New GMPs for Active Substances & Excipients. Presented by Eoin Hanley 4 July, 2016

Transcription

1 New GMPs for Active Substances & Excipients Presented by Eoin Hanley 4 July, 2016

2 What we will cover in this session The changing landscape EC Guideline on principles of GDP of active substances Formalised RA for ascertaining the appropriate GMP for excipients Proposed Optional Metrics Slide 2 PharmOut 2015

3 The changing GMP landscape EU: Falsified Medicines Directive (2011) US FDA Safety & Innovations Act-FDASIA (2012) EC Guideline on principles of GDP of active substances (March 2015) EU:Guidelines on the formalised risk assessment for ascertaining the appropriate GMP for excipients of medicinal products for human use (March 2015) NSF/IPEC/ANSI GMP for Pharmaceutical Excipients Slide 3 PharmOut 2015

4 EC Principles of GDP of active substances Issued by the European Commission on 19 March 2015 Follow the same principles as EudraLex Vol. 4 Part II Chapter 17 and the Guideline on GDP of medical products (2013) Standalone guideline for importers and distributers of active substances They compliment EudraLex Vol. 4 Part II and also apply to distributors of active substances manufactured by themselves Guide is 9 pages and has 8 Chapters Slide 4 PharmOut 2015

5 Chapter 1 Scope Very long definition! An active substance is any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis Distribution: procuring, importing, holding, supplying or exporting, apart from brokering. Does not apply to intermediates of active substances Slide 5 PharmOut 2015

6 Chapter 2 Quality System Responsibilities, processes and risk management principles (ICH Q9) Adequately resourced, competent personnel Suitable Premises, equipment and facilities Compliant with GDP for active substances Clear management responsibilities Active substances delivered to right excipients in a satisfactory time period Records made contemporaneously Deviations, Change Management and CAPA system Slide 6 PharmOut 2015

7 Chapter 3 - Personnel Distributor designate a person at each location where distribution activities are performed Must have authority/responsibility Can delegate duties-not responsibilities Clearly document responsibilities of all personnel Trained in GDP for active substances Competent/experience Initial & continuing training on written procedures with a written training program Training records should be kept Effectiveness of training periodically assessed/documented Slide 7 PharmOut 2015

8 Chapter 4 - Documentation Documentation should be readily available/retrievable upon request of competent authorities Sufficiently comprehensive in respect to scope of activities In a language understood by personnel Contains basic information on documentation practices Section on Procedures: From delivery to recall plans etc Reviewed regularly with version control Slide 8 PharmOut 2015

9 Chapter 4 - Documentation Section on Records: Retained for at least 1 year after expiry date of active substance batch or If has retest dates, retain for at least 3 years after batch is completely distributed Records for purchase/sale with records to show full traceability of the origin & destination of products Slide 9 PharmOut 2015

10 Chapter 5 Premises & Equipment Suitable & adequate to ensure proper storage and protection from contamination e.g. from Narcotics Highly sensitising materials Materials of high pharmacological activity/toxicity Other active substances Secure to prevent unauthorised access Calibrated monitoring devices (traceable standards) Slide 10 PharmOut 2015

11 Chapter 6 - Operations Orders: If procured from a manufacturer, importer, distributer established in the EU, they must be registered according to Directive 2001/83/EC Receipt: Section covers protected areas for receipt, separate reception area, examination of deliveries at receipt, quarantine/rejection/destruction procedures, specific storage requirements, reporting falsified materials. Storage: Section covers specified conditions e.g. temperature & humidity, prevention of contamination/mix-up, qualified storage areas, cleaning, stock rotation, electronic warehouse management systems should be validated, written contract between contract giver and contract acceptor. Slide 11 PharmOut 2015

12 Chapter 6 - Operations Deliveries to customers: Supplies in EU made only by registered distributors, transported under correct conditions, product/container/identity maintained at all times, system in place to permit a recall. Transfer of information: if potential to cause an interruption to supply, relevant customers should be notified, copy of original COA should be provided along with all active substance manufacturer information COA guidelines in Section 11.4 of Part II of Eudralex Vol 4 Slide 12 PharmOut 2015

13 Chapter 7 Returns, Complaints & Recalls Returns: should be identified and quarantined pending investigation. If the active substances have left the care of the distributor, they should only be returned to approved stock if all of the following conditions are met: Original unopened container (security seals present) Stored & handled under correct conditions Acceptable remaining shelf life Assessed by a trained/authorised person No loss of information/traceability If in any doubt, seek advice from manufacturer Only trained/authorised person release for return to stock Slide 13 PharmOut 2015

14 Chapter 7 Returns, Complaints & Recalls Complaints and recalls: Recorded & investigated according to written procedure. If a complaint about quality, distributor should review with the original active substance manufacturer to determine action, also with other customers and/or the competent authority. Complaint records should capture all of the relevant information and be retained for trending and inspection. Written procedure that defines the circumstances under which a recall should be considered. Slide 14 PharmOut 2015

15 Chapter 8 Self-Inspections The distributor should conduct and record self-inspections in order to monitor implementation of and compliance with these guidelines Regular self-inspections should be performed in accordance with an approved schedule. The Guide also has an Annex that contains a glossary of terms applicable to the document. Slide 15 PharmOut 2015

16 Formalised RA for ascertaining the appropriate GMP for excipients Also approved on 19 March 2015 The appropriate GMP for excipients shall be ascertained on the basis of a formalised RA in accordance with these guidelines The RA shall take into account requirements under other appropriate quality systems as well as the source and intended use of the excipients and previous instances of quality defects. The manufacturing authorization (MnA) holder shall ensure that the appropriate GMP ascertained is applied. The MnA holder shall document the measures taken. The excipient RA management procedure should be incorporated in the PQS of the MnA holder. Slide 16 PharmOut 2015

17 Formalised RA for ascertaining the appropriate GMP for excipients MnA holders should have the RA/RA management documentation for appropriate GMP for excipients available on site for review by GMP inspectors. Consideration should be given to sharing relevant information from the RA with the excipient manufacturer to facilitate continuous improvement. A risk assessment as set out in these guidelines should be carried out for excipients by 21 March Document has 4 Chapters (next slides) Slide 17 PharmOut 2015

18 Chapter 1 - Scope These guidelines apply to the RA for ascertaining the appropriate GMP for excipients for medicinal products for human use. According to Article 1(3b) of Directive 2001/83/EC, an excipient is any constituent of a medicinal product other than the active substance and the packaging material. These guidelines do not cover substances added to stabilise active substances that cannot exist on their own. Slide 18 PharmOut 2015

19 Chapter 2 Determination of appropriate GMP QRM principles should be used to assess the risks presented to the quality, safety and function of each excipient and to classify the excipient in question, e.g. as low risk, medium risk or high risk. Quality risk management tools such as those listed in ICH Q9 (e.g. hazard analysis and critical control points HACCP) should be used for this purpose. Slide 19 PharmOut 2015

20 Chapter 2 Determination of appropriate GMP For each excipient from each manufacturer used, the MnA holder should identify the risks presented to the quality, safety and function of each excipient from its source be that animal, mineral, vegetable, synthetic, etc. through to its incorporation in the finished pharmaceutical dose form. Areas for consideration should include, but are not limited to (see list in the document). Some examples on next page: Slide 20 PharmOut 2015

21 Chapter 2 Determination of appropriate GMP Examples: Transmissible spongiform encephalopathy (TSE) Potential for viral contamination, Potential for microbiological or endotoxin/pyrogen contamination Environmental control and storage/transportation conditions including cold chain management, if appropriate; Supply chain complexity Stability of excipient Packaging integrity evidence Slide 21 PharmOut 2015

22 Chapter 2 Determination of appropriate GMP Additionally, with respect to the use and function of each excipient, the MnA holder should consider: The pharmaceutical form, the function and the proportion of the excipient in the medicinal product Daily patient intake Any known quality defects/fraudulent adulterations, Whether the excipient is a composite Known or potential impact on the CQAs of the medicinal product; Other factors as identified or known to be relevant to assuring patient safety. Slide 22 PharmOut 2015

23 Chapter 2 Determination of appropriate GMP Having established and documented the risk profile of the excipient, the MnA holder should establish and document the elements of EudraLex Volume 4 that he believes are needed to be in place in order to control and maintain the quality of the excipient, e.g. Annex 1 or/and Annex 2; Part II: Basic Requirements for Active Substances used as Starting Materials. These elements will vary depending on the source, the supply chain and the subsequent use of the excipient, but as a minimum the following high level GMP elements should be considered by the MnA holder: (see list in the document). Some examples on next page: Slide 23 PharmOut 2015

24 Chapter 2 Determination of appropriate GMP Establishment and implementation of an effective PQS Systems for coding and identifying starting materials, intermediates and excipients to allow full traceability Qualification program of suppliers System for QC of the excipient Systems to ensure that any activity contracted out is subject to a written contract Complaints, recalls, change & deviation management systems Environmental control and storage conditions. Slide 24 PharmOut 2015

25 Chapter 3 Determination of Excipient Manufacturers Risk Profile After determination of the appropriate GMP, a gap analysis of the required GMP against the activities and capabilities of the excipient manufacturer should be performed. Data/evidence to support the gap analysis should be obtained through audit or from information received from the excipient manufacturer. Certification of quality systems and/or GMP held by the excipient manufacturer and the standards against which these have been granted should be considered as such certification may fulfil the requirements. Slide 25 PharmOut 2015

26 Chapter 3 Determination of Excipient Manufacturers Risk Profile Any gaps identified between the required GMP and the activities and capabilities of the excipient manufacturer should be documented. Furthermore, the MnA holder should perform a further risk assessment to determine the risk profile, e.g. low risk, medium risk or high risk, for that excipient manufacturer. The MnA holder should have a series of strategies ranging from acceptance through control to unacceptable for the different risk profiles and based on these a control strategy, e.g. audit, document retrieval and testing, should be established. Slide 26 PharmOut 2015

27 Chapter 4 Confirmation of application of appropriate GMP Once the appropriate GMP for the excipient and the risk profile of the excipient manufacturer have been defined, ongoing risk review should be performed: # of defects connected to batches of excipient received; type/severity of such defects; monitoring and trend analysis of excipient quality; loss of relevant quality system and/or GMP certification by excipient manufacturer; Slide 27 PharmOut 2015

28 Chapter 4 Confirmation of application of appropriate GMP Observation of trends in drug product quality attributes; this will depend on the nature and role of excipient; Observed organisational, procedural or technical/process changes at the excipient manufacturer; Questionnaires Control Strategy Based on the outcome of the risk review, the established control strategy should be reviewed and revised if needed. Slide 28 PharmOut 2015

29 Section recap? Based on FMD Both guidelines issued in March 2015 RA for excipients by 21Mar16 Slide 29 PharmOut 2015

30 Thank you for your time. Questions? Eoin Hanley Technical Manager Slide 30 PharmOut 2015