2. Drug Release Specification: In Vivo Relevance Ajaz S. Hussain, Ph.D. Deputy Director, OPS/CDER/FDA

3. Outline The regulatory role of Bioavailability (BA) and Bioequivalence (BE) testing for ensuring therapeutic utility why QbD principles quality assessment system pharmaceutical development will improve the level of quality assurance compared to what is achieved in current stateA few examples to illustrate why QbD principles and a quality assessment system that utilizes structured pharmaceutical development information will improve the level of quality assurance compared to what is achieved in current state

4. The regulatory role of BA and BE Sec. 320.23 Basis for measuring in vivo bioavailability or demonstrating bioequivalence. Sec. 320.24 Types of evidence to measure bioavailability or establish bioequivalence. Sec. 320.22 Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.

5. Sec. 320.24 Types of evidence to measure bioavailability or establish bioequivalence (a) BA may be measured or BE may be demonstrated by several in vivo and in vitro methods. –FDA may require in vivo or in vitro testing, or both, to measure the bioavailability of a drug product or establish the bioequivalence of specific drug products. –..conduct BA & BE testing using the most accurate, sensitive, and reproducible approach available among those set forth in paragraph (b) of this section.

6. Sec. 320.24 (b) The following in vivo and in vitro approaches, in descending order of accuracy, sensitivity, and reproducibility, are acceptable –(1)(i) An in vivo test in humans in which the concentration of the active ingredient or active moiety, and, when appropriate, its active metabolite(s), in whole blood, plasma, serum, or other appropriate biological fluid is measured as a function of time…… or (ii) An in vitro test that has been correlated with and is predictive of human in vivo bioavailability data; or –(2) An in vivo test in humans in which the urinary excretion of the active moiety, and, …..

7. Sec. 320.24….. 3) An in vivo test in humans in which an appropriate acute pharmacological effect of the active moiety, …..measured as a function of time if such effect can be measured with sufficient accuracy, sensitivity, and reproducibility. –….applicable to the category of dosage forms described in paragraph (b)(1)(i) of this section only when appropriate methods are not available for measurement of the….

8. Sec. 320.24….. (4) Well-controlled clinical trials that establish the safety and effectiveness of the drug product, for purposes of measuring bioavailability, or appropriately designed comparative clinical trials, for purposes of demonstrating bioequivalence. –This approach is the least accurate, sensitive, and reproducible of the general approaches for measuring bioavailability or demonstrating bioequivalence. –For dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution, this approach may be considered acceptable only when analytical methods cannot be developed to permit use of one of the approaches outlined in paragraphs (b)(1)(i) and (b)(2) of this section, when the approaches described in paragraphs (b)(1)(ii), (b)(1)(iii), and (b)(3) of this section are not available.

9. Sec. 320.24….. (5) A currently available in vitro test acceptable to FDA (usually a dissolution rate test) that ensures human in vivo bioavailability. (6) Any other approach deemed adequate by FDA to measure bioavailability or establish bioequivalence. (c) FDA may, notwithstanding prior requirements for measuring BA or establishing BE, require in vivo testing in humans of a product at any time if the agency has evidence that the product: –(1) May not produce therapeutic effects comparable to a pharmaceutical equivalent or alternative with which it is intended to be used interchangeably; –(2) May not be bioequivalent to a pharmaceutical equivalent or alternative with which it is intended to be used interchangeably; or

10. Quality & Therapeutic Utility Acceptable Goal Post Patient population Bioequivalence 90% CI T/R: Rate & Extent of absorption Quality Production lots Quality Bio batch 80%125%

11. Sec. 320.22 Criteria for waiver of evidence of in vivo BA or BE (b) For certain drug products, ….. may be self- evident. –… self-evident based on other data in the application if the product meets one of the following criteria.. (c) FDA shall waive..of a solid oral dosage form (other than a delayed release or extended release dosage form) …Drug Efficacy Study Implementation notice.. (d) …..demonstrated by evidence obtained in vitro in lieu of in vivo data..

12. Pharmaceutical Equivalent IR Products ReferenceTest Possible Differences Drug particle size,.. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Bioequivalence = Therapeutic Equivalence (Note: FDA/USP often insists on same dissolution spec.) Normal healthy subjects Crossover design Overnight fast* Glass of water 90% CI within 80-125% of Ref. (Cmax & AUC) Critical for patients and public confidence in our regulatory system Food Effect Studies

13. Remembering the Previous ACPS Debate (e.g., 7 May 1997) Individual Bioequivalence: Update: Mei ‑ Ling Chen, Ph.D. –“Basically, the average bioequivalence approach focuses only on the population averages of test and the reference product. –It ignores the distribution of the metric, such as AUC or Cmax. –It also ignores the possible subject ‑ by ‑ formulation interaction. –Another concern that the Agency has for the current bioequivalence criteria is that we use 80-125 rule to all the drugs. –The philosophy of "one size fits all" may not be appropriate in some of the cases, and obviously, it doesn't fit well for highly variable drugs or narrow therapeutic window drugs. Biopharmaceutics Classification System: Update: Ajaz Hussain, Ph.D. “Gut feeler’s” Vs. “Blood letter’s”  Moving towards QbD & mechanistic basis for regulatory decisions

14. Bio-availability “self-evident”? Hussain et al., (AAPS 2000) Average PK-Profiles (n=40) Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been blocked.

15. Subject*Formulation Interaction? Hussain et al., (AAPS 2000). Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been blocked.

16. Oral Solutions: Impact of excipients on absorption Hussain et al, (AAPS 2004, FDA Sci Forum 2005) and data from literature Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been blocked. Dissociation not accounted High permeability

17. Dissolution specification without pharmaceutical development information Test 1 Test 2 Mean Dissolution Profiles (n=6) Pivotal clinical lots Discriminating test FDA 75% Applicant

18. An Illustrative Example: “A degree of uncertainty in the “overall control” status” For IR solid oral dosage forms 0.1 N HCl is a popular dissolution media in the US –because the gastric fluid is acidic due to HCl secretion (and pH is generally assumed to be ~ 1-2) –Many currently approved products of drugs that are weak bases (exhibit rapid dissolution in acidic media) –Bioequivalence studies are conducted in normal health subjects (avoid any other medication while enrolled in the study)

19. An Illustrative Example: “A degree of uncertainty in the “overall control” status” Under these conditions (previous slide) it is suggested that conformance to dissolution specification may not provide the high degree of certainty in product quality and performance we expect and demand of our selves –It is the controls on critical variables (e.g., drug particle size..), established appropriately, that may be more important in assuring quality

20. Gastric pH & Bioavailability Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been blocked.

21. Differences between US & Japan? *Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been erased.

22. % of achlorhydric subjects aged 50 years in 1995-1999 was about 40%, lower than that (60%) in 1984. bioavailability and bioequivalence studies should be performed taking into consideration the effects of gastric acidity on the in vivo performance of drug products Is this relevant for US population? YES

23. Quality by Design ? BE?

24. QbD an opportunity to better understand in vivo relevance of product design To ensure an optimal and systematic control of critical product and process variables Improve regulatory assurance of product quality Improve available product designs?

25. An Example: Improve available product designs? DP is an antiplatelet agent that shows decreased oral bioavailability with increased gastric pH that occurs with commonly prescribed antacids. –An ER formulation of DP that employs tartaric acid to improve bioavailability in the presence of elevated gastric pH was developed as a combination antiplatelet product with immediate- release ASP –DP relative bioavailability was reduced 53% with conventional tablets compared to the composite buffered ER capsule in reduced gastric acid conditions. –Peak DP plasma concentrations were 57% lower with immediate-release tablets compared to the composite formulation with high stomach pH. –Substituting generic DP plus low-dose ASP may be less effective than the buffered DP composite product in patients with concomitant antacid therapies. Derendorf et al.J Clin Pharmacol. 2005 Jul;45(7):845-50.

26. Without the benefit of pharmaceutical development information Regulatory assessment and decisions focus primarily on dissolution test data –Trial-n-error, historical opinions, lack of understanding of critical variables and sources of variability –Different scientific disciplines have their own “preference ” for certain test methods –Specifications established late in the approval process based on limited test data –A degree of uncertainty in the “overall control” status “Immediate release does not mean the release profile can not be (or is not) designed and controlled!”

27. A Systems Approach for ensuring BA/BE: Elements of QbD (Example) BIOAVAILABILITY DRUGEXCIPIENTS FORMULATION GASTROINTESTINAL TRACT WHOLE BODY PHYSICAL-CHEMICAL PROPERTIES IN VITRO PHYSICAL- CHEMICAL ATTRIBUES IN VIVO PHYSICAL- CHEMICAL ATTRIBUTES PHYSIOLOGICAL VARIABLES PHARMACOKINETIC PROPERTIES MANUFACTRUING PROCESS