1. 1 2-2 FPP assessment: common deficiencies Wondiyfraw Worku 4 th Assessment training January 2012 Copenhagen

2. 2 Talk structure Types of deficiencies Common deficiencies –By CTD section –Specific examples and assessment concerns –Tips

3. 3 Types of dossier deficiencies Missing information or data –ex : Dissolution profile data for biobatch, missing blank record, Inadequate discussion –ex : Development of formulation & mfg process Wide limits with out adequate justification –ex: Limits for impurities, assay Undefined parameters –ex: Granulation & compression parameters Unsolicited changes (additional data) –ex: Widening of shelf life limits for impurities

4. 4 Where common deficiencies are located (FPP part) Note: Most of our dossiers are solid orals

5. 5 Section 3.2.S Submission of LOA & open part representing superseded APIMF version Submission of Superseded CEP –Changes that may impact the FPP may not be known to the FPP applicant ex: if there are changes in the mfg process including last purification step – May affect polymorph form and PSD – May need additional analytical validation and stability studies on the FPP (if there are new impurities) –Consider whether the API is water soluble or not –Consider asking for updated LOA & open part as well as summary of changes. Next assessors to consider the impact on the FPP –In case of CEP request for a copy of the current version and all annexes as well as a summary of changes

6. 6 Section 3.2.S Failure to discuss polymorphism and PSD when relevant –Future API batches may have different properties than the batches used in the biobatch ex: missing info on polymorph screening and absence of data on the biolot API batch ex: missing PSD data on the biolot API batch and absence of appropriate limits –As usual, check dose solubility and presence of known polymorphs –Look for results for the biolot API batch (COA and XRD or DSC plots) –Consider the need for inclusion of polymorph ID in the spec (one may use the ICH decision tree) –Set acceptable limits for PSD and check if proposed limits are ok

7. 7 Why are we so worried about Polymorphism and PSD? Both affect intrinsic solubility –Crystal structure could be closely compacted or loosely compacted Determines water penetration and wettability of the cyrstals – This affects release rate of drug molecules from the crystal structure to the release media –PSD determines available surface area for solute-water molecule interaction Note: –Wet granulation at the FPP mfg stage normally does not change the crystal nature nor the size of crystals (except in some cases formation of solvates) –Where as, crystal structure and particle size of the API may affect the granule characteristics (porosity/density and size)

8. 8 3.2.S Other deficiencies and considerations: –Failure to provide signed and dated spec used by the FPP manufacturer –Failure to provide info on the source and qualification of RS used at the FPP site –Failure to provide COAs for Exhibit API batches (including biolot API batch) as tested by the FPP site –Use of different analytical methods than those used by the API manufacturer (i.e. with out supporting validation data)

9. 9 Section 3.2.P.2 Failure to provide adequate discussion on: –Development of prototype formulation (ex: API- excipient compatibility) Stability studies may not be sufficient in detecting potential interactions (binary mixtures are better in detecting potential interactions) – Check also conditions used vs FPP process conditions – Check if specific excipients are included in the comparator formulation – In case of incompatibility, consider the step at which the excipient is introduced

10. 10 Section 3.2.P.2 Failure to provide adequate discussion on: –Optimization of formulation and mfg process parameters at lab or pilot scale and observations made from scale up activities Issues may arise later on when the process is scaled up to production scale (usually after PQ) – Check if common optimization activities such as determining levels of disintegrant and lubricant amounts were discussed. – Check if common process optimization activities such as mixing time, and water uptake were discussed – Take the absence in to consideration when you review BMR and Validation protocol – On case by case basis, demand improved development summary

11. 11 Section 3.2.P.2 Failure to provide adequate discussion on – Development/selection of dissolution methods and limits Method or limits may not be reliable for future variations – Challenge use of surfactants – Consult the FDA dissolution database – Consult methods approved for other PQD dossiers – For biowaiver based applications, consider the biowaiver conditions

12. 12 Section 3.2.P.2 Failure to provide full dissolution profile data on the biobatch –We need a reference profile to adequately assess variations later on Check presence of data in the usual three pH media without surfactant – If there is a need for surfactant, then with surfactant If biobatch has already expired, demand data on the next valid batch manufactured with same formulation, process and scale

13. 13 Section 3.2.P.2 Failure to provide adequate discussion on development/selection of container closure systems –For initial shelf life assessment we have limited stability data that should be supplemented with other considerations. For certain products one time performance tests (such as moisture permeation data) that must be seen in conjunction with the overall shelf life assessment – Data may be obtained from the container supplier

14. 14 Section 3.2.P.2 Other deficiencies: –Missing justification and supporting data for tablet scoring –Missing or incomplete dilution compatibility data for sterile products –Missing data on filter compatibility for filter sterilized products –Missing discussion on leachables/extractables for containers for liquid preparations

15. 15 Section 3.2.P.3 Failure to submit filled and/or blank records for all proposed batch sizes –The mfg process for production batches should be representative of those used for the bio/biowaiver batch Check availability of blank records for all proposed batch sizes and clearly state which size is the highest proposed batch size in the assessment report. Compare (page by page) each of the blank records with the filled biobatch record We need to be aware of differences so that we can evaluate their impact on future batches of the FPP

16. 16 Section 3.2.P.3 Failure to specify critical equipments and process parameters in batch records –ex: Granulation process, Drying, Compression, Sterile filtration parameters –Unspecified or widely open parameter leads to batch to batch variation Try to understand each specific steps at least for critical processing steps Identify missing parameters and check the values used for the primary (biobatch). Discuss the primary (biobatch) observed values in the assessment report and specify them in your question

17. 17 Impact of variation in mfg process: wet granulation Granulation can be characterized by a set of parameters (mixing mechanism, mixing time, mixing speed, fluid and its addition rate). –Each set of parameters may yield granules of different shape, size and porosity Porosity but also shape and size affect penetration and wettability of the granules in vivo – This may determine the release of drug particles from the granular matrix and further solubility of the drug molecules in the release medium. – Variations in shape and size of granules also affect processability (flowability and compressibility) and may lead to high wt and content variation, hardness and friability problems –Wet granulation may also change morphology of some APIs (from Anhydrous to hydrated form), there by changing the dissolution characteristics.

18. 18 High shear mixing

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20. 20 Section 3.2.P.3 Other common deficiencies: –Failure to include appropriate limits (as a range) for moisture content of final blend –Failure to provide supporting hold time data –Failure to include in PV the need for dissolution profile testing of process validation batches and similarity determination to the biobatch profile –Failure to include key SOPs referenced in BMRs for sterile products –Failure to provide adequate media fill data or protocol which matrixes the proposed product and process features

21. 21 Section 3.2.P.4 (Excipients) Failure to provide qualitative compositions and approval declaration for flavours –Flavours contain several constituents forming the flavour –Each substance in the flavour should have been approved for use in foods Demand for full listing of flavour forming substances – Confidential information can be sent directly from the supplier to WHO

22. 22 Section 2.3.P.5 (Control) Wider acceptance limits (impurities, moisture content, dissolution, etc) –Usually for shelf life spec in an anticipation of potential OOS/OOT stability results Make sure you also assess the shelf life/stability/regulatory specification – Impurities, except, metabolite impurities should be controlled with same qualified release limit – Dissolution- no change allowed – Moisture content- check stability trends vis à vis impacts on the other parameters (appearance, dissolution, assay and related substances)

23. 23 Section 3.2.P.5 Other common deficiencies –Failure to include specific identity test (or combination of tests) –Failure to provide adequate qualification data when observed limits are already above the qualification limit –Premature skip testing proposals –Assuming that monograph limits for impurities are adequate in all cases –Failure to provide analytical method validation results w.r.t all specified degradation products –Failure to demonstrate equivalence with claimed monograph method when in-house method is used.

24. 24 Section 3.2.P.7 (Containers) In case of oral liquids, failure to include dose measuring device and missing supporting data –Doses as low as 0.6ml may be withdrawn Missing ID tests from specifications for primary containers

25. 25 Section 3.2.P.8 (stability) Failure to provide full data corresponding to current acceptable protocol –Example: Testing limited to monograph tests (common in TB, Malaria & RH dossiers) –Studies not inline with ICH recommendations Should we ask fresh stability data as tested with current acceptable specifications before PQ? Ensure that stability results meet current acceptable specifications and not merely the limits specified in the stability sheet

26. 26 Section 3.2.P.8 (stability contd) Other common deficiencies –Failure to discuss results (variabilities, trend, OOS, OOT results) –Failure to provide photostability data or supporting data thereof –Failure to submit updated stability data unless requested –Failure to provide stability protocol and commitments for future stability programmes

27. 27 Deficiencies related to additional data Failure to submit quality related updates when new BE/biowiaver data is submitted –If there is a change in the bio/biowaiver batch, this means we lost our reference batch for Q assessment Always check the status of the BE assessment Check if the new study was made on new or same batch If on a new batch, consider additional requirements as Q part of the dossier

28. 28 QIS related deficiencies Indicating erroneous information Failure to include adequate summary Failure to update sections on submission of additional data –We need to carefully check the data in QIS as it will be the basis of prequalification.

29. 29 Thank you