PMTC - Good Cleaning Validation Practice

Pharmaceutical
Manufacturing
Technology
Centre
Advanced Technology Solutions
d Pharmaceutical Manufacturing Technology Centre
Good Cleaning Validation Practice

(GCVP)
Section 1 The Science of Cleaning and Cleaning Validation
1.1 Introduction
1.2 Regulatory Background

Foreword 1.3 A Life Cycle approach for Cleaning Validation
Ireland has a long and successful track record of pharmaceutical 1.4 Cleaning Methods
and biopharmaceutical manufacturing, with 9 of the worlds top 10 Automated
PharmaceuticalStagecompanies
2 Processhaving a significant
Qualification: presence
Testing the cleaning here.
process Thevalidation).
(cleaning
Stage 2 Process Qualification: Testing the cleaning process (cleaning validation).
Manual
sector is hugelyStage
impactful to the
3 Continued IrishVerification,
Process economy with over
particularly 25,000
for manual cleaning processes. Development
Stage 3 Continued Process Verification, particularly for manual cleaning processes.
people directly employed and accounting
Aspects of the lifecycle approach should include
for almost 50% of Irish Aspects of the lifecycle approach should include
Goods exports.
good project management and good archiving that capture scientific knowledge
1.5 Established Principles
an integrated team approach to process validation that includes expertise from a variety of
The Pharmaceutical Manufacturing
disciplines Technology
(e.g., process engineering, Centre
industrial (PMTC,
pharmacy, analytical chemistry, microbiology, MACO disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology,
statistics, manufacturing, and quality assurance).
www.pmtc.ie) is a leading industry informed research centre focused Health based
statistics, limits and quality assurance).
manufacturing,
consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant
on developing advanced solutions
to cleaning solutions etc for all stages of pharmaceutical Single Use, solutions
to cleaning Dedicated etc and Multi-Product Equipment
manufacturing. In studies
all responseshould to developments
be planned and conductedinaccording
the Regulatory
to sound scientific principles, all studies should be planned and conducted according to sound scientific principles,
appropriately documented, and approved in
environment relating to cleaning validation, the PMTC hosted accordance with the established
a procedure appropriately documented, and approved in accordance with the established procedure
appropriate for the stage of the lifecycle. 1.6 Choice of Target Molecule
appropriate for the stage of the lifecycle.
workshop where stakeholders identified a number of key areas of
concern and interest relating to cleaning validation. A key output from Worst case molecule
this event was the collective industry need for an integrated guidance Reference molecules (placebos)
document.1.4 Cleaning methods 1.4
Detergents
Cleaning methods
Automated Automated
The PMTC has prepared this guidance
Automated document
cleaning methods in response
are the preferred method of to these
cleaning pharmaceutical 1.7 Choice of Analytical Techniques
Automated cleaning methods are the preferred method of cleaning pharmaceutical
concerns to representequipment.
the best practice
Automated guidance
methods at the current
include Clean-in-Place (CIP)timemethods and Clean- equipment. Automated methods include Clean-in-Place (CIP) methods and Clean-
out-of-Place (COP) methods. Visual Inspection
out-of-Place (COP) methods.
of writing. This document has been prepared based on a review of
current guidelines and input
With from the
CIP methods Health
the piece Products
of equipment Regulatory
(e.g. a vessel or filling line) is attached to a
TOC With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a
cleaning skid or equivalent system which
Agency and the Pharmaceutical Industry in Ireland and abroad. provides cleaning solutions of water and/or HPLC andcleaning
UPLCskid or equivalent system which provides cleaning solutions of water and/or
other solvent(s) and/or detergents. other solvent(s) and/or detergents.
UV
COP systems consist of parts washers where equipment and components are placed COP systems consist of parts washers where equipment and components are placed
on racks and the racks are placed into the washing machine.
Conductivity
It is expected that both systems operate on the basis of established and validated It is expected that both systems operate on the basis of established and validated
fixed cycles. Cycles should not operate on the detection of a predetermined 1.8 Choice of Sampling
fixed cycles.Method
Cycles should not operate on the detection of a predetermined
conductivity level of effluent water as this breaches the guidance that a clean-until- conductivity level of effluent water as this breaches the guidance that a clean-until-
clean approach should not be used.
Visual clean approach should not be used.
In certain cases, sonication may be used to facilitate the cleaning of small equipment
SwabbingIn certain cases, sonication may be used to facilitate the cleaning of small equipment
parts such as filling needles. In considering the use of sonication, preferred systems Rinse samples
parts such as filling needles. In considering the use of sonication, preferred systems
are those which can monitor and report on the cycle (e.g. by power consumption). In are those which can monitor and report on the cycle (e.g. by power consumption). In
addition, companies should consider the impact to the production process / schedule
Sample stability
in the event that the sonication system is inoperable. in the event that the sonication system is inoperable.
1.9 Spray Coverage Testing

Manual Manual
Manual cleaning processes cannot be validated in the conventional meaning of 1.10 Cleaning Validation Failure
Manual cleaning processes cannot be validated in the conventional meaning of
validation, but it is possible to verify manual cleaning processes. Manual cleaning validation, but it is possible to verify manual cleaning processes. Manual cleaning
processes inevitably experience person to person variability. Regulatory processes inevitably experience person to person variability. Regulatory
engagements on manual cleaning validation often fail due to the identification of 1.11 Definitions engagements on manual cleaning validation often fail due to the identification of
residues on equipment which has been manually cleaned, dried, and is in storage as residues on equipment which has been manually cleaned, dried, and is in storage as
Clean equipment. Where GMP Inspectors identify residues on Clean equipment, Clean equipment. Where GMP Inspectors identify residues on Clean equipment,
the integrity of the manual cleaning process and therefore the cleaning validation 1.12 Frequently Asked Questions
the integrity of the manual cleaning process and therefore the cleaning validation
programme are called into question. programme are called into question.
Good
Good Cleaning Validation Cleaning Validation Practice
Practice Good
Good Cleaning Cleaning
Validation Validation Practice
Practice
GCVP GCVP
GCVP 2 GCVP 3
Section 2 The Communication of Cleaning Validation Section 1 The Science of Cleaning and Cleaning Validation
2.1 The Cleaning Validation Subject Matter Expert 1.1 Introduction
2.2 The PMTC Cleaning Validation Package. The Pharmaceutical Manufacturing Technology Centre (PMTC) was established in
2.2.1 The Cleaning Validation Hierarchy December 2013, is led by an industry steering board with an active research program
driven by its industry members.
2.2.2 Choice of Target Species / Product The vision of the PMTC is to apply research into advanced technology solutions in order
to
2.2.3 Cleaning Validation Protocols Improve Pharmaceutical Manufacturing Competitiveness
Hold Times EnhanceStage

the 3R&D Mandate
Continued ProcessofVerification,
Irish Pharmaceutical Manufacturing
particularly for manual Sites
cleaning processes.

In response to developments in the Regulatory environment relating to cleaning
2.2.4 Calculation of Acceptance Criteria good project management and good archiving that capture scientific knowledge
validation, the PMTC hosted a workshop in 2014 where a number of stakeholders
identified a number of key
disciplines (e.g.,areas
processof concernindustrial
engineering, and interest
pharmacy,relating
analytical to cleaning
chemistry, validation.
microbiology,
Chemical statistics, manufacturing, and quality assurance).
The PMTC has prepared this guidance document in response to these concerns to
consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant
represent the best practice guidance at the current time of writing.
to cleaning solutions etc
Microbiological all studies should be planned and conducted according to sound scientific principles,
appropriately has
The guidance document documented,
been and approved based
prepared in accordance
on awith the established
review procedure
of current guidelines
and input from the Health Products Regulatory Agency and the Pharmaceutical
2.2.5 Recovery Validation Industry in Ireland and abroad.
2.2.6 Basis for Method of Analysis 1.4

This document Cleaning
is methods
designed to take elements from multiple different sources and
present a practical approach
Automatedto the subject of Cleaning Validation.
2.2.7 Analytical Method Validation Automated cleaning methods are the preferred method of cleaning pharmaceutical
1.2 Regulatory Background
equipment. Automated methods include Clean-in-Place (CIP) methods and Clean-
2.2.8 Choice of Equipment/Sampling Locations
In the 1993, an article With
by Gary Fourman
CIP methods and
the piece Dr. Mike(e.g.
of equipment Mullen oforEli
a vessel Lilly
filling line)proposed
is attached to the
a use
cleaning skid or equivalent system which provides cleaning solutions of water and/or
of the following combination of limits for cleaning validation.
other solvent(s) and/or detergents.
2.2.9 Revalidation / Ongoing Verification / Periodic Monitoring
No more than COP
0.001 systems consist of parts washers where equipment and components are placed
dose of any product will appear in the maximum daily dose
2.2.10 Validation Results of another product
It is expected that both systems operate on the basis of established and validated
No more than fixed
10 ppm of a product will appear in another product
cycles. Cycles should not operate on the detection of a predetermined
No quantity ofconductivity
residue level
will of
beeffluent
visible on
water asthe equipment
this breaches afterthat
the guidance cleaning
a clean-until-
3.0 References
procedures are performed
4.0 Acknowledgements. In recent years, a number of Regulators
parts such (e.g.
as filling needles. Health Canada,
In considering World Health
the use of sonication, preferred Organisation)
systems
are those which can monitor and report on the cycle (e.g. by power consumption). In
have adopted this approach and have included the limits in their own guidance
documents. in the event that the sonication system is inoperable.
Other Regulators (EU, FDA) have not included the limits in their guidelines but have
Manual
accepted the application of the limits as the industry norm. Rather than focus on the
Manual cleaning
basis for the limits, Regulators processes have
in general cannot focused
be validated on
in the conventional
the correctmeaning of
implementation
validation, but it is possible to verify manual cleaning processes. Manual cleaning
of the limits. processes inevitably experience person to person variability. Regulatory
engagements on manual cleaning validation often fail due to the identification of
residues on
In February 2005 a Concept equipment
paper waswhich has been
issued manually
by the cleaned, dried,
European and is in storage
Medicines as
Evaluation
Clean equipment. Where GMP Inspectors identify residues on Clean equipment,
Agency (ref: EMEA/152688/04) which stated the need to updated existing GMP
guidance concerning programme
dedicated are facilities. The text in Chapters 3 and 5 relating to the
called into question.
necessity for dedicated facilities and was unclear in a number of circumstances.
Good
Practice
GCVP
GCVP 5
For example, the guidance stated that medicines and non-medicines should not be all studies should be planned and conducted according to sound scientific principles,
produced in the same facility. In some instances, a material may be considered a appropriately documented, and approved in accordance with the established
medicine in one jurisdiction and a non-medicine in another (e.g. extracts of St. Johns procedure appropriate for the stage of the lifecycle
Wort, Ginko Biloba) which presents difficulty for a facility producing for both jurisdictions.
1.4 Cleaning Methods
In parallel to the European discussions, ISPE prepared and issued A Guide to Managing
Risks Associated with Cross-Contamination. Automated
In November 2014 the EMA issued the document EMA/CHMP/ CVMP/ SWP/169430/ Automated cleaning methods are the preferred method of cleaning
2012, Guideline on setting health based exposure limits for use in risk identification pharmaceutical equipment. Automated methods include Clean-in-Place (CIP)
in the manufacture of different medicinal products in shared facilities. This guideline methods and Cleanout-of-Place (COP) methods.
is used for determining if dedicated facilities are necessary for the manufacture
Stage 2 Process Qualification: Testing the cleaning process (cleaning validation). Stage 2 Process Qualification: Testing the cleaning process (cleaning validation).
of medicinal products. The guidance has generated much debate in the industry With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached
Stage 3 Continued Process Verification, particularly for manual cleaning processes. Stage 3 Continued Process Verification, particularly for manual cleaning processes.
regarding cleaning validation requirements. to a cleaning skid or equivalent system which provides cleaning solutions of
Aspects of the lifecycle approach should include Aspects
water of theother
and/or lifecyclesolvent(s)
approach should includedetergents.
and/or
Other recent developments in themanagement
good project Regulatory and environment
good archiving thatinclude the concept
capture scientific knowledge of the good project management and good archiving that capture scientific knowledge
lifecycle approach and
risk management
an integrated as described
team approach in thethat
to process validation International Conference
includes expertise from a variety of an integrated
COP systems consist teamofapproach to process validation
parts washers where that includes expertise
equipment from a variety of are
and components
disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology,
on Harmonisation (ICH) guidance for industry, Q8(R2) Pharmaceutical Development, Q9
statistics, manufacturing, and quality assurance). placed onstatistics,
racks manufacturing,
and the racks are placed
and quality into the washing machine.
assurance).
Quality Risk Management,
consideration of Pharmaceutical
and Q10 Quality
plant design for cleanability, System.
smooth surfaces, drainability, materials resistant consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant
to cleaning solutions etc to cleaning
It is expected thatsolutions etc
both systems operate on the basis of established and
all studies should be planned and conducted according to sound scientific principles, all studies should be planned and conducted according to sound scientific principles,
1.3 A Life Cycle approach for Cleaning Validation
appropriately documented, and approved in accordance with the established procedure validated appropriately
fixed cycles. Cyclesand
documented, should
approvednot operate with
in accordance on the
theestablished
detection of a
procedure
appropriate for the stage of the lifecycle. predetermined conductivity
appropriate for the stage oflevel of effluent water as this breaches the guidance
the lifecycle.
In recent decades, companies have approached cleaning validation as a discreet that a clean-until-clean approach should not be used.
exercise. More current thinking on validation exercises views validation in a lifecycle
context such as is described
1.4 in methods
Cleaning the FDA guidance on process validation. In certain
1.4 cases, sonication
Cleaning methods may be used to facilitate the cleaning of small
equipment parts such as filling needles. In considering the use of sonication,
Automated Automated
It is recommended that a lifecycle approach be taken for cleaning validation. While the preferred systems are those which can monitor and report on the cycle (e.g. by
validation effort will inevitably Automated
be weighted cleaningtowards
methods are
thetheplanning
preferred method
and ofexecution
cleaning pharmaceutical
stages, Automated
power consumption). Incleaning methods
addition, are the preferred
companies method
should of cleaningthe
consider pharmaceutical
impact to the
equipment. Automated methods include Clean-in-Place (CIP) methods and Clean- equipment. Automated methods include Clean-in-Place (CIP) methods and Clean-
the ongoing monitoring will ensure that(COP)
out-of-Place the relevance
methods. of the validation will remain production process / schedule
out-of-Place in the event that the sonication system is
(COP) methods.
current. inoperable.
With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a
cleaning skid or equivalent system which provides cleaning solutions of water and/or cleaning skid or equivalent system which provides cleaning solutions of water and/or
Following the FDA model, theother
lifecycle forand/or
solvent(s) cleaning validation would be as follows;
detergents. Manual other solvent(s) and/or detergents.
Stage 1 Process Design: Designing
on racks theare
and the racks cleaning
placed intovalidation process
the washing machine. Manual cleaning on processes cannot
racks and the racks be validated
are placed in the
into the washing conventional meaning of
machine.
It is expected that both systems operate on the basis of established and validated validation, but itIt is possible to verify manual cleaning processes.
is expected that both systems operate on the basis of established and Manual
validated cleaning
Stage 2 Process Qualification:
fixed cycles.Testing the not
Cycles should cleaning
operate onprocess (cleaning
the detection validation).
of a predetermined processes inevitably experience
fixed cycles. Cycles shouldperson to person
not operate variability.
on the detection Regulatory
of a predetermined
clean approach should not be used. clean approach should not be used.
Stage 3 Continued Process Verification, particularly for manual cleaning residues on equipment which has been manually cleaned, dried, and is in
processes. In certain cases, sonication may be used to facilitate the cleaning of small equipment In certain cases, sonication may be used to facilitate the cleaning of small equipment
storage as Clean equipment. Where GMP Inspectors identify residues on Clean
parts such as filling needles. In considering the use of sonication, preferred systems parts such as filling needles. In considering the use of sonication, preferred systems
are those which can monitor and report on the cycle (e.g. by power consumption). In equipment, theare integrity of can
those which themonitor
manual cleaning
and report process
on the cycle (e.g. byand therefore
power theIn
consumption).
Aspects of the lifecycle approach should
addition, companiesinclude
should consider the impact to the production process / schedule cleaning validation programme
addition, areconsider
companies should calledthe into question.
impact to the production process / schedule
good project management and good archiving that capture scientific knowledge Despite the limitations of manual cleaning, this process of cleaning is widespread
Manual within the pharmaceutical
Manual industry and is likely to remain as an acceptable
an integrated team approachManual to process validation that includes expertise from a
cleaning processes cannot be validated in the conventional meaning of
process for the Manual
distant future.
cleaning processes cannot be validated in the conventional meaning of
variety of disciplines (e.g., process engineering,
validation, but it is possibleindustrial pharmacy,
to verify manual analytical
cleaning processes. Manual cleaning validation, but it is possible to verify manual cleaning processes. Manual cleaning
chemistry, microbiology, statistics, manufacturing, and quality assurance)
processes inevitably experience person to person variability. Regulatory In order to future proof
processes manual
inevitably cleaning,
experience personadopting concepts
to person variability. from automated
Regulatory
engagements on manual cleaning validation often fail due to the identification of engagements on manual cleaning validation often fail due to the identification of
residues on equipment which has been manually cleaned, dried, and is in storage as
cleaning systems (i.e. pre-configured steps) can help close the gap between
consideration of plant designClean
for cleanability,
equipment. Where smooth surfaces,
GMP Inspectors drainability,
identify materials
residues on Clean equipment, automated andClean
manual systems.
equipment. Where GMP Inspectors identify residues on Clean equipment,
resistant to cleaning solutions
theetc
integrity of the manual cleaning process and therefore the cleaning validation the integrity of the manual cleaning process and therefore the cleaning validation
Good
Practice Good
Practice
GCVP GCVP
GCVP 6 GCVP 7
A state of the art manual cleaning systems would consist of 1.5 Established Principles
o Pre-defined steps with detailed descriptions of each cleaning step (e.g. MACO
temperature of cleaning solutions, duration of soakage, duration and
description of manual cleaning steps) It is not possible to completely remove all traces of a product for cleaning. The
o Detailed step by step cleaning instructions including photographs of Maximum Acceptable Carry Over (MACO) is a means of defining the allowable
cleaning steps, start and end time of each step, amount of Product A (the first product) to be left on non-dedicated
o Double checks at key steps, and at least at the inspection of dried manufacturing equipment which will then be incorporated into the next
equipment prior to storage. product (Product B) produced using the equipment.
o Ongoing reassessment
As a model, there are some assumptions made being that the residue of
In latter sections of this document, reference will be made to validation / verification of Product A is evenly spread throughout the equipment, and that all of Product
cleaning procedures. With regard to manual cleaning procedures, consistency of A will be incorporated into Product B.
technique is essential where a company wishes to defend verification of a manual
cleaning process. In order to instil confidence
Aspects of the lifecycle ininclude
approach should the verification of a manual cleaning Aspects ofbased
Health the lifecycle approach should include
limits
process it is necessary to firstly define and secondly
good project management and good archiving followthatthat process.
capture scientific knowledge good project management and good archiving that capture scientific knowledge
an integrated
The health basedteam approachdetermines
method to process validation
thatthat
noincludes
more expertise
than the from a variety of
acceptable daily
Regardless, due the potential variability of manual cleaning, independent and periodic
statistics, manufacturing, and quality assurance). exposure (ADE)
statistics, of the product
manufacturing, (herein
and quality referred to as a Product A) being
assurance).
post validation monitoring is used
consideration of toplant
verify the
design forcontinued validated
cleanability, smooth surfaces,status. This
drainability, may resistant
materials cleaned appearsofinplant
consideration thedesign
maximum dailysmooth
for cleanability, dosesurfaces,
(MDD)drainability,
of the next product
materials (herein
resistant
be achieved by infrequent random unannounced swab sampling by QA/QC
to cleaning solutions etc to to
referred cleaning solutions etc
as Product B) being manufactured. The ADE is the amount of active
departments or by frequent visual checks performed by production personnel. In the
appropriately documented, and approved in accordance with the established procedure substance / drug
appropriately productand
documented, in mg/day
approved in that a person
accordance with thecan be exposed
established procedure to as a
even that such monitoring fails the
appropriate relevant
for the acceptance
stage of the lifecycle. criteria, appropriate contaminant in another product without
appropriate for the stage of the lifecycle. experiencing any adverse health
notification and assessment within the Quality Management System should be effects including, pharmacological effects attributed to the contaminating
performed. drug. This method is useful for biologic products which all have an ADE
1.4 Cleaning methods value,
1.4 and thus the
Cleaning methods health based method can be used to calculate the MAR
Development (Maximum Acceptable Residue) for these products.
Automated Automated
The development of cleaning Automated

methods should
cleaning be documented
methods withinof the
are the preferred method CVMP.
cleaning pharmaceutical Single Use,Automated
Dedicatedcleaning
andmethods are the preferred
Multi-Product method of cleaning pharmaceutical
Equipment
Documentation of the development of cleaning cycles should include discussion on
out-of-Place (COP) methods. out-of-Place (COP) methods.
the following; Where Single Use (i.e. disposable) equipment is used, it is not necessary to
cleaning skid or equivalent system which provides cleaning solutions of water and/or perform cleaning
cleaningvalidation for this
skid or equivalent equipment.
system which provides cleaning solutions of water and/or
o Cleaning technology which
other is accessible
solvent(s) to the facility
and/or detergents. other solvent(s) and/or detergents.
o Suitability of cleaning solutions
COP systems consist of parts washers where equipment and components are placed Where dedicated
COP systemsequipment
consist of is used
parts (e.g.
washers filter
where socks and
equipment forcomponents
fluid bedare dryers),
placed
o Assessment of active ingredients,
on racks and the racks excipients and
are placed into formulated
the washing machine. products from visual cleaning is the
on racks andprimary
the racks are method
placed intoofthe
cleaning validation / verification
washing machine.
the perspectives ofItsolubility, toxicity and cleanability
is expected that both systems operate on the basis of established and validated provided thatIt isanexpected
assessment has been
that both systems formed
operate to show
on the basis that product
of established strength
and validated
o Design of equipment fixed cycles. Cyclesaccount
taking into narrow
should not operate ondiameter
the detection pipework, acute
of a predetermined changeover would notCycles
fixed cycles. haveshould
an impact,
not operateand that
on the the of
detection potential for impurity
a predetermined
angles and welds conductivity level of effluent water as this breaches the guidance that a clean-until- conductivity
generation and level ofiseffluent
carryover not of water as this breaches the guidance that a clean-until-
concern.
o Hold times
o Experimental results to verify
In certain any
cases, hypothesis
sonication thatto was
may be used developed
facilitate the cleaning of small equipment In certain
For multi-product cases, sonication
equipment, may be used
cleaning to facilitate the
validation cleaning of small
/ verification mustequipment
be
are those which can monitor and report on the cycle (e.g. by power consumption). In performed. are those which can monitor and report on the cycle (e.g. by power consumption). In
Choice of the cleaning agent should be documented
addition, companies and
should consider theapproved by Quality
impact to the production process / schedule addition, companies should consider the impact to the production process / schedule
Assurance Department and should be scientifically justified based on:
in the event that the sonication system is inoperable.
1.6 in the event that the sonication system is inoperable.
Choice of Target Molecule
- Solubility of the materials
Manual
to be removed Worst case
Manual
- The design and construction of the equipment and surface materials to be
Manual cleaning processes cannot be validated in the conventional meaning of Manual cleaning processes cannot be validated in the conventional meaning of
cleaned validation, but it is possible to verify manual cleaning processes. Manual cleaning In a multi-product facility,
validation, rathertothan
but it is possible verify validate the cleaning
manual cleaning of each
processes. Manual product,
cleaning
- Safety of the cleaning agent
processes inevitably experience person to person variability. Regulatory processes inevitably experience person to person variability.
a worst case molecule (or product) may be selected to represent the worst Regulatory
- Ease of removal engagements on manual cleaning validation often fail due to the identification of engagements on manual cleaning validation often fail due to the identification of
residues on equipment which has been manually cleaned, dried, and is in storage as case challenge presented
residues on equipment to which
the cleaning process.
has been manually In selecting
cleaned, dried, and is inastorage
worstascase, it
- Detectability of residues
Clean equipment. Where GMP Inspectors identify residues on Clean equipment, is necessary Clean
that aequipment.
standard cleaning
Where procedure
GMP Inspectors identify is used.onInClean
residues the event that
equipment,
- Product attributes the integrity of the manual cleaning process and therefore the cleaning validation the integrity of the manual cleaning process and therefore
different cycles are used, worst case molecules must be selected for each the cleaning validation
- Knowledge gained programme
through are experience
called into question.

programme are called into question.
cycle. In addition, different worst case molecules may be identified for
- The minimum temperature and volume of cleaning agent and rinse solution solubility or toxicity, requiring multiple testing.
- Manufacturers recommendations
Good
Practice Good
Practice
GCVP GCVP
GCVP 8 GCVP 9
Reference products (placebos) Generally the method is used when it has been demonstrated that a
calculated MACO would leave a visible residue as it is not intuitive that a
While not a conventional method of cleaning validation, it would be possible validated method of cleaning would result in product residues.
for a company to use a reference molecule with a lower solubility and lower
ease of cleanliness. Thus cleaning of the more difficult to clean material TOC
validates the cleaning procedure.
Total Organic Carbon analysis is a non-specific method, looking merely for
An example of a situation where this approach would be used would be for residual carbon molecules. The source of the carbon is not determined
an Investigational Medicinal product where supplies of the active ingredient which arguably means the system detects potential residue from numerous
/ product are very limited. sources such as the active ingredients, detergent, and in the biotechnology
industry, cell debris and cell culture media.
Reference has also been made in the past to the use of placebo batches
where assessment of cleaning would be performed by running a placebo TOC analysis is commonly used in the biotechnology industry where the
(product containing no actives) through production equipment. The placebo exactStage 3 Continued Process Verification, particularly for manual cleaning processes.
composition of the production process and thus the residue may not
material would then be tested
Aspects of the lifecycle approachfor traces
should of Product A. This approach has not
include be known. However, TOC
Aspects of the lifecycle approach is not
should appropriate where the final rinsing solvent is
include
gained popularity and is not recommended
good project management and good archiving forthat
cleaning validation.
capture scientific knowledge organic.
Detergents disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology,
disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology,
The cleanest material available to the pharmaceutical industry is Water for
consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant Injection
consideration of(WFI)
in bulk which
plant design has a TOC
for cleanability, limit
smooth of 500ppb.
surfaces, There
drainability, areresistant
materials 2 common
Validation of the removal
to cleaning of detergents/cleaning
solutions etc agents/solvents should be approaches used in relation to TOC
incorporated into the cleaning validation / verification programme. Companies
appropriately documented, and approved in accordance with the established procedure
should select appropriate
detergents/solvents
for the stage of thewhich
lifecycle.are as innocuous as possible. That any rinseforsamples
appropriate the stage ofor
theswabs
lifecycle.would have a TOC result which is
<500ppb. This means that the samples are within the range of WFI.
Acceptance criteria must be determined for the detergents based on the
most stringent of the following That any rinse samples or swabs would have a TOC result of <100ppb (for
1.4 Cleaning methods 1.4 Cleaning methods
- MAC calculation for the indicator species example) above a blank of the WFI in use. This latter limit is used to take
Automated Automated
- no effect on the subsequent product or manufacturing process accountthat the WFI in-use may have an insignificant TOC level (e.g. 50ppb)
- as low as reasonably practical methods are the preferred method of cleaning pharmaceutical
Automated cleaning and that there would
Automated be amethods
cleaning potentially higher method
are the preferred amount of carry
of cleaning over (e.g.
pharmaceutical
400ppb) which would still meet
the former specification.
Limits must be justified by a scientific rationale and approved in the CVP. If
the cleaning agent With
is a CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a
chemical entity or a solvent that is subsequently used
HPLC andWith CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a
UPLC
in the production process as a and/or
other solvent(s) process chemical (e.g. NaOH for pH
detergents. other solvent(s) and/or detergents.
adjustment) or solvent, then calculating removal by MACO of such species is
COP systems consist of parts washers where equipment and components are placed
HPLC / UPLC are specific methods and are the methods of choice for
not applicable. These
on racks and must
cases be
the racks arejustified
placed intoand documented.
the washing machine. cleaning validation
on racks andwhere
the rackstheare active ingredient
placed into is well characterised (e.g. a
the washing machine.
small molecule API). There are standard guidelines available for the
Examples where detergents may should
fixed cycles. Cycles be more toxiconthan
not operate pharmaceutical
the detection of a predetermined validation of
fixed cycles.(ICH
HPLC guideline
Cycles Q2 (R1)),
should not operate and
on the particular
detection attention should be
of a predetermined
products would be where the medicinal products use substances
conductivity level of effluent water as this breaches the guidance thatcommonly
a clean-until- paid to the validation of limits of detection and quantitation.
conductivity level of effluent water as this breaches the guidance that a clean-until-
used as food items e.g. glucose injections, Glycerine, honey and lemon
cough syrup. In certain cases, sonication may be used to facilitate the cleaning of small equipment UV In certain cases, sonication may be used to facilitate the cleaning of small equipment
In the event that non-standard
addition, companiesdetergents arethe
should consider inimpact
use, to the production process / schedule Ultraviolet addition,
spectroscopy
companies is a method
should which
consider the impacthas
to thebeen used
production in the
process past for the
/ schedule
companies should treat the detergents as active ingredients.
in the event that the sonication system is inoperable. detection of residues, but is a non-specific method and is not as accurate as
HPLC and is therefore not considered generally to be a suitable option.
1.7 Choice of Analytical
ManualTechniques Manual
Conductivity
A number of analytical techniques
validation, are to
but it is possible available; the
verify manual following
cleaning processes.is aManual
description
cleaning validation, but it is possible to verify manual cleaning processes. Manual cleaning
of the most commonly used methods.
processes inevitably experience person to person variability. Regulatory Conductivity is a non-specific
processes method
inevitably experience personthat hasvariability.
to person been applied
Regulatoryto the analysis
engagements on manual cleaning validation often fail due to the identification of engagements on manual cleaning validation
of inorganic molecules which result in ionic species when often fail due to the identification
dissolved of in water.
Visual Inspection Clean equipment. Where GMP Inspectors identify residues on Clean equipment, The method is not generally used for the analysis of samples (swab or rinse)
the integrity of the manual cleaning process and therefore the cleaning validation but conductivity canof be
the integrity foundcleaning
the manual in parts washers
process where
and therefore the the cycle
cleaning is terminated
validation
Visual inspection is the examination of the dried equipment under suitable when a certain conductivity
programme isquestion.
are called into reached. A criticism of such a design is that the
lighting conditions by personnel with appropriate standard of vision. system essentially cleans until clean, resulting in variable and non-standard
cycles.
Good
Practice Good
Practice
GCVP GCVP
GCVP 10 GCVP 11
1.8 Choice of Sampling Method Typical guidelines within the swabbing SOP may include
A number of sampling methods are available and commonly used. The o the type of swab used
validation protocol should clearly define sampling locations and methods, o the swab surface area
ensuring that the most difficult to clean areas are sampled and the number o the number and location of swabs to be taken
and location of swabs/rinse volumes is adequate to represent the o Justification for the solvent used to saturate the swab
equipment and contents. o How the swab is desorbed
Visual Rinse samples
Visual inspection is an intuitive method in circumstances where other Rinse samples are used to sample difficult to reach areas. It should be ensured
methods result in 2a maximum acceptable residue that the rinse volume is sufficient to cover all equipment surfaces and that the
Stage Process Qualification: Testing the cleaningwhich
process would
(cleaningbe visibly
validation). Stage 2 Process Qualification: Testing the cleaning process (cleaning validation).
detectable. It Stage
also 3has advantages in that it is a quick detection method and rinse samples adequately represent the contents. The rinse solution is then
Continued Process Verification, particularly for manual cleaning processes.
it is a direct method for process contacting surfaces to verify that no visible analysed Stage 3 Continued Process Verification, particularly for manual cleaning processes.
for the target residue.
Aspects of the lifecycle approach should include Aspects of the lifecycle approach should include
residues, foreign objects or extraneous matter are present. Hand held UV
lights sources
goodmay be used
project to enhance
management visibility
and good archiving thatwhere applicable.
capture scientific knowledge In order togood
justify the
project use of rinse
management and goodsamples, thecapture
archiving that samescientific
levelknowledge
of validation (e.g.
recovery
from spiked
an integrated teamequipment / coupons)
approach to process validation applies rather
that includes than
expertise fromjust accepting
a variety of
The technique is alsomanufacturing,
statistics, appropriate and for inter
quality batch/campaign cleaning for the
assurance).
the absence the target molecule.
same product or intermediate
consideration families
of plant design where smooth
for cleanability, justified (e.g.drainability,
surfaces, a Levelmaterials
1 clean of
resistant consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant
a compressionto cleaning solutions etc
machine.) Sample tostability
cleaning solutions etc
appropriately documented, and approved in accordance with the established procedure appropriately documented, and approved in accordance with the established procedure
When visual inspection
appropriate for is
thethe direct
stage method, the visual limit of detection
of the lifecycle. In the event that samples
appropriate are
for the stage tolifecycle.
of the be stored for a period of >24 hours, stability
of
must be established through visual detection studies. the samples should be considered and validated. The stability of the samples
should account for the potential degradation of actives and excipients that could
Swabbing occur as a result of the cleaning process operating conditions and detergent
used. Otherwise, sample degradation may contribute to erroneously compliant
Automated Automated
Swabbing is generally the preferred method for sampling for cleaning results.
Automated cleaning methods are the preferred method of cleaning pharmaceutical Automated cleaning methods are the preferred method of cleaning pharmaceutical
validation. Subject to operator training, the method is relatively consistent
and recovery can be validated.
out-of-Place (COP)The most difficult to clean areas must be
methods. 1.9 Spray Coverage Testingout-of-Place (COP) methods.
sampled and the number and location of swabs taken should be adequate
to represent the equipment.
cleaning skid Justification for which
or equivalent system the solvent used solutions
provides cleaning to saturateof waterthe
and/or The use of spray ballsskid
cleaning fororcleaning is more
equivalent system which efficient than soaking
provides cleaning solutions ofas a cleaning
water and/or
swab (adequate stability, and solubility for the residues of interest i.e. process
other solvent(s) and/or detergents. method but can be challenged with regard to full coverage. Where spray balls
residue, cleaning agent) according
COP systems toparts
consist of thewashers
swabwhere
recovery study.
equipment and components are placed are the primaryCOP
method
systemsof cleaning
consist of partsused,
washersawhere
spray coverage
equipment test should
and components be
are placed
on racks and the racks are placed into the washing machine. performed which can and
on racks be the
summarised asintofollows;
racks are placed the washing machine.
The procedure for sampling
It is expectedsurfaces involves
that both systems wiping
operate theofsurfaces
on the basis established (e.g. areas
and validated It is expected that both systems operate on the basis of established and validated
of 5 cm x 5 cm and fixed
10cm cycles. Cycles are
x 10cm should not operate onused))
commonly the detection
withofaa swab,
predetermined
to Apply a solution
fixedof riboflavin
cycles. to the
Cycles should notsurfaces to detection
operate on the be cleaned by using a fine mist
of a predetermined
remove residues from a surface. A SOP should be in place to ensure the Verify complete coverage using a UV light source
consistency of swabbing which is a manual process. For example, companies Perform a water rinse using a cycle equivalent to the shortest phase of the
may use a stainlessparts
steel template placed againstthe the cleaning cycleInand
certain cases, sonication may be used to facilitate the cleaning of small equipment
record the cycle parameters
such as filling needles. In considering usesurface to be
of sonication, preferred systems parts such as filling needles. In considering the use of sonication, preferred systems
swabbed, the number andwhich
are those direction of strokes
can monitor and reportto
on be used
the cycle may
(e.g. be specified,
by power consumption). In Inspect all surfaces
are thoseusing themonitor
which can UV light, paying
and report on theparticular
cycle (e.g. by attention to difficult
power consumption). In to
addition,
the turning over of the swabcompanies
may be should consider the impact to the production process / schedule
specified. reach areas and for pooling.
addition, The inspection
companies should should
consider the impact to thebe performed
production process before
/ schedulethe
surfaces dry out as riboflavin does not fluoresce when dry
Personnel performing swabbing must be qualified and re-qualified on a
periodic basis. Manual 1.10 Cleaning Validation
Manual Failure
Justification for not validation,
performing but it isswab sampling
possible must
to verify manual be documented
cleaning processes. Manualand cleaning Cleaning Validation generally
validation, consists
but it is possible ofmanual
to verify the following sequence
cleaning processes. Manual cleaning
processes inevitably experience person to person
must include a reference to studies that demonstrate comparable sensitivity variability. Regulatory processes inevitably experience
Identification of the worst case product person to person variability. Regulatory
for visual, rinsing, and swabbing
residues on equipmenttechniques.
which has been manually cleaned, dried, and is in storage as Calculating the MACO
Clean equipment. Where GMP Inspectors identify residues on Clean equipment, Cleaning equipment after a Where
Clean equipment. production of a batch
GMP Inspectors identify residues on Clean equipment,
the integrity of the manual cleaning process and therefore the cleaning validation the integrity of the manual cleaning
Sampling the equipment to see if any remaining process and therefore
residue theiscleaning
below validation
the MACO
Good
Practice Good
Practice
GCVP GCVP
GCVP 12 GCVP 13
In the event that remaining residue is above the MACO, then the cleaning Cleaning Verification The process of establishing documented evidence that an
method is not considered to be validated and the following options should individual cleaning event will consistently reduce equipment
be taken; surface residuals (i.e. product and cleaning agents) to a pre-
determined acceptable level.
The cleaning method should be amended to be more effective, and this
effectiveness verified or Deviation Any unplanned / planned change to the established
Dedicated equipment should be used for at least the part of the process parameters, protocol instructions, or approved procedures,
which cannot be successfully cleaned. performed during the validation activities. Any test failure is
considered a deviation. Deviations must be documented in
the associated validation report.
1.11 Definitions
Dirty Equipment Hold This is the period of time between the end of manufacturing
Time to the start of the cleaning procedure for processing
Acceptance Criteria StageThe criteria
2 Process assigned
Qualification: before
Testing undertaking
the cleaning testing
process (cleaning that an
validation). Stage 2 Process Qualification: Testing the cleaning process (cleaning validation).
item, method, process or system must satisfy in order for equipment, as specified in the associated cleaning process
test results to be deemed acceptable. SOP.
Acceptable Daily A dose that is unlikely to cause an adverse health event or MaximumAspects of the lifecycle approach should include
Allowed ADI X B / LDDB
good project management and good archiving that capture scientific knowledge good
Carry over (MACO)
project management and good archiving that capture scientific knowledge
Exposure (ADE)
undesirable physiological effects if an individual is exposed
an integrated team approach to process validation that includes expertise from a variety of an integrated team approach to process validation that includes expertise from a variety of
at or(e.g.,
disciplines below thisengineering,
process dose forindustrial
the maximum expected
pharmacy, analytical duration
chemistry, microbiology,
Where:
of use
statistics, of the drug
manufacturing, carrying
and quality the contaminant. If this duration
assurance). statistics, manufacturing, and quality assurance).
cannot be estimated reliably, lifetime use is assumed LDDBsmooth
consideration of plant design for cleanability, = Largest daily
surfaces, dosematerials
drainability, of the resistant
next product
to cleaning solutions etc to cleaning solutions etc
(number of units taken per day).
Acceptable Daily all studies
Dailyshould be planned and
therapeutic dose conducted
of theaccording to sound scientific
first product X Safety principles,
Factor all studies should be planned and conducted according to sound scientific principles,
(=1/1000)
Intake for actives (ADI)appropriate in case of oral dosage
for the stage of the lifecycle.
forms (tablet, capsules or appropriate for the stage of the lifecycle. B = Smallest Batch Size of the next product
caplets)
Acceptable Daily NOEL X SF (=1/1000). (Number of dosage units per batch
Intake (for toxicity1.4 Cleaning methods 1.4 Cleaning methods of final mixture of next product).
based limit, cleaning
Automated Automated
agents and other items
Automated cleaning methods are the preferred method of cleaning pharmaceutical Maximum Allowed AutomatedMACO Xmethods
cleaning surfacearearea (S.A.) method
the preferred of swab in cmpharmaceutical
of cleaning / total S.A.
2
in cm2.
with no therapeutic
equipment. Automated methods include Clean-in-Place (CIP) methods and Clean- Residue (MAR) equipment. Automated methods include Clean-in-Place (CIP) methods and Clean-
dose) (ADI Tox) out-of-Place (COP) methods. out-of-Place (COP) methods.
No Observed Effective LD50 X Average human body weight (60kg)/2000
Analytical Methods The process
With CIP methodsbythe
which it equipment
piece of is established by laboratory
(e.g. a vessel or filling line) isstudies
attached to a With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a
Limit Where 2000 is empirical constant and 60kg is used as a
Validation under a pre-approved
cleaning protocol,
skid or equivalent system that the
which provides performance
cleaning solutions of water and/or cleaning skid or equivalent system which provides cleaning solutions of water and/or
other solvent(s) and/or detergents. other solvent(s) and/or detergents. conservative estimate.
characteristics of the method meet the requirements for the
intended
COP systemsanalytical applications.
consist of parts washers where equipment and components are placed COP systems consist of parts washers where equipment and components are placed
on racks and the racks are placed into the washing machine. on racks and the racks are placed into the washing machine.
Clean Equipment Hold This is the maximum period of time allowed for processing
Time equipment between
fixed cycles. Cycles shouldthe end of
not operate on a cleaning
the detection ofprocedure
a predeterminedto its fixed cycles. Cycles should not operate on the detection of a predetermined
next use inlevel
conductivity production or its
of effluent water as sterilization
this breaches theor sanitization,
guidance as
that a clean-until- conductivity level of effluent water as this breaches the guidance that a clean-until-
specified in the associated cleaning and/or sterilization SOP. clean approach should not be used.
In certain cases, sonication may be used to facilitate the cleaning of small equipment In certain cases, sonication may be used to facilitate the cleaning of small equipment
Clean-In-Place (CIP) A cleaning process that the tank, piping, and in-line devices
of are
processing equipment
those which can are cleaned
monitor and report on the cyclein their
(e.g. original
by power consumption). In are those which can monitor and report on the cycle (e.g. by power consumption). In
position, involving
addition, companies minimum
should connection/disconnection
consider the of
impact to the production process / schedule addition, companies should consider the impact to the production process / schedule
some piping after the processing.
Clean Out of Place COP systems are used for cleaning equipment that require
(COP) Manual
disassembly and/or transfer to another location for cleaning. Manual
In Manual
xx, small parts
cleaning will be
processes disassembled
cannot and
be validated in the washed
conventional in theof
meaning Manual cleaning processes cannot be validated in the conventional meaning of
validation,
parts washer.but it is possible to verify manual cleaning processes. Manual cleaning validation, but it is possible to verify manual cleaning processes. Manual cleaning
Cleaning Validation The processonofmanual
engagements establishing documented
cleaning validation evidence
often fail due that of
to the identification engagements on manual cleaning validation often fail due to the identification of
a particular cleaning procedure will consistently reduce
equipment
the integrity ofsurface
the manual residues (i.e. product
cleaning process and
and therefore thecleaning
cleaning validation the integrity of the manual cleaning process and therefore the cleaning validation
agents)
programmeto aarepredetermined
called into question. acceptable level. programme are called into question.
Good
Practice Good
Practice
GCVP GCVP
GCVP 14 GCVP 15
Personal Daily Intake NOEL x Weight Adjustment (50 kg) 1.12 Frequently Asked Questions
(Represents a F1 x F2 X F3 X F4 X F5
1.12.1 How should microbiological cleanliness be assessed?
substance-specific The modifying factors are as follows:
dose that is unlikely Microbial evaluation studies can be performed to determine:
to cause an adverse F1 = A factor to account for extrapolation between species
effect if an individual Time limit for unclean equipment (between end of use and start of cleaning);
is exposed at or F1 = 5 for extrapolation from rats to humans depending on:
below this dose F1 = 12 for extrapolation from mice to humans o Microbial contamination which is measured by swabbing.
every day for F1 = 2 for extrapolation from dogs to humans o The nature of the soil which may make the cleaning more difficult.
a lifetime) (PDE) Time limit for cleaned equipment (between end of cleaning and start of next
F1 = 2.5 for extrapolation from rabbits to humans
Stage 2 Process Qualification: Testing the cleaning process (cleaning validation). use); depending
Stage 2 Process on:
Qualification: Testing the cleaning process (cleaning validation).
F1 = 3 for extrapolation from monkeys to humans oStage
Microbial contamination which is measured by swabbing.
Stage 3 Continued Process Verification, particularly for manual cleaning processes. 3 Continued Process Verification, particularly for manual cleaning processes.
F1 = 10 for extrapolation from other animals to humans o Dust which can be measured by visual examination before and after
F2 = A factor of 10 to account for variability between individuals cleaning.
good project management and good archiving that capture scientific knowledge good project management and good archiving that capture scientific knowledge


A factor
disciplines ofprocess
(e.g., 10 is generally given for
engineering, industrial all organic
pharmacy, solvents,
analytical and
chemistry, microbiology,
Of more importance however are preventive measures:
10 is used consistently in this guideline.
statistics, manufacturing, and quality assurance). Equipment
statistics,should be dried
manufacturing, before
and quality storage.
assurance).
consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant Stagnant waterofshould
consideration notforbe
plant design allowed
cleanability, to remain
smooth surfaces,in the equipment.
drainability, materials resistant
to cleaning solutions etc to cleaning solutions etc
allF3 = A should
studies variable factor
be planned and toconducted
account for toxicity
according to soundstudies of short-
scientific principles,
Conditions of storage should be monitored.
all studies should be planned and conducted according to sound scientific principles,
termdocumented,
appropriately exposureand approved in accordance with the established procedure The control of the
appropriately bio-burden
documented, through
and approved environmental
in accordance monitoring
with the established procedure program.
appropriate for the stage of the lifecycle. appropriate for the stage of the lifecycle.
F3 = 1 for studies that last at least one half lifetime (1 year for
rodents or rabbits; 7 years for cats, dogs and monkeys).
1.4
F3 = 1 for reproductive studies in which the whole period of
Cleaning methods 1.4 Cleaning methods
organogenesis is covered.
Automated Automated
F3 = 2 for a 6-month study in rodents, or a 3.5-year study in
Automated cleaning methods are the preferred method of cleaning pharmaceutical Automated cleaning methods are the preferred method of cleaning pharmaceutical
non-rodents.
out-of-Place
F3 = 5 for (COP) methods.study in rodents, or a 2-year study in
a 3-month out-of-Place (COP) methods.
non-rodents.
F3 = solvent(s)
other 10 for studies of a shorter duration.
and/or detergents. other solvent(s) and/or detergents.
In allCOP systems
cases, theconsist
higherof parts washers
factor haswhere
beenequipment
used andfor components
study are placed COP systems consist of parts washers where equipment and components are placed
durations between the time points, e.g. a factor of 2 for a
It is expected
9-month rodentthatstudy
both systems operate on the basis of established and validated It is expected that both systems operate on the basis of established and validated
fixed cycles. Cycles should not operate on the detection of a predetermined fixed cycles. Cycles should not operate on the detection of a predetermined
F4 = clean
A factor thatshould
approach maynotbe be applied
used. in cases of severe clean approach should not be used.
toxicity, e.g.cases,
In certain non-genotoxic
sonication may becarcinogenicity,
used to facilitate theneurotoxicity
cleaning of small equipment In certain cases, sonication may be used to facilitate the cleaning of small equipment
or teratogenicity.
parts such as fillingIn studies
needles. of reproductive
In considering toxicity,preferred
the use of sonication, the systems parts such as filling needles. In considering the use of sonication, preferred systems
are those which can
following factors are used: monitor and report on the cycle (e.g. by power consumption). In are those which can monitor and report on the cycle (e.g. by power consumption). In
addition, companies should consider the impact to the production process / schedule addition, companies should consider the impact to the production process / schedule
F4 = 1event
in the for fetal
that thetoxicity
sonicationassociated with maternal toxicity
system is inoperable. in the event that the sonication system is inoperable.
F4 = 5 for fetal toxicity without maternal toxicity
F4 = 5 for a teratogenic effect with maternal toxicity
Manual Manual
F4 = 10cleaning
Manual for a teratogenic
processes cannot effect without
be validated in thematernal
conventionaltoxicity
meaning of Manual cleaning processes cannot be validated in the conventional meaning of
F5 = processes
A variable factor
inevitably that may
experience personbetoapplied if the Regulatory
person variability. no-effect processes inevitably experience person to person variability. Regulatory
level was not established
When the only an
integrity of LOEL is available,
the manual a factor
cleaning process of upthetocleaning
and therefore 10 could
validation the integrity of the manual cleaning process and therefore the cleaning validation
be used depending
programme on question.
are called into the severity of the toxicity. programme are called into question.
Good
Practice Good
Practice
GCVP GCVP
GCVP 16 GCVP 17
Section 2 The Communication of Cleaning Validation 2.2.2 Choice of Target Species/Product
In the past, the choice of target species was typically chosen from the
2.1 The Cleaning Validation Subject Matter Expert worst case(s) of active molecules from the categories of solubility,
potency, and cleanabilty (based on experience).
Good Manufacturing Practice (GMP) is normally communicated through direct
exchanges between personnel who represent Regulatory Authorities and The EU GMPs (paragraph 3.6, 5,20, 5,21) refers to a toxicological
representatives of companies/organisations (Inspected Parties). Unlike the evaluation of products in the decision making process for the necessity
communication of marketing authorisation information, GMP information is of dedicated facilities or equipment.
generally communicated via face to face exchanges.
The following is a proposed method for the combination of traditional
Competent, capable and credible Subject Matter Experts (SMEs) who represent assessments and the toxicological approach as described in the EMA
the Inspected Party can substantially improve the confidence of a Regulatory Guideline on setting health based exposure limits for use in risk
Agency in a particular
Stage subject. The
3 Continued particular
Process field
Verification, of cleaning
particularly validation
for manual has been
cleaning processes.
identification in the manufacture of different medicinal products in
identified byAspects
Regulatory Agencies
of the lifecycle inshould
approach the past
includefor the piecemeal approach of Aspectsshared facilities. should include
of the lifecycle approach
communication ofgood theproject
subject.
management and good archiving that capture scientific knowledge good project management and good archiving that capture scientific knowledge
Step 1 Determine
an integrated team approachthe Worst
to process Casethat
validation Molecule / Product
includes expertise A of
from a variety
It is highly recommended thatprocess
disciplines (e.g., each engineering,
Inspected Partypharmacy,
industrial identifyanalytical
a Cleaning Validation
chemistry, microbiology, disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology,
statistics, manufacturing, and quality assurance). statistics, manufacturing, and quality assurance).
Subject matter Expert who can provide a high level overview of all aspects of the
consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant In selecting
consideration the design
of plant worstforcase molecule,
cleanability, the following
smooth surfaces, worked
drainability, materials example
resistant
subject and who can competently
to cleaning solutions etcspeak to all aspects of the Cleaning Validation demonstrates a means of selection by ranking of products using the
Package (see below).
following criteria for each product:
appropriate for the stage of the lifecycle. appropriate for the stage of the lifecycle.
2.2 The Cleaning Validation Package - Solubility
- Toxicity
In order to communicate cleaning validation effectively and consistently to - Cleanliness
regulatory agencies, it is recommended that companies assemble all cleaning
Automated
validation information into a standard PMTC Cleaning Validation Package format Automated
Definitions in the risk ranking are as follows;
(PMTC CVP). The purpose of thecleaning
Automated PMTCmethods
CVP is areto
theprovide a template
preferred method of cleaning which
pharmaceutical Automated cleaning methods are the preferred method of cleaning pharmaceutical
provides a consistent rationale for the choice of target molecules, the calculation
of limits and to enable the CVSME to communicate a companys approach to
With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a With CIP methods the piece of Solubility
equipment (e.g. a vessel or filling line) is attached to a
cleaning validation.
2.2.1 The Cleaning Validation Hierarchy
COP systems consist of parts washers where equipment and components are placed COPTerm Approximate
systems consist of parts volume
washers where equipment ofcomponents
and Category
are placed
on racks and the racks are placed into the washing machine. solvent
on racks and the racks are placed into the in milliliters
washing machine.
The order for the PMTC ItCVP is as follows
is expected that both systems operate on the basis of established and validated It is expected that both systemsper gram
operate on theof solute
basis of established and validated
fixed cycles. Cycles should not operate on the detection of a predetermined fixed cycles. Cycles should not operate on the detection of a predetermined
very soluble less than 1 1
Section Title clean approach should not be used. clean approach should not be used.
freelyInsoluble from 1 to 10 2
1 IntroductionIn certain cases, sonication may be used to facilitate the cleaning of small equipment
certain cases, sonication may be used to facilitate the cleaning of small equipment
2 Development are of
those which canprocedure(s)
cleaning monitor and report on the cycle (e.g. by power consumption). In Soluble from
are those which can monitor and report 10cycle
on the to 30 3
(e.g. by power consumption). In
3 Choice of target species
in the event / sonication
that the productsystem is inoperable. in the event that the sonication system is inoperable.
sparingly soluble from 30 to 100 4
4 Overview of cleaning validation protocols
5 Calculation Manual
of acceptance criteria slightly soluble
Manual from 100 to 1000 5
6 Method validation including recovery studies
validation, but it is possible to verify manual cleaning processes. Manual cleaning validation, but
very slightly it is possible to verify
soluble from manual
1000cleaning processes. Manual cleaning
to 10,000 6
7 processes
Results for each inevitably
piece experience person
of equipment to person
for each variability. Regulatory
cleaning method for processes inevitably experience person to person variability. Regulatory
each product tested
residues on equipment which has been manually cleaned, dried, and is in storage as practically
residuesinsoluble,
on equipment which hasmore than 10,000
been manually cleaned, dried, and is in 7
storage as
Clean equipment. Where GMP Inspectors identify residues on Clean equipment, Insoluble
the integrity of the manual cleaning process and therefore the cleaning validation the integrity of the manual cleaning process and therefore the cleaning validation
Good
Practice Good
Practice
GCVP GCVP
GCVP 18 GCVP 19
Product API Solubility Sol. Cleanli LD50 Toxicit Total
Cleanliness Name Rank ness mg/kg y Rank Rank
(based on experience with the finished product) Product Amisulpride Practically 7 1 1024 3 21
01 insoluble
Term Category Product Pregablin Freely 2 1 5000 2 4
Easy to clean 1 02 soluble
Product Pregablin Freely 2 1 5000 2 4
Moderate to clean 2 03 soluble
Product Rivaroxaban Practically 7 3 500 3 63
Hard to clean 3 04 insoluble
Stage 2 Process Qualification: Testing the cleaning process (cleaning validation). Product Febuxostat Insoluble
Stage 2 Process 7 the cleaning
Qualification: Testing 3 process (cleaning
590 3
validation). 63
Very hard to clean 4 05

Product Lacosamide Sparingly 4
1 253 4 16
06 soluble
Product Aripiprazol Sparingly
an integrated team 4 validation1that includes705
approach to process expertise from 3a variety of 12
Toxicity (Based
disciplines (e.g.,on LD50
process of the active
engineering, industrial ingredient)
pharmacy, analytical chemistry, microbiology, 07 disciplines (e.g.,soluble
process engineering, industrial pharmacy, analytical chemistry, microbiology,
consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant Product Aripiprazol
consideration of Sparingly 4
plant design for cleanability, 1 surfaces, 705
smooth 3
drainability, materials resistant 12
to cleaning
Oral (mg/Kg) solutions etc Category 08 soluble
>5000 documented, and approved in accordance
appropriately 1 with the established procedure Product Aripiprazol Sparingly and approved
appropriately documented, 4 in accordance
1 705
with the 3
established procedure 12
appropriate for the stage of the lifecycle. 09 soluble
Up to 5000 2 Product Aripiprazol Sparingly 4 1 705 3 12

10 soluble
1.4 Up to 2000
Cleaning methods 3 Product 1.4Meformin Freely
Cleaning methods 2 1 1450 3 6
Automated 11 soluble
Automated
Up to 300 4
Automated cleaning methods are the preferred method of cleaning pharmaceutical Product PioglitazoneAutomated
Practically 7 are the preferred
cleaning methods 3 method181 4
of cleaning pharmaceutical 84
equipment. Automated methods include Clean-in-Place (CIP) methods and Clean- 12 insoluble
Up to out-of-Place
50 (COP) methods. 5 Product Meformin
Freely 2 1 1450 3 6
With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a 13 With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a
soluble
<5 cleaning skid or equivalent system which provides
6 cleaning solutions of water and/or cleaning skid or equivalent system which provides cleaning solutions of water and/or
COP systems consist of parts washers where equipment and components are placed In the above example,COP
Product
systems 12 would
consist bewashers
of parts considered to be the
where equipment worst case
and components product.
are placed
fixed cycles. Cycles should not operate on the detection of a predetermined
Rank Identification: fixed cycles. Cycles should not operate on the detection of a predetermined
o Multiply contents of each
clean approach shouldrow toused.
not be obtain the total rank. clean approach should not be used.
o The higher the rank number, the more critical the cleaning process.
Manual Manual
Good
Practice Good
Practice
GCVP GCVP
GCVP 20 GCVP 21
Step 2 Identify the lowest acceptable MACO for Product A in Product B Note 4 Calculation of the MACO by PDE
The table is used to select target active ingredient(s) for cleaning validation PDE - NOEL x Weight Adjustment (50 kg)
purposes. In the table below, the traditional approaches of calculating the MACO F1 x F2 X F3 X F4 X F5
(0.1%) and 10ppm carry over have been supplemented by the Acceptable Daily
intake (Toxicity approach) and the Permitted Daily Exposure to determine the F1 = 12 to account for the extrapolation from mice to humans as NOEL limit based on
worst case scenario. calculations of LD50 of mice
F2 = 10 to account for differences between individual humans
Product Batch Batch # MACO 10ppm Tox PDE F3 = 10 for studies of a short duration
size (Kg) size units/ 0.1% Approach Approach Approach F4 = 10 for a teratogenic effect without maternal toxicity
(Units) day Approach (mg) (mg) (mg) F5 = 1 because the no effect level was determined
Stage(B)
2 Process (LDD )
Qualification: (mg)the cleaning process (cleaning validation).
Testing Stage 2 Process Qualification: Testing the cleaning process (cleaning validation).
B
(Note 1)particularly
Stage 3 Continued Process Verification, (Note 2) cleaning
for manual (Note 3)
processes. (Note 4) Stage 3 Continued Process Verification, particularly for manual cleaning processes.
PDE = 101.67 x 50 = 0.424 mg/day
Product 1 150.000 1,000,000
Aspects of 6 should 1666.667
the lifecycle approach include 1500 16945 70666.67
12 x 10 x 10 x 10 x 1
Product 2 99.750 good project management
95,000 6 and good archiving that capture
158.33 997.5scientific knowledge
1609.775 6713.333 good project management and good archiving that capture scientific knowledge
Product 3 120.900 600,000
disciplines 8 engineering,
(e.g., process 750 1209analytical chemistry,
industrial pharmacy, 7625.25 microbiology,
31800 MACO PDE = PDE X B(e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology,
disciplines
statistics, manufacturing, and quality assurance). statistics,B manufacturing, and quality assurance).
Product 4 115.000 700,000 2 3500 1 150 35584.5 148400 LDD
Product 5 175.000 to 500,000
cleaning solutions etc1 5000 1750 50835 212000 to cleaning solutions etc
Product 6 195.000 300,000 documented,
appropriately 3 and approved
1000in accordance 1950 10167procedure 42400
with the established appropriately documented, and approved in accordance with the established procedure
appropriate for the stage of the lifecycle. 2.2.3 Cleaning Validation Protocols
Product 7 189.000 165,000 3 550 1890 5591.85 23320
Product 8 199.960 388,000 4 970 1999.6 9861.99 41128 Cleaning validation protocols should be in place. These protocols define
Product 9 189.000 180,000 2 900 1890 9150.3 38160 the activities to be performed in order to validate cleaning procedures /
processes.
Product 10 120.000 300,000
Automated 2 1500 1200 15250.5 63600 Automated
Automated cleaning methods are the preferred method of cleaning pharmaceutical Hold Times Automated cleaning methods are the preferred method of cleaning pharmaceutical
equipment. Automated methods include Clean-in-Place (CIP) methods and Clean- Dirty Equipmentequipment.
Hold TimesAutomated methods
(DEHT) include
- The Clean-in-Place
maximum (CIP)equipment
dirty methods and Clean-
Note 1 0.1% of minimum dose of
out-of-Place Product
(COP) A in largest daily dose Product B =
methods. out-of-Place (COP) methods.
hold time should be defined within the cleaning validation protocol. In
10mg x (0.1/100) x (B / LDD )
With CIP methods Bthe piece of equipment (e.g. a vessel or filling line) is attached to a With the
CIP methods
order to maximise benefitthefrom
piece cleaning
of equipmentvalidation,
(e.g. a vessel or
thefilling line) is attached to a
maximum
otherA
solvent(s) and/or in
detergents. hold time should besolvent(s)
other calculated and then exceeded for the cleaning
and/or detergents.
Note 2 - 10ppm of Product remaining the batch of Product B
validation study.
on racks
Note 3 - Calculation of the MACOand the
byracks are placed into the washing machine.
toxicity on racks and the racks are placed into the washing machine.
Clean Equipment Hold Times (CEHT) Cleaned equipment should not
fixed cycles. Cycles should not operate on the empirical
detection of a constant
predetermined be stored in an fixed
areas where
cycles. Cyclesit should
would notbe susceptible
operate to chemical
on the detection of a predetermined
NOEL = LD50 X Average human body weight (60kg)/ (2000)
conductivity level of effluent water as this breaches the guidance that a clean-until- recontamination (eg. in a processing area or close to the
conductivity level of effluent water as this breaches the washing
guidance of dirty
that a clean-until-
equipment. If this requirement is met, there is no requirement to validate
= 3389 X 60 / 2000 = 101.67 mg
In certain cases, sonication may be used to facilitate the cleaning of small equipment CEHTs. In certain cases, sonication may be used to facilitate the cleaning of small equipment
ADI Tox = NOEL X Safety
are Factor = 101.67
those which X 0.001
can monitor = 0.10167
and report mg
on the cycle (e.g. by power consumption). In are those which can monitor and report on the cycle (e.g. by power consumption). In
addition, companies should consider the impact to the production process / schedule If clean equipment is stored
addition, companies inshould
a bacteriostatic solution,
consider the impact a study
to the production must
process / schedule
in the event that the sonication system is inoperable. demonstrate removal of the bacteriostatic solution before equipment use.
MACO Tox = ADI Tox X B
LDDB In relation to microbiological contamination, in the event that equipment
Manual Manual
is to be stored in the same environment that it is to be used, it is not
necessary to perform microbiological clean equipment hold times.
Good
Practice Good
Practice
GCVP GCVP
GCVP 22 GCVP 23
2.2.4 Calculation of Acceptance Criteria Toxicity Approach Limit:
Chemical NOEL = LD50 X Average human body weight (60kg)/2000
In selecting the target species for cleaning validation, the assumed starting = 3389 X 60 / 2000 = 101.67 mg
position is that some product residue is permitted on non-dedicated equipment.
The following approach determines the Maximum Accepted Residue (MAR). In ADI Tox = NOEL X SF = 101.67 X 0.001 = 0.10167 mg
the event that the calculated MAR is below the validated method of analysis,
then cleaning validation is not a valid approach and dedicated equipment and/or MACO Tox = ADI Tox X B
facilities are required. LDDB
Stage 2 Process Qualification: Testing the cleaning process (cleaning validation). Swab limit (MAR)Stage
= 2 Process
MACO Tox X Swab
Qualification: Testing the cleaning processS.A
(cleaning validation).
The amount per swab is defined as the maximum allowed residue (MAR) is
calculated as follows: StageTotal
3 Continued
S.A of Process Verification,
equipment particularly
common for manual cleaning
between Product processes.
A & Product B
good project management and good archiving that capture scientific knowledge =good
(1609.775 x 25 / 30000)
project management and goodxarchiving
1000 =that
1341.48 mcg/swab
capture scientific knowledge
For dose based approach:
an integrated team approach to processADI validation
XBX that includes
S.A. swabexpertise from a variety of an integrated team approach to process validation that includes expertise from a variety of
disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, disciplines
5- PDE Approach Limit:(e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology,
Amount perstatistics,
swab manufacturing,
(MAR) LDDB X S.A. total
and quality assurance). statistics, manufacturing, and quality assurance).

to cleaning solutions etc PDE = NOEL x Weight Adjustment
to cleaning solutions etc (50kg)
- For toxicity
allbased approach:
studies should ADI Tox
be planned and conducted X B X to
according S.A.
sound scientific principles,
swab all studies should be planned and conducted according to sound scientific principles,
F1 x F2 x F3 x F4 x F5
appropriately
Amount per swab (MAR) documented, and approved in accordance with the established procedure appropriately documented, and approved in accordance with the established procedure
appropriate for the stage of the lifecycle. LDDB X S.A. total appropriate for the stage of the lifecycle.
F1 = 12 to account for the extrapolation from mice to humans as NOEL limit based on
calculations of LD50 of mice
- For personal daily intake PDE X B X S.A. swab
(PDE) 1.4
basedCleaning
approach :
methods F2 = 10 to1.4account formethods
Cleaning differences between individual humans
LDDB X S.A. total
Amount per swab (MAR)
Automated F3 = 10 for studies ofAutomated
a short duration.
Automated cleaning methods are the preferred method of cleaning pharmaceutical F4 = 10 for a teratogenic effect
Automated without
cleaning maternal
methods toxicity
are the preferred method of cleaning pharmaceutical
equipment. Automated methods include Clean-in-Place (CIP) methods and Clean- F5 = 1 because the no effect Automated
equipment. level was determined
methods include Clean-in-Place (CIP) methods and Clean-
Total S.A of equipment common between
out-of-Place Product
(COP) methods. A & Product B = 30,000 cm .
2
With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a
Dose Based Limit: cleaning skid or equivalent system which provides cleaning solutions of water and/or
PDE = 101.67 xWith CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a
50 = 0.424 mg/day
other solvent(s) and/or detergents. 12 x 10 x 10other
x 10solvent(s)
x1 and/or detergents.
Swab limit (MAR) = COP MACO X Swab
systems consist of parts washers whereS.A
equipment and components are placed COP systems consist of parts washers where equipment and components are placed
on racks and the racks are placed into the washing machine. MACO PDE = PDE XonB racks and the racks are placed into the washing machine.
Total S.A ofItfixed
is expected that both systems operate on the basis of established and validated
equipment common between Product A & Product B
LDDItfixed
B
is expected that both systems operate on the basis of established and validated
= (158.33 x 25 / 30000)
clean x 1000
approach should=not131.94
be used.mcg/swab clean approach should not be used.
Swab limit (MAR) = MACO PDE X Swab S.A
are those which can monitor and report on the cycle (e.g. by power consumption). In Total S.A of
are those equipment
which common
can monitor and between
report on the cycle (e.g. Product A & Product
by power consumption). In B
= (6713.33 x 25 / 30000) x 1000 = 5594.44 mcg/swab
Manual Manual

As dose based limit approach is the smallest this will be adopted as the acceptance
validation, but it is possible to verify manual cleaning processes. Manual cleaning criteria. validation, but it is possible to verify manual cleaning processes. Manual cleaning
Good
Practice Good
Practice
GCVP GCVP
GCVP 24 GCVP 25
Microbiological Swab Limit 2.2.7 Choice of Equipment Sampling Locations
Microbiological cleanliness is generally not required to be validated in the Sampling sites for each equipment piece are selected on the basis of the product
event that equipment is to be stored in the same environment that it is to be contact surfaces including those that are most difficult to clean. The following
used. Where a company believes that it is necessary, the acceptance criteria criteria will determine the worst-case sampling site:
should be set at the appropriate swab limits equivalent to the contact plates
(diameter 55 mm) cfu/plate for the relevant classification of the area. Direct or indirect product contact location or no product contact
Type of surface material/finish
i.e. Grade A (<1), Grade B (<5), Grade C (<25), Grade D (<50). Accessibility to swab
Surface area available to swab
Where solid dose manufacturing is performed, given the general coinciding Cleanability i.e. if it is difficult to clean e.g. grooves, crevices,
of the areas with Grade D, the limit of <50 cfu would be appropriate. hollows,Stage
gaps,
Stage 2 Process Qualification: Testing the cleaning process (cleaning validation). 2 channels, furrows,
Process Qualification: jagged/serrated
Testing the cleaning processedges,
(cleaning etc.
validation).

Method Stage
of cleaning i.e. CIP, COP or manual
3 Continued Process Verification, particularly for manual cleaning processes.
2.2.5 Recovery Validation
For identical (same dimensions, same configurations) pieces of equipment, a
Recovery studies
are
good performed by spiking
project management and good the target
archiving analyte
that capture on aknowledge
scientific coupon of family approach
good projectis acceptable
management i.e. validation
and good archiving that of onescientific
capture pieceknowledge
of equipment need
an integrated team
each material of construction (MOC)
approach to process validation that includes expertise from a variety of an integrated team approach to process validation that includes expertise from a variety of
disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, only be performed.
The same swabbing/rinsing
consideration oftechnique ascleanability,
plant design for performed onsurfaces,
smooth manufacturing
drainability, materials resistant consideration of plant design for cleanability, smooth surfaces, drainability, materials resistant
to cleaning
equipment is applied to thesolutions
coupon etc and a recovery factor is calculated based on 2.2.8 Revalidation / Ongoing Verification / Periodic Monitoring
the recovered amount of material.
appropriately documented,The andWHO defines
approved the following
in accordance ranges
with the established for the
procedure
recovery factor. appropriate for the stage of the lifecycle. This section describes
appropriate for the the
stagecircumstances
of the lifecycle. under which revalidation
/ ongoing verification / periodic monitoring is performed.
Percent Recovery = Amount detected X 100

1.4
Cleaning
methods Amount spiked 2.2.9 Validation
1.4 Results
Cleaning methods
Recovery result: Automated Automated
Automated cleaning methods are the preferred method of cleaning pharmaceutical This section includes a cleaning
Automated clear report
methodsof
arethe validation
the preferred results.
method of cleaning pharmaceutical
> 80% >50% Automated methods>50%
equipment. include Clean-in-Place (CIP) methods and Clean- equipment. Automated methods include Clean-in-Place (CIP) methods and Clean-
Good Reasonable Questionable
3.0 References With CIP methods the piece of equipment (e.g. a vessel or filling line) is attached to a
Spray Coverage Testing Jennifer Carlson, Cleaning Compliance
Depending on the recovery factor,consist
COP systems a correction factor
of parts washers may
where needand
equipment to be applied
components areto
placed

Forum, Journal on
ofracks
GXPandCompliance, Spring 2011, Volume 15 Number 2
on racks and the racks are placed into the washing machine. the racks are placed into the washing machine.
validation studies.
fixed cycles. Cycles should not operate on the detection of a predetermined 4.0 Acknowledgements
2.2.6 Analytical Method Validation conductivity level of effluent water as this breaches the guidance that a clean-until- conductivity level of effluent water as this breaches the guidance that a clean-until-
Dr. Ramy Mostafa, Validation section head, Al Andalous For Pharmaceutical
Analytical method validation should follow may
conventional ICH theguidelines for equipment Industries, 6/7, 6th Industrial Zone, 6th of October, Giza, Egypt,
In certain cases, sonication be used to facilitate cleaning of small In certain cases, sonication may be used to facilitate the cleaning of small equipment
method validation i.e. parts such as filling needles. In considering the use of sonication, preferred systems parts such as filling needles. In considering the use of sonication, preferred systems
Reproducibility in the event that the sonication system is inoperable. in the event that the sonication system is inoperable.
Test Method Linearity
Range Manual Manual
Accuracy Manual cleaning processes cannot be validated in the conventional meaning of Manual cleaning processes cannot be validated in the conventional meaning of
Limit of quantitation (mg/ml)
Limit of detection (mg/ml)
Stability of swab samples
Specificity (where applicable)
Good
Practice Good
Practice
GCVP GCVP
GCVP 26 GCVP 27
NOTES
1.4 Cleaning methods
Automated
Automated cleaning methods are the preferred method of cleaning pharmaceutical

are those which can monitor and report on the cycle (e.g. by power consumption). In
Manual

validation, but it is possible to verify manual cleaning processes. Manual cleaning
processes inevitably experience person to person variability. Regulatory
Good
Practice
GCVP
GCVP 28

PMTC - Good Cleaning Validation Practice

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Pharmaceutical

Advanced Technology Solutions

d Pharmaceutical Manufacturing Technology Centre

Good Cleaning Validation Practice

1.2 Regulatory Background

1.9 Spray Coverage Testing

Hold Times EnhanceStage

Aspects of the lifecycle approach should include

2.2.6 Basis for Method of Analysis 1.4

The development of cleaning Automated

Visual Rinse samples

Aspects of the lifecycle approach should include

Up to 5000 2 Product Aripiprazol Sparingly 4 1 705 3 12

Chemical NOEL = LD50 X Average human body weight (60kg)/2000

Manual cleaning processes cannot be validated in the conventional meaning of

Stage 3 Continued Process Verification, particularly for manual cleaning processes.

Recovery result: Automated Automated

Stage 2 Process Qualification: Testing the cleaning process (cleaning validation).

Stage 3 Continued Process Verification, particularly for manual cleaning processes.

Aspects of the lifecycle approach should include

1.4 Cleaning methods

Automated cleaning methods are the preferred method of cleaning pharmaceutical

Manual cleaning processes cannot be validated in the conventional meaning of

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