Process Validation Update

Jerry Holatko
PharmEng Technology Inc.
October 6, 2006

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 Regulatory Requirements
• Canada – Food and Drugs Act

• United States – Food, Drug and Cosmetic Act

• Both jurisdictions have corresponding GMP

or cGMP requirements

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 Regulatory Authorities
have duty to ensure products are safe and effective

• Integration of quality systems and risk

management
• Not dependent on commodity
• Require objective evidence
• Risk assessments and validation

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 Manufacturer’s Responsibility

• Know and meet regulatory requirements

• Document and approve development and processes

• Validate systems and equipment

• Develop a continuous improvement philosophy

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 US Requirements
• The FDA defines process validation as follows:
Process validation is establishing documented
evidence which provides a high degree of
assurance that a specific process will
consistently produce a product meeting its pre-
determined specifications and quality
characteristics.

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 Canadian Requirements
• Health Canada defines Validation as:
The action taken to demonstrate, and to
provide documented evidence that a process
will, with a high degree of assurance,
consistently achieve the desired and intended
results.

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 VALIDATION OBJECTIVES

– MEETS OR EXCEEDS SPECIFICATIONS

– PROPERLY INSTALLED, OPERATED AND
MAINTAINED
– CONFORMS TO cGMP
– REGULATORY COMPLIANCE
– ACHIEVES QUALITY, SAFETY &
PRODUCTIVITY

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Canadian Guidance on Responsibilities for
Cdn. fabricators, packagers/labellers or
testors

• Validation master plan

• Cleaning validation
• Test method validation
• Qualification of utilities, support systems and
equipment

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 Master Plan
The purpose of a Master Plan is:

• to serve as a liaison document to communicate to the

Regulatory Body an understanding of company responsibilities
concerning the validation of the facility
• plans to discharge that responsibility
• serves as a guide to those administering and performing
validation activities
• is a road map to successful project completion.

The Master Plan may be used as an instrument to define areas

of responsibility and accountability to validation team members

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 Master Validation Plan Contents
• Responsibilities of various departments
• Recognized validation approaches
• Conditions for using approach
• Compliance requirements for worst case and
reproducibility
• Revalidation criteria
• Documentation format requirements
• Review and approval requirements
• Change control system

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 MASTER PLAN FOCUS
• cGMP PROGRAMS
• OPERATIONS PROGRAM
• RESOURCE REQUIREMENTS
• SCHEDULE

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 Life Cycle
• The life cycle concept of validation is a recurring
theme throughout a Master Plan. Paramount is the
establishment of the infrastructure to ensure that a
facility will be supported by sufficient documentation
throughout its conceptual and functional lifetime.

• The life cycle will encompass project inception,

design, engineering, construction through testing,
certification, maintenance, revalidation and change
control. These programs are necessary to maintain
the processes and equipment in the state at which
they were originally validated.
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 Developing Validation
Documentation Hierarchy
• Quality Systems - QA
Quality Manual
Quality Policy
Established and approved by top management and
outlines the organization policy, objectives and
commitments to quality. Top management is
responsible of ensuring that the policy is understood,
implemented and maintained at all levels of the
organization.

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 Validation Program
Validation Program is a second level validation document. It is
a detailed document and outlines the following as examples;
· Definitions
· Format for validation protocols and reports
· Protocols review and approval
· Protocol number assignment
· Procedures for initiation, execution and reporting validation
activities
· Protocol Change Control

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 Validation Program (cont’d)
Impact Assessment on product quality
• System/Process Changes and its Impact
Assessment on the validation status and the
quality/efficacy of the product
• Methodology of handling non-conformance
• Revalidation
• Retention time, location and archiving of
validation record and reports

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 Validation Program (cont’d)
• There can be more than one program (i.e
Cleaning Validation Program, Computer
Validation Program.....etc.).

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 Components of Validation
• Facility Qualification
• Equipment Qualification
• Processing Equipment
• Utility Systems
• Testing Equipment
• Cleaning Validation
• Process Validation
• Computer Validation
• Methods Validation
• Revalidation
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 Validation SOP’s
• A detailed step-by-step procedure required to
be followed to accomplish a task (i.e. SOP for
sampling, testing...etc)

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 Establishing Methodology for Impact
Assessment and Validation Rational

• The Validation Program shall establish a

methodology for validation rational based upon
an impact assessment of systems and their
components.

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Establishing Methodology for Impact
Assessment and Validation Rational
(cont’d)

• Direct Impact System/Process (Critical)

• In-direct Impact System/Process
• No impact System/Process (Non-critical)

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 Key elements for successful
validation activities
• Timely planning and scheduling
• Impact assessment
• Validation/Qualification rational
• Good Documentation Practice
• Active participation of QA
• End-user participation and ownership
• Pre-determined acceptance criteria
• Additional checks, tests and verifications
• Methodology for handling non-conformance and changes

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 FACILITY CERTIFICATION
(OVERALL SCHEDULE)
• MASTER PLAN PREPARATION
• PROTOCOL PREPARATION & APPROVAL
• DQ/IQ/OQ
• REGULATORY LIAISON
• CERTIFICATION
• FACILITY TURNOVER

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 Facility/Equipment/Utility
Qualification
• Design Qualification (Review)
The following are some critical items to be considered for
successful Design Qualification
• Compliance with cGMP and all regulatory requirements
• Satisfy User/Functional Requirements Specification
(URS/FRS)
• Facility design layout, construction, air flow, differential
pressure, process flow and personnel flow to minimize
cross contamination
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 Facility/Equipment/Utility
Qualification (cont’d)
• Material of construction and cleaning
• Capacity and Efficiency
• Accessibility for maintenance and cleaning
• Commissioning, start-up and shut-down
process
• Safety and environmental requirements and
regulations
• Supporting documentations

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 Factory Acceptance Testing (FAT)

• When appropriate, the equipment shall be

tested/challenged at the supplier site by the user
to simulate actual production conditions.

• FAT allows for early identification of any problems

and troubleshooting prior to shipping and
provides confidence that the system will meet the
FRS and URS upon delivery.

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 Site Acceptance Test (SAT) and
Commissioning
When appropriate, the equipment shall be
tested/challenged on site prior to qualification by the user
to simulate actual production conditions. SAT allows
troubleshooting prior to qualification and provides
confidence that the system will meet the FRS and URS.

SAT and Commissioning when performed according to

Good Engineering Practice (GEP) and within the
qualification requirements can significantly support the
qualification activities and ensure successful qualification.

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 Installation Qualification

Installation qualification is a physical inspection/verification

of the system and its components to meet the Detail Design
Specification (DDS).

The IQ confirms that correct component has been properly

installed according to the design documents and all
supporting documentation is in place and instruments are
calibrated. The Validation Program shall establish the
general approach and pre-requisites for IQ activities.
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 Operational Qualification
Operational qualification testing confirms that the system and its
components operates within the limits and tolerance defined in the
Functional Requirement Specification (FRS).

The operating parameters are tested to confirm compliance with

URS and the design documents (i.e temperature, pressure,
flow….etc.).

The OQ also test for proper operation of components alarms and

interlocks and its integrated operations.

The Validation Program shall establish the general approach and

pre-requisites for OQ activities.
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 Performance Qualification
Performance Qualification combines the
performance of the systems procedures,
personnel and materials to deliver the desired
output within the desired quality attributes.

The Validation Program shall establish the

general approach and pre-requisites for PQ
activities.

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 GENERAL PRINCIPLES
• VALIDATION STUDIES ARE CONDUCTED AS PER
WRITTEN PROTOCOL

• ONE PROTOCOL PER EQUIPMENT, PROCESS OR

SYSTEM

• EACH PROTOCOL WILL REFERENCE ALL

INFORMATION NEEDED TO COMPLETE STUDY

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 GENERAL PRINCIPLES (Cont)
• ALL CRITICAL SYSTEMS, EQUIPMENT AND
PROCESSES REQUIRE VALIDATION
“CRITICAL” – HAVING A POTENTIAL TO
IMPACT PRODUCT CONFORMANCE TO
QUALITY SPECIFICATIONS

• SOME SYSTEMS REQUIRE MULTIPLE

VALIDATION STUDIES

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 MAINTAINING VALIDATED STATE
OF THE SYSTEM
• CALIBRATION
– CRITICAL INSTRUMENTS ARE CALIBRATED AS PER
DETERMINED SCHEDULE
• TRAINING
– TRAINING PROGRAM IS IN PLACE
– TRAINING IS DOCUMENTED
• PM AND CHANGE CONTROL
– NO EQUIPMENT MODIFICATION WITHOUT CHANGE
CONTROL

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 Validation Schedule
• Establish target dates

• Strive to ensure that validation (DQ,IQ,OQ) is completed

before any construction, regulatory authorizations etc.-allows
for approvals

• Revalidations for changes (equipment, processes)– that affect

product characteristics

• Assess the need for revalidation during APR’s regardless of

Change Controls

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 THANK YOU !

Jerry Holatko
[email protected]

PharmEng Technology Inc.

http://www.PharmEng.com

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