Biowaiver

A review on waiving in vivo bioequivalence tests or Biovaiwer, with a case review on the biowaiver monograph on Ibuprofen by H. POTTHAST, J.B. DRESSMAN, H.E. JUNGINGER, K.K. MIDHA, H. OESER, V.P. SHAH,
H. VOGELPOEL, D.M. BARENDS
in J Pharm Sci 94:2121–2131, 2005

Explaining different approaches to waive different BCS class medicines based on their solubility and permeability, as is described by FDA and WHO

1. Biowaiver Monograph for Ibuprofen Slide 1 of 31 May 2014 Tehran University of Medical Sciences School of Pharmacy

2. Purpose and Scope A monograph based on literature data is presented on ibuprofen concerning its properties related to the biopharmaceutics classification system (BCS) To evaluate data available from literature sources about ibuprofen To come to a conclusion whether or not to recommend a biowaiver for immediate release (IR) solid oral dosage forms containing ibuprofen, considering both the biopharmaceutical point of view and public health risks.

3. Biowaivers The term biowaiver is applied to a regulatory drug approval process when the dossier (application) is approved based on evidence of equivalence other than through in vivo equivalence testing . A biowaiver means that in vivo bioavailability and/or bioequivalence studies may be waived (i.e. not considered necessary for product approval). In 1995 the American Department of Health and Human Services, US Food and Drug Administration (HHS-FDA) instigated the Biopharmaceutics Classification System (BCS), with the aim of granting so-called biowaivers for SUPACs .

4. Biowaivers At that time the biowaiver was only considered for SUPAC to pharmaceutical products. More recently, the application of the biowaiver concept has been extended to approval of certain orally administered generic products Scope: Inside a product: Scale up processes Line extensions Variation after marketing authorisation between different products: Application of generics without clinical data

5. Biowaivers According to the HHS-FDA definitions, the four possible categories for an API according to the BCS are: BCS class I: “high” solubility – “high” permeability BCS class II: “low” solubility – “high” permeability BCS class III: “high” solubility – “low” permeability BCS class IV: “low” solubility – “low” permeability. In addition, IR solid oral dosage forms are categorized as having rapid or slow dissolution. low permeability high solubility low solubility HS/HP Class I HS/LP Class III LS/HP Class II LS/LP Class IV high permeability

6. Biowaivers BCS Class Boundaries: Objectives Solubility (Drug) High solubility- ensure that solubility is not likely to limit dissolution and, therefore, absorption Dissolution (Product) Very rapid/rapid dissolution - ensure that in vivo dissolution is not likely to be the “rate determining” step Permeability (Drug) High permeability - ensure that drug is completely absorbed during the limited transit time through the small intestine THIS SLIDE WAS TAKEN FROM: WHO Workshop on Prequalification of Medicines Programme , Abu Dhabi, 11-13 October, 2010 PRESENTED BY DR. JAN WELINK

7. Biowaivers High Solubility Definition: The highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 – 7.5 (37°C) 250 ml: derived from typical BE study protocols that prescribe the administration of a drug product to fasting human volunteers with a glass (approx. 250 ml) water High Permeability Definition: According to HHS-FDA, when 90 % or more of the orally administered dose is absorbed in the small intestine. Permeability can be assessed by pharmacokinetic studies (for example, mass balance studies), or intestinal permeability methods, e.g. intestinal perfusion in humans, animal models , Caco 2 cell lines or other suitable, validated cell lines.

8. Biowaivers Dissolution: In three different media: pH 1.2 HCl , pH 4.5 Acetate buffer and pH 6.8 Phosphate buffer, composition in a paddle (50 rpm) or basket (100 rpm) apparatus at 37 °C and a volume of 900 ml Very Rapid Dissolution: An IR drug product is considered VERY RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 15 minutes Rapid Dissolution An IR drug product is considered RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes

9. Biowaivers To be considered bioequivalent according to the HHS-FDA biowaiver procedure, a pharmaceutical product: Should contain a Class I API Should be rapidly dissolving , in three different media First Option: Very rapidly dissolving and no further profile comparison Second Option: Rapidly dissolving and Proving similarity of dissolution profiles of T and R (e.g. using f2-test) Should not contain excipients which could influence the absorption of the API (affecting motility or permeability) Should not contain an API with a narrow therapeutic index Should not be designed to be absorbed from the oral cavity .

10. Biowaivers It is clear that the HHS-FDA requirements for the classification of APIs and eligibility criteria for the biowaiver are very strict . Several publications and continuing scientific discussions have suggested that the original HHS-FDA criteria for application of the biowaiver procedure could be relaxed without substantially increasing the risk to public health or to the individual patient. On the basis of these publications and dialogue, WHO has proposed revised BCS criteria and additional considerations for the eligibility of a pharmaceutical product for the biowaiver procedure

11. Biowaivers WHO revisions to the criteria for BCS classification WHO high-solubility definition : ( Dose:Solubility ) ratio of 250 ml or lower at 37ºC over a pH range of 1.2– 6.8 The decrease in pH from 7.5 reflects the need to dissolve the drug before it reaches the mid-jejunum to ensure absorption from the gastrointestinal tract. The dose that is to be used for the calculation is the highest dose indicated in the Model List of Essential Medicines (EML). WHO permeability definition : API is absorbed to an extent of 85% or more, it is considered to be “highly permeable”. The permeability criterion was relaxed from 90% in the FDA guidance to 85% in the WHO “Multisource document”. Image belongs to nature

12. HHS-FDA WHO WHO extensions to the scope of application of the biowaiver

13. Back to Ibuprofen Case: Literature Data Ibuprofens chemical name is (RS)-2-(4-Isobutylphenyl) propionic acid. Usually administered as the racemic compound, but the S(+)- enantiomer ( dexibuprofen ) are available. Usually given as the free acid but various salts, esters, are also used: lysine and sodium salts, guaiacol and pyridoxine esters, isobutanolammonium and meglumine derivatives. In this monograph, ibuprofen is understood to be the free acid in the racemic form, unless otherwise indicated.

14. Literature Data Ibuprofen is a well-known and widely used nonsteroidal antiinflammatory drug (NSAID). Ibuprofen is regarded one of the safest NSAIDs available The S(+)- enantiomer was found to be a selective COX-1 inhibitor while R(-)-ibuprofen has little pharmacodynamic efficacy.

15. Literature Data : Physicochemical Properties Solubility: In the literature only data at 20ºC or room temperature were found. BCS classification requires data on the solubility at 37ºC, these values were experimentally determined. for each media in triplicate. Ibuprofen drug substance was suspended in medium and stirred for 24 h at 37ºC and then stored for a further 24 h without agitation. In each case sediment on the bottom of the flask was observed. The ibuprofen concentration in the clear supernatant was determined by UV-analysis.

16. Literature Data : Physicochemical Properties

17. Literature Data Polymorphism: Ibuprofen does not exhibit genuine polymorphism. Partition Coefficient Calculation of the octanol -water distribution coefficient gave log D values of 3.7, 3.6, 2.1, and 1.2 at pH values of 1, 4, 6, and 7, respectively. Log p(n- octanol /water) and Clog p values of 3.68 and 3.14 were estimated, respectively. for the highly permeable marker drug metoprolol , using the same methodology, log p and Clog p values of 1.72 and 1.35 were calculated. pKa The pKa of ibuprofen is in the range of 4.5–4.6 Dose Strength of Marketed Drug Products The WHO List of Essential Medicines includes strengths of 200 and 400 mg

18. Literature Data: Pharmacokinetic Properties Absorption and Permeability: Following oral administration of ibuprofen, Cmax = 1–2 h in humans with an absolute bioavailability(BA) of about 100% Antacids accelerate the rate of absorption due to pH changes However, the extent of absorption,AUC 0→∞ , was not affected. Food intake also affects the absorption rate (likely due to food induced pH elevation) resulting in earlier in vivo dissolution. Rapid and complete absorption suggests a high permeability through the GI membrane. Scintigraphic studies with sustained release products indicate that absorption occurs throughout the GI tract following oral administration, which again supports a high permeability.

19. Literature Data: Pharmacokinetic Properties Similar to other NSAIDs, high permeability of ibuprofen and its enantiomers has been observed in rats , where increased GI permeability was observed because NSAIDs promote their own transport. High permeability of ibuprofen and its enantiomers has been also observed in Caco-2 cell cultures . In a radiolabeled Caco-2 cell culture study, P-app of ibuprofen and propranolol were 53E-6 and 27.5E-6 cm/s, respectively.

20. Literature Data: Pharmacokinetics Linear pharmacokinetics in the dose range of 200–400 mg. At doses higher than 400 mg nonlinearity has been reported, but this is more likely due to changes of plasma protein binding than reduced absorption. Ibuprofen is extensively bound to plasma proteins (>99%) R(-)-ibuprofen undergoes systemic unidirectional inversion to S(+)-ibuprofen , which is known to be the main pharmacodynamically active moiety. Hepatic biotransformation results in two inactive main metabolites which are excreted either free or as conjugates in urine. Total urinary recovery of ibuprofen and its metabolites is 70-90% About 10% of the administered dose is eliminated via feces .

21. Dosage Form Performance The pharmacokinetic properties of two ibuprofen preparations were compared in a randomized crossover study on ten healthy volunteers; there was no statistically significant difference in the extent of absorption but ibuprofen peak plasma concentrations differed between the two preparations . In another study, the pharmacokinetic properties of a soft gelatin capsule and a film coated tablet were compared to liquid prepared from effervescent tablets . The fastest absorption was observed with soft gelatin capsule; liquid and film-coated tablet produced longer absorption half-lives , lower Cmax in serum and greater tmax values, but also in this study, the AUCs were close to similar for all products .

22. Dosage Form Performance In another study, ibuprofen containing capsules prepared either from hypromellose or gelatin were investigated in vitro and in vivo. There were no differences found in the extent of absorption . Some regulatory authorities classified ibuprofen as an active pharmaceutical ingredient (API) for which in vivo BE testing is not always necessary , in view of its wide therapeutic index and non critical therapeutic use .

23. Dissolution The current USP 34 specification for in vitro dissolution requires not less than 80% (Q) dissolved within 60 min in 900 mL phosphate buffer pH 7.2 at 50 rpm using the paddle apparatus.

24. Discussion: Solubility The several reports on the solubility at 20ºC are in reasonable agreement with each other and also support our experimental values at 37ºC, being somewhat higher than the values at 20ºC, as can be expected. Solubility for biowaiver purposes should be determined at 37ºC and at that temperature, at pH values below pH 5.5 their dose/solubility ratio exceeds the critical value of 250 mL for both strengths considered. So, ibuprofen is insoluble in acid and consequently not ‘‘highly soluble’’ as defined according to the present BCS guidances .

25. Discussion: Absorption and Permeability The BA of about 100% already classifies ibuprofen as ‘‘highly permeable’’ according to the present BCS Guidances . A P-app exceeding 10E-6 cm/s is considered to imply high permeability. The results reported from Caco-2 studies exceed this value, in line with the higher P-app found for ibuprofen than for propranolol . ( propranolol is recommended as a high permeability reference substance for Caco-2 permeability in the FDA guideline.) The partition coefficient of ibuprofen, being higher than of metoprolol , supports its high permeability. ( metoprolol was chosen as the reference compound for permeability since 95% of the drug is known to be absorbed from the GI tract.)

26. BCS Classification According to the present regulations, ibuprofen is a BCS class II drug , showing high permeability and pH-dependent solubility , that is, a high solubility according to BCS requirements only above a certain pH value. This is supported by an in vitro in vivo correlation (IVIVC) where a rank order was found between dissolution characteristics and the rate of absorption , since IVIVC’s are predicted for BCS Class II drugs. Current BCS Guidances allow the possibility for a biowaiver exclusively for BCS class I drugs . The limited solubility of ibuprofen at acid pH thus excludes it from the present biowaiver criteria.

27. BCS Classification At pH values near neutral, the solubility of ibuprofen is sufficient to comply with criterion for high solubility. As these pH values are closer to those at the absorption sites in the small intestine they are therefore more relevant in terms of systemic absorption of ibuprofen. Accordingly, ibuprofen may also fit in the newly proposed ‘‘intermediate solubility class’’ suggested for acids and bases that are highly soluble at either physiologically relevant pH 1.2 or 6.8.

28. Criteria from: TRS 937 Annex 8 part 6.3 For pharmaceutical products containing APIs with high solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high permeability (Class II with weak acidic properties ) These are eligible for a biowaiver provided that the multisource product: Is rapidly dissolving , i.e. 85 % within 30 minutes in standard media at pH 6.8 /paddle/ 75 rpm basket/ 100 rpm; and T he multisource product exhibits similar dissolution profiles , to those of the comparator product in buffers at all three pH values (pH 1.2, 4.5 and 6.8 ) .

29. Patient’s Risks Associated with Bioinequivalence When considering a biowaiver for a drug substance, its therapeutic index also needs to be taken into account. Ibuprofen has a wide therapeutic range between 10 and 50 mg/L, the toxic concentration being>100 mg/L and has no life threatening indication. So, the use of in vitro methodology as a surrogate for in vivo BE studies involves little therapeutic risk.

30. Conclusion A biowaiver for IR ibuprofen solid oral dosage form is scientifically justified, provided that: The dosage form is rapidly dissolving (85% in 30 min or less) in pH 6.8 buffer The test product shows dissolution profile similarity to the reference product in pH 1.2, 4.5, and 6.8 The test product contains only the non-critical excipients, in amounts that are usual for IR solid oral dosage forms.

31. References WHO – Technical Report Series No. 937, May 2006 Annex 7 : Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability Annex 8 : Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on a Biopharmaceutics Classification System” (2000) EU-guidance: “Note for Guidance on the Investigation of Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1 A systematic approach to the biowaiver decision: International Pharmaceutical Federation (FIP) published in the Journal of Pharmaceutical Sciences.