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

 FDA (U.S. Food and Drug Administration)

Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency (April 2021)

The guidance describes how the FDA will request and conduct voluntary remote interactive evaluation at facilities. The guidance outlines specific considerations for planning, conducting and concluding a remote interactive evaluation as well as discusses impacts on established commitments and timeframes. The FDA may request to conduct a remote interactive evaluation for many purposes and programs whenever a program office determines it is appropriate based on mission needs and any travel limitations. This policy applies to all drug inspection programs including, but not limited to:

• Pre-Approval Inspections (PAIs) and Pre-License Inspections (PLIs)
• Post-Approval Inspections (PoAIs)
• Surveillance Inspections
• Follow-Up and Compliance Inspections
• Bioresearch Monitoring (BIMO) Inspections

The policy described in the guidance is intended to remain in effect only for the duration of the public health emergency related to COVID-19 as declared by the Secretary of Health and Human Services (HHS) on January 31, 2020.

Coronavirus (COVID-19) Update: FDA Outlines Inspection and Assessment Activities During Pandemic, Roadmap for Future State of Operations (May 2021)

The FDA issued a new report titled, “Resiliency Roadmap for FDA Inspectional Oversight,” outlining the agency’s inspectional activities during the COVID-19 pandemic and its detailed plan to move toward a more consistent state of operations, including the FDA’s priorities related to this work going forward. The main contents of the report are as follows:

• The report highlights the number of mission-critical inspections and prioritized domestic inspections conducted, as well as inspections that the agency was unable to complete during the past year. 
• The report outlines the FDA’s continued successful use of alternative tools and approaches where inspections were or are not currently feasible, including remote interactive evaluations.
• The report further outlines the ongoing steps the agency is taking in order to resume standard operational levels of inspection activities.
• The agency will also soon begin a multi-year modernization effort to further transform data enterprise platforms and cross-program interoperability infrastructure to better support innovation related to its regulatory oversight role.
• The FDA is also establishing an agency-wide FDA Inspectional Affairs Council that will plan and coordinate inspectional activities.

FDA Emergency Use Authorization for Vaccines to Prevent COVID-19 (May 2021)

This guidance is issued by the FDA on May 25, 2021 and supersedes the guidance of the same title issued on February 22, 2021 and October 2020. The guidance aims to provide sponsors of requests for Emergency Use Authorization (EUA) for COVID-19 vaccines, with recommendations regarding the data and information needed to support the issuance of an EUA under section 564 of the FD&C Act (21 U.S.C. 360bbb-3) for an investigational vaccine to prevent COVID-19 for the duration of the COVID-19 public health emergency. 

The guidance gives instructions on the criteria and considerations for the issuance of an EUA, the key logistic recommendations for the request for an EUA, and the prioritization of requests for issuance of an EUA, as well as recommendations regarding regulatory, Chemistry, Manufacturing and Controls (CMC), safety and effectiveness information and data to be included in a request for an EUA for a COVID-19 vaccine. The guidance also lays out the considerations for continuing clinical trials following issuance of an EUA and the consideration of an EUA for a COVID-19 vaccine by an FDA advisory committee. Additionally, the appendixes provide instructions on the submission of information in preparation for a Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting, and detailed instructions on the evaluation of vaccines to address emerging SARS-CoV-2 variants.

Bispecific Antibody Development Programs Guidance for Industry (May 2021)

This guidance discusses unique aspects for chemistry, manufacturing, and controls (CMC), as well as nonclinical and clinical development programs for bispecific antibodies that are different from monoclonal antibody development programs. The guidance also addresses a range of general, regulatory and scientific considerations and provides recommendations regarding the type of data necessary to support the approval of bispecific antibodies.

For regulatory considerations, the FDA’s regulation on fixed-combination prescription drugs for humans (21 CFR 300.50) does not apply to the development of bispecific antibodies, which are single molecules. Although not generally expected, in some cases the FDA may request a comparison of the bispecific antibody to an approved monospecific product(s) directed against the same antigenic target(s) to inform the benefit-risk assessment of the bispecific antibody.

Q3D (R2) – Guideline for Elemental Impurities (Draft: May 2021)

ICH Q3D “Elemental Impurities” is a quality guideline for the control of elemental impurities in new drug products (medicinal products), and it establishes Permitted Daily Exposures (PDEs) for Elemental Impurities (EIs) for drug products administered by the oral, parenteral and inhalation routes of administration. The initial version of Q3D was finalized under Step 4 in November 2014.

The current version of Q3D (R2), published by the FDA in May 2021, is a draft version which was endorsed on September 25, 2020 and is currently under public consultation. This document is comprised of extracts of the Q3D (R2) Guideline made from the revisions to the Q3D (R1) Guideline. The extracts are as follows: Part 1 – Extract of Appendix 2: Correction of PDEs for Gold, Silver and Nickel; Part 2 – Extract of Appendix 3: Correction of Gold monograph; Part 3 – Extract of Appendix 3: Correction of Silver monograph; and, Part 4 – New Appendix 5. The revised draft guideline incorporates Permitted Daily Exposure (PDE) for new elemental impurities (EI) / routes of administration and revises the PDE for EI already listed in Q3D (R1) as new toxicological data becomes available.

Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Guidance for Industry (May 2021)

This guidance provides a framework to facilitate the management of post-approval chemistry, manufacturing, and controls (CMC) changes in a more predictable and efficient manner. 

This guidance applies to pharmaceutical drug substances and products (both chemical and biological) that require a marketing authorization and to drug-device combination products that meet the definition of a pharmaceutical or biological product. Changes needed to comply with new or revised pharmacopoeial monographs are not within the scope of this guidance. The harmonized regulatory tools and enablers are given below:

• Categorization of Post-approval CMC Changes 
• Established Conditions
• Post-approval Change Management Protocol
• Product Lifecycle Management Document
• Pharmaceutical Quality System and Change Management
• Relationship Between Regulatory Assessment and Inspection
• Structured Approaches for Frequent CMC Post-approval Changes
• Stability Data Approaches to Support the Evaluation of CMC Changes

Effective implementation of the tools and enablers with associated guiding principles will enhance the management of post-approval changes and transparency between industry and regulatory authorities, promote innovation and continual improvement.

Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Annexes (May 2021)

This document comprises two parts: (1) Illustrative Examples (Annex I) and (2) Structured Approach to Analytical Procedure Changes (Annex II). The examples provided in sections I.A through I.F of the ICH Q12 Annex I are mock examples provided for illustrative purposes. They only suggest how the tools described in sections III, IV, and V of the ICH Q12 guidance could be applied and should not be used as a template or the sole basis for a regulatory submission. In addition, the reporting categories, as described in section II of the ICH Q12 guidance, may differ across regions depending on regional legislation; the nature of the product; and the Marketing Authorization Holder’s (MAH’s) demonstrated understanding of the product, process, and analytical procedure. 

MAHs are expected to maintain existing analytical procedures for authorized products and ensure that these are kept up-to-date. The intent of the approach provided in Annex II is to incentivize structured implementation of at least equivalent analytical procedures that are fit for purpose. An approach wherein specific criteria are defined for changes to analytical procedures used to test marketed products is described.

Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products (June 2021)

This guidance is intended to assist applicants and manufacturers of certain licensed biological products in determining which reporting category is appropriate for a change in chemistry, manufacturing, and controls (CMC) information to an approved biologics license application (BLA). Licensed biological products that are within the scope of this guidance and of particular interest include vaccines, allergenic products, plasma-derived products and their recombinant analogs, and cellular and gene therapy products.

The guidance describes general and administrative information on evaluating and reporting changes and recommendations for reporting categories based on a tiered-reporting system for specific changes under 21 CFR 601.12. Special considerations regarding change in process parameters and change in a supplier of raw materials are given. In the Appendix, the FDA provides a list of examples of post-approval manufacturing changes and recommended reporting categories. Particularly, the FDA suggests that ICH Q12 guidance should be used by applicants in concert with any other applicable FDA guidance to report post-approval changes to the Agency when such reporting is required by the statute and regulation. 

This guidance finalizes the draft guidance, “Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products” dated December 2017, and supersedes the guidance entitled “Guidance for Industry: Changes to an Approved Application: Biological Products” dated 1997 (July 1997 guidance).

Drug Development and Quality Guideline News Updates 

Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products  (June 2021)

Regulatory Submission and Procedure News Updates

• Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs That Are Regulated Under a Biologics License Application, and Animal Drugs; Corrections (April 2021)
• Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency Guidance for Industry – Level 1 Guidance (April 2021)
• FDA Study Data Technical Rejection Criteria (TRC): What You Need to Know! (Updated: May 2021)
• What’s New in Regulatory Science (May 2021)

Coronavirus Disease (COVID-19) News Updates

• FDA Continues Important Steps to Ensure Quality, Safety and Effectiveness of Authorized COVID-19 Vaccines (April 2021)
• Guidance Documents Related to Coronavirus Disease 2019; Availability (April 2021)
• COVID-19 Vaccines: Development, Evaluation, Approval and Monitoring (Updated: May 2021)
• FDA Takes Steps to Increase Availability of COVID-19 Vaccine (June 2021)
• FDA COVID-19 Response At-A-Glance Summary as of June 14, 2021 (June 2021)

Non-clinical Study News Updates

• Nonclinical Testing of Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases; Draft Guidance for Sponsor-Investigators; Availability (April 2021)

Other Topics

• Patent Certifications and Suitability Petitions (Updated: April 2021)
• Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security Act (June 2021)
• Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification (June 2021)
• Enhanced Drug Distribution Security at the Package Level Under the Drug Supply Chain Security Act (June 2021)
• Product Identifiers Under the Drug Supply Chain Security Act: Questions and Answers (June 2021)
• FDA In Brief: FDA Encourages Inclusion of Patients with Incurable Cancers in Oncology Clinical Trials Regardless of Prior Therapies (June 2021)
• Assessment of the Use of Patient Experience Data in Regulatory Decision-Making (June 2021)
• Sponsor Responsibilities – Safety Reporting Requirements and Safety Assessment for IND and Bioavailability /Bioequivalence Studies (June 2021)
• Slides for the Patient Engagement & Regenerative Medicine: An FDA CBER Workshop for Patient Advocates (June 2021)

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

ICH guideline Q3C (R8) on Impurities: Guideline for Residual Solvents (May 2021)

ICH Q3C “Impurities: Guideline for Residual Solvents” is a quality guideline which provides recommendations on acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient, recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents (e.g., organic volatile impurities). The initial version of Q3C was finalized under Step 4 in July 1997.

The current version ICH Q3C (R8), published by the EMA in May 2021, is a final version under Step 5 (final adoption by the Committee for Medicinal Product for Human Use (CHMP), which will come into effect on November 20, 2021. A Maintenance process for the Q3C Guideline was set up to enable the revision and inclusion of new Permitted Daily Exposure (PDE) levels as new toxicological data for solvents become available. As part of the Maintenance Process, the Q3C (R8) Maintenance EWG (Expert Working Group) has been working on the PDE levels for 2-methyltetrahydrofuran, cyclopentylmethylether and tert-butanol.

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 (Updated: June 2021)

The updated contents are listed as follows:

3. For the ‘call for review’ for chemically synthesized and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities? (UPDATED)

19. What is the approach for line extensions and variations applications not linked to changes required as part of article 5 (3) recommendation? (NEW)

• No risk evaluation is generally necessary when submitting line extension or variation application. The risk evaluation is only required to be submitted for products in scope of the call for review as reported in Q&A 3. In some exceptional cases, questions on the presence of nitrosamines in the product may be raised if a potential risk is identified during the assessment.

Drug Development and Quality Guideline News Updates

• Nitrosamine Implementation Oversight Group Terms of Reference (April 2021)
• Joint EMA and FDA Guidance on Cancer Medicines for Use in Children-Pediatric-Oncology-Development (April 2021)
• Information Note on the Format and Validity Features of Electronic Certificates for Medicines Issued by the European Medicines Agency (April 2021)
• Guidance on Good Manufacturing Practice and Good Distribution Practice: Questions and Answers (April 2021)
• Certification of Medicinal Products (May 2021)
• Step 2 – Nitrosamine Detected Response Template (Updated: May 2021)

Regulatory Submission and Procedure News Updates

• Parallel Application for EU-M4all (Article 58) Opinion and Centralized Marketing Authorization Procedure (April 2021)
• Overview of Comments Received on ‘Public guidance: Parallel Application for EU-M4all (Article 58) Opinion and Centralized Marketing Authorization Procedure’ (EMA/104275/2021) (April 2021)
• Validation Checklist for Type II Quality Variations (May 2021)
• Validation Checklist for Type II (non) Clinical Variations (Update: May 2021)
• Clinical Trials Information System (CTIS): Training Program (Updated: June 2021)
• Initial (Full) Marketing Authorization Application Assessment Timetables (June 2021)
• Initial (Full) Marketing Authorization Application Accelerated Assessment Timetables (June 2021)
• Extension Application Assessment Timetables (June 2021)   
• Type II Variation and Worksharing Application Monthly Assessment Timetables (June 2021)
• Regulatory and Procedural Guideline: Procedural Advice for Orphan Medicinal Product Designation: Guidance for Sponsors (June 2021)
• Procedural Advice for Post-Orphan Medicinal Product Designation Activities (June 2021)

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

• Guideline on Data Requirements for Vaccine Antigen Master Files (VAMF) (June 2021)
• Scientific Recommendations on Classification of Advanced Therapy Medicinal Products (June 2021)

Coronavirus Disease (COVID-19) News Updates

• EMA and ECDC Join Forces for Enhanced Post-Marketing Monitoring of COVID-19 Vaccines in Europe (April 2021)
• COVID-19 Vaccine Janssen: Authorities in EU Take Steps to Safeguard Vaccine Quality (June 2021)
• Additional Manufacturing Capacity for Moderna’s COVID-19 Vaccine (June 2021)
• COVID-19 Guidance: Post-Authorization (June 2021)
• Procedural Guidance for Variant Strain(s) Update to Vaccines Intended for Protection Against Human Coronavirus (June 2021)
• COVID-19: Latest Updates (June 2021)

Other Topics

• European Union Individual Case Safety Report (ICSR) Implementation Guide (Updated: April 2021)
• Overview of Comments Received on ‘ICH Reflection Paper on Proposed ICH Guideline Work to Advance Patient Focused Drug Development’ (EMA/CHMP/ICH/415588/2020) (April 2021)
• Medicines for Use Outside the European Union (Updated: April 2021)
• Reflection Paper on Forecasting Demand for Medicinal Products in the EU/EEA (June 2021)
• Opinions and Letters of Support on the Qualification of Novel Methodologies for Medicine Development (June 2021)
• Draft Guideline on Computerized Systems and Electronic Data in Clinical Trials (June 2021)
• Outcome of Public Consultation on ICH Reflection Paper on Patient-Focused Drug Development (PFDD). (June 2021)
• ICH Reflection Paper – Proposed ICH Guideline Work to Advance Patient Focused Drug Development (PFDD) (June 2021)
• Success Rate for Marketing Authorization Applications from SMEs Doubles Between 2016 and 2020 (June 2021)
• Products Management Services – Implementation of International Organization for Standardization (ISO) Standards for the Identification of Medicinal Products (IDMP) in Europe: Introduction – EU Implementation Guide (June 2021)
• Product Management Services (PMS) – Implementation of International Organization for Standardization (ISO) Standards for the Identification of Medicinal Products (IDMP) in Europe – Chapter 2 (June 2021)
• Product Management Services (PMS) – Implementation of International Organization for Standardization (ISO) Standards for the Identification of Medicinal Products (IDMP) in Europe – Chapter 3 (June 2021)
• Product Management Service (PMS) – Implementation of International Organization for Standardization (ISO) Standards for the Identification of Medicinal Products (IDMP) in Europe – Chapter 8 (June 2021)
• Product Management Service (PMS) – Implementation of International Organization for Standardization (ISO) Standards for the Identification of Medicinal Products (IDMP) in Europe – Chapter 8 Annex I: Complete Representation (June 2021)

Health Canada

Canada’s Approach to Onsite Inspections during COVID-19: Notice (April 2021)

• The notice describes that Health Canada continues to take a risk-based approach to inspections. Health Canada stated that onsite work remains as a key tool to deliver essential inspection activities and will use remote or virtual tools to complement onsite inspection activities. 

Regulatory Submission and Procedure News Updates

• Guidance for Completing the Drug Submission Application Form (March 2021)
• Guidance Document: Patented Medicines (Notice of Compliance) Regulations (June 2021)

Coronavirus Disease (COVID-19) News Updates

• Updated Requirements for COVID-19 Drug Authorizations: Notice (March 2021)
• Interim Order No. 2 Respecting Clinical Trials for Medical Devices and Drugs Relating to COVID-19: Notice (May 2021)
• Applications for COVID-19 Drug and Medical Device Clinical Trials Under the Interim Order: Notice of Updated Guidance Documents (May 2021)

 WHO (World Health Organization)

WHO Guidelines on the Transfer of Technology in Pharmaceutical Manufacturing (QAS/20.869/Rev.1) (Update, Draft: April 2021)

As recommended in the 15th Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) meeting in 2020, the WHO started to update this transfer of technology guideline to meet the requirement and regulatory expectations on product life cycle management as well as to support the supply of therapies for critical needs, including a public health emergency.

The content includes updating the background and scope of transfer of technology, as well as related fundamental definitions and main principals which cover the following areas:

• Organization and management of the transfer;
• Transfer of relevant information in production, including but not limited to processing, packaging and analytical procedures;
• Documentation, premises, equipment;
• Personnel qualification and training;
• Quality management and risk management;
• Change management and life cycle approach;
• Control strategy; and
• Qualification and validation.

This draft will be finalized in August and presented in the 56th ECSPP meeting, in October 2021.

Statement for Healthcare Professionals: How COVID-19 Vaccines Are Regulated for Safety and Effectiveness (June 2021)

This joint statement from the International Coalition of Medicines Regulatory Authorities (ICMRA) and the WHO aims to help healthcare professionals answer questions about the role of regulators in the oversight of COVID-19 vaccines. It explains how vaccines undergo robust scientific evaluation to determine their safety, efficacy and quality prior to potential regulatory authorization and how safety is closely and continually monitored after approval. Particularly, the statement discusses in detail the adverse events for the approved mRNA vaccines and adenovirus vector vaccines in the global market. The statement also provides a list of “Questions and Answers on COVID-19 Vaccines” covering variable topics, e.g., “How long will COVID-19 vaccination provide protection for immunized people,” and “Will mRNA vaccines affect the DNA of vaccine recipients?”

Regulatory Submission and Procedure News Updates

WHO Publishes New Guidance to Promote Strong, Efficient and Sustainable Regulatory Systems (April 2021)

Additional Coronavirus Disease (COVID-19) News Updates

WHO Supporting South African Consortium to Establish First COVID mRNA Vaccine Technology Transfer Hub (June 2021)

Other Topics

• Putting People First in Managing Their Health: New WHO Guideline on Self-Care Interventions (June 2021)
• From 30 Million Cases to Zero: China is Certified Malaria-Free by WHO (June 2021)

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

Guide to Good Manufacturing Practice for Medicinal Products-Related Annexes (April 2021)

The PIC/S Guide to Good Manufacturing Practice (GMP) for Medicinal Products has been revised to include a new Annex 2A and 2B:

• Annex 2A: Manufacture of Advanced Therapy Medicinal Products for Human Use (ATMP)
• Annex 2B: Manufacture of Biological Medicinal Substances and Products for Human Use

The revised GMP Guide (PE 009-15), with the new Annex 2A and 2B, was entered into force on May 1, 2021.

Annex 2B provides guidance on the full range of active substances and medicinal products defined as biological with the exception of ATMPs. 

Annex 2B is divided into two parts:

• a) Part A contains supplementary guidance on the manufacture of biological active substances and medicinal products, from control over seed lots and cell banks through to finishing activities and testing. General principles for adventitious agents, multiple-product facilities, starting and raw materials, seed lot and cell bank system and other concepts of quality control are described. 

• b) Part B contains further guidance on selected types of biological active substances and medicinal products including monoclonal antibody products, vaccines, and recombinant products, amongst others.  

PIC/S Adapting EU GMP Annex 16 on Authorized Person and Batch Release (June 2021)

EU Good Manufacturing Practice (GMP) Annex 16 on Certification by a Qualified Person* and Batch Release entered into force in 2002. Following the revision of EU Annex 16 in 2016, the Pharmaceutical Inspection Convention (PIC) and the PIC/S Sub-Committee on GMDP Harmonization (SCH), was mandated to transpose a PIC/S version of EU GMP Annex 16 in accordance with a memorandum of understanding with the EMA.

The PIC/S Committee recently agreed to proceed to Step 2 of the PIC/S consultation process, which enables an opportunity for PIC/S Participating Authorities to consult with stakeholders and was launched on June 15, 2021. The consultation process will last for a period of three months. The consultation will focus on national stakeholders of non-EU/European Economic Area (EEA) Members of PIC/S, considering that EU/EEA Members of PIC/S already apply EU Annex 16. Comments from stakeholders will be considered carefully while working toward a general objective of ensuring continued harmonization and equivalence between the EU and PIC/S GMP Guides. Minimal deviations between the guides will help work toward improved global harmonization.

* The PIC/S term of “Authorized Person” and the EU term of “Qualified Person” are strictly equivalent.

MHRA (Medicines and Healthcare products Regulatory Agency)

Guidance on the Licensing of Biosimilar Products (May 2021)

This guideline is to provide developers of similar biological medicinal products (also known as biosimilars) with a clear outline of the requirements for biosimilar products in Northern Ireland/Great Britain/UK. The guideline lays out the requirements for biosimilars in sections identified as General principles, Content of a biosimilar application, Traceability, Interchangeability, and Substitution, as well as provides links for stakeholders in the Further information section.

Applicants should also consider the principles contained within the Committee for Medicinal Products for Human Use (CHMP) guidelines. 

• Guideline on Similar Biological Medicinal Products
• Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues
• Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues
• Guideline on Immunogenicity Assessment of Therapeutic Proteins Relevant Product-specific Biosimilar Guidelines

This MHRA guidance contains further clarifications and some revisions to these CHMP guidance documents, which take into account the scientific and regulatory experience gained since the first biosimilar product was licensed in 2006, including biosimilar monoclonal antibodies and fusion proteins licensed from 2013.

Drug Development and Quality Guideline News Updates

• New Guidance and Information for Industry from the MHRA (March 2021)

Regulatory Submission and Procedure News Updates

• Electronic Application Form and Cover Letter Tool (March 2021)
• MHRA Fees (April 2021)
• Medicines: Get Scientific Advice from MHRA (May 2021)
• MHRA Phase I Accreditation Scheme (June 2021)

Coronavirus Disease (COVID-19) News Updates

• Early Access Continues During the Coronavirus (COVID-19) Pandemic (April 2021)
• MHRA Guidance on Coronavirus (COVID-19) (Updated: June 2021)

Non-clinical Study News Updates

• Responding to a GLP and GCP Laboratory Inspection Report (March 2021)

PMDA (Pharmaceuticals and Medical Devices Agency)

Drug Development and Quality Guideline News Updates

• Japanese Pharmacopoeia 18th Edition (June 2021)

Other Topics

• Global Pharmaceutical Quality Knowledge Management: Enhancing Regulatory Reliance and Agility (June 2021)
• China and Japan Regional Joint Public Meeting on ICH (June 2021)

TGA (Therapeutic Goods Administration)

Drug Development and Quality Guideline News Updates

• GMP Clearances: Timeframes for Transfers and Name Change Applications (June 2021)

Regulatory Submission and Procedure News Updates

• Priority Determination Eligibility Criteria (April 2021)
• Orphan Drug Designation Eligibility Criteria (April 2021)
• Provisional Determination Eligibility Criteria (April 2021)
• Overview of Applying for Market Authorization (April 2021)
• Australian Electronic Submission Basics (June 2021)

ICH (International Council for Harmonisation of Technical

Non-clinical Study News Updates

• The ICH S12 Step 2 Presentation Available Now on the ICH Website (June 2021)

Other Topics

• A New Collaboration between SNOMED International and ICH Promotes Seamless Data Exchange in Support of Public Health (April 2021)
• ICH Guideline E6 on Good Clinical Practice – Draft ICH E6 Principles (June 2021)

EC (European Commission)

Drug Development and Quality Guideline News Updates

• Pharmeuropa 33.2 Just Released (April 2021)

Other Topics

• COVID-19 Therapeutics Matchmaking Event Open for Applications (June 2021)

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

Drug Development and Quality Guideline News Updates

• New General Chapter on Cell-Based Assay for Potency Determination of TNF-Alpha Antagonists (2.7.26) Published for Public Enquiry (June 2021)
• European Pharmacopoeia Supplement 10.6 Now Available (June 2021)
• European Pharmacopoeia to Put an End to the Rabbit Pyrogen Test (June 2021)

Other Topics

• Adoption of the Revised Raman Spectroscopy Chapter (March 2021)

National Medical Products Administration (NMPA)

China Regulatory Update Q2 2021

Update and Interpretation of NMPA Regulations Q2 2021

Drug Regulation Trend

The General Office of the State Council issued the “Opinions on Implementing Comprehensive Enhancement of Drug Regulatory Capacity” (hereinafter referred to as “the Opinions”). The Opinions outlines the work requirements on aspects including refining the statutory and regulatory system, improving regulatory personnel capacity, optimizing regulatory review process, establishing pharmacovigilance system, and promoting digitalized drug life-cycle management, amongst other topics. 

The State Administration for Market Regulation (SAMR) published the 2021 legislative work plan as below: 

• Submit to the State Council for review a total of 6 laws and administrative regulations, including the “Product Quality Law of the People’s Republic of China,” “Implementation Regulations of the Drug Administration Law of the People’s Republic of China,” and “Implementation Rules of the Patent Law of the People’s Republic of China”
• Revise a total of 61 Departmental regulations including the “Provisions on Standardize Patent Application”
• Cooperate with the legislature in the revision of laws and regulations such as the “Anti-Monopoly Law”, “Metrology Law,” “Provisions on the Registration and Administration of Mercantile Entity,” “Provisions on the Publication of Enterprise Information,” and “Provisions on Market Regulation,” amongst others

References

• 1.The General Office of the State Council Issued “Opinions on Implementing Comprehensive Enhancement of Drug Regulatory Capacity” (May 2021)
• 2.Office of the State Council: Opinions on Comprehensively Strengthening the Capacity Establishment of Drug Supervision (No. 16 [2021]) (May 2021)
• 3.The State Administration of Market Regulation Published the Legislative Work Plan of 2021 (April 2021)

Changes in Biological Products 

Post-marketing Changes in Biological Products

The Center for Drug Evaluation (CDE) issued the “Technical Guideline on Post-marketing Chemistry, Manufacturing and Controls Changes in Biological Products, Trial” (hereinafter referred to as “the Technical Guideline”). The Guideline provides suggestions on evaluating and reporting post-marketing changes in chemistry, manufacturing and controls (CMC), as well as studies and data required to support the changes in biological products. The Marketing Authorization Holder (MAH) is the main responsible entity for managing post-marketing changes, and a supplementary application should be submitted to the agency when MAH changes. Key considerations of comparability study are also provided in the Guideline. Relevant guidelines and requirements such as the ICH guideline shall also be considered when applying this guidance.   

Changes are categorized into three classes based on the risk of potential impacts on the safety, efficacy and quality of biological products. 

• Minor changes (Type I): Changes that have hardly any impact on the safety and efficacy related quality attributes of the biological products. Minor changes can be reported through Annual Reports.
• Moderate changes (Type II): Changes that may have moderate impact on the safety and efficacy related quality attributes of the biological products. Relevant studies are required to demonstrate that the changes do not negatively impact the quality, safety, and efficacy of the biological products. Moderate changes should be recorded to the provincial drug administrations, where the MAH is located for domestically manufactured biological products and be recorded to the CDE for biological products manufactured abroad.
• Major changes (Type III): Changes that may have significant impact on the safety and efficacy related quality attributes of the biological products. Extensive studies are required to demonstrate the changes do not negatively impact product quality, safety, and efficacy. Supplementary application to the National Medical Products Administration (NMPA) is required and the changes cannot be implemented before approval. 

Changing During the Review Period of Drug Registration Application

The CDE issued the “Work Procedures for Changes During the Review Period of Drug Registration Application (Draft Guidance)” (hereinafter referred to as “the Procedures”). The Procedures apply to changes that occur during the review of the clinical trial application (CTA), supplemental application, Biological License Application (BLA) and re-registration application. In principle, the applicant can only apply once for the changes, and the proposed changes do not affect the evaluability of the original application. In addition, technical changes are not accepted during the review process of the CTA and supplemental application during the clinical trial due to the limited review and approval timeline.

References

1. NMPA Notice on the Issuance of “Change Categories and Dossier Requirements for Post-marketing Biological Products (No. 40, 2021)” (June 2021)
2. CDE Notice on the Issuance of “Guidelines on the Acceptance for Review of Changes in Biological Products (Trial) (No. 30, 2021)” (June 2021)
3. CDE Notice on the Issuance of “Technical Guideline on Post-marketing Chemistry, Manufacturing and Controls Changes in Biological Products, Trial” (June 2021)
4. Notice on Seeking Comments on “Work Procedures for Changes During the Review Period of Drug Registration Application” (June 2021)

Drug Inspection

NMPA Notice on the Issuance of “Provisions of the Drug Inspection, Trial” (May 2021)

The NMPA issued the “Provisions of the Drug Inspection, Trial” (hereinafter referred to as “the Provisions”), which went into effect on the day of its promulgation. The Provisions stipulates the main responsibilities for regulatory authorities of all levels, inspection categories and procedures, as well as requirements for the authority and inspector. 

The NMPA is responsible for the management of drug inspections across the country, supervising and guiding the provincial medical products administrations to carry out on-site inspections of drug MAHs and manufacturers. The Center for Food and Drug Inspection (CFDI) of the NMPA is responsible for inspections of vaccines and blood products.

Pharmacovigilance

“Good Pharmacovigilance Practices” (hereinafter referred to as “the Practices”) will come into effect on December 1, 2021. The MAHs and the drug registration applicants who were approved to conduct clinical trials (hereinafter referred to as “the applicants”) should establish a special pharmacovigilance agency within China to develop an annual periodical analysis and evaluation plan based on the marketing time, risk characteristics or requirements of regulatory authorities and carry out the work as planned. The MAHs and the applicants should complete information registration in the National Adverse Event Surveillance System within 60 days of promulgation.

For the drug registration applicant, the drug safety update report (DSUR) during research and development (R&D) should be submitted to the CDE regularly after the clinical trial is approved. 

For the MAH, adverse drug reaction (ADR) monitoring data, clinical studies, literature and other data should be evaluated regularly. The MAH should record and report Periodic Safety Update Report (PSUR) as required. Serious adverse events should be reported no later than 15 days after information is obtained, and non-serious adverse reactions should be reported no later than 30 days after information is obtained. If the adverse event occurs abroad, the MAH should submit an individual case safety report (ICSR) to the National Center of ADR Monitoring. If a drug is required to be suspended for sale or use, or is withdrawn from the market by an overseas regulatory agency, the MAH should report to the national regulatory agency and National Center of ADR Monitoring within 24 hours after receiving the information.

References

1. Publish of Good Pharmacovigilance Practices (May 2021)

2. NMPA Announcement of the Issuance of Good Pharmacovigilance Practices (No. 65, 2021) (May 2021)

3. Q&A of Good Pharmacovigilance Practices, Part 1 (May 2021)

Marketed Product Information

COVID-19 Vaccines

By the second quarter of 2021, two Chinese vaccines (shown in Table 1) have been included in the WHO Emergency Use List (EUL). 

Table 1. Chinese vaccines on the EUL

Cell Therapy 

Axicabtagene ciloleucel by Fosun Kite Biotechnology Co., Ltd. is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy product, which has become the first cell therapy product approved for marketing through priority review in China.

References

• Inactivated Covid-19 Vaccine by Beijing Institute of Biological Products Co., Ltd. (Sinopharm) was Listed on the WHO Emergency Use List (May 2021)
• Inactivated Covid-19 Vaccine by Sinovac Research and Development Co., Ltd was Listed on the WHO Emergency Use List (June 2021)
• Inactivated Covid-19 Vaccine by Sinovac Research and Development Co., Ltd was Certified by WHO for Emergency Use (June 2021)
• NMPA Approved the Marketing Application of Axicabtagene ciloleucel (June 2021)

Common Q&A about For-inspection Drugs

• Q1：For the APIs and drug products applications submitted before the implementation of the new “Provisions for Drug Registration,” commercial scale process validation was not conducted before nor required upon submission. Thus, the on-site inspection application cannot be submitted to respond to the notice of inspection. 

• • The questions are: 

(1) When to submit the inspection application? 

A: In accordance with the previous “Provisions for Registration of Drug Products”, the applicant should submit the inspection application within 6 months upon receipt of the CDE notice.

(2) When is the deadline for the inspection? 

A: The CFDI should start the inspection within 30 days after the applicant submits the inspection application.

(3) How to submit the process validation materials? 

A: In accordance with the previous requirements, the PPQ batch numbers are required to be included in the application form, while process validation materials and other relevant documents can be provided to the inspection team during on-site inspection.

(4) Do all the products manufactured after the critical batches need to be preserved?

A: Yes. Samples should be kept for future inspection.

• Q2: Will dynamic or static inspections be notified in advance? 

A: The CFDI will notify the applicant in advance if dynamic production is needed during the inspection. Normally, no phone notice will be given for static inspections. The applicant should check the inspection information through the “Window for Drug Registration Applicants”. 

• Q3: Which department should the corrective materials for the inspection be submitted to?

A: For inspections conducted after the implementation of the new “Provisions for Drug Registration,” the correction reports of the defects should be submitted to the provincial medical products administration(s) for review. 

• Q4: For products under regular review, the inspection report should be returned to the CDE 40 days before the end of the 200-day review cycle. For products under priority review, should the report be returned to CDE 40 days before the end of the 130-day review?

A: The inspection report of products under priority review should be returned to CDE 25 days before the end of the 130-day review cycle.\

References

• Q&A About For-inspection Drug (sixth) (April 2021)
• Q&A About For-inspection Drug (seventh) (May 2021)