The CFDA is stepping up its game—after self-inspections, it will launch rigorous, no-holds-barred spot checks!

The General Administration’s Office is publicly soliciting comments on the “Notice on Conducting Verification of Pharmaceutical Manufacturing Processes (Draft for Comments).”

　　To further standardize the management of pharmaceutical manufacturing processes and ensure public drug safety, the State Administration for Market Regulation (SAMR) has drafted the “Notice on Conducting Verification of Pharmaceutical Manufacturing Processes (Draft for Public Comments).” We are now soliciting public comments. Please submit any proposed revisions via email to the Drug and Cosmetic Registration Management Division of the SAMR before September 10, 2016.
　　Contact: Xue Yanjiu
　　Email: yhzcszhc@cfda.gov.cn
　　Attachment: Notice on Conducting Verification of Pharmaceutical Manufacturing Processes (Draft for Comments)
　　General Office of the State Administration for Market Regulation of Food and Drugs
　　August 9, 2016 – Attachment: Notice on Conducting Verification of Pharmaceutical Manufacturing Processes (Draft for Comments)
　　The pharmaceutical manufacturing process is the set of procedures and methods used to consistently and reliably produce qualified pharmaceutical products. Organizing production in accordance with the manufacturing processes approved by regulatory authorities is a prerequisite for ensuring drug quality. To strengthen the management of pharmaceutical manufacturing processes, the former State Food and Drug Administration launched, in August 2007, an inspection and verification effort focused on the manufacturing processes and formulations of injectable drugs. The provincial bureaus reviewed the relevant documentation—including manufacturing processes—submitted and registered by enterprises, and preliminarily established archives of data on injectable drug manufacturing processes. The "Measures for Drug Registration Management," revised and implemented in October 2007, stipulate that a site inspection of the manufacturing facility must be conducted prior to the approval of a drug for market release, thereby ensuring the feasibility of the manufacturing processes as determined by the technical review authorities. Since then, the actual manufacturing processes of the vast majority of drugs approved for market release have been consistent with those originally approved. In recent years, during supervision and inspection activities, the food and drug regulatory authorities have found that some drug products approved before 2007 are still not being manufactured according to their approved processes, and that changes to manufacturing processes have not been studied and reported in compliance with regulations. For this reason, the Administration has decided to launch a comprehensive verification effort targeting pharmaceutical manufacturing processes. The relevant details are hereby announced as follows:
　　1. Pharmaceutical manufacturers bear the primary responsibility for the quality and safety of pharmaceutical products and must organize production strictly in accordance with the manufacturing processes approved by the food and drug regulatory authorities. If a pharmaceutical manufacturer intends to modify an already approved manufacturing process, it must conduct thorough research and validation and submit a supplementary drug registration application in compliance with the relevant provisions of the “Measures for Drug Registration Management.”
　　II. Starting from the date of issuance of this notice, pharmaceutical manufacturers shall conduct self-inspections of the manufacturing processes (for traditional Chinese medicine, the preparation method—same hereinafter) for each drug approved for marketing, to identify and eliminate potential quality and safety hazards.
　　III. The self-inspection shall cover whether the actual manufacturing process of the drug is consistent with the manufacturing process approved by the food and drug regulatory authorities. The manufacturing processes approved by the food and drug regulatory authorities include both the manufacturing processes approved when the drug production application was initially reviewed and those approved when related supplementary applications were reviewed.
　　4. Pharmaceutical manufacturers shall complete their self-inspections by October 1, 2016, and report the results of their self-inspections to the provincial-level food and drug administration authority in their respective localities. The provincial-level food and drug administration authorities shall compile the results of the enterprises’ self-inspections, fill out the Summary Table of Self-Inspection Results (Attachment 1), and submit it to the State Administration for Food and Drug Supervision by November 1, 2016.
　　V. Based on the results of their self-inspections, pharmaceutical manufacturers shall take the following measures accordingly:
　　(1) If the actual production process is consistent with the approved production process and can ensure the quality of the drug, the pharmaceutical manufacturer shall file the self-inspection report together with relevant documentation such as the drug production process, for use as reference materials by regulatory authorities during routine supervision and on-site inspections.
　　(2) If the actual manufacturing process differs from the approved manufacturing process, the relevant pharmaceutical manufacturer shall conduct thorough research and validation in accordance with the requirements set forth in the “Good Manufacturing Practice for Pharmaceuticals,” the “Administrative Measures for Drug Registration,” as well as relevant technical guidelines such as “Technical Guidance Principles for Post-Marketing Changes to Traditional Chinese Medicines (I),” “Technical Guidance Principles for Post-Marketing Changes to Chemical Drugs (I),” and “Technical Guidance Principles for the Management of Process Changes in Biopharmaceutical Production.”
　　After verification through research, if changes to the manufacturing process do not affect the quality of the drug, the pharmaceutical manufacturer shall submit a supplementary application in accordance with Item 18 of Annex 4 to the “Measures for Drug Registration Management.” The requirements for the submitted documentation are set forth in Annex 2. Within 5 days after receipt of the application, the provincial food and drug regulatory authority shall forward the application materials to the Center for Drug Evaluation under the National Medical Products Administration (hereinafter referred to as the “Drug Evaluation Center”). The Drug Evaluation Center will conduct a technical review based on the “Measures for Drug Registration Management” and may, if necessary, request the applicant to provide additional information; the time required for such requests shall not be counted toward the deadline for the technical review. The National Medical Products Administration will make its approval decision in accordance with the “Measures for Drug Registration Management.”
　　After research and verification, if changes in the manufacturing process are found to affect the quality of a drug, the enterprise shall immediately halt production. Pharmaceutical manufacturers shall submit a supplementary application for “Changes to Manufacturing Processes That Affect Drug Quality” in accordance with Item 7 of Annex 4 to the Measures for Drug Registration Management. Within 5 days of receipt of the application, the provincial food and drug regulatory authority shall forward the submitted documentation to the Center for Drug Evaluation. The Center for Drug Evaluation shall assign dedicated review personnel and establish a separate review channel, completing the technical review within 30 days of receiving the application materials. If necessary, the Center may request the applicant to provide additional information; such additional time shall not be counted toward the technical review deadline. The National Medical Products Administration shall complete the administrative approval within 5 days. Only after the supplementary application has been approved may the pharmaceutical manufacturer resume production.
　　Drug manufacturers shall complete the research and validation of manufacturing processes for currently marketed products, as well as submit supplementary applications and perform other related tasks, by June 30, 2017. For other products not yet in production, such work shall be completed by December 31, 2017. Those who fail to meet these deadlines shall cease production.
　　VI. Starting November 1, 2016, the National Medical Products Administration will organize experts to conduct unannounced inspections of pharmaceutical manufacturers. If the inspection reveals that the actual production process differs from the production process approved by the medical products regulatory authorities, the drugs produced in such cases shall be treated as counterfeit drugs in accordance with the relevant provisions of Article 48, Paragraph 2 of the Drug Administration Law of the People’s Republic of China. The drug regulatory authorities will impose penalties on the pharmaceutical manufacturers involved in accordance with the relevant provisions of Article 74 of the Drug Administration Law of the People’s Republic of China and will publicly disclose the names of the legal representatives and other persons bearing responsibility at these companies.
　　7. If a change in the manufacturing process has occurred that affected the quality of the drug, but the manufacturer can ensure that the product remains safe and effective, and the situation meets the following criteria, production may be temporarily suspended—but the manufacturer must submit the relevant supplementary application as required by this announcement.
　　(1) The relevant products had already undergone manufacturing process changes that affected drug quality prior to the 2007 revision and implementation of the “Drug Registration Management Measures,” but have since been in normal production, with a stable manufacturing process and no safety or efficacy issues detected.
　　(2) The relevant product undergoes a manufacturing process change that affects the quality of the drug, and the revised manufacturing process represents technological advancement or innovation.
　　8. This notice shall take effect from the date of its issuance; imported drugs shall be governed by its provisions.
　　Hereby announced.
　　Attachment: 1. Summary Table of Self-Inspection of Pharmaceutical Production Processes
　　2. Requirements for Submission of Documentation (Process Changes That Do Not Affect Drug Quality)
　　3. Appendix 2: Requirements for Submission Materials—Table of Pharmaceutical Production Process Change Information (Production Process Changes That Do Not Affect Drug Quality)

　　I. Content of the Application Materials
　　(1) Application Form
　　Corresponding registration—(supplementary)—application forms are provided separately for domestically produced drugs, imported drugs, and pharmaceutical products from Hong Kong, Macao, and Taiwan.
　　(2) Photocopies of the drug approval documents and their attachments
　　Including the drug registration approval and its attachments, the drug registration certificate, the “Supplementary Drug Application Approval” already obtained and its attachments, the “Approval Opinion Notification,” publicly available documents related to filing records, and copies of the acceptance notices/acknowledgment forms for supplementary applications currently under review.
　　For imported pharmaceuticals, a certificate issued by the drug regulatory authority of the country or region of manufacture permitting the change in pharmaceutical manufacturing processes, along with its Chinese translation, shall be submitted.
　　(3) Supporting Documents
　　Including a copy of the Pharmaceutical Production License and its amendment record page, a copy of the Business License, and a copy of the Pharmaceutical GMP Certificate.
　　(4) Pharmaceutical Research Data
　　Including pharmaceutical formulations, drug manufacturing processes, and documentation for change assessments.
　　The drug prescription shall include the active ingredients or Chinese medicinal herb components, as well as the types and quantities of excipients. It should specify the theoretical prescription amounts based on 1,000 dosage units, the commercial production batch size, and any instances of actual over- or under-dosing (with justification). Excipients include colorants, preservatives, flavoring agents, taste-masking agents, coating agents (whose specifications and models must be clearly indicated), empty capsules, pH adjusters, and solvents removed during the formulation process (such as ethanol, excluding purified water). Except for pH adjusters and specific excipients in traditional Chinese medicine prescriptions that must have their dosages adjusted to meet the target tablet weight specifications, all other excipients shall have their exact prescription amounts or validated prescription ranges clearly stated.
　　The production process should include a process flow diagram and a description of the process steps. If the originally submitted registration application’s process is overly simplistic or lacks clarity regarding key information, the missing key information must be fully supplemented in the filing and submission documents.
　　The process flow diagram should clearly indicate key information such as materials and batch sizes for feedstock, specific operational procedures for each process step, critical process parameters and monitoring during the production process, in-process quality control, names and models of major equipment, and cleanroom environment conditions.
　　The process description shall cover the entire production process, from material preparation to finished product packaging. The level of detail should be sufficient for technical personnel in this field to fully replicate the production process based on the declared manufacturing process and produce products that meet the specified standards. Each unit operation must be clearly defined, and the process should be described according to the sequence of unit operations, specifying the amounts or ratios of materials fed into the process, operational procedures, key process parameters and their ranges for each major step, types of primary equipment and materials used, sampling points during intermediate stages, and main quality control requirements (including the testing items and acceptance limits for intermediate products). Furthermore, the validated production scale and yield range must be indicated. If any special instruments, equipment, operating methods, inspection and testing methods, or other process control requirements are employed in the manufacturing process, they should be explicitly elaborated and explained.
　　The description of the active pharmaceutical ingredient (API) manufacturing process shall clearly specify the source, specifications, and standards of the starting materials, batch size, quantities/ratios/concentrations of materials used at each step (including starting materials, solvents, catalysts, gases, etc.), sequence and rate of material addition, temperature, pressure, vacuum level, duration, stirring speed, material and model of separation and purification columns, methods and number of purification steps, in-process control requirements for intermediates, and types of key equipment. For APIs originally approved using commercially available crude APIs or free acids/bases (excluding inorganic compounds or APIs already on the market) that are salted and purified in a single step, suppliers of the crude APIs or free acids/bases, as well as detailed production processes and process control documentation, shall be provided.
　　The extraction of traditional Chinese medicine should clearly specify the source of the medicinal materials (crude herbs or extracts), their standards, pre-processing methods and conditions, process parameters, extraction methods and conditions, types and amounts of solvents used, number of extraction cycles, extraction temperature and duration, methods and conditions for filtering the extract solution, methods and conditions for concentration, maximum allowable heating time during concentration, relative density of the concentrated solution, yield range of the concentrated solution or extract paste, storage conditions and shelf life of the concentrated solution, purification methods and conditions—including solvent concentrations, relative densities, measurement temperatures, stirring methods and conditions, material and model of separation and purification columns, refining methods and number of refining steps—as well as the drying method for the extract, upper temperature limit, maximum allowable heating time, vacuum level, and yield range.
　　The manufacturing process description for the formulation should clearly specify the handling methods for raw and excipient materials, particle size control, amounts (ratios) of ingredients added, sequence of ingredient addition, granulation method, mesh number/screen aperture size, stirring speed/frequency, mixing time, concentrations and amounts of solvents and binders used in formulation, drying method, drying temperature, drying duration, or other end-point control parameters, stirring or mixing method, rotational speed/frequency, mixing time, temperature, pH value, dissolution time, gas protection (if nitrogen purging is required, duration of nitrogen purging), types, model grades, specifications of filter media, filtration method, temperature and flow rate of the liquid pharmaceutical solution, parameter settings for the freeze-drying curve, sterilization method, type of sterilization cabinet, loading method, sterilization duration, set temperature, pressure, and F0 value, etc.
　　For studies requiring pharmacological, toxicological, or clinical research, the corresponding research activities shall be conducted in accordance with current drug registration requirements and procedures.
　　II. Submission of Application Materials
　　The applicant shall provide one complete set of the aforementioned application documents, organized in the order of the document item numbers. Each application document shall have a cover page and a unique identification number, and be bound separately. The cover page must bear the official seal of the applying entity.
　　The drug prescription and manufacturing process should be documented in Word-format electronic files, compressed into a single ZIP file, and named “Attachment: Last 9 Digits of Approval Code.” This electronic file must be submitted together with the application form and imported into the application form.
　　Attachment 3: Table of Changes in Pharmaceutical Production Processes
　　I. Production Process Changes That Do Not Affect Drug Quality
　　(1) Class I and Class II Changes to Traditional Chinese Medicine
　　1. Class I Changes: These changes do not alter the pharmaceutical substance’s fundamental composition, do not significantly affect the drug’s absorption or utilization, and do not lead to any noticeable changes in safety or efficacy. Examples include changes to the grinding process of drugs that do not contain volatile or thermally sensitive ingredients (provided the particle size remains essentially unchanged), as well as changes to concentration and drying processes or granulation processes (such as shortening the heating time or reducing the heating temperature). However, if the change involves adopting a special concentration and drying method—such as microwave drying—this would not be considered a Class I change.
　　2. Class II Changes: These changes affect the pharmaceutical substance basis or the absorption and utilization of the drug, but the impact is relatively minor. They include alterations to certain process parameters and process methods during manufacturing—for example, modifications to process operations involving heat temperature and heating time when dealing with drugs containing volatile or thermolabile components. A comparative study should be conducted in such cases. If the pharmaceutical substance remains largely unchanged, the change would be classified as a Class II change.
　　(2) Class I and Class II Changes to Chemical Drugs
　　1. Modify the manufacturing process of the active pharmaceutical ingredient:
　　Class I Change:
　　(1) Changing the source of reagents and starting materials;
　　(2) Enhance the quality standards for reagents, starting materials, and intermediates;
　　Class II Change:
　　(3) Changes to the quality standards of starting materials, solvents, reagents, and intermediates;
　　2. Modify the manufacturing process of the formulation:
　　Class I Change:
　　(1) Increase the quality control methods in the production process or strictly enforce control limits;
　　(2) Changes to the imprint on tablets, capsules, suppositories, or vaginal suppositories;
　　(3) Changes to the shape or size of conventional or enteric-coated tablets, capsules, suppositories, or vaginal suppositories; Class II change:
　　(4) Changing production equipment—including replacing one piece of equipment with another that has the same design and operating principles in the production of sterile preparations; replacing one piece of equipment with another that has different design and operating principles in the production of non-sterile preparations; or changing the type of mixing equipment used in the production of semi-solid preparations—from a high-speed shear mixer to a low-speed shear mixer, or vice versa. If the change involves sterile products, the alteration of production equipment must not compromise the product’s sterility assurance level.
　　(5) Changes to the formulation manufacturing process—including alterations to mixing time and mixing speed in the material blending step for oral solid dosage forms, as well as changes to mixing speed, mixing time, and cooling rate during the blending process for semi-solid dosage forms—also encompass modifications to the mixing process of aqueous and oily phases in semi-solid dosage forms. For sterile preparations, such changes include: ① for sterile preparations produced using a terminal sterilization process, elimination of the intermediate filtration step; ② modification of filtration parameters during the bacteriostatic filtration process (including flow rate, pressure, duration, or volume, while keeping the filter material and pore size unchanged). These types of changes should not result in fundamental alterations to the formulation manufacturing process nor cause significant changes to the key physicochemical properties and indicators of the product that are relevant to its in vivo absorption and therapeutic efficacy. Furthermore, any changes to the manufacturing process of sterile products must not compromise the level of sterility assurance provided by the product.
　　(6) Changes in the shape or size of sustained-release or controlled-release tablets, capsules, suppositories, or vaginal suppositories—including alterations in the shape of tablets, capsules, suppositories, or vaginal suppositories (e.g., from round tablets to irregular shapes such as rhombus-shaped tablets)—while the formulation composition remains unchanged. For sustained-release or controlled-release formulations, there is a certain relationship between the formulation’s physical shape and its drug-release behavior. Therefore, changes in external appearance may, in some cases, affect the drug-release profile; thus, it is essential to conduct a thorough comparative study of the drug-release behavior before and after such changes.
　　(3) Class III Changes to Biological Products
　　1. Strain and Cell Bank
　　Work Seed Bank
　　2. Production process: Buffer solution
　　3. Prepare the thinner (except for the new thinner).
　　(4) Other process changes that have been verified and evaluated through research and confirmed not to affect the safety, efficacy, or controllability of quality of the drug.
　　II. Process Changes Affecting Drug Quality
　　(1) Class III Changes to Traditional Chinese Medicine
　　Such changes may lead to significant alterations in the pharmaceutical substance’s foundation or have a marked impact on the absorption and utilization of the drug—for example, changes in the process route, including shifts between combined extraction and separate extraction of herbal materials, as well as changes in the type of extraction solvent; changes in process methods, such as switching from alcohol precipitation to clarification agent treatment for purification, or from vacuum drying to special drying methods like microwave drying, which can significantly affect the drug’s absorption and utilization; and changes in process parameters, such as variations in the alcohol concentration used in alcohol precipitation or changes in the number of extraction cycles.
　　(2) Class III Changes to Chemical Drugs
　　1. Change the manufacturing process of the active pharmaceutical ingredient.
　　(1) This primarily includes modifying reaction conditions, altering one or several steps of a reaction, or even the entire synthetic route—as well as process modifications that use an intermediate from the original synthetic route as the starting material.
　　2. Modify the manufacturing process of the formulation
　　(1) If significant changes occur in the formulation production process or manufacturing technology—for example, a change from wet granulation to dry granulation, or vice versa, in oral solid dosage forms; or a change in the drying method during the production process—from oven drying to fluid-bed drying, or vice versa—such changes shall be subject to appropriate evaluation and approval.
　　(2) Changes to the manufacturing process of a dosage form may affect its controlled-release or sustained-release characteristics, may impact the in vivo absorption of the dosage form (such as inhalers and sprays), or may influence other characteristics of the dosage form (such as drug particle size).
　　(3) Changes to the sterile manufacturing process that may affect the level of sterility assurance for pharmaceutical products include: ① Changes to the product sterilization process—from a sterile filtration sterilization process to a terminal sterilization process; for example, switching from a survival probability-based terminal sterilization method to an overkill method; or changing from one sterilization method (such as dry heat sterilization or radiation sterilization) to another. ② Replacing the original sterilization equipment with sterilization equipment based on a different operating principle. ③ Changing the loading capacity and loading method of the sterilization equipment in a way that exceeds the scope originally validated. ④ Changing the type or pore size of the filter media used in the sterile filtration process. ⑤ Replacing the original lyophilization equipment with lyophilization equipment of a different capacity, or adding lyophilization equipment of a different capacity, where the new lyophilization equipment has altered operational parameters and overall production times compared to the original equipment.
　　(3) Class I and Class II Changes to Biological Products
　　1. Main raw and auxiliary materials
　　Class I Change:
　　(1) Raw materials or starting raw materials
　　Class II Change
　　(2) Culture medium or its main components
　　(3) Source of key raw and auxiliary materials
　　(4) Bovine serum and trypsin, etc.
　　2. Strain and Virus Bank and Cell Bank
　　Class I Change: Original Seed Bank
　　Class II Change: Master Seed Bank
　　3. Production Process
　　Class I Change
　　(1) Change in virus inactivation method
　　Class II Change
　　(2) Reduce or add process steps
　　(3) Change in culture time
　　(4) Change in separation and purification methods
　　(5) Parameter Modification
　　(6) Changes in production scale
　　4. Preparation
　　Class II Change
　　(1) Preservative
　　(2) Adjuvants (excluding new adjuvants)
　　(3) Excipients
　　(4) Stabilizer
　　5. Production equipment
　　Class I Change:
　　(1) Major production equipment (such as sterilization equipment, freeze-drying equipment, filling and dispensing equipment, centrifuges used in the production of blood products, and filter presses)
　　Class II Change:
　　(2) General production equipment
　　(4) Other process changes that, after research, verification, and evaluation, are found to affect or potentially affect the safety, efficacy, and controllability of quality of the drug.