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10/10/2017

Cleaning Validation Theory and Practice Maurice Parlane ISPE PV Team CBE Pty Ltd (Australia) ISPE
Cleaning Validation
Theory and Practice
Maurice Parlane
ISPE PV Team
CBE Pty Ltd (Australia)
ISPE Thailand/ISPE Indonesia 2017
Agenda • Cleaning Validation Regulatory Requirements • Overview of Cleaning Validation Guidelines • PIC/S GMP
Agenda
• Cleaning Validation Regulatory Requirements
• Overview of Cleaning Validation Guidelines
• PIC/S GMP Guidance, Annex 15 Qualification and Validation
• Cleaning Mechanisms and Agents
• Cleaning Methods
• Sampling Methods
• Recovery Studies
• Worst Case site selection
• Grouping / Bracketing strategies
• Acceptance Criteria: How to calculate limits
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10/10/2017

Agenda • Ultrasonic Cleaning for Tablet Press Tooling • Cleaning Validation of Oral Solid Dose
Agenda
• Ultrasonic Cleaning for Tablet Press Tooling
• Cleaning Validation of Oral Solid Dose
• How to correctly choose hygienic pumps that are important in CIP
• Cleaning Validation on Liquid Dose
• Workshop
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Cleaning Validation Regulatory Requirements and Industry Guidance Maurice Parlane ISPE PV Team CBE Pty Ltd
Cleaning Validation
Regulatory Requirements
and Industry Guidance
Maurice Parlane
ISPE PV Team
CBE Pty Ltd (Australia)
ISPE Thailand/ISPE Indonesia 2017

10/10/2017

Agenda • Regulations and guidance on Cleaning/CV • Industry guidance • Key Considerations – Overview
Agenda
• Regulations and guidance on Cleaning/CV
• Industry guidance
• Key Considerations – Overview
• Evolution of CV requirements
o
EMA (Health-based exposure limits)
o
FDA (Lifecycle approach)
• PIC/S Annex 15 specifics
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Regulations on Cleaning/CV Regulations are a mix of Cleaning GMPs and supporting documents on validation
Regulations on Cleaning/CV
Regulations are a mix of Cleaning GMPs and supporting
documents on validation
• FDA: CFR 211.56 (Buildings) and 211.67 (Equipment); Guide to
Inspections - Validation of Cleaning Processes (7/93)
• EudraLex/PICs: Clause 3.6 (facilites) Clause 3.36, 3.37
(equipment and cleaning); Annex 15
• ICH Q7 (API): Sections 4.42, 5.21-5.25, 8.50, 12.7, 12.72-12.76
• WHO: TRS 936, Annex 4, Appendix 3
Canada, Japan, China, South Korea and other agencies all have
similar positions and requirements
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10/10/2017

Regulations on Cleaning/CV Common requirements in GMPs • Facilities and equipment must be designed to
Regulations on Cleaning/CV
Common requirements in GMPs
• Facilities and equipment must be designed to be cleanable
• Certain activities/equipment must be dedicated
• There must be written procedures for cleaning with
appropriate instructions on methods, chemicals, sampling
and frequency
• Appropriate/safe limits should be established (GMPs do not
specify limits) but do speak about considerations
• Cleaning processes/methods should be validated
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Regulatory Guidance on CV Much more detail in…. • FDA Inspection Guide 7/93 • FDA
Regulatory Guidance on CV
Much more detail in….
• FDA Inspection Guide 7/93
• FDA Questions and Answers on Current Good Manufacturing
Practices for Drugs
• PIC/S PI 006-3 (Recommendations on Validation Master Plan,
Installation and Operational Qualification, Non-sterile Process
Validation, Cleaning Validation) Sept 2007
• Q7 Implementation Working Group “ICH Q7 Guideline: Good
Manufacturing Practice Guide for Active Pharmaceutical
Ingredients Questions and Answers dated 10 June 2015
• Health Canada Cleaning Validation Guidelines (GUIDE-0028)
EMA Guidance and comment (see next slide)
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10/10/2017

Regulatory Guidance on CV EMA comment and guidance (Health Based Exposure Limits) • EMA/CHMP/SWP/598303/2011
Regulatory Guidance on CV
EMA comment and guidance (Health Based Exposure Limits)
• EMA/CHMP/SWP/598303/2011 “Concept Paper on the
development of toxicological guidance for use in risk identification
in the manufacture of different medicinal products in shared
facilities”
• 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”
• EMA/CHMP/CVMP/SWP/463311/2016 “Questions & answers on
implementation of risk based prevention of cross contamination in
production and ‘Guideline EMA/CHMP/ CVMP/ SWP/169430/2012”
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Regulatory Guidance on CV Contents FDA PICS PI ICH Q7 EMA WHO Health 7/93 006-3
Regulatory Guidance on CV
Contents
FDA
PICS PI
ICH Q7
EMA
WHO
Health
7/93
006-3
Canada
Principles

Validation

Equipment/Personnel
Micro considerations


Documentation

Analytical Methods


Detergents


Sampling


Limits


Change/Revalidation

References
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10/10/2017

Industry Guidance on CV Not an exhaustive list… • PDA TR 29 Points to Consider
Industry Guidance on CV
Not an exhaustive list…
• PDA TR 29 Points to Consider for Cleaning Validation (2012)
• PDA TR 49 Points to Consider for Biotechnology Cleaning
Validation (2010)
• APIC Guidance on Aspects of Cleaning Validation in Active
Pharmaceutical Ingredient Plants (3 rd Ed May 2014)
• ISPE Baseline Guide Volume 7: Risk-Based Manufacture of
Pharma Products [RiskMaPP] (2 nd Ed 2017)
Various other groups plus industry consultants
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Overview - Key Considerations • Establishing Residue Limits • Analytical Techniques • Sampling Techniques •
Overview - Key Considerations
• Establishing Residue Limits
• Analytical Techniques
• Sampling Techniques
• Grouping/Bracketing approaches (matrix)
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10/10/2017

Overview - Residue Limits Selection Criteria • What is being cleaned, and how it is
Overview - Residue Limits
Selection Criteria
• What is being cleaned, and how it is performed
• Effect on the next product
Typically consider active, cleaning agent and bioburden
• May also consider endotoxin (Steriles), degradants or by-products
(APIs, Biotech)
The residue limit is a function of
• Residue (cleanability) of the current process
• Acceptable level of that residue in a subsequent product
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Overview - Residue Limits Selection Criteria • For pharmaceutical APIs, limits specified in regulations and
Overview - Residue Limits
Selection Criteria
• For pharmaceutical APIs, limits specified in regulations and
guidance were dose based
• Recent approach is to also consider health based criteria to
establish the limit (we will come back to this)
o
Permitted daily exposure (PDE)
o
Acceptable daily exposure (ADE)
• Other compounds (e.g. detergents) are based on Acceptable
Daily Intake (ADI) using toxicity information (LD50)
• Microbial contamination limits are typically scientifically justified
as residue calculations are not practical
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10/10/2017

Overview - Residue Limits Selection Criteria As low as practically possible is the objective, but
Overview - Residue Limits
Selection Criteria
As low as practically possible is the objective, but what is
the practical minimum?
• Uncertainty due to constraints
o
Limits of method detection/precision
o
“Safety” factors
o
Difficulty in sample recovery
• Must be safe and not impact the product quality
• Should not be visible…
• Not all residues are the same. Residue may be
acceptable, but avoidable contamination is not
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Overview - Residue Limits “Limit” Criteria Can be expressed in a number of ways… •
Overview - Residue Limits
“Limit” Criteria
Can be expressed in a number of ways…
• Concentration in subsequent product (µg/mL)
• Absolute amount in an equipment train
[Maximum allowable carry over = MACO] (mg)
• Amount per surface area (µg/cm 2 )
• Amount per analytical sample (µg)
• Concentration in rinse sample (µg/mL)
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10/10/2017

Overview - Analytical Techniques Considerations • Do we have ability to (or want to) make
Overview - Analytical Techniques
Considerations
• Do we have ability to (or want to) make a direct
measurement of the residue?
o
Specificity (e.g interference from cleaning agent)
o
Analyte becomes degraded during the cleaning process
o
Difficulty in sample recovery
• Does the LOD/LOQ for the method match the limit?
• May consider a non-specific method (e.g TOC)
• These factors should be determined during cleaning
method/validation development
Written justification required
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Overview - Sampling Techniques • Swab (direct) sampling • Rinse (indirect) sampling • Worst case
Overview - Sampling Techniques
• Swab (direct) sampling
• Rinse (indirect) sampling
• Worst case locations
(Discussion of techniques and advantages later)
• Recovery study at or below the residue limit will
determine which is best in a particular situation
• Recovery study required during method development or
as a separate study
Written justification required
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10/10/2017

Overview – Sampling Study design • Dirty Hold Time o Worst case o Longest time
Overview – Sampling
Study design
• Dirty Hold Time
o
Worst case
o
Longest time equipment can be dirty before cleaning based on
intended SOPs
• Clean Hold Time
o Longest time before re-clean based on intended SOPs
• Number of runs
Written justification required
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Overview – Grouping/Bracketing Strategies • By Product o Similar product type o Same equipment train
Overview – Grouping/Bracketing
Strategies
• By Product
o
Similar product type
o
Same equipment train
o
Same cleaning method
o
Representative product/s
• By Equipment Train
o
Similar equipment type (for cleaning). May scale
o
Validate largest and smallest; or
o
Validate equipment together, using extremes (cleanability)
Written justification required
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10/10/2017

Overview – Grouping/Bracketing Representative Sample • Most difficult to product to clean o Basis for
Overview – Grouping/Bracketing
Representative Sample
• Most difficult to product to clean
o Basis for selection – history, risk, solubility, lab study
• Residue limit
o
Longest residue limit in the group
o
“Box study” of most difficult to clean (at its limit) and most toxic (at
lowest limit)
• Number of runs
Written justification required
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Recent Evolution of CV requirements EMA • Health Based Exposure Limits (HBEL) PIC/S • Working
Recent Evolution of CV requirements
EMA
• Health Based Exposure Limits (HBEL)
PIC/S
• Working party to consider EMA recommendations on
HBELs
FDA
• Lifecycle Validation (CPV)
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10/10/2017

Recent Evolution of CV requirements EMA • Health Based Exposure Limits (HBEL) o Arose out
Recent Evolution of CV requirements
EMA
• Health Based Exposure Limits (HBEL)
o
Arose out of consideration to dedicated facilities (Chapter 3 & 5)
o
Annex 15 Ver 12 requires “toxicological evaluation” for cleaning
validation (Clause 10.6); however includes a footnote specific to
EU/EEA guideline from EMA re shared facilities [with PDEs]
o
RiskMaPP (1 st Ed) extended the discussion of use of HBELs [with
ADEs]
o
Considerable industry confusion, but PDE & ADE are derived
differently, but considered equivalent.
o
Recent draft (Dec 2016) EMA document suggests can use 1/1000 th
criteria where not highly hazardous.
o
Consultation closed, but final guide not published
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Health Based Limits - EMA Q2: Are HBELs required for all products? Q4: HBELs for
Health Based Limits - EMA
Q2: Are HBELs required for all products?
Q4: HBELs for products that are not highly hazardous
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10/10/2017

Health Based Limits – EMA Q3: How do I define highly hazardous (partial excerpt only)
Health Based Limits – EMA
Q3: How do I define highly hazardous (partial excerpt only)
Final report not issued, but definition is being questioned
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Health Based Limits – PIC/S Where does this leave the rest of us using Annex
Health Based Limits – PIC/S
Where does this leave the rest of us using Annex 15
• If you use “old” Annex 15 (before PE 009-12)
o No mention of toxicological evaluation
• If you use Annex 15 (version 12 or 13)
o
Toxicological evaluation required (or defined), but does not specify method
(footnote only applied to EU)
o
1/1000 th is reported to be conservative compared to PDE for lower risk, so in
many cases would give a lower residue limit
o
Must take consideration to toxicological effects, but methods other than
PDE/ADE should be acceptable.
• But what about RiskMaPP?
o
It’s a guide you can reference
o
RiskMaPP does not state ADE is mandatory. Simply that its “more scientific”
which is true
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10/10/2017

Lifecycle Cleaning Validation- FDA FDA • Lifecycle Validation (CPV) o Some suggest cleaning validation using
Lifecycle Cleaning Validation- FDA
FDA
Lifecycle Validation (CPV)
o
Some suggest cleaning validation using “lifecycle approach” is
applicable; however;
– Cleaning design/development was often done
– Monitoring and control after validation was always required
“Health-based”
o FDA cGMP Questions and Answers (2015) states residues must;
– be medically safe
– not affect product quality
– be reasonably avoidable,
– leave the equipment visually clean
Requirements look equivalent – perhaps?
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SUMMARY • There are few requirements on cleaning validation specified in GMPs. • Regulatory and
SUMMARY
• There are few requirements on cleaning validation specified
in GMPs.
• Regulatory and industry guidance is available and has
many common considerations
• Recent EMA guidance has brought
HBELs into Annex 15
• PDE/ADE were associated with HBELs
for highly potent actives initially
• HBELs are appropriate when used
with science/risk based approaches
• International GMPs are aligned on the
current approach for cleaning validation
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10/10/2017

Group discussion 1. What is the key difference between PIC/S Annex 15 requirements for cleaning
Group discussion
1. What is the key difference between PIC/S Annex 15 requirements
for cleaning validation and EMA requirements
2. Why might a residue limit of 1/1000 th of a dose in a following
product not be appropriate
3. Does toxicological evaluation require calculation of PDEs or ADEs
4. Would you consider FDAs requirement that residue limits are
“medically safe” is the same as limits that are evaluated based on
toxicological criteria
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