Interpretation and Case Sharing of Resin Change for Marketed Drugs

On January 13, 2021, the National Medical Products Administration (NMPA) released the Provisions for Post-approval Changes of Drugs (Interim), hereinafter referred to as the Provisions, which came into effect on the same day. This is the first regulatory document in China specifically addressing the management of post-marketing drug changes. With the further implementation of the Market Authorization Holder (MAH) system and the significant increase in market vitality, new models for pharmaceutical research and production, such as diversification, cross-regional, and multi-point outsourcing, have become increasingly common. The regulatory authorities have also included site changes under supervision.

The Provisions include changes in the drug holder, production site, and registration management matters. A separate section on the management of changes in drug production sites is included, consisting of five clauses, further clarifying and regulating the management of post-marketing drug production site changes. The management of production site changes has been adjusted, and the application for a production site change is now only required to be submitted to the provincial-level drug regulatory authority for a Drug Manufacturing License change, simplifying the declaration and approval process, improving the efficiency of site changes, and facilitating the smooth progress of MAH outsourcing production.

A change in the drug production site refers to any alteration of the pharmaceutical production factory (including manufacturing, packaging, testing, and release) and production lines, including changes to the production address, the addition of new production sites, or the construction, renovation, or expansion of production areas at the same address. Due to differences in production equipment, environment, and technical personnel quality between the original and new production sites, the change in production sites can impact the quality of active pharmaceutical ingredients (API) and finished formulations, requiring comprehensive research and verification.

According to industry reports, in some provinces and cities, the NMPA has officially assigned the task of evaluating major drug changes to provincial-level authorities. In February 2024, the NMPA issued the Pilot Work Plan for Optimizing the Review and Approval Process of Supplementary Drug Applications, intending to carry out pilot work in capable and qualified provincial-level drug regulatory bureaus. After more than nine months, the NMPA identified ten provinces (cities) for the pilot program. On November 22, the NMPA issued another notice, approving the drug regulatory authorities in 10 provinces (municipalities) — Beijing, Tianjin, Hebei, Shanghai, Jiangsu, Zhejiang, Shandong, Guangdong, Chongqing, and Sichuan — to carry out a pilot program to optimize the review and approval procedures for supplemental drug applications. These provincial-level authorities can provide guidance, inspection, verification, and record-keeping services before the submission of major drug changes within their jurisdictions.

With changes in the international landscape and cost considerations, more and more enterprises need to add alternative suppliers. Resins, as the main raw material in biopharmaceuticals, also require consideration of alternative suppliers. New processes use domestically produced resins as substitutes. The change of resins is part of the process change, which is an aspect of the pharmaceutical changes for biopharmaceuticals after marketing approval. Pharmaceutical changes after marketing approval refer to changes in the production, quality control, and other aspects of already approved biological products. These changes are important for the holder to continuously optimize production processes, maintain process stability, control advancement, and ensure the safety, efficacy, and quality control of biological products.

The holder of a biopharmaceutical product is responsible for change management and should assume the following responsibilities:

• Manage the entire lifecycle of the product,

• Conduct continuous research on the product,

• Ensure that the product complies with current technical requirements after it is marketed.

Generally, process changes have three stages:

Each stage of change has different evaluation criteria, requiring communication and interaction with relevant institutions to determine the extent of the change and what supplementary data or other related information should be provided. Enterprises should also assess the subsequent impact of changes at the early stages.

In GMP, resins are managed as materials, and biopharmaceutical raw materials are divided into biological and chemical raw materials based on their origin. They can be classified into

 four categories based on risk levels and quality control requirements for production use: 

Category III, which includes materials of medium risk, such as components used in culture medium, non-animal-derived protein hydrolytic enzymes, monoclonal antibodies for targeted purification, and chemical reagents used in biopharmaceutical extraction, purification, and inactivation.

Case Study:

There are several types of chromatography resins, including affinity resins, ion exchange resins, size exclusion resins, and more, each serving unique purposes in the separation and purification of various molecules. BioLink helped a client complete a supplier change for resins. The process involved several key steps:

Supplier Qualification Review: The client needed to review relevant information regarding the resin change (e.g., instructions for use, stability study reports, comparison of parameters and COA with the changed resin, three-batch product testing reports) to confirm that the new supplier met the required standards. Subsequently, the resin production site was audited.

Small-scale Stability Testing: The chromatograms from the purification experimental reports showed that the three test chromatograms of the same subtype sample were almost identical, with consistent peak times and peak shapes, comparable to the commercial-scale chromatogram.

Pilot-scale Testing: Pack the same BioLink chromatography column as the original process, and conduct the subtype chromatography again. The test results and chromatograms were compared and found to be consistent with the original process, meeting quality requirements. Further resin-related validation, including resin lifetime validation and cleaning validation, was carried out.

After the purification trials, BioLink, a leading bioreactor bag manufacturer, assisted the client in providing the relevant product data as supplementary materials for the change. According to communications with provincial and municipal drug regulatory authorities, the change was classified as a medium change (Note: Different provincial authorities and clients may have slightly different views, with many clients considering changes of the same material and principle as minor changes). BioLink also provided related certifications such as non-animal-derived statements to assist in the change approval.This change was successfully completed.

As a high-quality supplier for biopharmaceuticals, BioLink offers comprehensive solutions to support drug manufacturing. Our own resin production sites can meet various needs, providing high-quality resin products.

BioLink Chromatography Resins Manufacturing Site (Lanzhou)

Lanzhou ChromaX® chromatography resins manufacturing site has a well-equipped quality control lab, and received the certifications in QMS of ISO9001:2015 and ISO13485:2016.

The site is responsible for the research, development, manufacturing, and large-scale production of chromatography resins, microcarriers, and other purification and cell culture products across all categories. The phase I production base covers a total area of about 7,000 sqm, while the phase II covers a total area of about 14,000 sqm and achieves 85%-90% automation. At present, the two bases have a total of four chromatography resin production lines (500L*1, 1000L*3), including dextran-based matrix, agarose-based matrix, and hydroxyapatite chromatography resins, covering six major chromatography principles, with a total production capacity of 120,000 liters per year.