Pmtc good cleaning validation practice

Advanced Technology Solutions
Pharmaceutical
Manufacturing
Technology
Centre
Good Cleaning Validation Practice
(GCVP)

Good Cleaning Validation PracticeGood Cleaning Validation Practice
Section 1 – The Science of Cleaning and Cleaning Validation
1. Introduction
2. Regulatory Background
1.3 A Life Cycle approach for Cleaning Validation
4. Cleaning Methods
•Automated
•M anual
•Development
5. Established Principles
•MACO
•Health based limits
•Single Use, Dedicated and Multi-Product Equipment
6. Choice of Target Molecule
•Worst case molecule
•Reference molecules (placebos)
•Detergents
7. Choice ofAnalytical Techniques
•Visual Inspection
•TOC
•HPLC and UPLC
•UV
•Conductivity
8. Choice of Sampling M ethod
•Visual
•Swabbing
•Rinse samples
•Sample stability
9. Spray Coverage Testing
1.10 Cleaning Validation Failure
1.11 Definitions
1.12 Frequently Asked Questions
Foreword
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Ireland has a long and successful track record of pharmaceutical
and biopharmaceutical manufacturing, with 9 of the world’s top 10
Pharmaceutical companies having a significant presence here.The
sector is hugely impactful to the Irish economy with over 25,000
people directly employed and accounting for almost 50% of Irish
Goods exports.
The Pharmaceutical M anufacturing Technology Centre (PMTC,
www.pmtc.ie)is a leading industry informed research centre focused
on developing advanced solutions for all stages of pharmaceutical
manufacturing. In response to developments in the Regulatory
environment relating to cleaning validation, the PMTC hosted a
workshop where stakeholders identified a number of key areas of
concern and interest relating to cleaning validation.A key output from
this eventwas the collective industry need for an integrated guidance
document.
The PMTC has prepared this guidance document in response to these
concerns to represent the best practice guidance at the current time
of writing. This document has been prepared based on a review of
current guidelines and input from the Health Products Regulatory
Agency and the Pharmaceutical Industry in Ireland and abroad.

Other Regulators (EU,FDA) have not included the limits in their guidelines but have
accepted the application of the limits as the industry norm. Rather than focus on the
basis for the limits, Regulators in general have focused on the correct implementation
of the limits.
In February 2005 a Concept paper was issued by the European M edicines Evaluation
Agency (ref:EMEA/152688/04) which stated the need to updated existing GMP
guidance concerning dedicated facilities. The text in Chapters 3 and 5 relating to the
necessity for dedicated facilities and was unclear in a number of circumstances.
Section 1 – The Science of Cleaning and Cleaning Validation
1.1 Introduction
The Pharmaceutical M anufacturing Technology Centre (PMTC) was established in
December 2013, is led by an industry steering board with an active research program
driven by its industry members.
The vision of the PMTC is to apply research into advanced technology solutions in order
to
•Improve Pharmaceutical M anufacturing Competitiveness
•Enhance the R&D M andate of Irish Pharmaceutical M anufacturing Sites
In response to developments in the Regulatory environment relating to cleaning
validation, the PMTC hosted a workshop in 2014 where a number of stakeholders
identified a number of key areas of concern and interest relating to cleaning validation.
The PMTC has prepared this guidance document in response to these concerns to
represent the best practice guidance at the current time of writing.
The guidance document has been prepared based on a review of current guidelines
and input from the Health Products RegulatoryAgency and the Pharmaceutical
Industry in Ireland and abroad.
This document is designed to take elements from multiple different sources and
present a practical approach to the subject of Cleaning Validation.
1.2 Regulatory Background
In the 1993, an article by Gary Fourman and Dr.Mike Mullen of Eli Lilly proposed the use
of the following combination of limits for cleaning validation.
•No more than 0.001 dose of any product will appear in the maximum daily dose
of another product
•No more than 10 ppm of a product will appear in another product
•No quantity of residue will be visible on the equipment after cleaning
procedures are performed
In recentyears, a number of Regulators (e.g. Health Canada, World Health Organisation)
have adopted this approach and have included the limits in their own guidance
documents.
Section 2 – The Communication of Cleaning Validation
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2.1 The Cleaning Validation Subject M atter Expert
2. The PMTC Cleaning Validation Package.
1. The Cleaning Validation Hierarchy
2. Choice ofTarget Species / Product
2.2.3 Cleaning Validation Protocols
•Hold Times
2.2.4 Calculation of Acceptance Criteria
•Chemical
•Microbiological
2.2.5 Recovery Validation
2.2.6 Basis for Method of Analysis
2.2.7 Analytical Method Validation
2.2.8 Choice of Equipment/Sampling Locations
2.2.9 Revalidation / Ongoing Verification / Periodic M onitoring
2.2.10 Validation Results
3.0 References
4.0 Acknowledgements.

For example, the guidance stated that medicines and non-medicines should not be
produced in the same facility.In some instances, a material may be considered a
medicine in one jurisdiction and a non-medicine in another (e.g. extracts of St.John’s
Wort, Ginko Biloba) which presents difficulty for a facility producing for both jurisdictions.
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In parallel to the European discussions, ISPE prepared and issued A Guide to M anaging
Risks Associated with Cross-Contamination.
In November 2014 the EMA issued the document EMA/CHMP/ CVMP/ SWP/169430/
2012, Guideline on setting health based exposure limits for use in risk identification
in the manufacture of different medicinal products in shared facilities. This guideline
is used for determining if dedicated facilities are necessary for the manufacture
of medicinal products. The guidance has generated much debate in the industry
regarding cleaning validation requirements.
Other recent developments in the Regulatory environment include the concept of the
lifecycle approach and risk management as described in the International Conference
on Harmonisation (ICH) guidance for industry,Q8(R2) Pharmaceutical Development,Q9
Quality Risk M anagement,and Q10 Pharmaceutical Quality System.
1.3 ALife Cycle approach for Cleaning Validation
In recent decades, companies have approached cleaning validation as a discreet
exercise. M ore current thinking on validation exercises views validation in a lifecycle
context such as is described in the FDA guidance on process validation.
It is recommended that a lifecycle approach be taken for cleaning validation.While the
validation effort will inevitably be weighted towards the planning and execution stages,
the ongoing monitoring will ensure that the relevance of the validation will remain
current.
Following the FDA model, the lifecycle for cleaning validation would be as follows;
Stage 1– Process Design: Designing the cleaning validation process
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
•good project management and good archiving that capture scientific knowledge
•an integrated team approach to process validation that includes expertise from a
variety of disciplines (e.g.,process engineering, industrial pharmacy,analytical
chemistry,microbiology,statistics, manufacturing, and quality assurance)
•consideration of plant design for cleanability,smooth surfaces, drainability,materials
resistant to cleaning solutions etc
•all studies should be planned and conducted according to sound scientific principles,
appropriately documented, and approved in accordance with the established
procedure appropriate for the stage of the lifecycle
1.4 Cleaning Methods
•Automated
Automated cleaning methods are the preferred method of cleaning
pharmaceutical equipment.Automated methods include Clean-in-Place (CIP)
methods and Cleanout-of-Place (COP) methods.
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 other solvent(s) and/or detergents.
COP systems consist of parts washers where equipment and components are
placed on racks and the racks are placed into the washing machine.
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 conductivity level of effluentwater as this breaches the guidance
that a clean-until-clean approach should not be used.
In 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 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 in the event that the sonication system is
inoperable.
•Manual
M anual cleaning processes cannot be validated in the conventional meaning of
validation, but it is possible to verify manual cleaning processes. M anual cleaning
processes inevitably experience person to person variability.Regulatory
engagements on manual cleaning validation often fail due to the identification of
residues on equipmentwhich has been manually cleaned, dried, and is in
storage as “Clean”equipment.Where GMP Inspectors identify residues on “Clean”
equipment,the integrity of the manual cleaning process and therefore the
cleaning validation programme are called into question.
Despite the limitations of manual cleaning, this process of cleaning is widespread
within the pharmaceutical industry and is likely to remain as an acceptable
process for the distant future.
In order to “future proof”manual cleaning, adopting concepts from automated
cleaning systems (i.e.pre-configured steps) can help close the gap between
automated and manual systems.

A state of the art manual cleaning systems would consist of
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o Pre-defined steps with detailed descriptions of each cleaning step (e.g.
temperature of cleaning solutions, duration of soakage, duration and
description of manual cleaning steps)
o Detailed step by step cleaning instructions including photographs of
cleaning steps, start and end time of each step,
o Double checks at key steps, and at least at the inspection of dried
equipment prior to storage.
o Ongoing reassessment
In latter sections of this document,reference will be made to validation / verification of
cleaning procedures. With regard to manual cleaning procedures, consistency of
technique is essentialwhere a company wishes to defend verification of “a”manual
cleaning process. In order to instil confidence in the verification of a manual cleaning
process it is necessary to firstly define and secondly follow that process.
Regardless, due the potentialvariability of manual cleaning, independent and periodic
post validation monitoring is used to verify the continued validated status. This may
be achieved by infrequent random unannounced swab sampling by QA/QC
departments or by frequentvisual checks performed by production personnel. In the
even that such monitoring fails the relevant acceptance criteria, appropriate
notification and assessmentwithin the Quality M anagement System should be
performed.
•Development
The development of cleaning methods should be documented within the CVMP.
Documentation of the development of cleaning cycles should include discussion on
the following;
oCleaning technology which is accessible to the facility o
Suitability of cleaning solutions
o Assessment of active ingredients, excipients and formulated products from
the perspectives of solubility,toxicity and “cleanability”
o Design of equipment taking into account narrow diameter pipework, acute
angles and welds
o Hold times
o Experimental results to verify any hypothesis thatwas developed
Choice of the cleaning agent should be documented and approved by Quality
Assurance Department and should be scientifically justified based on:
- Solubility of the materials to be removed
- The design and construction of the equipment and surface materials to be
cleaned
- Safety of the cleaning agent
- Ease of removal
- Detectability of residues
- Product attributes
- Knowledge gained through experience
- The minimum temperature and volume of cleaning agent and rinse solution
- M anufacturer’s recommendations
1.5 Established
Principles
•MACO
It is not possible to completely remove all traces of a product for cleaning. The
M aximum Acceptable Carry Over (MACO)is a means of defining the allowable
amount of “Product A”(the first product) to be left on non-dedicated
manufacturing equipmentwhich will then be incorporated into the next
product (“Product B”) produced using the equipment.
As a model, there are some assumptions made being that the residue of
Product A is evenly spread throughout the equipment,and that all of Product
A will be incorporated into Product B.
•Health based limits
The health based method determines that no more than the acceptable daily
exposure (ADE) of the product (herein referred to as a Product A) being cleaned
appears in the maximum daily dose (MDD)of the next product (herein referred
to as Product B) being manufactured. The ADE is the amount of active
substance / drug product in mg/day that a person can be exposed to as a
contaminant in another product without experiencing any adverse health
effects including, pharmacological effects attributed to the contaminating drug.
This method is useful for biologic products which all have an ADE
value, and thus the health based method can be used to calculate the MAR
(Maximum Acceptable Residue)for these products.
•Single Use, Dedicated and Multi-Product Equipment
Where Single Use (i.e.disposable)equipment is used, it is not necessary to
perform cleaning validation for this equipment.
Where dedicated equipment is used (e.g. filter socks for fluid bed dryers),
visual cleaning is the primary method of cleaning validation / verification
provided that an assessment has been formed to show that product strength
changeover would not have an impact, and that the potential for impurity
generation and carryover is not of concern.
For multi-product equipment,cleaning validation / verification must be
performed.
1.6 Choice of Target Molecule
•Worst case
In a multi-product facility,rather than validate the cleaning of each product,
a worst case molecule (or product) may be selected to represent the worst
case challenge presented to the cleaning process. In selecting a worst case, it
is necessary that a standard cleaning procedure is used. In the event that
different cycles are used, worst case molecules must be selected for each
cycle. In addition, different “worst case”molecules may be identified for
solubility or toxicity,requiring multiple testing.

•Reference products (placebos)
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While not a conventional method of cleaning validation, it would be possible
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
validates the cleaning procedure.
An example of a situation where this approach would be used would be for
an Investigational M edicinal product where supplies of the active ingredient
/ product are very limited.
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
(product containing no actives) through production equipment.The placebo
materialwould then be tested for traces of Product A. This approach has not
gained popularity and is not recommended for cleaning validation.
•Detergents
Validation of the removal of detergents/cleaning agents/solvents should be
incorporated into the cleaning validation / verification programme. Companies
should select detergents/solvents which are as innocuous as possible.
Acceptance criteria must be determined for the detergents based on the
most stringent of the following
- MAC calculation for the indicator species
- no effect on the subsequent product or manufacturing process
- as low as reasonably practical
Limits must be justified by a scientific rationale and approved in the CVP.If the
cleaning agent is a chemical entity or a solvent that is subsequently used in
the production process as a process chemical (e.g. NaOH for pH adjustment)
or solvent,then calculating removal by MACO of such species is not
applicable. These cases must be justified and documented.
Examples where detergents may be more toxic than pharmaceutical
products would be where the medicinal products use substances commonly
used as food items e.g. glucose injections, Glycerine, honey and lemon cough
syrup.
In the event that non-standard detergents are in use,
companies should treat the detergents as active ingredients.
1.7 Choice ofAnalytical Techniques
A number of analytical techniques are available; the following is a description
of the most commonly used methods.
•Visual Inspection
Visual inspection is the examination of the dried equipment under suitable
lighting conditions by personnel with appropriate standard of vision.
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
validated method of cleaning would result in product residues.
•TOC
Total Organic Carbon analysis is a non-specific method, looking merely for
residual carbon molecules. The source of the carbon is not determined
which arguably means the system detects potentialresidue from numerous
sources such as the active ingredients, detergent,and in the biotechnology
industry,cell debris and cell culture media.
TOC analysis is commonly used in the biotechnology industry where the
exact composition of the production process and thus the residue may not
be known. However,TOC is not appropriate where the final rinsing solvent is
organic.
The “cleanest” material available to the pharmaceutical industry is Water for
Injection in bulk (WFI) which has a TOC limit of 500ppb. There are 2 common
approaches used in relation to TOC
• That any rinse samples or swabs would have a TOC result which is
<500ppb. This means that the samples are within the range ofWFI.
• That any rinse samples or swabs would have a TOC result of <100ppb (for
example)above a blank of the WFI in use. This latter limit is used to take
account that the WFI in-use may have an insignificantTOC level (e.g. 50ppb)
and that there would be a potentially higher amount of carry over (e.g.
400ppb)which would still meet the former specification.
•HPLC and UPLC
HPLC / UPLC are specific methods and are the methods of choice for
cleaning validation where the active ingredient is well characterised (e.g. a
small molecule API). There are standard guidelines available for the
validation of HPLC (ICH guideline Q2 (R1)),and particular attention should be
paid to the validation of limits of detection and quantitation.
•UV
Ultraviolet spectroscopy is a method which has been used in the past for the
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.
•Conductivity
Conductivity is a non-specific method that has been applied to the analysis of
inorganic molecules which result in ionic species when dissolved in water.The
method is not generally used for the analysis of samples (swab or rinse)but
conductivity can be found in parts washers where the cycle is terminated
when a certain conductivity is reached.A criticism of such a design is that the
system essentially “cleans untilclean”,resulting in variable and non-standard
cycles.

1.8
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Choice of Sampling Method
A number of sampling methods are available and commonly used. The
validation protocol should clearly define sampling locations and methods,
ensuring that the most difficult to clean areas are sampled and the number
and location of swabs/rinse volumes is adequate to represent the
equipment and contents.
•Visual
Visual inspection is an intuitive method in circumstances where other
methods result in a maximum acceptable residue which would be visibly
detectable. It also has advantages in that it is a quick detection method and
it is a direct method for process contacting surfaces to verify that no visible
residues, foreign objects or extraneous matter are present.Hand held UV
lights sources may be used to enhance visibility where applicable.
The technique is also appropriate for inter batch/campaign cleaning for the
same product or intermediate families where justified (e.g. a “Level 1”clean of
a compression machine.)
When visual inspection is the direct method, the visual limit of detection
must be established through visual detection studies.
•Swabbing
Swabbing is generally the preferred method for sampling for cleaning
validation. Subject to operator training, the method is relatively consistent
and recovery can be validated. The most difficult to clean areas must be
sampled and the number and location of swabs taken should be adequate
to represent the equipment.Justification for the solvent used to saturate the
swab (adequate stability,and solubility for the residues of interest i.e.process
residue, cleaning agent)according to the swab recovery study.
The procedure for sampling surfaces involves wiping the surfaces (e.g. areas
of 5 cm x 5 cm and 10cm x 10cm are commonly used))with a swab, to remove
residues from a surface.A SOP should be in place to ensure the consistency
of swabbing which is a manual process. For example, companies may use a
stainless steel template placed against the surface to be swabbed, the
number and direction of strokes to be used may be specified, the turning over
of the swab may be specified.
Personnel performing swabbing must be qualified and re-qualified on a
periodic basis.
Justification for not performing swab sampling must be documented and
must include a reference to studies that demonstrate comparable sensitivity
for visual, rinsing, and swabbing techniques.
Typical guidelines within the swabbing SOP may include
o the type of swab used
o the swab surface area
o the number and location of swabs to be taken
o Justification for the solvent used to saturate the swab
o How the swab is desorbed
•Rinse samples
Rinse samples are used to sample difficult to reach areas. It should be ensured
that the rinse volume is sufficient to cover all equipment surfaces and that the
rinse samples adequately represent the contents.The rinse solution is then
analysed for the target residue.
In order to justify the use of rinse samples, the same level of validation (e.g.
recovery from spiked equipment / coupons) applies rather than just accepting
the absence the target molecule.
•Sample stability
In the event that samples are to be stored for a period of >24 hours, stability of
the samples should be considered and validated. The stability of the samples
should account for the potential degradation of actives and excipients that could
occur as a result of the cleaning process operating conditions and detergent
used. Otherwise, sample degradation may contribute to erroneously compliant
results.
1.9 Spray Coverage Testing
The use of spray balls for cleaning is more efficient than soaking as a cleaning
method but can be challenged with regard to full coverage. Where spray balls
are the primary method of cleaning used, a spray coverage test should be
performed which can be summarised as follows;
•Apply a solution of riboflavin to the surfaces to be cleaned by using a fine mist
•Verify complete coverage using a UV light source
•Perform a water rinse using a cycle equivalent to the shortest phase of the
cleaning cycle and record the cycle parameters
• Inspect all surfaces using the UV light,paying particular attention to difficult to
reach areas and for pooling. The inspection should be performed before the
surfaces dry out as riboflavin does not fluoresce when dry
1.10 Cleaning Validation Failure
Cleaning Validation generally consists of the following sequence
•Identification of the worst case product
•Calculating the MACO
•Cleaning equipment after a production of a batch
•Sampling the equipment to see if any remaining residue is below the MACO

In the event that remaining residue is above the MACO,then the cleaning
method is not considered to be validated and the following options should
be taken;
•The cleaning method should be amended to be more effective, and this
effectiveness verified or
•Dedicated equipment should be used for at least the part of the process
which cannot be successfully cleaned.
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1.11 Definitions
Acceptance Criteria The criteria assigned before undertaking testing that an
item, method, process or system must satisfy in order for
test results to be deemed acceptable.
Acceptable Daily
Exposure (ADE)
A dose that is unlikely to cause an adverse health event or
undesirable physiological effects if an individual is exposed at
or below this dose for the maximum expected duration of use
of the drug carrying the contaminant. If this duration cannot
be estimated reliably, lifetime use is assumed
Acceptable Daily
Intake for actives (ADI)
Daily therapeutic dose of the first product X Safety Factor
(=1/1000) in case of oral dosage forms (tablet, capsules or
caplets)
Acceptable Daily Intake
(for toxicity based
limit, cleaning agents
and other items with no
therapeutic dose) (ADI
Tox)
NOEL X SF (=1/1000).
Analytical Methods
Validation
The process by which it is established by laboratory studies
under a pre-approved protocol, that the performance
characteristics of the method meet the requirements for the
intended analytical applications.
Clean Equipment Hold
Time
This is the maximum period of time allowed for processing
equipment between the end of a cleaning procedure to its next
use in production or its sterilization or sanitization, as
specified in the associated cleaning and/or sterilization SOP.
Clean-In-Place (CIP) A cleaning process that the tank, piping, and in-line devices
of processing equipment are cleaned in their original position,
involving minimum connection/disconnection of some piping
after the processing.
Clean Out of Place
(COP)
COP systems are used for cleaning equipment that require
disassembly and/or transfer to another location for cleaning. In
xx, small parts will be disassembled and washed in the parts
washer.
Cleaning Validation The process of establishing documented evidence that a
particular cleaning procedure will consistently reduce
equipment surface residues (i.e. product and cleaning
agents) to a predetermined acceptable level.
Cleaning Verification The process of establishing documented evidence that an
individual cleaning event will consistently reduce equipment
surface residuals (i.e. product and cleaning agents) to a pre-
determined acceptable level.
Deviation Any unplanned / planned change to the established
parameters, protocol instructions, or approved procedures,
performed during the validation activities. Any test failure is
considered a deviation. Deviations must be documented in
the associated validation report.
Dirty Equipment Hold
Time
This is the period of time between the end of manufacturing to
the start of the cleaning procedure for processing equipment,
as specified in the associated cleaning process SOP.
Maximum Allowed
Carry over (MACO)
ADI X B / LDD
B
Where:
LDD = Largest daily dose of the next product
B
(number of units taken per day).
B = Smallest Batch Size of the next product
(Number of dosage units per batch
of final mixture of next product).
Maximum Allowed
Residue (MAR)
MACO X surface area (S.A.) of swab in cm2/ total S.A. in cm2.
No Observed Effective
Limit
LD50 X Average human body weight (60kg)/2000
Where 2000 is empirical constant and 60kg is used as a
conservative estimate.

Personal Daily Intake
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(Represents a
substance-specific
dose that is
unlikely to cause an
adverseeffect if an individual
is exposed at
or below this
dose every day
for
a lifetime) (PDE)
NOEL x WeightAdjustment (50 kg)
F1 x F2 X F3 X F4 X F5
The modifying factors are as follows:
F1 =A factor to account for extrapolation between species
F1 = 5 for extrapolation from rats to humans
F1 = 12 for extrapolation from mice to humans
F1 = 2 for extrapolation from dogs to humans
F1 = 2.5 for extrapolation from rabbits to humans
F1 = 3 for extrapolation from monkeys to humans
F1 = 10 for extrapolation from other animals to humans
F2 =A factor of10 to accountfor variabilitybetween individuals
A factor of 10 is generally given for all organic solvents, and
10 is used consistently in this guideline.
F3 =A variable factor to account for toxicity studies of short-
term exposure
F3 =1for studies that last at least one half lifetime (1year for
rodents or rabbits; 7 years for cats, dogs and monkeys).
F3 = 1for reproductive studies in which the whole period of
organogenesis is covered.
F3 = 2 for a 6-month study in rodents, or a 3.5-year study in
non-rodents.
F3 = 5 for a 3-month study in rodents, or a 2-year study in
non-rodents.
F3 = 10 for studies of a shorter duration.
In all cases, the higher factor has been used for study
durations between the time points, e.g. a factor of 2 for a
9-month rodent study
F4 =A factor that may be applied in cases of severe
toxicity,e.g. non-genotoxic carcinogenicity,neurotoxicity
or teratogenicity.In studies of reproductive toxicity,the
following factors are used:
F4 =1for fetal toxicity associated with maternal toxicity
F4 =5 for fetal toxicitywithout maternal toxicity
F4 =5 for a teratogenic effect with maternal toxicity
F4 =10 for a teratogenic effect without maternal toxicity
F5 =A variable factor that may be applied if the no-effect
level was not established
When only an LOEL is available, a factor of up to 10 could
be used depending on the severity of the toxicity.
1.12 FrequentlyAsked Questions
1.12.1 How should microbiological cleanliness be assessed?
Microbial evaluation studies can be performed to determine:
• Time limit for unclean equipment (between end of use and start of cleaning);
depending on:
o Microbial contamination which is measured by swabbing.
o The nature of the soil which may make the cleaning more difficult.
• Time limit for cleaned equipment (between end of cleaning and start of next
o Microbial contamination which is measured by swabbing.
o Dust which can be measured by visual examination before and after
cleaning.
Of more importance however are preventive measures:
• Equipment should be dried before storage.
• Stagnantwater should not be allowed to remain in the equipment.
• Conditions of storage should be monitored.
• The control of the bio-burden through environmental monitoring program.

Section 2 – The Communication of Cleaning Validation
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2.1 The Cleaning Validation Subject Matter Expert
Good M anufacturing Practice (GMP) is normally communicated through direct
exchanges between personnel who represent RegulatoryAuthorities and
representatives of companies/organisations (Inspected Parties). Unlike the
communication of marketing authorisation information, GMP information is
generally communicated via face to face exchanges.
Competent,capable and credible Subject M atter Experts (SMEs) who represent
the Inspected Party can substantially improve the confidence of a Regulatory
Agency in a particular subject. The particular field of cleaning validation has been
identified by RegulatoryAgencies in the past for the piecemeal approach of
communication of the subject.
It is highly recommended that each Inspected Party identify a Cleaning Validation
Subject matter Expert who can provide a high level overview of all aspects of the
subject and who can competently speak to all aspects of the Cleaning Validation
Package (see below).
2.2 The Cleaning Validation Package
In order to communicate cleaning validation effectively and consistently to
regulatory agencies, it is recommended that companies assemble all cleaning
validation information into a standard PMTC Cleaning Validation Package format
(PMTC CVP). The purpose of the PMTC CVP is to provide a template which
provides a consistent rationale for the choice of target molecules, the calculation
of limits and to enable the CVSME to communicate a company’s approach to
cleaning validation.
2.2.1The Cleaning Validation Hierarchy
The order for the PMTC CVP is as follows
2.2.2 Choice of Target Species/Product
In the past, the choice of target species was typically chosen from the
worst case(s) of active molecules from the categories of solubility,
potency,and “cleanabilty” (based on experience).
The EU GMPs (paragraph 3.6, 5,20, 5,21) refers to a toxicological
evaluation of products in the decision making process for the necessity
of dedicated facilities or equipment.
The following is a proposed method for the combination of traditional
assessments and the toxicological approach as described in the EMA
Guideline on setting health based exposure limits for use in risk
identification in the manufacture of different medicinal products in
shared facilities.
Step 1– Determine the Worst Case Molecule / “Product A”
In selecting the worst case molecule, the following worked example
demonstrates a means of selection by ranking of products using the
following criteria for each product:
- Solubility
- Toxicity
- Cleanliness
Definitions in the risk ranking are as follows;
Section Title
1 Introduction
2 Development of cleaning procedure(s)
3 Choice of target species / product
4 Overview of cleaning validation protocols
5 Calculation of acceptance criteria
6 Method validation including recovery studies
7 Results for each piece of equipment for each cleaning method for
each product tested
Solubility
Term Approximate volume of
solvent in milliliters
per gram of solute
Category
very soluble
freely soluble
Soluble
sparingly soluble
slightly soluble very
slightly soluble
practically insoluble,
Insoluble
less than 1
from 1 to 10
from 10 to 30
from 30 to 100
from 100 to 1000
from 1000 to 10,000
more than 10,000
1
2
3
4
5
6
7

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In the above example, Product 12 would be considered to be the worst case product.
Rank Identification:
o Multiply contents of each row to obtain the total rank.
o The higher the rank number,the more critical the cleaning process.
Cleanliness
(based on experience with the finished product)
Term Category
Easy to clean
Moderate to clean
Hard to clean
Very hard to clean
1
2
3
4
Toxicity (Based on LD50 of the active ingredient)
Oral (mg/Kg) Category
>5000
Up to 5000
Up to 2000
Up to 300
Up to 50
<5
1
2
3
4
5
6
Product
Name
API Solubility Sol.
Rank
Cleanli
ness
LD50
mg/kg
Toxicit
y Rank
Total
Rank
Product
01
Amisulpride Practically
insoluble
7 1 1024 3 21
Product
02
Pregablin Freely
soluble
2 1 5000 2 4
Product
03
Pregablin Freely
soluble
2 1 5000 2 4
Product
04
Rivaroxaban Practically
insoluble
7 3 500 3 63
Product
05
Febuxostat Insoluble 7 3 590 3 63
Product
06
Lacosamide Sparingly
soluble
4 1 253 4 16
Product
07
Aripiprazol Sparingly
soluble
4 1 705 3 12
Product
08
soluble
4 1 705 3 12
Product
09
soluble
4 1 705 3 12
Product
10
soluble
4 1 705 3 12
Product
11
Meformin Freely
soluble
2 1 1450 3 6
Product
12
Pioglitazone Practically
insoluble
7 3 181 4 84
Product
13
Meformin Freely
soluble
2 1 1450 3 6

Step 2 – Identify the lowest acceptable MACO for Product A in Product B
The table is used to select target active ingredient(s) for cleaning validation
purposes. In the table below,the traditional approaches of calculating the MACO
(0.1%) and 10ppm carry over have been supplemented by the Acceptable Daily
intake (Toxicity approach) and the Permitted Daily Exposure to determine the
worst case scenario.
Note 1– 0.1% of minimum dose of Product A in largest daily dose Product B =
10mg x (0.1/100)x (B / LDD )B
Note 2 - 10ppm of Product A remaining in the batch of Product B
Note 3 - Calculation of the MACO by toxicity
NOEL = LD50 X Average human body weight (60kg)/ empirical constant (2000)
= 3389 X 60 / 2000 = 101.67 mg
ADI Tox = NOEL X Safety Factor = 101.67 X 0.001 = 0.10167 mg
MACO Tox = ADI Tox X B
LDDB
Note 4 – Calculation of the MACO by PDE
PDE - NOEL x WeightAdjustment (50 kg)
F1x F2 X F3 X F4 X F5
F1 = 12 to account for the extrapolation from mice to humans as NOEL limit based on
calculations of LD50 of mice
F2 = 10 to account for differences between individual humans
F3 = 10 for studies of a short duration
F4 = 10 for a teratogenic effect without maternal toxicity
F5 = 1because the no effect level was determined
PDE = 101.67 x 50 = 0.424 mg/day
12 x 10 x 10 x 10 x 1
MACO PDE = PDE X B
LDDB
2.2.3 Cleaning Validation Protocols
Cleaning validation protocols should be in place. These protocols define
the activities to be performed in order to validate cleaning procedures /
processes.
•Hold Times
Dirty Equipment Hold Times (DEHT) - The maximum dirty equipment
hold time should be defined within the cleaning validation protocol. In
order to maximise the benefitfrom cleaning validation, the maximum
hold time should be calculated and then exceeded for the cleaning
validation study.
Clean Equipment Hold Times (CEHT) – Cleaned equipment should not
be stored in an areas where it would be susceptible to chemical
recontamination (eg. in a processing area or close to the washing of dirty
equipment.If this requirement is met,there is no requirement to validate
CEHTs.
If clean equipment is stored in a bacteriostatic solution, a study must
demonstrate removal of the bacteriostatic solution before equipment use.
In relation to microbiological contamination, in the event that equipment
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.
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Product Batch
size (Kg)
Batch
size
(Units)
(B)
#
units/
day
(LDD )B
MACO
0.1%
Approach
(mg)
10ppm
Approach
(mg)
Tox
Approach
(mg)
PDE
Approach
(mg)
(Note 1) (Note 2) (Note 3) (Note 4)
Product 1 150.000 1,000,000 6 1666.667 1500 16945 70666.67
Product 2 99.750 95,000 6 158.33 997.5 1609.775 6713.333
Product 3 120.900 600,000 8 750 1209 7625.25 31800
Product 4 115.000 700,000 2 3500 1 150 35584.5 148400
Product 5 175.000 500,000 1 5000 1750 50835 212000
Product 6 195.000 300,000 3 1000 1950 10167 42400
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
Product 9 189.000 180,000 2 900 1890 9150.3 38160
Product 10 120.000 300,000 2 1500 1200 15250.5 63600

2.2.4 Calculation of Acceptance Criteria
•Chemical
In selecting the target species for cleaning validation, the assumed starting
position is that some product residue is permitted on non-dedicated equipment.
The following approach determines the M aximum Accepted Residue (MAR). In
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
facilities are required.
The amount per swab is defined as the maximum allowed residue (MAR) is
calculated as follows:
Total S.A of equipment common between Product “A”& Product “B”= 30,000 cm2.
Dose Based Limit:
Swab limit (MAR) = MACO X Swab S.A
Total S.A of equipment common between Product “A”& Product “B”
= (158.33 x 25 / 30000)x 1000 = 131.94 mcg /swab
Toxicity Approach Limit:
NOEL = LD50 X Average human body weight (60kg)/2000
= 3389 X 60 / 2000 = 101.67 mg
ADI Tox = NOEL X SF = 101.67 X 0.001 = 0.10167 mg
MACO Tox = ADI Tox X B
LDDB
Swab limit (MAR) = MACO Tox X Swab S.A
= (1609.775 x 25 / 30000)x 1000 = 1341.48 mcg / swab
5- PDE Approach Limit:
PDE = NOEL x WeightAdjustment (50kg)
F1x F2 x F3 x F4 x F5
F1 = 12 to account for the extrapolation from mice to humans as NOEL limit based on
calculations of LD50 of mice
F2 = 10 to account for differences between individual humans
F3 = 10 for studies of a short duration.
F4 = 10 for a teratogenic effect without maternal toxicity
F5 = 1because the no effect level was determined
PDE = 101.67 x 50 = 0.424 m g /day
12 x 10 x 10 x 10 x 1
MACO PDE = PDE X B
LDD
B
Swab limit (MAR) = MACO PDE X Swab S.A
= (6713.33 x 25 / 30000)x 1000 =5594.44 mcg / swab
As dose based limit approach is the smallest this will be adopted as the acceptance
criteria.
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For dose based approach:
Amount per swab (MAR)
ADI X B X S.A. swab
LDDB X S.A. total
- For toxicity based approach:
ADI Tox X B X S.A. swab
LDDB X S.A. total
- For personal daily intake
(PDE) based approach :
PDE X B X S.A. swab
LDDB X S.A. total

•Microbiological Swab Limit
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Microbiological cleanliness is generally not required to be validated in the
event that equipment is to be stored in the same environment that it is to be
used. Where a company believes that it is necessary,the acceptance criteria
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.
i.e.Grade A (<1),Grade B (<5), Grade C (<25), Grade D (<50).
Where solid dose manufacturing is performed, given the general coinciding
of the areas with Grade D,the limit of <50 cfu would be appropriate.
2.2.5 RecoveryValidation
Recovery studies are performed by spiking the target analyte on a coupon of
each material of construction (MOC)
The same swabbing/rinsing technique as performed on manufacturing
equipment is applied to the coupon and a recovery factor is calculated based on
the recovered amount of material.The WHO defines the following ranges for the
recovery factor.
Percent Recovery = Amount detected X 100
Amount spiked
Recovery result:
This section includes a clear report of the validation results.
3.0 References
Depending on the recovery factor,a correction factor may need to be applied to
validation studies.
2.2.6 Analytical Method Validation
Analytical method validation should follow conventional ICH guidelines for
method validation i.e.
•Reproducibility
•Test Method Linearity
•Range
•Accuracy
•Limit of quantitation (mg/ml)
•Limit of detection (mg/ml)
•Stability of swab samples
•Specificity (where applicable)
2.2.7 Choice of Equipment Sampling Locations
Sampling sites for each equipment piece are selected on the basis of the product
contact surfaces including those that are most difficult to clean. The following
criteria will determine the worst-case sampling site:
• Direct or indirect product contact location or no product contact
•Type of surface material/finish
•Accessibility to swab
•Surface area available to swab
• Cleanability i.e.if it is difficult to clean e.g. grooves, crevices,
hollows, gaps, channels, furrows, jagged/serrated edges, etc.
•M ethod of cleaning i.e.CIP,COP or manual
For identical (same dimensions, same configurations) pieces of equipment,a
“family”approach is acceptable i.e.validation of one piece of equipment need
only be performed.
2.2.8 Revalidation / Ongoing Verification / Periodic Monitoring
This section describes the circumstances under which revalidation
/ ongoing verification / periodic monitoring is performed.
2.2.9 Validation
Results
Spray Coverage Testing Jennifer Carlson, Cleaning Compliance
Forum, Journal of GXP Compliance, Spring 2011, Volume 15 Number 2
4.0 Acknowledgements
Dr.Ramy M ostafa,Validation section head,Al Andalous For Pharmaceutical
Industries, 6/7,6th Industrial Zone, 6th of October,Giza, Egypt,
> 80% >50% >50%
Good Reasonable Questionable

NOTES
GCVP 28

Pmtc good cleaning validation practice

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