Drug Release Specification: In Vivo Relevance

Ajaz S. Hussain, Ph.D.

Deputy Director, OPS/CDER/FDA

Outline

• The regulatory role of Bioavailability (BA) and Bioequivalence (BE) testing for ensuring therapeutic utility

• A few examples to illustrate why QbD principleswhy QbD principles and a quality assessment systemquality assessment system that utilizes structured pharmaceutical developmentpharmaceutical development information will improve the level of quality will improve the level of quality assurance compared to what is achieved in assurance compared to what is achieved in current statecurrent state

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.

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.

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, …..

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….

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.

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

Quality & Therapeutic Utility

AcceptableAcceptableGoal PostGoal Post

Patient populationPatient population

BioequivalenceBioequivalence90% CI90% CI

T/R: Rate &T/R: Rate &Extent of absorptionExtent of absorption

QualityQuality

Production lotsProduction lots

QualityQuality

Bio batchBio batch

80% 125%

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..

Pharmaceutical EquivalentIR Products

Reference TestPossible 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 subjectsCrossover designOvernight fast*Glass of water

90% CI within 80-125%of Ref. (Cmax & AUC)

Critical for patientsand public confidence

in our regulatory system

FoodEffect Studies

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

Bio-availability “self-evident”?Hussain et al., (AAPS 2000)

Average PK-Profiles (n=40)

Time in Hours

0 2 4 6 8 10 12

Ra

nit

idin

e C

on

c.

(ng

/ml)

0

100

200

300

400

500

Sucrose Solution

Sorbitol Solution

Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been blocked.

Subject*Formulation Interaction?A

UC

I

0

1000

2000

3000

4000

5000

0

1000

2000

3000

4000

5000

Sucrose Sorbitol

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

Oral Solutions: Impact of excipients on absorption

Relationship Between AUC Ratioand Quantity of Excipient

0

0.5

1

1.5

0 20 40 60Excipient Amount (normalized with MW)

AU

C R

atio

- T

est/

Co

ntr

ol

Ranitidine solution with Sorbitol Ranitidine liquid with PEG 400

Ranitidine powder with SAPP Ranitidine tablet with SAPP

Cimetidine with Mannitol Metoprolol with Sorbitol

Theophylline with Sorbitol Amoxicillin with PEG 4000

Linear (Ranitidine solution with Sorbitol)

Hussain et al, (AAPS 2004, FDA Sci Forum 2005) and data from literatureDue to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been blocked.

Dissociationnot accounted

High permeability

Dissolution specification without pharmaceutical development information

Test 1

Test 2

Mean DissolutionProfiles (n=6)

Pivotal clinical lots

Discriminating test

FDA

75%

Applicant

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)

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

Gastric pH & Bioavailability

Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been blocked.

Differences between US & Japan?

*Due to ACS restrictions on discussing specific drugs, names of drugsavailable in open literature have been erased.

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

Quality by Design Quality by Design ?

BE?

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?

Pharmaceutical EquivalentPharmaceutical EquivalentIR ProductsIR Products

Reference TestPossible Differences

Drug particle size, ..

Excipients

Manufacturing process

Equipment

Site of manufacture

Batch size ….

Bioequivalence= Therapeutic Equivalence(Note: Generally, same dissolution spec.)

Normal healthy subjectsCrossover design

Overnight fastGlass of water

90% CI within 80-125%of Ref. (Cmax & AUC)

Critical for patientsand public confidence

in our regulatory system

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.

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!”

A Systems Approach for ensuring BA/BE: Elements of QbD (Example)

BIOAVAILABILITY

DRUG EXCIPIENTS

FORMULATION

GASTROINTESTINAL TRACT

WHOLE BODY

PHYSICAL-CHEMICAL PROPERTIES

PHYSICAL-CHEMICAL PROPERTIES

IN VITRO PHYSICAL-CHEMICAL ATTRIBUES

IN VIVO PHYSICAL-CHEMICAL ATTRIBUTES

PHYSIOLOGICAL VARIABLES

PHARMACOKINETIC PROPERTIES

MANUFACTRUING PROCESS