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FPP assessment: approaches and considerationsWondiyfraw Z. Worku
Assessors training
Copenhagen, January 2011
FPP assessment: Approaches &
Considerations | January 20112 |
Talk pointsTalk points
Dossier assessment– Why do we assess dossiers– Where does it fit
General assessment approaches
Approaches for specific dossier sections (quality part)
– Section by section recommendations
Points to re-emphasize
FPP assessment: Approaches &
Considerations | January 20113 |
Dossier assessment/evaluationDossier assessment/evaluation
Dossier assessment is an objective, scientific, written analysis of information relevant to prequalification of a dossier. It provides an account of all necessary points, in summary, of studies and findings related to efficacy, safety quality. It documents both the applicant’s and reviewer’s evidence-based findings, as well as the decisions taken regarding the dossier.
FPP assessment: Approaches &
Considerations | January 20114 |
Dossier assessment/evaluationContd
Dossier assessment/evaluationContd
At the centre of a medicine regulatory system
Establish the achieved and desired safety, efficacy and quality profile for a certain product
Assumes genuineness of submitted information
FPP assessment: Approaches &
Considerations | January 20115 |
General approaches for the assessorGeneral approaches for the assessor
Treat assessment as investigative work– To establish the current quality of the product– To help improve the quality further– To ensure consistency/reproducibility
We also need justifications for our comments– Guidance documents– Summarize available data and discuss the
background
FPP assessment: Approaches &
Considerations | January 20116 |
General approaches, contdGeneral approaches, contd
Look for details but don't get lost– There is never enough time – Know when and where to go deeply/lightly– Be pragmatic– Avoid nice to knows
FPP assessment: Approaches &
Considerations | January 20117 |
General approaches, contdGeneral approaches, contd
Dossier sections are not isolated to each other
Aim to do the full assessment in one go. Minimize interruptions
Take notes as you go through your assessment
If you are first assessor don't leave decisions to the second assessor.
Any issue you are uncomfortable with, highlight it in the report and seek advice from colleagues and the second assessor
FPP assessment: Approaches &
Considerations | January 20118 |
General approaches, contdGeneral approaches, contd
Don't forget to record in the report of what you have done
Record in the report reference /version numbers of signed and dated documents
Avoid copying too much data from the dossier, better to summarize it in your own words
Any data that looks suspicious, draft a communication to the inspectors
FPP assessment: Approaches &
Considerations | January 20119 |
General approaches, contdGeneral approaches, contd
Need to know the dossier well before you start the actual assessment (assessment preparation)
– New/existing applicant– New/existing product for the programme– New/existing product for the applicant– Get available public regulatory information of
approved products (eg. EPAR, Drugs @ FDA, National DRA web sites)
FPP assessment: Approaches &
Considerations | January 201110 |
General approaches, contdGeneral approaches, contd
– Collect relevant articles– Collect available monographs for the API and FPP
including drafts– Check how the API information is submitted– Check screening/preassessment notes– Check the Efficacy/Safety assessment status– Check key API properties: solubility, polymorphism,
stability or sensitivity to environmental conditions– Proposed process: complicated/less complicated – Dosage form: complicated/un complicated
FPP assessment: Approaches &
Considerations | January 201111 |
General approaches, contdGeneral approaches, contd
– Any known compatibility issues– Whether applicant has already manufactured
commercial validation batches and data is part of the submission
– Re-familiarize your self with alerts and internal guidelines
In case of additional data assessment,– Majority of the above considerations also work here– Good to quickly go through the previous assessment
reports (at minimum the most recent)– Try to understand the rationale behind each question
and the requirements thereof
FPP assessment: Approaches &
Considerations | January 201112 |
General approaches, contdGeneral approaches, contd
When ever available, the bio batch, bio waiver or clinical batch is our reference
We need to understand critical attributes of this batch and compare these with those proposed for production batches.
– API specification– Formulation– Manufacturing process specifics and controls– FPP specification
FPP assessment: Approaches &
Considerations | January 201113 |
API specification & retest periodAPI specification & retest period
Recommendations– Review the physico-chemical properties of the API– Identify the FPP applicant's specification– Identify your reference specifications
• Pharmacopoeial monograph, CEP• APIMF approved specifications• Any additional in-house test that may be needed (example
PSD)• Your assessment of the API information (if API assessment is
part of the FPP dossier)– Look for COAs for the API batches used in the
submission batches (especially the biolot)
FPP assessment: Approaches &
Considerations | January 201114 |
API specification & retest period, contdAPI specification & retest period, contd
– Check methods and consider the need for additional validation:
• adopted from the APIMF holder or pharmacopoeia,• in house
– Give attention to special notes by the APIMF assessor– Give attention to foot notes– Identify types and sources of reference substances– Retest period: if already assigned by the APIMF
assessment, inform the same to the FPP applicant• If FPP manufacturer wants shorter retest period, we accept this
FPP assessment: Approaches &
Considerations | January 201115 |
Development pharmaceuticsDevelopment pharmaceutics
Why do we need it as a regulatory submission?– To ensure that applicant has sufficient understanding
of the product attributes and the manufacturing process
– To give us better understanding of key product and process attributes (to help the review)
In certain cases, annual product review report may be considered a substitute
FPP assessment: Approaches &
Considerations | January 201116 |
Development pharmaceutics, contdDevelopment pharmaceutics, contd
Read and understand the whole development report; in the mean time try to answer the following:
– What are the target profile/attributes of the product– Which drug substance characteristics affect
performance and stability of the FPP– The purpose of each excipient and proposed amounts– Is there evidence of API-excipient compatibility– Why the preferred process over the others– Has the formulation been optimized
FPP assessment: Approaches &
Considerations | January 201117 |
Development pharmaceutics, contdDevelopment pharmaceutics, contd
– What are the critical steps and parameters– How does the desk designed, lab tried and piloted
formulation and process translates to a production/commercial manufacturing
– Is the proposed dissolution method satisfactory– Is the proposed container closure system suitable and
safe– Overages and justifications– Is there a need for tablet scoring and supporting data
provided– Microbiologic attributes– Additional considerations for injectables & other dosage
forms– etc
FPP assessment: Approaches &
Considerations | January 201118 |
Formulation, manufacturing process and controls
Formulation, manufacturing process and controls
To ensure that the formulation and mfg process for the commercial batches
– are sufficiently detailed regarding inputs, processing sequence, process parameters, equipment details and other factors which may affect batch to batch reproducibility/consistency
– are inline with the ones developed and used in the production of the clinical/bioequivalence/biowaiver batch/es
• Any difference should be known and justified
FPP assessment: Approaches &
Considerations | January 201119 |
Formulation, Mfg and controls-contdFormulation, Mfg and controls-contd
Recommendations:– Go through the batch record for the clinical batch and take note
of key process parameters, equipment types, in process results– Demand further details if necessary, example: granulation
parameters– Take the proposed blank master production record, ensure
equivalence of composition, excipient grades, details of the process, as described above, may be by page to page comparison
– Any difference should be understood and justified in light of reproducibility; consider variation and SUPAC requirements as necessary
• Also discuss differences with 2nd assessor and possibly bio assessors
FPP assessment: Approaches &
Considerations | January 201120 |
Formulation, Mfg and controls-contdFormulation, Mfg and controls-contd
– If required comment on a need for revision of the master record
– Also check that the narrative and process flow charts provided in the dossier are reflective of what's provided in the BMRs
– Highlight the reference observations in the assessment report (to help the subsequent assessment)
– Check if proposed controls including frequencies are satisfactory
– If the bio study has been rejected, request for batch record of the new bio/clinical batch
FPP assessment: Approaches &
Considerations | January 201121 |
Initial proposedInitial proposed
Wet granulation
FPP assessment: Approaches &
Considerations | January 201122 |
Comment to the applicantComment to the applicant
FPP assessment: Approaches &
Considerations | January 201123 |
RevisedRevised
FPP assessment: Approaches &
Considerations | January 201124 |
Process validationProcess validation
If available at the time of assessment, preliminary process validation data provides further assurance to the assessor that proposed mfg method can provide reproducible batches as the clinical batch.
– confirms what is already known
A good validation exercise supplemented with robustness studies provides additional assurance that the manufacturer has good understanding and control of the product and its attributes.
– Should be pushed to the “edge of failure”
FPP assessment: Approaches &
Considerations | January 201125 |
Process valdn-contdProcess valdn-contd
Recommendations– Ensure that process parameters and other variabilities
are representative of those proposed for production batches
– Provide particular attention to the specific steps where sampling and testing is made
– Not all specific step needs to be evaluated by sample analysis but at least the process parameters should have been monitored and understood as these will affect the down stream results
FPP assessment: Approaches &
Considerations | January 201126 |
Process valdn-contdProcess valdn-contd
– Ensure extensive sampling than normally required for in process testing
– Try to interpret and understand reported results – Consider improvements to the protocol, such as the
need for • additional sampling points, • Individual vs composite sample testing• robustness studies• Where applicable for comparative dissolution profile studies
FPP assessment: Approaches &
Considerations | January 201127 |
Example-tabletExample-tablet
Dispensing
Sifting and dry mixing
Granulation
Drying
Blending
Lubrication
Compression
Coating
Content uniformity on individual samples
Content uniformity on individual and composite samples, blend properties, LOD
In process (including robustness studies) and pooled sample testing
In process and pooled sample testing including dissolution profile
Weight checks
Sifting and mixing parameters
Wet and dry granulation parameters
Tray or FBD parameters
Blending parameters and equipment
Lubrication parameters & equipment
Compression parameters and equipment
Coating parameters and equipments
Process monitoringManufacturing steps Sampling and testing stages
Uniformity of drying
FPP assessment: Approaches &
Considerations | January 201128 |
ExcipientsExcipients
Need to have good quality and safety as the API– Most are well established – For the purpose of PQ, we have clearly stated in our
guideline that novel excipients are not acceptable
Recommendations– Ensure presence of specifications for every excipient
used – For colourants, ensure that these are permitted – For proprietary coating materials, ensure that
qualitative composition is provided
FPP assessment: Approaches &
Considerations | January 201129 |
Excipients, contdExcipients, contd
– For flavours, ensure that these are permitted and a qualitative composition is provided
– For excipients of animal or plant origin ensure that the necessary TSE/BSE free certification/declaration is provided
– Depending on the dosage form and formulation requirement, consider the need for additional in house tests (example, MLT, endotoxin, particle size, bulk density)
FPP assessment: Approaches &
Considerations | January 201130 |
Finished product specificationFinished product specification
Just one of the control mechanisms – Quality by design– Control of raw materials – Process monitoring and in process testing– Final product testing– etc
Should be relevant and realistic
Should be signed and dated
Can be viewed as a contractual agreement
FPP assessment: Approaches &
Considerations | January 201131 |
Finished product spec, contdFinished product spec, contd
Recommendations– Remind your self of the product attributes– Visit your notes from previous sections– Outline common and specific additional tests
• Identity, potency, purity, performance and microbiologic tests• Consider a need for additional identification test for the API• Identification test for non active excipients but which may have
safety importance such as colours• Identification and potency tests for preservatives, antioxidants• Limit tests for residual solvents
FPP assessment: Approaches &
Considerations | January 201132 |
Finished product spec, contdFinished product spec, contd
– Check all available pharmacopoeial monographs (including drafts), identify additional tests that may need to be considered
– Identify release, shelf/regulatory and/or stability specifications
– Identify periodic testing proposals and ensure that the necessary support is provided
– If additional data, compare the spec against the previous version (to identify any unsolicited changes)
FPP assessment: Approaches &
Considerations | January 201133 |
Finished product spec, contdFinished product spec, contd
– For related substances, • if pharmacopoeial, ensure that all the specified and unspecified
degradants are controlled by the applicant's specification/analytical methods
• If non pharmacopoeial, try to identify potential identified impurities that need to be controlled and ensure that the analytical method is demonstrated as capable of controlling these degradants
– Acceptance limits• If pharmacopoeial ensure that the product meets the
requirements of your recognized pharmacopoeia (including the general monograph requirements)
FPP assessment: Approaches &
Considerations | January 201134 |
Finished product spec, contdFinished product spec, contd
• Ensure that your specific requirements are met, e.g. Assay at release
• For additional tests (such as related substances and residual solvents) apply ICH requirements
• For tests whose limits can be justified by batch analysis/stability results (except those for which the pharmacopoeial monograph includes specific limits), check if proposed limits are reflective of the observed results
– Dissolution, metabolite impurities, water content/LOD, antioxidants, preservatives
FPP assessment: Approaches &
Considerations | January 201135 |
Analytical methods and validationAnalytical methods and validation
Most of the data in the dossier depends on reliability and reproducibility of the analytical methods
Recommendations: – before proceeding with the validation details go through
the proposed method & try to understand• how standard and sample solutions are processed • take note of concentrations of sample and standard solutions • if pharmacopoeial compare with the appropriate monograph• see how analytes particularly impurities are determined
FPP assessment: Approaches &
Considerations | January 201136 |
Analytical methods and Valdn, contdAnalytical methods and Valdn, contd
– As you evaluate the validation data,• Check if sample/std concentrations taken are relevant to the
method being validated• Check if results were correctly determined, eg RRF• If method is in-house while a pharmacopoeial monograph is
available, check if the method is demonstrated as capable of controlling all potential degradants specified in the pharmacopoeia
FPP assessment: Approaches &
Considerations | January 201137 |
Analytical methods and Valdn, contdAnalytical methods and Valdn, contd
• Check the supporting/representative chromatograms • Check if there is a need to include in the method details a
precautionary note to the analyst• Check if proposed SS criteria are adequate• see whether the RRT and RF values of the specified
degradants included in the method are appropriate
FPP assessment: Approaches &
Considerations | January 201138 |
Reference standardsReference standards
To ensure validity of the standard used to produce the dossier data and for future use
– When there is no official RS, applicant may receive the standard from the API supplier or may prepare one in-house (qualification)
– If official RS exists then check if the WS has been qualified against the official RS (calibration)
FPP assessment: Approaches &
Considerations | January 201139 |
Reference standards, contdReference standards, contd
Recommendations– Try to establish the type and source of the standard– Check the characterization/qualification data
preferably for lots of the standard lots used in the validation studies
• Establsih Identity, potency and purity – Other details better be left for the inspectors
FPP assessment: Approaches &
Considerations | January 201140 |
Container closure systemContainer closure system
One of the major product attributes
Recommendations– We need to understand the components and establish
• Components in immediate contact with the product (Primary components)
• Secondary functional components• Measuring devices• Secondary components
– ensure that specifications are inline with general pharmacopoeial monograph requirements (depending on the dosage form).
FPP assessment: Approaches &
Considerations | January 201141 |
Container closure system, contdContainer closure system, contd
– consider further aspects depending on the dosage form and stability concerns (which may have been partly addressed as part of development pharmaceutics)
• Extractables/leachables• Moisture and air permeation • Biological activity tests• Contaminants (for rubber elastomers) • Dose reproducibility for measuring devices
FPP assessment: Approaches &
Considerations | January 201142 |
Stability dataStability data
To ensure that the product quality as achieved at release can also be maintained throughout a reasonable product shelf life
Recommendations:– Start with the protocol
• specification and analytical methods • batch type and packaging • testing plan • future plans (ongoing and stability on production batches)
FPP assessment: Approaches &
Considerations | January 201143 |
Stability data, contdStability data, contd
– While assessing the stability data• Check if all reported results are within acceptable limits• Try to visualize any visible trend or variability (intra and inter batch)
– Summarize the data indicating any trend, variability of OOS
• When there are trends, variabilities, or OOS go back to the relevant other sections of the dossier
– Conclude if the data is sufficient to support a shelf life• When ever appropriate ask for updated data instead of
communicating an extrapolated shelf life– Consider if there is a need for revision of the protocol for
commitment batches
FPP assessment: Approaches &
Considerations | January 201144 |
Samples and product labellingSamples and product labelling
Submitted samples are primarily for visual evaluation of the product and its labels
– ensure that these are representative of the product as presented in the dossier
As quality assessors, we only need to comment on quality related aspects of the labels,
– Section 1.0, 2.0, 3.0 and 6.0– Occasionally also section 4.2(posology and administration)
WHOPAR– Make sure that in your assessment reports/QIS, information
vital for WHOPAR preparation are clearly spelled out, e.g. ink composition for capsules shell
FPP assessment: Approaches &
Considerations | January 201145 |
Example 1Example 1
Assume that you are preparing to start an assessment of a new application (quality part). As part of your preparation you have noticed that the BE data submitted had already been assessed and considered not acceptable. What does this tells you and how will this affect your assessment? Would you start a full assessment of the dossier?
FPP assessment: Approaches &
Considerations | January 201146 |
Example 2Example 2
Assume that you are assessing an API specification as used by an FPP manufacturer. The APIMF approved specification is based on a BP/EP monograph, while the FPP manufacturer's specification is based on USP monograph
– As FPP assessors what issues do you need to consider?
FPP assessment: Approaches &
Considerations | January 201147 |
Example 3Example 3
Assume that you are assessing control of degradation products of a certain FPP (as part of the FPP specification). It's noted that applicant is using an in-house developed method for control of degradants while a monograph exists in one of the recognized pharmacopoeias. Please describe your approaches in determining acceptability or non acceptability of the proposed controls.
FPP assessment: Approaches &
Considerations | January 201148 |
Some points to re-emphasizeSome points to re-emphasize
We are always under time pressure– We need to be pragmatic
Biobatch/clinical batch records– heart of the quality assessment
Process details and end points– Example: Wet granulation
API/FPP specifications and other signed records– Should be clear and changes should be known
Always re-familiarize your self with requirements, alerts, and internal guidance
FPP assessment: Approaches &
Considerations | January 201149 |
Additional materialAdditional material
Presentation on
– Quality assessment and the assessment report
• by Lynda Paleshnuik– On PQ web site, under trainings (Kampala Uganda,
23-27 February 2009)
FDA's Q and A guide on question based review (QbR)
FPP assessment: Approaches &
Considerations | January 201150 |
Thank you