EUROPEAN GENERIC MEDICINES ASSOCIATION

POSITION PAPER

EGA WHITE PAPER ON THE IMPLEMENTATION OF KEY API QUALITY AND GMP ASPECTS OF THE EU FALSIFIED MEDICINES DIRECTIVE (2011/62/EU)

31 JANUARY 2012 (REV06.1-FINAL)

Further information | JULIE MARCHAL-JAMIL

EGA - EUROPEAN GENERIC MEDICINES ASSOCIATION Rue d'Arlon 50 B-1000 Brussels Belgium Tel: +32 (0) 2 736 84 11 ~ Fax: +32 (0) 2 736 74 38 E: info@egagenerics.com | www.egagenerics.com The EGA is the official representative body of the European generic and biosimilar pharmaceutical industry, which is at the forefront of providing high-quality affordable medicines to millions of Europeans and stimulating competitiveness and innovation in the pharmaceutical sector.

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CONTENTS

1. EXECUTIVE SUMMARY .............................................................................. 3 2. Introduction ......................................................................................... 6 3. EMA GMP/GDP Inspectors Working Group (EMA GMDP IWG) Formal Mandate ........... 6 4. KEY ITEM 1 - Scope of application of import provisions for non-EU API (article 46b2) 7 5. KEY ITEM 2 Written Confirmation for the import of non-EU API (article 46b2) ...... 7 5.1. Nature of the written confirmation .......................................................7 5.2. Written confirmation EU template ........................................................7 5.3. Written confirmation scope - validity ....................................................8 5.4. Written confirmation issuance-retrieval .................................................8 5.5. Central repository ..............................................................................8 5.6. Role of EU border/customs officials .........................................................9 5.7. Implementation/entry into force ............................................................9 5.8. Open questions................................................................................ 10 6. KEY ITEM 3 - Waiver 1 for the written confirmation: List of Equivalent Countries by means of EC Implementing Acts (articles 46b3 & 111b) ...................................... 11 6.1. Awareness raising among key API exporting 3rd countries .............................. 11 6.2. Existence of appropriate arrangements (article 51(2) of Directive 2001/83/EC as amended) as a waiver for on-site review and inspection .................................... 12 6.3. Leverage on the EU Food and Veterinary Office (FVO) experience ................. 13 6.4. Staged approach to an EU list of equivalent countries: proposal for an interim list of equivalent establishments within countries .................................................... 14 7. KEY ITEM 4 - Waiver 2 for the written confirmation: Exceptionally and where necessary circumstances (article 46b(4)) ....................................................... 15 8. KEY ITEM 5 - Border Controls on non-EU APIs entering the EU: need for a separate legal act................................................................................................. 16 9. KEY ITEM 6 International Collaboration as key success factor for effective and timely implementation .............................................................................. 16 10. Other items for consideration ................................................................. 16 10.1. API GMP by means of an EC Delegated act .............................................. 16 10.2. API GDP Guidelines.......................................................................... 17 10.3. Excipient Formalised Risk Assessment Guidelines ...................................... 17

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EGA POSITION PAPER

EGA WHITE PAPER ON THE IMPLEMENTATION OF KEY API QUALITY AND GMP ASPECTS OF THE EU FALSIFIED MEDICINES DIRECTIVE (2011/62/EU)
1. EXECUTIVE SUMMARY A harmonised implementation of the Falsified Medicines Directive is not only desirable but necessary in the view of the EGA to achieve a level playing field worldwide as regards the quality of active substances and excipients. A continuous interaction between the EC, the EMA, EU Members States and stakeholders (industry and 3rd countries) is a key success factor. The EGA proposes the following pragmatic approaches to achieve the best results in the given timeframe: Secure continuity of GMP compliant API supply as a top priority Proceed with a grandfathering approach for long existing, well-known and GMP compliant pharmaceutical supply chain operators by temporarily waiving administrative requirements Integrate the necessary and realistic transition periods to accommodate substantial organisational changes and process elaboration while securing GMP compliance Raise awareness among all stakeholders who will have an active role to play in the implementation (i.e. non EU based supply chain operators, key non EU API exporting 3rd countries) by means of regulatory dialogue or joint competent authorities-industry information sessions Leverage on positive experience from other sectors (import of high quality regulated goods, involvement of customs, EU inspectorate) Foster collaboration with equivalent countries (optimise inspections resources allocation) Enhance the use of IT/electronic interfaces as enabler for efficient collaboration Leverage on existing guidelines and standards for the quality of excipients In the next pages, key enablers and success factors along with EGA proposals are first presented in the form of comprehensive summaries and then, in greater details.

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Key Enablers / Success Factors

(non exhaustive)

DIALOGUE:
- EU regulators / industry
- EU regulators / EU border officers - EU / Key API exporting 3rd countries - EU / non-EU regulators

CENTRALISED SYSTEM:
- EU template declaration - EU decision making process

TRANSPARENT SYSTEM:
- Public databases - Public list of EU decisions

PRAGMATISM:
- Leverage on existing knowledge of compliance
- Leverage on grandfathering approach - Leverage on successful experiences in other regulated industries (e.g. Food & Feed) - Leverage on existing mechanisms for assessing equivalence

- EU inspection coordination
- EU regulatory network on API supply continuity - EU databases

SECURED TRANSITION / IMPLEMENTATION PERIODS for GMP compliant operators

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2. Introduction The EU Falsified Medicines Directive (2011/62/EU) is a key legislative tool to achieve a level playing field worldwide as regards the quality of active substances and excipients. The EGA is looking forward to opportunities of interactions and exchange with the European Commission, the EU Member States and the European Medicines Agency in order to achieve a successful and pragmatic implementation.

Harmonisation of EU API Importation rules

Importation Requirements
- Scope of application - Written declaration - List of equivalent countries (Waiver 1) - 'Exceptional circumstances' (Waiver 2) - EU Member States - Non-EU API exporting 3rd countries - EU Competent Authorities - EU Member states border & customs officials

Importation Process

Acceptance

Figure 1 Overview of the implications of the Falsified Medicines Directive provisions on the API Importation rules

3. EMA GMP/GDP Inspectors Working Group (EMA GMDP IWG) Formal Mandate Directive 2011/62/EU introduces a number of provisions to be implemented by Member States (MSs). In order to ensure a harmonised and efficient implementation, we anticipate that the EMA (GMDP IWG) and CMD(h), although not referred to explicitly in the text, could play a key role in maximising the cooperation and coordination between EU Member States.

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4. KEY ITEM 1 - Scope of application of import provisions for non-EU API (article 46b2)

EGA Recommendations
The scope of application of the newly adopted import provisions for non-EU API import into the EU should clearly define what the term API import comprises or what it excludes (see 5.8 Open questions). 5. KEY ITEM 2 Written Confirmation for the import of non-EU API (article 46b2)

EGA Recommendations
Joint EU Member States guidelines to align and harmonise requirements (template) and processes to elaborate, verify and accept the written declaration of API GMP compliance. Involvement of customs/border officials in the drafting process is essential given the role they will play in authorising or refusing the entry of the shipment onto EU territory. Transition period of 6 years from the date the EU requirements and processes are laid out to allow 3rd countries to adapt.

Remark: These guidelines would concomitantly benefit non-EU API 3rd countries, helping them understand expectations, timelines as well as to set up national systems/procedures allowing issuance of the necessary written confirmation. Below are the detailed elements the EGA proposes to include in implementation guidelines. 5.1. Nature of the written confirmation of API GMP compliance The written confirmation is a shipment/customs document not a regulatory document. Justification: It accompanies a shipment and is not intended for review by assessors within the MAA or subsequent variations/notifications. o Consequently, the written confirmation issued by third countries should Remain distinct from any existing import licensing process. Not be cross referred in the QP declaration template.

5.2. Written confirmation EU template The EU should develop a template for written confirmation in order to clearly identify the necessary elements required. Justification: co-existence of multiple formats for the written declaration to be issued by the various non-EU API exporting country would be a great source of highly undesirable administrative work and possibly a great source of delays and misunderstanding.

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The EU should also include discussions on the written confirmation template when engaging with competent authorities from key non-EU API exporting countries in order to ensure clear wording and appropriate understanding. Justification: the earlier the involvement of 3rd countries, the greater the efficiency of the implementation process.

5.3. Written confirmation scope - validity The written confirmation should be issued for a manufacturing facility. Ideally, the handling of the written confirmation should mimic site GMP certificate. Justification: the issuance of written confirmation at the following levels would prove counter-productive through the creation of massive administrative bottlenecks in key exporting countries in greater proportion than the increase in public health protection). e.g. : active substance, active substance batch, active substance batch shipment (i.e. several shipped parcels/drums for a given batch) The preferred approach would be to have a transparent GMP compliance risk based assessment ranking of non-EU API exporting facilities (such as that available in the UK MHRA) which would indicate the appropriate frequency for re-issuance. Justification: this is preferable to a fixed 3 year-period which would not focus on the higher risk facilities.

5.4. Written confirmation issuance-retrieval API manufacturers exporting to the EU are primarily responsible for obtaining the written confirmation from their local competent authorities. Justification: they have direct interactions with their local competent authorities and are responsible for exporting API to the EU. o Remark: This aspect could be cross-referred in the delegated act on API GMP. The EC or EMA should establish and maintain a central list of API exporting 3rd countries local competent authorities responsible for the issuance of the written confirmation (according to the model of the EU Commissions single and central lists of approved food establishments published by each Member State1). Justification: this will facilitate the verification of the validity of the written confirmation by border/customs officials and manufacturing authorisation holders.

5.5. Central repository The written confirmation should be stored in a central and public EU repository for easy access by the EU and 3rd countries Competent Authorities, Manufacturing Authorisation holders as well as border/customs officers. Justification: The EudraGMP database already contains information related to importation (e.g. Import Licenses). It is already used for cross-referencing the latest available certificates and licenses and would allow manufacturing
1

http://ec.europa.eu/food/food/biosafety/establishments/list_en.htm

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authorisation holders to ensure compliance with the requirements of article 46b of the Falsified medicines directive. EU based Importers of APIs based should be in charge of notifying their local competent authorities of the issuance of a new written confirmation. Justification: They are the EU gatekeepers for API import and have up-to-date information to do so. The current procedures for EudraGMP update (e.g. timelines) could be applicable to this activity as they stand.

5.6. Role of EU border/customs officials A written confirmation template needs to be developed in conjunction with customs and border officers. Justification: EU borders/customs officials will be responsible for validating or allowing import o Remark: EU border officers would also play a part in uploading or verifying the written confirmation against the central repository entries. The language in which the written confirmation should be issued also needs to be addressed in conjunction with customs discussions o Remark: experience is available from the import of regulated goods from other regulated industries. o Remark: this should not pose any problem in case of a harmonised format. 5.7. Implementation/entry into force Only after EU Member States have clarified expectations/requirements and processes, will API exporting 3rd countries be in a position to develop their own implementation action plan, procedures and processes. EU Member States (and EMA guidelines) should therefore o Aim at a harmonised approach to minimise unnecessary complexity o Consider the necessity of a transition period after having clarified requirements allowing industry and API exporting 3rd countries to prepare for their entry into force Non-EU API 3rd countries would then have to o Develop request and issuance mechanisms for the written confirmation (signatories) as well as o Organise the necessary GMP supervision (where needed) o Establish a rapid alert mechanism with the EU (where needed) o Notify the EMA of the local competent authorities responsible for the issuance of the written confirmation The transition period (from the date the requirements and expectations are made clear) could be: o Scenario 1: 3 years for new API importation (provided GMP compliance is evidenced) and automatic importation allowance (so-called grand fathering approach) for all APIs which already have a history of GMP compliant API EU importation would

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Scenario 2: 6 years if applicable to all non EU API importations (provided GMP compliance is evidenced).

5.8. Open questions Are Investigational Medicinal Products (IMPs) in the scope of the applicability of the written confirmation for API imports? Our understanding is that the Falsified Medicines Directive further amends directive 2011/83/EC and does not apply to the Clinical Trials Directive and therefore would not apply to API for IMPs. However, a clarification would be needed so that implementation is homogeneous. Are Member States planning to include in the operational implementation of the FMD that active substance import shall be understood as both bulk API and API within a finished dosage form in order to fulfil the objective of harmonisation of GMP for APIs? Taking into account the definition of active substance as introduced in Dir. 2011/62/EU, it implies that article 46b would apply only to bulk non-EU API import (any substance [] intended to be used in the manufacture of a medicinal product). Understanding that the intentions of the FMD are to create a level playing field for API quality, the mere fact of not including the import of a non-EU API already within a finished dosage form would create a legal gap by which a difference in GMP/GDP supervision requirements and in the administrative steps would be required. This could likely trigger a shift from bulk non-EU API import to import of finished dosage forms (implying a shift of EU based production outside the EU) to circumvent the additional administrative burden. Would pre-treated APIs (i.e. manufacturing intermediates) be considered in the scope of applicability of the written declaration? e.g. API plus Aerosil for better flowability, direct compressible API (granulated) Existing legislation in certain Member States considers the above as finished products. It is therefore important to clarify this upfront. Are there considerations regarding the temporary acceptance of locally issued GMP certificates by a local inspectorate during the transition period where the written confirmation might not be readily available? Certain Member States currently require locally issued GMP certificates provided they specifically refer to the standards against which the certification was made e.g. WHO GMP. This would however not work for all countries (e.g. China), where some APIs can be produced for export only (and not for the local market, because of patent reasons) consequently they are not yet under scrutiny by the local authorities. What will be the consequences and processes in place in situations where following an EU GMP inspection or a company audit, a site already benefiting from a written confirmation is found to be out of compliance with EU GMP? The situation where an EU inspection does not confirm compliance seems clear from a Manufacturing Authorisation Holder perspective (already foreseen in current Community

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Procedures) however the consequences on the country issuing the statement and all other statements issued is not yet clear. Additionally, the mechanisms through which, after a non-satisfactory audit of a facility benefiting from an import allowance, information is communicated by the manufacturing authorisation holder to the EU authorities and then official actions undertaken needs clarification. 6. KEY ITEM 3 - Waiver 1 for the written confirmation: List of Equivalent Countries by means of EC Implementing Acts (articles 46b3 & 111b)

EGA Recommendations
Early awareness raising of key non-EU API exporting 3rd countries (prioritisation list): industry mailing to API manufacturers and, joint regulatory/industry information sessions. Develop an operational interpretation of the term appropriate arrangements to leverage on existing mechanisms for the establishment of equivalence including Mutual Recognition Agreements (even when APIs are not covered) PIC/S members Leverage on other regulated sectors experience, e.g. Food and Feed Centralised system with dedicated inspection resources Staged approach of accepting, for a defined period, API exports from compliant facilities within a country versus compliant country Minimum of an 8 year-transition period for such facilities and a requirement for documented track record of compliance

6.1. Awareness raising among key API exporting 3rd countries Article 111b reads At the request of a 3rd country []. This legal provision implies that, as a prerequisite, key non-EU API exporting 3rd countries are fully informed of: the new EU requirements for the importation of GMP compliant APIs and, EU expectations as to their new role and responsibilities in overseeing API GMP compliance and communicating towards the EU for API exported to the EU. In order to prioritise EU communication efforts towards key countries, the EGA has compiled and shared a list of key countries supplying APIs to its member companies. It is enclosed hereafter as Table 1- Key "non-EU API exporting countries". The EGA proposes to have joint efforts from industry/regulators and the EC in raising awareness in key countries. Industry should inform key API partners and operators outside the EU of upcoming changes via written letters.

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A more efficient alternative would be to host a series of joint EU regulators/EC/industry workshops with the competent authorities and API manufacturers of key countries during Q2/Q3 of 2012 to favour readiness. Key non-EU API exporting Countries
India China Turkey Mexico South Korea Taiwan Israel Switzerland USA South Africa Japan
Table 1- Key "non-EU API exporting countries"

6.2. Existence of appropriate arrangements (article 51(2) of Directive 2001/83/EC as amended) as a waiver for on-site review and inspection Article 111b(1) makes direct reference to Article 51(2) which deals with medicinal product import from a third country, where appropriate arrangements have been made by the Community [] to ensure [compliance] with standards of GMP at least equivalent to those laid down by the Community. The implementing acts shall clearly define the scope and extent of the interpretation of appropriate arrangements. Our view is that the term appropriate arrangements shall encompass at least all of the following: All countries where a Mutual Recognition Agreement (MRA) or Agreement on Conformity Assessment and Acceptance of Industrial Products (ACAA) exists which is in force, regardless of the MRAs respective scope and particularly regardless of whether or not APIs are formally included in such agreements (in agreement with the pragmatic approach laid out in the EMA GMP/GDP IWG Work Plan 20112). All countries which are official members of the Pharmaceutical Inspection Cooperation Scheme (PIC/S)

To include active substances in the operational phase of the current scope of MRAs where possible and to liaise with MRA partners on information exchange and collaboration on inspections performed outside of the respective territories., Work Plan for GMP/GDP Inspectors Working Group for 2011 - EMA/INS/GMP/678698/2010 corr1

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The basis for this is that in both situations, the principles of equivalent regulatory systems (the existence of GMP legislation), the existence of inspections and effective enforcement have already been assessed and validated3. In addition, the inclusion of PIC/S members is even more relevant now that: EMA and PIC/S have signed a formal co-operation agreement4 PIC/S has enhanced its focus on APIs (e.g. guidance, inspectors training) further to an EU Commission Concept Paperi PIC/S already foresees regular re-inspections of all its members to ensure harmonised compliance with the latest GMP standards This pragmatic approach to automatic inclusion of an equivalent country would efficiently and greatly reduce the key non-EU API exporting 3rd countries list to a total of six TOP priority countries out of which 5 have already applied or indicated an interest in applying for PIC/S membership.

HIGH Priority

Table 2- Key 'non-EU API exporting 3rd Countries, Arrangements and PIC/S Membership Legend: * Not operational **PIC/S Membership application pending or to be made

6.3. Leverage on the EU Food and Veterinary Office (FVO) experience While implementing article 111b, the EC should consider the creation of an EU inspectorate with dedicated resources which would be responsible for undertaking, among

PIC-S Accession procedure is described on the following website http://www.picscheme.org/accession.php : The main conditions are to have a law on medicinal products, a GMP Guide equivalent to that of PIC/S (or the EU GMP Guide), a GMP inspectorate, which fulfils PIC/S quality system requirements, and experienced GMP inspectors. 4 Co-operation between the Pharmaceutical Inspection Co-operation Scheme and the European Medicines Agency http://www.ema.europa.eu/ema/index.jsp?curl=pages/partners_and_networks/general/general_co ntent_000470.jsp&murl=menus/partners_and_networks/partners_and_networks.jsp&mid=WC0b01ac 05801f0a08#

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other tasks, the planning, audit and periodic re-evaluation of foreign inspectorates, as already proposed in the EGA Vision 20155 (released in 2010). Making a parallel with the food and feed sector, the Food and Veterinary Office (FVO), a directorate of the Directorate-General for Health and Consumers of the European Commission, works to ensure effective control systems and to evaluate compliance with EU standards in the areas of food and feed safety, animal health, animal welfare and plant health. It does this mainly by carrying out inspections and audits in Member States and third countries. It has its own dedicated expert resources (175 inspectors) working on an EU central inspection programme (involving re-assessment inspections) covering food producing establishments in the EU and in third countries. 6.4. Staged approach to an EU list of equivalent countries: proposal for an interim list of equivalent establishments within countries Based on the well-known fact that a vast majority of imported APIs are primarily manufactured in either India or China, and based on the current GMP status of these countries, their inclusion in the EC list of equivalent countries might require some time. The Food and Veterinary Office, referred to above, established a staged approach to compliance to food safety standards by means of drawing up a provisional list of third country establishments from which imports of certain products are permitted. This should be used as a positive experience towards regulating the importation of regulated goods. In this context, the EC and EMA should foresee provisions: To acknowledge the long history of compliance to GMP for APIs (EU GMP Guide part II or ICH Q7A) of certain manufacturing facilities located in those countries To guarantee GMP compliant API supply continuity from key non-EU API exporting countries In an implementing act, the EC should consider a minimum of an 8 year-transition period during which non EU exporting 3rd country API manufacturing facilities having a long history of GMP compliant API supply to the EU could continue exporting to the EU. A good track record of GMP compliance could potentially be defined as having had 2 successful inspections (by any EU inspector or PIC/S or MRA country or EDQM or equivalent) and the absence of any unaddressed/unresolved critical deficiencies highlighted in the last 6 years. This would prevent GMP compliant 3rd country manufacturers from being administratively disfavoured for being established in a 3rd country. This would also allow countries competent authorities that cannot be considered equivalent today to have sufficient time to progressively adapt resources, processes and practices to new requirements. An alternative and shorter transition period could be envisaged if the provision was limited to new API manufacturers (ie, new manufacturer or new API for a known manufacturer) and that existing GMP compliant API suppliers to the EU would be exempted (so called grandfathering approach).

www.egagenerics.com/doc/EGA_Vision_2015.pdf

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7. KEY ITEM 4 - Waiver 2 for the written confirmation: Exceptionally and where necessary circumstances (article 46b(4)) According to artice 46b(4), Member States are responsible for assessing the scarcity of GMP compliant API supply and the risk of supply discontinuation, to waive the need for a written confirmation of GMP compliance issued by a third country exporting API to the EU and to inform the EC of their decision. Industry operates in a global environment and would favour a transparent and central repository where supply availability trends for the whole EU appear.

EGA Recommendations
A single EU process to assess the state of GMP compliant API supply would be needed for all MSs. A single EU decision-making process for waiver granting would be needed. The EC should establish an EU priority list of at risk substances or medicines. This list would among others prioritise those substances for which the EU supply is highly dependent on non-EU supply and those for which the existing number of manufacturing sites is restricted (in number, or in a given geographic location) Expansion of the EU Incident Network to cover emerging issues such as API or medicines shortages. Risk-based inspection prioritisation should ensure that GMP compliant API manufacturers based in third countries are not at a disadvantage: as the EU GMP certification is a key condition for obtaining this waiver, there should be a contingency mechanism: o The EC (through the EMA or its EU inspectorate dedicated to APIs) should secure a sufficient number of contingency GMP inspections to accommodate for reduced API supply and patients access to medicines o As a complementary approach, the EC should consider establishing an expedite process for paper based GMP certification based on a manufacturing site history of compliance The above EU processes, decisions and EU priority list should be published on EC and/or EMA websites.

The EU regulatory network already has in place crisis management cooperation mechanisms, such as the EU Incident Network and its EU Regulatory System Incident Management Plan, for medicines for human use. Although the scope of activities of the EU Incident Network is currently limited to quality defects resulting in safety concerns, the perspective of potential shortages could also fall in the category of emerging safety issues for medicines for human use as some treatments might end up being interrupted and cause issues for patients.

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8. KEY ITEM 5 - Border Controls on non-EU APIs entering the EU: need for a separate legal act On the model of Council Directive 90/675/EEC laying down the principles governing the organisation of veterinary checks on products entering the Community from third countries, the EC should consider a separate legal act which would complement Dir. 2001/83/EC, as amended, as far as API import from 3rd countries is concerned in order to secure harmonised Member States implementation by customs at their border and prevent the creation of uneven ports of entry into the EU (i.e. absence of level playing field). 9. KEY ITEM 6 International Collaboration as key success factor for effective and timely implementation The EGA is a strong supporter of increased international cooperation as a key manner to meet the challenges of a globalised pharmaceutical industry. The EGA encourages the exchange of information among competent authorities as well as intensified recognition of inspection outcomes to limit redundant inspections and enhance overall regulatory supervision (e.g. of API manufacturers not inspected to date). We understand that mutual recognition is a complicated step to achieve outside the EU however we believe that the integration of 3rd country inspection outcomes in the riskbased assessment and prioritisation of inspections could already provide a significant relief for collaborating competent authorities worldwide. 10. Other items for consideration 10.1. API GMP by means of an EC Delegated act According to article 47 (third paragraph), the EC shall adopt by means of delegated acts the principles and guidelines of good manufacturing practices for API. The EGA supports the adoption of the principles and guidelines for API GMP as an amendment of 2003/94/EC laying the principles of GMP for medicinal products, provided the specificities of APIs are carefully considered. The key objective should be to maintain full harmonisation with agreed international standards, particularly with ICH Q7A (i.e. API GMP) in order to foster efficient and timely evaluation of equivalent GMP standards. In addition, the EGA supports that the EC considers addressing the legal responsibilities of API manufacturers, importers and distributors as key pharmaceutical sector operators playing an integral part in the supply chain continuity and oversight. These should be detailed regardless of the geographical location. For non-EU API manufacturers, a legal representative based in the EU should be established. All API manufacturers, importers distributors should identify an EU responsible person who would release batches of APIs in the EU. For pragmatic reasons, and based on experience with the batch release of medicinal products, the EU batch release for APIs could be waived under defined circumstances (eg, if originating from MRA, ACCA, PIC/S member countries or equivalent countries as per article 111b).

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Clear provisions should be foreseen for API manufacturers to provide to the Manufacturing Authorisation Holder and the Marketing Authorisation Holder (as applicable) the necessary information to fulfil the requirements of Dir. 2001/83/EC as amended (particularly by Dir. 2011/62/EU) and other EU quality and GMP/GDP guidelines. e.g. QP Declaration (information on early API supply chain from API starting materials to intermediate, specifically on qualified suppliers), written confirmation of compliance, confirmation of EU registration (where applicable). 10.2. API GDP Guidelines The EGA supports a simple approach to API GDP as all elements are already covered in the existing GMP guide. The establishment of EU API GDP guidelines should primarily refer to elements of API GDP that are aligned with ICHQ7A principles. For the sake of maintaining international harmonisation, any additional consideration regarding API GDP guidelines should preferably be proposed for discussion to the ICH programme in view of having common standards. 10.3. Excipient Formalised Risk Assessment Guidelines There already exists a number of quality standards to secure quality and safety of the excipients where manufacturers of medicinal products have a responsibility to apply necessary measures according to the intended use of the product. We therefore support a simple and pragmatic approach to formalisation of risk assessment for excipients where reference is made to existing guidance documents as well as to the principles of ICH Q9 Quality Risk Management. We also support the inclusion of the principles of formalised risk assessment into the existing supplier qualification programmes.

INTERNATIONAL COLLABORATION FOR THE QUALITY OF APIs The Committee has discussed a Concept Paper by the European Commission for enhanced cooperation in the field of APIs, in which PIC/S is identified as one of the main stakeholders. Members of the Committee believe that the proposal is a recognition of PIC/S and also a great opportunity to play an important role in the field of APIs, regarding: i) the assessment of Competent Authorities; ii) training (through the Expert Circle on APIs) and; iii) sharing of information related to APIs inspections. In relation with the Commissions proposal, the Committee has also considered a project developed by the PIC/S Expert Circle on APIs in co-operation with other partners (e.g. EDQM, EMA, ICH, US FDA, WHO, etc.) for organising an international training for inspectors on APIs. The training will focus on i) an introduction to ICH Q7 (basic course) and ii) on how to inspect APIs (advanced course). PIC/S Annual Report 2010 (July 2011)

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