Process Validation of API

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Process Validation in API Facilities:

What ? Why ? How?

P.S.Rao

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Validation is the term widely used in the pharmaceutical industry. It comes from the word “Valid” which means “ Can be justified or Legally Defined”.

It can be said as “Validation is demonstrating and documenting that something does (or is) what is supposed to do (or be)”.

In short validation is defined as “Full detailed documentation that all process and procedures are functioning in the manner they are designed for”

Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected result.

Validation: Definition

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Analytical Test Equipment Process Support process (Drying, Blending,

Micronization, Cleaning, sterilization, sterile filling, etc

facility systems (air, Nitrogen, water, AHU etc)

Validation studies

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verify the system/process under test, under the extremes expected during the process to prove that the system remains in control.

Critical equipment and processes are routinely revalidated at appropriate intervals to demonstrate that the process remains in control.

Validation studies

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Type of validation

Laboratory-and pilot-scale validations– some production processes cannot be carried out

in production facility

Plant-and Commercial-scale validations– Production processes carried out in production

facility with Defined Batch size.

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Facility systems and equipment: Stage of validation

Design qualification (DQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ)

Systems and EQ; PQ=validation

Depending on the function and operation of some EQ

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Facility systems and equipment

Design qualification (DQ)– necessary when planning and choosing EQ or systems to

ensure that components selected will have adequate capacity to function for the intended purpose, and will adequately serve the operations or functions of another piece of EQ or operation.

Which includes,– Utilities and building services– Equipment features– Auxiliary Equipment features– All Eng drawings, schematics, layouts and list of manufacturers

functional specifications (and its comparison with URS).

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Installation Qualification (IQ)

– This is the first step towards equipment validation– Upon receipt the equipment, the user shall inspect the equipment

to ensure that, it meets the spec’s submitted with the initial order– written for critical processing EQ and systems– list all the identification information, location, utility requirements,

and any safety features of EQ– verify that the item matches the purchase/Design specifications– It is the responsibility of the vendor, the operating dept and the

project team to complete the IQ successfully.

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Operational Qualification (OQ)– outlines the information required to provide evidence that all

component of a system or of a piece of EQ operate as specified.– At this stage COP’s should be finalized– There must be min 3 consecutive successful runs to demonstrate

repeatability– should provide a listing of SOPs for operation, maintenance and

calibration– define the specification and acceptance criteria – include information on EQ or system calibration, pre-operational

activities, routine operations and their acceptance criteria & frequency

– Training on operation of EQ

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Performance Qualification (PQ)

– performed after both IQ and OQ have been completed, reviewed and approved

– describes the procedures for demonstrating that a system or piece of EQ can consistently perform and meet required specification under routine operation and, where appropriate, under worst case situations

– include description of preliminary procedures required, detailed performance tests to be done, acceptance criteria

– other supporting EQ used during qualification have been validated.

– Process validation and PQ may overlap.

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pH meter, incubator, Temp Sensor, freezer; IQ,OQ

system: air (HVAC), compressed air, pure steam, raw steam, purified water, WFI, central vacuum; IQ, OQ, PQ

EQ: Reactor, oven, lyophilizer, centrifuge, Drier; IQ, OQ, PQ

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[To establish] documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting pre-determined specifications and quality attributes.

(FDA, May 1987)

Process Validation Overview

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Prospective– pre-planned protocol

– Prospective validation is the preferred approach, but there are exceptions where the other approaches (Concurrent/Retrospective) can be used

– Prospective validation performed on an API process should be completed before the commercial distribution of the final drug product manufactured from that API (ICH Q7 12.42).

Approaches to validation

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Concurrent– base on data collected during actual performance of a process

already implemented & Validated in a manufacturing facility– suit manufacturers of long standing, have well-controlled

manufacturing process

– Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or

– API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches (ICH Q7 12.43).


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Retrospective – for production for a long time, but has not been validated according to a

prospective protocol and concurrent validation is not realistic option– is not generally accepted

An exception can be made for retrospective validation for well established processes that have been used without significant changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where:

(1) Critical quality attributes and critical process parameters have been identified;

(2) Appropriate in-process acceptance criteria and controls have been established;

(3) There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability; and

(4) Impurity profiles have been established for the existing API. (ICH Q7 12.44)


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Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process (ICH Q7 12.44).


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Demonstrate process control and consistency

Comply with regulatory requirements for licensure or for filing

Provide assurance that release tests will be met; the need for some release testing may be eliminated.

Why Validate the Process ?

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Key Process Variables

Optimization/Process Understanding

RobustnessWorst case challenges?

Process Validation at Full-scale

Process Characterization

Process Validation

Phase I/II Trial process

Lab-scale process

Manufacturing process

Lab Scale Validation

Process Validationrequires a rational approach

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Characterization vs. Validation

Characterization– “Validation” studies at bench-scale using scaled-down models,

if possible.– Well-documented in Lab notebooks and key technical reports

(no protocol)– Learning, not “Validating”

Validation– Usually at Full-scale in actual process equipment– Conducted by Manufacturing under Protocol– Testing what we already know, NOT EXPERIMENTING!

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Understand Your Process

Ruggedness– Multiple lots of raw materials– Multiple lots of resins/filters– Explore failure limits at laboratory/pilot scale

Scaled-down process should reflect full scale manufacturing performance as closely as possible so that data generated are relevant.

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Definitions

Critical Process Parameter (CPP):

An input variable that must be controlled within a specified range to ensure success.

A critical parameter is that a processing parameter that directly influences the drug substance characterization and impurity profile at or after a critical step.

Critical Quality Attribute (CQA):

An output parameter from a unit operation that must be within a specified range to demonstrate control, consistency, and acceptable product quality.

CPP CQA

pH/Temp Yield

SM content/Reaction Time Purity

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1. Select CPPs, CQAs

2. Process Validation Protocol

3. Execute

4. Assay

5. Report

6. File

Process Validation

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Process Validation Protocol

CPPs, CQAs w/ acceptance criteria– Background / rationale for ranges

How will they be sampled / monitored ? How many validation lots ? How will deviations be handled ?

Define Roles and ResponsibilitiesManufacturing, Quality, Technology

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Step Goal CPPs

CPP Range

How controlled

CQA Samples CQA Range

Methods

Fermentation

High cell density

pHTemp

7.0± 0.5 DCS Final Glucose Concn.

Broth –final time point

1 – 3 g/L

Analytical methd SOP XYZ

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Detailed chemical synthesis of product List of approved vendors Reference of R&D and pilot scale up studies and technology transfer report Detailed manufacturing instructions List of EQ/Instruments used and its qualification/Calibration status Critical process steps and CPP identification/description/justification Sampling and testing plans (pictorials) Validated analytical methods for IP and Int/final product testing Statistical techniques to be used in the data analysis ACC with scientific rationale List of validation members Deviations/ conclusions/ Recommendations/certification & Report pattern

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Process Validation Program (ICHQ7)

The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered.

For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times).

For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified

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Process Validation Program (ICHQ7)

Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.

Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to or better than historical data and, where applicable, the profile determined during process development or for batches used for pivotal (key) clinical and toxicological studies.

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Periodic Review of Validated Systems(ICHQ7)

Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner.

Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation (?).

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RE-VALIDATION (HSA: GUIDE-MQA-007-007 )

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:

1. Re-validation in cases of known change (including transfer of processes from one company to another or from one site to another); and

2. Periodic re-validation carried out at scheduled intervals.

A system should be in place (Validation Master Plan requirements) to ensure both situations are addressed.

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RE-VALIDATION (HSA: GUIDE-MQA-007-007 )

The need for periodic re-validation of non-sterile processes is considered to be a lower priority than for sterile processes.

In the case of standard processes on conventional equipment, a data review similar to what would be required for Retrospective Validation may provide an adequate assurance that the process continues under control. In addition, the following points should also be considered:

The occurrence of any changes in the master formula, methods or starting material manufacturer;

Equipment calibrations carried out according to the established program;

Preventative maintenance carried out according to the program;

Standard operating procedures (SOPs) up to date and being followed;

Cleaning and hygiene program still appropriate; and

Unplanned changes or maintenance to equipment or instruments.

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CHANGE CONTROL-Revalidation

Change control is an important element in any Quality Assurance system. Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or support system operation.

All changes should be formally requested, documented and accepted by representatives of Production, QC/QA, R&D, Engineering and Regulatory Affairs as appropriate. The likely impact (risk assessment) of the change on the product should be evaluated and the need for, and the extent of re-validation discussed. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorized.

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Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the responsible personnel.

Changes that are likely to require re-validation are as follows:

Changes of raw materials (physical properties such as density, viscosity, particle size distribution may affect the process or product);

Change of starting material manufacturer;

Changes of packaging material (e.g. substituting plastic for glass);

Changes in the process (e.g. mixing times, drying temperatures);

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Changes in the equipment (e.g. addition of automatic detection systems).

Changes of equipment which involve the replacement on a ‘like for like’ basis would not normally require a re-validation;

Production area and support system changes (e.g. rearrangement of areas, new water treatment method);

Transfer of processes to another site; and

Unexpected changes (e.g. those observed during self-inspection or during routine analysis of process trend data).

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Major PV problems facing during regulatory audits.

• Failure in life cycle approach to validation• People are thinking that once they complete their

prospective validation that is end and they are on their way• Lack of scientific rationale in acceptance criteria & in

preparing protocol.• Lack of documentation execution• Lack of awareness on process validation• Lack of justification on CPP & CQA of the process• Lack of seriousness on validation, etc.

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New PV Guidance By FDA (Jan,2011)

Process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.

A series of activities taking place over the lifecycle of the product and process.

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Requirements of FDA Validation Guidance

FDA Guidance for Industry: Process Validation: General Principles and Practices, published January 2011 distinguishes three stages of validation:

– 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.

Further states that manufacturers should understand the sources of variation

– Detect the presence and degree of variation– Understand the impact of variation on the process and ultimately on product

attributes– Control the variation in a manner commensurate with the risk it represents

to the process and product

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Stage 3: Continued Process Verification

Stage 1

Stage 2

Stage 3

Process Validation

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Stage 3: Continued Process Verification

Goal=To continually assure that the process remains in a state of control (the validated state) during commercial manufacture.

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Learning progression

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Good planning, expected path

Comprehensive processdesign, scientific process understanding

Sound, thorough process qualification.Confirms design

Continued Verification,Process learning andimprovement

Poor design, planning, process understanding

Poor, minimal design

PQ checklistexercise w/little understanding

Unexplained variation,Product and process problems.Process not in control. Major learning!

Potentially substandard

product on market

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Process Validation: General Principles and Practices

1. Further the goals of the CGMPs for the 21st Century Initiative such as advancing science and technological innovation.

2. Update Guidance based on regulatory experience since 1987.

i. Emphasis on process design elements and maintaining process control during commercialization

ii. Communicate that PV is an ongoing program and align process validation activities with product lifecycle

iii. Emphasize the role of objective measures and statistical tools and analyses.

iv. Emphasize knowledge, detection, and control of variability.

Lifecycle approach is more rational, scientific and can improve control and assurance of quality.

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Stage 1: (Why)Process Design

“Focusing exclusively on qualification efforts without understanding the manufacturing process and associated variations may not lead to adequate assurance of quality.”

Poor quality drugs on the market, evidenced by recalls, complaints and other indicators, from supposedly “validated” processes pointed to a lack of process understanding and adequate process control. This was an impetus (drive) for revising the 1987 Guideline.

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Stage 2: Process Qualification

Two Aspects

Design of facilities and qualification of equipment and utilities

Process Performance qualification (PPQ)

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PPQ - Process Performance Qualification

Protocol(s) include

“Criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products.”

“A description of the statistical methods to be used in analyzing all collected data (e.g., statistical metrics defining both intra-batch and inter-batch variability).”

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Basis for commercial distribution

“Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify distribution of the product.”

Criteria for high level of assurance is specific to the particular product and process being validated (results of stages 1 & 2) and is judged by the firm.

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Concurrent Release in the PV Guidance

In the PV guidance, the term “concurrent release” is meant exclusively in terms of the process performance qualification (PPQ) study protocol. It means releasing a lot(s) included in a pre-planned study protocol before the study is completed, data collected and analyzed, and conclusions drawn.

PV Guidance definition Concurrent Release: Releasing for distribution a lot of

finished product, manufactured following a qualification protocol, that meets the [lot release criteria] standards established in the protocol, but before the entire study protocol has been executed.

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Stage 3 - Continued Process Verification

CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control (§211.180(e)).

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Stage 3- Continued Process Verification

A strategy for trending and monitoring. • What is the goal? • For example, determining machine-to-machine

variability? within a machine? Batch to batch variability for certain attributes?

• May need to tailor approaches, use different tools, for different products and processes.

Obtain expertise applying statistical tools and analysis to manufacturing data.

Further refine the control strategy.

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Stage 3- Continued Process Verification

“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.

The data should be statistically trended and reviewed by trained personnel.

The information collected should verify that the quality attributes are being appropriately controlled throughout the process.”

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Statistical expectations– from the Process Validation Guide

• Statistician or adequate trained personnel in statistical

process control techniques should develop

– Data collection plan, stage 2 and 3

– Statistical methods for evaluating process stability

and process capability

• Statistical methods to include:

– Trending

– Evaluation of process stability and capability

– Detection of unintended process variability

– Guarding against overreaction to individual events

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Basic statistical terms:

– Mean ( μ): Statistical average

• Mean,μ = Σxj/N

Sum of individual Measurements (xj)/number of measurements (N)

– Standard deviation (σ) : Common measure of statistical dispersion,

which measures how widely spread the values in a data set are.

It is calculated as the square root of variance:

A large standard deviation indicates that the data points are far from the mean and a small standard deviation indicates that they are clustered closely around the mean

– Normal distribution: The most common distribution.

Approx 68% of the values are within 1 standard deviation

of the mean, about 95% of the values are within two

standard deviations and about 99.7% lie within 3

standard deviations of the mean

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Process Capability

• Process capability analysis compares the performance

of a process against its specifications

• A process is capable if virtually all of the possible

variable values fall within the specification limits

• Uses “capability indices” to measure the ability of a

process to meet the specifications:

– Cp, Cpk, Ppk etc are common measures of process

capability

– They measure the spread of the specifications

relative to the six-sigma spread in the process

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Process Capability

Cpk = min(Cpu, Cpl)

– Cpu = (USL-μ)/(3σ)

– Cpl = (μ-LSL)/(3σ)

• Takes into account the location of the process mean relative to specifications

“Process Centering”

• Cpk = Cp when process is centered

• Cpk < Cp when process is not centered

LSL Width USL

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Process Capability

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Spécial Cause versus Common Cause variation

Common Cause (Random) Variation - Natural variationwithin a process

Special Cause Variation - Occasionally in a process

COMMON• Always present• Lots of them• Small cumulative effect• Hard to remove/ reduce

SPECIAL• Irregular occurrences• Relatively rare• Large impact• Mostly easy to correct

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Causes of Variation, Examples

Common Causes Special Causes

• ‘In Control’• Normal equipment wear• Material variation• Equipment tolerances• Process parameterswith set points, e.g.blending speed

•‘Out of Control’• Equipment breakdown• Change of supplier• Instability in processparameter, e.g. blending speed

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Knowledge and understanding Variability is the basis for manufacturing control

• Manufacturers should– understand the sources of variation,– detect the presence and measure degree of variation,– understand its impact on the process and ultimately product attributes, and– manage it in a manner commensurate with risk it represents to the process and product• Mechanisms for managing variability is part of the control strategy– e.g., may choose advanced manufacturing technologies that employ detection, analysis and control feedback loops to react to input variability (PAT)

Variable ProcessProcess Input

Fixed Process

Variable Process output

Variable ProcessProcess Input

Adjustable Process

Consistent Process output

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To summarize New approach versus traditional

Traditional

• Compliance focus

• Following rules

without thinking

• DQ/IQ/OQ/PQ

• Validating 3-

batches =

assumes product

quality assurance

New PV approach

• Science and risk based

• Basis of product quality understood

• PV leads ( i.e. equipment qualification

supports PV) & is not

an ‘add-on’

• Must have statistical

understanding

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The Question of Process Validation

• Do I have confidence in my manufacturing process?

• what scientific evidence assures me that my process is capable of consistently delivering quality product?

• How do I demonstrate that my process works as intended?

• How do I know my process remains in control?

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Validation: Type of Documentation

Validation master plan (VMP) Validation protocol (VP) Validation reports (VR) Standard operating procedures (SOPs)

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Master validation plan (MVP)

Is a document pertaining to the whole facility that describes which EQ, systems, methods and processes will be validated and when they will be validated.

provide the format required for each particular validation document (IQ, OQ, PQ for EQ and systems; process validation, analytical assay validation)

indicate what information is to be contained within each document indicate why and when revalidations will be performed who will decide what validations will be performed order in which each part of the facility is validated indicate how to deal with any deviations state the time interval permitted between each validation Enables overview of entire validation project List items to be validated with planning schedule as its heart like a map

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Validation: In summary, VMP should contain at least

Validation policy Organizational structure Summary of facilities, systems, equipment,

processes to be validated Documentation format for protocols and

reports Planning and scheduling Change control Training requirements

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Validation: Protocol

Objectives of the validation and qualification study

Site of the study Responsible personnel Description of the equipment SOPs Standards Criteria for the relevant products and

processes

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Validation: Report

Title objective of the study Refer to the protocol Details of material Equipment Programme’s and cycles use Details of procedures and test methods Conclusion and certification.

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Process Validation

Complete 3 Validation Lots Obtain, Analyze data Address deviations

Transient deviations Equipment malfunctions

Additional lots if needed Complete / approve report Include in license

Questions, please…. ?

Health & Medicine

Process Validation of API