EXAMPLE OF BIOTECH PROCESS VALIDATION MASTER PLAN

Table of Contents
1. VALIDATION MASTER PLAN APPROVAL ........................................................................ 2
2. VALIDATION MASTER PLAN MAINTENANCE ............................................................... 2
2.1. DOCUMENT REVISIONS ........................................................................................................... 2
2.2. REVISION HISTORY ................................................................................................................. 2
3. DEFINITIONS ............................................................................................................................ 2
4. ACRONYMS ............................................................................................................................... 2
5. VALIDATION MASTER PLAN OBJECTIVE ....................................................................... 3
6. VALIDATION MASTER PLAN SCOPE................................................................................. 3
7. PROCESS VALIDATION STRATEGY .................................................................................. 4
7.1. PROCESS VALIDATION INTRODUCTION ................................................................................. 4
7.2. PROCESS SUPPORT QUALIFICATION ...................................................................................... 4
7.3. PROCESS VALIDATION ............................................................................................................ 4
7.4. CRITICAL PROCESS PARAMETERS ......................................................................................... 5
7.5. NUMBER OF RUNS TO BE PERFORMED: ................................................................................. 5
7.6. PROSPECTIVE VALIDATION .................................................................................................... 5
7.7. CONCURRENT VALIDATION.................................................................................................... 5
7.8. RETROSPECTIVE VALIDATION ............................................................................................... 6
7.9. NON-CONFORMING RESULTS ................................................................................................. 6
8. PROCESS VALIDATION DOCUMENTATION.................................................................... 7
8.1. VALIDATION PROTOCOLS ...................................................................................................... 7
8.2. VALIDATION REPORTS ........................................................................................................... 7
8.3. STRATEGY DOCUMENTS / ASSESSMENTS .............................................................................. 7
8.4. RECORD RETENTION .............................................................................................................. 7
9. ROLES AND RESPONSIBILITIES ......................................................................................... 8
9.1. TECHNICAL SERVICES ............................................................................................................ 8
9.2. OPERATIONS ............................................................................................................................ 8
9.3. ENGINEERING .......................................................................................................................... 8
9.4. QUALITY CONTROL LABORATORY (QCL)............................................................................ 9
9.5. QUALITY ASSURANCE (QA) ................................................................................................... 9
9.6. EXTERNAL SERVICES .............................................................................................................. 9
10. PROCESS DESCRIPTION...................................................................................................... 10
11. PROCESS VALIDATION DESCRIPTION........................................................................... 10
11.1. PROCESS DESCRIPTION DOCUMENT .................................................................................... 10
11.2. PROCESS SUPPORT QUALIFICATION .................................................................................... 10
11.2.1. Hold Strategy .................................................................................................................. 11
11.2.2. Mixing Strategy ............................................................................................................... 12
12. MAINTENANCE OF THE VALIDATED AND QUALIFIED STATE .............................. 13
12.1. PROCESS VALIDATION SCHEDULE ....................................................................................... 13
12.2. PREVENTATIVE MAINTENANCE AND CALIBRATION........................................................... 13
12.3. ANNUAL PRODUCT REVIEW ................................................................................................. 13
12.4. CHANGE CONTROL ............................................................................................................... 13
12.5. PERIODIC REVIEW OF FACILITIES, UTILITIES, EQUIPMENT AND COMPUTER SYSTEMS . 14
12.6. CONTINUOUS PROCESS VERIFICATION ............................................................................... 14

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 EXAMPLE OF BIOTECH PROCESS VALIDATION MASTER PLAN

1. Validation Master Plan Approval

Author
Technical Review(s)
Quality Review(s)
Technical Approval
Quality Approval
Operations Approval
Engineering Approval
Regulatory Approval

2. Validation Master Plan Maintenance

2.1. Document Revisions

The Process Validation Master Plan shall be reviewed for accuracy and updated as required.
Authorized personnel listed in the approval section will approve the changes made to this Process
Validation Master Plan.

2.2. Revision History

Any differences between this document and previous versions of this document are resolved in
favour of the present document. If revisions are required in future, this section will include a
summary of the main revisions and a justification for same.

Revision Date Summary of Revision Section No. / Page No.

0 New Document All

3. Definitions

4. Acronyms

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5. Validation Master Plan Objective

The Process Validation Master Plan is an overarching document, which covers the overall validation
strategy for the manufacture of Molecule X

The purpose of the pVMP is to define the process validation studies required to support licensure of
drug substance / product manufacturing in Company X. The pVMP provides a general description of the
manufacturing process, outlines the process validation strategy and defines the validation studies that
will be conducted to support the full validation of the commercial scale drug substance manufacturing
process.

The pVMP will identify a number of documents (Strategies, Protocols/Reports) that describe in more
detail execution of this validation strategy and will clearly identify links and inter-dependencies
between the documents.

Drug Substance process validation is intended to demonstrate that the manufacturing process in
Company X, is reproducible, consistent & in control.

This pVMP is prepared in accordance to Company X Quality Standard, and is in compliance with
overall FDA rules and guidelines and with the European Commission’s Annex 15

6. Validation Master Plan Scope

The following is within scope for this document:

Unit Operation X
Unit Operation Y
Process Support Qualification Studies

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 EXAMPLE OF BIOTECH PROCESS VALIDATION MASTER PLAN

7. Process Validation Strategy

7.1. Process Validation Introduction

Process Validation is the documented evidence that the process, operated within established
parameters can perform effectively and reproducibly to produce an intermediate or API meeting
its pre-determined specifications and quality attributes (ICH Q7a).

Conformance batches are prepared to demonstrate that under normal conditions and defined
ranges of operating parameters, the commercial scale process appears to make acceptable
product. (FDA Compliance Policy Guide)

Process validation of the Molecule X process will be conducted, using pre-approved protocols, in
accordance with local and corporate policies.

The validation protocols will detail acceptance criteria and the number of process runs (batches).

Validation reports that reference the validation protocols will be prepared, summarising the
results obtained, commenting on any non-conformances observed, and drawing the appropriate
conclusions, including recommending any required changes to correct deficiencies.

7.2. Process Support Qualification

Process Support Qualification activities are a program of post Installation and Operational
Qualification (IQ / OQ), pre manufacturing activities, designed to qualify specific manufacturing
operations prior to Process Validation (PV).

Specific PSQ Strategies may be generated (e.g. Mixing Strategy, Hold Strategy), where
appropriate, prior to the generation and approval of the related PQ protocols and reports.

7.3. Process Validation

Commercial manufacturing processes associated with the Company X site shall be validated
according to pre-approved validation protocols, as defined in Company X local and corporate
standards.
In order for Process Validation to occur, the following minimum prerequisites must be complete:
Design Qualification for the equipment and facility being used is complete.
Commissioning and Qualification Plan and Reports for the equipment and facility being
used are complete.
Installation, Operational (and Performance) Qualification for the equipment and facility
being used is complete.
Raw Materials are approved for use.
Analytical Method validation (In process & release testing) is complete.
Automation and Computer system validation is complete.
Approved Process Flow Documents (PFDs) incorporating the product and process
description. Critical process parameters and criteria for forward processing for each
process must be identified in the PFDs.
Container Closure Integrity of the Drug Substance Bottles is complete.
Environmental Monitoring Qualification is complete.
Quality Systems (incl. Deviation and Change Management) are in place.

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 EXAMPLE OF BIOTECH PROCESS VALIDATION MASTER PLAN

Process Validation protocols are pre-approved for use.

Process Validation Master Plan is approved.

Process validation protocols shall detail testing strategies and contain acceptance criteria derived
from process development and process characterization data.

7.4. Critical Process Parameters

The process validation protocols will designate the critical process parameters that influence the
critical quality attributes. Operational parameters that have no direct impact on the product
quality, but which do have an effect on process effectiveness, if not maintained within specified
ranges will be designated operational process parameters.

Where appropriate, in process specifications will serve as acceptance criteria and will be detailed
in the validation protocols. IPS are defined tests or analytical procedures with acceptance criteria,
performed at the end of a unit operation to verify suitability for further processing. Failure to
meet the acceptance criteria will result in a non-conforming result in the validation protocol.

Manufacturing scale Process Validation will be performed at target set points within normal
operating ranges as defined in the manufacturing batch records.

The intent of Process Validation is to demonstrate that predetermined acceptance criteria for
performance parameters and DS release specifications are met for batches manufactured within
the normal operating ranges specified in the batch records and individual study protocols.

7.5. Number of Runs to be Performed:

The number of batches used to conduct process validation is determined based on the complexity
of the process, manufacturing history at the commercial scale (i.e. representative Clinical trial /
Registration/Stability batches) and the validation design. A minimum of three consecutive
batches meeting the protocol acceptance criteria and routine batch release criteria is a requirement
for process validation as per corporate guidelines

At least three consecutive successful runs will be performed for each validation study, unless
otherwise specified in the respective Validation protocol.

This approach (i.e. three validation batches for Molecule X) is supported by the
following…….justification needs to be given on the number of batches selected

7.6. Prospective Validation

The process validation of Molecule X is a prospective validation. Lots manufactured during a
prospective validation are not released for commercial sale until the validation package is
approved.

7.7. Concurrent Validation

Column Lifetime studies will be carried out on commercial batches after the BLA submission on
a concurrent basis. Prior to the completion of the Column lifetime study the batches can be
released based on monitoring and testing which will be detailed in the Validation Protocol.
Interim reports will be completed to extend the validated column reuse lifetime. A final summary
report will be completed when the final number of reuses has been determined. The final number
of reuses is dependent on the number of batches per campaign, the frequency of Molecule X
production and the performance of the resin over the assessed lifetime. Column lifetime studies

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are not a prerequisite for process validation. Further details on Column Lifetime are in Section
11.2

7.8. Retrospective Validation

Retrospective Validation will not be used as a method of validating the Molecule X
manufacturing process.

7.9. Non-Conforming Results

The following guidelines are to be used to describe non-conforming results (i.e. data that does not
meet the validation acceptance criteria). A failure to meet one of the validation acceptance criteria
is to be reported to the Quality Assurance unit as soon as is practical and a deviation investigation
initiated as per local procedure. The outcome of the investigation will determine the effect on the
validation status of the batch.
A thorough investigation must be conducted to determine the root cause of the non-
conforming result. The results of the investigation are to be documented in the deviation
report, which is to be referenced in the validation report.
If the cause for the non-conformance is a non-process related deviation extrinsic to the
process, such as a power outage, processing error, etc. then the validation study may
continue. An additional lot may be added to replace the failed validation lot. The failed
lot is to be included in the validation package with an explanation on the impact to the
validation documented.
If the cause for the non-conformance is a process related deviation intrinsic to the
process, such as incorrect identification of the Critical Process Parameters or their ranges,
the following approach is to be taken:
 Place the batch on hold along with all other completed validation lots
pending resolution of the investigation
 Re-evaluate and adjust the process as required and prepare a revised
validation protocol if applicable. The investigation must be completed
prior to performing additional validation work.
 The revised protocol (approved by the original signatories) must be re-
executed in its entirety – i.e. Three Lots. The failed validation lots must
be documented as part final Validation Package.

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8. Process Validation Documentation

8.1. Validation Protocols
A protocol will be written to describe each process validation study. The protocols will include,
as applicable:
Type of Validation (i.e. prospective or concurrent), with justification for the type chosen, if
applicable.
Validation Purpose and Scope.
Process Description
List of the main equipment and facilities to be used
List of analytical methods.
Functions & responsibilities of all groups involved in the validation study.
Number of runs and justification for same.
CQA’s of the drug substance and in process control tests for the process being validated.
Critical Process Parameters, PVACS.
Test data to be collected.
Sampling Plans, sample handling procedure and lists of SOP’s for manufacturing process
steps and analytical methods.
Methods for recording and evaluating results (including statistical methods).
Response Plan regarding validation failures.
Inclusion or reference to the proposed time.

8.2. Validation Reports

A final report will be written when each validation protocol is completed. The final report will
contain:
A summary of the test results.
A statement regarding the acceptability of the results.
An evaluation of the effect of process changes, where arising, on the process step and the
impact to the validation status of the batch.
Description of deviations occurring during validation, the resolution strategy, and
evaluations of the impact to the validation study.

Interim reports will be written for concurrent validations (e.g. Column lifetime at commercial
scale). The interim report will contain the information as above for the final report.

8.3. Strategy Documents / Assessments

A number of Strategy Documents/Assessments will be generated to describe general
approaches to drive the Process Support Qualification activities and to detail Molecule X
specific assessments. Examples of Strategy Documents / Assessments include:
o Mixing Strategy
o Hold Strategy
o Reprocessing Strategy
o Column Lifetime Strategy
o Extractables and Leachables Assessment
o Filtration Assessment

Further details of the strategy documents / assessments are contained in Section 11

8.4. Record Retention

Following final approval of the validation package, the documents will be retained in
accordance with Site Record Retention Requirements

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9. Roles and Responsibilities

Primary responsibility for the successful completion of the process validation activities defined in this
Process Validation Master Plan belong to the Technical Transfer Multidisciplinary team, including
members from, Technical Services, Operations, Quality Control, Quality Assurance plus other groups as
needed.
A high level overview of responsibilities is detailed below. Additional information on the roles of each
group is detailed in the Site Validation Master Plan

9.1. Technical Services

Ownership and co-ordination of Process Validation activities.
Author Process Flow Documents and Process characterizations summary reports that
specify the CPP, OPP and GMP Controls.
Verify that the acceptable ranges for CPP are accurately represented in the Batch Records
and/or automation.
Defining Sampling requirements
Reviewing timelines and identifying resources
Providing appropriate training of personnel engaged in applicable production operations
Author, review and approve Process Validation Documentation.
Lead and coordinate the relevant cross functional working groups associated with Process
Validation activities.
Technical support for process (unit) operations during the Process Validation activity /
routine production.
Performance of Batch Impact Assessments and investigation of manufacturing events
where appropriate.
Preparation of science and risk based assessments that support validation activities.
Ensuring that validation / qualification activities are in compliance with Company X
Global Quality Standards.

9.2. Operations
Generation, completion and revision of Work Instructions (WI), Overviews (OVRs) and
associated Batch Tickets.
Provide trained personnel resources, as appropriate, to participate in and to contribute to
validation activities.
Operation of the facility/ process during Process Support Qualification and Process
Validation.
Schedule ownership for the day to day running of the facility.
Review and approve validation / qualification protocols and validation / qualification
packages and reports where applicable.
Ensuring the maintenance of the qualified status of the facility during production.
Ensuring that validation / qualification activities are in compliance with Company X
Global Quality Standards.

9.3. Engineering
Ensuring that the facility (including utility systems, process equipment and production
support systems) is appropriately qualified prior to Process Validation.

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Ensuring the maintenance of the qualified status of the facility during production.
Performance of facilities and utilities Requalification (where applicable).
Supply procedures and documentation necessary for the generation and execution of
protocols and completion of final reports.
Performance of Batch Impact Assessments and manufacturing events investigation where
appropriate.
Review and approve validation / qualification protocols and validation / qualification
packages and reports where applicable.
Performance of Automation Validation.
Ensuring that validation / qualification activities are in compliance with Company X
Global Quality Standards.

9.4. Quality Control Laboratory (QCL)

Qualification of laboratory analytical methods (In-Process, Release) prior to initiation of
Process Validation.
Provision of guidance and scheduling of laboratory services for sample testing.
Receipt of samples collected for testing and performance of testing per protocol
requirements with approved laboratory methods.
Review and approve qualification protocols and qualification packages where applicable.
Review and approve validation protocols and reports where applicable.
Maintenance of the validated state of analytical methods.
Ensuring that validation / qualification activities are in compliance with Company X
Global Quality Standards.

9.5. Quality Assurance (QA)

Review and approve qualification and validations plans, protocols and reports.
Ensure that regulations, guidance and commitments made to regulatory agencies are
addressed in the validation protocols and reports.
Batch Disposition / Certification.
Co-ordination of the Stability Programme.
Review and approval of manufacturing event investigations.
Administration of Quality Systems.
Ensuring that validation / qualification activities are in compliance with Company X
Global Quality Standards.
Archiving official qualification and validation protocols and reports.

9.6. External Services

Qualified contractors may be utilized to perform validation activities. Validation contractors
will be trained on and adhere to Company X Quality System and GMP requirements. The
activities of the contractors will be overseen by the area that is responsible for the specific
validation activity.

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10. Process Description

Process Specific

11. Process Validation Description

11.1. Process Description Document

Process description documents are a pre-requisite for the Process Validation Documentation
and must include the following:

Reaction scheme or product batch and unit operation

Narrative on unit operations
Process and equipment flow, including all unit operations
Supporting rationale for specifications of critical attributes for raw materials,
intermediates and Drug Substance.
Critical process parameters (CPP) and associated ranges with justification including
data. Target values within operating ranges are included where appropriate.
Justification for classifying parameters as non critical.
Process Validation Acceptance Criteria

11.2. Process Support Qualification

In general, Process Validation requires qualified production support systems to be in place
prior to execution of process validation studies. Process Support Qualification studies shall be
performed to provide these qualified production support systems. These studies shall provide a
high degree of assurance that a specific process, method or system will consistently produce a
result meeting predetermined acceptance criteria. The studies will support the determination of
the process parameters to be used in manufacturing operations.

Process Support Qualification activities are a program of post Installation and Operational
Qualification (IQ/OQ), pre manufacturing activities, designed to qualify specific
manufacturing operations prior to Process Validation (PV) of Molecule X.

The documentation hierarchy is as follows:

Strategy Document
Development Study (if required)
Qualification Documents (Protocol / Report).
Key Assessments Documents may also be completed as part of the PSQ section of the
validation strategy.

Table 1 lists the key Process Support Qualification Strategy Documents that are a requirement
to ensure successful validation of Molecule X manufacture.

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Table 1: Key Process support Qualification Strategy Documents / Assessments

Process Support Qualification Strategies / Assessments

Hold Strategy
Buffers
Process Additions
Cell Culture media and feed preparations
Process intermediates
Mixing Strategy
Buffers
Process Additions
Cell Culture media and feed preparations
Process intermediates
Filtration Assessment
Upstream
Downstream
Buffers / Cell Culture media and feed preparations
Extractable / Leachables Assessment
Upstream
Downstream
Buffers / Cell Culture media and feed preparations
Reprocessing Strategy
Final Filtration
Nanofiltration
Column Lifetime Strategy (Commercial Scale)

11.2.1. Hold Strategy

The objective of the Hold Strategy Document is to outline the approach that will be
taken to qualify hold times for the following process solutions to be utilised in
manufacturing operations:

Buffers
Process Additions
Cell Culture media and feed preparations
Process intermediates

These studies will be used to generate qualified non-processing hold times and
conditions based on production hold requirements. These hold studies will demonstrate
that the process solutions and process intermediates are fit for use within the defined
hold parameters by assessing the quality impact of the hold parameters on the process
solutions and process intermediates. There shall be two separate types of hold studies,
namely Chemical Hold studies which shall monitor chemical stability where applicable,
and Microbial Hold studies which shall monitor bioburden and endotoxin levels.

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11.2.2. Mixing Strategy

The objective of this Mixing Strategy Document is to outline the approach that will be
taken to qualify mixing parameters for the following process solutions and
intermediates to be utilised in manufacturing operations:

Buffers
Process Additions
Cell Culture media and feed preparations
Process intermediates

These studies will generate qualified mixing parameters such as minimum mixing time
and minimum agitation speed. The mixing studies shall study the mixing of process
solutions (i.e. cell culture growth media, media feeds, chromatography buffers, dilution
buffers, process additions) and process intermediates.

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12. Maintenance of the Validated and Qualified State

The company views maintenance of the validated state of any given process / facility / system /
equipment as fundamental to the business of making medicine. This is accomplished through a
composite of ongoing control systems and procedures which are designed to assure that the product
specifications and acceptance criteria are met and that the critical process parameters are maintained
within specified ranges.

12.1. Process Validation Schedule

Revalidation of the process may be conducted as a result of the following circumstances:
Change to the process
Trends or data observed during processing or the Annual Product Review
Planned periodic revalidation.
Confirmation of the validated state must be performed periodically for all processes per local
procedures.

12.2. Preventative Maintenance and Calibration

A preventative maintenance program operates to ensure equipment and systems are maintained
in a qualified state.

During equipment qualification a list of equipment / components to be considered for

preventative maintenance is developed by the Engineering Department. The decision is based
on the following:

The system/ component classification

Regulatory impact
Safety Impact

12.3. Annual Product Review

The Annual Product Review (APR) is a process intended to monitor, measure and analyse
manufacturing processes and products, using statistical techniques, on a routine basis to
evaluate trends over time. This aligns with quality expectations for process monitoring and
allows for assessment of the specific technical aspects of the process defined in the Process
Description Document.

12.4. Change Control

All changes proposed for a manufacturing system, equipment, method or process must be
evaluated under Change Control as per local procedure. The impact on validation/ qualification
and the requirement for additional validation / qualification, for example IQ and / or OQ of new
equipment / instrumentation or revalidation of a critical processing parameter, is assessed
through change evaluation.

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12.5. Periodic Review of Facilities, Utilities, Equipment and Computer Systems

Utilities, facilities, equipment and computer systems that are used in the manufacture of drug
substance are periodically evaluated. The purpose of the Periodic Quality Evaluation (PQE) is
to evaluate trends, compare data with historical information to determine shifts and assess the
state of control of the facility, utility, equipment and computer system. This evaluation will aid
in determining the need for changes to control procedures, monitoring plans, qualification
requirements and alert levels.

Requalification plans will be developed, as appropriate, to address the requalification

requirements of facilities, equipment and/ or processes.

12.6. Continuous Process Verification

Continuous process verification (CPV) can be defined as provision of objective evidence, that
specified requirements for the process performance are fulfilled. CPV takes place from the point
of commercialisation and throughout the remaining product lifecycle.

The extent and frequency of this continued process verification activity (including verification
of attributes, parameters, end points, trends, adherence to control strategy, etc.) may be based
upon a Quality Risk Assessment, which for example takes into account aspects such as the
complexity of the manufacturing process, control strategy, process robustness and number of
manufactured batches. A recommendation on the nature and extent of the continuous process
verification will be made in the Process Validation Summary Report.

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