National Sanitary Surveillance Agency Ministry

of Health
www.anvisa.gov.br

Resolution - RDC No. 210, August 4, 2003

D.O.U. [Federal Gazette] from August 14, 2003

The Collegiate Directory of the National Sanitary Surveillance Agency, within its
attributions, granted to it by the art. 11, subparagraph IV, of the ANVISA Regulation, approved
by the Decree No. 3.029, from April 16, 1999, according to the art. 111, subparagraph I, item ‘b’,
paragraph 1 of the Internal Rule approved by the Guideline No. 593, from August 25, 2000,
republished on December 22, 2000, in a meeting called on July 30, 2003,

whereas Act No. 6.360, from September 23, 1976;

whereas Decree No. 79.094, from January 5, 1977;

whereas Act No. 9.782, from January 26, 1999;

whereas the need of updating the Good Manufacturing Practices of Drugs, with the
purpose of following the development of new technologies, in the last years, and the
significance of national and international documents on the issue;

whereas the World Health Organization (WHO) recommendations, on the Quality

Certification of Pharmaceuticals, international marketing object;

whereas the need to standardize the actions of Sanitary Surveillance;

adopts the following Collegiate Directory Resolution and I, CEO, determine its publication:

Art. 1 To determine to all manufacturing sites of drugs, the fulfillment of the guidelines
established in the Technical Regulation of Good Manufacturing Practice of Drugs, according to
Annex I of this Resolution.

Art. 2 To institute and approve the Classification and Evaluation Criteria of the items in
the Inspection Guide for Drug Manufacturing Companies, based on potential risk of quality and
safety, inner to the drug manufacturing processes, according to Annex II of this Resolution.

Art. 3 To institute as an inspection rule to the purpose of verifying the fulfillment of the
Good Manufacturing Practice of Drugs, to the sanitary surveillance authorities of the Single
Health System [Sistema Único de Saúde], the Inspection Guide for Drug Manufacturing
Companies, according to Annex III of this Resolution.

Art. 4 The drug manufacturing companies must perform self-inspections, according to the
Technical Regulation of the Good Manufacturing Practice of Drugs and the Inspection Guide in
Pharmaceutical Industry, foreseen in this Resolution, as part of the measures required to their
implementation.
 Single paragraph. The reports of self-inspection, related to this article, must be available,
to be handled and/or sent promptly to the fiscal authorities, whenever formally required by them.

Art. 5 The Resolution - RDC No. 134, from July 13, 2001, is revoked.

Art. 6 The Annexes A, B, I and L of Decree - No. 500, from October 9, 1997, are revoked.

Art. 7 The updates of this Resolution, viewing the follow-up of the development of new
technologies, in the pharmaceutical sector, must be approved by the Collegiate Directory of the
National Sanitary Surveillance Agency, and published in the Federal Gazette.

Art. 8 The non-conformity or disobedience to what is provided in this Resolution, figures a

sanitary misdemeanor, in the Act No. 6437, from August 20, 1977, subjecting the infractor to the
penalties foreseen in this legal diploma.

Art. 9 This Resolution is valid from the date of its publication.

CLÁUDIO MAIEROVITCH PESSANHA HENRIQUES

ANNEX I

TECHNICAL REGULATION OF GOOD MANUFACTURING PRACTICES TO THE

PRODUCTION OF DRUGS
Table of Contents

A. GENERAL CONSIDERATIONS

1. Glossary

B. FIRST PART: Quality Management on the Manufacturing of Drugs: philosophy and

fundamental elements.

1. Quality Assurance

2. Good Manufacturing Practices for Drugs (GMP)

3. Quality Control

4. Sanitization and Hygiene

5. Validation

6. Complaints

7. Products Withdrawal

8. Manufacturing and/or Analysis Agreement

9. Self-Inspection and Quality Audit

9.1 Self-inspection team

9.2 Frequency of the self-inspection

9.3 Report of self-inspection

9.4 Follow-up actions

9.5 Quality audit

9.6 Suppliers audit

10. Personnel

10.1 Generalities

10.2 Main Personnel

10.3 Training

10.4 Health, Hygiene, Garments and Conduct

11. Premises

11.1 Generalities

11.2 Auxiliary areas

11.3 Storage areas

11.4 Weighing area

11.5 Production area

11.6 Quality control area

12. Equipment

13. Materials

13.1 Generalities

13.2 Raw-material

13.3 Packaging material

13.4 Intermediary product and bulk products

13.5 Finished products

13.6 Reproved and returned materials and products

13.7 Withdrawn products

13.8 Returned products

13.9 Reagents and mean of culture

13.10 Reference standards

13.11 Waste materials

13.12 Diverse materials

14. Documentation

14.1 General aspects

14.2 Labels

14.3 Quality control essay specifications and procedures

14.4 Specifications to raw material and packaging material

14.5 Specifications to intermediary products and bulk products

14.6 Specifications to finished products

14.7 Master formula / Standard formula

14.8 Packaging instructions

14.9 Records of production batches

14.10 Packaging records of the batches

14.11 Standard Operation Procedures - SOPs and their records

B. SECOND PART: Good Manufacturing and Quality Control Practices

15. Good Manufacturing Practices

15.1 General aspects

15.2 Prevention of cross-contamination and bacterial contamination in the manufacturing

15.3 Production operations: intermediary and bulk products

15.4 Packaging operations

16. Good Quality Control Practices

16.1 Raw material, intermediary, bulk and finished products control

16.2 Required essays

16.3 In-process control

16.4 Finished products

16.5 Revision of the production records

16.6 Stability study

C. THIRD PART: Supplementary Guidelines

17. Sterile Products

17.1 General aspects

17.2 Sterile products manufacturing

17.3 Final sterilization products

17.4 Products sterilized by filtration

17.5 Sterile products prepared from sterile raw materials, in aseptic conditions

17.6 Personnel

17.7 Facilities

17.8 Equipment

17.9 Sanitization

17.10 Production

17.11 Sterilization

17.12 Sterilization by heat

17.13 Sterilization by humid heat

17.14 Sterilization by dry heat

17.15 Sterilization by radiation

17.16 Sterilization by ethylene oxide

17.17 Filtration of drugs which may not be sterilized in their final containers

17.18 Finalization of the manufacturing steps

17.19 Quality control

18. Biological Products

18.1 Reach

18.2 Glossary

18.3 General Considerations

18.4 Personnel

18.5 Premises and Equipment

18.6 Production

18.7 Labeling

18.8 Batch records

18.9 Quality Assurance

18.10 Quality Control

18.11 Premises to animals

19. Validation of the Manufacturing Processes

19.1 Reach

19.2 Glossary

19.3 General considerations

19.4 Types of process validation

19.5 Pre-requisites to the validation of a production process

19.6 Approaches

19.7 Organization

19.8 Scope of a process validation program

19.9 Master Validation Plan

A. GENERAL CONSIDERATIONS
Registered drugs must only be produced by licensed manufacturers, holding the Manufacturing
Authorization, with their activities regularly inspected by the National Sanitary Authorities in
charge. This Regulation of Good Manufacturing Practices (GMP), must be used as reference in
the inspection of the manufacturing site premises, the manufacturing and quality control
processes and as a training material of the drugs sector inspectors, as well as, in the training of
the professionals responsible for the production and Quality Control in industries.
GMP are applicable to all operations involved in the manufacturing of drugs, including those
drugs in development designed to clinical essays.
The Good Manufacturing Practices (GMP) described in this document are passive of continuous
updates, in order to follow the evolution of new technologies. Alternative actions may be
adapted in a way to meet specific needs of certain product, provided that they are validated to
ensure the product quality. GMPs do not cover aspects related to the safety of the personnel
involved in the manufacturing process; these aspects are regulated by a specific legislation.
However, the manufacturer must ensure the safety of its workers.
This document is divided within three parts:
B. First Part: “Quality Management on the Manufacturing of Drugs: philosophy and fundamental
elements” briefs the general concepts of Quality Assurance, as well as the main components
and subsystems of GMP, determines the responsibilities of the superior management team, of
the production management and of the Quality Control, including, but not restricted to, hygiene,
validation, personnel, premises, equipment, materials and documentation.
C. Second Part: “Good Manufacturing and Quality Control Processes”, which acts as a guide of
the actions to be taken separately by the people responsible for the production and the Quality
control in the implementation of the general principles of Quality Assurance.
D. Third Part: It contains the supplementary guidelines to the manufacturing of sterile drugs,
biological products and validation, but it is not a finished section, because it foresees the
inclusion of other matters, such as the ones related to phytotherapeuticals and pharmaceutical
active ingredients (PAIs).
1. Glossary
The definitions presented below apply to the terms used in this Regulation. They may have
different meanings in other contexts.
Adjustment
Operation designed to make a measuring instrument have a performance compatible to its use.
Area
Delimited physical space, where the operations are performed under specific environmental
conditions.
Clean area
Area with environmental control related to the contamination by viable and non-viable particles,
designed, constructed and used in a way to decrease the introduction, generation and detention
of contaminants in its inner part.
Antechamber
Closed space with two or more doors, placed between two or more areas of distinct cleanliness
classes, with the purpose of controlling the air flow between them, when they need to be
entered. The antechamber is designed in a way to be used by people or materials.
Reference sample
Raw materials and finished products samples kept by the manufacturer, duly identified, for a
determined period of time after the finished product expiration date. The amount of sample must
have, at least, the double of the units required to perform all the analyses foreseen in official
compendia.
Representative sample
Amount of sample statistically calculated, representing the sampled universe, taken for
purposes of the analysis to the batch release.
Certification
Verification, upon sanitary inspection, of the whole fulfillment of the Good Manufacturing
Practices in some working production lines, pharmaceutically.
Calibration
Set of operations establishing, under specific conditions, the relation among the values shown
by an instrument or measuring system or values represented by a materialized measure or a
reference material, and the correspondent values of the greatness established by patterns.
Certificate of product registration
Legal document issued by the Sanitary Authority in charge, where the qualitative and
quantitative formula of the product, including details on the package, label and expiration date,
are shown.
Certificate of Good Manufacturing Practices
Legal document issued by the Sanitary Authority in charge, certifying that a certain production
line of the company meets the requirements of the Good Manufacturing Practices.
Concentration
Quantity of active(s) or inactive(s) substance(s) in a determined mass or volume unit of the
product.
Cross-contamination
Contamination of certain raw material, intermediary product, bulk product or finished product by
another raw material, intermediary product, bulk product of finished product, during the
production process.
In-process control
Verifications performed during the production, in order to manage and, if necessary, to adjust
the process to ensure that the product is according to its specifications. The environmental or
equipment control may also be considered an integrating part of the process control.
Component
Any substance or material to be used in the manufacturing of a pharmaceutical product.
Quality deviation
Distancing of the established quality parameters for a product or process.
Edification
Set of architectural premises containing the areas, premises and auxiliary resources.
Packaging
All the operations, including filling and labeling, which the bulk product must go through in order
to become a finished product. Usually, the sterile filling is not considered as a part of the
packaging product, even though the bulk product is kept in the primary container.
Specification
Document describing, in details, the requisites that the products or material used or obtained
must meet during the manufacturing. The specifications act as the basis for the quality
evaluation.
Manufacturing
All the operations including the acquirement of materials, production, quality control, release,
storage, issuing of finished products and the related controls.
Manufacturer
Holder of the Authorization of Establishment to the manufacturing of drugs, issued by the
authority in charge of the Ministry of Health, according to the provided in the current sanitary
legislation.
Master formula/Standard formula
Document or set of documents specifying the raw materials and package materials with their
quantities, together with the description of the procedures and necessary precautions to the
production of a certain amount of finished product. Besides, it provides instructions on the
processing, including the in-process controls.
Installation
Delimited physical space containing machinery, apparatus, equipment and auxiliary systems
used to perform the processes.
Batch
Defined quantity of raw material, packaging material or finished product manufactured in only
one process or process series, which fundamental characteristic is the homogeneity and quality
within the specified limits. In the continuous manufacturing, the batch corresponds to a definite
fraction of the production. Sometimes it is necessary to divide the batch into sub-batches, which
will later be mixed in order to form a final homogeneous batch.
Raw material
Any active or inactive substance, with defined specification, used in the production of drugs.
Packaging material
Any material, used in the packaging process of a certain pharmaceutical product.
Drug
Pharmaceutical product, technically obtained or elaborated, with a prophylactic, healing,
palliative or diagnosis purposes
Batch number
Defined combination of numbers and/or letters identifying a certain batch.
Production order
Reference document to the production of a drug batch, comprehending the information of the
master formula/standard formula.
Authorized Person
Licensed professional in the area of drugs, indicated by the company, responsible for the
release of the batches of finished products to their distribution and selling.
Strength
Therapeutic activity of the pharmaceutical product according to the shown by lab essays, or by
clinical data properly developed and controlled.
Expiration Date
Limited date to the use of a pharmaceutical product defined by the manufacturer, based on its
respective tests of stability, the storage conditions kept and transportations established by it.
Standard Operation Procedure (SOP)
Written and authorized procedures providing detailed instructions to the performance of specific
operations in the manufacturing of a pharmaceutical product and other general nature activities.
Process
Set of procedures to the performance of a determined operation, following the techniques, rules,
and specifications.
Production
All the operations involved in the preparation of a determined pharmaceutical product, since
receiving the materials from the warehouse, passing by processing and packaging, until the
obtainment of the finished product.
Bulk product
Any product that went through all the production steps, not including the packaging process.
The injectables in their primary package are considered a bulk product.
Returned product
Finished product, marketed and issued, returned to the manufacturer.
Intermediary product
Product partially processed, which must go through the subsequent production steps.
Finished product
A product that went through all the production steps, including labeling and final packaging.
Medical Control Program of Occupational Health:
With the purpose of promoting and preserving the health of all the workers. It is an inner part of
the broader group of initiatives of the company in the workers health field. It shall consider the
incidental questions about the individual and the group of workers, giving place to the clinical-
epidemiological instrumental in the approach of the relation between your health and your work.
It shall have a prevention, tracking and early diagnosis character of the damages to health
related to work, including the ones of sub-clinical nature, besides of noticing the existence of
cases of professional disease or irreversible damages to the workers’ health.
Qualification
Operations documented according to a pre-determined tests plan and defined acceptance
criteria, ensuring that components, equipment and premises are appropriate to the intended
use.
Quarantine
Temporary detention of raw material, packaging material, intermediary products, bulk or finished
products, while awaiting the release decision, rejection or reprocessing.
Reanalysis
Analysis performed in a raw material, previously analyzed and approved, in order to confirm the
maintenance of the specifications established by the manufacturer, within its expiration date.
Reconciliation
Procedure with the purpose of comparing the actual production quantity and the established
theoretical quantity in the different production steps of a product batch.
Recovery
Total or partial incorporation of previous batches, of proven quality, to other batch, in a defined
production step.
Batch record
Set of documents related to the manufacturing of a determined batch of finished product. These
documents describe the production procedures and record all the operations related to the
batch quality.
Reprocessing
Rework of all or part of a batch of the product out of one or more established quality
parameters, from a defined production step, so its quality may become acceptable through one
or more additional operations. The reprocessing must be previously authorized and performed
according to approved procedures.
System
Regulated standard of activities and interactive techniques gathered to form an organized set.
Great Volume Parenteral Solutions (GVPS)
Aqueous, sterile, apyrogenic solutions, filled into a single container of 100 ml or more, with final
sterilization. In this definition are included the solutions to intravenous administration, solutions
for irrigation and solutions for peritoneal dialyses.
Active substance
Any substance presenting a pharmacological activity or other direct effect on the diagnosis,
healing, relieve, treatment or prevention of diseases, or which affects the human body
functioning.
Validation
Documented act attesting that any procedure, process, equipment, material, operation or
system really leads to the expected results.

B. FIRST PART: Quality Management on the Manufacturing of Drugs: philosophy and essential
elements.
The quality management is the aspect of the management function which determines and
implements the “Quality Policy”, i.e., the global intentions and directions related to quality,
formally expressed and authorized by the superior management team of the company.
The basic elements of the quality management are:
- appropriate infrastructure or “quality system”, comprehending organizational structure,
procedures, processes and resources;
- systematic and accurate actions in order to ensure that a certain product (or service) meets
the requirements as for its quality. The set of these actions is called “Quality Assurance”. Within
an organization, the Quality Assurance acts as a management tool. In situations provided in
agreements, the Quality Assurance acts, also, to provide truth in the supplier.
In the manufacturing and supply of drugs, the term “Quality Assurance” comprehends elements
such as the organization structure, processes and procedures. The concepts of Quality
Assurance, GMP and Quality Control are inter-related aspects of quality management. They are
written in this Regulation in order to emphasize their relations and essential significance to the
manufacturing of drugs.
1. Quality Assurance
1.1 “Quality Assurance” is the whole set of actions taken with the purpose of ensuring that the
drugs are within the quality standards requires, so they can be used for due purpose. Therefore,
Quality Assurance comprehends GMPs and other factors, including the design and
development of a product, which are not covered by the purposes of this Regulation.
1.2 An appropriate Quality Assurance system, applied to the manufacturing of drugs, must
ensure that:
(a) the drugs as designed and developed taking into consideration the need of fulfilling the GMP
and other requests such as Good Laboratory Practices (GLP) and Good Clinical Practices
(GCP);
(b) the operations of production and control are clearly specified, in written, and the GMP
requirements are met;
(c) the management responsibilities are clearly specified in the description of titles and
functions;
(d) actions are taken as for the manufacturing, supply and correct use of raw materials and
package materials;
(e) all the controls are performed in the raw materials, intermediary products, bulk products, as
well as other in-process controls, calibrations and validations;
(f) the finished product is correctly processed and checked, according to defined procedures;
(g) the drugs are not issued before authorized persons have certified that each production batch
was produced and controlled according to the requests of the record and other applicable
regulations related to the production, control and release of pharmaceutical products;
(h) instructions are provided and the necessary actions are taken in order to ensure that the
drugs are stored by the manufacturer, distributed, and subsequently, handled, so their quality is
maintained during all period before expiration date;
(i) there is a self-inspection and/or internal audit procedures of the quality, evaluating, regularly,
the effectiveness and the application of the Quality Assurance system.
1.3 The manufacturer is responsible for the quality of the drugs it manufactures, ensuring that
they are appropriate to the purpose they are intended for, meet the requirements established in
their records and do not place the patients’ at risk for presenting inappropriate safety, quality or
efficacy. Meeting this purpose is the responsibility of the superior management team of the
company and it required the participation and commitment of employees in the many
departments and in all organization, supplying companies and distributors levels. In order the
achieve the quality purpose trustfully, there must be a Quality Assurance system totally
structured and correctly implemented, incorporating the GMPs. This system must be totally
documented and must have its effectiveness monitored. All the parts of the Quality Assurance
system must be constituted by competent and licensed personnel, besides having enough and
appropriate space, equipment and premises.
2. Good Manufacturing Practices for Drugs (GMP)
2.1 Good Manufacturing Practice is the part of the Quality Assurance ensuring that the products
are consistently produced and controlled, with quality standards appropriate to the intended
use, requested by the registration. The fulfillment of GMP is firstly oriented to decrease the
inherent risks to any pharmaceutical production, which cannot be detected through essays in
the finished products. The risks are essentially constituted by: cross-contamination, particles
contamination and exchange or mixing of products.
2.2 The GMPs determine that:
(a) all the manufacturing processes must be clearly defined and systematically revised in
relation to the experience obtained. Besides, they must be able to manufacture drugs, within the
quality standards required, meeting the respective specifications;
(b) the critical steps of the manufacturing processes and any significant change must be
systematically validated;
(c) the production areas must be provided with all the infrastructure required, including:
qualified and duly trained personnel;
appropriate space and premises;
appropriate equipment and services;
appropriate materials, containers and labels;
approved procedures and instructions;
appropriate storage and transportation;
premises, equipment and qualified personnel, to the in-process control;
(d) the instructions and procedures must be written in a clearly, unambiguous language and
must be specifically applicable to the premises used;
(e) operators must be trained to perform the procedures correctly;
(f) records must be done (manually and/or through recording instruments) during the production,
in order to show that all the steps contained in the procedures and instructions were followed
and that the quantity and quality of the product obtained are according to the expected. Any
significant deviation must be recorded and investigated;
(g) the records related to the manufacturing and distribution, making the complete tracking of a
batch possible, must be kept organized and easy to access;
(h) the appropriate storage and distribution of products must minimize any risk to its quality;
(i) a system able to collect any batch, after its sale or supply, must be implemented;
(j) the complaints on marketed products must be examined, registered and the quality deviation
causes must be investigated and documented. Measures must be taken in relation to the
products presenting quality deviations and actions must be adopted in order to prevent
reoccurrences.

3. Quality Control
3.1 Quality control is a part of GMP related to the sampling, specifications, essays, organization
procedures, documentation and release procedures ensuring that the necessary and significant
essays are performed and that materials are not released to use, nor to sales or supply, until
their quality is considered satisfactory. The quality control must not be limited to the laboratory
operations, it must also be involved in all decisions related to the product quality.
3.2 All the holders of Authorization of Establishment to manufacture drugs must have a Quality
Control. It is essential that the quality control is independent of the production. The quality
control must be independent from the other departments and it must be under the direction of a
qualified and experienced person, with one or many control laboratories available. Appropriate
resources must be available in order to guarantee that all of the quality control activities are
effective and trustfully performed.
The minimum requirements to the quality control are the following:
(a) appropriate premises and personnel, trained personnel and operation procedures approved
must be available so the sampling, inspection and essays of raw materials, packaging materials,
bulk products and finished products may be performed, whenever necessary, to manage the
environmental conditions of the areas;
(b) the sampling of raw materials, packaging materials, intermediary products, bulk products
and finished products, must be performed through approved methods and by qualified
personnel;
(c) the analysis methods must be validated;
(d) the records must be done (manually and/or through recording instruments), showing that all
the sampling procedures, inspections and essays required, are really performed and that any
deviation is totally investigated and documented;
(e) the finished products must have inputs, meeting the quantitative and qualitative composition
described in the product registration; the substances must present the required purity, must be
packaged into appropriate containers, correctly labeled.
(f) the results obtained in the inspections and the materials, intermediary products, bulk
products or finished products control essays for meeting the specifications, must be recorded.
The products batches evaluation must include the revision and evaluations of the production
documentation, as well as, the evaluation of the deviations to specific procedures;
(g) no product batch may be released to expedition before being approved by the authorized
person, who must indicate that it is according to its specifications;
(h) sufficient samples of the raw materials and the finished products must be taken, in order to
perform later product examinations, if necessary; the samples of finished product taken must be
kept in their final packages, in the established storage conditions, unless they are exceptionally
large;
3.3 The quality control has, yet, other attributions, such as establishing, validating and
implementing its procedures to evaluate, keep and store the reference standards of the active
substances used; ensuring the proper labeling of the material and product containers; ensuring
that the active substances and the products stability is monitored; taking part in the investigation
of the complaints related to the product quality and taking part in the environmental
management. All these operations must be performed according to the approved, and
whenever required, registered Standard Operation Procedures (SOP).
3.4 The evaluation of the finished products must comprehend all the significant factors,
including the production conditions, the results of the in-process control, the manufacturing
documents, the meeting of the finished product specifications and the examination of the final
package.
3.5 The company Quality Control personnel must have access to the production areas in order
to perform the sampling and investigation activities, as appropriate.
4. Sanitization and Hygiene
4.1 The production of drugs requires a high sanitization and hygiene levels, that must be kept in
all manufacturing procedures. The sanitization and hygiene activities must comprehend
personnel, premises, equipment and apparatus, production materials and containers, cleaning
and disinfectant products and any other aspect which may constitute a contamination source to
the product. The potential contamination sources must be eliminated through a broad
sanitization and hygiene program.

5. Validation
5.1 The validation studies constitute an essential part of the GMP and, therefore, they must be
conducted according to predefined protocols. A written report must be kept with the summary of
the results obtained and the conclusions. The processes and procedures must be established,
according to the validation study results and they must be periodically revalidated, so to ensure
that they are able of reaching the planned results. Special attention must be given to the
validation of processes, control essays and cleaning procedures.
5.2 The processes considered critical must be validated, concurrently, prospectively and/or
retrospectively.
5.3 When there is a change in the master formula/standard formula or a new preparation
method is introduced to the usual manufacturing processes, the appropriateness of the new
method to the established routine processes must be shown by validation. The process defined
upon the use of the specified materials and equipment, must show to be able of originating
uniform products, within the required quality standards.
5.4 The manufacturing processes suffering any significant change, including any equipment or
materials change which may affect the quality and/or reproducibility of the process, must also be
validated.
6. Complaints
6.1 All the complaints and other information related to products with possible quality deviations,
must be carefully investigated and registered according to the written procedures.
6.2 A person responsible for the receiving of complaints and for the actions to be taken must be
indicated. This person must have enough support personnel to help him/her in this function. If
the person indicated is not the Technician Responsible for the product, he/she must be
informed.
6.3 In case of complaints of possible quality deviation of a product, the written procedures
describing the actions to be taken, including the need to perform a likely collection, must be
adopted.
6.4 Any complaint related to a quality deviation in a certain product must be registered, together
with all the details in the batch records and, then, it must be completely investigated. The
person responsible for the Quality Control must be involved in the study of the related deviation.
6.5 If a quality deviation is detected in some product batch, or if there is a likely suspicion of
deviation of a certain batch, the possibility that other batches present the same problem it must
be taken into account, therefore, they must also be verified. Other batches containing the
reprocessed product of the batch presenting deviations, must be specially investigated.
6.6 Whenever required, the appropriate actions of follow-up must be adopted after the
investigation and evaluation of the complaint, including the possibility of collecting the product.
6.7 All the decisions and measures taken as a result of certain complaint must be registered
and mentioned in the correspondent batch records.
6.8 The complaint records must be regularly revised, with the purpose of detecting any mark of
specific or recurrent problems, which require more attention and may justify the collection of the
marketed products.
6.9 The sanitary authorities in charge must be informed by the manufacturer when any
significant quality deviation in the manufacturing process, product deterioration is detected, and
when a serious problem with the quality of some product is under investigation.
7. Products Collection
7.1 There must be a system for the immediate and efficient withdrawal of products presenting
quality deviations or under suspicion from the market.
7.2 A person responsible for the measures to be adopted and the coordination of the product
collection from the market must be indicated. This person must have enough support personnel
in order to help him/her in all of the aspects of the collection and with the necessary urgency
level. Usually, this person must not belong to the selling and marketing authority, and if he/she
is not the Technician Responsible for the product, the latter must be informed of any action
taken.
7.3 There must be written procedures, regularly verified and updated, to proceed with any
collection activity. The collection operations of the product in the market must be immediate,
starting, most preferably, by hospitals and drugstores. The procedures viewing the destination
of the collected products, which were deviated from the transportation and/or distribution chains
must be foreseen.
7.4 All of the sanitary authorities in charge in the countries the product was sent to must be
immediately informed about any intent collection of the product presenting a quality deviation or
under suspicion.
7.5 The records about the batch distribution presenting a quality deviation or under suspicion
must be immediately available to the person responsible for the collection. The records must
have enough information on the distributors and on the buyers who may have been directly
supplied with the product, including in case of exported products information on the buyers who
received samples to perform clinical trials and medical samples, so the product is efficiently
withdrawn from the market.
7.6 The collection process progress must be recorded, including the reconciliation between the
distributed quantities and the collected quantities of the product, as well as a final report.
7.7 The efficiency of the activities related to the recollection must be periodically evaluated.
7.8 An instruction indicating the storage conditions of the products withdrawn from the market,
which must be kept in safety, in separated areas, while awaiting the decision about their
destination, must be included.
8. Manufacturing and/or Analysis Agreement
8.1 The manufacturing and/or analysis agreement must be mutually agreed and controlled
between the parties, to avoid mistakes which may result in a process, product or analysis of
unsatisfactory quality. A written agreement must be signed between the contracting and the
contracted parties, clearly establishing the attributions of each party. The agreement must
establish the procedure upon which the authorized person must exercise its responsibilities, as
for the release of each product batch for sale or as for the issuing of a certificate of analysis.
8.2 All the conditions established in the manufacturing and/or analysis agreement must include
any change proposed in the technical procedures which must be in accordance with the
registration of the respective product.
8.3 The written agreement signed must establish the manufacturing and/or analysis procedures
of the product with all the technical activities related to both.
8.4 The agreement must establish that the contacting party may perform an audit in the
contracted party premises.
8.5 In case of an analysis agreements, the final approval to the release of the finished product
for marketing, must be given by the contracting party authorized Person.
8.6 The contracting party is responsible for the qualification evaluation of the contracted party to
perform the contracted services. Besides, it must be assured, by the signed agreement, that the
GMP principles described in this Regulation are followed.
8.7 The contracting party must provide the contracted party with all the information required to
perform the contracted operations according to the product registration, as well as any other
legal requirements. The contracting party must ensure that the contracted party is informed of
any problem related to the product, service or essays, placing their premises, equipment,
personnel, other materials or products at risk.
8.8 The contracting party must ensure that all the processed products and materials delivered
by the contracted party meet their specifications or that the product has been released by the
Authorized Person.
8.9 The contracted party must have appropriate premises, equipment and knowledge, besides
experience and qualified personnel, in order to satisfactorily perform the service requested by
the contracting party. The manufacturing contract may only be performed by manufacturers
holding a Certificate of Establishment and Sanitary License.
8.10 The contracted party may not repass the services foreseen in the contract to third parties
without the previous evaluation and approval by the contracting party of this agreement change.
The agreements signed between the contracted party and third parties, must foresee the
availability of analytical information and information on the manufacturing, just as the
agreements signed between the contracting and the contracted parties.
8.11 The contracted party must abstain from performing any activity which may adversely affect
the quality of the manufactured and/or analyzed product to the contracting party.
8.12 The agreement signed between the contracting and the contracted parties must specify the
responsibilities of the related parties as for the manufacturing and the control of the product.
Technical aspects of the agreement must be written by qualified persons, with the required
knowledge in pharmaceutical technology, quality control analyses and GMP. All the actions
related to the manufacturing and analysis must be according to the product registration and
must be agreed by both parties.
8.13 The agreement must specify the mean by which the Authorized Person ensures that each
batch is manufactured according to the Product Registration.
8.14 The agreement must clearly describe the responsibilities for the acquirement, control essay and
material release, by the production and performance of the quality controls, including the in-process
controls, as well as the responsibilities by the sampling and performance of the analyses.
8.15 The agreement must establish that the manufacturing records, the analytical records and
the reference samples must be kept by the contracting party or must be available to it.
8.16 The agreement must establish that the distribution records must be kept by the contracting
party.
8.17 The agreement must predict the actions to be adopted when there is disapproval of raw
materials, intermediary products, bulk products and finished products.
9. Self-Inspection and Quality Audit
The purpose of the self-inspection is to evaluate the fulfillment of GMP by the manufacturer in
all of the aspects of production and the quality control. The self-inspection program must be
designed in a way to detect any deficiency in the GMP implementation and to recommend the
necessary corrective actions. The self-inspection must be routinely performed, in cases of
product withdrawal or repeated disapprovals. The team responsible for the self-inspection must
be constituted by professionals who may objectively evaluate the fulfillment of GMP. All the
recommendations on the corrective actions must be implemented. The procedures to the
performance of the self-inspection must be documented and also have an effective follow-up
program.
Written procedures must be elaborated on the self-inspection, in order to have a minimum and
uniform standardization of the requirements. These procedures must comprehend, at least, the
following aspects:
(a) personnel;
(b) premises;
(c) maintenance of buildings and equipment;
(d) storage of raw material, packaging material and finished product;
(e) equipment;
(f) manufacturing and in-process control;
(g) quality control;
(h) documentation;
(i) sanitization and revalidation;
(j) validation and revalidation programs;
(k) calibration of instruments and measuring systems;
(l) collection procedures of the product from market;
(m) management of complaints;
(n) labels control;
(o) wastes disposal;
(p) results of previous self-inspections and any corrective actions adopted.
9.1 Self-inspection team
9.1.1 The Quality Assurance management must designate a team to perform the self-
inspection, formed by qualified professionals and experts in their own acting areas and familiar
to the GMPs. The team members may be company employees or outer experts.
9.2 Frequency of the self-inspection
9.2.1 The frequency of the self-inspections must be, at least, annual.
9.3 Self-inspection report
9.3.1 A report must be done after the self-inspection is finished, and it must contain:
(a) the self-inspection results;
(b) evaluations and conclusions;
(c) the corrective actions recommended.
9.4 Follow-up actions
9.4.1 The Company Management and the Quality Assurance must evaluate the self-inspection,
as for the corrective actions recommended, if required.
9.4.2 The verification of the fulfillment of the corrective actions, recommended in the Self-
Inspection report must present a specific report.
9.5 Quality audit
9.5.1 The self-inspection complementation with quality audits may be necessary. The quality
audit consists in the examination and evaluation of part or totality of a certain quality system,
with the specific purpose of enhancing it. Generally, it is performed by outer, independent
experts or by a team designated by the management for this purpose. Besides, the audits may
be extended to suppliers and contracted parties.
9.6 Suppliers audit
9.6.1 The Quality Assurance must be responsible, together with the departments involved in the
manufacturing, by the qualification of the suppliers of raw materials and packaging materials, in
order to meet the established specifications.
9.6.2 Before the suppliers are approved and included in the suppliers list of the company, they
must be evaluated, whenever applicable, by audits, viewing the verification of the fulfillment of
GMPs.
10. Personnel
10.1 Generalities
10.1.1 The establishment and maintenance of a Quality Assurance system and the
manufacturing of drugs, depend on the personnel performing them. For this reason, there must
be qualified personnel enough to perform all the activities the manufacturer is responsible for.
All the individual responsibilities must be established on written procedures and they must be
clearly understood by all the people involved.
10.1.2 The manufacturer must have a sufficient number of qualified persons. The
responsibilities attributed to each employee must not be too extensive, putting the product
quality at risk.
10.1.3 The company must have an organization chart. All the employees with responsibility
status must have their specific attributions written and enough authority to perform them. Their
attributions may be delegated to designees, with a satisfactory qualification level. There may not
be a failure or overlapping in the personnel responsibilities as for the application of GMPs.
10.1.4 All personnel must know the GMP principles and receive initial and continuous training,
including hygiene instructions as needed. All personnel must be motivated to support the
company in maintaining the quality standards.
10.1.5 Actions must be taken in order to avoid the entrance of non-authorized persons in the
manufacturing, storage and Quality Control areas. People not working in these areas must not
use them as a shortcut.
10.2 Main Personnel
10.2.1 All professionals acting in the drugs manufacturing, occupying the main positions in the
company and having the power of decision. The main personnel includes the person
responsible for the manufacturing, for the Quality Assurance, for the quality control, for sales
and distribution and the technical responsible. The person responsible for the production and
Quality Control must be independent from each other.
10.2.2 The main positions must be occupied by people who work full time in the company. In
large companies, there may be the need to delegate some functions, however, responsibilities
may not be delegated.
10.2.3 The persons responsible by the departments of manufacturing, Quality Control and
Assurance of drugs, must have the graduation qualifications foreseen by the current legislation
and practical experience.
10.2.4 The persons responsible for the production, Quality Control and Assurance, under
certain circumstances, must work together, such as:
(a) authorization of procedures and documents, including their updating;
(b) management and control of the manufactory environment;
(c) hygiene;
(d) validation of process and calibration of analytical instruments;
(e) training, including the application of the quality assurance principles;
(f) approval and monitoring of material suppliers;
(g) approval and monitoring of the contracted manufacturers;
(h) specifications and monitoring of the storage conditions of materials and products;
(i) documents/ records archive;
(j) monitoring of the GMP achievement;
(k) inspection, investigation and sampling, in order to monitor factors that may affect the product
quality.
10.2.5 The person responsible for the production, usually, holds the following responsibilities:
(a) to ensure that the products are produced and stored according to the appropriate
procedures, with the quality required;
(b) to approve the instructions related to the manufacturing operations, including the in-process
controls, and ensuring their strict implementation;
(c) to ensure that the manufacturing records are evaluated and signed by a person designated,
before it is made available to the quality control;
(d) to verify the maintenance of the premises and equipment;
(e) to ensure that the processes validations, the calibrations and control of equipment are
performed and recorded and that the reports are available;
(f) to ensure that the appropriate initial and continuous training is performed with the personnel
in the production area, and that it is appropriate to the needs.
10.2.6 The person responsible for the Quality Control has the following responsibilities:
(a) to approve or reject the raw materials, the packaging materials and the intermediary
products, bulk or finished;
(b) to evaluate the batches records;
(c) to ensure that all the essays required are performed;
(d) to approve the sampling instructions, the specifications, the essay methods and the
procedures of quality control;
(e) to approve and manage the analyses performed, foreseen in an agreement;
(f) to verify the maintenance of the premises and equipment;
(g) to ensure that the necessary validations are done, including the validation of the analytical
procedures and the calibration of the control equipment;
(h) to ensure that initial and continuous trainings of the personnel of the Quality Control area are
performed, according to the sector needs.
10.3 Training
10.3.1 The manufacturer, upon a written and defined program, must train the people involved in
the production areas, quality control laboratories, as well as all people whose activities may
interfere with the product quality.
10.3.2 Besides the theoretical and practical basic training of GMP, recently hired people must
take part into the integration program and receive the appropriated training as for their
attributions and they must be continuously trained and evaluated. The training programs must
be made available for all personnel, as well as approved by the persons responsible for the
production, quality control and Quality Assurance, keeping records.
10.3.3 Personnel working in clean areas, in areas with contamination risks, where highly active,
toxic, infectious or sensitizing materials are handled, must receive a specific training.
10.3.4 The concept of Quality Assurance and all the measures which may enhance its
understanding and its implementation must be broadly discussed during the training.
10.4 Health, Hygiene, Garments and Conduct
10.4.1 All the personnel must be subjected to a health evaluation before their admission and
then, from time to time, required to the activities performed, according to the established
procedures.
10.4.2 All personnel must be trained in the personal hygiene practices. All the people involved
in the manufacturing processes must meet the hygiene rules; especially, they must be
instructed to wash their hands before getting into the production areas. In order to have this rule
obeyed, instructive signs must be affixed and they must be observed.
10.4.3 The people with suspicion or confirmation of an illness or exposed wound which may
adversely affect the products quality, may not handle raw materials, packaging materials,
intermediary products and bulk products or finished products until his/her health status does not
represent a risk to the product.
10.4.4 All the employees must be instructed and motivated to report immediately to their
supervisor any condition, related to the production, equipment or personnel, which they consider
that may adversely interfere in the products.
10.4.5 Direct contact between the operator’s hands and the raw materials, primary packaging
materials, intermediary products and bulk products must be avoided.
10.4.6 In order to ensure the product protection against contaminations, the employees must
wear clean garments, appropriate to each production area. If reusable, the uniforms must be
kept in closed environments, until they are washed, and when applicable, disinfected or
sterilized.
10.4.7 The uniforms must be provided by the manufacturer according to written procedures. The
washing of the uniforms is a company responsibility.
10.4.8 In order to ensure the employees safety, the manufacturer must have a Collective
Protection Equipment (CPE) and Individual Protection Equipment (IPE) according to the
activities developed.
10.4.9 It is prohibited to smoke, eat, drink, chew or keep plants, food, drinks, tobacco and
personal drugs in the production areas, quality control laboratory and storage areas or any other
areas where these actions may adversely affect the product quality.
10.4.10 The personal hygiene procedures, including wearing appropriate clothes, must be used
by all the people entering the production areas.
10.4.11 Visitors and non-trained people, must be prohibited of entering the production areas. If
this is unavoidable, these persons must be previously oriented on personal hygiene and
wearing appropriate garments and they must be accompanied by a designee.
11. Premises
11.1 Generalities
11.1.1 The premises must be located, designed, built, adapted and kept properly for the
operations being performed. Its design must minimize the risk of mistakes and make the
cleaning and maintenance possible, in a way to avoid cross-contamination, accumulation of
dust and dirt or any adverse effect that may affect the products quality.
11.1.2 The premises must have environments presenting a minimum risk of contamination of
materials or products handled there when taken into consideration together with the measures
designed to protect the manufacturing operations.
11.1.3 The premises used in the manufacturing of drugs must be designed and built in a way to
make the appropriate cleaning possible.
11.1.4 The premises must be kept in good conservation, hygiene and cleaning status. It must be
ensured that the maintenance and repairing operations do not present any risk to the products
qualities.
11.1.5 The electric power, illumination, air conditioning (temperature and humidity) and
ventilation supply must be appropriate, in order not to directly or indirectly affect the drugs
during the manufacturing and storage processes or the appropriate functioning of equipment.
11.1.6 The premises must be designed and equipped in order to allow the maximum protection
against the entrance of insects and other animals.
11.2 Auxiliary areas
11.2.1 The resting rooms and cafeteria must be apart from the other areas.
11.2.2 The locker rooms, lavatories, and restrooms must be of easy access and appropriate to
the number of users. The restrooms must not have direct communication with the production
and storage areas.
11.2.3 The maintenance areas must be at separated sites from the production areas. If the tools
and repair parts are kept in the production area, they must be in rooms or lockers reserved to
this purpose.
11.2.4 The biotherium must be isolated from the other areas, have a separate entryand an
exclusive ventilation system.
11.3 Storage areas
11.3.1 The storage areas must have capacity enough to make the organized storage of a
number of materials categories and products possible: raw materials; packaging materials;
intermediary products, bulk products and finished products, in their quarantine, approved,
reproved, returned or collected status.
11.3.2 The storage areas must be designed in a way to ensure the ideal storage conditions.
They must be kept clean, dry and with temperatures compatible to the materials stored. When
special storage, temperature and humidity conditions are required, they must be provided,
verified, monitored and registered.
11.3.3 In the receiving and issuing areas the materials must be protected against the
temperature ranges. The receiving areas must be designed and equipped to allow that the
materials containers are cleaned before their storage.
11.3.4 The quarantined products must be in a restricted and separated storage area. This area
must be clearly marked and their access allowed only to authorized persons. Any other system
substituting the physical quarantine must offer the same safety, ensuring its release to
marketing.
11.3.5 There must be a separated area to the collection of raw materials samples. If the
sampling is performed in the storage area, it must be performed in a specific environment for
this purpose, in order to avoid the possibility of microbiological contamination and/or cross-
contamination.
11.3.6 The storage of materials or products returned, reproved or collected must be done in a
separated and identified area.
11.3.7 The highly active materials, substances presenting risk of dependency, fire or explosion
and other dangerous substances must be stored in secure and protected areas, duly separated
and identified, according to the specific current legislation.
11.3.8 The storage of printed materials must be done safely, with restricted access, avoiding
mixings and deviations, and it must be handled by a designee, following the defined and written
procedures.

11.4. Weighing area

11.4.1 The areas designed to the weighing of raw materials may be located in the warehouse or
in the production area, and they must be designed and separated to this purpose, with an
independent and appropriate exhaustion system, avoiding cross-contamination.

11.5 Production area

11.5.1 To minimize the possibility of a cross-contamination, there must be exclusive and
separated premises to the production of certain drugs, such as biological preparations (alive
microorganisms), hormones and cytotoxic substances. The existence of separated buildings to
highly sensitizing substances (penicillin, cephalosporin and their derivatives) is recommended.
11.5.2 The production of certain drugs, such as some antibiotics and highly active products,
must not be performed in the same premises. In exceptional cases, such as damages (fire,
flood, etc) or emergency situations (war, etc.), the campaign work principle in the same
premises may be conducted, provided that all the specific precautions are taken and the
necessary validations performed.
11.5.3 The physical premises must be disposed according to the continuous operational flow, in
order to allow the production to correspond to the production operation sequences and to the
required cleaning levels.
11.5.4 The production and storage areas must allow the logical and ordered positioning of the
equipment and materials, in order to minimize the risk of mixings between different drugs or
their components and to avoid the cross-contamination and to reduce the risk of omission or
misapplication of any manufacturing or control step.
11.5.5 In the areas where the raw materials, primary package materials, intermediary products
or bulk products are environmentally exposed, the inner surfaces (walls, floor and ceiling) must
be covered by plain, impermeable, washable and resistant material, free of joints and cracks,
easy to clean, allowing the disinfection and it must not release particles.
11.5.6 The pipes, lamps, ventilation points and other installations must be designed and
installed in a way to make cleaning easy. Whenever possible, the maintenance access must be
located out of the production areas.
11.5.7 The drains must be of an appropriate size, siphoned, to avoid liquids or gas reflux and
they must be kept closed. Whenever possible, the installation of open drain pipes must be
avoided. If required, they must be flat to make cleaning and disinfection easier.
11.5.8 The production areas must have an effective ventilation system, with air control units,
including the temperature control and, whenever necessary, the humidity and filtration
appropriate to the products handled there, to the operations performed and to the environment
status. These areas must be regularly monitored during the production period and at rest, in
order to ensure that the area specifications are met.
11.5.9 The physical premises to the drugs packaging must be designed in a way to avoid
mixtures or cross-contaminations.
11.5.10 The production areas must be illuminated, according to each operation need, specially
in the places where the visual control in the production line is performed.

11.6 Quality control area

11.6.1 The quality control laboratories must be separated from the production areas. The areas
where the microbiological, biological or radioisotopic essays are going to be performed must be
independent and separated, and they must have independent installations, specially the air
system.
11.6.2 The control laboratories must be designed in a way to make the operations performed
there easier. They must have space enough to avoid mixtures and cross-contaminations.
Besides, there must be enough and appropriate space to the storage of reference samples,
reference standards and the documentation of the batches records.
11.6.3 The laboratory must be projected taking into account the use of appropriate building
materials and it must have an air system to avoid the formation of hazardous vapors.
11.6.4 The use of separated rooms may be necessary to protect certain instruments presenting
electric interference, vibrations, excessive contact with humidity and other external factors.
12. Equipment
12.1 The equipment must be designed, built, adapted, installed, located and kept in a way to
make the operations to be performed there easier. The design and the location of the
equipment must minimize the risks of mistakes and allow the appropriate cleaning and
maintenance to avoid cross-contamination, accumulation of dust and dirt, and, usually, to avoid
every effect that may have a negative influence in the products quality.
12.2 The fixed pipes designed to the conduction of fluids, must be duly identified, according to
the current legislation and, when applicable, the flow direction must be indicated. When dealing
with hazardous gases and liquids, connections or adaptors, not exchanged among themselves,
must be used.
12.3 All the instruments used must be duly identified.
12.4 The scales and measuring instruments in the production and quality control areas must
have the required capacity and accuracy and must be periodically calibrated.
12.5 The control laboratory instruments and equipment must be appropriate to the procedures
and analyses foreseen and in sufficient number to the volume of operations.
12.6 The equipment used in the production must not present any risk to the products. These
equipment parts in direct contact with the product must not be reactive, additive or absorptive,
influencing the product quality.
12.7 The cleaning and washing processes of the equipments must not constitute a
contamination source.
12.8 Every equipment out of use or presenting defects must be withdrawn from the production
and quality control areas, whenever possible, or it must be duly identified.
13.1 Generalities
13.1.1 All the materials and products must be placed in quarantine immediately after they are
received or produced, until they are released by the quality control, to use and distribution.
13.1.2 All the materials and products must be stored under appropriate conditions according to
the procedures established by the manufacturer. The separation of batches and the stock
rotation must follow the following rule: first to expire, first to leave (PEPS [FEFL]).
13.2 Raw materials
13.2.1 The acquisition of raw materials must be performed by qualified and trained employees.
13.2.2 The raw materials must only be acquired from the qualified suppliers, included in the
company’s suppliers list, preferably, directly from the producer. The specifications established
by the manufacturer related to the raw materials must be discussed with suppliers. All the
production and quality aspects of the raw materials, acquisition process, handling, labeling and
requirements related to package, as well as the complaint and disapproval procedures, must be
discussed between the manufacturer and the suppliers.
13.2.3 For every delivery of containers with raw material, the packages and the seal integrity
and the relation between the requisition, the invoice from supplier and the labels of the product,
which must be into the container, must be verified.
13.2.4 All the raw material received must be verified in order to ensure that the delivery is
according to the requisition. The packages must be externally clean and, whenever required,
labeled with the related data.
13.2.5 The containers damages or any other problem which might affect the raw material quality
must be recorded and reported to the quality control department, and they must be investigated.
13.2.6 If a single raw material shipment presents different batches, each batch must be
considered separately to sampling and release essays.
13.2.7 The raw materials placed in the storage area must be appropriately identified. The labels
must present, at least, the following information:
(a) name of the raw material and the related internal reference code, if the company has an
established system;
(b) batch number designated by the manufacturer/supplier and the number given by the
company when it is received;
(c) raw material status in storage (quarantined, under analysis, approved, reproved, returned);
(d) date of manufacturing, expiration date, and whenever applicable, the date of reanalysis;
(e) manufacturer, origin and source of the raw material.
13.2.8 The identification by a validated electronic system is allowed. In this case, it is not
necessary to show all the information described above on the label.
13.2.9 Procedures ensuring the identification of the content of each raw material container
must be used. The containers from where the samples are taken, must be identified.
13.2.10 Only the raw material released by the quality control department and that are within the
respective expiration dates must be used.
13.2.11 The raw materials must be fractioned only by the indicated employees, according to
written procedures. The raw materials must be carefully weighed or measured, in clean and
correctly identified containers.
13.2.12 The fractioned raw materials, as well as their weights or volumes, must be checked by
another employee and the checking must be recorded.
13.2.13 The fractioned raw materials for each production batch must be kept together and
visibly identified as such.
13.3 Packaging materials
13.3.1 The acquirement, handling, and quality control of the primary, secondary packaging
materials and printed materials must be performed the same way as with the raw materials.
13.3.2 The printed materials must be stored under safe conditions, in order to avoid the
possibility of unauthorized accesses. The labels and other reproved printed materials must be
kept and transported, safely and duly identified, before their destruction. There must be a record
of the printed materials destruction.
13.3.3 Every batch of printed material and packaging material must receive a specific reference
number or identification mark.
13.3.4 The printed materials, for primary or secondary packages, old and obsolete must be
destroyed and this procedure must be recorded.
13.3.5 All the package materials to be used must be checked as for quantity, identification and
conformity with the package instructions, at the moment they are delivered.
13.4 Intermediary products and bulk products
13.4.1 The intermediary products and the bulk products must be kept under specified conditions
determined for each product.
13.4.2 The intermediary products and the bulk products acquired must be handled upon
receiving just as raw materials.
13.5 Finished products
13.5.1 The introduction of part or the totality of the previous batches produced, meeting the
quality standards required, to another batch of the same product, at a certain stage of
manufacturing, must be previously authorized and performed according to the defined
procedures, after the evaluation of the risks involved, including any possible effect on the
expiration date. The process must be recorded.
13.5.2 The finished products must be kept in quarantine until they are finally released by the
quality control. Then, they must be stored as available stock, according to the conditions
established by the manufacturer.
13.6 Reproved and returned materials and products.
13.6.1 The reproved materials and products must be identified as such and stored separately,
into restricted areas. They may be returned to the suppliers, reprocessed, or destroyed. The
action adopted must be approved by the Authorized Person and duly recorded.
13.6.2 The reproved products reprocessing can only be allowed if the finished product quality is
not affected, if the specifications are met and if the operation is performed according to
authorized procedures and defined after the evaluation of the risks involved. A record of the
reprocessing must be kept. Any reprocessed batch must receive an identification that allows its
tracking.
13.6.3 The Quality Control must perform additional essays to any finished product that has been
reprocessed, or that has been incorporated to a certain recovered product.

13.7 Collected products

13.7.1 The products collected from market must be identified and stored separately in a safe
area, until its destination is defined. The final decision must be taken as soon as possible.
13.8 Returned products
13.8.1 The products returned by the market must be identified and stored separately in a safe
area until their destination is defined. Only after a critical evaluation by the Quality Control,
according to written procedures, these product may be considered to resale, repackaging or
incorporation into another posterior batch bulk. The nature of the product, as well as any special
storage conditions required, its conditions, background and running time since its expedition
until devolution, must be taken into account in the evaluation above mentioned.
13.8.2 When there is any doubt as for the product quality, this must not be considered
appropriate to be incorporated or reused. In this case, if possible, a chemical reprocessing may
be performed to recover the active substance. Every action must be duly recorded.
13.9 Reagents and means of culture
13.9.1 All the reagents and means of culture must be registered when received or prepared.
13.9.2 The prepared reagents must be elaborated according to written procedures and properly
labeled. The label must indicate the concentration, date of preparation, standard factor,
expiration date, date for new standardization and storage conditions. The label must be signed
and dated by the person who prepared the reagent.
13.9.3 Positive controls must be done, as well as negative controls, so the adequacy of the
means of culture may be checked. The size of the inoculum used in positive controls must be
appropriate to the required sensitivity.
13.10 Reference standards
13.10.1 The reference standards may be available as official reference standards. The
secondary references, work references, prepared by the manufacturer must be checked and
released, and then, kept just as the official standards. Besides, they must be kept under the
responsibility of a designee, in a safe area.
13.10.2 The official reference standards must only be used for the purposes described in the
monograph.
13.10.3 The secondary or work standards may be checked upon the appropriate verification
essays, at regular periods, in order to ensure the standardization. All the secondary reference
standards must be based in official reference standards.
13.10.4 All the reference standards must be kept and used in a way that does not affect their
quality.
13.11 Waste materials
13.11.1 Actions must be taken in relation to the appropriate and safe keeping of waste materials
to be eliminated. The toxic substances must be kept in restrict access locations. The
inflammable materials must be kept in separated locations, designed to this purpose, as
required by the current legislation.
13.11.2 The waste material must not be accumulated. It must be collected into appropriate
containers, in a specific place, and they must be safely and sanitarily disposed, regularly and
frequently.
13.12 Different materials
13.12.1 It must not be allowed that raticides, insecticides, fumigating agents and sanitizing
materials contaminate the equipment, raw materials, package materials, in-process materials
and finished products.
Documentation
The documentation is an essential part of the Quality Assurance system and it must be related
to all of the GMP aspects. Its purpose is to define the specifications of all the materials and
manufacturing methods and control, in order to ensure that all the personnel involved in the
manufacturing may decide what to do and when. Besides, its purpose is to ensure that the
Authorized Person has all the information required to decide whether to release or not a certain
drug batch to be sold, and it also makes possible a tracking to investigate the background of
any batch suspicious of quality deviation. All the documents may be gathered in only one folder,
or they may be kept separated, easily available, constituting the manufacturing batch record.
14.1 General aspects
14.1.1 The documents must be written, revised and delivered only to designees. They must
cover all the manufacturing steps, authorized by the registration.
14.1.2 Original documents must be approved, signed and dated by the designee. Any document
must be modified without previous authorization.
14.1.3 The documents contents cannot be ambiguous: its title, nature and purpose must be
clearly, accurately and correctly presented. Besides, they must be placed in order and easy to
check. Reproduced documents must be legible and have their truth guaranteed in relation to the
original.
14.1.4 The documents must be regularly revised and updated. When a document is revised,
there must be a system to avoid the misuse of the replaced version.
14.1.5 When documents require the entry of data, they must be clear, legible and indelible.
There must be space enough left to every data entry.
14.1.6 All the changes done in any document must be signed and dated, the change must allow
the reading of the original information. When applicable, the reason for the change must be
recorded.
14.1.7 A record must be kept on all the performed or finished actions, in a way that all the
significant activities related to the manufacturing of drugs, may be tracked. All the records,
including the ones related to the Standard Operation Procedure (SOP) must be kept for, at
least, a year after the expiration date of the finished product.
14.1.8 The data may be recorded by an electronic processing system or by photography or
other trustful means. The master formulas/standard formulas and the Standard Operation
Procedures - SOPs - related to the system being used, must be available, as well as the
accuracy of the data recorded must be checked. If the data records is done by an electronic
processing, only designees may change the data in the computers. There must be a record of
the changes performed. The access to the computers must be restricted by keywords or other
means. The entry of data considered critical must be checked by another designee. The
electronic records of the batch data, must be protected by transferring copies into magnetic
tapes, microfilm, paper impression or other means. It is specially important that, during the
retention period, the data are readily available.
14.2 Labels
14.2.1 The identification placed in containers, equipment, installations and products must be
clear, unambiguous and in a format approved by the company, presenting the necessary data.
Besides text, different colors to indicate the product status may also be used (e.g.: quarantined,
approved, reproved, clean).
14.2.2 All the finished products must be identified by labels, according to the required by the
current sanitary legislation.
14.2.3 The reference standard labels and the documents following them must indicate the
concentration, date of manufacturing, and expiration date, the date when the seal was broken
and the storage conditions, when appropriate.
14.3 Specifications and quality control essay procedures
14.3.1 The procedures of the quality control essays described in the document must be
validated taking into account the premises and equipments available, before they are adopted
as a routine.
14.3.2 All the specifications must be duly authorized and dated, in relation to the identification,
content, purity and quality essays of raw materials, packaging materials and finished products.
Besides, essays must be performed in the intermediary and the bulk products. There must be
specifications related to the water, solvents and reagents (acids and bases) used in the
production.
14.3.3 The essays procedures must be approved and kept by the Quality Control and they must
be available in the sites responsible for the performance of the essays.
14.3.4 Periodical revisions of the specifications must be performed in order to be updated
according to new issues of the national pharmacopoeia, or other official compendia.
14.3.5 The pharmacopoeia, reference standards, spectrometry references and other necessary
reference materials must be available in the quality control laboratory.
14.4 Specifications to raw materials and packaging materials
14.4.1 The specifications of raw materials, primary packaging materials and printed materials
must have a description, including, at least:
(a) name and internal reference code;
(b) reference of the pharmacopoeia monograph, if there is one; and
(c) quantitative and qualitative requests with their acceptance limits.
14.4.2 Depending on the practice adopted by the company, other data may be added to the
specifications, such as:
(a) supplier identification and the original manufacturer of the materials;
(b) template of the printed material;
(c) orientations about sampling, quality essays and reference used in the control procedures;
(d) storage conditions and precautions;
(e) maximum storage period before a new exam is performed.
14.4.3 The packaging material must meet the specifications, emphasizing their compatibility
with the pharmaceutical product contained. The material must be examined for visible physical
and critical damages, as well as for the required specifications.
14.4.4 The documents describing the control essay procedures must indicate the frequency new
tests of each raw material must be performed.
14.5 Specifications to intermediary products and bulk products
14.5.1 The intermediary and bulk products specifications must be available every time these
materials are acquired or expedited, or if the data on the intermediary product have to be used
in the final product evaluation. The specifications must be compatible with the specifications
related to raw materials or finished products.
14.6 Specifications to finished products:
14.6.1 The specifications must include:
(a) generic name of the product and trademark or commercial name, whenever applicable;
(b) name of the active principles with their respective DCB or DCI;
(c) formula or its reference;
(d) pharmaceutical presentation and package details;
(e) references used in sampling and control essays;
(f) qualitative and quantitative requests, with their acceptance limits;
(g) conditions and precautions to be taken in storage, whenever applicable;
(h) expiration date.
14.7 Master formula/ Standard formula
14.7.1 There must be a master formula/standard formula for each product and batch size to be
manufactured.
14.7.2 The master formula/standard formula must include:
(a) the name of the product with the reference code related to its specification;
(b) description of the pharmaceutical presentation, product concentration and batch size;
(c) list of all the raw materials to be used (with their respective DCB or DCI); with the quantity
used of each one, using the generic name and reference that are unique to each material. Any
substance which may disappear along the process must be mentioned;
(d) declaration of the expected final yield, with the acceptable limits, and of intermediary yields,
when applicable;
(e) indication of the processing place and the equipment to be used;
(f) methods (or their references) to be used in the preparation of the main equipment, such as
cleaning (specially after a product change), assembling, calibration, and sterilization;
(g) detailed instructions on the steps to be followed in the production (check of materials, pre-
treatments, sequence of materials addition, mixing time, temperature);
(h) instructions related to any in-process controls, with their acceptance limits;
(i) requirements related to the products packaging, including container, labeling, and any other
special storage condition;
(j) any special precautions to be observed.
14.8 Packaging instructions
14.8.1 There must be authorized instructions as for the packaging process, related to each
product and to the size and type of package. These instructions must include the following data:
(a) name of the product;
(b) description of its pharmaceutical presentation and application route, when applicable;
(c) package dimensions, shown as numbers, weight or volume of the product contained in the
final container;
(d) complete list of all the package material required to a standard batch size, including
quantities, sizes and types, with the code or reference number related to the specifications of
each material;
(e) sampling or reproduction of the materials used in the packaging process, showing the place
where they were printed or engraved, the batch number and its expiration date;
(f) special precautions must be observed, such as the attentive examination of equipment and
area where the packaging takes place, in order to ensure the absence of printed materials of
previous products in the packaging lines;
(g) description of the packaging operations, and equipment to be used;
(h) details of the in-process controls, together with the sampling instructions and the acceptance
limits.
14.9 Records of the production batches
14.9.1 A record must be kept on the production of each batch. These records must be based in
the master formula/standard formula approved and in use, avoiding transcription errors.
14.9.2 Before starting a production process, it must be checked if the equipments and the
working area are free from previously produced products, as well as the documents and
necessary materials to the planned process. Besides, it must be verified if the equipment are
clean and appropriate for use. The verification of these items must be recorded.
14.9.3 During the production process, all the steps developed must be recorded,
comprehending the initial and final time of execution of each operation and, duly signed and
dated by the persons responsible for the performance of each step, ratified by the area
supervisor. The records of the production batches must show, at least, the following information:
(a) name of the product;
(b) number of the batch being manufactured;
(c) dates and times of start and end of the main intermediary production steps;
(d) name of the person responsible for each production step;
(e) identification of the operators of the different production steps and, when applicable, of the
person(s) checking each one of these steps;
(f) number of batches and/or the number of analytical control and the quantity of each raw
material used, including the batch number and the quantity of any material returned or
reprocessed which has been added;
(g) any significant operation or event in the production, and the main equipment used;
(h) in-process controls performed, the identification of the person(s) performing them and the
results obtained;
(i) quantities obtained of the product in the different production steps (yielding), together with
comments or explanations about any significant deviation of the expected yielding;
(j) observations on special problems, including details such as the signed authorization for each
change of the manufacturing formula or instructions of production.

14.10 Records of the batches packages

14.10.1 Records of the package of each batch or part of batch must be kept, according to the
package instructions. The records must be prepared in a way to avoid transcription errors.
14.10.2 Before any process is started, it must be checked if the equipment and the working area
are free from products and documents previously used, if the equipment is clean and
appropriate to use. The verification of these aspects must be recorded.
14.10.3 During the packaging process, all the steps involved must be recorded, dated, and
signed by the responsible persons and the area supervisor, comprehending the starting time
and the ending time of each operation. The records of the manufacturing batches must contain:
(a) name of the product, bulk product batch number and quantity to be packed, as well as the
number of the finished batch, the final product planned quantity, the actual quantity obtained
and the reconciliation;
(b) date(s) and time(s) of the packaging operations;
(c) name of the person responsible for the packaging operation;
(d) identification of the operations in the main steps;
(e) verifications performed for the identification and accordance with the packaging instructions,
including the results of the in-process controls;
(f) details of the packaging operations, including references to equipment, packaging lines used
and, when applicable, the instructions and records related to the unpacked products storage;
(g) samples of printed packaging materials used, with the batch number, the manufacturing
date, when applicable, the expiration date and any additional print;
(h) observations about any special problems, including details about any deviation of the
instructions provided for the packaging process, with the written authorization of the designee;
(i) the quantities of all the printed packaging materials with the reference or identification
number and the bulk products delivered to be packaged, used, destroyed or returned to stock
and the quantity obtained of the product, in order to perform a correct reconciliation.
14.11 Standard Operation Procedures - SOPs and their records
14.11.1 There must be Standard Operations Procedures and records on the receiving of raw
materials and packaging materials.
14.11.1.1 Within the records done in the receiving, the following must be included:
(a) name of material described in the invoice and in the containers;
(b) internal name and/or code of the material;
(c) date of receiving;
(d) name of supplier and manufacturer;
(e) reference number or batch number indicated by the manufacturer;
(f) total quantity and number of containers received;
(g) number given to the batch after receiving it;
(h) any significant commentary (status of containers, for instance).
14.11.2 There must be Standard Operation Procedures for internal identification of the products
stored in quarantine and released (raw materials, packaging materials and other materials).
14.11.3 There must be Standard Operation Procedures for every instrument or equipment,
which must be available near the respective equipment and instrument.
14.11.4 There must be Standard Operation Procedures related to sampling and specifying the
designees to collect the samples.
14.11.4.1 The instructions related to sampling must include:
(a) method and sampling plan;
(b) equipment to be used;
(c) any precaution to be observed in the sense of avoiding contamination of the material or any
deterioration of its quality;
(d) quantity of sample(s) to be taken;
(e) instructions when a sample subdivision is required;
(f) type of container to be used in the samples packaging, as well as whether the sampling
procedures must be performed in aseptic conditions or not;
(g) any specific precautions to be observed, specially on the sampling of sterile or hazardous
materials;
14.11.5 There must be a Standard Operation Procedure describing the details of the batches
numbering system, with the purpose of ensuring that each intermediary product, bulk product, or
finished product batch is identified with a specific batch number.
14.11.5.1 The Standard Operation Procedures related to the batches numbering which are
applied to the packaging steps must be inter-related.
14.11.5.2 The Standard Operation Procedure related to the batches numbering must ensure
that the same batch numbers are not used more than once. This also applies to the
reprocessing.
14.11.5.3 The indication of a batch number must be immediately registered. The record must
include the date when the mentioned number was indicated, the product identification and the
batch size.
14.11.6 There must be written procedures related to the control essays performed in materials
and products, in the different manufacturing steps, describing the methods and the equipment
to be used. The essays performed must be registered.
14.11.6.1 The analyses records must include, at least, the following data:
(a) name of the material or product and, when applicable the pharmaceutical presentation;
(b) batch number and, when applicable, manufacturer and/or supplier;
(c) references to the analysis procedures;
(d) analytical results, including observations, calculations, references used and specifications
(limits);
(e) date when the essays are performed;
(f) identification of the people who performed the essays;
(g) identification of the people who checked the essays and the calculations;
(h) approval or disapproval declaration (or another decision), dated and signed by the
responsible person.
14.11.7 Written procedures must be available as for the approval or disapproval of materials
and products and, specially, as for the release for the finished product sale by the authorized
person.
14.11.8 Records must be kept on the distribution of each batch of a certain product, in order to
make their collection easier, if necessary.
14.11.9 Standard Operation Procedures and developed actions records must be available to the
manufacturing activities and when appropriate, the conclusions of the following aspects:
assembling and validation of equipment;
analytical and calibration apparatus;
maintenance, cleaning and sanitization;
personal data, including qualification, training, garments and hygiene;
environmental management;
plagues control;
complaints;
collection;
returns;
14.11.10 The daily log books must be kept together with the main equipment, and they must
register its use, validation, calibration, maintenance, cleaning or repairing operations, including
dates and the identification of the person who performed it.
14.11.11 The register of the use of equipment, as well as the areas where they are processed
must be done chronologically.
14.11.12 There must be written procedures attributing the responsibilities related to sanitizations
and describing, in details, the chronograms, methods, equipment and cleaning materials to be
used, as well as premises to be cleaned. The described procedures must be fulfilled.
B.- SECOND PART: Good Manufacturing Practices and Quality Control
15. Good manufacturing practices
The manufacturing operations must follow the Standard Operation Procedures -SOPs clearly
defined and approved, according to the approved Technical Report at the moment of the
registration granting before the sanitary authorization in charge, with the purpose of obtaining
products within the required quality standards.
15.1 General Aspects
15.1.1 All the handling of materials and products, such as receiving, quarantine, sampling,
storage, supply, processing, labeling, and packaging must be performed according to the
established and registered procedures and instructions.
15.1.2 Any instruction or procedure deviation must be avoided. If there are deviations, they must
be approved, in written, by a designee, with the participation of the Quality Assurance.
15.1.3 The procedures and reconciliation must be checked, in order to ensure that there is no
inconsistency beyond the acceptable limits.
15.1.4 The operations performed in different products must not be performed simultaneously or
consecutively in the same room, unless the absence of mixing or cross-contamination risk is
proved.
15.1.5 During all production period, materials, containers with products, main equipment and
rooms used must be duly identified, showing the product or material under process, its
concentration (when applicable), and the batch number. Whenever required, it must also show
the production step.
15.1.6 The access to the production premises must be restrict to authorized personnel.
15.1.7 The non-pharmaceutical products must not be produced in areas or with equipment
designed to the production of drugs.
15.1.8 The in-process controls are, usually, performed in the production areas. They must not
present any risk to the product quality.
15.2 Prevention of cross-contamination and microbial contamination in the production.
15.2.1 When powdered materials and products are used, special precautions should be taken to
avoid the formation and dissemination of particles.
15.2.2 The contamination of a raw material or a certain product by another material or product
must be avoided. The risk of accidental cross-contamination arises from the uncontrolled
release of powders, gases, steams, aerosols, or organisms from in-process materials and
products, from wastes in the equipment, from the entrance of insects, from the operators
garments and their skin, etc. The significance of this risk ranges with the type of contaminant
and contaminated product.
15.2.3 Among the most dangerous contaminants, we find the highly sensitizing materials, the
biological preparations with organisms in vivo, some hormones, cytotoxic substances and other
highly active materials. The products which contamination may cause larger damages to users
are the ones administered by parenteral route or applied on open wounds, as well as products
administered in large doses and/or for long terms.
15.2.4 The cross-contamination must be avoided through appropriate techniques or
organization measures, such as:
(a) production in exclusive and separated premises (which might be necessary for products like
vaccines, live bacteriological preparations), separated buildings (penicillin and cephalosporin),
in campaign (time separation) in case of damages (fire, flood, etc.) and in emergency situations
(war, etc.), in this case followed by a cleaning and decontamination processes, duly validated;
(b) use of antechambers, with differences in the air pressure;
(c) decrease to the minimum contamination risk caused by re-circulation or reentry of untreated
air or poorly treated;
(d) protecting garments worn in the areas where the products presenting cross-contamination
risk are processed.
(e)Use of validated cleaning and decontamination procedures;
(f) use of a “closed production system”;
(g) wastes essays;
(h) use of labels, showing the cleaning status in the equipment.
15.2.5 The efficiency of the measures adopted to prevent the cross-contamination must be
periodically verified. This verification must be done in accordance with the Standard Operation
Procedures.
15.2.6 The production areas where products susceptible to the contamination by
microorganisms are being manufactured must be periodically monitored.
15.3 Production operations: intermediary and bulk products
15.3.1 Before any production operation is started, the necessary actions must be taken so the
working areas and equipment are clean and free from any raw material, products, products
wastes, labels or documents unnecessary to the new operation to be started.
15.3.2 All the in-process controls and environmental controls must be performed and registered.
15.3.3 Procedures designed to detect failures in equipment or installations (e.g., water, gas)
must be adopted. The damaged equipment must be identified as such and must not be used
until its failures are corrected. The equipment used in the production must be cleaned according
to established procedures.
15.3.4 The containers used in the filling process must be previously cleaned and sterilized,
when applicable. Attention must be given to avoid and remove any contaminant.
15.3.5 Any significant deviation of the expected yielding must be investigated and registered.
15.3.6 It must be ensured that the piping or other equipment used to the transportation of
products from one area to another are correctly connected.
15.3.7 The pipes used in the purified water for injections transportation must be clean and
decontaminated, according to written procedures determining the limits of microbial
contamination and measures to be adopted.
15.3.8 The equipment and instruments used in the measuring, weighing, record and control
procedures must be subjected to maintenance and calibration at pre-established periods and
these operations records must be kept. In order to ensure a satisfactory functioning, the
instruments must be daily identified, or before they are used for analytical essays. The dates of
calibration, maintenance and when the future calibrations must be performed, must be clearly
established and registered.
15.3.9 The repairing and maintenance operations must not present risk to the quality of the
products.
15.4 Packaging operations
15.4.1 In the packaging operations schedule, special attention must be given to the procedures
that minimize the risks of cross-contamination, mixings or replacements. Different products must
not be packaged next to each other, unless there is a physical separation or electronic controls
are applied.
15.4.2 Before starting the packaging operations, measures to ensure that the working areas,
packaging lines, printing machines and other equipment are clean and free from any product or
material used previously and that is no longer needed to the new operation to be started must
be adopted. The liberation of the packaging line must be done upon an appropriate inspection
and it must be recorded.
15.4.3 The name and batch number of the in-process product must be shown in each
packaging step or in the packaging line.
15.4.4 The filling and closing steps must be immediately followed by labeling. If this is not
possible, appropriate procedures must be applied to endure that there is no mixings or labeling
errors.
15.4.5 The correct performance of the printing operations, done separately or along the
packaging process, must be checked. A greater attention must be given to manual printings,
which must be checked at regular periods.
15.4.6 In order to avoid mixing/exchange special cares must be taken, when detached labels
are used or when large amounts of printings are done out of the packaging line, as well as when
manual packaging operations are adopted. The checking of all the labels within the packaging
line using electronic controls may be useful to avoid mixings. However, the electronic code
readers, label counters and similar instruments must also be checked in order to see if they are
working properly.
15.4.7 The information printed and engraved in relief in the packaging materials must be clear
and resistant to wastage and adulteration.
15.4.8 The product line inspection during the packaging must include, at least, the following
verifications:
(a) general aspect of packages;
(b) if the packages are complete;
(c) if the correct products and packaging materials are being used;
(d) if the printings are correct;
(e) the correct functioning of the packaging line monitors.
15.4.9 The samples taken for in-line inspection must not return to packaging process, without a
proper evaluation.
15.4.10 The products involved in abnormal occurrences during the packaging procedure, must
only be reintroduced after subjected to inspection, investigation and approval by a designee. A
detailed record of this operation must be kept.
15.4.11 Any inconsistency, significant or uncommon, observed during the reconciliation of the
quantity of the bulk product, of the printed packaging materials and the number of units
packaged, must be investigated and satisfactorily identified before the release of the product
batch.
15.4.12 After the conclusion of each operation, all the codified package material with the batch
number that will not be used must be destroyed, and the destruction process must be recorded.
To return the non-codified printed material to stock, written procedures must be followed.
16. Good quality control practices
The Quality Control is responsible for the activities related to sampling, specifications and
essays, as well as the organization, documentation and release procedures guaranteeing that
the necessary and essential essays are performed and that the materials are not released to
use, neither the finished products released to be sold or supplied, until its quality has been
considered satisfactory. The Quality Control must not summarize to laboratory operations, it
must also take part and be involved in all the decisions which might be related to the product
quality. The independency of the quality control from the production is considered essential.
16.1 Control of raw materials, intermediary, bulk and finished products
16.1.1 All the essays must follow the instructions established by written procedures and
approved for each material or product. The result must be checked by the supervisor before the
materials or products are released or reproved.
16.1.2 The samples must be taken, according to written and approved procedures and be batch
representative.
16.1.3 The sampling must be performed in a way to avoid the occurrence of contamination or
other adverse effects on the quality of the product sampled. The containers sampled must be
identified and carefully closed after sampling.
16.1.4 During the sampling care must be taken to avoid contaminations or mixtures of the
material that is being sampled. All the equipment used in the sampling process which have
contact with the materials must be clean. Some particularly dangerous or strong materials may
require special precautions.
16.1.5 The equipment used in the sampling must be clean and, if required, sterilized before and
after each use and kept separated from the other laboratory equipment.
16.1.6 Each container with sample must be identified and show the following information:
(a) name of the sampled material;
(b) batch number;
(c) number of the container sampled;
(d) signature of the person taking the sample; and
(e) date when the sample was taken.
16.2 Necessary essays
16.2.1 Raw materials and package materials
16.2.1.1 Before releasing the raw materials and the package materials for use, the person
responsible for the Quality Control must ensure that they are tested as for the conformity with
the identification, strength, purity specifications and other quality parameters.
16.2.1.2 Identification essays must be performed in the samples taken from each raw material
container. If SPGV manufacturers, the content identification test must be performed in a
statistical sample from the excipients, provided that the supplier is qualified.
16.2.1.3 Each printed material batch to be used in the packaging process must be evaluated
after being received.
16.2.1.4 The manufacturer may accept the certificate of analysis issued by the supplier,
provided that its trustful is established through a periodical validation of the presented results
and through audits at the premises. This does not exclude the need to perform the identity test.
The certificates issued by the supplier must be original and its authenticity ensured. They must
show the following information:
(a) supplier identification, signature of the responsible employee;
(b) name and number of the tested material batch;
(c) description of the specifications and methods used; and
(d) description of the results of the essays and the date when they were performed.
16.3 In-process control
16.3.1 There must be records on the in-process control, which must be part of the batches
record.
16.4 Finished products
16.4.1 Before released the pharmaceutical products batches must have their accordance with
the established specifications guaranteed, upon laboratory essays.
16.4.2 The products not meeting the established specifications must be reproved. If viable, they
may be reprocessed. However, the reprocessed products must meet all the specifications and
quality criteria before being approved and released.
16.5 Revision of the production records
16.5.1 The production and control records must be revised. If a certain batch does not meet the
specifications or presents any divergence, it must be investigated. If required, the investigation
must be extended to the other batches of the same product or of other products which might be
related to the detected deviation. There must be a record of the investigation, where the
conclusion and the necessary follow-up actions are presented.
16.5.2 The sample taken from each finished product batch must be kept for, at least twelve (12)
months after the expiration date, except for Large Volume Parenteral Solutions (SPGV), which
must be kept for, at least, thirty (30) days after the expiration date. Usually, the finished products
must be kept in their final package and stored under the recommended conditions. If the
packages are large, exceptionally the samples may be kept in smaller containers with the same
characteristics and stored under the recommended conditions.
16.5.3 The active substances samples must be kept for, at least, one year after the expiration
date of the final products which originated. Samples from other raw materials (excipients),
except for solvents, gases and water, must be kept for the minimum period of two years, if
allowed by the respective stability studies performed by the raw material manufacturer. The
quantities of samples of materials and detained products must be sufficient to make, at least,
two complete reanalysis possible.
16.6 Stability study
16.6.1 The Quality Control must evaluate the quality and stability of the finished products and,
whenever required, of the raw materials, intermediary and bulk products.
16.6.2 The Quality Control must establish the expiration dates and the specifications related to
the expiration date, based on stability essays performed in accordance with the storage
conditions.
16.6.3 A written program of stability study must be developed and implemented, including the
following elements:
(a) complete description of the product involved in the study;
(b) all the methods and essays parameters, which must describe the procedures of the strength,
purity and physical characteristics essays, as well as documented evidence that the essays
performed indicate the product stability;
(c) prevision related to the inclusion of a sufficient number of batches;
(d) essay chronogram for each product;
(e) instructions on the special storage conditions;
(f) instructions related to the appropriate detention of samples; and
(g) a summary of all the data obtained, including the evaluation and the study conclusions.
16.6.4 The stability of a product must be determined before its marketing and it must be
repeated after any significant change in the production processes, equipment, packaging
materials, etc.
C. - THIRD PART: Supplementary guidelines
17. Sterile products
The guidelines presented herein does not replace any section from the first or the second parts,
but reinforce specific points on the manufacturing of sterile preparations, in order to minimize
the contamination risks by viable or non-viable particles or by pyrogenic substances.
17.1 General considerations
17.1.1 The sterile preparations production must be done in clean area, which personnel and
materials entry must be done through passage chambers. The areas must be kept within the
appropriate cleanliness standards and, they must have ventilation systems with filters of proved
efficiency.
17.1.2 The many operations involved in the preparation of materials (such as containers and
buffers), preparation of the product, filling and sterilization must be performed in separated
areas within the clean area.
17.1.3 The clean areas used in the manufacturing of sterile products are classified, according to
the characteristics required for the quality of air, in grades A, B, C and D (see Table 1).

TABLE 1
Air classification system for the production of sterile products a

At rest In operation
Maximum number allowed of Maximum number allowed of
Grade
particles/m3 particles/m3
0.5-5.0 µm Above 5.0 µm 0.5-5.0 µm Above 5.0 µm
 A* 3 500 0 3 500 0
B 3 500 0 350 000 2 000
C 350 000 2 000 3 500 000 20 000
D 3 500 000 20 000 Undefined Undefined
a
Source: WHO Technical Report Series, No. 902, 2002

17.1.4 To obtain air with the required characteristics, specific methods must be used and it must
be observed that:
(a) the air laminar flow system must have a homogeneous speed of about 0.30 m/s, in case of
vertical flow, and 0.45 m/s in case of horizontal flow. The speed accuracy of the air flow
depends on the type of equipment.
(b) to achieve grades B, C and D, the total number of air exchange of the area, usually must be
superior to 20 exchanges per hour, in a room with the appropriate standard of air flow with filters
HEPA (High Efficiency Particulate Air);
(c) the size of the air samples must be large and sufficient, in order to make the low
contamination determination trustful.
(d) The different air particle classification systems for clean areas are presented on Table 2.
(e) There may be difficulty to demonstrate the accordance to the air classification in the filling
point, during this operation, due to the formation of particles/droplets arising from the product
itself.
17.1.5 Each production operation required a determined purity level of the air to minimize the
risks of contamination by particles or microorganisms in the products or materials handled. The
levels of particles or microorganisms presented on Table 1 must be kept next to the product,
everytime it is exposed to the environment. These conditions must also be respected in all of
the surrounding areas.
17.1.6 If, for any reason, the air conditions in the working area are not kept in accordance with
the pre-established conditions, a cleaning/sanitization procedure must be performed to achieve
the appropriate conditions.
17.1.7 The use of the absolute barrier technology (closed systems) and automate systems to
minimize the human intervention in the production areas may bring advantages to the
maintenance of the manufactured products sterility. When these techniques are used, the
recommendations related to the air quality and its management must be applied and the
appropriate interpretation of the words “working place” and “environment” must be done.
17.2 Sterile products production
17.2.1 The production operations are divided, herein, into three categories:
First - when the product is filled and closed in its primary container and then sterilized;
Second - when the product is sterilized by filtration and filled into previously sterilized
containers;
Third - when the product cannot be sterilized by filtration neither by final sterilization,
consequently it has to be produced from sterile raw materials and filled aseptically into
previously sterilized containers.
17.2.2 The grades of each production area are specified on items 17.3, 17.4, and 17.5 and must
be selected by the manufacturer based on the type of product and the correspondent
validations.
17.3 Products with final sterilization
17.3.1 In general, the solutions must be prepared in areas presenting grade C, to a low initial
counting of microorganisms and particles, creating the appropriate conditions to the immediate
filtration and sterilization. The solutions preparation may be performed in grade D environments,
if additional measures to minimize contamination, such as the use of closed containers, are
taken.
17.3.2 In case of parenteral solutions, the filling must be done under a laminar air flow (grade
A), installed in a grade C area. The preparation of other sterile products, i.e., ointments, creams,
suspensions and emulsions, as well as the filling of the respective containers usually must be
conducted in a grade C environment, before final sterilization.
17.4 Products sterilized by filtration
17.4.1 The handling of raw materials and the preparation of solutions must be performed in
grade C areas. If additional measures are taken to minimize contamination, such as the use of
closed containers before filtration, these activities may be performed in a grade D environment.
After filtration, the product must be handled in a grade A or B area, surrounded by grade B or C,
respectively.
17.5 Sterile products prepared from sterile raw materials, in aseptic conditions
17.5.1 The handling of raw materials and all the additional processing must be done in grade A
or B areas, surrounded by grade B or C areas, respectively.
17.6 Personnel
17.6.1 During the development of the aseptic processes, it is essential that the minimum
personnel required is in the clean areas. If possible, the inspections and controls must be
performed outside these areas.
17.6.2 All personnel (including cleaning and maintenance staff) developing activities in these
areas must receive regular training on the issues significant to the sterile products production,
including the mention of personal hygiene and basic concepts of microbiology issues. If
required, the entrance of people not trained in these areas (i.e., people hired for construction or
maintenance), special cares must be taken in relation to their supervision.
17.6.3 The employees taking part in activities related to the production of products in animal
tissue substrate or microorganisms cultures different from the ones used in the manufacturing
process in course, must not enter the production areas of sterile products, unless previously
established decontamination procedures are applied.
17.6.4 The adoption of high standards on personal hygiene and cleaning is essential. People
involved in the manufacturing of drugs must be instructed to communicate their superior of any
change in their health condition, which might contribute to the dissemination of contaminants. It
is convenient to perform periodic health examinations. The actions to be taken in relation to the
people which might be introducing improper microbiological risks must be taken by people in
charge designated to it.
17.6.5 The personal clothes must not be brought into the clean areas. People entering the
lockers of these areas must already be wearing the standard uniforms of the manufacturing site.
The clothes changing and hygiene processes must follow written procedures.
17.6.6 The garments and their quality must be adapted to the process and working area.
Besides, it must be wore in order to protect the product from contaminations.
17.6.7 Wristwatches and jewelry must not be worn in the clean areas, as well as cosmetic
products.
17.6.8 The garments worn must be appropriate to the classification of the clean area where the
personnel is working, and the following must be observed:
Grade D: Hair and beard must be covered. Protecting garments and shoes, or shoe protectors,
proper for the are must be worn. Appropriate measures must be taken in order to avoid any
contamination from external areas.
Grade C: Hair and beard must be covered. Appropriate garments, tightened around the pulse
and with turtle neck must be worn. The garment may not have loose fibers or particles. Besides,
shoes or shoe protectors proper for the area must be worn.
Grade B: A hood covering all the hair and beard, with its inferior border inside the garments
must be worn. A mask must be used on the face, in order to avoid sweat drops to spread.
Sterilized gloves, with no talc, disinfected or sterilized boots must also be worn. The pants hem
must be placed inside the boots, as well as the sleeves must be placed inside the gloves. The
protecting garment must not loose any fiber or particle and it must detain the particles released
by the body of whom wears it.
17.6.9 All employees working in grades B and C rooms must receive clean and sterilized
garments at each working shift. Gloves must be regularly disinfected during operations, as well
as the masks and gloves exchanged at each working shift.
17.6.10 The garments worn in the clean areas must be washed and cleansed to avoid the
release of contaminants in the areas where they will be worn. It is convenient to have a laundry
uniquely for this kind of garments. Garments damaged by usage may increase the risk of
releasing particles. The cleaning and sterilization operations must follow the Standard Operation
Procedures- SOPs.
17.7 Premises
17.7.1 All the premises must be designed in a way to avoid the unnecessary entrance of the
supervision and control staff. The grade B areas must be designed in a way that all the
operations may be observed from outside.
17.7.2 In the clean areas, all the surfaces exposed must be plain, impermeable, in order to
avoid the accumulation or release of particles or microorganisms, allowing the repeated
application of cleaning and disinfecting agents, when applicable.
17.7.3 In order to decrease the dust accumulation and to make the cleaning easier, in the clean
areas there must not be surfaces which may not be cleaned. The installations must have the
minimum of projections, shelves, cupboards and equipment. The doors must also be designed
in a way to avoid surfaces which may not be cleansed; sliding doors must not be used.
17.7.4 The coating must be sealed in a way to avoid contamination from the space above them.
17.7.5 The pipes and ducts must be installed in a way to avoid spaces difficult to clean.
17.7.6 The sinks and drains must be avoided, whenever possible, and there must not be areas
sinks and drains in the areas where aseptic operations are being performed. When their
installation is required, they must be designed, placed and maintained in a way to minimize the
risk microbial contamination, it must have efficient siphons, easy to be cleaned and appropriate
to avoid air and liquids refluxes. The ground drainage channels, if there is any, must be open,
easy to clean and be connected to external drains in a way that the introduction of microbial
contaminants is avoided.
17.7.7 The locker rooms in the clean areas must be designed as closed antechambers and
used in a way to allow the separation of the different garments changing steps, thus minimizing
the microbial contamination and particles from the protecting garments. Besides, the locker
rooms must be efficiently insufflated with filtered air. The use of separated locker rooms for
entry and exit may be necessary in some occasions. The premises designed to the hygiene of
hands, must be located only in the locker rooms, never where the aseptic operations are
performed.
17.7.8 The doors of the antechamber cannot be simultaneously opened, and there must be a
system to avoid this. There must be an alarm system, sonorous and/or lightening, alerting to the
situation mentioned above.
17.8 Equipment
17.8.1 The clean areas must have a ventilation system which insufflates the filtered air and
maintains a positive pressure of the area, compared to the surrounding areas. The ventilation
must be efficient and appropriate to the required conditions. Special attention must be given to
the areas presenting a higher risk, where the filtered air is in contact with the products and clean
components.
17.8.2 It may be necessary that the many recommendations related to the air supply and the
differential pressure are changed in case of the need to detain pathogenic materials, highly
toxic, radioactive materials or bacterial and live virus materials.
17.8.3 In some processes, it may be required the use of premises designed to decontamination
and the treatment of air leaving the clean area.
17.8.4 It must be shown that the air system does not constitute a contamination risk. It must be
ensured that it does not allow the dissemination of particles from people, equipment or
operations, to the production areas at higher risk.
17.8.5 An alarm system must be installed to indicate failures in the ventilation system. Besides,
a differential pressure index must be placed between the areas where this difference is
important. The pressure differences must be recorded.
17.8.6 The unnecessary access of material and people at the critic areas (grades B and C) must
be avoided. Whenever required, it must be done through physical barriers.
17.8.7 Transporting tracks interconnecting grade B clean areas to areas presenting an inferior
air classification grade must not be used, unless the track is continuously sterilized (e.g.: an
sterilizing tunnel).
17.8.8 The equipments used in the sterile products production, must be chosen in order to be
sterilized by steam, dry heat or other method.
17.8.9 Whenever possible, the equipment and utilities disposition must be designed and
installed in a way that the maintenance and repairing operations may be performed from the
outer side of the clean areas. The equipment that has to be removed for maintenance must be
sterilized again after they are reassembled.
17.8.10 When the equipment maintenance is performed into de clean areas, the instruments
and tools used must also be clean/disinfected. If the required cleaning and/or asepsis standards
are not kept during the maintenance service, the areas must be disinfected, so the production
may be restarted.
17.8.11 All the equipment, including sterilizers, air filtration systems and the water production
systems, must be subjected to a periodic maintenance plan, validation and monitoring. The
approval to the use of equipment must be documented, after the maintenance service.
17.8.12 The installations to be used for quality purified water production for injection must be
designed and maintained in a way to ensure the trustful production of water, of appropriate
quality. The system must not be operated beyond its installed capacity. The quality purified
water for injection must be produced, stored and distributed, according to the procedures
ensuring the maintenance of its characteristics, avoiding the proliferation of microorganisms.
17.9 Sanitization
17.9.1 The sanitization of the clean areas constitutes a particularly important aspect. These
areas must be frequently cleaned and sanitized according to a specific schedule approved by
the Quality Assurance. When using disinfectants, more than one kind must be used, with
frequent changes. Periodically, the management of the disinfectant used must be performed to
prove that there is not the development of resistant microorganisms. Viewing the limited efficacy
of ultraviolet radiation, it must not be used as a substitute in the chemical disinfecting
operations.
17.9.2 The disinfectants and detergents must be kept into previously cleaned containers and
must not be kept for long terms, unless they are sterilized. The partially emptied containers must
not be completed.
17.9.3 The fumigation of clean areas may be useful to reduce the microbial contamination into
inaccessible places.
17.9.4 The conditions of the clean areas must be monitored at pre-established periods during
the production operations, through the counting of viable particles in the air and surfaces
(microbiological). When aseptic operations are developed, the monitoring must be done more
frequently in to ensure that the environment is within the specifications.
17.9.5 The results of the monitoring must be taken into account when the batches are evaluated
for its approval. The quality of air in relation to the number of particles must also be regularly
evaluated. In some moments, when there is no production operation (after the maintenance,
validation, cleaning or fumigation processes) there might be the need of an additional
monitoring.
17.10 Production
17.10.1 Precautions must be taken in the sense of minimizing the contamination during all the
production steps.
17.10.2 The microbiological products with live organisms cannot be produced or filled in the
areas used for the production of other drugs. On the other hand, vaccines produced from
inactivated microorganisms or bacterial extracts may be filled, after their inactivation in the same
premises as other drugs, provided that the inactivation and cleaning procedures are validated.
17.10.3 The use of means of culture favoring the microbial growth in essays to simulate aseptic
operations (fillings with sterile means) constitutes an important procedure in the validation of a
aseptic filling process. These essays must present the following characteristics:
(a) they must simulate as faithful as possible the actual operations, taking into account factors
such as the complexity of operations, the number of people involved in the operation and the
term of filling;
(b) the mean selected must be able to promote the growth of a large number of microorganisms,
including those ones likely to be found in the environment where the filling process is performed;
(c) they must include the sufficient number of production units to check a high grade of safety
detecting lower levels of contamination. The inclusion of at least 3,000 production units is
recommended in each filling essay with the nutrient soap. The ideal growth percentage is of 0%;
and it must never be higher than 0.1% of contaminated units. All contaminations must be
investigated;
(d) the fillings with means of culture must be repeated at regular periods and every time there is
a significant change in the premises, equipment or process, a new validation must be done.
17.10.4 Care must be taken so the validation processes do not have a negative influence on the
production processes.
17.10.5 The activities developed in the clean areas must be as minimum as possible, specially
when aseptic operations are being performed. The people’s moves must be methodic and
controlled, with the purpose of avoiding the excessive loose of particles and microorganisms.
17.10.6 The raw materials specifications must also include requirements as for the microbial
quality. The microbial contamination of the raw materials must be minimum, and the bioload
must be monitored before sterilization.
17.10.7 The presence of containers and materials arising particles in the clean areas must be
reduced at a minimum and completely avoided when an aseptic work is being performed.
17.10.8 After the final cleaning or sterilization process, the handling of components, containers,
bulk products and equipment must be done in a way to avoid that they contaminate again.
Each step of the processing of components, containers for bulk products and equipment must
be properly identified.
17.10.9 The period between washing, drying and sterilization of components, bulk products
containers and equipment, as well as the period between sterilization and use, must be as
shorter as possible and it must be subjected to an appropriate limited time to the storage
conditions.
17.10.10 The period between the start of the preparation of a certain solution and its sterilization
or filtration through a bacterial retention filter, must be as short as possible. A maximum period
allowed must be established to each product, taking into account its composition and the
recommended storage method.
17.10.11 All the gas destined to help in the filtration or filling process of solutions must go
through a sterilizing filter.
17.10.12 The microbiological contamination of products (bioload) must be minimum before the
sterilization process. A maximum contamination limit must be established before sterilization,
related to the efficiency of the method that will be used and the risk of contamination by
pyrogenic substances.
17.10.13 All the solutions, specially large volume parenteral solutions must be filtered, by
sterilizing filters, if possible, immediately after its filling process.
17.10.14 When aqueous solutions are placed into sealed containers, the compensatory
pressure openings must be protected with hydrophobic filters which prevent the passage of
microorganisms.
17.10.15 The components, bulk product containers, equipment and/or any other articles
required in the clean area, where aseptic activities are being developed, must be sterilized and,
whenever possible, by double door sterilizers in the wall. Other procedures used with the
purpose of not introducing contaminants into the clean area, may be accepted under some
circumstances (e.g., triple cover).
17.10.16 Any new manufacturing procedure must be validated for proving its efficacy. The
validation must be repeated at regular periods or when significant changes in the process or
equipment are done.
17.10.17 The water provision sources, the water treatment equipment and the treated water
must be regularly monitored, as for the presence of chemical and microbial contaminants, and,
when applicable, a control for endotoxins (biological contamination) must also be performed, to
check if the water meets the appropriate specifications for its use. Records of the results of the
monitoring and measures adopted must be kept.
17.11 Sterilization
17.11.1 The sterilization may be done upon dry or humid heat application, gas agents, sterilizing
filtration with a subsequent aseptic filling of the final sterile containers, or by ionizing radiation.
Each method has its applications and specific limitations. Whenever possible and viable, the
method choice must be the sterilization by heat.
17.11.2 All the sterilization processes must be validated. The sterilization process must
correspond to the one stated in the technical report of the Product Registration.
17.11.3 Before the adoption of any sterilization method, its efficacy and adequacy must be
proven, so to the desired sterilization conditions are achieved in all the points of each type of
load to be processed. This validation must be repeated periodically, at least once a year, and
every time significant changes in the load to be sterilized or equipment is done. The results
must be recorded.
17.11.4 The biological indicators must be considered just as an additional method of monitoring
the sterilization processes. If they are used, strict precautions must be taken to avoid the
transfer of microbial contamination from them.
17.11.5 Clear means to differentiate the products and materials sterilized from the non-sterilized
ones must be established. Each container, tray or other kind of products or materials transporter
must be visibly identified with the material or product name, its batch number and the indication
if it was sterilized or not. When appropriate, indicators such as autoclave tape may be used, in
order to indicate if a certain batch was subjected to sterilization process or not. But, these types
of indicators do not provide trustful information proving that the batch was really sterilized.
17.12 Sterilization by heat
17.12.1 Each heat sterilization run must be recorded with appropriate equipment, accurately
and trustfully, (e.g.: time/temperature graphic with the a sufficiently broad range). The
temperature must be recorded from a lead-line placed in the coldest point of the sterilization
chamber. This point is determined during the validation process. The record system adopted for
the sterilization run must be part of the batch documentation. Chemical and biological indicators
may also be used, but they must not replace the physical controls.
17.12.2 Enough time must be given for all the load to reach the required temperature, before
the sterilization time measures are started. This time must be determined for each type of load
to be processed.
17.12.3 After the maximum temperature phase of the sterilization run by heat, the required
precautions must be taken in order to avoid the contamination of the sterilized load, during the
cooling phase.
17.12.4 No fluid or gas used in the cooling phase may be in contact with the sterilized product,
unless it is shown that any container presenting holes or micro-holes will not be approved for
use.
17.13 Sterilization by humid heat
17.13.1 The sterilization by humid heat is indicated in the case of materials permeable to water
steam and aqueous solutions. The temperature and pressure must be used to monitor the
process, the lead-line of the temperature indicator must be independent of the lead-line used by
the autoclave controller, and there must be a temperature indicator, which reading during the
sterilization process must be routinely verified, by comparison with the values obtained in the
graphic. If the autoclaves have a drain at the lowest part of the sterilization chamber, it is also
necessary to register the temperature of this position during all the sterilization process. When a
vacuum phase is part of the sterilization run, periodical controls on the chamber air-tightness
must be performed.
17.13.2 The sterilized materials to be used (when they are not products into sealed containers)
must be wrapped in materials which allow the removal of air and the enter of steam, and also
avoid the recontamination after sterilization. All the parts of the load of the autoclave must be in
contact with the saturated steam or with the water, at the required temperature and during all
the time established.
17.13.3 It must be ensured that the steam used in the sterilization meets the appropriate quality
to the process and does not contain quarantined additives which might cause contaminations of
the product or equipment.
17.14 Sterilization by dry heat
17.14.1 The sterilization process by dry heat must include the forced circulation of air inside the
sterilization chamber and the maintenance of a positive pressure, in order to avoid the entry of
non-sterile air. If air is inserted into the chamber, it must be filtered through a sterilizing filter.
When the sterilization process by dry heat is also used for the removal of pyrogenics, essays
using endotoxins must be performed as part of validation.
17.15 Sterilization by radiation
17.15.1 The sterilization by radiation is mainly used with materials and products sensitive to
heat. On the other hand, many drugs and some packaging materials are sensitive to radiation.
Therefore, this method must only be applied when there is no damaging effect to the product,
experimentally proved. The ultraviolet radiation is not an acceptable method of sterilization.
17.15.2 If the sterilization by radiation is performed through an agreement with third parties, the
manufacturer have the responsibility of guaranteeing that the requirements established are met
and that the sterilization process is validated.
17.15.3 During the sterilization process the radiation doses used must be measured. With this
purpose, dosimeters which are independent from the amount of dose applied and which
indicate the real amount of radiation doses received by the product must be used. The
dosimeters must be included in the load in a number sufficient and so close one from the others
that they allow to ensure that there is always a dosimeter in the radiation chamber. When plastic
dosimeters are used, they must be used within a time limit established after their calibrations, as
well as the values readings must be performed as close as possible of the radiation incidence.
The biological indicators may only be used as an additional control mean.
17.15.4 Colored disks sensitive to radiation may be used to differentiate the packages subjected
to radiation from the ones not subjected; These disks may not be considered as indicators of
sterility guarantee. All the information obtained during the process must be registered in the
batch documentation.
17.15.5 The validation methods of the processes used must ensure that the effects of the
ranges of the packaging material densities were considered.
17.15.5 The procedures for the handling of materials must ensure that there is no possibility of
missing irradiated products with non-irradiated ones. Each package must have an indicator
sensitive to radiations identifying the irradiated ones.
17.15.6 The total radiation dose must be applied for a pre-established period of time.
17.16 Sterilization by ethylene oxide
17.16.1 The sterilization method using the ethylene oxide must only be used when any other
method is viable. During the process validation, it must be shown that there are no hazardous
effects for the product and that the ventilation time is enough for the reactive gas and products
wastes are below the limit established as acceptable for the product.
17.16.2 It is essential the direct contact between the gas and the microbial cells. The nature and
quantity of packaging materials may significantly affect the process.
17.16.3 Before being subjected to the gas action, the materials must reach and maintain the
balance with the temperature and humidity required by the process. The time used in this
process must be considered to minimize the time before sterilization.
17.16.4 Each sterilization run must be monitored with appropriate biological indicators, an
appropriate number of them must be used, distributed over all the load. The information
obtained must be part of the batch documentation.
17.16.5 The biological indicators must be preserved and used according to the manufacturer’s
instructions and their performance must be checked through positive controls.
17.16.6 For each sterilization run, a record of the sterilization running time, pressure,
temperature and humidity inside the chamber during the process and the gas concentration
must be kept. The pressure and temperature must be registered on a graphic during the run.
The records must be part of the batch documentation.
17.16.7 After sterilization, the load must be stored in a controlled way, under ventilation
conditions, so the presence of gas waste and reactive products decreases to acceptable levels.
This process must be validated.
17.17 Filtration of drugs which may not be sterilized in their final containers
17.17.1 Whenever possible, the products must be sterilized in the final containers, specially by
humid heat sterilization. Some solutions and liquids which may not be sterilized in their final
containers, may be filtered to previously sterilized containers, through sterile filters, with 0.22
µm (or less) sized pores or presenting similar properties, to the retention of microorganisms.
The possibility of supplementing the filtration process with some heating phases must be
considered.
17.17.2 Filters which loose fibers must not be used. The use of amianthus filters must be
definitely excluded.
17.17.3 The filter integrity must be checked though an appropriate method (e.g., application of
the “bubble point” essay), before its use and immediately after its use. The time spent to filter a
known volume of a certain solution and the difference of pressure used must be determined
during the process validation. Any significant differences related to established standards must
be recorded and investigated. The results of these verifications must be written in the batch
documentation.
17.17.4 The filter must not affect the product, removing its active ingredients or adding other
substances.

17.18 Finalization of the manufacturing steps

17.18.1 The containers must be sealed upon appropriate, duly validated procedures. Samples
must be controlled in relation to their integrity, according to established procedures. In case of
air-tightened closed containers, the samples must be controlled to check the air-tightness
maintenance according to the pre-established period of time.
17.18.2 The final container containing parenteral products must be individually inspected. If the
inspection is visual, it must be done under appropriate and controlled conditions of light and
contrast. The operators designated to this job must be subjected to periodical exams of visual
accuracy, considering the corrective lenses, if applicable, and frequent rest stops during the
work shift. If other inspection methods are used, the process must be validated and the
equipment trustfulness must be periodically verified.
17.19 Quality control
17.19.1 The samples collected to the sterility essay must be representative of the whole batch,
an special attention must be given in the batch parts representing a higher contamination risk,
such as:
(a) products that went through an aseptic filling process - the samples must include the initial
and final containers of the batch, and also after any significant interruption of work;
(b) products sterilized by heat in their final package - the samples must include the packages of
the potentially colder areas of the load.
17.19.2 The sterility essay applied to the final product must be considered as the last one of a
series of control measures, through which the sterility is guaranteed. The result of the essay can
only be interpreted together with the records on the environmental conditions and the records
related to the batch manufacturing.
17.19.3 The batches non-approved in the initial sterility test cannot be approved based on a
second test, except if an investigation is performed on the kind of microorganism found and the
records on the environmental conditions and on the batches processing, and the result of this
investigation shows that the initial test was not valid.
17.19.4 In case of injectable products, the presence of endotoxins in the water used must be
controlled, in the intermediary and finished products, using a pharmacopoeia method validated
for each type of product.

18. Biological products

18.1 Reach
18.1.1 The purpose of this chapter is to supplement the “Good Manufacturing Practices for the
Manufacturing of drugs”, reinforcing the specific points on the manufacturing of microbiological
products.
18.1.2 The regulatory procedures requires to the control of biological products are, in a great
part, determined by the products origin and by the manufacturing technology used. The
manufacturing procedures in this Regulation include:
growth of strains of microorganisms and eucaryotic cells;
extraction of active principles from biological fluids or animal or vegetal (allergenic) tissues;
recombining DNA technique (rDNA);
hybridome technique;
multiplication of microorganisms in embryos or animal organs.
18.1.3 The biological product manufactured with these technologies include antigens, vaccines,
hormones, cytokines, enzymes, human plasma derivatives, hyperimmune serum (heterologue),
biotechnology products and monoclonal antibodies.
18.2 Glossary
The definitions presented below apply to the terms used in this Regulation, and they may show
different meanings, in other contexts.
Clean area
Area with environmental control defined in terms of contamination by viable or non-viable
particles, designed, built and used in a way to reduce the introduction, generation and retention
of contaminants inside it.
Manufacturing Cells Bank (MCB)
Vials containing cells, obtained from a Seed Cell vial, preserved at temperature of <-70o C, used
for the production of Cell Growth.
Seed Cell
Vials containing animal cells, from known origin, preserved at temperature <-70o C.
Individual collection
Suspension of microorganisms obtained from a Production Inoculums inoculated and colleted in
a single production cycle.
Production Cell Growth
Suspension of cells, obtained from one or more vials from the Manufacturing Cells Bank
inoculated and collected in a single production cycle.
Production Inoculums
Suspension of microorganisms, of uniform composition, obtained from one or more vials from
the Secondary Batch.
Seed Batch
Vials containing preserved microorganisms, or uniform compositions, obtained from a preserved
strain and known origin.
Secondary Batch (Work)
Vials containing preserved microorganisms, of uniform composition, obtained from a Seed
batch.
Batch Registration
Collection of documents related to the manufacturing of a certain batch of finished product.
These documents describe the production procedures and record the operations related to the
batch quality, including the Certificate of Batch Release.
18.3 General considerations
18.3.1 The manufacturing of biological products must be done according to the basic principles
of the Good Manufacturing Practices (GMP). Therefore, the matters addressed in this chapter
are not considered supplementary to the general rules established in the “Good Manufacturing
Practices of Drugs” and are specifically related to the production and quality control of biological
drugs.
18.3.2 The way the biological products are produced, inspected and administered make some
special precautions necessary. On the contrary of the chemically defined drugs, which are
usually manufactured and controlled by chemical and physical reproducible techniques, the
biological products are manufactured with technologies involving processes and biological
materials not always reproducible.
18.3.3 The production processes of biological products have an inner variability and therefore,
the degradation and nature of the byproducts are not constant. For this reason, in the
manufacturing of biological products it is even more critical that the recommendations
established by GMPs are met, during all the production phases.
18.3.4 The quality control of the biological products almost always imply in the use of biological
techniques with a larger variability than the physical-chemical determinations. The control during
the process acquires a great importance in the production of the biological products because
some quality deviations are not detected in the quality control essays performed in the finished
product.
18.3.5 This Regulation does not establish detailed rules for specific classes of biological
products and, therefore, the pertinent orientation in the Rules of Production and Quality Control
specific to each product must be considered, when applicable.
18.4 Personnel
18.4.1 The manufacturing of biological drugs must be oriented by a person expert in the
manufacturing techniques and who knows the scientific principles upon which these techniques
are based. The staff must include experts with specific graduation for the products produced in
the premises.
18.4.2 The personnel working in the clean areas must be carefully selected, in order to ensure
the fulfillment of the requirements of the Good Manufacturing Practices. The employees
selected must not present any health disorder which might compromise the product integrity.
18.4.3 The personnel must rigorously follow the cleaning and personal hygiene procedures.
18.4.4 The personnel must be oriented to inform any health disorder (diarrhea, cough, cold,
contaminated skin, wounds, fever of unknown cause) which may cause microorganisms
contamination in the working environment, different to the ones used in the production.
18.4.5 Admission and periodical medical examinations must be performed in the staff to detect
any health disorder.
18.4.6 All the health condition change which might affect the product quality implies in the
exclusion of the person from the production areas.
18.4.7 When working in clean areas, only the minimum personnel required must be present.
Whenever possible, the inspection and control procedures must be performed from outside of
these areas.
18.4.8 During the working shift, the personnel must not pass from the areas where they
manipulate microorganisms or live animals to the premises where other products or organisms
are being worked with, unless the definite decontamination measures are applies, including the
change of uniform and shoes.
18.4.9 Person non-authorized must not enter into the production areas, unless for specific
purposes and, at last instance, they must be wearing appropriate and sterilized garments.
18.4.10 The designees for production must be different from the personnel responsible for the
animal care.
18.4.11 In order to ensure the quality of the manufactured products, personnel must be trained
in the Good Manufacturing Practices and have graduation and knowledge of the specific areas,
according to the product manufactured.
18.4.12 There must be records of the trainings. The training programs must be evaluated to
proved their efficacy.
18.4.13 All personnel directly or indirectly involved in the production must be immunized with
specific vaccines and, when required, subjected to periodic tests to the detection of infectious-
contagious diseases signs.
18.4.14 When BCG vaccine is manufactured, the access to the production areas must be
restrict to personnel carefully monitored through periodical medical examinations.
18.4.15 In case of the manufacturing of blood or human plasma derivatives, personnel must be
immunized with the vaccine for hepatitis B.
18.5 Premises and Equipment
18.5.1 As general principle, the premises must be located, designed, built, adapted and
preserved to be appropriate to the operations performed there. The areas used in the
production, the quality control laboratories and all the other areas (including the ones designed
to animals used in the manufacturing of biological products) must be designed to gather the
best hygiene conditions and protection against dust, insects and rodents, and they must be built
with materials appropriate to the purpose they are designed for.
18.5.2 The internal surfaces (walls, floor and ceiling) must be plain with no cracks; they must not
loose material and must be easy to clean and disinfect.
18.5.3 Drains must be avoided in the production areas to eliminate wastes, unless required and,
when there are drains, they must have siphons easy to clean and disinfect, with valves avoiding
counter-flow.
18.5.4 There must not be drains in the clean areas.
18.5.5 If there are external pipes for draining, in the floor, it must be open, plain, easy to clean,
and it must be connected to drainage, to avoid the entrance of contaminants in the area.
18.5.6 Lavatories must not be installed in the clean areas of classes A, B and C. The lavatories
installed in other clean areas must be made of materials easy to clean, such as stainless steel.
18.5.7 Special cares must be taken to avoid contamination of the wastes elimination system,
with dangerous effluents.
18.5.8 The air dissemination of pathogen microorganisms handled in the production must be
avoided.
18.5.9 The product contamination by other microorganisms and substances, including the ones
from the personnel involved in the production process, must be avoided.
18.5.10 The illumination, heating, ventilation and, when required, the air conditioning system
must be designed to maintain the temperature and relative humidity of the air in the appropriate
conditions for each product; reduce the contamination to a minimum and it must also take into
account the comfort of the personnel working with protecting garments.
18.5.11 The buildings must be in good preservation conditions and must be regularly inspected
to identify the need of repairs.
18.5.12 Special care must be taken to ensure that the repair or maintenance operations of
buildings do not affect the products.
18.5.13 The premises must provide space enough for the operations to be performed safely and
to allow the continuity and efficiency of work.
18.5.14 All the buildings and other areas must be in satisfactory cleaning and hygiene
conditions full time.
18.5.15 The areas used to work with animal tissues and microorganisms not used in the
production process, as well as, where the animals or microorganism essays are performed,
must be separated from the premises used in the production of sterile biological products, with
independent ventilation and different staff.
18.5.16 In the areas used for the production of products in campaign, the premises design and
placement of equipment must allow a rigorous cleaning and sanitization after production and,
when required, the efficient decontamination through sterilization and/or fumigation. All the
processes used must be validated.
18.5.17 The seed batch and the cell bank, used in the manufacturing of biological products
must be stored separated from the other materials. The access to these materials must be
restrict to authorized persons only.
18.5.18 The live microorganisms must be handled in equipment and with procedures ensuring
the maintenance of the cultures purity, as well as, protecting the operator from contamination
with the microorganism mentioned.
18.5.19 Biological products, such as vaccines with dead microorganisms, toxoids, extracts from
bacteria, including the ones prepared through the recombinant DNA technique, may, once
inactivated, be filled in the same premises used for other sterile biological products, provided
that appropriate measures of decontamination after filling are taken, including cleaning and
sterilization. All the processes used must be validated.
18.5.20 Biological products from sporulated microorganisms must be handled in exclusive
premises for this group of products, until the inactivation process is finished. When dealing with
Bacillus anthracis, Clostridium botulinum and Clostridium tetani, isolated and exclusively
designed premises must be used for each one of these products.
18.5.21 When in a premise or group of premises preparations of sporulated microorganisms for
the production in campaign are performed, only one product must be produced at a time.
18.5.22 The manufacturing of products derived from human blood or plasma, premises and
equipment designed exclusively for this purpose must be done.
18.5.23 All the containers with biological substances, of any production step, must be identified
with firmly adhered tags.
18.5.24 The cross-contamination must be avoided adopting any one of the following measures
or all of them:
18.5.24.1 to perform the production and filling in specific areas;
18.5.24.2 to avoid the production of different products at the same time; unless they are
effectively in physically separated areas;
18.5.24.3 to transfer biological materials safely;
18.5.24.4 to change garments when entering different production areas;
18.5.24.5 to clean and decontaminate carefully the equipment;
18.5.24.6 to take precautions against the contamination risks caused by recirculation of air in
the clean environment or by the accidental return of the disposed air;
18.5.24.7 to use “closed systems” in the production;
18.5.24.8 to avoid the formation of aerosols (mainly by centrifugation and mixings);
18.5.24.9 to prohibit the entry of pathological samples in the areas used for the production of
biological substances;
18.5.24.10 to use sterilized containers, and when requires, depyrogenized containers.
18.5.25 The preparation of sterile products must be performed in clean area with positive air
pressure. But, all the organisms considered as pathogens must be handled with negative air
pressure, in places specially separated for this purpose, according to the isolation rules for
these products.
18.5.26 The areas where pathogen microorganisms are handled must have an exclusive
system of air circulation. The air must be disposed through sterilizing filters which functioning
and efficiency must be periodically checked. The filters used must be incinerated after disposal.
18.5.27 When used in the production of pathogen microorganism products, the production area
must have specific decontamination systems of effluents.
18.5.28 The ventilation pipes, valves and filters of the equipment must be designed to make
their cleaning and sterilization easier. The fermentation container valves must be sterilizable
and appropriate to use.
18.5.29 Small amounts of substances to be used during the production process may be left in
the production areas, provided that they are not returned to warehouse.
18.5.30 The powdered raw material, used in the preparation of means of culture, buffers, etc.,
must be handled outside the clean areas and purification areas, viewing the minimum
contamination of the product with particles.
18.6 Production
18.6.1 In all manufacturing operations the duly updated Standard Operation Procedures (SOP)
must be followed.
18.6.2 The specifications of raw materials must include details, such as manufacturer, origin,
production process and quality control analyses performed. The release of the raw material to
be used in the production is conditioned to its previous approval by the company’s quality
control.
18.6.3 The mean of culture must be added to the fermentation tank or to another container
under controlled conditions to avoid contamination. Care must be taken in order to endure that
the containers are correctly connected during the transfer of the mean of culture.
18.6.4 When possible, the means of culture must be sterilized in situ.
18.6.5 When possible, sterile filters installed and sterilized in-line must be used to add gas,
means of culture, acids, alkalis, anti-foaming agents, etc., to the fermentation containers.
18.6.6 The sterilization process must be validated.
18.6.7 When an inactivation process is performed during the production, measures must be
taken in order to avoid the risk of cross-contamination between the active and inactive products.
18.6.8 The chromatography column used in the production of biological products, must be
designed to the purification of only one product, and it must be sterilized or sanitized after each
process run. The shelf-life of the resin used and the method of sterilization and/or sanitization
used must be defined. The maximum limits of microbial load and endotoxins in the column must
be established.
18.6.9 In the production of Hemoderivatives, human plasma used as raw material must originate
from whole blood units and/or plasmapheresis individually subjected to the binding serological
control established by the National Rules. Each plasma unit tested must be non-reagent to the
serological controls performed.
18.7 Labeling
18.7.1 All the products must be clearly identified. The labels used must maintain well adhered to
he containers, no matter the storage conditions. If the definite filling container does not allow to
place a label, it must be placed in a labeled package.
18.8 Batch records
18.8.1 The batch records must provide the complete data of the background of the
manufacturing of each batch and show that they were produced, filled, and controlled according
to the approved procedures
18.8.2 There must be a production order for each batch size, that is the faithful copy of the
master/standard formula.
18.8.3 All the data required to the following of the different steps of the production process and
quality control tests of each batch must be recorded.
18.8.4 The record of each product batch must be kept by the manufacturer for, at least, two
years after the batch expiration date.
18.9 Quality assurance
18.9.1 The Quality Assurance and/or the Quality Control have, but are not limited to, the
following responsibilities:
18.9.1.1 To approve the Standard Operation Procedures (SOPs) for each production process
and quality control;
18.9.1.2 to ensure that the samples used in the tests are identified and packaged in a way to
maintain their integrity;
18.9.1.3 to ensure that constant managements of the environmental conditions are performed;
18.9.1.4 to ensure the perfect functioning of the equipment and instruments used in the
production steps and quality control;
18.9.1.5 to evaluate and approve raw materials, packaging materials, intermediary products,
bulk products and finished products;
18.9.1.6 to ensure the appropriate storage conditions of raw materials, intermediary and finished
products;
18.9.1.7 to determine the stability of the finished products and, when required, of the raw
materials, intermediary products and bulk products.
18.9.1.8 to establish the expiration date for each product as for the specific stability conditions;
18.9.1.9 to establish the specifications of materials, the production and quality control
procedures and the date for revision;
18.10 Quality control
18.10.1 The Quality Control must be independent from the production.
18.10.2 The Quality Control must have the area and equipment required and sufficient to
operate as a complete unit with proper areas to file documents, keep reference samples and
perform quality control tests.
18.10.3 The quality control essays which may not be performed in the finished product, must be
performed in a defined step of the production.
18.10.4 Some production steps must be monitored and registered continuously, by the quality
control, during all the production process.
18.10.5 It must be taken special care in the quality control procedures when using continuous
cell lines to obtain a biological product.
18.11 Animals premises
18.11.1 The animals used in the production and quality control must be placed in premises
independent from the other areas of the company, with independent ventilation systems.
18.11.2 The design of the premises and the construction materials used must allow the
maintenance of the areas in hygiene conditions and have counter-entrance for insects and other
animals.
18.11.3 The personnel working with the animals must wear garments for exclusive use in the
area.
18.11.4 The premises to animal care must include an isolation area to quarantine animals
entering and an area to store food.
18.11.5 The animals inoculation area must be distinct from the one designed to the performance
of necropsy.
18.11.6 There must be a premise to disinfect cages, if possible, to sterilize them with steam.
18.11.7 It is required to control and record the health condition of the animals used.
18.11.8 Special precautions are required when using monkeys in the production or quality
control.
18.11.9 The wastes and corpses of animals must be eliminated with safety, decontaminated by
sterilization and, if possible, incinerated.
19. Validation of the Manufacturing Processes
19.1 Reach
19.1.1 The purpose of this chapter is to establish the principles and concepts of the validation
procedures to supplement the “Good Manufacturing Practices of Drugs”, reinforcing the specific
points on validation of manufacturing processes of drugs.
19.1.2 Validation is a documented act attesting that any procedure, process, equipment,
material, operation, or system really conduct to the expected results.
19.1.3 The validation of processes is an additional requirement to the “Good Manufacturing
Practices of Drugs”, therefore, it has a general application to all drugs.
19.1.4 Any procedure different from the described general procedures in this chapter is not
recognized, unless, its validity is shown.
19.1.5 The fulfillment of the “Good Manufacturing Practices of Drugs” require the validation of
the production processes, as well as the validation of any change introduced in the production
processes, which might affect the quality of the product.
19.1.6 The validation of all the manufacturing processes and support activities must be
performed, including the cleaning operations.
19.1.7 The validation of the analytical procedures has the purpose of showing that the essay
methods used present results allowing the objective evaluation of the quality of the drugs,
according to the specified parameters. Each new analytical procedure must be validated.
19.1.7 The equipment, instruments and glassworks used in the analytical essays must be
qualified and/or certified. The measuring instruments used for this qualification, must be
calibrated.

19.2 - Glossary
The definitions presented below apply to the terms used in this Regulation. The same terms
may present different meanings, on another context.
Calibration
Group of operations establishing, under specified conditions, the relation between the values
shown by a measuring instrument, system or values presented by a measuring material
compared to the ones obtained with a correspondent reference standard.
Acceptance criterion
Criterion establishing the acceptance limits of the specifications of raw materials, products or
processes/systems, required to take the decision of accepting or not, related to a certain
sampling plan, when applicable.
Specifications
Document describing in details the requirements the products or materials used or obtained
during the manufacturing must meet. The specifications act as the base for the quality
evaluation.
Validation Master Plan (VMP)
Planning of all the validation activities with the purposes, procedures, deadlines and
responsibilities defined.
Production Process
Production of drugs from defined raw materials, in a single process or in a sequence of
processes, involving premises, personnel, documentation, and environment.
Validation Protocol
Company document specific for each activity describing the procedures to be performed in the
validation, including the acceptance criteria for approval of a production process or part of it.
Equipment qualification (EQ)
Collection of operations establishing, under specified conditions, that the results of the tests of a
certain equipment show that it presents the expected performance. The measuring instruments
and systems must be calibrated.
Installations qualification (IQ)
Collection of operations establishing, under specified conditions, that the installation of
equipment, utilities, weighing and measuring instruments and production areas, in the drug
manufacturing, were properly selected and are correctly installed, according to established
specifications.
Operational qualification (OQ)
Collection of operations establishing, under specified conditions, that the system or sub-system
presents the expected performance, in all operational bands considered. All the equipment used
to perform the tests, must be identified and calibrated before their use.
Validation report
Document where the records, results and evaluation of a finished validation process or system
are gathered.
Revalidation
Repetition of the approved validation process, that provides the guarantee that the changes
introduced in the process/equipment, according to the changes of procedures or periodical
repetition performed at scheduled periods, do not adversely affect the characteristics of the
process neither the product quality.
Choice tests/ worst case
A condition or collection of conditions comprehending the higher and lower limits of processing
and the respective circumstances, within the specifications of the Standard Operation
Procedures, presenting the higher possibilities of product or process defect, when compared to
the ideal conditions.
Validation
Documented act attesting that any procedure, process, equipment, material, operation or
system, really conduct to the expected results.
19.3 - General considerations
19.3.1 The validation is part of the Quality Assurance. The validation involves the systematic
study of the premises, systems, and processes with the purpose of determining if they perform
their function properly and consistently, according to the specified. A validated operation
ensured the production of uniform batches which meet the required specifications.
19.3.2 On the contrary of many GMP requirements, validation by its own does not improve the
processes. It may only confirm or not, depending on the case, that the process was properly
developed and the it is under control.
19.3.3 All the activities of product developing must be concluded with a validation phase, this
includes, specially, the manufacturing of products under clinical trial and when the large scale
production of products developed in pilot designs is started.
19.3.4 The validations performed during the development phase of the products do not
guarantee that all production processes are properly validated. Consequently, validation must
be discussed within a broader context, as an activity started during the development and that
continues until the large scale production.
19.3.5 The validation processes required the mutual collaboration of all sectors involved, such
as development, production, engineering, maintenance, quality assurance and quality control.
19.3.5 Validation allows:
19.3.5.1 To enhance the knowledge in the production processes and, thus, to ensure that the
processes are under control.
19.3.5.2 To decrease the risks of quality deviation.
19.3.5.3 To decrease the risks of the non-conformity to the established requirements.
19.3.5.4 To decrease the quantity of quality control tests in the in-process control steps and in
the finished product.
19.4 Types of process validation
19.4.1 Prospective validation
The prospective validation is a documented act, based in the execution of a previously defined
tests plan, showing that the new system, process, equipment or instrument, not in operation yet,
meets the functional specifications and performance expectations.
19.4.1.1 The prospective validation is performed during the product development step, through
the analysis of the risk of the manufacturing process, which is detailed in individual steps; these
steps, by their turn, are defined based on the previous experience to determine if they can
cause critical situations.
19.4.1.2 The critical points must be identified, evaluated as for their probability and extension,
and have their causes researched. The research plans are defined, establishing the priorities
and their final evaluation.
19.4.1.3 If, at the end of the validation process, the results are acceptable, the process is
satisfactory. If the results are unsatisfactory changes in the process must be searched until it
presents acceptable results. This validation form is essential to limit the risk of errors occurring
in the large scale production.
19.4.2 Concurrent or simultaneous validation
The concurrent validation is performed during the routine production. This method is only
efficient if the product development step resulted in the appropriate knowledge of the process
basis. The first batches of the industrial production must be monitored as broadly as possible.
The nature and specifications of the subsequent in-process tests and final tests are based in the
evaluation of the results of the mentioned management.
19.4.2.1 The concurrent validation, together with a analysis of trend including the stability
studies, must be performed with the appropriate extension along the product life.
19.4.3 Retrospective validation
Retrospective validation is a documented act, based on the revision and analysis of the
background records, attesting that a system, process, equipment or instrument, already being
used, meets the functional specifications and performance expectations.
19.4.3.1 The retrospective validation involves the verification of the past experience of
production, assuming that the composition, procedures and equipment keep unchanged; the
mentioned experience and the results of the in-process control and final control tests are
evaluated. The difficulties and defects registered in the production are analyzed to determine
the limits of the process parameters. A trend analysis may be performed to determine the
extension in which the process parameters are within the allowable range.
19.4.3.2 Obviously, the retrospective qualification is not, in itself, a guarantee measure of
quality, and it must never be applied to new processes or products. It can only be considered in
special circumstances, e.g., when the validation requirements are established for the first time
within the company. In this case the retrospective validation may be useful to establish the
priorities in the validation program. If the retrospective validation results are positive, this
indicates that the process does not require immediate attention and may be validated according
to the normal schedule.
19.4.4 Revalidation
The revalidation is required to ensure that the intentional or non-intentional changes in the
production process, equipment and environment, do not adversely affect the process
characteristics and the product quality. The revalidation may be divided into two broad
categories:
19.4.4.1 - Revalidation after any change may alter the product quality.
19.4.4.1.1 The revalidation must be performed when any changes which might affect the
manufacturing and/or standard procedure, influencing the performance characteristics
established for the product are introduced.
19.4.4.1.2 Each raw material, packaging material, manufacturing process, equipment, in-
process controls, manufacturing areas and utilities (water, steam, etc), must be evaluated by the
company validation group, which decides if it is significant enough to justify a revalidation and,
its extension.
19.4.4.1.3 The revalidation after the changes may be based on the performance of the same
tests and activities performed during the original validation, including the in-process tests and
the ones related to the equipment.
Some typical changes requiring revalidation are:
Raw material: changes in the physical properties, such as density, viscosity, granulometry and
type of crystal, which might adversely affect the process or product.
Packaging material: any packaging procedure change which might affect the product stability,
e.g., replacement of a plastic material for filling for a glass material.
Process: any change which might affect the subsequent steps of the process and the product
quality, e.g., mixing time, drying temperature and cooling procedure.
Equipment, including measuring instruments: any replacement, repair and maintenance which
might affect the process as well as the product;
In the production area and utilities: any replacement, repair and maintenance which might affect
the process as well as the product, e.g., repair and maintenance of the ventilation system might
change the environmental conditions and, consequently, its revalidation might be required,
specially in the manufacturing of sterile products.
When deviations are detected during the self-inspection or audit, or during the continuous
analysis of the process data trend.
19.4.4.2 Periodic revalidation:
The changes of process might occur gradually, even when experimented operators work
correctly, according to the established methods. Similarly, the excessive use of the equipment
might also cause gradual changes. The revalidation into scheduled periods is recommended,
including cases where no change is detected, considering the use of the equipment and
possible human errors.
19.4.4.2.1 The decision of implementing periodical revalidation must be based specially on the
background data revision, generated during the in-process tests and finished product tests, after
the last validation, with the purpose of checking if the process is under control. During the
revision of the background data mentioned, any bias of the collected data must be evaluated.
19.4.4.2.2 In some production processes, the following points must be checked in the
revalidation:
19.4.4.2.2.1 If there is any change in the formula, procedures, batch size, etc. If positive, if its
impact on the product was evaluated.
19.4.4.2.2.2 If the calibrations were performed according to a established schedule.
19.4.4.2.2.3 If the prevention maintenance was performed according to a established schedule.
19.4.4.2.2.4 If the Standard Operation Procedures (SOPs) were properly updated.
19.4.4.2.2.5 If the SOPs were implemented.
19.4.4.2.2.6 If hygiene and cleaning program were implemented.
19.4.4.2.2.7 If any change on the control analytical methods was performed.
19.5 Pre-requisites to the validation of a production process.
19.5.1 Before starting the process validation, the equipment used in the production and the
control instruments, as well as the formulation must be qualified. The drug formulation must be
studied in detail and qualified in the development step. This involved the pre-formulation
studies, studies on the compatibility of active principles and excipients, as well as the finished
product and the packaging material, stability studies, etc.
19.5.2 Other aspects on the production must be validated, including the utilities (water, air,
nitrogen, electrical power, etc.) besides the support operations, such as cleaning and
sanitization of equipment and premises. The appropriate training and motivation of personnel
are pre-requisite to a successful validation.
19.6 Approaches
19.6 There are two basic approaches to the process validation:
19.6.1 Experimental approach, which is applicable to the prospective and concurrent
validations:
19.6.1.1 Broad product test.
19.6.1.1 One of the most practical process validation, specially to non-sterile products, is the
final product test with a larger extension than the required by the routine quality control. It may
involve the broad sampling, much beyond the one used to the routine quality control and tests
according to the normal quality control specifications, and usually only for some parameters.
Thus, for instance, some hundreds of tablets may be weighed by batch to determine the dose
uniformity. Then, the results are statistically treated in order to check the distribution normality
and to determine the average weight standard deviation. The trust limits to individual results and
to the batch homogeneity are also estimated. A broad safety that the samples randomly
collected meet the requirements of the regulation is provided if the trust limits are met within the
compendia specifications.
19.6.1.1.2 Similarly, sampling and broadening tests may be performed in relation to any quality
requirement. Additionally, the intermediary steps may be validated the same way, samples may
be individually essayed to validate the mixing steps or granulation steps in the low dose tablets
production, using the content uniformity test. The non-visible particle, in parenteral preparations,
may be detected through electronic devices.
19.6.1.2 Process conditions simulation
19.6.1.2.1 The process simulation characteristics are mainly used to validate the aseptic filling of
parenteral products which may not be sterilized in their final presentation. This involves the vials or
vial-flasks with mean of culture under normal conditions, followed by the incubation and control of
microbial growth, the number of vials and vial-flasks contaminated must be less than 0.1%.
19.6.1.3 Choice conditions / worst case
19.6.1.3.1 The procedure choice to be validated must have as a priority the activities related to
the process capacity, e.g., the process capacity may operate with no difficulties when the
parameters are close to acceptable limits. The use of acceptance bands to the raw material
quality in experimental batches may make the estimation of the extension where the process is
still able to produce a final product meeting the specifications possible.
19.6.1.4 Process parameters control
19.6.1.4.1 The physical parameters of the process are monitored in normal production runs in
order to obtain additional information on the process and its trust. Additional devices sensitive to
temperature, installed in an autoclave or in a sterilization/depirogenization heater, allow to
perform a detailed study on the distribution of the heat to the many loads. Heat penetration
measures must be performed to the products for injection presenting a higher viscosity or
volumes above 5 mL. The equipment for compression and production of tablets equipped with
cells sensitive to pressure is useful to the collection of statistical data on the compression
uniformity and, therefore, on the weight uniformity.
19.6.2 Approach based on the background data analysis
19.6.2.1 In the approach based on the background data analysis retrospective validation
experiments are not performed, but, on the contrary, all the background data available related to
a number of batches are combined and analyzed together. If the production is being developed
with no difficulties during the period previous to the validation, the in-process tests data and the
product final tests must be statistically collected and evaluated. The results, including the
process capacity studies, bias analysis, etc., indicate whether the process is under control or
not.
19.6.2.2 The results and quality control and process records may be used, to the retrospective
validation. A careful revision of the graphics allows to estimate the process trust. A process can
be considered trustful if the data recorded are within the control limits and the individual results
range are stable.
19.6.2.3 Additionally, the information on the problems related to the product is also analyzed.
The process trustful is shown if, during a considerable time, there are no rejections, complaints,
returns, unexpected adverse reactions, etc. The process may be certified as retrospectively
validated if the statistical analysis results are satisfactory, and the absence of quality deviation is
documented. But, it must be emphasized that this approach is not applicable to the
manufacturing of sterile products.
19.6.3 Example of priorities to a production process validation program
Table 1
Type of process Validation requirements
New Process
All new processes must be validated before their
approval for routine production.
Routine process to the All the processes affecting the sterility and the
production of sterile environment of the manufacturing must be validated;
products specially the sterilization process.
Routine production for Low dose tablets and capsules containing highly active
the production of Non- substances: mixing validation and granulation related to
Sterile products the content uniformity.
Other tablets and capsules: validation of the operation of
tablets compression and capsules filling related to the
weight uniformity.
19.6.4 It may be noticed that, once prepared the previous batches control graphics, they
become a potent tool to the prospective quality management. The data to new batches are
recorded over the same graphics, and, for each result out the control limits, a reason for this
deviation is searched and once found, it must be eliminated. Applying this approach,
consistently during a certain period of time, the process may be considered satisfactory.
19.7 Organization
19.7.1 In the Organization chart of the company the responsibilities to the validation activities
must be established. For this purpose, the company Board, must designate a person
responsible for the validation activities (head of validation), who institutes a validation group
(team, committee). This group must have representatives of all the main sectors: Development,
Production, Engineering, Maintenance, Quality Assurance and Quality Control. The group
composition must be periodically renewed, in order to propitiate the opportunity for other people
to contribute with new ideas and to acquire experience. The group prepares a validation
program defining its priorities, schedule, required resources, etc. A program must be revised
and approved by the sectors involved. The final revision and approval are a responsibility of the
head of validation.
19.8 Scope of a process validation program
The priorities suggested for a validation program are related in Table 1. For new processes it is
recommended that the first three (3) industrial production batches are not released from
quarantine after their approval by the quality control, until their validation is concluded, the
results presented and revised and the process approved.
19.9 Validation Master Plan
The Validation Master Plan of a specific process, must contain, at least, the following topics:
1. Purpose (and previous requirements)
2. Presentation of the whole process and sub-processes, flow chart, critical points / risks
3. Organization structure of the validation activities
4. Reason for inclusion or exclusion from a certain validation
5. Tracking system for reference and revisions
6. Required trainings for a validation program
7. Type of validation defined for each system or project
8. Planning and chronogram of the activities to be performed
9. Cross-reference and other documents
The Validation Master Plan must include the cleaning procedures and analytical methods
validation.

ANNEX II

Evaluation Classification and Criteria to the items in the Inspection Guide to Companies
Manufacturing Drugs.
The criterion established for the classification is based in the potential risk inner to each item in
relation to the quality and safety of the product and worker safety in his/her interaction with the
products and processes during manufacturing.
INDISPENSABLE - I
The item considered INDISPENSABLE is the one that meets the Good Manufacturing Practices
recommendations, which might influence in a critical level the quality or safety of the products
and the safety of the workers in their interaction with the products and processes during the
manufacturing.
Defined by YES or NO
NECESSARY - N
The item considered NECESSARY is the one that meets the Good Manufacturing Practices
recommendations, which might influence in a less critical level the quality or safety of the
products and the safety of the workers in their interaction with the products and processes
during manufacturing.
Defined as YES or NO
The item NECESSARY not met in an inspection, will be consequently classified as
INDISPENSABLE in the following inspections.
RECOMMENDABLE - R
It is considered RECOMMENDABLE the item which meets the recommendations of Good
Manufacturing Practices which might influence in a non-critical level the quality or safety of the
products and the safety of workers in their interaction with the products and processes during
the manufacturing.
Defined as YES or NO
The RECOMMENDABLE item not met in an inspection, will be consequently classified as
NECESSARY in the following inspections. However, it will never be considered
INDISPENSABLE.
INFORMATIVE - INF
The item considered INFORMATIVE is the one that presents a descriptive information, which
does not affect the quality and safety of the products and the safety of the workers in their
interaction with the products and processes during the manufacturing.
It may be answered optionally as YES or NO, or descriptively.
 ANNEX III
Inspection Guide to Companies Manufacturing Drugs
1.- MANAGEMENT AND GENERAL INFORMATION

The company must present the proving documents required.

No. Qualif. Items YES NO N/A
1.1 INF Name of the Company?______________________________
1.1.1 INF CNPJ [National Directory of Legal Entities]:_______________________
Address Street/Ave:
_____________________________________________
No._______________, Complement: __________________________
Neighborhood ___________________ Municipality: ________________
1.1.2 INF
State: _______________ CEP [ZIP CODE]:_______________
Telephone: ___________________________________
Fax: __________________________________________
E-mail: ________________________________________
1.2 INF Inspection period ___/___/___ to ___/___/___
1.2.1 INF Reason for inspection _________________________________
1.3 INF Date of last inspection: ___/___/___
1.3.1 INF Reason for the last inspection: ___________________________
Does it have a Good Manufacturing Practice
1.4 INF
Certificate?
1.4.1 INF Date of issue of the certificate ___/___/___
1.5 INF Name of the Technical Responsible ________________________________
1.6 I Is the responsible pharmaceutical present?
Is there a proof of his/her inscription in the
1.7 I
competent authority?
1.8 N Did the company present any organization chart?
Does the company have a Certificate of
Establishment granted by the competent
1.9 I
Authority of the National Sanitary Surveillance
System?
1.9.1 INF Number _______________________________________________
Authorized activities:
1.9.2 INF Store Package Distribute Export Import
Manufacture Produce Transport Repackage Extract
Issue Fractionate Synthesize Transform Purify
Does the company have a Special Certificate of
Establishment granted by the competent
1.10 I
Authority of the National Sanitary Surveillance
System?
1.10.1 INF Number: _______________________________________________
Authorized activities:
1.10.2 INF Store Package Distribute Export Import
Manufacture Produce Transport Repackage Extract
Issue Fractionate Synthesize Transform Purify
Manipulate
 The entries and balance of substances subject to
1.11 I the special control regimen are done following
the current Sanitary Legislation?
Are the losses from the manufacturing processes
1.12 I of manufacturing of products subject to the
special control regimen duly entry?
Does the company have a Certificate of
1.13 I Establishment / Sanitary Authorization from the
local Authority?
1.13.1 INF Number: ______________________________________________
1.14 Does the company have authorization from the competent Authorities for:
1.14.1 N Environmental protection?
1.14.2 N Premises safety (fireman)?
Does the company responsible for transportation
of raw materials and/or finished product have a
1.14.3 N
certificate of establishment for this activity before
the competent Sanitary Authorization?
1.15 N Were the building plans presented?
1.15.1 INF Which is the terrain surface? ____________________ m2
1.15.2 INF Which is the total built area? ____________________ m2
1.15.3 INF How many buildings does the plan have? ____________________________
1.16 INF Is there a restaurant / cafeteria in the company?
Is there an Occupational Health Program
1.17 N updated and duly signed by the responsible
physician?
Was a list of products of the company’s property
1.18 N presented, with the marketed and the non-
marketed products?
Are all these products duly registered in the
1.18.1 I
competent National Sanitary Authority?
Which is the installed capacity of production of
1.19 INF the company by line/pharmaceutical
presentation? (Annex documentation)
Was a ground plan updated and approved by the
1.20 R
competent Sanitary Authority presented?
Is the flow of personnel and materials indicated in
1.21 R the ground plan updated and approved by the
competent Sanitary Authorization?
Does the company hires third party services to
1.22 INF
the production of its products?
What are the products and steps performed by third parties? ____________
1.22.1 INF
_____________________________________________________________
Which are the hired companies?
1.22.2 INF
____________________________________
Were the contracts of third parties filed to
1.22.3 N
evaluation of the competent Sanitary Authority?
Does the company hire services from third
1.22.4 INF parties to the production of products subject to
the special control regimen?
1.22.4.1 INF Which are the hired companies? ___________________________________
Does the company hire the services of third
1.23 INF parties to the analysis of raw materials and/or
products?
1.23.1 INF Which are the hired companies? ___________________________________
1.23.2 N Which are the essays performed?
Were the contracts for third parties to analyze
1.23.3 N raw materials and/or products filed to evaluation
of the competent Sanitary Authority?
1.24 INF Does the company import raw material?
1.25 INF Does the company import intermediary products?
1.26 INF Does the company import bulk material?
1.27 INF Does the company import finished products?
Did the company present a list of the imported
1.28 R
products (intermediary, bulk, finished)?
Were the lines where the imported products are
1.29 INF manufactured already certified by the competent
Sanitary Authority in Brazil?
If not, did the company request the inspection to
1.29.1 N
the competent Sanitary Authority in Brazil yet?
1.30 INF Does the company export finished products?
Did the company present a list of the exported
1.30.1 R
finished products?
Does the company perform activities related to
the industrialization of products of different nature
1.31 INF
or purpose subject to the competent Sanitary
Authority Authorization?
1.31.1 INF Specify the products. ___________________________________________
Did the company produce three (3) pilot batches
1.32 N of registered product according to the current
legislation?
1.32.1 INF What was the destination of these batches?
1.32.2 N Are there records?

2. -PREMISES

2.1- General conditions

No. Qualif. Items YES NO N/A
Are there environmental pollution or
2.1.1 INF contamination sources next to the
company?
2.1.2 R Are the access routes paved?
Are the building surrounding areas
2.1.3 N
clean?
As for the external aspect, do the
2.1.4 R buildings show a good conservation
(absence of cracks, infiltrations, etc.)
2.1.5 N Are the effluents treated?
 What are the treatments used?
2.1.5.1 INF
______________________________
2.1.5.2 N Are there records?
Are the premises built in a way to
2.1.6 N allow the protection against the
entrance of insects and other animals?
Is there a prevention and fighting
2.1.6.1 N
program to insects and other animals?
2.2. Auxiliary premises
No. Qualif. Items YES NO N/A
2.2.1 Garments and Restrooms
2.2.1.1 R Are there enough locker rooms?
Are they in appropriate hygiene
2.2.1.1.1 N
conditions?
2.2.1.2 R Are there enough restrooms?
Are they in satisfactory hygiene
conditions and provided with cold
2.2.1.2.1 N
and/or hot water, soap and
dischargeable towels or hand-driers?
Is the access to the restrooms
2.2.1.2.2 N independent in the production areas
and in the warehouse?
2.2.2 Maintenance/Utilities
Are the maintenance areas physically
2.2.2.1 INF
separated from the production areas?
Is there a specific area to the steam
2.2.2.2 INF
generator equipment?
2.2.2.2.1 INF Is industrial steam produced?
2.2.2.2.2 INF Is pure steam produced?
Is there an area to the compressed-air
2.2.2.3 INF
compressor equipment?
Is there a specific area to the
2.2.2.4 INF
equipment to produce purified water?
Is there a specific area to the
2.2.2.5 INF equipment to produce water for
injection?
Is there a specific area to the air-
2.2.2.6 INF
conditioning equipment?
Is there a capture center of post-
2.2.2.7 INF
wastes from the exhaustion system?
Is there an electric power generator to
2.2.2.8 N
emergency cases, if required?
Are the water, steam, gas,
2.2.2.9 N compressed air, and electricity pipes
duly identified?
2.2.3 Creation biotherium
Are the creation biotherium premises
2.2.3.1 N
independent from the other premises?
 Do all the activities performed in this
2.2.3.2 N area meet the previously defined
SOPs?
Are there records of the critical
2.2.3.2.1 N operations defined in the respective
SOPs?
Are the hygiene conditions
2.2.3.3 N
appropriate?
Are there separated restroom and
2.2.3.4 N locker room to the personnel working
with animals?
Are the hygiene conditions
2.2.3.4.1 N
appropriate?
What are the animal species growth?
2.2.3.5 INF
______________________
2.2.3.6 INF Is the animals origin known?
Is the creation area enough to
2.2.3.7 INF accommodate the many animal
species used?
Is the ventilation system and/or air
conditioning system of the biotherium
2.2.3.8 N
independent from the other
installations of the company?
2.2.3.9 N Is the illumination enough?
2.2.3.10 N Is there a quarantine area to animals?
2.2.3.11 N Is there a room for inoculated animals?
Is there a room for disinfection and
2.2.3.12 N drying of the boxes, cages, feeders,
and other required materials?
Is there an appropriate place to the
2.2.3.13 N storage of materials, food and beds of
animals?
Is the treatment of animals disposals
2.2.3.14 N
and corpses established in the SOP?
Is there an appropriate place to the
2.2.3.14.1 N animals disposals and corpses be
stored?
Is there a qualified professional
2.2.3.15 N
responsible for the Biotherium?

3.- WAREHOUSES/ MATERIALS AND PRODUCTS

3.1.- General conditions

No. Qualif. Items YES NO N/A
Are the floors, walls and ceilings
3.1.1 N appropriate to the activities developed
in the area?
Are they in a good conservation
3.1.1.1 N
condition?
3.1.1.2 N Are they easy to clean?
3.1.1.3 N Are they clean?
Is there protection against the entry of
3.1.2 N rodents, insects, birds and other
animals?
3.1.2.1 N Is there a system to fight them?
Who is the person responsible for its execution?
3.1.2.2 INF
_____________________________
Was an incidence of the presence of
3.1.2.3 INF rodents, insects, birds, or other
animals shown?
3.1.4 R Is the illumination appropriate?
Is there the need to control humidity
3.1.5 INF
and temperature in the warehouses?
If so, there are apparatus controlling
3.1.5.1 N
the humidity and temperature?
3.1.5.2 N Are there records?
Are the temperature and humidity
consistent with the established
3.1.6 N
parameters for the materials and
products stored?
In case of deviations related to the
established parameters is an
3.1.6.1 N
investigation done to evaluate the
causes?
Are preventive and/or corrective
3.1.6.2 N actions taken in relation to the
identified causes?
3.1.6.3 N Are there records?
3.1.7 INF Is there the need for a cold chamber?
3.1.7.1 I Is there a cold chamber?
3.1.7.1.1 N Is the temperature controlled?
3.1.7.1.2 N Are there temperature records?
Is there an alarm system alerting
about the occurrence of deviations
3.1.7.1.3 R
related to the programmed
temperature of the cold chamber?
Which is the temperature registered at the time of
3.1.7.1.4 INF
inspection? ______oC
3.2.- Specific conditions
No. Qualif. Items YES NO N/A
Do all the activities performed in this area meet
3.2.1 N
the previously defined SOPs?
Are there records of the critical operations
3.2.1.1 N
defined in the respective SOPs?
3.2.2 N Do the employees wear uniforms?
3.2.2.1 N Are the uniforms clean and in good conditions?
Are the scales regularly checked and periodically
3.2.3 N
calibrated?
3.2.3.1 INF What is the frequency the scales are checked? _______________________
3.2.3.1.1 N Are there records?
Is the verification performed with duly calibrated
3.2.3.1.2 N
standard weights?
3.2.3.2 INF What is the frequency the scales are calibrated? ____________________
3.2.3.2.1 N Are there records?
Is the storage disposition correct and rational,
3.2.4 N with the purpose of preserving the integrity and
identity of the materials and products?
Is there an area/system delimitating or restricting the use of materials/products
3.2.5
respecting the previously defined status for:
3.2.5.1 N Quarantine?
3.2.5.2 N Approved?
3.2.5.3 N Reproved?
3.2.6 Are there areas/systems to keep materials:
3.2.6.1 N Raw materials?
3.2.6.2 N Packaging materials?
3.2.6.3 N Intermediary products?
3.2.6.4 N Bulk products?
3.2.6.5 N Finished products?
Is there a unique place with a device which offers safety to keep substances and
3.2.7
products subjected to the special control regimen:
3.2.7.1 I Raw materials?
3.2.7.2 I Bulk product?
3.2.7.3 I Finished product?
Does the storage records and control system of
intermediary and bulk products include the
3.2.8 N
maximum storage time allowed before its
packaging?
Does the record and control system of expedition
3.2.9 N observe the relative sequential relation of
batches and expiration dates?
Are all the material and products stored within
3.2.10 N
the expiration date?
Is there a separated, safe and identified area to
3.2.11 N the storage of expired materials and/or products
while waiting for their final destination?
Are these materials and/or products destroyed
3.2.11.1 N
later?
3.2.11.2 N Are there records?
3.2.12 N Is there a system to control the stock?
3.2.12.1 INF Which one? ________________________________________________
If computerized systems are used to the
3.2.12.2 N management of the materials and products, does
the company prove the system safety?
3.2.13 INF Are periodical inventory performed?
3.2.13.1 N Are there records?
Are the materials and products stored isolated
3.2.14 R from the floor and far from the walls, to make the
cleaning and conservation easier?
3.3.- Receiving and storage of raw materials
No. Qualif. Items YES NO N/A
Is the area occupied consistent with
3.3.1 N
the volume of operations?
Do all the activities performed in this
3.3.2 N area meet the previously defined
SOPs?
Are there records of the critical
3.3.2.1 N operations defined in the respective
SOPs?
Are the raw materials correctly
3.3.3 N
identified by its manufacturer/supplier?
Is the label of identification tag duly
3.3.3.1 N
adhered to its container?
When received, does each raw
3.3.4 N material batch received a registration
number?
Is the registration number used to
3.3.4.1 N identify the raw material until the end
of its use?
Does the label or tag issued by the
company allow the correct
3.3.5 N identification, visualization or control
by electronic system of the raw
materials status?
Is the label or tag duly adhered to its
3.3.5.1 N
container?
Before its release by the Quality
Control, does the raw material remains
3.3.6 N
in quarantine and duly identified as
such?
In case of stocks controlled by a
computerized system, is the use of raw
3.3.6.1 N materials in quarantine blocked until
they are released by the authorized
person?
Is a raw material already approved and
3.3.7 N identified as such transferred to a
correspondent area/system?
Are the raw materials only used after
3.3.8 I
release by the quality control?
Is the expiration date shown in the
3.3.9 N
label?
Is there a re-analysis program if raw
materials, in stock, respecting the
3.3.10 N
expiration date established by their
manufacturer?
When required, is the date of re-
3.3.10.1 N
analysis indicated in the label/system?
Is there a program for the Qualification
3.3.11 N
of Suppliers?
 Are the active substances suppliers
3.3.11.1 N N
qualified?
Are there defined criteria to the
3.3.11.2 N
program management?
3.3.12 Does the program include:
The evaluation of the supply
3.3.12.1 INF
background?
The preliminary evaluation through a
3.3.12.2 INF
questionnaire?
3.3.12.3 INF Quality audits?
Are the reproved raw materials duly
3.3.13 N
identified and separated?
3.4.- Receiving and Storage of packaging materials
No. Qualif. Items YES NO N/A
Is the area occupied consistent with
3.4.1 N
the volume of operations?
Do all the activities performed in this
3.4.2 N area meet the previously defined
SOPs?
Are there records of the critical
3.4.2.1 N operations defined in the respective
SOPs?
Are the packaging materials correctly
3.4.3 N identified by their
manufacturer/supplier?
When received, do the packaging
3.4.4 N material receive a registration
number?
Is the registration number used to
3.4.4.1 N identify the packaging materials until
the end of their use?
Does the label or tag issued by the
company allow the correct
3.4.5 N identification and visualization of the
packaging materials status (reproved,
quarantine and approved)?
Are all the materials batches sampled
by the Quality Control, according to
3.4.6 N
appropriate and trustful statistical
systems?
Is the amount of material sampled in
3.4.7 N accordance with the sampling
procedure established?
Before its release by the Quality
Control, does the packaging material
3.4.8 N
remain in quarantine duly identified as
such?
Is a material already approved and
3.4.9 N identified as such transferred to the
related area/system?
 Are the reproved materials identified
3.4.10 N
and separated?
Are the materials considered old or
3.4.11 R
obsolete destroyed?
3.4.11.1 N Are there records?
Is there a locked section, into the
3.4.12 N Warehouse, with restrict access to the
printed material?
Is the permission to entry this area
3.4.12.1 N
given only to authorized persons?
3.5.- Receiving and storage of intermediary and bulk products
No. Qualif. Items YES NO N/A
3.5.1 Is there an area to store:
3.5.1.1 N Intermediary products?
3.5.1.2 N Bulk products?
Do all the activities performed in this
3.5.2 N area meet the previously defined
SOPs?
Are there records of the critical
3.5.2.1 N operations defined in the respective
SOPs?
Are there defined procedures to receive and store intermediary
3.5.3
and bulk products:
3.5.3.1 N Locally produced?
3.5.3.2 I Imported?
Are there locked deposits or premises,
with restrict access, to intermediary
3.5.4 I
and bulk products subjected to special
control regimen?
Does the record and control system of
the expedition of intermediary and bulk
3.5.5 N products respect the sequential batch
relation and the maximum storage
period established to each product?
Is the storage of intermediary and bulk
products duly organized and safe,
3.5.6 N avoiding possible mixings in the
control and expedition, as well as
accidents with their handling?
Before their release by the Quality
Control, do the intermediary and bulk
3.5.7 N
products remain in quarantine and duly
identified as such?
3.6.- Receiving and storage of finished products
No. Qualif. Items YES NO N/A
Is there an area to store the finished
3.6.1 N
products?
Do all the activities performed in this
3.6.2 N area meet the previously defined
SOPs?
 Are there records of the critical
3.6.2.1 N operations defined in the related
SOPs?
Does the record and control system of
expeditions of the finished products
3.6.3 N
respect the sequential relation of the
batches and the expiration date?
Is the storage duly organized and safe,
avoiding possible mixings in their
3.6.4 N
control and expedition, as well as
accidents when handling them?
Before their release by the Quality
Control, do the finished products
3.6.5 N
remain in quarantine and identified as
such?
If computerized systems are used to
3.6.5.1 N the management of the products, does
the company prove the system safety?
3.6.6 N Are the products safely piled up?
Are there locked deposits or premises,
with restrict access, to the products
3.6.7 I
subjected to the special control
regimen?
Does the company have procedures
3.6.8 N related to the products close to the
expiration date?
3.6.8.1 N Are these procedures met?
3.6.8.2 N Are there records?
Does the company have records on
the distribution of products allowing the
3.6.9 N
tracking of the primary distribution
client(s)?
Are all the primary distribution clients
3.6.9.1 N duly authorized by the competent
Sanitary Authorization?
3.7.- Sampling area for raw materials
No. Qualif. Items YES NO N/A
Is there a specific room to the
3.7.1 N
sampling of raw materials?
Do all the activities performed in this
3.7.2 N area meet the previously defined
SOPs?
Are there records on the critical
3.7.2.1 N
operations in the respective SOPs?
3.7.3 N Do the employees wear uniforms?
3.7.3.1 N Are the uniforms clean?
When required, do they wear individual
3.7.4 N
protection equipment?
Do the premises have appropriate
3.7.5 N
hygiene conditions?
 If required, does the area have
3.7.6 R temperature and relative humidity
control?
3.7.6.1 N Are there records?
In case of deviations related to the
established parameters, is an
3.7.7 N
investigation done to evaluate the
causes?
Are preventive and/or corrective
3.7.7.1 N actions taken related to the causes
identified?
3.7.7.2 N Are there records?
Is there the need of differential
3.7.8 INF
pressure measure equipment?
3.7.8.1 N If yes, is there one?
3.7.8.2 N Are there records?
3.7.9 INF Are sterile raw materials sampled?
Is the sampling performed under a
3.7.9.1 N Laminar Flow installed in classified
areas?
Are the Laminar Flow and the area
3.7.9.2 N
qualified?
3.7.9.3 N Are there records?
Are the instruments and tools used
3.7.10 N
appropriate?
Are the instruments and tools, with
contact to the raw materials, clean
3.7.10.1 N
and/or sterilized, before and after each
use?
Are they identified as for the cleaning
3.7.10.2 N
status?
3.7.11 N Are the sampled containers identified?
Is the content identification test performed in the containers of
3.7.12
active substances:
3.7.12.1 N In all the containers?
In a statistical sample, in case of
3.7.12.2 N SPGV manufacturers, provided that
the supplier is qualified?
Is a content identification test
3.7.13 N performed in a statistical sample of the
containers?
Are the containers with samples
3.7.14 N
identified, and closed after sampling?
4.- COMPLAINT
No. Qualif. Items YES NO N/A
Is there a designee for receiving the
4.1 NN
complaints?
Are there SOPs to the evaluation
4.2 NN and measures to be adopted in
case of complaints?
 Is there a person responsible for the
4.3 N decision and measures to be
adopted?
Is any complaint registered and fully
4.4 NN
evaluated/investigated?
Is the person responsible for the
4.5 N Quality Control involved in the
complaint investigation?
Are follow-up actions taken after the
investigation and evaluation of the
4.6 N
complaint, including the possibility
of withdrawing the product?
Is the investigation result recorded
4.7 N or mentioned in the batch
registration of the related product?
Are there statistical data on the
4.8 R
complaint causes?
5.- RETURNS
No. Qualif. Items YES NO N/A
Is there a separated or restricted area
5.1 N
to the storage of returned products?
Is there a designee for the receiving
5.2 N
the returns?
Are there SOPs to the receiving,
5.3 N storage and investigation on the
causes of the products returns?
Are the returned products duly
5.4 N
identified as such?
Are the returned products inspected
5.5 N and/or analyzed before its final
destination is defined?
After the inspection and/or analysis of
the returned products, are the required
5.6 N
measures taken, including the
possibility of withdrawing the product?
Are there records of the results of the
inspection and/or analysis of the
5.7 N
returned products, including the final
destinations?
6.- COLLECTION
No. Qualif. Items YES NO N/A
Is there a separated, safe and
identified area to store the products
6.1 N
collected from market while waiting for
their finzbal destination?
Are the products collected from market
6.1.1 N
duly identified as such?
Does the company have an
operational system, duly structured, to
6.2 N
collect the products with quality
deviation from the market?
 Are there SOPs to the collection of
6.3 N
products?
Does the company establish and keep
the assurance of the correct
6.3.1 N
application of these procedures
systematic?
Do the records related to the
distributors allow the tracking of their
6.4 I
products viewing their effective
collection?
In case of withdrawal, for quality
6.5 I deviation, are the sanitary authorities
in charge immediately informed?
Is there a responsible person for the
6.6 N coordination, performance of these
procedures?
If the designee does not belong to the
Quality Control and is not the
6.7 N Responsible Technician, are these
ones informed about the operations
performed?
Are immediate actions taken to the
6.8 N withdrawal of the product all over the
area it was distributed?
Are records of the products collection
6.9 N from the market kept, including the
investigation of the causes?
Does the information available allow to
6.10 N determine the percentage of the
expedited product collection?
Are there records on the products
6.11 N
collected from the market destination?

7.- WATER SYSTEMS AND INSTALLATIONS

7.1.- Drinkable water

No. Qualif. Items YES NO N/A
7.1.1 Which is the origin of the water used in the company:
7.1.1.1 INF Public System?
7.1.1.2 INF Artesian Well?
Does the company have a water
7.1.2 INF
reservoir?
Before the water is stored is there any
7.1.3 INF
treatment?
7.1.3.1 INF Which one? __________________________________________
Is a cleaning performed in the water
7.1.4 N
reservoirs?
7.1.4.1 INF What is the frequency? _________________________________
7.1.4.2 N Are there records?
Are there SOPs for the cleaning of the
7.1.4.3 R
water reservoirs?
 Are the drinkable water control
7.1.5 INF parameters in accordance with the limits
established by the current legislation?
Are physical-chemical tests of the
7.1.6 N
drinkable water performed?
Which ones?
7.1.6.1 INF
___________________________________________________
What is the frequency?
7.1.6.2 INF
___________________________________________
7.1.6.3 N Are there records?
Are microbiological tests of the drinkable
7.1.7 N
water performed?
What is the frequency?
7.1.7.1 INF
___________________________________________
7.1.7.2 N Are there records?
Are water samples collected periodically
in different points of the manufacturing
7.1.8 N
site, including in the water fountain, to
perform the microbial counting?
7.1.8.1 N Are there records?
In case of results above the established
7.1.8.2 N limits is an investigation performed to
evaluate the causes?
Are preventive and/or corrective actions
7.1.8.2.1 N
taken in relation to the causes identified?
7.1.8.2.2 N Are there records?
7.2- Purified water
No. Qualif. Items YES NO N/A
Does the company have a production system to
Purified Water, meeting the defined
7.2.1 N
specifications in the Pharmacopoeia adopted by
the Ministry of Health?
7.2.1.1 INF Method to obtain purified water:___________________________________
7.2.1.2 INF Type of equipment: ____________________________________________
7.2.1.2.1 INF What is the capacity in liters/hour? _________m3 : _____________Liters
Is there qualified personnel to operate the
7.2.1.3 N
system?
Is there an updated diagram on the system of
production and distribution of purified water,
7.2.2 R
including the system components, sampling
points and using points?
Is the water supplying the purified water system
7.2.3 INF
treated?
7.2.3.1 INF How? ______________________________________________________
Do all the activities performed in this are meet
7.2.4 N
the previously defined SOPs?
7.2.5 INF Is there a deposit for the purified water?
7.2.5.1 INF What is its capacity? _________ m3 : _____________ Liters
7.2.5.2 INF For how long it is stored? _____________/ hours
7.2.5.3 INF Is there a purified water recirculation system?
Is there any treatment to avoid the
7.2.6 N
microbiological contamination?
7.2.6.1 INF Which one? _________________________________________________
Are there in line instruments to manage the
7.2.7 N
quality parameters of the water?
7.2.7.1 INF Which ones? _______________________________________________
7.2.8 N Are physical-chemical tests performed?
7.2.8.1 INF Which ones? _____________________________________________
7.2.8.2 INF What is the frequency?________________________________________
7.2.8.3 N Are there records?
7.2.9 N Are microbiological tests performed?
7.2.9.1 INF What is the frequency? _______________________________________
7.2.9.2 N Are there records?
In case of results above the established limits is
7.2.10 N an investigation performed to evaluate the
causes?
Are preventive and/or corrective actions taken in
7.2.10.1 N
relation to the identified causes?
7.2.10.2 N Are there records?
What is the material used to build the distribution
7.2.11 INF
lines of purified water?
Is the water produced used as raw material for
7.2.12 INF
non-sterile products?
Is there a procedure to release the water used in
7.2.13 N
the production?
7.2.13.1 N Are there records?
Is the water produced used as feeding source to
7.2.14 INF
the production system for water for injection?
7.2.15 N Is a sanitization of the system performed?
7.2.15.1 INF What is the frequency? ________________________________________
7.2.15.2 N Are there records?
Is a preventive maintenance performed in the
7.2.16 N
system equipment?
7.2.16.1 INF What is the frequency? _________________________________________
7.2.16.2 N Are there records?
7.2.17 R Are there filtrating means in the system?
7.2.17.1 INF Which ones? _________________________________________________
Are there records on the changing of the filtrating
7.2.18 N
means?
Is a sanitization of the filtrating means
7.2.19 N
performed?
7.2.19.1 INF What is the frequency? _________________________________________
7.2.19.2 N Are there records?
Are the measuring and/or control instruments
7.2.20 N
installed in line calibrated?
7.2.21 INF Is there an UV unit installed in the system?
 Are there records on the changing of the UV unit
7.2.21.1 N
lamps?
Are there records on the regeneration of ionic
7.2.22 N
exchange resins?
Is the production system of Purified Water
7.2.23 N
validated?
What is the period of evaluation tests established in the approved protocol?
7.2.24 INF
___
Did the results of the tests conducted during the
7.2.25 N validation meet the acceptance criteria
established in the approved protocol?
Were the deviations found in relation to the
7.2.26 N parameters established in the approved protocol
duly investigated?
Is there a pre-established frequency to the
7.2.27 N
periodical revalidation?
7.2.27.1 INF Which one? __________________________________________________
Are the results obtained in the revalidation in
7.2.27.2 N
accordance with the approved protocol?
7.3.- Water for injections
No. Qualif. Items YES NO N/A
Does the company have a system to the
production of Water for Injection
according to the processes established by
7.3.1 I
the current issues of the European
Pharmacopoeia or the U.S.
Pharmacopoeia?
Method to obtain water for injection:
7.3.1.1 INF
______________________________
Type of equipment:
7.3.1.2 INF
___________________________________________
What is the capacity in liters/hour? ______ m3;
7.3.1.2.1 INF
_____________ Liters
Is the water produced used as raw
7.3.2 I
material for sterile products?
Is there qualified personnel to operate the
7.3.3 N
system?
Do all the activities performed in this area
7.3.4 N
meet the previously defined SOPs?
7.3.5 INF Is there a deposit for water for injection?
7.3.5.1 INF What is the deposit capacity? ________ m3; _________ Liters
What is the material used in the building
7.3.5.2 INF
of the deposit?
7.3.5.3 INF For how long is the water stored? ______________ hours
7.3.5.4 INF Storage temperature: _________________ oC
Is there a closed circulation system
7.3.6 INF
(looping)?
 Does the material used in the piping in the
distribution lines assure the water purity
7.3.6.1 N
and the specified level of microbial
contamination?
7.3.6.1.1 INF Which is the material?
7.3.6.2 N Are the circulation pumps sanitary?
Are the valves existing in the circuit
7.3.6.3 N
sanitary?
If there is no closed circulation system, how is the water for
7.3.7 INF injection transported?
______________________________________________
7.3.8 Are there apparatus in the system to measure:
7.3.8.1 INF Temperature?
7.3.8.2 INF pH?
7.3.8.3 INF Conductivity?
7.3.8.4 INF Total organic carbon (TCO)?
7.3.9 Are there records on:
7.3.9.1 N pH?
7.3.9.2 N Conductivity?
7.3.9.3 N Total organic carbon?
7.3.10 INF Is there any kind of filter in the system?
Which one?
7.3.10.1 INF
_________________________________________________
Are there records on the exchange of
7.3.10.2 N
filtrating means?
Is the sanitization of the filtrating means
7.3.10.3 N
performed?
What is the frequency?
7.3.10.3.1 INF
________________________________________
7.3.10.3.2 N Are there records?
7.3.11 N Are physical-chemical tests performed?
Which ones?
7.3.11.1 INF
________________________________________________
What is the frequency?
7.3.11.2 INF
________________________________________
7.3.11.3 N Are there records?
7.3.12 N Are microbiological tests performed?
What is the frequency?
7.3.12.1 INF
________________________________________
7.3.12.2 N Are there records?
7.3.13 N Are endotoxin tests performed?
What is the frequency?
7.3.13.1 INF
________________________________________
7.3.13.2 N Are there records?
In case of results above the established
7.3.14 N limits, is an investigation to evaluate the
causes performed?
 Are preventive and/or corrective actions
7.3.14.1 N
taken in relation to the identified causes?
7.3.14.2 N Are there records?
Is there a procedure to the release of the
7.3.15 N
water used in the production?
7.3.15.1 N Are there records?
Is the production system of water for
7.3.16 N
injection sanitized?
What is the
7.3.16.1 INF
frequency?________________________________________
7.3.16.2 N Are there records?
Is a preventive maintenance performed in
7.3.17 N
the system equipment?
What is the frequency?
7.3.17.1 INF
_______________________________________
7.3.17.2 N Are there records?
Is the production system of Water for
7.3.18 N
Injection validated?
What is the period of evaluation tests established in the approved
7.2.19 INF protocol?
_____________________________________________________
Do the results of the tests conducted
during the validation meet the acceptance
7.2.20 N
criteria established in the approved
protocol?
Were the deviations found in relation to
7.3.21 N the parameters established in the
approved protocol duly investigated?
Is there a pre-established frequency to
7.3.22 N
the periodical revalidation?
Which one?
7.3.22.1 INF
_________________________________________________
Are the results obtained in the periodical
7.3.22.2 N revalidation in accordance with the
approved protocol?

8.- PRODUCTION

8.1. General considerations

No. Qualif. Items YES NO N/A
8.1.1 N Is there a production planning?
Are there authorized Standard/Master
8.1.2 I Formula for each product and batch
size to be manufactured?
Is the Production Order for each batch
of product faithfully based on the
8.1.3 I
established instructions by the
Master/Standard Formula?
Are records on all the produced
8.1.4 I
batches kept?
 Are the production areas consistent
8.1.5 N
with the operations volume?
Does the production areas design
allow the effective cleaning and
8.1.6 N maintenance, in order to avoid cross-
contamination or any adverse effect on
the products quality?
Are the maintenance and repair
operations of equipment in the
8.1.7 N
production areas performed in a way to
avoid any risk to the products?
Are the premises built in a way that
8.1.8 N allows the protection against the
entrance of insects and other animals?
When required, are there instruments
to control the temperature, humidity
8.1.9 N
and differential pressure between the
areas?
8.1.9.1 N Are there records?
In case of deviations, in relation to the
8.1.9.2 N established limits, is an investigation
performed to evaluate the causes?
Are preventive and/or corrective
8.1.9.3 N actions taken in relation to the
investigated causes?
8.1.9.4 N Are there records?
Is the illumination in the production
8.1.10 N areas appropriate to the activities
developed?
Is the ventilation in the production
8.1.11 N areas appropriate to the activities
developed?
Are the walls, ceiling and floor covered
with a easily washable material and
8.1.12 N
free from cracks or desquamating
painting?
Is the floor plain, impermeable and
8.1.13 N
easy to clean?
8.1.14 N Are the areas clean?
Does the company have SOPs to all
8.1.18 N the activities developed in the
production areas?
Are the SOPs related to the activities
8.1.19 N of each area available in the respective
working place?
Is there a procedure regulating the
8.1.20 N entrance of non-authorized persons in
the production areas?
8.1.21 N Do the personnel wear uniform?
Are the uniforms clean and in good
8.1.21.1 N
conservation status?
 Do the employees wear the
8.1.22 N appropriate garments to the production
activities, only in these areas?
Is the company responsible for the
8.1.23 N
washing of the employees uniforms?
When required, is the individual
8.1.24 N
protection equipment (IPE) worn?
Are there drains in the production
8.1.25 INF
areas?
8.1.25.1 N If yes, are they siphoned?
Are there drain cleaning and
8.1.25.2 N
disinfection records?
Are the garbage containers identified
8.1.26 R
and covered?
Is the equipment distribution ordered
8.1.27 N
and rational?
Are the equipment placed in order to
8.1.28 N
avoid cross-contamination?
8.1.29 N Are the circulation areas free?
Are all the equipment in use in the
production identified with the product
8.1.30 N
name, batch number and production
step?
Are the measuring and/or control
8.1.31 N
instruments calibrated?
8.1.31.1 N Are there records?
Are the in-process control tests
performed in the frequencies
8.1.32 N
established in the related operation
procedures?
8.2.- Weighing and measuring area
No. Qualif. Items YES NO N/A
Is there an area for the weighing and
8.2.1 N
measuring activities?
Does the weighing and measuring
8.2.2 N area have an independent exhaustion
system?
Is there a cross-contamination
8.2.3 N prevention system during the weighing
and/or measuring operation?
Is the contamination risk with the
8.2.4 N
environment avoided?
Is there an specific area to weigh
8.2.5 I
highly sensitizing substances?
Does the area have negative
8.2.5.1 N
pressure?
Are the materials used for weighing
and/or measuring (containers,
8.2.6 N spatulas, pipettes, etc.) clean,
identified as such, protected and
stored in a defined place?
 Are the scales regularly verified and
8.2.7 N
periodically calibrated?
Which is the frequency they are verified?
8.2.7.1 INF
__________________________
8.2.7.1.1 N Are there records?
Are the verifications performed with
8.2.7.1.2 N
duly calibrated standard weights?
Which is the frequency of calibration?
8.2.7.2 INF
________________________________
8.2.7.2.1 N Are there records?
Are the measuring materials
8.2.8 N
calibrated?
8.2.8.1 N Are there records?
During the weighing and/or measuring
operations, do the employees wear
8.2.9 N
protection (goggles, caps, masks,
etc.)?
Is the weighing and/or measuring
8.2.10 I operation performed in accordance
with a Production Order?
Are the outer package of raw materials
to be weighed and/or measured
8.2.11 N
cleaned before entering the weighing
areas?
Are the packages with the product of
the raw materials used in the weighing
8.2.12 N and/or measuring operation well
closed to protect their contents and to
avoid their contamination?
Is the weighing or measuring operation
8.2.13 N
of raw materials checked?
8.2.13.1 N Are there records?
Are the weighed and/or measured
8.2.14 N
materials identified?
Which is the system used?
8.2.14.1 INF
______________________________________
Is there physical separation of the
8.2.15 N weighed and/or measured materials for
each production batch?

8.3.- Solid Products

8.3.1.- General information

No. Qualif. Items YES NO N/A
To specify the pharmaceutical presentations produced:
8.3.1.1 INF ________________________________________________
__________________________
8.3.1.2 N Is there an specific area to the manufacturing of solid products?
8.3.2. Production
No. Qualif. Items YES NO N/A
Are the instructions of the Production
8.3.2.1 I
Order accurately followed?
Are all the production steps registered
8.3.2.1.1 N
and signed by their performer?
Are all the production critical steps
8.3.2.1.2 N
signed by the indicated supervisor?
Are there measuring scales and
8.3.2.2 INF
containers in the production area?
8.3.2.2.1 N Are they periodically calibrated?
What is the frequency of calibrations?
8.2.7.2.1.1 INF
______________________________
8.3.2.2.1.2 N Are there records?
8.3.2.2.2 N Are the scales periodically checked?
8.3.2.2.2.1 N Are there records?
Are the verifications performed with
8.3.2.2.2.2 N
duly calibrated standard weights?
When required, do the equipment
8.3.2.3 N used in the production processes have
a dust aspiration system?
What is the destinations of these wastes?
8.3.2.3.1 INF
___________________________________
Are all the containers used in the
production of a product batch duly
8.3.2.4 N
identified in accordance with their
contents?
After their use, are all the tools,
8.3.2.5 N containers and equipment hygienically
cleaned and identified as such?
8.3.2.6 Mixing/homogenization step
Type(s) of equipment:
8.3.2.6.1 INF
______________________________________
Are in-process control tests
8.3.2.6.2 N
performed?
8.3.2.6.2.1 INF Which ones? _______________________________________
8.3.2.6.2.2 N Are there records?
8.3.2.7 Agglutination step
Type(s) of equipment:
8.3.2.7.1 INF
______________________________________
8.3.2.8 Compactation step
Type(s) of equipment:
8.3.2.8.1 INF
______________________________________
8.3.2.9 Granulation step
8.3.2.9.1 INF Type(s) of equipment: ________________________________
Are in-process control tests
8.3.2.9.2 N
performed?
8.3.2.9.2.1 INF Which ones? _______________________________________
8.3.2.9.2.2 N Are there records?
8.3.2.10 Drying step
Is the equipment used in the
8.3.2.10.1 INF granulated drying the Drying
Chamber?
Does the granulated drying chamber
8.3.2.10.1.1 I
receive only product of a same batch?
Is the equipment used in the
8.3.2.10.2 INF
granulated drying the fluid bed?
Are the filters designated to each
8.3.2.10.2.1 N
product category?
8.3.2.10.3 INF Are other drying equipment used?
Which ones?
8.3.2.10.3.1 INF
______________________________________________
Do the granulated drying equipment
8.3.2.10.4 N have instruments to record the
temperature and time for drying?
8.3.2.10.4.1 N Are there records?
8.3.2.10.4.2 N Are the record instruments calibrated?
Are in-process control tests
8.3.2.10.5 N
performed?
Which ones?
8.3.2.10.5.1 INF
_____________________________________________
8.3.2.10.5.2 N Are there records?
8.3.2.11 Encapsulating step
Type(s) of equipment:
8.3.2.11.1 INF
______________________________________
Are in-process control tests
8.3.2.11.2 N
performed?
Which ones?
8.3.2.11.2.1 INF
_____________________________________________
8.3.2.11.2.2 N Are there records?
8.3.2.12 Compression step
Type(s) of equipment:
8.3.2.12.1 INF
______________________________________
Are in-process control tests
8.3.2.12.2 N
performed?
Which ones?
8.3.2.12.2.1 INF
______________________________________________
8.3.2.12.2.2 N Are there records?
8.3.2.13 Coating steps
Type(s) of equipment:
8.3.2.13.1 INF
______________________________________
8.3.2.13.2 N Are tests performed after the coating?
Which ones?
8.3.2.13.2.1 INF
______________________________________________
8.3.2.13.2.1
N Are there records?
.1
If required, are tests performed
8.3.2.13.3 N
through the process?
Which ones?
8.3.2.13.3.1 INF
______________________________________________
8.3.2.13.3.2 N Are there records?
Is there a storage place of
8.3.2.14 INF intermediary products in the
production area?
Is there a place/system for quarantine
8.3.2.15 N of intermediary products which
delimitates or restricts their use?
Is there a storage place for bulk
8.3.2.16 INF
products in the production area?
Is there a place/system of quarantine
8.3.2.17 N to the bulk products which delimitates
or restricts their use?
Are the recipients containing these
8.3.2.18 N
products well closed and identified?
Which is the identification system used?
8.3.2.18.1 INF
_________________________
Does the Validation Master Plan
8.3.2.19 N include all the steps of the process of
solids production?
Are there approved protocol to the
8.3.2.19.1 N
ongoing validations?
8.3.2.20 What kind of validation is expected:
8.3.2.20.1 INF Prospective?
How many batches will be evaluated?
8.3.2.20.1.1 INF
__________________________
8.3.2.20.2 INF Retrospective?
What is the number of batches considered?
8.3.2.20.2.1 INF
______________________
Were all the batches considered in the
Retrospective Validation produced
8.3.2.20.2.2 N
according to the same operational
parameters and specifications?
8.3.2.20.3 INF Concurrent?
How many batches will be considered?
8.3.2.20.3.1 INF
________________________
Do the results of the tests meet the
8.3.2.21 N acceptance criteria established in the
approved protocol?
Were the deviations found in relation
8.3.2.22 N to the parameters established in the
approved protocol duly investigated?
Is there a pre-established frequency to
8.3.2.23 N
the periodical revalidation?
Which one?
8.3.2.23.1 INF
___________________________________________
Are the results obtained in the
8.3.2.23.2 N periodical revalidation in accordance
with the approved protocol?
Are the companies which hold the
generic products registration with all
8.3.2.24 N
the steps of the process of solids
production of this category validated?
8.3.3. Packaging

8.3.3.1 Packaging area

No. Qualif. Items YES NO N/A
Is there an exclusive area to the primary
8.3.3.1.1 N packaging of drugs under the solid
pharmaceutical presentation?
Are there places requiring controlled
8.3.3.1.2 INF
environmental conditions?
8.3.3.1.2.1 If required, are there instruments to control:
8.3.3.1.2.1.
N Temperature?
1
8.3.3.1.2.1.
N Air relative humidity?
2
8.3.3.1.2.1.
N Differential pressure of the areas?
3
8.3.3.1.2.1.
N Are there records?
4
Are the packaging lines identified in
8.3.3.1.3 N accordance with the product that is being
packaged?
Are the instructions of Production
8.3.3.1.4 I
Order/Packaging Order accurately followed?
Are the packaging lines released before their
8.3.3.1.5 N
use?
8.3.3.1.5.1 N Are there records?
When required, are there extraction system of
8.3.3.1.6 N dusts from the area, arising from the
packaging operations?
When required, do the equipment used in the
8.3.3.1.7 N dusts filling process have a dust aspiration
system?
8.3.3.1.7.1 INF What is the destination of these wastes?
Are controls performed during the packaging
8.3.3.1.8 N
process?
8.3.3.1.8.1 INF Which ones? ______________________________________________
8.3.3.1.8.2 N Are there records?
Is an in line inspection performed during the
8.3.3.1.9 N
packaging process?
8.3.3.1.9.1 N Are there records?
Is the reconciliation among the theoretical
8.3.3.1.10 N amount of printed, filling materials and bulk
products and the actual amount used?
8.3.3.1.10.1 N Are there records?
8.3.3.2. Labeling
No. Qualif. Items YES NO N/A
Is the access to the labels, in the
8.3.3.2.1 I packaging area, allowed only to
duly authorized persons?
 Are the labels inspected to check if
they correspond to the product to
be labeled and the conformity with
8.3.3.2.2 N
the Production Order/Packaging
Order, before delivered to the
packaging line?
Are the labeling machines
8.3.3.2.3 N inspected and released before their
use?
8.3.3.2.3.1 N Are there records?
Are the labels printed with unused
8.3.3.2.4 I batch number and expiration dates
destroyed?
8.3.3.2.4.1 N Are there records?
Are the quantities of labels
received, used, including the
8.3.3.2.5 N
damaged ones and the destroyed
ones registered?
Are all the differences among the
number of labels received, number
8.3.3.2.6 I of labels used, including the
damaged ones and the destroyed
ones investigated?
8.3.3.2.6.1 N Are there records?
Are the non-printed labels with the
8.3.3.2.7 N batch number and expiration date
returned to the warehouse?
Is there a person responsible for
8.3.3.2.7.1 N
this return?
8.3.3.2.7.2 N Are there records?

8.4.- SEMI-SOLID PRODUCTS

8.4.1. General information

No. Qualif. Items YES NO N/A
8.4.1.1 INF Specify the pharmaceutical presentations produced:
_______________________________________________
________________________
8.4.1.2 N Is there an area for the manufacturing of semi-solid products?
8.4.2. Production
No. Qualif. Items YES NO N/A
Are there measuring scales and
8.4.2.1 INF
containers in the production area?
8.4.2.1.1 N Are they regularly calibrated?
8.4.2.1.1.1 N Are there records?
8.4.2.1.2 N Are they regularly verified?
8.4.2.1.2.1 N Are there records?
Are the verifications performed with
8.4.2.1.2.2 N
duly calibrated standard weights?
 Is the Production Order accurately
8.4.2.2 I
followed?
Are all the production steps registered
8.4.2.2.1 N
and signed by their performer?
Are all the production critical steps
8.4.2.2.2 N
signed by the indicated supervisor?
Are all the containers used in the
production of a product batch duly
8.4.2.3 N
identified in accordance to their
content?
Are all the equipment used in the
8.4.2.4 N production of a batch identified in
accordance with the product?
After their use, are all the tools,
8.4.2.5 N containers, and equipment hygienically
cleaned and identified as such?
Are the equipments properly placed in
order to avoid mixings/cross-
8.4.2.6 N contamination when simultaneous
batches of different products are
manufactured?
Are in-process control tests
8.4.2.7 N
performed?
8.4.2.7.1 INF Which ones? ______________________________________
8.4.2.7.2 N Are there records?
Is there a place to store the bulk
8.4.2.8 INF
products in the production area?
Is there a place/system to quarantine
8.4.2.9 N the bulk products which delimitates or
restricts their use?
Are the recipients containing these
8.4.2.10 N
products well closed and identified?
What is the identification system
8.4.2.10.1 INF
used?________________________
Does the Validation Master Plan
8.4.2.11 N include all the steps of the process of
semi-solids production?
Are there approved protocol to the
8.4.2.11.1 N
ongoing validations?
8.4.2.12 What kind of validation is expected:
8.4.2.12.1 INF Prospective?
How many batches will be evaluated?
8.4.2.12.1.1 INF
__________________________
8.4.2.12.2 INF Retrospective?
What is the number of batches considered?
8.4.2.12.2.1 INF
______________________
Were all the batches considered in the
Retrospective Validation produced
8.4.2.12.2.2 N
according to the same operational
parameters and specifications?
8.4.2.12.3 INF Concurrent?
How many batches will be considered?
8.4.2.12.3.1 INF
_________________________
Do the tests results meet the
8.4.2.13 N acceptance criteria established in the
approved protocol?
Were the deviations found in relation
8.4.2.14 N to the parameters established in the
approved protocol duly investigated?
Is there a pre-established frequency to
8.4.2.15 N
the periodical revalidation?
8.4.2.15.1 INF Which one? _____________________________________
Are the results obtained in the
8.4.2.15.2 N periodical revalidation in accordance
with the approved protocol?
8.4.2.16 Sterile semi-solid products:
Is the preparation of sterile semi-solid
8.4.2.16.1 INF products performed in an open
system?
Are they prepared in a clean area
8.4.2.16.1.1 N
grade C (class 10,000)?
Is the preparation of sterile semi-solid
8.4.2.16.2 INF products performed in a closed
system?
Are they prepared in a clean area,
8.4.2.16.2.1 N
grade D (class 100,000)?
Are they filled in a clean area, grade D
8.4.2.16.3 N
(class 10,000)?
What is the process used to assure the sterility of the products?
8.4.2.16.4 INF
__________
Does the Validation Master Plan
8.4.2.17 N include the steps of the process of
sterile semi-solids production?
Are there approved protocols to the
8.4.2.18 N
ongoing validations?
8.4.2.19 What type of validation is expected:
8.4.2.19.1 INF Prospective?
8.4.2.19.1.1 INF How many batches will be evaluated? ____________________
8.4.2.19.2 INF Retrospective?
How many batches will be considered?
8.4.2.19.2.1 INF
__________________________
Were all the batches considered in the
Retrospective Validation produced
8.4.2.19.2.2 N
according to the same operational
parameters and specifications?
8.4.2.19.3 INF Concurrent?
8.4.2.19.3.1 INF How many batches will be evaluated?
Do the tests results meet the
8.4.2.20 N acceptance criteria established in the
approved protocol?
 Were the deviations found in relation
8.4.2.21 N to the statements established in the
approved protocol duly investigated?
Is there a pre-established frequency to
8.4.2.22 N
the periodical revalidation?
8.4.2.22.1 INF Which one? _______________________________________
Are the results obtained in the
8.4.2.22.2 N periodical revalidation in accordance
with the approved protocol?

8.4.3. Filling

8.4.3.1. Filling area

No. Qualif. Items YES NO N/A
Is there an specific area to the filling of
8.4.3.1.1 N drugs in the sterile semi-solid
pharmaceutical presentation?
Are the filling lines identified according
8.4.3.1.2 N
to the product that is being packaged?
Are the Production Order instructions
8.4.3.1.3 I
accurately followed?
Are the filling lines inspected and
8.4.3.1.4 N
released before their use?
8.4.3.1.4.1 N Are there records?
Are in-process controls performed
8.4.3.1.5 N
during the filling operations?
Which ones?
8.4.3.1.5.1 INF
___________________________________________
8.4.3.1.5.2 N Are there records?
Is the reconciliation among the
theoretical quantity of filling materials
8.4.3.1.6 N
(printed or not) and bulk products and
the actual quantity used?
8.4.3.1.6.1 N Are there records?

8.4.4 Packaging

8.4.4.1 Packaging area

No. Qualif. Items YES NO N/A
Is there an exclusive area to the
secondary packaging of drugs in
8.4.4.1.1 N
the semi-solid pharmaceutical
presentation?
Are the packaging lines identified
8.4.4.1.2 N according to the products that is
being packaged?
Are the Production
8.4.4.1.3 I Order/Packaging Order instructions
accurately followed?
Are the packaging lines released
8.4.4.1.4 N
before use?
8.4.4.1.4.1 N Are there records?
Is a line inspection performed
8.4.4.1.5 N
during the packaging process?
8.4.4.1.5.1 N Are there records?
Is the reconciliation among the
theoretical quantity of printed, filling
8.4.4.1.6 N
materials and bulk product and the
actual quantity used?
8.4.4.1.6.1 N Are there records?

8.5.- LIQUID PRODUCTS

8.5.1. General information

No. Qualif. Items YES NO N/A
8.5.1.1 INF Specify the pharmaceutical presentations produced:
_________________________________________________
_______________________
8.5.1.2 N Is there an area to the manufacturing of liquid products?
8.5.2. Production
No. Qualif. Items YES NO N/A
Are there measuring scales and
8.5.2.1 INF
containers in the production area?
8.5.2.1.1 N Are they regularly calibrated?
8.5.2.1.1.1 N Are there records?
8.5.2.1.2 N Are the scales regularly checked?
8.5.2.1.2.1 N Are there records?
Are the verifications performed with
8.5.2.1.2.2 N
duly calibrated standard weights?
Are the Production Order instructions
8.5.2.2 I
accurately followed?
Are all the production steps registered
8.5.2.2.1 N
and signed by their performer?
Are all the production critical steps
8.5.2.2.2 N
signed by the indicated supervisor?
Are all the containers used in the
production of a product batch duly
8.5.2.3 N
identified in accordance with their
contents?
After use, are all the tools, containers,
8.5.2.4 N and equipment hygienically cleaned
and identified as such?
Are all the equipment placed correctly
in order to avoid mixings/cross-
8.5.2.5 N contamination when simultaneous
batches of different products are
manufactured?
Is the water used in the production at
8.5.2.6 N
least purified?
8.5.2.7 R Are the solutions filtered?
8.5.2.7.1 INF Type of filter: ________________________________________
 Are there records on the filters
8.5.2.7.2 N
sanitization?
Are in-process control tests
8.5.2.8 N
performed?
8.5.2.8.1 INF Which ones? ________________________________________
8.5.2.8.2 N Are there records?
Is there a place to store the bulk
8.5.2.9 INF
products in the production area?
Is there a place/system to quarantine
8.5.2.10 N the bulk products which delimitates or
restricts their use?
Are the recipients containing these
8.5.2.11 N
products well closed and identified?
Does the Validation Master Plan
8.5.2.12 N include all the steps of the process of
liquids production?
Are there approved protocols to the
8.5.2.13 N
ongoing validations?
8.5.2.14 What kind of validation is expected:
8.5.2.14.1 INF Prospective?
How many batches will be evaluated?
8.5.2.14.1.1 INF
__________________________
8.5.2.14.2 INF Retrospective?
How many batches will be considered?
8.5.2.14.2.1 INF
_________________________
Were all the batches considered in the
Retrospective Validation produced according
8.5.2.14.2.2 N
to the operational parameters and
specifications?
8.5.2.14.3 INF Concurrent?
8.5.2.14.3.1 INF How many batches will be evaluated?
Do the tests results meet the acceptance
8.5.2.15 N
criteria established in the approved protocol?
Were the deviations found in relation to the
8.5.2.16 N parameters established in the approved
protocol were duly investigated?
Is there a pre-established frequency to the
8.5.2.17 N
periodical revalidation?
Which one?
8.5.2.17.1 INF
_____________________________________________
Are the results obtained in the periodical
8.5.2.17.2 N revalidation in accordance with the approved
protocol?
Are the companies which hold the generic
products registration with all of their steps of
8.5.2.18 N
the liquids production process of this
category?
8.5.3-Packaging

8.5.3.1 Filling area

No. Qualif. Items YES NO N/A
Is there an specific area to the filling of drugs
8.5.3.1.1 N
in the liquid pharmaceutical presentation?
Are the instructions of the Production Order
8.5.3.1.2 I
accurately followed?
Are the filling lines inspected and released
8.5.3.1.3 N
before their use?
8.5.3.1.3.1 N Are there records?
Are in-process controls performed during the
8.5.3.1.4 R
filling operations?
8.5.3.1.4.1 INF Which ones? _____________________________________________
8.5.3.1.4.2 N Are there records?
Is the reconciliation among the theoretical
8.5.3.1.5 N quantity of the printed, filling materials and
bulk product and the actual quantity used?
8.5.3.1.5.1 N Are there records?

8.5.3.2. Labeling

No. Qualif. Items YES NO N/A

Is the access to the labels, in the
8.5.3.2.1 I packaging area, allowed only to
duly authorized persons?
Are the batches inspected to check
if they correspond to the product to
be labeled and the accordance with
8.5.3.2.2 N
the Production Order/Packaging
Order, before being delivered to the
packaging line?
Are the labeling machines
8.5.3.2.3 N
inspected and released before use?
8.5.3.2.3.1 N Are there records?
Are the printed batches with unused
8.5.3.2.4 N batch number and expiration date
destroyed?
8.5.3.2.4.1 N Are there records?
Are the quantities of labels
8.5.3.2.5 N received, used, including the
damaged and destroyed ones?
Are all the differences among the
number of labels received, labels
8.5.3.2.6 I used, including the damaged ones
and the destroyed ones
investigated?
8.5.3.2.6.1 N Are there records?
Are the labels non-printed with
8.5.3.2.7 N batch number and expiration date
returned to the warehouse?
 Is there a person responsible for
8.5.3.2.7.1 N
this return?
8.5.3.2.7.2 N Are there records?
8.5.3.3 - Secondary Package
No. Qualif. Items YES NO N/A
Is there an exclusive area to the
secondary packaging of drugs in
8.5.3.3.1 N
the non-sterile liquid
pharmaceutical presentation?
Are the packaging lines identified in
8.5.3.3.2 N accordance with the product that is
being packaged?
Are the Production
8.5.3.3.3 I Order/Packaging Order instructions
accurately followed?
Are the packaging lines released
8.5.3.3.4 N
before use?
8.5.3.3.4.1 N Are there records?
Is an in line inspection performed
8.5.3.3.5 N
during the packaging process?
8.5.3.3.5.1 N Are there records?
Is the reconciliation among the
theoretical quantity of printed, filling
8.5.3.3.6 N
materials and bulk product and the
actual quantity used?
8.5.3.3.6.1 N Are there records?

8.6. Products of therapeutic classes requiring special production conditions in addition to the
requirements already established by the production line

8.6.1.- Hormone products

No. Qualif. Items YES NO N/A
Specify the pharmaceutical presentations produced (solid,
semi-solid, liquid, injection):
8.6.1.1 INF ________________________________________________
______________________________
_____________________________________
Is there an exclusive and separated area to the production of
8.6.1.2 N
hormone products?
Is the production of these products done avoiding cross-
8.6.1.3 I
contamination?
Is the air insufflating and exhausting system independent
8.6.1.4 I
from the ones present at the other areas or premises?
Does the air exhaustion system have devices to avoid the
8.6.1.5 N
environment contamination?
Does the production area have a negative air pressure in
8.6.1.6 N
comparison to the other appended areas?
8.6.1.6.1 N Are there records of the differential pressure?
Do the employees wear individual protection equipment
8.6.1.7 N
during all the production process?
 Are specific and periodical medical exams performed in
8.6.1.8 N
people manipulating hormones?
8.6.1.8.1 N Are there records?
Are periodical shifts performed among the employees in the
8.6.1.9 N
production area?
8.6.1.9.1 INF What is the periodicity? ____________________________
Does the Validation Master Plan include all the steps of the
8.6.1.10 N
process of hormone products production?
8.6.1.10.1 N Are there approved protocols to the ongoing validations?
8.6.1.11 What kind of validation is expected:
8.6.1.11.1 INF Prospective?
8.6.1.11.1.1 INF How many batches will be evaluated?__________________________
8.6.1.11.2 INF Retrospective?
8.6.1.11.2.1 INF How many batches will be considered? _________________________
Were all the batches considered in the Retrospective
8.6.1.11.2.2 N Validation produced according to the same operational
parameters and specifications?
8.6.1.11.3 INF Concurrent?
8.6.1.11.3.1 INF How many batches will be evaluated? ________________________
Do the tests results meet the acceptance criteria established
8.6.1.12 N
in the approved protocol?
Were the deviations found in relation to the parameters
8.6.1.13 N
established in the approved protocol duly investigated?
Is there a pre-established frequency to the periodical
8.6.1.14 N
revalidation?
8.6.1.14.1 INF Which one? __________________________________________
Are the results obtained in the periodical revalidation in
8.6.1.14.2 N
accordance with the approved protocol?

8.6.2.- Products containing highly active substances

(e.g., prostaglandins, thalidomide, immunosuppressants, some psychoactive substances and
others)

No. Qualif. Items YES NO N/A

Specify the pharmaceutical presentations produced:
8.6.2.1 INF ______________________________________________
_______________________
Is there an exclusive area to the production of products
8.6.2.2 INF
containing highly active substances?
Is the production of these products performed avoiding cross-
8.6.2.3 I
contamination?
If there is an exclusive room, is the air insufflating and
8.6.2.4 I exhausting system independent from the ones present in the
other areas or premises?
Does the air exhaustion system have devices to avoid the
8.6.2.5 N
environment contamination?
Do the employees wear individual protection equipment
8.6.2.6 N
during all the production process?
 Are periodical specific medical exams performed in the
8.6.2.7 N people handling products subjected to the special control
regimen?
8.6.2.7.1 N Are there records?
Are the cleaning procedures of the equipment used in the
8.6.2.8 N production of products subjected to special control regimen
validated?
If there is an exclusive room, does the Validation Master Plan
8.6.2.9 N includes all the steps of the production of products containing
highly active substances?
8.6.2.9.1 N Are there approved protocols to the ongoing validations?
8.6.2.10 What kind of validation is expected:
8.6.2.10.1 INF Prospective?
8.6.2.10.1.1 INF How many batches will be evaluated?__________________________
8.6.2.10.2 INF Retrospective?
8.6.2.10.2.1 INF How many batches will be considered? __________
Were all the batches considered in the Retrospective
8.6.2.10.2.2 N validation produced according to the same operational
parameters and specifications?
8.6.2.10.3 INF Concurrent?
8.6.2.10.3.1 INF How many batches will be evaluated?
Do the tests results meet the acceptance criteria established
8.6.2.11 N
in the approved protocol?
Were the deviations found in relation to the parameters
8.6.2.12 N
established in the approved protocol duly investigated?
Is there a pre-established frequency to the periodical
8.6.2.13 N
revalidation?
8.6.2.13.1 INF Which one? ___________________________________
Are the results obtained in the periodical revalidation in
8.6.2.13.2 N
accordance with the approved protocol?

8.6.3.- Antibiotic products non-betalactamic

No. Qualif. Items YES NO N/A

Specify the pharmaceutical presentations produced: ______
8.6.3.1 INF ________________________________________________

Is there an exclusive area to the production of non-

8.6.3.2 INF
betalactamic antibiotics?
Is their production performed avoiding the cross-
8.6.3.5 I
contamination?
If there is an exclusive area, is the air insufflating and
8.6.3.3 I exhausting system independent from the other ones present
in the other areas or premises?
Does the air exhausting system have devices to avoid the
8.6.3.4 N
environment contamination?
Do the employees wear individual protection equipment
8.6.3.6 N
during all the production process?
Are periodical specific medical exams performed in the
8.6.3.7 N
people handling antibiotics?
8.6.3.7.1 N Are there records?
Are the cleaning procedures of the equipment used in the
8.6.3.8 N
production of non-betalactamic antibiotics validated?
Does the Validation Master Plan include the production of
8.6.3.9 N
non-lactamic antibiotic products?
8.6.3.9.1 N Are there approved protocols to the ongoing validations?
8.6.3.10 What kind of validation is expected:
8.6.3.10.1 INF Prospective?
8.6.3.10.1.1 INF How many batches will be evaluated?
8.6.3.10.2 INF Retrospective?
8.6.3.10.2.1 INF How many batches will be considered?
Were all the batches considered in the Retrospective
8.6.3.10.2.2 N Validation produced according to the same operational
parameters and specifications?
8.6.3.10.3 INF Concurrent?
8.6.3.10.3.1 INF How many batches will be evaluated?
Do the tests results meet the acceptance criteria established
8.6.3.11 N
in the approved protocol?
Were the deviations found in relation to the parameters
8.6.3.12 N
established in the approved protocol duly identified?
Is there a pre-established frequency to the periodical
8.6.3.13 N
revalidation?
8.6.3.13.1 INF Which one? ________________________________
Are the results obtained in the periodical revalidation in
8.6.3.13.2 N
accordance with the approved protocol?

8.6.4.- Penicillin products

No. Qualif. Items YES NO N/A

8.6.4.1 INF Specify the pharmaceutical presentations produced: ________________
8.6.4.2 The production of penicillin products is performed:
8.6.4.2.1 R In an exclusive and separated building?
8.6.4.2.2 I In exclusive and separated areas?
If there is an exclusive area, is the air
insufflating and exhausting system
8.6.4.3 I
independent from the ones present in the
other areas or premises?
Does the air exhaustion system have devices
8.6.4.4 N
to avoid the environment contamination?
Do the employees wear individual protection
8.6.4.5 N
equipment during all the production process?
Are periodical specific medical exams
8.6.4.6 N performed on people handling penicillin
products?
8.6.4.6.1 N Are there records?
Are periodical changing shifts performed
8.6.4.7 R
among the production area employees?
8.6.4.7.1 INF What is the periodicity? __________________________
8.6.4.7.2 N Are there records?
 Does the Validation Master Plan include all
8.6.4.8 N the steps of process of the production of
penicillin products?
Are there approved protocols to the ongoing
8.6.4.8.1 N
validations?
8.6.4.9 What kind of validation is expected:
8.6.4.9.1 INF Prospective?
8.6.4.9.1.1 INF How many batches will be evaluated?
8.6.4.9.2 INF Retrospective?
8.6.4.9.2.1 INF How many batches will be considered? __________________________
Were all the batches considered in the
Retrospective Validation produced according
8.6.4.9.2.2 N
to the same operational parameters and
specifications?
8.6.4.9.3 INF Concurrent?
8.6.4.9.3.1 INF How many batches will be evaluated?
Do the tests results meet the criteria
8.6.4.10 N
established in the approved protocol?
Were the deviations found in relation to the
8.6.4.11 N established parameters in the approved
protocol duly investigated?
Is there a pre-established frequency to the
8.6.4.12 N
periodical revalidation?
8.6.4.12.1 INF Which one? _____________________
Are the results obtained in the periodical
8.6.4.12.2 N revalidation in accordance with the approved
protocol?
8.6.5.- Cephalosporin products
No. Qualif. Items YES NO N/A
8.6.5.1 INF Specify the pharmaceutical presentations produced:
8.6.5.2 The production of cephalosporin products is performed:
In an exclusive and separated
8.6.5.2.1 R
building?
8.6.5.2.2 I In exclusive and separated areas?
If there is an exclusive area, is the air
insufflating and exhausting system
8.6.5.3 I
independent from the ones present in
the other areas or premises?
Does the air exhaustion system have
8.6.5.4 N devices to avoid the environment
contamination?
Do the employees wear individual
8.6.5.5 N protection equipment during all the
production process?
Are periodical specific medical exams
8.6.5.6 N performed on people handling
penicillin products?
8.6.5.6.1 N Are there records?
 Are periodical changing shifts
8.6.5.7 R performed among the production area
employees?
8.6.5.7.1 INF What is the periodicity? __________________________
8.6.5.7.2 N Are there records?
Does the Validation Master Plan
8.6.5.8 N include all the steps of process of the
production of penicillin products?
Are there approved protocols to the
8.6.5.8.1 N 7
ongoing validations?
8.6.5.9 What kind of validation is expected:
8.6.5.9.1 INF Prospective?
8.6.5.9.1.1 INF How many batches will be evaluated?
8.6.5.9.2 INF Retrospective?
How many batches will be considered?
8.6.5.9.2.1 INF
__________________________
Were all the batches considered in the
Retrospective Validation produced
8.6.5.9.2.2 N
according to the same operational
parameters and specifications?
8.6.5.9.3 INF Concurrent?
8.6.5.9.3.1 INF How many batches will be evaluated?
Do the tests results meet the criteria
8.6.5.10 N
established in the approved protocol?
Were the deviations found in relation
8.6.5.11 N to the established parameters in the
approved protocol duly investigated?
Is there a pre-established frequency to
8.6.5.12 N
the periodical revalidation?
8.6.5.12.1 INF Which one? _____________________
Are the results obtained in the
8.6.5.12.2 N periodical revalidation in accordance
with the approved protocol?
8.6.6.- Cytostatic products
No. Qualif. Items YES NO N/A
8.6.6.1 INF Specify the pharmaceutical presentations produced: _________________
Is there an exclusive and separated area to
8.6.6.2 N
the production of cytostatic products?
Is the production of these products performed
8.6.6.3 I
avoiding cross-contamination?
Is the air insufflating and exhausting system
8.6.6.4 I independent from the other ones present in
the other areas or premises?
Does the air exhaustion system have devices
8.6.6.5 N
to avoid the environment contamination?
Do the employees wear individual protection
8.6.6.6 N
equipment during all the production process?
Are periodical specific medical exams
8.6.6.7 N performed on people handling the cytostatic
substances?
8.6.6.7.1 N Are there records?
Are periodical shifts performed among the
8.6.6.8 R
employees of the production area?
8.6.6.8.1 INF What is the periodicity?
8.6.6.8.2 N Are there records?
Does the Validation Master Plan include all
8.6.6.9 N the steps of the process of cytostatics
production?
Are there approved protocols to the ongoing
8.6.6.9.1 N
validations?
8.6.6.10 What kind of validation is expected?
8.6.6.10.1 INF Prospective?
8.6.6.10.1.1 INF How many batches will be evaluated?
8.6.6.10.2 INF Retrospective?
How many batches will be considered?
8.6.6.10.2.1 INF
__________________________
Were all the batches considered in the
Retrospective Validation produced according
8.6.6.10.2.2 N
to the same operational parameters and
specifications?
8.6.6.10.3 INF Concurrent?
8.6.6.10.3.1 INF How many batches will be evaluated?
Do the tests results meet the criteria
8.6.6.11 N
established in the approved protocol?
Were the deviations found in relation to the
8.6.6.12 N established parameters in the approved
protocol duly investigated?
Is there a pre-established frequency to the
8.6.6.13 N
periodical revalidation?
8.6.6.13.1 INF Which one? _____________________
Are the results obtained in the periodical
8.6.6.13.2 N revalidation in accordance with the approved
protocol?

8.7.- STERILE PRODUCTS

8.7.1 - Specific Conditions

No. Qualif. Items YES NO N/A
8.7.1.1 Is there a clean area for:
Preparation of products with final
8.7.1.1.1 I
sterilization or sterilizing filtration?
Aseptic preparation of products
8.7.1.1.2 I
without final sterilization?
Filling of products with final
8.7.1.1.3 I
sterilization?
Aseptic filling of products without final
8.7.1.1.4 I
sterilization?
Manufacturing of plastic containers by
8.7.1.1.5 N lamination for SPGV [Large Volume
Parenteral Solution]?
8.7.1.2 Is there an area for:
Washing and
8.7.1.2.1 N sterilization/depyrogenization of vials
and/or vial-flasks?
8.7.1.2.2 N Final sterilization of products?
8.7.1.2.3 N Visual inspection of filled products?
Does the design of the production
areas make the effective cleaning and
8.7.1.3 N maintenance possible reducing the
introduction, generation and retention
of contaminants inside?
Are the junctures among the floor,
8.7.1.4 N
walls and ceiling free from angles?
Are the walls, ceiling and floor
8.7.1.5 N
sanitized?
8.7.1.5.1 N Are there records?
Are the windows or viewers perfectly
8.7.1.6 N
sealed?
Is there a procedure to regulate the
8.7.1.7 I entrance of persons in the sterile
products production area?
Are the vials, vial-flasks, caps and
8.7.1.8 N tools transferred to the filling areas
duly sterilized and/or depyrogenized?
8.7.2.- Washing, sterilization and depyrogenization area for containers and materials
No. Qualif. Items YES NO N/A
Is the area occupied appropriate to the
8.7.2.1 N
operations volume?
8.7.2.2 N Is the circulation area free?
8.7.2.3 N Is the place clean?
8.7.2.4 R Is the area classified?
What is the classification of this area?
8.7.2.4.1 INF
__________________________
8.7.2.4.2 N Are there records?
Does the area have air filtration
8.7.2.5 INF
installations?
Are there records of the filtered air
8.7.2.5.1 N
controls?
8.7.2.6 N Are all the equipment identified?
Do all the equipment in use in the
preparation of a product batch have
8.7.2.7 N
tags identifying the in-process product
and the batch number?
Is the water used in the last rinse of
8.7.2.8 N the vials and vial-flasks of injection
grade?
Is there some kind of filter in the water
and compressed air systems which
8.7.2.9 N
supplies the vials and vial-flasks
washing equipment?
8.7.2.9.1 INF Types of filters ___________________________
Are there records on the filters
8.7.2.9.2 N
exchange?
8.7.2.10 The washing procedure of the vials and vial-flasks is:
8.7.2.10.1 INF Automatic?
8.7.2.10.2 INF Semi-automatic?
8.7.2.10.3 INF Manual?
Are the washed vials and vial-flasks
8.7.2.11 INF
packaged into metallic boxes?
Is there a sterilization and
8.7.2.12 N
depyrogenization oven?
Is the sterilization and
8.7.2.12.1 INF depyrogenization oven a double-door
one?
If there is none, are the sterilized and
8.7.2.12.1.1 N depyrogenized vials and vial-flasks
transferred to the filling area safely?
Is there a sterilization and
8.7.2.13 N
depyrogenization tunnel?
Is the automatic washing machine of
vials and vial-flasks connected to the
8.7.2.14 INF
sterilization and depyrogenization
tunnel?
Do the sterilization and
8.7.2.15 N depyrogenization equipment have
recorders of time and temperature?
8.7.2.15.1 N Are there records?
Are there sterilization autoclaves in the
8.7.2.16 N
area?
8.7.2.16.1 INF Are the autoclaves double-door ones?
If there is none, are the materials
8.7.2.16.1.1 N sterilized by humid heat transferred to
the filling area safely?
Does the humid heat sterilizer have
8.7.2.17 N
time and temperature recorders?
8.7.2.17.1 N Are there records?
Are indicators which might identify if
8.7.2.18 N the product was subjected to the
sterilization process used?
8.7.2.19 N Are the sterilized materials identified?
Are the equipment measuring
8.7.2.20 N
instruments calibrated?
8.7.2.20.1 N Are there records?
Is the sterilization by humid heat
8.7.2.21 N
process validated?
Is there an approved protocol to the
8.7.2.22 N validation of the sterilization process of
materials by humid heat?
Were three (3) consecutive satisfactory runs presented for each
8.7.2.23 N
approved protocol?
 Is there a standardized diagram of the
8.7.2.24 N minimum and maximum materials
load?
Were established sterilization control
8.7.2.24.1 N parameters for each standardized
load?
Do the tests results meet the
8.7.2.25 N acceptance criteria established in the
approved protocol?
Were the deviations found in relation
8.7.2.26 N to the parameters established in the
approved protocol duly investigated?
8.7.2.27 N Is the periodical revalidation foreseen?
What is the frequency?
8.7.2.27.1 N
______________________________________
Are the results obtained in the
8.7.2.27.2 N periodical revalidation in accordance
with the approved protocol?
Is the sterilization process by dry heat
8.7.2.28 N
validated?
Is there an approved protocol to the
8.7.2.29 N validation of the sterilization process
by dry heat?
Were three (3) consecutive satisfactory runs presented for each
8.7.2.29.1 INF
approved protocol?
Is there a standardized diagram of the
8.7.2.29.2 N minimum and maximum materials
load?
Do the tests results meet the
8.7.2.30 N acceptance criteria established in the
approved protocol?
Were established sterilization control
8.7.2.31 N parameters for each standardized
load?
Were the deviations found in relation
8.7.2.32 N to the parameters established in the
approved protocol duly investigated?
8.7.2.33 N Is the periodical revalidation foreseen?
What is the frequency?
8.7.2.33.1 INF
______________________________________
Are the results obtained in the
8.7.2.33.2 N periodical revalidation in accordance
with the approved protocol?
Is the depyrogenization process
8.7.2.34 N
validated?
Were three (3) consecutive
8.7.2.34.1 INF satisfactory runs presented for each
approved protocol?
Is there a standardized diagram of the
8.7.2.36 N minimum and maximum
products/materials load?
 Were established sterilization control
8.7.2.36.1 N parameters for each standardized
load?
Were the deviations found in relation
8.7.2.37 N to the parameters established in the
approved protocol duly investigated?
8.7.2.38 N Is the periodical revalidation foreseen?
Which one?
8.7.2.38.1 INF
_____________________________________________
In case of the use of plastic bottles, what is the method
8.7.2.39 INF
employed? _______
8.7.2.39.1 N Are there records?
Does the company use the sterilization
8.7.2.40 INF
process by ethylene oxide?
8.7.2.40.1 INF In what kinds of components?

8.7.3.- Area for the preparation of products with final sterilization or with sterilizing filtration

No. Qualif. Items YES NO N/A

Is the preparation clean area
8.7.3.1 N
appropriate for the operations volume?
8.7.3.2 The preparation of sterile products is performed:
8.7.3.2.1 INF Open system?
Are the sterile products prepared in a
8.7.3.2.1.1 N
grade C clean area (class 10,000)?
8.7.3.2.2 INF Closed system?
Are the solutions prepared in a grade
8.7.3.2.2.1 N
D clean area (class 100,000)?
Does the area have a positive
8.7.3.3 N pressure in comparison to the
appended areas?
Is there an antechamber to the
8.7.3.4 N entrance of personnel in the area of
preparation of sterile products?
Is there an antechamber to the
8.7.3.5 N entrance of materials in the area of
preparation of sterile products?
Is there a pressure graduator from the
8.7.3.6 N sterile products preparation area to the
antechambers and appended areas?
8.7.3.7 Are there records of:
Differential pressure among different
8.7.3.7.1 N
areas?
8.7.3.7.2 N Relative humidity of the areas?
Environmental temperature of the
8.7.3.7.3 N
areas?
Are the registered values in
8.7.3.7.4 N accordance with the established in the
SOP?
 Are the measuring instruments
8.7.3.7.5 N
calibrated?
8.7.3.7.5.1 N Are there records?
8.7.3.8 Is the monitoring of particles performed:
8.7.3.8.1 N Viable?
8.7.3.8.2 N Non viable?
8.7.3.8.1 N Are there records?
Are microbiological controls of the
8.7.3.9 N
surfaces performed?
8.7.3.9.1 N Are there records?
In case of deviations in relation to the
8.7.3.10 N limits established is an investigation
performed to evaluate the causes?
Are preventive and/or corrective
8.7.3.10.1 N actions taken in relation to the
identified causes?
8.7.3.10.2 N Are there records?
Are the garment and personal hygiene
8.7.3.11 N
procedures for this area fulfilled?
Are the uniforms worn in the grade C
8.7.3.11.2 N
area sterilized?
Is the fabric used in the uniforms from
8.7.3.11.3 N a material that avoids the loose of
fibers or particles?
Are the gloves free from lubricants
8.7.3.12 N
which release particles?
Is there a procedure defining the
entrance conditions of raw materials,
8.7.3.13 N
materials and equipment in the clean
area of preparation?
Are all the sterile products preparation
8.7.3.14 N operations registered and signed by
their performer?
Are all the production critical steps
8.7.3.14.1 N
signed by the indicated supervisor?
Are all the equipment used in the
8.7.3.15 N production of a sterile product batch
identified?
If there are measuring scales and containers in the preparation area of
8.7.3.16
sterile products, are they:
8.7.3.16.1 N Regularly calibrated?
8.7.3.16.1.1 N Are there records?
8.7.3.16.2 N Regularly checked?
8.7.3.16.2.1 N Are there records?
Are the verifications done with duly
8.7.3.16.3 N
regulated standard weights?
 Is there an appropriate separation
between the equipment in order to
8.7.3.17 N avoid mixings or cross-contamination
when batches of different products are
simultaneously produced?
Is water for injection used in the sterile
8.7.3.18 I
products preparation?
Is the water for injection released by
8.7.3.18.1 N
the Quality Control before being used?
Are the reactor sterilized by pure
8.7.3.19 R
steam?
8.7.3.20 N Are in-process controls performed?
Which ones?
8.7.3.20.1 INF
______________________________________________
8.7.3.20.2 N Are there records?
Is the pipes used to transfer a solution
8.7.3.21 N or suspension to the filling area
sanitized/sterilized?
Is the solution filtered through an
8.7.3.22 INF
sterilizing filter?
Are tests to determine the integrity of
8.7.3.23 N
the sterilizing filter performed?
8.7.3.23.1 N Are there records?
After used, are all the tools, equipment
and containers thoroughly washed,
8.7.3.24 N
and if required, sterilized and kept this
way until the next use?
Are they identified with tags certifying
8.7.3.25 N
this condition?

8.7.4. Filling area of products with final sterilization

No. Qualif. Items YES NO N/A

Is the clean area of final sterilization
8.7.4.1 N products filling appropriate to the
operations volume?
Is the clean area of final sterilization
8.7.4.2 N products filling of grade C (class
10,000)?
Does the area have a positive
8.7.4.3 N pressure in comparison to the
appended areas?
Is there an antechamber to the
8.7.4.4 N entrance of personnel in the sterile
products filling area?
Is there an antechamber to the
8.7.4.5 N entrance of materials in the sterile
products filling area?
Is there a pressure graduator of the
8.7.4.6 N sterile products to the antechambers
and the appended areas?
8.7.4.7 Are there records of:
Differential pressure among different
8.7.4.7.1 N
areas?
8.7.4.7.2 N Relative humidity of the area?
Environmental temperature of the
8.7.4.7.3 N
area?
Are the values registered in
8.7.4.7.4 N accordance with the established in the
SOP?
Are the measuring instruments
8.7.4.8 N
regulated?
8.7.4.8.1 N Are there records?
8.7.4.9 The monitoring of particles is performed:
8.7.4.9.1 N Viables
8.7.4.9.2 N Non-viables
8.7.4.9.3 N Are there records?
In case of deviations in relation to the
8.7.4.10 N limits established is an investigation
performed to evaluate the causes?
Are preventive and/or corrective
8.7.4.11 N actions taken in relation to the
identified causes?
8.7.4.11.1 N Are there records?
Are the garments and personal
8.7.4.12 N hygiene procedures fulfilled for this
area?
Are the uniforms worn in the clean
8.7.4.13 I area of parenteral solutions filling
sterilized?
Is the fabric used in the uniforms of a
8.7.4.13.1 N material that avoid the loose of fibers
and particles?
Are the gloves free from lubricants
8.7.4.14 N
which release particles?
Is there a procedure to define the entry
conditions of raw materials, materials
8.7.4.15 N
and equipment in the clean area of the
parenteral solutions filling?
Are the vials, vial-flasks, caps and
tools which are transferred to the final
8.7.4.16 N
sterilization product filling area duly
sterilized?
Are the Production Order instructions
8.7.4.17 I
accurately followed?
Are all the filling operations registered
8.7.4.18 N
and signed by their performer?
 Is there an appropriate separation
between the equipment to avoid
8.7.4.19 N mixings and cross-contamination when
different products batches are
simultaneously filled?
Are all the equipment used in the
8.7.4.20 N
sterile products filling identified?
8.7.4.21 The filling procedure of sterile products with final sterilization is:
8.7.4.21.1 INF Automatic?
8.7.4.21.2 INF Semi-automatic?
8.7.4.21.3 INF Manual?
Is the filling of parenteral solutions
8.7.4.22 N performed under a grade A laminar
flow (class 100)?
8.7.4.22.1 N Is the class A laminar flow certified?
8.7.4.22.2 N Are there records?
Are frequent controls on
8.7.4.23 N
volume/weight of filling performed?
8.7.4.23.1 N Are there records?
Is there a system to identify the
8.7.4.24 N
sterilized products?
Is the sterile products filling area
8.7.4.25 N
qualified?
8.7.4.25.1 N Are there records?
Is the filling of sterile ointments,
creams, suspension, and emulsions
8.7.4.26 N
with final sterilization performed in a
grade C environment(class 10,000)?
Does the Validation Master Plan
8.7.4.27 N include the filling of sterile ointments,
creams, suspensions and emulsions?
Are there approved protocols to the
8.7.4.28 N
ongoing validations?
8.7.4.29 What kind of validation is expected:
8.7.4.29.1 INF Prospective?
How many batches will be evaluated?
8.7.4.29.1.1 INF
____________________________
8.7.4.29.2 INF Retrospective?
How many batches will be considered?
8.7.4.29.2.1 INF
__________________________
Were all the batches considered in the
Retrospective Validation produced
8.7.4.29.2.2 N
according to the same operational
parameters and specifications?
8.7.4.29.3 INF Concurrent?
How many batches will be considered?
8.7.4.29.3.1 INF
_________________________
Do the tests results meet the
8.7.4.30 N acceptance criteria established in the
approved protocol?
 Were the deviations found in relation
8.7.4.31 N to the parameters established in the
approved protocol duly investigated?
Is there a pre-established frequency
8.7.4.32 N
for the periodical revalidation?
Which one?
8.7.4.32.1 INF
___________________________________________
Are the results obtained from the
8.7.4.32.2 N periodical revalidation in accordance
with the approved protocol?
8.7.5 Products final sterilization area
No. Qualif. Items YES NO N/A
Is there a specific area to the final
8.7.5.1 R
sterilization of products?
Are individual protection equipment
8.7.5.2 N
worn?
8.7.5.3 R Is there an exhaustion system?
8.7.5.4 N Are the autoclaves identified?
Are there sterilization temperature
8.7.5.5 N
records?
8.7.5.6 N Are there sterilization time records?
Are biological indicators used to
8.7.5.7 N
manage the sterilization process?
8.7.5.7.1 N Are there records?
After autoclavage, is any air-tightness
8.7.5.8 R test performed in the sterilized
containers?
Are the sterilization records annexed
8.7.5.9 N
to the Production Order?
Are there safe procedures to avoid the
8.7.5.10 N mixing of non-sterilized products from
the already sterilized ones?
Are the sterilized products identified as
8.7.5.11 N
such?
Are the recipients containing the
sterilized products well closed and
8.7.5.12 N
identified in accordance to their
contents?
Is the final sterilization of products
8.7.5.13 N
process validated?
Is there an approved protocol to the
8.7.5.14 N validation of the products of final
sterilization process?
Were three (3) consecutive satisfactory runs presented for each
8.7.5.14.1 N
approved protocol?
Do the tests results meet the
8.7.5.15 N acceptance criteria established in the
approved protocol?
 Were the deviations found in relation
8.7.5.16 N to the parameters established in the
approved protocol duly investigated?
8.7.2.17 N Is the periodical revalidation foreseen?
What is the frequency?
8.7.5.17.1 INF
_________________________________
Are the results obtained from the
8.7.5.17.2 N periodical revalidation in accordance
with the approved protocol?
8.7.6.- Aseptic preparation area
No. Qualif. Items YES NO N/A
Is there a clean area for the aseptic
8.7.6.1 I preparation of products with final
sterilization?
Is the clean area for the aseptic
8.7.6.2 N preparation appropriate for the
operations volume?
Are the sterile products prepared in a
8.7.6.3 N grade B (class 100) or C (class
10,000) area?
Does the area have a positive
8.7.6.4 N pressure in comparison to the other
appended areas?
Is there and antechamber to the
8.7.6.5 N entrance of personnel in the sterile
products preparation area?
Is there an antechamber for the
8.7.6.6 N entrance of materials in the aseptic
preparation of sterile products?
Is there a pressure graduator of the
8.7.6.7 N aseptic preparation area to the
antechambers and appended areas?
8.7.6.8 Are there records of:
Differential pressure among the
8.7.6.8.1 N
different areas?
8.7.6.8.2 N Relative humidity of the areas?
Environmental temperature of the
8.7.6.8.3 N
areas?
Are the registered values in
8.7.6.8.4 N
accordance with the established SOP?
8.7.6.9 The monitoring of particles is performed:
8.7.6.9.1 N Viable
8.7.6.9.2 N Non-viable
8.7.6.9.2.1 N Are there records?
In case of deviations in relation to the
8.7.6.10 N limits established is an investigation
performed to evaluate the causes?
Are preventive and/or corrective
8.7.6.11 N actions taken in relation to the
identified causes?
8.7.6.11.1 N Are there records?
Are the garment and personal hygiene
8.7.6.12 N
procedures for this area fulfilled?
Are the uniforms worn in accordance
8.7.6.12.1 N
with the clean area cleaning grade?
Are the uniformed worn in the grade B
8.7.6.12.2 I
or C area sterilized?
Is the fabric used in the uniforms made
8.7.6.12.3 N of a material that avoid the loose of
fibers or particles?
Are the gloves free from lubricants
8.7.6.13 N
which release particles?
Is there a procedure to define the
entrance conditions of raw materials,
8.7.6.14 N
materials and equipment in the aseptic
preparation area?
8.7.6.14.1 N Are there records?
Are all the aseptic preparation
operations of sterile products
8.7.6.15 N
registered and signed by their
performer?
Are all the containers used in the
8.7.6.16 N aseptic preparation of a product batch
identified?
Are all the equipment used in the
8.7.6.17 N preparation of a product batch
identified?
Is there an appropriate separation
between the equipment to avoid
8.7.6.18 N mixings and cross-contamination when
different products batches are
simultaneously produced?
Is water for injection used in the
8.7.6.19 I
aseptic preparation of sterile products?
Is the water for injection released by
8.7.6.19.1 N
the Quality Control before use?
Are the reactors sterilized with pure
8.7.6.20 I
steam?
Are the tools entering the aseptic area
8.7.6.21 I
sterilized?
Is the products handled under a grade
8.7.6.22 I
A laminar flow (class 100)?
8.7.6.22.1 N Is the laminar flow qualified?
8.7.6.22.2 N Are there records?
8.7.6.23 N Are in-process controls performed?
Which ones?
8.7.6.23.1 INF
____________________________________________
8.7.6.23.2 N Are there records?
Is the solution filtered through a
8.7.6.24 INF
sterilizing filter?
8.7.6.24.1 INF What is the sterilizing filter size [pore size]? ____________µ
Are tests to determine the integrity of
8.7.6.24.2 N
the sterilizing filter performed?
8.7.6.24.3 N Are there records?
After use, are all the tools, equipment
and containers thoroughly
8.7.6.25 N
washed/sterilized and kept this way
until the next use?
Are they identified with tags certifying
8.7.6.26 N
this status?
8.7.7 Products aseptic filling area (sterile raw materials or products with sterilizing filtration)
No. Qualif. Items YES NO N/A
Is the sterile products filling clean area
8.7.7.1 N a grade B (class 100) or C (class
10,000)?
Does the area have a positive
8.7.7.2 N pressure in comparison to the
appended areas?
Is there an antechamber for the
8.7.7.3 N entrance of personnel in the sterile
products filling area?
Is there and antechamber to the
8.7.7.4 N entrance of materials in the sterile
products filling area?
Is there a pressure graduator of the
8.7.7.5 N aseptic preparation area to the
antechambers and appended areas?
8.7.7.6 Are there records of:
Differential pressure among the
8.7.7.6.1 N
different areas?
8.7.7.6.2 N Air relative humidity?
Environmental temperature of the
8.7.7.6.3 N
area?
Are the values registered in
8.7.7.6.4 N accordance with the established in the
SOP?
8.7.7.7 The monitoring of particles is performed:
8.7.7.7.1 N Viable?
8.7.7.7.2 N Non-viable?
8.7.7.7.3 N Are there records?
Are microbiological controls on the
8.7.7.8 N
surface performed?
8.7.7.8.1 N Are there records?
In case of deviations in relation to the
8.7.7.9 N limits established is an investigation
performed to evaluate the cause?
Are preventive and/or corrective
8.7.7.10 N actions taken in relation to the
identified causes?
8.7.7.10.1 N Are there records?
 Are the garments and personal
8.7.7.11 N hygiene procedures fulfilled for this
area?
Are the uniforms worn in accordance
8.7.7.12 N with the cleaning grade of the clean
area?
Are the uniforms worn in the clean
8.7.7.13 I
area of aseptic filling sterilized?
Is the fabric used in the uniform made
8.7.7.13.1 N from a material that avoids the loose of
fibers or particles?
Are the sterile gloves free from
8.7.7.14 N
lubricants which release particles?
Is there a procedure to define the
entrance conditions of raw materials,
8.7.7.15 N materials and equipment into the clean
area of aseptic filling of products
without final sterilization?
8.7.7.15.1 N Are there records?
Are the vials, vial-flasks, caps and
tools entering the clean area of aseptic
8.7.7.16 N
filling duly sterilized and/or
depyrogenized?
Are all the aseptic filling operations
8.7.7.17 N registered and signed by their
performer?
Is there a physical separation
appropriate between the equipment to
8.7.7.18 N avoid mixings or cross-contamination
when different products batches are
simultaneously filled?
Are all the equipment used in the
8.7.7.19 N aseptic filling of sterile products
identified?
8.7.7.20 The procedure of aseptic filling of sterile products is:
8.7.7.20.1 INF Automatic?
8.7.7.20.2 INF Semi-automatic?
8.7.7.20.3 INF Manual?
The product filling is performed under
8.7.7.21 N
a grade A laminar flow (class 100)?
8.7.7.21.1 N Is the class A laminar flow qualified?
8.7.7.21.2 N Are there records?
Are in-process volume/weight controls
8.7.7.22 N
of the products filled performed?
8.7.7.22.1 N Are there records?
Are the recipients containing bulk
8.7.7.23 N
products identified?
Is the aseptic filling of the product
8.7.7.24 N
validated?
 Is a simulated filling performed with the
8.7.7.25 N
mean of culture?
Is there an approved protocol to the
8.7.7.26 N validation of the process of aseptic
filling of products?
Were three (3) consecutive satisfactory runs presented for each
8.7.7.26.1 N
approved protocol?
Do the tests results meet the
8.7.7.27 N acceptance criteria established in the
approved protocol?
Were the deviations found in relation
8.7.7.28 N to the parameters established in the
approved protocol duly investigated?
8.7.7.29 N Is a periodical revalidation foreseen?
What is the frequency?
8.7.7.29.1 INF
_______________________________________
Are the results obtained from the
8.7.7.30 N periodical revalidation in accordance
with the approved protocol?
8.7.7.31 INF Is the filled products lyophilized?
Is the lyophilizer installed in the aseptic
8.7.7.32 N
filling area?
Is the transfer of the containers with
the product to the lyophilizer
8.7.7.33 N
performed under a class A laminar
flow?
Are the temperature, time and air-
8.7.7.34 N tightness parameters monitored during
the lyophilization process?
8.7.7.34.1 N Are there records?
Are the records annexed to the
8.7.7.34.2 N
Production Order?
8.7.7.35 N Is the lyophilization process validated?
Is there an approved protocol to the
8.7.7.36 N validation of the lyophilization
process?
Were three (3) consecutive
8.7.7.37 N satisfactory runs presented for each
approved protocol?
Do the tests results meet the
8.7.7.38 N acceptance criteria established in the
approved protocol?
Were the deviations found in relation
8.7.7.39 N to the parameters established in the
approved protocol duly investigated?
8.7.7.40 N Is a periodical revalidation foreseen?
8.7.7.40.1 INF What is the frequency? _____________________________
Are the results obtained from the
8.7.7.41 N periodical revalidation in accordance
with the approved protocol?
 Is the re-riveting performed under a
8.7.7.42 N
class C laminar flow?
8.7.8- Filled product inspection area
No. Qualif. Items YES NO N/A
Is there a separated place to the visual
8.7.8.1 N
inspection of the filled products?
Is the occupied area appropriate to the
8.7.8.2 R
operations volume?
Are individual protection equipment
8.7.8.3 N
worn?
Is there the need to control
8.7.8.4 R temperature and humidity in the visual
revision area to certain products?
Are there equipment to control the
8.7.8.5 R
area temperature and humidity?
8.7.8.6 N Are there records?
Are there records on the cleaning and
8.7.8.7 R
disinfection procedures?
Was the area inspected to check the
8.7.8.8 N presence of previously inspected
products?
8.7.8.8.1 N Are there records?
Is there a separation between the
visual inspection lines when different
8.7.8.9 N
product batches are simultaneously
inspected?
Are the recipient containing the
8.7.8.10 N products identified in accordance with
their contents?
Is the inspection performed by
8.7.8.11 INF
automatic equipment?
Is the equipment periodically
8.7.8.11.1 N
calibrated?
8.7.8.11.2 N Are there records?
8.7.8.12 INF Is the visual inspection manual?
Is the visual inspection performed
8.7.8.12.1 N
against a clear or dark background?
Are the inspectors subjected to regular
8.7.8.12.2 N
ophthalmologic examinations?
What is the periodicity?
8.7.8.12.3 INF
______________________________________
8.7.8.12.4 N Are there records?
Are periodical resting stops of
8.7.8.13 N
inspectors maintained?
How long does the inspector remains in the revisions operation?
8.7.8.13.1 INF
______hours
How long is the inspectors resting stop?_____________
8.7.8.13.2 INF
minutes
Are there records of products disposal
8.7.8.14 N
in the visual inspection process?
8.7.9.- Packaging
8.7.9.1- Secondary packaging area
No. Qualif. Items YES NO N/A
Is there an area to the secondary packaging
8.7.9.1.1 N
operations?
8.7.9.1.2 Is the secondary packaging area:
8.7.9.1.2.1 INF By production line?
Common to all of the products manufactured
8.7.9.1.2.2 INF
in the company?
8.7.9.1.3 N Is the area clean?
Is there a place that required controlled
8.7.9.1.4 INF
environmental conditions?
8.7.9.1.5 If required, are there equipment to control:
8.7.9.1.5.1 N Temperature?
8.7.9.1.5.2 N Are there records?
Is the secondary packaging operation
8.7.9.1.6 I performed according to the Production
Order/Packaging Order?
Are all the packaging operations registered
8.7.9.1.7 N
and signed by their performer?
Are all the recipients containing the filled
8.7.9.1.8 N product duly identified in accordance with
their content?
Is the secondary packaging line identified in
8.7.9.1.9 N accordance with the product batch to be
packaged?
Is there an appropriate separation between
8.7.9.1.10 N the equipment when different product batches
are simultaneously packaged?
Are in-process controls performed during the
8.7.9.1.11 N
secondary packaging operation?
8.7.9.1.11.1 INF Which ones?
8.7.9.1.11.2 N Are there records?
After the packaging, do the products remain in
8.7.9.1.13 N
quarantine?
8.7.9.1.13.1 N Are there records?
Is the reconciliation among the theoretical
8.7.9.1.14 N quantity of printed, filling materials and bulk
product and the actual quantity used?
8.7.9.1.14.1 N Are there records?
8.7.9.2. Labeling
No. Qualif. Items YES NO N/A
Is the access to the labels, in the
8.7.9.2.1 I packaging area, allowed only to
duly authorized persons?
Are the packaging lines inspected, in
order to verify if they correspond to
8.7.9.2.2 N the product to be labeled and to the
conformity with the Production
Order/Packaging Order/ before use?
 Are the labeling machines
inspected, before use, in relation to
8.7.9.2.3 N
the absence of printed materials
from previous products?
Are the unused labels printed with
8.7.9.2.4 I the batch number and the
expiration date destroyed?
8.7.9.2.4.1 N Are there records?
Are the quantities of labels
received, used, including the
8.7.9.2.5 N
damaged ones and the destroyed
ones, registered?
Are all the differences between the
number of received labels, used
8.7.9.2.6 N
labels, including the damaged and
destroyed ones, investigated?
8.7.9.2.6.1 N Are there records?
Are the labels unprinted with the
8.7.9.2.7 R batch number and the expiration
date returned to the warehouse?
Is there a person responsible for
8.7.9.2.7.1 N
this return?
8.7.9.2.7.2 N Are there records?

9. QUALITY CONTROL

9.1. General Conditions

No. Qualif. Items YES NO N/A
Is the Quality Control independent
9.1.1 I
from the production?
Are the Quality Control areas
9.1.2 N
consistent with the operations volume?
9.1.3 N Are the areas clean?
9.1.4 N Do the personnel wear uniforms?
Are the uniforms clean and in good
9.1.5 N
preservation status?
9.1.6 INF Are there drains in the area?
9.1.6.1 N If yes, are they siphoned?
Are there records on the cleaning and
9.1.7 N
disinfection procedures?
9.1.8 N Is the illumination appropriate?
What is the professional background of the person responsible
9.1.9 INF for the Quality Control?
________________________________________________
To whom is the responsible for the Quality Control subjected to?
9.1.10 INF
__________
Does the company have defined
9.1.11 R qualification criteria for the main
personnel in the Quality Control?
Is there a training program ensuring
9.1.12 R the performance of the employees in
the laboratory activities?
9.1.12.1 N Are there records?
Are there essays performed by hired
9.1.13 INF
laboratories?
9.1.13.1 INF What essays? ______________________________
9.1.13.2 INF What laboratories?______________________________
Are there written specifications to all
the raw materials, packaging
9.1.14 N
materials, intermediary, bulk and
finished products?
Are the SOPs related to the activities
9.1.15 N of each area available in the
respective working places?
9.1.16 Are there sampling plans defined for:
9.1.16.1 N Raw materials?
9.1.16.2 N Packaging materials?
9.1.16.3 N Intermediary products?
9.1.16.4 N Bulk products?
9.1.16.5 N Finished products?
9.1.17 Is the Quality Control responsible for the analysis of:
9.1.17.1 I Raw materials?
9.1.17.2 I Packaging materials?
9.1.17.3 I Intermediary products?
9.1.17.4 I Bulk products?
9.1.17.5 I Finished products?
Are there designees to supervise the
9.1.18 R performance and evaluate the results
of the tests performed?
Is the Quality Control responsible for
the performance of analytical essays
9.1.19 N
of products manufactured upon the
contract of third parties?
Is there an authorized person to
evaluate the analysis report issued by
9.1.20 N
the third party as for the product
release?
Does the Quality Control keep records
9.1.21 I
on the analyses performed?
Are reference samples kept in quantities sufficient to perform the quality
9.1.22
control tests, if required:
9.1.22.1 I Raw materials?
9.1.22.2 I Finished product?
Is the retention period of these
9.1.23 N
samples defined?
Are the finished products samples,
9.1.24 R when possible, kept in their final
package?
Are there procedures for the raw material
9.1.25 R re-analysis respecting the expiration date
established by the manufacturer?
9.1.25.1 N Are there records?
Are there operation procedures of the
9.1.26 N equipment used by the Quality
Control?
9.1.27 The Quality Control equipment/instruments have procedures of:
Preventive maintenance of equipment
9.1.27.1 N
and instruments?
9.1.27.1.1 N Are there records?
9.1.27.2 N Equipment and instruments use?
9.1.27.2.1 N Are there records?
Equipment and instruments
9.1.27.3 N
calibration?
9.1.27.3.1 N Are there records?
Does the quality control verify if each
product batch produced meets the
9.1.28 I
established specifications, before
being released?
9.2. Physical-chemical quality control
No. Qualif. Items YES NO N/A
Are the Laboratory premises
9.2.1 N
appropriate for the work volume?
Are the procedures related to the
analytical methods referred to and
9.2.2 N
followed for the analyses
performance?
Is the distribution of
9.2.3 N equipment/instruments ordered and
rational?
Are there biosafety equipment, if
9.2.4 N
required?
9.2.4.1 N Are they regularly checked/tested?
9.2.4.2 N Are there records?
9.2.5 N Are there reference standards?
9.2.5.1 INF Primary standards?
9.2.5.1.1 INF Origin: ___________________________________________
9.2.5.2 INF Secondary standards?
Are they authorized against the
9.2.5.2.1 INF
primary standards?
9.2.5.2.2 INF Who certified? ______________________________________
9.2.5.3 N Reference materials?
9.2.5.3.1 INF Origin: __________________________________________
Does its preservation meet the
9.2.5.4 N recommendations established by the
manufacturer?
9.2.5.5 The standards record presents the following information:
9.2.5.5.1 N Batch number?
9.2.5.5.2 N Strength/purity?
9.2.5.5.3 N Expiration date?
9.2.5.5.4 N Origin?
9.2.5.5.5 N Storage conditions?
Are the solutions prepared from
reference standards identified with the
following data: substance name,
concentration, solvent (when it is not
an aqueous solution), expiration date,
9.2.5.6 N
storage conditions, precautions or
special care (when applicable),
restrictions to use, preparation date,
identification of the technician
responsible for the preparation?
Are reference standards used in the
9.2.5.7 I identity and content tests, when
required?
Are there reference standards to
9.2.5.7.1 N identify and quantify impurities, when
required?
Are there reference standards to
9.2.5.7.2 N identify and quantify decomposing
products, when applicable?
Are there reference standards for all
9.2.5.8 I the active substances used by the
company, when applicable?
Does the laboratory perform all the
tests required in the technical
9.2.6 I
specification of the manufactured
products?
Are the equipment/instruments
installed in accordance with the
9.2.7 N
recommendations determined by their
manufacturers?
Is there an equipment to stabilize the
9.2.7.1 R
electrical current?
Is the operation manual of each
9.2.7.2 N
equipment available in the laboratory?
Are there procedures to the
9.2.8 N preparation of the reagent solutions
used?
Are the recipients containing the
reagent solutions identified with the
following data: solution name,
concentration, correction factor,
9.2.9 N precautions or special care (when
applicable), expiration date, storage
condition, preparation date,
identification of the technician
responsible for the preparation?
Are the quality control essays
9.2.10 N methodologies validated according to
the Validation Master Plan?
9.3. Microbiological quality control
No. Qualif. Items YES NO N/A
Are the Laboratory premises
9.3.1 N
appropriate to the work volume?
Is there a defined cleaning program
which takes into consideration the
9.3.2 N result of the environmental
management and the contamination
possibility?
9.3.2.1 N Are there records?
Is the equipment distribution
9.3.3 N
ordered and rational?
Are there biosafety equipment,
9.3.4.1 N
when required?
9.3.4.1.1 N Are they regularly checked/tested?
9.3.4.1.2 N Are there records?
Is there an exclusive autoclave to
9.3.5 INF
the materials decontamination?
If not, is there a written procedure
containing precautions to the
9.3.5.1 N
separation of loads to sterilization
and contaminated loads?
9.3.5.1.1 N Are there records?
Is there a defined program to the
9.3.6 N internal cleaning and external
environment of the autoclave?
9.3.6.1.1 N Are there records?
Were performance qualification
studies conducted for each
9.3.7 N
operational run and each type of
load used in the autoclaves?
9.3.7.1 N Are there records?
Does the Validation Master Plan
include the qualification of heat
9.3.8 N ovens, incubators, water-baths and
clean rooms with controlled
temperature?
Are microbiological tests performed
9.3.9 INF
in the raw materials?
9.3.9.1 N Are there records?
Microbiological tests are performed to determine viable
9.3.10
particles:
In the clean areas of sterile
9.3.10.1 N
products production?
In the production areas of non-
9.3.10.2 N
sterile products?
9.3.10.3 N In the sterility tests rooms?
9.3.10.4 N Are there records?
 Are there alert limits and action
9.3.10.5 N limits established to the
determination of viable particles?
9.3.11 Surface microbiological tests are performed:
In the clean areas of sterile
9.3.11.1 N
products production?
9.3.11.2 N In the sterility tests rooms?
Are there alert limits and action
9.3.11.3 N limits established to the surface
microbiological tests?
In case of results above the
established alert limits, is an
9.3.11.3.1 N
investigation performed to evaluate
the causes?
Are immediate actions taken in
9.3.11.3.2 N case of results above the action
limits?
9.3.11.3.3 N Are there records?
Are sterility tests performed in
9.3.12 N
sterile products?
9.3.12.1 N Are there records?
Is the sterility test performed in
9.3.13 R
clean water?
What is the area classification?
9.3.13.1 INF
_______________________________
9.3.13.2 INF Is there an antechamber?
Are the floor, walls and ceiling in
9.3.13.3 N
good preservation status?
Are they covered with washable
9.3.13.4 N
material?
9.3.14 The clean area have the control of:
9.3.14.1 INF Temperature?
9.3.14.2 INF Air relative humidity?
9.3.14.3 INF Differential pressure?
9.3.14.4 INF Particles monitoring?
Are the sterility tests performed
9.3.15 N
under a laminar flow?
Type of laminar flow?
9.3.15.1 INF
__________________________
9.3.15.2 N Is the laminar flow qualified?
9.3.16 The company uses:
Means of culture prepared by the
9.3.16.1 INF
laboratory itself?
9.3.16.2 INF Means of culture ready to use?
9.3.16.3 INF Both
Is there a procedure for the
9.3.17 N preparation of the means of culture
batches?
 Is there a record on the means of
culture batches preparation used in
the sterility tests, containing at least
9.3.18 N
one of the following data: name of
the mean, batch number, expiration
date?
9.3.19 The means of culture are controlled in relation to:
9.3.19.1 N Fertility?
9.3.19.2 N Sterility?
Are the reagent solutions (including
the stock solutions), means,
diluents, and other suspension
fluids identified with the following
data: name, concentration,
9.3.20 N
expiration date and/or
recommended storage periods,
preparation date, identification of
the technician responsible for the
preparation?
Are there reference cultures
9.3.21 INF acquired from acknowledged
national or international sources?
Are there written procedures for the
preparation and preservation of
9.3.22 N
sub-cultures to be used as
reference stock?
Are purity and biochemical tests
performed, when required, in
9.3.23 N
reference stocks and/or working
cultured?
9.3.23.1 N Are there records?
Are there written procedures to the
collection and handling of samples
9.3.24 N
to avoid the material
contamination?
Are there written procedures to the
disposal of means of culture and
dischargeable materials
9.3.25 N
contaminated to avoid the
environment and other materials
contamination?
Are endotoxin tests (LAL) or animal
9.3.26 N tests performed in the apyrogenic
products?
Which is the methodology used?
9.3.26.1 INF
_______________
9.3.26.2 N Is the method valid?
Does the Validation Master Plan
include the validation of the
9.3.27 N
microbiological and biological
essays used?
 Is there a general protocol
approved and an individual protocol
to each method being validated
according to the chronogram, taking
9.3.28 N
into account the parameters to be
tested, characteristics and number
of tests to be performed, statistical
evaluation of the results?
9.4. Biological quality control
No. Qualif. Items YES NO N/A
Is there an area separated from the other
9.4.1 N premises to perform the animal biological
tests?
Is the laboratory in satisfactory cleaning
9.4.2 N
conditions?
9.4.3 INF What is the origin of the animals? ___________________________
9.4.4 N Is the animals supplier qualified?
9.4.5 N Is there a quarantine place?
Are controls performed for the liberation of the
9.4.6 N
animals from quarantine?
9.4.6.1 N Are there records?
9.4.7 INF What are the biological tests performed: ________________________
9.4.8 INF Are in vivo pyrogen tests performed?
Is the rabbits temperature reading test
9.4.8.1 N
performed automatically?
9.4.8.2 INF Are rectal probes used?
9.4.8.3 N Are the probes calibrated?
9.4.8.3.1 N Are there records?
9.4.9 N Are the test animals identified?
9.4.9.1 INF How? ____________________________________________________
9.4.9.2 N Are there records?
What is the destination of the discharged animals
9.4.10 INF
_____________________
9.4.10.1 N Are there records?
Are toxicity tests performed in plastic
9.4.11 N containers for SPGV [Large Volume
Parenteral Solutions]?
10. QUALITY ASSURANCE
No. Qualif. Items YES NO N/A
Is there a Quality Assurance system in
10.1 I
the company?
Is this program released to all
10.2 N
employees?
Are the responsibilities for the Quality
10.3 N Assurance management clearly
defined?
Are there procedures for the release of
10.4 N the Good Manufacturing Practices
fulfillment?
10.4.1 N Are these procedures followed?
Is there a planning and chronogram of
10.5 N
personnel training?
Are there records on each employee
10.5.1 N
training?
Are the employees trained and
oriented to ensure the correct and
10.6 N
complete performance of the defined
processes and procedures?
Is the introduction of new knowledge in
the processes, or enhancements, only
10.7 N implemented after the complete
evaluation and approval by the Quality
Assurance?
Are self-inspections performed with the
10.8 I purpose of verifying the fulfillment of
the Good Manufacturing Practices?
What is the frequency of the self-inspections?
10.8.1 INF
_______________________
10.8.2 N Are there records?
Is there a formal system to the
10.9 N
investigation on quality deviations?
Are there written procedures to the
adoption of corrective and/or
10.9.1 N preventive measures after the
identification of the quality deviations
causes?
10.10 Is there a stability study program to:
10.10.1 N Products to be registered?
10.10.2 N Marketed products?
10.10.3 N Primary packaging material change?
Are the long term stability studies
performed in conformity with the
10.11 N
established conditions to Zone IV,
according to the current legislation?
If the company imports bulk products,
are there studies proving the stability
10.12 N
and storage period in the packages
used?
10.13 In case of imported products the stability study for Zone IV is conducted:
10.13.1 INF At the manufacturing site?
10.13.2 INF In Brazil?
10.13.3 N Were results presented?
10.14 Is there a weather controlled chamber to:
10.14.1 INF Accelerated studies?
10.14.2 INF Long term Zone IV studies?
Do the weather controlled chambers
10.14.3 N have a record system of its operational
conditions?
 Is there a follow-up system that allows
to check if the storage conditions are
10.15 INF
being met, and if the product maintains
its quality during its validity period?
10.15.1 N Are there records?
10.16 Is there a Validation Master Plan containing at least:
10.16.1 N Company validation policy?
Description of the premises and
10.16.2 N
procedures?
Planning and chronogram of the
10.16.3 N
activities?
10.16.4 N Responsibilities?
Description of equipment, instruments,
10.16.5 N processes and systems to be
validated?
Reason to the inclusion or exclusion of
10.16.6 N
a certain validation?
10.16.7 N Documents tracking system?
Frequency of the periodical
10.16.8 N revalidation based on the process
risk?
10.16.9 N Cross-reference to other documents?
10.16.10 N Specific training requirements?
10.17 Does the Validation Master Plan also include:
10.17.1 N Equipment Cleaning Validation?
10.17.2 N Analytical Methods Validation?
10.17.3 N Area cleaning?
10.17.4 N Sanitization, when applicable?
Are revalidations performed when
changes which might affect the quality
10.18 N or reproducibility of a process or a
control analytical method are
introduced?
Is there a pharmacotechnical
10.19 INF development laboratory in the
company?
Are the pharmaceutical products
designed and developed according to
10.19.1 N
the Good Manufacturing Practices
requirements?
10.20 Is the Quality Assurance sector responsible:
For the approval of all the Standard
10.20.1 N Operation Procedures (SOPs) of the
company?
10.20.2 N For keeping the original SOPs?
10.20.3 N For the distribution of SOPs?
10.20.4 N For the SOPs distribution control?
For the evaluation of the
10.20.5 I documentation of the produced
batches?
 For keeping the documentation of the
10.20.6 N
produced batches?
Does the documentation of each batch
produced allow the tracking of the
10.21 I materials and equipment used,
procedures and quality controls
performed?
What is the period established for the documentation to be
10.21.1 INF
kept? __________