监管机构资讯

WuXi Biologics Regulatory Updates

Quarter 2 – 2019

Purpose & Disclaimer: The intent of this update is to provide the global regulatory agencies’ updates and new or revised documents during the period stated here. The items listed should neither be considered comprehensive nor exhaustive of all updates from the regulatory agencies but as such, the list contains items that the WuXi Biologics’ Regulatory Affairs team deems relevant to our potential or existing clients and partners developing biological therapeutics and vaccines. Therefore, this update is for information purposes only and is provided “as is” without any warranty, expressed or implied, as to the completeness or accuracy of the contents or its use or fitness for a particular purpose. Without limiting the generality of the foregoing, the document and information contained therein should not be construed as regulatory advice or representing, speaking or acting for any regulatory agency. The information is provided to support your efforts to remain informed and should not be used as a substitute for your own regulatory due diligence or actions.

FDA

Draft Guidance Document: Bispecific Antibody Development Programs Guidance for Industry (Posted: April 2019)

A general summary of the draft is provided below:

• This draft guidance addresses considerations and recommendations regarding the development programs and the type of data necessary to support the approval of bispecific antibodies.
• Discussions include general considerations and recommendations for bispecific antibody development programs, as well as regulatory, quality, nonclinical, and clinical considerations in the context of bispecific antibody development programs.
• There are unique development considerations for each different format of bispecific antibodies, such as stability and production yields, but in general the products should be characterized and the manufacturing processes should be developed in accordance with standard monoclonal antibody development practices.
• Quality attributes of bispecific antibodies, such as the relative amounts of homodimers, should be assessed.

Guidance Document: Considerations in Demonstrating Interchangeability with a Reference Product Guidance for Industry (Posted: May 2019)

This guidance provides a definition of interchangeability and an overview in demonstrating interchangeability. It discusses data and information required for application, considerations for the design and analysis of a switching study/studies, and considerations regarding the comparator product in a switching study/studies. A few other key considerations mentioned include:

• The term interchangeable or interchangeability means that “the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” To support a demonstration of interchangeability, a sponsor must show that the proposed interchangeable product “is biosimilar to the reference product.”
• Abbreviated considerations are provided for developing container closure systems and delivery device constituent parts for proposed interchangeable products. It is important to carefully consider the presentation of the proposed interchangeable product relative to the reference product. Sponsors are encouraged to contact the U.S. FDA early during product development to discuss the proposed presentation.
• Product complexity and the extent of comparative and functional characterization are product-dependent factors that may impact the data needed to support a demonstration of interchangeability.

Draft Guidance Document: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations Guidance for Industry (Posted: May 2019)

This draft guidance describes U.S. FDA’s recommendations on the design and evaluation of comparative analytical studies to support a demonstration of biosimilarity. A few key considerations and recommendations include:

• The scientific and technical information to be included in the CMC portion of a marketing application for a proposed product. Recommendation that comprehensive and robust comparative physicochemical and functional studies should be performed to evaluate the proposed product and the reference product.
• Description of the capabilities and limitations of the analytical methods used in these analytical assessments should be provided.
• U.S. FDA encourages sponsors to submit comprehensive comparative analytical data early in the development process: at the pre-IND stage; with the original IND submission; or with the submission of data from the initial clinical studies.
• When performing the comparative analytical assessment to support a demonstration of biosimilarity, manufactures should consider a number of factors, including expression system, manufacturing process, physicochemical properties, functional activities, target binding, impurities, reference product and reference standards, finished drug product, and stability of the proposed product and its reference product. For the comparative analytical assessment, considerations for the proposed product and reference products (including number of lots), considerations for data analysis (risk-assessment and quantitative and qualitative analysis), and comparative analytical assessment conclusions are discussed.

21 CFR Part 600 Revision: Removal of Certain Time of Inspection and Duties of Inspector Regulations for BiologicalProducts (Posted: April 2019)

U.S. FDA is revising section 600.21 to remove the biennial inspection requirement for biological product establishments that are registered as drug establishments. General summary is provided below:

• This rule was made effective May 2, 2019.
• U.S. FDA is taking this action to remove outdated requirements and accommodate new approaches, such as a risk-based inspection frequency for drug and device establishments, thereby providing flexibility without diminishing public health protections.
• Revision and removal of these regulations do not change the biological product establishment inspection requirements.

U.S. FDA’s Efforts to Advance the Development of Gene Therapy (May 2019)

FY20 PDUFA Dear Colleague Letter (May 2019)

Regulatory Education for Industry (REdI) Annual Conference (May 2019)

Report on the State of Pharmaceutical Quality, 2018 (May 2019)

Submitting Documents Utilizing Real-World Data and Real-World Evidence to U.S. FDA for Drugs and Biologics; Draft Guidance for Industry (May 2019)

New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication (June 2019)

Modernizing U.S. FDA’s New Drugs Regulatory Program (June 2019)

Guidance Agenda: Guidance Documents CBER is Planning to Publish During Calendar Year 2019 (June 2019)

E19 Optimisation of Safety Data Collection; International Council for Harmonisation; Draft Guidance for Industry (June 2019)

CDER Conversation: Ensuring That Standardization Does Not Impede Biological Product Innovation (June 2019)

U.S. FDA Takes New Step to Help Advance the Transition of Certain Biological Products (June 2019)

Biological License Applications and Master Files (June 2019)

EMA

European Medicines Agency post-authorisation procedural advice for users of the centralised procedure (Posted: April 2019)

This guidance document addresses a number of questions which Marketing Authorization Holders (MAHs) may have on post-authorization procedures. It provides an overview of the Agency’s position on issues, which are typically addressed in discussions or meetings with MAHs in the post-authorization phase. Key revisions include:

4.12 How shall my Extension Application be handled (timetable)?

Revisions of the extension application timetables:

• The Agency shall ensure that the opinion of the CHMP is given within 210 days (less any clock-stops for the applicant to provide answers to questions from the CHMP).
• A positive opinion can be adopted either at Day 120 or Day 180 should no questions remain at these milestones.

7.2.13 Variation classification category for transfer of test methods for testing of biological medicinal products to a new or already authorized testing site:

• In case of physical, chemical and microbiological test methods to be transferred to a new testing site, submission of a variation classified in variation code B.II.b.2 is required. The variation category and documentation to be submitted is defined in the EC Variation Classification Guideline.
• In the case of biological, immunological, or immunochemical test methods to be transferred to a new testing site or to an already approved testing site, a variation classified in variation code B.I.a.1 or B.II.b.2 is to be submitted. The method transfer protocols should be submitted. Additional data such as a summary of the analytical method transfer test results may be required depending on a risk based evaluation.

Practical guidance for procedures related to Brexit for medicinal products for human and veterinary use within the framework of the centralised procedure (Posted: April 2019)

This practical guidance addresses the situation where the United Kingdom (UK) withdraws from the European Union (EU) on March 30, 2019, which was postponed to October 31, 2019, without a withdrawal agreement and hence without a transition period provided in the draft Withdrawal Agreement. MAHs and applicants of centrally authorized products for human or veterinary use need to ensure that the necessary changes are made by the withdrawal date, unless indicated otherwise in this guidance.

1. How will the UK’s withdrawal affect ongoing applications that include manufacturing sites with GMP certificates issued by UK authorities?

• For marketing authorization and post-authorization applications in centralized procedure that are under assessment at the time of UK’s withdrawal from the Union, a risk based approach will be applied by the assessing competent authorities concerning the sites with GMP certificates issued by the UK.
• The need to request a GMP inspection will be considered by an EU/EEA Competent Authority.

1. Can I request a delay for transfer of batch control testing to the EU/EEA? (NEW)

• Competent authorities may for a limited time after UK’s withdrawal from the Union allow, in justified cases, batch release to continue to rely on quality control testing performed in the UK.
• For centrally authorized medicinal products, such requests should be submitted to the EMA.

Draft Guideline on the Quality Requirements for Drug-device Combinations (June 2019)

Annual Reports and Work Programmes (March 2019)

United Kingdom’s Withdrawal from the European Union (‘Brexit’) (Updated: April 2019)

IRIS Quick Guide to the Portal for Orphan Industry Users (Updated: May 2019)

How to Prepare and Review a Summary of Product Characteristics (Updated: June 2019)

Small and Medium-sized Enterprise (SME) Office Annual Report 2018 (June 2019)

Two Additional Countries to Benefit from EU-US Mutual Recognition Agreement for Inspections (June 2019)

One additional country (Germany) to benefit from EU-US mutual recognition agreement for inspections (June 2019)

Questions and Answers on the Impact of Mutual Recognition Agreement between the European Union and the United States as of 27 June 2019 (Updated: June 2019)

EU GMP Guide Part IV: GMP Requirements for Advanced Therapy Medicinal Products (ATMP): Guidelines on GMP Specific to ATMPs (June 2019)

WHO

WHO Expert Committee on Specifications for Pharmaceutical Preparations; Fifty-third report (Posted: May 2019)

This report summarizes the key decisions and recommendations made by the WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) at its fifty-third meeting in 2018. The report also updates ECSPP’s progress in standard-setting and guideline draft evaluations for global medicine quality control and quality assurance purposes. Below are some of the updates from this document.

• Some key new guidelines adopted include:
  • Good manufacturing practices: guidelines on validation
• Guidelines on import procedures for pharmaceutical products
  • WHO Good Manufacturing Practices for Sterile Pharmaceutical Products is currently under revision to achieve a harmonized text with the EU and PIC/S, which will be presented to ECSPP in October 2019.
  • A list of International Nonproprietary Names (INNs) are published in the journal WHO Drug Information, as well as in a cumulative list.
  • The eighth edition (2018) of The International Pharmacopoeia is now available online on the WHO website.
  • The final draft of guidance documents that merges the principles of quality management systems with those of good regulatory practices will be available in October 2019.

WHO Expert Committee on Biological Standardization; Sixty-ninth report (Posted: June 2019)

This report presents the key decisions and recommendations of the WHO Expert Committee on Biological Standardization (ECBS) at its sixty-ninth meeting in 2018. Topics include the adoption of international recommendations for the production and control of vaccines and other biological substances, and the establishment of international biological reference materials. Below are some of the updates from this document.

• Four WHO written standards were adopted:
  • Recommendations to assure the quality, safety and efficacy of recombinant hepatitis E vaccines
  • Guidelines for the safe development and production of vaccines to human pandemic influenza viruses and influenza viruses with pandemic potential
  • Guidelines for the safe production and quality control of poliomyelitis vaccines
  • WHO Questions and Answers: Evaluation of similar biotherapeutic products.
• The ECBS also recommended:
  • The immediate discontinuation of the inclusion of the innocuity test in all future WHO documents on vaccines and other biologicals published in the Technical Report Series
  • The standardization of cellular and gene therapies should be included in the work of WHO as an area of great importance from the global public health perspective
  • The standardization of priority pathogens for public health emergencies should remain a WHO priority.

Quality Systems Requirements for National Inspectorates (QAS/19.811) (May 2019)

Cross-Agency Collaboration

U.S. FDA and PMDA

JP Drafts for Public Comments, End of Consultation (June 2019)

• A Basic Concept of the Quality Assurance on Biotechnological Products (Biopharmaceuticals)
• Control of Culture Media and Strains of Microorganisms Used for Microbial Test Methods
• Packaging Integrity Evaluation of Sterile Products
• Leak Tests for Packaging of Sterile Products

Half Yearly Performance Snapshot: July to December 2018 (April 2019)

Vaccines Overview (May 2019)

GMP Clearance Guidance Update (Version 18.3) (June 2019)