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Copenhagen Workshop May 2014

Copenhagen Workshop May 2014. Quality assessment principles Part II L. Paleshnuik Lead Quality Assessor PQ T. 1. Overview. • FPP sections of the dossier - General considerations • Tips for assessing stability studies • Example FPP issues • Excipients • Questionable information

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Copenhagen Workshop May 2014

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  1. Copenhagen Workshop May 2014 Quality assessment principles Part II L. Paleshnuik Lead Quality Assessor PQT • 1

  2. Overview • FPP sections of the dossier - General considerations • Tips for assessing stability studies • Example FPP issues • Excipients • Questionable information • Finalizing the assessment report • 2

  3. General considerations The applicant must: • Develop the product appropriately (PD talk) • Show evidence of the product developed (data on pilot/primary batches) • Fully describe the intended production batches i.e. scale-up (batch records talk) • 3

  4. General considerations • Demonstrate the ability to control the product now (COAs) and in the future (specifications talk yesterday) • Validate the scale-up (PV talk later today) • Demonstrate the stability of the product (stability talk later today) in the proposed pack (previous talk) • 4

  5. General considerations Assessors must: • Show that all the above have been accomplished in the detailed report. Finalization of the report will be covered later in this talk. • 5

  6. Tips for stability studies • 6

  7. Stability studies Stability is one of the most complex parts of the assessment The talk later today will give the overview of how the studies should be done. Some tips follow to make the assessment smoother • 7

  8. Tips regarding stability - #1 Demonstration of the stability of the product Usually at least 24 month shelf-life is proposed. BUT Only a small amount of stability data is required to be in the original dossier (6 months data, 3 months in exceptions (e.g. RH, 2nd line TB for PQ). • 8

  9. Assessors must ensure they always have the most updated data during the review. This means: • Checking the dates of the study to ensure current data was provided (1-2 months required to compile/submit for a station) • Requesting available updated data in each roundof questions. Tips regarding stability - #1 • 8

  10. Tips regarding stability - #1 Requesting updated stability: • Often this is forgotten, multiple assessment rounds with no request for updated data, and either: • Request comes at the end, when all other significant issues are resolved, or • Request is never sent, and the product is approved/ accepted without review of the available data - poor practice • 8

  11. Tips regarding stability - #2 • Extrapolation of the shelf-life should not be automatic. If the applicant does not propose it, do not offer/grant it. • If the applicant proposes it, only grant it if the data truly supports it. (ICH Q1E) • 9

  12. Tips regarding stability - #3 The very best stability summaries can fail when… … the assessor does not carefully read over their own summary…. … and fails to note an obvious issue. • 10

  13. Tips regarding stability - #4 • Specifications commonly change over the course of the assessment process, but the stability data does not incorporate the change • This means the product gets to the approval stage but there is no data on certain parameters • 11

  14. Tips regarding stability - #4 • Now we must settle for data at the last station only, or on retained samples past the shelf-life • We lose the benefit of multi-station data that would show trends Include current limits in the stability summary each time stability is reviewed • 12

  15. Tips regarding stability - #4 Stability summary Appearance (Blue round biconvex tablets…) Conforms Dissolution (NLT 80%(Q) in 30 minutes) lowest individual value 88.3%, no trend Related compounds A (NMT 0.2%) up to 0.13%, no trend B (NMT 0.3%) up to 0.22%, increasing trend Individual unknowns (NMT 0.2%) up to 0.13%, no trend Sum (NMT 0.6%) up to 0.37%, no trend… etc… • 12

  16. Tips regarding stability - #5 Stability conditions Overlooked deficiency: • Long-term stability conditions are incorrect in the stability protocol (e.g. protocol states 25ºC/60%) Seems minor, but this can mean inadequate future testing of the production batches • 12

  17. Tips regarding stability - #6 Alu-Alu blisters • Advantage: do not need a demonstration of moisture permeability or light transmission • However, Alu-Alu blisters are not magical. • 13

  18. Tips regarding stability - #6 Alu-Alu blisters • The protective ability depends on: • thickness • pinholes • sealing process • 14

  19. Tips regarding stability - #6 Alu-Alu blisters • Do not assume that a change from HDPE bottles to Alu-Alu blisters means a more protective package that does not need its own stability studies • I have seen numerous examples where stability is better in HDPE bottles, and in Alu-Alu had to be below 25°C • 15

  20. Tips regarding stability - #6 Alu-Alu blisters • WHO PQ variation GL (TRS981) providesa good example of how to consider changes, including a change to Al-Al • GL states, “demonstrated equivalent or more protective packaging” • This means, don’t make assumptions • 15

  21. Example issues • 15

  22. Example issues - Issue #1 • 15

  23. Example issues- Issue #1 Excipients: risk-benefit decisions can be made to reduce assessment: Excipients meeting an accepted compendial standard: Can accept the declaration of standard* (e.g. NF) in lieu of: Specifications Certificates of Analysis * Assumes the current standard will be adopted • 15

  24. Example issues - Issue #1 BUT… In-house (IH)standards always require more attention. Common in-house standard: Opadry film-coating excipients Main consideration: Ensure IR identity is included in the IH specifications. • 15

  25. Example issues - Issue #1 In-house standards always require more attention. What if it is an IH standard for a common excipient, do these require more attention? • 15

  26. Example issues - Issue #1 Realexample #1:an IH excipient was not looked at carefully and the ramifications could have been serious. Dosage form: Dispersible tablet Excipients: included some less common excipients, e.g. mannitol, aspartame, saccharin sodium and monoammonium glycyrrhizinate (MAG). First issue: the above were not discussed in the report • 15

  27. Example issues - Issue #1 Consider two sources: Excipient handbook: “applications (normal use and concentration), “incompatibilities”, “comments” European Commission GL: “Excipients in the label and package leaflet of medicinal products for humanuse” • 15

  28. Example issues - Issue #1 Less common excipients: The report should have mentioned, at minimum, whether these excipients are flagged by the European Commission GL: “The Annex provides a list of the excipients which should be stated on the labeling and outlines the information which should appear in the package leaflet, for these excipients.” • 15

  29. Example issues - Issue #1 Quality assessor’s responsibility: Identify excipientsflaggedin the EC GL, AND Label: ensure excipients are declared on the label as per EC GL SmPC section 2: ensure excipients aboveare listed PIL: send the general comment for the excipients above: "Due to the contents of xx in the formulation, a specific warning/precautionary statement may have to be included in the product information. This will be provided with the draft WHOPAR, including the WHO recommended product information, at a later stage." • 15

  30. Example issues - Issue #1 Recall: Excipients: includedless common excipients mannitol, aspartame, saccharin sodium and monoammonium glycyrrhizinate (MAG). • 15

  31. Example issues - Issue #1 In this case, mannitol and aspartame are listed in the GL. Mannitol: to be declared on the label if > 10 g (N/A) Aspartame: to be declared on the label always(zero threshold), and PIL statement indicated (left to WHOPAR stage):“Contains a source of phenylalanine. May be harmful for people with phenylketonuria.” None of the other excipients are mentioned in the EC GL. • 15

  32. Example issues - Issue #1 First issue: not discussing non-common excipients Second issue: an IH standard is declared for MAG. The specifications were reviewed, tests listed in the report, and a request went out to include an identity test in the specs. However, A compendial monograph exists, therefore a comparison must be made/discussed. • 15

  33. Example issues - Issue #1 At the QA stage, assessors were asked to make this comparison. Outcome: BP or NFlimits were not met. The QA comment went out, to revise the specifications to conform to BP or NFlimits. • 15

  34. Example issues - Issue #1 The applicant respondedthat the excipient is not actually MAG. It is a mixture of MAG, maltose and ethyl maltol. And interestingly, MAG is not even the main component, which is maltose (about 80%). • 15

  35. Example issues - Issue #1 This raises three new concerns. 1. The applicant has not fully declared the composition of the tablets. This could be deliberate (to hide a problematic excipient) (to avoid issues with a non-compendial excipient), or due to lack of experience with stringent regulations. 2. Ethyl maltol is an uncommon excipient. • 15

  36. Example issues - Issue #1 3. We need to look carefully at maltose, in case they were trying to avoid declaring it. (This is a concern because a mixture of mainly maltose was called MAG, a minor component of the mixture) • 15

  37. Example issues - Issue #1 We must learn more about ethyl maltol. We check the recognized compendia: there is no monograph in the recognized compendia. We check the excipient handbook for uses and concentrations and incompatibilities. Nothing unusual comes up. (Flavourant used at the proposed concentrations, no relevant incompatibilities) • 15

  38. Example issues - Issue #1 We must look closely at maltose. Maltose is a well-known excipient and they are declaring NF standard. There are no warnings regarding maltose in the EC excipient GL. The excipient handbook has no cautions for the amount used, the use, or compatibility. • 15

  39. Example issues The API in this product is also sensitive to problems with excipients (absorption can be affected). A consultation/search had to be done for any record of issues with the API and maltose or ethyl maltol. No issues were identified. • 15

  40. Example issues - Issue #1 Comment to applicant It is noted that you did not previously disclose the composition of the mixture <Tradename>. It is of critical importance that the full quantitative formulation of each product be declared in the dossier, QOS-PD and QIS. The only exception is many-component flavourants, for which the quantitative formulation can be separately provided in the dossier or by reference to a DMF, but need not be declared in the QOS-PD and QIS.Note that section P.1 b) ii) of the QIS and QOS-PD states, “Composition of all components purchased as mixtures”and should have included the composition of this mixture. In addition, as monoammonium glycyrrhizinate is not the main component of this mixture, it should preferably be identified in the formulation as “maltose mixture ([Tradename])”, with all components and their relative percentages listed below the formulation tablesin the QIS. • 15

  41. Example issues - Issue #1 The comment goes on to ask for revised blank manufacturing records and product information, that correctly identifies the product composition. • 15

  42. Example issues - Issue #1 The applicant responds with the revised documents that fully declare the composition. We could find no indication that this was a deliberate omission, and it is considered to be due to inexperience (this is the applicant’s first dossier in PQ). • 15

  43. Example issues - Issue #1 Conclusion: what could have happened in such a situation, if the IH standard had not been looked into? A company could be “hiding” the presence of excipients in a product by declaring one excipient instead of a mixture. This could lead to issues with the product after approval. In such a case, it would be hard to defend how the regulators had not observed this. The fact that the excipient did not meet standards of a compendial monograph was the clue that it was not really the excipient claimed. • 15

  44. Example issues - Issue #2 Handling questionable data, or What to do when the data (or applicant’s responses to questions) don’t add up • 15

  45. Example issues - Issue #2 Real example #2: In the course of the QA, the credibility/truthfulness of the data came into question. The applicant made confirmatory statements that were later found to be incorrect, and provided data that seemed too good to be true. • 24

  46. Example issues - Issue #2 Dossier is an FDC containing a critically low solubility API Reliable data is critical for such a product. Assessors have spent rounds trying to set appropriate PSD limits, based on the API lots used in the biobatch • 15

  47. Example issues - Issue #2 Example 1: Applicant confirms: “Please find enclosed the COAs of the API manufactured by the same manufacturing process, including purification steps and milling/micronization step, as that of the biolot API”. The bold point was critical for the review. The lots are later found to be manufactured by a significantly different manufacturing process. • 25

  48. Example issues - Issue #2 Example 2: in the response to our request for PSDresults for BE lots, they respond in November 2012: “Kindly note that for COA generation, the API lots used in the biobatch is not available.” But suddenly in December 2013, to resolve the issue, they are able to test these API lots for PSD and provide the results. • 26

  49. Example issues - Issue #2 The approach during QA was to include the following comment to the applicant: It is noted that in your response dated 5 November 2012 you stated, "Kindly note that for COA generation, the API lots used in the bio batch is not available."  You are requested to explain how you have obtained data on these lots. • 27

  50. Example issues - Issue #2 Response: In Nov 2012, we informed you that there was no material from the API lots used in biobatch to re-analyze and generate COA. However we didn’t consider the existing histogram from initial analysis. Now we havetaken PSD data (at D10 and D50) from the histograms generated during initial analysis and reported the results. • 28

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