Inspection of API Manufacturers & Update on Registration Process

Transcription

1 Inspection of API Manufacturers & Update on Registration Process Catherine Neary, GMP Inspector GMP Conference 7 February 2017 Dublin

2 Presentation Contents HPRA Inspection Programme for API Manufacturers Drug Product Manufacturer Oversight of API Manufacturers - Evaluation program - Audits - Technical/quality agreements - QP declarations - Importation & the written confirmation Active Substance Registration (ASR) Requirements ASR Change Management 07/02/2017 2

3 HPRA Inspection Programme HPRA conduct inspections as follows: All API Manufacturers registered in Ireland (26 sites, as of December 2016) For cause inspection of API Manufacturers & Distributors located in third countries API Manufacturers located in third countries at the request of EMA Importation of APIs from third countries require a written confirmation to be provided with each consignment The written confirmation is not required for APIs imported from the following countries considered to have a regulatory framework equivalent to that in the EU:- Australia, Brazil, Israel, Japan, Switzerland, United States The equivalence assessment is on-going in South Korea 07/02/2017 3

4 HPRA Inspection Programme Key Areas of Focus: Part II of EU GMP Guide Quality Risk Management Product Quality Review Change control Deviation management Sampling, testing & storage of incoming solvents Containment & contamination control Blending batches of APIs Packaging & labelling operations Stability monitoring Equipment qualification Process validation, cleaning validation Reworking, reprocessing Recovery of materials & solvents Data integrity 07/02/2017 4

5 HPRA Inspection Programme Key areas in which deficiencies identified : Deviation management Complaint investigation Laboratory/out of specification investigations & procedures Data integrity & controls related to computerised systems Maintenance of facilities/equipment Cleaning of equipment Pest control API release process 07/02/2017 5

6 07/02/ Drug Product Manufacturer Oversight of API Manufacturers

7 Robust evaluation programme for API manufacturers & distributors Supply chain traceability should be established and the associated risks, from API starting materials to the finished medicinal product, should be formally assessed and periodically verified Pre-approval audit of site followed by further audits at an appropriate frequency & of appropriate duration, determined using principles of quality risk management Comprehensive audit reports, available at the site for inspection 07/02/2017 7

8 Content of audit reports to include the following: Full name & address(es) of site(s) audited Dates & duration of audit; names, job functions of auditors Clear indication of the scope of the audit, including API s, building/plant numbers (as applicable), any off-site locations, etc. Clear indication of the role of the site in manufacture of each of the APIs being audited, i.e. full or partial manufacture Clear indication that the audit was conducted in accordance with the requirements of Part II of the EU GMP Guide 07/02/2017 8

9 Content of audit reports continued: Clear indication of the manufacturing buildings, manufacturing stages, storage facilities, laboratory facilities, utilities, water system(s) and quality system elements covered during the audit High risk areas specific to the site should be identified and covered, e.g. risk of cross contamination with other APIs or other substances, potential for generation of unknown impurities, risk of mix up of materials & products through materials handling or packing, processing, cleaning, validation, change management, deviation management, laboratory investigation management, security sealing of API containers, security & temperature control of shipments Details of the activities which were not covered during the audit 07/02/2017 9

10 API Manufacturer response to audit report available at site for inspection A summary of the review & assessment of the responses received should be recorded. This should indicate whether the responses provided & corresponding timelines for implementation of CAPAs are considered acceptable Conclusion/summary from the audit with clear statement regarding the GMP compliance status of the site should be recorded A proposed re-assessment period should be recommended 07/02/

11 Comprehensive Technical/Quality Agreement implemented with manufacturers & distributors Content of agreement to include the following: Full names & address(es) of site(s) to which the agreement relates Responsibilities for notification and pre-approval (if applicable) of changes with clear indication of the nature of changes which are required to be notified/pre-approved Responsibilities for notification and pre-approval (if applicable) of deviations with clear indication of the nature of deviations which are required to be notified/pre-approved Responsibilities for notification and pre-approval (if applicable) of laboratory investigations including those related to stability, with clear indication of the nature of investigations which are required to be notified/pre-approved Criteria related to re-processing and rework, as applicable Criteria related to security sealing of containers & transportation 07/02/

12 QP Declaration concerning GMP compliance of API manufacture MAs require a QP declaration to confirm the API has been manufactured in accordance with GMP QP declaration is required from each registered EEA manufacturer and Importer Authorisation Holder (MIAH) that uses the API as a starting material and/or is responsible for QP certification of the finished batch of a human or veterinary medicinal product 07/02/

13 QP Declaration concerning GMP compliance of API manufacture (cont.) When more than one MIAH is involved, rather than provide multiple declarations it may be acceptable to provide a single declaration signed by one QP if the declaration is clear that: it is signed on behalf of all the involved QPs the arrangements are underpinned by a technical agreement the QP providing the declaration is the one identified in the agreement as taking specific responsibility for the GMP compliance of the API manufacturer(s) 07/02/

14 QP Declaration concerning GMP compliance of API manufacture (cont.) MIAHs (using the API as a starting material and/or QP batch certification sites) should act appropriately to: verify the GMP compliance for each registered API manufacturer, even if this site is not routinely used define and fully understand the supply chain and verify that APIs used in the manufacture of medicinal products have been sourced through this supply chain where the MIAH is not directly responsible for audit of the API manufacturing site(s), the QP of the MIAH should ensure that appropriate technical arrangements/agreements are in place with the companies responsible for such audits 07/02/

15 QP Declaration concerning GMP compliance of API manufacture (cont.) For human and veterinary medicinal products, the QP declaration should be based upon an audit of the API manufacturers. It is established good practice that the audit should be conducted at the manufacturing site i.e. an on-site audit. Audits should be by or on behalf of the MIAH, by suitably trained and experienced person(s), who may be a third party contractor 07/02/

16 QP Declaration concerning GMP compliance of API manufacture (cont.) The audit cannot be replaced by GMP certificates from a relevant competent authority Audits of each site for GMP compliance should be undertaken at regular intervals, normally within three years. Justification should be provided if the date since the last audit exceeds this period Where the auditor s on-site access is unreasonably restricted or not permitted by the API manufacturer, then alternative sources should be sought on public health grounds 07/02/

17 Importation of APIs & the written confirmation Document requirements relating to active substances imported from outside of the EU under the quality system Verify the authenticity of the written confirmation on the official regulatory authority website, as applicable Be aware of the validity date of the written confirmation Conduct a review of the continued validity of sites on a regular periodic basis Maintain records of checks conducted 07/02/

18 07/02/ Active Substance Registration (ASR) Requirements

19 Active Substance Registration (ASR) Requirements Who needs to register? Manufacturers, importers and distributors of APIs located in Ireland are required to register with the HPRA Which APIs do the requirements relate to? APIs used in the manufacture of human medicinal products only. The requirements do not apply to active substances used for manufacture of investigational medicinal products for human use, medical devices or to veterinary medicines Which activities constitute importation? The procurement (purchase), for the purpose of importation into the EEA, of active substances from sites in third countries or acting as site of physical importation of active substances from third countries are activities which require registration as an importer with the HPRA 07/02/

20 Active Substance Registration (ASR) Requirements Which activities constitute distribution? The procurement (purchase from sites in the EEA), holding, supplying or exporting of an active substance are activities which require registration as a distributor with the HPRA What are the requirements for MIA Holders who also manufacture APIs? MIA holders are required to register any manufacturing activities relating to active substances What are the requirements for MIA Holders who import APIs? MIA holders are required to register in relation to importation of active substances where the site procures and/or acts as the site of physical importation of an active substance from a third country 07/02/

21 Active Substance Registration (ASR) Requirements What are the requirements for MIA Holders who distribute APIs? An MIA holder who supplies active substances to another registered/authorised site in the EEA or exports the active substance outside the EEA is required to register as a distributor of active substances MIA holders who procure and store active substances sourced within the EEA for the purpose of manufacture of medicinal products at its site is not required to register as a distributor of active substances What are the requirements for WDA Holders? WDA holders are required to register any activities carried out in relation to the manufacture, importation or distribution of active substances 07/02/

22 ASR Change Management ASR holders are required to communicate annually to the HPRA an inventory of the changes which have taken place as regards the information contained within the registration document. Any changes that may have an impact on the quality or safety of the active substances that are manufactured, imported or distributed must be notified immediately. When should the annual communication with the HPRA occur? Annual communications should be submitted one month in advance of the registration renewal due date. 07/02/

23 ASR Change Management What documentation is required to be provided with the annual communication? Statement indicating that there are no changes to the registration form or List of changes Manufacturers are requested to submit a site master file (SMF) Signed application form 07/02/

24 Regulatory References EU GMP Guide, Part I & Part II EMA Q&A: Good Manufacturing Practice HPRA Guide to Registration Requirements for Active Substance Manufacturers, Importers and Distributors in Ireland: AUT-G0105-5, July 2016 Guide to Managing Changes to Registrations of Active Substance Manufacturers, Importers and Distributors: AUT-G0130-1, May 2014 EMA Guidance for the template for the qualified person s declaration concerning GMP compliance of active substance manufacture The QP declaration template, May /02/

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