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ICH Q8 Pharmaceutical Development

Workshop: Quality by Design in pharmaceutical development and

manufactureStockholm 2006-03-28

Christina Graffner

(christina.graffner@mpa.se)

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Background

FDA´s new initiative cGMPs for the 21st Century (2002):

..closer look at the regulation of pharmaceutical manufacturing and product quality for human and veterinary drugs as well as selected human biological products

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Benefit for pharmaceutical industry: Improved efficiency and flexibility whilst

maintaining high quality standards.

• Rapid introduction of state-of-the art science and technology

• Encouraged continuous manufacturing process improvements

• Real-time quality control → reduced

end-product release testing

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FDA´s initiative:

Careful scrutiny of both chemistry, manufacturing, and controls (CMC) regulatory programs and the processes resulting in pharmaceutical products.

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FDA´s guiding principles

• risk-based orientation

• science-based policies and standards

• integrated quality systems orientation

• international cooperation

• strong public health protection

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Present tripartite discussions*

• ICH Q8 Pharmaceutical Development, in operation from May 2006

• ICH Q8, Annex: Specific Dosage forms, draft

• ICH Q9 Quality Risk Management– draft in consultation phase

• ICH Q10 – Quality system, concept paper

• PAT and biological products

*No veterinary equivalents at the moment. However, VICH is considering Q9-10.

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ICH guidelines simplifying regulatory implementation of FDA´s initiative

Q10

Q9Q8

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ICH Q8: Pharmaceutical Development (in operation from May 2006)

• An opportunity to present the knowledge gained through the application of scientific approaches to product and process development (= scientific understanding)

• Create a basis of flexible regulatory approaches by reducing uncertainty

- Facilitate risk based regulatory decisions

- Continuous improvements without the need for

regulatory review

- ”real time” quality assurance

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ICH Q9 Quality Risk Management(Step 2, in consultation)

A process* consisting of well defined steps which, when taken in sequence, support better decision making by contributing to a greater insight into risks and their impacts.

*includes assessment, control, communication and review of risk.

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ICH Q10 Quality System(Drafting group)

• Key elements from ISO 9001:2000 and ISO 9004 to complement existing GMPs(active substance, products)

• To promote continual improvements over the life-cycle of the product without regulatory submission when it is clear that the changes are low risk.

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Quality system for continuous improvements

Procedure(well understood, designed/planned & documented)

Application(planned procedure is used)

Improvement(of procedure and/or application)

Results(criterion/specification-referenced)

Procedure

Application Improvement

Results

Procedure

Application

Results

Improvement

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Quality by design is about doing things consciously.

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Quality by design and well understood product and processes

• All critical sources of variability are identified and explained

• Variability is controlled by the process

• Product quality attributes can be accurately and reliably predicted over the design space established for materials used, process parameters, environmental and other conditions.

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Basic issue

To gain enhanced knowledge of product performance over a range of material attributes, manufacturing process options and process parameters considering appropriate use of quality risk management principles.

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Understanding gained by e.g.

• prior knowledge

• formal experimental designs

• process analytical technology (PAT)

• experienced lifecycle knowledge

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Pharmaceutical Development:To give reviewers and inspectors a

comprehensive understanding

• increased reliance owing to focus on

– critical quality attributes and their relevance to Safety and Efficacy

- to which extent the variation of critical

formulation attributes/ processing options/

process parameters have an impact on

product quality

• to justify control strategies

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Design space (ICH Q8)

Established multidimensional combination and interaction of material attributes and/or process parameters demonstrated to provide assurance of quality.

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Examples on possible controlling/interacting parts in a space

• Starting materials (e.g. by NIR): particle size distribution, specific surface area or other functionality-related characteristics, ratio of ingredients to each other, etc.

• Process operations (e.g. by NIR, acoustics): water content of mass/granule over time, blending profile over time, etc.

• Machine parameters: weight discharged by blender, feedback control of compression force, etc

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Design space (ICH Q8), cont.

• Working within design space (multidimensional region) not generally considered as a change

• Movement out of design space is a change → regulatory post approval change process

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Expanded Design Space to facilitate more flexible regulatory

approaches*

Inclusion of continuous increased under-

standing during product lifecycle of

- material attributes

- manufacturing processes

- ” controls

* reduction of post-approval submissions

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Question 1:When PAT is implemented will the manufacturer be allowed to make changes to the process without need for regulatory “approval“?

On the assumption

• understanding of variables that affect product quality attributes, methods to monitor and control

• process control strategy falls within the boundaries of knowledge i.e. in established design space

↓

Adjustments possible without need of variation submission

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Question 3:Will it be possible to widen the limits for an approved product and process specification”if, post-approval, such changes are found to have no significant effect on product quality

• Process specifications are not finished product specifications

• Adjustments within “design space” possible without further variation application

• Changes to finished product specification → variation regulations

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Pharmaceutical Development(CTD-Module 3.2.P.2)

• dosage form, formulation, manufacturing process, container closure system, microbiological attributes, usage instructions appropriate for purpose

• formulation/process attributes critical for batch reproducibility, product performance, product quality identified and described

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ICH Q8: Material attributes

• Drug substance – physicochemical and biological properties in relation to product performance and manufacturability

• Excipients

- concentration, characteristics and functionality in relation to product performance and manufacturability

- functionality during shelf-life

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ICH Q8: Formulation/Dosage form

Summary describing

- pharmaceutical development from initial

concept to final design

- identification of attributes and interacting

variables critical for product quality

i.e. drug substance, excipients (ranges), container closure system, dosing device (if relevant), manufacturing process,…

- formulations from pivotal clinical safety/efficacy studies

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Some additional new concepts for discussion/clarification

1. Process signature

2. Real-time release

3. Process specification

4. Comparability protocols

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1. Process signature

Proposal for comments before 31 August*:

“A collection of batch specific information that shows a batch has been produced within the design space for the product.”

* www.emea.eu.int/Inspections/PAT

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ASTM definition of Process signature

“A single or multi-dimensional signal indicative of the attributes of the process.”

(Compare: “A collection of batch specific information that shows a batch has been produced within the design space for

the product.”)

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1. Process signature, cont.

• Operating within design space

• No unique process signature

• Family of process signatures with common characteristics (salient features)

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1. Process signature, cont.

Process signature e.g. amount of water added in relation to time (wet massing),air flow rate and bed temperature during fall rate drying (fluidized bed drying)

(Compare in-process control points: end-point limits for e.g. granule moisture content)

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2. Real-time release (RTR) instead of finished product testing?

• RTR control based on prediction modelling of finished product quality attributes.

• Current EU legislation requires two specifications: release and end of shelf-life.

• Does RTR mean a third specification?

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Question 2:Is it possible for a product to have two specifications-one for real-time release based on on-line measurements and another for end-of-life testing?

• At present release and shelf-life specifications taking account to relevant monographs of the Ph.Eur.

• How to ensure compliance to release specification is open but has to be described in submission → a third specification?

cont.

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Question 2, cont.

Release decisions made on a third specification:

• Relationship between process measurements & controls and release specifications key issue in submission

• After release: Compliance to shelf life specifications (conventional methods)

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Examples on finished product testswhich are shown possible to be

replaced by RTR

• Identification of active substance/excipients (including functionality properties)

• Water content

• Uniformity of mass

• Uniformity of content

• Dissolution

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3. Process specification

• Proposal:

Recognises the interrelationship between various process parameters and describes ranges within which the process needs to be operated.

• Compare RTR, a third specification?

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Commission directive 2003/94/EC(Principles and guidelines of GMP in respect of medicinal products for human use…)

Transposition to

Swedish regulation LVFS 2004:

§21 Quality control

……

When a manufacturer has applied and has got approval from MPA to apply another means (than results from tests on final product etc.) like parametric release or real-time release, the approval from MPA will describe how the requirements in this paragraph should be applied.

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4. Comparability protocols

• Not part of EU regulatory system.

• Current EC regulations concerning variations to marketing authorisation (No 1084/2003; 1085/2003) are valid.

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Challenges for Industry

• Amount/level of information to present to regulators (e.g. chemometrics/statistics)

• Validation of association between measurements during manufacture versus release testing according to specification → basis for release of batch

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Challenges for Regulators

• Change in review process

• Enhanced collaboration between assessors and inspectors:

- at submission and during lifecycle

- clarification of respective responsibility

• New definitions and specifications (?)

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EU PAT Team - Reflections

• Lot of activity in the area

• Companies using different approaches and philosophies and are at different stage of progress

• Internal discussions within companies are key factor

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Several EFPIA interactions

• June 2005: Presentation of mock application of fictitious product “Examplain”

• Discussions to follow: what level of data should be included in the dossier?

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DESIGN SPACE- exploring its scientific, developmental and

regulatory dimensions (8-9 May 2006, London)*

"Creating a shared vision between industry and regulators"

*This highly interactive workshop will be attended by reviewersand inspectors from Regulatory Authorities of all 25 European Member StatesOrganised by FIP in co-operation with EMEA andEFPIA. Supported by EUFEPS, ISPE and APV.

(www.qualityworkshop.nl)