A history and overview of the 2011 FDA Guidance on Process Validation and the subsequent documentation requirements.

1. VALIDATION BOOT CAMP
A LIFECYCLE APPROACH TO PROCESS
VALIDATION –
PRINCIPLES, IMPLEMENTATION AND
PRACTICES
Seow Choon How, BSc (Chemistry), MBA, Production Manager,
Vela Operations Singapore Pte Ltd
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2. Seow Choon How BSc MBA
Vela Operations Singapore Pte Ltd
Choon
How
is
a
Process
and
Produc9on
Professional
with
exper9se
in
Plant
Management
and
Opera9ons,
Technology
Transfer,
Valida9on,
Lean
Manufacturing,
Change
Control,
Con9nuous
Improvement,
current
Good
Manufacturing
Prac9ces
(cGMP)
and
CAPA.
In
the
past
13
years,
he
has
worked
with
Schering-­‐Plough
(SP),
Ecolab
(ECL)
and
currently
with
Vela
Diagnos9cs
(VelaDx)
within
the
Pharmaceu9cal,
Hygiene
Chemicals
and
Medical
Devices
industries.
Choon
How
has
a
Specialist
Diploma
in
Biomedical
Engineering
from
Singapore
Polytechnic
(SP),
a
MBA
from
Southern
Cross
University
(SCU)
and
Bachelor
of
Science
(BSc)
from
Na9onal
University
of
Singapore
(NUS).
He
is
one
of
the
recipients
for
SCU’s
top
academic
achievement
award
and
valedictorian
in
SCU
Gradua9on
2008.
He
is
an
ac9ve
member
of
the
Community
of
25
February
2013
Prac9ces
(CoPs)
within
the
industries
and
in
sharing
the
2
best
prac9ces
and
technologies.

3. CONTENT
I. Process Validation Lifecycle Approach
Overview
• History and development
• FDA’s Process Validation Guidance
• cGMPs and process validation for drug
manufacturing
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4. CONTENT
II. FDA Process Validation Guidance
• Stage 1 – Process design may be generally
described as “process understanding”
• Stage 2 – Process qualification may be
described as “validation performance”
• Stage 3 – Continued process verification may
be simply described as “maintaining
validation”
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5. CONTENT
III. Critical Documentation Requirements
• Validation policy documents
• Process design documents
• Process qualification documents
• Continued process verification
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6. CONTENT
IV. Interactive Exercise – Case Study
• Attendees participate in an exercise on
submission preparation and inspection
readiness for the process validation of an
API
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7. I. Process Validation Lifecycle
Approach Overview
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8. History and Development
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9. FDA’s Process Validation
Guidance
• Notified industry in 2006
• Issued in draft Nov 2008
• Most recent issue Jan
2011 Rev 1
• “reflection of industry
practice”
• PDA SAB formed a
committee to collect and
collate member comments
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10. FDA’s Process Validation
Guidance
• Introduction
“This guidance outlines the general principles and
approaches that FDA considers appropriate elements of
process validation for the manufacture of human and
animal drug and biological products, including active
pharmaceutical ingredients (APIs or drug substances),
collectively referred to in this guidance as drugs or
products. This guidance incorporates principles and
approaches that all manufactured can use to validate
manufacturing processes.”
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11. FDA’s Process Validation
Guidance
• Introduction
“The lifecycle concept links product and process
development, qualification of the commercial process, and
maintenance of the process in a state of control during
routine commercial production.”
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12. FDA’s Process Validation
Guidance
• Introduction
This guidance covers the following categories of drugs:
− Human drugs
− Veterinary drugs
− Biological and biotechnology products
− Finished products and active pharmaceutical
ingredients (APIs or drug substances)
− The drug constituent of a combination (drug and
medical device) product
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13. cGMPs and Process Validation
for Drug Manufacturing
• The Validation Process
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14. II. FDA Process Validation
Guidance
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15. II. FDA Process Validation
Guidance
• Process validation (FDA 1987) is defined
as establishing documented evidence
which provides a high degree of
assurance that a specific process will
consistently produce a product meeting its
predetermined specifications and quality
characteristics.
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16. II. FDA Process Validation
Guidance
• For purpose of the guidance, process
validation (FDA 2011) is defined as the
collection and evaluation of data, from the
process design stage through commercial
production, which establishes scientific
evidence that a process is capable of
consistently delivering quality product.
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17. II. FDA Process Validation
Guidance
• Process validation involves a series of
activities taking place over the lifecycle of
the product and process. The guidance
describes process validation activities in
three stages.
o Stage 1 – Process Design
o Stage 2 – Process Qualification
o Stage 3 – Continued Process Verification
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18. Stage 1 – Process Design
• The commercial manufacturing process is
defined during this stage based on
knowledge gained through development
and scale-up activities.
• Process design may be generally
described as “process understanding” and
“pre-qualification”.
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19. Stage 2 – Process Qualification
• During this stage, the process design is
evaluated to determine if the process is
capable of reproducible commercial
manufacturing.
• Process qualification may be described as
“validation performance” and
“manufacturing qualification”.
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20. Stage 3 – Continued Process
Verification
• Ongoing assurance is gained during
routine production that the process
remains in a state of control.
• Continued process verification may be
simply described as “maintaining
validation” or “life cycle qualification”.
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21. II. FDA Process Validation
Guidance
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22. III. Critical Documentation
Requirements
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23. III. Critical Documentation
Requirements
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24. III. Critical Documentation
Requirements
• Validation policy documents
• Process design documents
• Process qualification documents
• Continued process verification
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25. III. Critical Documentation
Requirements
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26. III. Critical Documentation
Requirements
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28. IV. Interactive Exercise – Case
Study
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29. IV. Interactive Exercise – Case
Study
Process Validation of an API:
An exercise in Submission Preparation
and Inspection Readiness
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30. IV. Interactive Exercise – Case
Study
• 3 Stages of Process Validation
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31. IV. Interactive Exercise – Case
Study
• Relationship of Process Validation to
Submission Preparation and PAI
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32. IV. Interactive Exercise – Case
Study
Process Validation of an API
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33. IV. Interactive Exercise – Case
Study
• Define the Process to Validate
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34. IV. Interactive Exercise – Case
Study
• Phase 1: Define the Manufacturing Process
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35. IV. Interactive Exercise – Case
Study
• Phase 2: Process Validation
Stage 1
Stage 2
Stage 3
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36. IV. Interactive Exercise – Case
Study
• Stage 1: Pre-Qualification
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37. IV. Interactive Exercise – Case
Study
• Stage 1: Pre-Qualification
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38. IV. Interactive Exercise – Case
Study
• Stage 1: Pre-Qualification – Ishikawa Diagram
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39. IV. Interactive Exercise – Case
Study
• Stage 1: Pre-Qualification – Critical Process
Parameters (CPPs)
CPP is the identification of process parameters as
critical based on the review of current data for
acceptable and operating ranges for these
parameters.
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40. IV. Interactive Exercise – Case
Study
• Stage 1: Pre-Qualification – Critical Process
Parameters
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41. IV. Interactive Exercise – Case
Study
• Stage 1: Pre-Qualification – API Pre-
Qualification Report
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42. IV. Interactive Exercise – Case
Study
• Stage 2: Manufacturing Qualification
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43. IV. Interactive Exercise – Case
Study
• Stage 2: Manufacturing Qualification – API
Manufacturing Report
Batch
#1
Batch
#2
Batch
#3
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44. IV. Interactive Exercise – Case
Study
• Stage 3: Life Cycle Qualification
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45. IV. Interactive Exercise – Case
Study
• Phase 2: Process Validation – Lists, References
and Reports for the Validated Process
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46. IV. Interactive Exercise – Case
Study
Submission Preparation and
Inspection Readiness
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47. IV. Interactive Exercise – Case
Study
• API Validation Team Membership
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48. IV. Interactive Exercise – Case
Study
• Coordinating Roles and Responsibilities
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49. IV. Interactive Exercise – Case
Study
API NDA / ANDA Submission
Preparation
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50. IV. Interactive Exercise – Case
Study
• Drug Substance – Chemistry, Manufacturing
and Controls Information
A. Manufacturers
B. Description of Manufacturing Process and Process Controls
1. Flow Diagram
2. Description of the Manufacturing Process and Process
Controls
3. Reprocessing, Reworking and Other Operations
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51. IV. Interactive Exercise – Case
Study
• Drug Substance – Chemistry, Manufacturing
and Controls Information
C. Control of Materials
1. Starting Materials
2. Reagents, Solvents, and Auxiliary Materials
3. Diluents
D. Control of Critical Steps and Intermediates
E. Process Validation and / or Evaluation
F. Manufacturing Process Development
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52. IV. Interactive Exercise – Case
Study
Pre-Approval Inspection
Readiness
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53. IV. Interactive Exercise – Case
Study
• API Site Approval Master Plan
1. Product Description
2. Process
− Manufacturing Instructions
− Historical Batch Performance
− Process Development
− Support Validations
− Process Equipment
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54. IV. Interactive Exercise – Case
Study
• API Site Approval Master Plan
3. Analytical
− Lab Practices
− Analytical Equipment
− Lab Investigations and Method Issues
− Method Validation and Qualification: Site specific and
Outsourced methods
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55. IV. Interactive Exercise – Case
Study
• API Site Approval Master Plan
4. Facility
− Systems and Utilities
− PM/Calibration
− Change Over / Cleaning
− Support Equipment (ie Freezers, stopper and glass washers
etc)
− Environmental Monitoring
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56. IV. Interactive Exercise – Case
Study
• API Site Approval Master Plan
5. Quality and Compliance
− Quality Agreements
− Investigations/Deviations Review/Remediation
− CAPA closeouts
− Training
− Raw Material and Component Management
− Storage and Warehousing
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57. IV. Interactive Exercise – Case
Study
• API Site Approval Master Plan
6. Supply Chain
− Shipping Procedures
− Shipping Validation
7. Stability
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58. IV. Interactive Exercise – Case
Study
• Summary
1. Define Manufacturing Process prior to the start of Process
Validation.
2. Officiate a Validation Team including members from Process,
Manufacturing, QA and RA.
3. Review of protocols and reports to ensure the 3 stages of Process
Validation are completed
4. Coordinate with the team on the validation document for
Submission Preparation and Inspection Readiness
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59. Bonus Material
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60. Bonus Material - A
template
of
process
valida;on
protocol
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61. 25
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