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The Form and Substance of Higher Order Structure Studies Used to Support Comparability and Biosimilarity in Biological Drug Submission; a Regulator’s Perspective Omar Tounekti A/Manager Monoclonal Antibodies Division, Biologics and Genetic Therapies Directorate, Health Canada

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Page 1: The Form and Substance of Higher Order Structure Studies ... · biosimilar and the reference biologic drug. • The manufacturer should attempt to determine that the higher order

The Form and Substance of Higher Order

Structure Studies Used to Support

Comparability and Biosimilarity in

Biological Drug Submission; a Regulator’s

Perspective

Omar Tounekti

A/Manager Monoclonal Antibodies Division,

Biologics and Genetic Therapies Directorate, Health Canada

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Disclaimer

The opinions expressed by the speaker do not reflect the official position of Health Canada, and shall not be used for advertising or endorsement

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8th International Symposium on Higher Order Structure of Protein Therapeutics (HOS 2019)

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Presentation Outline

• Introduction

• HOS studies during product development

• HOS studies & the control strategy

• HOS studies to support comparability

• HOS studies to support biosimilarity

• Regulatory Perspective: other points to consider

• Conclusion

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8th International Symposium on Higher Order Structure of Protein Therapeutics (HOS 2019)

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Biologics and Genetic Therapies Directorate (BGTD)

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8th International Symposium on Higher Order Structure of Protein Therapeutics (HOS 2019)

Director’s General’s Office

Centre for Biologics Evaluation

Centre for Evaluation of

Radiopharmaceuticals and Biotherapeutics

Office of Regulatory Affairs

Office of Quality and Information

Management

Office of Policy and International Collaboration

Office of Business Integration and Risk

Management

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Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics

Chemistry and Manufacturing Review Divisions:

– Cytokines

– Hormones & Enzymes

– Monoclonal Antibodies

– Radiopharmaceuticals & Gene Therapies

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Biologics are generally large and complex molecules.

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Source: NIH

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HOS analytical methods could have a significant value

added throughout the product lifecycle

– Selection of the best candidate

– Process design

– Formulation development studies

– Characterisation studies

– Storage conditions (stability studies)

– Establishment of the appropriate control strategy (better risk assessment)

– Process consistency: comparability studies

– Investigation of deviations

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8th International Symposium on Higher Order Structure of Protein Therapeutics (HOS 2019)

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Product development

Determination of product's HOS, including secondary and tertiary structure,

mechanisms of aggregation and degradation, will increase the knowledge of the

structure/function relationship.

HOS data may contribute to the assessment of risk for some product attributes

and could allow the identification of drug substance critical quality attributes

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8th International Symposium on Higher Order Structure of Protein Therapeutics (HOS 2019)

ICHQ8 Pharmaceutical Development

ICHQ11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

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Product development

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8th International Symposium on Higher Order Structure of Protein Therapeutics (HOS 2019)

Analytical procedures used for determination of HOS are an important

element of the Quality by Design approach:

- understanding the molecular structure of the biologic

- identification of risk and definition of CQAs

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Control Strategy

• The physicochemical characterization program is important for setting the

appropriate specifications.

• Heterogeneity of Biologics defines their quality, the degree and profile of

this heterogeneity should be characterized, to assure lot-to-lot consistency.

This includes information regarding higher-order structure of the desired

product.

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S.3 Characterization

Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

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The product is the process!

– Production by a living organism (microorganism, or plant or animal

cells)

– Intricacy of the manufacturing process (raw materials, upstream,

downstream)

– Inherent complexity of the product

→ Biologics can be sensitive to very minor changes in the manufacturing

process

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Comparability (Consistency of Manufacturing)

• Following a manufacturing process change, manufacturers should attempt

to determine that higher order structure (secondary, tertiary, and

quaternary structure) is maintained in the product.

• Use of orthogonal methods to evaluate the same quality attribute (e.g.,

molecular weight, impurities, secondary/tertiary structures) to maximise the

possibility that differences in the product caused by a change in the

manufacturing process might be detected.

Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process

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Comparability (Consistency of Manufacturing)

• Determinations of product comparability can be based solely on quality

considerations if the manufacturer can provide assurance of comparability

through analytical studies

• The nature and the level of knowledge of the product is critical: relationship

between physicochemical Characteristics, HOS and biological activities.

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Biosimilarity

• A final determination of similarity will be based on all relevant data from

structural, functional, non-clinical and clinical studies.

• The comparative structural and functional studies will determine the type and

extent of data to be derived from non-clinical and clinical studies on the drug

product.

Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs (Health Canada)

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Biosimilarity

• Analytical tests should be carefully selected and optimised to maximise the

potential for detecting relevant differences in the quality attributes of the

biosimilar and the reference biologic drug.

• The manufacturer should attempt to determine that the higher order structure

(secondary, tertiary, and, where applicable, quaternary) is comparable. If

appropriate higher order structural information cannot be obtained, a relevant

biological activity assay (see biological activity below) could indicate a correct

conformational structure.

Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs (Health Canada)

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Regulatory Perspective: points to consider

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Analytical procedures used for HOS studies have a very high potential

New analytical technology and

modifications to existing technology

are continually being developed and

should be utilized when appropriate.

Source: Joomi Ahn, St. John Skilton, LCGC North America, Volume 31, Issue 6, pg 464–471

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Regulatory Perspective - Points to Consider

• The measurement of quality attributes in characterisation studies does not

necessarily entail the use of validated assays but the assays should be

scientifically sound and provide results that are reliable (ICH Q5E).

• Challenge to include certain HOS analytical procedures in the control

strategy

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Regulatory Perspective: Points to Consider

– HOS techniques are more complex than other conventional characterization

methods: Include description of important features such as sensitivity

(resolving power), variability, robustness and limitations of the HOS technique

– Several studies in different sections of the

file, absence of a document to tell the story:

What do these results mean?

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Source: https://visme.co/blog/how-to-tell-stories-with-data/

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Conclusion

• Use of modern biophysical techniques to characterise and assess the HOS

of biological therapeutics is a fundamental component of their development

process and the regulatory file.

• Use of these techniques to demonstrate comparability following a

manufacturing change and as part of the analytic similarity package for

biosimilar is encouraged.

• Relevance of the results as well as key features, advantages and

limitations of the techniques used to characterise and assess the HOS

should be well explained in the submission.

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Acknowledgments

• Dr Nancy Green

• Dr Wallace Lauzon

• Dr Evangelos Bakopanos

• Fiona Cornel

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