly from the data, these parameters
are subject to two error terms. The first is the usual experimental error term,
while the second error term applies to the estimation of the parameters from the
multi-exponential model and depends on the goodness of fit of the model to the
data. Even when a good fit is obtained, the use of compartmental methods is
not recommended for bioequivalence studies.

4.10.4.1.7 Statistical analysis
The appropriate statistical analyses of comparative bioavailibility data is
essential for determining equivalence. All statistical procedures performed on
such data for bioequivalence evaluation must be fully reported in the
registration application. An analysis based on the null hypothesis alone is not
acceptable. It is widely accepted that testing a null hypothesis for no difference
is not adequate to test for bioequivalence.

Various statistical procedures have been described for evaluation of
bioequivalence. For further information the papers by Steinijans & Hanschke,

108
X
and
X R T
1992; Schuirmann, 1987; and Westlake, 1988. compare the various
methodologies. The minimum statistical requirement accepted for
bioequivalence testing is the use of 90 % confidence intervals for the mean
ratio or mean difference between two products.

Analysis of each individual bioavailability parameter required for single and
multiple dose studies must be performed. In general, bioequivalence is
accepted if the test product/formulation is within the specified limits of 80-125 %
of the reference product/formulation for AUC and 75-143 % for Cmax.
However, for veterinary medicines a variety of circumstances preclude the use
of a simple fixed rule.
In analysis of variance (ANOVA) with treatment, subject and period (for cross-
over studies), as the main effects, plus an error term is required to obtain the
estimate of S
2
, the error variance. A simpler analysis is using a paired t-test.
The estimator S
2
, which will be used in the calculation of the 90 % confidence
interval is obtained from the "error" mean square term found in the ANOVA
table. Lower and upper 90 % confidence intervals are found by formulae based
on Student's t-distribution.

are the means of the particular bioavailability parameter for N trial
subjects for the test and reference product/formulation, respectively; v is the
degrees of freedom and S
2
the mean square error obtained from the ANOVA;
and N
A
and N
B
are the number of subjects in each sequence group that
successfully completed the study.

The procedure of declaring two product/formulations bioequivalent if the 90 %
confidence interval is completely contained in the fixed bounds, is statistically
equivalent to performing two one-sided statistical tests ( =0,05) at the end-
points of the interval.

A multiplicative model is assumed for the un-transformed bioequivalence
characteristics, such as AUC, which in the case of a parametric analysis,
implies the assumption of a logarithmic normal distribution. If the assumption of
a logarithmic normal distribution in the parametric approach is doubtful, the
decision based on the inclusion of the non-parametric (distribution-free) 90 %
confidence interval according to Moses in the bioequivalence range, is
recommended. With regard to Tmax, a distribution-free 90 %-confidence
interval for the difference of the medians for test and reference
products/formulations, are recommended.

)
N
1
+
N
1
(
S
2
t
- )
X
-
X
( - L
B A
2
0,05 df R T

)
N
1
+
N
1
(
S
2
t
+ )
X
-
X
( - U
B A
2
0,05 df R T

109
4.10.4.1.8 Trial reporting

Full details on the purpose of the study, trial design, test and reference
products, subject selection (inclusion and exclusion criteria) and health, sample
collection and storage, analytical method and validation, sample analyses,
individual subject results, pharmacokinetic and statistical procedures and any
adverse drug reactions observed during the course of the study must be
reported.

Graphical presentation of the mean test and reference blood drug C-T curves
and pair-wise presentation of the C-T curves of each subject are required.
Individual and mean (SD) of the pharmacokinetic values for each
product/formulation obtained and confidence intervals for each parameter must
be tabulated. Reasons for any subject drop-out must be explained.

4.10.4.2 Pharmacodynamic (Pharmacological end-point) studies
Where the direct measurement of the rate and extent of absorption of the
medicine in biological fluids is inappropriate or impractical, the evaluation of an
appropriate pharmacologic end-point will be acceptable.

Typically the design of a pharmacological end-point study should follow the same
general considerations as the comparative bioavailability studies. However,
details such as the number of subjects or sampling times will depend on the
pharmacological end-point monitored. The parameters to be measured will also
depend upon the pharmacological end-points and may differ from those used in
comparative bioavailability studies.

Even though the parameters of interest for pharmacological end-points may differ
from those of a blood level bioequivalence study, the method of statistical
analysis is essentially the same as for the comparative bioavailability studies.
For most pharmacological end-points, it may be necessary to show, for both the
test and reference products separately, that the means of the parameter of
interest at a specified post-treatment time are significantly different from baseline.
Prior to conducting the study, a time such as two hours post-treatment should be
selected and the observed values compared to baseline values. If the means are
not significantly different ( =0.05), the study is invalid. The appropriate test for
the significant change from baseline is given by the time effect in the ANOVA.
(Note: This analysis is a generalisation of the paired t-test accounting for period
effect.)

4.10.4.3 Clinical end-point (Efficacy) studies
If measurement of the drug or its metabolites in blood, biological fluids or tissues
is inappropriate or impractical, and there are no appropriate pharmacological
end-points to monitor then clinical end-point studies as outlined below for each
group of drugs are acceptable for the demonstration of bioequivalence.

Generally, a parallel group design with two or three treatment groups will be
required. The groups should include an untreated or placebo treated control
group, the test (generic) product group and preferably a positive control

110
(reference/innovator) group. Dosage(s) approved for the reference product
should be used in the study.

In general, response(s) to be measured in a clinical end-point study should be
based on the labelling claims of the reference product. It may not be necessary to
collect data on some overlapping claims (e.g. for veterinary medicines a
production improver which is added at the same amount per ton of feed for
growth rate and feed efficiency, data from only one of the two responses need be
collected).

The statistical procedures required for clinical end-point trials will be determined
by the type of product being compared. However, as with comparative
bioavailability trials, the use of 90 % confidence intervals is generally advocated.

Efficacy trials are required for demonstration of bioequivalence of all veterinary
medicine anthelmintics, unless specifically exempted.

4.10.5 TRIAL PROTOCOL REQUIREMENTS

Applicants are to submit all bioequivalence study protocols for review prior to
initiating the study. The trial must be approved by an independent ethics committee
and the study must be conducted in compliance with good laboratory and clinical
practices.

The protocol should include the following:

(a) A description of the product and its intended use;
(b) The dosage regimen that will be used;
(c) The selection criteria used in the study;
(d) A description of the experimental design, including treatment groups (i.e.
test, reference, placebo (or negative) control), number of subjects,
randomisation procedure for assigning subjects to groups, blinding
procedures, parameters to be measured, sampling times, and statistical
analyses; and
(e) Procedures for recording any adverse reactions during the study.

4.10.6 DISSOLUTION

Dissolution as proof of efficacy may be used in the following instances:

1) When a dissolution requirement has been included in the current edition of the
USP for a particular product containing either a single active ingredient or a
combination of active ingredients, and the active is not on the attached list A,
pharmaceutical availability data in support of efficacy will generally be accepted
for such a product, unless otherwise determined by the Council.

2) Pharmaceutical availability data may also, at the discretion of the Council, be
considered for other combination products, provided that each active
ingredient, in the same type of dosage form being applied, is subject to a
monograph of the USP which includes a requirement for dissolution rate, and
provided that the reference product used in the study is identical in

111
composition, with respect to the content of active ingredient(s) and the actives
are not on the attached list A.

3) Pharmaceutical availability data may be submitted for multivitamin and vitamin
and mineral combination products. For these products, the dissolution rate of
at least the least water-soluble plus one other vitamin should be determined. If,
however, specific claims are made for specific ingredients contained in such a
product, pharmaceutical availability data for each such ingredient shall be
required, unless otherwise determined by the Council. Raw materials should
be used as the standards.

4) Dissolution tests in the USP, currently only relates to tablets, capsules, one
suppository and one suspension, indomethacin. Bioavailability data shall
generally be required for all other suspensions and suppositories intended for
systemic use and all solid dosage forms containing one or more of the active
ingredients listed in the attached Annexure A.

Exemption from the above will be considered on merit of individual motivation.

5) Submission of dissolution data:
5.1 Assay results of the reference and test product must be submitted.
5.2 Content uniformity test results, if a requirement for lot release;
alternatively, mass uniformity of the reference and test product must
be submitted.
5.3 Dissolution must be done in 3 media, whereof:

a) The first medium must be that specified in the USP
monograph. The USP dissolution apparatus (or equivalent
apparatus), USP method, USP dissolution medium and the
acceptance criteria as specified in the current edition of the
USP shall be used.

The apparatus used shall be validated by means of the
approved suitability test of the USP

b) The "other dissolution media" shall generally be from the
following and shall span a wide pH range:
an acidic medium e.g., gastric fluid USP;
water
an alkaline medium e.g., intestinal fluid USP

c) If the active ingredient is insoluble in the "other two media"
prescribed by the Council, dissolution testing need not be
performed in these media. A statement to this effect shall be
made and motivation supplied for the omission of these tests

d) The results of each dissolution study shall be generated from
at least six units of the product

e) For the other 2 media 6 units each must be used for both the
reference and test products. The USP requirements for the
apparatus, medium volume and rotation speed specified in the
monograph, for the media required by the USP may be

112
followed. The rotation speeds of paddle or basket for the
dissolution media chosen above shall be such that dissolution
is not too rapid and that the dissolution profile extends to a
minimum of at least 30 minutes where possible for 75 %
dissolution

f) Filters used in the dissolution apparatus shall be 1 micron or
less or as reflected in the USP monograph, whichever is the
smallest.

g) The dissolution methods shall be fully described including
media used, apparatus, filter size, rotation speed of the paddle
or basket as the case may be, volume of dissolution medium,
method of taking samples, method of quantitative analysis,
calculations to compensate for dilution of ingredients due to
withdrawal of dissolution medium.

h) The study shall be a multi-point study.

i) The dissolution data shall be presented in a tabulated and a
graphic form as a function of percentage of the labelled
quantity of active dissolved to time. Such data shall reflect
multiple points. The tabulated form shall include the individual
results of the dosage forms, the mean and the standard
deviation of the dosage forms. The graphical form will be the
mean of the studies of the reference and test products set out
on a graph for each medium.

j) Permissible deviations in results.
The significance of deviations in data when decisions are
taken in declaring medicines to be efficacious and/or
therapeutically equivalent will be discussed at the time of
evaluation. Rigid requirements will not be stipulated.

4.10.7 OTHER

4.10.7.1 Disintegration

Disintegration as proof of efficacy may be used for the following products:
a) Vitamins or vitamins and mineral combinations when a claim is made as a
supplement.
b) Phenolphthalein.
c) Sucralfate.

Submission of disintegration data:
a) The disintegration test included for Nutritional Supplements in the USP must
be used for the vitamins.
a) The general disintegration test included in the USP may be used for the other
substances.

4.10.7.2 Acid-neutralising capacity
Acid-neutralising capacity as proof of efficacy may be used in the following
instances:

113
For all products having an antacid or acid neutralising claim.

The acid neutralising capacity test included in the USP must be used.

4.10.7.3 Microbial growth inhibition zones
Microbial growth inhibition zones as proof of efficacy may be used for all products
having a bacteriostatic/bacteriocidal/antiseptic claim.

4.10.7.4 Proof of release by membrane diffusion
Release by membrane diffusion as proof of efficacy may be used for all creams,
ointments and gels.

4.10.7.5 Particle size distribution
Particle size distribution as proof of efficacy may be used for inhalations
The Anderson sampler or equivalent apparatus may be used.

4.10.7.6 Blanching test
The blanching test as proof of efficacy may be used for cortisone containing
creams and ointments.

4.10.7.7 Any other method an applicant wishes to submit, provided the rationale for
the particular method is included.
Please note that it is the prerogative of the applicant to submit any other data as
proof of efficacy, provided the reason for doing so is motivated.

4.10.8 DEFINITIONS:

4.10.8.1 Pharmaceutical equivalents -
Medicines are considered to be pharmaceutical equivalents if they contain the
same active ingredients and are identical in strength or concentration, dosage
form and route of administration.
They are formulated to contain the same amount of active ingredient/s in the
dosage form and to meet the same comparable standards (i.e strength, purity
and quality), but may differ in characteristics such as colour, flavour, shape,
packaging, shelf-life and within certain limits, package insert details.

4.10.8.2 Therapeutic equivalent -
Therapeutic equivalents are pharmaceutical equivalents that can be expected to
have a comparable therapeutic effect when administered to patients under the
conditions specified in the package insert.

The concept of therapeutic equivalents applies only to products containing the
same active ingredients and does not encompass a comparison of different
therapeutic agents used for the same condition (e.g. propoxyphene hydrochloride
vs pentazocine hydrochloride for the treatment of pain).

Products are declared to be therapeutically equivalent when they meet the
following criteria:

4.10.8.2.1 They are pharmaceutical equivalents, as defined above;
4.10.8.2.2 They are bioequivalent in that -

114
i) they do not present a known or potential bioequivalence
problem and there is no known medically significant bio-
inequivalence problem with products where 75 % is
dissolved in water at 37 C within 45 minutes using either
official apparatus at the usual speed, or
ii) if they do present such a known or potential bioequivalence
problem, they are shown to meet an appropriate
bioequivalence standard;

4.10.8.2.3 They are manufactured in compliance with current Good
Manufacturing Practice standards.

115
LIST A

Medicines containing the following chemical entities, certain combinations, specific groups of
entities or medicines falling into a specific pharmacological group, which will usually require
data other than comparative dissolution data as evidence of efficacy

Additions and deletions to the following list may be made by the Council from time to time.
Acetyldigitoxin
Acetyl furazole
N-Acetylprocainamide
Alseroxylon
Amiodarone
Antibiotics (unless otherwise determined by Council)
Aspirin, phenacetin, caffeine
Benzthiazide
Benzoylpas calcium
Butalbital, carbamazepine, cephalosporins
Carisoprodol, phenacetin, caffeine (with or without codeine)
Chlorambucil
Chlorpromazine
Conjugated oestrogens with meprobamate
Cyclosporin A
Cytotoxic agents
Deserpidine
Deserpidine and hydrochlorothiazide
Deserpidine and methyclothiazide
Dicoumarol
Dienoestrol
Digoxin
Disopyramide
Doxycycline
Erythromycin (base and esters)
Ethinyl oestradiol
Ethotoin
Ethoxyzolamide
Fludrocortisone acetate
Fluprednisolone
Guanethidine sulphate
Hydralazine hydrochloride and hydrochlorothiazide
Hydralazine hydrochloride and reserpine
Hydrocortisone acetate
Hydroxyzine pamoate
Isoproterenol sublingual
Liothyronine sodium
Lithium compounds
Menadione
Methdilazine
Methocarbamol with aspirin
Methyltestosterone
Minocycline
Oxtriphylline (choline theophyllinate)
PAS, PAS calcium
PAS potassium , PAS sodium

116
PAS and isoniazid
PAS sodium and isoniazid
Paramethadione
Paramethasone acetate
Phenacetin
Phenobarbitone
Phenylaminosalicylate
Phenytoin
Phytonadione
Procainamide
Prochlorperazine
Promazine
Promethazine
Quinethazone
Quinidine
Quinidine polygalacturonate
Rauwolfia serpentina
Rescinnamine
Reserpine
Reserpine and chlorothiazide
Reserpine and hydrochlorothiazide
Reserpine and hydralazine
Reserpine, hydralazine hyrochlorothiazide and hydrochloride
Reserpine and hydroflumethiazide
Reserpine and trichlormethiazide
Sodium sulfoxone
Spironolactone
Spironolactone and hydrochlorothiazide
Stilboestrol
Stilboestrol diphosphate
Sulfoxone sodium
Sulphadiazine sodium bicarbonate
Sulphadiazine, sulphadimidine and sulphamerazine
Sulphadimethoxine
Sulphafurazole
Sulphamethoxypyridazine acetyl sulphaphenazole
Sulphasomidine
Tuberculostatics including rifampicin
Theophylline
Theophylline sodium glycinate
Thioridazine
Thyroglobulin
Tretamine
Trifluoperazine
Triflupromazine
Trimeprazine
Uramustine
Warfarin, sodium and potassium

117
4.10.9

APPLICATION CONTROL DOCUMENT FOR BIOEQUIVALENCE STUDIES

Prerequisite for application submission

REPORT

Page no

Summary

Full study report

Introduction (product review and motivation for study)

Conclusions

Protocol

Expert report

STUDY LOCATION AND INVESTIGATORS

.

Description of study location

Curriculum vitae of study investigators

Date of study

Confirmation of GLP/GCP compliance

STUDY DESIGN

o.

Design in accordance with requirements*

Description of allocation procedure of subjects

Description of wash-out period

*In accordance with the Councils requirements for conventional and modified release dosage
forms

118
SUBJECTS

o.

Number of subjects used in study in accordance with requirements*

Summary of demographics of subjects

Description of inclusion and exclusion criteria

Description of dropouts

Description of adverse reactions experienced

*In accordance with the Councils requirements for single and multi-dose studies forms

PRODUCT INFORMATION

o.

Batch numbers of test and reference products used

Reference product in accordance with requirements*

Description of method of intake/administration

Confirmation of product content (analysis certificate)

*In accordance with the Councils requirements of an innovator product and the use of medicines
not from South Africa

COLLECTION OF SAMPLES

o.

Sample collection (number and intervals) in accordance with requirements*

Description of method of collection and storage of samples

*In accordance with the Councils requirements of an innovator product and the use of
medicines not from South Africa

DRUG ANALYSES

o.

Description of analytical method(s)

Report of validation results

Confirmation that validation was performed for current study

PHARMACOKINETIC ANALYSES

o.

Confirmation of use of non-compartmental analyses procedures

Analysis in accordance with requirements for single and multi-dose studies*

*In accordance with the Councils requirements

119

STATISTICAL ANALYSIS

o.

Analysis performed in accordance with requirements for bioequivalence testing*

Confirmation that the required absorption parameters fall within the standard
confidence intervals for bioequivalence

*In accordance with the Councils requirements

RESULTS

o.

Individual subject drug concentration data

Individual subject pharmacokinetic parameter data

Mean tabulated pharmacokinetic data

Individual subject data and mean graphical illustration of data

120
5 APPLICATION FOR THE AMENDMENT TO A REGISTRATION DOSSIER FOR A
MEDICINE

5.1 GENERAL INFORMATION APPLICABLE TO ALL APPLICATIONS FOR
AMENDMENTS

5.1.1 Applications for amendments to existing dossiers must be submitted under cover of
the appropriate application form for the relevant type of amendment as detailed in
5.2, 5.3 and 5.4 below respectively

5.1.2 Incomplete submission or submissions which do not comply with the
requirements as described will not be evaluated by the Medicines Control
Council. These must be collected within 14 working days, failing which the
applications will be cancelled.

5.1.3 Presentation:

Amendment applications may not address more than one product unless it is a
product range for which a single application for registration dossier was submitted
at the time of application for registration. Exception: For change of name or
address of applicant only, details for a range of products may be submitted in
accordance with 5.2.3

All applications for amendments must be properly bound on the left side as this
allows for easy update/addition of pages. It is preferred that documents be bound
with plastic ring-binding or punched (2-hole) and secured; however, the use of
lever-arch files and any kind of paper clip is not recommended.

The date of the covering letter must be reflected on every page of the
submission/letter in black.

Paginate all pages and index according to the existing MRF 1.O Parts/MBR1
Annexure (e.g. page 2B.1 referring to PART 2 B, first page).

Include dividers where necessary

Submit the front page of the amended MRF Parts/MBR1 Annexures and the
amended pages only when amendments are made which involve updating of a
limited number of pages.

However when extensive updating of the dossier is done, a completely updated
dossier must be submitted and the amended sections clearly indicated. It is not
acceptable to submit selected pages only when a full update is submitted. Such
full updates must preferably be bound with plastic ring binding or punched (2-
hole). The use of lever-arch files or any kind of paper clip is not recommended.

All documents in a foreign language (including German and Dutch documents)
must be translated to English.

5.1.4 When an application for amendment is submitted, the Administrative Data of the
MRF1 form must be updated with regard to C. UPDATE HISTORY. Date of
application of each amendment (previous and current) for the last three

121
amendments, summarised details of the amendment/s, and date of approval by the
Medicines Control Council must be provided in tabulated format.

5.1.5 Amendments whilst an application for registration is in the pre-registration phase are
not permitted, unless advised by or negotiated with the Medicines Control Council.

5.2 APPLICATION TO AMEND THE PARTICULARS REGARDING PROPRIETARY
NAME, APPLICANT, MANUFACTURER, PACKER, FINAL PRODUCT RELEASE
CONTROL AND FINAL PRODUCT RELEASE RESPONSIBILITY

5.2.1 GENERAL INFORMATION

5.2.1.1 Applications pertaining to the above must be submitted under cover of form MRF
3A.O.

5.2.1.2 Amendments must be accompanied by the amendment fee. If a cheque is
submitted to cover the amendment fees for more that one product, a list of the
products involved with the reference numbers and date of requesting the specific
amendment for each product must be supplied. A copy of this letter as well as a
copy of the cheque must be included in the application for each individual product.

5.2.1.3 Amendments to registered products must be accompanied by the original
registration certificate. A copy of the registration certificate can not be accepted as
the original must be replaced. Should the certificate already be with the MCC, this
must be indicated on Form 3.O. (Original certificate already submitted with
application dated .., reference no. .)

5.2.1.4 All amendments must be accompanied by updated administrative details (front
page) of the MRF 1.O/MBR1 front page (See 4.6.1 9v).

5.2.1.5 As the processing of these amendments results in the updating of the database
and the issue of amended registration certificates, applicant should ensure that
details with regard to previously approved facilities are updated to reflect name and
address changes of companies through the years. Changes must be detailed as
indicated in 5.4.1.1, and the appropriately amended Parts/Annexures included in
the submission.

Should there be a discrepancy between the administrative data submitted with the
amendment request and the relevant Parts/Annexures, the data in the Registration
Dossier on file will be reflected on the registration certificate.

5.2.1.6 It is the applicants responsibility to ensure that details with regard to the facilities /
laboratories applied for are correctly reflected on the front page, and to check
registration certificates for correctness and communicate discrepancies to the MCC
within 30 days of receipt thereof.

If the applicant is of the opinion that the information reflected on the registration
certificate is incorrect, the applicant must provide the correct approved information
together with the letter/s of approval by the MCC. An amended registration
certificate will be issued free of charge should the error have occurred at this office.

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5.2.1.7 A change can only be considered final once the applicant has been supplied with
the new registration certificate for registered medicines, or a final letter of approval
of the amendment from the MCC in the case of an old medicine.

5.2.1.8 Updating of dossier: If the dossier has not been updated during the previous 5
years, or an application for a major change is lodged, a fully updated dossier must
accompany an application for transfer of applicancy or change in manufacturer.

5.2.1.9 All relevant documentation must be submitted as one document and different Parts
should not be submitted separately. Duplicate documents may not be submitted to
different sections.

5.2.1.10 The processing of the request is not merely a formality. Each application has to be
evaluated on an individual basis before such a request may be approved. The
authorisation for change is dependent on various aspects including the proposed
new applicant / manufacturer / packer / laboratorys infrastructure and its
compliance with Good Manufacturing Practice in terms of the guidelines as
recommended by the World Health Organisation and SA Guide to GMP.

5.2.1.11 In order to assess the suitability of the proposed applicant, manufacturer, packer or
laboratory, an inspection by the MCC Inspectorate may have to be performed prior
to the authorisation of change could be processed

5.2.1.12 Please note that once a change in applicant/manufacturer/packer/FPRC/FPRR has
been approved, the updated pages to the Parts/Annexures are placed on file.
Subsequent updates of the dossier should not again indicate an application for
change in applicant / manufacturer/ packer / FPRC / FPRR

5.2.2 CHANGE OF PROPRIETARY NAME

5.2.2.1 Application to amend the proprietary name of a product must be submitted on a
official letterhead and the reason for the amendment must be clearly stated.
5.2.2.2 Amendments the proprietary name during pre-registration phase will only be
permitted if the MCC has not accepted the name or for safety reasons.
5.2.2.3 The applicant must be accompanied by an amended Administrative Section of
Form 1.0, Part 2B (Formulation) and the professional package insert and patient
information leaflet.
5.2.2.4 Policy on proprietary names detailed in these guidelines should be consulted.

5.2.3 CHANGE OF APPLICANT

5.2.3.1 The proposed applicant must have submitted an AMF prior to any application for
transfer of applicancy.

5.2.3.2 An application for a change of applicant must be submitted on a company
letterhead under cover of MRF 3A.O together with the following documentation:

details of applicant and all other companies involved in the manufacturing of
this product (Format as stipulated in Appendix A1)

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statement by applicant of possession of master documents, existence of
contacts, commitment to updating dossiers and detailing changes in the
manufacturing process (Format as stipulated in Appendix A2)
letter of cession on an official letterhead (see iii)
letter of acceptance by the new applicant on an official letterhead
the original registration certificate (registered products
the amendment fee
updated administrative data (MRF 1.O/MBR1 front page cover)
inspection flow diagram for the product
organogram of proposed new applicant (including the names of key personnel
with specific reference to production and quality assurance)

5.2.3.3 A letter of cession from the current legal applicant addressed to the MCC must be
submitted. This letter must confirm that the full application dossier (MFR
1.O/MBR1) and product history have been provided to the proposed applicant. It
must be provided by the current applicant, on a company letterhead to the new
applicant, for submission to the MCC.

5.2.3.4 It should be noted that the final product release responsibility (FPRR) often
changes when a change in applicancy takes place. The application for registration
dossier must be appropriately updated to reflect this change. (Front page cover).
This change must be clearly indicated (see 5.4.1.1)

5.2.3.5 The Registration dossier must be fully updated to the current statutory format and
current scientific standards within 12 months of transfer of applicancy. In the case
of mergers the applicant must adhere to the programme of updating of dossiers as
approved by the Inspectorate. The date by which the dossier will be fully
updated must be clearly reflected in the covering letter.
However, if the dossier had not been updated during the previous 5 year period a
fully updated dossier must accompany the application for transfer of applicancy.

5.2.3.6 The current applicant must hand over the registration dossier and complete product
master documentation to the new applicant. Applicants are advised to ensure that
the dossier presented to them has been fully updated recently (at least during the
last 5 years) and that the full product history is provided by the current applicant.

5.2.3.7 An applicant must be in possession of all specifications relevant to a product

5.2.3.8 The current applicant remains legally responsible and liable until transfer of
applicancy has been confirmed

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5.2.4 CHANGE OF / ADDITIONAL: MANUFACTURER, PACKER/ FPRC/FPRR

5.2.4.1 An application for change of manufacturer/packer/FPRC/FPRR must be
submitted on an official company letter head under cover of form MRF 3A.O

5.2.4.2 The following documentation must be included:
- details of applicant and all other companies involved in manufacturing of this
product (Format as stipulated in Appendix A 1)
- statement by applicant confirming possession of master documents,
existence of contracts, committing to updating of dossiers and detailing
changes in the manufacturing process ( Format as stipulated in Appendix A 2)
- Inspection flow diagram for the product
- the original registration certificate (registered products)
- the amendment fee.
- updated administrative data MRF 3.0

5.2.4.3 The following data pertaining to manufacturing/packing/laboratory sites (local and
overseas) will be required.
- Site Master File if not previously submitted
- Organogram listing all the key personnel

5.2.4.4 For manufacturers/packers outside the borders of South Africa the following
additional information will be required:
-
- Copy of the latest inspection report:
For a recognised countries with competent authorities, a GMP certificate
compliance in terms of WHO Certification Scheme or a GMP certificate
issued by a competent Council for the manufacturing site or copy of the
manufacturing licence (not older than 2 years) will be sufficient.OR
For manufacturers in non-recognised countries, that havent been inspected
by a recognised Council, an inspection report from a recognised Council will
be required.OR
For manufacturers in a non-recognised countries, that havent been
inspected by a recognised Council , an inspection by the MCC inspectorate
may be required.

5.2.4.5 For change in manufacturer:

5.2.4.5.1 Where the manufacturing procedure (including equipment) is identical to the
manufacturing procedure currently used, the following must be submitted:

i) a statement signed by the managing director (or in the case of an overseas country
the head of the production plant or chief technical officer) that the manufacturing
procedures and equipment are the same as that currently used;

ii) updated Front Page

iii) However, if the dossier had not been updated during the previous 5 year
period a fully updated dossier must accompany the application for change
of/additional manufacturer.

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5.2.4.5.2 Where the manufacturing procedure (including equipment) differs, but falls within the
minor amendments . (See 5.4.2), the following must be submitted:

i) a statement signed by the managing director (or in case of an overseas country,
the head of the production plant or chief technical officer ) that the changes to the
manufacturing procedures falls within the minor amendments;

ii) updated PARTS / Annexures according in prescribed format (see 5.4.1.1). The
changes in the manufacturing process must be clearly stated to facilitate evaluation
PART 2 E/ Annexure 11
PART 2 C/ Annexure 6 where relevant.
- Other amendments complying to guidelines for minor changes.

iii) However, if the dossier had not been updated during the previous 5 year
period a fully updated dossier must accompany the application for change
of/additional manufacturer.

5.2.4.5.3 For an alternative or additional manufacturer where the manufacturing procedure (or
equipment) is different from the manufacturing procedure (or equipment) currently on
file falling out of the permitted amendments, the following must be submitted:

i) Changes to PARTS/ Annexures in prescribed format (see 5.4.1.1). The changes
in the manufacturing process must be detailed to facilitate evaluation

ii) A fully updated dossier.

iii) details of the proposed validation programme to be followed for at least the first
three production batches.

iv) stabililty data and comparative efficacy data as required for major amendments

Note: Major deviations: sale of product may only commence after written
approval had been granted by the Council. When such batches are
manufactured, all documents and bulk and/ or intermediate stock should be
clearly marked as being validation batches.

5.2.4.6 Change in packer

- Statement confirming that the packing process is unchanged

or

- Updated PART2 E and D(where relevant) /Annexures 11 &9B in prescribed format (see
5.4.1.1). The changes in the packing process must be detailed to facilitate evaluation.

5.2.4.7 Change of final product release laboratory of final product release responsibility

- Updated Administration Front Page.

5.2.4.8 Applicants should study the requirements in Chapter 12 of the SA Guide to GMP.

Attention is particularly invited to the following from the GMP Guide:
12.2.1 A Contract Giver should assure himself that the Contract Acceptor has
adequate premises, equipment, and staff with sufficient knowledge and
experience, to carry out satisfactorily the work placed with him. In order to do this,

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the Contract Giver should audit the Contractor Acceptor's premises, equipment
and systems both before the contract is given and at regular intervals thereafter.
Audit reports should be issued and kept on record. A Contract Giver may only
use the contract manufacturer or packer as approved in the registration dossier.

5.2.4.9 Applicants are advised to discuss the latest MCC inspection report of the proposed
contract acceptor with the contract acceptor prior to entering into an agreement
with the contract acceptor.

5.2.4.10 In the case of contract packaging by a third party, the relevant c GMP requirements
should be adhered to.

5.2.5 CHANGE OF NAME OF APPLICANT ONLY

5.2.5.1 In this case application to change the name of the applicant may be
submitted for a whole range of products. Old medicines and registered
products must be dealt with under separate cover.

5.2.5.2 The application for change of name of applicant must be submitted on an official
letter head under cover of MRF 3A.O

5.2.5.3 The updated AMF, updated organogram of the proposed applicant, copies of the
registration certificates (IPCSA and Registrar of Companies) as well as copies of
the old and new company letterheads have to be submitted.

5.2.5.4 In alpha-numerical order according to application number of the product:

The registration certificate of each product (for registered products)
Updated front page
Updated front page to reflect the name change only of the FPRR, if the
applicant is also the FPRR.

5.2.5.5 Amendment fee

5.2.6 CHANGE OF ADDRESS OF APPLICANT

5.2.6.1 In the case of a change in address of an applicant, the AMF has to be updated.

5.2.6.2 The front page of the Registration dossier for each product must be updated
during the first subsequent update of the dossier.

5.2.6.3 A separate letter addressed to DATA CONTROL section must be submitted
reflecting details of the change of applicants address to ensure the updating of all
lists.

5.2.6.4 However, if the applicant is also the FPRR, the requirement for change of applicant
(5.2.3) will apply as this will result in a changed Registration certificate.

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5.2.7 CHANGE OF ADDRESS OF APPLICANT / MANUFACTURER / PACKER /
LABORATORY

5.2.7.1 In the case of any of the above, the following has to be provided:

Updated SMF
Organogram of the proposed applicant (including the names of key personnel
with specific reference to production and quality assurance departments)
The relevant amendment fee
The original registration certificate
An updated front page reflecting the name and address of manufacturer(s),
packer(s), FPRC and FPRR
Updated Parts/Annexures, as relevant, in the prescribed format (see 5.4.1.1)

128

APPENDIX A1

1.1 PRODUCT TO WHICH THIS APPLICATION REFERS

Proprietary name of product Registration/
Reference No.
Registered
medicine (R)
Old Medicine
(OM)

1.2 DETAILS

Information Current Proposed
Proprietary name
Applicant
Name:
Address:
MCC Licence No:
SMF Reference No:
Contact person:
Name:
Designation:
Telephone No:
Manufacturer:
Name:
Address:
MCC Licence No:
SMF Reference No:
Packer:
Name:
Address:
MCC Licence No:
SMF Reference No:
FPRC:
Name:
Address:
MCC Licence No:
SMF Reference No:
FPRR:
Name:
Address:
MCC Licence No:
SMF Reference No:

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APPENDIX A2

STATEMENT BY THE APPLICANT (On official letterhead)
(In the case of change of applicant, this must be done by the proposed applicant)

I, (insert full name and surname) Managing Director / responsible pharmacist of (insert
Company name) confirm that:

a) I am in possession of the master documentation pertaining to the above mentioned
medicine,
b) this master documentation is the same as that which was in existence when the
medicine was initially registered or which has been updated in accordance with
amendments of the Registration dossier form in accordance with the provisions of the
regulations under the Medicines and Related Substances Control Act, 1965 (Act 101 of
1965).
c) the master documentation conforms with the Registration dossier;
d) the master documentation is properly authorised i.e. signed and dated by at least the
managing director/responsible pharmacist, and the quality assurance or production
manager;
e) The master documentation has been supplied to the new manufacturer / packer or
laboratory (state company and role) and that applicable control records have been
compiled. I confirm further that I have signed these to indicate my approval that they
contain all the requirements listed in the relevant master documents.

- formula and method of manufacture and packaging
- in process control procedures
- specifications for raw materials
- specifications for the final product
- specifications for the packaging material
- specifications for the label
- specifications for the package insert
- testing procedures for the raw materials
- testing procedures for the final product
- testing procedures for the packaging materials

f) I confirm that a technical agreement and signed contract(s) exist(s) with all third party
manufacturer(s) / packer(s) / laboratory(ies) involved in manufacturing of this product

g) For an alternative/additional manufacturer:

I confirm that the manufacturing procedure (including equipment) is identical to the
manufacturing procedure currently used

or

I confirm that the manufacturing procedure (including equipment) differs, but falls within the
permitted amendments

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or

I confirm that the manufacturing procedure (or equipment) is different from the
manufacturing procedure (or equipment) currently on file outside of the permitted
amendments and that comparative data (efficacy) stability data and a validation protocol for
the first three production batches are submitted.

h) I confirm that the package insert will be updated to reflect the new applicant details and will
submit the amended package insert with the first update of the dossier after authorisation of
this amendment. (For applicant change only).

i) I confirm that the Registration dossier will be fully updated to the current statutory format
and current scientific standards within 12 months of transfer of applicancy/approval of
additional/change of manufacturer. (Not applicable for major changes)
or

I confirm that the Registration dossier will be fully updated to the current statutory format
and current scientific standards by (stipulate date) in accordance with the programme as
approved by the Inspectorate. (Not applicable for major changes)

_______________________
Signature, date

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5.3 APPLICATION FOR THE AMENDMENT TO A PACKAGE INSERT

All amendments to the package insert should be submitted to
MCC for approval before they may be implemented.
Applications to amend a package insert should be submitted
under cover form 3.C.0 and in the following manner:

1. A covering letter reflecting ALL the proposed changes and a motivation / explanation for
these changes. A copy of the covering letter should be bound into each set of the
supporting data.
2. Three typed copies of the current approved package insert
3. Three typed copies of the proposed package insert. Each page of amended
package insert should be dated and the reference or registration number should be
reflected on the first page of the package insert.
4. Two copies of clearly indexed supporting data.
5. Complete safety updates should be directed to the National Centre of Adverse Drug
Reactions Monitoring in Cape Town.

Note: Binding is left to the discretion of the applicant however the use of leverarch files is not
accepted.

Amendments should be highlighted as follows:
Underlining added text
Strikethrough deleted text
Shaded text rephrasing text
Italics text moved text

5.4 GUIDELINES FOR AMENDMENT OF REGISTRATION DOSSIER ALREADY LODGED
WITH THE MEDICINES CONTROL COUNCIL, PERTAINING TO SECTION 2A, 2B,
2C, 2D, 2E, 2F, 2G AND 2H OF THE APPLICATION REGISTRATION DOSSIER

(The active ingredient, formulation, active and inactive raw material,
specifications and procedures; manufacturing and packaging procedures;
in-process and final product specifications and control procedures;
container specifications and control methods; stability and shelf-life of the
product;

5.4.1 GENERAL.

i) Applications pertaining to the above amendments must be submitted under cover
of the Medicines Registration form.

ii) General information under 5.1 applies to these applications.

iii) All submissions with regard to amendments to existing MBR1 as well as reply to
Council Resolutions must be accompanied by a covering letter in the format
indicated in 5.4.1.1.

- All differences between the current and the amended SECTIONS/
Annexure(s) must be reflected in detail in the covering letter. The reasons

132
for the changes must be clearly and succinctly stated. Vague statements
like "General Update" and "M.C.C. Policy" are meaningless. The changes
requested must be pinpointed.

iv) When answering a letter from the Registrar of Medicines, a copy of the relevant
letter must be included in the response and the reply cross-referenced to the
actual questions raised.

v) In case of a general change in the manufacturer of an active raw material, or in
raw material specification, where more than one product (same dosage form) is
affected, the updated PARTS/Annexures of the products involved can be
submitted only upon approval of the general changes.

Example: For an additional supplier of active raw material, the additional supplier
should be first approved for one product and then all the relevant SECTION 2As
/Annexure 3's of the various products involved updated. A copy of the letter of
approval of the first product must be included in the subsequent updates.

vi) Where extension of the shelf-life of a product is requested, SUPPORTING
STABILITY DATA MUST BE SUBMITTED. Refer to Addendum A (Stability
Guidelines).

(a) An indication of the requested shelf-life must be included.

(b) Stability data sheets must state the specification limits of parameters as
reflected in PART 2F/ Annexure 7A.

(c) Stability data should ideally be submitted in tabulated format according to
the specifications in PART 2 F/ Annexure 7 (same sequence).

5.4.1.1 FORMAT OF SUBMISSION OF AMENDMENTS
PARTS 2 A-H or MBR1: ANNEXURES 2 TO 11, 13 AND 16

(Suitably amended documents to be appended to this form).

NOTE
Only relevant data in support of the proposed changes/amendments should be
submitted together with the reasons for submitting such data.

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1. Name and Address of applicant (i.e. the relevant letter-head): Date of Letter.

2. Proprietary name of product: Application No:
Registration Status:

3. I declare that no other amendments other than those stated in 6 have been made
and that the compilation of this submission has been checked.

SIGNATURE;

4. Previous update history if applicable (Particulars of at least last 3 amendments to
PARTS 2 A - H & PART 3 or Annexures 2-11, 13 & 16

DATE PARTS OR ANNEXURE/S
AMENDED
DATE APPROVED

5. This amendment involves: (Specify amendment e.g. formulation change, extension
of shelf-life, revised raw material specification etc.)

134

6. List of all* the changes/amendments in consecutive order for each PART/ Annexure, with the reasons/s** for the amendment
and the effect of the amendment.

ACTUAL DIFFERENCES
PART/S

ANNEXURE/S

CURRENT /
OLD
ANNEXURE /
SECTION

AMENDED/NEW
ANNEXURE /
SECTION

REASON FOR
AMENDMENT

EFFECT OF
AMENDMENT
(FORMULATION
CHANGES
ONLY)

COMMENT OF
REVIEWER
(OFFICE USE
ONLY)

*Each change to the MCC1 SECTION or MBR1 Annexure must be listed with the relevant page numbers.

** Meaningful and scientific reason for the changes must be provided.

(Suitably amended documents to be appended to this form).

NOTE

Only relevant data in support of the proposed changes/amendments must be submitted together with the reasons for submitting such data.

135
5.4.2 PERMITTED AMENDMENTS PERTAINING TO PART 2A, 2B, 2C, 2D, 2E, 2F, 2G
AND 2H OF THE APPLICATION REGISTRATION DOSSIER

i) The purpose of these guidelines is to expedite the evaluation and approval
process relating to pharmaceutical and chemical amendments to the medicine
registration dossier. Hence, certain amendments will be permitted and it will not
be required of applicants to first obtain written permission from the Medicines
Control Council before the changes may be instituted, subject to the following
conditions:

ii) This office shall be informed in writing by the applicant when a "permitted"
amendment is made to the Registration dossier. The letter shall be
accompanied by the relevant updated Sections of the Registration dossier. The
notification shall include the proposed date of implementation and shall be sent to
the Medicines Control Council prior to the commencement of said change. One
set only of amendments relating to a change shall be made in this manner:
thereafter prior written authorization of the Registration dossier amendments will
be required until the applicant is notified otherwise;

iii) It is the responsibility of the applicant to ensure that any permitted amendments
being made do not in any way negatively affect the quality, safety and efficacy of
the medicine. Should doubt exist, prior written authorization of the amendment(s)
must be obtained from the Medicines Control Council;

iv) The Medicines Control Council retains the right to withdraw this permission at any
stage from any applicant whose manufacturing facility does not have an
acceptable inspectorate rating;

v) Suitably authorised amended master documents shall be prepared wherein the
"amended" information appears prior to the manufacture of such medicines after
compliance with the instruction above;

vi) In the event of a "once off" minor formula change to a specific batch of medicine
being made within the guidelines of this document, the applicant shall inform the
Medicines Control Council in writing immediately thereof and the applicant shall
permit final release of the said batch only after 14 days of submission of such
notification. Information of this "once off" amendment must also be clearly
reflected on the batch manufacturing or packaging records;

vii) Where amendments are made to the Registration dossier (current regulated
format) Part 1A (COMPOSITION, IDENTIFICATION, PRESENTATION AND
STORAGE CONDITIONS) AND Parts 2A - 2H of this document must be fully
updated and shall be submitted to the Medicines Control Council within a period
to be determined. Where Registration dossiers are not yet in the regulated
format, updated documents in this format must be submitted together with the
notification. A copy of each letter referred to above shall be appended to the
Registration dossier;

viii) The applicant undertakes to ensure that the stability of the affected medicines is
established and that the necessary validation and qualification procedures are
instituted on at least the first three production batches to ensure that the quality,
safety and efficacy remains the same as that of the medicine previously

136
registered or lodged with the Medicines Control Council in the case of an old
product;

ix) The applicant ensures that in the case of solid dosage forms, the dissolution
pattern of the modified formula corresponds with that of the original medicine.
Such dissolution testing shall be done in accordance with the quality aspects of a
product and no change to formula or manufacturing process shall be made
without acceptable dissolution data; and

x) The Amendment Application Form is completed in full and the relevant
supporting documentation submitted.

5.4.2.1 THE PERMITTED AMENDMENTS ARE:

a) Tablets and capsules:

i) Analytical methodology (changed but VALIDATED assay methodology).

ii) Additional raw material or final product specifications.

iii) Alteration of process timings (validated by compliance to final product
specifications and content uniformity).

iv) Alteration of process temperatures (validated by compliance to final
product specifications).

v) Alteration of process machinery EXCEPT where fundamental processing
principles are not identical e.g. low energy / high energy wet massing
equipment.

vi) Any alteration of inert excipient levels deviating by less than 5 % of the
stated level.

vii) New supplier of active substance without raw material specification
changes, provided that the method of synthesis is identical, and that
physical parameters with regard to particle size, presence of polymorphic
forms, appearance and solubility remain unchanged.

viii) Changes to flavour, fragrance or colourant raw materials
(replacement/addition) must be substantiated with stability data derived
from one batch of the product stored at elevated conditions (refer to
Addendum A regarding stability data) for at least 3 months (except capsule
shell colourant changes). The above mentioned data must be submitted.

ix) Removal of flavour, fragrance or colourant raw materials without
replacement provided that this removal does not affect final product
specifications, excluding taste, odour and colour.

x) Changes to existing lubricant level up to up to 25 % of originally stated
level, provided that the final product specifications remain unchanged.

xi) Alteration to sugar/film coating section of the formulation (diluent, colour,
etc) excluding sealant, except where the active substance is incorporated

137
into the dosage form at the coating stage. Any change must be within the
existing final product specification.

xii) Changes in batch size (validated by compliance to final product
specification).

xiii) Changes to granulation solvent levels up to 15 % of originally stated level.

xiv) Any alteration of active substance levels up to a maximum of 1 % of the
stated level.

xv) Changes to container and/or immediate contact closure system provided it
can be demonstrated that the new container system:

a) Complies with or offers superior protection to the original system in
respect of the moisture permeability classification as defined in the
USP under "containers - permeation."

b) Offers equal or superior protection to the original system as tested
according to the USP method provided that adequate follow-up
stability data to determine dosage/container interaction be performed
and submitted within at least 12 months

(xvi) Changes to the colour of containers, with the proviso that the applicant will
take light sensitivity and any other relevant aspects of the active ingredient
into consideration.

b) Other dosage forms:

Any change in formulation and documentation with regard to dosage forms
other than tablets and capsules which is implemented without obtaining
permission from the Medicines Control Council is valid if the following criteria
are met:

- Quality, safety and efficacy of the product remain the same.

- The dissolution pattern of the new formulation, where applicable, remains
unchanged (no dissolution, no change).

- Permission limited to:

(i) Analytical methodology (changed but VALIDATED assay methodology).

(ii) Additional raw materials and final product specifications.

(iii) Alteration of process timings (validated by compliance to final product
specifications and content uniformity).

(iv) Alteration of process temperatures (validated by compliance to final
product specifications).

138
(v) Alteration of process machinery EXCEPT where fundamental
processing principles are not identical e.g. low energy / high energy
equipment.

(vi) Changes to flavour, fragrance or colourant raw materials
(replacement/addition) must be substantiated with stability data derived
from one batch of the product stored at elevated conditions (refer to
Addendum A regarding stability data) for at least 3 months. The above
mentioned data must be submitted.

(vii) Removal of flavour, fragrance or colourant raw materials without
replacement provided that this removal does not affect final product
specifications, excluding taste, odour and colour.

(viii) Changes in batch size (validated by compliance to final product
specifications).

(ix) Any alteration of inert excipient level up to a maximum of 5 % of the
stated level.

(x) Any alteration of active substance levels up to a maximum of 1 % of the
stated level.

(xi) New supplier of active substance without raw material specification
changes, provided that the method of synthesis is identical, and that
physical parameters with regard to particle size, presence of
polymorphic forms, appearance and solubility remain unchanged.

(xii) Changes to inert viscosity builder levels up to 15 % of originally stated
level, provided that the final product specifications remain unchanged.

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MRF 1.O
APPLICATION FOR REGISTRATION
OF A MEDICINE

ADMINISTRATIVE DATA
APPLICATION NUMBER

A. PARTICULARS OF APPLICANT
Name:--------------------------------------------------------------------------------------------------------------------------
Business address: ----------------------------------------------------------------------------------------------------------
Postal address: --------------------------------------------------------------------------------------------------------------
Telephone No: ---------------------------------------------------------------------------------------------------------------
Fax No: ------------------------------------------------------------------------------------------------------------------------
E-Mail address: --------------------------------------------------------------------------------------------------------------
Applicant master file Number:--------------------------------------------------------------------------------------------

B. PARTCULARS OF MEDICINE

Proprietary name: -----------------------------------------------------------------------------------------------------------
Dosage form:-----------------------------------------------------------------------------------------------------------------
Dosage unit: ------------------------------------------------------------------------------------------------------------------
Active ingredients and strength per dosage unit:
-----------------------------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------------------------
Descriptive name of Biological medicine: -----------------------------------------------------------------------------
Route of administration: ---------------------------------------------------------------------------------------------------
Pharmacological classification: ------------------------------------------------------------------------------------------
Manufacturer: ----------------------------------------------------------------------------------------------------------------
Address: ------------------------------------------------------------------------------------------------------------
Site master file reference number: ---------------------------------------------------------------------------
Packer:------------------------------------------------------------------------------------------------------------------------
Address: ------------------------------------------------------------------------------------------------------------
Site master file reference number : --------------------------------------------------------------------------
Final product release control (FPRC): ---------------------------------------------------------------------------------
Final product release responsibility (FPRR): -------------------------------------------------------------------------
The undersigned hereby declares that all the information herein and in the PART'S hereto
are correct and true and are relevant to this particular formulation.

..................................................................
Signature of applicant

................................................................... .......................................................................
Name in block letters Date of application

................................................................... .......................................................................
Designation Date of amendment of application

140

C. UPDATE HISTORY

DATE OF APPLICATION FOR
AMENDMENT

SUMMARISED DETAILS OF
AMENDMENT

DATE OF APPROVAL BY
COUNCIL

141

PART 1 A SCIENTIFIC PACKAGE INSERT

The under-mentioned information with regard to this medicine shall appear on the scientific
package insert. The information shall be presented in the format stipulated: Provided that the
Council may authorise any deviation from such information or such format.

1. Scheduling status.

2. Proprietary name

3. Dosage form

4. Composition.

5. Pharmacological classification.

6. Pharmacological action.
Pharmacokinetics

7. Indications.

8. Contra-indications.

9. Warnings.

10 Pregnancy and lactation

11. Dosage and directions for use.

12. Side-effects and special precautions
Interactions

13. Known symptoms of overdosage and particulars of its treatment.

14. Identification.

15. Presentation.

16. Storage instructions.

17. Registration number (or reference number).

18. Name and Business Address of the Applicant.

19. Date of notification of approval of the scientific package insert.

142
PART 1 B PATIENT INFORMATION LEAFLET

The under-mentioned information with regard to this medicine shall appear on the patient
information leaflet. The information shall be presented in the format stipulated, provided that
the Council may authorise any deviation from such information or such format.

1. Scheduling Status

2. Proprietary Name and Dosage Form of the Medicine

3. What this medicine contains

4. What this medicine is used for

5. Before taking this medicine

6. How to take this medicine

7. Side-effects

8. Storage and Disposal Information

9. Presentation

10. Identification

11. Registration number

12. Name and Business Address of the Applicant

13. Date of Publishing the Patient Information Leaflet

143

PART 1 C FACSIMILE OR SPECIMEN OF THE LABEL

A facsimile or specimen of the label shall be included here and this shall include a copy or
facsimile of the information on the blister strip. This shall conform to regulation..

144
PART 1 D FOREIGN REGISTRATION

a) A list of countries in which an application has been lodged and the status of these
applications shall be furnished, detailing approvals (with indications), deferrals,
withdrawals and rejections.

b) If the medicine has been registered in another country, the conditions of registration
and proof therof shall be furnished. If registered in the EU commission, Australia, UK,
USA, Canada, The Netherlands and Sweden the approved package insert (data sheet)
shall be provided.

c) Details of any negative decision by any recognised Regulatory Council shall be
provided

145
PART 1 E PRE-CLINICAL STUDIES

A) Expert Report

b) The following are Parts obtained and conclusions drawn from tests performed pre-
clinically to demonstrate all aspects of the toxicity of the medicine, and to prove the
safety of its use, with special reference to -

(i) acute toxicity,
(ii) subacute toxicity studies;
(iii) chronic toxicity studies;
(iv) reproduction toxicity and teratogenicity studies;
(v) carcinogenicity studies;
(vi) mutagenicity studies; or
(vii) other tests to substantiate the safety of the medicine;
(viii) pharmacokinetics studies:

c) The methods and experimental results of and the conclusions drawn from tests
performed pre-clinically with reference to the efficacy of the medicine, with special
emphasis on the relationship between the tests performed and the purpose for which
the medicine is or will be used, or for which it will be propagated, and further with
regard to the dosage and method of administration of the medicine, are as follows:

In cases where well-known active constituents are concerned, the Council may grant
exemption from the submission of some or all of the above information.

146
PART 1 F CLINICAL STUDIES

a) Expert Report

b) The clinical trials performed on human volunteers and patients with regard to the
safety of the use of the medicine, with special reference to the particular dosage,
routes of administration used and the side-effects observed, are as follows:

c) Particulars of clinical trials conducted to establish the efficacy of the use of the
medicine are as follows:

d) Experimental details and results of the studies performed to establish the correlation
between the applicable blood and other suitable physiological levels and the
pharmacological action claimed for the medicine are as follows:

e) Periodic Safety Update Report

In cases where well-known active constituents are concerned, the Council may grant exemption from the
submission of some or all of the above information.

147
Part 2 A (i) MEDICINES OTHER THAN BIOLOGICALS
ACTIVE RAW MATERIAL (DEVELOPMENT
CHEMISTRY AND CHARACTERISATION)

a) The name(s), structural formulae, empirical formulae, molecular mass, solubility and
storage requirements are as follows:

Approved name
(INN)

Structural
formula,
empirical
formula,
molecular mass

Solubility

Storage
requirements

Shelf-life

b) The active ingredients are obtained from the following sources:
(i) name and address of the manufacturer(s)
(ii) name and address of the broker(s)

c) Active Ingredient. File

d) Certificate of analysis

(e) Proof of physical and chemical equivalence (where more than one manufacturer is used)

148
Part 2 A (ii) PRIMARY PRODUCTION LOT (BIOLOGICAL
MEDICINES)

1. DESCRIPTION OF THE PREPARATION AND PRODUCTION OF THE PRIMARY
PRODUCTION LOT.

a) Name and address of the manufacturing facility in which production of the primary
production lot takes place:

b) The complete description of the preparation and manufacturing process of the primary
production or bulk lot, the tests carried out on the product and the stages at which such
tests are carried out to confirm the integrity of the product are:

2. SPECIFICATIONS OF RAW MATERIALS USED IN THE PRIMARY PRODUCTION
LOT.

a) The following are the specifications that apply to the raw materials used in the primary
production or bulk lot of a biological medicine, including the titles of the tests and the
limits and criteria of acceptance of each parameter contained in the specification.
(Where the test mentioned correspond to a recognised pharmacopoeia, the source shall
be mentioned)

3. TESTS CARRIED OUT ON RAW MATERIALS USED IN THE PRIMARY
PRODUCTION LOT

a) The following is a complete description of the tests carried out on all the raw materials
used in the primary production or bulk lot, specifying the name and address of the
laboratory(ies) in which such tests are carried out.

149
PART 2 B FORMULATION

SECTION 2 B (i)

FORMULATION OF THE FINAL DOSAGE FORM
FORMULATION OF THE FINAL FILLING LOT FOR BIOLOGICAL
MEDICINES

(a) Below is a schedule of the names and quantities of each active and inactive ingredient
contained in a dosage unit or, where no dosage unit exists, other suitable unit of mass
or volume of the medicine, and it shall conform to the relevant particulars in the
package insert and on the label with regard to the active ingredients.

(b) The purpose of each inactive ingredient in the formulation shall be specified, and raw
materials used, even if not present in the final dosage form but used during
manufacture, shall be mentioned.

Approved name or
chemical name of
constituent

Quantity per
dosage unit*

Active or inactive

Purpose of
inactive

*mg per tab/cap/loz/supp or mg or ml per specified volume or mass of product

(c) If potency calculations are be made, a statement to the effect that the actual quantity of
the active ingredient will depend on the potency shall be included.

(d) Composition of inactive ingredients in combination, mixtures, etc.

(e) Overages and reasons for their inclusion.

(f) Toxicity level per dosage unit must be indicated for all solvents and when required by
Council. Levels as per USP DI or Martindale The complete drug referece etc

150
PART 2 B (ii)

FORMULATION OF THE RECONSTITUTING LIQUID FOR A THE
FINAL FILLING LOT FOR BIOLOGICAL MEDICINES

(a) Below is a schedule of the names and quantities of each ingredient contained in the
diluent.

(b) The purpose of each ingredient in the formulation shall be specified, and raw materials
used, even if not present in the final diluent shall also be given.

Approved name or chemical
name of constituent

Quantity

Purpose

151
PART 2 C

SPECIFICATIONS AND CONTROL PROCEDURES FOR RAW MATERIALS
USED IN THE MANUFACTURE OF THE FINAL PRODUCT (MEDICINES)
OR FINAL FILLING LOT AND DILUENT (BIOLOGICALS)

(a) Pharmacopoeial ingredients (the latest edition of the pharmacopoeia is implied, unless
otherwise specified by the appilcant.)

Raw Material

Pharmacopoeia

Additional Requirements (e.g.
particle size)

b) Non- pharmacopoeial ingredients. In- house specifications and control procedures for
these ingredients should be included.

(c) The following minimum requirements must be complied with:

(i) Identification and assay of the active raw material will be performed
irrespective of the possession of a certificate of analysis from the supplier;
(ii) Identification of the inactive raw material will be performed irrespective of the
possession of a certificate of analysis from the supplier; and that
(iii) Any tests not included in a valid certificate of analysis will be performed.

(d) Frequency of testing of water must be included

152
PART 2 D CONTAINER AND PACKAGING MATERIAL

(a) DESCRIPTION OF CONTAINERS

(i) Bulk products (Type of material of container)
(ii) Immediate container, closure, wadding, desiccant (Type of material and
dimensions including sketches)
(iii) Outer container (Type of material of container)
(iv) Application and administrative sets (Type of material and dimensions including
sketches)

(b) PROCEDURES PERFORMED BY SUPPLIER

The following must be completed:

Specification

Limit

Reference to pharmacopoeia if
relevant

(c) PROCEDURES PERFORMED BY MANUFACTURER/PACKER OF FINAL
PRODUCT

(i) The following must be completed:

Specification

Limit

(ii) Description of the control procedures

153
PART 2 E MANUFACTURING PROCEDURES

MANUFACTURING PROCEDURES OF FINAL PRODUCT (MEDICINES)
OR FINAL FILLING LOT AND DILUENT (BIOLOGICAL MEDICINES)

a) INSPECTION FLOW DIAGRAM:

b) MANUFACTURING PROCEDURES:

(i) Batch Manufacturing Formula and Batch Size(s)

(ii) Master Manufacturing document or a comprehensive flow diagram, or a
detailed description of the manufacturing procedures detailing the various
stages of manufacturing, including the type of equipment (including sieve sizes
in m), duration of treatment, temperature, light and humidity conditions, as
well as machine settings (e.g. rotation speed or rpm), must be submitted. All in-
process controls (analytical, microbiological, and physical) must also be
shown in the flow diagram:

c) PACKAGING PROCEDURES:

Comprehensive procedures of manufacture, detailing the various stages packaging
and labelling and titles of the in-process control procedures carried out during the
packaging process, are as follows:

d) PROCESS VALIDATION PROTOCOL:

The process validation protocol is as follows:

154
PART 2 F FINISHED PRODUCT
FINAL FILLING LOT & DILUENT (BIOLOGICALS)

(a) SPECIFICATIONS and LIMITS
The following tables include the specifications, limits and the responsible laboratories
for:
(i) In-process control
(ii) Final product control
(iii) Stability studies
(iv) Manipulated final product

Specification

Limits

See the stability guideline for specifications to be considered for each dosage form.

(b) Indicate the following tests to be performed:

Title of specification

FPRC

Tests after importation

FPRR

Appearance of dosage form
Container
Package insert
Label
Batch No.
Expiry date.
Certificate of Analysis

(c) CONTROL PROCEDURES
Control procedures for all the specifications included in section A must be included

(d) CERTIFICATE OF ANALYSIS OF THE FINAL PRODUCT

(e) VALIDATION
-Validation data for all quantitative methods must be submitted.
It must be demonstrated that the assay method is stability indicating, i.e. will
distinguish between the active ingredient and the degradation product(s). If the assay
method is not stability indicating the validation data of the procedures used to
determine the assay and that used to determine the degradation product must be
submitted separately.

155
PART 2 G STABILITY DATA - THE FINISHED PRODUCT

(a) STABILITY PROGRAM
Indicate the stability programme to be followed, including the following:

(i) Conditions (temperature, humidity)
(ii) Time points of determination, e.g. months, 6 months etc
(iii) Specifications to be determined
(iv) Frequency of stability testing on future batches (Refer to WHO and cGMP
stability testing guidelines.)

(b) STABILITY DATA (Refer to Point 2 Addendum A)

(c) DISCUSSION AND CONCLUSION OF SHELF-LIFE FOR EACH TYPE OF
CONTAINER

156
PART 2 H PHARMACEUTICAL DEVELOPMENT

a) Highlight and motivate any differences in formulation and/or method of manufacturing
of the different batches used in stability or efficacy.

b) Pharmaceutical Expert Report

i) Active Ingredient(s):
ii) Formulation:
iii) Production/Manufacture:
iv) Stability:
v) Conclusion of Expert Report:
vi) Name, Signature and date of the responsible person:
vii) Reference list used in the compilation of the report:

157
PART 2 I EXPERTISE AND PREMISES USED FOR
MANUFACTURING OF BIOLOGICAL MEDICINES

i) DETAILS RELATING TO THE PREMISES WHERE PRIMARY
PRODUCTION IS UNDERTAKEN AND TO THE STAFF INVOLVED IN
PRODUCTION AND TESTING OF A BIOLOGICAL MEDICINE.

a) Description of the premises where all procedures involve in the preparation of the
primary production or bulk batch are carried out. ( A floor plan must be included) :

b) Details of other purposes for which the premises are used:

c) Names, qualifications and field and duration of experience of the persons responsible
for the manufacture, testing and release of the biological medicine, in the form of the
primary production or bulk lot and the final containers ready for sale:

ii) NAME AND ADDRESS OF FACILITY WHERE THE IMPORTED
FINAL FILLING LOT IS STORED

158
PART 3

IN VIVO AND/OR IN VITRO EQUIVALENCE STUDIES AS PROOF OF
EFFICACY

a) STATE THE PURPOSE OF THE STUDY

(i) As proof of formulation to be marketed versus formulation used in clinical trials
(ii) Proof of. efficacy for a generic application
(iii) Proof of efficacy of new formulation

(b) REFERENCE PRODUCT USED

(i) Clinical trial formulation
(ii) Innovator product
(iii) Current formulation (for change of formulation)

The following must be indicated:

Reference product

Formulation applied for

Name of product

Batch no

Applicant

Country were purchased

Assay results

Active source

(c) METHOD USED
Describe the method in full, e.g. bioavailability, dissolution etc

(d) DATA

(e) DISCUSSION AND CONCLUSION

159
MCC
SCREENING FORM FOR APPLICATIONS FOR REGISTRATION OF
MEDICINES

All shaded fields are for official use only

Where appropriate, abbreviations Y, N, N/A should be used in filling out this form. Comment section
may be used for additional information
MRF 2.O

Note: Applicants must ensure that the application is completed fully and accurately,
presented in the prescribed format and that all required documentation is included.

Name of Applicant:

Product Name:

Date of Submission:

ADMINISTRATIVE INFORMATION

Is each container in which the application for registration is
delivered clearly labelled, on the outside, to specify the
contents (files and or documents contained)?

Is the correct application fee included?

Is the non-refundable screening fee included?

APPLICANT INFORMATION:

Date of submission of Applicant Master File:

Applicant Master File Number

Provide number and date of Applicant licence

Is proof of registration of the responsible person as a
pharmacist included?

Are full particulars of the applicant included on the
application for registration front page?

Is the application signed by the Managing Director or
authorised designee?

PRODUCT INFORMATION/DOCUMENTATION

Please indicate type of application using a check mark
______ AMRP
______ New Chemical Entity
New Indication
_____ Biotechnological Medicine _____ New Dosage Form
_____ Biological Medicine _____ Generic Medicine
______ Fast Tracking

160

Is the correct number of copies of documents submitted?

If applying for Fast Tracking, is a motivation included?

Has the application been submitted in the format prescribed
by Regulation ... (PREVIOUSLY 15)?

Has the application been submitted in the European Union
(EU) format?

If yes, has a separate document referencing the MRF01
format to the European Union dossier been submitted?

Is the application for registration dossier properly bound?

Is each Part of the application for registration dossier
properly indicated by tabbing?

Is each Part of the application for registration dossier
properly indexed?

Is each page of the application for registration dossier
numbered?

New Chemical Entities, Indications, Dosage Forms:

Is product registered in other countries? If yes, is proof of
registration included?

Have pre-clinical data been submitted?

Have clinical data been submitted?

Has either a Clinical expert report or an SBRA been
submitted?

Generic Medicines:

Have Bioavailability data been submitted?

Have Dissolution data been submitted?

State other data submitted as proof of efficacy of the formulation:

Completeness /acceptability of dossier
Do the details of the manufacturer and packer as indicated
in PART 2 E concur with the details on the front page of the
application for registration e?

Do the details of the final product release control
laboratories (FPRC) and final product release responsibility
(FPRR) as indicated in PART 2 F concur with the details
provided on the front page of the application for
registration?

Is the proposed package insert included in PART 1 A?

Does the presentation and format of the package insert
comply with Regulation .....?

161

Is the package insert cross-referenced to PART 1 F?

Does PART 1 D list the registration status of the product in
other countries?

Are all ingredients (raw materials) in the product formulation
included in PART 2 B (also those not present in final
formulation)?

Are chemical details provided for the raw material included
in PART 2 A?

Is a Certificate of Analysis of the active ingredient/s
included in PART 2 A?

Is a summary of the specifications of all the raw material
(active and inactive) used in manufacturing the product
included in PART 2 C?

Is a list of raw material control procedures included in
PART 2 C?

Are raw material testing and control laboratories reflected in
PART 2 C?

Is documentation detailing testing of product (procedures,
specifications) included in PART 2 F?

Is assay method validation included in PART 2 F?

Are container specifications and control procedures
included in PART 2 D?

Are final product testing and control laboratories reflected in
PART 2 F?

Have stability data been submitted in PART 2 G?

Have stability data been derived with active ingredient
sourced from the supplier identified in PART 2 A

Have stability data been derived from the product packed in
packaging material detailed in PART 2 D

Have stability data been derived from a pilot or production
batch?

Is documentation detailing Manufacturing of product
(procedures, production stages, equipment) included in
PART 2 E?

Is documentation detailing Packaging procedures included
in PART 2 E?

Has a validation protocol been included in PART 2 E?

Have complete pharmaceutical development data been
submitted in PART 2 H?

Is a motivation for exemption included for PARTS not
addressed?

162

Other

Is a copy of the latest inspection report (not older than 2
years) from the Regulatory Council of country of origin
included for the manufacturer of imported products?

Has a properly labeled sample of product applied for been
submitted?

Is the batch manufacturing record of the sample included?

Is a permit to manufacture a Schedule 6 or 7 product
included?

Is Master documentation available?

MANUFACTURING, TESTING AND PACKAGING FACILITIES
Please provide details by completing the following :

Date of
submission of
SMF & number

Date of last
inspection /

MCC Licence no

GMP
Status

Is contract
with
applicant in
place?

Manufacturer
1
2.

Packer
1
2

Testing Laboratory
1
2

Comments:

Recommendation FILE NO:

Accept Reject Hold

Reasons for rejecting or holding an application
..................................................................................................................................................................
..................................................................................................................................................................
..................................................................................................................................................................
..................................................................................................................................................................
......................................................................

Screening performed by: Date:

163
MCC - AMENDMENT APPLICATION
MRF 3A.O
APPLICATION TO AMEND THE PARTICULARS REGARDING PROPRIETARY NAME,
APPLICANT, MANUFACTURER, PACKER, FPRC OR FPRR IN A REGISTRATION DOSSIER
ALREADY REGISTERED BY THE COUNCIL ( AND OLD MEDICINES)

DETAILS OF PRODUCT:
PROPRIETARY NAME: ........................................................................................
APPLICATION/REGISTRATION NUMBER:......................................................

Tick the appropriate box with to indicate all
issues relevant to this application. Section A
must be complete for all applications. Indicate all
amendments in Section B

Tick in each appropriate box to indicate the
documentation submitted to facilitate this
amendment.

SECTION A

- Registered product
-- Old medicine
* Changes not permitted to pending
applications.

- Original registration certificate
- Amendment fee
- Fee for amended certificate
already Submitted with Application
dated.Reference No..

SECTION B

- Proprietary name change

- Letter detailing request
- Amended front page to Registration
dossier
- Amended package insert
- PART 2 B / Annexure 2
Label
Patient Information Leaflet

- Transfer of applicancy

Application to change in accordance
with
format prescribed in guidelines

- Letter of cession & Letter of
acceptance.
- Master documentation details
dossier
- Amended PART 2 F /Annexure 9A

164

Tick the appropriate box with to indicate all
issues relevant to this application. Section A
must be complete for all applications. Indicate all
amendments in Section B

Tick in each appropriate box to indicate the
documentation submitted to facilitate this
amendment.
- Due date of update of dossier
stipulated
- New applicant information

- Change of manufacturer
- Change of packer
- Change of final product release
control (FPRC)
- Change of final product release
responsibility (FPRR)

- Application to change in accordance
with format prescribed in guidelines
- Amended front page to registration
dossier
- Statement on master documentation
- Due date of update of dossier
stipulated.

- No change of manufacturing
procedure/ equipment
- Minor change of manufacturing
- Major change of manufacturing

- Statement confirming
minor/major/no change
- Updated PARTS .................................
/Annexures...........................................
- Application for amendments relevant
to change in manufacturer detailing
changes.

- Change of name of applicant

dossier

- Change of name of manufacturer
- Change of name of packer
- Change of name of final product
release control (FPRC)
- Change of name of (FPRR)

- Amended front page to registration
dossier
- Updated PART 2F / Annexure 9A
- Updated PART 2 E /Annexure 11
- Updated PART 2 C /Annexure 6

165
1. DETAILS OF CHANGE:
PROPRIETARY NAME OF MEDICINE
Existing name: New name:

2. DETAILS OF APPLICANT
Current applicant:
Address:

New applicant:
Address:

3. DETAILS OF MANUFACTURER/PACKER/FPRC/FPRR
Current Manufacturer/s
Address:

*Proposed Manufacturer/s:
Address:

Current Packer/s:
Address:

*Proposed Packer/s:
Address

Current FPRC/s
Address

*Proposed FPRC/s
Address:

Current FPRR:
Address

*Proposed FPRR
Address:

* Details of all the facilities to be used must be stated, i.e.those that are already
approved as well as those for which an application is now submitted

________________________________________________________________________________
I declare that the application has been checked and that the information supplied herewith is
accurate. I further declare that the information on the updated front page concur with the
approved application for registration dossier and amendments detailed above, with regards to
all details specified.

The amendment fee is not included with this submission but is covered by cheque number
..................................... submitted under cover of my letter..............................,
dated ..........................Copies of this letter and cheque are attached.
I confirm that the package insert, label and patient information leaflet where applicable will be
appropriately updated to reflect the change in applicancy.

_________________________ ____________________________
NAME IN BLOCK LETTERS SIGNATURE

______________ ____________________________________
DESIGNATION DATE OF AMENDMENT APPLICATION

166
AMENDMENT APPLICATION FORM
MRF3B.O

Application to amend a registration dossier lodged with council regarding the:

(1) active ingredient;
(2) formulation;
(3) active and inactive raw material specifications and procedures;
(4) manufacturing and packaging procedures;
(5) in-process and final product specifications and control procedures;
(6) container specifications and control methods;
(7) stability and shelf-life of the product;

Applicant :
Business address :

Product proprietary name :
Product application number :
Registration status :

Incomplete applications for amendments and discrepancies with regard to details and
requirements will result in rejection of application for amendment. A further amendment
fee will be payable for a re-submission.

SECTION A All applications
GENERAL

Registered product
Reply to Committee Recommendation
1
st
2nd 3rd
Old Medicine

SECTION B Amendments and supporting documentation
ACTIVE INGREDIENT
Change of approved name
Change of method of synthesis
Change of source (manufacturer)
Active Ingredient File
Certificate of Analysis
Physical/ Chemical equivalence
FORMULATION
Minor change Major change
Change of quantity of active
Updated formula
Update of raw material

167
ingredient(s)
Change of quantity of inactive
ingredient(s)
Addition of inactive ingredient(s)
Deletion of inactive ingredient(s)
Substitution of inactive ingredient(s)
specifications and control methods
Stability data
Efficacy data (in vitro)
Efficacy data (in vivo)
RAW MATERIAL SPECIFICATIONS AND
CONTROL PROCEDURES
Change of raw material specifications
Change of raw material control
procedures
Update of specifications
Update of control procedures
CONTAINER SPECIFICATIONS AND
CONTROL PROCEDURES
Change of container material
Change of container specifications
Change of container control
procedures
Stability data
Updated specifications
Updated Control Procedures
Equivalency of containers
MANUFACTURING PROCEDURE
Change/addition of batch size
Change of equipment
Change of process
Change of process conditions
Change of in-process controls
Change of packaging process
Updated Manufacturing procedures
Update packaging procedures
Validation protocol
Stability data (Major change)
Efficacy data (Major change)

FINAL PRODUCT SPECIFICATIONS AND
CONTROL PROCEDURES
Change of product specifications
Change of control procedures
Change of Assay procedure
Other procedures
Updated specification
Updated control procedure
Validation data

168
SHELF-LIFE EXTENSION Stability data

DECLARATION
I declare that the application has been checked and that the information supplied herewith is
accurate.
I further declare that the information on the updated front page concurs with the approved
application for registration dossier and amendments detailed above, with regard to all
details.

_________________________ ________________________
NAME IN BLOCK LETTERS SIGNATURE

______________ ____________________________________
DESIGNATION DATE OF APPLICATION FOR AMENDMENT

169
MCC

APPLICATION FORM FOR THE AMENDMENT TO A PACKAGE INSERT
MRF 3C.O

DETAILS OF PRODUCT: -------------------------------------------------------------------------------------
PROPRIETARY NAME: -------------------------------------------------------------------------------------
APPLICATION NUMBER: -------------------------------------------------------------------------------------
REGISTRATION STATUS: -------------------------------------------------------------------------------------

INCOMPLETE APPLICATIONS AND APPLICATIONS WHICH DO NOT COMPLY TO THE
PRESCRIBED FORMAT WILL RESULT IN THE APPLICATION BEING RETURNED TO THE
APPLICANT FOR CORRECTION.

This application should consist of:

1. A covering letter reflecting ALL the proposed changes and a motivation for the changes.
2. Three typed copies of the currently approved package insert.
3. Three typed copies of the proposed package insert.
4. Two copies of data in support of the changes.
5. A copy of the covering letter bound into each set of the supporting data.

Note: The submission should be presented as follows:

1. The covering letter.
2. Three sets each of the current and proposed package insert, suitably bound.
3. Two sets of supporting data suitably bound. Bound copies should not be bigger than A4 size

Tick the appropriate box

Yes No

Are all amendments reflected in the
Covering letter?

Are all additions indicated by underlining with a
solid line?

Are all deletions indicated by bolded square
brackets?

170

Tick the appropriate box

Yes No

Is all rephrasing denoted by a broken line?

Is the package insert properly cross referenced
to the relevant substantiating data?

Is the correct number of copies of the current
approved package insert included?

Is the correct number of copies of the proposed
package insert included?

Is the correct number of supporting data
submitted?

Does this amendment include a new indication
or an amendment to a current indication?

Does this amendment include a new dosage
instruction or an amendment to a current
dosage instruction?

Does this submission relate only to minor
amendments to the package insert?

Does this submission contain a complete safety
update?

I declare that the application has been checked and that the information supplied herewith is complete
and complies to the prescribed requirements.

................................. .................................
Name in block letters Signature

................................. ......................
Designation Date

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