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Overview of Validation Requirements


The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes. – PowerPoint PPT presentation

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Title: Overview of Validation Requirements

  • Overview of Validation Requirements
  • in
  • Pharmaceutical Industry
  • Kaushik Desai
  • Chairman,
  • Industrial Pharmacy Division
  • Indian Pharmaceutical Association
  • www.ipapharma.org

  • A definition
  • Where did validation come from ?
  • Why do it ?
  • What are the benefits ?
  • How far do we have to go ?

Definition ( FDA)
  • Establishing the documented evidence which
    provides a high degree of assurance that a
    specific process will consistently produce a
    product of predetermined specifications and
    quality attributes.
  • (FDA Guidelines 1987)

Definition ( FDA)
  • Process validation is defined as the collection
    evaluation of data, from the process design
    stage through commercial production, which
    establishes scientific evidence that process is
    capable of consistently delivering quality
  • (FDA Guidelines, 2011)

Definition (EU GMP)
  • Action of proving, in accordance with the
    principles of Good Manufacturing Practice (GMP),
    that any procedure, process, equipment, material,
    activity or system actually leads to expected
  • (EU GMP 1997)

Where did validation come from ?
  • Began in 1970s
  • Originally sterilized based.
  • Now evolved into all Product, Process and
    Facility matters.

Why Validate ?
  • Assures Quality
  • Regulatory Requirement
  • Reduces Cost
  • Its the LAW !

  • Validation can reduce costs by reducing,
  • Rejects
  • Reworks
  • Reliance on In-process controls
  • Down time

When it goes wrong ..?
  • Reliance on product testing
  • Loss of confidence
  • Possibility of adulterated products
  • Inspection Observations / 483s

Validation Terminology
  • User Requirement Specification (URS)
  • Design Qualification
  • Impact Assessment
  • Factory Acceptance Testing
  • Installation Qualification

Validation Terminology
  • Calibration
  • Site Acceptance Testing
  • Operational Qualification
  • Standard Operating Procedures
  • Performance Qualification
  • Process Validation
  • Change Control

Validation Terminology
  • User Requirement Specification (URS)
  • A description of the requirements of the facility
    (project) in terms of product to be manufactured,
    required throughput and conditions in which the
    product should be manufactured.
  • Approved statements prepared by the user which
    defines what is required by the project.

Validation Terminology
  • Design Qualification (DQ)
  • Documented review of the design, at an
    appropriate stage in a project, for conformance
    to operational and regulatory expectations.
  • (Note Not an obligation)

Validation Terminology
  • Impact Assessment
  • The process of evaluating the impact of the
    operating, controlling, alarming and failure
    conditions of a system on the quality of a

Validation Terminology
  • Factory Acceptance Testing (FAT)
  • Inspection and static and/or dynamic testing of
    systems or major system components to support the
    qualification of an equipment system conducted
    and documented at a supplier site.
  • (Note Not an obligation)

Installation Qualification (Definition)
  • Documented verification that all aspects of a
    facility, utility or equipment that can affect
    the product quality adhere to approved
    specifications and are correctly installed.
  • The process of checking/verifying the
    installation to ensure that the critical
    components meet the approved specifications and
    that they are installed correctly in accordance
    with design documentation.

Installation Qualification (PURPOSE)
  • To establish that the critical components are
    installed correctly and in accordance with design
    documentation requirements (i.e. POs, Contracts
    etc.), that supporting documentation is in place
    and of suitable quality.
  • To record the checks and verifications for
    critical components in Direct Impact Systems.

IQ Protocol (Contents)
  • Approval Page
  • Objectives
  • System Description
  • Responsibilities
  • Acceptance Criteria
  • Engineering Documentation Requirements
  • Records of Signatures
  • Qualification Test Equipment/Instrument List
  • Product Contact Materials Review
  • Utilities Verification
  • Control System Verification

IQ Protocol (Contents)
  • Instrument/Control Devices Verification
  • Equipment Verification
  • Piping Installation Verification
  • Discrepancy/Justification and corrective Action
  • As built PI Diagrams
  • Specifications
  • Conclusions
  • References
  • Modification/ Change Control
  • Attachments / Appendices

Basic IQ Mfg. vessel
  • Parameters
  • Does the vessel meet the design specification?
  • Does the agitator assembly meet the design
  • Is the motor housing earthed?
  • Is the motor over current device set to correct
  • Is all the pipe work connected?
  • Are all instruments installed as per PI diagram?
  • Have all the temperature indicators been
  • Is calibration procedure available?
  • Are operation and maintenance manuals available?
  • all electrical connections securely and safely
  • Is insulation complete?
  • Is vessel clean and free from dirt?

IQ Protocol Approval
  • After protocol execution is complete and
    deviations evaluated, post execution approval is
  • Requires sign off by original signatories.
  • IQ execution should be complete and approved
    prior to the start of OQ.

Validation Terminology
  • Calibration
  • Demonstrating that a measuring device produces
    results within the specified limits of those
    produced by a reference standard over an
    appropriate range of measurements.
  • The devices are normally tagged and supported by
    a maintenance procedures.

Validation Terminology
  • Site Acceptance Testing (SAT)
  • Inspection and dynamic testing of systems or
    major system components to support the
    qualification of an equipment system conducted at
    a client site.
  • (Note Not an obligation)

Operational Qualification (Definition)
  • Documented verification that all aspects of a
    facility, utility or equipment that can affect
    product quality operate as intended throughout
    all anticipated ranges. It is the process of
    testing to ensure that individual components and
    systems operate as specified, and how that
    information is recorded.

Operational Qualification (PURPOSE)
  • To establish through documented testing, that all
    critical components and direct impact systems are
    capable of operating within established limits
    and tolerances.
  • To test parameters that regulate the process or
    product quality. To verify the proper operation
    of controllers, indicators, recorders, alarms and
    interlocks, is performed and documented during
    the operational qualification testing.

Operational Qualification (Protocol)
  • Approval page
  • Pre-requisites
  • Objectives
  • System Description
  • Responsibilities
  • Acceptance Criteria
  • Records of signatures
  • Qualification test Equipment/Instruments list
  • Alarm and Interlocks test
  • Operation testing
  • Capacity testing
  • Power failure testing

Operational Qualification (Protocol)
  • Sequence testing
  • Test data sheets
  • SOPs
  • Conclusions
  • Modification / change control
  • Discrepancy/Justification and corrective action
  • Operational Qualification Summary
  • References
  • Attachments/Appendices
  • - Verification of test instruments
  • - Chart recordings
  • - PI diagrams
  • - Printouts

OQ Mfg. vessel
  • Parameters
  • Have all Installation Qualification been
    completed for this system?
  • Is the system clean and free from dirt?
  • Is the direction of the rotation of agitator
  • Check the operation of the agitator emergency
  • Check the operation of all agitator controls,
    both on the main and local panels?
  • Check that the agitator in the vessel free to
  • Pressurize the vessel and record the pressure
    drop for 10 min.
  • Perform a vacuum test and record the vacuum drop.

Performance Qualification (Definition)
  • Documented verification that all aspects of a
    facility, utility or equipment that can affect
    the product quality perform as intended in
    meeting the predetermined acceptance criteria.

Performance Qualification (Purpose)
  • To integrate procedures, personnel, systems and
    materials to verify that the utility /
    environment / equipment / support systems
    produces the required output. This output may be
    a product contact utility, sterilization
    condition or environment.

Performance Qualification (Protocol)
  • Approval page
  • Pre-requisites
  • Objectives
  • System Description
  • Responsibilities
  • Acceptance Criteria
  • PQ test plan
  • Challenge test plan
  • Records of signatures
  • Test equipment/Instrument list
  • Test data sheets
  • SOPs
  • References
  • Conclusions
  • Attachments

Validation Terminology
  • Process Validation
  • The documented verification providing a high
    degree of assurance that a specific process will
    consistently produce a product meeting its
    predetermined specifications and quality
  • The new guidelines aligns process validation
    activities with a product life cycle concept.

US FDA (21 cfr) Process Validation
  • 211.42, 211.63, 211.68, 211.84
  • 211.100(a) , 211.110(a), 211.110(b)
  • 211.160(b), 211.165(c), 211.165(d), 211.180(e)

Process Validation
  • Life Cycle of the product the process
  • Stage 1 Process Design
  • Stage 2 Process qualification
  • Stage 3 - Continuous process verification

Stage 1 - ProcesS dESIGN
  • It is the activity of defining the commercial
    manufacturing process that will be reflected in
    planned master production and control records.
  • The goal of this stage is to design a process
    suitable for routine commercial manufacturing
    that can consistently deliver a product that
    meets its quality attributes.
  • It is based on the knowledge gained through
    development scale-up activities.

Stage 2 Process qualification
  • During this stage, the process design is
    evaluated to determine if the process is capable
    of reproducible commercial manufacturing. The
    products manufactured during this stage, if
    acceptable , can be released for distribution.
  • Two Aspects
  • Design of facility and qualification of equipment
    and utilities.
  • Process Performance Qualification ( PPQ).

Concurrent rELEASE
  • Def. Releasing for distribution a lot of
    finished product, manufactured following a
    qualification protocol, that meets the standards
    established in the protocol, but before the
    entire study has been executed.
  • Orphan Drugs
  • Specific drug for specific use
  • Short Shelf-life radio pharmaceuticals

SATGE 3 Continued process verification
  • The goal of this stage is continual assurance
    that the process remains in a state of control (
    the validated state) during commercial
  • The cGMP requirements, specifically the
    collection evaluation of information data
    about the performance of the process will allow
    detection of undesired process variability.
  • This stage is also applicable for legacy

Validation Terminology
  • Change Control
  • Formal evaluation of the potential impact of
    planned modifications on the validated status of
    a product, process or facility.

  • Training personnel for IQ/OQ execution.
  • The purpose of the equipment/ system.
  • Use of test equipment
  • Applicable SOPs
  • cGMP documentation of training
  • Document all training
  • Periodically review training requirements

Final Summary Report
  • A document that summarizes and analyses the test
    results at the end of PQ.
  • Provides a conclusion about the ability of the
    system to consistently meet acceptance criteria.
  • May be a stand alone document at each stage of
    IQ/OQ and PQ to summarize results.

Basic IQ/OQ/PQ
  • Commissioning and Qualification
  • Project Phases Validation Phases
  • Technology Transfer Collecting
  • Conceptual Design
  • Basic Design Preliminary VMP
  • Detailed Design Detailed VMP
  • Procurement Detailed
  • Construction IQ
  • Pre commissioning
  • Commissioning OQ
  • Process operation /

Validation Master Plan
Preventive Maintenance
Change Control
Procedures Documents Appendices
Validation Policy
  • The companys overall policy, intentions and
    approach to validation, including
  • Validation of production processes
  • Cleaning procedures
  • Analytical methods
  • In-process control test procedures
  • Computerized systems
  • Persons responsible for design, review, approval
  • Documentation of each validation phase

Product Validation
  • Product validation is NOT
  • - just 3 batches that meet specifications
  • Product validation is
  • - an ongoing process to build confidence into
  • the manufacturing activities
  • - an ability to demonstrate consistency at any
  • time.

Cleaning Validation
  • Cleaning validation is establishing documented
    evidence that the equipment is consistently
    cleaned from product, microbial and cleaning
    agent residues to predetermined acceptable levels.

FDA Expectations
  • A written procedure for cleaning validation
  • which includes
  • Responsibility for development, performance and
    approval of the validation study.
  • Establishment of SOPs
  • Acceptance criteria
  • - defined to prevent cross contamination
  • - definition of residue limits

Prior to Cleaning ValidationEstablish specific
  • Cleaning procedure for each piece of equipment
  • - Flow charts and diagrams
  • - Cleaning agents, concentration, volume
  • - Frequency
  • - time left dirty

Cleaning Validation
  • Sampling procedures
  • - swabs, rinse, location
  • Residue limits
  • Analytical methods

Cleaning Validation
  • Validation report
  • - Results Vs. acceptance criteria
  • - Deviations and how handled
  • - Conclusion that cleaning process is
  • validated

  • Major change in cleaning procedure
  • Change in cleaning agent
  • New equipment

Establishment of limits
  • Knowledge of the materials
  • - Potency of the drug
  • - Pharmacological and toxic properties
  • - Degradation products
  • - Cleaning agents
  • - Micro residues

Establishment of Limits
  • Residual Limits must be.
  • Practical
  • Achievable
  • Verifiable
  • Safe
  • FDA does not set acceptance specifications

Setting of Limits
  • MAC TD x BS x SF / LDD
  • MAC Maximum Allowable Carryover
  • TD Single Therapeutic Dose
  • BS Batch size of next product to be
  • manufactured on the same equipment.
  • SF Safety Factor
  • LDD Largest Daily Dose of the next product
  • in the same equipment.

  • Ranitidine Tablets - Ibuprofen Tablets
  • TD Single Therapeutic Dose 150 mg
  • BS Batch Size 100 kg of Ibuprofen
  • SF Safety Factor 1/1000
  • LDD Largest Daily Dose of the next product in
    the same
  • equipment 200 mg X 5 tablets of
  • MAC Max Allowable Carryover 150 X 100 X 1000
  • 1000 X 1/1000 X 1/1000
  • i.e 15000 mg in 100 kg Batch size
  • i.e 150 mg in 1 kg 150 ppm

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