Requirements in Other Countries PQRI+USP EI Workshop; Rockville, MD, Dr. Helmut Rockstroh

Transcription

1 Requirements in Other Countries PQRI+USP EI Workshop; Rockville, MD, 2015 Dr. Helmut Rockstroh

2 Overview Introduction - Scope Pharmacopoeial + HA Positions Examples / Case Studies Discussion 2

3 Introduction: Repetition of Q3D Basics ICH Q3D applies to: human drug products. new finished drug products Does not apply to: IMP.. As the commercial process is developed,..this guideline can be useful. Components, i.e. Drug Substance/ Excipients Application of Q3D to existing products is not expected prior to 36 months after publication of the guideline by ICH. 3

4 Requirements: Same or Different for Suppliers / DP Maker / HA? Communication strategy - formalistic - scientific Cultural factors national/regional DP / DS / Supplier Supplier: DP cgmps / Regulatory requirements vs : SPU requirements Other markets HA: Training issues - National policy - Misalignment DP Maker: - Purpose? - Requirements - Asking too much? 4

5 Pharmacopoeias: Implementation Scope EDQM / EMA.. it is planned to delete cross-references to the wet chemical tests for heavy metals described in chapter from all individual monographs (except for monographs on products for veterinary use only). (EPCOM Bulletin July 2014). the choice of an appropriate analytical strategy will be left to the user, in line with.. ICHQ3D. Chapter (guidance). 151 EPCOM (17. Mar) has confirmed the 36 months implementation period for legacy products ICH. June 2016 for NDAs. JP plans to retain the old Heavy Metals Test Even after implementation of ICHQ3D because JP is used for many purposes (Informal quote JPMA). 5

6 Pharmacopoeias (continued) ChP No activities i.e. requirements with regard to moving towards a change to classical HM testing to be expected before USP <232>/<233> The limits indicated in this chapter are not required for articles intended only for veterinary use and conventional vaccines.. When testing is done to demonstrate compliance,..minimally include As, Cd, Pb, and Hg in the Target Element evaluation. Unique!? USP also announces a revision to General Chapter <231> Heavy Metals and its references to delay omission until January 1,

7 Examples: DP NDA Submission HA Requests APEC 2014 Applicant (NDA) received a request from HA asking for addition of a test for HMs (limit test) on both DS and Product despite the presentation of extensive data showing absence below Q3D limits (<<30%) in both API and final intermediate. LATAM 2013 As soon as the USP General Chapters were official we were asked for data. We explained that the General Chapters were not referenced in any USP monograph items and would not be implemented until USP General Notice was official. We also explained that ICH Q3D was only at step 2 at the time and there was no implementation time line. We were not asked again for any data. 7

8 Example: IPEC EI Questionnaire - original From a DP maker to an excipient supplier Request: Please note if any metals are intentionally used in the manufacturing process in the Comments column. Material = Substance for Pharmaceutical Use (SPU) 8

9 Example: Japanese DP maker EI Questionnaire: 1 -- Why mined? Culture?? 2 Language?? -- inorganic reagents + raw materials 5 3 Language?? -- 3 latest batches!? -- Controls? = Specs? Language?? 6 Culture?? -- testing site? 4 Culture?? -- test method?* -- LOD not LOQ? * Also part of IPEC Questionnaire 9

10 DP maker EI Questionnaire (2) Excipient maker s view IPEC Questionnaire sent to Excipient maker by DP maker from Japan: Questionnaire was modified: Unknown was deleted (DP maker: There can be no Unknown ) DP maker wanted to know whether the source of any of these elements was a mineral (Supplier: It did not make sense to ask that) DP maker asked for statements that the elements in ICH Q3D were not intentionally added and... not being used in any form as a catalyst when that information was already covered in the information provided. 10

11 For Discussion What are your views? / or 1. Does Unknown exist? 2. What (if anything) is special about mined material? 3. Of what value to the DP maker is it to know which test method was used? 4. LOD/ LOQ? 5. Test site? 6. What s missing? Recommendations?

12 Conclusions The major Pharmacopoeias have moved closer to harmonized requirements, but there is some way to go: EP implementation for NDA: June 2016; legacy: End 2017 JP way forward with old HM test/ implementation timelines unclear USP: minimally include As,Cd,Hg,Pb in Target Element evaluation Implementation Jan The dialogue between DP makers / Suppliers / HA s is still evolving Industry would like the Authorities to be aligned. Would industry in turn utilize a standard approach amongst themselves? (Re: Supplier Questionnaire) 12

13 Acknowledgements Yosuke Momose, Chugai, Japan David Schoneker, Colorcon, USA Mark Schweizer, Novartis, USA Andrew Teasdale, Astra Zeneca, UK Phyllis Walsh, Merck, USA Priscilla S Zawislak, Ashland, USA 13

14 Thanks 14

15 Impacted Monographs EP: The list of all impacted monographs will be published in Pharmeuropa, in January 2015 (issue 27.1). It is currently foreseen to publish the revised individual monographs in the 9th edition with an implementation date of 1 January Listing postponed to issue 27(2) (April 1) USP: List of affected monographs 15

16 Modes of Contamination Generalized from Q3D Drug Substance Water Excipients Environment Elemental Impurities in Drug Product Containers Closures Manufacturing Equipment Primary Packaging Materials 16

17 Elements to include in the Risk Assessment If not intentionally added (ICHQ3D) Element Class If intentionally added (all routes) Oral Parenteral Inhalation As 1 yes yes yes yes Cd 1 yes yes yes yes Hg 1 yes yes yes yes Pb 1 yes yes yes yes Co 2A yes yes yes yes Ni 2A yes yes yes yes V 2A yes yes yes yes Ag 2B yes no no no Au 2B yes no no no Ir 2B yes no no no Os 2B yes no no no Pd 2B yes no no no Pt 2B yes no no no Rh 2B yes no no no Ru 2B yes no no no Se 2B yes no no no Tl 2B yes no no no Ba 3 yes no no yes Cr 3 yes no no yes Cu 3 yes no yes yes Li 3 yes no yes yes Mo 3 yes no no yes Sb 3 yes no yes yes Sn 3 yes no no yes 17

18 Doing now what patients need next 18