Shi Yao Jian Zhu Han  No. 118
Issued on June 1, 2012
To further strengthen the management over the production and use of pharmaceutical excipients and ensure the quality of drugs, we organize and developed Relevant Regulations on Supervision and Management of Pharmaceutical Excipients (Exposure Draft) (Annex) in accordance with the Drug Administration Law, Regulations for Implementation of the Drug Administration Law and other laws and regulations, and now are asking for opinions from the society. Please visit the website of China National Food and Drug Administration (website: http//www.sfda.gov.cn), enter “Asking for Opinions” and click “Seeking Public Opinions about Relevant Regulations on Strengthening Supervision and Management of Pharmaceutical Excipients (Exposure Draft)”. The public can provide feedback through the following channels and ways:
1. E-mail firstname.lastname@example.org
2. Fax: +86-10-88363236
3. Address: General Office of Drug Administration Division, China National Food and Drug Administration, Building 2, Court 26, Xuanwumen West Street, Xicheng District, Beijing
Zip Code: 100053
Feedback Deadline: June 8, 2012
1. Relevant Regulations on Strengthening Supervision and Management of Pharmaceutical Excipients (Exposure Draft)
2. Drafting note of Relevant Regulations on Strengthening Supervision and Management of Pharmaceutical Excipients (Exposure Draft)
Drug Administration Division of China National Food and Drug Administration
June 1, 2012
Relevant Regulations on Strengthening Supervision and Management of Pharmaceutical Excipients
Medicinal excipients are an important part of drugs and affect the quality of drugs. In order to further strengthen supervision over the production and use of pharmaceutical excipients and ensure the quality and safety of pharmaceuticals, we hereby develop the relevant regulations as follows in accordance with Drug Administration Law of the People’s Republic of China, Special Provisions of the State Council on Strengthening the Supervision and Management of Safety of Food and Other Products, Measures for the Supervision over and Administration of Pharmaceutical Production, Provisions for Drug Registration, Good Manufacture Practice of Medical Products and relevant regulations.
1. Pharmaceutical preparation production enterprises must strengthen the management of the quality of the purchased medicinal excipients
(1) Pharmaceutical preparation production enterprises are responsible for the quality of drugs. These enterprises must strengthen the quality management of medicines and ensure the quality safety of the drug. They must be strict with the management of the use of medicinal excipients, use pharmaceutical excipients in line with the medication safety to produce drugs in accordance with the formulation and process approved by the drug regulation authorities. Where there is any drug quality problem caused by the illegal use of pharmaceutical excipients, the pharmaceutical preparation production enterprise must assume the primary responsibility.
(2) Pharmaceutical production enterprises should improve the quality management system to ensure the quality management department to effectively fulfill its quality assurance and quality control responsibilities. Owners of the enterprises and other department personnel shall not interfere with or impede the quality control department to fulfill its duties. The material supplier shall be audited and approved by the enterprise quality management department.
(3) Pharmaceutical preparation manufacturers should strengthen audit to the pharmaceutical excipients supplier. Pharmaceutical preparation manufacturers should conduct quality assessment to pharmaceutical excipients manufacturers regularly in accordance with relevant requirements described in Good Manufacture Practice of Medical Products (2010 revision), carry out field quality audit and retrospective analysis to the quality system of the pharmaceutical excipients manufacturer, establish quality files for all purchased pharmaceutical excipients and suppliers and report them to the provincial drug regulatory authorities for record.
(4) Pharmaceutical preparation manufacturers must control the quality of pharmaceutical excipients strictly. All pharmaceutical excipients purchased must be inspected in accordance with the quality standard approved when the drug is approved to register to ensure it is in line with medicinal requirements. All pharmaceutical excipients with national standards must meet the requirements of national standards.
(5) Pharmaceutical preparation enterprises shall enter into quality agreements with suppliers of pharmaceutical excipients, keep abreast of the changes of the pharmaceutical excipients used, study and evaluate the impact of changes on the quality of the preparations and declare by following the requirements of the Drug Registration Management Measures.
2. Pharmaceutical excipients manufacturers must strengthen product quality management
(6) Pharmaceutical excipients manufacturers must be responsible for product quality and organize production in accordance with the Good Practice in the Manufacturing and Quality Control of Pharmaceutical Excipients. Pharmaceutical excipients manufacturers should improve the enterprise quality management system, strengthen audit to production and raw material supplies, control the quality of raw materials strictly, organize production according to the technology approved in product registration, standardize the establishment of product lot number and ensure the product quality is stable. For pharmaceutical excipients that have not obtained the approval number but have been used in history, pharmaceutical excipients manufacturers should organize production with the prescription process stipulated in the contract signed with pharmaceutical preparation enterprises.
(7) Pharmaceutical excipients manufacturers must conduct comprehensive inspections to each batch of products in accordance with the quality standard approved by registration or agreed with the pharmaceutical manufacturing enterprise in the contract, and the products cannot be stored or sold until they are qualified. Pharmaceutical excipients that have had national standards must be in line with the relevant requirements of the national standard at the same time. Before the product is released, all production documents and records, including inspection data, should be reviewed by the quality management department and meet the requirements, and shall not be released or leave the factory if they do not meet the requirements.
(8) Pharmaceutical excipients manufacturers should cooperate with pharmaceutical preparation production enterprises to carry out supplier audit. If there is any change in the production process, source of raw materials that may affect the quality of pharmaceutical excipients, pharmaceutical excipients manufacturers should take the initiative to carry out corresponding assessment, notify the pharmaceutical preparation production enterprise and report to the provincial drug regulatory authority for record.
3. Improve the access threshold and be strict with management of pharmaceutical excipients permit
(9) Improve the requirements to the amplification documents of drug registration. Pharmaceutical preparation enterprises to declare the registration of drugs should submit the types, suppliers, quality standards, supplier audit reports and other information of the pharmaceutical excipients used; for supplementary application for the change of types of pharmaceutical excipients, pharmaceutical preparation enterprises should conduct corresponding study and submit the study documents and supplier audit report, and cannot use it until the national bureau approves; and for application for change just in suppliers but not the type of pharmaceutical excipients, pharmaceutical preparation enterprises should submit the corresponding study documents and supplier audit report, and cannot use it until they have report the provincial drug regulatory authority for record.
(10) Implement classified management to pharmaceutical excipitents. Permission management shall be carried out to new pharmaceutical excipients and pharmaceutical excipients with higher safety risks. That is, pharmaceutical excipients should obtain the Drug Production License and the variety must obtain a registration permit. Recording management to other excipients should be conducted records management, that is, enterprise and its product records. The variety catalog implementing permission management shall be developed by the national bureau and published in batches. For pharmaceutical excipients implementing permission management, the production enterprise should submit relevant materials in accordance with Requirements of Application Materials for Registration of Pharmaceutical Excipients; and the pharmaceutical excipients shall be registered after the provincial regulatory department carries out production site inspection and dynamic sampling inspection according to the requirements of the Good Practice in the Manufacturing and Quality Control of Pharmaceutical Excipients, and the national bureau confirms that the technology examination is passed. The technology examination conducted by the national bureau for application for registration of excipients should be related to the corresponding pharmaceutical preparations.
For pharmaceutical excipients implementing record management, the production enterprise should submit relevant materials and report to the provincial drug regulatory authority for record. The provincial drug regulatory department can carry out on-site and sampling inspections as needed. Pharmaceutical excipients manufacturers should promptly update the record information.
(11) Complete and improve the pharmaceutical excipients standards. The national bureau shall organize the State Pharmacopoeia Commission to speed up the development and revision of pharmaceutical excipients quality standard, release national standards for pharmaceutical excipients, and organize to develop pharmaceutical excipients recommendation standards. Drug supervision departments at all levels shall carry out supervision, inspection and license record according to national standards.
4. Focus on the construction of basic data and establish an integrity management mechanism
(12) Establish a pharmaceutical excipients database. Pharmaceutical preparation enterprises should fill in and report the information of pharmaceutical excipients used in the products according to the pharmaceutical excipients use situation approved by the drug regulatory department, notify and assist with the pharmaceutical production enterprises to fill in and report the pharmaceutical excipients’ production information, and report it to the provincial drug regulatory department they are in respectively. Then the national and provincial bureaus aggregate relevant information and establish a pharmaceutical excipients database to comprehensively master the dynamic production and using information of pharmaceutical excipients.
(13) The national bureau and all provincial drug regulatory authorities should establish a pharmaceutical excipients production enterprise credit file and open the inspection and sampling inspection results to pharmaceutical excipients manufacturers for pharmaceutical preparation manufacturers’ reference when selecting pharmaceutical excipients.
(14) Encourage and support industry associations, third-party agencies and the public to participate in supervision and management, report illegal acts and jointly safeguard the quality of drugs and pharmaceutical excipients. Relevant industry associations should strengthen industry self-disciplines, promote the construction of the industry integrity, promote the classification management, guide and standardize all pharmaceutical preparation manufacturers and pharmaceutical excipients manufacturers to be honest, abide by laws, and operate according to law.
5. All levels of drug regulatory departments must strengthen supervision throughout the production and use of pharmaceutical excipients
(15) Local drug regulatory authorities at all levels should implement the regulatory responsibilities and strengthen the daily supervision to the pharmaceutical preparation manufacturers in their respective administration region. They should focus on checking whether the pharmaceutical preparation manufacturer has produced in accordance with the approved standards; whether has audited to the pharmaceutical excipients manufacturer according to the requirements of supplier audit; whether have inspected the pharmaceutical excipients used according to the corresponding quality standard; whether has changed the pharmaceutical excipients or supplier arbitrarily without approval, etc.
(16) Local drug regulatory authorities at all levels should carry out daily supervision to pharmaceutical enterprises in the administrative area and conduct extended inspection to pharmaceutical excipients manufacturers according to the problem found through supervision and inspection over the pharmaceutical preparation manufacturers. They should lay the key point in inspecting whether the production of pharmaceutical excipients is in line with the Good Practice in the Manufacturing and Quality Control of Pharmaceutical Excipients; whether the quality of raw materials is strictly controlled; whether the production is carried out in accordance with the approval process; and whether complete lot number management system and ex factory inspection system have been established. For pharmaceutical enterprises that do not accept the inspection, pharmaceutical preparation manufacturers shall not use the pharmaceutical excipients they produce.
(17) Drug regulatory departments at all levels should strengthen supervision, sampling inspection and evaluation sampling inspection to pharmaceutical excipients based on the supervision and inspection results; should implement fund guarantee, refine the scope and requirements of sampling inspection, and cover the pharmaceutical excipients production enterprises, drug production enterprises, preparation production medical institutions and other units using pharmaceutical excipients. Sampling inspection times and intensity should be enhanced to those enterprises and institutions where problems have ever found during previous supervision and inspection.
(18) If drug regulatory departments at all levels find any pharmaceutical preparation manufacturer or pharmaceutical excipients manufacturer infracts laws in the production or use of pharmaceutical excipients, they should investigate and punish the relevant enterprise and principals according to regulations in the Drug Administration Law of the People’s Republic of China, Special Provisions of the State Council on Strengthening Supervision and Management over Safety of Food and other Products; and punish those cases of gross violation strictly and heavily according to law; and even investigate for criminal responsibility in the cases constituting a crime.
Relevant Regulations on Strengthening Supervision and Management over Pharmaceutical Excipients (Exposure Draft)
1. Drafting Background
Pharmaceutical excipients refer to excipients and additives used in the manufacturing of pharmaceuticals and in the formulation of prescriptions. They are an important part of the pharmaceuticals and can directly affect the quality and safety of drugs. Seen from the reason for the recent event of drug capsules with excessive chrome, some pharmaceutical capsule manufacturers takes the inferior as the superior or produce capsules with industrial gelatin instead of pharmaceutical gelatin; some pharmaceutical manufacturing enterprises violate the Good Practice in the Manufacturing and Quality Control of Pharmaceutical Excipients, use unqualified capsules to produce inferior drugs and lead to serious results, which also reflects that there are some prominent problems in the production, use and supervision of pharmaceutical excipients in China: First, some pharmaceutical manufacturers’ subjective consciousness of responsibility is weak. The do not inspect the excipients purchased strictly, do not conduct supplier audit according to the requirements of GMP; shirk the responsibility to excipients manufacturing enterprise or supervision department if there is any pharmaceutical quality problem; or even put profit first, break the law, regulations and GMP and use unqualified excipients to produce pharmaceuticals; some pharmaceutical excipients manufacturers violate knowingly, they just put profit in the first place, take the inferior as the superior and pass industrial raw materials off as pharmaceutical excipients, never consider the hazards brought by the use of unqualified excipients to the public health. Second, due to inadequate legal basis, underdeveloped information technologies and other reasons, supervision departments at all levels cannot learn about the dynamic situation of pharmaceutical excipients manufacturers in their production of excipients, and compared with drugs, no matter the inspection frequency or attention to the management of pharmaceutical excipient manufacturers is far not enough.
Therefore, for the prominent problems existing in the production and use management of pharmaceutical excipients currently, it is necessary to combine China’s national conditions and introduce regulations on strengthening management over pharmaceutical excipients and further improve intensity of supervision and management over pharmaceutical excipients through implementing information registration, associated review, strengthening responsibility, extending inspection, intensifying punishment and other measures.
2. Core ideas of the Regulations and measures to be taken
In the basic ideas of “Based on the Current, Focus on Long Term, Plug Loopholes, Strengthen Supervision”, the following several measures would be taken to further strengthen the management over the production and use of pharmaceutical excipients: the first is through further implementing the responsibilities of pharmaceutical production enterprises to urge them consciously fulfill their audit and management to the pharmaceutical excipient manufacturers and their products; the second is through further implementing the responsibilities of the supervision department to realize extended supervision to pharmaceutical excipients manufacturers; the third is through implementing GMP to carry out classified management and associated review with pharmaceutical preparations, so as to improve the access threshold of pharmaceutical excipients; and the fourth is through strengthening striking intensity to awe behaviors infracting laws and guide pharmaceutical preparation production enterprises and pharmaceutical excipients manufacturers to standardize their production and use.
(1) Clarify corporate responsibilities and implement the subject responsibilities
The Regulations clearly put forward that pharmaceutical preparation manufacturers are the person in charge of the quality of pharmaceuticals. It is required that pharmaceutical preparation production enterprises must control the quality of the excipients used strictly. The purchased pharmaceutical excipients must be strictly inspected according to relevant standards and approved qualified before being used in the production of pharmaceuticals. The Regulations also stress that pharmaceutical preparation manufacturers must produce pharmaceuticals according to the prescribed prescription process; and should conduct study in accordance with relevant regulations and fulfill the change procedures if there is any change. It should be said that the Regulations are conducive to promoting pharmaceutical preparation manufacturers to strengthen the sense of responsibility and practically assume the responsibility of product quality.
(2) Implement regulatory responsibility and strengthen supervision over the whole process
The main regulatory target of drug regulatory authorities in the past is the pharmaceutical production enterprise, and few pharmaceutical excipients production enterprises are involved in. There is certain dead zone in supervision in this area, so some security risks are left. The Regulations clarify the regulatory responsibilities of pharmaceutical supervision departments at all levels to pharmaceutical preparation manufacturers and pharmaceutical excipients production enterprises. It is required that all levels of pharmaceutical regulatory departments should take pharmaceutical production enterprises as the key regulatory targets and can conduct extended inspection to the excipients production enterprises based on the inspection results to pharmaceutical preparation manufacturers, include the production and use of pharmaceutical excipients in the scope of supervision and realize whole process of supervision to the pharmaceutical production and supply chain.
(3) Improve the access threshold and clarify the supervision model
As part of the pharmaceutical preparation, the quality of pharmaceutical excipients will directly affect the safety of drugs. The Regulations manage the pharmaceutical excipients by referring to management to active ingredients and intensify the supervision: first, require pharmaceutical excipients production enterprise to organize production in accordance with the requirements of the Good Practice in the Manufacturing and Quality Control of Pharmaceutical Excipients and improve the production enterprise access threshold; second, carry out classified management to excipients according to the degree of risks, implement a strict access system to excipients with high risks and their production enterprises, and enhance risk control; third, require the new drug used excipients must undergo associated review with pharmaceutical preparations, stress pharmaceutical manufacturing enterprises’ inspection audit responsibilities to new excipients and be further stricter to the fixed source and technical requirements of pharmaceutical used pharmaceutical excipients; and fourth, take improving and completing the pharmaceutical excipients standard as the focus of the current work, which will facilitate to the further improvement of pharmaceutical preparation quality.
(4) Fully grasp the situation of excipients and reduce the dead zone of supervision
The Regulations clearly require that pharmaceutical preparation production enterprises and pharmaceutical production enterprises should fill in and report the relevant information of production and excipients used and the national bureau shall establish a pharmaceutical excipients database according to the information filled by enterprises. Through the construction of database, we can be clear about the types of excipients used in the pharmaceutical production of China and lay a foundation for promoting the classified management of pharmaceutical excipients; and more importantly, all pharmaceutical excipients production enterprises can be included in the visual field of supervision, thus reducing the dead zone of supervision.
(5) Take strict punishment standards, intensify deterrent against illegal acts
The Regulations clearly point out that illegal acts should be handled in accordance with the Drug Administration Law and Special Provisions of the State Council on Strengthening the Supervision and Management of Safety of Food and Other Products, which means further stricter punishment to illegal behaviors. In the mean time, establishing bad information record, opening illegal activities, limiting customer use and other measures will also be taken to intensify deterrent to relevant enterprises.
3. Instructions on the Implementation of the Regulations
(1) About the implementation date of the Regulations. The Regulations have put forward some new requirements to pharmaceutical production enterprises and pharmaceutical excipients manufacturers on strengthening quality guarantee, leave certain time for the enterprise to make rectification, so as to perform the Regulations better. It is planned to set the implementation date of the Regulations on October 1, 2012, by when the production enterprise must organize production in accordance with relevant regulations, otherwise, they shall not be allowed to carry out production or marketing.
(2) About the implementation date of Good Practice in the Manufacturing and Quality Control of Pharmaceutical Excipients. In order to ensure the pharmaceutical excipients production enterprises have sufficient time to carry out the transformation of production equipment, plant conditions etc. to meet the requirements of GMP, the specific implementation time will be notified further.
(3) About the pharmaceutical excipients database and related supporting documents. For the filling and report of pharmaceutical excipients production and use information and the construction of the database, we shall notify in another document. For the registration of pharmaceutical excipients and requirements of the filing materials, we shall develop separately.
Information Source: China National Food and Drug Administration http://www.sfda.gov.cn/WS01/CL0778/72296.html
2.8 Notice on the publication of Technical Guidance for Clinical Trial Data Management
Clinical trial data are the most important evidence to support drug licensing. Well-regulated data management is the key to ensure the quality of clinical trials. China's Provisions for Drug Registration and Good Clinical Practice (GCP), and other relevant regulations all have corresponding principle requirements to this. Corresponding detailed technical guidance is also needed in the technical operation level.
In order to strengthen the standardized management of clinical trial data in China, ensure the quality of clinical data of drug research and make the evaluation of drugs based on scientific evidence, our Center has drafted the Technical Guidance for Clinical Trial Data Management since 2009 by referring the relevant international norms and technical guidelines and combining the current clinical trial data management reality, and the final draft has been formed through repeated discussion on expert meetings. Hope insiders can put forward your feedback and suggestions to facilitate the Center to complete further improvement work.
The Center for Drug Evaluation will further detail and formulate the specific technical requirements on data quality assessment and data submission in clinical trial declaration materials. All research and development units, drug clinical trial institutions, clinical trial relevant personnel and related parties please pay close attention to that!
Technical Guidance Feedback Contact: Wang Jun
Information Source: Center for Drug Evaluation of China National Food and Drug Administration