GMP Training:

Process validation

Dr. A. Amsavel

Content

• Introduction• Definitions• Purpose of Validation• Types of Validation• Revalidation• Documentation

Background

• Validation is a concept that has been evolving continuously since its first formal appearance in the United States in 1978.

• Validation guideline - FDA's 1987

Reference

• ICH: GMP - Q7 (12.4, 12.5 &12.6)

• USFDA: Process Validation- General principles and Practices Jan-2011

• WHO: TRS # 937-2006- Annex-4

• PIC/s : VMP… Non-sterile process validation- Aug 2001

• EMEA: Note for Guidance on process validation

Definitions: (USFDA)

“Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”

DefinitionValidation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled. [CFR 21 Part 820.3(z)]

Verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled. [CFR 21 Part 820.3(aa)]

Validation Examples:

•Process Validation, cleaning validation, Sterilization Validation, Test Method Validation, Software Validation, and (dynamic)

Verification Examples:

•Design Verification and Process Verification. (static)

Definition• Process performance qualification - Establishing

confidence that the process is effective and reproducible.• Product performance qualification - Establishing

confidence through appropriate testing that the finished product produced by a specified process meets all release requirements for functionality and safety.

• Prospective validation - Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product's characteristics.

DefinitionPredetermined Specification:

Validation activities start with the definition of specifications. The performance of equipment is then verified against these specifications. Acceptance Criteria must be defined prior to testing.

Documented Evidence: Validation requires a through documentation

everything that is not documented is considered incomplete.

Advantages of validation

• Reduction in rejection and reworking • Reduction in utility cost avoidance of capital

expenditure • Reduce down time • improving efficiency and productivity by optimisation• Easier scale up from development work• Improved employee awareness of processes• Reduced testing in process and in finished goods. • Compliance to meet regulatory requirement

Validation approach

FDA guidance describes process validation activities as below;

• Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and 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.

• Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

Purpose• To gain high degree of assurance in the performance of the

manufacturing process such that it will consistently produce APIs and drug products meeting those attributes relating to identity, strength, quality, purity, and potency.

• To confirm the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change

• Manufacturers should use ongoing programs to collect and analyze product and process data to evaluate the state of control of the process.

Sequence to Validation Process Development / (Lab scale)

Optimized Laboratory Process

Validation of Sub-Processes (Analytical Methods, Lab instruments; Equipment and

Utility Qualification; Cleaning process &methods etc.)

Optimized Plant Batch (Plant scale)

Process Validation (Plant Scale)

Ongoing Process Validation

Sequencing Validation Activities Process Validation

Equipment Method Cleaning Water System AHU Qualification validation validation validation Qualfn (IQ, OQ, PQ) (In-process (Reactor Impurities Drier & Intermediate) Blender) Sampling Qualifn

Qualification ( DQ,IQ, OQ) (DQ, IQ,OQ &PQ)

Instrument method Validation

Qualification of detection (DQ,IQ,OQ) method

Validation Approach

Multi Functional activity Team approach QA co-ordination Protocol Driven (Planning)

Types of process validation

• Prospective Process Validation • Concurrent Validation • Retrospective Validation • Revalidation

Types of Process Validation • Prospective Validation: It would normally be

expected that Process Validation be completed prior to the manufacture of finished product that is intended for sale.

• Concurrent Validation: Where this is not possible, it may be necessary to validate processes during routine production .

• Retrospective Validation: Processes which have been in use for some time should also be validated .

Prospective Validation

• Prospective validation involves manufacturing, sampling, and testing of validation batches according to a pre-approved validation protocol.

• Validation conducted prior to distribution either of – new product, – process, – Products transferred between plants, – Changes to existing processes

Prospective Validation• It is establishing documented evidence prior to

process implementation that a system what it purports to do based on a preplanned protocol.

• It is conducted prior to distribution of either a new product or a product made under a modified Production process, where modifications are significant and may affect product characteristics.

• This is a preplanned scientific approach and includes initial stages of equipment validation.

Concurrent Validation• It is establishing documented evidence that a

process does what it purports to do, based on information generated during actual implementation of the process.

• It may be practical approach under certain circumstances. – When a previously validated process is being

transferred to a third party contract manufacturer or to another manufacturing site

– When number of batches produced are limited.

Retrospective Validation• It is establishing documented evidence that a

system does what it purports to do, based on review and analysis of historical information.

• It has become synonymous with achieving validation by documenting all historical information, – e.g. release data for existing products and using

that data to support position that process is under control.

– 20 to 30 batches

Revalidation This is nothing but the repetition of the whole validation process

or a specific portion of it. It becomes necessary in certain situations. Some of the changes are as follows.

• Changes in source of active Raw material manufacturers• Changes in Raw Materials• Changes in Packaging Materials• Changes in process parameter e.g. Mixing, Time, Drying

Temperature, and Batch Size etc.• Changes in Equipment• Changes in Plant Facility• Monitoring of equipment capabilities over a period of time.• Changes in the Specification of API

Documentation

Plan of work• Literature Review • Review of Product Development Report• Identification of Critical Process Parameters• Preparation of Process Validation Protocol • Monitoring of Manufacturing Process • Review of Process Validation Batches • Data collection• Data evaluation• Documentation of Process Validation Report

Validation Protocol1. Purpose & Scope2. Type of Validation & Justification3. Responsibilities4. Batch Selection Criteria & Time schedules, (cover

2nd crop, ratio of intermediate, varying batch size)

5. Process description & flow chart including sub process

6. Batch Manufacturing Instructions7. Key equipments, Reference to qualification, calibration 8. Quality of raw materials

Validation Protocol9. Critical Process parameters & operations10. Critical Quality Attributes & additional analysis. 11. Sampling plan: where, when, how and how many,12. Acceptance Criteria13. Deviation13. Format for validation report: (Details of methods for

recording and evaluating results, including statistical analysis)

14. Approval by concerned authority & QA (May be in first page)

Responsibilities Validation team responsibilities :• Head - Quality Assurance: Responsible for protocol authorization and

preparation of summary report

• Head - Quality Control: Responsible for analysis of samples collected

• Head - Production: Responsible for manufacturing of batches and review of protocol and report.

• Team - Quality Assurance: Sampling and monitoring of process as per process validation protocol

• Team - Quality Control: Sample analysis as per standard test procedures.

• Team – Production: Execution of the process, data collection

MethodologyPurpose & Scope• Background• Purpose• Scope

Define Process:• Description of process• Flow chart• Batch production instructions• Key equipments• Batch size

Define RM quality

KSM & other material quality • Specification• Fresh solvents / Recovered • Test methods (validated as required)

Equipment Qualification

• Demonstrate that utilities and equipment are suitable for their intended use and perform properly. – Utilities are appropriate for their specific uses

– Equipment- MOC, operating principles, and performance characteristics

• Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).

• Eg. Water, HVAC, compressed air, etc…

Equipment Qualification

• Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges.

• This should include challenging the equipment or system functions while under load comparable to that expected during routine production.

• It should also include the performance of interventions, stoppage, and start-up as is expected during routine production.

• Operating ranges should be shown capable of being held as long as would be necessary during routine production

Calibration of critical Instruments

List of critical measuring instruments(Temp & Pressure gauge, Balances, Flow meters etc.)

Measuring range – Operating rangeAccuracy and Process tolerance

(Fitness for the purpose)

In-process Controls To assure that the final drug product will meet

its quality requirements and control batch-to-batch variability.

• Establish levels and frequency of routine sampling and monitoring

• Consider the extended sampling and monitoring based on volume of production, process complexity, level of process understanding

• In-process specifications• Test methods (validated)• Acceptance limits

Sampling Plan • The sampling plan for each unit operation and attribute.

– sampling points,

– number of samples, and the frequency of sampling

• where, when, how, how many, and how much

• Selection can be based on risk analysis as it relates to the particular attribute under examination.

• Additional tests: Sampling during this stage should be more extensive than is typical during routine production.

Sampling Procedures Use PAT

Critical Process Steps / Parameters

Parameters having Impact on product quality Temp, time, pH, agitation/speed, etc

Establish the manufacturing condition based on scientific judgment and cumulative data from; Design Of Experiment, Laboratory, Pilot and commercial

batches. Define and monitor the critical process parameters

and critical operations. Define the acceptance range :Specification Limit and

control limits where required.

Critical Steps / Parameters (cont..)

Examples:- Critical Steps:

Finished Dosage API’s

Granulation Phase changes Drying Chemical Rxn Blending Physical change Tablet Compression (Crystallisation, Drying,

Distilling etc.)

Training: All personnel involved in the validation:• Production, QC, microbiology, QA Engineering• Production staff must know critical steps / parameters,

execution, sampling, data collection • Analyst/microbiologist should know the sampling plan,

technique, analysis, method, data etc• Engineering to support, qualification & calibration • Identify any special training needs

Acceptance Criteria

Criteria for Validation to be Successful: Product Quality Yield / efficiency Critical process parameters Quality attributes; In-process test

results

Carry out the Process

Monitor Closely Record relevant data Analyse the Data Validation Report

Evaluation of Validation Data

The data to be collected and when and how it will be evaluated.

• Evaluate deviations; Assignable causes• Statistical Tools: Trend analysis - Critical process parameters,

In-process results & YieldsControl /Alert limits

Process Capability Analysis Cp & Cpk values

Deviation

• Provision for addressing deviations from expected conditions and handling of nonconforming data.

• Data should not be excluded from further consideration in terms of PPQ without a documented, science-based justification

Examples: Minor: Time delay due to power failure in non-critical operation,

minor equipment failure in short time etc .. and product meets the quality attributes.

Major: Deviation in critical process parameter and resulting in quality failure

Validation report:• Background , Scope & responsibility• A description of the process • Batch/Packaging Document reference• Equipment qualification & calibration status• KSM quality• Input and out put of RMs • Details of critical process parameter and operation data,• A detailed summary of the results obtained from in-process

and final testing, including data from failed tests. • Additional tests : Different spec (USP/EP/IP) PSD, bulk

density(BD/TD), XRD etc

Validation report:• Any work done in addition to that specified in the

protocol or any deviations from the protocol should be recorded along with an explanation

• Summarize and discuss all manufacturing non-conformances such as deviations, unexpected observations, aberrant test results, or other information that has bearing on the validity of the process.

• A review and comparison of the results with those expected,

• Conclusion: Formal acceptance/rejection of the validation work

Conclusion

• State a clear conclusion as to whether the data indicates the process met the conditions established in the protocol and whether the process is considered to be in a state of control.

• If not, the report should state what should be accomplished before such a conclusion can be reached.

• This conclusion should be based on a documented justification for the approval of the process, and release of lots produced by it to the market in consideration of the entire compilation of knowledge and information gained from the design stage through the process qualification stage.

Stage 3-Continued Process Verification • The goal is continual assurance that the process remains in a

state of control (the validated state) during commercial manufacture.

• Evaluating the performance of the process identifies problems

• CAPA to ensure the process remains in control (§ 211.180(e)). • An ongoing program to collect and analyze product and

process data that relate to product quality must be established (§ 211.180(e)).

• The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products.

• Review of facility, utilities, and equipment and maintenance

Revalidation• Re-validation provides the evidence that changes in a

process and/or the process environment, introduced either intentionally or unintentionally, do not adversely affect process characteristics and product quality.

• There are two basic categories of Re-validation:• (a) Re-validation in cases of known change • (b) Periodic Re-validation carried out at scheduled intervals.

• Documentation requirements will be the same as for the initial validation of the process, and in many cases similar protocols can be employed.

• Change to a process or process environment

Q&A

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