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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. 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.

–  –  – 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.


1. Annex 1 C, Article 39. In: Marrakesh Agreement Establishing the World Trade Organization.

Marrakesh, GATT, 1994.

2. Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products. Thirty-sixth Report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. WHO Technical Report Series, No. 902, 2002: 161-180. (update in process)

3. HHS/FDA Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations, March 2003.


4. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. In: The use of essential drugs. Sixth report of the WHO Expert Committee. WHO Technical Report Series, No.

850, 1995:97-137.

5. Midha KK, Rawson MJ, Hubbard JW. Commentary: The Role of Metabolites in Bioequivalence. Pharmaceutical Research, 2004, 21:1331-1344.

6. OECD Series on Principles of Good Laboratory Practice and compliance Monitoring, Number 1: OECD Principles on Good Laboratory Practice (as revised in 1997). Organization for Economic Co-operation and Development. ENV/MC/CHEM (98)17.26.Jan, 1998.

7. Shah VP, Midha KK, Findlay JWA, et al. Bioanalytical Method Validation – A revisit with a decade of progress. Pharmaceutical Research: 2000, 17: 1551 – 1557.

8. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. Journal of pharmacokinetics and biopharmaceutics, 1987,15:657-680.

Working document QAS/04.093/Rev.4 page 38

9. Westlake WJ. Bioavailability and Bioequivalence of Pharmaceutical Formulations, in Biopharmaceutical Statistics for Drug Development (Peace KE, ed.), Marcel Dekker, Inc., 1988, 329Hauschke D, Steinijans VW, Diletti E. A distribution-free procedure for the statistical analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol, 1990, 28:72-78.

11. ICH E3, Structure and Content of Clinical Study Reports.

12. Guidelines for Registration of fixed dose combination medicinal products. In: WHO Expert Committee on Specifications for Pharmaceutical prepatoins. Thirty-nonth report of the WHO Expert Committee. WHO Technical Report Series, No. 929, 2005, Annex 5: 94-142.

13. Blume HH, Midha KK. Bio-International 92, Conference on bioavailability, bioequivalence and pharmacokinetic studies. Journal of Pharmaceutical Sciences, 1993, 82:1186-1189.

14. Note for Guidance on the investigation of bioavailability and bioequivalence, London, July 2001. Committee for Proprietary Medicinal Products (CPMP). The European Agency for the Evaluation of Medicinal Products - Evaluation of Medicines in Human Use.


15. Tothfalusi L, Endrenyi L, Midha KK, Rawson MJ, Hubbard JW. Evaluation of bioequivalence of highly variable drugs. Pharmaceutical Research, 2001, 18:728-733.

16. Tothfalusi L, Endrenyi L, Midha KK. Scaling of wider bioequivalence limits for highly variable drugs and for the special case of Cmax. International Journal of Clinical Pharmacology and Therapeutics, 2003, 41:217-225.

17. Tothfalusi L, Endrenyi L,. Limits for scaled average bioequivalence of highly variable drugs and drug products. Pharmaceutical Research, 2003, 20:382-389.);

18. Guideline for bioequivalence studies of generic products (Japan).


19. Expert Advisory Committee on Bioavailability and Bioequivalence, Record of Proceedings (June 26 and 27, 2003) Health Canada

20. Midha KK, Hubbard JW, Rawson MJ, Gavalas, L., The application of partial areas in the assessment of rate and extent of absorption in bioequivalence studies of conventional release products: experimental evidence. European Journal of Pharmaceutical Sciences, 1994, 2:351-363;

21. Midha KK, Hubbard JW, Rawson MJ. Retrospective evaluation of relative extent of absorption by the use of partial areas under the plasma concentration versus time curves in bioequivalence studies of conventional release products. European Journal of Pharmaceutical Sciences, 1996, 4:381-384.

–  –  –

23. Yusif et al., Journal of the American Medical Association. 1988, 260: 2259-22263.

24. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators, New England Journal of Medicine, 1991: 325.


25. The International Pharmacopoeia, WHO, Geneva

26. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability.

Pharm. Res., 1995, 12: 413-420.

27. HHS/FDA Guidance for Industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system, August 2000. http://www.fda.gov/cder/guidance/index.htm

28. Yu LX, Amidon GL, Polli JE, et al. Biopharmaceutics Classification System: The scientific basis for biowaiver extensions. Pharm. Res. 2002, 19: 921-925.

29. Moore JW, Flanner HH. Mathematical comparison of curves with an emphasis on in vitro dissolution profiles. Pharm. Tech., 1996, 20(6): 64-74.

30. Shah VP, Tsong Y, Sathe P, Liu JP. In vitro dissolution profile comparison-Statistics and Analysis of the Similarity factor, f2. Pharm. Res. 1998, 15: 889-896.

31. Kasim NA, Whitehouse M, Ramachandran C et al. Molecular Properties of WHO Essential Drugs and Provisional Biopharmaceutical Classification. Molecular Pharmaceutics, 2004, 1: 85- 96.

32. Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health Organization model list of essential medicines according to the biopharmaceutics classification system. Eur J. Pharmaceutics and Biopharm. 2004, 58: 265-278.

33. Biowaiver monographs references: examples : J.Pharm.Sci 2004: 93(8): 1945-1956, J.Pharm.Sci 2005: 94(7): 1389-1395, J.Pharm.Sci 2005: 94(8): 16171-1617

34. Proposal to waive in vivo bioequivalence requirements for the WHO Model List of Essential Medicines immediate release, solid oral dosage forms, Working document QAS/04.109/Rev.1 ***

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