Talk:biowaiver

The World_Health_Organization (WHO) defines biowaivers the regulatory pharmaceutical procedures in which exemption from in vivo bioavailability studies to demonstrate bioequivalence between a multisource (generic) medicinal products and its comparator is granted. The scope is to predict in vivo performance of multisource medicinal products using in vitro dissolution studies and relying on the knowledge of the product physical and biopharmaceutical characteristics.

The WHO foresees the exemption from in vivo [[1]] studies for multisource (generic) products formulated as immediate released solid oral pharmaceutical form containing active pharmaceutical ingredients (API) Class 1 and Class 3 according to the Biopharmaceutical Classification System (BCS) framework. According to the WHO guidelines on Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 1003, 2017, Annex 6),"a BCS-based biowaiver approach considers the following aspects:

1. the solubility and intestinal permeability of the API;
2. the similarity of the dissolution profiles of the multisource and comparator products in pH 1.2, 4.5 and 6.8 media;
3. the excipients used in the formulation;
4. the risks of an incorrect biowaiver decision in terms of the therapeutic index of and clinical indications for the API".

The WHO defines API as "highly soluble when the highest single therapeutic dose reccomended by the labelling of the comparator product, is soluble in 250 mL or less of aqueous media over the pH range of 1.2–6.8. The WHO considers API highly permeable when the extent of absorption in humans is 85% or more based on a mass balance study or in comparison with an i.v. dose of the comparator product".

Only API belonging to Class 1 and Class 3 are eligible for biowaiver, therefore, a correct BCS-based classification is deemed crucial when considering such regulatory pathway. On the basis of their dissolution properties, finished pharmaceutic products (FPP) can be categorized as having “very rapid”, “rapid”, or “not rapid” dissolution characteristics. According to the WHO guidances,"dosage forms of APIs that are highly soluble, highly permeable (BCS Class 1) with acceptable excipient content and favorable benefit-risk analysis and which are rapidly dissolving, are eligible for a BCS-based biowaiver provided:

i. the dosage form is rapidly dissolving and the dissolution profile of the multisource product is similar to that of the comparator product in aqueous buffers at pH 1.2, pH 4.5 and pH 6.8 using the paddle method at 75 rpm or the basket method at 100 rpm and meets the criteria of dissolution profile similarity, f₂ ≥ 50 (or equivalent statistical criterion);
ii. if both the comparator and the multisource dosage forms are very rapidly dissolving the two products are deemed equivalent and a profile comparison is not necessary.

Dosage forms of APIs that are highly soluble and have low permeability (BCS Class 3) are eligible for biowaivers provided all the criteria listed above (1-4) are met and the benefit—risk is additionally addressed in terms of extent, site and mechanism of absorption. Only when there is an acceptable benefit- risk balance in terms of public health and risk to the individual patient should bioequivalence testing be waived and the in vitro methods applied as a test of product equivalence".

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