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Regulatory Newsletter

H1 2023 Regulatory Updates
Jul. 31, 2023
H1 2023 Regulatory Updates

WuXi Biologics’ Regulatory Affairs team is honored to provide you with a summary of what we deem as the relevant (i.e., product development and CMC-related) regulatory updates that are either in draft or final status by agency and by topic. We have compiled these updates to support your efforts to stay current in the ever-changing regulatory environment for biological therapeutics and vaccines.

 

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.

 

Quick Links to Agency Sections:

 

FDA (U.S. Food and Drug Administration)

Notifying FDA of a Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients Under Section 506C of the FD&C Act Guidance for Industry

April 5, 2023

 

This is a draft guidance and is being distributed for comment purposes only. When finalized, this guidance will replace the March 2020 guidance for industry Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing Under Section 506C of the FD&C Act.

 

Section 506C of the FD&C Act requires applicants and manufacturers of certain finished drugs and biological products to notify FDA of (1) a permanent discontinuance in the manufacture of such products, (2) an interruption in the manufacture of such products that is likely to lead to a meaningful disruption in supply of those products in the United States, (3) a permanent discontinuance in the manufacture of API for such products, or (4) an interruption in the manufacture of API for such products that is likely to lead to a meaningful disruption in the supply of the API for those products. Notifications must include disclosure of reasons for the discontinuation or interruption.

 

The persons who must submit notifications under section 506C (collectively referred to in this guidance as manufacturers) are as follows:

  • Applicants with approved new drug applications (NDAs) or approved abbreviated new drug applications (ANDAs) for certain finished drug products
  • Applicants with approved biologics license applications (BLAs) for certain finished biological products other than blood or blood components
  • Applicants with approved BLAs for blood or blood components for transfusion that manufacture a significant percentage of the U.S. blood supply
  • Manufacturers of certain finished drug products marketed without approved NDAs or ANDAs

 

Manufacturers of covered finished products must submit a notification to FD at least 6 months in advance. However, if 6 months’ advance notice is not possible, the notification must be submitted as soon as practicable thereafter. Manufacturers should submit a separate notification for each permanent discontinuance or interruption in manufacturing. A single initial notification may include a list of all affected covered finished products or API.

 

The full document can be found in the following address:

Notifying FDA of a Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients Under Section 506C of the FD&C Act Guidance for Industry

 

Understanding CDER’s Risk-Based Site Selection Model, MAPP 5014.1 Rev.1

Jun 26, 2023

 

This MAPP outline how the Office of Pharmaceutical Quality will manage the Site Selection Model (SSM) used by Center for Drug Evaluation and Research (CDER) staff to prioritize manufacturing sites for routine quality-related (i.e., current good manufacturing practice (CGMP)) surveillance inspections. This version is updated to include FDORA 2022, CARES Act, and quality system effectiveness, updated OS to OQS, and made non-substantive, editorial changes.

The Office of Quality Surveillance (OQS) is responsible for producing CDER’s Site Surveillance Inspection List (SSIL) that prioritizes sites for surveillance inspections. This MAPP identifies specific risk factors and allows FDA to determine additional ones. It also introduces the procedures how OQS run the SSM.

 

The full document can be found in the following address:

OFFICE OF PHARMACEUTICAL QUALITY MAPP 5014.1 | Understanding CDER’s Risk-Based Site Selection Model (fda.gov)

 

Other FDA Drug Development and Quality Guideline Updates

 

Other FDA Regulatory Submission and Procedure Updates

 

Other FDA Coronavirus Disease (COVID-19) Updates

  • FDA: The guidance of Development and Licensure of Vaccines to Prevent COVID-19; Guidance for Industry is intended to remain in effect until November 7, 2023, unless superseded by a revised final guidance before that date. FDA plans to further revise this guidance with any appropriate changes based on comments received and the Agency’s experience with implementation.

  • The full document can be found in the following address:

    Development and Licensure of Vaccines to Prevent COVID-19; Guidance for Industry (fda.gov).

 

Other FDA Updates

 

 EU (European Union) / EMA (European Medicines Agency)

EMA: Report on Divergent Opinion between EFSA and EMA on Bisphenol-A

April 19, 2023

 

The European Food Safety Authority (EFSA) revised the tolerable daily intake (TDI) for bisphenol A (BPA) from 4 µg/kg body weight (bw) per day to 0.2 ng/kg bw per day (EFSA CEP Panel, 2023). European Medicines Agency (EMA) and EFSA had a dialogue regarding the revision of the TDI of BPA. The conclusion is that EMA is not in agreement with the change of TDI as EMA and EFSA make use of difference assessment tools and methodologies to evaluate the risk for human.

 

The full document can be found in the following address:

Report: Report on Divergent Opinion between EFSA and EMA on Bisphenol-A

 

EMA: Statement on the Scientific Rationale Supporting Interchangeability of Biosimilar Medicines in the EU

April 28 2023

 

The EU experts on biosimilar medicines (Biosimilar Medicines Working Party or BMWP) and the Heads of Medicines’ Agencies (HMA) Biosimilar Working Group have drafted a joint statement explaining the rationale for considering biosimilars approved in the EU as interchangeable from a scientific perspective. This statement has been endorsed by the Committee for Medicinal Products for Human Use (CHMP) and the Biologics Working Party (BWP).

 

HMA and EMA consider that once a biosimilar is approved in the EU it is interchangeable, which means the biosimilar can be used instead of its reference product (or vice versa) or one biosimilar can be replaced with another biosimilar of the same reference product. Interchange should only take place after careful consideration of the approved conditions of use (i.e., consulting the most recent product information). From a scientific viewpoint, interchangeability of approved biosimilars has always been considered acceptable and did not raise any concern. However, EMA has to date not issued any recommendation on interchangeability. At present the EU medicines regulatory network has identified the need to explicitly state that from a scientific point of view, biosimilars approved in the EU can be considered interchangeable.

 

However, decisions on how to implement interchangeability either through switching and/or substitution, are not within the remit of EMA and are managed by individual member states. Member States will continue to decide which biological medicines are available for prescribing in each territory and whether automatic substitution is allowed at pharmacy level.

According to the Q&A document which addresses questions received after publication of the statement, the interchangeability applies to the following situations:

  1. Biosimilars cover situations where multiple switches are taking place – independent of frequency of switches and number of products involved;
  2. Biosimilars with a more complex molecular structure;
  3. Biosimilars that do not have all the indications of the reference or another biosimilar medicine provided each medicine is used according to its approved conditions of use, as reflected in the EU product information.
  4. Biosimilars do not have exactly the same conditions of use as the reference or another biosimilar medicine with the same therapeutic intent.

 

The full document can be found in the following address:

Statement-scientific-rationale-supporting-interchangeability-biosimilar-medicines – EMA review following PROM endorsement

QA – Biosimilars Interchangeability Statement – for publication 21 Apr 2023 (europa.eu)

 

Concept Paper on the Development of a Guideline on the Quality Aspects of mRNA Vaccines

Jun 20, 2023

 

Currently there is no guideline which reflects the quality requirements for regulators and industry on mRNA containing vaccines. Whereas the production of mRNA vaccines has to align with the general guidance for human vaccines, specific quality considerations may apply to these novel products. The proposed guideline will provide information and regulatory considerations regarding the following key aspects of the manufacture and quality control:

  • Definitions of starting materials, active substance, finished product intermediate, excipients and finished product
  • Control of starting materials(linear DNA template for the preparation of mRNA transcript and plasmid DNA where relevant)
  • Development of an integrated control strategy for the active substance and finished product manufacturing process to ensure consistent quality of mRNA vaccines, based on relevant critical quality attributes (CQAs)
  • Characterisation approaches including investigation of the impurity profile
  • Purity control strategy: process-related and product-related impurities as well as other potential contaminants and methods to control them
  • Active substance and finished product specifications
  • Potency testing: different tests may be required to control various aspects of potency also including functionality (e.g. mRNA expression, protein expression in transduced cells)
  • Various aspects with respect to the formulation strategies including considerations on formation and method of manufacturing of lipid nanoparticles (LNPs) and their stability
  • Stability studies for active substanceand finished product
  • The proposed guideline will also discuss relevant regulatory considerations and challenges relating to:
  • the development and testing of bivalent and multivalent vaccines, as well as to changes in the existing mRNA vaccine strains
  • self-amplifying mRNA (sa-mRNA) packaged in LNPs
  • other delivery systems (i.e. non-LNPs)
  • the use of platform technology/prior knowledge approach for new targets
  • This concept paper will be published for a three-month public consultation period. The Biologicals Working Party will take account of all comments received during the public consultation on the concept paper when preparing the draft guideline. The draft guideline will be published for a six-month public consultation period.

 

The full document can be found in the following address:

Concept paper on the development of a guideline on the quality aspects of mRNA vaccines (europa.eu)

 

EMA Coronavirus Disease (COVID-19) Updates

The European Center for Disease Prevention and Control (ECDC) and the European Medicine Agency (EMA) have issued a joint statement on adapted COVID-19 vaccines and considerations for their use during the upcoming autumn 2023 vaccination campaigns. Currently authorized vaccines continue to be effective at preventing hospitalization, severe disease and death due to COVID-19. However, protection against the virus declines over time as new SARS-CoV-2 variants emerge. Timing of recommendations to update vaccine composition has an impact on some platform technologies that require longer time for manufacturing, and this aspect needs to be considered. Besides, based on decades of experience with influenza and discussions with different developers, it can be foreseen that a recommendation on the potential need to adapt vaccine composition should be issued at regular intervals to allow stakeholders to deliver a timely vaccination campaign.

 

The full document can be found in the following address:

Statement from Emer Cooke on the End of the COVID-19 Public Health Emergency

EMA and ECDC statement on updating COVID-19 vaccines to target new SARS-CoV-2 virus variants | European Medicines Agency (europa.eu)

 

Other EMA Drug Development and Quality Guideline Updates

 

Other EMA & EC Regulatory Submission and Procedure Updates

 

Other EMA & EC Vaccines, Gene Therapy, and Advanced Therapy Medicinal Products Updates

 

Other EMA Updates

 

TGA (Therapeutic Goods Administration)

TGA Updates

 

Health Canada

Health Canada Drug Development and Quality Guideline Updates

 

WHO (World Health Organization)

 

WHO Coronavirus Disease (COVID-19) Updates

On 5th May 2023, the WHO Director General declared an end to the Public Health Emergency of International Concern (PHEIC) for the disease caused by the coronavirus SARS-CoV-2 (the news link is as follows: WHO: Statement on the fifteenth meeting of the IHR (2005) Emergency Committee on the COVID-19 pandemic). EMA remains fully committed to supporting the EU response to the COVID-19 threat and ensuring that new or adapted vaccines and therapeutics can be made available as needed. In terms of operations, EMA will make adjustments regarding certain activities that are only needed or are even reserved for these types of crises. Updates about these changes will be provided in the coming weeks.

 

MHRA 

 

MHRA Drug Development and Quality Guideline Updates

 

PMDA (Pharmaceuticals and Medical Devices Agency)

 

PMDA Drug Development and Quality Guideline Updates

 

ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use)

ich-logo

 

Q13 Continuous Manufacturing of Drug Substances and Drug Products Guidance for Industry

March 01 2023

 

On 1 March 2023, a new industry guidance, Q13 Continuous Manufacturing of Drug Substances and Drug Products, issued by FDA, explains the scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing (CM). Building on existing International Council for Harmonization (ICH) Quality guidance, ICH Q13, this guidance provides clarification on CM concepts and describes scientific approaches and regulatory considerations specific to CM of drug substances and drug products.

First of all, a key component of the guidance is related to the CM Control Strategy, which considers the principles within Q7, Q8, Q9, and Q10 and includes: process for evaluating the performance of CM operations; understanding/characterization of process dynamics; material characterization and control, including those incoming material critical attributes and their impact on the CM operations; equipment design and system integration, including an understanding of the characteristics of the integrated and individual equipment and impact on CM process performance; process monitoring and control, which includes the use of process analytical technology (PAT) as a means of automated process adjustment along with realtime release testing; material traceability and diversion, which addresses the risk of process disturbances and the ability to divert potential nonconforming product; and the role of process models when developing the CM operation.

Secondly, there is also discussion and guidance addressing various approaches to changing CM production output and consideration of the impact on the control strategy.  It is clear from the guidance that PAT tools are integral to CM, which is somewhat intuitive as realtime process monitoring is essential to ensuring the state of control and allows the generation of development data at the same scale of commercial manufacture supporting early execution of process validation and the adoption of continuous process verification.

Last, there is a significant section dedicated to Regulatory Considerations that provides guidance for the CM process dossier per ICH M4 as well as Annexes.

Impact Assessment: the guidance applies to CM of drug substances and drug products for chemical entities and therapeutic proteins. The principles described in this guideline may also apply to other biological/biotechnological entities. It can be applicable to CM for new products, such as new drugs, generic drugs, and biosimilars, and for the conversion of batch manufacturing to CM for existing products. The Table 1 Recommended CM-Related Information in the CTD, on Pages 14-16 is useful for CM related CMC dossier preparation and drafting.

 

ICH Q13 Implementation status:

  • ANVISA, Brazil – In the process of implementation; Date: 1 December 2023;
  • EC, Europe – In the process of implementation; Date: 10 July 2023;
  • FDA, United States – Implemented; Date: 1 March 2023; Reference: Vol. 88, No. 40, p. 12941-12942
  • HSA, Singapore – In the process of implementation;
  • Health Canada, Canada – In the process of implementation;
  • MFDS, Republic of Korea – In the process of implementation; Date: 1 December 2023;
  • MHLW/PMDA, Japan – Implemented; Date: 31 May 2023; Reference: PSEHB/PED Notification No. 0531-1
  • MHRA, UK – Not yet implemented;
  • NMPA, China – In the process of implementation;
  • Swissmedic, Switzerland – Implemented; Date: 16 November 2022; Reference: ICH Guidelines apply in Switzerland automatically upon reaching Step 4: Swissmedic Journal 05/2006, p. 504
  • TFDA, Chinese Taipei – In the process of implementation;

 

The full document can be found in the following address:

Q13 Continuous Manufacturing of Drug Substances and Drug Products (fda.gov)

https://www.ich.org/page/quality-guidelines

 

Other ICH Updates

 

EDQM (European Directorate for the Quality of Medicines & HealthCare)

 

Ph. Eur. Commission Kicks off Elaboration of Three General Texts on mRNA Vaccines and Components

May 05,2023

 

The notice describes that the European Pharmacopoeia Commission (EPC) agreed to elaborate three new general texts addressing aspects related to the production and control of mRNA vaccines and their components, namely:

  • mRNA Vaccines for human use (5.36), the mRNA packaged in lipid nanoparticles, i.e. mRNA-LNP medicinal product;
  • mRNA Substances for the production of mRNA vaccines for human use (5.39), the mRNA active substances in the manufacture of mRNA vaccines;
  • DNA Template for the preparation of mRNA transcript (5.40), the starting material for the preparation of the mRNA component.

Addressing the quality of mRNA vaccines and their components has been identified as a significant ongoing project for the EPC in the field of nanomedicines, and preparing for a more comprehensive incorporation of these medicines in the European Pharmacopoeia (Ph. Eur.) is among its priorities for 2023-2025.

 

The full document can be found in the following address:

Ph. Eur. Commission Kicks off Elaboration of Three General Texts on mRNA Vaccines and Components

 

PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme)

 

PIC/S Drug Development and Quality Guideline Updates

 

 

Health Products Regulatory Authority (HPRA)

HPRA Drug Development and Quality Guideline Updates

 

National Medical Products Administration (NMPA)

 

Critical Regulatory Update Summary:

 

Notice on the Release of the “Technical Guidelines for the Study of Microbial Limits of Non-Sterile Chemical Drugs and Excipients (Draft) (No. 11 of 2023)” by the Drug Evaluation Center of the National Medical Products Administration

Feb 21, 2023

 

Summary: Microbial limits control for non-sterile chemical drugs and excipients are essential indicators reflecting product safety and quality. To further strengthen the application of quality risk management in product quality control and enhance the scientific and rational formulation of microbial limits for non-sterile chemical drugs and excipients, under the deployment of the National Medical Products Administration, the Drug Evaluation Center has developed the “Technical Guidelines for the Study of Microbial Limits of Non-Sterile Chemical Drugs and Excipients (Draft).”

 

This guidance focuses on providing a systematic exposition of control strategies, detection methods, limit formulation, production process control, and key considerations in the study of microbial limits for non-sterile chemical drugs and excipients. It also clarifies the requirements for the submission of microbial limit application materials.

 

The full document can be found in the following address:

https://www.cde.org.cn/main/news/viewInfoCommon/b522b0ea49412b5edc52f002a1d1036a

 

Guideline on Quality Risk Management (QRM) in the Manufacture of Different Medicinal Products in Shared Facilities 

2023-03-06

 

Objective: This guideline is intended to provide the analysis and guide strategies for the design, implementation and improvement of the medicinal products manufacturing in shared facilities throughout the product lifecycle, help relevant personnel understand the relationship between hazards, exposures and risks of the products manufactured in shared facilities based on QRM principles, analyze the routes of contamination and cross-contamination, scientifically determine the acceptable limits of residues, take measures to mitigate contamination and cross-contamination, continuously monitor the level of contamination and cross-contamination, ensure that the risks associated with contamination and cross-contamination can be effectively controlled, and ensure the product quality and patient safety. 

 

Definition: The products manufactured in shared facilities in this guideline refer to the multiple medicinal products are manufactured in the shared production lines, including shared buildings, equipment and utilities. QRM of the other shared facilities and instruments such as quality control laboratories, warehouses and sampling rooms, could also refer to the principles outlined in this guideline.  

 

Scope: The guideline applies to the products or drugs manufactured in shared facilities by the Marketing Authorization Holder (MAH) and manufacturers (including the DMF holder) using the commercial production lines, including Active Pharmaceutical Ingredient (API), pilot production samples of non-commercial production scale, Investigational Medicinal Products (IMP) and simulated materials introduced by the Process Validation, etc. The requirements presented in this guideline may also apply to the shared non-commercial production lines for the IMP production.

 

The full document can be found in the following address:

https://www.cfdi.org.cn/resource/attachment/ueFile/2023/03/TW9uIE1hciAwNiAxNTowODoyNiAyMDIzNDU5Nzg=.pdf

 

National Medical Products Administration Drug Evaluation Center Notice on the Release of the “Technical Guidance for Pharmaceutical Research and Evaluation of Human Stem Cell Products (Trial)” (No. 33 of 2023)

April 27, 2023

 

Summary: This guidance principle is mainly aimed at providing technical guidance for the pharmaceutical research during the marketing application stage of human stem cell products that are developed and registered in accordance with relevant drug administration regulations.

 

“Human stem cell products” in the guideline refers to the therapeutic products originating from human adult (stem) cells (adult stem cells ASCs or adult cells, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). After a series of in vitro operations involving stem cells, generally including expansion, gene modification, induced differentiation and transfer (differentiation), the obtained stem cells and their derived cells are added with preparation excipients, dispensed into specific containers, and meet the specification of drug release, which can be directly applied or combined with tissue engineering materials for clinical application. Among them, because it involves human cells, the cells for production need to comply with the relevant national ethical regulations.

 

The main body of this guideline consists of eight chapters: ‘Introduction’, ‘Scope of application’, ‘General considerations’, ‘Materials for manufacture’, ‘Manufacturing process’, ‘Quality studies and specifications’, ‘Stability studies’, and ‘Packaging and closure container systems.’

 

The full document can be found in the following address:

https://www.cde.org.cn/main/news/viewInfoCommon/1dfacaa7804aca84d648edb83b10c40b

 

State Administration for Market Regulation’s Announcement on Issuing the “Evaluation Criteria for the Accreditation of Inspection and Testing Institutions”

2023-06-01

 

Summary: To implement the requirements of deepening the reform of the accreditation approval system for inspection and testing institutions, carrying out comprehensive informed commitments, and optimizing approval services as set forth in the “Outline for Building a Strong Nation in Quality,” the State Administration for Market Regulation has revised the “Evaluation Criteria for the Accreditation of Inspection and Testing Institutions.” The document was approved at the 9th Administrative Meeting on May 15, 2023, and is now announced to be put into effect starting from December 1, 2023.

I. Purpose and Scope of Application

In accordance with the legal and regulatory implementation of the “Administrative Measures for the Accreditation of Inspection and Testing Institutions,” and related accreditation technical review requirements, the work of technical review for the accreditation of inspection and testing institutions within the territory of the People’s Republic of China (including verification of informed commitments) shall comply with these guidelines.

II. Review Content and Requirements

The technical review content for accreditation includes examining whether the inspection and testing institution, personnel, site environment, equipment, facilities, and management systems meet the accreditation requirements. Inspection and testing institutions should establish a management system that ensures the independence, impartiality, scientificity, and integrity of their inspection and testing activities, verifies that the system can be effectively, controllably, and stably implemented, and continuously meets the accreditation conditions and related requirements for inspection and testing institutions.

Review Methods and Procedures

The technical review methods for the general accreditation procedure include on-site review, written review, and remote review. Different technical review methods are adopted for reviewing specific issues related to the accreditation applied for by the institution, depending on the specific situation of the institution. The on-site review is applicable to initial review, expansion review, re-examination for certification (when actual capabilities have changed), and modification review for changes affecting its compliance with accreditation conditions and requirements. The written review method is suitable for a small number of parameter expansions or changes (not affecting meeting the accreditation conditions and requirements) within the already accredited technical capabilities and the re-examination for certification review of inspection and testing institutions with no illegal or irregular behaviors in the previous permit period, not listed on the blacklist, and with no substantial changes to the application matters. The remote review refers to the technical review of inspection and testing institutions using information and communication technology.

 

The full document can be found in the following address:

https://www.samr.gov.cn/zw/zfxxgk/fdzdgknr/rkjcs/art/2023/art_b97b0b1addbf4e8aaca43cb26f13883b.html

 

Other NMPA Updates

 

Other Regulatory Updates

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