Research on the Development and Industrialization of Pharmaceutical Preparation Technology

Compared with developed countries, China's drug research and development ability is relatively weak. The main reasons are different R&D subjects and insufficient R&D investment. The short-term goal of R&D and the lack of R&D resources. There is a big gap between China and foreign countries in drug innovation ability, and there is also a big gap in preparation technology development and industrialization research. For various reasons, there are many problems in the transition of pharmaceutical preparations from declaration process to production process.

First, the drug quality management concept

The quality of drugs is related to human health and safety. How to effectively control the quality of drugs has always been a problem actively explored by the medical community. In the 1990s, the domestic pharmaceutical industry realized that drug quality was produced, not tested. In recent years, China has emphasized that enterprises are the first responsible person for product quality.

QbD is the abbreviation of quality comes from design, which emphasizes that design is the basis of ensuring product quality, is a scientific and risk-based total quality management concept of drug research and development, is a careful design from product research and development to industrialization, and is a thorough understanding of the relationship between product characteristics, production technology and product quality. Drug quality =f (drugs, excipients and manufacturing), and drug quality is a dependent variable. The characteristics, compatibility and manufacture of drugs and excipients determine the quality of drugs. Developed countries in Europe and America with high R&D level, early implementation of cGMP and strict drug supervision have put forward QbD quality management concept in recent years, which is intriguing and worth pondering.

In China, the new Measures for the Administration of Drug Registration came into effect on June 65438+ 10/day, 2007. In order to solve the problem that the declared production process is quite different from the actual production process, the production approval process is pushed back. In May, 2008, the State Food and Drug Administration of the United States issued the Technical Guiding Principles for Change Research of Listed Chemicals (I), which further strengthened the supervision in this respect. It is helpful for domestic enterprises to learn and establish QbD drug quality management concept, improve quality management system, ensure drug quality, and help solve the problem of pharmaceutical preparation industrialization.

Second, pay attention to the influence of process amplification effect.

The process amplification effect of various preparations and specific varieties is different, and the key points to be considered are also different. For example, the process amplification effect of powder directly filling hard capsules is generally small; The process amplification effect of some solution-type small-volume injections before sterilization is generally not great; Emulsions, liposomes, microspheres, some solid preparations and sustained-release preparations are multi-component and multi-phase systems, which involve multi-unit operations such as multi-phase stirring, extrusion and mixing, and their process amplification effect is much greater. In the process of process amplification, it is greatly influenced by equipment, operating conditions and process parameters, and the interaction between components and the change degree of physical state are difficult to predict.

In order to ensure the safety and effectiveness of experimental drugs verified in clinical stage to reappear in production and marketing, the consistency of product quality must be maintained in the process of pharmaceutical preparation process scale-up. It is necessary to strengthen the experimental study on the correlation between in vitro release and in vivo absorption of some varieties, and the release performance of the preparation must be monitored during the process scale-up test. For varieties with large process amplification effect, their production scale should be gradually enlarged. In foreign countries, when the production scale of sustained-release microspheres is gradually expanded, it is generally twice as large as before. Various parameters of the expanded microspheres are evaluated and verified to confirm whether the product quality meets the design requirements and related standards, and even the bioavailability (BA) or bioequivalence (BE) is evaluated at a certain stage. Pilot test and industrialization research are extremely important links, not simple process amplification. It is related to whether the declaration process can be applied to large-scale production, to the reproducibility of product quality, and to the safety and effectiveness of drugs. If there is a big change in the amplification process, BA or BE test should be re-conducted, and even clinical research and stability research should be re-conducted.

Three, the reasons that affect the industrialization of pharmaceutical preparation technology

The smooth transition of laboratory stage-pilot-small-scale production-large-scale production of preparation technology is based on comprehensive and solid research in the early stage. The whole process needs a lot of investment, an experienced technical team and corresponding supporting equipment and instruments.

In the process of drug research and development, the research and development of drug preparation technology is an important link. Most domestic pharmaceutical enterprises or related research institutions often lack research on prescription technology because of insufficient R&D investment, imperfect R&D conditions, low level of R&D, limited number of experiments and limited amount of experiments in laboratory stage, and lack of raw materials and tight time, and the research on various prescription technology factors affecting product quality is not in-depth. Some preparation technology transfer projects rarely consider the factors such as process amplification effect, raw material source and quality, equipment applicability and so on. Therefore, a considerable number of preparations have some defects in the application process. Immature laboratory prescriptions and processes often bring great difficulties to pilot and industrialization research, and prescriptions and processes often change in the process of pilot scale-up and industrialization.

In developed countries, the industrialization research stage started earlier, and this batch of experimental products had reached a large production scale before the start of the third phase of clinical trials. The use of production-scale experimental samples is also a prerequisite for obtaining objective and reliable pharmacokinetic and clinical trial data, although this will greatly increase the research and development costs; In addition, the industrialization research and related verification are carried out by special departments, and the research is completed in special places with various equipment and instruments (including production equipment). After the products pass the examination and approval, the mature and standardized process regulations will be handed over to the production workshop. Comparatively speaking, most domestic research institutions and pharmaceutical enterprises do not have this model, and the disadvantage of lacking industrialization research links is obvious. There are technical problems in trial production in the workshop, which often disturb the normal production order and GMP management and affect the product quality.

Four. suggestion

In view of the industrialization of pharmaceutical preparation technology in China, research institutions and pharmaceutical enterprises should first establish QbD drug quality management concept, ensure and control product quality through design, and consider industrialization and final product quality from the beginning of research and development. But to achieve this goal, we need to create conditions to solve related problems, which requires a long process. According to the current situation in China, it is suggested to pay attention to the following aspects:

1, macro-control, advocating innovation and increasing investment in research and development. Medicine is a special commodity, and excessive competition and disorderly competition will certainly endanger the development of the pharmaceutical industry. A considerable number of pharmaceutical companies lack R&D funds, and the proportion of low-level re-developed varieties is high, resulting in low R&D investment and waste of R&D resources. Therefore, it is necessary to carry out macro-control and formulate relevant policies to guide and support enterprises to increase investment and innovation in R&D.

2. Improve the research level of preparation technology development. The research and development of pharmaceutical preparation technology involves many disciplines and is also an empirical experimental study. In the study, factors such as process prescription design, equipment, process parameters, raw materials, verification, preparation quality evaluation, and standard formulation need to be considered comprehensively. According to the actual situation, using extreme technology and conditions, we can carry out the influence factor test of this technology, find out the key factors affecting the technology and product quality, determine the corresponding design space, improve the applicability or durability of laboratory formula technology, and lay a good foundation for pilot and industrial research.

3, strengthen the pilot and industrialization research. There are often many uncertain factors in technological achievements without pilot test, and the risk of direct process amplification or industrialization transfer is great. Pilot test and industrialization research are indispensable and important links. It is necessary to establish a corresponding base, set up a corresponding technical team and evaluate the process amplification effect of specific varieties in order to complete the smooth transition from pilot to small-scale production and then to large-scale production.

4. Promote enterprises to become the main body of research and development. The main body of drug research and development in developed countries is enterprises, while domestic pharmaceutical companies are mostly production-oriented enterprises. Promote the pace of scientific research institutes entering enterprise groups, integrate R&D resources, and accelerate enterprises to become the main body of R&D. Only when enterprises become the main body of R&D and establish the concept of QbD drug quality management, R&D projects will be linked to the market, pilot projects and industrialization will be considered in the design, and the quality of final products will be considered in the design.

5. others. Adjuvants directly affect the quality of drugs, so we should strengthen the management of domestic pharmaceutical excipients and improve the quality and related standards of excipients. The research and industrialization of pharmaceutical preparation technology need to cultivate relevant talents, and colleges and universities should attach importance to and strengthen relevant courses such as industrial pharmacy, pilot test and industrialization, so as to lay a good foundation for cultivating relevant technical talents.