Regulatory Newsletter

WuXi Biologics Regulatory Updates

Quarter 4 – 2019

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: Agency Collaboration | Australian Department of Health Therapeutic Goods Administration (TGA) | European Medicines Agency (EMA) | International Council for Harmonisation (ICH) | National Medical Products Administration (NMPA) | Pharmaceutical Inspection Co-operation Scheme (PIC/S) | U.S. Food & Drug Administration (FDA) | World Health Organization (WHO)

FDA

Regulatory Submission and Procedure Updates:

Identification of Manufacturing Establishments in Applications Submitted to CBER and CDER Questions and Answers (Posted: October 2019)

Key elements and information provided in this guidance document include:

• The Agency clarifies expectations regarding facility information that should be included in Form U.S. FDA 356h and Module 3 of original NDA, ANDA, original BLA, amendments, supplements, CMC supplements and resubmissions to these submission types
• Questions related to the inclusion and withdrawal of proposed commercial facilities and development facilities, the appropriate location within an application for facility information, and the type of facility information that should be included in applications

Drug Development and Quality Guideline News/Updates:

Site Visit Training Program for Office of Pharmaceutical Quality Staff; Information Available to Industry (Published 10/18/2019)

Novel Excipient Review Program Proposal; Request for Information and Comments (Published 12/05/2019)

Bridging for Drug-Device and Biologic-Device Combination Products; Draft Guidance for Industry; Availability (Published 12/19/2019)

Regulatory Submission and Procedure News/Updates

SOPP 8101.1: Regulatory Meetings with Sponsors and Applicants for Drugs and Biological Products (Published 11/4/2019)

Reorganization of the Office of New Drugs with Corresponding Changes to the Office of Translational Sciences and the Office of Pharmaceutical Quality (Published/Updated Q4/2019 and on 3/17/2020)

U.S. FDA Releases New BsUFA Performance Dashboard on U.S. FDA-Track (Published 9/30/2019)

Prescription Drug User Fee Act Waivers, Reductions, and Refunds for Drug and Biological Products Guidance for Industry (Published 10/16/2019)

Agency Information Collection Activities; Proposed Additional Collection; Comment Request;

General Licensing Provisions; Section 351(k) Biosimilar Applications; Formal Meetings Between the Food and Drug Administration and Sponsors or Applicants (Published 11/22/2019)

Drug Master Files Guidance for Industry (Draft) (Published 10/18/2019)

Importation of Certain U.S. FDA-Approved Human Prescription Drugs, Including Biological

Products, under Section 801(d)(1)(B) of the Federal Food, Drug, and Cosmetic Act: Draft

Guidance for Industry (Published Q4/2019 and updated on 1/14/2020)

Requesting U.S. FDA Feedback on Combination Products : Draft Guidance for Industry and U.S. FDA Staff (Published 12/23/2019)

Non-clinical Guideline News/Updates

Qualification Process for Drug Development Tools; Draft Guidance for Industry; Availability (Published 12/26/2019)

EMA

Drug Development and Quality Guideline Updates

Guideline on the Sterilisation of the Medicinal Product, Active Substance, Excipient and Primary Container (Effective as of 10/1/2019)

Key elements and information contained in this guideline, amongst other topics, includes:

• Biological medicinal products for human use, including sterile finished products, sterile active substances, sterile excipients, and sterile primary containers in a new marketing authorization application or a variation application for a medicinal product
• The selection of appropriate methods of sterilization for sterile products and information on when other terminal sterilization processes, sterilizing filtration, or aseptic processing could be accepted as an alternative

Regulatory Submission and Procedure Updates

European Medicines Agency Pre-authorisation Procedural Advice for Users of the Centralised Procedure (Posted: November 2019)

The EMA provided updates to this document in section 1.9.3, 2.6, and 2.8.2. Key elements and information updated include:

• An emphasis on the time of the filing that the marketing authorization application needs to be mature, including all relevant data that is needed to support the application. This is particularly important to enable an accelerated assessment of the application within 150 days instead of up to 210 days.
• Information for when submitting a PRIME application, the EMA strongly advises applicants to make full use of the pre-submission opportunities to discuss the completeness of the data package supporting a marketing authorization application and the scientific and regulatory support offered by the scheme

Drug Development and Quality Guideline News/Updates:

Procedural Advice for Orphan Medicinal Product Designation (Posted: 12/11/ 2019)

Procedural Advice for Post-orphan Medicinal Product Designation Activities (Published Q4/2019 and updated on 3/18/2020)

Regulatory Submission and Procedure News/Updates

European Pharmacopoeia Supplement 10.1 Available Now (Published 10/11/2019)

Outcome of the 165th Session of the European Pharmacopoeia Commission (Published 12/11/2019)

Validation Checklist for Initial MAA – Pharmaceuticals (Applicable to Submissions under Article 12(3) of Directive 2001/82) (Published 10/2019)

Site Suitability Form – EudraLex (Volume 10 – Clinical Trials Guidelines – Set of Documents

Applicable to Clinical Trials under Regulation EU No 536/2014) (Published 10/9/2019)

Dialogue with Chinese Authorities on Medicine Regulation (Published 10/10/2019)

Draft Questions and Answers Document (Version 2.3) (Eudralex Volume 10 – Clinical Trials (Published 11/2019)

Guidelines – Set of Documents Applicable to Clinical Trials under Regulation EU No 536/2014) (Published 11/2019)

Regulatory Science to 2025

Cross-Agency Collaboration

Drug Development and Quality Guideline Updates

Pilot Programme for International Cooperation in GMP Inspection of Manufacturers of Sterile Medicinal Products for Human Use, Terms of Reference for Participating Authorities (Posted: December 2019)

EMA and its European and international partners launched this pilot program to share information on GMP inspections of manufacturers located outside the participating countries and to organize joint inspections of sterile medicinal products for human use. Key elements and information, amongst other topics, provided in this document includes:

• Objectives, scope, requirements and general principles of an international inspection pilot program covering manufacturers of sterile medicinal products
• The participating authorities include WHO, U.S. FDA (US), MHRA (UK), PMDA (Japan), ANSM (French), EMA (Europe), HC (Health Canada), and TGA (Australia). The pilot will include only third country manufacturing sites of interest to at least two participating authorities
• Products in the scope are marketed sterile pharmaceutical medicinal products for human use of chemical origin and certain marketed therapeutic biotechnology-derived biological products. Vaccines, cell and gene therapies, and plasma derived pharmaceuticals are currently out of scope.

TGA

Drug Development and Quality Guideline News/Updates:

Presentation: How to Submit an Effective Good Manufacturing Practice Clearance Application (Published 2019)

Releasing Medicines Manufactured at Multiple Sites (Published 11/2019)

WHO

Drug Development and Quality Guideline Updates

Guideline on Data Integrity (Draft) (Posted: October 2019)

This guidance provides recommendations to facilitate compliance with data integrity, GXP in documentation, and record keeping requirements. Some of the key recommendations provided in this guidance document include:

• Recommendations for a risk-based approach over the life cycle of data and that data integrity risk assessment (DIRA) should be carried out in order to identify and assess areas of risk.
• These aspects apply to contract givers and contract acceptors, and the guideline should be read with other WHO GXP guidelines and publications.

PIC/S

Drug Development and Quality Guideline Updates

Draft PIC/S Recommendation on How to Evaluate / Demonstrate the Effectiveness of a Pharmaceutical Quality System in Relation to Risk-based Change Management (Draft) (Posted: November 2019)

Some key recommendations and practical guidance that this document provides, amongst others, include:

• GMP inspectors to evaluate the effectiveness of a company’s pharmaceutical quality system (PQS) in relation to risk-based change management
• Update to relevant steps in the change management process, including change proposal, change assessment, change planning and implementation, change review and effectiveness checks. It indicates within each step the aspects that render the PQS to be effective in that area

ICH

Drug Development and Quality Guideline Updates

ICH Q12 and Annexes reach Step 4 of the ICH Process (Posted: November 2019)

The ICH Q12 Guideline is intended to complement the existing ICH Q8 to Q11 Guidelines and provides a framework to facilitate the management of post-approval CMC changes in a more predictable and efficient manner across the product lifecycle.

• The adoption of this new ICH Guideline will promote innovation and continual improvement in the biopharmaceutical sector, and strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustments.
• It will allow regulators (assessors and inspectors) to better understand the firm’s Pharmaceutical Quality Systems (PQSs) for management of post-approval CMC changes.

Regulatory Submission and Procedure News/Updates

Report of 2019 Implementation Survey Available Now on the ICH Website (Published 11/04/2019)

The NMPA guidance documents and updates are written in Chinese, therefore, we have provided more detailed summaries in English for your benefit. The WuXi Biologics Regulatory Affairs team may be available for consultation should your organization be actively pursuing drug development or entering clinical trials in China.

Drug Administration Law of the People’s Republic of China

The second revision of the Drug Administration Law of the People’s Republic of China (hereinafter referred to as “the Drug Administration Law”) was submitted to the State Council in September, 2018. After three rounds of public opinions were sought, it was deliberated and adopted at the end of August, 2019, and came into force on December 1, 2019. This Law applies to the development, production, distribution, use, supervision and administration of drugs within the territory of the People’s Republic of China.

A summary and some of the key points of this document is provided as follows:

MAH

Marketing Authorization Holder (MAH) is the key point of the entire product lifecycle. Domestic enterprises, or drug research and development institutions, which have the quality management, risk prevention and control, liability compensation and other capabilities to ensure the safety, efficacy and quality controllability of drugs, may perform the obligations of a drug MAH. The MAH can transfer the drug approval license after approval. The acquiring party should meet all the MAH qualification requirements.

An overseas enterprise shall have an enterprise legal person within the territory of China, namely a subsidiary company or branch company, and meet the relevant conditions.

MAH may entrust qualified enterprises to manufacture drugs, and both parties shall sign an entrustment agreement and a quality agreement, and perform the stipulated obligations in accordance with the agreement. The legal representative and main responsible person of the marketing authorization holder shall be fully responsible for the drug quality. Entrusted manufacturing of blood products, narcotic drugs, psychotropic drugs, and medicinal toxic drugs, as well as drug precursor chemicals are prohibited, unless otherwise stipulated by the drug administrative department(s) of the State Council. In addition, the Provisions for the Supervision of Drug Manufacturing (Draft for Comments) stipulates that the entrusted party shall not subcontract to a third party to manufacture the drug.

Clinical Trial Application and Marketing Registration Application

In accordance with the new Drug Administration Law, drug registration applications can be divided into following categories including drug clinical trial applications, drug marketing authorization applications, post-marketing supplementary applications, renewal applications and other record or report items. The Drug Administration Law mandated that the review period for IND application shall be 60 working days, and Measures for the Administration of Drug Registration specified that review period of NDA is 200 working days.

Drug Traceability System

The new Drug Administration Law clearly requires to establish and improve the drug traceability system. MAHs and manufacturers may establish or adopt third-party services to meet relevant technical requirements. For specific drug traceability technical requirements, five information standards were issued in April and September last year to compile the basic technical requirements/coding specifications of the system.

Pharmacovigilance System

MAH shall establish a special pharmacovigilance agency within the territory of China to develop an annual periodical analysis and evaluation plan based on the marketing time, risk characteristics or requirements of regulatory authorities, and then carry out the work as planned.

The new Drug Administration Law requires that the applicant shall regularly submit the drug safety update report (DSUR) during R & D to the CDE after the clinical trial is approved.

After the drug is marketed, MAH shall regularly evaluate ADR monitoring data, clinical studies, literature and other data, and properly write and report PSUR (Periodic Safety Update Report) as required.

Related Documents:

1. Drug Administration Law of the People’s Republic of China, August 26, 2019
2. Announcement of NMPA on Implementing the Drug Administration Law of the People’s Republic of China ([2019] No. 103) November 29, 2019
3. NMPA Announcement on Soliciting Public Opinions on the Measures for the Administration of Drug Registration (Draft for Comments) December 10, 2019
4. Measures for the Supervision and Administration of Drug Production (Draft for Comments) December 10, 2019
5. Announcement on the publication of the “Construction principle of the Drug Information Traceability System” and “Encoding Requirements for Drug Traceability Code” April 28, 2019
6. Notice on Soliciting Public Opinions on Five Standards Including the Basic Data Set for Traceability of Drug Manufacturers (Draft for Comments), September 11, 2019
7. Requirements for safety update report during R & D as well as the regulatory provisions on November 8, 2019 (For Comments)
8. Notice on Issuing the Guidelines for the Preparation of Annual Report on Pharmacovigilance of Drug Marketing Authorization Holder (Interim) on November 29, 2019

Vaccine Administration Law of the People’s Republic of China

The Vaccine Administration Law of the People’s Republic of China (hereinafter referred to as “the Vaccine Administration Law”) is the first law on vaccine management in China. It was submitted to the State Council in November 2018. After three rounds of public opinions were sought, it was deliberated and adopted at the end of June 2019. It came into force on December 1, 2019. This Law applies to the research and development, production, distribution, vaccination, supervision and administration of vaccines within the territory of the People’s Republic of China.

Vaccine MAH shall have its own vaccine production capacity. Vaccine MAH can only entrust production if the demand exceeds its own production capacity of the vaccine or it may be carried out upon approval by the drug regulatory authority under the State Council.

Related Documents:

1. Vaccine Administration Law of the People’s Republic of China, June 29, 2019

Drug Production

In April 2019, NMPA officially initiated the revision of the Provisions for the Supervision of Drug Manufacturing. It focuses on meeting the needs of drug manufacturing supervision and administration when considering the trend of international standardization and the actual situation in China. According to the latest Draft for Comments (3rd Edition), the revised contents contain the following topics:

1. Drug manufacturing license
2. Entrustment manufacturing requirements
3. Bundling review of raw materials, excipients and packaging materials
4. New requirements after the cancellation of GMP certification
5. Provincial Regulatory Principles and Inspection

Related Documents:

1. Provisions for the Supervision of Drug Production (current) (November 7, 2017)
2. Provisions for the Supervision of Drug Manufacturing (Draft for Comments) (September 30, 2019)
3. Provisions for the Supervision of Drug Manufacturing (Draft for Comments, Draft II) October 15, 2019
4. Measures for the Supervision and Administration of Drug Production (Draft for Comments, Draft III) December 10, 2019
5. Announcement on the Management of Subpackaging, Storage and Transportation of Biological Products and Draft National Drug Standards (August 6, 2019)
6. Notice of the National Medical Products Administration on Measures of Random Inspection and Testing of Drug Quality (August 12, 2019)
7. The Center for Food and Drug Inspection publicly solicited comments on the Appendix of Biological Products to the Good Manufacturing Practice for Drugs (Draft for Comments) on November 28, 2019
8. Announcement of the National Medical Products Administration on Implementing the Drug Administration Law of the People’s Republic of China ([2019] No. 103) November 29, 2019

Drug Inspection

According to the regulations, drug inspection at national level may be conducted with the application of clinical trials and the application of drugs marketing registration. Inspection of clinical trial application is risk-based on-site inspection of pre-clinical studies during the review process. Research and development site inspection and on-site manufacturing inspection shall be conducted along with the application of the drug marketing registration. In addition, unannounced inspections shall be conducted by NMPA for problems without prior notification. For provincial regulatory authorities, routine inspection shall be conducted at least once a year for vaccines, blood products, sterile drugs and other high-risk products.

Related Documents:

1. Measures for the Supervision and Administration of Drug Production (Draft for Comments, Draft III) December 10, 2019
2. Measures for the Administration of Drug Registration (Draft for Comments, the third draft) December 10, 2019

Post-approval Variation To Biological Products

The second revision of the Technical Guideline for CMC Changes to an Approved Biological Products (Draft for Comments) was issued by CDE in November. This Guideline is suitable for guiding biological product marketing authorization holders (hereinafter referred to as the holders) or manufacturers to carry out pharmaceutical studies on variations for marketed biological products. The Guideline is applicable to vaccines, blood products, biotechnology products and in vitro diagnostic reagents managed as drugs. Gene and cell therapy products are also available for reference. Holders and manufacturers are responsible for studies on changes and they should establish effective change-related risk management systems. Depending on the degree and risk of potential impact on quality, safety and efficacy of products, changes are categorized into three classes:

• Minor changes (Type Ⅰ): changes that have mild or basically no impact on quality, safety or efficacy of biological products.
• Moderate changes (Type Ⅱ): changes that have moderate impact on quality, safety or efficacy of biological products and necessitate studies to demonstrate that the changes will not affect safety, efficacy or quality controllability of the products.
• Major changes (Type Ⅲ): changes that will probably exert significant impact on quality, safety or efficacy of biological products. Extensive study is necessary to demonstrate the changes have no negative impact on safety, efficacy or quality controllability of products.

Related Documents:

1. Technical Guideline for CMC Changes to an Approved Biological Products (Draft for Comments) November 9, 2019

Routes for the Accelerated Marketing and Registration of Drugs

The document discusses routes for Accelerated Marketing and Registration including: breakthrough therapeutic drug procedure, conditional approval for marketing, priority review and approval procedure, and special review and approval procedure. Five notices were issued in November and December last year to compile the basic applicable condition, review time and special provisions of these four procedures.

1. Related Documents:
   1. Procedures for Resolving Disputes over the Conclusion of Drug Registration Review (Draft for Comments) November 26, 2019
   2. Working Procedures for Breakthrough Therapeutic Drugs and the Working Procedures for Priority Review and Approval (Draft for Comments) November 8, 2019
   3. Technical Guidelines for Conditional Approval of Clinical Urgent Drugs for Marketing (Draft for Comments) November 8, 2019
   4. NMPA Announcement on Soliciting Public Opinions on the Measures for the Administration of Drug Registration (Draft for Comments) December 10, 2019
   5. Special Review and Approval Procedure for Drugs of National Medical Product Administration (NMPA Order No. 21), November 18, 2005

ICH Implementation in China

The ICH Office of CDE was established on July 12, 2019 and is responsible for the overall coordination of the ICH work of NMPA and the drafting, transformation and implementation of ICH technical guidelines. The implementation requirements and work plan are as follows:

Related Documents:

ICH Office

1. eCTD Technical Specification and eCTD Verification Criteria (Draft for Comments) March 1, 2019
2. Guidelines for Application of eCTD (Draft for Comments) September 17 2019
3. Implementation Suggestions on the Transformation of ICH Q Series Guidelines (Draft for Comments) September 30, 2019

Regulations of the People’s Republic of China on the Administration of Human Genetic Resources

The Regulations of the People’s Republic of China on the Administration of Human Genetic Resources came into force on July 1, 2019.

Where it is necessary to transport, mail or take any human genetic resources (HGR) materials out of China, the relevant conditions shall be met, and the exit certificate of HGR materials issued by the science and technology administrative department of the State Council shall be obtained, upon which the customs formalities shall be handled. The science and technology administrative department of the State Council shall, within 20 working days from the date of acceptance, make a decision of approval or disapproval. See the official website of the Ministry of Science and Technology for the specific handling procedure.

Related Documents:

1. Regulations of the People’s Republic of China on the Administration of Human Genetic Resources (May 28, 2019)
2. Website of the Ministry of Science and Technology: http://en.most.gov.cn/eng/index.htm