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GMP News No. 143
9 November 2001
Essentials of the 4thCEFIC/APIC European Conference on
This year, APIC (Active Pharmaceutical Ingredients Committee), a sectorgroup of CEFIC (European Chemical Industry Council) had launched the 4thCEFIC/APIC European Conference on Active Pharmaceutical Ingredients thattook place in Vienna, Austria, from 26 to 28 September 2001.
This fourth CEFIC/APIC conference was divided into a GMP part andRegulatory Affairs Part. More than 120 participants from API manufacturersall over Europe had joined the conference, where high-levelrepresentatives from the EU Commission, the Food and Drug Administration,inspectorates and industry came together to discuss current hot topics inthe field of Good Manufacturing Practices (GMP) and Regulatory Affairs(RA) for Active Pharmaceutical Ingredients. Furthermore participants hadthe opportunity to choose one out of 6 parallel working group with GMP- orRA topics and to visit the Table Top Exhibition, where computer softwaresuppliers for electronic document management systems and contractmanufacturers presented their products and services.
The main emphasis of the GMP part of the conference was put on theinterpretation of ICH Q7a on one hand and on the problems regarding costsand compliance on the other hand. Hot topics of the Regulatory Affairs daywere the new variation regulation, updates of post-approval changes in theUSA and initiatives of the EU and the USA to combat counterfeiting.
Please find a summary of some hot topics of the API conference in thefollowing:
Stephen Fairchild, former head of the inspections sector at the EMEAand former member of the ICH Q7a Expert working group, gave an overview ofthe regulatory implementation of the ICH Q7a guideline, inparticular about the current basis for the inspection of APIs in the EU,proposals for the inspection of APIs in the inspection of APIs in the'2001 review' and about the implementation of Q7a in the US and Japan.
In Europe, ICH Q7a was adopted and published as Annex 18 of theEU GMP Guidelines. This has no 'community' legal requirement for APImanufacturers to follow GMP nor is it a legal basis for inspections. Thelegal basis for the inspection of API manufacturers is being developed forimplementation over the next 2 to 3 years, in the meantime the memberstates will start to use Q7a on a national or voluntary basis, e.g. whereit considers that there is non-compliance with GMP.
To sum up, the situation of the implementation of Q7a worldwide, theregulatory control of APIs varies between countries and regions, and onlyfew authorities have significant overseas programs. One further problem isthat the regulatory control is limited in (developing) countries that aremajor API producers, therefore control of API manufacture is supported byWHO.
With ICH Q7a released and implementation beginning, what is the situationwith the Mutual Recognition Agreement (MRAs) about with regard to theinternationally harmonized GMP Guidelines for APIs and the mutualrecognition of inspections of API manufacturer? Stephen Fairchild gave anoverview of the MRAs between Europe, Canada and USA and the currentimplementation status of the MRA.
To sum up, there has been made significant progress with the process ofimplementation of the EC-Canada MRA what provides a model and thepreparation for other MRAs. The start of the operational phase depends onthe success of measures being taken by Italy.
The MRA between EC-USA on the other hand is the MRA with the greatestimpact and the greatest potential benefit. However, there is a significantlack of progress over the 3 year transitional period. Reasons for this areunresolved, serious 'sticking points' that may lead to a redefinition ofthe scope and the operation. The implementation seems likely to be delayedfor a minimum of two years.
Highlights of the Regulatory Affairs part of the conference were thepresentations from Arielle North, European Commission, Enterprise DG,Belgium, about the new variation regulation and the presentations of twoFDA speakers, Dr. Yuan-yuan Chiu, Director of the Center for DrugEvaluation and Research, and Benjamin England, Regulatory Counsel to theAssociate Commissioner for Regulatory Affairs, Office of RegulatoryAffairs.
Dr. Yuan-yuan Chiu presented new developments of post-approvalchanges with the focus on a new FDA initiative, a risk basedCMC-review, the Quality Risk Assessment of Approved Drugs. The aimis to reduce regulatory oversight (the CMC filing requirements) for lowrisk drugs, in detail to minimize the types of post approval CMC changesrequiring a submission of prior approval supplement of changes-beingeffected supplement, to reduce the amount of CMC information needed to bereported in annual reports to an approved application and to reduce theamount of CMC information needed to be filed in an original ANDA.
Despite (or caused by) increasing regulation for the manufacture ofAPIs and an improved API quality on one hand, there are rising risks ofcounterfeiting on the other hand as a result of the higher quality costsand the pressure to reduce prices.
Professor Schnädelbach, BfArM Germany, discussed the impact ofglobalisation and counterfeiting on Pharmacopoeias. In the last years,different cases of fraud related to minor product quality or fraudulentmislabelling of APIs or excipients caused the dead of many people. Forinstance, last year in the USA 17 people died due to Gentamicin ofinsufficient purity. This case demonstrates that the purity of an APIstill may be a matter of concern and that pharmacopoeias should providesuitable monographs and support the establishment of the suitability ofmonographs. Insufficient quality is a risk to public health.
Benjamin England, FDA, presented the new FDA initiative to combatcounterfeiting. At October 2, 2000, FDA issued guidance in ImportAlert 66-66 addressing APIs that are of the type that require a new drugapplication for manufacture of a finished product, but for which eitherthe end user has not filed an application identifying the foreign supplierof the API as a source, or the foreign supplier has not been inspected byFDA. Meanwhile Revisions to Import Alert 66-66 includes compoundingpharmacy, over-the-counter products, research, pre-launch batches, andclinical IND applications. The office of Regulatory Affairs (ORA) isanticipating using the revisions to return to an audit stance for importedAPIs.
ORA and CDER have committed resources for Fiscal Year 2002 (beginningOctober 1) to perform a joint survey of imported APIs. The aim is toevaluate quality and authenticity. Finally, Benjamin England stated that'(…) any result that encourages a counterfeiter to counterfeit someoneelse's product is a measurement of success (…)'.
To sum up, the 4th CEFIC/APIC Conference on APIs gave aninteresting insight into hot topics of questions arising with theimplementation of GMP for APIs. The complete conference documentation ofthe 4th CEFIC/APIC Conference on APIs can be bought at CONCEPTHEIDELBERG.