Center for Drug Evaluation, National Medical Products Administration

　　November 2024

I. Introduction

　　In order to support the high-quality development of the biomedical industry, the National Medical Products Administration has formulated the "Pilot Work Plan for Segmented Manufacturing of Biological Products". Due to the complexity, diversity and easy degradation of biological products, so segmented manufacturing may bring into more risks. The more the segments are, the greater the risks are. For the drug marketing authorization applications or post-marketing change applications related to the segmented manufacturing, the applicant/marketing authorization holder (MAH), as the primary responsible entity, shall fully assess the possible risks caused by the segmented manufacturing and carry out sufficient studies and necessary validation.

　　For the registration applications of the products manufactured by segments, the focus shall be on the studies on transportation stability of intermediate products, the formulation of outbound specifications and inbound acceptance specifications, and the analysis method transfer and bridging studies. At present, the technical guidelines issued in China and implemented ICH technical guidelines can basically cover the requirements for studies for segmented manufacturing of biological products. Antibody-Drug Conjugate (ADC) is a drug with small molecules conjugated with common biological product and should be manufactured in a special way. CDE has formulated such technical requirements for the segmented manufacturing of such products in addition to the issued Technical Guidelines for CMC Studies and Evaluation of Antibody-Drug Conjugate, aiming to provide technical guidance for pilot products. Subsequently, relevant technical requirements shall be improved and updated as needed with the implementation of the pilot work of segmented manufacturing taken into account.

II. Scope

　　This document is applicable to the marketing application or post-marketing change supplement application of ADC products under the pilot plan of segmented manufacturing, in order to guide the R&D and registration application related to the segmented manufacturing of small molecules, drug substances or drug products.

III. General Principles

　　In accordance with the requirements in the "Pilot Work Plan for Segmented Manufacturing of Biological Products”, the applicant/MAH participating in the pilot program and relevant contract manufacturers of segmented manufacturing shall implement a unified quality management system to ensure that the production process of products continuously meets the relevant regulations and technical requirements. ADC products have complex manufacturing processes and can be effected by many factors. The use of many materials during the production poses a risk of introducing adventitious agents or toxic chemical materials. Therefore, it is necessary to establish a comprehensive quality control strategy based on risk assessment. Differences in quality attributes of intermediate products (e.g., small molecules, drug substance) from upstream manufacturing processes may impact subsequent processes or critical quality attributes of ADC drug substances/drug products. Therefore, it is necessary to carry out studies and validation covering the whole manufacturing chain and life cycle for the segmented manufacturing of ADC products.

IV. Technical Requirements

　　Compared with the non-segmented manufacturing, the new risks of the segmented manufacturing mode of ADC products are mainly in the transfer and handover links of intermediate products. The applicant/MAH shall focus on the quality control of intermediate products during the transportation, the formulation of outbound specifications and inbound acceptance specifications, and the studies on the changes.

(I) Transportation of intermediate products

　　Since the transportation may have potential impact on the quality of intermediate products, the applicant/MAH shall carry out risk assessment and study validation based on the potential adverse factors during transportation and comprehensively consider the worst conditions during transportation. The transportation qualification study/transportation stability studies of intermediate products may be standardized by reference to the requirements in the Technical Guidelines for Stability Study of Biological Products (Interim), Technical Guidelines for CMC Studies and Evaluation of Antibody-Drug Conjugates and relevant guidelines such as ICH. The control of transportation conditions of intermediate products should be monitored and recorded in real time during commercial manufacturing. For toxic small molecules, the associated safety precautions during transportation should be considered.

　　Transportation validation study shall take full consideration of transportation route and mode (ground/air/sea), transportation conditions (temperature, humidity, light exposure, vibration, etc.), seasonal temperature (winter and summer), primary/secondary packaging, configuration of transportation containers and temperature monitoring management during product transportation (quantity and location of temperature monitoring probes, etc.), and pay attention to the packaging integrity of the products manufactured in each segment during transportation. During the study, it is also necessary to conduct sufficient comparative study and analysis on the quality of intermediate products before and after transportation, reasonably set the stability testing parameters based on the structures, physical and chemical profiles and potential degradation modes of the intermediate products, pay close attention to the quality changes which may affect the safety and efficacy, such as the protein aggregation level and payload shedding level, so as to ensure that the transportation will exert no adverse effect on the quality of intermediate products.

(II) Handover of intermediate products between the supplier and the recipient and formulation of outbound specifications and inbound acceptance specifications

　　The applicant/MAH should fully study the risks of storage, transfer and handover of intermediate products by entities at different manufacturing segments, and define the division of labor and responsibilities of each party.

　　The release test at the previous stage shall be conducted according to the release specification for intermediate products. The finished products can only be released after obtainment of satisfactory inspection results. The applicant/MAH shall reasonably establish the inbound acceptance specifications for intermediate products at the next stage based on the possible confusion, contamination and other risks during transportation as well as the stability profiles of intermediate products and in combination with the actual manufacturing and transportation conditions. The applicant/MAH shall provide and justify the basis for the formulation of outbound release specifications and inbound acceptance specifications, so as to ensure that the transferred intermediate products meet the quality requirements and can be used for the subsequent manufacturing steps.

　　The applicant/MAH may carry out the analytical method transfer studies by referring to Chinese Pharmacopoeia and applicable ICH guidelines to ensure that the analytical methods implemented for the same sample at different testing sites have consistent test results.

(III) Change studies

　　Segmented manufacturing could cause changes to the manufacturing sites for the intermediate products/drug products. The applicant/MAH shall carry out the comparability study of the changes and process validation based on the change stage, change items and change risk level by referring to the Technical Guidelines for CMC Studies and Changes of Biological Products during Clinical Trials (Interim), Technical Guidelines for CMC Change Studies of Marketed Biological Products (Interim), Technical Guidelines for CMC Changes of Innovative Drugs (Chemical Drugs) during Clinical Trials (Interim), Technical Guidelines for CMC Change Studies of Marketed Chemical Drugs (Interim), ICH and other applicable guidelines.

V. Inspection and Testing

　　According to the applicable regulations for inspection and testing for drug registration, registration inspection and testing shall be initiated based on risks.