Whilst, in most jurisdictions, manufacturers are not obliged to use the test methodology of the locally applicable pharmacopoeia, they do have to ensure that their products will meet that standard. Consequently when a pharmacopoeial monograph already exists for an FDC and its APIs, the task of the regulator in assessing a dossier and testing samples is simplified. The absence of monographs on a number of FDCs therefore means that regulatory agencies must commit more resources to assessment and testing, including often scarce technical skills.

Complexity of analyses increases with the number of active ingredients. However today s analytical procedures can cope provided they have been suitably validated. High pressure liquid chromatography (HPLC) is commonly the method of choice today, being relatively inexpensive and usually not complex. Suitable equipment and columns are now widely available, although this may be less true in developing countries. In relation to the International Pharmacopoeia, the Essential Drugs and Medicines Policy team at WHO has stated:

Whenever possible, classical procedures are used in the analytical methods so that the pharmacopoeia can be applied without the need for expensive equipment. In addition, alternative methods have been introduced for use whenever a more complex method is suggested. ³⁸

Validation of HPLC methods is called system suitability testing. Contrary to popular opinion, an HPLC method is not always specific for the target analyte. Methods should be tested in the presence of known and likely contaminants, and refined as necessary. Note also that a long retention time does not in itself guarantee that an assay will separate the target analyte from related substances.

In an unpublished and confidential report to WHO, Wieniawski has reviewed analytical specifications for the antiretroviral and antimalarial combination products that were assessed during the WHO pilot project on drug procurement and sourcing³⁹. Some of the following comments address issued raised in that report.

Availability of reference standards for quality control

To allow for variation in the conditions under which an analysis is conducted, assay of a test sample is always conducted in parallel with an identical assay of a standard reference substance that has a nominal 100% response. This is true for assays of the active and of impurities in APIs and finished products, and during dissolution studies. Assays of unknown impurities, or of impurities present in very small proportions, are sometimes conducted without a reference standard and these are termed semiquantitative assays.

Availability of reference standards is then an important factor in conducting meaningful quality control. Reference standards are not available for all of the actives under consideration at this meeting. Even when they are available, there is often a substantial cost. For example, reference standards provided by the United States Pharmacopeia can be at a significant cost because companies based in the USA can afford those prices.

Specifications at batch release and throughout the shelf life (expiry limits)

Although many companies resist, DRAs should seek tighter limits at release than at expiry, especially for drugs that show chemical or physicochemical instability. This provides a margin of patient safety in the event of instability and interlaboratory variation.

Monographs on individual APIs

It is preferable, but not an absolute requirement, that monographs on individual APIs be available before a monograph is published on an FDC containing those APIs. I do not believe that monographs on single component dosage forms need be available prior to monographs on FDCs.

Impurities

A degree of contamination with impurities is an inevitable result of chemical synthesis and, in some cases, instability of the active ingredient or interaction with excipients. The responsibility of the regulator is to ensure that active ingredients are as pure as is consistent with patient safety and the economic viability of the product.

Wieniawski suggests³⁹ that separate tests for impurities are not necessary because limits can be incorporated into an HPLC assay procedure for the active. This may often be true but only if the assay procedure has been validated for the impurities in question. HPLC assays are often conducted with short retention times to allow fast laboratory throughput and may not be capable in that form of separating and quantifying (or semiquantifying) impurities.

It is not necessary to identify impurities or degradation products in active ingredients and finished products if they are present below threshold concentrations that depend on the daily dose of the active^40,41.

Registration packages

Networks exist internationally amongst generic manufacturers for the sale of complete registration packages. These comprise a complete registration dossier including formulation, method of manufacture (with in-process controls and limits), quality control methodology and specifications, and the results of stability and bioavailability studies. Whilst some adaptation may be necessary for certain jurisdictions, the package is often acceptable to even relatively advanced regulatory authorities.

WHO may wish to consider purchasing, or even commissioning, regulatory packages for FDCs that could be made available free of charge in less well-resourced nations. The economics of such a strategy would have to be carefully considered.