Human Journals

Review Article
April 2016 Vol.:6, Issue:1
© All rights are reserved by Patwekar S.L et al.

Current Features of USFDA and EMA Process Validation Guidance

Keywords: Pharmaceutical validation, cGMP regulations,
CQA, PPQ, USFDA, EMA, ISPE, life cycle approach

ABSTRACT
*
Patwekar S.L ., Gattani S.G., Sakhare R., Khan S.A., Pharmaceutical validations are part of cGMP regulations. The
Gaikwad M.S., Pedewad S., Potulwad A. validation provides justification based on sound scientific
knowledge of product quality attributes for in-depth process
School of Pharmacy S.R.T.M.U. Nanded 43606, India.
understanding to develop process control strategy in first stage.
Submission: 5 April 2016 In second stage confirmation of process control parameters
Accepted: 10 April 2016 influencing the quality attributes of products by designing of
Published: 25 April 2016 experiments. Further in stage to process performance
qualification is done whereas in third stage continuous
monitoring of process is carried out to provide the strong
evidence that the process is under control during the
manufacturing of products with required quality attributes. The
present review describes the way how to go for validation of
particular process. Also the review describes USFDA and EMA
www.ijppr.humanjournals.com guidance on validation with modern lifecycle approach. ISPE
discussion on solid tablet dosage form validation is taken as
example for process validation guidance understanding in
depth.
 www.ijppr.humanjournals.com

INTRODUCTION

Quality is concept applicable at everywhere from business to successful life. Everyone wanted to
buy the quality product and live the quality life as per the standards determined by them for it.
As concern with pharmaceutical products, these were built for to bring the quality in health of
human and animal beings. Quality directly relic on health of human and animals so control on
quality parameters is became necessary, so there are stringent rules and regulation for the
pharmaceutical industry all over the world. This renders them as strictly regulatory controlled
industries [1,5].

Regulatory bodies took the lot of efforts to maintain the quality of pharmaceutical products as
per its quality specifications that are safety, efficacy, purity, identity, strength. The USFDA,
EMA regulatory agencies have been taken initiative in the form of development of new concept
and strategies for maintaining the quality of pharmaceutical products. Validation refers to
producing the acceptable evidence and assures that the given process can be useful for its
predictable use.[1]

The revised guidance on process validation promotes the use of different ICH Q8, Q9, and Q10
guideline recommendations to bring the pharmaceutical quality as central accent in
pharmaceutical industry. Process validation incorporates a life cycle approach linking product
and process development to continue process verification through continuous monitoring of
process parameters for assure the process is in-control during its commercial manufacturing.
Process qualification is intermediate stage by which evaluation of the method constraint is done.
The validation guidance is based on understanding of process and product knowledge with sound
scientific methods.[1, 2,3,5]

ORIGIN OF PROCESS VALIDATION

Process validation guidance was come in force from 1987 in US through USFDA notification in
Federal Register May 2011, with elaboration of different elements of the process validation.
Process validation is part of current good manufacturing practices which had its basic foundation
in CFR 211.110 (a) as follows, “There shall be written procedures for production and process

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control designed to assure that the drug products have the identity, strength, quality, and purity
they purport or are represented to possess.[3].

Current process validation guidance has modern approach towards validation with basic
considerations of its principle and widening the scope of validation for inclusion of modern
technology implementation in pharmaceutical industry, application of quality concept and tool
and quality system for production of pharmaceuticals.[1,3] The objective of process control is
quality should built in products by follow up the cGMP regulation [1,3,4].

In 2008, it incorporates the collection and evaluation of data i.e. applying the statistical tools for
establishing the scientific evidences of specific process to deliver the quality products[5].

Whereas in 2011, validation involves the risk-based approach and lifecycle approach for
products and processes and by which one can do continue process verification for assurance of
manufacturing quality pharmaceutical product by the process reproducibly.

According to 1987 USFDA guideline validation is defined as ,

“An 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”.

According to EMA 2001 guidance[4]

“Ensuring and providing the documentary evidences that process within their specified designed
parameters are capable of consistently produced finished product of the required quality”.

According to 2011 USFDA process validation guidance[1]

“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 products”.

According to EMA 2014 guidance,

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“The documented evidence that the process, operated within established parameters, can
perform effectively and reproducibly to produce a medicinal product meeting its predetermined
specifications and quality attributes”.

According to recent validation guidance of USFDA, EMA provides a broad meaning to

validation it recommends the risk management system, sound scientific method application to
the process validation. Continued process verification is new approach include the guidance for
routine monitoring of the process performance to build the assurance about process in control
during lifecycle of process and products. According to newer approach of guidance validation is
considered as continuous event.[5]

APPROACHES TO PROCESS VALIDATION

There were two types of approaches of process validation according to USFDA 1987 guidelines
i.e. prospective approach and retrospective approach. The prospective approach is applicable to
new process, new product approval whereas retrospective approach is based on total historical
data for evaluation of process which is implemented for saleable built-up of eminence
products[4,6,7].

Whereas according to 2011 USFDA process validation guidance it recommends the product or
process lifecycle approach which made up of three stages i.e. process design, process
qualification, continued process verification[1,5]. According to EMEA guideline on process
validation it recommends the traditional approach which is based on historical data by which
evaluation of process is done. [2,8,9].

Regulatory Requirements For Process Validation

Process validation is legal requirement under section 501(a)(2)(B) of the Act (21 U.S.C.
351(a)(2)(B)). According to this,

“A drug. . . shall be deemed to be adulterated. . . If. . . the methods used in, or the facilities or
controls used for, its manufacture, processing, packing, or holding do not conform to or are not
operated or administered in conformity with current good manufacturing practice to assure that

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such drug meets the requirements of this Act as to safety and has the identity and strength, and
meets the quality and purity characteristics, which it purports or is represented to possess.”

STAGES OF PROCESS VALIDATION

It requires sound knowledge of products quality attributes, the process knowledge by which one
can produce the quality products, identification of process variables and their impact on quality
attributes of product, for development of strategy to process control and monitoring[1,10,11,15,].

Stage 1: Process Design :

It can be possible with product development stage, the lab scale designing of products require
different understanding process parameters and their impact on product quality. The general
manufacturing pathway can be established at this stage and knowledge gain from process and
product development is responsible for process and product understanding [1,15].

Process knowledge understanding :

Lab scale process design, pilot plant scale-up technique, and technology transfer to commercial
production leads to require thoroughly understanding of real working of process. Quality based
design, design of experiment are the tool used for design the process at different level i.e. from
lab scale to commercial production of quality products with predetermined specifications. It can
be completed with the aid of numerous sources as follows,

Development phase :

Determination of different variability during product development and characterization can be

possible with design of experiment. Analytical capability is required condition for monitoring the
parameters which are leads to variation. Process understanding through the development stage is
not possible for generic manufacturer, they find out another source for gain process
understanding[16].

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Prior Knowledge :

Prior knowledge is associated with another similar process which can be easily understood with
experience. For natural product annual product review, deviation, complaint investigation,
change control information may be used for process understanding [16].

Process Understanding through Knowledge of Unit Operation :

Process understanding is possible by having the in-depth knowledge of unit operation. Trained
personnel, Selection of equipments, controlling parameters of unit operations are useful for
appreciative the process.

Process certainty and Modeling :

Lab scale and small scale modeling simulation are also helpful for predicting the impact of
variation output on commercial production.

Effect of Scale Change :

On large-scale up the process understanding becomes broader with multi variability parameters
determination and its impact on superiority.

Approach/ Strategy for Process Control :

Once scheming of the process based on its product and process development knowledge one may
require to design the process parameter for evaluating the process on the basis of strategy
developed for control of different process parameters which affect the product quality [1,2].

To develop the strategy of process control, one can monitor the equipment operational limits and
material analysis, which leads to production of master manufacturing and control records.
Process analytical technology (PAT) is modern strategy implementation for process control.
[1,2,17]
.

Approach for process control depends on factor like

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Raw material specification :

Process control is also required the raw material which qualified its specification. The variability
in raw material specification leads to wrong result with great control of process. Raw material
quality control has first priority in strategy of process control6.

Experiences with process performance :

Process performance is managing the variability with adequate control on scale effect. The
determination and control of variability of process which determine same kind of control
parameters and its extent to influencing the quality of product which is required for commercial
production.

Stage 2: Process Qualification:

It is second stage of process validation in which confirmation is done on actual efficiency and
reproducibility of process during its commercial production by evaluation of process control
parameters established during process design phase. The aim of this phase is to offer strong
scientific justification, increase process and product understanding level, prove adequate control
on production of quality products. It is main stage of process validation because the result of this
stage data will be responsible for taking the decision about market release of manufactured
products6. It consists of two rudiments as follows,[6,15,16]

Design of facility and qualifications of utilities and equipments :

The facility is required for commercial production as per the cGMP regulation. Qualification of
utility and equipment means that all the actions performed for proving that utilities and
equipment are suitable for their specific use. Different planning of activity is done under this
involved its IQ, OQ, PQ protocols, their reports respectively.

Process performance qualification (PPQ):

It consists of use of facility, qualified utilities and equipments, trained personals, manufacturing
procedure, control procedures which are ready for production of commercial production batches.
PPQ involved higher sampling, testing, and scrutiny to evaluate the process performance in

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typical manufacturing conditions. The evaluation of data is done with the objective measure. The
statistical methods are applied for generation of meaningful inferences. The implementation of
such methods provides great scientific evidence about providing adequate assurance [6,15,22]

PPQ batches are studied for providing intra and inter-batch variability. Determination of number
of batches studied for PPQ is based on risk assessment. The variables responsible for high risk
required more no. of batches for PPQ study whereas low-risk variables require the very few PPQ
batches in revise6. There are unlike strategies for determining the no. of PPQ batches require for
process validation, like based on rationale or experience, target process confidence and target
process capability, expected coverage. Number of batches required for PPQ based on rational
and experience are as follows [22].

Residual Risk level No. of batches

Severe Not ready for PPQ
High 10
Moderate 5
Low 3
Minimal 1-2

Stage 3: Continued/ Persistent Process Verification:

This is part of lifecycle approach applied to process validation by FDA. EMA Process validation
guidelines also recommend the new approach to process validation based on lifecycle approach
with continues process verification[1,2].

Development of well designed approach towards maintenance of facility, utilities, equipment is

important part of stage three. [23].

Establishing Continued Process Verification Plan :

The goal of CPV plan is to assure throughout the commercial manufacturing phase of lifecycle
that the process is in state of control. The plan includes the evaluation of process capability,
material specificity, in-process testing, finished product testing, qualification of equipments,
utility, statistical tool for acceptance of process control criteria, estimation of variability. The

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statistical method applies for estimating the strength between input-output relationship. CPV
plans provide the stage for process development[17,18,23].

Continued process verification plan is done for continues monitoring of process performance
during manufacturing. It gives space for process improvement as well as assures that the process
is well controlled and monitored during its life cycle[1].

Concurrent Release of PPQ Batch :

Concurrent release of PPQ batches is recommended under specific condition like drug of limited
demand, having short life span, to alleviate the short supply. Concurrent release batches
accompanied with careful monitoring of distributed batches to get easily the customer feedback
for product quality. Any complaint, failure leads to improvement of process to production of
quality products by taking appropriate corrective actions[1].

FEATURES OF USFDA PROCESS VALIDATION GUIDANCE 2011

1. It utilizes the basic concept of validation and uses the statistical tool for developing the
scientific evidence that process is in under control.
2. It introduces continued process verification by which one can monitor the process and having
space for process improvement.
3. It further ruled out the magic No. System that manufacturer followed without
recommendation regulatory bodies.
4. It replaces the validation as only documented system with collection and evaluation of data
by using scientific Statistical approaches.
5. Critical Quality Attributes is replaced with process variables which directly or indirectly
affect on quality specification of products.
6. Guidance based on thinking that quality should be built in products.

FEATURES OF EMA PROCESS VALIDATION GUIDANCE 2014

1. Continuous process verification is included as new approach for process validation which is
based on routine monitoring on process to remain in state of control.

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2. The use of extensive in-line, on-line, at-line testing is recommended for evaluation of process
performance.
3. Guideline covers all the critical elements consider for commercial production process
inclusion as regulatory submission for pharmaceutical products.
4. Life cycle approach is adopted in newer validation guidance. Science and risk-based approach
is used to assure the process is operated within specified parameters.
5. Justification for the number of batches is based on the complexity and variability of process.
6. Re-validation becomes the part of process change or continuous process improvement.
7. Hybrid approach is suggested by the EMA guidance in which both the traditional as well as
enhanced validation approach are used wherever suitable in different steps of the process.

Comparison between USFDA and EMA updated process validation guidance[24]

Table No.1: Comparison between USFDA and EMA updated process validation guidance.

USFDA Guidance EMA guidance

For marketing approval minimum no. of Minimum three batches are recommended for
batches for validation are not recommended, process validation for market authorization of
sufficient no. of batches are required to provide product, with justification.
assurance based on statistical and scientific
justification.
CPV is part of process validation CPV is considered as new approach to process
validation
Development and execution of validation Validation activity is recommended for dossier
activity are assisted by USFDA. submission
USFDA consider all the qualifications activity EMA consider qualification as separate
as overall validation activity. guideline as annex 15.

PROCESS VALIDATION OF SOLID DOSAGE FORM WITH MODERN RISK-BASED

APPROACH:

Tablet is solid dosage form which is validated by using newer risk-based approach before the
market release. The design of experiments for risk assessment, determination of equipment

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qualifications, products specifications, process parameters and raw material attributes,

development of process control strategy in such a way that outputs obtained through the efficient
and safe process design, operation, and its evaluation of process performance leads to build the
strong scientific justification for production of quality product consistently and efficiently is the
main objective of process validation[20,21,22].

Product knowledge determines its critical quality attribute which are given the information about
the quality products. E.g. for tablet dosage form appearance, identity, assay, impurities,
dissolution, content uniformity are the quality parameters which directly affect the general
specification of pharmaceutical products i.e. quality, safety, efficacy[22].

Cause of risk is associated with the variables monitored in each unit operation and effects are
obtained results from testing of CQA of products which directly affect the quality of the product
by designing of experiment are helpful for risk evaluation prior to process development study[22].

Cause and effect matrix diagram can be prepared as follows.

Table No. 02: Cause and effect matrix diagram.

CQA/Unit Dispensing Blending Lubrication Compression Coating Packaging

operation
Appearance L L L L M L
Identity M L L L L M
Assay M M L M L L
Impurities L L L L L L
Content
L H M M L L
uniformity
Dissolution L L H H L L
Microbiology L L L L L L

L: Low, M: Medium H: High, CQA: Critical Quality Attributes,

Dissolution and content uniformity are having highest risk associated with three different unit
operations. Now after the application of process control strategy now all the associated risk

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becomes low. This is requirement for submission to regulatory agencies to give justification for
removal of associated risk from the process performance during manufacturing of quality
product. Cause and effect matrix diagram of the application of process control strategy and after
process development studies are as below. [23]

Table No. 03: Cause and effect matrix diagram of the application of process control
strategy and after process development

CQA/Unit Dispensing Blending Lubrication Compression Coating Packaging

operation
Appearance C C C C C C
Identity C C C C C C
Assay C C+E C C+E C C
Impurities C C C C C C
Content
C C+E C+E C+E C C
uniformity
Dissolution C C C+E C+E C C
Microbiology C C C C C C

C: Conventional Control Strategy including cGMP, C+E: Conventional Control Strategy

including cGMP and elements of Enhance QBD Approach.

Continuous monitoring of process performance during routine manufacturing operation becomes

the basis of stage 3 process validation strategy i.e. continued process verification which gives
lifecycle approach to process validation program. It provides the room for process improvement,
requalification strategy of equipments used in operations, any change control system required for
process performance, and residual risk assessment evaluation during routine manufacturing
conditions [23].

CONCLUSION

Pharmaceutical process validation is now becoming mandatory requirement of ANDA

submission from 2013 and new drug approval for various regulatory agencies as it is important

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parameter of cGMP Practices. It ensures that the process is capable of producing pharmaceutical
products with quality attributes reproductively and consistently.

The earlier thinking was that process validation was useful for generating documented evidence
for assurance of the process that it manufactures the products with predetermined specifications.
Now the FDA changes in thinking about validation give rise to scientific evidences based on
sound knowledge about products specifications and process variables evaluation.

EMA guidance also suggests the enhanced approach for process validation which is based on
ICH Q8, Q9, Q10, requirements. Furthermore, it also adopts the lifecycle approach to validation
from process design to commercial production of quality products consistently and efficiently.
Hybrid approach, Design space verification are some important features of process validation
guidance. In-line, at-line and on-line material testing are recommended by EMA guideline.

Continuous monitoring on process variables gives the risk management advantage. Furthermore,
it leads to best control on process which renders for production of quality pharmaceutical
products. CPV provides space for process improvement. The process validation provides all the
justifications based on scientific knowledge with process design, process qualifications,
continued process verification stages and using appropriate statistical tools methodology
wherever required for evaluation of data during different stages of process validation to assure
the given process perform efficiently and consistently and produce quality pharmaceutical
products within its life span.

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