Process Validation for Beginners - FDA - EMA Approach

www.drugragulations.org 1
Presentation prepared by Drug Regulations – a not for
profit organization. Visit www.drugregulations.org for the
latest in Pharmaceuticals.
August 15

 This presentation is compiled from freely available resources like the
website of FDA & EMA specifically
 “Guidance for Industry Process Validation: General Principles and
Practices , Revision 1, 2011” “EU Guidelines for Good Manufacturing
Practice Annex 15: Qualification and Validation” and” EMA Guideline on
process validation for finished products - information and data to be
provided in regulatory submissions”
 “Drug Regulations” is a non profit organization which provides free
online resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest information from the world
of Pharmaceuticals.
8/18/2015 2
Drug Regulations : Online
Resource for Latest Information

 Effective process validation contributes
significantly to assuring drug quality.
 Quality, safety, and efficacy are designed or
built into the product.
 Quality cannot be adequately assured merely
by in-process and finished-product
inspection or testing.
www.drugragulations.org 3August 15

 Process Validation is now 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. Process validation
involves a series of activities taking place over
the lifecycle of the product and process

 Validation is the act of demonstrating and
documenting that a procedure operates
effectively.
 Process validation is the means of ensuring and
providing documentary evidence that processes (
within their specified design parameters) are
capable of consistently producing a finished
product of the required quality.

 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.

 Stage1: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
◦ Continued Process Verification: Ongoing assurance is gained during
routine production that the process remains in a state of control.

 Manufacturing process should consistently produce APIs
and drug products meeting quality attributes.
 Assurance based on objective information and data from
laboratory-, pilot-, and/or commercial-scale studies.
 Information and data should demonstrate that the
commercial manufacturing process is capable of
consistently producing acceptable quality products within
commercial manufacturing conditions.

 Information and knowledge from product and
process development.
 Understanding sources of variation
 Detecting the presence and degree of variation
 Understanding the impact of variation on the process
and ultimately on product attributes
 Controlling the variation in a manner commensurate
with the risk it represents to the process and product.

 Manufacturer judging whether it has gained sufficient understanding of
the process.
 Not focusing exclusively on qualification efforts
 Understanding the manufacturing process and associated variations.
 Maintaining the process in a state of control over the life of the process,
even as materials, equipment, production environment, personnel, and
manufacturing procedures change.
 Collecting and analyzing product and process data to evaluate the state
of control of the process.

 Life cycle approach
 Good project management
 Good archiving
 An integrated team approach
 Studies based on sound scientific principles
 Risk based decision making
 Criticality as a continuum rather than a binary
state

 Evaluate attribute(s) (quality, product, component) &
parameter(s)( process, operating, & equipment) in
terms of their roles in the process and impact on the
product or in-process material.
 Reevaluate above as new information becomes
available.
 Exercise degree of control on attributes &
parameters commensurate with their risk to the
process and process output

 cGMP conditions not required at this stage
 Follow good documentation practices
 Use sound scientific methods and principles
 Conduct internal review & document decisions and
justification of the controls
 Use knowledge and data from product development
◦ Critical quality attributes
◦ Critical material attributes
◦ Critical process parameters
 Consider functionality and limitations of commercial
manufacturing equipment

 Consider contributions to variability posed by
◦ Different component lots,
◦ Production operators,
◦ Environmental conditions, and
◦ Measurement systems in the production setting.
 Use laboratory or pilot-scale models designed to
be representative of the commercial process

 Use DOE to develop process knowledge by
◦ Revealing relationships,
◦ Multivariate interactions, between the variable inputs
(e.g., component characteristics or process parameters)
and the resulting outputs (e.g., in-process material,
intermediates, or the final product).
 Use risk analysis tools to screen variables for
DOE

 Based on the DOE results Establish ranges of
◦ Incoming component quality,
◦ Equipment parameters, and
◦ In-process material quality attributes
 FDA does not generally expect manufacturers to develop and test the
process until it fails.
 Use lab or pilot scale to predict performance at commercial scale
 Use the data to model or simulate a commercial scale process
 Understand the degree to which the models represent a commercial
process

 Process controls should address variability
 Design process control to
◦ Reduce Input variation, or
◦ Adjust for input variation during manufacturing or
◦ Combine both approaches
 Controls can consist of
◦ Material analysis and
◦ Equipment monitoring at significant processing points
 Use risk assessment for type and extent of process controls

 Use operational limits & in-process monitoring
◦ When the product attribute is not readily measurable due
to limitations of sampling or detectability (e.g., viral
clearance or microbial contamination or
◦ When intermediates and products cannot be highly
characterized and well-defined quality attributes cannot
be identified
 Establish these controls in Master production &
controls record

 Advanced strategies like PAT can be used
 Strategies can include timely analysis and control loops to
adjust the processing conditions so that the output
remains constant.
 These systems can provide higher degree of process
control than non-PAT systems.
 In case of PAT system approach to process validation will
be different

 Process Qualification
◦ Determines if the process designed is capable of reproducible
commercial manufacture.
◦ Has two elements
 Design of the facility and qualification of the equipment and utilities
 Process performance qualification
◦ Requires cGMP compliant procedures
◦ Completion of this stage is required before commercial distribution.
◦ Products manufactured during this stage can be released for distribution , if
they are acceptable.

 Design & commissioning of facilities & utilities precede
process performance qualification ( PPQ).
 Qualification refers to demonstration that utilities and
equipment are suitable for their intended use and perform
properly.

 Qualification of utilities and equipment generally
include
◦ Selection of utilities and equipment construction materials,
operating principles, and performance characteristics.
◦ Verification that utility systems and equipment are built and
installed in compliance with the design specifications.
◦ Verification that utility systems and equipment operate in in all
anticipated operating ranges.

 Qualification of utilities and equipment generally
include
◦ Challenge to the equipment or system functions while under load
comparable to that expected during routine production.
◦ Performance of interventions, stoppage, and start-up as is
expected during routine production.
◦ Performance for as long as necessary during actual production at
operating ranges

 Can be preformed under individual plans or part of
overall plan
 Use risk assessment for prioritization
 Use risk assessment for level of effort in
performance & documentation

 Plan should identify the
◦ Studies or tests to use,
◦ Criteria appropriate to assess outcomes,
◦ Timing of qualification activities,
◦ Responsibilities of relevant departments and the quality
unit, and
◦ Procedures for documenting and approving the
qualification.

 Process Performance Qualification Combines following to
produce commercial batches.
◦ Actual facility
◦ Utilities
◦ Equipment (each now qualified)
◦ Trained personnel with
◦ Commercial manufacturing process,
◦ Control procedures
◦ Components

 Process Performance Qualification
◦ Confirms process design
◦ Demonstrates that the commercial manufacturing
process performs as expected.
 Commercial distribution succeeds PPQ
completion

 Process performance qualification should be based on
◦ Overall level of product and process understanding
◦ Level of demonstrable control
◦ Data from lab, pilot & commercial batches
◦ Effect of scale
◦ Previous credible experience with sufficiently similar products and
processes
◦ Objective measures to achieve adequate assurance

 Process performance qualification should be based on
◦ Higher level of sampling
◦ Additional testing,
◦ Greater scrutiny of process performance than would be typical of
routine commercial production
◦ Level of monitoring and testing sufficient to confirm uniform product
quality throughout the batch
◦ Not necessary to explore entire operating range at commercial scale

 Establish levels and frequency of routine sampling
and monitoring based on increased sampling
 Base duration of increased sampling on
◦ Volume of production
◦ Process complexity
◦ Level of process understanding
◦ Experience with similar products and processes.

 Different approach for processes using PAT
 PAT process designed to
◦ Measure attributes of in process material
◦ Adjust the process in a control loop
◦ Maintain desired quality of output
 The process design and qualification stage should
focus on measurement system and control loop.

 The protocol should address following:
◦ The manufacturing conditions, including operating
parameters, processing limits, and component (raw
material) inputs
◦ The data to be collected and when and how it will be
evaluated.
◦ The sampling plan, including sampling points, number of
samples, and the frequency of sampling for each unit
operation and attribute.

◦ The number of samples should be adequate to provide
sufficient statistical confidence
◦ The confidence level selected can be based on risk analysis
as it relates to the particular attribute under examination
◦ 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
◦ Provision for addressing deviations from expected conditions
and handling of nonconforming data.
◦ Design of facilities and the qualification of utilities and
equipment, personnel training and qualification, and
verification of material sources.
◦ Status of the validation of analytical methods used
◦ Review and approval of the protocol

 Execution to begin after approval of protocol
 Any departures form protocol should follow quality
system
 All departures should be justified & approved
 Follow commercial manufacturing process &
routine procedures

 Normal operating conditions should include
the
◦ Utility systems,
◦ Material,
◦ Personnel,
◦ Environment, and
◦ Manufacturing procedures.

 Report should
 Discuss and cross-reference all aspects of the protocol.
 Summarize data collected and analyze the data, as specified
by the protocol.
 Evaluate any unexpected observations and additional data not
specified in the protocol.
 Summarize and discuss all manufacturing nonconformance
 Describe in sufficient detail any corrective actions or changes

 Report should
 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
 Review and sign off

 Goal to ensure that process remains in a state of
control during commercial manufacture
 System to detect unplanned departures from
designed process is essential to achieve the goal
 Collect & evaluate data to determine process
variability
 Identify problems and implement corrective actions
if required

 Establish a program to collect & analyze product & process
data
◦ Process trends
◦ Quality of incoming materials or components,
◦ In-process material,
◦ Finished products
 Statistically review and trend the data
 Use statistical and qualitative tools to detect variation
 Scrutinize inter batch and intra batch variation

 Continue monitoring and sampling of process
parameters and quality attributes at the level
established during the process qualification stage
until sufficient data are available to generate
significant variability estimates.
 These estimates can provide the basis for
establishing levels and frequency of routine
sampling and monitoring for the particular product
and process.

 Monitoring can then be adjusted to a statistically
appropriate and representative level.
 Process variability should be periodically assessed
and monitoring adjusted accordingly.

 Detect variation by assessment of
◦ Defect complaints,
◦ Out-of-specification findings,
◦ Process deviation reports,
◦ Process yield variations,
◦ Batch records,
◦ Incoming raw material records, and
◦ Adverse event reports.

 Periodic meeting between quality unit and
production staff to
◦ Evaluate data
◦ Discuss possible trends
◦ Undesirable process variation
◦ Co-ordinate any correction or follow-up actions by
production.

 Improve/optimize the process based on the data by
altering
◦ Operating conditions (ranges and set-points),
◦ Process controls,
◦ Component, or
◦ In-process material characteristics
 Document, justify & approve the change as per PQS
 Additional process design and process qualification
activities could be warranted

 Important to maintain facility, utilities, and equipment
 Maintain qualification status through routine
monitoring, maintenance, and calibration procedures
and schedules.
 Re-assess data periodically to determine the need of
re-qualification
 Adjust maintenance and calibration frequency based on
above inputs.

 Commercial distribution of product only after
◦ Successful completion of PPQ
◦ After obtaining high degree of assurance in process
 Under special circumstances PPQ batches can be released
concurrently
 FDA expects that concurrent release will be used rarely
 Circumstances and rationale for concurrent release should be
fully described in the PPQ protocol

 Lot released concurrently must comply with all
CGMPs, regulatory approval requirements, and PPQ
protocol lot release criteria
 Lot release under a PPQ protocol is based
upon meeting confidence levels appropriate
for each quality attribute of the drug

 Appropriate for processes used infrequently for various
reasons
 Manufacture drugs for which there is limited demand
◦ Orphan drugs,
◦ Minor use and
◦ Minor species veterinary drugs
 Drugs with short half live
◦ Radio pharmaceuticals
◦ Positron emission tomography drugs
 Drugs manufactured in co-ordination with agency to alleviate
short supply

 Document each step for life cycle management
 Documentation ensures knowledge gained is accessible
to others
 Documentation is dependent on the stage of validation
 Documentation requirements are greatest during
Stage 2, process qualification, and Stage 3,
continued process verification

 Diagram the process flow for the full-scale
process.
◦ Describe each unit operation,
◦ its placement in the overall process,
◦ monitoring and control points, and
◦ the component, as well as other processing material inputs (e.g.,
processing aids) and
◦ expected outputs (i.e., in-process materials and finished product).

 Accurate & precise analytical techniques are essential.
 Validated methods not required for product/process-
development. However
◦ Sound & reliable methods are required.
◦ Assurance of proper equipment function.
◦ Documented maintenance & calibration procedures.
◦ New analytical technology and modifications to existing technology
can be used to characterize the process or the product.
 Methods for commercial batch release must follow cGMP’s

 Replaces the emphasis on the first few commercial-scale validation
batches with enhanced assurance of product quality in many, or
even all, batches;
 Provides the foundation for a robust process performance and
product quality monitoring system, increasing product and process
knowledge and facilitation of continual improvement opportunities
for process and product quality;
 Enables earlier detection of manufacturing-related problems and
trends;

 Provides immediate feedback of the effect of a change,
thereby facilitating the management of changes;
 Provides a higher assurance of an ongoing state of control, as
more data from CPV provide higher statistical confidence for
ongoing monitoring and trending;
 Is particularly suited to the evaluation of continuous
manufacturing processes; and
 Contributes to the verification of the design space, if used,
throughout the product lifecycle.

 Irrespective of whether a medicinal product is
developed by a traditional approach or an enhanced
approach, the manufacturing process should be
validated before the product is placed on the market.
 In exceptional circumstances concurrent validation
may be accepted.
 Please refer to GMP Annex 15 for further guidance or
our presentation on the same. ( Click here )

 Process validation
◦ Should confirm that the control strategy is adequate to the process design and the
quality of the product.
◦ Should cover all manufactured strengths
◦ Should cover all manufacturing sites used for production of the marketed product.
◦ Data should be generated for all products to demonstrate the adequacy of the
manufacturing process at each site of manufacture.
◦ Should be carried out in accordance with GMP
◦ Data should be held at the manufacturing location and made available for inspection
if not required in the dossier
◦ A bracketing approach may be acceptable for different strengths, batch sizes and
pack sizes.

 Process validation can be performed in a traditional way,
regardless of the approach to development taken.
 Continuous process verification can be implemented if
◦ An enhanced approach to development has been performed or
◦ Where a substantial amount of product and process knowledge and
understanding has been gained through historical data and manufacturing
experience.

 Traditional process validation is normally
performed when
◦ The pharmaceutical development and/or process
development is concluded, after scale-up to production
scale and prior to marketing of the finished product.

 As part of the process validation lifecycle, some process validation
studies may be conducted on pilot scale batches if the process has
not yet been scaled up to production scale.
 It should be noted that pilot batch size should correspond to at least
10% of the production scale batch (i.e. such that the multiplication
factor for the scale-up does not exceed 10).
 For solid oral dosage forms this size should generally be 10% of the
maximum production scale or 100,000 units whichever is the
greater.

 Where the intended batch size is less than 100,000 units, the
predictive value of the pilot batches may be limited
 A justified approach should be followed.
 For other dosage forms the pilot batch size should be justified
taking into account risk to the patient of failure of the dosage form.
 Since it is not generally considered useful to conduct full validation
studies on pilot scale batches, the process validation scheme
outlined in subsequent slides should be completed for each product
for subsequent execution at production scale;
 Bracketing may be acceptable.

 Where validation data on production scale batches are not provided
with the application and traditional process validation is proposed,
the process validation scheme described below should be submitted
by the applicant.
 This should outline the formal process validation studies to be
conducted on production scale batches.
 The number of batches used would depend on the variability of the
process, the complexity of the process / product and the experience
of the manufacturer,
 However would usually be a minimum of 3 consecutive batches.

 The information from these studies should be available for
verification post authorization by the supervisory authority.
 The process validation scheme should be submitted in the
marketing authorization dossier and should include the following
information as a minimum:
◦ Short description of the process with a summary of the critical
processing steps or critical process parameters to be monitored
during validation;
◦ Finished product release specification (references to the dossier);
 details of analytical methods (references to the dossier);

 The process validation scheme should be submitted in the
marketing authorization dossier and should include the following
information as a minimum:
◦ In-process controls proposed with acceptance criteria;
◦ Additional testing intended to be carried out (e.g. with proposed
acceptance criteria and analytical validation as appropriate);
◦ Sampling plan - where, when and how the samples are taken; 
details of methods for recording and evaluation of results; 
proposed timeframe

 Following completion of the scheme, a report containing the
following information and signed by the appropriate authorized
person should be generated and made available for inspection:
◦ Batch analytical data
◦ Certificates of analysis
◦ Batch production records
◦ Report on unusual findings, modifications or changes found
necessary with appropriate rational
◦ Conclusions.

 It is a science and risk-based real-time
approach to verify and demonstrate that a
process that operates within the predefined
specified parameters produces material which
meets all its Critical Quality Attributes (CQAs)
and control strategy requirements.

 Again, the focus is put explicitly on extensive
◦ In-line or
◦ At-line controls and
◦ On monitoring process performance and product quality
in a timely manner.
 Relevant process quality attributes of incoming
materials or components should be collected.

 This should include the verification of
◦ Attributes
◦ Parameters
◦ End points
◦ Assessment of CQA and Critical Process Parameter
(CPP) trends.

 Process analytical technology applications can be
viewed as enablers for continuous process
verification.
◦ NIR spectroscopy with or without feedback loop
 End point determination of blend homogeneity
 Determination of granules surface area
 Determination of content uniformity with large sample size)
 Multivariate statistical process control (MSPC)

 Scope and extent of CPV are influenced by a
number of factors including:
◦ Development and manufacturing knowledge from similar
products and/or processes;
◦ The extent of process understanding gained from
development studies and commercial manufacturing
experience;
◦ The complexity of the product and/or manufacturing
process;

◦ The level of process automation and analytical
technologies used;
◦ With reference to the product lifecycle, process
robustness and manufacturing history since point
of commercialization as appropriate.
 The process should be verified on commercial
scale batches prior to marketing.

 Continuous process verification can be
introduced at any time of the lifecycle of the
product:
 It can be used to design
◦ Process validation protocols for the initial
commercial production,
◦ To re-validate as part of process changes or
◦ To support continual improvement throughout the
lifecycle.

 If a design space has been implemented
continuous process verification may
contribute to ensuring its validity throughout
the product lifecycle.

 Continuous process verification performance
depends strongly on compliance with GMP, if
necessary complemented by Pharmaceutical quality
systems (PQS) as described in ICH Q10.
 GMP matters and PQS should not be included in the
submission.
 They are assessed and handled by GMP inspectors.

 It may be necessary to use either the
traditional process validation or the
continuous process verification approach for
different steps within the manufacturing
process.
 A justification for using this hybrid approach
should be presented in the dossier

 It should be clear which approach to
validation has been taken for which part of
the manufacturing process.
 The validation requirements in terms of batch
size and number of batches would depend on
the extent to which continuous process
verification has been used.

 A design space will normally be developed at laboratory or
pilot scale.
 During scale-up the commercial process is generally
conducted and validated in a specific area of the design
space, defined as the target interval or Normal Operating
Range (NOR).
 During the product lifecycle, moving from one area to
another within the design space (i.e. change in the NOR)
may represent higher or unknown risks not previously
identified during initial establishment of the design space.

 For this reason there will be situations where it will be
necessary to confirm the suitability of the design space
and verify that all product quality attributes are still being
met in the new area of operation within the design space.
 This is termed ‘design space verification’.

 Verify Design Space when
◦ The parameters investigated during development of the
design space have not been shown to be scale independent
and
◦ The process has been validated using traditional process
validation
 If continuous process verification has been utilized,
this may contribute towards ensuring the validity of
the design space throughout the product lifecycle.
 In this case, a design space verification strategy
should be included as part of the continuous
process verification strategy.

 Depending on the change and the extent of
movement within the design space protocols
for verification may include
 Controls of quality attributes (QA’s)
 Process parameters (PP’s) not included in the
routine control system
◦ (e.g. monitoring or testing of QA’s and PP’s that are
expected to be scale dependent and when applicable,
equipment dependent).

 It is not necessary to verify entire areas of the
Design Space or the edge of failure.
 In principle more than one area of the design
space should be verified
 A stepwise approach taking into consideration
the need to adjust the NOR within the approved
design space during product lifecycle is
acceptable.

 A discussion on the appropriateness and
feasibility of the CPV strategy should be
included in the development section of the
dossier and should be supported with data
from at least lab or pilot scale batches.

 A description of the CPV strategy including the
process parameters and material attributes that
will be monitored as well as the analytical
methods that will be employed should be
included (reference to Annex 1), with cross
reference in the validation section of the dossier.

 Actual CPV data generated at commercial
scale should be held at the site for inspection
 The applicant should define the stage at
which the product is considered to be
validated and the basis on which that
decision was made.

This rationale should include a justification for
the number of batches used based on the
complexity and expected variability of the
process and existing manufacturing experience
of the company.

 The objectives of process validation are
unchanged when using ICH Q8, Q9, and Q10.
 The main objective of process validation
remains that a process design yields a
product meeting its predefined quality
criteria.

 ICH Q8, Q9, and Q10 provide a structured way to
define product critical quality attributes, design
space, the manufacturing process, and the
control strategy.
 This information can be used to identify the type
and focus of studies to be performed prior to and
on initial commercial production batches.

 As an alternative to the traditional process
validation, continuous process verification
can be utilized 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.

 For detail of Stage 2 of Process Validation
click on link below for a presentation on :
 “ No. of batches required in Stage 2 Process
Performance Qualification”
 For Details on stage 3 of Process Validation
click on link below for a presentation on
 “ Continued Process Verification”

 This presentation is compiled from freely available resources like the
website of FDA & EMA specifically
 “Guidance for Industry Process Validation: General Principles and
Practices , Revision 1, 2011” “EU Guidelines for Good Manufacturing
Practice Annex 15: Qualification and Validation” and” EMA Guideline on
process validation for finished products - information and data to be
provided in regulatory submissions”
 “Drug Regulations” is a non profit organization which provides free
online resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest information from the world
of Pharmaceuticals.
8/18/2015 89
Drug Regulations : Online
Resource for Latest Information

Process Validation for Beginners - FDA - EMA Approach

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