1. Overview of Guidance Documents and Decision process: Biopharmaceutics Section Mehul Mehta, Ph.D. Director Division of Pharmceutical Evaluation I OCPB, CDER, FDA

2. ACKNOWLEDGEMENTS
Dr. Uppoor
Dr. Marroum

3. Outline
Overview of biopharmaceutical aspects of dissolution related guidances
Examples of dissolution specification setting of IR and MR products
Opportunities

4. Guidances covered
BCS Guidance (Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System”); August 2000
IR Dissolution Guidance (Dissolution Testing of Immediate Release Solid Oral Dosage Forms); August 1997
IVIVC Guidance (Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations); September 1997
General BA/BE Guidance (Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations); 2003

5. Guidances covered
SUPAC-IR Guidance (SUPAC-IR: Immediate Release Solid Oral Dosage Forms Scale-Up and Post Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution and In Vivo Bioequivalence Documentation); 1995
SUPAC-MR Guidance (SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Post-approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation); 1997

6. BCS Guidance Summary

7. BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: solubility, intestinal permeability, and dissolution.
4 BCS classes are: 1 = HS, HP; 2 = LS, HP; 3 = HS, LP; 4 = LS, LP
Different formulations of rapidly dissolving BCS class 1 product can be given biowaiver if they show rapid and similar dissolution profiles over the physiological pH range.
BCS defines rapid dissolution, i.e., 85% in 30 minutes. If dissolution is this rapid across the pH range, absorption not dissolution rate limited.

8. IR Dissolution Guidance Summary

9. Topics Covered:
Approaches to setting dissolution specifications for an NCE
Approaches for setting dissolution specifications for generic products
Mapping or Response Surface methodology
Model independent approach to compare dissolution profiles using a similarity factor, f2

10. The dissolution specifications are established in consultation with biopharmaceutics and CMC review staff.

11. General BA/BE Guidance Summary

12. Dissolution Method Development Report: For an NDA:
The pH solubility profile of the drug substance
Dissolution profiles generated at different agitation speeds. Dissolution profiles generated on all strengths in at least three dissolution media.
Select the agitation speed and medium that provide adequate discriminating ability, taking into account all the available in vitro and in vivo data.

13. For ANDAs:
Appropriate USP method, or; the FDA method if publicly available, or; the dissolution method development report described above.
For MR products, dissolution profiles using the appropriate USP method (if available), or; the FDA method for RLD if available. In addition, profiles using at least three other dissolution media and water recommended.

14. IVIVC Guidance Summary

15. IVIVC Levels: Level “A” Correlation
A point-to-point relationship between in vitro dissolution and the in vivo input rate of the drug from the dosage form.
Usually estimated by a two stage procedure (e.g., deconvolution followed by comparison of the fraction absorbed to the fraction dissolved).
Generally linear, but non-linear are also acceptable.

16. IVIVC Levels: Level “A” Correlation

17. Dissolution Specifications
Ideally, all lots within the lower and upper limit of the specifications are bioequivalent
Minimally, these lots should be bioequivalent to the clinical trials lots or an appropriate reference standard chosen by the Agency

18. Dissolution Specifications
Variability alone should no longer be a primary consideration
Specifications wider than 20 % are acceptable only when evidence is submitted that lots with mean dissolution profiles that are allowed by the upper and lower limits are bioequivalent

19. Dissolution Specifications With No IVIVC
Minimum of 3 points required
Last time point should be the time where 80% of claimed labeled amount is dissolved
Specifications set to pass at stage 2 level of testing of the USP acceptance criteria

20. Dissolution Specifications with IVIVC
External validation is not required to use the IVIVC for setting specifications
Wider specifications based on what the correlation predicts

21. IVIVC Applications: Dissolution Specifications
FINAL DISSOLUTION SPECIFICATIONS:
Set such that the predicted Cmax and AUC range NMT 20%

22. SUPAC-IR (1995) and MR Guidances (1997) Summary
(Equipment Addendum (1999); FDAMA (1997) and “Changes Approved to an NDA or ANDA” Guidance (2000))

23. General Aspects: (Change) Variables Covered
Components and Composition
Non Release Controlling
Release Controlling
Site
Batch Size (Scale-Up/Scale-Down)
Manufacturing
Equipment
Process

24. General Aspects: Supporting Data
Level I (Minor) change
Level II (Moderate) change
Level III (Major) change
Chemistry (A/C test, Stability)
In Vitro dissolution/release
In Vivo bioequivalence test / IVIVC
Annual report
Change being effected supplement
Prior approval supplement
Level of Change
Tests
Filing

25. SUPAC-IR Excipient Levels
Level Excipients % Change (w/wtotal) Allowed
I - Glidant: Talc; Other /- 1.0%; +/- 0.1%
- Disintegrant: Starch; Other /- 3.0%; 1.0%
- Binder /- 0.5%
- Lubricant: Ca/Mg Strt; Other /- 0.25%; +/-1.0%
- Filler /- 5.0%
- Film Coat /- 1.0%
II - Glidant: Talc; Other /- 2.0%; +/- 0.2%
- Disintegrant: Starch; Other /- 6.0%; 2.0%
- Binder /- 1.0%
- Lubricant: Ca/Mg Strt; Other /- 0.5%; +/-2.0%
- Filler /- 10.0%
- Film Coat /- 2.0%
III - Higher than SUPAC-IR Level 2
Excipient ranges

26. SUPAC-MR Excipient Levels
For the release controlling excipients, the SUPAC-MR guidance defines change in quantity as percentage (weight / weight) of total release-controlling excipients. For these:
A level 1 change means that the total additive effect of all RCE should not be more than +5%.
A level 2 change allows a range of +10%
Changes beyond +10% are considered level 3.

27. SUPAC- IR and MR SUMMARY
The guidance defines tests, filing recommendations and levels of changes in: C and C (RC and NRC); Site; batch size; equipment and process.
The following changes need a bio study (or IVIVC): level 3 RC and NRC, level 2 RC for NTR drugs, level 3 site change, and level 3 process change.
“Equipment Addendum” identifies equipment by class and subclass for all major unit operations; change to a different class generally considered a change in design and principle.
“Changes” guidance allows for multiple different level changes, the most restrictive individual change should be followed.

28. Examples

29. Data available for a typical IR product in an NDA:
Dissolution results under a variety of agitation and media conditions.
A method that provides rapid dissolution profile; Mean and range of dissolution values of 12 units from the bio lot(s) plus a few to several production lots under this condition.
BA results of one or more lots (relative BA trials, BE trials).
Lots used in efficacy trials.
Stability data.

30. Factors taken into consideration when setting specs for IR products:
In vivo behavior, particularly how rapidly the drug is absorbed (Tlag, Tmax)
Dissolution behavior across all the conditions in vitro
Adequately discriminating in vitro method from all the in vitro conditions attempted, based on qualitative or quantitative in vitro – in vivo inference

31. Factors taken into consideration when setting specs for IR products:
Comparison with more rapidly dissolving formulation, e.g., solution very helpful in assessing in vivo dissolution; this can guide how discriminating the in vitro method needs to be;
look at all available dissolution data; pay particular attention to the lots that have in vivo data, e.g., the bio lots and efficacy trial lots;
discuss with Chemists data from the stability lots;

32. Possible Outcomes: Sufficient data submitted; specs finalized
Insufficient data submitted; interim specs set for a limited time frame; additional data submitted; specs finalized.
Insufficient data submitted; specs can’t be finalized, including interim specs; additional data required; approval decision finalized.

33. Dissolution Specifications for IR Drug A

34. Solubility: Highly soluble over the pH range of 1.2 to 6.9
Permeability: Highly permeable based on in-vitro and absolute bioavailability studies
Dissolution: rapidly dissolving over pH range of 1.2 to 6.8
Dissolution results of the BA lot and the clinical lot utilized
12 month controlled room temperature stability data and accelerated storage conditions results also taken into consideration.

35. Method: USP I at 100 rpm in 900 ml 0.1 N HCl
Spec: Q=80% in 30 minutes
(Apparatus I was chosen by the sponsor to avoid mounding or coning of the product at the bottom of the dissolution vessel)

36. Dissolution Specifications for IR Drug B

37. The drug is a free base with pKas of 5.4 and 7.2
Highly soluble at pH 1.0 but practically insoluble at pH 7, with the solubility dropping sharply between pH 4 and 5
Tmax range is 3-5 hours
Half life is around 45 hours
Fraction absorbed around 0.75

39. Initial dissolution method showed clinical and TBM formulations to have similar profiles

41. But the BE study showed a clear failure on Cmax, with the TBM formulation showing about a 17% lower Cmax.
The method optimized further to have adequate discrimination.

45. Proposed method and specs:
USP Apparatus 2, 50 rpm; 1000 ml Tween 80 (5% v/v) in water; Q=75% in 45 minutes
Recommendation:
USP Apparatus 2, 50 rpm; 1000 ml Tween 80 (5% v/v) in water; Q=80% in 45 minutes

46. Dissolution Specifications for an MR Product with IVIVC

47. IVIVC Level A correlation established.
Correlation was obtained from in vivo data obtained from 6 different studies
Media Consisted of PH 1.5 for the first 1.5 hours then PH 6.8 buffer for the remainder of the 24 hours

48. Dissolution Limits

49. Opportunities

50. “The Concept of Pharmaceutical Quality”, Dr
“The Concept of Pharmaceutical Quality”, Dr. Janet Woodcock, Pharmaceutical Review, 7, 10, 2004:
"For the purposes of clinical use, the established drug quality attributes are generally adequate because they achieve much tighter control of the level of variability than could be detected in patients without extensive study.”

51. “The Concept of Pharmaceutical Quality”, Dr
“The Concept of Pharmaceutical Quality”, Dr. Janet Woodcock, Pharmaceutical Review, 7, 10, 2004:
“In contrast, for regulatory and manufacturing processes, the lack of detailed understanding of the real-world importance of quality attributes is a serious problem, leading to many disputes that might be resolved easily were relevant information available on the relationships between various quality parameters and clinical performance."

52. Sources of Variability in Therapy
Manufacturing
Drug exposure (PK)
Drug response (PD)
Compliance

53. Snapshot: 17 drugs selected randomly from an Internal BCS database of 194 NDAs and variability (%CV) in their exposure parameters – AUC and Cmax – assessed.

54. I*
(n=3)
II*
(n=2)
III*
(n=7)
IV*
(n=4)
AUC
%CV
17-24%
19-25%
16-100%
16-48%
Cmax
18-23%
24-35%
25-49%
30-40%

55. Assuming that the clinical trial formulation is optimized, even for BCS class I products (no high first-pass metabolism), there is in vivo exposure variability of about 20%. Utilize this to come up with rational specs!

56. Opportunities for improvement:
Select appropriate dissolution method based on physicochemical, in vitro and in vivo characteristics of drug and drug product
Estimate in-vitro variability for LS and LP IR forms
Estimate of dissolution variability of lot(s) used in pivotal efficacy trial(s) would facilitate rational specs
For MR products, estimate in vitro release variability and utilize it to improve upon current IVIVC method which involves mean estimates only.

57. Opportunities for improvement:
New technology (e.g., PAT) can provide in vitro in vivo relationships based on performance of individual dosage form units!
Elution / release from Complex dosage formulations, e.g., Drug Eluting Stents, Liposomes, should be studied using mechanistic models and new techniques in imaging and fluid dynamics.
Future specs would be based on in vitro mean and variability estimates.

58. Opportunities for improvement
Early communication
e.g., EOP2 meeting between sponsor and FDA Biopharmaceutics and CMC staff to discuss the development plan.

59. Good homework will always bring dividends!