API EUROPEAN GMP REQUIREMENTS Alessio Ferrari
SUMMARY GUIDELINES IMPLICATIONS FOR THE INDUSTRY ARTICLE 46 (F) OF DIRECTIVE 2001/83/EC PART I EU GMP Chapter 5 OFFICIAL MEASURES TO PROTECT. PROCEDURE TO REQUEST EU GMP FUTURE TREND
GUIDELINES 2004/27/EC - Directive 2004/27/EC Amended by Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use (Official Journal L 136, 30/4/2004 p. 34-57).
GUIDELINES Terms of the new directives (2004/27 for human health and 2004/28 for animal health) call for inspections of API manufacturers, traders and brokers as well as non-cep APIs. Moreover, the directives are intended to focus on incoming-api aspects during inspections at dosage-form manufacturers and keep an eye out for the possibility of fraud and counterfeiting.
GUIDELINES More specifically, under the new directives: A qualified person must declare the API in compliance; A GMP certificate from health authorities is not sufficient evidence that the the GMP requirements are being met; Guidelines require that an audit report be on file and available to regulators.
BEHIND THE GUIDELINES The move was hailed by members of the European Fine Chemicals Group (EFCG), who called the directives a long time in the making and suggested that they are one way of ensuring that there is a level playing field for European API manufacturers. According to some estimates, more than 80% of APIs used in European pharmaceuticals now originate from China and India. EFCG estimates that there may be as many as 10,000 plants in these Countries supplying APIs to Europe.
BEHIND THE GUIDELINES The health of the European consumer is at the crux of all this, explained Cefic s Tony Scott, who also serves as a member of the EFCG board. The new law will make us trust the system.
Implications for the Industry As a result of these new directives, pharmaceutical suppliers will no longer be able to just buy the API from a trader, according to Guy Villax, president of Hovione and president of the EFCG pharmaceutical business committee. In fact, manufacturers must obtain a declaration and data to support directive compliance from the API producer.
Implications for the Industry Audits of API producers will also occur more frequently and they will be performed by API users as well as third parties. These audit reports will be available to regulators and will cease to be confidential. Moreover, EFCG members are concerned that the EU member state health authorities may not be equipped to carry out the inspections called for under the new directive. The industry is asking regulators are they adequately equipped to regulate?
The High Cost of Compliance Although the new directives are aimed at ensuring the health of European consumers, they also go some way in maintaining the health of European API producers. According to the EFCG, GMP compliance increases a plant s operating costs by 25%, reduces its flexibility and lengthens time to market. Although some may view the directives as direct attacks on the Indian and Chinese API market, EFCG noted that every company must abide by the same regulations, pointing out that in Europe,some API company facilities are substandard and some in Asia are excellent. So who knows?
Article 46 (f) of Directive 2001/83/EC In accordance with Article 46 (f) of Directive 2001/83/EC as amended, manufacturing authorisation holders are required to use as starting materials only active substances which have been manufactured in accordance with the detailed guidelines on European Good Manufacturing Practice (GMP) for starting materials. Confirmation of compliance with the Regulation is required from the Qualified Person (QP) at the European site responsible for batch release (and/or site of finished product manufacture) for applications for new marketing authorisations, renewals and variations in which a change is proposed to the manufacturer of the active substance, finished product or site of batch release.
Article 46 bis (f) of Directive 2001/83/EC to comply with the principles and guidelines of good manufacturing practice for medicinal products and to use as starting materials only active substances, which have been manufactured in accordance with the detailed guidelines on European good manufacturing practice for starting materials. This point shall also be applicable to certain excipients, the list of which as well as the specific conditions of application shall be established by a Directive adopted by the Commission in accordance with the procedure referred to in Article 121(2).";
Part I EU GMP Chapter 5 Production Starting materials 5.25 The purchase of starting materials is an important operation which should involve staff who have a particular and thorough knowledge of the suppliers 5.26 Starting materials should only purchase from approved suppliers named in the relevant specifications and, where possible, directly from the producer. It is recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers..omissis
HEPARINE GATE FDA position: US drug firms qualification of overseas vendors will be subject to increased FDA scrutiny in the coming years.
MHRA- UK Medicines and Healthcare products Regulatory Agency API Focused MHRA Inspections at Dosage Form Manufacturers In this document the MHRA underlines the responsibilty of final dosage form manufacturers to assure that all APIs used for the manufacture of the medicinal products are manufactured according to GMP as defined in Part 2 of the EC GMP Guide (ICH Q7).
MHRA- UK Medicines and Healthcare products Regulatory Agency API Focused MHRA Inspections at Dosage Form Manufacturers The document the MHRA defines that Manufacturing Authorisation holders must have a supplier evaluation and approval programme covering APIs (this must be in place irrespective of whether a QP declaration has been required, i.e. it applies to all existing drug products as well as new applications). This program must accumulate a body of evidence which enables the GMP compliance status of each API supplier to be determined. The programme must also include periodic re-evaluation of each supplier s status.
Official Measures to Protect against Low- Quality APIs and Investigational Medicinal Products Co-ordinated throughout Europe Within the compilation of community procedures on inspections and exchange of information, on 9 July the EMEA published two documents describing measures for dealing with cases of serious GMP noncompliance or the suspension of a Certificate of Suitability (CEP) as well as the Europe-wide rapid alert system for these cases. The two documents bear the following titles: Procedure for dealing with serious GMP non-compliance or voiding/suspension of CEPs thus requiring co-ordinated administrative action Procedure for handling rapid alerts arising from quality defects.
Official Measures to Protect against Low- Quality APIs and Investigational Medicinal Products Co-ordinated throughout Europe Both documents are directed at the supervisory- and registration authorities of the EC member states and stipulate a harmonised procedure for the rapid exchange of information and immediate actions to protect the public health from potentially dangerous, i.e. low-quality, active pharmaceutical ingredients (APIs) and medicinal products. This standardised procedure also includes the registration authorities of the individual countries, the EDQM and the EMEA itself.
Procedure for dealing with serious GMP non-compliance or voiding/suspension of CEPs... If an inspector of a supervisory authority finds serious GMP deficiencies with potentially health-threatening consequences for the end user of pharmaceutical products when inspecting an API manufacturing site, in the report, he/she has to suggest measures as an appropriate reaction to the GMP deviations - if necessary also a rapid alert notification.
Procedure for dealing.. These suggestions must be approved by the authorities of all EC member states. Should the site of an API manufacturer be partially or wholly in a state that is unacceptable from a GMP viewpoint, the following measures can come into consideration: Withdrawal of the GMP certificate or issue of a GMP certificate with restricted scope Suspension of or refusal to grant a manufacturing authorisation Prohibition on supply Disciplinary measures against the Qualified Person Suspension of marketing authorisation Suspension of Certificate of Suitability (CEP)
Procedure for dealing.. These requirements can have highly unpleasant consequences for pharmaceutical manufacturers in Europe sourcing their APIs from third countries, like e.g. China. If e.g. a Chinese API manufacturer's CEP is voided for reasons of non-compliance, the marketing authorisation for the medicinal product is invalid on the condition that no other source has been indicated for the API. Validity is not restored until documents indicating a new API source are submitted within the framework of the variations procedure! In the past two months, a number of Chinese and Indian API manufacturers lost their CEPs. We reported about this in our News of 1 July.
Procedure for dealing.. The suspension/voiding of a CEP falls within the competence of the EDQM, which also conducts inspections of API manufacturers. Even if a CEP has been suspended for other than GMP reasons, the authorities of all EC member states have to be notified. Then it is up to them to decide whether the quality, safety and efficacy of the products that are already on the market is affected.
Procedure for handling rapid alerts... This standard operating procedure standardises the EU-wide rapid alert system and defines the following classification scheme for quality deficiencies: Class I: Potentially life-threatening or posing a serious risk to health. In any case, an EU-wide notification is required. Examples: Wrong product, label and contents are different; contamination with serious medical consequences; microbial contamination of parenterals or ophthalmics Class II: Illness or mistreatment are probable. If the product distribution is known, only the concerned authorities have to be notified. Examples: Missing or incorrect data on package leaflets; microbial contamination of non-parenteral sterile products; non-compliance with specifications
Procedure for handling rapid alerts... Class III: Low risk to health, consequences improbable. Depending on the assessment of the issuing authority, the rapid alert system may be used. Examples: wrong or missing batch number; faulty closure; contamination with particulate matter. These two standard operating procedures for the authorities of the EU member states aim to swiftly and efficiently co-ordinate effective measures against firms operating outside the binding GMP rules, to keep the European Market clear of APIs and investigational medicinal products of inferior quality and thus to reduce the risk to the end users' health. The two documents have not yet been adopted; however, it is of the utmost importance to be prepared for the forthcoming reinforced activities by supervisory authorities, EDQM and registration authorities.
GxP Inspections within the Centralised Procedure Majority of Inspections Sector operations are related to applications submitted to the EMEA (centralised procedures, pre&postauthorisation and referrals) EMEA co-ordinates Inspection activities within the agreed timetable, There are no inspectors at the EMEA, we use the expertise of the EU Member States
Co-ordination of Pre-authorisation: GMP Inspections in order to complete the assessment process. Legal basis: Article 8.2 (or 30.2 for vet medicinal products) Council Regulation 726/2004. Responsibility for carrying out inspections rests with the Supervisory Authority Supervisory Authority which is defined as the Competent Authority of the MS in which the product is either manufactured or imported within the EEA.
COUNCIL REGULATION 726/2004 (CAP/EMEA) ART 57...THE AGENCY SHALL UNDERTAKE THE FOLLOWING TASKS WITHIN ITS COMMITTEES: i) co-ordinating the verification of compliance with the principles of good manufacturing practice, good laboratory practice and good clinical practice and the verification of compliance with pharmacovigilance obligations
Co-ordination of GMP Inspections Type of inspections: GMP: - For sites located in third countries, where EU-GMP is unconfirmed (no satisfactory EU inspection in the last 2 years on same building, similar type of product and equipment. Product & Process: To assess Quality issues raised by Rapp/CoRapp during assessment of Part II of the application. Can apply to all sites wherever they are located (EEA/Third countries)
Timetable for Inspections
Shorter timetables Some procedures have shorter timetables; Generic Applications Applications granted accelerated assessment If inspection requested during the assessment then there will be a clock stop and secondary evaluation phase
Composition of Inspection Teams Inspection team: Leading inspector(s) Scientific experts appointed on the advice of the Rapporteur and or Co-Rapporteur. Number of inspectors: Normally two inspectors Higher numbers may be justified.
Fees Council Regulation 297/95 specifies fees payable for inspections Implementing rules for Council Regulation adopted by EMEA management Board set the level of the fees. Inspection fee per site inspected, and sub-divided between EMEA and inspectorates; For 3rd country inspections, travel expenses etc. are payable separately. DON T FORGET TO APPLY FOR YOUR FEE REDUCTION
GMP Inspections Information in the Dossier Part 1A Application Form Annexes manufacturing licences, GMP Certificates, QP Declaration. Module 3.
Common Dossier Validation Problems Manufacturing Authorisations Site not licensed Site has IMP Licence Licence does not include activities to be performed. Inconsistent manufacturing/testing site information throughout dossier QP Declarations QP cannot provide declaration. Declaration does not cover all drug substance manufacturing sites Declaration not signed by QP or by all QP s Testing upon importation
Post-Authorisation GMP Inspections Co-ordination of GMP inspections during post authorisation procedures Variations, Line extension Co-ordination of for cause inspections GMP Problems Quality Defects
Post-Authorisation GMP Inspections Co-ordination of routine GMP inspections The EMEA prepares a program of re-inspections in Third Countries (TC) for centralised products. Re-inspections are also adopted by the CxMP. MSs may provide feedback on the program (e.g. delegation, assistance from another MS, combination with national products). Inspections are carried out at least every 2-3 years, unless a more frequent basis is recommended by the inspectors.
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THANKS FOR YOUR ATTENTION Alessio Ferrari