Overview of Validation Requirements in

Pharmaceutical Industry

Kaushik DesaiChairman,

Industrial Pharmacy DivisionIndian Pharmaceutical Association

www.ipapharma.org

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

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“ 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)

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“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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“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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Began in 1970’s

Originally sterilized based.

Now evolved into all Product, Process and

Facility matters.

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Assures Quality

Regulatory Requirement

Reduces Cost

It’s the LAW !

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Validation can reduce costs by reducing,

Rejects Reworks Reliance on In-process controls Down time

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Reliance on product testing

Loss of confidence

Possibility of adulterated products

Inspection : Observations / 483’s

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User Requirement Specification (URS)

Design Qualification

Impact Assessment

Factory Acceptance Testing

Installation Qualification

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

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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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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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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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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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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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To establish that the critical components are installed correctly and in accordance with design documentation requirements (i.e. PO’s, 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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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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Instrument/Control Devices Verification Equipment Verification Piping Installation Verification Discrepancy/Justification and corrective Action As built P&I Diagrams Specifications Conclusions References Modification/ Change Control Attachments / Appendices

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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 P&I 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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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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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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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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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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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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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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Sequence testing Test data sheets SOP’s Conclusions Modification / change control Discrepancy/Justification and corrective action Operational Qualification Summary References Attachments/Appendices - Verification of test instruments - Chart recordings - P&I diagrams - Printouts

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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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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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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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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 SOP’s References Conclusions Attachments

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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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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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Life Cycle of the product & the process

Stage 1 – Process Design

Stage 2 – Process qualification

Stage 3 - Continuous process verification

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

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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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Commissioning and Qualification

Project Phases Validation PhasesTechnology 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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Introduction Qualification Personnel SchedulePreventive

Maintenance

Installation

Operation

Process

Responsibilities

Training

Change Control

ProceduresDocumentsAppendices

The company’s 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 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 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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A written procedure for cleaning validation which includes :

Responsibility for development, performance and approval of the validation study.

Establishment of SOP’s Acceptance criteria - defined to prevent cross contamination - definition of residue limits

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

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Sampling procedures - swabs, rinse, location

Residue limits

Analytical methods

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Validation report

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

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Major change in cleaning procedure

Change in cleaning agent

New equipment

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Knowledge of the materials - Potency of the drug - Pharmacological and toxic

properties - Degradation products - Cleaning agents - Micro residues

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Residual Limits must be…………. Practical Achievable Verifiable Safe

FDA does not set acceptance specifications (limits).

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MAC = TD x BS x SF / LDDMAC = 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.54

Ranitidine Tablets - Ibuprofen Tablets

TD = Single Therapeutic Dose = 150 mg Ranitidine-Tab

BS = Batch Size = 100 kg of IbuprofenSF = Safety Factor = 1/1000LDD = Largest Daily Dose of the next product in the

same equipment = 200 mg X 5 tablets of IbuprofenMAC = 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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