ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE GMPs for APIs: “How to do” Document Interpretation of the ICH Q7a Guide Version 6 Cefic/APIC "How to do"-Document Page 2 of 69 Table of Contents (Revised chapters in this Version are highlighted in blue) 1 Introduction 2 Quality Management 3 Personnel 4 Buildings and Facilities 5 Process Equipment 6 Documentation and Records 7 Materials Management 8 Production and In-Process Controls 9 Packaging and Identification Labelling of APIs and Intermediates 10 Storage and Distribution 11 Laboratory Controls 12 Validation 13 Change Control 14 Rejection and Reuse of Materials 15 Complaints and Recalls 16 Contract Manufacturers (including Laboratories) 17 Agents, Brokers, Traders, Distributors, Repackers, and Relabellers 18 Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 19 APIs for Use in Clinical Trials 20 Glossary (please refer to the original Q7a-guideline for any definitions) How to do - ICH Q7a_Feb2010.docx Version 6 Cefic/APIC "How to do"-Document Page 3 of 69 Chapter 1 Introduction 1.1 Objective Historical Background When the initiative was taken by PIC/S at the Canberra meeting in September 1996 to draft a globally harmonised Good Manufacturing Practices (GMP) guide for the Production of Active Pharmaceutical Ingredients (API‟s), the recommendation was made that this should essentially be a “what to do”, rather than a “how to do” docu- ment. After that initiative the International Conference on Harmonisation (ICH), which consists of the three major pharmaceutical regions of the world - USA, Japan and Europe - took the topic on board. The ICH established an Expert Working Group (EWG) which membership was due to the importance of the topic extended beyond the three regions to WHO, PIC/S members, India, China and OTC and Generic in- dustry representatives. The EWG, of which CEFIC APIC was a member of, has compiled the 'GMPs for APIs' Guide within 2 ½ years time. The document was finalised by November 2000 and is now at the stage to be implemented within the three regions. Purpose of the Document This document was written by experts from the European Industry (CEFIC APIC). It is essentially an interpretation of “how to” implement the ICH Q7a Guide based on practical experience. Other relevant publications (e.g. ISPE Baseline Guides, other ICH Guidelines) were taken into account and references included. This document does not intend to provide an exhaustive list of “how to” comply with the above mentioned requirements and recommendations. It does however pro- vide examples of commonly applied solutions and practical assistance on how re- quirements and recommendations can be met and /or interpreted. Industry should avoid needless paperwork and administrative burden. As indicated in the Q7a document the focus should be - for the benefit of the patient - on identify- ing the critical controls and procedures that assure the quality of the API. Therefore, sound scientific judgement should prevail when setting up a quality system incorpo- rating GMP. Finally, APIC/CEFIC cannot guarantee that adhering to the principles laid down in this document will consistently result in trouble free inspections. Adoption of the guidance given will however provide both industry and regulators with a much greater confidence in the quality of global bulk active pharmaceutical ingredients manufacture. The word « should » is extensively used in the final version of the ICH Q7a Guide. It indicates requirements and recommendations that are expected to apply unless shown to be inapplicable or replaced by an alternative that can be shown to provide at least an equivalent level of quality assurance. Hence, « should » does not mean that because it is only a «should», and not a «must», then this requirement does not have to be met. This document is meant to be a “living document” to describe current practice and How to do - ICH Q7a_Feb2010.docx Version 6 Cefic/APIC "How to do"-Document Page 4 of 69 to help with the implementation of the GMP Guide for APIs. Suggestions and/or questions from industry or regulators to CEFIC APIC (http://apic.cefic.org) are wel- comed. These will be discussed regularly by the industry experts and clarifications and improvements incorporated into the document. Regulatory Requirements Companies should be aware that the regulatory filing requirements might differ from the application of GMP as defined by Q7a. There may be cases where more information may be required by regulatory authorities, but inspections for compli- ance with the Q7a Guide should only cover the GMP relevant steps. 1.2 Regulatory Applicability - 1.3 Scope API Starting Materials Companies are responsible for proposing the API Starting Material(s). This is one of the most significant changes proposed in the ICH Q7a document. The technical and quality groups should work closely with regulatory groups to ensure no disagree- ment occurs on the proposed starting materials. Ideally the registration of New API‟s will start from the same Starting Materials defined from a GMP perspective. However, based on current regulatory requirements it is likely that the regulatory authorities will require further information on API Starting Materials where only one or two synthetic steps exist between the API starting Material and the API or where the API Starting Material is an API itself. The companies should review the synthetic process of each API and based on tech- nical and quality assessments define what are the significant structural fragments beyond which the GMP standards defined in ICH Q7a should apply. In general, the source of the API Starting Materials is not the major factor. The regulatory authorities may also require further details for late stage API Starting Materials, though recent examples are known that in specific cases FDA has ac- cepted final intermediates as API Stating Materials (e.g. the widely commercially available substance 6-APA for the manufacture of semi-synthetic penicillin's) How to do - ICH Q7a_Feb2010.docx Version 6 Cefic/APIC "How to do"-Document Page 5 of 69 Guidance on How To Define API Starting Materials Follow the guidance given in ICH Q7A and involve technical, quality and regulatory departments in agreeing the definition of the API Starting Materi- als. Where possible use the same definition of API starting material in regu- latory filings and in defining the steps for which the GMP requirements of ICH Q7a apply. Further guidance on How To Define the API Starting Materials and regula- tory strategy is given in the article:  “The Active Pharmaceutical Ingredients Starting Material (APISM) and other materials in API manufacture: Scientifically-based principles for the Common Technical Dossier” by Helga Möller and Chris Oldenhof, Drug Information Journal, Volume 33, Number 3, 1999, pages 755 – 761.  See also Eudralex Vol. 2b, page 162 (“Validation of the process should be carried out…for steps of the manufacturing process which are critical for the product”) The API Starting Material Decision Tree, developed by CEFIC/APIC and FIP, is the central feature of this guidance (see table at the end of the chap- ter). Where the proposed API Starting Material is close to the API itself ensure that details on the synthetic process and analytical controls used to manufac- ture the API Starting Material are available in case these would still be (justi- fiably) requested by the regulators. Where the API Starting Material is a commercial molecule the requirement to provide these details (if needed for confidentiality reasons: directly to the authorities only) may be included in the commercial contract. Similarly, Change Control requirements should be defined in the commercial contract for supply of API Starting Materials. Any significant changes to the synthetic route, analytical controls or specifications by the manufacturer of the API Starting Materials in general needs notification to and acceptance by the API manufacturer. While API Starting Materials do not require to be manufactured to the GMP requirements defined in ICH Q7a, manufacturers of intermediates and / or API‟s should have a system for evaluating the suppliers of critical materials (Reference Q7a Section 7.11). Appropriate qualification of API Starting Ma- terial suppliers is required. Companies should consider redefining the API Starting Material for well- established products. This offers the opportunity to reduce the overall GMP requirements for early manufacturing steps and to shift the focus to be on the control of the critical synthetic steps starting from the redefined API Starting Materials. Any proposed re-definitions to API Starting Materials should of How to do - ICH Q7a_Feb2010.docx Version 6 Cefic/APIC "How to do"-Document Page 6 of 69 course be agreed with the regulatory authorities. The FDA have already indi- cated their willingness to reduce the filing requirements for certain well es- tablished "Qualified Products", including those relating to the final API syn- thesis steps. Table: Decision Tree for help to define the API Starting Material Is the API synthetic or semi-synthetic? NO YES Is the API produced by YES Start process description with direct fermentation? description of micro-organism and media components plus their specifications. No specific Is there sufficient starting material to be defined, evidence that the last NO unless one component is intermediate is YES structually closely related to the analytically fully The last intermediate is the starting API controlled in terms of identity, assay and material Is the API extracted from impurities? (cf. ICH natural sources? YES guideline on impurities in drug substances) NO Describe the purification process NO and/or define API SM based on Is the API manufactured a scientific rationale which may Same question for the YES from mined ore? include risk assessment next to the last The next to the last intermediate is YES intermediate the starting material NO Same question for the intermediate YES preceeding the The intermediate preceeding the next to the last next to the last intermediate is the intermediate starting material NO Continue until the YES answer is yes This substance is the starting material (may be more than one in convergent synthesis schemes) EUROPEAN CHEMICAL INDUSTRY COUNCIL How to do - ICH Q7a_Feb2010.docx Version 6 Cefic/APIC "How to do"-Document Page 7 of 69 Chapter 2 Quality management 2.1 Principles Among GMP other aspects, such as quality systems, environmental controls, and safety, are necessary to be taken into account in order to be in compliance with regulations. Business effi- ciency and continuous improvement are needed to be competitive. Therefore GMP compliance should be incorporated into an overall Quality Management Systems (QMS) as it is recom- mended in the EU GMP philosophy. The importance of an effective QMS on customer relations, continuous improvement, regula- tory compliance and inspection readiness should be pointed out, which directly ensures benefit to the patient. To implement a QMS integrating GMP issues, please refer to the Guide "Quality Management System for Active Pharmaceutical Ingredients Manufacturers", APIC, September 2005. 2.10 Company management should empower Quality responsibility to the appropriate or- ganisational functions to apply the Quality policy and procedures. Assignment of clear Roles & Responsibilities for duties and decisions is the basic rule and can be achieved by e.g. process descriptions including principles of RASCI (Re- sponsible, Accountable, Consulted, Supportive and Informed) and decision trees. Delegated responsibilities should be trained, documented and periodically re-trained. 2.11 A clearly defined QMS (as defined e.g. in the APIC Guide (see above), ICH Q10 and ISO 9001: 2000 or later) integrating API GMP requirements, should be documented, implemented and described e.g. in the Quality Policy. 2.12 - 2.13 For the release of APIs there is no need for a “Qualified Person” (pharmacist) as defined by the European GMP Guideline (EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4: EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use) unless required by a spe- cific law of the EU member state. The responsibilities for quality duties (e.g. process and control review, validation, change control, equipment qualification, batch documentation review, batch release, regulatory compliance, auditing, deviation handling, OOS treatments and complaint investigation) should be clearly assigned to one or more person(s) or function(s). The QU should be involved in many, if not all, of these issues. If the QA and QC department are separated units the roles and responsibilities of each unit must be clearly described and approved by the management. 2.14 Release of raw materials and intermediates meeting the specifications (for internal use only) by Production is acceptable, provided QU has approved specifications and test methods. Production personnel should be adequately trained for these duties, the train- ing recorded and all equipment used qualified and calibrated at regular intervals. The QU, as part of their responsibility for batch release, has the right to review all test re- sults and data. APIs and intermediates (for use outside of the control of the company) have to be re- leased by a designated person of the QU. Deputy(s) for such designated person should be nominated. 2.15 All activities should be directly recorded at the time they are performed in legible How to do - ICH Q7a_Feb2010.docx Version 6 Cefic/APIC "How to do"-Document Page 8 of 69 documents like note-books, electronic records, etc., which are retrievable and trace- able. Recording in non-traceable documents like a blank sheet of paper (re-writing after- wards into traceable documents) is not acceptable. Electronic documents and recording requires appropriate validation of the systems used (see chapter 5.4 and 6.10). 2.16 Documented explanations should be in place for every deviation. When deviations are considered critical, the QU should make sure that a formal investigation occurs, the findings should be recorded and, if defined, corrective actions should be implemented. See chapter 8.15 for a more detailed explanation. 2.17 The release of an API or intermediate does not automatically require that all corrective measures or actions identified in deviation investigations have to be completed in ad- vance (e.g. corrective actions related to ongoing training, maintenance, process inves- tigations). 2.18 As an example a regular report system should be made available to senior management by the QU informing of acute occurrences (quality related complaints, critical devia- tions, recalls, etc.). Senior management should review and agree any recommendations and ensure that appropriate resources are made available. Quality (or: key) performance indicators could be installed to evaluate continuous quality improvement of the department. 2.2 Responsibilities of the Quality Unit(s) 2.20 QU duties may be delegated to other departments/functions provided there are systems in place to ensure that the QU has adequate control / supervision. Different levels of control depending on the nature of the activity are required by ICH: "make sure” (for example: put systems in place, verify by auditing, assigns responsibilities), "be in- volved” (means personal involvement of the QU responsible) or "establishing" (QU issues a system or procedure on its assigned duties). 2.21 - 2.22 Although in this section it is stated “…should not be delegated” it is likely that com- pany‟s will face problems during inspections if they come up with alternatives; this “should” has to be interpreted as “must”. Only the batch production records of critical (Reference to critical see Glossary) steps (a step could be the entire unit operation, e.g. conversion of the final intermediate to the API or a single parameter such as temperature control at an earlier step) including laboratory records have to be reviewed by the QU, whilst the review of all other steps may be delegated (6.71). (sub-point 3). There should be a system in place defining what changes are likely to “impact inter- mediate or API quality” (sub-point 9). Nevertheless any change has to be evaluated and communicated. Stability data for intermediates are only required if they are intended to be sold (for reference see chapter 11.60), but there isn't the need to apply a full stability program as described in ICH Q1a and Q1b documents. In many instances, a retest of the material prior to use or shipment is sufficient to demonstrate that the product is still meeting its specifications. (However it is recommended to derive some data during the develop- How to do - ICH Q7a_Feb2010.docx Version 6 Cefic/APIC "How to do"-Document Page 9 of 69 ment phase or during validation to support storage periods of intermediates during campaign production or storage of left–over between two campaigns.) For details see also chapter 8.2.1. (sub-point 14) For filed specifications of Raw Materials and Intermediates, documented periodical review by the quality unit for delegated release to production should occur (ref. 2.5). 2.3 Responsibility for Production Activities 2.30 An additional advice for the assignment of quality related duties to Production and other functions / departments can be found in "EudraLex, The Rules Governing Me- dicinal Products in the European Union, Volume 4: EU Guidelines to Good Manufac- turing Practice, Medicinal Products for Human and Veterinary Use." 2.4 Internal Audits (Self-Inspections) 2.40 See draft of CEFIC „Auditing‟ Guideline for how to manage an effective internal audit/self inspection programme. Internal Audits (Self Inspections) are a valuable management tool to evaluate if the company is in compliance with the principles of GMP and additional requirements of the company which are integrated in the QMS. The evaluation should be made by trained auditors, experienced in auditing skills and recruited from various departments of the company, if possible. Quality Inspection Teams (QIT) of normally 2 persons are recommended, however (depending on the focus of the audit) recruiting of additional experts (e.g. engineers, micro-biologists etc.) could increase audit efficiency. QU should always be represented in a team, but not always taking the lead for not being accused to be the "policeman”. The QU should be responsible for co-ordinating activities such as follows: pre-audit meetings for the QIT (brain storming) identifying major areas of concern and preparation of questions (questionnaire) collecting historic information such as deviations, changes, complaints, previous internal audit reports issuing the agenda and distribution to the auditee in due time co-ordinating the activities of the QIT starting the (internal) audit and summarising the findings in a close out meeting issuing the audit report, on the basis of the close out meeting propose corrective measures or improvements to management schedule (propose) a re-audit in case of major findings follow-up. Other members of the QIT could be involved in asking and taking extensive notes. The whole auditing process should be clearly defined and the following standard docu- ments should be considered to be available in a generic layout form: Definition of auditing process, system or product Covering Letter Report Form Audit Team Evaluation Form Follow-up Report Training Programme How to do - ICH Q7a_Feb2010.docx Version 6 Cefic/APIC "How to do"-Document Page 10 of 69 The frequency of the self-inspections should be based on risk (a formal risk assessment may not be necessary) as well as the compliance status of the area to be audited. It may vary from half a year to three years, and the rationale behind the frequency should be documented. The compliance status of the area to be audited and may vary from half a year to three years. All participants in the QIT should have the commitment from the management to use the specified time for preparing, performing and reporting the internal audit. Also un-announced audits or spot checks should be considered besides the “normal” audit programme. If possible internal audits should not take more than to 3 - 4 hours. Remember to in- clude at a minimum twice the time for preparing and writing the audit reports. It is important to define deadlines for issuing (recommendation: 2 weeks) and finalis- ing (recommendation: 4 weeks) the report and for the first follow-up meeting. The internal Audit Report as well as the Follow-up Report should be kept confidential and should not be shown to external personnel, especially inspectors from authorities. All (Internal) Audit Reports should be made available for the management, and the findings discussed. Management is responsible to initiate necessary corrective actions and investments. If the API manufacturer at the same time the MA holder for the final drug product, there is an expectation that the finished product QP has access to all internal audit re- ports. 2.41 - 2.5 Product Quality Review 2.50 The major objective of the Product Quality Review is to evaluate the compliance status of the manufacture (process, packaging, labelling and tests) and to identify areas of improvement based on the evaluation of key data. Product quality reviews should not be solely performed by QU personnel. It is impor- tant that other departments, like Production, Engineering, Maintenance, Purchase, etc. are also involved. QU is held responsible for the release and approval of the final re- port. To ensure that key data is reviewed it is essential for each production process to iden- tify the critical in process controls and critical API (or relevant intermediate) test re- sults. These would normally be the critical API test results which may be used to indi- cate the consistency of the process or to assess potential deviations in the quality of the API itself. In addition the critical reaction parameters should be evaluated. Ideally the critical parameters are identified in the development report prepared prior to process validation but may also be based on experience for well established processes. In nearly all cases specification limits for the critical test results are in place. Therefore the first evaluation would consider the failure frequency to meet such limits. In addi- tion any trends in data should be evaluated across the batches produced during the re- view period. Appropriate statistical tools may be used to assess process capability when data from a large number of batches is being reviewed. An example of these statistical tools can be the establishment of key performance indi- How to do - ICH Q7a_Feb2010.docx Version 6