ICH Q8 Pharmaceutical Development

Workshop: Quality by Design in pharmaceutical development and manufacture
Stockholm 2006-03-28 Christina Graffner (christina.graffner@mpa.se)


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

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

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


FDA´s guiding principles
• risk-based orientation • science-based policies and standards • integrated quality systems orientation • international cooperation • strong public health protection

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.

ICH guidelines simplifying regulatory implementation of FDA´s initiative




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

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.

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.

Quality system for continuous improvements

Results Improvement

Application Procedure




(planned procedure is used)

(of procedure and/or application)


(well understood, designed/planned & documented)

Quality by design is about doing things consciously.


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.


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.


Understanding gained by e.g.
• • • • prior knowledge formal experimental designs process analytical technology (PAT) experienced lifecycle knowledge


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

Design space (ICH Q8)
Established multidimensional combination and interaction of material attributes and/or process parameters demonstrated to provide assurance of quality.


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

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


Expanded Design Space to facilitate more flexible regulatory approaches*
Inclusion of continuous increased understanding during product lifecycle of - material attributes - manufacturing processes ” controls * reduction of post-approval submissions

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

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


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

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

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

Some additional new concepts for discussion/clarification
1. 2. 3. 4. Process signature Real-time release Process specification Comparability protocols


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


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.”)


1. Process signature, cont.
• Operating within design space • No unique process signature • Family of process signatures with common characteristics (salient features)


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: endpoint limits for e.g. granule moisture content)

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 shelflife. • Does RTR mean a third specification?

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.

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)

Examples on finished product tests which 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

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?


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.

4. Comparability protocols
• Not part of EU regulatory system. • Current EC regulations concerning variations to marketing authorisation (No 1084/2003; 1085/2003) are valid.


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


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 (?)


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


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?


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 reviewers and inspectors from Regulatory Authorities of all 25 European Member States Organised by FIP in co-operation with EMEA and EFPIA. Supported by EUFEPS, ISPE and APV.


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