Enforcement of Compliance with GMPs in API manufacture

Enforcement of Compliance with GMPs in API manufacture Guy Villax Copyright Hovione 2004 No one is more active in pharmaceutical ingredients

Agenda What are APIs, GMP What is the legal framework What is the issue What do we want Where to find data Important Note: The following presentation namely the slides with the EU action items summarise the position taken by the following industry associations: APIC - the Active Pharmaceutical Ingredients Committee of CEFIC AFAQUIM - the Spanish Fine Chemical Association/ APIs producers APEQ - The Portuguese Chemical Companies Association CPA - The Chemical Pharmaceutical Generic Association, Italy. The other slides have been put together by Guy Villax to explain the current situation based on available information. 2

What are APIs Active Pharmaceutical Ingredients! Are the pharmacologically active substances that! Pharmaceutical companies formulate into finished product (tablets, capsules, injectables, unhalers).! APIs are very pure substances any impurities >0.1% need to be well understood APIs are produced by a variety of techniques:! fermentation, synthesis, biotechnology, plant extracts etc...! Following strict quality system rules known as GMPs (Good Manufacturing Practices). The formulation of pharmaceuticals! mixing the API with excipients! and dosing it with precision into measured dose formulations! is unable to improve the quality of the API The quality of the finished pharmaceutical cannot be better than the quality of the API 3

Why is GMP compliance important " GMP aims to ensure that product is made in a way that! Assures consistency of quality, batch after batch! Ensures that any change is only implemented after its impact on quality is assessed! Ensures that recordkeeping ensures traceability of all actions, and therefore verification of compliance " Absence of GMP means:! Batch-to-batch quality consistency is not assured! Changes may be implemented without consideration for impact on quality! Deficient Record keeping makes investigations impossible " Quality consequences of weak GMP - examples:! Different purity profiles (new untested impurities, eventually toxic)! Contamination by other APIs from poorly cleaned multipurpose equipment! Different crystal form/particle size (different bioavailability)! Inability to evidence what production operations were carried out! Production operations different from the filings at the authorities! Poor control and traceability of distribution 4

GMP compliance is expensive GMP requires: " A higher standard of facilities " Any critical changes to process, batch size, equipment, raw-materials etc... requires i) validation of the process and ii) stability testing of the API and the Formulations " Qualified staff! To understand the chemistry, write up the protocols, justify the changes, and document what was done Business impact:! Ensures quality and consistency / Virtual absence of complaints! More costs / More qualified staff! Reduced speed! Reduced flexibility GMP is very expensive...hence much temptation to forget GMPs and take short-cuts 5

What is the current legal framework This is the latest information on the GMP for API issue provided by the Belgian Inspectorate. " The concerned articles of 2001/83/EC as amended are Art. 46 (manufacture of medicinal products and APIs), 46bis (manufacturer of APIs)and 111 (surveillance and sanctions). # There is no obligation to inspect API manufacturers and no obligation to perform routine inspections # Inspection of the API manufacturer is not a routine pre-requisite for granting a marketing authorisation (exceptions: e.g. biologicals) # Today the authorities do not know how many sites need to be inspected. # What will trigger an inspection (still under discussion)? $ All biologicals $ In case of suspicion of non GMP compliance $ At the request of a Member State, EDQM, EMEA, API manufacturer $ In case of problems detected during the testing of samples $ If insufficient data is introduced for a change in manufacturing site $ In case of a recall following a quality defect $ In case of recurrent problems while testing individual lots by the FP manufacturer $ In case of re-packaging and re-labelling (broker) " Member States (MSs) are going to share the information via the GMP database (run by the EMEA), which will comprise the GMP certificates, information on non-compliance, information on the planning of inspections). Access to this database will be secured. MSs discuss currently about a mechanism how to share information on manufacturers of APIs which are not inspected and if access should be given to MRA countries. " There is no transition period for ongoing MA applications. 1.11.2005 is the deadline for compliance. 6 " Some excipients will fall under the same GMP rule. The final list is not yet established. A

Belgium example - NOW: What is the current legal framework % There is no obligation to inspect API manufacturers and no obligation to perform routine inspections % Inspection of the API manufacturer is not a routine pre-requisite for granting a marketing authorisation (exceptions: e.g. biologicals) % Today the authorities do not know how many sites need to be inspected. 7

Belgium example - NOW: What is the current legal framework % There is no obligation to inspect API manufacturers and no obligation to perform routine inspections % Inspection of the API manufacturer is not a routine pre-requisite for granting a marketing authorisation (exceptions: e.g. biologicals) % Today the authorities do not know how many sites need to be inspected. On or before 30th October 2005 EU Directive 2004/27 must be transposed into national legislation BUT: % The GMP Certificates are not mandatory. % The Directive only gives the POSSIBILITY for API inspections, upon request % The system remain essentially a self-regulation one however for the 1 st time there is a GMP regulation (ICHQ7a 0 Annex 18) 8

Belgium example - NOW: What is the current legal framework % There is no obligation to inspect API manufacturers and no obligation to perform routine inspections % Inspection of the API manufacturer is not a routine pre-requisite for granting a marketing authorisation (exceptions: e.g. biologicals) % Today the authorities do not know how many sites need to be inspected. On or before 30th October 2005 EU Directive 2004/27 must be transposed into national legislation BUT: % The GMP Certificates are not mandatory. % The Directive only gives the POSSIBILITY for API inspections, upon request % The system remains essentially a self-regulation one however for the 1 st time there is a GMP regulation (ICHQ7a 0 Annex 18) In summary: % There is silence as to enforcement of the GMP compliance on imported APIs % There is growing expectation in Member States that active substances used as starting materials should be subject to good manufacturing practices and possibly to inspections as they are in the US and Japan. However, our approach will be based on the principle of strict proportionality. We do not want a proliferation of inspections. Position of the Directorate F Single market: management & legislation for consumer goods within Enterprise DG of the European Commission % EDQM inspections will in the near future be discontinued. 9

What will (continue to) happen if we don t act " Europe has GMP regulations in its legislation:! Applicable to all API producers selling in EU! Enforcement is up to national regulations, otherwise its is self-regulation! There is no mandatory Foreign Inspection Service The EU will enforce GMPs in the producers most likely to be in compliance! " 70% of APIs used in EU pharmaceuticals today are imported from India and China the vast majority of generic medicines! Usually imported via brokers whose long-term profits depend in part from keeping the manufacturer s name undisclosed! A number of CEPs (EP DMFs) are in the name of, and held, by brokers Since 1999 EDQM has carried out 58 inspections targetting the most sensitive APIs this has resulted in:! Zero suspension of CEP in Europe! 7 CEPs suspended (4 India, 3 China) 5 out of 28 sites failed. 10

" Suppliers of API to GMP enforcement does make a difference! USA : several hundred inspected establishments! EU: many thousands of uninspected establishments! Just about anyone whose product can meet the spec " API X sold in the USA will usually have a price higher than that sold in EU " Compliant EU producers export successfully to the USA, but... are unable to compete in EU market against Asian low cost product. Yet: US compliance enforcement has not reduced generics:! The USA is the largest generic market in the world, with one of the highest penetration in terms of prescriptions US compliance has not kept high prices:! E.g. Prices of generics in Italy are higher than those in the US 11

The issues are: There is no level playing field! EU based producers have high compliance => higher costs & less flexibility, can only compete in highly regulated markets such as the USA, are being pushed out of their home market by Asian lower prices Quality of generic medicines in the EU is not comparable to that of the USA GMP enforcement is not mandatory, it relies on self-regulation... Yes it is our achilles heel the pharma companies we inspect don t really know who makes the APIs they use they come via Hamburg from India and China, they come from Argentina... An EU Inspector, November 2004. 12

The EU API industry is requestion the Commmission that: 1. The European Medicines Agency (EMEA), in London, UK, and the European Directorate for the Quality of Medicines (EDQM), in Strasbourg, France be mandated to cooperatively set up a service that will concentrate the know-how on API GMP compliance in Europe. 2. That the EMEA and EDQM together be exclusively responsible for verifying compliance with GMP requirements at all non-eu- and EU-based producers of APIs irrespective whether the MA refers to a CEP (Certificate of Conformity) or to a DMF (Drug Master File) or whether all information on the manufacture of the API is included in the MA. 3. That the EMEA and EDQM be mandated to perform the central role of training of EU inspectors so that the Competent Authorities (CA) in the Member States that perform compliance inspections can all follow the same standards and lead the Industry towards the same best-practices. 4. That the modus operandi of the API inspections, upon which the CA of the various member states will model their inspections, should be the current EDQM inspection model an inspection format that mirrors approximately the FDA inspection process. 5. That no new MAs be approved without a Certificate of GMP compliance being issued for the involved API. 6. That all existing approved MAs be withdrawn unless the holder of the MA provides a Certificate of GMP compliance for the API in question. 7. That the implementation date set out in the Directive, as defined as 30 th October 2005, be observed whenever possible. 13

A way forward: 1. EMEA and EDQM to be mandated to set up the EU s foreign inspection service. 2. EMEA and EDQM be exclusively responsible for verifying compliance with GMP requirements at all APIs producers supplying the EU. 3. EMEA and EDQM to train EU inspectors, so all follow the same standards and lead the Industry towards the same best-practices. 4. Modus operandi of the API inspections to mirror FDA inspection process 5. No new Marketing Authorization be approved without a Certificate of GMP compliance being issued for the involved API. 6. All existing approved MAs be withdrawn unless the holder of the MA provides a Certificate of GMP compliance for the API in question. 7. That the implementation date set out in the Directive, as defined as 30 th October 2005, be observed whenever possible. We want an EU Foreign Inspection Service We want MAs to include GMP certificates for the API 14

No Buts... Every manufacturer committed to Quality and GMP has one single goal: to being inspected by FDA that is the Gold Standard! EU mandatory inspections will be welcomed by all quality producers irrespective of location User fees are acceptable to all producers The EU foreign inspection service can be self-financed Evidence of GMP compliance issued as a result of inspections by reputable authorities (e.g. FDA, TGA) should be acceptable. The EU has the largest pool of trained API professionals! Recruiting inspectors is not a problem The EU Commission cannot just wait for an adverse event to occur before it acts. 15

Thank you For more information, please contact: Guy Villax ceo@hovione.com Tel: +351 21 982 380 Hovione SA Sete Casas 2674-506 Loures Portugal www.hovione.com A complete data-base on this matter can be found on www.gmpapi.migg.com 16