Biopharmaceutics Classification System

Biowaivers

1. By Shereen Mohamed Shehata Supervised by Dr/ Amal El- Kamel Biopharmaceutics Classification System

2. Introduction: IND S , ND S , ANDA S and supplements to these applications require a waiver of in vivo bioavailability (BA) and/or bioequivalence (BE) studies for immediate release (IR) solid oral dosage forms. Biowaivers can be requested for IR solid oral dosage forms based on an approach termed the Biopharmaceutics Classification System (BCS). Investigational new drug applications Abbreviated new drug applications New drug applications

3. The biopharmaceutics classification system:

4. The biopharmaceutics classification system (cont.): The BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: dissolution, solubility, and intestinal permeability.

5. The biopharmaceutics classification system (cont.): Dissolution rate has a negligible impact on bioavailability of highly soluble and highly permeable (BCS Class I) drugs when their formulation’s dissolution is sufficiently rapid. Various regulatory agencies allow bioequivalence of formulations of BCS Class I drugs to be demonstrated by in vitro dissolution (‘ biowaiver ’).

6. Biowaivers for BCS I drugs: Solubility:

7. Determining drug solubility class: Define the pH-solubility profile at different pH conditions based on the ionization characteristics of the test drug substance. For example, when the pK a of a drug is in the range of 3-5, solubility should be determined at pH = pK a , pH = pK a +1, pH = pK a -1, and at pH = 1 and 7.5. At least three determinations for each pH by: ➔ traditional shake-flask method ➔ acid or base titration methods

8. Biowaivers for BCS I drugs (cont.): B. Permeability: Drug considered highly permeable when: F a (fraction of dose absorbed) ≥ 90 % ➔ human in-vivo studies ➔ non-human in-vitro studies (epithelial cell culture) Absence of evidence suggesting instability in the GIT.

9. Determining drug permeability class: Pharmacokinetic studies in humans: Mass Balance Studies: Unlabeled, stable isotopes or a radiolabeled drugs Sufficient number of subjects Reliable estimate of extent of drug absorption Highly variable Not preferred

10. Determining drug permeability class (cont.): b. Absolute Bioavailability Studies: Intravenous administration as reference To determine oral BA When absolute BA ≥90% Data documenting drug stability in GI fluid not necessary

11. Determining drug permeability class (cont.): 2. Intestinal permeability methods: in vivo intestinal perfusion studies in humans; in vivo or in situ intestinal perfusion studies using suitable animal models; in vitro permeation studies using excised human or animal intestinal tissues; or in vitro permeation studies across a monolayer of cultured epithelial cells.

12. Determining drug permeability class (cont.): For application of the BCS, an apparent passive transport mechanism can be assumed when one of the following conditions is satisfied: A linear PK relationship between the dose and measures of BA (AUC) of a drug is demonstrated in humans. Lack of dependence of the measured in vivo or in situ permeability is demonstrated in an animal model on initial drug concentration. Lack of dependence of the measured in vitro permeability on initial drug concentration.

13. Suitability of a permeability method: A rank-order relationship between test permeability values and the extent of drug absorption data in human subjects should be established using a sufficient number of model drugs. For in vivo intestinal perfusion studies in humans: six model drugs are recommended. For other methods: twenty model drugs are recommended. Depending on study variability, a sufficient number of subjects, animals, excised tissue samples, or cell monolayers should be used in a study to provide a reliable estimate of drug permeability.

14. Suitability of a permeability method(cont .): Model drugs should represent a range of low (e.g., < 50%), moderate (e.g., 50 - 89%), and high (≥ 90%) absorption. Sponsors may select compounds from the list of drugs and/or chemicals provided in Attachment A or they may choose to select other drugs for which there is information available on mechanism of absorption and reliable estimates of the extent of drug absorption in humans.

15. Attachment A:

16. Attachment A (cont.): A low and a high permeability model drug should be used as internal standards with the test drug substance fluid volume marker (or a zero permeability compound such as PEG 4000) that is included in certain types of perfusion techniques (e.g., closed loop techniques).

17. Instability in the Gastrointestinal Tract: Incubated at 37 o c Drug concentrations determined by validated stability-indicating assay method Gastric and intestinal fluids from human subjects For invivo contact periods to these fluids Significant degradation (>5%) of a drug potential instability

18. Biowaivers for BCS I drugs: C. Dissolution: Drug considered rapidly dissolving when ≥85 % of labeled content dissolved within 30 minutes using: USP Apparatus I (100 rpm) or USP Apparatus II (50 rpm) in a volume of ≤900 ml in: ➔ 0.1 N HCl or Simulated Gastric Fluid USP without enzymes ➔ pH 4.5 buffer ➔ pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes For capsules and tablets with gelatin coating, Simulated Gastric and Intestinal Fluids USP (with enzymes) can be used.

19. Dissolution(cont.): USP Apparatus I ( basket method) For capsules and products that tend to float USP Apparatus II ( paddle method) Preferred for tablets ≥12 dosage units Sampling intervals: FDA ≥ 4 (e.g., 10, 15, 20, and 30 minutes).

20. Dissolution(cont.): Similarity Factor f 2 When comparing dissolution profiles of test & reference products. Not necessary if both ≥ 85 % dissolved in ≤15 minutes in all three dissolution media. f 2 = 50 • log {[1 + (1/n) (R t - T t ) 2 ] -0.5 • 100} Where: n is the no. of time points R t is the dissolution value of the reference product at time t T t is the dissolution value of the test product at time t

21. Dissolution(cont.): Products are considered similar if f 2 ≥50 Coefficient of Variation, (to allow the use of mean data): ➔ ≤ 20 % at earlier time points (e.g., 10 minutes) ➔ ≤ 10 % at other time points

22. Additional considerations for requesting a biowaiver : A. Excipients : Generally, excipients will not affect BA of BCS I drugs. Quantity of excipients should be consistent with the intended function (e.g., lubricant). New excipients / atypically large amounts of commonly used excipients : additional information is needed. ➔ Relative BA: aqueous solution as reference ➔ The review division of FDA should by contacted if: large quantities of surfactants (e.g., polysorbate 80 ) and sweeteners (e.g., mannitol or sorbitol ) used.

23. Additional considerations for requesting a biowaiver (cont.): B. Prodrugs : Prodrug Drug Before intestinal permeation Measure permeability of drug Measure permeability of prodrug After intestinal permeation Dissolution, pH-solubility Dissolution, pH-solubility

24. Additional considerations for requesting a biowaiver (cont.): C. Exceptions: BCS-based biowaivers are not applicable for the following: Narrow therapeutic range drugs: e.g. digoxin , lithium, phenytoin , theophylline , and warfarin . Products designed to be absorbed in the oral cavity (e.g., sublingual or buccal tablets ).

25. Data to support a request for biowavers : A. Data supporting high solubility:

26. B. Data supporting high permeability: Information on study design and methods used along with the human pharmacokinetic studies. For direct permeability methods, information supporting the suitability of a selected method that includes: a description of the study method, criteria for selection of human subjects, animals, or epithelial cell line, drug concentrations in the donor fluid, description of the analytical method, and method used to calculate extent of absorption or permeability.

27. B. Data supporting high permeability(cont.): Permeability values for each model drug, and a plot of the extent of absorption as a function of permeability (mean ± standard deviation or 95% confidence interval) with identification of the low/high permeability. Selected internal standard and stability information.

28. C. Data supporting rapid and similar Dissolution: A brief description of the IR products used for dissolution testing, including information on batch or lot number, expiry date, dimensions, strength, and weight. Dissolution data obtained with 12 individual units of the test and reference products using recommended test methods. The mean percent dissolved, range (highest and lowest) of dissolution, and coefficient of variation (relative standard deviation) should be tabulated.

29. Two samples dissolution profile: Data supporting similarity in dissolution profiles between the test and reference products in each of the three media, using f 2 .

30. D. Additional information: Method of manufacture (e.g., wet granulation vs. direct compression). A list of excipients used, the amount used, and their intended functions should be provided. Excipients used in the test product should have been used previously in FDA-approved IR solid oral dosage forms.