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«WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS: GUIDELINES ON REGISTRATION REQUIREMENTS TO ...»

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An API is considered highly soluble when the highest dose recommended by WHO (if the API appears on the WHO Model List of Essential Medicines) or highest dose strength available on the market as a oral solid dosage form (if the API does not appear on the WHO Model List of Essential Medicines) is soluble in 250 mL or less of aqueous media over the pH range of 1.2 to 6.8. The pH-solubility profile of the API should be determined at 37 ± 1°C in aqueous media. A minimum of three replicate determinations of solubility at each pH condition is recommended. Initial recommendations in the BCS Guidance (27) suggested that the solubility should be measured over a pH range of 1.2 to 7.5. But successive scientific discussions and publications suggest that a pH range of 1.2 to 6.8 is more appropriate (28).

9.1.1.2 High permeability

An API is considered highly permeable when the extent of absorption in humans is 85% or more based on a mass balance determination or in comparison to an intravenous comparator dose. Initial recommendation in the BCS Guidance (27) suggested an absorption value of 90% as a prerequisite for classification as highly permeable. However, successive scientific discussions and scientific publications suggested relaxing the criteria to 85% absorption for classifying a drug as highly permeable (28). Acceptable alternative test methods for permeability determination of the drug

substance include:

(i) in vivo intestinal perfusion in humans, or (ii) in vitro permeation using excised human or animal intestinal tissue.

When one of these two alternative methods is used for permeation studies, suitability of the methodology should be demonstrated, including determination of permeability relative to the permeability of a reference compound whose fraction dose absorbed has been documented to be at least 85%.

Supportive data can be provided by the following additional test methods:

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(iv) in vitro permeation across a monolayer of cultured epithelial cells (e.g. Caco-2) using a method validated using APIs with known permeabilities, although data from either of the two latter methods would not be considered acceptable on a standalone basis. In these experiments high permeability is assessed with respect to a high permeability of a series of reference compounds with documented permeabilities and fraction absorbed values, including some for which fraction dose absorbed is at least 85% (28).

9.1.2 Determination of dissolution characteristics of multisource products in consideration of a biowaiver based on the BCS For exemption from an in vivo pharmacokinetic bioequivalence study, an immediate release multisource product should exhibit very rapid or rapid in vitro dissolution characteristics (see below), depending on the BCS properties of the API. In vitro data should also demonstrate the similarity of dissolution profiles between the test and comparator products.

9.1.2.1 Very rapidly dissolving

A multisource product is considered to be very rapidly dissolving when no less than 85% (total dissolution) of the labelled amount of the drug substance dissolves in 15 minutes or less using a paddle apparatus at 75 rpm or a basket apparatus at 100 rpm in a volume of 900 ml or less in each of the following media: (i) pH 1.2 HCl solution; (ii) a pH 4.5 acetate buffer; and (iii) a pH 6.8 phosphate buffer.

9.1.2.2 Rapidly dissolving

A multisource product is considered to be rapidly dissolving when no less than 85% (total dissolution) of the labelled amount of the drug substance dissolves in 30 minutes using a paddle apparatus at 75 rpm or basket apparatus at 100 rpm in a volume of 900 ml or less in each of the following media: (i) pH 1.2 HCl solution; (ii) a pH 4.5 acetate buffer; and (iii) a pH 6.8 phosphate buffer.

9.2 Qualification for a biowaiver based on the BCS

A biowaiver based on the Biopharmaceutics Classification Scheme (BCS) considers:

a) the solubility and permeability of the active pharmaceutical ingredient (see section 9.1),

b) the dissolution profile similarity of the multisource and comparator products in pH 1.2,

4.5 and 6.8 media (see below),

c) the excipients used in the formulation (see below), and

d) the risks of an incorrect biowaiver decision in terms of the therapeutic index and indications for the active pharmaceutical ingredient (see section 5.1 for cases where an in vivo study would be required to demonstrate bioequivalence).

Only when there is an acceptable benefit/risk balance in terms of public health and risk to the individual patient should bioequivalence testing according to the guidelines given in this Section be permitted.

Working document QAS/04.093/Rev.4 page 32 Risk analysis The risk of reaching an inappropriate decision that the multisource product is equivalent to the comparator product can be reduced by correct classification of the API and by following the recommendations for dissolution testing and comparison of the dissolution profiles. In all cases it should be further demonstrated that the excipients included in the formulation of the multisource product are well established for products containing that API, and that the excipients used will not lead to differences between the comparator and multisource product with respect to processes affecting absorption (e.g. via effects on gastrointestinal motility or interactions with transport processes), or which might lead to interactions that alter the pharmacokinetics of the API. The underlying basic principle being that the products are consistently of the same quality, i.e. produced in accordance with good manufacturing practices (GMP).





Excipients Evidence, that each excipient present in the multisource product is well established and does not effect gastrointestinal motility or other process affecting absorption, can be documented using part of

the following informaton:

i) the excipient is present in the comparator product, or the excipient is present in a number of other products which contain the same API as the multisource drug product and which have marketing authorizations in countries participating in the International Committee on Harmonisation (ICH) or associated countries, and ii) the excipient is present in the multisource product in an amount similar to that in the comparator, or the excipient is present in the multisource drug product in an amount typically used for that type of dosage form.

Information with respect to composition of drug products with marketing authorization is available on several websites of some national drug regulatory authorities. Examples of excipients known to have caused bioinequivalence that would not have been predicted by dissolution testing include surfactants, mannitol and sorbitol.

As a general rule, the closer the composition of the multisource product to that of the comparator product with regard to excipients, the lower the risk of an inappropriate equivalence decision using a biowaiver based on the BCS.

Sub- and supra-bioavailable products A further consideration is the potential risk to public health and the individual patient, should an inappropriate decision with respect to bioequivalence be reached. Essentially there are two possible negative outcomes.

The first arises when the multisource product is sub-bioavailable. In this case substitution of the comparator with the multisource product could lead to reduced therapeutic efficacy. APIs which must reach a certain concentration to be effective (e.g. antibiotics) are most susceptible to problems with sub-bioavailability.

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supra-bioavailability. For these reasons, both the indication and therapeutic index are important considerations in determining whether the biowaiver based on BCS can be applied or not.

Dissolution Profile Comparison Approval of multisource formulations using comparative in vitro dissolution studies should be based on generation of comparative dissolution profiles rather than a single point dissolution test. When comparing the multisource and comparator products, dissolution profiles can be compared using a similarity factor (f2). This is a model independent mathematical approach for comparing the dissolution profiles of two products. The dissolution profile of the two products (multisource (test) and comparator (reference) or two strengths from a given manufacturer should be made under the same test conditions. The dissolution profile of the multisource and comparator products should be made under the same test conditions using an apparatus that conforms to the Ph. Int. specifications using either the paddle method at 75 rpm or the basket method at 100 rpm in pH 1.2, 4.5 and 6.8 buffers (Int.Ph. buffers are recommended; alternative compendial buffers with same pH and buffer capacity are also acceptable) at 37°C.

Samples should be collected at a sufficient number of intervals to characterize the dissolution profile of the drug product completely for example at 10, 15, 20, 30, 45 and 60 minutes. A minimum of 12 dosage units of each product (multisource and comparator) should be evaluated (29,30).

When comparing the multisource and comparator products, dissolution profiles can be compared using a similarity factor (f2). Data with less than 20% variance at the first timepoint and less than 10% variance at subsequent time-points can be used for the f2 calculation, noting that a maximum of one time point should be considered after 85% dissolution of the comparator product has been reached. An f2 value of 50 or greater (50-100) reflects sameness or equivalence of the two curves and thus equivalence of the in vitro performance of the two

products. The similarity factor f2 is to be computed using the equation:

f2 = 50 log {[1+(1/n) t=1n ( Rt - Tt )2 ]-0.5 100} where Rt and Tt are the cumulative percentage of the drug dissolved at each of the selected n time points of the comparator (reference) and multisource (test) product respectively (4, 5).

If the comparator and multisource products are very rapidly dissolving, i.e. more than 85% dissolution in 15 minutes or less in all three media using the recommended test method, a profile comparison is not necessary.

Other appropriate statistical methods can also be used for dissolution profile comparison, provided that the same criterion is used for acceptance (maximum 10% difference between the profiles).

9.2.1 Dissolution criteria for biowaivers based on the BCS according to API properties The major application of BCS is to provide criteria for biowaiver of multisource products. Kasim et al. (31), Lindenberg et al. (32) have partially classified the drugs listed under WHO Model List of Essential Medicines according to available literature data for solubility and permeability and a series of individual biowaiver monographs has been initiated in J. Pharm Sci. (33). To date the BCS Guidance of the HHS-FDA recommends the biowaiver only for drug products containing Class 1 Working document QAS/04.093/Rev.4 page 34 drugs (27). These biowaiver criteria have been described as very conservative. Discussions at scientific workshops after the guidance became available and in subsequent publications

recommended that biowaiver can, in principle, be extended to:

(i) BCS class 3 drug products, if the multisource and comparator product are very rapidly dissolving (85% or greater in 15 minutes or less at pH 1.2, 4.5 and 6.8), and (ii) BCS class 2 weak acids if the multisource product is rapidly dissolving (85% or greater in pH 6.8 in 30 minutes or less) and its dissolution profile is similar to that of the comparator product at pH 1.2, 4.5 and 6.8 under the dissolution test conditions described in section 9.2.

On the basis of the above concept WHO has collated a draft proposal to waive in vivo bioequivalence requirements for the WHO Model List of Essential Medicines immediate release, solid oral dosage forms (34).

In summary, biowaivers for solid oral dosage forms based on BCS can be considered under following

conditions:

1. Dosage forms of APIs which are highly soluble, highly permeable (BCS Class 1), and

are rapidly dissolving are eligible for a biowaiver based on the BCS provided:

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