Virtual cGMP Training Marathon

Local Production & Assistance Unit (LPA)

Regulation and Prequalification Department (RPQ)
Access to Medicines and Health Products Division (MHP)
September 7 to November 30, 2020 World Health Organization
Geneva, Switzerland

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 Cleaning Validation

September 7 to November 30, 2020

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 Disclaimer

This document, in part or in whole, may not be reviewed,

abstracted, quoted, copied, transmitted, distributed,
translated or adapted in any form or by any means
without the permission from the WHO Local production
and Assistance unit. This is for your personal use only
and reliance of any information contained on this
document is solely at your own risk.

© LPA
17/12/2020
Topic
• General Principle
• Cleaning Validation Execution
• Process development
• Process validation
• Continued process verification
• Revalidation
• When cleaning validation fails….

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General Principle

© LPA
 WHO TRS 1019, Annex 3, 2019
Good manufacturing practices: guidelines on validation
Other
Technical guides

Key GMP PIC/S GMP PE 009-14 (Annexes), 1 July 2018

Annex 15: Qualification and Validation CLEANING VALIDATION
FOR THE 21ST CENTURY
References
WHO TRS 999, Annex 2, 2016: WHO GMP for
Biological Products Points to consider for
cleaning validation, PDA
TR 29, 2012
EMA Guideline on setting health based exposure limits for
use in risk identification in the manufacture of different
medicinal products in shared facilities 01 June 2015 Points to Consider for
Biotechnology Cleaning
Validation, PDA TR 49,
US FDA Validation of Cleaning Processes (7/93) 2010

ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC):

GUIDANCE ON ASPECTS OF CLEANING VALIDATION IN ACTIVE
PHARMACEUTICAL INGREDIENT PLANTS –May 2014

© LPA
 WHO TRS 1019, 2019 Annex 3, Appendix 3: Cleaning validation

• Cleaning validation : Documented evidence to establish that cleaning

procedures are removing residues to predetermined levels of acceptability,
taking into consideration factors such as batch size, dosing, toxicology and
equipment size.
• One of objectives of GMP is “Prevention of possible contamination and cross-
contamination of pharmaceutical starting materials and products”.
• Contamination: Undesired introduction of impurities of chemical , microbiological, or
foreign matter, into or onto a starting material, intermediate or pharmaceutical product
during handling, production, sampling, packaging, repackaging, storage or transport.
• Cross-contamination: Contamination of a starting material, intermediate product or
finished product with another starting material or product during production.

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PIC/S GMP PE009-14, Annex 15- 01 July 2018:
Qualification and Validation

• Cleaning validation should be performed in order to confirm the

effectiveness of any cleaning procedure for all product contact
equipment.

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• WHO TRS 999, Annex 2, 2016: WHO GMP for Biological Products

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 21 CFR211.67(a)

US-FDA • Equipment and utensils shall be cleaned, maintained, and, as appropriate for the
nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent
malfunctions or contamination that would alter the safety, identity, strength,
quality, or purity of the drug product beyond the official or other established
requirements.

21 CFR111.27(d)

• You must maintain, clean, and sanitize, as necessary, all equipment, utensils, and
any other contact surfaces used to manufacture, package, label, or hold
components or dietary supplements.

21 CFR 810.70(e)

• Contamination control. Each manufacturer shall establish and maintain

procedures to prevent contamination of equipment or product by substances that
could reasonably be expected to have an adverse effect on product quality.

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Possible Contaminants in Pharmaceutical
Products to be removed by cleaning
• Contaminants associated with microbes (Bioburden and endotoxins)
• Previous products
• active pharmaceutical ingredients [APIs]
• excipient residues
• Residues of cleaning agents
• Airborne materials,
• Dust and particulate matters
• Lubricants
• Ancillary material, such as disinfectants, and decomposition residues from:
• product residue breakdown caused by using strong acids and alkalis during the cleaning
process;
• breakdown products of the detergents, acids and alkalis that may be used as part of the
cleaning process.

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Objective of cleaning validation
• To prove that the equipment is consistently cleaned of
• product,
• detergent and
• microbial residues
to an acceptable level
• To prevent possible
• contamination and cross-contamination

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Scope of cleaning validation
• Cleaning validation considered as important in multiproduct
facilities
• …..(Cleaning validation) SHOULD be performed, among others, for
• Equipment
• Sanitization procedures  disinfection process validation
• Garment laundering
• Normally, cleaning validation would be applicable for critical cleaning
such as
• Cleaning between manufacturing of one product and another
• Cleaning of surfaces that come into contact with products, drug products and
APIs

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 Scope of cleaning validation
• Cleaning validation NOT necessarily
required for NON-CRITICAL cleaning such
as
• cleaning takes place between batches of the
same product
• cleaning takes place on different lots of the
same intermediate in a bulk process
• cleaning of floors, walls
• cleaning outside of vessels,
• cleaning following some intermediate steps
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“In general, cleaning validation
should be directed to situations or
process steps where contamination
or carryover of materials poses the
greatest risk to API quality.
For example, in early production it
may be unnecessary to validate
equipment cleaning procedures
where residues are removed by
subsequent purification steps.”
ICH Q7
 General
Validation

Documents required policy/

procedure

• Cleaning validation policy Cleaning validation

policy

• Cleaning validation procedures

Cleaning validation
• Cleaning procedure SOPs procedures

Cleaning SOPs
• Cleaning validation plan (master plan)
• Cleaning validation protocols Cleaning
validation
• Cleaning validation reports (master) plan

Protocol
Data integrity - important

Report
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Manufacturer’s Cleaning policy and/or
cleaning procedure
• To cover these followings:
• Cleaning of Product contacted surfaces
• Cleaning after product changeover e.g. when changing one pharmaceutical
formulation to another
• Between batches in campaigns (when the same formula is being
manufactured over a period of time, and on different days);

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Cleaning policy and/or cleaning procedure
(continued)
• Bracketing products for cleaning validation.
• where products contain substances with similar properties [such as
solubility]
• where products contain the same substance in different strengths. An
acceptable strategy is to first manufacture the more dilute form [not
necessarily the lowest dose] and then the most concentrated form.
• There are sometimes “families” of products which differ slightly as to actives
or excipients.)
• Periodic evaluation
• Revalidation

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Bracketing
• Cleaning procedures for products and processes that are very similar
do not need to be individually validated.
• A validation study of the “worst case” may be considered acceptable.
There should be a justified validation programme for this approach,
referred to as “bracketing”, addressing critical issues relating to the
selected product, equipment or process.
• Where “bracketing” of products is done, consideration should be
given to the type of products and equipment.

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 Bracketing strategies
By Product
• Similar products by nature, risk,
therapeutic or other properties and
• Processed by the same equipment
and
• Identical cleaning procedure
• Worst case – Product most difficult
to clean
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By Equipment
•Similar type of equipment
•Similar MOC
•Same type of equipment but
different size e.g. 300 L, 500 L and
1000 L tanks
•Alternative approach -Smallest and
largest batch size of the products to
be validated separately
Grouping of products by Therapeutic Use
• The risk associated with contamination and cross-contamination from one
product to another product in one therapeutic group, and between products in
different therapeutic groups in shared facilities, should be considered.
• For example, due to the risk, certain products should be manufactured in
dedicated or segregated self-contained facilities, including
• Certain antibiotics,
• certain hormones,
• certain cytotoxics and
• certain highly-active drugs
even though these are in the same therapeutic class.
• The risk assessment should include, for example, PDE values, batch size,
maximum daily dose of the next product, as well as other criteria associated with
cleaning.

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Cleaning Validation Execution

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Process Validation Principle
Principle of Process Validation to be applied:

• 3 stages of validation –
• Stage 1 - Process design (Process development)
• Stage 2- Process validation (Process performance
qualification)
• Stage 3 –Continued process verification
• Revalidation

Quality risk management applied

Scientific knowledge management

© LPA
Terms related to new approach for cleaning
validation
• margin of safety. The margin of safety is the distance between a calculated acceptance
limit and the actual residues after cleaning. It indicates the probability that a patient has
to be exposed to the API residues resulting from cleaning.

• maximum safe Carryover (MSC). Mathematically calculated quantity of residue from a

previous product when carried over into a different product that can represent potential
harm to the patients.
• It is calculated from ADE (FDA) or PDE (EMEA)
• ADE/PDE : substance-specific dose unlikely to cause an adverse health event or
undesirable physiological effects, if an individual is exposed to this dose or to a lower
dose everyday for a lifetime
• It is based on scientific evaluation of all pharmacol. And toxicol. Data…
• maximum safe surface residue (MSSR). The maximum safe surface residue is
mathematically calculated dividing the quantity of residue on a contact surface by the
total area of contact (Maximum Safe Carryover/Total Equipment Surface Area)

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Maximum Safe Carryover (MSC)
• MSC calculation = ADE*(N/D)*(SWA/SSA)*Rs

Abbreviation Description
ADE Acceptable daily exposure (mg/day)
N Number of doses in the batch
D Maximum number of daily doses
SWA Surface area of the sample point
SSA Shared surface area between product A and B
R Recovery factor for a surface type

The equation is executed for all combinations of Product A to B within a product matrix, not just worst case.
Reference : PDA TR29

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Process validation element mapping

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Designing cleaning process -knowing historical
and scientific data
Factors to be considered:

• Chemistry/biochemistry of the residue,

• Manufacturing process,
• Equipment design
• Testing methods for the target analyte.

Cleaning process Parameters:

• i. Time
• ii. Temperature
• iii. Cleaning agent & concentration
• iv. Flow rate

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Cleaning process development: Laboratory-
scale first!
• Laboratory-scale studies can answer typical cleaning validation
questions such as:
• Which product is the hardest to clean?
• Which cleaning agent provides the best cleaning?
• Can we demonstrate that two cleaning agents are equivalent?
• Which cleaning input parameters are critical?
• What are the optimal cleaning parameter settings?
• How long does it take to clean the equipment?
• Are dirty-hold-time studies necessary at commercial scale?
• Are clean-hold-time studies necessary at commercial scale?

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UNDERSTANDING CLEANING MECHANISM
to remove residues from equipment
• Mechanical / Physical action e.g.
• brushing
• scrubbing
• pressurized water to remove particulates
• Dissolution
• Water -most common and practical solvent
• non-toxic, cheap, does not leave residues, environment friendly
• Non-aqueous solvent or Aqueous + Non-aqueous solvents due to the
solubility characteristics of the materials.
• Alkaline or acidic solvents may enhance dissolution of the materials and could
be advantageous.
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UNDERSTANDING CLEANING MECHANISM
to remove residues from equipment (continued)
• Detergent requires the use of surfactant, usually in an aqueous
system. Detergents act in four different ways:
• wetting agent
• solubilizers
• emulsifiers
• dispersants.
• Chemical reactions e.g.
• Oxidation and hydrolysis in which the residues are chemically changed.
Example: Sodium Hypochlorite

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CLEANING AGENT/DETERGENT/SOLVENT :
Cleaning agents or detergents should be selected carefully.

• Acceptable to the process and for use with pharmaceutical products

• Detergents should facilitate the cleaning process and be easily removable.
• Detergents that have persistent residues such as cationic detergents which adhere very
strongly to glass and are difficult to remove, should be avoided where possible.
• The composition of the detergent should be known to the manufacturer and its removal
during rinsing, demonstrated.
• Acceptable limits for detergent residues after cleaning should be defined - using scientific
rationale similar to limits for product residues ( obtained during cleanability studies).
• The possibility of detergent breakdown should also be considered when validating
cleaning procedures.
• Detergents should be released by quality control and, where possible, should at least
meet local food standards or regulations.
• Have proof of effectiveness and appropriateness studies - to be included in the
cleanability

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Cleaning method:
Manual Cleaning Method
• Difficult to validate
• Most extensive and elaborate cleaning procedures required
• High quality and extensive training program required.
• Risk involved in manual cleaning processes is taken care of with
following technical and organizational control:
• Proper washing room design with drying, protection and storage
requirement.
• Detailed cleaning SOP
• Training / Qualification of cleaning operators
• Quality of water use
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Cleaning method:
Clean-In-Place(CIP)Method
• Cleaning of the equipment is performed in place without
disassembling
• Cleaning process may be controlled manually or by an automated
program
• Very consistent and reproducible cleaning method
• Can be validated readily
• Being a closed system visual inspection of all components is difficult.

© LPA
Cleaning method:
Clean-Out-Of-Place (COP) Method
• Cleaning of disassembled equipment is performed in a central
washing machine.
• The washing machine also requires validation such as :
• Temperature
• Ultrasonic activity
• Cycle time
• Cleaning operation sequence
• Detergent quantity dispensed
• etc.

© LPA
Choosing the Cleaning Method
CIP : Clean in Place

• Cleaning of permanently stationed items

• Performed by circulating cleaning solutions
through the equipment.
• Automated, semi automated

COP: Clean out of place

• Equipment is removed and cleaned remotely

• Semi automated, manual

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Developing Cycle Times for Cleaning Procedure
CIP- Cycle times
determined by
controlling the • detergency,
primary factors contact time.
of cleaning
efficacy

• temperature
conductivity
Online monitors pH
and sensors for detergent supply flow rate,
pressure sensors
etc.

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Automatic process
• Validation should consider the level of automation in the cleaning
process.
• Where an automatic process is used, the specified normal operating
range of the utilities and equipment should be validated.

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Microbiological Risk
• Risk presented by microbial and endotoxin contamination should be considered
during the development of cleaning validation protocols.
• Influence of the time between manufacture and cleaning and the time between
cleaning and use should be taken into account to define dirty and clean hold
times for the cleaning process.
• Impact on the ease of cleaning at the end of the campaign should be considered
and the maximum length of a campaign (in time and/or number of batches)
should be the basis for cleaning validation exercises.

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Microbiological risk
• Equipment should be stored in a dry condition after cleaning. Stagnant water
should not be allowed to remain in equipment after cleaning.
• Control of the bioburden through adequate cleaning and appropriate storage of
equipment is important to ensure that subsequent sterilization or sanitization
procedures achieve the necessary assurance of sterility, and the control of
pyrogens in sterile processing.
• Equipment sterilization processes may not be adequate to achieve significant
inactivation or removal of pyrogens.

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• For all cleaning processes an assessment should be performed to
determine the variable factors which influence cleaning effectiveness
and performance, e.g. operators, the level of detail in procedures
such as rinsing times etc.
• If variable factors have been identified, the worst case situations
should be used as the basis for cleaning validation studies.

© LPA
 Worst Case considerations
Once the product groups have been established, the next step is to determine the
so-called “worst case” representative of each group.
It is that member(s) who shows the highest challenge on cleaning program.
Worst case product : Toxicity / solubility / highly characterized / difficult to clean
ingredients.
Worst case eq. train : Longest train.
Worst case equipment : Larger size equipment (identical design), hardest to clean
Worst case acc. criteria: Stringent acceptance criteria.
Hold time studies : Longest possible duration.
Campaign Mfg. : Highest possible nos. of batches.

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 Sampling procedure

Rinse
For inaccessible areas Swab
and sampling large For most desirable direct method of
surface areas surface sampling

Combination of swab and rinse

• Most desirable!

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Swab sampling (Direct method)
• Factors that should be considered include
• supplier of the swab,
• Area swabbed,
• number of swabs used,
• whether they are wet or dry swabs,
• Swab handling and swabbing technique.
• Critical areas, that is, those that are hardest to clean, should be
identified, particularly in large systems that employ semi-automatic or
fully automatic clean-in-place systems.
• The sampling medium and solvent used should be appropriate to the
task.

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Rinse sample (Indirect method)
• Allows sampling of a large surface, of areas that are inaccessible or that
cannot be routinely disassembled, and provides an overall picture.
• Rinse samples may give sufficient evidence of adequate cleaning where
accessibility of equipment parts can preclude direct surface sampling, and
may be useful for checking for residues of cleaning agents, for example,
detergents.
• Rinse samples should be used in combination with other sampling methods
such as surface sampling.
• There should be evidence that samples are accurately recovered. For
example, a recovery of >80% is considered good, >50% reasonable and
• <50% questionable.

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Batch Placebo Method
• The batch placebo method should be used in conjunction with rinse
and/or surface sampling method(s).
• Samples should be taken throughout the process of manufacture.
Traces of the preceding products should be sought in these samples.
(Note that the sensitivity of the assay may be greatly reduced by
dilution of the contaminant.)

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Sampling Locations
Worst case locations for contaminants

• Critical area e.g. Hardest to clean

Sampling details described in protocol

• i. Sample volumes required for specific tests

• ii. Sampling containers
• iii. Sampling for positive and negative controls
where applicable
• iv. Storage conditions for collected samples

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Critical Supportive Data/Information for
Cleaning Validation
• Surface recovery studies e.g. Stainless steel, glass etc.
• Hold time studies-
• Clean equipment hold times,
• Dirty equipment hold times,
• Sample hold times
• Procedure for collecting rinse, swabs and performing visual inspection
• Analytical test method validation

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Sampling Recovery Studies

• Recovery studies performed to qualify

the rinse and swab sampling procedure
• Acceptable recovery range from 100% –70 %
• Recoveries between 70% to 50 % must be
included in the calculation of acceptance
criteria
• At recoveries below 50% sampling method
should be re-evaluated

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Test Methods for Cleaning Validation

Validated method required

Extent of validation depends on

• type of method employed,
• capabilities of the method,
• scientific and regulatory needs of the resulting data and
anticipated outcome of the testing.
© LPA
© LPA
Selecting Analytical Test Methods
• Product/ Substance Specific Assay e.g.
• GC
• Capillary electrophoresis
• Protein methods e.g.. ELISA
• TLC
• HPLC
• Specified ions
• Etc.

© LPA
 Analytical Test Methods
Non Specific Assay
TOC
pH (cleaning agent residue)
Conductivity (cleaning agent residue)
Titrations
UV-spectroscopy
Bioburden
Limulus Amoebocyte Lysate (LAL)

If it is not feasible to test for specific product residues, other

representative parameters may be selected, e.g. total organic
carbon (TOC) and conductivity.

© LPA
 Acceptance criteria

How clean is clean ?

What are the bases of defining limits ?
What are the impacts of after cleaned residue ?

“Should equipment be as clean as the best possible method of residue detection or

quantification?”

Answer: “No,……absolute cleanliness is neither valuable nor feasible…. It should be as

clean as can be reasonably be achieved, to a residue limit that is medically safe and
that causes no product quality concerns…………….”

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Limit Setting Approach
• The limit-setting approach can:
• be product-specific;
• group products into families and choose a worst-case product;
• group products into groups according to risk, for example, very soluble
products, products with similar potency, highly toxic, or difficult-to-detect
products;
• use different safety factors for different dosage forms, based on physiological
response (this method is essential for potent materials)

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Limit Setting Approach
• Limits may be expressed as a concentration in
• a subsequent product (parts per million – ppm),
• limit per surface area (µg/cm2), or
• in rinse water as ppm.
• The sensitivity of the analytical methods should be defined, to enable
• reasonable limits to be set.
• The rationale for selecting limits for carry-over of product residues
should meet defined criteria.

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• Certain allergenic ingredients
• penicillins and cephalosporins) and
• highly potent material (e.g. anovulent steroids, potent steroids and cytotoxics)
should be undetectable by the best available analytical methods.
• In practice, this may mean that dedicated manufacturing facilities
should be used fr the manufacture and processing of such products.)

© LPA
Acceptance criteria
• A visual check for cleanliness is an important part of the acceptance
criteria for cleaning validation. It is not generally acceptable for this
criterion alone to be used.
• Repeated cleaning and retesting until acceptable residue results are
obtained is not considered an acceptable approach.

© LPA
 Limits for the carryover of product residues

• Should be based on a toxicological evaluation

• Justification for the selected limits should be documented in a risk
assessment which includes all the supporting references.
• Limits should be established for the removal of any cleaning agents used.
• Acceptance criteria should consider the potential cumulative effect of
multiple items of equipment in the process equipment train.
Criteria such as Margin of safety, Maximum Safe Carryover (MSC) and Maximum Safe Surface
Residue (MSSR) values should be calculated from HBEL (ADE/PDE).

• Therapeutic macromolecules and peptides are known to degrade and

denature when exposed to pH extremes and/or heat, and may become
pharmacologically inactive. A toxicological evaluation may therefore not be
applicable in these circumstances.

© LPA
Maximum Safe Carryover (MSC)
• MSC calculation = ADE*(N/D)*(SWA/SSA)*Rs

Abbreviation Description
ADE Acceptable daily exposure (mg/day)
N Number of doses in the batch
D Maximum number of daily doses
SWA Surface area of the sample point
SSA Shared surface area between product A and B
R Recovery factor for a surface type

The equation is executed for all combinations of Product A to B within a product matrix, not just worst case.
Reference : PDA TR29

© LPA
 Acceptance Criteria for Cleaning
Acceptance criteria for selected test markers include the following:
• Visual inspection –Visual cleanliness
• Bioburden -Microbial load cfu/ml
• LAL -Endotoxin (EU/ml)
• Conductivity -Cleaning agent uS/cm
• TOC -Total organic carbon (ppm)
Test method for any analyte associated with process/product/ cleaning
agent and critical for demonstrating effectiveness of cleaning procedure.

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 • Time when equipment dirty to equipment cleaned
Dirty Equipment • Nature of soil may change overtime with drying or
Hold Times microbial proliferation Changes make soil more
difficult to remove by the cleaning process

Information Clean Equipment • Time equipment cleaned to time equipment sterilized

• Possible Microbial proliferation (FDA cleaning 45
on Hold Hold Times validation guidance- 1993)

Times
Sample Hold • Time test samples collected to time test samples
tested
times

© LPA
Cleaning validation of Chromatography-
Biopharmaceutical Products/ Biological Products
• During regulatory inspections, manufacturers of biopharmaceuticals
and biological products often find attention directed to cleaning and
cleaning validation of chromatography resins and multiuse
purification systems.
• Chromatographic resins must either be disposed of or sufficiently
cleaned to ensure reproducibility in subsequent cycles.
• The decision to recycle or dispose of resins is typically driven by cost.
The economics depend on unit operation scale, resin cost and
compatibility with cleaning agents, feedstream quality, position of the
resin in the purification scheme, and stage of product development.

© LPA
Same questions to be asked when cleaning/
Cleaning validating Chromatography-1
• How will you measure cleanliness?
• TOC , HPLC , SDS-PAGE, UV-Spectro, pH, Conductivity – to be justified
• Visual inspection
• What are you trying to remove? To consider…
• Basic chemistry of what to be removed, Nature of surface of what to be removed
from it.

“In general, cleaning validation should be directed to situations or process steps

where contamination or carryover of materials poses the greatest risk to API quality.
For example, in early production it may be unnecessary to validate equipment
cleaning procedures where residues are removed by subsequent purification steps.”-
ICH Q7

© LPA
Same questions to be asked when cleaning/
Cleaning validating Chromatography-2
• What is the best cleaning method?
• Compatibility of the resin and associated equipment wetted surfaces with available
and affordable cleaning agents (Data from vendor –important!)
• Capability to use a cleaning agent in production environments, and ability of the
cleaning protocol to deliver a resin meeting its acceptance criteria.
• NaOH, NaCl - most used cleaning agents
• Additional cleaning agents may be required. When selecting a cleaning agent, make
sure you can detect it to demonstrate its removal before reuse of resins and
equipment.
• For example, anion-exchange column loaded with high level of DNA during protein
purification, very difficult to remove DNA.
• Dnase could be used to clean the column; cost of disposing the resin comparing with cost of
cleaning agent and validation of its removal to be determined.
• Alcohols are sometimes used for cleaning, and their removal must also be validated.
• Safety concern when using alcohol, Heated NaOH, etc.

© LPA
Same questions to be asked when cleaning/
Cleaning validating Chromatography-3
• How clean is clean?
• Maximum carry over limit to be determined based on QRM
• Cleanability studies to be performed
• Adequately cleaned columns should repeatedly provide an intermediate
product that possesses its critical quality attributes.
• To understand the product and the impurities that are removed in every
purification step.
• Attention to Virus clearance

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Process validation

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Cleaning Validation Protocol

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Cleaning validation report
• Relevant cleaning records (signed by the operator, checked by
production and reviewed by quality assurance)
• Source data (original results) should be kept.
• The results of the cleaning validation should be presented in cleaning
validation reports stating the outcome and conclusion.

Data integrity concern

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Continued Process Verification

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 Goal - to operate at process capability that
ensures that predefined acceptance limits are
consistently met in a reproducible manner
Considerations
for Process Residue data used to generate process limits
Capability,
Reliability and
Consistency
Acceptance limits - scientifically justifiable,
achievable and risk-based.

© LPA
 Goal - to operate at process capability that
ensures that predefined acceptance limits are
consistently met in a reproducible manner
Considerations
for Process Residue data used to generate process limits
Capability,
Reliability and
Consistency
Acceptance limits - scientifically justifiable,
achievable and risk-based.

© LPA
Process capability

Reference: PI 006-3

© LPA
Reference: www.rockfordpowertrain.com/supplier
What is process capability? It is a
measure of how well
a process is within a specification. A
CpK =
A divided by
B B

Specification Specification
Limit Limit

CpK = A divided by B
A = Distance from process mean to closest spec limit
B = 3 Standard Deviations (also called “3 Sigma”)

A bigger CpK is better because fewer units will be beyond spec.

(A bigger “A” and a smaller “B” are better.)

© LPA
 “Process Capability” is the ability of a process
to fit its output within the tolerances.
A
CpK =
A divided by
B B

Specification Specification
Limit Limit

…a LARGER “A”
…and a SMALLER “B”
…means BETTER “Process Capability”

© LPA
 An Analogy

A
CpK =
A divided by
B B

Specification Specification
Limit Limit

Analogy:
The bell curve is your automobile.
The spec limits are the edges of your garage door.
If A = B, you are hitting the frame of your garage door with your car.

© LPA
 What does a very good CpK do for us?
A
This CpK is
B about 2.
Very good!

Specification Specification
Limit Mean Limit

This process is producing good units with a good safety margin.

Note that when CpK = 2, our process mean is 6 standard deviations from
the nearest spec, so we say it has “6 Sigma Capability.”

© LPA
 What does a problem CpK look like?
A
This CpK is just
B slightly greater
than 1. Not good!

Specification Specification
Limit Limit

This process is in danger of producing some defects.

It is too close to the specification limits.

(Remember: the bell curve tail goes further than B…

…we only show the bell to 3-sigma to make it easier to draw.)

© LPA
 What does a very bad CpK look like?
A
This CpK is less
B than 1. We desire
a minimum of 1.33
and ultimately we
want 2 or more.

Specification Specification
Limit Limit

A significant part of the “tail” is hanging out beyond the spec limits.
This process is producing scrap, rework, and customer rejects.
Notice that if distance “A” approaches zero…
…the CpK would approach zero, and…
…the process would become 50% defective!

© LPA
 Monitoring data provides important information
Application of for defining the cleaning process capability.
Continued
Process
Verification and The trend is to depart from the use of general
default limits, no-observed-effect levels (NOELs)
Continual and toxicity limits to risk and statistically derived
improvement criteria that are based on process performance

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 What does a very good CpK do for us?
A
This CpK is
B about 2.
Very good!

Specification Specification
Limit Mean Limit

This process is producing good units with a good safety margin.

Note that when CpK = 2, our process mean is 6 standard deviations from
the nearest spec, so we say it has “6 Sigma Capability.”

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Cleaning validation vs. Cleaning Verification

Cleaning validation Cleaning verification

Documented evidence The gathering of evidence

that an approved through chemical analysis
cleaning procedure will after each
reproducibly remove the batch/campaign to show
previous product or that the residues of the
cleaning agents used in previous product or
the equipment below the cleaning agents have
scientifically set been reduced below the
maximum allowable scientifically set
carryover level. maximum allowable
carryover level.

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Revalidation
• To be done when there is a change of the cleaning procedure e.g.
• Type of cleaning agent
• Cleaning agent concentration
• Equipment
• Etc.

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 What about you?

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References
• WHO TRS 1019, Annex 3, Appendix 3: Cleaning validation
• PIC/S GMP Annex 15 Qualification and Validation
• US FDA, Validation of Cleaning Processes (7/93): GUIDE TO
INSPECTIONS VALIDATION OF CLEANING PROCESSES, 2014
• Cleaning Validation for The 21st Century, Pharmaceutical Online
• Ruijin Song; Alfredo Canhoto, Ph.D.; and Andrew Walsh: Cleaning
Process Development: Cleanability Testing And "Hardest-To-Clean"
Pharmaceutical Products, Pharmaceutical Online, January 18, 2019
• PDA TR 29 and PDA TR 49

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 Disclaimer

This document, in part or in whole, may not be reviewed,

abstracted, quoted, copied, transmitted, distributed,
translated or adapted in any form or by any means
without the permission from the WHO Local production
and Assistance unit. This is for your personal use only
and reliance of any information contained on this
document is solely at your own risk.

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17/12/2020
Thank you

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