CGMP and Process Validation

CDR Tara Gooen Bizjak

Director, Manufacturing Quality Guidance and Policy Staff
Office of Manufacturing Quality
Office of Compliance, CDER

Compounding Quality Center of Excellence Virtual Conference: Working Together for Patient Safety September 21, 2020
Patients expect safe and effective
medicine with every dose they take.

www.fda.gov 2
Process Validation is the
collection and evaluation of
data which establishes
scientific evidence that a
process is capable of
consistently delivering
quality product throughout
the product lifecycle. 3
 Process Validation Links the Patient, Product
& Process

Patient Clinical
Outcome

Drug Product Critical Quality

Attributes

Material Attributes &

Process Process Parameters
Inputs: Personnel, Machines, Materials,
4
FDA Guidance for Industry, Process Validation: Methods, Measurements, Environment 4
General Principles and Practices (2011)
 General Principles and Practices
• Quality must be designed into the manufacturing process (i.e.,
in-process and release testing is a verification) (21 CFR 211.110(a))
• Variation is a key focus of process validation
– Understanding
– Detecting
– Responding
– Controlling from input through output

“Uncontrolled variation is the enemy of quality.” Dr. W. Edwards Deming

5
 Regulatory Foundation

The CGMP regulations require that

manufacturing processes be
designed and controlled to assure
that in-process materials and the
finished product meet pre-
determined quality requirements,
and do so consistently and reliably.
(21 CFR 211.100(a))

FDA Guidance for Industry, Process Validation: 6

General Principles and Practices (2011)
 Regulatory Foundation
• Written procedures designed to assure product quality attributes (21 CFR 211.100(a))
• In process controls to monitor the output and to validate the performance of those
processes that may cause variability (21 CFR 211.110(a))
• Equipment must be of appropriate design and suitable for its intended use (21 CFR
211.63)
• Representative sampling with statistical confidence and predetermined acceptance
criteria (21 CFR 211.110(b))
• Product quality data is periodically reviewed to determine whether any changes to
the established process are needed (21 CFR 211.180(e))

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 Process Validation Overview

Stage 1 Stage 2 Stage 3

• Development studies; • Qualification to ensure • Monitoring of process and
understanding the equipment is suitable for its equipment performance
manufacturing process intended use • Improving the process as
• Design of the control • Design and execution of a more information and
strategy based on learning study that demonstrates experience are gained
from studies and risk process robustness
assessment

FDA Guidance for Industry, Process Validation: 8

General Principles and Practices (2011)
 Process Validation: Lifecycle Stages
Description of Activities Goals
Stage 1: Process Design
Lab, pilot, small scale and Functional understanding between
commercial scale studies to parameters (material and process)
establish process based on and quality attributes
knowledge
Stage 2: Process Qualification
 Facility, utilities and equipment Scientific measurable evidence
 Performance Qualification that
(Confirm commercial process  product meets specifications
design) consistently and
 process performance meets
acceptance criteria; reproducible
Stage 3: Continued Process Verification
 Monitor, collect information, Maintain or improve control and
assess during commercialization reduction in product and process
 Maintenance, continuous variability
verification, process improvement FDA Guidance for Industry, Process Validation:
General Principles and Practices (2011)
Journal of Pharmaceutical Sciences, Vol. 55, No. 1,
January 1966

• The new era for quality control statistics may well be in product
design, control system design, or quality control simulation – all
things to be done before the product is ever manufactured”
– Olson, T. and Lee, I., “Application of Statistical Methodology in Quality
Control function of the Pharmaceutical Industry”

10
 Two approaches to learning
Commercial

Tech Transfer

Development

Good planning, expected Poor design, planning,

path process understanding 11
 Stage 1: Process Development
• Connection of incoming and intermediate material attributes to Critical
Quality Attributes (CQAs)
• Connection of process parameters to CQAs
• Can be accomplished by understanding failure modes, through Quality Risk
Management and Design of Experiment (DOE) studies
• Enhance process understanding with scale up and technology transfer
activities
• Consider principles in FDA Guidance on Pharmaceutical Development (Q8),
Quality Risk Management (Q9), and Pharmaceutical Quality System (Q10)

FDA Guidance for Industry, Process Validation:12

General Principles and Practices (2011)
 Stage 1: Control Strategy Development
• Identify process controls for critical points using development data and quality risk
management principles
• Establish monitoring appropriate for each level of the control strategy
• The filed regulatory control strategy is built on a foundation of acceptable CGMP
systems and the facility’s broader controls
• Q8(R2) Pharmaceutical Development

FDA Guidance for Industry, Q8(R2) Pharmaceutical

Development, 2009
Draft FDA Guidance for Industry: Established Conditions,
May 2015
FDA Guidance for Industry, Process Validation: 13
General Principles and Practices (2011)
 Process Validation: Lifecycle Stages
Description of Activities Goals
Stage 1: Process Design
Lab, pilot, small scale and Functional understanding between
commercial scale studies to parameters (material and process)
establish process based on and quality attributes
knowledge
Stage 2: Process Qualification
 Facility, utilities and equipment Scientific measurable evidence
 Performance Qualification that
(Confirm commercial process  product meets specifications
design) consistently and
 process performance meets
acceptance criteria; reproducible
Stage 3: Continued Process Verification
 Monitor, collect information, Maintain or improve control and
assess during commercialization reduction in product and process
 Maintenance, continuous variability
verification, process improvement FDA Guidance for Industry, Process Validation:
General Principles and Practices (2011)
 Stage 2a: Equipment Qualification
(21 CFR 211.63)
• Appropriateness, capability, and reliability of equipment
• Establish typical variation of equipment and whether this is suitable for the process
• Study design should consider the expected demands of the commercial
manufacturing conditions

• Consider commercial phase activities during

process/equipment design (e.g., cleaning, calibration,
maintenance)

FDA Guidance for Industry, Process Validation:15

General Principles and Practices (2011)
 Stage 2b: PPQ Study Design
• Thoughtful design of the Process Performance Qualification (PPQ) protocol is
important to draw meaningful conclusions
• Potential Pitfalls
– Not utilizing development and qualification knowledge
– Missed opportunities to customize the protocol
– Insufficient sampling and/or acceptance criteria
• The completed study should enable manufacturers to determine if the
process is within a state of control*
State of Control: A condition in which the set of controls
consistently provides assurance of continued process
performance and product quality. (FDA Guidance Q10)
FDA Guidance for Industry, Q10 Pharmaceutical Quality
System (2009)
FDA Guidance for Industry, Process Validation: 16
General Principles and Practices (2011)
 Concurrent Release
• “Concurrent release” is meant exclusively in terms of the
process performance qualification (PPQ) study protocol
– Releasing for distribution a lot of finished product, manufactured
following a qualification protocol, that meets the lot release criteria
established in the protocol, but before the entire study protocol has been
executed.

FDA Guidance for Industry, Process Validation:17

General Principles and Practices (2011)
 Concurrent Release
• Why does this matter?
• Under normal circumstances, a firm’s decision to begin to
commercially distribute product from a particular process is based on
having achieved that high degree of assurance threshold.
• Unless there are special circumstances (e.g., orphan drugs, short
shelf-life radiopharmaceuticals, medically necessary drugs to alleviate
short supply) there is no reason to distribute products before that
threshold has been reached.
– For these special circumstances, the process should still be evaluated after
the product is distributed.
– In these special circumstances, the benefit of having these drugs available to
patients is judged to be greater than the risk of a lower degree of assurance.
FDA Guidance for Industry, Process Validation:18
General Principles and Practices (2011)
 Process Validation: Lifecycle Stages
Description of Activities Goals
Stage 1: Process Design
Lab, pilot, small scale and Functional understanding between
commercial scale studies to parameters (material and process)
establish process based on and quality attributes
knowledge
Stage 2: Process Qualification
 Facility, utilities and equipment Scientific measurable evidence
 Performance Qualification that
(Confirm commercial process  product meets specifications
design) consistently and
 process performance meets
acceptance criteria; reproducible
Stage 3: Continued Process Verification
 Monitor, collect information, Maintain or improve control and
assess during commercialization reduction in product and process
 Maintenance, continuous variability
verification, process improvement FDA Guidance for Industry, Process Validation:
General Principles and Practices (2011)
 Stage 3: Continued Process Verification
• Establish a system or systems for detecting unplanned departures from the
process as designed (re-examine criteria periodically)
• Confirmation that the control strategy remains valid
• Continual assurance that the process remains in a state of control
• Identify and implement process and systemic improvements with new
knowledge and process experience (e.g., corrective action, preventive action)
• Regular examination for identification and implementation of process
improvements with new knowledge and experience
– “Annual” product quality reviews may not be sufficient to identify, correct, anticipate, and
prevent problems
– Robust change management is important
FDA Guidance for Industry, Q10 Pharmaceutical Quality http://media2.smashingmagazine.
com/images/science-posters-
System (2009) illustrations/extended%20bell%20
curve.jpg
FDA Guidance for Industry, Process Validation: 20
General Principles and Practices (2011)
 Q10: Facilitate Continual Improvement
To identify and
implement appropriate
product quality
improvements, process
improvements, variability
reduction, innovations
and pharmaceutical
quality system
enhancements, thereby
increasing the ability to
fulfill quality needs
consistently.

FDA Guidance for Industry, Q10 Pharmaceutical Quality

21
System (2009)
 Is Your Process Stable and Capable?
Corrective Actions Reduce “Common Cause” On Continuous
Eliminate “Special Cause” Variability Improvement Path

Minor,
Unstable Frequent,
Occasional
Major
OOS
OOS

LSL USL
Target
Stable- Yes; Capable? Stable & Capable
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Case Studies
 Case Study: Manual Scooping
• What happened
– Prompt release tablet, low dose, two actives, narrow therapeutic
– Inspection identified significant process-related issues:
• Manual scooping of partial drums potentially causing segregation
• Compositing of blend uniformity samples masking variability
– Inspection also identified other issues, including: (1) investigations of out-of-specification
results with inadequate root cause determination and Corrective Action and Preventive
Action (CAPA), (2) complaints involving PPQ batches, (3) use of failing components
– Samples were collected by FDA and failed for potency and content uniformity
• Outcome
– Warning Letter
– Recalled all of this product from the market (multiple strengths)
– Out-of-business at follow-up

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 Case Study: Manual Scooping
• Key Takeaways
– Important to have an adequate ongoing program for monitoring process
control to ensure stable manufacturing operations and consistent drug
quality
– Important to demonstrate that the manufacturing process is reproducible
and controlled
– Important to have a data-driven and scientifically sound analysis that
identifies all sources of variability including, but not limited to, raw materials
and manual steps
– Important to determine the capability of each manufacturing process step
and implement appropriate CAPA
– Important to determine any process improvements needed

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 Case Study: Patches
• What Happened
– After approval of an opioid patch, manufacturer had a problem with the
process at commercial scale (e.g., several non-consecutive PPQ batches did
not pass release testing). The manufacturer implemented many “small”
changes to the process; it was unclear that the manufacturer identified the
root cause of the failures.
• Outcome
– Manufacturer was unable to demonstrate a reproducible and controlled
process and distribute product
• Key Take-Aways
– Investigation into PPQ batch failures was incomplete; the root cause analysis was
inadequate
– PPQ is not the time to find out the process is under-developed

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 Two approaches to learning
Commercial

Tech Transfer

Development

Good planning, expected Poor design, planning,

path process understanding
27
 Future of Pharmaceutical Quality

• Six sigma manufacturing for

higher process capability and
product quality assurance
• Robust process validation is a
data-rich tool for achieving
high quality manufacturing

Yu., L. X.; Kopcha, M. Int. J Pharm. (2017) 528, 354-359

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 Summary: Process Validation

Key Focus - Variation

– Understand
– Detect
– Respond
– Control from input
through output
– Throughout
Lifecycle of Product

“Uncontrolled variation is the enemy of quality.”

Dr. W. Edwards Deming
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