VALIDATION

O PROTOCOLS
O OCO S
Execution of the Validation Plan
T ti details
Testing d t il
Sampling details
Data sheets
Data treatment
Acceptance criteria
Minimal text repetition from Validation Plan

PROTOCOL EASILY WRITTEN IF

VALIDATION PLAN IS THOROUGH
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 VALIDATION PROTOCOL
Objective of validation specific protocol
Validation description specific
V lid ti approach
Validation h
Testing and rationale -- specific
Sampling and rationale -- specific
Data sheets (summary)
Data treatment -- specific
p
Acceptance criteria specific
All testing must have acceptance criteria
No FYI testing in validation

VALIDATION IS CONFIRMATION
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 VALIDATION PROTOCOL
TESTING AND SAMPLING
Based on p
product specifications
p and testing
g
Exceed routine QA testing based on impact and risk

Consider the following:

Product for seizures
Product for hypertension
New product
Change in compressing machine
Increase compressing
p g machine speed
p
Change in granulation method
Change in batch size

Risk analysis in above

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 VALIDATION PROTOCOL
FDA Powder Blends and Finished Dosage Units
Stratified Sampling and Assessment
Blend sampling. n = 10, Individuals, RSD
Tablets. 20 samples, n = 3-7 per location, mean,
range, RSD.
RSD

pp
Application is p
possible approach
pp for high
g risk
products
pp
Supportive of USP Uniformityy of Dosageg Units on
composite / stratified samples
Product types: Potency and weight testing
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 VALIDATION SAMPLING
What is routine QA sampling?
Impact
p of change
g
High impact
Medium impact
Low impact
No impact

Risk analysis Related to numerical RPN analysis

High risk
Medium risk
Low risk

RISK LEVEL MUST BE ACKNOWLEDGED

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 ENGINEERING STUDY
Conducted in advance of validation
No acceptance
p criteria
Trial run

Examples: Manufacturing process without

g ((low dose API))
bulk drug
Process runs with placebo
Categories of Engineering Studies
Conduct Engineering Study concurrently with validation? -
- Not recommended
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 SAMPLING PAGES

Designed sheet with space for expected data

D t ttreatment
Data t t specified
ifi d
Signature and data of person supplying data
Highly recommended for Operators or persons not
familiar with sampling
D t pages consistent
Data i t t with
ith sampling
li pages

Prevents missing data in complex protocols

Record sampling and / or testing

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 SAMPLING / DATA PAGE EXAMPLE
UNIT OPERATION: Tablet compressing, lot # ________________
TEST: Content Uniformity (SOP # XX
XX-XXX)
XXX)
SAMPLE: 10 Tables each from beginning, middle, and end of batch
Sample #1 by _________ Date _________
Sample #2 by _________ Date _________
Sample #3 by _________ Date _________

TEST RESULTS (Circle P -- Pass or F -- Fail)

Sample #1 Sample #2 Sample #3
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
RECORDED BY:
__________ __________ __________
VERIFIED BY:
_____________ _____________ _____________

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 PROCESS VALIDATION PROTOCOL (PPQ)
FDA GUIDLINE RECOMMENDATIONS
Higher level of sampling, testing, and scrutiny of process performance.

Protocol should address:

Operating parameters, processing limits, and raw material inputs
Data to be collected and how evaluated
Test to be performed and acceptance criteria
Sampling plan sampling points, number of samples, frequency
Statistical methods used
Statistical confidence levels
Provisions to address deviations and non-conformances
Facility,
Facility utility
utility, and equipment qualification
Status of analytical method validation

Review and approval

pp by
y appropriate
pp p departments
p and q
quality
y unit

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 VALIDATION PROTOCOL OUTLINE
Introduction
Unit operations
p
Testing with justification
Sampling with justification
Sampling and data pages
Data treatment
Acceptance
p criteria with jjustification
HAVE MODEL DOCUMENTS AVAILABLE

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 VALIDATION PROTOCOL -- PROBLEMS
No plan
No basic explanation of validation
N statement
No t t t off strategy
t t and
d approach
h
No test rationale
No sampling rationale
Missing samples missing data
How to treat data
No discussion of results
No acceptance criteria rationale
No validation statement
Poorly written
WRITTEN FOR THE READER
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VALIDATION PROTOCOL -- PROBLEMS
How many lots should be tested?

Consider impact of change.

Consider product.
p
Consider process.
Consider risk
risk.

ABOVE ADDRESSED IN VALIDATION PLAN

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 VALIDATION RESULTS

Compilation of testing required in protocol

Deviations or adverse events
Discussion
Conclusion
WRITE GOOD PLAN
PROTOCOL CONSISTENT WITH PLAN
RESULTS CONSISTENT WITH PROTOCOL
WRITE DISCUSSION FIRST MOST IMPORTANT SECTION

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 VALIDATION RESULTS OUTLINE
Introduction
Data sheets compiled
Data treatment
Results
Deviations, Non-conformances, etc.
Di
Discussion
i
Results pass is not sufficient.

Validation statement:
Results indicate that ___ is validated.
Post-validation monitoring plan

WRITE DISCUSSION SECTION FIRST MOST IMPORTANT SECTION

HAVE MODEL DOCUMENTS AVAILABLE

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 VALIDATION RESULTS PROBLEMS

Missing data
Documentation practices on raw data
Raw data and results inconsistent
I d
Inadequate
t or no discussion
di i off results
lt
Inadequate or no discussion of amendments or
deviations
No conclusion statement
Poor
P grammar and d composition
iti

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 VALIDATION RESULTS / REPORT -- PROBLEMS

Protocol requires BME samples for potency.

Acceptance criteria: 95
95-105%
105%
B = 95%
M = 100%
E = 105%
All results pass
Conclusion?
POST PQ MONITORING?

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 VALIDATION RESULTS / REPORTS -- PROBLEMS

Protocol requires BME testing

Acceptance Criteria: Not More Than 6.0%

Results:
B = 2.0%
M = 2.1%
E = 6.0%
6 0%

All data pass acceptance conclusions.

Conclusions?
POST PQ MONITORING?

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 VALIDATION REPORT

Recommended for complex projects

Recommended for multiple protocol projects

PRIMARY REPORT FOR AUDIT

Cut and Paste exercise from multiple documents
Best approach to avoid inconsistency

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 VALIDATION REPORT FORMAT
Introduction
Key information from Validation Plan
Supporting information
Protocol #1 results Cut and paste
Protocol #2 results Cut and paste
P t
Protocoll #3 results
lt Cut
C t and
d paste
t
Protocol #n results Cut and paste
Write transitional narrative
Project conclusions (for Validation Plan)
Validation statement
Results
Results indicate that ______ is validated
validated.

HAVE MODEL DOCUMENTS AVAILABLE

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