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PDA TR60

Technical Report No. 60 Process Validation:

A Lifecycle Approach

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

Authors

Scott Bozzone, Ph.D., Chair, Pfizer, Inc.

Harold S. Baseman, Co-Chair, Valsource, LLC Vincent Anicetti, Parenteral Drug Association, Keck Graduate Institute

John A. Bennan, Ph.D., ComplianceNet, Inc. Michael N. Blackton, Imclone Systems, Inc.

Vijay Chiruvolu, Ph.D., MBA, Amgen, Inc. Rebecca A. Devine, Ph.D., Consultant to the Bio-pharmaceutical Industry

Stephen Duffy, Covidien, LLC

Panna L. Dutta, Ph.D., The Medicines Company Kurtis Epp, BioTechLogic, Inc.

Igor Gorsky, Shire Pharmaceuticals, Inc.

Norbert Hentschel, Boehringer Ingelheim Pharma GmbH & Co., KG

Pedro Hernandez, Ph.D., PHPD, LLC

Irwin Hirsh, Novo Nordisk A/S Raj Jani, Baxter Healthcare Corporation

Peter F. Levy, PL Consulting, LLC

Michael Long, PhD Concordia Valsource, LLC John McShane, Roche-Genentech, Inc.

Victor G. Maqueda, Sr., Consultant

José Luis Ortega, Pharma Mar S.A. Sociedad Unipersonal Elizabeth Plaza, Pharma-Bio Serv, Inc.

Praveen Prasanna, Ph.D., Shire Human Genetic Therapies, Inc.

David Reifsnyder, Roche-Genentech, Inc.

Markus Schneider, Ph.D., Novartis Pharma AG Iolanda Teodor, Baxter Healthcare Corporation Mark Varney, Abbott Laboratories

Alpaslan Yaman, Ph.D., Biotech, Pharma and Device Consulting, LLC

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.

Process Validation: A Lifecycle Approach Technical Report No. 60

ISBN: 978-0-939459-51-3

? 2013 Parenteral Drug Association, Inc.

Paradigm Change in Manufacturing Operations (PCMO SM )

PDA launched the project activities related to the PCMO SM 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 W orking Groups and Implementation W orking 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

Product Discontinuation

Commercial Manufacturing

Technology Transfer

Pharmaceutical Development

The Product Lifecycle

1.0 INTRODUCTION (1)

1.1 Purpose and Scope (1)

1.2 Background (1)

2.0 GLOSSARY OF TERMS (6)

2.1 Acronyms (9)

3.0 BUILDING AND CAPTURING PROCESS

KNOWLEDGE (STAGE 1 — PROCESS DESIGN) 10

3.1 Deliverables from Stage 1

Process Validation (12)

3.2 Quality Target Product Profile (QTPP) (12)

3.3 Critical Quality Attributes (13)

3.4 Define the Manufacturing Process (14)

3.5 Analytical Methods (20)

3.6 Risk Assessment and Parameter Criticality

Designation (20)

3.7 Process Characterization (23)

3.8 Product Characterization Testing Plan (23)

3.9 Control Strategy (24)

3.10 Clinical Manufacturing Experience – Batch

Records and Production Data (25)

3.11 Process Design Report (26)

3.12 Process Validation Master Plan (26)

3.13 Stage 1 Manufacturing and Technology

Considerations (26)

4.0 PROCESS QUALIFICATION (STAGE 2) (28)

4.1 Strategies for System Design and

Qualification (28)

4.1.1 Engineering and Design (29)

4.1.1.1 Risk Assessment (29)

4.1.2 Installation (29)

4.1.3 Qualification Plan (29)

4.1.3.1 Test Functions and

Acceptance Criteria (30)

4.1.4 Maintaining Systems in a

State of Control (30)

4.2 Process Performance Qualification (31)

4.2.1 PPQ Readiness (31)

4.3 Design Strategy for Process Performance

Qualification (PPQ) (33)

4.3.1 Use of Prior Knowledge and Stage 1

Data to Support PPQ (33)

4.3.2 PPQ Study Design (34)

4.3.2.1 Number of Batches (35)

4.3.2.2 PPQ at Normal Operating Conditions .35

4.3.2.3 PPQ Using Individual Unit Operation

Studies (36)

4.3.2.4 PPQ Using Bracketing, Matrix,

and Family Approaches (36)

4.3.2.5 Bracketing Approach (36)

4.3.2.6 Matrix Approach (36)

4.3.2.7 Family (Grouping) Approach (37)

4.3.2.8 Process Analytical Technology (38)

4.3.2.9 Sampling Strategy (39)

4.3.2.10 Setting PPQ Acceptance Criteria (39)

4.4 PPQ Protocol (40)

4.5 PPQ Report (42)

4.6 Transition to Continued Process Verification 43

5.0 CONTINUED PROCESS VERIFICATION

(STAGE 3) (44)

5.1 Establishing a Monitoring Program (44)

5.1.1 Purpose and Strategy (44)

5.1.2 Documenting the CPV Program (44)

5.1.3 Legacy Products and Continued Process

Verification (46)

5.1.4 Demonstrating Continued Process

Verification (47)

5.1.5 CPV Monitoring Plan (48)

5.1.6 Data Analysis and Trending (48)

5.2 Incorporation of Feedback from

CPV Monitoring (49)

5.2.1 Quality Systems and CPV (49)

5.3 CPV Data Review and Reporting (50)

6.0 PROCESS VALIDATION ENABLING SYSTEMS

AND TECHNOLOGY (51)

6.1 Application of Risk Management (51)

6.1.1 Risk Management in Stage 1 –

Process Design (52)

6.1.2 Risk Management in Stage 2 –

Process Qualification (53)

6.1.3 Risk Management in Stage 3 –

Continued Process Verification (54)

6.1.4 Raw Material Risk Management

Considerations (54)

6.2 Statistical Analysis Tools (55)

6.2.1 Design of Experiments (DoE) (57)

6.2.2 Statistical Process Control and Process

Capability (59)

6.2.2.1 Statistical Process Control Charts (60)

6.2.2.1.1 Factors to Consider in Designing a

Control Chart (62)

6.2.2.1.2 Types of Control Charts (62)

6.2.2.1.3 Process Capability (62)

6.2.3 Statistical Acceptance Sampling .............

6.2.4 Number of Lots for Stage 2 Process

Performance Qualification (PPQ) (66)

6.3 Process Analytical Technology (PAT) (66)

6.3.1 Selection of PAT System (67)

6.3.2 Process Validation Considerations

During the PAT System Design Stage (69)

6.3.2.1 Risk Assessment (69)

6.3.2.2 In-Process Application and

Method Development (69)

6.3.3 Process Qualification

Considerations for PAT (69)

6.3.4 Continued Process Verification

Considerations for PAT (70)

6.4 Technology Transfer (70)

6.5 Knowledge Management (73)

7.0 EXAMPLES (75)

7.1 Large Molecule (Biotech) (75)

7.2 Small Molecule (Parenteral) (77)

8.0 APPENDICES (81)

8.1 Appendix 1: Statistical Methods for

Determining the Number of Lots (81)

8.1.1 Average Run Length (ARL) to detect a

p×100% lot failure rate (81)

8.1.3 Within and Between Lot Normal Tolerance

Intervals (82)

8.1.4 Statistical Process Control Charts (82)

8.1.5 P

, C

Process Capability Metrics (83)

8.1.6 Assure the Lot Conformance

Rate is Above an Acceptable Rate

With Specified Confidence (84)

8.1.7 Wald Sequential Probability Ratio (84)

8.1.8 Narrow Limit Gauging (85)

8.1.9 Demonstrate Between-Lot Variation is

Less Than Within-Lot Variation (Anova) 85

8.1.10 Sample Size (86)

8.1.11 Demonstrate the Between-Lot Standard

Deviation σ

≤ Acceptable Value X (86)

8.1.12 Demonstrating equivalence

between lots (86)

8.2 Appendix 2: Types of Control Charts (87)

8.2.1 Control Charts for Variables Data (87)

8.2.2 Control Charts for Attributes Data (88)

8.2.3 Performance of Control Charts:

Average Run Length (ARL) (88)

9.0 REFERENCES (89)

FIGURES AND TABLES INDEX

Figure 1.2-1Applicability of ICH Q8 (R2) through Q11

Relative to the FDA Stage Approach to

Process Validation (3)

Figure 1.2-2 Common Timing of Process Validation

Enablers and Deliverables to Validation

Stage Activities (5)

Figure 3.0-1Overall Sequence of Process

Validation Activities (11)

Figure 3.4-1 Example Process Diagram for a

Tangential Flow Filtration Step (15)

Table 3.4-1 Example Process Parameter Table

for a Tangential Flow Filtration Step ..16 Figure 3.6-1 Decision Tree for Designating

Parameter Criticality (22)

Figure 4.1-1 Typical System Qualification Sequence ..28 Table 4.1.3-1Qualification Information (30)

Figure 4.3.1-1Relationship of Prior Knowledge to the

Amount of PPQ Data Required (33)

Table 4.3.2.6-1 Illustration of a Matrix Approach for

Filling Process PPQ (37)

Table 4.4-1Example of PPQ Acceptance

Criteria Table (42)

Figure 5.1.2-1Development of a Continued Process

Verification Plan (45)

Figure 5.1.2-2 CPV Plan within Validation

Documentation System (45)

Figure 5.1.3-1 CPV Plan Determination for

Legacy Products (47)

Figure 5.2.1-1 Body of Knowledge and Maintenance

of Process Control (49)

Figure 6.1-1 Quality Risk Management: A Lifecycle

Tool for Process Development and

Validation (52)

Figure 6.1-2 Product Attribute Criticality Risk

Assessment Example (53)

Table 6.1-1Risk-Based Qualification Planning (53)

Table 6.1.2 Severity Rating and Sampling

Requirements (54)

Table 6.2-1 Statistical Methods and the Typical

Stages at Which They Are Used .......56Figure 6.2.2-1 Process in Classical Statistical Control;

Common Cause Variation only (59)

Figure 6.2.2-2 Process Not in Statistical

Control -Special Cause Variation (60)

Figure 6.2.2-3 A Process with Both Within-lot and

Between-lot Variation (60)

Figure 6.2.2.1-1Xbar/S Control Chart for Fill Weight,

n=5 per group (61)

Figure 6.2.2.1.3-1Process Capability Statistics C

and C

(63)

Figure 6.2.2.1.3-2Examples of Process Capability

Statistics C

and C

(63)

Table 6.2.2.1.3-2Relationship Between Capability and

% or Per Million Nonconforming (64)

Figure 6.2.3-1Example of an Operating Characteristic

Curve (65)

Table 6.3.3-1Examples of PAT Tools and Their

Application (68)

Table 6.4-1 Technology Transfer Activities

Throughout Product Lifecycle (71)

Figure 6.4-1 Distribution of Technology Transfer

Activities throughout the Product

Lifecycle (73)

Table 7.1-1 Stage 1: Process Design (75)

Table 7.1-2 Stage 2: Process Qualification

(Continued) (76)

Table 7.1-3 Stage 3: Continued Process Verification (77)

Table 7.2-1 Stage 1: Process Design (77)

Table 7.2-2 Stage 2: Process Qualification (79)

Table 7.2-3 Stage 3: Continued Process Verification (80)

Table 8.1.2-1Expected Between-Lot Variation

Coverage in n

Lots (81)

Table 8.1.6-1Number of lots to demonstrate

confidence for lot conformance rate ..84 Figure 8.1.7-1Wald’s Sequential Probability Ratio

Example (85)

Table 8.1.9-1Effect of between-lot variation on the

total process variance (85)

Table 8.1.10-1Sample Size to estimate a standard

deviation to within ±X% of true value (86)

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

? V eterinary 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.

ment (ICH Q8 (R2)), Quality Risk Management (ICH Q9) (12), Pharmaceutical Quality Systems (ICH

Q10), and Development and Manufacture of Drug Substances (ICH Q11). The principles they contain

provide the product lifecycle framework and quality system enablers that have been used in recent

pharmaceutical process validation guidance documents. A central concept in these documents is that

PV is not a one-time event, but rather, an activity that spans the product lifecycle, linking process de-

velopment, validation of the commercial manufacturing process, and its maintenance during routine

commercial production.

The ICH Q8 (R2) guidance document for pharmaceutical development defines procedures for link-

ing product and process development planning to the final commercial process control strategy and

quality system. It describes an enhanced scientific and risk-based approach to product and process

development that emphasizes statistical analysis, formal experimental design, and the incorporation

of knowledge gained from similar products and processes. Manufacturing capabilities and the quality

system must be integrated into the process development plan to ensure effective and compliant com-

mercial operations. The functionality and limitations of commercial manufacturing equipment are a

primary consideration in the process design.

The ICH Quality Risk Management guidance document (ICH Q9) describes the use of a risk-based

approach to pharmaceutical development and manufacturing quality. These approaches identify and

prioritize those process parameters and product quality attributes with the greatest potential to af-

fect product quality. Specific guidance on the application of the ICH Q9 concepts can be found in

PDA Technical Report 54: Implementation of Quality Risk Management for Pharmaceutical and Biotechnology

Manufacturing Operations and PDA Technical Report 59: Utilization of Statistical Methods for Production

and Business Processes(13,14).The FDA process validation guidance document stresses a risk-based

approach to develop criteria and process performance indicators, and improve the design and execu-

tion of other validation-related activities, such as developing confidence levels and sampling plans (3).

Both the FDA and EMA process validation guidance documents aim to integrate PV activities into the

pharmaceutical quality system. To achieve the goals outlined in ICH Q10, it is essential to integrate

the process design stage into the quality system. Throughout the development effort, product and

process development input and alignment from the Quality Unit are required to ensure compatibility

with the quality system. Key considerations in product and process design include the commercial

control strategy and use of modern quality risk management procedures. Quality and Regulatory

organizational components should be part of the cross-functional product team from the beginning

of the process validation study design. Their participation is essential to ensure that the study design

is compatible with the firm’s quality system, and that submissions will meet regulatory agency ex-

pectations.

The Quality Unit should provide appropriate oversight and approval of process validation studies re-

quired under GMPs. Although not all process validation activities are performed under GMPs (for

example, some Stage 1 – Process Design studies) (4), it is wise to include the Quality and Regulatory

representatives on the cross-functional team. The degree and type of documentation required varies

during the validation lifecycle, but documentation is an important element of all stages of process

validation. Documentation requirements are greatest during the process qualification and verification

stages. Studies during these stages should conform to GMPs and be approved by the Quality Unit.

The Process Validation Master Plan (PVMP) should describe the rationale, overall validation strategy,

and list of specific studies. It should reside within the firm’s quality documentation system (15). A suc-

cessful validation program is one that is initiated early in the product lifecycle and is not completed

until the process or product reaches the end of that lifecycle. A comprehensive corporate policy that 2? 2013 Parenteral Drug Association, Inc. Technical Report No. 60

defines the expectations and commitment to process validation lifecycle principles is the foundation

of a successful validation program. This policy should define the quality management philosophy, components of validation, periodic review or requalification time frames, documentation require-

ments (including a process validation master plan), validation protocols and reports, and responsibili-

ties of key stakeholders within the organization (16).

This TR follows the principles and general recommendations presented in current regulatory process validation guidance documents. Of particular note, is that the TR uses the traditional/nontraditional (enhanced) process validation terminology employed by EMA (1). In this context, nontraditional or enhanced process validation may use Continuous Process Verification as an alternative approach to traditional PV. In the enhanced approach, manufacturing process performance is continuously moni-

tored and evaluated. It is a science and risk-based real-time approach to verify and demonstrate that

a process operates within specified parameters and consistently produces material that meets quality

and process performance requirements.

The FDA three-stage process validation lifecycle nomenclature (Stage 1-Process Design, Stage 2– Pro-

cess Qualification, and Stage 3–Continued Process Verification) is used in this TR. Implementation of

these stages is discussed in detail in Sections 3–5. It should be noted that Continued Process Verifica-

tion and Continuous Process Verification are distinct terms and have different meanings. Continuous Process Verification refers to validating manufacturing processes that utilize advanced manufacturing

and analytical technologies (e.g., PAT systems). FDA uses the term Continued Process Verification generally to mean those activities which maintain the process in a state of control and encompasses

all manufacturing scenarios, i.e., traditional manufacturing, manufacturing employing advanced tech-nologies of any kind or any combination thereof.

These are defined in Section 2.0 and are also discussed later in this TR. Figure 1.2-1 shows the re-lationship between the relevant ICH guidance documents and the FDA stage approach to process

Technical Report No. 60 ? 2013 Parenteral Drug Association, Inc.

This TR is based on the experiences and knowledge of the Task Force on Process Validation: A Lifecy-

cle Approach. It represents a cross-section of industry professionals covering products within its scope

(e.g., large and small molecules, and sterile and non-sterile products), and presents approaches to best

practices that are scientifically sound, good business practices, and designed to meet current regulatory

expectations. The document does not include isolated responses to individual inspection or review is-

sues. These are most often case-by-case requirements particular to specific organizational needs.

The intent of this TR is not to establish mandatory standards, but rather to be a single-source over-

view that complements existing regulatory authority guidance documents. References throughout

the document provide greater detail on various topics. It is always advisable to consult with the ap-

propriate regulatory authorities for agreement on the strategies employed for product development

and lifecycle management strategies.

Figure 1.2-2 illustrates the progression of typical process validation enablers or deliverables relative

to validation activities that are conducted throughout the product lifecycle. The figure represents

stages and validation studies as single “point in time” events. However, in practice, the exact timing

of product development activities or validation studies may vary with the specific product develop-

ment strategy. For example, the enablers for Stage 1 process validation activities will be much less

extensive for a production formulation change than for development of a new molecular entity. Thus,

the figure presents an overall sequence of activities and their approximate correlation to the stages of

process validation.

4? 2013 Parenteral Drug Association, Inc. Technical Report No. 60

Technical Report No. 60 ? 2013 Parenteral Drug Association, Inc.Figure 1.2-2 Common Timing of Process Validation Enablers and Deliverables to Validation Stage Activities

T ools used throughout the lifecycle (e.g., risk management, statistical analysis, Process Analytical T ech-nology [PAT], technology transfer, documentation, and knowledge management) are described in Sec-tion 6.0. Examples of the lifecycle approach for a large and small molecule are described in Section 7.0.

Process Validation Stages

S t a g e 1Process Validation Enablers and Deliverables

Quality Target Product Profile (initial)Quality Attributes Evaluation (initial)

Clinical Process Description

Clinical Production Master Batch Records

Reference Standard(s)

IND APPLICATION

Quality Attributes Evaluation (updated)Quality Target Product Profile (updated)

Process Validation Master Plan Process Parameter – Categorization Process Parameter – Acceptable Ranges

Process Equipment Qualification Protocols and Reports

Commercial Process Description Defined Process Control Strategy

Risk Assessment for Commercial Manufacturing Commercial Production Master Batch Records

Process Performance Qualification

Protocols and Reports

Process Performance Qualification Technical

Summaries for Filing / Inspection REGULATORY LICENSE APPLICATION

Review and Update:Risk Assessments

Process Monitoring Review / Periodic Report

Completion of Lifetime Validation Studies

Product Lifecycle Validation Stage Activities Early Drug Substance Process Development Initial Formulation and DP Process Development Development of PAT and/ or Analytical methodologies

Risk Assessment for Robustness Studies Initiate Formal Stability Studies Clinical Manufacturing

Qualify Manufacturing Equipment & Facility Continued Assay and Process Development Develop and Qualify Scaled — down Models Process Characterization Studies — Clearance,

Robustness, and Other Qualification Studies (Design Space Established, if applicable)

Assay Qualification / Validation

Assess Risk (Process + Equipment + Operation) Implementation of Process Control Strategies Manufacture PPQ Batches

PRE-APPROVAL INSPECTION REGULATORY APPROVAL

Implement Continued Verification Program Commercial Manufacturing & Distribution

Lifecycle Management within Quality System

S t a g e 2S t a g e 3

Terminology usage may differ by company, at individual companies and some terms may be subject to change over time. Those terms used in a validation program should be clearly defined, docu-mented, and well-understood. Terminology definitions that are widely recognized by the industry should be considered when establishing internal definitions. These can be found in regulatory guid-ance documents. Definitions of company-specific terminology should also be included in the valida-tion documents to provide clarity and context. This Technical Report uses the terms below, which are accompanied by their definitions, synonyms, and references where applicable:

Active Pharmaceutical Ingredient (API; Equivalent to Drug Substance for large molecules)

Any substance or mixture of substances intended to be used in the manufacture of a drug (medici-nal) product and that, when used in the produc-tion of drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treat-ment, or prevention of disease or to affect the structure and function of the body (17). Active Pharmaceutical Ingredient (API) Starting Material

A raw material, intermediate, or an API that is used in the production of an API and that is in-corporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a mate-rial purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials normally have defined chemical properties and structures (17). Attributes

Critical Quality Attribute (CQA)

A physical, chemical, biological or microbio-logical property or characteristic that should be within an appropriate limit, range, or distribu-tion to ensure the desired product quality (11). Process Performance Attribute (Synonym – Process Performance Parameter)

An output variable or outcome that cannot be directly controlled, but is an indicator that the process performed as expected (15).

Quality Attribute

A molecular or product characteristic that is

selected for its ability to indicate the quality of the product. Collectively, the quality attributes

define identity, purity, potency and stability of the product, and safety with respect to adven-titious agents. Specifications measure a select-ed subset of the quality attributes (18). Attribute

A physical, chemical, or microbiological prop-erty or characteristic of an input or output ma-terial (19).

Continued Process Verification (CPV) Assuring that during routine production the pro-cess remains in a state of control (3). Continuous Process Verification

An alternative approach to process validation

in which manufacturing process performance is continuously monitored and evaluated (11). Continuum of Criticality

As Used for Parameters

A non-discrete scale where parameters or attri-butes are evaluated relative to their impact on drug substance and drug product quality(3). As Used for Attributes

Following comprehensive assessments of sci-entific evidence and risk, quality attributes are ranked according to the degree of criti-cality. The continuum, as opposed to binary classifications of Critical and Non-Critical, is thought to “more accurately reflect complex-ity of structure-function relationships and the reality that there is some uncertainty around attribute classification”

(20).

6? 2013 Parenteral Drug Association, Inc. Technical Report No. 60

Control Strategy

A planned set of controls, derived from current product and process understanding, which en-sures process performance and product quality. The controls can include parameters and attri-butes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated meth-ods and frequency of monitoring and control (4). Design Space

The multidimensional combination and interac-tion of input variables (e.g., material attributes) and process parameters that have been demon-strated to provide assurance of quality. Working within the design space is not considered a change. Movement out of the design space is considered to be a change, and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval (11). Drug Product (DP)

The dosage form in the final immediate packag-ing intended for marketing (17).

Drug Substance (DS; Equivalent to Active Pharmaceutical Ingredient for small molecules)

The material which is subsequently formulated with excipients to produce the drug product. It can be composed of the desired product, prod-uct-related substances, and product- and process-related impurities. It may also contain excipients including other components such as buffers (21). Formal Experimental Design (Synonym – Design of Experiments)

A structured, organized method for determin-ing the relationship between factors affecting a process and the output of that process (11). Good Engineering Practice (GEP)

Those established engineering methods and standards that are applied throughout the life-cycle to deliver appropriate and cost-effective solutions (22).Intermediate (or In-Process Material)

A material produced during the steps of the pro-

cessing of an API that undergo further molecu-

lar change or purification before it becomes an

API. Intermediates may or may not be isolated (17).

Lifecycle

All phases in the life of a product, from the initial development through marketing until the prod-

uct’s discontinuation (11).

Normal Operating Range (NOR)

A defined range, within (or equal to) the Proven Acceptable Range, specified in the manufactur-

ing instructions as the target and range at which

a process parameter is controlled, while pro-

ducing unit operation material or final product meeting release criteria and CQAs (23).

Parameters

Critical Process Parameter (CPP; Synonym

– Critical Operational Parameter)

A process parameter whose variability has an

impact on a critical quality attribute and there-

fore should be monitored or controlled to en-

sure the process produces the desired quality (11).

Key Process Parameter (KPP; Synonym –

Key Operational Parameter)

An input process parameter that should be carefully controlled within a narrow range

and is essential for process performance. A

key process parameter does not affect product

quality attributes. If the acceptable range is exceeded, it may affect the process (e.g. yield, duration) but not product quality (15).

Non-Key Process Parameter (Non-

KPP; Synonym – Non-key Operational Parameter)

An input parameter that has been demonstrat-

ed to be easily controlled or has a wide accept-

able limit. Non-key operational parameters

may have an impact on quality or process per-formance if acceptable limits are exceeded (15).

Technical Report No. 60 ? 2013 Parenteral Drug Association, Inc.

Process Parameter (Synonym – Operational Parameter)

An input variable or condition of the manufac-turing process that can be directly controlled in the process. Typically, these parameters are physical or chemical (e.g. temperature, process time, column flow rate, column wash volume, reagent concentration, or buffer pH) (15). Platform Manufacturing

Development of a production strategy for a new drug starting from manufacturing processes simi-lar to those used to manufacture other drugs of the same type (the production for which there already exists considerable experience) (6). Process Analytical Technology (PAT)

A system for designing, analyzing, and control-ling manufacturing through timely measure-ments (i.e., during processing) of critical quality and performance attributes of raw and in-pro-cess materials and processes with the goal of en-suring final product quality (11).

Process Performance Qualification (PPQ) The second element of the Process Qualifica-tion. It includes a combination of the actual facility, utilities, equipment, and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process per-forms as expected. Batches prepared are also called Conformance batches or PPQ batches (3). Process Qualification

Confirming that the manufacturing process, as designed, is capable of reproducible commercial manufacturing (3).

Process Robustness

Ability of a process to tolerate variability of materials and changes of the process and equip-ment without negative impact on quality (11). Process Validation

US FDA

The collection and evaluation of data from the process design stage to commercial pro-duction,, which establishes scientific evidence that a process is capable of consistently deliv-ering quality products (3)..

EMA

The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to pro-duce a medicinal product meeting its predeter-mined specifications and quality attributes (2). Process Validation Master Plan (Synonym – Validation Master Plan)

A document that defines the process validation scope and rationale and that contains the list of process validation studies to be performed (15). Proven Acceptable Range (PAR)

A characterized range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria (11).

Quality

The suitability of either a drug substance or drug product for its intended use. This term in-cludes such attributes as the identity, strength and purity (24).

Quality by Design (QbD)

A systematic approach to development that be-gins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management (11).

Quality Target Product Profile (QTPP)

A prospective summary of the quality charac-teristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product (11).

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Target Product Profile (TPP)

A format for a summary of a drug development program described in terms of labeling concepts to facilitate communication regarding a particu-lar drug development program (25). Validation Master Plan

See Process Validation Master Plan. Verification

A systematic approach to verify that manufactur-ing systems, acting alone or in combination, are fit for intended use, have been properly installed, and are operating correctly. This is an umbrella term that encompasses types of approaches to ensure the systems are fit for such as qualifica-tion, commissioning and qualification, verifica-tion, system validation, or other (26).

Worst Case

A set of conditions encompassing upper and lower processing limits and circumstances, in-cluding those within standard operating proce-dures, that pose the greatest chance of process or product failure (when compared to ideal con-ditions). Such conditions do not necessarily in-duce product or process failure (8).

2.1 Acronyms

API — Active Pharmaceutical Ingredient CMA — Critical Material Attribute

CPP — Critical Process Parameter

CPV — Continued Process Verification CQA — Critical Quality Attribute

DoE — Design of Experiments

DP — Drug Product

DS — Drug Substance

FMEA — Failure Mode Effects Analysis HCP — Host Cell Protein

ICH — International Conference Harmonization KPP — Key Process Parameter

NOR — Normal Operating Range

PAR — Proven Acceptable Range

PAT — Process Analytical Technology

PPQ — Process Performance Qualification

PTT — Product Technical Team

PVMP — Process Validation Master Plan

QbD — Quality by Design

QTPP — Quality Target Product Profile

TPP — Target Product Profile

TT — Technology Transfer

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This section focuses on approaches used during development to implement robust manufacturing processes. It addresses the first Stage of process validation in which process and product knowledge are explored to establish the control strategy . Risk assessment and management are used to focus the development effort. Process and product knowledge evolve through the course of the pharmaceutical development program. Designing a comprehensive and efficient program for a lifecycle approach to process validation compels thoughtful planning very early in development. Early planning facilitates appropriate data gathering in Stage 1, with the objective of enhancing the effectiveness and success of Stage 2 Commercial Process Qualification. It also establishes a foundation for continued process verification in Stage 3.

Sources of knowledge available prior to (and that may be used during) Stage 1 of the Process Valida-tion lifecycle, include:

? Previous experience with similar processes (e.g., platform processes) ? Product and process understanding (from clinical and pre-clinical activities)? Analytical characterization ? Published literature ? Engineering studies/batches ? Clinical manufacturing

? Process development and characterization studies

The following sections outline the Stage 1 outputs from a general lifecycle approach to Process Valida-tion, as depicted in Figure 3.0-1

Figure 3.0-1 Overall Sequence of Process Validation Activities

Technical Report No. 60 ? 2013 Parenteral Drug Association, Inc.

3.1 Deliverables from Stage 1 Process Validation

The list below summarizes the information needed to transition from Stage 1 (Process Design) to

Stage 2 (Performance Qualification) in the Process Validation Lifecycle. The sections in this section

discuss these deliverables in more detail and provide references for additional information.

? Quality Target Product Profile (QTPP) — This is done at the initiation of Stage 1

? Critical Quality Attributes (CQAs) with corresponding Criticality Risk Assessment and desired confidence

? Manufacturing Process Design

? Process description showing process inputs, outputs, yields, in-process tests and controls, and process

parameters (set points and ranges) for each unit operation

? Process solution formulas, raw materials, specifications

? Batch Records and production data from laboratory or pilot scale production

? Analytical Methods (for product, intermediates, and raw materials)

? Quality Risk Assessment

? Initial risk-based categorization of parameters prior to process characterization

? Criticality and Risk Assessments

? Identification of Process Parameters with corresponding criticality and risk analysis

? Process Characterization

? Process Characterization Plan and Protocols

? Study Data Reports

? Process Control Strategy

? Release Specifications

? In-Process Controls and Limits

? Process Parameter set points and ranges

? Routine Monitoring requirements (including in-process sampling and testing)

? Storage and time limitations for intermediates, process solutions, and process steps

? Raw Material/Component Specifications

? Design Space (if applicable)

? Process Analytical T echnology applications and algorithms (if PAT is used)

? Product Characterization T esting Plan (i.e., tests not included in the product Release T est panel)

? Manufacturing T echnology – assessment of production equipment capability and compatibility with process

requirements (may be covered in Stage 2a)

? Scale-up/Scale-down Approach (Evaluation/Qualification of Laboratory Models)

? Development Documentation

? Process Design Report

? Process V alidation Master Plan

3.2 Quality Target Product Profile (QTPP)

The aim of pharmaceutical development is to design a quality product with a manufacturing process

that consistently delivers the intended performance of the drug product. Pharmaceutical develop-

ment begins with the establishment of pre-defined objectives. These are described in the Quality Tar-

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get Product Profile (QTPP). The QTPP is defined at the initiation of Stage 1 and is referenced through-

out the product lifecycle.

The QTPP captures all relevant quality requirements for the drug product. Consequently, it is peri-

odically updated to incorporate any new data that may be generated during pharmaceutical develop-

ment. However, the QTPP should not depart from the core targets established in the drug product

Target Product Profile (TPP).

Note: TPP is used as a tool that facilitates sponsor-regulator interactions and communication. Con-sequently, the TPP contains such information as Drug Indications and Use; Dosage and Administra-

tion; Dosage Forms and Strengths; Contraindications; Warnings and Precautions; Adverse Reac-

tions; Drug Interactions; Abuse and Dependence; and Overdose that are not covered under the

scope of this document (25).

It addresses relevant characteristics that include:

? Intended use in the clinical setting (e.g., dosage form and strength, route of administration, delivery systems, container and closure system).

? Drug substance quality attributes appropriate to the drug product dosage form being developed (e.g., physical, chemical, and biological properties).

? Drug product quality attributes appropriate for the intended marketed product (e.g., purity/impurities, stability,

sterility, physical, and chemical properties)

? Therapeutic moiety release or delivery, and attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) appropriate to the drug product.

? Excipient and component quality attributes, drug-excipient compatibility, and drug-container compatibility that

affect the process ability, stability, or biological effect of the drug product.

The QTPP summarizes the quality attributes of the product that ensure safety and efficacy. It pro-

vides a starting point for assessing the criticality of product quality attributes.

3.3 Critical Quality Attributes

A Critical Quality Attribute (CQA) is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired

product quality. CQAs can be associated with drug substances, drug products, excipients, intermediates

(in-process materials), and container/closure components. At an early stage of process development,

the information available on product attributes may be limited. For this reason, the first set of CQAs

may come from prior knowledge obtained during early development and/or from similar products

rather than from extensive product characterization. The degree of criticality assigned to quality attri-

butes is derived using risk-based tools and the potential impact of the attributes on safety and efficacy. Following comprehensive assessments of scientific evidence and risk, quality attributes are ranked ac-

cording to the degree of criticality, which may be a continuum that more accurately reflects the com-

plexity of structure-function relationships and varying levels of uncertainty around attribute classifica-

tion. Attributes not assigned as CQAs should also be considered in the development of the process.

CQAs are not synonymous with specifications. In addition, there is not necessarily a one-to-one rela-

tionship between CQAs and specifications. Specifications are a list of tests, references to analytical pro-cedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the

tests described. Several product attributes identified as CQAs may be detected by a single test method,

and therefore, built into a single test specification (e.g., API solubility, hardness, porosity are CQAs evaluated using a single test: dissolution). Some CQAs may not be included in the specifications if they

Technical Report No. 60 ? 2013 Parenteral Drug Association, Inc.