Overview of Validation Requirements

1

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

2
Agenda

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

3
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)

4
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
  product.
• (FDA Guidelines, 2011)

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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
  results.
• (EU GMP 1997)

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Where did validation come from ?

• Began in 1970s
• Originally sterilized based.
• Now evolved into all Product, Process and
  Facility matters.

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Why Validate ?

• Assures Quality
• Regulatory Requirement
• Reduces Cost
• Its the LAW !

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Benefits

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

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When it goes wrong ..?

• Reliance on product testing
• Loss of confidence
• Possibility of adulterated products
• Inspection Observations / 483s

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Validation Terminology

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

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Validation Terminology

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

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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.

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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)

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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
  product

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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)

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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.

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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.

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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

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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

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Basic IQ Mfg. vessel

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

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IQ Protocol Approval

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

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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.

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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)

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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.

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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.

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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

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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

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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
  correct?
• Check the operation of the agitator emergency
  stop?
• Check the operation of all agitator controls,
  both on the main and local panels?
• Check that the agitator in the vessel free to
  turn?
• Pressurize the vessel and record the pressure
  drop for 10 min.
• Perform a vacuum test and record the vacuum drop.

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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.

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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.

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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

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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
  attributes.
• The new guidelines aligns process validation
  activities with a product life cycle concept.

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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)

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Process Validation

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

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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.

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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).

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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

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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
  manufacture.
• 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
  products.

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Validation Terminology

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

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Training

• 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

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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.

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Basic IQ/OQ/PQ

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

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Validation Master Plan
Introduction
Qualification
Personnel
Schedule
Preventive Maintenance
Installation
Responsibilities
Change Control
Operation
Training
Procedures Documents Appendices
Process
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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

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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.

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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.

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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

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Prior to Cleaning ValidationEstablish specific
SOPs

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

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Cleaning Validation

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

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Cleaning Validation

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

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Revalidation

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

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Establishment of limits

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

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Establishment of Limits

• Residual Limits must be.
• Practical
• Achievable
• Verifiable
• Safe
• FDA does not set acceptance specifications
  (limits).

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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.

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Example

• Ranitidine Tablets - Ibuprofen Tablets
• TD Single Therapeutic Dose 150 mg
  Ranitidine-Tab
• 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
  Ibuprofen
• MAC Max Allowable Carryover 150 X 100 X 1000
  x
• 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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Thank you