Common Deficiencies in FPP Dossier Assessments

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

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

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

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 Section 3.2.S • Submission of LOA & open part representing superseded APIMF version • Submission of Superseded CEP • Changes that may impact the FPP may not be known to the FPP applicant • ex: if there are changes in the mfg process including last purification step •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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. High shear mixing

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. 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. 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. 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. 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. 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. 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. 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. 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. Thank you