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ICH Q8 Pharmaceutical Development
Workshop: Quality by Design in pharmaceutical development and
manufactureStockholm 2006-03-28
Christina Graffner
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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 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 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)