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Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability...

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Process Performance Qualification Demonstrating a High Degree of Assurance in Stage 2 of the Process Validation Lifecycle
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Page 1: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Process Performance Qualification

Demonstrating a High Degree of Assurance in Stage 2 of the Process Validation Lifecycle

Page 2: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of
Page 3: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

A LIFECYCLE Approach to Process Validation?

The Validation Group Management

Lifecycle [ICH Q8(R2)]: All phases in the life of a product from the initial

development through marketing until the product’s discontinuation.

Page 4: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Medical Devices

• Global Harmonization Task Force Process Validation Guidance Reference

• The Power of Process Validation in Devices

Stage 1 – Process Development

• Large Molecule Development: Always an Enhanced Approach

• Enablers

Stage 2 – Process Performance Qualification

• A High Degree of Assurance

• PPQ: What could possibly go wrong?

Stage 3 - Continued Process Verification

• Leveraging Quality Planning to Achieve High Level of Assurance

The views expressed are solely those of the presenter

Page 5: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

“Quality Management Systems – Process Validation Guidance”

Global Harmonization Task Force – Medical Devices Referenced in US FDA Guidance for Industry “Process Validation: General Principles and Practices” January 2011

Similarities between GHTF and FDA Guidances • Similar lifecycle approach

• Use of statistical methods emphasized

• Robust Quality Systems expected to support the an on-going state of control

“The product should be designed robustly enough to withstand variations in the manufacturing process…process should be capable and stable to assure continued safe products that perform adequately”

“Process Validation is conducted in the context of a system including design and development control, quality assurance, process control and corrective and preventative action.”

Page 6: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

“Process Validation is a term used in the medical device industry to indicate that a process has been subject to such scrutiny that the result of the process …can be practically guaranteed”

Page 7: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Auto-Injector Components: A High Degree of Assurance

Injection Molding (Theoretical Example)

12 cavity mold (each cavity = 1 part)

120 second cycle

Tool Qualification: Dimensional Inspection

1 part X 0.5 cycles X 60 minutes = 30 parts

cycle minute hour hour

Cycle Validation X 3:

Parameter range high, midpoint, low

12 parts X 0.5 cycles X 60 minutes = 360 parts

cycle minute hour hour

Page 8: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

A High Degree of Assurance

Medical Devices • Design and Development Controls • Process Validation (IQ, OQ, PQ) • Monitor and Control / Revalidation

Engineering Focus: Adequate component sample sizes = Heavy reliance on statistical methods

Biopharmaceuticals • Development • Process Qualification • Continued Process Verification

Life Science Focus: Biological systems, few data = Additional measures where statistics alone may be impractical.

Page 9: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

“Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product.”

• Stage 1 – Which and how much data can be used in conjunction with PPQ data to provide confidence the continuing process control?

• Commercial Manufacturing – How much commercial scale data is needed?

• Established platform manufacturing - Less?

• Contract manufacturing organizations – More?

• Quality System - Can the quality system support an ongoing state of control?

• Has Stage 1 process and product knowledge been integrated into the system?

Stage 1 Development

Stage 2 Process Qualification

Stage 3 Continued Process Verification

High Degree of Assurance at End of Stage 2

Page 10: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Analytical Characterization

ICH Q6B

Process Development and

Characterization

ICH Q8

Risk and Criticality Assessments

ICH Q9

Cell Line Qualification

ICH Q5A, Q5B, Q5D

Comparability

ICH Q5E

Stability Testing

ICH Q5C

Clinical

Manufacturing

ICH Q7

The complexity of the molecule and manufacturing processes have necessitated enhanced approaches to development

Stage 1: An Enhanced Approach in Biopharma

Page 11: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Complex Structure and Properties

1º 4º

2º 3º

Physiochemical Properties

• Structural Heterogeneity

• Post-translational Modifications

• Product Related Substances

Biological Activity

• Higher Order Structure

Immunochemical Properties

“Since the heterogeneity of these products defines their quality, the degree and profile of this heterogeneity should be characterized to assure lot to lot

consistency.” ICH Q6B

Impurities

• Process Related Impurities

• Product Related Impurities

• Degradation Products

Contaminants

• Endogenous Virus

• Adventitious Agents

Quality Attributes can be influenced by Molecular Design, Process Design, and Process Control

Page 12: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

It’s all about Control Strategy

Specifications / Release testing • Clinical Justification most important • Criticality, process capability and delectability

Analysis and Characterization • Process characterization • Extended product characterization / comparability

Process Control and Monitoring • Process and product impurities • Raw materials • Process monitoring / in-process testing • Controls, set points, ranges, hold times • Process qualification / validation • Process Data Tracking and Trending

Derived from: S. Kozlowski, P Swann / Advanced Drug Delivery Reviews 58 (2006)

UNKNOWN

Page 13: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Communicating a High Degree of Assurance

Enablers:

• Standardized Terminology

• Knowledge Management

• Quality Systems – Quality Planning

Page 14: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Perspective on Standardized Terminology

“it was recognized from both industry and

regulators that there is a need for standardized

terminology and use of ICH nomenclature when

present. There might be a need for additional

terms such as….”

Page 15: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

A-mAb Product Lifecycle

Page 16: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

A-mAb: Criticality Continuum

Quality Attributes In development, the degree of criticality may be assigned to quality attributes based on potential safety and efficacy consequences. Following comprehensive assessments of scientific evidence and risk, quality attributes are ranked according to the degree of criticality.

Avoids “non-critical” terminology which may suggest uncontrolled.

High Criticality

Quality Attributes

The continuum, as opposed to binary classifications of Critical and Non-Critical, is thought to “more accurately reflect complexity of structure-function relationships and the reality that there is some uncertainty in attribute classification”

Low Criticality

Quality Attributes

Page 17: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Quality Attributes: No “NONs”

ICH Q5E: Quality Attribute A molecular or product characteristic that is selected for its ability to help indicate the quality of the product. Collectively, the quality attributes define identity, purity, potency and stability of the product, and safety with respect to adventitious agents. Specifications measure a selected subset of the quality attributes.

Quality Attributes

Critical

Quality

Attributes

ICH Q6B: Product-Related Substances Molecular variants of the desired product formed during manufacture and/or storage which are active and have no deleterious effect on the safety and efficacy of the drug product. These variants possess properties comparable to the desired product and are not considered impurities.

Page 18: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

A-mAb Process Parameter Classification

Reproduced/Derived from A-mAb Case study

Page 19: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Process Performance

“Input parameters that must be controlled within a narrow range and are essential for optimum process performance.”

Key process parameters do not affect critical quality attributes.

Page 20: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Standardized Terminology: Control and Criticality

?

If a parameter

controllability is high

risk even within the

design space, can

this be considered a

state of control?

Should a robust

control strategy

provide

assurance that all

process

parameters are

well-controlled?

Page 21: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Process Control Strategy Vocabulary

ControlCan the variable be

controlled?

No

Process OutputProcess Performance Attribute

or

Product Quality Attribute

Process Variable

Yes

Process Input Process Parameter

Functional Relationships and Parameter Classification

Critical Process Parameters Critical Quality Attributes

Key Process Parameters Process Performance Attributes Non-Key Parameters Low Risk of Impact

Page 22: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Process Performance Attributes

Process performance monitoring: Maintaining a state of control • Monitoring of product quality attributes alone incomplete - changes in

process performance may represent “early warning sign”

• Monitored, tracked, trended in Continued Process Verification

• Process performance attributes demonstrate inter-batch consistency

Production

Bioreactor

Key Parameter:

Osmolality

Performance Attribute:

Antibody Titer

IEX

Chromatography

Key Parameter:

Load Conductivity

Performance Attribute:

Recovery

Page 23: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Documentation and Knowledge Management

“In all stages of the product lifecycle, good project management and

good archiving that capture scientific knowledge will make the

program more effective and efficient.”

Page 24: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Turning Documents into Knowledge

Engaging the Quality Unit early can be a wise investment in

managing documents and knowledge!

QA?

Engage the Quality Group to enable knowledge management • Comprehensively communicating a high degree of assurance through

PPQ reports and in S.2.5 is more likely • Ensure knowledge integration into the quality system (ICH Q10)

Page 25: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Documentation and Knowledge Management

Development

Reports

Analytical

Reports

Batch

Records

Qualification

Reports

Technical

Summary

Process Development

Product Characterization

Pilot Scale Production

Robustness Studies

Risk Assessment

Lifecycle Document

FMEA

Report

Page 26: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

PPQ Protocols and Reports: Comprehensive Story

PPQ documents as tools to describe a high degree of assurance

• Provide a comprehensive description of the control strategy. – Include “non-critical” process variables even though only a subset of

parameters and attributes will comprise PPQ

• Describe how the subset of PPQ parameters and attributes demonstrates a state of control

• Reference appropriate stage 1 data and discuss relevance.

• PPQ Acceptance Criteria – How established and why

TELL THE WHOLE STORY / MAKE NO ASSUMPTIONS

Page 27: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Stage 2: High Degree of Assurance

Qualification of Facilities, Utilities, and Equipment Contamination Control Strategy

• Facilities Flow and segregation

• Equipment Preventative Maintenance

• Procedures Changeover

• Monitoring Environmental, Process Gas, Water

• Validation

• Cleaning and Sterilization

• Membrane & Resin Lifetime

• Bioburden & Endotoxin Limits (and on-going monitoring)

Page 28: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Specifications,

Acceptance Criteria,

Action Limits

Product

Characterization

Quality Systems

and GMP

Raw Materials

Analysis

In-Process

Testing

Stability

Testing

Release

Testing

Process Controls

and Monitoring

Qualification of Process Performance: Process Control Strategy

Page 29: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

PPQ Not Limited to Stage 2

• Scaled down predictive, qualified models – Viral Spiking Studies – (ICH Q5) Stage 1

– Process Robustness – (ICH Q8) Stage 1

– Impurity Clearance – (ICH Q8) Stage 1, 2

– Chromatography Resin Lifetime – Stages 1, 2, 3

• Extended Analytical Product Characterization – Structure Function Relationships (ICH Q6B) – Stage 1

– Comparability (ICH Q5E) – Stages 1, 2, 3

• Real Time (Parametric) Release – Viral inactivation and clearance parameters Stage 3

– Impurity clearance: DNA, Protein A Stage 3

Page 30: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Enhanced Sampling During PPQ

Filtration Viral

Inactivation

Cation

Exchange

Capture Viral

Removal

Filtration

Anion

Exchange

Filtration

Routine Samples

Characterization-Demonstrates comparability

Impurity Clearance – Validates small scale models

Protein Stability – Qualifies non-microbial hold time

Page 31: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Perspective on Enhanced Sampling

Enhanced sampling and testing to be discontinued after PPQ: • PPQ is fully supportive of the predictive small scale models (impurities:

Protein A, DNA)

Enhanced sampling to continue: • Unexpected results obtained in PPQ

• Trends suspected in PPQ data

Plan for data collected FIO (significant variability estimates): • Rationale for continued sampling

• Plan for evaluation of accumulated data

• Timeframe or amount of data needed to for decision on continuation.

“We recommend continued monitoring and sampling …at the level established during the process qualification stage until sufficient data are available to generate significant variability estimates”

Page 32: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Use of Statistical Methods at End of Stage 2

Likely to rely on means other than statistics alone to achieve a high degree of assurance

Often insufficient data to correctly apply traditional statistics.

• Few clinical batches

• Limited number of commercial scale batches

• Statistically based sampling plans not useful for homogeneous bulk pools

Achieving a high degree of assurance with limited use of statistics requires clear, comprehensive rationale with references to supporting studies conducted in Stage 1.

Page 33: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Quality Planning for Commercial Manufacturing What to Measure, Where to use Statistics

Inoculum

Expansion

Seed

Bioreactors

Production

Bioreactor Thaw

Quality Plan / CPV Plan finalized at end of Stage 2. • What is to be measured and why, accounting for interactions • Statistical methods to be used for data evaluation. • Frequency with which data will be evaluated • Frequency of Management Review

Action Limits and Acceptance Criteria Statistical Monitoring

Page 34: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Feed Rate / Volume

increased after 1st

PPQ run to to increase

titer.

What next?

Production Chromatography Operations Drug Substance

Bioreactor

Titre

(2.7 – 4.0)

Recovery

Capture

(70-100)

Recovery

AEX

(90-100)

Recovery

CEX

(90-100)

Acidic

Variants

(25-35)

Oxidation

(3-10)

Aggregate

<4%

Process Performance Attributes Quality

Attribute

Critical Quality Attributes

Pilot 1 3.5 97 99 80* 25 10 2.0%

Pilot 2 3.9 95 99 90 30 5 3.1%

Pilot 3 3.0 93 95 99 28 7 2.6%

Pilot 4 3.2 91 92 92 27 5 3.0%

Pilot 5 3.8 98 100 97 30 10 1.9%

Eng 2.6 86 95 98 28 8 3.0

PPQ 2.7 89 98 90 22 7 2.0%

PPQ 3.5 90 97 95 23 9 2.2%

PPQ 3.2 91 96 89 25 9 1.8%

Unexpected Results in PPQ

Page 35: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Unexpected PPQ Results: High Degree of Assurance in Continued Process Verification

“… a reduced number of batches cannot adequately capture the expected process variability at commercial manufacturing scale. To provide continued assurance that the process remains in a state of control throughout the life of commercial manufacturing, we will create a multivariate statistical partial least squares model (PLS) as part of continued process verification.”

Page 36: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Appropriate Statistical Methods

“PLS is more powerful than standard univariate Statistical Process Control (SPC) approaches in that it ensures that the internal correlations among the different variables are also considered. For example if at any given time the titer is lower than expected for the measured viable cell concentration, the PCA model will be able to detect this as a potential out of norm signal even if both parameters are within their respective univariate ranges.

Thus, a PLS model can be used to create a fingerprint of the process that detects a larger number of potential shifts, trends and excursions that would not be detected by univariate monitoring tools.”

Page 37: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Quality System: Alert and Action Limits

“For those parameters that are not built into this PLS model, additional monitoring such as univariate SPC charts, and other routine process monitoring will be carried out. Because of its utility as a process monitoring tool, the PLS model will also have alert and action limits; and when the process result exceeds the action limit a deviation will be initiated.”

Page 38: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Quality System and Planning Supports CPV

Management

Review

Feedback Loop

Adjust Process

Feedback Loop

Avoid Surprise

Feedback Loop

Root Cause

Qualification

Plan / Schedule

Data Collection and Evaluation

Trending and Calculations

Change Control System

Deviation System

Complaint System

Continued Facility Maintenance

Feedback Loop

No overreaction

Page 39: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Acknowledgements

The A-mAb Case Study Team – Abbott

– Amgen

– Eli Lilly

– Genentech

– GSK

– MedImmune

– Pfizer

Page 40: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Back Up

Page 41: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Process: Monoclonal Antibody Production

Thaw:

Working Cell

Bank

Harvest-

Centrifugation /

Depth Filtration

Filtration Viral

Inactivation

Cation

Exchange Capture

Protein A

Viral

Removal

Filtration

Anion

Exchange

Filtration

Inoculum

Expansion

Seed

Bioreactors Production

Bioreactor

Antibodies

Produced

Page 42: Process Performance Qualification€¦ · Cell Line Qualification ICH Q5A, Q5B, Q5D Comparability ICH Q5E Stability Testing ICH Q5C Clinical Manufacturing ICH Q7 The complexity of

Quality Group to Enable the KM Program

GMP

Pharmaceutical

Development

Commercial

Manufacturing Discontinuation

Technology

Transfer

Investigational products

Management Responsibilities

Process Performance & Product Quality Monitoring System

Corrective Action / Preventive Action (CAPA) System

Change Management System

Management Review

PQS

elements

Knowledge Management

Quality Risk Management Enablers


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