This is a preview of "PDA TR 60-2013". Click here to purchase the full version from the ANSI store.

Technical Report No. 60

Process Validation:
A Lifecycle Approach

Paradigm Change in
Manufacturing OperationsSM

Bethesda Towers
4350 East West Highway
Suite 200
Bethesda, MD 20814 USA
Tel: 1 (301) 656-5900
This is a preview of "PDA TR 60-2013". Click here to purchase the full version from the ANSI store.

PDA Task Force on Technical Report No. 60: Process Validation: A Lifecycle Approach
Authors

Scott Bozzone, Ph.D., Chair, Pfizer, Inc. Raj Jani, Baxter Healthcare Corporation
Harold S. Baseman, Co-Chair, Valsource, LLC Peter F. Levy, PL Consulting, LLC
Vincent Anicetti, Parenteral Drug Association, Keck Michael Long, PhD Concordia Valsource, LLC
Graduate Institute
John McShane, Roche-Genentech, Inc.
John A. Bennan, Ph.D., ComplianceNet, Inc.
Victor G. Maqueda, Sr., Consultant
Michael N. Blackton, Imclone Systems, Inc.
José Luis Ortega, Pharma Mar S.A. Sociedad Unipersonal
Vijay Chiruvolu, Ph.D., MBA, Amgen, Inc.
Elizabeth Plaza, Pharma-Bio Serv, Inc.
Rebecca A. Devine, Ph.D., Consultant to the Bio-
pharmaceutical Industry Praveen Prasanna, Ph.D., Shire Human Genetic
Therapies, Inc.
Stephen Duffy, Covidien, LLC
David Reifsnyder, Roche-Genentech, Inc.
Panna L. Dutta, Ph.D., The Medicines Company
Kurtis Epp, BioTechLogic, Inc. Markus Schneider, Ph.D., Novartis Pharma AG

Igor Gorsky, Shire Pharmaceuticals, Inc. Iolanda Teodor, Baxter Healthcare Corporation
Norbert Hentschel, Boehringer Ingelheim Pharma Mark Varney, Abbott Laboratories
GmbH & Co., KG Alpaslan Yaman, Ph.D., Biotech, Pharma and Device
Pedro Hernandez, Ph.D., PHPD, LLC Consulting, LLC
Irwin Hirsh, Novo Nordisk A/S Wendy Zwolenski-Lambert, Abbott Laboratories

This technical report was developed as part of PDA’s Paradigm Change in Manufacturing Operations (PCMO)
project. The content and views expressed in this Technical Report are the result of a consensus achieved by the
members of the authorizing Task Force, and are not necessarily the views of the organizations they represent.
This is a preview of "PDA TR 60-2013". Click here to purchase the full version from the ANSI store.

Process Validation: A
Lifecycle Approach
Technical Report No. 60

ISBN: 978-0-939459-51-3
© 2013 Parenteral Drug Association, Inc.
All rights reserved.

Bethesda Towers
4350 East West Highway
Suite 200
Bethesda, MD 20814 USA
Tel: 1 (301) 656-5900
Fax: 1 (301) 986-0296
E-mail: [email protected]
Web site: www.pda.org
This is a preview of "PDA TR 60-2013". Click here to purchase the full version from the ANSI store.

Paradigm Change in Manufacturing Operations (PCMOSM)

PDA launched the project activities related to the PCMOSM program in December 2008 to help imple-
ment the scientific application of the ICH Q8, Q9 and Q10 series. The PDA Board of Directors ap-
proved this program in cooperation with the Regulatory Affairs and Quality Advisory Board, and the
Biotechnology Advisory Board and Science Advisory Board of PDA.

Although there are a number of acceptable pathways to address this concept, the PCMO program fol-
lows and covers the drug product lifecycle, employing the strategic theme of process robustness with-
in the framework of the manufacturing operations. This project focuses on Pharmaceutical Quality
Systems as an enabler of Quality Risk Management and Knowledge Management.

Using the Parenteral Drug Association’s (PDA) membership expertise, the goal of the Paradigm
Change in Manufacturing Operations Project is to drive the establishment of ‘best practice’ docu-
ments and /or training events in order to assist pharmaceutical manufacturers of Investigational
Medicinal Products (IMPs) and commercial products in implementing the ICH guidelines on Phar-
maceutical Development (ICH Q8, Q11), Quality Risk Management (ICH Q9) and Pharmaceutical
Quality Systems (ICH Q10).

The PCMO program facilitates communication among the experts from industry, university and regula-
tors as well as experts from the respective ICH Expert Working Groups and Implementation Working
Group. PCMO task force members also contribute to PDA conferences and workshops on the subject.

PCMO follows the product lifecycle concept and has the following strategic intent:
• Enable an innovative environment for continual improvement of products and systems
• Integrate science and technology into manufacturing practice
• Enhance manufacturing process robustness, risk based decision making and knowledge management
• Foster communication among industry and regulatory authorities

The Product Lifecycle

Pharmaceutical Technology Commercial Product

Development Transfer Manufacturing Discontinuation

For more information, including the PCMOSM Dossier, and to get involved, go to
www.pda.org/pcmo
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Table of Contents

1.0  INTRODUCTION...................................................1 4.3.2.4 PPQ Using Bracketing, Matrix,

1.1 Purpose and Scope......................................... 1 and Family Approaches ..................... 36
1.2 Background.................................................... 1 4.3.2.5 Bracketing Approach.......................... 36
4.3.2.6 Matrix Approach ............................... 36
2.0  GLOSSARY OF TERMS.........................................6 4.3.2.7 Family (Grouping) Approach............... 37
4.3.2.8 Process Analytical Technology .......... 38
2.1 Acronyms....................................................... 9
4.3.2.9 Sampling Strategy.............................. 39
3.0 BUILDING AND CAPTURING PROCESS 4.3.2.10 Setting PPQ Acceptance Criteria..... 39
KNOWLEDGE (STAGE 1 — PROCESS DESIGN).10 4.4 PPQ Protocol ................................................ 40
4.5 PPQ Report................................................... 42
3.1 Deliverables from Stage 1
4.6 Transition to Continued Process Verification.43
Process Validation........................................ 12
3.2 Quality Target Product Profile (QTPP)............ 12
5.0 CONTINUED PROCESS VERIFICATION
3.3 Critical Quality Attributes.............................. 13 (STAGE 3) ...........................................................44
3.4 Define the Manufacturing Process ............... 14
3.5 Analytical Methods....................................... 20 5.1 Establishing a Monitoring Program............... 44
3.6 Risk Assessment and Parameter Criticality 5.1.1 Purpose and Strategy.............................. 44
Designation................................................... 20 5.1.2 Documenting the CPV Program............... 44
3.7 Process Characterization.............................. 23 5.1.3 Legacy Products and Continued Process
3.8 Product Characterization Testing Plan........... 23 Verification............................................... 46
3.9 Control Strategy............................................ 24 5.1.4 Demonstrating Continued Process
3.10 Clinical Manufacturing Experience – Batch Verification............................................... 47
Records and Production Data....................... 25 5.1.5 CPV Monitoring Plan................................ 48
3.11 Process Design Report.................................. 26 5.1.6 Data Analysis and Trending..................... 48
3.12 Process Validation Master Plan.................... 26 5.2 Incorporation of Feedback from
3.13 Stage 1 Manufacturing and Technology CPV Monitoring............................................. 49
Considerations.............................................. 26 5.2.1 Quality Systems and CPV........................ 49
5.3 CPV Data Review and Reporting................... 50
4.0 PROCESS QUALIFICATION (STAGE 2)................28
6.0 PROCESS VALIDATION ENABLING SYSTEMS
4.1 Strategies for System Design and
AND TECHNOLOGY.............................................51
Qualification.................................................. 28
4.1.1 Engineering and Design........................... 29 6.1 Application of Risk Management ................... 51
4.1.1.1 Risk Assessment................................ 29 6.1.1 Risk Management in Stage 1 –
4.1.2 Installation............................................... 29 Process Design........................................ 52
4.1.3 Qualification Plan..................................... 29 6.1.2 Risk Management in Stage 2 –
4.1.3.1 Test Functions and Process Qualification............................... 53
Acceptance Criteria............................ 30 6.1.3 Risk Management in Stage 3 –
4.1.4 Maintaining Systems in a Continued Process Verification................ 54
State of Control ...................................... 30 6.1.4 Raw Material Risk Management
4.2 Process Performance Qualification .............. 31 Considerations ........................................ 54
4.2.1 PPQ Readiness........................................ 31 6.2 Statistical Analysis Tools ............................. 55
4.3 Design Strategy for Process Performance 6.2.1 Design of Experiments (DoE)................... 57
Qualification (PPQ)........................................ 33 6.2.2 Statistical Process Control and Process
4.3.1 Use of Prior Knowledge and Stage 1 Capability................................................. 59
Data to Support PPQ................................ 33 6.2.2.1 Statistical Process Control Charts...... 60
4.3.2 PPQ Study Design ................................... 34 6.2.2.1.1 Factors to Consider in Designing a
4.3.2.1 Number of Batches............................. 35 Control Chart................................... 62
4.3.2.2 PPQ at Normal Operating Conditions.. 35 6.2.2.1.2 Types of Control Charts................... 62
4.3.2.3 PPQ Using Individual Unit Operation 6.2.2.1.3 Process Capability........................... 62
Studies............................................... 36 6.2.3 Statistical Acceptance Sampling.............. 64
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6.2.4 Number of Lots for Stage 2 Process p×100% lot failure rate.......................... 81
Performance Qualification (PPQ).............. 66 8.1.3 Within and Between Lot Normal Tolerance
6.3 Process Analytical Technology (PAT)............ 66 Intervals................................................. 82
6.3.1 Selection of PAT System.......................... 67 8.1.4 Statistical Process Control Charts ......... 82
6.3.2 Process Validation Considerations 8.1.5 Ppk , Cpk Process Capability Metrics........ 83
During the PAT System Design Stage...... 69 8.1.6 Assure the Lot Conformance
6.3.2.1 Risk Assessment................................ 69 Rate is Above an Acceptable Rate
6.3.2.2 In-Process Application and With Specified Confidence..................... 84
Method Development......................... 69 8.1.7 Wald Sequential Probability Ratio.......... 84
6.3.3 Process Qualification 8.1.8 Narrow Limit Gauging............................ 85
Considerations for PAT............................. 69 8.1.9 Demonstrate Between-Lot Variation is
6.3.4 Continued Process Verification Less Than Within-Lot Variation (Anova) 8. 5
Considerations for PAT............................. 70 8.1.10 Sample Size .......................................... 86
6.4 Technology Transfer ..................................... 70 8.1.11 Demonstrate the Between-Lot Standard
6.5 Knowledge Management.............................. 73 Deviation σb ≤ Acceptable Value X........ 86
8.1.12 Demonstrating equivalence
7.0 EXAMPLES.........................................................75 between lots.......................................... 86
7.1 Large Molecule (Biotech).............................. 75 8.2 Appendix 2: Types of Control Charts............. 87
7.2 Small Molecule (Parenteral).......................... 77 8.2.1 Control Charts for Variables Data............. 87
8.2.2 Control Charts for Attributes Data........... 88
8.0 APPENDICES.......................................................81 8.2.3 Performance of Control Charts:
8.1 Appendix 1: Statistical Methods for Average Run Length (ARL)...................... 88
Determining the Number of Lots................... 81
8.1.1 Average Run Length (ARL) to detect a 9.0 REFERENCES.......................................................89
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FIGURES AND TABLES INDEX

Figure 1.2-1 Applicability of ICH Q8 (R2) through Q11 Figure 6.2.2-1 Process in Classical Statistical Control;
Relative to the FDA Stage Approach to Common Cause Variation only............ 59
Process Validation................................ 3 Figure 6.2.2-2 Process Not in Statistical
Figure 1.2-2 Common Timing of Process Validation Control -Special Cause Variation......... 60
Enablers and Deliverables to Validation Figure 6.2.2-3 A Process with Both Within-lot and
Stage Activities.................................... 5 Between-lot Variation......................... 60
Figure 3.0-1 Overall Sequence of Process Figure 6.2.2.1-1 Xbar/S Control Chart for Fill Weight,
Validation Activities ........................... 11 n=5 per group.............................. 61
Figure 3.4-1 Example Process Diagram for a Figure 6.2.2.1.3-1 Process Capability Statistics Cp
Tangential Flow Filtration Step........... 15 and Cpk........................................... 63
Table 3.4-1 Example Process Parameter Table Figure 6.2.2.1.3-2 Examples of Process Capability
for a Tangential Flow Filtration Step... 16 Statistics Cp and Cpk...................... 63
Figure 3.6-1 Decision Tree for Designating Table 6.2.2.1.3-2 Relationship Between Capability and
Parameter Criticality........................... 22 % or Per Million Nonconforming.... 64
Figure 4.1-1 Typical System Qualification Sequence... 28 Figure 6.2.3-1 Example of an Operating Characteristic
Table 4.1.3-1 Qualification Information..................... 30 Curve.................................................. 65
Figure 4.3.1-1 Relationship of Prior Knowledge to the Table 6.3.3-1 Examples of PAT Tools and Their
Amount of PPQ Data Required............ 33 Application......................................... 68
Table 4.3.2.6-1 Illustration of a Matrix Approach for Table 6.4-1 Technology Transfer Activities
Filling Process PPQ............................. 37 Throughout Product Lifecycle............. 71
Table 4.4-1 Example of PPQ Acceptance Figure 6.4-1 Distribution of Technology Transfer
Criteria Table...................................... 42 Activities throughout the Product
Lifecycle............................................. 73
Figure 5.1.2-1 Development of a Continued Process
Verification Plan.................................. 45 Table 7.1-1 Stage 1: Process Design..................... 75
Figure 5.1.2-2 CPV Plan within Validation Table 7.1-2 Stage 2: Process Qualification
Documentation System...................... 45 (Continued)......................................... 76
Table 7.1-3 Stage 3: Continued Process Verification.......77
Figure 5.1.3-1 CPV Plan Determination for
Legacy Products................................. 47 Table 7.2-1 Stage 1: Process Design..................... 77
Figure 5.2.1-1 Body of Knowledge and Maintenance Table 7.2-2 Stage 2: Process Qualification ........... 79
of Process Control.............................. 49 Table 7.2-3 Stage 3: Continued Process Verification.... 80
Figure 6.1-1 Quality Risk Management: A Lifecycle Table 8.1.2-1 Expected Between-Lot Variation
Tool for Process Development and Coverage in nL Lots............................. 81
Validation............................................ 52
Table 8.1.6-1 Number of lots to demonstrate
Figure 6.1-2 Product Attribute Criticality Risk confidence for lot conformance rate... 84
Assessment Example......................... 53
Figure 8.1.7-1 Wald’s Sequential Probability Ratio
Table 6.1-1 Risk-Based Qualification Planning....... 53 Example.............................................. 85
Table 6.1.2 Severity Rating and Sampling Table 8.1.9-1 Effect of between-lot variation on the
Requirements..................................... 54 total process variance........................ 85
Table 6.2-1 Statistical Methods and the Typical Table 8.1.10-1 Sample Size to estimate a standard
Stages at Which They Are Used........ 56 deviation to within ±X% of true value..... 86
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This is a preview of "PDA TR 60-2013". Click here to purchase the full version from the ANSI store.

1.0  Introduction

1.1 Purpose and Scope

This Technical Report (TR) is intended to provide practical guidance on the implementation of a
lifecycle approach to pharmaceutical process validation (PV). It contains information that enables
manufacturers to implement globally-compliant PV programs consistent with the principles of re-
cent lifecycle-based PV guidance documents and current expectations for Pharmaceutical Quality
Systems (1-4). In pharmaceutical manufacturing, “process validation” is the collection and evaluation
of data -from the process design stage through commercial production that establishes scientific evi-
dence that a process is capable of consistently delivering quality product (3). The U.S. FDA and EMA
consider PV a requirement in both general and specific terms in current Good Manufacturing Prac-
tice (cGMP) guidelines and an essential element in the assurance of drug quality (2,3,5).

The PV lifecycle concept links product and process development, the qualification of the commercial
manufacturing processes, and maintenance of the commercial production process in a coordinated
effort (3). When based on sound process understanding and used with quality risk management prin-
ciples, the lifecycle approach allows manufacturers to use continuous process verification (enhanced
approach) in addition to, or instead of, traditional PV (1,2,6).

The information in this TR applies to the manufacturing processes for drug substances and drug
products, including:
• Pharmaceuticals, sterile and non-sterile
• Biotechnological/biological products, including vaccines
• Active Pharmaceutical Ingredients (APIs)
• Radiopharmaceuticals
• Veterinary drugs
• Drug constituents of combination products (e.g., a combination drug and medical device)

This report is prepared for global use and applies to new and existing (i.e., legacy) commercial manu-
facturing processes. Its scope does not include manufacturing processes for:
• Medical devices
• Dietary supplements
• Medicated feed
• Human tissues

Although these product categories are outside the scope of this TR, its recommendations are based
on modern quality concepts, ICH Quality Guidelines, and recent regulatory authority guidance docu-
ments. As such, it may be a useful reference in the development of PV lifecycle approaches for other
product categories. The validation of ancillary supporting operations used in pharmaceutical manu-
facturing processes is not discussed in the report. Many PDA TRs already provide specific guidance for
such procedures; for example, cleaning, aseptic process simulation, moist heat sterilization and dry
heat sterilization (7-10).

1.2 Background
The lifecycle concept includes all phases in the life of a product from initial development through
commercial production and product discontinuation (4,11). The use of a lifecycle approach to phar-
maceutical product quality is widely thought to facilitate innovation and continual improvement as
well as strengthen the link between pharmaceutical development and manufacturing (ICH Q10). The
lifecycle philosophy is fundamental in the ICH guidance documents for Pharmaceutical Develop-

Technical Report No. 60 © 2013 Parenteral Drug Association, Inc. 1