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)
CDER Conversation: Novel Excipient Review Pilot Program October 2021
The FDA’s Center for Drug Evaluation and Research’s (CDER) Office of New Drugs (OND) recently launched a pilot program on Novel Excipient Review. The program offers a new pathway for drug manufacturers to obtain FDA review of certain novel excipients (inactive ingredients) before the excipients are used in drug formulations. The pilot program aims to promote development and use of new excipients that may be beneficial when excipient manufacturers and drug developers find it difficult to use existing excipients.
The pilot program is addressed in the CDER conversation with regards to the following aspects:
- What is a novel excipient?
- What exactly is the Novel Excipient Review Pilot Program and what does it do?
- What prompted the FDA to introduce this pilot program now?
- What are the current challenges of using excipients in drug development, and how the pilot program aims to address those challenges?
- What are the FDA’s expectations for the Novel Excipient Review Pilot Program? What does the FDA hope to gain?
- What is the FDA looking for from participants?
- How will the FDA measure the pilot program’s success?
Updates on Possible Mitigation Strategies to Reduce the Risk of Nitrosamine Drug Substance-related Impurities in Drug Products November 2021
The FDA updated mitigation strategies for applicants to develop control strategies and/or design approaches to reduce nitrosamine drug substance-related impurities (NDSRIs) to acceptable levels if NDSRIs are detected at objectionable levels in the drug product.
In addition to the mitigation strategy described in the FDA’s guidance and the supplier qualification program, the FDA encourages manufacturers to explore other approaches to mitigate or prevent formation of NDSRIs. Examples of possible mitigation strategies related to formulation design were provided by the FDA. Examples include the addition of antioxidants to formulations and modifying the micro-environment of the formulations to neutral or basic pH by incorporating excipients such as sodium carbonate. Manufacturer should determine the potential benefit from, and demonstrate the suitability of, any reformulation approach.
The announcement also expressed the FDA’s willingness to communicate with manufacturers on any innovative mitigation strategies. It further introduced possible pathways to submit the formulation changes to the agency as well as the meeting data package required in case a meeting is needed with the FDA.
CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports December 2021
This guidance provides recommendations to holders of biologics license applications (BLAs) for the types of chemistry, manufacturing, and controls (CMC) postapproval changes that the Food and Drug Administration (FDA) generally considers to have a minimal potential to have an adverse effect on product quality and therefore, to be documented in an annual report under 21 CFR 601.12.
The guidance applies to the following biological products as specified in 21 CFR 601.2 (a): therapeutic DNA plasmid products, therapeutic synthetic peptide products of 40 or fewer amino acids, monoclonal antibody products for in vivo use, and therapeutic recombinant DNA-derived products.
The guidance further provides in the Appendix examples of such changes. It is also worth noting that the FDA intends to notify the applicant of the correct category and may request additional information if the FDA disagrees with the reporting categorization. The guidance further notifies the applicant to only use this reporting mechanism when they are confident that documentation in an annual report is appropriate.
Inspection of Injectable Products for Visible Particulates December 2021
This draft guidance addresses the development and implementation of a holistic, risk-based approach to visible particulate control that incorporates considerations from many aspects. The guidance pointed out that controlling the visible particulate by meeting the criterion outlined in United States Pharmacopeia (USP) alone is not sufficient to ensure compliance with the applicable cGMP requirements. Full compliance with cGMP in terms of a broader array of manufacturing practices than just product inspection is needed to ensure the purity, safety, and effectiveness of the injectable products.
The guidance provided examples of serious adverse events involving injectable products contaminated with visible particulates as well as clinical risk factors that applicants should consider when developing their quality target product profile. It further addresses the importance of a risk-based approach to visible particulate control during product development and lays out different considerations for the corresponding category of particulates found during the risk assessment.
Most importantly, the guidance outlines the considerations for the visual inspection program which includes: 100% inspection, statistical sampling, training and qualification, quality assurance through a life cycle approach, and actions to address nonconformance.
Comments are expected to be submitted by 02/15/2022.
Manual of Policies and Procedures (MAPP) 5019.1 Rev.1 Allowable Excess Volume/Content in Injectable Drug and Biological Products December 2021
This MAPP document provides information related to the implementation of the final guidance for industry Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products (June 2015). It outlines policies and procedures to be used by the Office of Pharmaceutical Quality’s (OPQ’s) product quality assessors to ensure consistent assessment of excess injectable liquid or solid drug products that require reconstitution/constitution filled into vials.
The MAPP also describes “procedures for obtaining information in applications in support of excess volumes for single-dose and multiple-dose injectable drug products submitted in new drug applications (NDAs), biologics license applications (BLAs), abbreviated new drug applications (ANDAs), and applicable supplements to these applications.”
This MAPP will be effective on January 28th, 2022.
Other FDA Drug Development and Quality Updates
Other FDA Regulatory Submission and Procedure Updates
FDA Vaccines, Gene Therapy, and Advanced Therapy Medicinal Products Updates
FDA Coronavirus Disease (COVID-19) Updates
FDA Non–clinical Study and Other Topic Updates
EMA & EC
Dossier Administrative Validation Checklist for Initial Marketing Authorization Applications by Applicants (updated) October 2021
In order to make the validation process for initial marketing authorization applications (MAAs) more efficient, predictable and easier to navigate, the EMA provided this “validation checklist” which includes a number of questions helping applicants to assess the level of completion and consistency of various sections in a MAA dossier, and encourages applicants to submit it as part of the MAA dossier.
The checklist is an excel file containing various worksheets including “Cover Page”, “Checklist”, “Glossary”, “Revisions”, etc. This is the fourth time that the EMA has revised the checklist since its initial release in September 2019. The updates mainly include: added check about nitrosamines risk evaluation, added a new tab with ‘Common VSI issues’, and clarification of acronyms used in the GMP tab under ‘Guidance’. For applicants with a MAA submission plan, this checklist would be helpful for reference.
Version 4.1 (September 2021) – Clinical Trials Regulation (EU) No 536/2014 Draft Questions & Answers October 2021
Clinical Trials Regulation (EU) No 536/2014 is coming into application on January 31, 2022. This regulation harmonizes the assessment and supervision processes for clinical trials throughout the EU, via a Clinical Trials Information System (CTIS).
On October 14, 2021, European Commission (EC) released “Version 4.1 (September 2021) – Clinical Trials Regulation (EU) No 536/2014 Draft Questions & Answers” which aims to inform on the technical aspects of the Regulation with a view to facilitating its implementation, and to advise that the views in this document are not legally binding. Certain sections of this Q & A document are not yet complete and updated versions will be published progressively.
The current version of this Q & A document contains 12 aspects: (1) the scope of Clinical Trial Regulation in the EU; (2) applications limited to Part I, additional member state and other measures related to the application procedure; (3) substantial modifications; (4) withdrawals; (5) sponsor/legal representatives, investigator; (6) submission of results of clinical trials; (7) safety reporting; (8) authorizations of manufacturing and importation of IMPs; (9) “informed consent” and other substantial requirements for conducting clinical trials; (10) start, end, temporary halt, and early termination of a clinical trial; (11) arrangements for the transitional period; (12) miscellaneous.
Tailored Scientific Advice to Support Step-by-Step Development of New Biosimilars October 2021
The document was published to address questions that biosimilar developers may have on the tailored scientific advice procedures, which are as follows:
- I am considering submitting a tailored biosimilar scientific advice request. Who should I contact?
- Who can apply?
- What should be included in the briefing package?
- What should not be included in the briefing package?
- How will the procedure be handled?
- Can I submit a follow-up tailored scientific advice?
- Will the review of data conducted by the SAWP have an impact on the assessment at the time of MAA?
- What fee will be applied?
Detailed answers from the EMA can be found on the page.
European Medicines Agency Pre-authorisation Procedural Advice for Users of the Centralised Procedure (updated) December 2021
Two important updates regarding Organisation Management Service (OMS) and ending of Irish language derogation are addressed in this guidance.
Starting from November 1, 2021, for centrally-authorised medicinal products, new site and organisation registration is mandatory before related regulatory submissions are provided to the Agency. It is highlighted that these site and organisation registrations should be conducted prior to pre- and post-authorisation submissions to avoid delay in these procedures.
From January 01, 2022, Irish has become the authentic language of Commission decisions on marketing for marketing authorisation holders in Ireland unless a language waiver is requested by companies/individuals. Companies should note that the Irish language may be widely used in the future.
This guidance overall provides a comprehensive Questions & Answers section for issues typically addressed during pre-submission meetings for users of centralized procedure from the following five perspectives:
- Types of application and applicants
- Steps prior to submitting the application
- Preparing the dossier
- Submission, validation and fees
- Assessment of the application
The Questions & Answers (Q & A) are being updated continuously. It should be noticed that the Q & A is for guidance only and should be read together with “The rules governing medicinal products in the European Union”, Volume 2A, Notice to Applicants.
Nitrosamine Implementation Oversight Group (NIOG) – Second Meeting with Pharmaceutical Industry December 2021
The 2nd meeting between the NIOG and industry stakeholders was held to provide an update on the 2021 workplan and discuss priorities and workplan for 2022. Agenda, highlights and presentations from both NIOG and industry stakeholders can be found on the webpage. Highlights of the meeting are summarized as follows:
- The progress of the Step 1 “call for review” recommended by CHMP article 5 (3) scientific opinion was updated and the response rate received was high for both chemical and biological medicines for centrally authorized products.
- Intensified engagement and scientific discussion between industry and European regulators has facilitated the progress of the 2021 workplan as well as the update of the published guidance.
- More scientific data is needed for topics such as structure-activity relationship studies, root cause investigations and extrapolation of Acceptable Intake limits from other substances.
- International discussion is supported by EU regulators.
Other EMA Drug Development and Quality Updates
Other EMA & EC Regulatory Submission and Procedure Updates
EMA Vaccines, Gene Therapy, and Advanced Therapy Medicinal Products Updates
EMA & EC Coronavirus Disease (COVID-19) Updates
EMA Non–clinical Study and Other Topic Updates
TGA (Therapeutic Goods Administration)
Australian Manufacturing Licences and Overseas GMP Certification-Step by Step Guide November 2021
The Therapeutic Goods Administration (TGA) issued a step-by step guide for Australian manufacturers of therapeutic goods to apply for manufacturing licences and for overseas manufacturers obtaining GMP Certification. The guide does not apply to manufacturers of medical devices or overseas manufacturers obtaining GMP clearance using the Mutual Recognition Agreement (MRA) or Compliance Verification (CV) pathways.
According to this guide, only Australian manufacturing sites can obtain a manufacturing licence. Overseas manufacturers can instead obtain GMP certification following a successful on-site inspection by the TGA. The Australian sponsor or an agent acting on the Australian sponsor’s behalf are required to submit the application for GMP certification. From application to completion, the process (including the on-site inspection) can take up to 12 months to obtain a manufacturing licence for an Australian manufacturing site and 15 months for a manufacturing licence GMP certification of an overseas manufacturing site. More details regarding the manufacturer’s and sponsor’s responsibilities can be found on the website.
It is also noteworthy that “No batch of product (including validation batches) manufactured prior to licensing or certification can be sold or supplied within Australia, or exported from Australia, unless prior approval has been obtained”.
Other TGA Drug Development and Quality Updates
Other TGA Regulatory Submission and Procedure Updates
TGA Coronavirus Disease (COVID-19) Updates
WHO (including Coronavirus Disease [COVID-19] Updates)
Drug Registration Review
In order to facilitate the implementation of eCTD, the Center for Drug Evaluation (CDE) developed two free software to help the applicant verify and electronically sign the eCTD dossiers. In addition, CDE drafted “Rules on Timing Suspension and Recovery during Registration Review by NMPA (Trial)” soliciting public comments. The document details the circumstances and specific reasons for suspension of timing and the specific operation of recovery of timing is clarified.
- Rules on Suspension and Recovery during Registration Review by NMPA (Trial) 2021-11-04
- Notice on Issuing Electronic Common Technical Document (eCTD) Validation Software for Drugs and Batch Electronic Stamp Software for PDF Documents 2021-12-10
Inspection and Testing for Drug Registration
The Center for Food and Drug Inspection of NMPA (CFDI) published a series of documents to further clarify the implementation principles, procedures, timeline, requirements and judgement principles for the drug registration inspection. Standardization of the joint conduction of on-site inspection and pre-approval GMP inspection was also clarified. In the meantime, the CDE published “Procedures for Initiating the Drug Registration Inspection and Testing (Trial)” to regulate the initiation of drug registration inspection and testing. The regulations came into force on January 1, 2022.
The documents further emphasized that the initiation of inspection and testing shall be risk-based. Two factors, including product type and compliance, shall be considered for risk evaluation and the risks are categorized into three levels. For marketing application, biological products are considered to be at high risk, and therefore, on-site inspection and testing shall be conducted in principle. For supplementary application, if the changed manufacturing process is innovative or if new technology is introduced into the regular production process, the biological product would fall into the high-risk category when the change could increase risks after evaluation. Biological products that undergo major changes in the production process or manufacturing sites fall into the medium-risk category. The risk level of compliance is evaluated in combination with the recent registration inspection, regulatory inspection, relationship between research institutes and sponsors and previous rectification results. Registration inspection conducted by foreign regulatory authorities should also be taken into consideration. The risk levels are determined with a graded adjustment mechanism. It is noteworthy that high-risk level registration applications, determined due to issues of authenticity and improper interests, the compliance risk level shall not be adjusted within five years.
Since the implementation of the new Provisions for Drug Registration on July 1, 2020, the applicant may apply for drug registration testing after determining the specifications of the drug and completing the process validation at commercial scale but before the acceptance of the New Drug Application (NDA). Alternatively, the CDE may initiate the testing and notify the drug testing institution upon acceptance of the registration application.
- Announcement on Five Published Documents Including Working Procedures for Drug Registration Inspection (Trial) by CFDI ( No. 30) 2021-12-20
- Announcement on Procedures for Initiating the Drug Registration On-site Inspection and Testing (Trial) ( No. 54) 2021-12-20
- Announcement on Issues Related to the “Confirmation” of Drug Registration Applicants to Accept On-site Inspection 2021-12-30
Jiangsu Province and Zhejiang Province have issued relevant rules to implement “The Provisions for Post-Approval Changes of Drugs (Trial).” The two provinces have different requirements for application in terms of manufacturing site changes.
- Announcement of Zhejiang Medical Products Administration on Issuing Implement Rules for the Management of Post-approval Changes of Drugs in Zhejiang Province (Trial) 2021-12-22
- Policy Interpretation of Implement Rules for the Management of Post- approval Changes of Drugs in Zhejiang Province (Trial) 2021-12-22
- Notice of the Management Requirements for the Post-approval Change of Manufacturing Site of Drugs (Jiangsu Medical Products Administration  No. 160) 2021-12-24
- Zhejiang Medical Products Administration Issues Implement Rules for the Management of Post-approval Changes of Drugs in Zhejiang Province (Trial) 2021-12-22
On November 12, 2021, the CFDI published “Guidelines for the Quality Management of Shared Facility Drug Manufacturing [Draft for Comments]” (Guideline) and has been soliciting public comments.
The Guideline aims to provide analysis and guidance for the design, implementation and improvement of strategies in shared facility drug manufacturing throughout the drug life cycle. The marketing authorization holder (MAH) and drug manufacturers shall understand the relationship among the harm, exposure and risks of shared facility drug production, scientifically determine the acceptable limit of residues, analyze possible ways of contamination and cross-contamination, and formulate corresponding mitigation strategies. The contamination and cross-contamination levels shall be continuously monitored to ensure that the risks are effectively controlled, and therefore ensure drug quality and patient safety.
The Guideline is not mandatory, and the final version has not yet been issued. However, the Guideline provides technical reference for the MAHs, drug manufacturers, facility design, equipment manufacturing, drug regulation and other relevant parties. The Guideline is drafted based on the current scientific and technological knowledge and does not prohibit the adoption of new technologies and new methods. MAHs and drug manufacturers may adopt validated alternative methods to meet the requirements in this guideline.
- Notice of Soliciting Public Opinions on Guidelines for the Quality Management of Drug Manufacturing in Shared Facilities (Draft for Comments) 2021-11-12
Adoption of ICH Guidelines
“ICH Q3C (R8) Impurities Guideline for Residual Solvents” was adopted by NMPA. The studies conducted after February 21, 2022, shall comply with the requirements of Q3C (R8).
“ICH M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” and “ICH Q9 (R1) Quality Risk Management” are at stage 3 of the adoption process and soliciting comments.
- Notice on Soliciting Public Advice on the Implementation of ICH E14 and Q & A and Q3C (R8) Guidelines 2021-11-02
- NMPA Announcement on the Adoption of ICH Q3C (R8) Impurities Guideline for Residual (No. 152, 2021) 2021-12-20
- Notice on Soliciting Public Comments on ICH Guideline M7 (R2): Assessment and Control of DNA Active (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk 2021-12-21
- Notice on Soliciting Public Comments on ICH Guideline Q9 (R1) Quality Risk Management 2021-12-28
Draft General Rules
The Chinese Pharmacopoeia Commission issued four draft documents, which include “The General Rules for Microbiological Testing of Cell Products (Draft)”, “The General Rules for In Vitro Pyrogen Testing [Reporter Gene Method] (Draft)”, “The Guidelines for Biological Examination of Genetically Modified Cell Lines (Draft)” and “The General Chapter of Recombinant DNA Protein Products for Human Use (Revised Draft).” The process for soliciting comments is ongoing.
Excipient and Container Closure System
In November, the Chinese Pharmacopoeia Commission published the “Answers to the Common Questions on the 2020 Chinese Pharmacopoeia” for both excipients and container closure systems (CCS). In addition, the revised standard for sodium acetate was published again to solicit public comments.
The Chinese Pharmacopoeia (CP) issued the “Publication on the Chinese Generic Names of Biological Products Included in WHO INN P-list 125” on November 4, 2021. It aims to determine the Chinese generic names of biological products included in the World Health Organization’s (WHO) recommended catalogue for International Nonproprietary Names (INN) 125 (P list125). The CP catalogue includes the information of the Chinese generic names corresponding to the English generic names of a total of 102 biological products including adintrevimab, amubarvimab, enuzovimab and pavunalimab (bavunalimab).
- Publication on the Draft General Rules for Microbiological Examination of Cell Products 2021-10-26
- Publication of the Draft General Chapter on In Vitro Pyrogen Test (Reporter Gene Method) 2021-10-26
- Guideline on Bioassays Based on Genetically Modified Cell Lines (Draft) 2021-12-14
- Publication on the General Monograph of Recombinant DNA Protein Products for Human Use (Revised Draft) 2021-12-20
- Publication of the Draft Standard for Pharmaceutical Excipients of Sodium Acetate (Second Revised) 2021-11-03
- Reply to the Common Questions on the Standards for Pharmaceutical Excipients in Chinese Pharmacopoeia 2020 (I) 2021-11-17
- Reply to the Common Questions on the Standards for Pharmaceutical CCS in Chinese Pharmacopoeia (I) 2021-11-26
- Publication on Chinese Generic Names of Biological Products Included in WHO INN P-list 125 2021-11-04