THE LIFECYCLE OF PROCESS VALIDATION: AN INDUSTRY CASE STUDY ON CONTINUED PROCESS VERIFICATION (CPV) OUTPUT FROM BIOPHORUM OPERATIONS GROUP (BPOG) COLLABORATION OF BIOTECH COMPANIES Stefanie Pluschkell, Ph.D., Pfizer Inc. Presenting to the CASSS CMC Strategy Forum Japan, Dec 2014 on behalf of the BPOG CPV Workstream

CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

What are the Messages we like to convey?

Science and Risk should Drive Decisions

Not all CMC Changes are created equal

“Bioidentical” expectations are unrealistic

“Non-comparables” are unacceptable

“Fit for Purpose” is better than trying to do Everything

Changing the Address Does not cause Mutations

Repetitious Testing or Inspecting Does not change the result

Innovation and Continuous Improvement benefit from Harmonized standards

Pfizer Confidential │ 2

INDUSTRY CASE STUDY: CONTINUED PROCESS VERIFICATION (CPV) FOR A BIOTECH PRODUCT OUTPUT FROM BIOPHORUM OPERATIONS GROUP (BPOG) COLLABORATION OF BIOTECH COMPANIES

Summary Continued Process Verification (CPV) encompasses a written plan for monitoring a licensed biopharmaceutical manufacturing process, then documenting and reporting the results. CPV reporting provides a basis from which to improve process understanding, and hence risk assessment, control strategy, and ultimately process improvement. This presentation describes one of the first cross-company efforts to be compiled on CPV in response to the FDA’s 2011 process validation guidance. It has been created by representatives from 20+ biopharmaceutical companies, sharing and building knowledge, with support and facilitation from the BioPhorum Operations Group (BPOG) (www.biophorum.com). We describe general approaches to implementing CPV and offer some specific recommendations on the content of a CPV Protocol, along with associated rationale. These recommendations are based on a typical cell culture production process for making a fictitious monoclonal antibody product described in the ‘A-Mab Case Study’. Consequently, these recommendations may not apply directly to specific products or processes, but the principles and concepts described can be considered where applicable.

CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

Outline – Case Study on Continued Process Verification 1. Background on BPOG and CPV Working Team 2. Why CPV? 3. Case Study Paper

4. CPV Plan Construction 5. CPV Execution and Application Example 6. CPV Costs and Benefits 7. Conclusions and Future Opportunities

CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

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1. Background

BioPhorum Operations Group (BPOG) CPV Team CPV Informatics Team

BioPhorum BioPhorum Development Group

 The BioPhorum Operations Group (BPOG) is an industry-wide collaboration to enable networking and to share best practice in the area of Operations.  Beginning in 2008, it now has 26 member companies with over 600 participating representatives.  The community primarily consists of experts from biopharmaceutical drug substance operations, who meet and work together at face-to-face meetings in the USA and Europe, on regular teleconferences and via web meetings.  The group has established best practice on a wide range of quality, engineering and organizational topics considered central to the challenge of mastering effective biotech drug substance operations. CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

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BPOG CPV Team and Operating Company Affiliations Aaron Abel Alekhya Angela Anneli Bert Beth Brett Christian Christopher Cillian Cynthia Dan Darren Derek Eric Gareth Graham Graham Jenny Joerg John Julia

Goerke Hastings Gummaregula White Niemi Frohlich Junker Hanna Menzel Taylor McCabe Ball Baker Whitman Mak Hamann Priestley McCartney McCreath McNay Gampfer Grunkemeier O'Neill

Roche / Genentech FDB Merck & Co Onyx Pfizer Shire Merck & Co Janssen Merck Serono Shire Eli Lilly AstraZeneca GSK BPOG Pfizer Pfizer Shire Eli Lilly FDB Regeneron Baxter Healthcare Bayer Healthcare Merck & Co

CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

Kerry Kevin Kevin Kyle Lada Lilong Madeline Marcus Mark Mark Martha Mike Nicole Otmane Pamela Paul Paul Rajesh Rajesh Ranjit Vijay

Hawitt Legg Pipkins Langham Laenen Huang Roche Boyer DiMartino Smith Rogers Doremus Jackson Boussif O'Brien McCormac Wong Ahuja Beri Deshmukh Chiruvolu

Shire Genzyme Janssen GSK Genzyme Biogen Idec Gallus BMS Amgen Roche / Genetech Abbvie Abbvie Pfizer Sanofi Pasteur Eli Lilly Pfizer Bayer Regeneron Lonza AstraZeneca Amgen

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2. Why CPV? Moving Towards the FDA’s “Desired State”!!

‘Desired State’ for the Pharmaceutical Sector  Maximallyl efficient, agile, flexible pharmaceutical manufacturing sector that produces reliable high-quality products without extensive regulatory oversight.*  This state would encourage: • A regulatory process that is consistent, transparent and science-based • A regulatory process that allows for efficient and effective continuous improvement • A pharmaceutical sector that understands its products and the processes, uses risk assessment/mitigation tools and modern effective quality systems, and takes full ownership of the product

Control Strategy!! A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, inprocess controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10) CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

* Janet Woodcock, CDER, FDA

2. Why CPV?

Control Strategy a Regulatory Expectation! Controlling Variability….. ICH Q8(R2): PHARMACEUTICAL DEVELOPMENT; Current Step 4 version; August 2009

 “A comprehensive pharmaceutical development approach will generate process and product understanding and identify sources of variability.“  “….control of the process such that the variability (e.g., of raw materials) can be compensated for in an adaptable manner to deliver consistent product quality.” ICH Q11: DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES (CHEMICAL ENTITIES AND BIOTECHNOLOGICAL/ BIOLOGICAL ENTITIES): Current Step 4 version dated 1 May 2012

 “ Every drug substance manufacturing process, whether developed through a traditional or an enhanced approach (or some combination thereof), has an associated control strategy.”  Regardless of whether a traditional or enhanced process development approach is taken, the use of upstream controls should be based on an evaluation and understanding of the sources of variability of a CQA.

CPV an integral part of Control Strategy ICH Q10: Pharmaceutical Quality Systems

 Sect. 3.2.i “…….execute a system for the monitoring of process performance and product quality to ensure a state of control is maintained. An effective monitoring system provides assurance of the continued capability of processes and controls to meet product quality and to identify areas for continual improvement.”

CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

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2. Why CPV?

PDA Technical Report #60

Lifecycle Approach to Process Validation

Lifecycle approach to Process Validation……

FDA: Guidance for Industry, Quality Systems Approach to Pharmaceutical CGMP Regulations. U.S. Department of Health and Human Services, Food and Drug Administration, September 2006

•

Stage 1 Process Validation: Process Design

PROCESS & ANALYTICAL DEVELOPMENT

“Building in quality from the development phase and throughout a product’s life cycle”

FDA: Guidance for Industry, Process Validation………. U.S. Department of Health and Human Services, Food and Drug Administration, September 2011

• • •

“The goal of the third validation stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture. “ “A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal.” “Adherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability.”

CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

Stage 2 Process Validation: Process Performance Qualification

Stage 3 Process Validation: Continued Process Verification

PROCESS & ASSAY IMPLEMENTATION

COMMERCIAL MANUFACTURING & LIFE CYCLE MANAGEMENT

Commercial Product PRODUCT DISCONTINUATION

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2. Why CPV?

Reasons to Pursue a Common Approach  Gain consensus of interpretation of CPV requirements as third stage of process validation lifecycle in response to new regulatory guidelines’  Establish consistency of approach within the BioPharm industry. Convenient and clear way to share perspectives across the industry and with regulators  Gain efficiencies across companies to conserve resources. Share the Load! • Resource intensive effort affecting several functions and disciplines • Cross-functional and complex and impacting GMP systems

 An efficient way of obtaining collective feedback from government regulators. • To identify and ultimately realize the benefits of implementing CPV as soon as possible for industry and regulatory agencies alike! CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

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3. CPV Paper

Purpose of Case Study Paper  New Business Process for Biopharmaceutical Industry o Very few articles on the topic and most literature covers only some aspects of the topic o Little experience within Industry in submitting new license applications under these guidelines o To exemplify implementation of Continued Process Verification (CPV)

 Leverage Collective Experience and Expertise o Very few articles written by actual practitioners

o Includes perspectives from wide cross-section of biotech industry participants

 Case Study Format to Include Realistic Examples o Comprehensive industry mock example to illustrate CPV program implementation o Embedded detailed available process design and process development information from widely available prior case study o Convenient and clear way to share perspectives across the industry and with regulators

 Provide Groundwork for further useful discussion on implementation

CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

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3. CPV Paper

Concept and Basis of Case Study  Process description and development taken from industry generated:

“A-mAb: A Case Study in Bioprocess Development”,

CMC Biotech Working Group. 2009 (Available free download at ispe.org) [Exception: Although A-mAb claims a design space, this case study does not address CPV concepts associated with design space implementation]

• Assumes product development based on a “QbD approach” (ICH guidelines Q8, Q9, Q10 and Q11).

 Case study focuses on Drug Substance • Drug Product effort planned (with analogous DP Biophorum group)

 Broad input and contributions from all participating member companies

 Free of charge access to full case study • http://www.biophorum.com/page/123/BPOG-CPV-Case-Study.htm CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

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3. CPV Paper - continued

What does the Case Study contain? Selected Outline Purpose and Scope Roles and Responsibilities References (as used in CPV Plan) Product and Process Description Development of a CPV Strategy – Scope of Data Collection and Analysis Plans – Establishing Initial Control Limits • CPV Execution Plan - Including Lifetime Limits and Other Monitoring - Change control decision tree • Sampling and Data Management - Sample Plans/Templates – Data Entry and Verification – Data Analysis Methods and Responses • Discretionary Elements of Guidance External CPV •Document Slide Packreferences V5.4 • • • • •

18-Feb-15

Process Desccription based on: A-mAb: A Case Study in Bioprocess Development  Assumes a QbD approach But!..... “Regardless of whether a traditional or enhanced process development approach is taken, the use of upstream controls should be based on an evaluation and understanding of the sources of variability of a CQA. Requires risk evaluation to identify Critical Quality Attributes (CQAs) and classification of process parameters linked to product quality (i.e. Critical Process Parameters - CPPs)

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4. CPV Plan Construction:

Objectives and Considerations Objectives of CPV    

Demonstration of consistent robust production within validated parameters Addresses long-term variability (can not all be captured during development cycle) Identify special-cause variation Monitor process changes

Objectives of CPV Plan  Written plan to examine data that establishes process capability and control limits that account for normal process variability  Provide justification for what is included/not included. Explain why included items sufficient to meet CPV plan’s objectives  Should be risk-based (To focus attention on areas of greatest risk)

Considerations for Plan:  Product history and knowledge  Frequency of production  Not required to include every CQA, CPP, CMA, etc. in CPV plan, but provide justification for what is included/not included (why included items sufficient to meet CPV plan’s objectives)  May be possible to aggregate some data sources to establish highly sensitive multivariate performance indicators. PLS model utilized in A-mAb for production bioreactor CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

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4. CPV Plan Construction

QbD Work Flow Leading to Control Strategy and CPV

TPP

QTPP

TPP

Target Product Profile QTPP

CQA

PIA

VMP

SDM

PC

MANUFACTURING

PROCESS & ASSAY IMPLEMENTATION

PROCESS & ANALTICAL DEVELOPMENT

PRODUCT DEVELOPMENT

P&A CS

Class

Eng

Intro

& LIFE CYCLE MANAGEMENT

PPQ

Com

CPM

CPV

CPI

Control Strategy

Quality Target Product Profile (QTPP) CQA

Process Parameter Impact Assessment

 CQAs

Product Quality Attribute Assessment (Identification of CQAs) PIA

VMP

Process Development and Validation Master Planning SDM

Scale-down Model Development and Characterization PC

Process Characterization Class

Parameter (Criticality) Classification

Product-specific Control Strategy

PCS

Engineering Design

 PARs/MARs  CPPs  IPCs

Eng

Process Introduction

Intro

Equipment Commissioning/Validation

Com

PPQ

Process Performance Qualification

Continuous Process Monitoring Continued Process Verification CMC Strategy Forum Japan, Tokyo, December 2014 09-Dec-2014

Continuous Process Improvement

CPM CPV CPI

4. CPV Plan Construction:

Selection of Parameters CQAs, Process Parameters and Attributes

Risk Assessment Impact Potential? Controllability?

Example: Production Culture Bioreactor Step - CPV Recommendations Variable

Class

CPV Plan

CQAs impacted

CPV Recommendation & Justification

Culture duration

CPP

Aggregates, glycosylated glycans, HCP, DNA; can also impact turbidity at harvest, yield variation

Included to establish SPC capability and verify large tolerance for variation

Maximum (dissolved) pCO2

CPP

Glycosylated glycans, deamidated isoforms; also product yield

Included to establish SPC capability and establish correlate with in-vitro cell age (IVCA)

(Bioreactor) pH

CPP

Glycosylated glycans, deamidated isoforms

Included to demonstrate that appropriate monitoring and automated adjustments are properly established

Afucosylated glycans, Galactosylated glycans

CQAs

Not Applicable

Included to verify process consistency

Product yield (titer at harvest)

KPA

Not Applicable

Included to verify process consistency

Antifoam lot

CMA

Residual antifoam C

(Medium) osmolality

CPP

Glycosylated glycans, deamidated isoforms

Time of glucose feeds (hrs since innoculation)

KPP

Not Applicable

CPV Plan

Optional, may be included to track lot changes. If included, test clearance at bulk drug substance for 3 different lots Unnecessary, since large tolerance for variation has been shown. Optional, may be included to verify process consistency

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 Sample plan and frequency Routine test

•

ο

Product variant

•

ο

10 mls