Regulatory Newsletter

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 & Drug Administration)
• EU (European Union) / EMA (European Medicines Agency) / EC (European Commission) 
• TGA (Therapeutic Goods Administration) 
• Health Canada 
• WHO (World Health Organization) 
• MHRA (Medicines and Healthcare products Regulatory Agency) 
• PMDA (Pharmaceuticals and Medical Devices Agency) 
• ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use)
• EDQM (European Directorate for the Quality of Medicines & HealthCare)
• PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme)
• Health Products Regulatory Authority (HPRA)
• National Medical Products Administration (NMPA)

FDA (U.S. Food and Drug Administration)

Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA October 2022

The Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in  an NDA, ANDA, or BLA guidance document is intended to provide recommendations for the use of a comparability protocol (CP) to implement a chemistry, manufacturing, and controls (CMC) post-approval change of approved new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs). It is acceptable to submit a CP in an original application or in a prior approval supplement (PAS) to an approved application to assess the effect of a proposed post-approval CMC change(s). Submission and approval of a CP may advance the implementation of CMC changes, and the FDA may allow the reporting of certain changes instead of requiring approval, which could result in distribution of a product with the change or facilitating a proactive approach to reinforcing the supply of the product sooner than if a CP were not used. According to this guidance, a CP should include the following content:

• Summary
• Description of and rationale for the proposed CMC change(s)
• Supporting information and analysis
• Comparability protocol for the proposed CMC change(s)
• Proposed reduced reporting category
• Other information

Different from provisions in 21CFR 314.70(e) and 601.12(e), not all proposed modification to an approved CP must be submitted as a PAS. This guidance provides for a less burdensome notification of certain types of modifications to an approved CP as provided for in 21 CFR 314.70(a)(3) and 601.12(a)(3), to make CPs more useful and flexible, and to facilitate keeping CPs current. Some examples are given in this guidance for which modification(s) must be submitted as a CBE-30 supplement, CBE-0 supplement, or annual report rather than a PAS. At the end of this guidance, the FDA provides recommendations for what should be done/considered when making a CMC change(s) in accordance with an approved CP and reporting the change(s) using the reporting category specified in the approved CP. Some questions and answers on CP(s) are provided in the Appendix.

Federal Register: Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin; International Council for Harmonisation; Draft Guidance for Industry; Availability November 2022

The Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin is currently listed on the FDA’s website as a draft version that is expected to be finalized in 2023. It has been 23 years since the ICH published the Q5A(R1). The updated version, Q5A(R2), introduces nucleic acid amplification techniques and next generation sequencing as two new molecular methods under section 3.2 Recommended Virus Detection and Identification Assays. Sections 6.6 Application of Prior Knowledge for Evaluation of Viral Clearance and 7. Points to Consider for Continuous Manufacturing Processes are also newly added.

The purpose of this document is to provide a general framework for virus testing, experiments for the assessment of viral clearance, and a recommended approach for the design of viral tests and viral clearance studies. The guidance states that manufacturers should avoid using human- and animal-derived raw materials (e.g., human serum, bovine serum, porcine trypsin) in their manufacturing processes when possible. In general, in order to determine the amount of endogenous virus particles that enter the purification process, quantification should be performed on three cell culture campaigns, lots or batches. This data should be submitted as part of the marketing application or registration package.

Investigational New Drug Application Annual Reporting (Proposed Rule) December 2022

The Food and Drug Administration (FDA) is proposing to replace its current annual reporting requirement for investigational new drug applications (INDs) with a new requirement: the annual FDA development safety update report (FDA DSUR). The proposed rule would modify the format and content of the IND annual report to be generally consistent with those of the annual DSUR standards devised by the ICH. The proposed harmonization would result in reduced labor costs for certain sponsors who may no longer have to prepare different types of periodic safety reports for submission to certain other countries or regions wherea drug might be studied. Moreover, the FDA would receive safety data on investigational new drugs that is more comprehensive, which would enhance its ability to oversee the progress and safety of clinical investigations. Electronic or written comments on the proposed rule should be submitted by March 9, 2023.

Other FDA Drug Development and Quality Guideline Updates

• M10 Bioanalytical Method Validation and Study Sample Analysis 2022-11-07
• Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived Form Cell Lines of Human or Animal Origin 2022-11-10
• Initiative to Benchmark and Profile Monoclonal Antibody and Large Biomolecule Stability 2022-11-21
• Acceptance Criteria for Residual Solvents_MAPP 2022-12-01
• MAPP 5040.1: Product Quality Microbiology Information in the Common Technical Document – Quality (CTD-Q) 2022-12-07
• MAPP 5310.7: Acceptability of Standards from Alternative Compendia (BP/EP/JP)  2022-12-07
• MAPP 5015.5: CMC Reviews of Type III DMF’s for Packaging Materials 2022-12-09

Other FDA Regulatory Submission and Procedure Updates

• SOPP 8417: Implementation and Management of Risk Evaluation and Mitigation Strategies (REMS) 09-May-2022
• Split Real Time Application Review (STAR) (New) 2022-10-03
• SOPP 8405.1: Procedures for Resubmissions to An Application or Supplement (fda.gov)  2022-11-14
• SOPP 8403: Issuance, Reissuance and Voluntary Revocation of Biological Products Licenses (fda.gov) 2022-11-14
• 2022 Biological License Application Supplement Noteworthy Approvals | FDA  2022-11-16
• Accelerated Approval Program 2022-12-01
• Circumstances That Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection; Draft Guidance for Industry, Revision 1; Availability 2022-12-15
• Biosimilars | Science and Research (New) 2022-12-13

Other FDA Vaccines, Gene Therapy, and Advanced Therapy Medicinal Products Updates

• OTAT Town Hall: Cell Therapy Chemistry, Manufacturing, and Controls 2022-10-26
• Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial 2022-11-04
• FDA CBER OTAT Town Hall: Gene Therapy Chemistry, Manufacturing, and Controls  2022-11-17
• Assessing Genetic Heterogeneity in the Context of Genome Editing Off-Targets in Gene Therapy Products 2022-11-25

Other FDA Coronavirus Disease (COVID-19) Updates

• Coronavirus (COVID-19) Update: FDA Authorizes Updated (Bivalent) COVID-19 Vaccines for Children Down to 6 Months of Age 2022-12-08

Other FDA Updates

• PDUFA VI: Fiscal Years 2018 – 2022 (Updated) 2022-10-03
• Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Text Analysis of Proprietary Drug Name Interpretations 2022-10-14
• Federal Register: Protection of Human Subjects and Institutional Review Boards, and Institutional Review Boards; Cooperative Research; Extension of Comment Period  2022-11-14
• Federal Register: Referencing the Definition of “Device” in the Federal Food, Drug, and Cosmetic Act in Guidance, Regulatory Documents, Communications, and Other Public Documents; Guidance for Industry and Food and Drug Administration Staff; Availability 2022-11-14
• FDA Roundup: November 29, 2022 2022-11-29
• Drugs@FDA Data Files | FDA (Updated) 2022-12-13
• Human Medicines Highlight Newsletter 2022-12-13

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

ICH Guideline Q3C (R8) on Impurities: Guideline for Residual Solvents November 2022

The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements.

Residual solvents in drug substances, excipients, and in drug products are within the scope of this guideline. This guideline does not apply to potential new drug substances, excipients, or drug products used during the clinical research stages of development, nor does it apply to existing marketed drug products.

Residual solvents assessed in this guideline are listed in Appendix 1 by common names and structures. They were evaluated for their possible risk to human health and placed into one of three classes：

• Class 1 solvents: Solvents to be avoided. Known human carcinogens, strongly suspected human carcinogens, and environmental hazards (Class 1, Table 1).
• Class 2 solvents: Solvents to be limited. Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity; Solvents suspected of other significant but reversible toxicities (Class 2, Table 2). Two options for describing limits of class 2 solvents were provided as well.
• Class 3 solvents: Solvents with low toxic potential. Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day (Class 3, Table 3).

This guideline provides residual solvent limits or assessment methods  for  Class1, Class2, Class3 solvents and solvents for which no adequate toxicological data have been found.

Compared to the previous version, “Methyltetrahydrofuran” is removed from Table 4 on page 13 in this version due to editorial corrections approved by the Q3C(R8) Topic Leaders.

Type-II Variations: Questions and Answers November 2022

These Questions and Answers (Q&A), are the supportive and updated document list questions that marketing-authorization holders (MAHs) may have on type-II variations. It provides an overview of the European Medicines Agency’s position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorization phase.

These Q&A have been produced for guidance only and should be read in conjunction with the rules governing medicinal products in the European Union, Volume 2, Notice to Applicants.

These 27 questions and answers further update aspects that need to be noticed for MAHs including when and how to submit type-II variations, which committee will be involved in the assessment of type-II variation and how to pay for a type-II variation.

For some questions, it provides recommended answers and related guidance for reference. For example:

• What changes are considered type-II variations?

The Q&A provides clear explanations, guidance, and four references to support the conclusion. The MAHs can also find more helpful information according to internal links within the EMA website.

Concept Paper on the Revision of Annex 11 of the Guidelines on Good Manufacturing Practice for Medicinal Products – Computerised Systems November 2022

This concept paper addresses the need to update Annex 11, Computerised Systems, of the Good Manufacturing Practice (GMP) guide. Annex 11 is common to the member states of the European Union (EU)/European Economic Area (EEA) as well as to the participating authorities of the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The current version was issued in 2011 and does not give sufficient guidance within a number of areas. Since then, there has been extensive progress in the use of new technologies.

The new revised text will expand the guidance given in the document and embrace the application of new technologies which have gained momentum since the release of the existing version. There are a total of 33 reasons for the revision of Annex 11. More improvements may prove to be necessary as inputs continue to be received. The EMA GMP/GDP Inspectors Working Group and the PIC/S Sub-committee on GMDP Harmonisation jointly recommends that in the current version of Annex 11, computerised systems should be revised according to this concept paper. Please see the concept paper for details.

Guideline on the Development and Data Requirements of Potency Tests for Veterinary Cell-Based Therapy Products and the Relation to Clinical Efficacy November 2022

The aim of this guideline is to provide guidance on the requirements for developing and implementing a suitable potency assay or a combination of assays, which is linked to relevant biological properties of the cell-based product and further to clinical efficacy.

The scope of the guideline covers the development of suitable potency assays for cell-based veterinary medicinal products and their link to clinical efficacy by taking into consideration the intended mechanism of action.

Additionally, the guideline also highlights important clinical aspects that should be taken into consideration when developing the assay to ensure that the test adequately reflects the in vivo environment into which the cell-based product is administered.

All types of cellular medicinal products are considered within the scope of the guideline. This includes viable cell products of all origins (e.g. autologous, allogeneic, xenogeneic) and sources (i.e. Guideline on the development and data requirements of potency tests for veterinary cell-based therapy products and the relation to clinical efficacy EMA/CVMP/NTWP/179287/2022 Page 4/13 materials) that have been substantially manipulated, including, but not limited to, being expanded, genetically modified, differentiated, stimulated and/or digested from a tissue, and may also be relevant to cell fractions (e.g. sub-cellular fractions/cell organelles), if appropriate.

For cell products, which are not within the scope of Regulation 2019/6, manufacturers may take into account the present guidance in the course of the development of their cell-based product, when applicable.

Aspects on potency testing of cell-based veterinary medicinal products mainly include mechanism of action/biologics function, development of potency tests/assays and important aspects on the relation between potency assays and clinical efficacy. For more details, please visit Guideline on the Development and Data Requirements of Potency Tests for Veterinary Cell-Based Therapy Products and the Relation to Clinical Efficacy.

Questions and Answers for Marketing Authorisation Holders/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 Referral on Nitrosamine Impurities in Human Medicinal Products December 2022

The Q&A provides the questions and answers for MAHs/Applicants on the CHMP opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. Compared with the version published in June 2022, Q&A 3, 10, 20 and 21 were updated and Q&A 22 was newly added. The questions are as follows:

• Q1: Should the risk of presence of nitrosamines be considered for all human medicinal products?
• Q2: What is the ‘call for review’?
• Q3: For the ‘call for review’ for chemically synthesised and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities?
• Q4: What are the currently identified risk factors for presence of nitrosamines?
• Q5: What to do if after submission of step 1 and /or step 2 responses, new information (e.g. related to new potential risk factors or root causes) is identified?
• Q6: What factors should be considered in prioritising the risk evaluation?
• Q7: How should the risk evaluation be performed?
• Q8: How should confirmatory tests be conducted by MAHs and manufacturers?
• Q9: What are the requirements of the analytical method(s)?
• Q10: Which limits apply for nitrosamines in medicinal products?
• Q11: What should I do if a nitrosamine is detected in my medicinal product?
• Q12: Which are the measures to mitigate the risk of presence of nitrosamines?
• Q13: Which changes would be required for Marketing Authorisations?
• Q14: What is the approach for new and ongoing marketing authorisation applications (MAA)?
• Q15: When should a test for nitrosamines be included in the MA dossier?
• Q16: What are the responsibilities of MAHs for APIs with CEPs or ASMFs?
• Q17: How does the lessons learnt exercise from presence of nitrosamines in sartans relate to the Article 5(3) Referral Outcome?
• Q18: What about regulatory requirements in other regions?
• Q19: What is the approach for line extensions and variations applications not linked to changes required as part of article 5(3) recommendation?
• Q20: What are the regulatory steps taken by authorities following the identification of an N-nitrosamine exceeding the AI? (updated)
• Q21: What is the approach to control the presence of nitrosamines until a substance specific AI is established? (updated)
• Q22: What is the approach to control presence of Nitrosamine exceeding the AI during CAPA implementation? (new)

Commission Delegated Regulation (EU) 2022/2239 of 6 September 2022 Amending Regulation (EU) No 536/2014 of the European Parliament and of the Council as Regards Labelling Requirements for Unauthorised Investigational (IMPs) and Unauthorised Auxiliary Medicinal Products (AxMPs) for Human Use December 2022

Regulation No 536/2014 is the new clinical trial regulation (CTR), which harmonises the processes for assessment and supervision of clinical trials throughout the Europe (EU). The evaluation, authorization and supervision of clinical trials are the responsibilities of EU Member States and European Economic Area (EEA) countries. Prior to the Regulation No 536/2014, clinical trial sponsors had to submit clinical trial applications separately to national competent authorities and ethics committees in each country to gain regulatory approval to run a clinical trial. The Regulation No 536/2014 enables sponsors to submit one online application via a single online platform known as the Clinical Trials Information System (CTIS) for approval to run a clinical trial in several European countries, making it more efficient to carry out such multinational trials.

The proposed European Commission Delegated Regulation 2022/2239 amending the CTR as regards labelling requirements for IMPs and AxMPs eliminates the obligation to include an expiry date on the primary packaging of unauthorized medicinal products used in clinical trials in specific circumstances (e.g. on syringes). In specific circumstances, the period of use (expiry date or re-test date as applicable) can be omitted on the primary packaging incases where the primary and secondary packaging are intended to remain together. Additionally, if the primary packaging takes the form of blister packs or small units such as ampoules, a secondary packaging shall be provided bearing a label with all particulars (including the expiry date) required by the CTR.

The aim is to prevent additional safety and quality risks associated with the re-labelling procedure and the need for more frequent re-supply, which may lead to delays in clinical trials.

Other EMA Drug Development and Quality Guideline Updates

• ICH: Q 5 A (R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin – Step 2b 2022-10-10
• ICH: S 1 B (R1): Testing for Carcinogenicity of Pharmaceuticals – Step 5 2022-10-10
• Opinions and Letters of Support on the Qualification of Novel Methodologies for Medicine Development 2022-10-14
• Guidance on Good Manufacturing Practice and Good Distribution Practice: Questions and Answers (Updated) 2022-10-26
• Type-II Variations: Questions and Answers 2022-11-04
• Concept Paper on the Revision of Annex 11 of the Guidelines on Good Manufacturing Practice for Medicinal Products – Computerised Systems 2022-11-16
• Clinical Trials in Human Medicines 2022-11-22
• ICH Guideline Q3C (R8) on Impurities: Guideline for Residual Solvents 2022-11-28
• Guidance for Applicants/MAHs Involved in GMP and GCP Inspections Co-Ordinated by EMA 2022-12-12
• Good Manufacturing Practice (Updated) 2023-01-05
• Commission Delegated Regulation (EU) 2022/2239 of 6 September 2022 Amending Regulation (EU) No 536/2014 of the European Parliament and of the Council as Regards Labelling Requirements for Unauthorised Investigational and Unauthorised Auxiliary Medicinal Products for Human Use 2022-12-09

Other EMA & EC Regulatory Submission and Procedure Updates

• Clinical Trials Information System (CTIS) Bitesize Talk: Notifications – Part 1, Online, 14:30 – 16:00 Amsterdam time (CEST), from 28/09/2022 to 28/09/2022 (Updated)  2022-10-03
• Template – Translations Required with the Submission of An Application for Orphan Medicinal Product Designation (Updated) 2022-10-06
• Template – Translations Required With the Submission of An Application for Transfer of Orphan Medicinal Product Designation (Updated) 2022-10-06
• Guidance on parallel EMA / EUnetHTA 21 Joint Scientific Consultation (Updated)  2022-10-06
• Parallel Consultation: Briefing Document Template (Updated) 2022-10-06
• Reflection Paper on the Use of Interactive Response Technologies (Interactive Voice/Web Response Systems) in Clinical Trials, With Particular Emphasis on the Handling of Expiry Dates (Updated) 2022-10-06
• IRIS Guide for Applicants – How to Create and Submit Scientific Applications, for Industry and Individual Applicants (Updated) 2022-10-11
• Instructor’s Guide: How to Create, Submit and Withdraw a Clinical Trial Application – CTIS Training Programme – Module 10 (Updated) 2022-10-14
• Notification on Arrangements for Requesting EMA Certificates Through Urgent and Standard Procedure for December 2022 2022-10-14
• Scientific Advice and Protocol Assistance (Updated) 2022-10-14
• European Medicines Agency Guidance for Applicants Seeking Scientific Advice and Protocol Assistance (Updated) 2022-10-14
• Clinical Trial Information System (CTIS) Evaluation Timelines (Updated) 2022-10-20
• Quick guide – Part I: How to Evaluate A Clinical Trial Application: Assessment and Decision – CTIS Training Programme – Module 08 (Updated) 2022-10-24
• Quick Guide – Part II : How to Evaluate A Clinical Trial Application: Assessment and Decision – CTIS Training Programme – Module 08 (Updated) 2022-10-24
• Clinical Trials Information System (CTIS) bitesize Talk: Notifications – Part 1, Online, 14:30 – 16:00 Amsterdam Time (CEST), from 28/09/2022 to 28/09/2022 (Updated)  2022-10-26
• Timetable: Initial (Full) Marketing Authorisation Application Accelerated Assessment Timetables (Updated) 2022-10-28
• Clinical Trials Information System (CTIS) Webinar – 9 Months on and Going Forward  2022-10-28
• European Medicines Agency Pre-Authorisation Procedural Advice for Users of the Centralised Procedure 2022-11-04
• Procedural Advice for Orphan Medicinal Product Designation 2022-11-07
• Marketing-Authorisation Procedures for Advanced-Therapy Medicinal Products  2022-11-08
• Recommendations on Eligibility to Prime Scheme – Adopted at the CHMP Meeting of 7-10 November 2022 (PDF/152.95 KB) (New) 2022-11-16
• Committee for Medicinal Product for Human Use; Rules of Procedure 2022-11-18
• CHMP Opinions on Consultation Procedures | European Medicines Agency (europa.eu)  2022-12-09
• Nitrosamines EMEA-H-A5(3)-1490 – QA Art. 5(3) Implementation_ for December PROM (QA10) 2022-12-13
• Pharmaceuticals: Commission Proposes Updated EMA Fees 2022-12-13

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

• Advanced Therapy Classification 2022-11-15
• Committee for Advanced Therapies (CAT), Rules of Procedure 2022-11-17
• Guideline on the Development and Data Requirements of Potency Tests for Veterinary Cell-Based Therapy Products and the Relation to Clinical Efficacy 2022-11-18

Other EMA & EC Coronavirus Disease (COVID-19) Updates

• COVID-19 Vaccines: Studies for Approval (Updated) 2022-10-06
• COVID-19 Treatments: Research and Development (Updated) 2022-10-06
• COVID-19 Vaccines: Research and Development (Updated) 2022-10-06
• COVID-19: Latest Updates (Updated) 2022-12-22
• Draft Opinion on “Facing the Impact of the Post-COVID-19 Condition on Health Systems” 2022-10-10

Other EMA Updates

• EMA Management Board: Highlights of October 2022 Meeting 2022-10-07
• Data Quality Framework for EU Medicines Regulation 2022-10-10
• Human Medicines Highlights – September 2022 2022-10-12
• Management Board Meeting: 6 October 2022, European Medicines Agency, Amsterdam, the Netherlands, from 06/10/2022 to 06/10/2022 (Updated) 2022-10-12
• Medicinal Products for Human Use: Monthly Figures – September 2022 2022-10-13
• European Medicines Agency Mid-Year Report 2022 (January-June 2022) 2022-10-14
• Organisation Chart: Human Medicines (Updated) 2022-10-7
• Ninth Meeting of the Nitrosamine Implementation Oversight Group, from 21/11/2022 to 21/11/2022 2022-10-19
• Clinical Trials Highlights – October 2022 2022-10-21
• CAT Quarterly Highlights and Approved ATMPs – October 2022 2022-10-28
• European Medicine Agency’s Data Protection Notice for the Raw Data Proof-of-Concept Pilot 2022-10-28
• Committee for Medicinal Products for Human Use (CHMP) 2022-11-03
• Template: Confirmation of Nitrosamine Detected 2022-11-15
• Data on Antimicrobial Resistance (AMR): Use of Antibiotics in the EU Decreases but More Needs to Be Done 2022-11-17
• Overview Report – Member States’ One Health National Action Plans Against Antimicrobial Resistance 2022-11-17
• Factsheet – Managing Antimicrobial Resistance Across the Health System 2022-11-17
• Opinion – Managing Antimicrobial Resistance Across the Health System 2022-11-17
• Criteria to Be Considered for the Evaluation of New Active Substance (NAS) Status of Biological Substances 2022-11-18
• Ninth Meeting of the Industry Stakeholder Platform on the Operation of the Centralised Procedure for Human Medicine (24/11/2022) 2022-11-18
• Scientific Advice on Medicines for Human Use in the EU Medicines Regulatory Network 2022-11-22
• List of NCA’s Participating in the Simultaneous National Scientific Advice (SNSA) Pilot Phase 2 2022-11-22
• Guidance for Applicants on Simultaneous National Scientific Advice (SNSA) Phase 2 Pilot (from October 2022) – Optimized Process 2022-11-22
• Guidance for Applicants on Simultaneous National Scientific Advice (SNSA) Briefing Book Format and Content 2022-11-22
• Application Form to Request a National Scientific Advice (SNSA) 2022-11-22
• Accelerating Clinical Trials in the EU (ACT EU) 2022-11-22
• ONCWP Workplan 2022-2024 (europa.eu) 2022-12-08
• Antimicrobial Resistance | European Medicines Agency 2022-12-12

TGA (Therapeutic Goods Administration)

TGA Regulatory Submission and Procedure Updates

• GMP Approach to Overseas Manufacturers Of Medicines And Biologicals During the COVID-19 Pandemic 2022-10-07

Other TGA Updates

• Concept Paper on the Revision of EU-PIC/S GMP Annex 11 (Computerised Systems) 2022-11-17

Health Canada

Health Canada Drug Development and Quality Guideline Updates

• Consultation: Release of Draft (Step 2) ICH Guideline, ICH Q5A(R2) 2022-11-02
• International Council for Harmonisation (ICH) – Consultations and Notices – Canada.ca  2022-11-18

WHO (World Health Organization)

WHO Drug Development and Quality Guideline Updates

• Variations to FPPs | WHO – Prequalification of Medical Products (IVDs, Medicines, Vaccines and Immunization Devices, Vector Control) 2022-12-15

Other WHO Updates

• WHO Expert Consultation on Updating the 2005 Toxic Equivalency Factors for Dioxin Like Compounds, Including Some Polychlorinated Biphenyls 2022-11-14
• Message by the Director of the Department of Immunization, Vaccines and Biologicals at WHO – December 2022 2022-12-06
• WHO Member States Agree to Develop Zero Draft of Legally Binding Pandemic Accord in Early 2023 2022-12-07

MHRA 

MHRA Drug Development and Quality Guideline Updates

• Guidance on the Licensing of Biosimilar Products (Updated)  2022-11-07
• Innovation Accelerator 2022-11-16

Other MHRA Regulatory Submission and Procedure Updates

• Medicines: Apply for A Parallel Import Licence – GOV.UK (www.gov.uk) 2022-12-09

Other MHRA Updates

• The Medicines and Healthcare Products Regulatory Agency Delivery Plan 2021-2023  2022-10-27
• Medicines and Healthcare Products Regulatory Agency – Our Governance 2022-10-28
• Access Consortium Good Manufacturing Practice (GMP) Statement 2022-11-16
• Register Medical Devices to Place on the market 2022-11-16
• Notify the MHRA About a Clinical Investigation for a Medical Device 2022-11-21

PMDA (Pharmaceuticals and Medical Devices Agency)

Notifications Related to Safety Measures (Drugs): “Labeling of Codes on Containers to Identify Prescription Drugs” Posted October 2022

The “labeling of codes on containers to identify prescription drugs” provides recommendations for how to show the product code, expiration date, manufacturing number or manufacturing code and quantity on the labeling based on the unit of packing and the type of prescription drug. The unit of packing includes unit of dispensing packaging, unit of packaging to be sold, and unit of original packaging. The type includes specified biological products, biological products (excluding biological products), oral drugs (excluding biological products), injection drugs (excluding biological products), and topical drugs (excluding biological products). Exceptions to labeling of identification codes on containers, requirements for product code, and circumstances where Global Trade Item Number (GTIN) change is neededare described as well. Different barcodes or two-dimensional codes should be used based on the unit of packaging and data to be labeled. This guideline applied to products which will be released on or after December 1, 2022.

Other PMDA Drug Development and Quality Guideline Updates

• A Regulatory Pharmaceutical Quality Knowledge Management System (PQ KMS) to Enhance the Availability of Quality Medicines 2022-10-20

Other PMDA Updates

• PMDA-ATC E-learning Videos Are Now Available on YouTube 2023-01-04

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

ICH Drug Development and Quality Guideline Updates

• The ICH Q5A(R2) Draft Guideline Reaches Step 2 of the ICH Process 2022-10-11
• ICH Guideline Q3C (R8) on Impurities: Guideline for Residual Solvents 2022-11-28

Other ICH Updates

• Press Release: ICH Assembly Meeting, Incheon, Republic of Korea, November 22 2022-11-22

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

EDQM Drug Development and Quality Guideline Updates

• Revised General Chapter on Chemometrics Published in Supplement 11.1 of the European Pharmacopoeia 2022-10-05
• General chapter 2.2.46. Chromatographic Separation Techniques: Comparison of Requirements in the Ph. Eur. 10th and 11th Editions 2022-10-13
• Joint EDQM–EPAA Event on the Future of Pyrogenicity Testing: Phasing Out the Rabbit Pyrogen Test 2022-10
• 5 New Ph. Eur. Reference Standards and 12 Replacement Batches Released in November 2022 – European Directorate for the Quality of Medicines & HealthCare (edqm.eu) 2022-12-06
• Signal-To-Noise Ratio: Revision of the General Chapter on Chromatographic Separation Techniques (2.2.46) of Ph. Eur. – European Directorate for the Quality of Medicines & Healthcare 2022-12-14

Other EDQM Updates

• DCEP Sharing Tool User Guide Revised 2022-10-04
• The EDQM participated in A Conference on Next Generation Sequencing 2022-10-07
• Certification Monthly Report of Activities: End of September 2022 2022-10-07
• 7 New Ph. Eur. Reference Standards and 14 Replacement Batches Released in October 2022 2022-11-03
• European Paediatric Formulary: Revised Phosphate Oral Solution Monograph Published 2022-11-15

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

PIC/S Drug Development and Quality Guideline Updates

• Concept Paper on the Revision of Annex 11 of the Guidelines on Good Manufacturing Practice for Medicinal Products – Computerised Systems 2022-11-16

Health Products Regulatory Authority (HPRA)

HPRA Updates

• MDR and IVDR Regulatory Information Published by the HPRA 2022-11-23
• Outcome of the Process – Public Consultation on Proposed Human Medicines, Compliance Fees, Medical Device Fees and Veterinary Medicines for 2023 2022-11-24

National Medical Products Administration (NMPA)

Submission & Acceptance:

Adjustment of Registration Application Methods and The Requirements for Receiving Filing Dossiers

On January 29, 2022, based on the needs of prevention and control of the pandemic, the Center for Drug Evaluation (hereinafter referred to as “CDE”) of the National Medical Products Administration (hereinafter referred to as “NMPA”) issued a notice on adjusting the acceptance methods and the requirements for receiving filing dossiers during the epidemic. On February 18, 2022, the CDE issued “Guideline for Acceptance and Review of Registration of Biological Products (Draft for Solicitation of Comments)”, which clarified that applicants should fill in the application form through the online system and complete online submission, following the requirements in “Announcement of NMPA on Online Application for Drug Registration”. See Newsletter 2022 Q1 for details.

On November 4, 2022, to facilitate electronic regulatory submission and registration, NMPA issued the draft for solicitation of comments for the electronic application announcement and relevant requirements. On November 30, 2022, NMPA officially issued “Announcement on Implementing the Electronic Application for Drug Registration Application ([2022] No. 110)”. The guidance clarified that starting on January 1, 2023, an electronic submission is recommended for the initial drug application, registration, as well as the submission of additional supplements and amendments. On December 2, 2022, the CDE issued “Notice on the Requirements for Electronic Application for Drug Registration Application”.

The Review of Drug Registration Applications

On November 11, 2022, CDE issued “Working Procedures for Changes during the Review of Drug Registration Applications (Interim)” (Drug Review Industry [2022] No. 597), which clarified that for any major changes that may affect the safety, efficacy and quality of drugs during the review of marketing authorization applications, applicants should withdraw the original registration application and re-apply after conducting additional investigational studies. The procedure applies to other changes during the technical review period, such as clinical trial application, marketing authorization application, supplements application and re-registration application of overseas drugs. Note that the change of sponsor or technical changes is not accepted during the review of clinical trial applications.

Temporary Timeline Extension of Supplements Submission

On October 14, 2022, the NMPA issued “Announcement on Temporarily Extending the Time Limit of Supplementary Materials for Drug Registration Applications ([2022] No. 86)”, which specified three circumstances to extend the submission timeline for supplements.

Drug Electronic Registration Certificate

On October 9, 2022, the NMPA issued “Announcement on Issuing the Electronic Drug Registration Certificate ([2022] No. 83)”, which clarified that from November 1, 2022, the scope of electronic drug registration certificate is the certificates of drug clinical trial, drug marketing authorization, drug re-registration, supplements application for drugs, protection of traditional Chinese medicine varieties, imported medicinal materials, and active pharmaceutical ingredients,  as well as the certificate of Good Laboratory Practice. On October 31, 2022, NMPA issued “Notice on Matters concerning the Use of the Electronic Seal of “Dedicated Seal for Drug Registration of NMPA” for the Electronic Registration Certificate of Drugs Approved by NMPA”.

Reference

1. CDE Notice on Adjusting the Work Method and Requirements for Acceptance and Receiving Filing Dossiers during the Epidemic Period 2022-01-29
2. Notice on Public Solicitation of Opinions on “Guideline for Acceptance and Review of Drug Registration (Trial Version) (Draft for Solicitation of Comments) 2022-02-18
3. Announcement on Temporarily Extending the Time Limit of Supplementary Materials for Drug Registration Applications ([2022] No. 86) 2022-10-14
4. Announcement on Issuing the Electronic Drug Registration Certificate ([2022] No. 83) 2022-10-09
5. Notice on Matters concerning the Use of the Electronic Seal of “Dedicated Seal for Drug Registration of NMPA 2022-10-31
6. Announcement on Implementing the Electronic Application for Drug Registration Application (Draft for Solicitation of Comments) 2022-11-04
7. Working Procedures for Changes during the Review of Drug Registration Applications (Interim) (Drug Review Industry [2022] No. 597) 2022-11-11
8. Announcement on Implementing the Electronic Application for Drug Registration Application ([2022] No. 110) 2022-11-30
9. Notice on the Requirements for Electronic Application for Drug Registration Application 2022-12-02

Review & Examine and Approve & Inspection:

Working Procedure for the Review of New Drug Marketing Application

To accelerate the research and development of new drugs, the CDE drafted and issued “Working Procedure to Accelerate the Review Process of Marketing Application of Innovative Drugs (Trial)”, and opened the document for solicitation of comments. This working procedure applies to breakthrough designated innovative drugs and therapeutics. It is applicable to drugs in research and development stage when exploratory clinical trial has been completed, and the conditions to carry out pivotal clinical trials are met and before approval of marketing application. For details, please refer to Newsletter 2022 Q1.

Marketing Authorization Holder (MAH) Inspection Key Points and Main Responsibility for Drug Quality

On Mar 31, 2022, the NMPA drafted and issued the “Key Points for Inspection of Drug Marketing Authorization Holder (Draft for Solicitation of Comments)”, which is aimed to further regulate the supervision and inspection activities on the MAH. This is the second revision and solicitation of the document.

The current version (second revision) specifies that scope of application is the supervision and inspection on the domestic MAH. It’s required that MAHs are responsible for the whole product life cycle including manufacturing compliance, material management, quality control and quality assurance, documents and records, sales management and post-marketing commitment and study. The regulatory authorities will also carry out supervisory inspection of these responsibilities and obligations of the MAH. In addition, supervision and inspection of vaccine MAH are specified, including vaccine contract manufacturing, vaccine sales management, vaccine risk control, vaccine liability compulsory insurance and suspension report, and vaccine information disclosure. For detailed guidance, please refer to Newsletter 2022 Q1.

In order to assure the main responsibility for drug quality of the MAH, the NMPA drafted and issued the “Provisions on the Supervision and Administration of the Main Responsibility for Drug Quality and Safety of Marketing Authorization Holder (MAH)”.These provisions clarified the responsibilities and requirements of key position personnel, quality management procedures and system of the MAH, and required Provincial Medical Products Administration to strengthen the supervision and inspection on MAH within their respective administrative regions in accordance with their responsibilities. The Provisions will be implemented on Mar. 01, 2023.

Regulations for Implementation of Drug Administration Law

In order to implement the newly drug-related laws and regulations and further strengthen drug supervision and administration, the NMPA drafted and issued the “Regulations for the Implementation of the Drug Administration Law of the People’s Republic of China (Draft for Solicitation of Comments)” (hereinafter referred to as “Draft”) on May 9, 2022. The “Draft” consists of 181 articles in 10 chapters. It introduces newly added regulations to encourage innovation, protection of drug intellectual property rights and drug marketing authorization holders (MAHs), and the original clauses have also been supplemented. For the key contents closely related to pharmaceutical manufacturers, please refer to Newsletter 2022 Q2.

GMP Appendix for Investigational Drugs

Given that the individualized and complex manufacturing and quality management of investigational drugs, the Center for Food and Drug Inspection of the NMPA (CFDI) drafted the “Appendix for Investigational Drugs” (hereinafter referred to as “Appendix”) of the “Good Manufacturing Practice (GMP) for Drugs” by summarizing the previous work practices and referring to relevant international rules. The “Appendix (Trial Version)” was issued on May 24, 2022 and came into force on July 1, 2022.

The manufacturing and quality control of investigational drugs should, overall, comply with the core principles of the “Good Manufacturing Practice (GMP) for Drugs”. Because of novel investigational drugs, the characteristics of different research and development stages and the requirements of clinical trial design, the “Appendix” sets out corresponding special provisions on the manufacturing and quality control of investigational drugs ensuring the safety of subjects is not affected while conducting clinical trials. To facilitate the implementation of this “Appendix”, CFDI published the Questions and Answers for “Appendix”. For details, please refer to Newsletter 2022 Q2.

Drug Traceability Code

The NMPA issued two informatization standards on June 27, 2022, namely “Specifications for the Identification of Drug Traceability Codes” and “Specifications for the Inquiry Results of Drug Traceability Consumers”. “Specifications for the Identification of Drug Traceability Codes” stipulates the principles, general requirements, style requirements, location requirements and quality requirements for the identification of drug traceability codes. The document details the specifications that are applicable to regulating and guiding marketing authorization holders and manufacturers to mark drug traceability codes by printing and pasting on the packaging units at all levels of sales of drugs sold when used within the territory of China. “Specifications for the Inquiry Results of Drug Traceability Consumers” stipulates the overall requirements, requirements for display mode and content of drug traceability information results when inquired in the drug traceability system through drug traceability codes. The document details the specifications that are applicable to regulating and guiding the inquiry results of drug traceability information provided by drug marketing authorization holders and manufacturers to consumers through the drug traceability system. See Newsletter Q2 2022 for specific interpretation.

Recall of Drugs

In order to implement relevant provisions of the “Drug Administration Law and the Vaccine Administration Law”, and further regulate the work related to drug recall, the NMPA issued the new version of “Provisions for Drug Recall” on October 26, 2022. The new version (Provisions) will be effective on November 1, 2022. The Provisions highlight the subject responsibility of the MAH, legally adjust the implementation subject of recall from drug manufacturers to the MAH, further detail the scope of drug recall, provide operational handling requirements for the recalled drugs, strengthen the connection between drug recall and drug traceability, information disclosure and other related work, and make corresponding provisions for the implementation of overseas drug recall.

On-site Inspection for Antibody Drugs

In order to guide the on-site inspection for antibody drugs, the CFDI drafted and issued the “Guideline for On-site Inspection on Antibody Drugs (Draft for Solicitation of Comments)” on May 27, 2022. The draft is open for solicitation of comments within one month after release.

This guideline is applicable to the manufacturing site inspection where monoclonal antibodies are produced, which are covered in routine inspection, including inspection of the whole production process and quality management involving vial thaw, cell culture, purification, drug substance manufacturing, filling and lyophilization, quality systems, cell banks, materials supply, equipment, and facilities. Meanwhile, the guideline covers specific contents for the production and quality control of bispecific antibodies (bsAb) and antibody-drug conjugates (ADCs) which are different from monoclonal antibodies. Refer to Newsletter 2022 Q2 for detailed information.

For-cause Inspection in the Process of Drug Review

In order to assure risk management control and standardize the initiation of for-cause inspection in the process of drug review, refer to Article 49 of the new version “Measures for the Administration of Drug Registration”, combined with the relevant procedural requirements of “Work Procedures for the Initiation of Drug Registration Verification and Inspection (Trial)”, “Work Procedures for Drug Registration and Verification (Trial)” and “Guiding Principles for Pharmacovigilance Inspection”. The Center for Drug Evaluation (CDE) organized and drafted the “Work Procedures for Starting For-cause Inspection in the Process of Drug Review (Draft for Solicitation of Comments)”, which was issued on July 7, 2022. “Work Procedures for the Initiation of for-cause inspection” is applicable to the drug registration application under technical review by CDE.

Reference

1. Notice on “Working Procedure to Accelerate the Review Process of Marketing Application of Innovative Drugs (Trial Version)” Open for Soliciting Comments 2022-02-22
2. The General Affairs Department of NMPA solicits public comments on “Drug Good Manufacturing Practice (GMP) – Appendix of Investigational Drugs (Draft for Solicitation of Comments)” 2022-01-18
3. NMPA Office Solicits Public Comments on “Good Manufacturing Practice (GMP) for Investigational Drugs (Draft for Solicitation of Comments)” 2018-07-13
4. NMPA Solicits Public Comments on “Key Points for Inspection of Drug Marketing Authorization Holders (MAHs) (Draft for Solicitation of Comments) 2022-03-31
5. NMPA Solicits Public Comments on “Procedure for Inspection of Drug Marketing Authorization Holder (Draft for Solicitation of Comments)” and “Key Points for Inspection of Drug Marketing Authorization Holder (Draft for Solicitation of Comments) 2020-03-02
6. NMPA Solicits Public Comments on “Regulations for the Implementation of the Drug Administration Law of the People’s Republic of China (Draft for Solicitation of Comments)” 2022-05-09
7. NMPA Announcement on Issuing Two Informatization Standards including “Standards for Drug Tracing Code” (No. 50 of 2022) 2022-06-27
8. NMPA Issues Two Standards including “Standards for Drug Tracing Code” 2022-06-28
9. Interpretations of Two Standards including “Standards for Drug Tracing Code” 2022-06-28
10. Announcement on Issuing the “Appendix for Investigational Drugs to the Good Manufacturing Practice (GMP) for Drugs (2010 Revision)” 2022-05-27
11. Questions and Answers on “Appendix of Investigational Drugs to the Good Manufacturing Practice (GMP) for Drugs” Supplement 2022-05-27
12. Notice on Soliciting Public Comments on “Guidelines for On-site Inspection of Antibody Drugs (Draft for Solicitation of Comments)” 2022-05-27
13. Notice on the Public Solicitation of Opinions on the Initiation of Work Procedures for For -cause Inspection in the Process of Drug Review (Draft for Solicitation of Comments) 2022-07-07
14. Announcement on Issuing the Provisions for Drug Recall ([2022] No.92) 2022-10-26
15. Interpretations on Provisions for Drug Recall 2022-10-26
16. Provisions for Drug Recall (new version) implemented on Nov. 1 2022-10-26
17. Provisions on the Supervision and Administration of the Main Responsibility for Drug Quality and Safety of Marketing Authorization Holder (MAH) ([2022] No.126) 2022-12-29

Vaccine:

Vaccine Production and Distribution Management

Under routine COVID-19 prevention and monitoring, the increase in vaccine demand has promoted the promulgating and updating of relevant laws and regulations to a certain extent. In order to further implement the regulatory requirements for vaccine production and circulation under the Vaccine Administration Law, the Regulations on the Administration of Vaccine Production and Circulation were officially issued and took effect on July 8 this year after two public consultations in 2020 and 2021. The full text of the Provisions on the Administration of Vaccine Production and Circulation consists of seven chapters and 44 articles, which specify the Vaccine Administration Law from the aspects of the main responsibility of the holder of marketing authorization, vaccine production, vaccine circulation, vaccine change and vaccine supervision. At the same time, the standard documents related to the commissioned production of vaccines (i.e., Application Form for Commissioned Production of Vaccines, Catalogue of Application Materials for Commissioned Production of Vaccines and Approval Document for Commissioned Production of Vaccines by the State Medical Products Administration) were also released simultaneously. For other details, please refer to the interpretation of the 2022 Q3 Regulation and the body of the “Provisions”.

China’s Vaccine Regulator Reaches New WHO Rank to Ensure Safety, Quality & Effectiveness

On August 23, 2022, the World Health Organization (WHO) announced that China had passed the vaccine National Regulatory System assessment.

WHO’s assessment of national vaccine regulatory system is a key measurement of national vaccine regulatory capacity and is a globally recognized international assessment that can scientifically and comprehensively evaluate a country’s vaccine regulatory level. China’s vaccine regulatory system has passed two evaluations, in 2011 and 2014, and in July 2022, it has ushered in a new round of comprehensive evaluations based on the upgraded evaluation criteria by WHO. This assessment has significantly increased the number of indicators, more comprehensive content, and stricter standards.

This time, China’s vaccine regulatory system passed the WHO evaluation, demonstrating the improvement of China’s vaccine regulatory system in compliance with international standards, regulatory capacity and level. It can ensure the safety, efficacy and quality of vaccine products, so as to better protect people’s health, and open the door for China’s vaccine products to export to the rest of the world and contribute China’s share of global health and development.

Reference

1. Announcement of the National Medical Products Administration on the Issuance of the Regulations on the Administration of Vaccine Production and Distribution (No. 55 of 2022) 2022-07-08
2. The Comprehensive Department of the National Medical Products Administration once again solicits opinions on the Regulations on the Administration of Vaccine Production and Distribution (Draft for Comments) 2021-03-01
3. The Comprehensive Department of the National Medical Products Administration publicly solicits opinions on the “Provisions on the Administration of Vaccine Production and Distribution (Draft for Comments) 2020-04-30
4. China’s vaccine regulator reaches new WHO rank to ensure safety, quality & effectiveness 2022-08-23

Pharmaceutical Packaging:

The Guideline on Equivalency/Substitutability and Compatibility Study of Packaging Changes of Postapproval Drugs (T/CNPPA3019-2022), including Chinese and English versions, was issued and implemented by the Chinese Pharmaceutical Packaging Association on January 20, 2022. This guidance is a specific working method based on the guiding ideology of the above documents. The guidance is one of the evaluation approaches. The equivalence/substitutability evaluation and compatibility study of drug packaging materials take the applicability (including protection, functionality, safety and compatibility) of drug packaging materials as the evaluation object to determine the acceptability of applicability risks before and after the change, rather than whether they are the same.

The Chinese Pharmaceutical Packaging Association issued the “Technical Guidelines for Drug Package Change Studies” (T/CNPPA 3009-2020), which proposes that “drug marketing license holders and registrants of drug packages, based on the results of drug package change studies and comprehensive assessments, jointly carry out the equivalence/substitutability evaluation of drug package changes.”

Reference

1. Guidance on Equivalency/Substitutability and Compatibility Study of Packaging Changes of Marketed Drugs (T/CNPPA3019-2022) 2022-01-20
2. Guidance for Postapproval CMC Changes Control to Biologicals (Trial Implementation) 2021-02-10
3. Technical Guidelines for Study on the Change of Pharmaceutical Packaging Materials （T/CNPPA 3009-2020（T/CNPPA 3009-2020）2020-05-29

Provincial Medical Products Administration:

According to the “Drug Administration Law of the People’s Republic of China”, “Provisions for the Supervision and Administration of Drug Manufacturing”, and other relevant provisions, and in combination with the local situation, Jiangsu Medical Products Administration and Beijing Drug Administration issued “Compliance Inspection of Drug Good Manufacturing Practice in Jiangsu Province (Trial) (Draft for Solicitation of Comments)” and “Implementing Rules of the Provisions for the Inspection of Drug Manufacturing chain in Beijing (Draft for Solicitation of Comments)”, respectively.

In order to support the economic development of biomedical R & D in Shanghai, the Shanghai Municipal People’s Government issued “Several Policies and Measures of Shanghai for Accelerating the Building of a Global Biomedical R & D Economy and Industrialization Highland” on October 24, 2022. The policies and measures shall be implemented from October 31, 2022 to October 30, 2027.

Reference

1. Jiangsu Medical Products Administration Solicited Public Opinions on the “Compliance Inspection of Drug Good Manufacturing Practice in Jiangsu Province (Trial) (Draft for Solicitation of Comments) “ 2022-07-04
2. Adoption of the Opinions on the “Compliance Inspection of Drug Good Manufacturing Practice in Jiangsu Province (Trial) (Draft for Solicitation of Comments) “ 2022-10-28
3. Notice of the General Office of Shanghai Municipal People’s Government on Printing and Distributing “Several Policies and Measures of Shanghai Municipality for Accelerating the Building of a Global Biomedical R & D Economy and Industrialization Highland” 2022-11-21
4. Announcement on Soliciting Public Opinions on the “Implementing Rules of the Provisions for the Inspection of Drug Manufacturing chain in Beijing (Draft for Solicitation of Comments)” 2022-07-05
5. Feedback on Soliciting Public Opinions on the Announcement on Soliciting Public Opinions on the “Implementing Rules of the Provisions for the Inspection of Drug Manufacturing chain in Beijing (Draft for Solicitation of Comments)” 2022-09-02

ICH:

In 2022, the CDE issued a notice to solicit comments on draft guidelines of “ICH Q2 (R2) Validation of Analytical Procedures” and “Q14 Analytical Method Development”, implementation suggestions and Chinese versions of the guideline  “M10 Bioanalytical Method Validation and Study Sample Analysis”, implementation suggestions and Chinese versions of “Q3D (R2) Guidelines for Elemental Impurities”, and the guidance  “Q5A (R2) Viral Safety Evaluation of Biotechnology Products Derived from Human or Animal Cell Lines”.

The draft ICH guidelines for “Q2 (R2) Validation of Analytical Procedures” and “Q14 Development of Analytical Procedures” were issued on 25 April 2022 and the public review and comments ended on 15 July 2022. Q2 (R2) is a comprehensive revision of the guideline based on Q2 (R1) to incorporate recent applications of analytical methods and align the content with “Q14 Analytical Method Development”. See Newsletter 2022 Q2 for detailed interpretation.

The implementation suggestions and Chinese version of “ICH M10: Bioanalytical Method Validation and Sample Analysis” were issued on August 17, 2022, and the publicity period was ended on September 17, 2022. The final version of M10 was adopted at Step 4 by the regulatory members of the ICH Congress on 24 May 2022. The purpose of this Notice is to solicit suggestions on the implementation of the Guidelines from the public and simultaneously solicit comments on Chinese translations. Recommendations for the implementation of M10 are as follows: the applicant shall conduct the study in accordance with the requirements of the M10 guideline; the relevant study (subject to the time point of trial record) starting 6 months after the date of issuance of the announcement shall be subject to the M10 guideline. This guideline is intended to provide recommendations for the validation of bioanalytical methods for chemical and biological drug quantification and their application in the analysis of study samples. The objective of the validation of a bioanalytical method is to demonstrate that it is suitable for its intended purpose. This guideline describes the validation of bioanalytical methods and study sample (e.g., blood, plasma, serum, other body fluids or tissues) analysis that are expected to support regulatory decisions.

The implementation suggestions and Chinese version of “ICH Q3D (R2): Guideline for Elemental Impurities” were issued on September 8, 2022, and the publicity period ended on October 8, 2022. Q3D (R2) was approved at Step 4 by the regulatory members of the ICH Congress on 26 April 2022. Q3D (R2) is based on Q3D (R1) to correct Gold, Silver and Nickel PDE (Appendix 2); to correct Gold and Silver monographs (Appendix 3); to add Appendix 5: Limits for Elemental Impurities for Dermal and Transdermal Routes of Administration; to add reference to Appendix 5 in Section 3.2. The implementation suggestions of Q3D (R2) are as follows: the applicant shall carry out the study in accordance with the requirements of Q3D (R2) guideline on the basis of the current technical requirements for pharmaceutical research; for the relevant studies (subject to the time point of trial record) starting 6 months after the date of issuance of this Announcement, Q3D (R2) guideline shall be applicable, and Q3D (R1) guideline shall be abolished at the same time. This guideline presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product.

The original and Chinese translations of the ICH guideline “Q5A (R2): Viral Safety Evaluation of Biotechnology Products Derived from Human or Animal Cell Lines” were issued on November 28, 2022, and the publicity period ended on January 20, 2023. ICH Guideline Q5A (R2) is now entering Step 3 for Regional Public Comment. The purpose of this Notice is to solicit comments on the original English version of the Guidelines from the public and simultaneously solicit comments on the Chinese translation. This guideline concerns the testing and evaluation of the viral safety of biotechnology products, and it outlines what data should be submitted in marketing application and registration packages for those products. Biotechnology products include biotherapeutics and certain biological products derived from cell cultures initiated from characterized cell banks of human or animal origin (e.g., mammalian, avian, insect). This document covers products derived from in vitro cell culture using recombinant DNA technologies such as interferons, monoclonal antibodies, and recombinant subunit vaccines. It also covers products derived from hybridoma cells grown in vivo as ascites: special considerations apply for these products, and Annex 1 contains additional information on testing cells propagated in vivo. The document also applies to certain genetically-engineered viral vectors and viral vector-derived products, which can undergo virus clearance without a negative impact on the product. These products may include viral vectors produced using transient transfection or from a stable cell line, or by infection using a recombinant virus. It also includes viral vector-derived recombinant proteins, for example, baculovirus-expressed Virus-Like Particles (VLPs), protein subunits and nanoparticle-based vaccines and therapeutics. Furthermore, the scope includes Adeno-Associated Virus (AAV) gene therapy vectors that depend on helper viruses such as baculovirus, herpes simplex virus or adenovirus for their production. Specific guidance on genetically engineered viral vectors and viral vector-derived products is provided in Annex 7. Inactivated viral vaccines and live attenuated viral vaccines containing self-replicating agents are excluded from the scope of this document.

Reference

1. Notice on “ICH Q2 (R2) Validation of Analytical Procedures (Draft Version) and Q14 Analytical Procedure Development (Draft Version) “Open for Solicitation of Comments 2022-04-25
2. Notice on “Soliciting Public Opinions on Implementing the Guideline of ICH M10 Bioanalytical Method Validation and Study Sample Analysis and Chinese Version” 2022-08-17
3. Notice on “Soliciting Public Advice on Implementing ICH Q3D (R2) Guideline for Elemental Impurities and Chinese Version” 2022-09-08
4. Notice on “Soliciting Public Comments on ICH Guideline Q5A (R2) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin” 2022-11-28

Chinese Pharmacopoeia for Comments:

General Draft

A series of publicity drafts and notifications have been issued by the Chinese Pharmacopoeia Commission. These include < Publicity Draft of Guiding Principles for Amino Acid Analysis >, < Notice on Soliciting Opinions and Suggestions on the Preparation and Quality Control of Animal Cell Matrix for the Production and Verification of Biological Products in Chinese Pharmacopoeia (2020 Edition, Volume III) >, < Notice on Soliciting Opinions on the Guidelines for Biological Evaluation and Test Selection of Pharmaceutical Packaging Materials in Chinese Pharmacopoeia >, < Notice on Soliciting Opinions and Suggestions on the Guidelines for Inspection Rules for Pharmaceutical Packaging Materials in Chinese Pharmacopoeia >, < Notice on Soliciting Opinions on 6 General Rules of Glass Containers for Drug Packaging in the Chinese Pharmacopoeia >, < Notice on Soliciting Opinions on the Draft of 12 General Test Methods for Glass Containers for Drug Packaging in Chinese Pharmacopoeia >, < Notice on Soliciting Opinions on Bacterial Endotoxin Test of Pharmaceutical Excipients >, < Letter on Soliciting Opinions on Pharmaceutical Excipient Standards of the Chinese Pharmacopoeia and ICH Q3C Coordination Scheme >, < Publicity on the Draft Guidelines for Biological Evaluation and Test Selection of Pharmaceutical Packaging Materials >, < Publicity on the Revised Draft of 9201 general for Validation of Alternative Methods for Microbiological Testing of Drugs >, < Publicity on the Draft Standards for the Guidelines for Microbiological Examination of Cell Products (Second Time) >, < Publicity on the Draft Standards for In Vitro Pyrogen Test (Reporter Gene Assay) (Second Notice) >, < Publicity on the Generic Name of WHOINNPlist127 Biological Products >, Chinese Pharmacopoeia (2025 edition) preparation outline and other documents.

< Publicity Draft of Guiding Principles for Amino Acid Analysis > has been issued on  March 9, 2022, the publicity period ended on April 8, 2022. Amino acid analysis method is a method that detects the composition or content of amino acids in complex amino acid preparations, polypeptides drugs, protein drugs, tissues extract from amino acids/polypeptides/proteins, Chinese traditional medicines and others. Guidance for amino acid analysis has been included in the current edition of European Pharmacopoeia, British Pharmacopoeia, USP and Japanese Pharmacopoeia, but not in the general chapter of the Chinese Pharmacopoeia. The Chinese Pharmacopoeia Commission formulated the “Draft Guidelines for Amino Acid Analysis” based on the contents and style collected in the above Pharmacopoeias, which was first published in September 2020. Supplements and revisions were generated by Chinese Pharmacopoeia Commission according to feedback and suggestions on the first publicity draft. Please refer to Elucidation in Newsletter 2022 Q1.

< Notice on Soliciting Opinions and Suggestions on the Preparation and Quality Control of Animal Cell Matrix for the Production and Verification of Biological Products in Chinese Pharmacopoeia (2020 Edition, Volume III) > issued on May 18 2022, the publicity period ended on June 30, 2022. All pharmaceutical manufacturers, distributors, user units, regulatory authorities, inspection institutions, scientific research institutes, relevant social groups and individuals may put forward relevant comments or suggestions in combination with the implementation of the current version of Animal Cell Matrix Preparation and Quality Control for Production and Verification of Biological Products during the process of production, R & D and technical supervision. Please refer to Elucidation in Newsletter 2022 Q2.

< Notice on Soliciting Opinions on the Guidelines for Biological Evaluation and Test Selection of Pharmaceutical Packaging Materials in Chinese Pharmacopoeia > issued on June 10, 2022, soliciting opinions for 1 month. This standard specifies the basic principles of biological evaluation and test selection of pharmaceutical packaging materials, which is suitable for the selection of biological evaluation methods and test conditions of pharmaceutical packaging materials. Please refer to Elucidation in Newsletter 2022 Q2.

< Notice on Soliciting Opinions on the Guidelines for Inspection Rules for Pharmaceutical Packaging Materials in Chinese Pharmacopoeia > issued on June 16, 2022, soliciting opinions for 1 month. This document provides guidelines for pharmaceutical packaging material manufacturers, users or other relevant third parties to formulate inspection rules for drug packaging materials. Please refer to Elucidation in Newsletter 2022 Q2.

< Notice on Soliciting Opinions on 6 General Rules of Glass Containers for Drug Packaging in the Chinese Pharmacopoeia > issued on June 28, 2022, soliciting opinions for 1 month. The purpose of this document is to improve the standard system of pharmaceutical packaging materials in the Pharmacopoeia and establish a standard framework that takes the classification of glass, rubber, plastic, metal and other materials as the general principle, and different varieties (products) of each material as the minor general principle. In addition, the purpose is to keep in sync with the Chinese Pharmacopoeia and harmonize with USP, EP, ICH and other relevant standards as far as possible. Please refer to Elucidation in Newsletter 2022 Q2.

< Notice on Soliciting Opinions on the Draft of 12 General Test Methods for Glass Containers for Drug Packaging in Chinese Pharmacopoeia > issued on June 28, 2022, soliciting opinions for 1 month. The draft standard includes 12 general testing methods, such as measuring the internal stress of glass containers, internal pressure resistance of glass containers, and the breaking force of glass ampoules. Please refer to Elucidation in Newsletter 2022 Q2.

< Notice on Soliciting Opinions on Bacterial Endotoxin Test of Pharmaceutical Excipients > issued on July 6,2022, soliciting opinions period ending on August 15, 2022. It is proposed to systematically study the bacterial endotoxin examination items of the key varieties of pharmaceutical excipients and formulate a reasonable standardized bacterial endotoxin examination item. Key species include but are not limited to: the preparation of large amounts of species, non-water-soluble samples, the development of bacterial endotoxin inspection limits of questionable species, has certain difficulties in bacterial endotoxin inspection etc., not limited to the species included in the < Chinese Pharmacopoeia >. Please refer to Elucidation in Newsletter 2022 Q3.

< Letter on Soliciting Opinions on Pharmaceutical Excipient Standards of the Chinese Pharmacopoeia and ICH Q3C Coordination Scheme > issued on August 1, 2022, soliciting opinions period ended on September 25,5 2022. The harmonization between Chinese Pharmacopoeia and ICHQ3C involves General Notices 0251 and 0861, Guideline 9102, main body of drug substance and pharmaceutical excipient varieties, etc. Except in special cases, the test items of residual solvents are not included in the text of pharmaceutical excipient varieties in Chinese Pharmacopoeia. Regardless of whether the Chinese Pharmacopoeia pharmaceutical excipients are included in the body, the residual solvents of pharmaceutical excipients should meet the requirements. The harmonization plan of the Chinese Pharmacopoeia standard for pharmaceutical excipients was consulted, and other harmonization plans will be announced separately.

< Publicity on the Draft Guidelines for Biological Evaluation and Test Selection of Pharmaceutical Packaging Materials > issued on November 21, 2022, soliciting opinions period end on February 20, 2023. The draft guideline focuses on the connection between “evaluation” and “testing”, considers the bioequivalence of drug packaging materials, proposes a biological evaluation pathway, and re-conducts the timing of biological evaluation of drug packaging materials, the selection of samples and extraction solvents, etc. to enhance the practicality of the guideline.

< Publicity on the Revised Draft of 9201 general for Validation of Alternative Methods for Microbiological Testing of Drugs > issued on November 29, 2022, soliciting opinions period ending on March 9, 2023. The revision includes five parts, specifically an overview, types and validation parameters of microbiological testing, the general requirements for the validation of alternative methods, the validation of qualitative microbiological test methods in samples, and the validation of quantitative microbiological test methods in samples. The overall framework of the text has not been substantially adjusted. However, the revised draft adds newly or redefines the application scenarios, validation methods, validation types, and result analysis of alternative methods.

< Publicity on the Draft Standards for the Guidelines for Microbiological Examination of Cell Products (Second Time) > issued on December 1, 2022, soliciting opinions period ending on March 10, 2022. Pharmaceutical products are usually evaluated for microbial contamination using the aseptic inspection method (General Rule 1101), which requires at least 14 days of culture to observe microbial growth and culture signals. Due to the short validity period and small production volume of cell-based products, the number of available tests is limited, and the production is more closely integrated with clinical needs. The use of aseptic inspection methods may not ensure that the release inspection is completed before the products are used, and the sampling plan is limited. Therefore, on the basis of risk assessment, it has become an essential means for safe nature control to conditionally use rapid microbiological examination method (recommended respiratory signal method) instead of classical sterility test method for cell products.

< Publicity on the Draft Standards for In Vitro Pyrogen Test (Reporter Gene Assay) (Second Notice) >  issued on December 1, 2022, soliciting opinions period ending on December 10, 2022. This method quantitatively or qualitatively detects the pyrogen content in the test sample by detecting and comparing the signal quantity of relevant pyrogen markers produced by the standard sample and the test sample acting on the transgenic cells. This method can be used as a supplementary method for pyrogen inspection, and microbial and pyrogen pollution shall be prevented during operation. This method is not applicable to pyrogen markers that can stimulate or inhibit themselves (such as NF- κ B activated test article).

< Chinese Pharmacopoeia (2025 edition) > preparation outline issued on December 19, 2022, It is intended to guide the preparation of the new edition of the Chinese Pharmacopoeia, mainly including: moderately increasing the scope of the affected varieties of the pharmacopoeia, improving the overall level of drug standards, improving the drug standard system, improving the drug standard formation mechanism, strengthening international exchanges and cooperation, and accelerating the information construction of drug standards.

Reference

1. Notice on Soliciting Relevant Opinions and Suggestions on Chinese Pharmacopoeia (2020 Edition) Volume III Preparation and Quality Control of Animal Cell Matrix for Production and Verification of Biological Products 2022-05-18
2. Notice on Soliciting Opinions on the Guidelines for Biological Evaluation and Test Selection of Pharmaceutical Packaging Materials in Chinese Pharmacopoeia 2022-06-10
3. Notice on Soliciting Opinions on the Guidelines for Inspection Rules for Pharmaceutical Packaging Materials in Chinese Pharmacopoeia 2022-06-16
4. Notice on Soliciting Opinions on Bacterial Endotoxin Test for Pharmaceutical Excipients 2022-07-06
5. Notice on Soliciting Opinions on the Draft Standards Related to Pharmaceutical Packaging Materials in Chinese Pharmacopoeia (the first round) 2022-07-18
6. Letter on Soliciting Opinions on the Harmonization Scheme between the Pharmaceutical Excipient Standard of Chinese Pharmacopoeia and ICHQ3C 2022-08-01
7. Notice on Soliciting Opinions on Sterility and Microbial Limit Tests for Pharmaceutical Excipients 2022-10-25
8. Publicity on the Draft Guidelines for Biological Evaluation and Test Selection of Pharmaceutical Packaging Materials 2022-11-21
9. Notice on Issuing the Compilation Outline of Chinese Pharmacopoeia (2025) 2022-12-19