The guidance on CMC study of in vivo gene therapy products was issued by the Center for Drug Evaluation, NMPA, on May 26, 2022, to encourage and promote the development of in vivo gene therapy products. This paper gives a detailed interpretation of the main contents and some important issues of the guidance and provides a reference for the market authorization application, combined with the drafting process of the guidance, so that the industry can better understand the technical requirements of the guidance during the development of in vivo gene therapy products.

A large number of investigational new drug (IND) applications of cellular products have been submitted in recent years. Up to October 2022, two cellular products have been approved to be marketed in China, which provide effective therapeutic approach to treat serious diseases. Genetic manipulation systems are used to modify or edit genes in various types of cellular products, including lentivirus, γ-retrovirus, adenovirus, sendaivirus or other viral vectors, as well as DNA, RNA, protein, protein-RNA complex or other non-viral vector systems. A guidance on CMC study and evaluation of ex vivo genetic manipulation systems was issued by CDE, NMPA on May 2022, in order to illustrate criterions on CMC research and evaluation of such systems. This paper provides a detailed interpretation of the guidance, combined with the guidance drafting logic, to help readers better understand the content of the guidance.

A guidance on CMC study and evaluation of immune cell therapy products was issued by CDE, NMPA on May 2022 in order to illustrate criteria on CMC research and evaluation of such products. This paper provides a detailed interpretation of the guidance, combined with the guidance drafting background and characteristics of immune cell therapy products, to help readers better understand the content of the guidance.

"Risk Assessment and Mitigation Strategies" (REMS) are procedures used by the U.S. Food and Drug Administration (FDA) to manage known or potentially serious risks associated with a drug to ensure that the benefits of the drug outweigh its risks. CAR-T cell therapy has brought new hope and new options for cancer patients due to its excellent efficacy. However, due to the characteristics of its treatment principle, almost all CAR-T cell therapy may lead to some adverse reactions. Cytokine release syndrome (CRS) and neurologic toxicities (NT) are the most common. This paper intends to analyze the post-marketing risk management strategies of CAR-T drugs in the United States by exploring the content of REMS in the risk management strategies of CAR-T drugs, and takes Kymriah, a CAR-T product currently on the market in the United States, as an example to analyze the specific implementation of the strategies. The purpose of this paper is to provide reference for the authorities to develop related policies of CAR-T drug listing risk management in China.

Continuous manufacturing is one of the development directions of the production process of recombinant biotechnology products in the future. The promulgation of important technical documents such as ICH Q13 also provides guidance for its application practice. However, in the field of viral safety control, there are great differences in control concepts and measures between continuous manufacturing and previous batch manufacturing mode. Starting with the process characteristics of continuous manufacturing, this paper makes a preliminary discussion on three aspects, which are the control of raw materials, in-process test, and virus removal/inactivation process validation. At the same time, as the cases of continuous manufacturing of recombinant biotechnology products are still limited, more comprehensive and meticulous control strategies and measures still need further accumulated and improved based on R&D and production experience. It is suggested that the applicants of this kind of products should fully communicate with the regulatory authorities before the application, so as to ensure the safety of the subjects or patients through scientific and rigorous trial design.

As a continuous cell culture technology, perfusion fermentation is more beneficial to cost control than traditional batch fermentation and can be flexibly arranged according to the supply change. In this paper, the characteristics and advantages of perfusion fermentation are clarified by comparing the batch fermentation with perfusion fermentation. In combination with the guidelines currently being drafted by the International Council on Harmonization, the considerations for pharmaceutical evaluation of cell passage stability study, batch and scale definition, process control, viral safety, and process verification of perfusion fermentation are summarized in this paper.

Antibody radionuclide conjugates (ARC) conjugate radionuclides and antibodies through a linker and chelator, which can perform different functions of diagnosis or treatment. To date, ARC is an important product type of radionuclide drug conjugates (RDC), and there are many approved drugs and drug candidates in clinical trials. However, the domestic industry faces many challenges in the development of clinical application-grade ARC products. This article summarizes the latest research progress of ARC products, from raw materials, production process and quality control, expecting to promote the clinical transformation and application of such products.

Stem cells have the potential of self-renewing and multilineage differentiation. Different types of stem cells have different advantages and limitations. It has become a hot topic of basic research and clinical application. Currently human-derived stem cell products to be developed as drugs come mainly from adult stem cells, embryonic stem cells, and induced pluripotent stem cells. Human-derived stem cell products are complex and diverse, showing unique therapeutic advantages in the treatment of a variety of diseases. This paper summarizes the characteristics and the latest research progress of human-derived stem cell products. According to the drug development and evaluation rules, this article brings up some quality assessment concerns and discussions in the major fields, such as raw materials, manufacturing process, quality research and control, stability, packaging container system, for the industry and regulators to discuss and communicate, expecting to promote the clinical transformation and application of this class of products.

Single-cell sequencing advances the research of molecular biology and cell biology to the single cell level by integrating the latest technologies such as single-cell dissociation, microfluidic, microfluidics system, high-throughput sequencing, and bioinformatics. It is a milestone technology in the history of biotechnology. Single-cell sequencing technology provides a new dimension for the study of basic biomedical problems such as ontogeny, cell differentiation, cell heterogeneity in tissues, and the etiology and development of diseases, and has been widely used. In this review, we briefly introduced the development of single cell sequencing technology and assocatied bioinformatics methods, and reviewed its application in the process of drug development, such as study on mechanism of disease, target discovery, drug discovery and optimization, mechanism of action and clinical trial design.

The manufacturing process of fermented new drugs is complicated, and the quality control is difficult. Referring to the relevant technical guidances of new drug chemistry, manufacturing, and control research, centering on the quality control characteristics of fermented new drugs, this article discusses the general considerations on the manufacturing process, elucidation of structure, specification research, to provide a reference for the research of fermented new drugs.

Complex injections are usually a kind of modified new drugs with new dosage forms, formulations and manufacture processes. It is an effective method to reduce inherent deficiencies of active ingredients with advanced techniques. Complex injections can reduce side effects of drug substances, improve drug efficacy, promote patients' compliance and so on. In the increasingly competitive generic drug market, they have obvious clinical advantages and market competitiveness. However, complex injections usually own complicated formulations and processes. Based on guidances and policies at home and abroad, in this paper, we briefly discussed the CMC requirements for complex generic injections according to the characteristics of different complex injections.

Blood products are manufactured by separation of plasma from healthy donors, which have a wide range of indications and play a critical role in the prevention and treatment of certain major diseases. However, because of the uniqueness of their source, the viral safety of blood products is always highly concerned by various national regulatory authorities. This manuscript discussed viral safety-related issues of blood products in combination with technical review practice, from aspects like source plasma, virus removal/inactivation processes, regulation requirements and considerations in technical review, etc., in order to provide references for future research and development.

In this paper, the author investigated and compared the domestic and foreign laws and regulations and current pharmacopoeias of different countries related to the storage conditions of chemical drugs, then put forward some thoughts and suggestions in combination with the existing problems of the storage conditions of chemical drugs, so as to provide reference for the establishment and standardization of the storage conditions of chemical drugs.

The concept of analytical quality by design (AQbD) guides pharmaceutical industries in the development and maintenance of systematic analytical procedures using scientific knowledge and quality risk management approach. The quality control of biological products is the critical content of the pharmaceutical research and evaluation, and is important to ensure the safety, effectiveness and stability of products. The analytical procedures used for quality control contribute to the quality control system. Lifecycle management of analytical procedures includes analytical procedure development, validation, transfer, change and continual improvement. This article introduced the concept and application of lifecycle management of analytical procedures and regulatory considerations according to the quality control characteristics of biologics and the experience of drug evaluation.

In order to encourage clinical value-oriented drug innovation, the current "Drug Registration Regulation" proposes four expedited regulatory approval procedures. For innovative drugs with early clinical trial data that can likely predict the efficacy and clinical benefit of the drugs, the marketing authorization might be granted before the completion of the confirmatory clinical trial through the conditional approval procedure, with all data comprehensively reviewed. By implementing the procedure, patients with serious diseases or conditions can expect more opportunities to prolong their lives or improve their quality of life. Since conditional approval procedures can shorten the time for pre-market clinical research and development, its supporting policies and criteria have attracted much attention. This paper takes the innovative anti-tumor drugs as the starting point, systematically sorts out the policy requirements of conditional approval in China and the criteria that have been formed in the review process, and tries to analyze the problems encountered in the implementation of conditional approval and put forward solutions.

Clinical study for medicine products is a time-consuming and high-cost project. As a great tool of optimizing trial design, simulation technology plays an important role in different phases and different indications of clinical trials. At present, different regulatory agencies have established corresponding technical requirements for simulation technology. This paper summarized the development of the guidelines of NMPA, FDA, EMA, and ICH to elaborate the regulatory status of simulation technology. Without additional clinical trial data, one pharmaceutical company successfully expanded the indications of adalimumab in adults for hidradenitis suppurativa to adolescent by virtue of only model simulation results. This article analyzed this case in detail to illustrate the importance of simulation technology. Finally, this paper discussed the advantages and disadvantages of simulation technology, as well as the considerations in practical application.

For post-approval CMC Changes, ICH Q12 proposed management tools such as categorization of post-approval CMC changes, ECs, PACMP, and PLCM documents. The United States, the European Union and China have different approaches in implementing these management tools. It is of great significance to learn from and refer to the implementation experience of the United States and the European Union for optimizing China's post-approval CMC change management. We hope to change the supervision department's concept of post-approval CMC change management, manage changes by category, and optimize change management tools.

Taken literature in the field of pharmacovigilance risk management from 2002 to 2021 in the Web of Science Core Collection database as sample data, used Excel and Cite Space software to conduct bibliometric analysis on research trends, literature sources, research subjects and research hot spots of relevant literature, and to construct the knowledge map in the field of international pharmacovigilance risk management. Study shows that the field of international pharmacovigilance risk management presents obvious phase increasing characteristics overall. The research institutions are divided into four cooperative groups: the United States, France, the Netherlands, and Italy. There are three models of groups with close cooperative relationships: university-university, university-medical institution, and government agency-medical institution, and the cooperative relationship among institutions has been gradually strengthened. Research hot spots are focused on adverse drug reactions, signal detection, pharmacoepidemiology, etc. Drawing on the international research results, the development of pharmacovigilance risk management in China can be enlightened from their research subjects and research hot spots.