E-drug: Registration Requirement for Combination Products (cont)
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Dear Dr K. Weerasuriya, Mr P. Graff and Dr A. Seita,
Thank you for bringing attention to the important issue of quality of Fixed
Dose Combination drugs (FDC). It is correct, as mentioned by Dr
Weerasuriya, that there are some worries concerning the bioavailability
individual drugs in FDCs, in particular of the rifampicin component in
the FDCs.
When producing anti-TB fixed dose combination tablets, there is a
considerable risk of not obtaining satisfactory bio-availability of various
drugs. Particularly the bioavailability of rifampicin is at risk when
presented in FDCs together with other drugs, as exemplified by the 3-drug
isoniazid/ rifampicin/ pyrazinamide combination. Even when the right amount
of rifampicin is present in the tablet, there can still be sub-optimal
bio-availability of rifampicin. Consequently, dissolution test are not able
to reveal with certainty whether or not a particular FDC will give a
satisfactory bio-availability of rifampicin.
The WHO (World Health Organization), IUATLD (International Union Against TB
and Lung Disease) and partners have been promoting FDCs for anti-TB
treatment for several years, with the rationale that FDCs of good quality
will simplify treatment and reduce the risk of mono-therapy, thereby also
reducing the risk of creating drug resistant TB. The recommendations from
WHO and IUATLD in regards to FDCs are:
"WHO and IUATLD recommend the use of only those combinations for which
human studies have demonstrated satisfactory bioavailability of rifampicin.
In purchasing drugs, countries should specify that clinically employed
preparations of fixed dose combinations must be periodically tested for
pharmacological evidence of adequate bioavailability by laboratories
independent of drug providers."
from "Treatment of tuberculosis, guidelines for national programmes", p.52,
WHO, Geneva, 1997, WHO/TB/97.220.
This means that bioavailability testing indeed is a necessary step in order
to assure that an FDC has adequate bioavailability of rifampicin. Further
complicating the matter is that if a company makes an FDC with good
bioavailability, even small changes in the manufacturing procedures may
result in loss of bioavailability, and therefore repeated bioavailability
testing may be necessary under certain circumstances. So far, there has not
been a strictly defined strategy for how to assure that FDCs are of good
quality. WHO, IUATLD (International Union Against TB and Lung Disease) and
partners are currently examining the issue of how to assure good quality of
FDC tablets.
To answer your question, it is agreed upon by international bodies
(WHO,IUATLD) that testing of bioavailability is necessary for registration
of FDC drugs. WHO and IUATLD are currently in the process of establishing
an international network of laboratories that will be qualified to
undertake bioavailability testing of FDCs. The International Journal of
Tuberculosis and Lung Disease, published by the IUATLD, will issue a
particular supplement on FDCs in the near future, featuring articles on the
recent
developments concerning bioavailability and quality of FDCs.
For further information on FDC tablets you may find the attached list of
publications to be of interest.
Best regards,
Dr Bjorn Blomberg
Medical Officer
Communicable Diseases Cluster
World health Organization
Geneva
Switzerland
[Dr Blomberg kindly provided references. They have been omitted here to
lessen the load on the email. If readers are interested to have them I
will supply them directly. BS co-moderator]
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