Clinical Relevance of Dissolution Testing in Quality by Design

AAPS workshop on BE, BCS and Beyond, May 2007, co-sponsored with FDA
Bertil S. Abrahamsson Ph.D. Paul A. Dickinson Ph.D.
bertil.abrahamsson@astrazeneca.com paul.dickinson@astrazeneca.com

Outline:
Introduction to Quality by Design (QbD)
A driver to go beyond BE and BCS

Review the current accepted practices for demonstrating clinical quality Focus on approaches for BCS2 compounds
Case study FDA pilot programme Establishment of the Clinical Boundary of the Design Space

Evaluation of clinical impact of key product and process variables Potential Regulatory Flexibility and Continuous Improvement Generic overview

Aim:
Propose to demonstrate how BCS and dissolution testing can be applied to QbD to assure clinical quality

Acknowledgments

PAR&D Paul Stott Sheena Behn Andy Townsend Ryan Gibb Andy Sheridan John Smart Chris Potter

Clin Pharm Peter McCormack Parvis Ghahramani Tracey Hammett Reg CMC Linda Billett Bob Timko Carol Stinson

AstraZeneca have Adopted a Science and Risk Based Approach to Clinical Quality

ICH Q8
Design Space
Multi-dimensional space that encompasses combinations of product design, manufacturing process design, critical manufacturing process parameters and component attributes that provide assurance of suitable product quality and performance

ICH Q9
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Maximally Efficient, Agile and Flexible Manufacturing

Regulatory Flexibility to Change:
Site Scale Process conditions Process Type Excipient Grade Formulation Drug Form

What are the expectations for demonstrating clinical quality (safety and efficacy) today?

High Biowaiver:
Permeability Low High

Solubility

Dissolution: Rapid and complete, across the physiological PH range

Bioequivalence Study.
Dissolution for some SUPAC changes

1 2 3 4
6

Low Bioequivalence Study.

Dissolution for some SUPAC changes

Bioequivalence Study.
Dissolution for some SUPAC (smaller) changes

So what does this mean in practice?

The previous approach to development didnt build knowledge and encourage understanding Thus was long and risk laden and resource intensive

Ajax Hussain, FDA, 2005

(One of ) AZs Response(s) to this initiative

The next part of the presentation will cover how we have applied a SCIENTIFIC and RISK BASED approach to produce a Quality by Design Development package for an AZ BCS2 product
We believe this will meet the desired state as described by Janet Woodcock This approach has already allowed us to streamline pharmaceutical development
No final BE study No clinical PK bridging study between Phases

Drug Substance Properties

Molecular Weight: 475 pKa: 9.41 and 5.33 (dibasic) ClogP : 5.7 LogD(octanol): 2.6 displays high permeability Low solubility Stable in GI Fluid has a prolonged absorption rate (~Ka 0.33hr -1) long half life (~10-15 days)
dissolved in 250 mL (mg)

Permeability of Caco-2 Monolayers to Drug Substance (mean sd, n=3)

Conc (M) Papp (A to B) (x 10-6 cms-1) 1 10 50 17.90.9 23.80.1 31.21.0 Papp (B to A) (x 10-6 cms-1) 14.03.3 17.81.7 16.82.0 B to A :A to B Absorption Papp ratio potential 0.78 0.75 0.54 High High High Efflux

No No No

Amount dissolved in 250 mL (mg)

1000

>300mg
100

10

BCS Class II

1
0 1 2 3 4 5 6 7 8 9

pH

Key High Level Risks for the Drug Product

Applying a scientific and risk based approach an High Level Quality Risk Assessment (QRA) was performed predicated on prior knowledge from other projects and specific knowledge about the drug substance. This identified two high level risks for the drug substance 1. Impact of product / process variables on in vivo performance (BCS Class II) 2. Compression properties leading to poor physical quality
Wet granulated IR tablet

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Clinical Quality Boundary

In order to fully understand the Design Space it is important to assess the clinical impact of the most relevant process variables and material attributes i.e. the impact of these variables on safety and efficacy For a BCS Class II (and III, IV) it is not possible to test all the potential tablet variants generated during the establishment of the manufacturing design space in the clinic. Therefore need to establish a link between an in vitro test (we have chosen dissolution) and safety and efficacy (volunteer PK) Once this link has been established the dissolution test can be used as a surrogate of clinical performance and the clinical performance of all variants from the design space establishment can be assessed.

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Most Relevant Variables for Clinical Quality

For a BCS Class II compound factors that are most likely to impact on clinical performance are those that will retard drug release (dissolution rate) A risk analysis, based on prior knowledge of this and other products, was used to identify the most relevant process parameters and quality attributes that could affect in vivo dissolution of the product and thereby impact on Clinical Quality. These were/are: API physical properties (API Design Space) particle size Extent of granulation (Process Design Space) Level of binder and disintegrant (Formulation Design Space)

These variables retard drug dissolution by different mechanisms, namely:

Impact of API surface area on rate of dissolution Impact of granule density and porosity on the rate of ingress of water Impact of slowed disintegration rate of the tablet on subsequent drug dissolution

Tablet variants, encompassing the extremes of these variables, were manufactured with the intention of producing tablets with retarded dissolution rates.

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Initial Clinical Quality Risk Assessment

Highest risks assessed in vivo

Raw materials and formulation 13

Process

Evaluation of most relevant variables

The four tablet variants were: Standard Clinical Manufacture; Large Particle Size Variant; Process Variant (Over granulation); Formulation Variant (less disintegrant, more binder) Tested in vitro to develop dissolution method capable of identifying changes in product quality due to changes in these most relevant process parameters and quality attributes Tested in vivo evaluate impact of these variables on in vivo performance and if appropriate develop a mathematical relationship (IVIVC)

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Dissolution Method Development

Dissolution in pharmacopoeial media demonstrate either a lack of differentiation (pH 1.2), higher variability (both pH 1.2 and 4.5) or incomplete recovery (pH 6.8) and therefore are sub-optimal (when discrimination was observed it was the same rank order as that seen in the chosen media) The most appropriate dissolution method identified discriminates between most relevant process parameters and quality attributes in the tablet variants

% Dissolution

Variant A (Standard tablet) Variant B (Larger particle size) Variant C (Process variant) Variant D (Formulation variant)

12 Time (minutes)

15

Geometric Mean and Individual Plasma Concentrations from Tablet Variants (n = 10 for Variants A and B, n = 11 for Variant C and n = 9 for Variant D) versus Oral Solution (n = 15) after dosing to healthy volunteers

No difference in PK performance (Cmax and AUC) after dosing the tablet variants to volunteers 16 i.e. not appropriate to try to develop an IVIVC

Study Conclusions The in vivo evaluation demonstrated that changes in the most relevant Process Parameters and Quality Attributes did not affect PK in volunteers
i.e. will have no impact on safety and efficacy in patients

Cannot develop an IVIVC because the PK profiles overlap and there are no differences in vivo However, the impact of these variables on dissolution when tested by the most appropriate method, could be detected
i.e. over discriminatory method

As the variants dosed encompassed three different mechanisms to alter drug release from the tablet the overly discriminatory dissolution test is an appropriate surrogate to assess clinical quality of all outputs from further processing studies

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Proposed Design Space for Clinical Quality If product has a dissolution profile faster than that of slowest profile dosed to volunteers (Variant D) then clinical efficacy and safety will be comparable to clinical trials material (Clinical Quality Boundary)

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Implications of clinical evaluation of product & process variables

This approach defines the clinical boundary of the Design Space for the product the dissolution method is a suitable surrogate for clinical performance The dissolution limits using this method will be based on the profile from Variant D, not on process capability
A new way to set specifications

Future changes such as site, scale, equipment, method of manufacture can be qualified using this dissolution method and limit Question posed to the Agency at recent face to face meeting: If we present the clinical boundary of Design Space in this way and include the supporting data in the NDA, does this meet the FDA expectation of Drug Product design space?

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Developing Process Understanding and the Impact on Clinical Performance - How this might work in practice.

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Outputs from the processing studies

An DoE was used to investigate the most important process variables relating to the granulation and drying process and subsequent process steps. All at the commercial scale The most important variables have been further investigated using a Response Surface Design All batches were tested by the discriminatory dissolution method to investigate the impact on clinical performance
Dissolution Profile of Process Optimisation Batches Compared to Variant C & D

Dissolution Profile of Process Optimisation Batches Compared to Variant C & D

Dissolution Profile of Process Optimisation Batches Compared to Variant C & D

% Dissolved

% Dissol ved

P/4156/7A P/4156/7B P/4156/8A P/4156/8B P/4156/9A P/4156/9B P/4156/10A P/4156/10B P/4156/11A P/4156/11B Variant C Variant D Time (minutes)

P/4156/1A P/4156/1B P/4156/2A P/4156/2B P/4156/3A P/4156/3B P/4156/4A P/4156/5A P/4156/5B P/4156/6A P/4156/6B Variant C Variant D Time (minutes)

% Dissolved

P/4156/12A P/4156/12B P/4156/13A P/4156/13B P/4156/14A P/4156/14B P/4156/15A P/4156/15B P/4156/16A P/4156/16B Variant C Variant D Time (minutes)

We have demonstrated that Product manufactured at the extremes of the manufacturing parameters studied exhibits a dissolution profile significantly faster than variant D Therefore, all variants within the manufacturing parameters studied will be bioequivalent

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Proposed control strategy

Discriminatory dissolution method with a limit based on variant D will be used to control the clinical boundary of the Design Space For future manufacturing operations within the proven ranges no dissolution testing will be performed for release For future manufacturing operations outside the proven ranges the discriminatory dissolution method will be use to qualify the changes Question posed to the Agency at recent face to face meeting: If we implement a control strategy for the Design Space as described above does this meet the FDA expectation for drug product release and post approval flexibility?

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Generic Summary/Overview

Key steps in ascertaining clinical performance by dissolution testing in QbD

1. 2. Applied scientific and risk based thinking based on prior knowledge of this and other products Quality Risk Assessment (QRA) allows the most relevant risk to clinical quality to be identified based on prior knowledge of this and other products Develop dissolution test(s) with physiological relevance that is most likely to identify changes in the relevant manufacturing variables, e.g. testing at lowest acceptable solubility/mild agitation. Understand the importance of changes to these most relevant manufacturing variables on clinical quality based on dissolution data combined with BCS based prior knowledge and/or clinical bioavailability data Establish the dissolution limit which assure clinical quality (i.e. no effect by changes) Clinical bioavailability/exposure data Classical IVIVC (already accepted today in SUPAC) In vivo safe space Prior knowledge (BCS)
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3.

4.

5.

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Understanding clinical importance of relevant manufacturing variables role of dissolution and BCS

High
Dissolution accepted

Solubility

Low

Dissolution should be acceptable, provided no new excipients affecting transit or permeability

1 2 3 4
25

Permeability Low High

Dissolution combined with bioavailability study on most relevant manufacturing/product variables

Bioequivalence Study Or Follow principles of BCS2 or BCS3 if can demonstrate that compound behaves more like BCS2 or BCS3 in vivo

Why dissolution testing acceptable surrogate for clinical for class III drugs in QbD
Modelling indicates that class III drug products with rapid dissolution is insensitive to changes in dissolution, eg
Difference Cmax <10% for solid with complete dissolution after 1 hour vs solution for wide range of elimination rates and permeabilities, Kortejrvi, Eur J Pharm Sci 2007, 30, 155 Metformin, Cheng Eur J Pharm Sci 2004, 22, 297 Ranitidine, Polli Adv Expr Med Biol 1997, 423, 191-198

This is confirmed by in vivo studies, eg

Published biowaiver monographs for class III drugs based on literature data, show no BA differences for different IR formulations eg
Atenolol Ranitidine

QbD implies higher level of understanding of manufacturing process and product compared to historical position

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The dissolution limits which assure clinical quality by BCS Class

High

Solubility

Low

Permeability Low High

Limit set based on clinical Complete dissolution within bioavailability data 30 minutes in most discriminating simple media (physiological pH range). If slower: bioavailability data or additional mechanistic information Complete dissolution within Limit set on case by case 15 minutes in most basis discriminating simple media (physiological pH range). If slower: bioavailability data or additional mechanistic information

1 2 3 4
27

Setting a BCS 2 dissolution limit that assures clinical quality based on BA data two acceptable approaches

Classical IVIVC
Cmax or AUC

Safe space*
Cmax or AUC

*A

10% *B limit *C

*A

*B

*C

limit
in vitro dissolution

in vitro dissolution

A = biobatch, B and C = side batches based on most relevant manufacturing variables *For this type of approach to be acceptable the most relevant risks to clinical quality need to have been assessed (i.e. in a QbD setting)

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Conclusions

Dissolution testing should be applicable to assure desired clinical performance for wide range of drugs in QbD based on BCS considerations and specific product knowledge Failure to establish classical IVIVC, could be succesful outcome of in vitro/in vivo study in context of QbD, if all variants produce the same exposure

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