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

ACKNOWLEDGEMENTS Dr. Uppoor Dr. Marroum

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

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

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

BCS Guidance Summary

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.

IR Dissolution Guidance Summary

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

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

General BA/BE Guidance Summary

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.

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.

IVIVC Guidance Summary

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.

IVIVC Levels: Level “A” Correlation

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

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

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

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

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

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

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

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

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

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.

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.

Examples

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.

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

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;

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.

Dissolution Specifications for IR Drug A

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.

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)

Dissolution Specifications for IR Drug B

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

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

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.

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

Dissolution Specifications for an MR Product with IVIVC

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

Dissolution Limits

Opportunities

“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.”

“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."

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

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

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%

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!

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.

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.

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

Good homework will always bring dividends!