ICH Q8 Pharmaceutical

Development

Workshop: Quality by Design in

pharmaceutical development and
manufacture
Stockholm 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.

4
FDA´s guiding principles

• risk-based orientation
• science-based policies and
standards
• integrated quality systems
orientation
• international cooperation
• strong public health protection

5
 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

Q8 Q9

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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 Results

Application Improvement
Results
Results Procedure
(criterion/specification-referenced)
Application Improvement

Procedure
Application Improvement
(planned procedure is used) (of procedure and/or
application)

Procedure
(well understood, designed/planned &
documented)
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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 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
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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 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.

(www.qualityworkshop.nl)
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