Diapositiva 1

CONVALIDA E QUALIFICA:
I NUOVI ORIENTAMENTI DELL’ANNEX 15
Anna Fumagalli
Labochim
19 aprile 2016
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REFERENCE
• EudraLex - Volume 4 - EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use Annex 15: Qualification
and Validation (October 2015)
• ICH Q8, Q9, Q10 and Q11
• EudraLex - Volume 4, Part I, relationship to Part II
• EudraLex - Volume 4 - Annex 11
• FDA – Guidance for Industry – Process Validation: General Principles and
Practices (January 2011)
• EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1: Guideline on process
validation for finished products -information and data to be provided in
regulatory submissions (February 2014)
• EMA/CHMP/ CVMP/ SWP/169430/2012 – Guideline on setting health
based exposure limits for use in risk identification in the manufacture of
different medicinal products in shared facilities (November 2014)
Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15
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ANNEX 15
«QUALIFICATION AND VALIDATION»
HISTORY
• First issue: July 2001
• EMA/INS/GMP/705397/2012 Concept paper on
revision of Annex 15 of the GMP guide: Nov 2012
• Draft release: February 2014
• Final version release: March 2015 effective from
01st of October 2015
Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15
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COMPARISON
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WHAT ARE THE CHANGES?
Key change: reference to ICH Q8/Q9/Q10/Q11
Use of concepts such as Quality by Design, Risk
Assessment and Quality Systems.
References made to validate computerised systems
according to Annex 11
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WHAT ARE THE CHANGES?
NEW SECTIONS ADDED
• Transport verification
• Packaging validation
• Qualification of the utilities
• Validation of the test methods
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WHAT ARE THE CHANGES?
The term “validation” has been replaced with
“qualification and validation” to reflect the true
intent of the Annex 15
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PRINCIPLE
Annex 15 contains the requirements for
qualification and validation of processes,
equipment, utilities and facilities used to
manufacture pharmaceutical products.
May be used as supplementary optional guidance
for active substances without introduction of
additional requirements to EudraLex, Volume 4,
Part II
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PRINCIPLE
The root principles address a product / process
lifecycle which should be accompanied by
qualification and validation activities.
In addition, it is now highlighted that changes
should also assess the influence on the validation
status or "control strategy".
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GENERAL
There is a brand new section ("General") in
which a "justified and documented" risk analysis
(as part of the quality risk management
approach) should be the basis for decision
making regarding the scope and depth of the
qualification/ validation activities.
Retrospective validation is no longer an
acceptable approach
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GENERAL
According to the last section of this chapter
"data supporting qualification and/or validation
studies which were obtained from sources
outside of the manufacturers own validation
program may be used provided that this
approach has been justified and that there is
adequate assurance that controls were in place
throughout the acquisition of such data"
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PLANNING, ORGANIZATION AND LIFE CYCLE
APPROACH
VMP should describe:
• Qualification/validation strategy,
• Roles and responsibilities,
• List of systems/processes and current
qualification/validation status
• Guidance for acceptance criteria.
VMP no longer needs to include:
• Protocol and report template
• Scheduling and planning information
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PLANNING, ORGANIZATION AND LIFE CYCLE
APPROACH
Qualification /validation activities performed by
trained personnel following approved
procedures
Qualification/validation personnel should report
as defined in the pharmaceutical quality system
not essential to be a quality management or a
quality assurance function.
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PLANNING, ORGANIZATION AND LIFE CYCLE
APPROACH
The importance of Quality Risk Management is
evident
Risk assessment to be repeated if further
knowledge and understanding is gained from
any changes during the project phase or during
commercial production.
Incorporate appropriate checks to ensure the
integrity of all data obtained
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GOOD DOCUMENTATION PRACTICES
Prepare validation protocols which defines the
critical systems, attributes and parameters and the
associated acceptance criteria
Documents may be combined together, where
appropriate e.g. installation qualification (IQ) and
operational qualification (OQ).
Any significant changes to the approved protocol
during execution should be documented as a
deviation and scientifically justified
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GOOD DOCUMENTATION PRACTICES
If validation protocols are delivered by third
parties, the manufacturer has to confirm their
suitability and compliance with the internal
procedure before any approval.
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GOOD DOCUMENTATION PRACTICES
Releases of validation steps
part of the release of the validation report, or
summarised on a document.
Something new:
Conditional approval to proceed to the next stage
"given where certain acceptance criteria or
deviations have not been fully addressed and there
is a documented assessment that there is no
significant impact on the next activity."
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QUALIFICATION ACTIVITIES
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QUALIFICATION ACTIVITIES
All stages from initial development of the user
requirements should be considered.
Specifications for new facilities, systems or
equipment should be defined in a user
requirements specification (URS) and/or a
functional specification. This should help building in
quality at this stage and minimising GMP risks.
The URS should be "a point of reference"
throughout the validation life cycle.
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QUALIFICATION ACTIVITIES
Factory acceptance tests (FAT) are new, and site
acceptance tests (SAT) have been included in the
draft.
For equipment with novel or complex
technology, the FAT is binding ("should be
evaluated at the vendor prior delivery").
On the contrary, the use of SAT is mentioned as
"may be" option.
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QUALIFICATION ACTIVITIES
• Installation qualification (IQ) (Equipment,
Facilities, Utilities, Systems)
• Operational qualification (OQ) (following or
combined with IQ (IOQ))
• Performance qualification (PQ) (following IQ and
OQ or combined with OQ or Process Validation)
Generally, the section on the qualification of
established (in-use) facilities, systems and
equipment has disappeared.
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RE-QUALIFICATION
The term “revalidation” has been replaced with
“re-qualification”:
• Equipment
• Facilities
• Utilities
• Systems
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PROCESS VALIDATION
Applicable to the manufacture of all
pharmaceutical dosage forms.
Used in conjunction with the current EMA
guideline on Process Validation for Finished
Products.
Robust product development process required
to enable successful process validation
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PROCESS VALIDATION
Manufacturing processes may be developed using a
• Traditional approach
• Continuous verification approach
• Hybrid approach
Retrospective validation is no longer an acceptable
approach
Concurrent validation can be used under
exceptional circumstances
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PROCESS VALIDATION
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PROCESS VALIDATION
Critical Quality Attributes and Critical Process
Parameters: important for ensuring the validated
state and acceptable product quality
Process validation should establish whether these
can be consistently met by the process
Data from process and product development form
the basis for informative process validation.
Research and Development data used in process
validation must be GMP-compliant.
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TRADITIONAL APPROACH
It must be shown that the process consistently
delivers the defined quality.
Classic three-batch approach is accepted, but
this is only a minimum requirement.
This must subsequently be documented with
informative data (representative number of
batches, standard range, batch size as in routine
production).
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CONTINUOUS VERIFICATION APPROACH
The approach known as «continuous process
verification (CPV)» is brand new and can be used
only for processes already developed in
accordance with QbD.
CVP should be based on a “science based
control strategy for the required attributes for
incoming materials, critical quality attributes
and critical process parameters to confirm the
product realization"
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HYBRID APPROACH
A hybrid of the traditional approach and
continuous process verification approach could
be used where there is substantial amount of
product and process knowledge
Could be used for any validation activities after
changes and during ongoing process verification.
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ONGOING PROCESS VERIFICATION
The term «ongoing process verification» (OPV)
has been introduced.
Together with the product quality review (PQR),
OPV will replace revalidation.
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CLEANING VALIDATION
Cleaning validation more detailed:
use of quality risk assessment,
toxicological evaluation
automated cleaning processes.
The visual check for cleanliness is an important criterion
for acceptance, but exclusively visual monitoring is not
acceptable.
The requirement of three consecutive cleaning
procedures for cleaning validation has been replaced by a
risk-based assessment for the specification of the
necessary number of validation runs.
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NEW SECTIONS
Transport verification
This is intended to ensure that products are
transported in compliance with the approval
dossier and specification. Transport routes must
be clearly specified. For example, seasonal
fluctuations, delays, data logger malfunctions,
etc. must be included and their influence on
product quality analyzed.
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NEW SECTIONS
Packaging validation
This applies to the critical process parameters
(e.g. temperature, speed, sealing pressure) in
primary packaging that potentially have a direct
influence on the product.
Validation should encompass the entire range of
operations.
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NEW SECTIONS
Qualification of the utilities
This includes water, steam, air and gases, for
example.
Direct (e.g. heating, ventilation, airconditioning) or indirect (e.g. heat exchanger)
product contact must be subjected to risk
assessment in order to keep control over the
effects in the event of faults.
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NEW SECTIONS
Validation of the test methods
The analytical methods used for qualification,
validation and cleaning must be validated.
Here reference is made to EU GMP Part 1.
For microbial testing, the validation should confirm
that the product itself does not promote bacterial
growth.
Likewise, the validation of wipe tests in cleanrooms
should show that the cleaning agents used do not
influence the result.
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CHANGE CONTROL
The «Change Control» section has been
expanded to include new content.
The change process is an important part of
knowledge management within the framework
of the pharmaceutical quality system.
When Design space is used the impact on
changes to the design space as registered in MA
should be considered
Assess need for any regulatory actions
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CHANGE CONTROL
• Review supporting data to confirm that the
impact of change has been demonstrated
prior to final approval.
• Perform an evaluation of the effectiveness of
change to confirm that the change has been
successful
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CONCLUSION
Overall, this reform is a big step toward
standardization.
The concepts described in ICH Q8, Q9, Q10 and
Q11 must be explicitly taken into account.
With an integrated life cycle concept, QRM and
contemporary PV approaches, Annex 15 has
responded to practical experience and
harmonization goals, including those of the FDA
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