Generic Drug (also known as Generic Drug) refers to a generic drug that is the same as the original drug (or brand-name drug) in terms of dosage, safety and strength (strength), quality, performance and intended use Products, also known as generic drugs, generic drugs, etc. The goal of generic R&D is to achieve the "substitutability" of generic drugs and original research drugs in clinical applications. According to the US FDA's point of view, a generic drug that can be approved must meet the following conditions: contain the same active ingredients as the generic product, and the inactive ingredients can be different; and the indications, dosage forms, specifications, and administration routes of the generic product are consistent. ; Bioequivalent; quality meets the same requirements; GMP standards produced are the same as those of the imitation products.
The listing of generic drugs can provide more adequate clinical supplies, greatly reduce drug prices, ease the economic burden of patients, and have important economic and social benefits such as reducing medical expenditures, improving drug accessibility, and improving medical service levels. Foreign statistics show that with the increase in the number of generic drugs on the market, the lowest drug price will drop to about 9% of the original price of the original drug.
Nevertheless, the difference between generic drugs and original research drugs must also arouse due attention and focus on effective control. Generic drugs just copy the molecular structure of the main ingredients of the original drug, and the key process steps, key reagents, "design space" of the production process or the quality control of key excipients in the production of the original drug are the core confidential content of the enterprise, which is difficult for the imitation company to be legal. Copying, leading to the impurity profile of generic drugs, drug release behavior and other key quality attributes, in some cases it is difficult to be completely consistent with the original drug; at the same time, the relevant laws and regulations do not require the addition of other ingredients (excipients) in generic drugs and the original drug must Same; in the licensing of generic drugs, its bioavailability should be about ±20% of the original drug. These factors make it difficult to completely eliminate the difference between the safety and effectiveness of generic drugs and the original drugs. The American Academy of Family Physicians used facts in research reports to show that the efficacy and safety of original drugs are not completely replaceable by generic drugs, especially when treating critical patients and critical diseases that require great attention. In fact, how to maintain the "consistency" between generic drugs and original drugs, how to study and verify the "differences" between generic drugs and original drugs, and how to accurately assess and effectively control the risks brought by these "differences" are exactly what is needed in the development of generic drugs. The focus of great attention.

1. Basic ideas and strategies for imitation research and development

1.1 Designing and ensuring "consistency" with the original drug is the basic idea of ​​generic drug development

A generic drug is a "generic" of an original drug that has been marketed. Since the Waxman Act passed by the FDA in 1983, countries do not require repeated animal studies and human clinical studies before the approval of the original drug, but have passed certification and The bioequivalence of the original research drug can be approved, and it can be clinically substituted with the original research drug. Therefore, imitation research and development needs to research and verify the following key issues: The quality profile of imitation products, especially the key quality attributes (Critical Quality Attributes, CQAs) include? Are the key quality attributes of the generic drug and the original drug consistent? What are the key process elements that determine the key quality attributes of the product? How to ensure the consistency of the key quality attributes of the original drug from the key process elements and the key quality control items of the quality standard? How to maintain this consistency during product storage? Can the established quality assurance system effectively guarantee the consistency between the developed product and the marketed original research drug?
However, the "consistency" of generic drugs and original drugs does not only refer to the consistency of product inspection results. The quality of drugs is not tested, but is guaranteed and realized through scientific design. The quality of medicines first comes from the design of early products and processes, and is formed in the production process of medicines. The design of products and processes at the early stage of research and development determines the "innate" quality characteristics of the products, and the actual quality status is assigned to specific conditions through specific production processes. In products, quality standards are used to further demonstrate and reveal the quality of products. They are an important part of the quality assurance system, but not the only one. The assurance of drug quality depends on compliance with GMP, production processes, control and stability of raw materials and production processes. Sexual research, etc.; the quality of drugs requires a combination of end-point control of quality standards and production process control. At the same time, research reveals the changes in the quality of medicines over time under the influence of various environmental factors (such as temperature, humidity, and light conditions), and establishes the validity period and storage conditions to ensure their quality.
ICH introduced the concepts of quality from design, quality risk management, and drug quality system in Q8 and Q9, pointing out that the quality of drugs is not assigned by inspection, but from design, and uses the information obtained in the drug development process to produce Acquired by quality risk management in the process. Based on the comprehensive International Organization for Standardization (ISO) quality concept, combined with the Good Manufacturing Practice (GMP), the concept of a drug quality system is proposed in ICH Q10. It is believed that drug quality control should cover the development of drugs from R&D, technology transfer, commercial production, and The entire life cycle until the end of the drug. Therefore, in the entire life cycle of a drug, understand and recognize the differences, connections, and different goals of different stages of the drug, and promote innovation and continuous improvement based on scientific and risk-based methods to ensure the quality of the drug throughout the life cycle. The "consistency" between the generic drug and the original drug requires verification and assurance of the above-mentioned various links.

1.2 The concept of Quality by Design (QbD) is an effective tool for the development of generic drugs

Different from the traditional quality management model, the concept of quality by design (QbD) requires a full understanding of the product quality profile (Quality Target Product Profile, QTPP) and key quality attributes (CQAs), as well as the key process parameters and their relationship with each other. The correlation between CQAs and potential high-risk variables are fully studied and screened, and Design Space (DS) is established, that is, the range of key process parameters that affect the product CQAs, so as to strengthen the understanding and control of the pharmaceutical process and ensure Continuous control of product quality. Therefore, to some extent, QbD is an effective and targeted drug research and development tool. Drug research and development under QbD is a dynamic and systematic research and development process based on the concept of "quality can be designed into products". The QbD management model and quality control concept play an increasingly important role in the research and development of generic drugs. The QbD concept has been implemented in the relevant technical requirements and guidelines issued by the ICH and FDA in recent years. The FDA Office of Generic Drugs (OGD) in 2013 At the beginning of the year, ANDA was required to submit application materials in accordance with QbD related requirements.
QbD is a systematic drug research and development concept. Its basic logical path is to start from a predetermined goal, based on science and quality risk management, and focus the research on the understanding, design and control strategy of products and production processes, and clarify the key Material attributes, key process parameters, and potentially high-risk variables, understand and control the main sources of process variation. Integrate quality risk management into a deep understanding of drugs and processes, and promote process evaluation, control and improvement to continuously ensure product quality and consistency with the original drug. For generic drug development, the basic logical path of QbD can be as follows:

Figure 1. Basic logic path of QbD

2. QbD concept in process design and research

2.1 QbD is a comprehensive and proactive drug development concept based on risk

The main purpose of process research is to obtain products that meet the quality attribute requirements of the target product and establish a commercial production process that can continuously and stably produce the expected quality requirements. Through research and evaluation of the critical quality attributes (CQAs) of products, determine the relationship between CQAs and key material attributes, key process steps, and key process parameters, evaluate product process characteristics and formulate corresponding control strategies to form complete and effective process control measures and Quality assurance system, establish and maintain the controlled state of products, and promote continuous improvement of product quality. According to the FDA’s point of view, QbD is a basic component of cGMP, a scientific, risk-based, comprehensive and active drug development method. It is scientifically designed from product concept to industrial production, and it is a relationship between product attributes, production processes and product quality characteristics. Thorough understanding of the relationship. In the 2011 version of the process verification guidelines, the FDA further strengthened the QbD management concept, and implemented the QbD concept throughout process design, process validation, and continuous process validation. The goal of generic R&D is to research and design generic drugs that are clinically replaceable with marketed products and their effective drug quality assurance system. Therefore, the process research of generic drugs needs to confirm the critical quality attributes (CQAs) of the product based on a deep understanding of the product quality profile (QTPP) and key quality attributes (CQAs), design products and processes to meet CQAs, and pass risk assessment , Understand how material properties and process parameters affect CQAs, aim to reduce risks, establish design space, confirm and control the root causes of product/process variation, and set control space; through continuous monitoring and upgrading of the process Continue to ensure the consistency of product quality.
The traditional formulation process research and development method is to determine the initial formulation and process through simple experiments (or trial and error) on the basis of experience, so that the product can meet the requirements of quality standards. This kind of R&D concept highly relies on the personal experience and preferences of the R&D personnel. The optimization and amplification of prescriptions and processes are highly dependent on the production experience of clinical trial sample batches, and the production of these clinical sample batches is generally based on fixed prescription process parameters. Under circumstances. Therefore, the traditional R&D method is also a process of "problem solving". R&D work focuses on solving the problems that have appeared and observed during the development and production process, and the potential problems that have not been observed are basically not studied. It should be admitted that the traditional R&D methods of prescription technology have a long history and are often effective, especially when the API has good physicochemical and pharmacokinetic properties, the drug loading of the preparation is appropriate, and the product is suitable for ordinary preparations and In the case of craftsmanship, traditional R&D ideas are also effective. However, due to the limited batches produced in the development process, the observed problems often cannot cover the problems that may arise in the long-term commercial production, so the traditional research and development methods lack systematic and comprehensiveness.
In general, the observed risks are higher risks, but not necessarily all risks. The traditional R&D thinking focuses on the observed risks. Although it is also a "risk-based assessment" thinking and is dealing with higher risks, it is not a comprehensive and systematic risk control method, because it basically does not The potential risks that may exist in the system analysis have not taken into account the risks that have not been observed. Due to the limited batches of products produced in the research and development, some risks may not be considered because they have not been observed, but they may appear in the future. Especially in more complex products, it is more likely to happen in process amplification and verification, and in long-term commercial production.
It should be said that traditional R&D methods are not opposed to the QbD concept: the former is an incomplete part of the latter; QbD is based on traditional R&D methods; most of the elements in QbD already exist in traditional R&D methods. Compared with traditional research and development methods, QbD emphasizes the conscious and systematic use of relevant elements, rather than doing more experiments. For example: A written product target quality requirement must be established at the beginning of research and development; quality risk assessment must be carried out and filed at all stages of research and development; key process parameters and key material characteristics determined during research and development must be listed and control plans formulated; how will the product be realized The means of each quality characteristic are systematically included in the comprehensive quality control plan and so on.

2.2 The basic elements of QbD in preparation process research

In the QbD concept, the focus of quality control is placed in the R&D stage, which is more active, systematic, and effective than the traditional R&D concept, and is more conducive to the continuous improvement of drug quality. Based on a comprehensive understanding of the product and its process, risk control is adopted The tool identifies the raw material attributes and key process parameters, sources of variation and control measures that affect product CQAs, and establishes a control strategy based on the risk assessment results, establishes a "design space", and sets a "control space" to ensure constant product quality. Therefore, the basic elements of QbD in preparation process research should generally include the following content.

2.2.1 Quality requirements of the target product

First define the quality profile of the target product. You can inquire about the clinical administration characteristics, route of administration, dosage form, specifications, container characteristics and other information through the original drug instructions, quality standards, and literature information. If necessary, analyze the original drug to "anatomy" Obtain relevant information, make a forward-looking summary, and define QTPP. On this basis, the key quality attributes of the product are identified. Preparation CQAs refer to the physical, chemical, biological or microbiological properties or characteristics of the drug, which should be within the appropriate limits, scope or distribution to ensure the expected product quality. CQAs under QbD should be based on clinical effects rather than process conditions. For example, dissolution methods and limits of poorly soluble BCS II and IV drugs should reflect their clinical effects, rather than simply being used to evaluate the consistency of the production process; impurities can The acceptance limit should be determined based on the safety requirements or toxicity thresholds of clinical drugs, not just the batch inspection data of large-scale products.

2.2.2 Quality risk assessment

Determine the content of the research key quality risks based on the characteristics of the dosage form, the risk level, the nature of the API, and the experience in the development and production of similar products. For example, compared with oral and topical preparations, injections are the most risky dosage form because they directly enter the blood circulation or directly contact human tissues. Exogenous impurities introduced by sterility protection, pyrogens, pipeline filters, etc., and stability and recovery Solubility should be the key source of quality risk considered.

2.2.3 Design of Experiments (DoE)

Reasonably adopt systematic and methodical methods of mathematical statistics to study and determine the relationships or interactions among multiple factors that affect a process and its results. Specifically, it can include factorial design (Factorial), Taguchi method (Plackett-Burman design), response surface method (multiple quadratic regression equation fitting), orthogonal design, mixed design and other common multi-factor experimental design methods for product development. On the basis of in-depth research and in-depth understanding of products and processes, by studying the relationship between process parameters and CQAs, the key process steps and the range of key process parameters are determined to provide scientific data for establishing the "design space".

2.2.4 Critical Process Parameters (Critical Process Parameters, CPP) and Critical Material Attributes (CMA):

On the basis of the above experiment, determine the raw and auxiliary materials