28/29 March 2023
This year, APIC (Active Pharmaceutical Ingredients Committee), a sector group of CEFIC (European Chemical Industry Council) had launched the 4th CEFIC/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 manufacturers all over Europe had joined the conference, where high-level representatives 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 had the opportunity to choose one out of 6 parallel working group with GMP- orRA topics and to visit the Table Top Exhibition, where computer software suppliers for electronic document management systems and contract manufacturers presented their products and services.
The main emphasis of the GMP part of the conference was put on the interpretation of ICH Q7a on one hand and on the problems regarding costs and compliance on the other hand. Hot topics of the Regulatory Affairs daywere the new variation regulation, updates of post-approval changes in the USA 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 EMEA and former member of the ICH Q7a Expert working group, gave an overview ofthe regulatory implementation of the ICH Q7a guideline, in particular 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 API manufacturers to follow GMP nor is it a legal basis for inspections. The legal 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, the regulatory 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 are major API producers, therefore control of API manufacture is supported byWHO.
With ICH Q7a released and implementation beginning, what is the situation with the Mutual Recognition Agreement (MRAs) about with regard to the internationally harmonized GMP Guidelines for APIs and the mutual recognition of inspections of API manufacturer? Stephen Fairchild gave anoverview of the MRAs between Europe, Canada and USA and the current implementation status of the MRA.
To sum up, there has been made significant progress with the process of implementation of the EC-Canada MRA what provides a model and the preparation 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 greatest impact and the greatest potential benefit. However, there is a significant lack of progress over the 3-year transitional period. Reasons for this are unresolved, serious 'sticking points' that may lead to a redefinition ofthe scope and the operation. The implementation seems likely to be delayed for a minimum of two years.
Highlights of the Regulatory Affairs part of the conference were the presentations from Arielle North, European Commission, Enterprise DG, Belgium, about the new variation regulation and the presentations of two FDA speakers, Dr. Yuan-yuan Chiu, Director of the Center for Drug Evaluation and Research, and Benjamin England, Regulatory Counsel to the Associate Commissioner for Regulatory Affairs, Office of Regulatory Affairs.
Dr. Yuan-yuan Chiu presented new developments of post-approval changes with the focus on a new FDA initiative, a risk based CMC-review, the Quality Risk Assessment of Approved Drugs. The aim is to reduce regulatory oversight (the CMC filing requirements) for low risk drugs, in detail to minimize the types of post approval CMC changes requiring a submission of prior approval supplement of changes-being effected supplement, to reduce the amount of CMC information needed to be reported 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 costs and the pressure to reduce prices.
Professor Schnädelbach, BfArM Germany, discussed the impact of globalisation and counterfeiting on Pharmacopoeias. In the last years,different cases of fraud related to minor product quality or fraudulent mislabelling of APIs or excipients caused the dead of many people. For instance, last year in the USA 17 people died due to Gentamicin of insufficient purity. This case demonstrates that the purity of an API still may be a matter of concern and that pharmacopoeias should provide suitable monographs and support the establishment of the suitability of monographs. Insufficient quality is a risk to public health.
Benjamin England, FDA, presented the new FDA initiative to combat counterfeiting. At October 2, 2000, FDA issued guidance in Import Alert 66-66 addressing APIs that are of the type that require a new drug application for manufacture of a finished product, but for which either the end user has not filed an application identifying the foreign supplier of the API as a source, or the foreign supplier has not been inspected by FDA. Meanwhile Revisions to Import Alert 66-66 includes compounding pharmacy, over-the-counter products, research, pre-launch batches, and clinical IND applications. The office of Regulatory Affairs (ORA) is anticipating using the revisions to return to an audit stance for imported APIs.
ORA and CDER have committed resources for Fiscal Year 2002 (beginning October 1) to perform a joint survey of imported APIs. The aim is to evaluate quality and authenticity. Finally, Benjamin England stated that'(…) any result that encourages a counterfeiter to counterfeit someone else's product is a measurement of success (…)'.
To sum up, the 4th CEFIC/APIC Conference on APIs gave an interesting insight into hot topics of questions arising with the implementation of GMP for APIs. The complete conference documentation of the 4th CEFIC/APIC Conference on APIs can be bought at CONCEPTHEIDELBERG.
Dr Barbara Jentges,