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Process Validation – What the Future Holds. Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011. Course Objective. Take an in depth look at the regulatory requirements (EU and FDA) for process validation FDA process validation guidance

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Process validation what the future holds

Process Validation – What the Future Holds

Presented by: Karen S Ginsbury

PCI Pharmaceutical Consulting Israel Ltd.


February 2011

Course objective

Course Objective

Take an in depth look at the regulatory requirements (EU and FDA) for process validation

  • FDA process validation guidance

  • Q10 – Pharmaceutical Quality System Guidance

    • Management Review

    • Ongoing product and process performance monitoring

The objective

The Objective…

  • Gain an overall understanding of the topic of Process Validation over a product lifecycle tied in with Product Quality Review in the context of ongoing verification of process and product performance

  • Tie in with CAPA programs to provide an enhanced quality system

To be discussed

To be discussed…

  • The GMP regulations:- EU on Product Quality Reviewand Process Validation- US on Annual Product Reviewand Process Validation

  • Q10 – Pharmaceutical Quality System:Ongoing Process and Product Performance Monitoring

  • FDA Process Validation guidance

To be discussed1

To be discussed…

  • What industry is currently doing

  • Critical Process Parameters and their review

  • Critical Quality Attributes and their inclusion in the review

  • Data trending (Use of simple statistical tools)

  • Validation, deviations and changes

To be discussed2

To be discussed…

  • Organizational Structure, escalation policy

  • SOPs

  • CAPA and Follow-up

  • Critical systems, support systems

  • Management involvement / commitment

  • Mobilizing resources

Purpose of validation

Purpose of Validation:

  • To satisfy the regulators!!

  • Ensure you got what you intended

  • In accordance with design / development

  • Map critical elements / show reproducibility

  • Allow for:

    • Continuous Improvement / Change management

    • Ongoing maintenance

    • Ongoing qualification

    • CAPA

The future is now

The future is now

The future is now1

The future is now

  • Your firm failed to provide validation protocols that evaluated the impact of the increasing batch sizes on product quality. You failed to conduct a study to demonstrate at what point each batch size is uniformly blended. You have not conducted any analysis comparing data between your validation batches. Further, your firm uses a general "Master Validation Plan" for process validation on all products. Validation must be demonstrated for each product and process. The critical controls and processing parameters must be known and shown to be in control, and a demonstration of process reproducibility with objective measures must be made.1

  • 1 Further information on FDA's current thinking on process validation is available in Food and Drug Administration, Draft Guidance for Industry, Process Validation: General Principles and Practices November 2008, available at

The future is now2

The Future is Now

The future is now3

The Future is Now

Regulatory basis for validation usa fda

Regulatory Basis for Validation USA / FDA

Sec. 211.68 Automatic, mechanical, and electronic equipment

  • “Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product

  • Such equipment shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those … inspections shall be maintained”

  • Input to and output from the computer or related system of formulas or other records or data shall be checked for accuracy. The degree and frequency of input/output verification shall be based on the complexity and reliability of the computer or related system

Regulatory basis for validation eu

Regulatory Basis for Validation – EU

Annex 15 – Qualification and Validation (2001)

  • …a GMP requirement that manufacturers identify what validation work is needed to prove control of critical aspects of their particular operations

  • Significant changes to facilities, equipment and processes, which may affect the quality of the product, should be validated

  • A risk assessment approach should be used to determine the scope and extent of validation

Warning letters

Warning Letters

Some concepts

Some Concepts

  • Uncertainty: The lack of certainty, A state of having limited knowledge where it is impossible to exactly describe existing state or future outcome or there is more than one possible outcome

  • Measurement of Uncertainty: A set of possible states or outcomes where probabilities are assigned to each possible state or outcome

  • Risk: A state of uncertainty where some possible outcomes have an undesired effect or significant loss



  • “It is not enough to satisfy the customer…You MUST delight them” W. Edwards Deming

Two more that have to be understood

Two More that have to be understood

Critical Quality Attribute (CQA):

A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality

[= safety, efficacy, performance]

Critical Process Parameter (CPP):

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality

Production yield y is a cqa affected by the variable inputs x

Production Yield (Y) is a CQA affected by the Variable Inputs (X)


Inputs to the process

control variability

of the Output









y = ƒ(x)






Adapted from slide by Moheb Naser, FDA


Quality Attributes

Process Parameters


From the fda guide

From the FDA Guide

  • CGMP regulations require that batch samples represent the batch under analysis e.g. § 211.160(b)(3) and that the sampling plan result in statistical confidence § 211.165(c)

  • in-process specifications “. . . shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate” This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability

From the guide

From the Guide

  • We recommend an integratedteam approach to process validation that includes expertise from a variety of disciplines, e.g. process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance

From the guide1

From the Guide

  • The approach to PQ should be based on sound science …

  • we strongly recommend firms employ objective measures (e.g., statistical metrics), wherever feasible and meaningful to achieve adequate assurance

From the guide2

From the Guide

  • In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance

  • The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch during processing

From the guide3

From the Guide

  • The increased level of scrutiny, testing, and sampling should continue through the process verification stage as appropriate, to establish levels and frequency of routine sampling and monitoring for the particular product and process

  • Considerations for the duration of the heightened sampling and monitoring period could include, but are not limited to:

    • volume of production

    • process complexity

    • level of process understanding

    • experience with similar products and processes

From the guide4

From the Guide

  • The extent to which some materials, such as column resins or molecular filtration media, can be re-used without adversely affecting product quality can be assessed in relevant laboratory studies

  • The usable lifetimes of such materials should be confirmed by an ongoing PPQ protocol during commercial manufacture

Life cycle approach

Life Cycle Approach


No more magic 3

No more magic #3!

Process validation fda

Process Validation – FDA

  • Current Process Validation is from 1987

  • Guidance is out-dated and no longer reflects current GMPs

  • The new document is closer to ICH Q8, 9 and 10 philosophy of lifecycle approach to product (risk) management

Process validation eu

Process Validation - EU

Process validation eu1

Process Validation - EU

  • The current guideline was developed before ICH Q8/9/10

  • Additional means are available to verify the control of the process by alternative means to the traditional process validation batches

  • The main objective is that a process design yields a product meeting its pre-defined quality criteria

  • Q8/9/10 provide a structured way to define CQAs, design space, manufacturing process and the control strategy

  • Continuous process verification can be utilised in process validation protocols for the initial commercial production and for manufacturing process changes for the continual improvement throughout the remainder of the product lifecycle

Surprised you shouldn t be

Surprised?…You Shouldn’t be!

  • Q10, section 1.6 Enablers:

    • 1.6.1 Knowledge management“…process validation studies over the product lifecycle”

  • Q10, section 3.1 Lifecycle Stage Goals:

    • 3.1.2 Technology Transfer“This knowledge [from tech transfer] forms the basis for manufacturing process, control strategy, process validation approach and ongoing continual improvement”

Surprised you shouldn t be1

Surprised?…You Shouldn’t be!

  • Q10, section 3.2 Quality System Elements:

    • 3.2.1 Process Performance and Product Monitoring System“…provide knowledge to enhance process understanding, enrich the design space (where established), and enable innovative approaches to process validation”

Definition 1987 guide

Definition: 1987 Guide

  • Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics

Current definition january 2011

Current Definition: January 2011

Proposed definition:

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

Preapproved Protocols?

Completion of Optimization?

Revised process validation guide

Revised Process Validation Guide

  • Three phases to the validation:

    • Process Design

    • Process Qualification

    • Continued Process Verification

  • Lifecycle Approach

  • No more magic “three”

  • Can use data from lab scale / pilot batches to support process qualification

Fda process validation guide

FDA Process Validation Guide

Worst case

Worst Case

  • A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions

  • Such conditions do not necessarily induce product or process failure

    - Annex 15 glossary

Fda guide

FDA Guide

  • Each step of a manufacturing process is controlled to ensure that the finished product meets all design characteristics and quality attributes including specifications

  • Each step of a manufacturing process is controlled (Product Control Strategy) to assure that the finished product meets its Critical Quality Attributes and Performance Characteristics as defined in the Quality Target Product Profile

Stages of validation process design

Stages of Validation - Process Design

Stage 1 – Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities

This is a pre-requisite for process validation

Process qualification

Process Qualification

  • During the process qualification the process design is confirmed as being capable of reproducible commercial manufacture. This stage has two elements:

  • Design of facility and qualification of equipment and utilities

  • Process Performance qualification (PQ)

Continued process verification

Continued Process Verification

  • Ongoing assurance is gained during routine production that the process remains in a state of control

Continued process verification1

Continued Process Verification

Ongoing verification reports capa


Annual Product Review

Critical Systems Review

Environmental Monitoring

OOS / Out of trend results

Deviations (planned / not)

Rejected Batches

Change Control

Validation /Calibration Status


Batch Records (statistics)



Ongoing Verification / Reports / CAPA

Demonstrating ongoing control

Demonstrating Ongoing Control

  • A 10 year old car will notperform in the same manneras a brand new one

  • BUTif you can demonstrate, byongoing process monitoringthat product performanceis unchanged (within thelimits of the specification)then the old car is still validated

Demonstrating ongoing control1

Demonstrating Ongoing Control

  • Which means looking after the equipment:

    • Maintenance records:preventive and breakdown

    • Cleaning records

    • Use logs

    • Calibration logs

  • And periodically performingreview of the logs looking for:

    • Increased frequency / severity of breakdown

    • Failed calibrations

    • Failed or non-conforming batches of product

    • Borderline product – close to specification

What about grandfather products

What about Grandfather Products

  • Grandfather products shouldn’t be a concern: Product Quality Review and vast knowledge accumulated over years should provide an excellent basis for ongoing process validation – if you don’t have it already…you should have (more or less)But – new products, IMPs…when will regulators expect to first hear the term Process Validation and see data?

Quality review gmp requirements

Quality Review - GMP Requirements

  • USA

    • 21 cfr part 211.180 General Requirementsection (e)

  • EU Guide

  • Chapter 1 to the EU Guide to Good Manufacturing Practice (October 2005)[since updated to include Quality Risk Management]

21 cfr 211 180 e

21 cfr 211.180 (e)

Written records required by this part shall be maintained so that data therein can be used for evaluating at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. Written procedures shall be established and followed for such evaluations and shall include provisions for:

21 cfr 211 180 e cont

21 cfr 211.180 (e) cont/

(1)A review of a representative number of batches, whether approved or rejected, and where applicable, records associated with the batch.

(2)A review of complaints, recalls, returned or salvaged drug products, and investigations conducted under 211.192 for each drug product.

Chapter 1 1 4 product quality review

Chapter 1 – (1.4) Product Quality Review

  • Regular periodic or rolling quality reviews of all licensed medicinal products,

  • including export only products

  • Such reviews should normally be conducted and documented annually, taking into account previous reviews

1 4 pqr objective

(1.4) PQR Objective


  • The consistency of the existing process

  • The appropriateness of current specifications for:

    • starting materialsand

    • finished productto highlight any trends and to identify product and process improvements

Include at least

Include at least…

(i) A review of starting materials including packaging materials used in the product, especially those from new sources

(ii) A review of critical in-process controls and finished product results

(iii) A review of all batches that failed to meet established specification(s) and their investigation.

(iv) A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventative actions taken.

Include at least1

Include at least…

(v) A review of all changes carried out to the processes or analytical methods

(vi) A review of Marketing Authorisation variations submitted/granted/refused, including those for third country (export only) dossiers

(vii) A review of the results of the stability monitoring programme and any adverse trends

(viii) A review of all quality-related returns, complaints and recalls and the investigations performed at the time

Include at least2

Include at least…

(ix) A review of adequacy of any other previous product process or equipment corrective actions

(x) For new marketing authorisations and variations to marketing authorisations, a review of post-marketing commitments

Include at least3

Include at least…

(xi) The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc.

(xii) A review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date

Chapter 1 continued

Chapter 1 continued…

  • The manufacturer and marketing authorisation holder should evaluate the results of this review, where different, and an assessment made of whether corrective and preventative action or any revalidation should be undertaken

Chapter 1 continued1

Chapter 1 continued…

  • Reasons for such corrective actions should be documented

  • Agreed corrective and preventative actions should be completed in a timely and effective manner

  • There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during self inspection

What parameters should be included

What parameters should be included

  • Number of batches manufactured

  • Number of batches released

  • Number of batches rejected

  • Number of batches in quarantine / hold

  • More / less than previous year? Why?

  • Comments

What parameters should be included 2

What parameters should be included 2

  • Raw Materials specifications

  • Raw Materials manufacturers (changes at least)

  • Raw Materials: batch numbers used for:

    • API

    • Key excipients?

  • Product specifications

  • Review of batch records

What parameters should be included 3

What parameters should be included 3

  • Review of manufacturing data:

    • were there changes in:

      • facility

      • raw material suppliers?

      • equipment

      • manufacturing instructions?

      • product specs

      • test methods?

    • If yes, when exactly did the change happen

What parameters should be included 4

What parameters should be included 4

  • Review of manufacturing data:set up charts of data or collect on line

    • batch yields: theoretical, actual, reconciliationcan the reconciled yield be improvedwas it improved / worse than previous yearwhere are the most losses? Why?E.g. visual inspection

What parameters should be included 5

What parameters should be included 5

  • Review of manufacturing data / laboratory results:

    • in-process pH, conductivity

    • in-process assays: before / after filtration

    • in-process assays: before / after mixing

    • physical parameters: particle size distribution other?

    • Tablet weight, thickness, hardness, friability etc.

    • Fill volume / uniformity of content

What parameters should be included 6

What parameters should be included 6

  • Review of finished product data:

    • LOD

    • assay

    • Uniformity of content

    • pH

    • impurities?

    • OVIs?

    • other

What parameters should be included1

What parameters should be included

  • Review related SOPs?

  • Reserve samples ?

  • Stability data: to what level of detail?

  • What are you looking for

  • Why do you need to do it?

    • If the batches are in limits they are released

    • If not rejected

Data trending

Data Trending

  • Easiest to assess as line graphs

  • Average

  • Standard Deviation

  • Upper and lower control limits (2 or 3 SDs)

  • Compared to Upper and lower specification limits

  • Can all be done on Excel (what about validation????)

  • cf with previous years / similar products



  • Don’t list all deviations

  • Give an overview

  • Categorize and look at root causes

  • Compare with previous years

  • Up or down e.g. equipment deviations, maintenance - indicative of aging equipment, consider re-validation? Replacement?

Q10 pharmaceutical quality system june 2008

Q10 – Pharmaceutical Quality SystemJune 2008

  • model for an effective quality management system for the pharmaceutical industry

  • that can be implemented throughout the different stages of a product lifecycle

  • Product Quality Review is concerned with the PRODUCT LIFECYCLE – ongoing control

Q10 management responsibility

Q10 Management Responsibility

  • Ensure a timely and effective communication and escalation process exists to raise quality issues to the appropriate levels of management

  • Conduct management reviews of process performance and product quality and of the pharmaceutical quality system;

  • Advocate continual improvement;

  • Commit / mobilize appropriate resources

Q10 management responsibility1

Q10 Management Responsibility

  • Management should assess the conclusions of periodic reviews of process performance and product quality and of the pharmaceutical quality system

Continual improvement of process performance and product quality

Continual Improvement of Process Performance and Product Quality

  • Section 3 of Q10 = PQR

  • 3.1.3 Commercial Manufacturing

  • The goals of manufacturing activities include …establishing and maintaining a state of control and facilitating continual improvement

  • The pharmaceutical quality system should assure that:

    • the desired product quality is routinely met

    • suitable process performance is achieved

    • the set of controls are appropriate

    • improvement opportunities are identified and evaluated

    • the body of knowledge is continually expanded

3 2 1 process performance and product quality monitoring system

3.2.1 Process Performance and Product Quality Monitoring System

  • plan and execute a system for the monitoring of process performance and product quality to ensure a state of control is maintained

  • An effective monitoring system provides assurance of the continued capability of processes and controls to produce a product of desired quality and to identify areas for continual improvement

3 2 1 process performance and product quality monitoring system1

3.2.1 Process Performance and Product Quality Monitoring System

  • Use risk management to establish product control strategy

  • Provide tools for measurement and analysis of parameters and attributes identified in the control strategy (e.g., data management and statistical tools)

  • Analyse parameters and attributes identified in the control strategy to verify continued operation within a state of control

  • Identify sources of variation affecting process performance and product quality for potential continual improvement activities to reduce or control variation

  • Include feedback on product quality from internal and external sources, e.g., complaints, product rejections, non-conformances, recalls, deviations, audits and regulatory inspections and findings

  • Provide knowledge to enhance process understanding, enrich the design space (where established), and enable innovative approaches to process validation

Change control

Change Control

  • Need ongoing change control

  • Need change control for changes resulting from the annual review

  • Do not assume that because it was written in the conclusions it can be implemented straight out in production

Organizational structure

Organizational Structure

  • Who does the review?

  • Get as much as possible from computers

  • Get production / ops involved - they are the owners of the process

  • Make sure that Process Development signs off on the report - they will need to troubleshoot

Process validation what the future holds


  • Purpose

  • Responsibility

  • Procedure

  • Limits and Limitations

  • Corrective Actions

  • Documentation

Follow up


  • Part of CAPA program

  • Won’t happen on its own

  • Requires troubleshooting, which means process development and change control and maybe process validation / revalidation

  • Documentation

  • Approvals

Critical systems review

Critical Systems Review

  • WFI

  • Purified Water

  • HVAC system

  • Clean Steam

  • Autoclave?

  • Oven?

  • Media Fill

  • (Aseptic Process)

  • Validation Program

  • Audit Program

  • Training Program

  • Stability Program?

  • SOPs

  • Reserve Samples?

Management involvement

Management Involvement

  • 21 cfr 211.180 (f) (directly after annual review)

  • “Procedures shall be established to assure that the responsible officials of the firm, if they are not personally involved in or immediately aware of such actions are notified in writing of any investigations conducted under 211.198 (complaints), 211.204 (returns), 211.208 (salvaging), any recalls, reports of inspectional observations or any regulatory actions relating to GMP…..

  • Management needs to be informed of outcome of annual review

Management involvement1

Management Involvement

  • Management needs to provide the resources to implement corrective actions

  • Means:

    • people

    • equipment

    • time

    • production down time

Fda risk based approach to cgmp

FDA - Risk based Approach to cGMP



  • Critical parameters must be understood

  • Critical process parameters must be defined

  • Critical process parameters must have ranges

  • Trends need to be followed, understood and acted upon

  • Change control may need to follow trends



Process Validation is a continuum not a one time event

It should encompass the product lifecycle

It can be tied in with product and process quality reviews to demonstrate maintenance of an ongoing state of control

  • a MANAGEMENT tool

  • an opportunity to correct a process before the process gets out of hand

  • a money saving tool if used properly

  • to be used in investigation of deviations

  • to be used in estimating effects of changes to the process

Thank you for your attention

Thank you for your attention


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