EMA Qualification & Validation Requirements

This presentation is compiled by “ Drug Regulations” 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.
4/19/2014 1

This presentation is compiled from freely available
resources like the website of EMA & specifically
“Volume 4 : EU Guidelines for Good Manufacturing
Practice for Medicinal Products for Human and
Veterinary Use Annex 15: Qualification and
Validation”
“Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
4/19/2014 2
Drug Regulations : Online
Resource for Latest Information

 Qualification and validation of facilities, equipment,
utilities and processes used for the manufacture of
medicinal products is a GMP requirement.
 Manufacturer’s should control the critical aspects of their
operations through qualification and validation over the
life cycle of the product and process.
 Any planned changes to the facilities, equipment, utilities
and processes, which may affect the quality of the
product, should be formally documented.
4/19/2014 3Drug Regulations : Online Resource for Latest Information

 The impact of above changes on the validated status
or control strategy should be assessed.
 Computerised systems used for the manufacture of
medicinal products should be validated according to
the requirements of Annex 11.
 The relevant concepts and guidance presented in ICH
Q8, Q10 and Q11 should also be taken into account.

 Apply a quality risk management approach throughout the
lifecycle
 Base the scope and extent of validation and qualification on
documented risk assessment of the facilities, equipment, utilities
and processes.
 Apply principles of ICH Q8, Q9, Q10 and Q11 to support
validation and qualification activities.
 Outsourced data supporting qualification and/or validation
studies may be used with documented justification.

 Plan all qualification and validation activities
 Consider the life cycle of equipment, process and product
 Suitably trained persons should perform validation activities
 Use & follow approved validation procedures
 Preferable for validation personnel to report into Quality Management
or Quality Assurance
 However Validation personnel should report as defined in the
pharmaceutical quality system
 Essential to have appropriate oversight over the whole validation life
cycle

 Define key elements of the site validation programme
 Documented it in a validation master plan (VMP) or equivalent document.
 The VMP should be a summary document which is brief, concise, clear
and contain data on at least the following:
1. Validation policy.
2. The organisational structure for validation activities.
3. Summary of the facilities, systems, equipment, processes on site and
the current validation status.
4. Template formats to be used for protocols and reports.

 The VMP should be a summary document which is brief, concise, clear and contain
data on at least the following:
5. Planning and scheduling.
6. Change control and deviation management for validation.
7. Handling of acceptance criteria
8. References to existing documents.
9. An assessment of the resources required.
10. The ongoing validation strategy, including revalidation and / requalification,
where applicable.
11. Confirmation that the materials used for validation are of the required quality
and suppliers are qualified to the appropriate level.

 For large and complex projects, planning takes on added
importance and it may be necessary to create a separate VMP.
 Use a quality risk management approach for validation activities
 Repeat risk assessments as required in light of
◦ Increased knowledge
◦ Changes during the project phase
◦ Changes during commercial production.
 Clearly document the risk assessments

 Support knowledge management throughout the validation
lifecycle with Good Documentation Practices
 Approve & authorize all documents by appropriate
personnel as defined in the pharmaceutical quality system
 Define & document relationship between documents in
complex validation projects
 Prepare a written validation protocol
◦ Define the critical systems, attributes and parameters which are
important and the acceptance criteria for each.

 Confirm suitability and compliance of validation protocols with
company procedures before approval when supplied by a third
party
 Document & scientifically justify any changes/deviations to the
approved protocol during execution
 Record as deviation any results which fail to meet the pre-
defined acceptance criteria
 Investigate all deviations and determine any implications for the
validation

 Report the conclusions of the validation
 Summarize results obtained against the acceptance criteria
 Scientifically justify any subsequent changes to acceptance criteria
 Make a final recommendation as to the outcome of the validation
 Document & authorise formal release for the next step in the validation process
 Make it part of either the validation report or as a separate summary document
 Give conditional approval to proceed to the next stage where acceptance criteria
or deviations have not been fully addressed
 Document assessment that there is no significant impact on the next activity.

 Consider
◦ User requirements specification
◦ Process development
◦ End of use of the equipment, facility or process
 The main stages are indicated in following
slides :

 User requirements specification (URS)
◦ Define the specification for new facilities, systems
or equipment in a URS and/or a functional
specification
◦ Build essential elements of quality
◦ Minimize any GMP risks
◦ The URS should be a point of reference throughout
the validation life cycle.

 Design qualification (DQ)
◦ Next element in the validation of new facilities,
systems or equipment
◦ Demonstrate & document the compliance of the
design with GMP
◦ Verify the user requirement specification during this
stage

 Factory acceptance testing (FAT) /Site acceptance testing
(SAT)
◦ Evaluate the equipment at the vendor site prior to delivery
◦ Confirm compliance to URS & functional specifications prior to
installation, at the vendor site unless otherwise justified
◦ Perform documentation review and some tests at the FAT stage
without the need to repeat on site if it can be shown that the
functionality is not affected by the transport and installation.
◦ Supplement FAT by the execution of a SAT following the receipt of
equipment at the manufacturing site

 Installation qualification (IQ)
◦ Perform IQ on new or modified facilities, systems and
equipment.
◦ Include following in IQ
 Installation of equipment, pipe work, services and
instrumentation as detailed in the design
 confirmation of current engineering regarding drawings and
specifications.
 Verification of the correct installation against pre-defined
criteria.

◦ Include following in IQ
 Collection and collation of supplier operating and
working instructions and maintenance requirements.
 Calibration of instrumentation.
 Verification of the materials of construction.

 Operational qualification (OQ)
◦ OQ normally follows IQ
◦ Depending on the complexity of the equipment it may be performed as a
combined Installation/Operation Qualification (IOQ).
◦ OQ could include but is not be limited to the following:
 Tests that have been developed from the knowledge of processes, systems
and equipment.
 Tests to confirm upper and lower operating limits, and /or “worst case”
conditions.
◦ Finalise maintenance plans, standard operating and cleaning procedures,
operator training and preventative maintenance requirements upon
completion of OQ

 Performance qualification (PQ)
◦ Perform PQ after completion of IQ and OQ.
◦ PQ is a separate activity
◦ In some cases it may be appropriate to perform it in conjunction with OQ
or Process Validation.
◦ Use production materials, qualified substitutes or simulated product
proven to have equivalent behaviour under normal operating conditions
with worst case batch sizes
◦ Justify the sampling frequency used to confirm process control
◦ Cover the operating range of the intended process
 unless documented evidence from the development phases which confirm
the operational ranges are available

 Principles outlined applicable to
◦ All dosage forms
◦ The initial validation of new processes
◦ Subsequent validation of modified processes
◦ Site transfers and ongoing process verification

 Use this section in conjunction with the current EMA
guideline on Process Validation.
 Guideline on Process Validation is intended to provide
guidance on the information and data to be provided in
the regulatory submission
 GMP requirements extend beyond this
 Lifecycle approach is applied linking product and process
development, validation of the commercial manufacturing
process and maintenance of the process in a state of
control during routine commercial production.

 Traditional approach
 Continuous verification approach
 Irrespective of the approach used, processes must be
shown to be
◦ Robust and
◦ Ensure consistent product quality before any product is
released to the market
 Prospective validation programme wherever possible
prior to marketing of the product

 Cover all intended marketed strengths and sites of
manufacture for new products
 Products transferred from one site to another or within the
same site the number of batches could be reduced.
◦ Use Bracketing approach
 Different strengths,
 batch sizes
 pack sizes
 container types
◦ For above approach there should be product knowledge including
the content of the previous validation.

 Site transfer of legacy products the
manufacturing process and controls should
◦ Comply with the Marketing Authorisation
◦ Meet current expected licensing standards for that
product type
◦ If necessary, variations to the Marketing
Authorisation should be submitted

 Establish whether all quality attributes and
process parameters can be consistently met by
the process
 Document the process by which process
parameters and quality attributes were identified
as being critical or non-critical
 Consider the results of any risk assessment
activities

 Batch size should be the same as commercial
scale
 Use of any other batch sizes should be justified
◦ e.g. for a continuous manufacturing process.
 Facilities, systems, utilities and equipment
should be qualified first
 Test methods should be validated

 Process knowledge from development studies should be
the basis for validation activities
 For process validation batches, production, development,
or other site transfer personnel may be involved
 Only trained personnel should manufacture batches
 Manufacture in accordance with GMP using approved
documentation
 Involve production personnel
 Facilitates product understanding when commercial
manufacture starts.

 Qualify suppliers of critical starting and
packaging materials prior to validation
 Alternatively document justification based on
quality risk management
 Document underlying process knowledge for the
design space justification (if used)
 Development of any mathematical models used
to confirm a state of control should be available

 Pre define the release of validation batches to
the market
 Manufacturing conditions should fully comply
with
◦ GMP
◦ Validation acceptance criteria
◦ Continuous process verification criteria
◦ Marketing Authorisation

 Concurrent validation
◦ Use when strong risk – benefit to the patient
◦ Justify & document decision
◦ Should be approved by authorised personnel
◦ Product uniformity & compliance with acceptance criteria
should be based on sufficient data.
◦ Document results and conclusions
◦ Data should be available to the Qualified Person prior to
certification of the batch

 Manufacture number of batches under routine conditions
to confirm reproducibility.
 Determine and justify the number of batches necessary to
demonstrate a high level of assurance that the process is
capable of consistently delivering quality product
 Decide number of batches on QRM principles
 Decide number of samples on QRM principles
 Allow the normal range of variation and trends to be
established
 Provide sufficient data for evaluation

 A minimum of three consecutive batches for sucessful
validation still may be acceptable
 Alternative number of batches may be justified
◦ Standard methods of manufacture are used
◦ Whether similar products are used at the site
◦ Whether similar processes are used at the site
 Supplement initial validation exercise with three batches
with further data obtained from subsequent batches as
part of an on-going process verification exercise

 Prepare a process validation protocol
 Define
◦ Critical process parameters (CPP)
◦ Critical quality attributes (CQA) and
◦ Associated acceptance criteria
 Base above on
◦ Development data or
◦ Documented process knowledge

 Validation protocols should include, but are
not be limited to the following:
a) A short description of the process
b) Summary of the CQA’s to be investigated
c) Summary of CPP’s and their associated limits
d) Summary of other (non-critical) attributes and
parameters which will be investigated or monitored
during the validation activity, and the reasons for
their inclusion.

 Validation protocols should include, but are not be
limited to the following:
e) List of the equipment/facilities to be used (including
measuring/
f) monitoring/recording equipment) together with the calibration
status.
g) List of analytical methods and method validation, as
appropriate.
h) Proposed in-process controls with acceptance criteria and the
reason(s) which each in-process control is selected.
i) Additional testing to be carried out, with acceptance criteria.

 Validation protocols should include, but are
not be limited to the following:
j) Sampling plan and the rationale behind it.
k) Methods for recording and evaluating results.
l) Process for release and certification of batches (if
applicable).
m) Functions and responsibilities.
n) Proposed timetable.

 Use Continuous Process Verification for
◦ Products developed by a quality by design
◦ Processes with scientifically established routine
process controls
◦ Processes which provide a high degree of assurance
of product quality

 Define process verification system
 Have in place a science based control strategy for
◦ Required attributes for incoming materials
◦ Critical quality attributes and
◦ Critical process parameters
 Evaluate control strategy regularly
 Use Process Analytical Technology and multivariate statistical
process controls
 Each manufacturer must determine and justify the number of
batches necessary to demonstrate a high level of assurance that
the process is capable of consistently delivering quality product

 A hybrid approach
◦ Traditional approach and continuous process
verification for different production steps
◦ Initial Validation can be based on traditional
approach
 Once substantial product and process knowledge is
gained continuous verification may also be used

 Monitor product quality
 Maintain state of control throughout product
lifecycle
 Evaluate relevant process trends
 Review the extent and frequency of ongoing
process verification
 Modify process controls based on process
understanding and process performance

 Conduct on going process verification under an approved protocol
 Document the results in a report
 Use statistical tools where appropriate to support conclusions about
◦ Variability
◦ Capability
◦ And ensure a state of control.
 Support the validated status of the product in the Product Quality Review
 Consider incremental changes over time and the need for any additional
actions (e.g. enhanced sampling)
 Evaluate any individual change or successive incremental changes during
the product lifecycle
 Evaluate impact on the validated status of the process

 Transportation as per conditions defined in the Marketing
Authorisation, product specification file for
◦ Finished medicinal products
◦ Investigational medicinal products
◦ Bulk product
 Validation of transportation may be challenging due to the
variable factors
 Define transportation routes clearly
 Consider seasonal variation for transport across continents

 Perform a risk assessment to consider the impact of
◦ Temperature
◦ Humidity
◦ Vibration
◦ Handling
◦ Delays
◦ Failure of data-loggers
◦ Topping up liquid Nitrogen
◦ Product susceptibility
◦ Any other relevant factors.
 Perform continuous monitoring of any critical environmental
conditions

 Primary packaging processes should undergo validation
◦ Variation in equipment processing parameters during primary packaging
◦ Significant impact on the integrity and correct functioning of the pack (e.g.
blister strips, sachets and sterile components)
 Perform qualification of the machine settings at the minimum &
maximum operating ranges for the critical components &
parameters such as
◦ Temperature,
◦ Machine speed
◦ Sealing pressure
◦ For any other factors

 Qualify utilities as descried under qualification
 Confirm the quality of steam, water, air, other inert
gases, coolants
 The period and extent of qualification should also
reflect any seasonal variations if applicable
 Perform a risk assessment
◦ where there may be direct contact with the product e.g.
 HVAC systems
◦ Indirect contact
 Such as through heat exchangers

 Validate all analytical test methods used in qualification,
validation or cleaning exercises
 Set an appropriate detection and quantification limit, where
necessary, as described in Chapter 6 of the EU-GMP guide Part I.
 Where microbial testing of product is carried out, the method
should be validated to confirm that the test product does not
influence the result.
 Where microbial testing of surfaces in clean rooms is carried out,
validation should be performed on the test method to confirm
that sanitising agents do not influence the result.

 Perform cleaning validation to confirm the effectiveness of
any cleaning procedure for all product contact equipment
 Provide justification of the specific equipment selected for
cleaning validation when equipment are grouped.
 A visual check for cleanliness is important
 Visual check can not be the only criteria for cleaning
validation
 Repeated cleaning “until clean” is also not considered an
acceptable approach

 Cleaning validation programme may take some time to complete
 Validation with ongoing verification after each batch may be required
 Evaluate data from the verification to support a conclusion that the equipment is
clean
 Consider the level of automation in the cleaning process
 Validate the specified normal operating range of the utilities for automated
process
 Preform assessment to determine the variable factors which influence cleaning
effectiveness in a manual process
◦ Operators
◦ Level of detail in procedures such as rinsing times
 For manual cleaning, if variable factors have been identified, the worst case
situations should be used as the basis for cleaning validation studies

 Base limits for the carry over of product residues on a
toxicological evaluation
 Determine the product specific permitted daily exposure
(PDE) value
 Document the justification for the selected PDE value in a
risk assessment
 Confirm the removal of any cleaning agents
 Consider multiple equipment in the process equipment
train while determining Acceptance criteria

 Assess the potential for microbial and, or if relevant,
endotoxin contamination
 Define hold time : Dirty & Clean
 Consider the influence of the storage time on hold
time
 Consider the impact on ease of cleaning for campaign
manufacturing
◦ The maximum length of a campaign (in both time and
number of batches) should be the basis for cleaning
validation exercises.

 Where a worst case product approach
 Justify the rationale for selection of the worst case product
 Assess the impact of new products to the site assessed
 Consider toxicity , PDE value & solubility when there is no single
worst case product for multi purpose equipment
 Preform worst case cleaning validation for each cleaning method
used
 Detail in cleaning validation protocols
◦ Locations to be sampled
◦ Rationale for the selection of these locations
◦ Define the acceptance criteria

 Sampling
◦ Swabbing and/or
◦ Rinsing at the last stage of cleaning or
◦ By other means depending on the sampling location.
◦ Swab material should not influence the result.
 Rinse Method
◦ Perform sampling during the final rinse in the cleaning procedure.
 Demonstrate recovery from all materials used in the equipment with all
the sampling methods
 Perform the cleaning procedure an appropriate number of times based
on a risk assessment
 Meet the acceptance criteria in order to prove that the cleaning method
is validated

 Investigational medicinal products or products
which are only manufactured infrequently,
◦ Use cleaning verification instead of cleaning validation.
◦ Perform cleaning verification after each batch
◦ Use principles enumerated earlier
◦ Use dedicated equipment where
 Cleaning validation has shown to be ineffective
 Cleaning validation is not appropriate for some equipment

 Evaluate facilities, utilities, systems, equipment
at an appropriate frequency to confirm that they
remain in a state of control.
 Perform requalification at a specific time period
 Define & justify the criteria for evaluation
 Asses the possibility of incremental changes
 Confirm the effectiveness periodically where
manual processes are used ( e.g. cleaning )

 Important part of knowledge management
 Handle within the pharmaceutical quality system
 Have written procedures in place for changes in
◦ Starting material
◦ Product component
◦ Process
◦ Equipment
◦ Premises
◦ Product range
◦ Method of production or testing
◦ Batch size
◦ Design space
◦ Any other change during the lifecycle that may affect product quality or
reproducibility

 Consider the impact on changes to the design space against the registered design
space
 Assess the need for any regulatory actions
 Use Quality risk management to evaluate planned changes to determine the
potential impact on
◦ Product quality,
◦ Pharmaceutical quality systems,
◦ Documentation,
◦ Validation,
◦ Regulatory status,
◦ Calibration,
◦ Maintenance and
◦ On any other system to avoid unintended consequences
◦ To plan for any necessary process verification or requalification efforts

 Authorize & approve changes in accordance with
the pharmaceutical quality system
 Generate supporting data to confirm that the
impact of the change has been demonstrated
prior to approval
 Evaluate the effectiveness of change carried out
to confirm that the change has been successful

This presentation was compiled from freely
available resources like the website of EMA &
specifically “Volume 4 : EU Guidelines for Good
Manufacturing Practice for Medicinal Products for
Human and Veterinary Use Annex 15: Qualification
and Validation”
“Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
4/19/2014 59
Drug Regulations : Online
Resource for Latest Information

EMA Qualification & Validation Requirements

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