Validation Master Plan

1. Purpose

The purpose of this Validation Master Plan is to define the scope of necessary activities to
successfully validate the NEW facilities, utilities, equipment, and processes used in the
manufacture of PRODUCT at COMPANY in CITY, ST.

Company is building additional production and warehouse Buildings B and C to support

manufacturing Product A, B, C at the existing production facility in City, ST.

2. Scope

The scope of this Validation Master Plan is limited to the following:

Company
New Buildings B, C
Product A, B, C
Existing Building A.

The following topics will be discussed in this Validation Master Plan:

• The scope and intended use of the facility

• A description of critical utilities, process equipment, and support equipment.
• The qualification / validation overview and approach

3. Responsible Functions

Manufacturing
Facilities
Engineering
Validation
Quality Control
Quality Assurance

Table 1 below provides an overview of the Validation Lifecycle documents and activities and the
departmental responsibilities related to each. Specific roles and responsibilities will be included in the
corresponding qualification or validation protocols.

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Table 1: Qualification Documents and Activities

Engineering
User/Owner
Validation

System

QA
Document or Activity / Role

System Impact Assessment A A R A

1 2 2
Specifications (URS , FS and DS ) A R/A R/A A

Validation Master Plan R A A A

1
Qualification Protocols & Reports R A A A

1
Qualification Protocol Execution R A A A

1 2
Notes: Required for equipment and automated systems. FS and DS documents are required for Computerized
Systems only (such as LIMS, MCS, and BMS). For other equipment and Commercial Off The Shelf (COTS) units,
design documents consist of, but are not limited to, P&IDs, Drawings, Schematics, and Equipment Manuals. R=
Responsible/ Creator/ Author. A= Reviewer/Approver.

4. Supporting Standard Operating Procedures

The following is a list of SOPs that will describe, guide, or support the validation program.

Validation SOPs
Validation Policy
Validation & Engineering Documents Numbering Procedure
Protocol Preparation and Execution
Computer System/Software Validation Program
Analytical Methods Validation Program
Process Validation Program

Metrology, Facilities, and Engineering SOPs

Removal from service procedure
Facility Shutdown Procedure
Out Of Service Procedure
Site Maintenance Program
Site Calibration Program
P&ID Review and Revisions Procedure

Quality Control SOPs

LIMS
Facilities Environmental Monitoring Program
Critical Utilities Sampling Program
Personnel Monitoring Program
Out Of Specification Results

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Quality Assurance SOPs

Training Program
Change Management Program
Deviations
CAPA program
Equipment Release and Return to Service

5. Validation Overview

Validation is an integral part of the overall product quality assurance program. The main purpose
of validation is to demonstrate through documented evidence that the entire manufacturing
system (critical utilities, process, support, and testing equipment and manufacturing processes)
performs consistently and reliably.

The following types of validation will be implemented to achieve a Validated state of the entire
manufacturing process and facility:

• Equipment, Utilities, Facilities, Computer Systems

• Cleaning, Sterilization
• Methods, Process

5.1. Installation Qualification

The purpose of installation qualification is to verify that (a) the installed system or
equipment is acceptable with respect to the approved specifications or equipment
manuals.

5.2. Operation Qualification

The purpose of the operational qualification is to evaluate the performance of the system
or equipment, in accordance with the manufacturer’s operating parameters and design
specifications.

5.3. Computerized System Validation

Qualification of computerized systems and the associated software is performed for the
purpose of demonstrating that systems and equipment, which are controlled by computer
system(s) or programmable logic controller(s), are capable of performing the range of
automated functions, within the limits of predetermined specifications.

5.4. Performance Qualification

The Performance Qualification is used to test those systems where performance or
process parameters are known and would affect the product. The purpose of the
performance qualification testing is to establish the ability of the system or equipment to
perform within the production process criteria. Generally, performance qualification
testing will involve challenging systems or equipment within a predetermined range of
operation. PQ studies are performed to qualify cleaning procedures, steam sterilization,
water quality, steam quality, air quality, etc, under normal operations.

5.5. Method Validation

Analytical test methods, in-process control testing methods and Analytical Equipment will
be validated. Analytical parameters for analytical methods validation are determined, where

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applicable, for:
• Accuracy
• Precision
• Specificity
• Limits of Detection
• Limits of Quantitation
• Linearity
• Range
The analytical methods requiring validation and the status of these validations are
documented on appendix B.

6. Product Validation

After facility, utility, and equipment qualifications are completed, each manufacturing process will
be validated. A protocol will be developed to demonstrate that the manufacturing process
consistently produces product meeting all in-process/final product specifications. The study will
consist of performing all process manipulations, according to the manufacturing batch record. In-
process testing will involve sampling product at appropriate manufacturing steps. Other
parameters, such as manufacturing time, product temperature, room temperature, volume,
weights, equipment settings, and filter integrity testing, will also be recorded as in-process data.
The Process Validation in this Master plan consists of two categories: aseptic processing and
product processing.

7. Process Description

Describe your process here.

7.1. Product Processing

The Product Processing portion of the Process Validation will demonstrate that the actual
manufacturing process consistently produces product meeting all in-process and final
product specifications.

The study will consist of performing all process functions and manipulations according to
the manufacturing batch record, and sampling the in-process and final product at
appropriate steps. All pertinent data will be documented.

Three batches each of the pre-determined product formulations and filling/packaging

configurations will be manufactured and placed on stability. Initial process validation will
consist of performing three studies of each product formulation and filling/packaging
configuration to ensure that all pre-determined in-process and final product specifications
are met and provide an accurate measure of variability among successive runs.

All documentation associated with manufacturing activities will be retained for review and
used as criteria to determine acceptability of product release.

8. Validation Scheduling and Control

The sequential approach first requires that equipment, services, and systems scheduled for
qualification/validation are mechanically complete, and that process parameters are defined.
System/Equipment construction or installation must be complete and have been commissioned.
Once this is complete, adequate documentation and change control systems are established.
Implementation of these systems allow establishment of programs to generate documentation for

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Standard Operating Procedures, calibration, qualification/validation protocols, batch records,

training, preventive maintenance, etc. This documentation facilitates the validation program and
is generated in a sequential manner that is compatible with the execution of the validation
program.

In order to achieve the final goal of facility control and successful process validation, all
qualifications/validations must be performed and all compliance programs and documentation
systems must be developed and implemented. Some tasks may be performed simultaneously
while others must be performed prior to undertaking subsequent tasks. Process validation, which
is the integration of all other facility activities and processes, is the final task to be performed.
This sequential approach ensures that conclusive, accurate data is generated to demonstrate and
prove a reproducible process.

Initially, a change control program is established and implemented to ensure that once a piece of
equipment, utility or process has been validated, it will remain in that state. Once the change
control program is established and implemented, the Installation Qualification (IQ) studies may be
started.

During the initial IQ phase, the Drawing and Equipment History Files for each system or piece of
equipment to be validated is established. Critical Instrument Calibration verification is confirmed
within this phase.
Existence of approved SOPs is confirmed during the OQ Phase.
During the subsequent PQ activities, the approved Standard Operating Procedures are field
verified for content and accuracy.

Programs for routine preventive maintenance and calibration are established and necessary
equipment use logs instituted prior to closing the change management record, before releasing
the systems for GMP use.

Upon successful completion of the IQ, OQ, and CSV phases, PQ, as applicable, is conducted.
The data obtained is used to develop routine sampling, cleaning, environmental monitoring, and
revalidation schedules. Data collected is evaluated to determine the effectiveness of the facility
cleaning program, and is used to determine the on-going strategy, schedule, and alert, action,
and state-of-control levels.

9. Facility Validation

The manufacturing facility is located in City, ST. This building is comprised of approximately BIG
square feet of manufacturing, laboratory, and office space.

9.1. Warehousing
Procedures for receiving, identifying, storing, and dispositioning incoming raw material
and compounds as well as the operation of the warehouse storage area can be found on
SOP. All climate control units storing materials are validated. The room-temperature
areas are monitor and temperature control.

9.2. Facility Cleaning Validation

A Facility Sanitation Program is in place for non-product contact surfaces. Room cleaning
utilizes at least two different disinfectants that are rotated monthly. The program was
developed to maintain the quality of the environment, thereby reducing the potential for
microbial (aerobic and anaerobic) and particulate contamination of the product. The
program was implemented and is periodically evaluated in conjunction with the
environmental monitoring program. The data collected is to be used to evaluate on-going
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effectiveness of the cleaning procedures.

9.2.1. Procedures are in place to evaluate the following criteria:

• Testing the sanitizing agents’ ability to adequately control the indigenous
microbial flora
• Sanitizing schedule for specific areas
• Rotation of cleaning agents
• Storage and preparation of sanitizing agents and disposal of cleaning wastes
• Specific sanitizing procedures
• Removal and use of status tags and use of area logbooks
• Inspection of area for cleanliness prior to use
• Revalidation studies when significant changes to sanitizing agents, methods,
etc., are implemented

9.3. Microbial Contamination Prevention and Control

Microbial contamination of the production areas is controlled through the implementation of
standardized cleaning techniques for critical processing equipment and production areas.
Appropriate process steps take place in controlled production areas. Process steps are
carried out, wherever feasible, in closed systems designed to minimize exposure to the
controlled areas. During critical processing steps and sampling, environmental exposure
of the intermediates and bulk drug solution is minimized.

9.4. Environmental Monitoring

An environmental monitoring program was developed and implemented to manage and
evaluate environmental control. Routine monitoring activities are performed to determine
total particle counts, bioburden, differential pressure, etc.

10. Utilities Validation

10.1. Heating Ventilation & Air Conditioning System

The purpose of the Air Handling System is to control environmental conditions within the
production facility. The Air Handling System provides clean, conditioned air to the
controlled environments within the facility. Conditioning of the air includes temperature,
humidity, and particulate control. Particulate control is accomplished by passing air
through pre-filters within the air handling units and terminal HEPA filters in the room
ceilings. Maintenance of differential pressure between adjacent areas and room air
change rates are accomplished by balancing the supply air flow from each air handler and
the supply air flow to each room or area.

Major components of the Air Handling System servicing the cGMP manufacturing areas
include air handler units, chiller, exhaust fans, distribution ductwork and HEPA filters.

Refer to the Plant drawing and Clean Room Classifications drawing.

10.2. WFI Generation and Distribution System

Water For Injection is used throughout the facility as process ingredients, for cleaning.
Sterilization, etc. The system will require Commissioning, IOQ, and PQ testing.

10.3. Clean Steam Generation and Distribution System

Clean Steam is used sterilization. The system will require Commissioning, IOQ, and PQ

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testing.

10.4. Nitrogen Gas System

The Nitrogen is supplied by a vendor. A distribution system supplies N2 gas throughout
the facility. The system will require Commissioning, IOQ, and PQ testing.

10.5. Clean Compressed Air (CCA)

CCA is generated in house. A distribution system supplies CCA throughout the facility.
The system will require Commissioning, IOQ, and PQ testing.
The PQ will provide ≥ 6 days of monitoring in a 32 day period for air quality (Hydrocarbon
content, dew point, particulate counts, and bioburden) at all points of use.

10.6. Plant Steam

The Plant Steam System produces saturated steam and distributes the steam through
valves and regulators to various components throughout the facility. The plant steam is
mainly utilized in the Heating Hot Water System at other designated utilities and process
systems for temperature regulation and control. This system will require commissioning.

10.7. Chilled Water System (CHW)

The Chill Water system produces and distributes chilled water, to non-product contact use
points. The chilled water is mainly utilized in the HVAC system for cooling and
dehumidification. It is also utilized at other designated utility and process systems for
temperature regulation and control. This system will require commissioning.

10.8. Heating Hot Water System (HHW)

The Heating Hot Water System is designed to provide heating hot water in a closed loop
system to use points in the HVAC systems in the production building, including
manufacturing, research, laboratory, and office spaces. This system will require
commissioning.

11. Equipment Validation

See attachment A for a completed list of equipment validations. Detail for an individual piece of
equipment can be found in that equipment validation file.

11.1. Tanks, Vessels, and Skids

Various tanks, vessels, and skids are used throughout the facility for various steps of the
production process. All tanks are stainless steel, carbon steel, or polymer, as appropriate,
and are equipped with appropriate nozzles, penetrations, utility connections, and
monitoring devices necessary to maintain process control. Individual IOQ protocols are
written and executed for each system or skid. PQ studies will be performed on all Tanks,
Vessels, and production skids.

11.2. Temperature Controlled Chambers and Rooms (CTUs and CTRs)

The various cold rooms and freezers are utilized for in-process and finished product and
samples storage. They are designed to maintain the specified temperature appropriate
for that stage of the process. They are generally located in the appropriate path of
materials and product flow. Each cold room or freezer typically is constructed of pre-
manufactured insulated walls and doors with a galvanized aluminum finish, and contains
self-contained air cooling equipment (fans, compressors, controls). CTUs will require

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commissioning and IOQs: empty chamber studies. For-Information-Only studies such as

Open Door and Power failure studies can be performed either within the Engineering
phase or within the IOQ phase.

11.3. Equipment Cleaning & Sterilization Validation

11.3.1. Glassware Washer

The Glassware Washer is operated through an HMI, which contains 3 fixed programs and
four “variants” (optional added steps). The system will require Commissioning, IOQ, and
Cleaning Validation.

11.3.2. Autoclave
The Autoclave is operated through an HMI, which contains four fixed programs:
• Dry Goods cycle
• Liquid Goods cycle
• Vacuum Test cycle
• Bowie-Dick Test cycle
The system will require Commissioning, IOQ, and PQ testing. Any cycle development will
take place within the Engineering testing phase (SAT or CMG).

12. Additional Programs

12.1. Training
Training on applicable SOPs is required prior to PQ execution.

12.2. Calibration
Critical Instrument Calibration is required prior to OQ execution. Approval of the
calibration requirements takes place before the equipment is released for GMP use.

12.3. Change Control

A change control program is in place to ensure that existing documents, utilities,
equipment, and processes including software remain in a state of control.

12.4. Maintenance & Spare Parts

Approval of the spare parts list and the maintenance requirements takes place before the
equipment is released for GMP use.

12.5. Logbooks, Status Tagging, and Checklists

A system for determining the day-to-day status of critical utilities, equipment, controlled
areas and activities is in place. Activities such as batch production, cleaning, preventive
maintenance, and calibration are documented in logbooks. Status tags are utilized to
indicate the status such as dirty, in-process, clean, quarantine, out-of-service, released,
etc.

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13. Attachments

13.1. Attachment 1 Systems Commissioning and Validation Checklist (Included)

13.2. Attachment 2 Required Documents Process Flow (Included)

13.3. Attachment 3 Laboratory Equipment Qualification List

13.4. Attachment 4 Process Flowcharts

13.5. Attachment 5 Facilities drawings: Personnel Flow, Raw Material Flows, Product
Flows, Sample Flow. And Waste Flow

13.6. Attachment 6 Pressurization Plan drawing and Clean Room Classifications drawing.

13.7. Attachment 7 Validation schedule

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Attachment 1 – Systems Commissioning and Validation List

System

Commissioning

Sterilization
Equipment

Cleaning

Process
CSV
Main Production Line
Portable Bioreactors X X N/A X X X
Production Bioreactors X X N/A X X X
Media Vessels X X N/A X X X
Centrifuge X X N/A X N/A X
Pool Vessels X X N/A X X X
Chromatography Skids X X X X N/A X
Viral Filtration Skid X X X X N/A X
Production Vessels X X N/A X X X
Buffer Vessels X X N/A X X X
UF/DF Skid X X X X N/A X
Supporting Systems
Parts Washers X X N/A X N/A N/A
Autoclaves X X N/A N/A X N/A
Laminar Flow Hoods X X N/A N/A N/A X
Biosafety Cabinets X X N/A N/A N/A X
CTUs X X N/A N/A N/A N/A
Facilities,
HVAC X X N/A N/A N/A N/A
ISO 8 Rooms X X N/A N/A N/A X
ISO 7 Rooms X X N/A N/A N/A X
ISO 5 Rooms and Skids X X N/A N/A N/A X
Utilities
Clean Steam X X N/A N/A N/A X
(1)
AWFI X X N/A N/A X X
HWFI X X N/A N/A N/A X
CCA X X N/A N/A N/A X
N2 X X N/A N/A N/A X
CO2 X X N/A N/A N/A X
O2 X X N/A N/A N/A X
Plant Steam X N/A N/A N/A N/A N/A
Plant CA X N/A N/A N/A N/A N/A
Vacuum X N/A N/A N/A N/A N/A
Computerized Systems
LIMS X N/A X X X X
MCS X N/A X X X X
BMS X N/A X X X X
Notes: (1) The AWFI requires Sanitization verification.

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Attachment 2 – Required Documents Process Flow

Item # Document Input Output Responsible Group
User Requirements Specification
1 - 5, 12 System Owner
(URS)
(1)
2 System Impact Assessment (SIA) - 3 All
3 Site Master Validation Plan 2 12 Validation
4 Change Management record(s) 3 12 System Owner
5 Functional Specification (FS) 1 6 Engineering
(2)
6 Design Specification (DS) 5 12 Engineering
7 Factory Acceptance Test (FAT) - - Engineering
8 Site Acceptance Test (SAT) - - Engineering
9 Turn Over Package (TOP) - 12 Engineering
Commissioning Qualification
10 9 12 Engineering
Protocols
Requirements Traceability Matrix (3) (5)
11 6 12 Engineering/Validation
(RTM)
(2) (3)
1, 3, 4, 6 , 9 ,
12 Installation qualification (IQ) (4) 13 Validation
11
13 Operational qualification (OQ) 12 16, 17 Validation
(2) User, Facilities,
14 SOPs 6 15 (6)
Engineering
15 SOP Training 14 16 User
16 Performance qualification (PQ) 13 17 Validation
Per individual
17 Equipment Release 18 System Owner
CM
Per individual
18 CM Record(s) closure - System Owner
CM

Notes: (1) A list of utilities and major equipment list is needed. (2) A DS is required only for
Automated Systems. Equipment Manuals are sufficient for COTS units. (3) A TOP is not
required for Commercial Off The Shelf units. (4) An RTM is required for Computerized Systems
only. (5) Engineering is responsible for updating the RTM once the DS is approved. Validation
is responsible for updating the RTM once the qualification is complete. (6) The user is
responsible for Operations SOPs, Engineering may be responsible for Maintenance and
Metrology SOPs, Facilities may be responsible for Cleaning SOPs.

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