CLEANING VALIDATION PROGRAM -

- EU ANNEX 15 COMPLIANCE
Paul L. Pluta, PhD
Journal of Validation Technology and Journal of GXP Compliance
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
 OUTLINE
• Annex 15 Qualification and Validation
• EMA Process Validation for Finished Products
• Annex 15 Cleaning Validation Requirements
• US FDA Process Validation Guidance
• Implementation Strategy
• Interactions – Throughout Discussion
 ANNEX 15 QUALIFICATION AND VALIDATION
• Principles and general considerations
– Validation of facilities, equipment, utilities, and processes
– Supplementary for API manufacturing
– Evaluation and validation of changes
– Computerized systems
– ICH Q8, Q9, Q10, Q11 should also be considered
– Risk management should also be applied throughout lifecycle
– Retrospective validation not acceptable
– Outside data OK if justified.
• Organizing and planning
• Documentation including VMP
• Equipment, utilities, facilities, and systems – Stages of qualification
– URS, DQ, FAT, SAT, IQ, OQ, PQ, Requalification
• Processes
– Validation: Traditions, Continuous, Hybrid
• Transportation
• Packaging
• Test methods
• Cleaning
• Change control
 EMA PROCESS VALIDATION FOR
FINISHED PRODUCTS
• Regulatory submissions
• Lifecycle application
• Traditional, continuous, and hybrid
approaches
• Supportive Documents: ICH Q8, Q9, Q10,
Q11.
 ANNEX 15 CLEANING VALIDATION
REQUIREMENTS
• Fifteen individual statements
• Sources of variation should be identified
• Toxicological evaluation of residues
• Microbial considerations
• Recovery studies
Future meeting in November for discussion
 10. CLEANING VALIDATION
(Definition)
10.1 Cleaning validation should be performed in order
to confirm the effectiveness of any cleaning procedure
for all product contact equipment. Simulating agents
may be used with appropriate scientific justification.
Where similar types of equipment are grouped
together, a justification of the specific equipment
selected for cleaning validation is expected.
• Simulation OK with justification
• Equivalent equipment OK with justification
 10. CLEANING VALIDATION
(Visual Cleanliness)
10.2 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.
• Visual cleanliness alone is not acceptable
• No “test until clean.”
 10. CLEANING VALIDATION
(Incomplete Cleaning Validation)
10.3 It is recognised that a cleaning validation
programme may take some time to complete and
validation with verification after each batch may be
required for some products, e.g., investigational
medicinal products. There should be sufficient data
from the verification to support a conclusion that the
equipment is clean and available for further use.
• If cleaning validation not complete, must have sufficient
data to use equipment.
 10. CLEANING VALIDATION
(Automated Cleaning Equipment)
10.4 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.
• Automated equipment must be validated.
 10. CLEANING VALIDATION
(Variables)
10.5 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.
• Validate worst case variables.
 10. CLEANING VALIDATION
(Residue Carryover)
10.6 Limits for the carryover of product residues should be based on a
toxicological evaluation. The 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.
10.6.1 Therapeutic macromolecules and peptides are known to degrade and
denature when exposed to pH extremes and/or heat, and my become
pharmacologically inactive. A toxicological evaluation may therefore not be
applicable in these circumstances.
10.6.2 If it is not feasible to test for specific residues, other representative
parameters may be selected, e.g., total organic carbon (TOC) and
conductivity).
• Toxicologic evaluation of residues required.
 10. CLEANING VALIDATION
(Microbial)
10.7 The risk presented by microbial and
endotoxin contamination should be considered
during the development of cleaning validation
protocols.
• Consider microbial contamination as part of
cleaning if necessary.
 10. CLEANING VALIDATION
(Dirty and Clean Hold Times)
10.8 The influence of the time between
manufacture and cleaning and the time
between cleaning and use should be taken in
account to define dirty and clean hold times for
the cleaning process.
• Define dirty and clean hold times.
 10. CLEANING VALIDATION
(Campaigns)

10.9 Where campaign manufacture is carried

out, the impact on the ease of cleaning at the
end of a campaign should be considered and be
maximum length of a campaign (in time and/or
number of batches) should be the basis for
cleaning validation exercises.
• Campaigns should consider worst case conditions.
 10. CLEANING VALIDATION
(Cleaning Worst-Case Matrix)
10.10 Where a worst case product approach is used as
a cleaning validation model, a scientific rationale
should be provided for the selection of the worst case
product and the impact of new products to the site
assessed. Criteria for determining the worst case may
include solubility, cleanability, toxicity, and potency.
• Provide justification when using worst-case matrix.
 10. CLEANING VALIDATION
(Sampling Locations)
10.11 Cleaning validation protocols should
specify or reference the locations to be sampled,
the rationale for the selection of these locations
and define the acceptance criteria.
• Sampling locations must be defined and
justified.
 10. CLEANING VALIDATION
(Sampling and Recovery)
10.12 Sampling should be carried out by swabbing and/or
rinsing or by other means depending on the production
equipment. The sampling materials and method should not
influence the result. Recovery should be shown to be possible
from all product contact materials sampled in the equipment
with all the sampling methods used.
• Swab and rinse sampling OK.
• Recovery studies for all equipment materials.
 10. CLEANING VALIDATION
(Repeatability)
10.13 The cleaning procedure should be performed an
appropriate number of times based on risk assessment
and meet the acceptance criteria in order to prove that
the cleaning method is validated.
• Number of lots required based on risk assessment.
 10. CLEANING VALIDATION
(Dedicated Equipment)
10.14 Where a cleaning process is ineffective or
is not appropriate for some equipment,
dedicated equipment of other appropriate
measures should be used for each product as
indicated in chapters 3 and 5 of EudraLex,
Volume 4, Part I.
• Dedicated equipment considerations.
 10. CLEANING VALIDATION
(Manual Cleaning)
10.15 Where manual cleaning of equipment is
performed, it is especially important that the
effectiveness of the manual process should be
confirmed at a justified frequency.
• Must revalidate manual cleaning processes at
justified frequency.
 US FDA PROCESS VALIDATION
GUIDANCE (November, 2011)
• Stage 1. Design and development
• Stage 2. Performance qualification
• Stage 3. Monitoring and maintenance
 US FDA GUIDE TO INSPECTIONS
VALIDATION OF CLEANING PROCESSES (7/93)
I. Introduction
II. Background
III. General Requirements
• Written procedures for cleaning.
• Dedicated fluidized bed dryer bags
IV. Evaluation of Cleaning Validation
• At what point does equipment become clean?
• Is manual scrubbing needed?
• Variability?
• “Visually clean” between batches in campaign.
• Equipment design considerations and operator training.
• Dirty hold time and clean hold time (storage)
• Cleaning process written. SOP and “batch record” with signatures
• Analytical methods specificity, sensitivity, recovery
• Swab and rinse sampling. In-process sampling.
V. Establishment of Limits
VI. Other Issues
• Placebo product
• Detergent residues
• “Test until clean” unacceptable.
 PIC/S CLEANING VALIDATION (9/07)
7. Cleaning Validation
7.1 Principle
7.2 Purpose and Scope
7.3 General
7.4 Documentation
7.5 Personnel
7.6 Equipment
7.7 Microbiological Aspects
7.8 Sampling
7.9 Detergents
7.10 Analytical Methods
7.11 Establishment of Limits
 WORLD HEALTH ORGANIZATION
ANNEX 3, APPENDIX 3, CLEANING VALIDATION (2006)
1. Principle
2. Scope
3. General
4. Cleaning validation protocols and reports
5. Personnel
6. Equipment
7. Detergents
8. Microbiology
9. Sampling
10. Analytical methods
11. Establishing acceptable limits
 CLEANING VALIDATION PROBLEMS
• Product problems – Residue properties, solubility,
“dirty hold time,” and cleanability
• Equipment problems -- Non-uniform contamination,
worst case sampling , equivalent equipment
• Cleaning Process -- Manual cleaning and
documentation
• Laboratory – Residue stability, recovery, swab
sampling reliability, and training.
• Culture – Cleaning is a process.
 SELF-AUDIT QUESTIONS
• Is residue chemistry considered in developing cleaning procedure?
• Is pH-solubility profile considered in worst-case matrix analysis?
• Is residue “cleanability” considered in worst-case residue
determination?
• Is non-uniform contamination considered in residue calculations?
• Are most difficult-to-clean equipment locations proceduralized?
• Are manual cleaning personnel qualified and requalified?
• Are cleaning procedures quantitative and documented?
• Are dirty hold times controlled?
• Is residue stability considered in cleaning residue analytical?
• Have analytical recovery studies been conducted? On
representative materials?
• Are swab sampling personnel trained / qualified?
 SUMMARY
• Specific points from EU Annex 15 reviewed
– Total 15 key points
o Variation determination
o Worst case matrix
o Dirty and clean hold times and campaigns
o Sampling
o Risk
o Dedicated equipment

• Content equivalent to PIC/S, WHO, FDA (1993)

– Wording sometimes identical
• Clarification of PDE / ADE evolving
• Lifecycle approach evolving – not explicit in
current documents
 CONTACT INFORMATION

PAUL L. PLUTA, PhD

Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
UBM Advanstar Communications

Adjunct Associate Professor

University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA

Editor and Chapter Author

Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and Principles, 2009
Cleaning and Cleaning Validation, Volume 2. Application of Basics and Principles, 2013
PDA and Davis Healthcare International (DHI) Publishing

Contact: ppluta@uic.edu