determination of potency for cellular and tissue-based ...€¦ · 11 q5a; viral safety evaluation...
TRANSCRIPT
Determination of Potency for Cellular
and Tissue-based Products:
Considerations and Challenges
The views and opinions expressed in this presentation are those of the presenter and
should not necessarily represent the views and opinions of the PMDA.
Kazunobu Oyama, PhDPrincipal Reviewer, Office of Cellular and Tissue-based Products,
PMDA, Japan
CMC Strategy Forum Japan 2016December 5-6, 2016, Tokyo Marriot Hotel, Tokyo, Japan
Key Message
My Expectations…
Current
Future
What is the issues in determining specifications
of CTPs
2
Presentation Outline
3
General Consideration
Specification
Potency
Procedures and Validation
Meaning and Purpose of Quality
4
Safety
Quality
Efficiency
Quality Assurance
5
TOTAL QUALITY
CONTROL
Understanding of Product Quality
6
Design Quality
Product Quality
･ Quality Management
Procedure
Equipment
Process
Material
Quality Risk Management / Knowledge Control
･Characterization･Control Strategy (Specification etc.)
Establishment of Specification
7
Can be established and used for :
Specifications are one part of total control strategy designed to ensure product quality and process consistency.
Specification items are chosen to confirm the quality ensuring safety and efficacy, focus on biological characteristics.
Fundamentals of Specification
Release Testing
(Specification)
Process Consistency
・Process Control
・Process Validation
Prior Knowledge
Control of variable factors of final product
The release criteria of the final products
Quality control of the raw materials and intermediate products
Verification of the suitability of the manufacturing process
The method of maintaining consistency
Extended Characterization
Stability Profile
8
Determination of Specification
9
TPP QTPP
Quality Attributes
CQA
Release Testing
Material Controls
Intermediate Controls
In-process Controls
Non-CQA
Material Controls
Intermediate Controls
In-process Controls
Justification of Specification
Acceptance Criteria
Existing Knowledge of Mfg and Analysis
Historical Data of Process Controls and Release Testing
Prior Knowledge
Clinical Consideration
For Safety and Efficacy
Characterization Material Control Manufacturing Process and in-process control Process Validation of Verification Analytical Capability and Validation of Procedures Batch Analysis Stability
Specification items
10
11
Q5A; Viral safety evaluation of biotechnology products derived from cell lines on human or animal origin
Q5B; Analysis of the expression construct in cells used for production of R-DNA derived protein products
Q5C; Stability testing of biotechnological/biological products
Q5D; Derivation and characterization of cell substrates used for production of biotechnological/biological products
Q5E; Comparability of biotechnological/biological products subject to changes in their manufacturing process
Q6B; Specifications: Test procedures and acceptance criteria for biotechnological/biological products
Guidelines for Quality of Biological Products
Regulatory Aspects
12
The applicant should provide the rationale and justification for including and/or excluding testing for specific quality attributesICH Q6B [Test Procedures and Acceptance Criteria for Biotechnological/Biological Products]
Section 2.1.2 Biological activityAssessment of the biological properties constitutes an equally essential step in establishing a complete characterization profile. An important property is the biological activity that describes the specific ability or capacity of a product to achieve a defined biological effect.
Section 4.1.4 and 4.2.4 PotencyPotency is the quantitative measure of biological activity based on the attribute of the product which is linked to the relevant biological properties, whereas, quantity (expressed in mass) is a physicochemical measure of protein content. Mimicking the biological activity in the clinical situation is not always necessary. A correlation between the expected clinical response and the activity in the biological assay should be established in pharmacodynamic or clinical studies.
Specific Points to Consider for CTPs
http://www.jcrpharm.co.jp/news/201511
26_3991
Ref. Japan Tissue Engineering Co., Ltd. (J-TEC), HPhttp://www.mhlw.go.jp/stf/shingi2/000
0104129.html
Live cells
Heterogeneity, lot-to-lot quality consistency
Variability of test methods
Difficulty in identifying quality attributes to describe product efficacy and safety
13
14
Specifications for CTPs could be well linked to clinical procedures and handling.
Medical specialists engage in handing CTPs at critical stages of cell therapy (e.g., biopsy, transplantation) relying on medical institution.
The aspects as medical technology for cell therapy can be taken into considerations when setting specification of the final product of CTPs.
Specific Features to Consider for CTPs
Differences between Cells and Proteins
15
Setting specification for CTPs would be different from those of traditional biotechnological/biological products.
Key Consideration of QbD Approach
Identify the critical quality attributes based on the potential risks
Linking material attributes and process parameters to CQAs, in this case, risk assessment is useful
Establishment and implementation of control strategy
Knowledge and understanding obtained could facilitate continual improvement
QTPP
CQAs/CPP
Risk Management
Control Strategy
Continual improvement
16
Understanding of Process
DifferentiationPurification
↓
Final Product
Process for collection of desirable cells • Designed culture system • Monitoring of cultivation• Confirming variability of desirable cells • Verification of intended process
Process for expansion of desirable cells• Designed culture system• Confirming growth profile• Consistency of cell attributes• Verification of intended process
Process for engineering of desirable cells• Designed culture system• Efficiency of differentiation and purification• Consistency of final product attributes
↓
↓
Cell/Tissue Collection
↓Primary Culture
ExpandCulture
Process Design and Quality Risk Management17
Different Quality Concepts of Regenerative Medical Products
characterization
specification
In-process control
Source materials, process variability
Regenerative Medical ProductsBiotechnological/biological products
characterization
specification
In-process control
Source materials, process variability
18
Specifications
Identification Biochemical markers, immunological markers,
characteristic products, and other appropriate genotypes
or phenotypes of the intended target cells and tissues
Purity Undifferentiated cells, cells exhibiting abnormal growth,
transformed cells, contaminating cells
Tests for process-related
impurities
Raw materials, non-cellular components, media
ingredients (including feeder cells), chemical reagents, or
any other process-related materials
Tests for cell-derived undesirable
physiologically active substances
Sterility tests, Tests for the presence
of mycoplasma, Endotoxin tests,
Virus tests
Potency tests, Specific biological
tests
Secretion of a specific physiologically-active substance
from the cell, specific (quantitative or qualitative) biological
testing that takes into account the cell type
Mechanical compatibility tests
Assay Cell number and cell viability
Specifications for the Final Products
19
・Mature physiological function
・Mechanical/Structural function
・Immune response
・・・etc
・Physiological response/modulation
・Immune response/modulation
・Differentiation
・・・etc
Key elements of Potency
20
Dilemma for Biological Assay
21
Selection of assay method
In vivo assay
Ex vivo assay
In vitro assay based on primary cells
In vitro assay based on cell lines
alternative method
Impacts for assay method
MoA vs Quality Control
Relation to clinical effects vs Technical capability/QC suitability
22
Potency should support prediction of efficacy of product.
If the secretion of a specific physiologically active substance from the cells or tissues is responsible for the efficacy or the essential effect of a product during its intended use, establish test parameters and/or acceptance criteria related to this substance in order to demonstrate the intended effect.
It should be more desirable to chose assay method that mimic and reproduce the intended physiological responses and functions by which the CTPs in patient focal site.
Point to Consider for Potency Assay
Assay Method and Procedure
23
Method and Procedure
The following points should be taken into consideration for the design of the assay method.
The action principle more relevant to MOA is adapted.
Physiological responses and functions can be measured.
More understanding the key points that affect assay results.
Appropriate QC system suitability has been established.
Analytical Validation (1)
24
ICH Q2 (R1)The following points should be taken into consideration for implementation.
More knowledge for the action principle of assay method
Further understanding assay skills and performance at each step and/or all step of testing
Identification of key parameters relevant to assay method and performance
Key parameters; Specificity, Linearity, Rage, Accuracy, Precision, Robustness
Analytical Validation (2)
25
Validation : ICH Q2 (R1)
What is the issues
The assay method is not a simple testing system, there may be multiple complicated steps.
The factors of variability in cell-based assay are complicated, it is not easy to control of testing system.
There in no appropriate reference standard substance.
It is often difficult to implicate according to ICH Q2.
More flexible approaches for each product
Conclusion
26
Key Enablers
Knowledge of product quality and process robustness Quality control strategy Determination on case-by-case basis for each product
More science and risk-based approaches
Flexible approaches to current requirement
Earlier & more frequent communication between industry and regulatory authority during development
Kazunobu Oyama, Ph.D.
Office of Cellular and Tissue based ProductsPharmaceuticals and Medical Devices Agency
Thank you for your attention!