监管机构资讯

WuXi Biologics Regulatory Updates

Quarter 1 – 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

Rare Diseases: Common Issues in Drug Development Guidance for Industry (Posted: February 2019)

This guidance revises and replaces the draft guidance document Rare Diseases: Common Issues in Drug Development Guidance for Industry issued in August 2015. Revisions made from the previous version include additional information on changes to drug substance or manufacturing process with clarification on areas of flexibility. A summary of changes include:

• The agency encourages sponsors to discuss pharmaceutical quality development plans in early-phase development, including during the pre-IND meeting with the agency, and throughout drug development to decrease the potential for development or approval delays related to drug manufacturing.
• It is recommended that CMC changes be carefully assessed at every phase of development. These assessments might include both nonclinical studies and clinical trials. Assessment studies should be conducted with each change, and could inform whether nonclinical and clinical bridging studies will be needed. To minimize possible delays in development, manufacturing changes should be made as early as feasible.
• U.S. FDA may exercise some flexibility on certain components expected at the time of submission and approval (e.g., stability updates, validation strategies, inspection planning, manufacturing scale-up). U.S. FDA can explore the level of flexibility on a case-by-case basis after considering factors such as the following: (1) product characteristics, (2) seriousness of the condition and medical need, (3) manufacturing processes, (4) the robustness of the sponsor’s quality system, and (5) the strength of the sponsor’s risk-based quality assessment.

Draft guidance on CDER’s Program for the Recognition of Voluntary Consensus Standards Related to Pharmaceutical Quality Guidance for Industry (Posted: February 2019)

• The purpose of this program as outlined in the draft guidance is to use the Agency’s expertise to evaluate and informally recognize voluntary consensus standards related to pharmaceutical quality for products under CDER’s jurisdiction.
• This process will allow CDER to receive a candidate voluntary consensus standard (candidates in the past have included standards related too but not limited too: dosage forms, testing methodologies, manufacturing practices, product standards, scientific protocols, compliance criteria, ingredient specifications, labeling criteria), evaluate and determine whether to informally recognize it and list the informally recognized standard in a searchable database on CDER’s website. An information sheet should accompany every recognized standard.
• CDER’s Pharmaceutical Quality Standards Working Group (PQSWG) will take public comments of this draft guidance and develop an internal standards development process for informally recognizing a standard. The process will be documented in a publicly available Manual of Policies and Procedures (MAPP).
• For pharmaceutical industry, use of an informally recognized standard has the potential to streamline the compilation and review of marketing applications for products that are under CDER’s jurisdiction. Because CDER would have already evaluated the validity of a particular standard, the Agency would be able to focus on the output of that standard (e.g., the attribute evaluated by the standard).

Draft guidance for industry on Quality Considerations for Continuous Manufacturing (Posted: February 2019)

This draft guidance provides information regarding U.S. FDA’s current thinking on the quality considerations for continuous manufacturing of small molecule, solid oral drug products.

• U.S. FDA supports the development and implementation of continuous manufacturing for drug substances and all finished dosage forms, including those submitted in NDAs, ANDAs, DMFs, BLAs, and OTC products. Scientific principles described in this guidance may be applicable to continuous manufacturing technologies used for these classes of drugs.
• However, this guidance is not intended to provide recommendations specific to continuous manufacturing technologies used for biological products under a BLA.

Draft Guidance Document: Nonproprietary Naming of Biological Products: Update Guidance for Industry (Posted: March 2019)

A few summary points on this draft guidance include:

• U.S. FDA is reconsidering whether vaccines should be within the scope of the naming convention.
• U.S. FDA considered two approaches to the format of the suffix for interchangeable products:
  • A unique suffix that distinguishes an interchangeable product from other products sharing the same core name, or
  • A suffix shared with the reference product.
• Manual of Policies and Procedures (MAPP) 6720.5 Procedures for Handling Requests for Nonproprietary Name SuffixReview for Biological Products Newly Licensed Under Section 351 of the PHS Act was issued to describe procedures for handling requests for nonproprietary name suffix review for INDs and BLAs for originator biological products, related biological products, and biosimilar products to be used in the CDER. This MAPP will be revised to reflect the changes once the guidance is finalized.

Guidance Agenda – New & Revised Draft Guidances CDER Plans to Publish during Calendar Year 2019 (Posted: March 2019)

CDER (Center for Drug Evaluation and Research) has issued its guidance agenda for new and revised draft guidances it plans to publish for calendar year 2019. Guidances of different categories related to biological products or the type of work and services that WuXi Biologics performs for its clients and partners are listed below. Guidances listed in bold style are already published and are included in this newsletter.

• Pharmaceutical Quality/CMC:
  • CDER’s Program for the Recognition of Voluntary Consensus Standards
  • Quality Considerations for Continuous Manufacturing (CM)
  • Risk Management Plans for Drug Manufacturers
  • Inspection of Injectable Products for Visible Particulates
  • Setting Endotoxin Limits During Development of Investigational Oncology Drugs and Biologics
  • Stability Considerations for NDAs, ANDAs and BLAs
• Biosimilars:
  • Comparative Analytical Assessment to Support a Demonstration of Biosimilarity to a Therapeutic Protein Product
• Rare Disease:
  • Common Issues in Drug Development
• Procedural:
  • Implementation of the “Deemed to be a License” Provision of the BPCI Act: Questions and Answers
• Electronic Submissions:
  • Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
  • Establishment Registration and Drug Listing
  • Providing Regulatory Submissions in Electronic Format: IND Safety Reports

Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (January 2019)

OPQ’s Public Annual Report (January 2019)

Labeling for Human Prescription Drug and Biological Products Approved Under the Accelerated Approval Regulatory Pathway Guidance for Industry (January 2019)

EMA

Regulation (EU) 2019/5 of the European Parliament and of the Council of 11 December 2018 (Posted: January 2019)

This regulation is to amend Regulation (EC) No 726/2004, Regulation (EC) No 1901/2006 and Directive 2001/83/EC. The major amendments are listed as below. For more details of the revisions for Regulation (EC) No 726/2004, please refer to the consolidated version of Regulation (EC) No 726/2004. Some of the key highlights of the regulation include:

• Amendments to Regulation (EC) No 726/2004 forming European Union procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency:
  • The word ‘Community’ is replaced by the word ‘Union’.
  • Article 14-a and Article 20a: For unmet medical needs, conditional marketing authorization may be granted prior to the submission of comprehensive clinical data. Failure to comply with the Marketing Authorization Applications (MAA) obligation can result in suspension or revocation of the MAA.
  • Article 16a and 16b: Variations shall be classified and reported properly. The transfer to a new Marketing Authorization Holder (MAH) is not considered to be a variation. Appropriate submissions are needed.
  • Article 84a: The Commission may impose financial penalties on a MAH if it fails to comply with any of the obligations of the MAA.
• Amendments to Directive 2001/83/EC on the Community code relating to medicinal products for human use:
  • Article 1, 23b: Variation-related articles are updated according to the amendments to Regulation (EC) No 726/2004.
• Regulation (EC) No 1901/2006 on medicinal products for pediatric use:
  • Article 49: Penalty-related content is updated according to the amendments to Regulation (EC) No 726/2004.

European Medicines Agency Pre-authorisation Procedural Advice for Users of the Centralised Procedure: Document with Tracked Changes (Updated: February 2019)

A subset of the EMA provided updates within this document is provided below:

• 3.4.1: Applicants should provide declaration in the cover letter where they confirm that the detailed information in relation to the manufacturing sites contained in Module 3 (sections 3.2.P.3.1 and 3.2.S.2.1) is correct in terms of names, addresses and manufacturing activities and that this information is consistent throughout the dossier, in particular with the corresponding information contained in Module 1.
• 3.4.1: Should discrepancies be found after the start of procedures, EMA will rely on the information in the electronic application form for registered manufacturing sites and applicants will have to take the next opportunity to bring Module 3 in line with the application form.
• 4.3: The Agency has made the checklist of the regulatory and administrative content validation available to applicants (Dossier administrative validation checklist) to facilitate initial marketing authorization applications. The list is not exhaustive; however, it will provide an indication of issues that may be raised during validation. It is recommended to include a completed validation checklist in your application among the ‘working documents’ of the submission.

Guideline on the Sterilisation of the Medicinal Product, Active Substance, Excipient and Primary Container (Posted: March 2019)

It is anticipated that this guidance will come into effect by October 1, 2019. Some of the highlights include:

• Guidance is provided on the selection of appropriate methods of sterilization for sterile products. Terminal sterilization (e.g. terminal sterilization by steam, dry heat and ionizing irradiation) using the most appropriate reference condition listed in the European Pharmacopeia (Ph. Eur.) for your product/process is the method of choice whenever possible. See 5.1.1 “Methods of preparation of sterile products” and other conditions stated in that monograph.
• This guideline provides information on when other terminal sterilization processes, sterilizing filtration or aseptic processing, (either alone or when combined with an additional post-aseptic processing terminal heat treatment), could be accepted as an alternative.
• The guideline applies to chemical and biological medicinal products for human and veterinary use, including sterile finished products, sterile active substances, sterile excipients and sterile primary containers in a new Marketing Authorization Application (MAA) or a variation application for a medicinal product.

20 Years of Sampling and Testing Programme for Medicines Authorised for the EU (Posted: March 2019)

The updates are summarized below:

• EMA supervises the quality of the centrally authorized medicines available on the European market through its yearly sampling and testing program. The main objective is to check the compliance with the authorized specifications.
• The program will be expanded from 2019 to include testing of biosimilar medicines and testing of centrally authorized products (CAPs) from parallel distribution chains to verify their authenticity.
• The selection of medicines for sampling and testing follows a risk-based approach and considers specific criteria such as products with a narrow therapeutic range, complex manufacturing process, poor stability or a high exposure, as well as the pharmaceutical forms and patient profiles.
• Human vaccines and plasma-derived medicinal products are excluded from this program.

Human Medicines: Highlights of 2018 (January 2019)

This update is an overview of key EMA recommendations from 2018. A few notes from this overview include:

• 84 medicines were submitted for marketing authorization.
• Among them, 42 had a new active substance which has never been authorized in the EU prior to 2018.

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

EU and Switzerland to Improve Information-Sharing on Good Manufacturing Practice Through Use of the EudraGMDP Database (February 2019)

Overview of Comments Received on ICH Guideline Q12 on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (January 2019)

European Medicines Agency Post-authorisation Procedural Advice for Users of the Centralised Procedure – (Track Changes) (Updated: February 2019)

European Medicines Agency Procedural Advice for Users of the Centralised Procedure for Similar Biological Medicinal Product Applications (Track Changes) (Updated: February 2019)

National Registers of Authorised Medicines (February 2019)

Checking Process of Mock-ups and Specimens of Outer/Immediate Labelling and Package Leaflets of Human Medicinal Products in the Centralised Procedure (March 2019)

Electronic Product Information for Human Medicines in the European Union – Draft Key Principles (January 2019)

Guideline on Quality, Non-clinical and Clinical Requirements for Investigational Advanced Therapy Medicinal Products in Clinical Trials (Draft) (January 2019)

Product-Information Requirements (Updated: January 2019)

Procedural Update on Submission of Type I Variations to EMA in March, April and May 2019 (February 2019)

EU Adopted ICH Q3D(R1) on Elemental Impurities, Effective from March 29, 2019 (March 2019)

Regulatory Information – Adjusted Fees for Applications to EMA from 1 April 2019 (March 2019)

Practical Guidance for Procedures Related to Brexit for Medicinal Products for Human and Veterinary Use Within the Framework of the Centralised Procedure (March 2019)

PIC/S

PIC/S Guidance on Classification of GMP Deficiencies (PI 040-1) Posted: January 2019

• This guidance came into effect from January 1, 2019. It is intended to provide a tool to support the risk based classification of GMP deficiencies from inspections and to establish consistency amongst inspectors.
• This guidance also provides examples of the classification of different types of deficiencies, including “Critical”, “Major”, and “Other.”