28DickinsonClinical Relevance of Dissolution

7/28/2019 28DickinsonClinical Relevance of Dissolution

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Clinical Relevance of DissolutionTesting in Quality by Design

AAPS workshop on BE, BCS and Beyond, May

2007, co-sponsored with FDA

Bertil S. Abrahamsson Ph.D. [email protected]

Paul A. Dickinson Ph.D. [email protected]

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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

Evaluation of clinical impact of key product and process variables

Establishment of the Clinical Boundary of the Design Space

Potential Regulatory Flexibility and Continuous Improvement

Generic overview

Aim:

Propose to demonstrate how BCS and dissolution testing can be applied toQbD to assure clinical quality


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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

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AstraZeneca have Adopted a Science and Risk Based

Approach to Clinical Quality

ICH Q8

Design Space

Multi-dimensional space that encompasses combinations of productdesign, manufacturing process design, critical manufacturing processparameters and component attributes that provide assurance of suitableproduct 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

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1

3

2

4

What are the expectations for demonstrating clinical quality

(safety and efficacy) today?

Bioequivalence

Study.

Dissolution for someSUPAC changes

Biowaiver:Dissolution:

Rapid and complete,

across the physiological PH

range

Bioequivalence

Study.Dissolution for some

SUPAC changes

Bioequivalence

Study.

Dissolution for someSUPAC (smaller) changes

SolubilityHigh Low

PermeabilityH

igh

Low


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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

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(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


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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)

BCS Class II

Amount dissolved in 250 mL (mg)

1

10

100

1000

0 1 2 3 4 5 6 7 8 9

pH

dissolvedin

250mL(mg)

>300mg

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

Conc (M) Papp (A to B)

(x 10-6

cms-1

)

Papp (B to A)

(x 10-6

cms-1

)

B to A :A to B

Papp ratio

Absorption

potential

Efflux

1 17.90.9 14.03.3 0.78 High No

10 23.80.1 17.81.7 0.75 High No

50 31.21.0 16.82.0 0.54 High No

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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 materialattributes

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 clinicalperformance are those that will retard drug release (dissolution rate)

A risk analysis, based on prior knowledge of this and other products, wasused to identify the most relevant process parameters and quality attributesthat could affect in vivo dissolution of the product and thereby impact onClinical 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 drugdissolution

Tablet variants, encompassing the extremes of these variables, weremanufactured with the intention of producing tablets with retardeddissolution rates.


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Initial Clinical Quality Risk Assessment

Raw materials and formulation Process

Highest risks assessed in vivo

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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)

Evaluation of most relevant variables


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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 rankorder 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 Method Development

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Time (minutes)

%D

issolution

Variant A (Standard tablet)

Variant B (Larger particle size)

Variant C (Process variant)Variant D (Formulation variant)

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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

i.e. not appropriate to try to develop an IVIVC


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The in vivo evaluation demonstrated that changes in the most

relevant Process Parameters and Quality Attributes did not affectPK 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

Study Conclusions

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If product has a dissolution profile faster than that of slowest profiledosed to volunteers (Variant D) then clinical efficacy and safety will

be comparable to clinical trials material (Clinical Quality Boundary)

Proposed Design Space for Clinical Quality


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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?

Developing Process Understanding

and the Impact on Clinical

Performance

- How this might work in practice.


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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

Outputs from the processing studies

DissolutionProfile of Process OptimisationBatches Compared to Variant C & D

Time(minutes)

%D

issolved

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

VariantC

VariantD

DissolutionProfile ofProcessOptimisationBatches Comparedto VariantC & D

Time(minutes)

%D

issolved

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

VariantC

VariantD

DissolutionProfile ofProcess Optimisation Batches ComparedtoVariant C & D

Time (minutes)

%D

issolved

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

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

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Key steps in ascertaining clinical performance by

dissolution testing in QbD

1. Applied scientific and risk based thinking

based on prior knowledge of this and other products

2. Quality Risk Assessment (QRA) allows the most relevant risk to clinicalquality to be identified

based on prior knowledge of this and other products

3. Develop dissolution test(s) with physiological relevance that is most likely toidentify changes in the relevant manufacturing variables, e.g. testing atlowest acceptable solubility/mild agitation.

4. Understand the importance of changes to these most relevantmanufacturing variables on clinical quality based on dissolution datacombined with

BCS based prior knowledge

and/or clinical bioavailability data

5. Establish the dissolution limit which assure clinical quality (i.e. no effect bychanges)

Clinical bioavailability/exposure data

Classical IVIVC (already accepted today in SUPAC)

In vivo safe space

Prior knowledge (BCS)


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Understanding clinical importance of relevant

manufacturing variables role of dissolution and BCS

1

3

2

4

Dissolution should be

acceptable, provided no new

excipients affecting transit or

permeability

Dissolution accepted 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

SolubilityHigh Low

PermeabilityH

igh

Low

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Why dissolution testing acceptable surrogate for

clinical for class III drugs in QbD

Modelling indicates that class III drug products with rapid dissolution isinsensitive to changes in dissolution, eg

Difference Cmax


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The dissolution limits which assure clinical quality by BCS

Class

1

3

2

4

Complete dissolution within

15 minutes in most

discriminating simple media

(physiological pH range). If

slower: bioavailability data or

additional mechanistic

information

Complete dissolution within

30 minutes in most

discriminating simple media

(physiological pH range). If

slower: bioavailability data or

additional mechanistic

information

Limit set based on clinical

bioavailability data

Limit set on case by case

basis

SolubilityHigh Low

PermeabilityH

igh

Low

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Setting a BCS 2 dissolution limit that assures clinical

quality based on BA data two acceptable approaches

Classical IVIVC Safe space*

in vitro dissolution

CmaxorAUC

in vitro dissolution

CmaxorAUC*A *A

*B

*C

*B *C

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)

10%

limit limit


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Conclusions

Dissolution testing should be applicable to assuredesired clinical performance for wide range ofdrugs in QbD based on BCS considerations andspecific product knowledge

Failure to establish classical IVIVC, could besuccesful outcome of in vitro/in vivo study incontext of QbD, if all variants produce the sameexposure

28DickinsonClinical Relevance of Dissolution

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