Pharmaceutical Development O i ICH Q8/Q9/Q10Overview ICH ... · PDF filePharmaceutical...
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Pharmaceutical DevelopmentO i ICH Q8/Q9/Q10Overview ICH Q8/Q9/Q10
Dr. Burkhard Kriwet Head of Technical Development Olivier Michel Consultant TOPRA in Switzerland Bern, 4th December 2012
VIFOR PHARMA, THE PHARMA BUSINESS SECTOR OF THE GALENICA GROUP
CONTENTS1) Quality: a new paradigm1) Quality: a new paradigm
2) O er ie of ICHQ8/9/102) Overview of ICHQ8/9/10
3) Li k b t ICHQ8/9 d th CTD3) Link between ICHQ8/9 and the CTD
4) Is there a link between ICHQ and CTD
Quality: A New ParadigmM iMain message
Science is no longer isolated; it is living across the lifecycle
of the product/process within a Quality Management System
⇒ The authorities change their regulatory guidance on⇒ The authorities change their regulatory guidance on
pharmaceutical development and process validation
d d i f h lif land regard it as part of the lifecycle
Related ICH guidelinesDevelop an harmonised pharmaceutical quality systemDevelop an harmonised pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science
- Q8: Pharmaceutical Development
Q9: Quality Risk Management- Q9: Quality Risk Management
- Q10: Pharmaceutical Quality System
Quality: A New Paradigm
The new paradigm emphasizes:
1. Quality must be mainly built in during pharmaceutical development and it will not only improve by additional testing
2. Better utilization of modern science throughout product lifecycle
3. Quality Risk Management is a key enabler throughout product lifecycle
4 Robust Pharmaceutical Quality System with appropriate knowledge4. Robust Pharmaceutical Quality System with appropriate knowledge management, assures quality throughout product life cycle
5. An integrated approach to development, manufacturing and quality for both g pp p , g q yindustry and regulators
ICH guidelines: Q8 Pharmaceutical Development
Describes science and risk-based approaches for pharmaceutical product and manufacturing process development without forgetting routine manufacture constraints
Introduced concepts of design space and flexible regulatory approaches
Introduced concepts of Quality by Design (QbD) and provided p y y g ( ) pexamples of QbD development approaches and design space
© ICH, November 2010
ICH guidelines: Q8 Pharmaceutical DevelopmentExample QbD Approach
Quality Target Product Profile (QTPP)
Determine “potential” critical quality attributes (CQAs)
Link raw material attributes and process parameters to CQAs and perform risk assessment
Develop a design space (optional and not required)
Design and implement a control strategy (relate CQAs and Critical Processing Parameters)
Manage product lifecycle, including continual improvement
Quality by designSome definitions
_ Quality Target Product Profile (QTPP): the critical quality attributes to be achieved by the product to meet the needs of the intended end use.
Ri k t id tif i t i l tt ib t d t_Risk assessment: identifying material attributes and process parameters as CQAs and CPPs (by means of Failure Mode Effects Analysis or other tools).
_Critical Quality Attribute (CQA): the quality of ingredients and intermediates required to assure the Quality Target Product Profile
_Critical Process Parameter (CPP): the process parameters required to assure the Quality Target Product Profile
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Quality by designWhy?T d i lit d t d it f t i t i t tl_To design a quality product and its manufacturing process to consistently
deliver the intended performance of the product
To gain knowledge by application of scientific approaches and quality risk_To gain knowledge by application of scientific approaches and quality risk management to the development of a product and its manufacturing process.
_To gather knowledge on new product
_To support the establishment of the design space, specifications and manufacturing controlsmanufacturing controls
_To provide a comprehensive understanding of the product and manufacturing process in house and for reviewers and inspectors.
_To create a basis for flexible regulatory approaches9 © Galenica Group 19.12.2012
ICH guidelines: Q9 Quality Risk ManagementDescribes systematic processes for the assessment controlDescribes systematic processes for the assessment, control,
communication and review of quality risks
Applies over product lifecycle: development manufacturing andApplies over product lifecycle: development, manufacturing and distribution
Includes principles, methodologies and examples of tools forIncludes principles, methodologies and examples of tools for quality risk management
Assessment of risk to quality should:q y
- Be based on scientific knowledge
- Link to the protection of the patient- Link to the protection of the patient
- Extend over the lifecycle of the product
ICH guidelines: Q10 Pharmaceutical Quality SystemDescribes key systems that facilitate establishment and maintenance of a state of
control for process performance and product quality
Facilitates continuous improvementFacilitates continuous improvement
Applies to drug substance and drug product throughout product lifecycle
Sound pharmaceutical development (Q8) and risk management (Q9) inSound pharmaceutical development (Q8) and risk management (Q9) in combination with a robust PQS (Q10) provide opportunities for flexible regulatory approaches. Relevant PQS elements include systems for:
- Track and trend product quality
- Maintain and update models as needed
- Internally verify that process changes are successful
ICH Q8, Q9 and Q10 Working TogetherFormulation Activities: PFormulation Activities:• QTPP Definition• Pre-Formulation Studies• Formulation Screening
Pharm
a
Qualit
Pharm
ac
• Optimization & SelectionProcess Development Activities:• Process Screening
Lab Scale DevelopmentQ
aceutica Qty R
isk Qceutical
• Lab Scale Development• Scale-Up Studies
Manufacturing Activities:• Commercial Scale
Q8al D
evelo
Q9M
anage
10Quality S• Commercial Scale
Manufacturing• Batch Release• Continual Verification &
opment
ement
System
s
Improvement
s
Process validation: at the interface between process development and manufacturing activities
Influence of ICHQ8/9/10 on Process validation guidelinesFDAFDA
From General Principles of Process Validation, May 1987
To Process Validation: General Principles and Practices; January 2011
EMAEMA
From Process Validation: General Principles and Practices, Sept. 2001
To Draft Guideline on Process Validation, March 2012
Lifecycle
Filing Inspection Approval Production
Process Design
Process Scale-up & Tech Transfer
ProcessQualification
Ongoing Process Verification
© ICH, November 2010
Implications/links of the Lifecycle approach on Pharmaceutical Development and Dossier submission
1. From the Note for Guidance Development Pharmaceuticsto the ICH Q8 Pharmaceutical developmentas basis for the preparation of the CTD chapter 2as basis for the preparation of the CTD chapter 2
2. Introduce Quality by design
3 Make use of Design of Experiments3. Make use of Design of Experiments
4. Establish a design space (if wanted)
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NfG Development pharmaceuticsHypothesis:
The information was not sufficient to present the development and was therefore not be understood by Quality Reviewerswas therefore not be understood by Quality Reviewers
They wanted to understand the development process
They wanted the documented proof that we understand the processThey wanted the documented proof that we understand the processas well as that we have taken into account the risks
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Link between ICHQ8 and CTD_Contents of part 1 Pharmaceutical Development :
2.1Components of the Drug Product2.1.1 Drug Substanceg2.1.2 Excipients2.2Drug Product2.2.1 Formulation Development2 2 2 Overages2.2.2 Overages2.2.3 Physicochemical and Biological Properties2.3Manufacturing Process Development2.4Container Closure System2.5Microbiological Attributes2.6Compatibility
The part 1 describes the structure and the required basic information ofThe part 1 describes the structure and the required basic information of the chapter 3.2.P.2 of the CTD
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Link between ICHQ8 and CTD : Information on development process
_Components of the Drug Product:
_Compatibility of the drug substances with excipients
Explanation of the choice of the excipients their concentration their characteristics_Explanation of the choice of the excipients, their concentration, their characteristics that can influence the drug product performance, should be discussed relative to their respective function
Description of container closure system_Description of container closure - system
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Link between ICHQ8 and CTD : Information on development process
_Formulation Development
_Summary describing the development of the drug product taking into consideration the proposed route of administration and usage.p p g
_Results from comparative in vitro studies (dissolution)
_Information on developments studies.
_Identification and description of the formulation and the critical parameters that can influence batch reproducibility.
It is recommended that an in vitro dissolution test is developed which is able to_It is recommended that an in vitro dissolution test is developed which is able to indicate predict changes, which may have an effect on the efficacy or safety of the product
Relevant parameters (viscosity pH value of preparation) of the performance of the_Relevant parameters (viscosity, pH value of preparation) of the performance of the drugs should be addressed
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Link between ICHQ8 and CTD:Information on development process
_Manufacturing Process Development
_Explanation of the manufacturing process (reference to part P3.3).
The difference between the primary stability batches and the process used to_The difference between the primary stability batches and the process used to produce commercial batches should be well documented. The differences that can influence the performance or manufacturability of the product should be discussed.
_The process should enable the definition of appropriate specifications of the finished product.
Process validation plan (in part P 3 5)_Process validation plan (in part P.3.5)
20 © Galenica Group 19.12.2012
Link between ICH Q8/9 and CTD
_Contents of part 2 ELEMENTS OF PHARMACEUTICAL DEVELOPMENT
2.1Quality Target Product Profile
2.2Critical Quality Attributes
2.3Risk Assessment: Links Material Attributes and Process Parameters to CQA
2.4Design Space
2.5Control Strategy
2.6Product Lifecycle Management and Continual Improvement
Incorporation of ICH Q9 Risk Management in the development process >> ICHQ8 >> CTD
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The missing link ? ICHQ10 and CTD
_Yes there is one link for a flexible approach to process improvement
Design Space: Th ltidi i l bi ti d i t ti f i t i bl (The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not
id d h D i i d b th li t dconsidered as a change. Design space is proposed by the applicant and is subject to regulatory assessment and approval.
But there are documentation challenges there:But there are documentation challenges there:
_How to present a quality by design in chapter 2 without overwhelming the quality reviewers?
_How to link design space with the process description in CTD chapter 3 on manufacturing?
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The missing link ? ICHQ10 and CTD
_there are means to survey continuous process improvement e.g.ProductQuality Review and continual process verification, but
h t i t thi i th D i ?_how to incorporate this in the Dossier ?
_ is there means to envision and incorporate IPCs , CPPs and even Product specifications adjustmentsspecifications adjustments
_how to refine these based upon gained knowledge CQAs and CPPs whenlong proven under efficient state of control
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SummaryWith ICH Q8/Q9/Q10 th i i t t d h f th- With ICH Q8/Q9/Q10 there is an integrated approach for the lifecycle of the product quality
- The contents of ICH Q8 Pharmaceutical Development is reflectedThe contents of ICH Q8 Pharmaceutical Development is reflected in the CTD chapter 2
- ICHQ9 and Q8 are strongly linked to enable a risk-based approach to development (in addition to science based)
However, some points are not clarified yet:
- How to integrate the post-approval phase with Continuous Verification & Improvement in the CTD (i.e. control strategy with IPCs and release
testing might change)?
e.g. Microbial cleanliness skip testing / UDU 2.9.40 and sample amount24 © Galenica Group 19.12.2012