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Regulatory Newsletter

Q2 2022 Regulatory Updates
Jul. 20, 2022
Q2 2022 Regulatory Updates

WuXi Biologics’ Regulatory Affairs team is honored to provide you with a summary of what we deem as the relevant (i.e., product development and CMC-related) regulatory updates that are either in draft or final status by agency and by topic. We have compiled these updates to support your efforts to stay current in the ever-changing regulatory environment for biological therapeutics and vaccines.

 

Purpose & Disclaimer: The intent of this update is to provide the global regulatory agencies’ updates and new or revised documents during the period stated here. The items listed should neither be considered comprehensive nor exhaustive of all updates from the regulatory agencies but as such, the list contains items that the WuXi Biologics’ Regulatory Affairs team deems relevant to our potential or existing clients and partners developing biological therapeutics and vaccines. Therefore, this update is for information purposes only and is provided “as is” without any warranty, expressed or implied, as to the completeness or accuracy of the contents or its use or fitness for a particular purpose. Without limiting the generality of the foregoing, the document and information contained therein should not be construed as regulatory advice or representing, speaking or acting for any regulatory agency. The information is provided to support your efforts to remain informed and should not be used as a substitute for your own regulatory due diligence or actions.

 

Quick Links to Agency Sections:

 

FDA (U.S. Food and Drug Administration)

 

M7(R2) Addendum: Application of The Principles of The ICH M7 Guideline to Calculation of Compound-Specific Acceptable Intakes – Apr 2022

 

The focus of this guideline is on DNA reactive substances that have a potential to directly cause DNA damage when present at low levels leading to mutations and therefore, potentially cancer. The addendum to M7(R2) is a draft version that was endorsed on 6-Oct-2021, and currently is under public consultation.

 

This document contains only the list of the revisions to the M7(R1) Guideline as well as new monographs for 7 new compounds (Acetaldehyde, 1,2-Dibromoethane, Epichlorohydrin, Ethyl Bromide, Formaldehyde, Styrene, Vinyl Acetate), which are submitted for public consultation.

 

The main changes to the M7 Guideline and Addendum, when finalized, will include the M7 document now separated into a main Guideline and a separate Addendum including the monographs. In the main M7 Guideline, the HIV duration will be changed from “>1-10 years to >10 years” to “lifetime”, and the final sentence of Note 1 will be edited for clarification as “In cases where the amount of the impurity is less than or equal to 1 mg, no further genotoxicity testing is required regardless of other qualification thresholds”. 

 

All of these revisions would be integrated into a complete M7(R2) Guideline and Addendum documents prior to reaching Step 4,.

 

Providing Submissions in Electronic Format: Post-marketing Safety Reports – Apr 2022

 

This guidance finalizes the revised draft guidance and contains recommendations on submitting post-marketing safety reports electronically in accordance with the final rule, which was published on June 10, 2014 by the FDA to amend its post-marketing safety reporting regulations for human drug and biological products.  According to the update, persons subject to mandatory reporting requirements must submit safety reports in an electronic format to the Agency.

 

This guidance provides general information on the electronic submission of post-marketing safety reports under the following provisions:

 

  • 21 CFR 314.80 and 314.98 (regarding products with approved new drug applications (NDAs) and abbreviated new drug applications (ANDAs), including combination products or drug constituent parts with approved NDAs or ANDAs respectively.
  • 21 CFR 600.80 (regarding products with approved biologics license applications (BLAs), including combination products or biological product constituent parts with approved BLAs.
  • 21 CFR part 4, subpart B (requiring additional reports for combination products with approved NDAs, ANDAs, or BLAs).
  • 21 CFR 310.305 (regarding prescription drug products marketed for human use without approved NDAs or ANDAs, including prescription drug products that are compounded by facilities registered as outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 353b)).
  • 21 CFR 329.100 and section 760 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21S.C. 379aa) (regarding nonprescription drug products marketed for human use without approved NDAs or ANDAs).

 

This guidance does not apply to the following:

 

  • Vaccines (a separate guidance entitled “Providing Submissions in Electronic Format-Post-marketing Safety Reports for Vaccines (August 2015)” applies).
  • Whole blood or blood components.
  • Combination products with a drug or biological product constituent part marketed under a device application.
  • Lot distribution reports.
  • Human cells, tissues, and cellular tissue-based products (HCT/Ps) regulated solely under section 361 of the Public Health Service Act.

 

This guidance provides general information on the electronic submission of post-marketing safety reports mainly from the following aspects:

 

  • Individual Case Safety Report (ICSR) submissions
  • Notification of receipt of submissions by FDA
  • Contingencies when the ESG (Electronic Submissions Gateway), FAERS (FDA Adverse Event Reporting System), or SRP (Safety Reporting Portal) is temporarily unavailable
  • Descriptive Information in Periodic Safety Reports (eCTD format, ICSRs and ICSR attachments not to be submitted)
  • Waiver Requests

 

Draft Guidance for Industry: Benefit-Risk Considerations for Product Quality Assessments – May 2022

 

This draft guidance,  which is being distributed for comment purposes only, discusses theFDA’s benefit-risk considerations when assessing chemistry, manufacturing, and controls (CMC) information of a new drug application (NDA), biologics license application (BLA) or supplements to NDA/BLA, including:

 

  • Quality related statutory and regulatory requirements for approval of an NDA/BLA.
  • Potential sources of product quality-related uncertainty and how the FDA conducts a product quality assessment.
  • Guiding principles applied by the FDA when assessing product quality.
  • How to address unsolved product quality issues when making regulatory decision.

 

This guidance also specifically discusses how the FDA addresses unsolved product quality issues when conducting the quality assessment of an abbreviated new drug applications (ANDA).

 

Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production – Level 2 Revision – May 2022

 

This guidance applies to chemistry–based laboratory testing performed for drugs regulated by CDER and describes how to conduct an out-of-specification (OOS) test results investigation, including the requirements for different investigation phases, responsibilities of laboratory personnel, principles used to report and interpret test results, and requirements for concluding the investigation. There are two phases of the investigation: laboratory investigation (phase 1) and full-scale OOS investigation (phase 2). The phase 2 investigation should be initiated when the cause of the OOS was not identified. A review of production should be conducted during the phase 2 investigation,  and may include additional laboratory testing, such as retesting and resampling. The investigation results should be evaluated and interpreted to conclude the investigation.

 

Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors – May 2022

 

The guidance provides a series of recommendations and principles on how to guarantee the critical elements of a product’s container label and carton labeling of human prescription drugs and biological products. The guidance will also be a reference for over-the-counter drug products, compounded products, marketed prescription products used in clinical or bioequivalence studies, and  investigational products.

 

The recommendations include:

 

  • General considerations to the format and content of the product container labels and carton labeling.
  • Special considerations to information on the container labels and carton labeling, including considerations to proprietary, established, and proper names, tall man lettering, product strength, route(s) of administration, warning or cautionary statements, expiration dates and beyond–use dates, barcodes, national drug code numbers, and controlled substance schedule.
  • Considerations to special product’s container label and carton labeling, including (1) products packed in blister packs, products packed in medication vials with ferrules and cap overseals, products containing concentrated potassium chloride, large-volume injections, insulin pens, oral liquid drug products packaged in unit dose cups, diluents, products packaged for institutional distribution and the container is not child – resistant; (2) transferable peel-off labels for injectable medications; (3) double-sided container labels and carton labeling; (4) pharmacy bulk packages container labels; (5) important product changes; (6) dosing devices for oral liquid drug products; (7) product sample labels; (8) package type term on container labels and carton labeling for injectable drugs for parenteral administration; (9) quick response code; (10) labels of transdermal and topical systems; and (11) labels of infusion containers with hangers.

 

CDER Manual of Policies & Procedures – MAPP – Assessment of the Appropriate Net Container Content for Injectable Drug and Biological Products – Jun 2022

 

This MAPP provides the thoughts of the Office of Pharmaceutical Quality (OPQ) on the assessment of the net container content for injectable drug products filled into vials. This MAPP came into effect on June 6, 2022.

 

The scope of the MAPP is shown as follows:

 

  • Injectable drug products including drug products requiring constitution/reconstitution prior to administration
  • Single and multiple dose with dosage based on body weight or body surface area drug product
  • Different injection packaging types (e.g., prefilled syringe package systems and intravenous infusion bags), and abbreviated new drug applications (ANDAs) in which a suitability petition for a different drug product strength has been approved.

 

For INDs, NDAs, BLAs, and their supplements, this MAPP gives Quality Assessors a general practice on assessing the appropriateness of the net container content(s) for an injectable drug product. The scientific consideration and examples of the importance of net container is detailed in this MAPP.

 

The policy of this MAPP outlines that the Office of Biotechnology Products (OPQ) is supposed to communicate to the sponsors as early as possible during the development regarding the appropriateness of net container content(s). The justification for the net container content(s) from the sponsor will be requested by the OPQ according to various scenarios presented in this MAPP. For scenarios not provided in this MAPP and where justification is needed to support the change of net container content for NDA/BLA submission, the OPQ will request no later than end of phase 2 to give sponsors sufficient time for collecting stability data.

 

Other FDA Drug Development and Quality Guideline Updates

 

 

Other FDA Regulatory Submission and Procedure Updates

 

 

Other FDA Vaccines, Gene Therapy, and Advanced Therapy Medicinal Products Updates

 

 

Other FDA Coronavirus Disease (COVID-19) Updates

 

 

Other FDA Updates

 

 

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

 

European Medicines Agency Guidance for Applicants Seeking Scientific Advice and Protocol Assistance (Updated) – Apr 2022

 

This guidance document addresses a number of questions that users seeking scientific advice or protocol assistance procedures may have and gives guidance to Applicants in preparing their request for consultation. This guidance document also explains the scope and nature of scientific advice and protocol assistance and provides an overview on the procedure for obtaining such information.

 

The CHMP (Committee for Human Medicinal Products) has established the Scientific Advice Working Party (SAWP) as a standing working party with the sole remit of providing scientific advice and protocol assistance to Applicants. Scientific advice received from the Agency is applicable throughout the EU. A SAWP/CHMP consultation does not preclude the possibility of consultations with national competent authorities. Scientific advice will be given by the SAWP/CHMP on questions concerning quality (manufacturing, chemical, pharmaceutical and biological testing), non-clinical (toxicological and pharmacological tests) and clinical aspects (studies in human subjects in either patients or healthy volunteers, including clinical pharmacological trials designed to determine the efficacy and safety of the product for pre- or post-authorization activities including risk-management programmes). Scientific advice may be given on issues relating to interpretation and implementation of (draft) EU guidelines.

 

The Applicant submits a request and draft briefing document via the IRIS platform for feedback. Following EMA review, the Applicant submits an Electronic Final Package (final request) for validation which has been updated based on the  feedback provided. In order to submit an application via IRIS, a research product identifier (RPI) is required to track medicines and methodologies through pre-authorization procedures. Companies and individuals that approach EMA for the first time with a new product will need to request a new RPI via IRIS.

 

The Agency Secretariat should be formally notified of the intent to submit a scientific advice or protocol assistance request via the IRIS platform. If a scientific advice or protocol assistance preparatory meeting is requested when applying, the deadline is approximately 8 weeks before the intended start of the procedure. If no preparatory meeting is requested, the deadline for submission is approximately 4 weeks before the intended start of the procedure.

 

The Briefing document is the most important section of the request. It is highly recommended to use the CHMP scientific advice/protocol assistance briefing document template.

 

The dates of forthcoming SAWP meetings and deadlines for scientific advice or protocol assistance submissions are available on the scientific advice website. Applicants can follow this guidance to receive specific and useful information to guide their activities or to prepare their discussions when meeting with the SAWP.

 

IRIS Guide for Applicants (How to Create and Submit Scientific Applications, for Industry and Individual Applicants) – Jun 2022

 

This guide provides the applicants with operation instructions for IRIS platform use, including:

 

  • Instructions on common activities for all scientific submission types, such as search / create / delete / withdraw a submission, respond to requests, etc.
  • Instructions on specific operations for orphan designation application.
  • Instructions specific to activities related to scientific advice.
  • Instructions specific to activities related to ITF briefing meeting requests.
  • Instructions specific to activities related to marketing status changes.
  • Instructions on how to submit the required information when a GMP/GCP inspection request is adopted by the CHMP or CVMP.
  • Instructions specific to activities related to annual statements submission and veterinary signal management submission.
  • Instructions on standard steps for registering an industry single point of contact (i-SPOC).

 

Questions and Answers for Marketing Authorization 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) – May 2022 to June 2022

 

Compared with the version published in March 2022, Q&A 5, 10 and 14 were updated and new Q&A 20 was added.

 

Q&A 5: What to do if after submission of step 1 and /or step 2 responses, new information (e.g. related to new potential risk factors or root causes) is identified?

 

MAHs are suggested to check this Q&A document and in particular Q&A 4 which will be kept up to date regarding newly identified risk factors for formation of nitrosamines, and also Q&A 10 concerning limits for nitrosamines.

 

Q&A 10: Which limits apply for nitrosamines in medicinal products?

 

Updated to include newly adopted AI for N-nitrosodabigatran and indicate APIs where related nitrosamines have been identified. Clarification of how to set limits for products containing salt, hydrate or solvate forms of the API was added.

 

Q&A 14: What is the approach for new and ongoing marketing authorisation applications (MAA)?

 

Refer to the new risk evaluation template for use in marketing authorisation applications.

 

Q&A 20: What are the regulatory steps taken by authorities following the identification of an N-nitrosamine exceeding the AI (acceptable intake).

 

Regulatory steps for N-nitrosamine exceeding the AI scenario are provided in this Q&A.

 

Other EMA Drug Development and Quality Guideline Updates

 

 

Other EMA & EC Regulatory Submission and Procedure Updates

 

 

Other EMA Vaccines, Gene Therapy, and Advanced Therapy Medicinal Products Updates

 

 

Other EMA & EC Coronavirus Disease (COVID-19) Updates

 

 

Other EMA Updates

 

 

TGA (Therapeutic Goods Administration)

 

TGA Regulatory Submission and Procedure Updates

 

 

Other TGA Updates

 

 

Health Canada

 

Health Canada Drug Development and Quality Guideline Updates

 

 

Health Canada Regulatory Submission and Procedure Updates

 

 

WHO (World Health Organization)

 

WHO Coronavirus Disease (COVID-19) Updates

 

 

Other WHO Updates

 

 

MHRA 

 

Compliance Monitor (CM) Overview and Application Process – GOV.UK (www.gov.uk) – Jun 2022

 

From April 2022, the MHRA will be running a pilot scheme to monitor companies that fail to comply with Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) and are referred to the Inspection Action Group (IAG) after an inspection that has resulted in the compliance escalation process being initiated.

 

The pilot facilitates reducing potential shortages in the supply of safe medicines through the use of risk-based supervision and monitoring. The process will also assist the MHRA in concentrating resources on delivery of the routine risk-based inspection program, thus further ensuring patient safety.

 

Companies that enter the pilot scheme will use consultant(s) selected from the MHRA Compliance Monitors (CMs) register to monitor the implementation of an agreed Compliance Protocol (CP). The CP will be approved by the MHRA, the Company, and the CM. The CP will include the agreed activities, due dates, CM resource to be applied, and frequency of periodic updates to the IAG. Independent oversight from the CM will enable the company to focus on remediation of the corrective actions and augment the regulatory oversight of the MHRA.

 

Other MHRA Regulatory Submission and Procedure Updates

 

 

Other MHRA Coronavirus Disease (COVID-19) Updates

 

 

Other MHRA Updates

 

 

PMDA (Pharmaceuticals and Medical Devices Agency)

 

Other PMDA Updates

 

 

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

ich-logo

 

ICH Guideline Q3D (R2) on Elemental Impurities (Step 5, Revision 2) – May 2022

 

The ICH Guideline Q3D (R2) on Elemental Impurities is a quality guideline for the control of elemental impurities in medicinal products, and it establishes a three part control strategy, including evaluation of potential elemental impurities, Permitted Daily Exposure (PDEs) for 24 elemental impurities, and application of a risk-based approach to control elemental impurities. The current ICH Q3D (R2) Guideline reached Step 4 in April 2022, and the ICH working group published ICH Guideline Q3D (R2) on Elemental Impurities (Step 5, Revision 2) on 3rd May 2022 that will come into effect on 24th September 2022.

 

The newly updated ICH Q3D (R2) Guideline included the correction of PDEs for Gold, Silver and Nickel (Appendix 2); correction of Gold and Silver monographs (Appendix 3); addition of limits for elemental impurities by the cutaneous and transcutaneous route (Appendix 5); and an addition of a reference to Appendix 5 in Section 3.2.

 

Other ICH Updates

 

 

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

 

EDQM Drug Development and Quality Guideline Updates

 

 

Other EDQM Coronavirus Disease (COVID-19) Updates

 

 

Other EDQM Updates

 

 

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

 

Other PIC/S Updates

 

 

National Medical Products Administration (NMPA)

 

Drug Annual Report  

 

On April 12, 2022, the NMPA issued a notice on printing and distributing the “Provisions on Administration of Drug Annual Report”. The notice contains 4 appendices: “Provisions on Administration of Drug Annual Report” (Annex 1), “Template for Drug Annual Report” (Annex 2), “Operation Manual for Enterprise End of Drug Annual Report Collection Module” (Annex 3), and “Operation Manual for Supervisory End of Drug Annual Report Collection Module” (Annex 4). The Provisions shall come into force on the date of issuance, and the annual report collection module shall be enabled at the same time.

 

The Provisions are formulated to implement relevant requirements in the Drug Administration Law, Provisions for Drug Registration, and Provisions for Supervision and Management of Drug Manufacturing documents. Marketing authorization holders (MAHs) are responsible for the filing of the annual report. If the MAH is an overseas enterprise, then the obligations are fulfilled by the assigned enterprise legal person located in China who bears joint responsibilities.

 

In order to ensure the implementation of the annual report system, the NMPA has built a collection module which is divided into enterprise and supervision components.

 

It is stated in the Notice that, considering this is the first time for implementation of a drug annual report system in China and the drug annual report collection module is still in the trial operation stage, the deadline for the filing of the 2021 annual report shall be August 31, 2022; and starting from next year, the annual report for the previous year shall be filed before April 30 each year.

 

In order to help enterprises understand the Provisions and relevant requirements, the NMPA issued with graphical illustrations “Policy Interpretation – Content of Drug Annual Report” and “Policy Interpretation – Drug Marketing Authorization Holders Shall Fulfill the Obligation of Annual Report” on April 15, 2022.

 

References

 

  1. NMPA Notice on Printing and Distributing “Provisions on Administration of Drug Annual Report” 2022-04-12
  2. Policy Interpretation – Content of Drug Annual Report 2022-04-15
  3. Policy Interpretation – Drug Marketing Authorization Holders Shall Fulfill the Obligation of Annual Report 2022-04-15

 

Regulations for the Implementation of Drug Administration Law   

 

In order to implement the new drug-related laws and regulations, and to further strengthen drug supervision and administration, the NMPA drafted and issued the “Regulations for the Implementation of the Drug Administration Law of the People’s Republic of China (Draft for Solicitation of Comments)” (hereinafter referred to as “Draft”) on May 9, 2022. The “Draft” was opened for solicitation of comments until June 9, 2022.

 

The original version of “Regulations for the Implementation of the Drug Administration Law of the People’s Republic of China” was issued in 2002, first revised in 2016 and second revised in 2019. Its upper laws include the Drug Administration Law and the Vaccine Administration Law. Current version of both laws were published in 2019.

 

The “Draft” consists of 181 articles in 10 chaptersand introduces newly added measures to encourage innovationand the protection of drug intellectual property rights and drug marketing authorization holders (MAHs).Along with these additions, the original clauses have also been supplemented. The key contents closely related to pharmaceutical manufacturers are as follows: 1) requirements for applicants, sponsors and MAHs; 2) obligation of pharmacovigilance; 3) illustration of manufacturing activities including new vaccine manufacturers, production in overseas sites and segmented production (production of Drug Substance [DS] and Drug Product [DP] in different sites); 4) conditions for product batches manufactured before marketing approval which are allowed to sell.

 

References

 

NMPA Solicits Public Comments on “Regulations for the Implementation of the Drug Administration Law of the People’s Republic of China (Draft for Solicitation of Comments)” 2022-05-09

 

Drug Tracing Code  

 

On June 27, 2022, the NMPA issued two informatization standards namely “Standards for Drug Tracing Code” and “Standards for Display of Drug Tracing Results for Customer Inquiry”.

 

The drug tracing code refers to the identification of drug tracing code and relevant information printed or pasted on drug package, which consists of numbers, letters, characters and bar codes. “Standards for Drug Tracing Code” specifies the principles, general requirements and specific requirements for style, location and quality of drug tracing codes. “Standards for Display of Drug Tracing Results for Customer Inquiry” specifies the overall requirements, and specific requirements for display mode and content of the results about drug tracing information when inquired through the drug tracing system using the drug tracing code.

 

“Standards for Display of Drug Tracing Results for Customer Inquiry” shall be implemented as of the date of issuance, and “Standards for Drug Tracing Code” shall be implemented starting from June 23, 2023.

 

References

 

  1. NMPA Announcement on Issuing Two Informatization Standards including “Standards for Drug Tracing Code” (No. 50 of 2022) 2022-06-27
  2. NMPA Issues Two Standards including “Standards for Drug Tracing Code” 2022-06-28
  3. Interpretations of Two Standards including “Standards for Drug Tracing Code” 2022-06-28

 

GMP Appendix for Investigational Drugs

 

Appendix of Investigational Drugs (Trial Version)

 

In view of the particularity of the production and quality management of investigational drugs, the Center for Food and Drug Inspection of the NMPA (CFDI) drafted the “Appendix for Investigational Drugs” (hereinafter referred to as “Appendix”) within the “Good Manufacturing Practice (GMP) for Drugs” document by summarizing the previous work practices and referring to relevant international rules. The published draft version was opened for soliciting public comments twice. The first time was on July 13, 2018 and the second was on January 18, 2022.. The “Appendix (Trial Version)” was issued on May 24, 2022, which shall come into force on July 1, 2022.

 

FAQs for Appendix of Investigational Drugs (Trial Version)

 

In order to facilitate interpretation of this “Appendix”, the CFDI published the Questions and Answers for the “Appendix” on May 27, 2022, including the following specific questions:

 

Question 1: What is the scope of the “Appendix”?

 

Question 2: What are the special requirements of the “Appendix” compared with the “Good Manufacturing Practice (GMP) for Drugs”?

 

Question 3: What are the special requirements of equipment and facilities in the “Appendix”?

 

Question 4: What are the special requirements of document management in the “Appendix”?

 

Question 5: What are the special requirements for process validation in the “Appendix”?

 

Question 6: How to understand the qualification of the person responsible for release in the “Appendix”?

 

Question 7: For commercial drugs or drugs for which confirmatory clinical trials have been carried out, if early clinical trials are planned to add new indication(s), can the investigational drugs be produced by referring to the “Appendix”?

 

References

 

  1. Announcement on Issuing the “Appendix for Investigational Drugs to the Good Manufacturing Practice (GMP) for Drugs (2010 Revision)” 2022-05-27
  2. Questions and Answers on “Appendix of Investigational Drugs to the Good Manufacturing Practice (GMP) for Drugs” Supplement 2022-05-27
  3. The General Affairs Department of NMPA solicits Public Comments on “Drug Good Manufacturing Practice (GMP) – Appendix for Investigational Drugs (Draft for Solicitation of Comments)” 2022-01-18
  4. NMPA Office Solicits Public Comments on “Good Manufacturing Practice (GMP) for Investigational Drugs (Draft for Solicitation of Comments)” 2018-07-13

 

On-site Inspection for Antibody Drugs

 

In order to guide the on-site inspection for antibody drugs, the CFDI drafted and issued the “Guideline for On-site Inspection on Antibody Drugs (Draft for Solicitation of Comments)” on May 27, 2022, open for solicitation of comments within one month starting from release.

 

This guideline is applicable to the manufacturing site inspection of monoclonal antibodies which are covered in the routine inspection, including the whole production process and quality management involving vial thaw, cell culture, purification, drug substance preparation, filling and lyophilization, as well as quality systems, cell banks, materials, equipment and facilities. Meanwhile, the guideline contains the special contents for production and quality control of bispecific antibodies (bsAb) and antibody-drug conjugates (ADCs).

 

System-based horizontal strategy and product-based vertical strategy are applied in the on-site inspection. The system-based horizontal inspection consists of seven parts: quality management system, organization and personnel system, facility and equipment system, material system, production system, quality control system and data reliability. The product-based vertical inspection includes cell expansion stage (cell vial thaw, cell expansion and production culture), purification stage (clarification filtration or centrifugation, affinity chromatography, viral inactivation, anion exchange chromatography, cation exchange chromatography, viral filtration, ultrafiltration/diafiltration, drug substance preparation, etc.), and finished product stage (product intermediate preparation, filtration and filling, lyophilization, visual inspection, labelling and packaging).

 

The key points of inspection for monoclonal antibodies are divided into four aspects: upstream process, downstream purification, drug product production and continuous manufacturing. Compared with the traditional monoclonal antibody process, bsAb is more likely to have mismatch in higher-order structure, and the inspection for bsAb will focus on process control and monitoring, and quality control. Special inspection points for ADCs include facilities, public engineering system and equipment system, qualification of air systems, material management, production control and quality control.

 

References

 

Notice on Soliciting Public Comments on “Guidelines for On-site Inspection of Antibody Drugs (Draft for Solicitation of Comments)” 2022-05-27 

 

Analytical Procedure Development and Validation 

 

CDE issued “Notice on ICH Q2 (R2) Validation of Analytical Procedures (Draft Version) and Q14 Analytical Procedure Development (Draft Version) Open for Solicitation of Comments” on April 25, 2022.

 

“Q2 (R2) Validation of Analytical Procedures” presents a discussion of elements to consider for the validation of analytical procedures when drug registration applications are submitted to ICH member regulatory authorities. Q2 (R2) provides guidance and recommendations on how to derive and evaluate the various validation tests for each analytical procedure. This guideline applies to new or revised analytical procedures used for the release and stability testing of commercial drug substance and drug products (chemical and biological/biotechnological). The scientific principles described in this guideline can be applied in a phase-appropriate manner during clinical development. The guideline is directed to the most common purpose of analytical procedures, such as content/potency, purity, impurity (quantitative or limit test), identity and other quantitative or qualitative assays.

 

“Q14: Analytical Procedure Development” describes science and risk-based approaches for developing and maintaining analytical procedures in order to fit the purpose of quality assessment of drug substances and drug products. This guideline is intended to complement “ICH Q2 Validation of Analytical Procedures.” Submitting knowledge and information related to the development of analytical procedures to regulatory agencies may provide additional evidence to demonstrate that the analytical procedures are appropriate for their intended purpose.

 

References

 

Notice on ICH Q2 (R2) Validation of Analytical Procedures (Draft Version) and Q14 Analytical Procedure Development (Draft Version) Open for Solicitation of Comments 2022-04-25

 

Chinese Pharmacopoeia

 

List