Generic drugs are alternative drugs that have the same active ingredients, dosage forms, routes of administration, and therapeutic effects as the generic drugs. They have important economic and social benefits such as reducing medical expenditures, increasing the availability of drugs, and improving the level of medical services. Due to the relatively weak medical research foundation of the early approved generic drugs, the quality of some generic drugs is far from that of the generic drugs, and the clinical efficacy of the generic drugs cannot be achieved. Improving the quality of the generic drugs is of great significance to the maintenance of public health. The "National Drug Safety "Twelfth Five-Year Plan"" clearly states that it will take 5-10 years to conduct a comprehensive comparison study of generic drugs before the implementation of the "Administrative Measures on Drug Registration" revised in 2007 by phases and batches. , So that the generic drug is consistent with the generic drug. In order to implement the relevant requirements of the National Drug Safety "Twelfth Five-Year Plan", this work plan is specially formulated. To

1. Work Objectives The quality consistency evaluation of generic drugs is that the State Food and Drug Administration organizes relevant technical departments and experts to evaluate the self-assessment data of generic drugs proposed by drug manufacturers according to the given evaluation methods and standards, and evaluate whether they are compatible with the undertakings. Generic drugs have a consistent process in terms of intrinsic substance and clinical efficacy. Through the quality consistency evaluation of generic drugs, it is necessary to eliminate varieties whose internal quality does not meet the requirements, and promote the improvement of the overall level of generic drugs in my country to reach or approach the international advanced level. ,

　　 2. Working methods

　　 (1) Pilot projects first, then roll out, and gradually advance. Choose from the list of essential medicines with a large population of drugs, large market sales, many manufacturers, and a clear original research company’s varieties, first try first, accumulate experience, and then gradually roll out, comprehensively promote, gradually improve the quality evaluation system of generic drugs, and build continuous drug quality Improved working mechanism. To

　　 (2) Use scientific and reasonable technical methods to classify and process. Based on the principle of scientific, rational, and classified development, the quality consistency evaluation of generic drugs is combined with the improvement of drug standards and evaluative sampling, and the implementation is divided into categories and dosage forms according to the nature of the drug itself and the characteristics of the drug formulation. First, carry out the consistency evaluation of oral solid preparations; second, carry out the consistency evaluation of injections; and finally carry out the consistency evaluation of other dosage forms. To

　　 Three, job responsibilities

　　 (1) The State Food and Drug Administration is responsible for the organization and implementation of the quality consistency evaluation of generic drugs. Organize the formulation of a work plan for the quality consistency evaluation of generic drugs, publish relevant evaluation methods, standards and technical guidelines, and organize the review of the consistency evaluation materials submitted by the drug manufacturers. The State Food and Drug Administration will set up a special office to take charge of this work. To

　　 (2) The provincial drug supervision and administration department is responsible for the organization and coordination of the quality consistency evaluation of generic drugs within its jurisdiction. Responsible for the implementation and publicity of the quality consistency evaluation of generic drugs, supervise the drug inspection agencies in the jurisdiction to complete the tasks undertaken on time, carry out relevant training in accordance with the consistency evaluation work deployment, and complete the acceptance and production of the consistency evaluation materials as required On-site inspections and sampling inspections. To

　　 (3) Pharmaceutical manufacturers are the main body to carry out quality consistency evaluation of generic drugs. In accordance with the unified deployment of the State Food and Drug Administration, and in accordance with relevant technical guidelines, evaluation methods and standards, comprehensive and in-depth comparative studies with the generic drug should be carried out to solve the key issues affecting the internal quality of the generic drug, and to achieve the Consistent in terms of intrinsic substance and clinical efficacy.

Manufacturers of reference preparations should cooperate with the drafting of evaluation methods and standards, as well as the supply of reference preparations, in accordance with the requirements of the State Food and Drug Administration. To

　　Four, work content

The quality consistency evaluation of generic drugs mainly focuses on the varieties of essential drugs and commonly used clinical chemicals. The work mainly includes: selection of the varieties to be evaluated, determination of reference preparations and establishment of evaluation indicators, enterprise self-evaluation, and review of enterprise self-evaluation data by the drug regulatory authority, etc. Steps (see the attachment for the work flow chart).

　　 (1) Determine the varieties to be evaluated The special office formulates an annual work plan, determines the list of varieties for quality consistency evaluation each year, and the drug inspection agency responsible for the research of evaluation methods for each variety, and publishes them to the public. Pilot products in the early stage to confirm that there are drugs from original manufacturers to explore first.

　　 (2) Determination of reference preparations and related detection and analysis methods

1. The special office organizes drug inspection agencies and reference preparation manufacturers to formulate quality consistency evaluation methods and standards for various varieties according to the "procedures and requirements for reference preparation determination" and "technical guidelines for drug quality consistency evaluation", and Solicit opinions from relevant drug manufacturers.

2. The special office organizes experts from relevant drug inspection institutions and technical experts from relevant drug manufacturers to improve the quality consistency evaluation methods and standards of various varieties based on the opinions solicited.

3. The manufacturer of the reference preparation shall make the reference preparation as required, and the drug inspection agency shall conduct the quality review of the reference preparation and submit the result to the special office. To

4. The State Food and Drug Administration reviews the reference preparations and quality consistency evaluation methods and standards submitted by the special office, and publishes them if they meet the requirements.

　　 (3) Drug manufacturing companies carry out quality consistency evaluation research All relevant drug manufacturing companies carry out quality consistency evaluation of generic drugs in accordance with the evaluation methods and standards announced by the State Food and Drug Administration, using reference preparations as control drugs. After the company completes the evaluation, it submits the research data and samples to the local provincial drug supervision and administration department.

If it is necessary to change the prescription, process, etc., the relevant change research data (see the "Administrative Measures for Drug Registration") and the consistency evaluation research data can be reported to the provincial bureau.

　　 (4) Acceptance and on-site inspection of quality consistency evaluation materials for generic drugs

After receiving the research materials of the drug manufacturer, the provincial drug supervision and management department shall organize the production site inspection according to the approved or declared process, select 3 batches of samples from continuous production on site, and send them to the drug inspection agency responsible for the quality consistency evaluation of the product Perform a review inspection. After receiving the samples, the drug inspection agency will conduct a review in accordance with the methods and standards announced by the State Food and Drug Administration, and report the review results to the relevant provincial drug regulatory authority.

After receiving the review results of the drug inspection institute, the provincial drug supervision and management department shall submit the research data and inspection report to the special office.

　　 (5) Review the quality consistency evaluation data of generic drugs

　　 After receiving the consistency evaluation research data, the special project office shall organize an expert committee to review the research data submitted by the enterprise. After reviewing and meeting the requirements, the special office shall report to the State Food and Drug Administration for approval, and the State Food and Drug Administration shall publish relevant information (name of the manufacturer, name of the drug, approval number, etc.).

　　 If the requirements are not met after review, the special office shall inform the drug manufacturer.

　　 If there are changes to prescriptions and processes, the special office will organize experts to review them together, and report to the State Food and Drug Administration together with the results of the quality consistency evaluation review, and the State Food and Drug Administration will issue the "Approval for Supplementary Drugs".

　　 Pharmaceutical manufacturers can also, if necessary, carry out their own research work on the varieties that the National Bureau has not yet deployed for quality consistency evaluation, and report to the special office after completing the drafting of the evaluation methods and standards. The special office organizes the drug testing institutes and experts to review and confirm the evaluation methods and standards drafted by the drug manufacturers, and announce them to the outside world to initiate the consistency evaluation of related varieties.

　　 5. Work plan

　　 (1) In 2012, we carried out variety research, promulgated relevant guidelines for the quality consistency evaluation of generic oral solid dosage forms, and initiated the screening and evaluation of reference preparations.

　　 (2) In 2013, establish a catalog of reference preparations; construct a generic drug database for oral solid preparations, establish an information transmission system between national bureaus, drug inspection agencies and enterprises; complete the selection and confirmation of reference preparations.

　　 (3) In 2014, comprehensively carried out the comparative research and evaluation of the generic drugs of oral solid preparations and the reference preparations. Improve the construction of the information system and complete the quality consistency evaluation of some varieties.

　　 (4) In 2015, completed the task of evaluating the quality consistency of solid oral preparations in the essential medicine catalog.

　　 (5) From 2015 to 2020, carry out the quality consistency evaluation of injections and other dosage forms.

Six, job security

　　 (1) Establish a leading group and a supervisory team for quality consistency evaluation of generic drugs. Responsible for the organization and leadership of the work, overall coordination and external publicity work, reviewing the work plan, researching and solving major problems in the work, guiding and supervising the implementation of various tasks. A special office is set up under the leading group, and the office is located at the China Food and Drug Control Research Institute, responsible for the implementation of the quality consistency evaluation of generic drugs.

Establish a quality consistency evaluation and inspection team for generic drugs. Mainly perform supervisory duties to ensure that the consistency evaluation work is objective, fair and fair.

　　 (2) Establish relevant committees and technical working groups. The establishment of a generic drug quality consistency evaluation technical working group, which is mainly responsible for the review of related technical guidelines and related methodology for the quality consistency evaluation of generic drugs; the establishment of a generic drug quality consistency evaluation expert review committee, responsible for the quality consistency evaluation of generic drugs The review of evaluation materials is responsible for the check of major technical issues.

　　 (3) Establish a special information management platform. Establish an electronic information column for the quality consistency evaluation of generic drugs, publish generic drug evaluation plans, technical guidelines and product information that have passed generic drug evaluation, and guide and standardize enterprises to conduct research. It is necessary to make full use of information technology, improve internal management, optimize management processes, and ensure the openness and transparency of quality consistency evaluation.

　　 (4) Strengthen the management of archives. In accordance with the relevant requirements of the national archives management, the preservation and management of the work archives for the quality consistency evaluation of generic drugs should be carried out to ensure the completeness and traceability of the documents and materials.

　　 (5) Make good use of funds. All task-bearing units shall establish special accounts and personnel to strengthen the management of work funds in accordance with the relevant provisions on fund management, and ensure the safe and efficient use of funds.

　　 (6) Strict work discipline. All relevant units shall select and send personnel with high political quality and strong professional ability to participate in the quality consistency evaluation of generic drugs. It is necessary to strengthen business training and education on integrity and confidentiality for participants, unify standards, strict standards, and strict work discipline to ensure that the consistency evaluation work is fair and just.

Attachment: Flowchart for the Quality Consistency Evaluation of Generic Drugs 2012-Monthly Drafting Plan for Drug Quality Consistency Evaluation of Drug Registration (Department of Drug Quality Evaluation for the Year of 2012)

　　 1. Drafting background At present, my country has 16,000 drugs approved for marketing and 187,000 drug approval numbers. Among them, 7,000 kinds of chemical drugs, 121,000 approved number, most of them are generic drugs. On the whole, the development of generic drugs in my country has made considerable progress, effectively solving the prominent problem of the people’s lack of medicines and medicines, and playing an important role in safeguarding public health. With the in-depth development of medical reform and the gradual improvement of the public's living standards, the requirements for the quality of medicines from all walks of life are also increasing. Some potential problems in my country's generic drugs have become more and more prominent, and the quality of some generic drugs has a large gap with the quality of the generic drugs. , To a certain extent, affect the clinical efficacy of generic drugs, and even affect the safety of public use of drugs. In order to implement the task deployment of improving the quality of generic drugs in the National Drug Safety 12th Five-Year Plan, and to improve the quality of generic drugs in an all-round way, the "Generic Drug Quality Consistency Evaluation Work Plan" (hereinafter referred to as the "Work Plan") was formulated. It is proposed to adopt the "Work Plan", put forward work objectives, clarify work methods, determine work content and requirements, implement work tasks and responsibilities, ensure the orderly and reasonable development of the quality consistency evaluation of generic drugs, promote the overall improvement of generic drugs quality, and promote pharmaceuticals The healthy development of the industry. To

　　 2. Drafting principles

(1) Guided by the scientific concept of development, in accordance with the requirements of scientific regulatory concepts, fully consider the development status of my country's pharmaceutical industry and the public's drug demand, and adopt reasonable and feasible evaluation methods and standards to comprehensively improve the quality of my country's generic drugs and ensure the safety of public drug use .

(2) On the basis of clarifying the overall work objectives, make overall planning for the quality consistency evaluation work, clarify the working time and content, and promote the quality consistency evaluation work in accordance with the principle of priority and priority.

3. Drafting process In order to implement the tasks deployed in the National Drug Safety 12th Five-Year Plan, in accordance with our Bureau's "Notice on Printing and Distributing the National Drug Safety 12th Five-Year Plan Task Division Plan" (State Food and Drug Administration [2012] No. 40) requested that our company started drafting the "Work Plan" from the beginning of the year. In order to ensure that the "Work Plan" is scientific, reasonable and operable, our company has organized a delegation to Japan to learn about Japan’s experience in quality consistency evaluation and 7 times solicited opinions from domestic and foreign enterprises, industry associations and experts. After many studies, the first draft of the "Work Plan" was formed. During the period, it was perfected according to the spirit of the 5th office meeting of Deputy Director Wu Zhen, and solicited opinions from political law, safety supervision, inspection, the Central Procuratorate, the Pharmacopoeia Commission, and the Center for Drug Evaluation, and finally formed the "Work Plan" (Draft for Solicitation of Comments).

　　Four. Main Contents The "Work Plan" is divided into six parts, the main contents are as follows: The first part is "Work Goals". Clarified the definition of the quality consistency evaluation of generic drugs, and put forward the overall goal of the work.

　　 The second part "Methods of work". The work methods and strategies used in the consistency evaluation are put forward. One is to first pilot and then roll out, which is helpful for timely correction of possible problems in the work; the second is reasonable classification and orderly development. The first is to carry out strong public feedback and mature experience. Followable oral solid preparations, and then carry out the evaluation of other dosage forms.

　　 The third part is "Job Responsibilities". Clarified the responsibilities and obligations of national bureaus, provincial bureaus, and pharmaceutical manufacturers in the quality consistency evaluation work. In particular, it is clarified that the drug manufacturing enterprise is the main body of the consistency evaluation work, which is conducive to improving the responsibility awareness of the drug manufacturing enterprise.

　　 The fourth part "work content". Clarified the consistency evaluation work content and related steps. The main process and content are: the National Bureau announces the varieties to be evaluated and determines the evaluation methods, standards and corresponding reference preparations → → The enterprise takes the reference preparations as a control, evaluates the products according to the evaluation methods and standards, and forms evaluation data and submits them to the local provincial bureau →→The provincial bureau conducts on-site inspection of the enterprise and takes samples to the drug inspection institute for inspection, and then submits the enterprise evaluation data, on-site inspection report and sample inspection report to the special office of the national bureau→→the special office organizes experts to review, and if it meets the requirements, announce it to the public If the information does not meet the requirements, it shall be returned to the enterprise for further study.

　　 Part V "Work Plan". Clarified the work goals for each year.

　　 Part VI "Job Security". Relevant requirements were put forward in terms of organization, personnel, funding, informatization, and archives.

　　 Five, some issues that need to be explained

1. Regarding the step-by-step evaluation According to the preliminary work ideas, the evaluation of oral solid preparations will be carried out first. There are three reasons. One is that among the essential drugs, the number of oral solid preparations is the largest, and the most inconsistent clinical efficacy is reflected in the oral solid preparations; the second is that there are more mature experience in the quality evaluation of oral solid preparations (Japan has carried out quality re- Evaluation project). In summary, we first carry out the evaluation of oral solid preparations, and then gradually accumulate experience, and then carry out the evaluation of injections and other dosage forms in turn. When and how to carry out the consistency evaluation of various dosage forms will be gradually initiated through the issuance of guidelines. At present, the China Inspection Institute has completed the drafting of relevant technical guidelines for the consistency evaluation of oral solid preparations. After the plan is issued, the evaluation of oral solid preparations will be fully initiated. After that, we successively issued technical guidelines for the evaluation of other dosage forms, and started the evaluation of related dosage forms in turn.

2. Regarding the evaluation methods Quality consistency mainly refers to the consistency of the material basis and clinical efficacy. The consistency of the material basis is mainly determined by whether it meets the quality standards, and the consistency of the clinical efficacy is mainly evaluated by some in vivo and in vitro tests. It should be said that clinical verification (including bioequivalence and clinical trials) is the "gold standard" for determining consistency evaluation. However, since the object of the consistency evaluation is a marketed drug, which involves a wide range of areas, it is very difficult to use clinical verification to conduct the consistency evaluation. Therefore, in vitro tests that can sensitively reflect in vivo efficacy are our priority evaluation methods, and at the same time retain the right of enterprises to carry out clinical research. On the one hand, it can avoid the shortage of resources caused by large-scale clinical research. On the other hand, in vitro tests can be used for daily supervision to ensure long-term consistency of product quality. For oral solid preparations, the comparison of dissolution profiles in multiple media is mainly selected to evaluate whether it is consistent with the original research; for injections, since there is no drug absorption problem, the main focus is on safety indicators, and the evaluation will be mainly performed by improving the quality standards; In other cases, reasonable evaluation methods and standards will be set based on the characteristics of the dosage form.

3. Regarding the in vitro dissolution curve The reasons for using the dissolution curve for evaluation are as follows: First, the dissolution curve in a variety of media has become a research required by the drug regulatory authorities of many countries to conduct drug research and development. The U.S. FDA’s relevant guidelines for generic drugs clearly point out that before conducting a bioequivalence (BE) study, multiple dissolution profiles must be compared with the FDA-published reference product; Japan’s PMDA also requires that the research and development of generic drugs must be conducted with reference Comparing multiple dissolution profiles than preparations, and Japan’s drug re-evaluation project also uses multiple dissolution profiles for evaluation; during drug review in my country, applicants are also required to provide a comparison with the original product’s dissolution profile; second, existing data It shows that if multiple curves in vitro of the imitation product are consistent with those of the original research product, the probability of the same in vivo bioavailability is as high as 90%. The probability of inconsistent utilization will also be as high as 90%. Therefore, the comparison of dissolution profiles under multiple media can better reflect the efficacy of the drug in vivo, and can be used for the quality consistency evaluation of oral solid preparations.

4. Regarding the review of prescription process changes. Quality consistency evaluation will inevitably lead to changes in drug prescriptions and processes. According to the "Administrative Measures for Drug Registration", changes in prescriptions and processes should be reported to the Drug Evaluation Center for technical review. With only the current registration and application volume, the Drug Evaluation Center is already operating at full capacity and is unable to undertake the related technical review work derived from quality consistency. To this end, we have formulated a work process for the expert committee organized by the China Inspection Institute to review the prescription and process changes when reviewing the consistency evaluation data. In order to ensure the consistency of the technical review standards for process and prescription changes, the Drug Evaluation Center will participate in the expert committee and be responsible for related technical reviews.

5. Regarding the selection of reference preparations The most important thing for consistency evaluation is the selection of reference preparations. Only when the reference preparation is determined can the evaluation be consistent with whom. The reference preparation is not only an honor, but also a policy preference in terms of bidding and price. Therefore, the determination of reference preparations is very important for enterprises. To ensure that the selection of reference preparations is scientific, fair and reasonable, we will formulate the selection principles of reference preparations to ensure that the selection of reference preparations is open, fair and just.

6. Regarding strengthening post-marketing supervision. In addition to the weak research foundation, the reasons for the inconsistency between generic drugs and original drugs are also an important factor for companies to change prescriptions and processes at will, cutting corners and materials. The reason is that in addition to quality standards, we still lack other technical standards for post-marketing supervision. In the future, we will establish a database of corporate prescriptions, processes, and dissolution profiles through consistency evaluation, and strengthen post-marketing supervision of drugs based on the consistency evaluation data reported by companies such as prescriptions, processes, and dissolution profiles: on the one hand, we will deter companies and make them Don't dare to change prescriptions and processes at will to ensure the long-term stability of the quality of listed products; on the other hand, strengthen post-marketing supervision to solve the persistent problems of non-production of approved processes and non-approved production processes, and ensure the truthfulness and reliability of the application materials.