Working document QAS/15.606/Rev2 July 2016 Draft document for comment 1 2 DRAFT NOTE FOR GUIDANCE ON ORGANIC IMPURITIES IN 3 ACTIVE PHARMACEUTICAL INGREDIENTS AND FINISHED 4 PHARMACEUTICAL PRODUCTS 5 (July 2016) 6 7 DRAFT FOR COMMENT 8 Should you have any comments on the attached text, please send these to Dr Herbert Schmidt, Medicines Quality Assurance, Technologies, Standards and Norms, World Health Organization, 1211 Geneva 27, Switzerland; email: [email protected]; fax: (+41 22) 791 4730) by 16 September 2016. In order to speed up the process for receiving draft monographs and for sending comments, please let us have your email address (to [email protected]) and we will add it to our electronic mailing list. Please specify if you wish to receive monographs. 9 10 ____________________________________________________________________________________________________ 11 © World Health Organization 2016 12 All rights reserved. 13 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 14 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, 15 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 16 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 17 website. 18 Please send any request for permission to: 19 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential 20 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. 21 Fax: (41-22) 791 4730; email: [email protected]. 22 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 23 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 24 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 25 border lines for which there may not yet be full agreement. 26 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 27 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 28 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 29 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 30 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 31 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 32 Organization be liable for damages arising from its use. 33 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 34 Working document QAS/15.606/Rev 2 page 2 35 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/15.606 36 DRAFT NOTE FOR GUIDANCE ON ORGANIC IMPURITIES IN ACTIVE 37 PHARMACEUTICAL INGREDIENTS AND FINISHED PHARMACEUTICAL 38 PRODUCTS 39 Date First draft prepared by the Secretariat of January–March 2015 The International Pharmacopeia with feedback from a group of experts Discussion at consultation on new 13–15 April 2015 medicines, quality control and laboratory standards First draft sent out for public consultation April 2015 Review of comments received by the August 2015 Secretariat of The International Pharmacopoeia and a group of experts; possible revision of the text Presentation to WHO Expert Committee on October 2015 Specifications for Pharmaceutical Preparations for adoption Preparation of the first revised draft (Rev.1) November 2015–March 2016 by Dr M. Brits, considering the feedback received from the members of the Subgroup and the members of the Expert Committee during the 51st meeting First draft sent out for comments to April 2016 Working group as recommended during the 50th meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations Discussion at consultation on quality 9–11 May 2016 control laboratory tools and specifications for medicines Preparation of second revised draft (Rev.2), June–July 2016 2 Working document QAS/15.606/Rev2 page 3 considering comments received from the working group. Draft (Rev.2) sent out for public July 2016 consultation Review of comments received September 2016 Presentation to WHO Expert Committee on October 2016 Specifications for Pharmaceutical Preparations for adoption Further follow-up action as required 40 41 3 Working document QAS/15.606/Rev 2 page 4 42 DRAFT NOTE FOR GUIDANCE ON ORGANIC IMPURITIES IN 43 ACTIVE PHARMACEUTICAL INGREDIENTS AND FINISHED 44 PHARMACEUTICAL PRODUCTS 45 46 [Note from the Secretariat. Considering current practices in use for The International 47 Pharmacopoeia and available guidance on how to establish limits for impurities, the 48 following note for guidance on organic impurities in active pharmaceutical substances and 49 finished pharmaceutical products was drafted. 50 It is intended to replace the text on Related substances in finished pharmaceutical product 51 monographs in the folder Notes for guidance, Supplementary information section with the 52 following chapter.] 53 54 1. SCOPE 55 Purity is a critical attribute of active pharmaceutical ingredients (APIs) and finished 56 pharmaceutical products (FPPs), which potentially affects their safety and efficacy. 57 Therefore, API and FPP monographs in The International Pharmacopoeia (Ph.Int.) shall 58 contain specifications for purity which include requirements for the control of impurities, 59 wherever possible. 60 Impurities in APIs and FPPs may include starting materials, by-products, intermediates, 61 degradation products, reagents, ligands, residual catalysts and residual solvents. They can be 62 classified as either organic, inorganic or biological. 63 This guidance note covers requirements for controlling organic process-related impurities and 64 degradation products in APIs and FPPs, and provides guidance on how to assess compliance 65 with Ph.Int. requirements. 66 Statements in this document are applicable to monographs included in the Ph.Int. after the 67 publication of this guidance note. Compliance with monographs published before this 68 updated guidance shall be evaluated against the previous text Related substances in dosage 69 form monographs1 unless required otherwise by the competent authority. A list of all 70 monographs included in the Ph.Int. before the publication of this guidance note is presented 71 in the document titled Monographs to be evaluated against the text Related substances in 72 dosage form monographs which can be found in The International Pharmacopoeia under 73 Supplementary information. [Note from the Secretariat. The mentioned list is attached at the 74 end of this document.] 1 Once this new guidance note is adopted by the Expert Committee on Specifications for Pharmaceutical Substances, the replaced text can be found on the homepage of The International Pharmacopoeia under Omitted texts. 4 Working document QAS/15.606/Rev2 page 5 75 Excluded from this guidance note are biological/biotechnological products, peptides, 76 oligonucleotides, radiopharmaceuticals, herbal products and crude products of animal and 77 plant origin. 78 Further excluded are the following: 79 extraneous contaminants that should not occur in APIs and FPPs and are more 80 appropriately addressed as good manufacturing practices (GMP) issues; 81 crystallographic modifications (“polymorphic forms”); 82 residual solvents resulting from API or FPP manufacture; 83 impurities that arise from printing inks or excipients (reaction products between 84 excipients and APIs are not excluded); 85 organic impurities that are leached from container-closure systems; 86 fermentation products and semisynthetic products derived therefrom; 87 highly toxic (e.g. genotoxic) impurities or degradation products and residual solvents 88 (volatile organic impurities) are addressed using separate applicable guidance. 89 2. DEFINING THE PURITY OF APIS AND FPPS 90 To control relevant organic impurities individual monographs will contain a stability- 91 indicating test entitled Related substances. This test may be supplemented by a specific test 92 where a given impurity is not adequately controlled by the related substances test or where 93 there are particular reasons (for example, safety reasons a genotoxic/mutagenic or an 94 enantiomeric impurity) requiring specific control. 95 Monographs of APIs shall include specification limits for all impurities (i.e. process-related 96 impurities that result from the manufacturing process and degradation products) observed at 97 levels above the identification threshold. Monographs on FPPs must include appropriate 98 limits for degradation products and, if possible to be detected by the method, impurities from 99 the manufacturing process. This approach provides, in conjunction with the monograph on 100 the API, the means for an independent control laboratory without access to manufacturer’s 101 data to establish whether or not an API of pharmacopoeial quality has been used to 102 manufacture the FPP under examination.2 103 Instruction for control of impurities may also be included in the manufacture section