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FPP assessment: approaches and considerations Wondiyfraw Z. Worku Assessors training Copenhagen, January 2011 FPP assessment: approaches and considerations Wondiyfraw Z. Worku Assessors training Copenhagen, January 2011

Talk points l Dossier assessment – Why do we assess dossiers – Where does Talk points l Dossier assessment – Why do we assess dossiers – Where does it fit l General assessment approaches l Approaches for specific dossier sections (quality part) – Section by section recommendations l Points to re-emphasize 2| FPP assessment: Approaches & Considerations | January

Dossier assessment/evaluation Dossier assessment is an objective, scientific, written analysis of information relevant to Dossier 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. 3| FPP assessment: Approaches & Considerations | January

Dossier assessment/evaluation Contd l At the centre of a medicine regulatory system l Establish Dossier assessment/evaluation Contd l At the centre of a medicine regulatory system l Establish the achieved and desired safety, efficacy and quality profile for a certain product l Assumes genuineness of submitted information 4| FPP assessment: Approaches & Considerations | January

General approaches for the assessor l Treat assessment as investigative work – To establish General approaches for the assessor l Treat assessment as investigative work – To establish the current quality of the product – To help improve the quality further – To ensure consistency/reproducibility l We also need justifications for our comments – Guidance documents – Summarize available data and discuss the background 5| FPP assessment: Approaches & Considerations | January

General approaches, contd l Look for details but don't get lost – – 6| General approaches, contd l Look for details but don't get lost – – 6| There is never enough time Know when and where to go deeply/lightly Be pragmatic Avoid nice to knows FPP assessment: Approaches & Considerations | January

General approaches, contd l Dossier sections are not isolated to each other l Aim General approaches, contd l Dossier sections are not isolated to each other l Aim to do the full assessment in one go. Minimize interruptions l Take notes as you go through your assessment l If you are first assessor don't leave decisions to the second assessor. l Any issue you are uncomfortable with, highlight it in the report and seek advice from colleagues and the second assessor 7| FPP assessment: Approaches & Considerations | January

General approaches, contd l Don't forget to record in the report of what you General approaches, contd l Don't forget to record in the report of what you have done l Record in the report reference /version numbers of signed and dated documents l Avoid copying too much data from the dossier, better to summarize it in your own words l Any data that looks suspicious, draft a communication to the inspectors 8| FPP assessment: Approaches & Considerations | January

General approaches, contd l Need to know the dossier well before you start the General approaches, contd l Need to know the dossier well before you start the actual assessment (assessment preparation) – – 9| 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

General approaches, contd – Collect relevant articles – Collect available monographs for the API General 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 10 | FPP assessment: Approaches & Considerations | January

General approaches, contd – Any known compatibility issues – Whether applicant has already manufactured General 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 l 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 11 | FPP assessment: Approaches & Considerations | January

General approaches, contd l When ever available, the bio batch, bio waiver or clinical General approaches, contd l When ever available, the bio batch, bio waiver or clinical batch is our reference l We need to understand critical attributes of this batch and compare these with those proposed for production batches. – – 12 | API specification Formulation Manufacturing process specifics and controls FPP specification FPP assessment: Approaches & Considerations | January

API specification & retest period l Recommendations – Review the physico-chemical properties of the API specification & retest period l 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) 13 | FPP assessment: Approaches & Considerations | January

API specification & retest period, contd – Check methods and consider the need for API 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 14 | FPP assessment: Approaches & Considerations | January

Development pharmaceutics l Why do we need it as a regulatory submission? – To Development pharmaceutics l 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) l In certain cases, annual product review report may be considered a substitute 15 | FPP assessment: Approaches & Considerations | January

Development pharmaceutics, contd l Read and understand the whole development report; in the mean Development pharmaceutics, contd l 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 16 | FPP assessment: Approaches & Considerations | January

Development pharmaceutics, contd – What are the critical steps and parameters – How does Development 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 17 | FPP assessment: Approaches & Considerations | January

Formulation, manufacturing process and controls l To ensure that the formulation and mfg process Formulation, manufacturing process and controls l 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 18 | FPP assessment: Approaches & Considerations | January

Formulation, Mfg and controls-contd l Recommendations: – Go through the batch record for the Formulation, Mfg and controls-contd l 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 2 nd assessor and possibly bio assessors 19 | FPP assessment: Approaches & Considerations | January

Formulation, Mfg and controls-contd – If required comment on a need for revision of Formulation, 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 20 | FPP assessment: Approaches & Considerations | January

Initial proposed l Wet granulation 21 | FPP assessment: Approaches & Considerations | January Initial proposed l Wet granulation 21 | FPP assessment: Approaches & Considerations | January

Comment to the applicant 22 | FPP assessment: Approaches & Considerations | January Comment to the applicant 22 | FPP assessment: Approaches & Considerations | January

Revised 23 | FPP assessment: Approaches & Considerations | January Revised 23 | FPP assessment: Approaches & Considerations | January

Process validation l If available at the time of assessment, preliminary process validation data Process validation l 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 l 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” 24 | FPP assessment: Approaches & Considerations | January

Process valdn-contd l Recommendations – Ensure that process parameters and other variabilities are representative Process valdn-contd l 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 25 | FPP assessment: Approaches & Considerations | January

Process valdn-contd – Ensure extensive sampling than normally required for in process testing – Process 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 26 | FPP assessment: Approaches & Considerations | January

Example-tablet Manufacturing steps Process monitoring Dispensing Weight checks Sifting and dry mixing Sifting and Example-tablet Manufacturing steps Process monitoring Dispensing Weight checks Sifting and dry mixing Sifting and mixing parameters Granulation Wet and dry granulation parameters Drying Tray or FBD parameters Blending parameters and equipment Content uniformity on individual samples Lubrication parameters & equipment Content uniformity on individual and composite samples, blend properties, LOD Compression parameters and equipment In process (including robustness studies) and pooled sample testing Coating parameters and equipments 27 | FPP assessment: Approaches & Considerations | January Sampling and testing stages Uniformity of drying In process and pooled sample testing including dissolution profile

Excipients l Need to have good quality and safety as the API – Most Excipients l 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 l 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 28 | FPP assessment: Approaches & Considerations | January

Excipients, contd – For flavours, ensure that these are permitted and a qualitative composition Excipients, 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) 29 | FPP assessment: Approaches & Considerations | January

Finished product specification l Just one of the control mechanisms – – – Quality Finished product specification l Just one of the control mechanisms – – – Quality by design Control of raw materials Process monitoring and in process testing Final product testing etc l Should be relevant and realistic l Should be signed and dated l Can be viewed as a contractual agreement 30 | FPP assessment: Approaches & Considerations | January

Finished product spec, contd l Recommendations 31 | – Remind your self of the Finished product spec, contd l Recommendations 31 | – 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 FPP assessment: Approaches & Considerations | tests for residual solvents • Limit January

Finished product spec, contd – Check all available pharmacopoeial monographs (including drafts), identify additional Finished 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) 32 | FPP assessment: Approaches & Considerations | January

Finished product spec, contd – For related substances, • if pharmacopoeial, ensure that all Finished 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) 33 | FPP assessment: Approaches & Considerations | January

Finished product spec, contd • Ensure that your specific requirements are met, e. g. Finished 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 34 | FPP assessment: Approaches & Considerations | January

Analytical methods and validation l Most of the data in the dossier depends on Analytical methods and validation l Most of the data in the dossier depends on reliability and reproducibility of the analytical methods l Recommendations: 35 | – 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 FPP assessment: Approaches & Considerations | how analytes particularly impurities are • see January

Analytical methods and Valdn, contd – As you evaluate the validation data, • Check Analytical 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 36 | FPP assessment: Approaches & Considerations | January

Analytical methods and Valdn, contd • Check the supporting/representative chromatograms • Check if there Analytical 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 37 | FPP assessment: Approaches & Considerations | January

Reference standards l To ensure validity of the standard used to produce the dossier Reference standards l 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) 38 | FPP assessment: Approaches & Considerations | January

Reference standards, contd l Recommendations – Try to establish the type and source of Reference standards, contd l 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 39 | FPP assessment: Approaches & Considerations | January

Container closure system l One of the major product attributes l Recommendations – We Container closure system l One of the major product attributes l 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). 40 | FPP assessment: Approaches & Considerations | January

Container closure system, contd – consider further aspects depending on the dosage form and Container 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 41 | FPP assessment: Approaches & Considerations | January

Stability data l To ensure that the product quality as achieved at release can Stability data l To ensure that the product quality as achieved at release can also be maintained throughout a reasonable product shelf life l Recommendations: – Start with the protocol • specification and analytical methods • batch type and packaging • testing plan • future plans (ongoing and stability on production batches) 42 | FPP assessment: Approaches & Considerations | January

Stability data, contd 43 | – While assessing the stability data • Check if Stability data, contd 43 | – 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

Samples and product labelling l Submitted samples are primarily for visual evaluation of the Samples and product labelling l 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 l 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) l 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 44 | FPP assessment: Approaches & Considerations | January

Example 1 l Assume that you are preparing to start an assessment of a Example 1 l 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? 45 | FPP assessment: Approaches & Considerations | January

Example 2 l Assume that you are assessing an API specification as used by Example 2 l 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? 46 | FPP assessment: Approaches & Considerations | January

Example 3 l Assume that you are assessing control of degradation products of a Example 3 l 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 inhouse 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. 47 | FPP assessment: Approaches & Considerations | January

Some points to re-emphasize l We are always under time pressure – We need Some points to re-emphasize l We are always under time pressure – We need to be pragmatic l Biobatch/clinical batch records – heart of the quality assessment l Process details and end points – Example: Wet granulation l API/FPP specifications and other signed records – Should be clear and changes should be known l Always re-familiarize your self with requirements, alerts, and internal guidance 48 | FPP assessment: Approaches & Considerations | January

Additional material l Presentation on – Quality assessment and the assessment report • by Additional material l Presentation on – Quality assessment and the assessment report • by Lynda Paleshnuik – On PQ web site, under trainings (Kampala Uganda, 23 -27 February 2009) l FDA's Q and A guide on question based review (Qb. R) 49 | FPP assessment: Approaches & Considerations | January

l Thank you 50 | FPP assessment: Approaches & Considerations | January l Thank you 50 | FPP assessment: Approaches & Considerations | January