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: Process Design Stage 2a: Equipment &

Facility Qualification

Stage 3: Continued Process Verification Stage 2b: Process

Performance Qualification

Stage 2: Process Qualification

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

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

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”)

Validation = Intensive Testing

"My Bread is Fresh and Tasty”

Can’t test quality into a product

Must design quality into a product

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

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

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

ICH Q10 Pharmaceutical Quality System

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

Annex 15 -EU

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

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

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

FDA PV Guidance

15

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

Life Cycle Approach

Identification of process variables

Control strategy

Process qualification

Process monitoring

and improvement

Process design

PROCESS

VALIDATION

FDA Process Validation 2011 Stage Purpose Activities

Process Design Define commercial process based on

knowledge gained through

development and scale up activities

Outcome: design a process for routine

manufacture that will consistently

deliver product meeting its (critical)

quality attributes

Integrated product and process design

Product development activities

DOE combined with Risk Assessment

to explore process parameters,

variability, effect on quality attributes

and process controls

Process

Qualification

Confirm process design as capable of

reproducible commercial manufacturing

Facility design

Equipment & utilities 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

Process

Verification

Provide ongoing assurance that the

process remains in a state of control

during routine production through

quality procedures and continuous

improvement initiatives

Organized data collection every batch

Data trending and statistical analysis

Product review

Equipment and facility maintenance

Calibration

Management review and production

Employee feedback

Continuous improvement

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

GHTF Guidance 2004

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

PV Decision Tree

Warning Letter

Water System Warning

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

EMA Draft Guideline (March 2012)

Any problems you can see here?

EMA Draft Guideline (March 2012)

EMA Draft Guideline (March 2012)

EMA Draft Guideline (March 2012)

And now to policy and practice: implementation