In accordance with Article 310 of the Good Manufacturing Practice for Pharmaceuticals (Revised in 2010), the Appendix to the Drugs for Clinical Trial Use (Trial) is hereby issued as a supporting document for the Good Manufacturing Practice for Pharmaceuticals (Revised in 2010), which will be implemented on July 1, 2022.
This is hereby announced.
Appendix to "Clinical Trial Drugs (Trial)"
Chapter 1 Scope
Article 1 This appendix applies to the preparation of clinical trial drugs (including trial drugs and placebos). When marketed drugs are used as control drugs or trial drugs, changes in packaging and labels are also applicable to this appendix.
Chapter 2 Principles
Article 2 The preparation and quality control of clinical trial drugs shall comply with the relevant basic principles of the "Good Manufacturing Practice for Pharmaceuticals" and data reliability requirements, minimize the risks of contamination, cross-contamination, confusion and errors in the preparation process, ensure the quality of clinical trial drugs, and protect the safety of subjects.
Article 3 The preparation and quality control of drugs for clinical trials have the following particularities:
(I) In the early clinical trial stage of new drugs, mature preparation processes are usually not yet formed, and the conditions for full confirmation and verification are not yet available;
(II) The understanding of the characteristics, potential effects and toxicity of new drugs is not sufficient, and the identification of key quality attributes of test drugs and the research on quality control indicators and methods need to be further deepened;
(III) The preparation process of drugs for clinical trials may involve different activities such as preparation of test drugs, preparation of placebos, change of packaging labels of control drugs and test drugs. The requirements of randomization and blinding also increase the risk of confusion and errors in the preparation process of drugs for clinical trials.
Based on the above particularities, as well as the characteristics of different research and development stages and the requirements of clinical trial design, drugs for clinical trials should be controlled accordingly.
Article 4 Under the premise of ensuring the safety of subjects and not affecting the quality of clinical trials, the quality risk management strategy of drugs for clinical trials can be adjusted accordingly according to the research and development rules. Drug research and development urgently needed for the prevention and control of public health emergencies should be prepared according to the principles of safety, reliability and scientific feasibility based on emergency needs.
Chapter III Quality Management
Article 5 The clinical trial drug preparation unit shall establish a quality management system based on risk. The system shall cover the necessary factors affecting the quality of clinical trial drugs, and establish a documentation system to ensure the effective operation of the quality management system.
Article 6 The applicant shall be responsible for the quality of clinical trial drugs. If the clinical trial drugs are entrusted for preparation, the applicant shall audit and confirm the quality management system of the entrusted unit, and sign a commission agreement and a quality agreement to clearly define the responsibilities of all parties to ensure that the clinical trial drugs meet the intended use and quality requirements.
Article 7 When changes occur in the preparation site, prescription process, batch size, quality standards, key raw materials, auxiliary materials and packaging materials of clinical trial drugs, and when technology transfer is carried out, changes that may affect the safety of clinical trial drugs shall be evaluated, and changes and evaluations shall be recorded to ensure that related activities can be traced. Deviations from the preparation process, quality standards, and other deviations that may affect the quality of clinical trial drugs shall be investigated and evaluated, and corresponding records shall be kept.
Chapter IV Personnel
Article 8 Personnel involved in the preparation of clinical trial drugs shall have appropriate qualifications and training, and have the ability to perform corresponding duties. Personnel responsible for preparation and quality management shall not hold concurrent posts.
Article 9 The applicant shall be assigned a person responsible for release, who shall be responsible for the release of drugs for clinical trials.
(I) Qualifications:
The person responsible for release shall have at least a bachelor's degree in pharmacy or related majors (or an intermediate professional and technical title or a licensed pharmacist qualification), and at least five years of practical experience in drug research and development or drug production quality management, including at least one year of drug quality management experience. The person responsible for release shall have the necessary professional theoretical knowledge and undergo training related to release.
(II) Main responsibilities:
The person responsible for release shall be responsible for the release of drugs for clinical trials, ensure that the preparation of each batch of drugs for clinical trials released complies with relevant regulations and quality standards, and issue a release review record.
Chapter V Plants, Facilities and Equipment
Article 10 The plants, facilities and equipment for the preparation of drugs for clinical trials shall comply with the basic requirements of the Good Manufacturing Practice for Pharmaceuticals and related appendices. The scope of confirmation of plants, facilities and equipment shall be determined based on risk assessment.
Article 11 The feasibility of co-production of clinical trial drugs with other clinical trial drugs or marketed drugs shall be evaluated based on the toxicity, pharmacological activity and potential allergenicity of the clinical trial drugs, combined with the applicable population, route of administration, risk of subjects and other factors. When co-production is carried out, appropriate control measures (such as phased production methods, etc.) shall be taken to minimize the risk of contamination and cross-contamination during the preparation process.
In the early clinical trial stage, if the understanding of the toxicity and pharmacological activity of the test drug is insufficient, the preparation of the test drug should use dedicated or independent facilities and equipment.
Chapter 6 Material Management
Article 12 The quality standards for raw materials, excipients and packaging materials shall be established, and the level of detail of the content shall be consistent with the stage of drug research and development, and shall be re-evaluated and updated in a timely manner.
The preparation unit shall conduct corresponding inspections and tests on the raw materials, excipients and packaging materials used in the preparation of clinical trial drugs, and they may be released for use only after they are qualified. Excipients and packaging materials used in early clinical trial drugs may be released based on the inspection report of the supplier, but at least they should be identified or checked to ensure that they are correct. If the drug used in clinical trials is a sterile drug, the excipients used in its preparation and the packaging materials in direct contact with the drug shall also be tested for safety aspects such as microorganisms and bacterial endotoxins.
Article 13 Operating procedures shall be established to manage the retention of material samples. Samples shall be retained for each batch of raw and excipients used in the preparation of clinical trial drugs and packaging materials in direct contact with the drug. The number of retained samples shall at least meet the needs of identification. The retention time shall not be shorter than the retention time of the corresponding clinical trial drugs (except for raw and excipients with poor stability). Packaging materials in direct contact with drugs (such as infusion bottles) do not need to be retained separately if the finished product has been retained.
Chapter 7 Document Management
Article 14 The prescription process, operating procedures, quality standards and inspection operating procedures for the preparation of clinical trial drugs, as well as the raw and excipients and packaging materials, intermediate products and finished products used, shall be formulated. The content of the document shall reflect the product knowledge that has been mastered as comprehensively as possible, and at least cover the key quality attributes and key process parameters of the known or potential clinical trial drugs at the current research and development stage.
At different stages of drug development, the prescription process, quality standards, operating procedures and other documents should be evaluated and updated when necessary. The updated documents should take into account the latest acquired data, applicable technical requirements and regulatory requirements, and should be able to trace the revision history of the documents.
Article 15 During the preparation of drugs for clinical trials, if the prescription process is adjusted or changed, the different prescription processes should be uniquely identified and numbered, and the corresponding preparation process can be traced back.
Article 16 The applicant shall formulate procedures to clarify the requirements for the generation, confidentiality, distribution, processing and storage of drug codes in the packaging of drugs for clinical trials. If it involves blind trials, emergency unblinding procedures and documents shall also be formulated.
Article 17 The applicant shall establish a file of drugs for clinical trials and continuously update it with the progress of drug development to ensure traceability.
(I) The archives shall at least include the following:
1. An overview of the research status of the drug used in the clinical trial, including chemical structure, physicochemical properties, biological properties, pharmacological and toxicological properties, proposed clinical indications and characteristics of the drug population;
2. Manufacturer information of raw materials and packaging materials in direct contact with the drug;
3. Quality standards and analytical methods of raw materials, packaging materials in direct contact with the drug, intermediates, stock solutions, semi-finished products and finished products;
4. Prescription process;
5. Intermediate control methods;
6. Labels of previous finished products;
7. Previous clinical trial plans and drug codes (if applicable);
8. Quality agreements related to the trustee (if applicable);
9. Stability data;
10. Storage and transportation conditions;
11. Batch production records, batch packaging records and inspection reports;
12. Instructions for control drugs (if applicable);
13. If the drug used in clinical trials is a traditional Chinese medicine preparation, it is also necessary to include the origin of the medicinal materials, medicinal parts, origin, harvest period, preparation methods of medicinal pieces, quality standards of medicinal materials and medicinal pieces, etc.;
14. If the drug used in clinical trials is a biological product, it shall include relevant information on the bacteria (virus) species and cell lines/strains used for preparation and verification.
(II) The archives shall serve as the basis for the evaluation of the release of clinical trial drugs.
(III) When the clinical trial drugs are processed in different preparation steps at different sites, the applicant shall summarize and preserve the above-mentioned relevant documents or their certified copies of all sites in the archives.
Article 18 The archives of clinical trial drugs shall be kept for at least 2 years after the drug is withdrawn from the market. If the drug is not approved for marketing, it shall be kept for 2 years after the termination of the clinical trial or the termination of the registration application.
Chapter 8 Preparation Management
Section 1 Preparation
Article 19 Measures shall be taken to prevent contamination, cross-contamination, confusion and errors in the preparation of clinical trial drugs as much as possible. Cleaning operating procedures shall be formulated to clarify the cleaning methods, and necessary confirmation or verification shall be carried out to confirm the effectiveness of cleaning.
Article 20 During process development, key quality attributes shall be gradually identified, key process parameters shall be determined, and appropriate intermediate control shall be performed on the preparation process. With the deepening of the understanding of quality attributes and the accumulation of preparation process data, process procedures shall be formulated to clarify process parameters and control ranges.
The preparation management of drugs for clinical trials shall be continuously improved, optimized and enhanced to ensure that the drugs for clinical trials meet the quality requirements.
Article 21 The key preparation process of drugs for clinical trials shall be evaluated and demonstrated in accordance with relevant technical requirements. In the early clinical trial stage, if the preparation process of the test drug cannot be fully determined, necessary monitoring shall be carried out to ensure that it meets the quality requirements and ensure the safety of the subjects.
The scope and extent of process validation during the confirmatory clinical trial stage shall be determined based on risk assessment. If the drug for clinical trial is a sterile drug, the validation of the sterilization process or aseptic production process shall follow the current relevant technical requirements to ensure that its sterility assurance level meets the requirements; if the drug for clinical trial is a biological product, it shall also ensure the inactivation/removal effect of pathogens such as viruses or other exogenous factors to ensure the safety of the subjects.
Article 22 The preparation of drugs for clinical trials shall ensure the uniformity of the quality of the same batch of products. After determining the prescription process, the quality of the drugs used in clinical trials shall be ensured to be consistent between batches.
Article 23 When the drugs used in clinical trials are prepared at different sites, the comparability study of the drug quality between the different sites shall be carried out.
Section 2 Control Drugs
Article 24 When using marketed drugs for control trials, the quality of the control drugs shall be ensured. In blind trials, when it is necessary to change the packaging, labeling, etc. of the control drugs, it shall be fully evaluated and there shall be data (such as stability, dissolution, etc.) to prove that the operations performed have no significant impact on the quality of the original product.
Article 25 When different packaging materials are used to repackage the control drugs for the needs of blind trials, the shelf life of the repackaged control drugs shall not exceed the shelf life of the original products.
When the shelf life of the test drug and the control drug in the blind trial is inconsistent, the expiration date shall be marked with the more recent shelf life.
Article 26 When using placebo for control trials, the prescription process of the placebo shall be determined to avoid the appearance and properties of the placebo causing the blind to be broken. The materials used to prepare the placebo shall meet the corresponding quality requirements. Quality standards for placebos should be established, and they can only be released for clinical trials after passing the inspection. The storage conditions and shelf life of placebos should be determined based on stability studies.
Section 3 Packaging and Labeling
Article 27 Drugs for clinical trials are usually provided to subjects in clinical trials in the form of independent packaging. The sample size of the clinical trial design and the number of drugs for clinical trials required for quality inspection, retention and change research should be fully considered, and sufficient preparation, procurement or import/export should be made according to the clinical trial progress plan. In order to ensure the accuracy of the quantity of each product at each operation stage, material balance calculations should be performed, and deviations from material balance should be explained or investigated.
Article 28 In order to ensure the accuracy of packaging and labeling of drugs for clinical trials, operating procedures should be established to clarify measures to prevent mislabeling, such as label quantity balance calculations, clearing the site, and in-process control inspections by trained personnel. In case of blind trials, effective measures should also be taken to prevent labeling errors between test drugs and control drugs (including placebos). For operations that require the removal of original product labels and packaging, appropriate measures should be taken to prevent contamination, cross-contamination, confusion, and errors between the test drug and the control drug (including placebo).
Article 29 The packaging of drugs used in clinical trials should be able to prevent and avoid deterioration, contamination, damage, and confusion during storage and transportation, and any activities of opening or changing the packaging should be identifiable.
Article 30 Test drugs and control drugs should not usually be packaged at the same time on the same packaging line. If the clinical trial needs to be packaged at the same time on the same packaging line, there should be appropriate operating procedures and equipment, and ensure that the relevant operators are trained to avoid confusion and errors.
Article 31 The labels of drugs used in clinical trials shall be clear and easy to identify, and usually include the following contents:
(I) The name of the clinical trial applicant and the drug used in the clinical trial, etc.;
(II) The batch number and/or number for identifying the product and packaging operation (the label information of the drug used in the clinical trial for blinded trials shall be able to maintain the blind state);
(III) The clinical trial number or other unique code corresponding to the clinical trial;
(IV) The words "for clinical trial only" or similar instructions;
(V) The validity period, expressed in a way that can clearly indicate the year, month and day, such as XXXX (year)/XX (month)/XX (day) or XXXX (year)/XX (month);
(VI) Specifications and instructions for use (an instruction manual or other written instructions provided to the subjects may be attached, and the content shall comply with the requirements of the clinical trial protocol);
(VII) Packaging specifications;
(VIII) Storage conditions;
(IX) If the drug used in the clinical trial is allowed to be taken home by the subject for use, it must be specially marked to avoid misuse.
Article 32 The inner and outer packaging shall contain all the label contents in Article 31 of this Appendix. If the size of the inner packaging label is too small to indicate all of the above contents, at least items (i) to (iv) of the label contents in Article 31 of this Appendix shall be marked.
Article 33 If the expiration date needs to be changed, the drug used in the clinical trial shall be affixed with an additional label, and the new expiration date shall be marked on the additional label, while covering the original expiration date. The original batch number or drug code shall not be covered when the additional label is affixed.
After evaluation by the applicant, the additional label with a changed expiration date may be affixed in the institution conducting the clinical trial.
The operation of affixing additional labels shall be carried out in accordance with the operating procedures approved by the applicant.
The operator must be trained and approved, and the operation site must be reviewed and confirmed by personnel. The attachment of additional labels should be correctly recorded in the relevant documents or batch records of the clinical trial and ensure traceability. The applicant shall conduct a quality audit of the clinical trial drugs with additional labels.
Article 34 The similarity of the appearance and other characteristics of the packaging of clinical trial drugs shall be checked and recorded according to the blinding requirements of the clinical trial protocol to ensure the effectiveness of blinding.
Chapter 9 Quality Control
Article 35 Quality control activities shall be organized and implemented in accordance with quality standards, relevant operating procedures, etc. Each batch of clinical trial drugs must be inspected to confirm that they meet the quality standards. An investigation and evaluation shall be conducted on the inspection results that exceed the standards.
Article 36 Samples shall be retained for each batch of clinical trial drugs:
(I) The retained samples shall include the test drugs and placebos. The packaging form of the retained samples shall be the same as that of the clinical trial drugs. The number of retained samples shall generally be at least enough to ensure that two full inspections are completed in accordance with the corresponding quality standards, and at least one finished product with the smallest package shall be retained.
(II) The number of samples retained for marketed control drugs can be determined based on the risk principle. The number of samples retained should meet the possible quality investigation needs of the control drugs, and at least one finished product with the smallest package should be retained.
(III) If the packaging of clinical trial drugs is changed, samples should be retained according to the packaging forms before and after the change, and at least one finished product with the smallest package should be retained for each packaging form.
(IV) The retained samples should include blinded clinical trial drugs, and at least one complete package of test drugs and control drugs (including placebos) should be kept to verify product information when necessary.
(V) The retention period of clinical trial drugs shall be based on the longer of the following circumstances:
1. Two years after the approval of the drug marketing authorization application or two years after the termination of the clinical trial;
2. Two years after the expiration of the validity period of the clinical trial drug.
Article 37 A stability study plan shall be formulated, and the sample packaging of the stability study shall be consistent with the packaging form of the clinical trial drug. For clinical trial drugs with changed packaging materials, the stability of the samples after the packaging change shall be examined.
Chapter 10 Release
Article 38 The release of drugs for clinical trials shall at least meet the following requirements:
(I) Before approving the release, the person responsible for release shall conduct a quality evaluation of each batch of drugs for clinical trials to ensure that they comply with laws, regulations and technical requirements, including:
1. Batch records, including batch production records, batch packaging records, batch inspection records, etc.;
2. All deviations and changes, subsequent investigations and evaluations have been completed;
3. The packaging of drugs for clinical trials meets the requirements and the labels are correct;
4. The production conditions meet the requirements;
5. The confirmation status of facilities and equipment, and the verification status of preparation processes and inspection methods;
6. The release of raw materials and auxiliary materials and the inspection results of intermediates and finished products;
7. Relevant inspection results of control drugs (including placebo) (if applicable);
8. Stability study data and trends (if applicable);
9. Storage conditions;
10. Qualification certificate of control substances/standard substances (if applicable);
11. Audit report of the quality management system of the entrusted unit (if applicable);
12. Proof of legal source of control drugs (if applicable);
13. Other requirements related to the quality of the batch of clinical trial drugs.
(II) The quality evaluation of clinical trial drugs shall have a clear conclusion, such as approval for release, non-release or other decisions, and signed by the person responsible for release.
(III) A review record of the release of clinical trial drugs shall be issued.
Chapter 11 Shipment
Article 39 Before shipping clinical trial drugs to clinical trial institutions, the applicant shall at least confirm the following and keep relevant records:
(I) The clinical trial drugs have been approved for release;
(II) The relevant requirements necessary for initiating clinical trials have been met, such as approval or consent from the ethics committee and drug supervision and administration department;
(III) Inspection and confirmation of transportation conditions.
Article 40 The shipment of clinical trial drugs shall be carried out in accordance with the applicant's shipment instructions and specific requirements.
Article 41 The applicant shall select an appropriate mode of transportation based on the packaging, quality attributes and storage requirements of the clinical trial drugs, take corresponding measures to prevent deterioration, damage, contamination, temperature control failure and other problems, and confirm that the clinical trial drugs are delivered to the designated clinical trial institution.
Article 42 The clinical trial drugs delivered to the clinical trial institution shall be accompanied by at least a certificate of conformity, a delivery list and a receipt confirmation form for use by the research institution personnel.
The delivery of clinical trial drugs shall keep complete written records, which shall generally include the name or code of the clinical trial drug, dosage form, specification, batch number or drug code, quantity, expiration date, applicant, preparation unit, packaging form, storage requirements, receiving unit and address, contact information, shipment date, transportation method, temperature monitoring measures during the process, etc. If entrusted transportation, relevant information of the carrier shall also be included. The content of the transportation record may be appropriately adjusted according to the need for blinding.
Article 43 Clinical trial drugs shall generally not be directly transferred from one clinical trial institution to another. If necessary, the applicant and the clinical trial institutions of both parties shall have a complete quality assessment and operating procedures for the transfer of clinical trial drugs, which can only be implemented after full assessment and approval by the applicant.
Chapter 12 Complaints and Recalls
Article 44 For complaints caused by quality problems of clinical trial drugs, the applicant shall jointly investigate with the preparation unit and the clinical trial institution to assess the potential impact on the safety of subjects, clinical trials and drug development. The person responsible for release and the relevant persons in charge of the clinical trial shall participate in the investigation. The investigation and handling process shall be recorded.
Article 45 When it is necessary to recall clinical trial drugs, the applicant shall organize the recall in a timely manner according to the operating procedures. Clinical researchers and monitors shall perform their respective duties during the recall of clinical trial drugs.
Article 46 When the supplier of control drugs or other therapeutic drugs specified in the clinical trial protocol initiates a drug recall, if it involves product quality and safety issues, the applicant shall immediately recall all issued drugs after learning of the recall information.
Chapter 13 Recall and Destruction
Article 47 The applicant shall establish corresponding operating procedures to clarify the recall process and requirements for clinical trial drugs. Recalls shall be recorded. Recovered clinical trial drugs shall be clearly marked and stored in a controlled, dedicated area.
Article 48 Recovered clinical trial drugs shall not usually be used again in clinical trials. If necessary, the applicant shall fully evaluate the quality of the recovered clinical trial drugs, and only use them again after there is evidence that the quality of the recovered clinical trial drugs has not been affected and they are disposed of in accordance with the corresponding operating procedures.
Article 49 The applicant is responsible for destroying unused and recovered clinical trial drugs. If the clinical trial institution or a third party is authorized to destroy, it shall be authorized in writing, and the applicant shall conduct inspections when necessary to prevent clinical trial drugs from being used for other purposes.
Unused and recovered clinical trial drugs may only be destroyed after confirming that the number of issued, used and recovered clinical trial drugs is balanced. Destruction shall be fully recorded, including at least the reason for destruction, destruction time, batch number and/or drug code involved in destruction, actual destruction quantity, destroyer, supervisor and other information. The destruction record shall be kept by the applicant.
Chapter 14 Supplementary Provisions
Article 50 The following terms in this Appendix have the following meanings:
(I) Person responsible for release
Refers to a person who has certain professional qualifications and experience in drug development and production quality management and is responsible for the release of each batch of clinical trial drugs.
(II) Drug files for clinical trials
Includes a set of documents and records related to the development, preparation, packaging, quality inspection, release and shipment of clinical trial drugs.
(III) Drug code
The code assigned to each independent package by random grouping.
(IV) Early clinical trial
Refers to clinical pharmacology and exploratory clinical trials, which should, in principle, include preliminary safety evaluation, pharmacokinetic studies, preliminary pharmacodynamic studies and dose exploration studies.
Article 51 The raw materials used for clinical trial drugs shall refer to this Appendix.
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