«WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS: GUIDELINES ON REGISTRATION REQUIREMENTS TO ...»
2. Dosage forms of APIs which are highly soluble and have low permeability (BCS Class 3) are eligible for biowaivers provided all the criteria described in section 9.2.
are met and the risk/benefit is additionally addressed in terms of extent, site and mechanism of absorption.
In general, the risks of reaching an inappropriate biowaiver decision need to be more critically evaluated when the extent of absorption is lower (especially if fabs 50%), if the sites of absorption are restricted to the proximal regions in the gastrointestinal tract and if the mechanism of absorption is subject to induction/competition. If any of these cases apply, the excipients used will also need to be scrutinized carefully in terms of both qualitative and quantitative composition – the greater the deviation from the comparator composition, the greater the risk of an inappropriate biowaiver decision.
For multisource products containing Class 2 APIs with dose:solubility ratios of 250 ml or less at pH 6.8, the excipients should additionally be critically evaluated in terms of type and amounts of surfactants in the formulation.
9.3 Biowaivers based on dose-proportionality of formulations Under certain conditions, approval of different strengths of a multisource product can be considered on the basis of dissolution profiles if the formulations have proportionally similar compositions.
9.3.1 Proportionally similar formulations For the purpose of this guidance proportionally similar formulations can be defined in two ways, based on the strength of dosage forms.
(i) All active and inactive ingredients are exactly in the same proportion between different strengths (e.g. tablet of 50 mg strength has all the inactive ingredients exactly half that of a tablet of 100 mg strength, and twice that of a tablet of 25 mg strength).
(ii) For a high potency API (up to 10 mg per dosage unit), where the amount of the API in the dosage form is relatively low, the total weight of the dosage form remains nearly the same for all strengths (within ± 10% of the total weight), the same inactive ingredients are used for all strengths, and the change in strength is obtained by altering essentially only the amount of the API(s).
9.3.2 Qualification for biowaiver based on dose-proportionality of formulations
A prerequisite for qualification for a biowaiver based on dose-proportionality of formulations is that the multisource product at one strength has been shown to be bioequivalent to the corresponding strength of the comparator product. The second requirement is that the further strengths of the multisource product are proportionally similar in formulation to that of the studied strength. When both of these criteria are met and the dissolution profiles of the further dosage strengths are shown to be similar to the one of the studied strength on a percentage released vs. time basis, the biowaiver procedure can be considered for the further strengths.
Working document QAS/04.093/Rev.4 page 36 As in the case of biowaivers based on BCS, a biowaiver based on dose-proportionality of formulations should only be considered when there is an acceptable benefit/risk balance in terms of public health and risk to the individual patient, as discussed in section 9.2.
9.3.3 Dissolution profile comparison for biowaivers based on dose-proportionality of formulations As for the biowaiver based on BCS, a model independent mathematical approach (e.g. f2 test) can be used for comparing the dissolution profiles of two products. The dissolution profile of the two products (multisource (test) and comparator (reference)) should be made under the same test conditions.
The dissolution sampling times for both multisource and comparator product profiles should
be the same:
for example for immediate release products 10, 15, 20, 30, 45, 60 minutes for example for 12 hour extended release products 1, 2, 4, 6 and 8 hours and for example for 24 hour extended release products 1, 2, 4, 6, 8 and 16 hours.
Only one time point should be considered after 85% dissolution from the comparator product. An f2 value of 50 or greater (50-100) reflects equivalence (less than 10% difference) of the two curves, and thus equivalence of in vitro performance of the two products. To allow the use of the mean data, the coefficient of variation should not be more than 20% at the earliest time point (e.g. 10 minutes in the case of the example given for immediate release products), and should not be more than 10% at other time points.
18.104.22.168 Immediate release tablets Different strengths of a multisource formulation, when the pharmaceutical products are
manufactured by the same manufacturer at the same manufacturing site, where:
(i) all strengths are proportionally similar in formulation (see definition above);
(ii) an appropriate equivalence study has been performed on at least one of the strengths of the formulation (usually the highest strength unless a lower strength is chosen for reasons of safety); and (iii) the dissolution profiles between the strengths are similar, f2 50.
As for the biowaiver based on BCS, if both the multisource and comparator product release 85% or more of the label amount of the API in 15 minutes using all three dissolution media as recommended in 9.2., the profile comparison with an f2 test is unnecessary.
22.214.171.124 Extended release tablets For extended release tablets, when the multisource product is in the same dosage form but in a different strength, and is proportionally similar in its active and inactive ingredients and has the same drug release mechanism, a lower strength can be granted a biowaiver if it exhibits similar dissolution profiles, f2 50, in three diverse pH buffers (between pH 1.2 and 7.5) by the recommended test method.
9.4 Biowaivers for scale-up and post-approval changes
Although this guideline comments primarily on registration requirements for multisource pharmaceutical products, it is to be noted that under certain conditions in vitro dissolution testing may also be suitable to confirm similarity of product quality and performance characteristics with minor formulation or manufacturing changes after drug approval.
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