Pharmaceutical Development - Predevelopment Activities

Pharmaceutical Development - Predevelopment Activities


2.1 Desk Research:

Desk Research includes all relevant documentation being collected and evaluated prior to initiation of any laboratory activities. This documentation may include information such as is found in:

WHO, European Medicines Agency (EMA) and United States Food and Drug Administration (US-FDA) web sites that contain regulatory information, for example, the qualitative composition, mode of administration and the primary packing materials of the innovator and multi source FPPs;

– Compendial monographs, scientific literature, patents, technical information typically found in the applicant’s (open) part of the API Master File (APIMF), technical information on excipients and
prior company knowledge.

2.1.1 Quality Risk Management:

An essential part of desk research entails the identification of possible risks prior to the development of a multi source product.

An important consideration when selecting the API manufacturer is the fact that the FPP manufacturer is responsible for the control of the API and as such must have a comprehensive understanding of the API. Analysis of the applicant’s part of the APIMF (or Drug Master File) is, therefore, important.

Poor solubility in aqueous medium is an important quality risk factor for APIs administered in the solid state as there is a high risk that inter-batch variability in physical properties may translate into significant differences in the in vivo performance.

It is recommended that polymorphism, pseudo-polymorphism and the implications of variability in particle size be routinely considered. Variability in any of these key physical properties is likely to be of particular significance for APIs that have low solubility according to the Biopharmaceutics Classification System (BCS). The requirement for routine control of polymorphic form and particle size should be considered in accordance with advice in Decision Trees 3 and 4 of ICH Q6A (2). When controls are necessary they should be established based on the results obtained for the API lot(s) used in the biostudies.

For example, The International Pharmacopoeia (Ph. Int.) (3) restricts the polymorphic form of mebendazole API to form C and furthermore states that the formulation, manufacturing process and product packaging of chewable mebendazole tablets are designed and controlled so as to minimize the conversion of the polymorphic form of mebendazole from C to A.

The initial risk assessment of potential CQAs and CPPs of a multi source product should be based on desk research and the applicant’s own experience with the manufacture of the dosage form.

Literature, preferably peer-reviewed, may contain risk information essential for predevelopment. For example, the presence of meso-ethambutol hydrochloride in commercial ethambutol hydrochloride API material has been demonstrated in the literature (4), although some pharmacopoeial monographs do not clearly reveal the presence of this impurity. Recently a specific test was included in the European Pharmacopoeia (Ph. Eur.) (5) for control of this impurity.

The least risky strategy for multi source product development is to use the same qualitative and, where possible, quantitative formula as that of the comparator FPP – so long as this does not lead to the possibility of patent infringement – in order to minimize the risks related to compatibility, stability and bioequivalence.

Accompanying reconstitution diluents should also be included in the development strategy where appropriate. This topic is discussed further in section 3.

Pharmaceutical Development of multi source (generic) Finished Pharmaceutical Products - points to consider,  (Annex 3, WHO Technical Report Series 970, 2012)

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