Proposed minimum registration requirements for fixed-dose combination anti-tuberculosis drugs

Registration requirements for combined pharmaceutical preparations have been published before, but not specifically for fixed-dose combination (FDC) anti-tuberculosis preparations. With tuberculosis being a high priority disease world-wide and concerns being raised over substandard FDC anti-tuberculosis preparations being marketed on a wide scale, specific guidelines for industry seem to be indicated. This is predominantly necessitated by the fact that rifampicin bioavailability can be adversely affected when put in combination with isoniazid and pyrazinamide, and by the need for standardisation of the formulations to only a few essential combinations in order to better control quality. This paper proposes certain minimum requirements to be met when standardising dose in the combinations and when ensuring bioavailability of the preparations. Nine rifampicin-containing combinations are listed as essential. Furthermore, bioavailability testing of the rifampicin component only by a restricted assay protocol of six sample times over 8 hours is advocated, whilst in vitro procedures for other actives in the combination would suffice for registration purposes.