the role and future of dissolution testing in a qbd ... in a qbd product development framework paul...

The role and future of dissolution testing in a QBD product development framework

Paul Dickinson, AstraZeneca, Alderley Park, CheshireSenior Clinical Pharmacology [email protected] 2012

The future

• The future is already here. But it is very unevenly distributed. William Gibson.

2 Paul Dickinson GMD | Clinical Pharmacology and Pharmacometrics

Outline and Acknowledgements

• “specifically looking for a forward-looking view of how the need for and development of dissolution QC methodology can be better linked to clinical performance”

• So I’ll focus on that but at the end I want to be a bit more future looking

• Obviously these ideas have been developed in conjunction with a lot of colleagues but particularly some of these slides were co-authored by David Holt and presented at

- http://www.rpharms.com/courses/dissolution-testing.asp

• Note: the views expressed in this presentation reflect my personal interpretation and the experience of some individuals within AstraZeneca


4 Paul Dickinson | Sept 2012 GMD | Clinical Pharmacology and Pharmacometrics

QbD – New CMC Approach: What is Different?

Aspects Traditional QbD

Pharmaceutical Development

Empirical; typically univariateexperiments

Risk-based; Systematic; multivariate experiments

Manufacturing Process Fixed Adjustable within design space;

opportunities for innovation (PAT)

Process ControlIn-process testing for go/no-go; offline analysis slow response

PAT utilized for feedback and feed forward at real time

Product Specification

Primary means of quality control; based on batch data

Part of the overall quality control strategy; based on desired product performance (safety and efficacy)

Control Strategy Mainly by intermediate and end product testing

Risk-based; controls shifted upstream; reducing product variability; real-time release

Lifecycle Management

Reactive to problems & OOS; post-approval changes needed

Continual improvement enabled within design space

QbD and Biopharm:• ICHQ8R1 (Nov 2008) (http://www.ich.org/LOB/media/MEDIA4986.pdf)

- Quality By Design is defined as• “A systematic approach to development that begins with predefined objectives and emphasizes product and process

understanding and process control, based on sound science and quality risk management”- Defining the quality target product profile (QTPP) as it relates to quality, safety and efficacy,

Biopharmaceutics

Biopharmaceutics

QTPP• From ICH Q8R1

Quality Target Product Profile (QTPP):• A prospective summary of the quality characteristics of a drug product that

ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.

Quality Target Product Profile• The quality target product profile forms the basis of design for the development of

the product. Considerations for the quality target product profile could include:

- Intended use in clinical setting, route of administration, dosage form, delivery systems;- Dosage strength(s);- Container closure system;- Therapeutic moiety release or delivery and attributes affecting pharmacokinetic

characteristics (e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form being developed;

- Drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for the intended marketed product.

Specifications?

A changing perception (post 2008)

• There is some ground swell that puts patients at the centre of drug product development

• The FDA have moved the biopharmaceutics reviewers from clinical pharmacology into ONDQA


Selen A, Cruañes MT, Müllertz A, Dickinson PA, Cook JA, PolliJE, Kesisoglou F, Crison J, Johnson KC, Muirhead GT, SchofieldT, Tsong Y. Meeting report: applied biopharmaceutics andquality by design for dissolution/release specification setting:product quality for patient benefit. AAPS J. 2010;12:465–72.doi:10.1208/s12248-010-9206-0.

Patient Needs: QTPP: Specifications Based on Desired product Performance

• My talk limited to Standard IR tablets so the PK part of the QTPP is ensuring rapid and complete release and then bioequivalence between batches

Clinically Relevant Specs

Mechanistic understanding?

Predictive tools?

Risk Assessment?

Clinical studies?

QTPP

Patient NeedsMechanistic understanding?

Prior knowledge ?

Specification to ensureManufacturing

Consistency / QC methodCruañes and Dickinson

What evidence is required to build confidence that a QC-like method controls drug exposure in patients

• Probably up until recently most of us have thought that an IVIVC is required for poorly soluble compounds.

• However Amidon and co-workers recognised some time ago that variation in dissolution rate may not lead to a change in in vivo performance

• This is because other physiological absorption processes can be (are) slower than dissolution- Gastric emptying, permeation

• This means dissolution could guarantee in vivo performance without an IVIVC- Across a limited dissolution range to ensure dissolution never becomes slower

than physiological processes (‘safe space’)

BCS Class IVIVC Expectation

1234

IVIVC if dissolution rate slower than gastric emptying rate, otherwise limited or no correlationIVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very highAbsorption (permeability) is rate determining and limited or no IVIVC with dissolution rateLimited or no IVIVC expected

Amidon et al. Pharm. Res. 12:413-20, 1995

For any product three* potential outcomes exist for the relationship between in vitro dissolution and bioavailability, these are:

1. A Level A or C IVIVC could be established, where changes in in vitro dissolution are directly correlated to changes in bioavailability.

2. An IVIVR in which no effect on bioavailability would be observed across a range of in vitro dissolution rates (referred to below as a ‘Safe Space’).

3. The final option is a mixed safe space / IVIVC result in which bioavailability is only affected for a few of the variants tested clinically.

Cha

nge

in C

max

or A

UC

(%)

0

-10

-20

-30

Time to x% dissolution (min)

-40

-50

++

+ + +

+

+

+

1. IVIVC

2. IVIVR (Safe Space) 3. Mixed safe space / IVIVC

+ = standard and side batches incorporating the highest risk drug product and process variables

Possible relationships between dissolution and drug bioavailability in subjects:

What evidence is required to build confidence that a QC-like method controls drug exposure in patients

* Assuming in vitro dissolution mechanistically similar to in vivo dissolution. A 4th outcome is differences in vivo that are not replicated in vitro.

Dissolution limits which assure exposure by BCS Class for a QbD based development

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

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

Dickinson et al. (2008) AAPS Journal. 10: 380-90.

Collate Prior Knowledge

Perform High Level Risk Assessment

Conduct Experimental Evaluation

2nd Iteration of Risk Assessment

Evaluate impact of highest risk variables on in vivo performance

Develop detailed process understanding

Review Risk Assessment

Construct Design Space

Construct Quality Target Product Profile

Establish Control Strategy

Product Risk

Product Knowledge

Overview of Steps in A Typical QbD development

Product Risk

Product Knowledge

Overview of Steps in a typical QbD Development Focus of the AZ Case Studies





















1. Conduct Quality Risk Assessment

2. Develop Appropriate CQA tests

3. Understand the in vivo importance of changes

4. Establish Appropriate CQA limits

5. Use the product knowledge in subsequent QbD steps

Development of in vivo understanding

Structured five-step approach to build in vivo understanding:Specific Example for Dissolution CQA

Step Example

1. Conduct Quality Risk Assessment (QRA)

QRA to allow the most relevant risks (product and process variables) to in vivo dissolution to be identified (ICH Q9)

2. Develop appropriate CQA tests

Develop in vitro dissolution test(s) with physiological relevance that is most likely to identify changes in the relevant mechanisms for altering in vivo dissolution (identified in Step 1).

3. Understand the in vivoimportance of changes

Determine the impact of the most relevant risks (from Step 1) to clinical pharmacokinetics based on in vitro dissolution data combined with:

1. prior knowledge including BCS and/or mechanisticabsorption understanding

2. and/or clinical ‘bioavailability’ data

4. Establish appropriate CQA limits

Establish the in vitro dissolution limit that assures acceptable bioavailability.

5. Use the Product Knowledge in Subsequent QbD steps

Define a Design Space to deliver product CQAs e.g. ensure in vitrodissolution performance within established limits.

Develop a Control Strategy to ensure routine manufacture remains within the design space e.g. that assures dissolution limits are met during routine manufacture (ICH Q10).

Structured five-step approach to build in vivo understanding:Specific Example for Dissolution CQA

Step Example

1. Conduct Quality Risk Assessment (QRA)

QRA to allow the most relevant risks (product and process variables) to in vivo dissolution to be identified (ICH Q9)

2. Develop appropriate CQA tests

Develop in vitro dissolution test(s) with physiological relevance that is most likely to identify changes in the relevant mechanisms for altering in vivo dissolution (identified in Step 1).

3. Understand the in vivoimportance of changes

Determine the impact of the most relevant risks (from Step 1) to clinical pharmacokinetics based on in vitro dissolution data combined with:

1. prior knowledge including BCS and/or mechanisticabsorption understanding

2. and/or clinical ‘bioavailability’ data

4. Establish appropriate CQA limits

Establish the in vitro dissolution limit that assures acceptable bioavailability.

5. Use the Product Knowledge in Subsequent QbD steps

Define a Design Space to deliver product CQAs e.g. ensure in vitrodissolution performance within established limits.

Develop a Control Strategy to ensure routine manufacture remains within the design space e.g. that assures dissolution limits are met during routine manufacture (ICH Q10).

In some cases:• Make product variants with retarded

dissolution• Test in man

My interpretation of FDA View in this areaP. Marroum, PSWC2010, New Orleans, October, 2010

17 Paul Dickinson | June 2011 GMD | Pharmaceutical Development

Case Study 1: A BCS2 compound with reasonable solubility

EMEA/Efpia QbD Application Workshop - London19

Case Study 1: In vivo data needed – BCS2

Step 1: QRA

Produce Tablets variants with highest risks

Test tablets in several dissolution conditions and find best

Step 3: Understand in vivo importance

BCS2: Need clinical data

Step 2: Develop CQA Test

Step 4: Establish appropriate CQA limit

SAFE SPACE: Variant D is the limit

Step 5: Use in subsequent QbD stepsDesign space boundaries defined to ensure CQA limits are always met

Exposure is the same for all tablet variants


Step 5: Use the product knowledge in subsequent QbD Steps –Design Space

• The Design Space was defined using the in vivo knowledge in conjunction with formulation and process understanding to ensure the delivery of the CQAs

• Design space boundaries defined to ensure that batches with acceptable bioavailability would always be produced

– (i.e. batches that have dissolution faster than Variant D).

• Encompassing:

– Formulation Composition

– Input material quality (API and excipients)

– Manufacturing Process

Design Space verified :Variant X: • Multivariate worse case

from design space

Standard Tablet

Variant D

Final QC Method and Specification

22 Paul Dickinson | Sept 2012 GMD | Pharmaceutical Development

Pharmacopoieal QC Method Requirements

• e.g. USP <1092> THE DISSOLUTION PROCEDURE: DEVELOPMENT AND VALIDATION– General Comments – method capability (e.g. discrimination, reproducibility, variability)– Dissolution Media – aqueous buffered media, sink conditions, surfactants– Dissolution Volume – 500, 900, 1000ml most common– Deaeration – assess the impact of air bubbles– IVIVC Considerations – e.g. biorelevance of media choice– Apparatus/Agitation – e.g. Apparatus 1 (baskets) at 100 rpm or Apparatus 2 (paddles) at 50 or 75 rpm

are most common– Use of Sinkers – e.g. for capsules– Study Design during development - A sufficient number of time points should be selected to

adequately characterize the ascending and plateau phases of the dissolution curve. For immediate-release dosage forms, the duration of the procedure is typically 30 to 60 minutes.

– Visual Observations – e.g. of product dissolution and disintegration behaviour are very useful because dissolution and disintegration patterns can be indicative of variables in the formulation or manufacturing process.

– Sampling/Filters – Manual vs. Autosampling; adsorption of the drug(s) onto the filter needs to be evaluated.

– Assay of samples – usually sample assay is either spectrophotometric determination or HPLC– Validation Requirements – e.g. specificity, linearity, range, accuracy, precision, robustness, solution

stability– Acceptance Criteria – Typical acceptance criteria for the amount of active ingredient dissolved,

expressed as a percentage of the labelled content (Q), are in the range of 75% to 80% dissolved.


Clinically Relevant Dissolution Specifications: My interpretation of FDA View

• Clinically relevant dissolution specification help assure:– Consistent in-vivo performance– Consistent safety and efficacy profiles for the marketed product relative to

those achieved in the clinical trials– Delivery of the intended dose to the patient– Optimal rate of drug delivery to the patient

• Clinically relevant dissolution methods:– Are required to set clinically relevant dissolution specification– Demonstrate in vivo predictability– Predict the in-vivo impact of changes in the formulation and/or

manufacturing processes– Do not always require sophisticated dissolution methods

C. Moore, DIA CMC Workshop: Translating Science into Successful Submissions, Washington, D.C. February 9, 2011


ICH Q6A Decision tree


Dissolution - What are the aspects we are trying to balance ?

Under-Discrimination(Patient Risk)

Over-Discrimination

(Producer Risk)

Impact Manufacturing Process Capability (introduce variation)

Fail clinically acceptable batches

Fail to measure important failure

mechanisms

Poor Quality batches released – impact on

safety & efficacy

Challenges • Global method and specification• Based on ensuring BE between

batches• That allows the manufacturing

process capability to be monitored (Continuous Process Verification) and corrective actions taken if trends observed

• That considers traditional ‘quality aspects’

• To understand and justify all these aspects a quite complicated dataset needs to be presented and interpreted.

• Interpretation may depend on which of above aspects is most important to whoever is looking at the data


QC Dissolution Method Selection – assessing capability requirements

Performance of the different dissolution methods against desired method capabilitiesDesired method

capability pH 1.2 aqueous buffer pH 4.5 aqueous buffer pH 6.8 aqueous buffer Surfactant

The ability to detect the impact of minor process and formulation changes (within design space)

Low. Only able to discriminate the extreme retardation

mechanism

Low. Shows same rank order discrimination as surfactant,

however high intra-batch variability, hence poor method

capability/robustness.

High. Able to discriminate between tablet variants and

hence all dissolution retardation mechanisms probed in clinical

study.

High. Able to discriminate between tablet variants and

hence all dissolution retardation mechanisms probed in clinical

study.

The ability to detect changes in performance of the product on storage (stability indicating)

Low. Does not discriminate stability changes

Not tested due to high intra-batch variability.

Not tested due to incomplete release in a reasonable time(and shows same rank order discrimination as surfactant).

High. Discriminates minor stability changes

To achieve complete dissolution within a timescale appropriate for a routine control test

Yes. Complete release in areasonable time for an IR tablet

Yes. Complete release in areasonable time for an IR tablet

No. Incomplete release in areasonable time.

Yes. Complete release in areasonable time for an IR tablet.

Practical for routine use (timescale, ease of use of media)

Yes. Media simple to prepare.No. Small changes in media pH

likely to affect dissolution performance.

No. Complete release not achieved within a timescale

appropriate for a routine control test.

Yes. Media relatively simple to prepare.

The methodology should be able to assure in vivo performance, ie, it can be used to set a specification which assures that tablets will give equivalent clinical performance to those used in pivotal clinical studies

Medium/High. Over-discriminatory with respect to one

in vivo failure mode. Based on the knowledge of clinical study,

and dissolution in the small intenstinal environment (pH 6.8,

FaSSIF) a conventional IR specification can be set to assure equivalent exposures to pivotal

clinical studies.

Low. There is high intra-batch variability, hence poor method

capability/robustness; difficult to set a specification that would

pass acceptable batches and fail unacceptable batches.

Low. Over-discriminatory with respect to all in vivo failure modes. Incomplete release

means that it is difficult to set a conventional IR specification to assure equivalent exposures

pivotal clinical studies.

Medium/High. Over-discriminatory with respect to all

in vivo failure modes; specification can be set to assure equivalent exposures to pivotal

clinical studies.

Physiological relevance of the media

Medium/High. Acidic media reflects average stomach environment and resonance time.

Low. At best pH 4.5 is only found at the proximal duodenum.

Medium. pH 6.8 reflects the small intestine, but solubility lower due to lack of bile acid mixed micelle solubilisation.

Medium/High. Surfactant mimics small intestinal environment including bile acid mixed micelle solubilisation, and similar drug solubility as HIF and FaSSIF.


Traditional vs QbD approach to Specification Setting


My interpretation of FDA View in this areaC. Moore, DIA CMC Workshop: Translating Science into Successful Submissions,Washington, D.C. February 9, 2011


Suggested three possible situations:

• Situation 1: No in vivo data / clinical relevance not clear

• Conventional and ‘tight’ spec based on batch history, potentially narrow design space

• Situation 2: In vivo data of different disso profile inc ‘Safe space’

• ‘Wider’ dissolution spec could be acceptable (later timepoint but Q = 80%), potential for design space with more regulatory flexibility opportunities

• Situation 3: IVIVC

• Spec controls differences in Cmax and AUC to <20%


e.g. F2 similarity testing vs target formulation as reference


My interpretation of FDA View in this area



Most applicable to IR products




Most applicable to MR products



Specification Setting – Process Capability considerations

Lean manufacturing criteria can be applied to set a specification limit based on Six Sigma manufacturing capability (if it is known that this would not affect clinical performance):

• Evaluated data from development batches• Pass clinically acceptable batches (ICHQ6A)• Minimise unnecessary Stage 2 testing• Specification to apply throughout shelf life so should take into account stability data

Case Study 1: A BCS2 compound with reasonable solubility

• Dissolution profiles in aqueous buffers and optimum surfactant:

Where we ended up with a Release Test / QC Method and Specification: FDA

pH 1.2 pH 4.5

pH 6.8 surfactant

AstraZenecaFDA

Okay with Surfactant for Design Space definition but felt it was over

discriminating changes in the product that was not clinically relevant, and more

comfortable with a more conventional method, with some biorelevance, and

conventional Q value and time point for IR product

36 Paul Dickinson | July 2012 GMD | Clinical Pharmacology and Pharmacometrics

Where we ended up with a Release Test / QC Method and Specification: EMA

• Dissolution profiles in aqueous buffers and optimum surfactant:

pH 1.2 pH 4.5

pH 6.8 surfactant

AstraZenecaEMA

Day 150: “The tightened dissolution specification as

proposed, Q=x% in y minutes, can be considered acceptable

based on the dissolution results of the batches used in

the clinical studies and manufactured using typical

and realistic process parameters ranges”

Day 180: “A discriminating dissolution method has been developed. Results of a study

comparing different formulation and process variants showed that important in vitro

differences did not have an impact on in vivo performance. An issue remains dealing with

the dissolution specification to be set in order to ensure consistency in the quality of drug

product.”

Other Developments in the Future

Complex dissolution‘No’ dissolution – RTRIn silico dissolutionExposure or Disease Outcome

Advanced dissolution models: becoming more common

• Allow more and more of the complexity of the human GI Tract to be captured- Ideally these could be used to develop a product that meets the patients needs

without extension clinical investigations- At the moment most reports are to solve unexpected problems- Currently an adjunct to standard dissolution- But could it build product understanding and mean standard dissolution is defunct

(see later)


TNO TIM-1

Dickinson et al., An Investigation into the Utility of a Multi-compartmental, Dynamic, System of the Upper Gastrointestinal Tract to Support Formulation Development and Establish Bioequivalence of Poorly Soluble Drugs. AAPS J. 4: 196-205 DOI: 10.1208/s12248-012-9333-x

PBL Dynamic Gastric ModelJames Mann


James Mann


Real Time Release (RTR) is all about product understanding

• Quality cannot be tested into products.

• Quality by Design and Real Time Release depends on the sound, scientific understanding of our products, processes and test methods.

• Sound understanding requires a structured development approach from product conception through launch to the end of a products life.

• This structured development approach allows us to understand how product and process attributes relate to product performance. In turn this can be used to establish a Design Space.

• Thorough knowledge and understanding supports the establishment of a rational, science based Control Strategy and where appropriate Real Time Release.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/04/WC500125401.pdf


Real Time Release (RTR) – Example based on a multivariate predictive model

A priori mathematical prediction of dissoltuion performance

Time (min)

0 50 100 150 200 250 300

Con

cent

ratio

n (µΜ)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Aggregates, 200 rpmAggregates, 25 rpmTheoretcial dissolution for aggregatesTheoretical dissolution for primary particlesPrimary, 200 rpmPrimary, 25 rpm

Bertil Abrahamsson

• We are getting much better at mathematical prediction of dissolution (at least for primary and aggregates particles)

• As QbD drives better formulation understanding I could see a future where fundamental mathematical description of dissolution replace dissolution testing

• I think this is an obvious step from the empirical models used in RTR currently

Complex models that link through to clinical outcomesAre being discussed at least at a theoretical level


Arzu Selen

See also Short et al. J. Pharm. Sci. 2010

Summary• The QTPP links product quality to product performance in the patient and biopharmaceutics is a key

element of a Quality by Design Development– CQAs should be linked to safety and efficacy– Thinking in this area has been evolving over the last few years and the Regulatory landscape is

evolving– A framework exists for developing clinically relevant specifications

• Dissolution can be used to ensure similar bioavailability and therefore guarantee safety and efficacy. The specification can be derived from:

– Prior knowledge (e.g. BCS 1) and consideration of conventional QC requirements in line with ICH– An IVIVC– An IVIVR – which allows a safe space to de defined, that is the extent by which dissolution can

slow without affecting bioavailability

• For well-designed moderate BCS2/4 product ‘safe space’ is a likely outcome

• Review– EMA and FDA accept linking dissolution to clinical performance– Wrt specification setting

• FDA seem to place a higher emphasis on bio / clinical relevance, standard conditions and complete release

• EMA seem to place higher emphasis on discriminatory QC method and Q reflecting current batch history

• Potential to end up with different specifications in different regions


the role and future of dissolution testing in a qbd ... in a qbd product development framework paul...

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