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)
Field Alert Report Submission: Questions and Answers Guidance for Industry July 2021
“This guidance provides the FDA’s current thinking regarding the requirements for submission of field alert reports (FARs) by applicants of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) and outlines the FDA’s recommendations for FAR submissions to help improve their consistency and relevancy. The guidance also addresses certain frequently asked questions.”
Impact of Continuous Manufacturing Processes on the Viral Safety of Therapeutic Proteins August 2021
The article, which was published by the Center for Drug Evaluation and Research (CDER) on August 20, 2021, reflects CDER’s thoughts on how to ensure the safety of therapeutic proteins produced by continuous manufacturing.
The following are key elements taken directly from the guidance:
- The manufacture of therapeutic proteins often consists of expression of the target protein in an engineered cell line followed by a series of purification steps to remove product- and process-related impurities. Recently there has been a push from batch manufacturing processes toward continuous manufacturing (CM) paradigms. CDER researchers collaborate with external stakeholders to investigate these unique challenges and their impact on viral safety.
- CDER researchers found three process steps to be key for promoting viral clearance during CM operations: capture chromatography, viral inactivation, and viral filtration.
- Continuous capture chromatography employs multiple smaller capture columns that can be overloaded, washed, or eluted simultaneously in a cyclical pattern. These results suggest that there may be minimal impact to viral safety with the use of a multicolumn chromatography and that a simulated batch small-scale design is feasible with proper regulatory guidance.
- In the case of continuous viral filtration, the results demonstrated that while there was an impact on filtration pressure with a dynamic fluid stream, there was minimal impact on viral clearance, with observed increase in virus passage being related to total virus particles loaded and the filter being used.
Electronic Common Technical Document; Data Standards; Specifications for Electronic Common Technical Document Validation Criteria-Notice August 2021
The following summary includes excerpts taken directly from the FDA documents:
“The Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) is announcing the date that FDA will begin rejecting submissions that fail either Electronic Common Technical Document (eCTD) validation 1551 or 1553, which are high severity validation errors as described in the Specifications for eCTD Validation Criteria. Validation errors 1551 and 1553 have been added to the Specifications for eCTD Validation Criteria. Rejection for failing to pass either eCTD validation 1551 or 1553 under a submission to CDER will begin on October 18, 2021.”
Electronic common technical document (eCTD) is the standard format for submitting applications, amendments, supplements, and reports to FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER).
On May 5, 2015, FDA issued the final guidance for industry on Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.1 Submission types including new drug application (NDA), abbreviated new drug application (ANDA) and Biologics License Application (BLA) must be submitted in eCTD format beginning May 5, 2017. IND submissions and master files, other than Type III DMFs, must be submitted in eCTD format beginning May 5, 2018. Timetable for the Initial Implementation of the Electronic Submission Requirement is listed below as shown and taken directly from the FDA document:
The version of eCTD currently supported by FDA is specified in the Data Standards Catalog.
The guidance: Providing Regulatory Submissions In Electronic Format — Standardized Study Data describes the requirements for an electronic submission of standardized clinical and nonclinical study data. The Technical Rejection Criteria for Study Data have been added to the existing eCTD validation criteria to determine compliance with the requirements for submitting standardized study data would be implemented on September 15, 2021. Submissions which fail this validation will be subject to rejection.
Per the guidance “Providing Regulatory Submissions in Electronic and Non-Electronic Format—Promotional Labeling and Advertising Materials for Human Prescription Drugs” (The Promotional Labeling Guidance), certain types of promotional-material-related submissions, including post-marketing submissions of promotional materials using Form FDA 2253, fall within the scope of section 745A(a) of the FD&C Act and are, therefore, subject to the mandatory electronic submission requirements (unless such submission is exempt from the electronic submission requirements or if FDA has granted a waiver). Submissions to CDER that are subject to section 745A(a) of the FD&C Act and fail to pass either eCTD validation 1551 or 1553 would start being rejected on October 18, 2021.
Benefit-Risk Assessment for New Drug and Biological Products (Draft Guidance) September 2021
This draft guidance is being distributed for comment purposes only, and comments should be submitted by November 29, 2021.
As taken from the FDA document:
“The intent of this guidance is to clarify for drug sponsors and other stakeholders how considerations about a drug’s benefits, risks, and risk management options factor into certain premarket and post-market regulatory decisions that the Food and Drug Administration (FDA) makes about new drug applications (NDAs) submitted under section 505(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) as well as biologics license applications (BLAs) submitted under section 351(a) of the Public Health Service Act (PHS Act). This guidance first articulates FDA’s approach to the benefit-risk assessment of new drugs and biologics including FDA’s Benefit-Risk Framework, then it articulates important considerations that factor into the Center for Drug Evaluation and Research’s (CDER) and the Center for Biologics Evaluation and Research’s (CBER) benefit-risk assessments, including how patient experience data can be used to inform the benefit-risk assessment. It then discusses how sponsors can inform FDA’s benefit-risk assessment through the design and conduct of a development program, as well as how they may present benefit and risk information in the marketing application. It also discusses opportunities for interaction between FDA and sponsors to discuss benefit-risk considerations in connection with the development of an NDA or BLA. This guidance concludes with additional considerations on benefit-risk assessments that inform regulatory decision-making in the post-market setting.”
Other FDA Drug Development and Quality Updates
Other FDA Regulatory Submission and Procedures Updates
Other FDA Vaccines, Gene Therapy, and Advanced Therapy Medicinal Products News Updates
FDA Coronavirus Disease (COVID-19) Updates
EU (European Union) / EMA (European Medicines Agency)
Procedural guidance for variant strain(s) update to vaccines intended for protection against human coronavirus August 2021
This guideline was released by EMA on August 5, 2021, which lays down the procedural aspects related to the submission of a variation to change the composition of a marketing authorisation for COVID-19 vaccines in the centralised procedure.
“In order to ensure the continued effectiveness of authorised COVID-19 vaccines, it may be necessary to modify the authorised human coronavirus vaccines composition so as to protect against new or multiple variant strain(s). Such changes, which include the replacement or addition of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences, should be considered as variations to the marketing authorisation in accordance to the Commission Regulation (EC) No 1234/2008 as amended by Commission Delegated Regulation (EU) 2021/756, provided the technological platform of the vaccine remains similar. The same approach should be followed for all human coronaviruses as set out in the Commission Delegated Regulation (EU) 2021/756.” The guideline provides guidance on the regulatory and procedural requirements for applications to change vaccine composition (pandemic strain change) during a pandemic, including instructions for Variation Classification, Pre-submission step, Submission step (format, product information, traceability and naming) and Evaluation steps.
EMA Initiatives for Acceleration of Development Support and Evaluation Procedures for COVID-19 Treatments and Vaccines (Update) Sep 2021
This document provides an overview of EMA’s rapid formal review procedures related to COVID-19 which complements other documents published under the guidance for medicine developers and companies on COVID-19 and the respective guidance provided for regular procedures published on the EMA website for research and development and for marketing authorisation.
It is outlined as seven sections: 1. Rapid scientific advice; 2. Rapid agreement of a paediatric investigation plan and rapid compliance check; 3. Rolling review; 4. Marketing authorization; 5. Extension of indication and extension of marketing authorization; 6. Compassionate use; 7. Other considerations.
With this accelerated procedure, the timeline could be significantly reduced compared with the normal application procedure. For example, the total scientific advice review time is reduced to 20 days, compared to the regular 40/70 days timeframe; the total evaluation time for a paediatric investigation plan (including waiver or deferral) will be reduced to a minimum of 20 days, compared to normally up to 120 days active review time and its compliance check in advance of a marketing authorisation application can be reduced to four days if necessary; the maximum active review time of the marketing authorization is reduced from 210 to 150 days, which in practice may even be shorter. Please refer to the document for more details.
Other EU/EMA Drug Development and Quality Updates
Other EU/EMA Regulatory Submission and Procedures Updates
EU/EMA Vaccines, Gene Therapy, and Advanced Therapy Medicinal Products News Updates
Other EU/EMA Coronavirus Disease (COVID-19) Updates
Other EU/EMA Updates
Health Canada Regulatory Submission and Procedures Updates
Health Canada Non-Clinical Studies Updates
Other Health Canada Updates
WHO (World Health Organization)
WHO Regulatory Submission and Procedures Updates
WHO Coronavirus Disease (COVID-19) Updates
Other WHO Updates
PIC/S (Pharmaceutical Inspection Convention (PIC) and the Pharmaceutical Inspection Co-operation Scheme (PIC Scheme)
Adoption and Entry into Force of PIC/S Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1) July 2021
This guidance has been developed primarily for inspectors and entered into force on July 1, 2021. By laying out the details on Data Governance System and specific Data Integrity Considerations under various situations, the guidance provides a consolidated, illustrative guide on risk-based control strategies, assists Inspectorates in the interpretation of GMP/GDP requirements in relation to good data management and ultimately facilitates the effective implementation into routine planning and the conduct of inspections. This guidance, together with Inspectorate resources such as aide memoire, should enable the inspector to make optimal use of the inspection time and an optimal evaluation of data integrity elements during an inspection. The guidance applies to both on-site and remote inspections but is not intended to provide specific guidance in support of “for-cause” inspections following detection of significant data integrity vulnerabilities where forensic expertise may be required.
Entry into Force of PI 054-1 PQS Recommendation July 2021
The PIC/S Recommendation document titled “How to Evaluate and Demonstrate the Effectiveness of the Pharmaceutical Quality System with regard to Risk-Based Change Management”, PI 054-1 came into force on July 15, 2021. This document addresses two fundamental and inter-related elements of the PIC/S GMP Guide – PQS effectiveness and the management of changes. It provides practical guidance for GMP Inspectors in these areas. It covers all relevant steps in the change management process – change proposal, change assessment, change planning and implementation, change review and effectiveness checks and indicates within each step the aspects that render the PQS to be effective in that area. The implementation of that guidance has the potential to ultimately lead to the timelier management of risks to product quality and patient safety, as well as better quality and manufacturing performance, continual improvement and innovation.
Adoption and Entry into Force of PI 055-1 “COVID-19 Risk Assessment for Routine On-Site Inspections” July 2021
The guidance entered into force on July 15, 2021. This guidance for inspectorates includes a detailed checklist of tasks and potential hazards associated for a thorough risk assessment. Risk Assessment covers announced GXP inspection of national sites. It is to be completed during the inspection planning phase, in consultation with the site to be inspected, and prior to the inspection taking place. The site must confirm that the necessary measures identified in the risk assessment will be implemented. Consideration should also be given to Covid testing of Inspectors / Investigators pre- and post-inspection and may be requested by some sites.
MHRA (Medicines and Healthcare products Regulatory Agency)
MHRA Drug Development and Quality Updates
MHRA Regulatory Submission and Procedures Updates
MHRA Coronavirus Disease (COVID-19) Updates
PMDA (Pharmaceuticals and Medical Devices Agency)
PMDA Regulatory Updates
TGA (Therapeutic Goods Administration)
Statement for healthcare professionals: How COVID-19 vaccines are regulated for safety and effectiveness July 2021
“This joint International Coalition of Medicines Regulatory Authorities (ICMRA) and World Health Organization (WHO) statement 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 and how safety is closely and continually monitored after approval.”
Other TGA Regulatory Submission and Procedures Updates
Other TGA Coronavirus Disease (COVID-19) Updates
ICH (International Council for Harmonisation of Technical
ICH guideline Q13 on continuous manufacturing of drug substances and drug products Step 2b July 2021
This summary provides excerpts taken directly from the guidance document:
This guideline describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing (CM). This guideline provides clarification on CM concepts, describes scientific approaches, and presents regulatory considerations specific to CM of drug substances and drug products.
This guideline applies to CM of drug substances and drug products for chemical entities and therapeutic proteins. It is applicable to CM for new products (e.g., new drugs, generic drugs, biosimilars) and the conversion of batch manufacturing to CM for existing products. The principles described in this guideline may also apply to other biological/biotechnological entities.
Annexes I through IV augments the main guideline by providing examples and additional scientific and regulatory considerations of the manufacture of drug substance of chemical entities, drug products, drug substance of therapeutic proteins and integrated drug substance and drug product CM, respectively. Annex V describes examples of approaches for managing transient disturbances that may occur during CM.
Q2(R1) Validation of Analytical Procedures: Text and Methodology Guidance for Industry (Final, Level 2 Guidance) Sep 2021
“FDA incorporated Q2B Validation of Analytical Procedures: Methodology (May 1997)(Q2B) on methodology with the parent document Q2A Text on Validation of Analytical Procedures (March 1995)(Q2A) and retitled the combined document Q2(R1) Validation of Analytical Procedures: Text and Methodology (Q2(R1). This guidance consists of the previously published FDA guidances, Q2A and Q2B. It is the same, in substance, as those two guidances, and it is the same, in substance, as the November 2005 ICH Q2(R1) guideline.”
Other ICH Drug Development and Quality Updates
EDQM (European Directorate for the Quality of Medicines & HealthCare)
EDQM Drug Development and Quality Updates
National Medical Products Administration (NMPA)
The following is an update and interpretation of NMPA Regulations from Q3 2021
In accordance with the “Patent Law of the People’s Republic of China”, “The Civil Procedure Law of the People’s Republic of China” and other relevant laws, “Provisions on Several Issues Concerning the Application of Suitable Laws in Drug Patent Rights – related Civil Disputes” was formulated and came into effect on July 5, 2021. To provide specific guidance, the “Implementation Measures for the Early Resolution Mechanism for Drug Patent Disputes (Trial),” was published and entered into force on July 4, 2021, starting from which, the State Intellectual Property Office officially accepts the administration adjudication cases of the early resolution mechanism of drug patent disputes.
On July 4, 2021, China Listed Drug Patent Information Registration Platform was officially launched and began operating. Marketing Authorization Holders (MAHs) shall register their drug patent information in advance and proactively make it public. When submitting the marketing application of a biosimilar, the patent announcement shall be submitted along with the application package. The applicant shall also provide the patent announcement as well as the justification for the announcement to the MAH of patented drugs.
Reformation of “Separation of Permit and License”
- To provide more convenience and predictability for enterprises in the Drug, Medical Device and Cosmetics field, from July 1, 2021, the Operating License Full-Coverage List Management of enterprises in the drug regulation area was implemented nationwide. The reformation of the Approval system is carried out in four ways: direct cancellation of the approval, approval to record, implementation of notification commitment, and optimization of approval services.
- For the approval of contracted manufacturing of drug, direct cancellation was implemented. The contracted manufacturing of drug shall follow the relevant provisions in the “Drug Administration Law of the People’s Republic of China.” Vaccine production shall be in compliance with the relevant regulations laid out in the “Vaccine Administration Law of the People’s Republic of China,” where approval by the drug regulatory department under the State Council is required prior to contracted manufacturing.
- The review duration is shortened to 14 working days for the Manufacturing License application of new drug manufacturing and marketing application.
Transformation and Implementation of ICH Guidelines
On September 1, 2021, the NMPA Center for Drug Evaluation (CDE), issued a notice asking for public comments on the transformation and implementation recommendations for ICH E18, M3 (R2) and Q&A (R2). CDE has developed the transformation and implementation recommendations for ICH “E18: Guideline on Genomic Sampling and Management of Genomic Data” and “M3 (R2) and Questions and Answers (R2): Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals Questions & Answers”. Solicitation of opinions was closed on September 30, 2021.
CDE Drug FAQs
1Q: Before clinical trial application of a therapeutic biological drug, does the applicant have to apply for a Pre-IND communication meeting?
A: According to the “Announcement of the National Medical Products Administration (NMPA) on Adjusting the Review and Approval Procedures for Drug Clinical Trials” (No. 50 of 2018), applicants shall submit the application of communication meeting to the Center for Drug Evaluation (CDE) before for the first clinical trial application of a new drug. For drugs produced overseas, and if clinical trials have been approved in countries and/or regions with well-established regulatory systems, applicants can self-assess the relevant risks and apply for clinical trials. For drugs that have already been approved for clinical trials and need to apply for new indications, the communication meeting can be waived. For the application of clinical trials for biosimilars, it is recommended to apply for a Pre-IND communication meeting.
2Q: If a drug has been approved for a clinical trial and needs to be used in combination with a domestically marketed drug, is it required to submit a new clinical trial application for the combined use?
A: If the drug to be used in combination has been approved for marketing within the Chinese territory, it is not mandatory to submit a drug clinical trial application at the same time.
3Q: Can the resident representative office of a foreign company act as an Agent within the Chinese territory for a foreign MAH?
A: According to the “The Provisions for Drug Registration,” overseas applicants shall appoint an enterprise legal person in China to handle relevant drug registration matters. The resident representative offices of foreign enterprises do not qualify as legal person and can only engage in non-profit activities related to the business of the foreign enterprise in China.
4Q: Is it possible not to submit the Manufacturing and Testing Procedures for the application of clinical trials of biological products?
A: It is not mandatory to submit Manufacturing and Testing Procedures for clinical trial applications.
Announcement of “General Format and Drafting Guidance of the Manufacturing Process and Specifications for Traditional Chinese Medicine, Chemical Drugs and Biologics”（No. 32, 2021）
The “General Format and Drafting Guidance of the Manufacturing Process and Specifications for Traditional Chinese Medicine, Chemical Drugs and Biologics” is issued and implemented on July 19, 2021. Since the date of publication, the applicant shall submit the corresponding documents in the required format.
Chinese Pharmacopeia 2020
Corrections in Chinese Pharmacopoeia 2020
The National Pharmacopoeia Commission issued a notice on the errata of the 2020 edition of the Chinese Pharmacopoeia in July 2021, which involved monographs and general rules from Volume I to Volume IV.
Revision of Chinese Pharmacopoeia 2020
The National Pharmacopoeia Commission revised the national standards for Sabin strain polio inactivated vaccine (Vero cell) and 11 types of other live attenuated vaccines.
“Technical Guidelines for Impurity Control of Human Vaccine”
The national pharmacopoeia committee publicized the “Technical Guidelines for Impurity Control of Human Vaccine (Draft)” and solicited opinions from the industry. The guideline provides suggestions for the following aspects:
- Source of vaccine impurities
- Principles and strategies of vaccine impurity control
- Life cycle management
- Key points in control of impurities in different types of vaccines
- Impact of changes on vaccine impurity control