This workshop examines the approach to Continued Process Verification and demonstrating that your product and process are operating in a state of control and continue to do so over the life of the product. Without any prior coordination, the theme was elaborated by the afternoon speakers once the conference itself was underway. The concept of “step up step down” for adjusting the level of product scrutiny both for process parameters monitoring and for sampling and testing quality attributes was explored and developed.

1. Incorporate CPV and Continual
Improvement into Your Validation Plan
Presented by: Karen S Ginsbury
PCI Pharmaceutical Consulting Israel Ltd
IVT’s 4th Annual Validation Week
Copenhagen, Denmark
March 2013
Stage 1: Stage 2: Process Qualification
Stage 3: Continued
Process
Stage 2a: Equipment & Stage 2b: Process Process Verification
Design
Facility Qualification Performance Qualification

2. To be considered…
• Regulatory requirements for Process Validation
• 21 CFR part 820 QSR
• 21 CFR part 211
• ICH Q10: PQS and Lifecycle
• EU Annex 15 and EU PV Guideline March 2012
• FDA process validation guide January 2011
• GHTF Guidance, 2004
• Inspectional observations and expectations

3. To be considered…
• II. Policy and Practice
• Adopt the lifecycle concept (Validation Policy)
• Policy:
– Post launch for new products
– Legacy products
• CPV templates
• Data collection plan: product / process and CAPA
sources
• Data analysis and feedback

4. To be considered…
III. Continual Improvement through managing
variation
– Studying variables and variation
using DOE in design
– Post Launch Scrutiny and Ongoing verification
– An ongoing exercise to increase efficiency (the real
“lean”)

5. Validation = Intensive Testing
"My Bread is Fresh and Tasty”
Can’t test quality into a product
Must design quality into a product

6. 21 CFR 820 Subpart C:
820.30(f) Design verification
• Each manufacturer shall establish and maintain
procedures for verifying the device design
• Design verification shall confirm that the design
output meets the design input requirements
• The results of the design verification, including
identification of the design, method(s), the date,
and the individual(s) performing the verification,
shall be documented in the DHF

7. 21 CFR 820 Subpart C:
820.30(g) Design validation
• Each manufacturer shall establish and maintain procedures
for validating the device design
• Design validation shall be performed under defined
operating conditions on initial production units, lots, or
batches, or their equivalents
• Design validation shall ensure that devices conform to
defined user needs and intended uses and shall include
testing of production units under actual or simulated use
conditions
• Design validation shall include software validation and risk
analysis, where appropriate
• The results of the design validation, including identification
of the design, method(s), the date, and the individual(s)
performing the validation, shall be documented in the DHF

8. GMP Regulations - cfr
 21 cfr 211.68
Automatic/mechanical/electronic equipment..routinely
calibrated /inspected/checked to assure proper
performance
 21 cfr 211.110
Establish control procedures to assure batch uniformity.
Monitor output, validate performance or manufacturing
processes that may be causing product variability

9. ICH Q10 Pharmaceutical Quality System

10. Annex 15 -EU
DQ, VMP, PQ / PV, Cleaning

11. Annex 15 -EU

12. Validation
Action of proving, in accordance with
principles of GMP, that any procedure,
process, equipment, material, activity or
system actually leads to the expected
results
(see also Qualification)
EU Rules & Guidance for Pharmaceutical Manufacturers
Annex 15

13. Qualification
Action of proving that any equipment
works correctly and actually leads to the
expected results.
The word “validation” is sometimes
widened to incorporate the concept of
qualification
EU Rules & Guidance for Pharmaceutical Manufacturers

14. Annex 15 – “In-Use” Facilities
Qualification of established (in-use) facilities,
systems and equipment
• Evidence should be available to support and
verify the operating parameters and limits for
the critical variables of the operating
equipment
• Additionally, the calibration, cleaning,
preventative maintenance, operating
procedures and operator training procedures
and records should be documented

15. FDA PV Guidance
15

16. Process validation definition
• …the collection and evaluation of data, from
the process design stage throughout
production, which establishes scientific
evidence that a process is capable of
consistently delivering (product meeting its
CQAs and intended use KSG) quality product
• …involves a series of activities taking place
over the lifecycle of the product and process
2011 FDA Guidance

17. Life Cycle Approach
Identification
Process
of process
design
variables
PROCESS
Process VALIDATION
monitoring Control
and strategy
improvement
Process
qualification

18. Stage
FDA Process Validation 2011
Purpose Activities
Process Design Define commercial process based on  Integrated product and process design
knowledge gained through  Product development activities
development and scale up activities  DOE combined with Risk Assessment
Outcome: design a process for routine to explore process parameters,
manufacture that will consistently variability, effect on quality attributes
deliver product meeting its (critical) and process controls
quality attributes
Process Confirm process design as capable of  Facility design
reproducible commercial manufacturing  Equipment & utilities qualification
Qualification
 Process Performance qualification
 Emphasis on use of statistically based
sampling plans, statistically valid
acceptance criteria and statistical
analysis of process data to understand
process consistency and performance
Continued Provide ongoing assurance that the  Organized data collection every batch
Process process remains in a state of control  Data trending and statistical analysis
Verification during routine production through  Product review
quality procedures and continuous  Equipment and facility maintenance
improvement initiatives  Calibration
 Management review and production
 Employee feedback

19. Worst Case
• A condition or set of conditions encompassing
upper and lower processing limits and
circumstances, within standard operating
procedures, which pose the greatest chance
of product or process failure when compared
to ideal conditions
• Such conditions do not necessarily induce
product or process failure
- Annex 15 glossary

20. GHTF Guidance 2004

21. GHTF: PV within the QMS
• Process validation is part of the integrated
requirements of a Quality Management System
• It is conducted in the context of a system including
design and development:
– Control
– Qualiity assurance
– Process control
– CAPA

22. PV Decision Tree

23. Warning Letter

24. Water System Warning

25. And the Big One….
• Failure to establish a written procedure to calibrate, inspect,
and check automated, mechanical, or electronic equipment
used to manufacture drug products to assure proper
performance. [21 CFR 211.68 (a)]
• Specifically, there is no data to demonstrate that production
equipment (two mixers, one filler, a water system) has been
properly validated (installation qualification, operational
qualification, and performance qualification) as acceptable
for its intended uses

26. EMA Draft Guideline (March 2012)
Any problems you can see here?

27. EMA Draft Guideline (March 2012)

28. EMA Draft Guideline (March 2012)

29. EMA Draft Guideline (March 2012)

30. And now to policy and practice:
implementation