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Regulatory Newsletter

Q3 2022 Regulatory Updates
Nov. 03, 2022
Q3 2022 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)

 

Instructions for Use – Patient Labeling for Human Prescription Drug and Biological Products – Content and Format – July 2022

 

This guidance provides suggestions on developing the content and format of a patient’s Instructions for Use (IFU) document for human prescription drugs, biological products and drug-led or biologic-led combination products submitted under a new drug application (NDA) or a biologics license application (BLA). Such content includes:

 

  • Recommendations for general content, including consistency with the FDA-approved Prescribing Information (PI), language and readability, and headings.
  • Recommendations for specific content, if applicable, that the following information appear in the order listed to ensure consistency and to help patients become familiar with the type and location of information in the IFU: title, product title, purpose statement, visual of drug product, important information for patents, preparation instructions, administration instructions, storage instructions, disposal instructions and additional information. Recommendations for format, including typeface styling, page layout and design.

 

Changes to Disposable Manufacturing Materials: Questions and Answers Guidance for Industry – July 2022

 

This guidance describes CMC post-approval changes related to disposable manufacturing materials used in drug and biological product manufacturing Three questions and answers are included:

 

  • Q1: What are some possible changes an applicant can make to disposable manufacturing materials and what reporting categories are applicable?
  • Q2: Are there steps to lower the reporting category of a supplement?
  • Q3: When and how should an applicant contact the FDA for feedback on a proposed change?

 

SOPP 8103: Headquarters Contacts with Regulated Manufacturers during Agency Inspections (Version 5, Effective Date: July 31, 2022)

 

The FDA updated SOPP 8103: Headquarters Contacts with Regulated Manufacturers during Agency Inspections according to current procedures. This is the fifth version and the effective date is July 30th 2022.

 

Steps that Center for Biologics Evaluation and Research (CBER) staff should follow when contacted by regulated manufacturers during inspections being conducted by CBER and/or Office of Regulatory Affairs (ORA) staff are described in this Standard Operating Policy Procedure (SOPP). CBER-regulated products are within the scope of this SOPP. When contacted by regulated industry about licensed or unlicensed products, CBER staff members should determine if such inquiries are related to an ongoing inspection/investigation or regulatory action so as not to interfere with any ongoing inspection or investigation. It is CBER staff’s responsibility to determine if inquiries are related to an ongoing inspection/investigation or regulatory action, and conduct following actions based on procedures of this SOPP. Since incoming communications may be related to ongoing inspection/investigation or completed inspections or general inspection questions, different actions to be conducted are also defined in this SOPP.

 

Other FDA Drug Development and Quality Guideline Updates

 

 

Other FDA Regulatory Submission and Procedure Updates

 

 

Other FDA Coronavirus Disease (COVID-19) Updates

 

 

Other FDA Updates

 

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

 

ICH Guideline M10 on Bioanalytical Method Validation and Study Sample Analysis (Step 5) – July 2022

 

This ICH Guideline M10 on Bioanalytical Method Validation and Study Sample Analysis provides general recommendations for the development, full validation, partial validation, cross validation of bioanalytical methods for chemical and biological drug quantification, as well as incurred sample reanalysis (ISR). The guideline also provides the specific recommendations for the validation of chromatographic methods, ligand binding assays (LBAs) and their application in the study sample analysis, additional considerations and documentation. The current ICH M10 Guideline is on Step 4, and ICH working group published ICH Guideline M10 on Bioanalytical Method Validation and Study Sample Analysis (Step 5) on 25th July 2022 that will come into effect on 21st January 2023.

 

EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines – Annex 1 Manufacture of Sterile Medicinal Products – Aug 2022

 

The current revised Annex 1 Manufacture of sterile medicinal products was issued on August 22th, 2022. The deadline for coming into operation of Annex 1 is 25 August 2023, except for point 8.123 Lyophilizers and associated product transfer and loading/unloading areas, which is postponed until  August 25, 2024.

 

The manufacture of sterile products covers a wide range of sterile product types, packed sizes, processes and technologies. This Annex provides general guidance that should be used in the design and control of facilities, equipment, systems and procedures used for the manufacture of all sterile products applying the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product. With comparison of the previous Annex 1, some new requirements are included but not limited to contamination control strategy (CCS), pre-use post terilization integrity test (PUPSIT), first air, isolator, single use systems (SUS), etc.

 

Guidance for Applicants/MAHs Involved in GMP, GCP and GVP Inspections Coordinated by EMA – August 2022

 

The third version of the guidance was updated by the EMA on August 31. This guidance includes actions of Applicants/MAHs relevant involved in GMP, GCP and GVP inspections coordinated by the EMA.

 

GMP, GCP, GVP inspections Coordinated by the EMA are defined as following:

 

  • GMP inspections are requested by the Committee for Medicinal Products for Human Use (CHMP) and/or the Committee for Medicinal Products for Veterinary Use (CVMP) to verify compliance with Good Manufacturing Practice of sites responsible for the manufacture of centrally authorised products
  • GCP inspections are requested by the CHMP) in order to verify compliance with Good Clinical Practice for centrally authorised products
  • GVP inspections are requested by the CHMP to verify compliance with Good Pharmacovigilance Practice for centrally authorised products

 

According to this guidance, the IRIS Industry portal is a very useful window to get details of each of the inspections adopted by the Committee(s). IRIS can be used to contact the EMA Inspection Coordinator if any information about the procedure is needed. Details for inspection fees including small and medium sized enterprise (SME) fee reduction, can be found on the EMA Fees website.

 

Applicant/MAH should ensure the sites of inspection are notified and relevant documentation, facilities and personnel are readily available for the inspection within 10 working days from inspection announcement. A written statement is required to accept the inspection which can be provided by IRIS Industry Portal EMA and inspection team. Electronic copies of some documents should be prepared and submitted within 10 working days after the inspection announcement. The detailed list can be found in the guidance.

 

List of Products Granted Eligibility to PRIME – September 2022

 

PRIME is a scheme launched by the European Medicines Agency (EMA) to enhance support for the development of medicines that target an unmet medical need. This voluntary scheme is based on enhanced interaction and early dialogue with developers of promising medicines, to optimise development plans and speed up evaluation so these medicines can reach patients earlier. PRIME builds on the existing regulatory framework and tools already available such as scientific advice and accelerated assessment.

 

The scheme focuses on medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options. These medicines are considered priority medicines by EMA. To be accepted for PRIME, a medicine has to show its potential to benefit patients with unmet medical needs based on early clinical data.

 

EMA updates the list of all products granted access to the PRIME scheme below on a monthly basis. The information is also contained in the annexes of the monthly CHMP highlights. EMA removes products from the list if they receive a marketing authorisation application for them, if they are withdrawn from the scheme or no longer meet the eligibility criteria.

 

While PRIME is open to all companies on the basis of preliminary clinical evidence, applicants can apply earlier on the basis of compelling non-clinical data and tolerability data from initial clinical trials. There are reference documents on how to prepare the request for PRIME. Guidance is also available regarding scientific and regulatory approaches that medicine developers can use in their applications targeting unmet medical needs.

 

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 & EC Coronavirus Disease (COVID-19) Updates

 

 

Other EMA Updates

 

TGA (Therapeutic Goods Administration)

 

TGA Drug Development and Quality Guideline Updates

 

 

TGA Vaccines, Gene Therapy, and Advanced Therapy Medicinal Products Updates

 

 

Other TGA Updates

 

Health Canada

 

Health Canada Drug Development and Quality Guideline Updates

 

 

Health Canada Regulatory Submission and Procedure Updates

 

Health Canada Coronavirus Disease (COVID-19) Updates

 

 

Other Health Canada Updates

 

MHRA 

 

MHRA Drug Development and Quality Guideline Updates

 

 

MHRA Regulatory Submission and Procedure Updates

 

 

Other MHRA Updates

 

PMDA (Pharmaceuticals and Medical Devices Agency)

 

PMDA Drug Development and Quality Guideline Updates

 

 

Other PMDA Updates

 

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

ich-logo

 

Overview of Comments Received on ICH Guideline on Q2(R2) Validation of Analytical Procedures (EMA/CHMP/ICH/82072/2006) – Aug 2022

 

ICH Q2(R2) is at Step 3 (Regulatory consultation and Discussion) now, and comments are received from different organizations and individuals, including APIC (the Active Pharmaceutical Ingredients Committee), EFPIA (European Federation of Pharmaceutical Industries and Associations) and so on. The comments are classified as general comments and specific comments, the comments will be sent to ICH Q2(R2) EWG (Expert Working Groups) for consideration.

 

Overview of Comments Received on ICH Guideline Q14 on Analytical Procedure Development (EMA/CHMP/ICH/195040/2022) – Aug 2022

 

ICH Q14 is at Step 3 (Regulatory consultation and Discussion) now, and comments are received from different organizations and individuals, including APIC (the Active Pharmaceutical Ingredients Committee), GE Healthcare, EFPIA (European Federation of Pharmaceutical Industries and Associations) and so on. The comments are classified as general comments and specific comments, the comments will be sent to ICH Q2(R2) EWG for consideration.

 

Other ICH Drug Development and Quality Guideline Updates

 

 

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

 

EDQM Drug Development and Quality Guideline Updates

 

 

Other EDQM Updates

 

 

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

 

Publication of revised PIC/S Annex 1  – September 2022

 

The revised Annex 1 to the PIC/S GMP Guide on the manufacture of sterile products has been published and will enter into force on 25 August 2023, except for point 8.123 which is postponed until 25 August 2024. The date of entry into operation is aligned with that of the revised EU Annex 1, which is identical to PIC/S Annex 1 (with some very minor editorial differences).

 

Annex 1 to the PIC/S GMP Guide was first published in 1971, and has undergone a number of partial revisions since its publication.  This is, however, the first full revision aiming at restructuring this Annex, adding clarity to the requirements on the sterile manufacturing of medicinal products and introducing the principles of Quality Risk Management to allow for the inclusion of new technologies and innovative processes.

 

A joint Working Group including representatives of the Competent Authorities of PIC/S and EEA as well as WHO has engaged in the revision and review of Annex 1. The revised Annex was submitted to adoption to the EMA IWG on GMDP and the PIC/S Committee on 1 March and 29 April 2022, respectively, and then has been published by the EC on Eudralex and by PIC/S on the PIC/S website.

 

Other PIC/S Updates

 

Health Products Regulatory Authority (HPRA)

 

Guide to New Applications and Variations to Manufacturer’s Authorisations – September 2022

 

In September 2022, Ireland HPRA published an updated version (AUT-G0140-9) of guidance on applying to the HPRA for a new manufacturer’s authorisation or to vary an existing manufacturer’s authorization. This guidance applies to human and veterinary medicinal products as well as to investigational medicinal products (IMPs). This document also provided guidance on the supporting information required for the inclusion of contract sites based in MRA (mutual recognition agreement) partner territories, on the import or supply of unlicensed/exempt medicinal products for the Irish market, guidance regarding Qualified Person declarations and remote batch certification by the Qualified Person.

 

Guidance that relates specifically to new applications, to variations to an existing manufacturer’s authorization, and to both types of applications, are identified by headings with different colors in this document.

 

Other HRPA Drug Development and Quality Guideline Updates

 

 

Other HRPA Regulatory Submission and Procedure Updates

 

National Medical Products Administration (NMPA)

 

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

 

The World Health Organization (WHO) ranked China’s vaccine regulatory system at a functional level of maturity according to WHO’s global classification system for national medical products regulatory authorities on 23 August, 2022. This means that China has a stable, well-functioning and integrated regulatory system to ensure the quality, safety, and effectiveness of vaccines that are manufactured, imported or distributed in the country.

 

The WHO confirmed the country’s attainment of maturity level three (ML3)—the third of four levels in the WHO’s classification with maturity level four (ML4) being the highest.

 

The WHO performed an assessment of the Chinese National Regulatory Authority (NRA) in April 2014, based on the indicators in the WHO vaccines assessment tool and and performed additional benchmarking activities in 2019 and 2021, focusing on the Chinese vaccine regulatory system. As a follow up to these activities, a WHO expert team conducted the formal benchmarking of the Chinese NRA, represented by NMPA, in July 2022 using an updated and more comprehensive assessment tool, the WHO Global Benchmarking Tool. During the benchmarking, WHO noted that the NMPA had considered and addressed recommendations made following the activities in 2014, 2019 and 2021, confirming the country’s ML3 achievement for the regulation of vaccines in China.

 

Reference

 

China’s vaccine regulator reaches new WHO rank to ensure safety, quality & effectiveness-2022-08-23

 

For-cause Inspection in the Process of Drug Review

 

In order to strengthen risk control in the process of drug review and standardize the initiation of for-cause inspection in the process of drug review, in accordance with 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 the Initiation of For-cause Inspection in the Process of Drug Review (Draft for Solicitation of Comments)”, which was issued on July 7, 2022. The time period for soliciting opinions is 1 month from the date of issuance.“Work Procedures for the Initiation of For-cause Inspection” is applicable to the drug registration application under technical review by CDE.

 

Figure 1. Flow Chart of the Initiation of For-cause Inspection in the Process of Drug Review

 

Reference

 

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

 

Update of marketed drugs

 

In the third quarter of 2022, the information of marketed new drugs for therapeutic biological products is shown in table 1.

 

Table 1. Summary information of therapeutic biological products on the market

No.

Drug Name

Category

Acceptance No.

1

Eftrenonacog alfa for Injection

7 (old classification)

JXSS1900062

JXSS1900063

JXSS1900064

JXSS1900065

2

Atezolizumab Injection

2.2

JXSS2101014

3

Tislelizumab Injection

2.2

CXSS2100030

4

Disitamab Vedotin For Injection

2.2

CXSS2101011

5

Bevacizumab Injection

3.1

JXSS2100023

6

Emapalumab Injection

3.1

JXSS2000058

JXSS2000059

JXSS2000060

7

Blinatumomab for Injection

3.1

JXSS2100020

8

Infliximab for Injection

3.3

CXSS2000054

9

Adalimumab Solution for Injection

2 (old classification）

CXSS2000026

10

Serplulimab Injection

1

CXSS2101000

11

Camrelizumab for Injection

2.2

CXSS2100031

CXSS2100032

12

Envafolimab Injection

1

CXSS2000060

13

Sugemalimab Injection

1

CXSS2000056

14

Bevacizumab Injection

3.3

CXSS2000046

15

Bevacizumab Injection

3.3

CXSS2000047

16

Bevacizumab Injection

2 (old classification）

CXSS2000027

17

Bevacizumab Injection

2 (old classification）

CXSS2000029

CXSS2000030

18

Tislelizumab Injection

2.2

CXSS2101009

19

Toripalimab Injection

2.2

CXSS2100016

CXSS2100017

CXSS2100018

20

Insulin Glargine Injection

3.4

CXSS2000058

21

Durvalumab Injection

3.1

JXSS2000029

JXSS2000030

22

Teriparatide Injection

3.3

CXSS2100011

23

Toripalimab Injection

2.2

CXSS2101014

CXSS2101015

24

Tislelizumab Injection

2.2

CXSS2101021

25

Sugemalimab Injection

1

CXSS2101026

26

Cadonilimab Injection

1

CXSS2101032

27

Tocilizumab Injection

therapeutic biologicals

JXSS2000026

 

Reference

 

  1. Information of marketed drugs, Eftrenonacog alfa for Injection 2022-07-06
  2. Information of marketed drugs, Atezolizumab Injection 2022-07-06
  3. Information of marketed drugs, Tislelizumab Injection 2022-07-06
  4. Information of marketed drugs, Disitamab Vedotin For Injection 2022-07-13
  5. Information of marketed drugs, Bevacizumab Injection 2022-07-19
  6. Information of marketed drugs, Emapalumab Injection 2022-07-25
  7. Information of marketed drugs, Blinatumomab for Injection 2022-07-27
  8. Information of marketed drugs, Infliximab for Injection 2022-08-08
  9. Information of marketed drugs, Adalimumab Solution for Injection 2022-08-12
  10. Information of marketed drugs, Serplulimab Injection, Camrelizumab for Injection, Envafolimab Injection 2022-08-09
  11. Information of marketed drugs, Sugemalimab Injection 2022-08-16
  12. Information of marketed drugs, Bevacizumab Injection 2022-08-25
  13. Information of marketed drugs, Bevacizumab Injection 2022-09-02
  14. Information of marketed drugs, Tislelizumab Injection, Toripalimab Injection 2022-09-06
  15. Information of marketed drugs, Insulin Glargine Injection 2022-09-08
  16. Information of marketed drugs, Durvalumab Injection 2022-09-15
  17. Information of marketed drugs, Teriparatide Injection 2022-09-16
  18. Information of marketed drugs, Toripalimab Injection, Tislelizumab Injection, Sugemalimab Injection 2022-09-23
  19. Information of marketed drugs, Cadonilimab Injection 2022-09-27
  20. Information of marketed drugs, Tocilizumab Injection 2022-09-30

 

Q&A Update of CDE

 

FAQ Update of eCTD

 

Question 1: According to the requirements of the eCTD Implementation Guidelines V1.0, when an application is submitted in eCTD format, electronic signatures of the applicant or the registration agency are required for all PDF documents, and the electronic signature of the legal representative is required for application forms. When an applicant’s legal person authorizes a designated person from the domestic registration agency to sign, how should the application forms be signed electronically?

 

Question 2: What should an applicant pay attention to after completing eCTD application dossier compilation and CD burning.How is self-inspection conducted?

 

Question 3: According to the requirements of the eCTD Implementation Guidelines V1.0, applicants should provide a hard copy of the application materials within 5 days of application acceptance. Is physical seal or printed electronical seal required on application materials?

 

Common Problems of Acceptance

 

Question 1: How do you supplement stability research data in the review process?

 

Question 2: What is the application pathway for completing post marketing related technical research according to the requirements of drug approval documents?

 

Question 3: How do you obtain a transition period when applying for a supplementary application for change?

 

Question 4: According to the requirements of the Notice of the Center for Drug Evaluation on Adjusting the Working Method of Acceptance and Requirements for Receiving Application Materials during the Epidemic Period on February 7, 2022, what should be included in the CD of electronic application materials?

 

Question 5: After accepting the electronic application materials, how should the applicant organize the paper application materials and clinical trial database CD?

 

Reference

 

  1. FAQ Update of eCTD 2022-09-21
  2. Frequently Asked General Technical Questions 2022-09-23

 

Chinese Pharmacopeia

 

In Q3 2022, the main drafts open for solicitation of public comments issued by the Chinese Pharmacopeia Commission (ChPC) included “Notice on Soliciting Opinions on Bacterial Endotoxin Test for Pharmaceutical Excipients”, “Notice on Soliciting Opinions on the Draft Standards Related to Pharmaceutical Packaging Materials in Chinese Pharmacopoeia (the First Round)” and “Letter on Soliciting Opinions on the Harmonization Scheme Between Pharmaceutical Excipients Standards in Chinese Pharmacopoeia and ICH Q3C”.

 

Reference

  1. Notice on Soliciting Opinions on Bacterial Endotoxin Test for Pharmaceutical Excipients 2022-07-06
  2. Notice on Soliciting Opinions on the Draft Standards Related to Pharmaceutical Packaging Materials in Chinese Pharmacopoeia (the First Round) 2022-07-18
  3. Letter on Soliciting Opinions on the Harmonization Scheme Between Pharmaceutical Excipients Standards in Chinese Pharmacopoeia and ICH Q3C 2022-08-01

 

Center for Food and Drug Inspection of NMPA

 

In Q3 2022, the Center for Food and Drug Inspection of NMPA (CFDI) updated several “Responses to Questions” in the module of “Interactive Communication”, which includes records storage issues, requirements for laboratory address, adding new manufacturing site for biological products during clinical trial, establishment of quality standard for primary packaging materials, product name in the application dossiers for on-site verification and ethylene oxide sterilization verification.

 

International drug inspection trends: The 29th and 30th issues of Study on International Drug Inspection Trends include 18 articles each, which introduce the annual reports, guidelines and regulatory trends recently issued by regulatory authorities and international organizations such as FDA, EMA, WHO and PIC/S.

 

Reference

 

  1. General Questions & Answers – Added Questions & Answers 2022-07-05
  2. General Questions & Answers – Added Questions & Answers 2022-09-12
  3. General Questions & Answers – Added Questions & Answers 2022-09-14
  4. Study on International Drug Inspection Trends Vol. 6 No. 2 (Total No. 29) 2022-08-09
  5. Study on International Drug Inspection Trends Vol. 6 No. 3 (Total No. 30) 2022-09-29

 

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.

 

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. 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
  3. 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
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