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 that
took place in Vienna, Austria, from 26 to 28 September 2001.
This fourth CEFIC/APIC conference was divided into a GMP part and
Regulatory 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 in
the 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- or
RA 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 day
were 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 the
following:
Stephen Fairchild, former head of the inspections sector at the EMEA
and former member of the ICH Q7a Expert working group, gave an overview of
the 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 the
EU 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 for
implementation over the next 2 to 3 years, in the meantime the member
states will start to use Q7a on a national or voluntary basis, e.g. where
it 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 only
few authorities have significant overseas programs. One further problem is
that the regulatory control is limited in (developing) countries that are
major API producers, therefore control of API manufacture is supported by
WHO.
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 an
overview 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 on
the 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 of
the 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 the
amount of CMC information needed to be filed in an original ANDA.
Despite (or caused by) increasing regulation for the manufacture of
APIs and an improved API quality on one hand, there are rising risks of
counterfeiting 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 CONCEPT
HEIDELBERG.
Writer:
Dr Barbara Jentges,
CONCEPT HEIDELBERG
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