*M.Pharmaceutics (3rd Semester), Anand Pharmacy College, Anand. Review Biowaiver status on World Health Organization Model list of Essential Medicines –Biopharmaceutical classification system. By: *Ms.Sonali Dalwadi, Mrs. Vaishali Thakkar, Mrs. Tejal Soni, Dr. Tejal Gandhi *M.Pharmaceutics (3rd Semester), Anand Pharmacy College, Anand.

Biopharmaceutical Classification System II III IV Solubility High Low Permeability Absorption number Dissolution number Rate limiting step Dissolution or gastric empty rate Invivo Dissolution (Exception : High Dose number) Permeability so High bioavailability variation Lot of problems Challenges in drug development Target release Micronization, lyophilization, surfactant, complexing Technology address limitation of permeability Route of administration with use of solubility enhancer Examples Metoprolol, Diltiazem, Verapamil, Propranolol Phenytoin, Danazol, Ketoconazol, Mefanamic acid Cimetidine, Acyclovir, Neomycin B, Captopril Taxol Chlorthalidone Chlorothiazide Colistin

According to WHO Qualification for Biowaiver Based on BCS Solubility and Permeability of API WHO high solubility – D:S ≤ 250ml WHO high permeability – rate and extent of absorption ≥ 85% If very rapidly dissolving - 85% in 15 minutes in in pH 1.2, 4.5 and 6.8 media can be waive. Excipients will have no unexpected consequences for bioavailabillity of product. Therapeutic index, therapeutic indication, and risk assessment

Biowaiver based on dose – proportionality of formulation Multisource product at one strength shown in invivo studies to be bioequivalent to corresponding strength comparator product. Dissolution profiles are shown to be similar to corresponding strength comparator product. When both criteria are met, biowaiver can be considered for further strengths with acceptable benefit-risk balance.

Orally Administered Drugs Classification of WHO-Essential Medicine List as per BCS. According to Dressman et al, drugs EML is divided into 3 parts for better comprehension. Table 1: Drugs with sufficient data for both solubility and permeability. 61 of 130 drugs of EML assigned to BCS with certainty. Table2: Drugs for which complete solubility and / or permeability data are lacking. 28 of drugs be provisionally assigned to one of BCS classes. Table3: Drugs with inconclusive data. Assignment to specific BCS not possible but decision could be narrowed to one of two classes. 41 drugs of WHO-EML.

Table 1:. First pass effect; Table 1:* First pass effect; ** Degradation in the GI-Tract; # active transport.

Table2:

Table3:

Form Table 1 and 2 : Total 89 drugs classified as per BCS: Class I Class II Class III Class IV 32 (Highlighted in Italics) 15 34 8 Potential candidates of biowaiver for orally administered dosage forms Based on pH 7.4 solubility data alone can be classified as class I 13 ( Highlighted in bold) out of 34 with permeability consistent > 80% absorption considered as potential candidates for biowaiver -

Now, Class III copmound are eligible biowaiver if they dissolve within 15 minutes in buffer media pH 1.2 –6.8 (75 rpm) with permeability data having greater than 80% absorption. Example:Ethambutol HCl, Chloramphenicol Class II acids are eligible for biowaiver with D:S ratio < 250 ml in at pH 6.8 and > 85 % dissolved within 30 minutes at pH 6.8. Example: Ibuprofen - pH 1.2: 0.04 mg/ml, pH 5.5: 0.09 mg/ml, pH 6.8: 2.47 mg/ml, D/SpH 6.8: 162 ml

For all such drug product - approval is done based on dissolution tests rather than bioequivalence studies in humans so avoiding unnecessary human experiments. Help manufacturer of generic drug products to lower cost bringing product into market

References Jennifer B. Dressman, European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) 265–278 Annex 7 World Health Organization, WHO Technical Report Series, No. 937, 2006 Annex 8 World Health Organization, WHO Technical Report Series, No. 937, 2006. http://www.who.int/medicines/publications/EML15.pdf http://www.pharmainfo.net K. Briggs, Pharmaceutical Reaserch, Vol.21, No.2, February 2004, pg 293 – 299.

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