1. Definitions & Scope
Inspection on drugs under registration involves sample analysis and specification verification. Sample analysis means the drugs will be inspected according to the exhibit specification. Specification verification is the laboratory assessment the scientific nature of the testing item, suitability of the testing method, rationality of the Quality control items, etc regarding to the exhibit specification.
This regulation is applicable to sample analysis and specification verification carried out by drug inspection institute to support the review and approval of Chinese medicine, chemical drugs, biological products and in-vitro diagnostic reagents marketed according to drug management, as well as chemical APIs, Inspection of medicinal accessories, packaging materials and containers in direct contact with drugs.
2. Applicant of inspection on drug under registration and Drug inspection Department
A. Applicant of Inspection on drug under registration
(a)、Applicant of Inspection on drug under registration (addressed as Applicant) is the companies which aim to register and launch their drugs in China. Because of this, inspection are requested by these companies.
(b)、The quality of the drug filed for inspection must comply with the general technological requirement of Chinese Pharmacopeia (CP). Quality below the specification of CP is not allowed. Also, conformance with the specification format issued from Center of Drug Evaluation (CDE) is necessary. For any test items or limits which are not applicable to CP, applicants must also provide supportive support.
(c)、Applicant must cooperate with the Chinese authorities on sample collection. The documents, samples, standards, etc. must be delivered to the respective inspection department before the proposed deadline.
(d)、Before applying for inspection on the drug under registration, applicant must understand the requirements of documents, samples, standards, etc. regarding to the drug. If there are any doubts, please contact the relevant authorities. Applicant must cooperate with the authorities and solve the technical problems during the inspection.
(e)、When supplement is required, applicant shall provide the full set of supplement within the provided timeframe. For special cases which the supplements cannot be submitted by the deadline, applicant must inform the relevant authorities beforehand to reschedule the timeframe. If no supplements are provided during the timeframe, the application on inspecting the drug under registration shall be granted as cancelled.
(f)Applicants shall provide the materials and samples for inspection in both hard (with stamp by applicant) and soft copy. For overseas drugs which are under registration in China, applicant shall provide the materials and sample in Chinese and English version.
庚、In principle before the registration of the drug is approved, applicant could only apply once for the inspection on drugs under registration. Applying for inspection on multiple drugs simultaneously is not allowed. The documents provided for the inspection must be same as the documents filed for registration of the drugs. During the inspection, applicant is not allowed to change the authorities responsible for the tests, providing additional supplements or changing materials and sample, etc.
According to the stages of the registration of the drugs, the inspection on drugs under registration can be classified into 4 types:
(a) Pre-registration inspection:
Applicant can request an inspection on the drug under registration, before the acceptance of the market authorization of the drug. Once the applicant has the data on pharmaceutical related research, confirming quality standards, completing validation on commercial batches production, submission of application for inspection to the National Institutes for Food and Drug Control (NIFDC) is allowed.
(b) Drug inspection during the acceptance of market authorization:
Refer to NCEs, modified new drugs, imported drugs, or drugs that are justified by the authorities. Applicant who have not requested for pre-registration inspection. The inspection shall begin automatically after 40 days from the acceptance of market authorization of the drug.
(c) Drug inspection during the review of the market authorization application:
During the review of the market authorization application, inspection is required by CDE due to the following situation:
(i) Re-testing on items of quality standards based on risks.
(ii) On-site sampling
(iii) Authenticity of the filed drug applications or receival of complaints regarding to the drug
(d) Drug inspection for supplementary application after the approval of the Market Authorization:
For supplementary applications which are submitted after the approval of the Market Authorization. CDE shall start the drug inspection in 40 working days based on risks.
4. Procedures for Drug Registration Inspection
1.1. Document preparation and samples
If the inspection for drug registration is required, applicants must prepare the materials and samples in advance.
1.1.1. For inspection during pre-registration and acceptance of market authorization, applicants shall follow the request on “Material requirements of inspection on drugs under registration (Documents, Samples, Standards, Experimental materials)”
1.1.2. For inspection during the market authorization review, applicants shall combine the request from the reviews of standards and on-site sampling inspection. For inspection which are not mentioned in the filed standard, the provision of inspection scheme which is agreed by the authorities and related materials are required.
1.1.3. For inspection after the approval of market authorization, applicants shall combine the request from CDE and execute the requirements.
1.2. Communication with drug inspection institutes
If needed, applicants can contact the respective drug inspection institutes on questions regarding to the following issues: Materials requirements for inspection of drug registration, samples, standards, special experimental materials and apparatus, technical queries about samples inspection and standard reviews.
2.1. Pre-registration inspection: Applicants submit the materials about inspection for drug registration online, and provide the samples as requested.
Applicants shall provide TWICE the amount of samples and standards for a complete quality analysis and send them to designated port drug inspection institutes. Also, 1 set of samples and standards shall send to NIFDC.
After the justification of the filed documents, applicants shall provide 3 TIMES the amount of samples and standards for a complete quality analysis to NIFDC.
2.2. For drug inspection during the acceptance of market authorization, applicants shall request for drug inspection to CDE and provide the requested samples and materials to the relevant drug inspection institutes. All these actions must be done within 30 days after the applicant gets the acceptance notice issued by CDE. For prioritized review, samples shall be provided within 5 days after the applicant gets the acceptance notice. For emergencies which requires drugs that are launched in overseas, samples shall be provided within 2 days. The requirements of samples and materials please refer to Section 2.1.
2.3. For drug inspection during the justification of market authorization, applicants shall request for drug inspection once they have received the notice for drug inspection or supplements. For requirements of samples and materials, please refer to Section 2.2.
2.4. For drug inspection after the approval of the market authorization, please refer to section 2.2.
3.1. Data Review. NIFDC organizes the drug registration inspection conducted by the port drug inspection institutes. Within 5 working days, the NIFDC will complete the review of the completeness and standardization of the registration inspection-related data, and determine the port drug inspection institutes to undertake the registration inspection. The authorities will send the NOTICE OF TESTING FOR DRUG MANUFACTUERED OVERSEAS to the applicants. After that, applicants shall provide samples to the designated inspection institutes. For those who cannot pass the review, correction and provision of required documents shall be done within allowed timeline. Samples shall provide to the designated inspection institutes.
3.2. Sample inspection. NIFDC organizes the drug registration inspection conducted by the port drug inspection institutes. Port drug inspection institutes will assess the samples, standards, etc. and revert to applicants on their assessment results on whether the samples are valid. Authorities shall confirm the inspection results with the applicants with signature, with regards to appearance, seals, storage conditions, batches, amount, validity period, etc.
For samples which passed the inspection, NIFDC shall issue the Notice of Inspection Approval.
For samples which failed the inspection, NIFDC shall issue the Notice of Inspection Rejected with reasons of rejection. Applicants shall retrieve the submitted materials.
4.1. Sample inspection, standard review and other requirements about the inspection can refer to Section 4 for local manufactured drugs. If supplements is required, designated port authorities will direct provide the supplement notice to the applicants.
4.2 Review of Quality standard review opinions. NIFDC shall review on the quality standard review opinions by the port inspection institutes. The results from the NIFDC will be considered as the final opinion.
5.1. The inspection report by the port inspection institutes shall delivered to NIFDC. The official report shall be released by the NIFDC.
5.2. For the official report, the recipients are chosen according to the nature of the drug registration inspection. For pre-registration inspection, report shall be sent to the applicants. For the inspections carried out during the market authorization application, the report shall be sent to both the CDE and the applicants.
A. For drugs manufactured overseas, applicants shall retrieve their own samples.
B. The process of sample retrieval shall follow the requirements by the Chinese authorities.
C. Samples for drug registration inspection should be retrieved from 3 COMMERCIAL BATCHES (Excluded for special occasions and drugs for rare diseases). For each batch, the sample amount shall be 3 TIMES THE AMOUNT FOR COMPLETING ONE FULL ANALYSIS ON ALL TEST ITEMS. For the validity period of the samples, they should be long enough to complete 2 drug registration inspection. If drug registration inspection and standard review are performed simultaneously, the validity period must be at least 180 working days. If only drug registration inspection is required, the validity period must be at least 120 working days.
For chemical medicines, the API of the drug shall also be extracted. For biological medicines, the stock shall be extracted. Number of batches, sample amount and validity period shall comply to the relevant regulations.
A. For application that are involved in breakthrough medical treatment, conditional approval, priority review and special review, respective drug registration inspections will be prioritized and completed in the earliest fashion.
B. If the drug registration inspection cannot be started because additional supplements is required, authorities will discuss with the applicant and pause the inspection. The applicant will receive a notice on supplements requirements (Annex 4.3), the inspection will restart once the required supplements have been submitted.
C. CDE will stop the drug inspection in accordance to the progress of review.
D. If applicants have any doubts and comments about the inspection report, they can submit an objection to the CDE within 7 working days upon the receival of report. CDE shall provide a conclusion within 20 working days. Extra samples might be necessary for additional testing. Testing time would not count in the 20 working days.
A. For CDE initiated drug registration inspection, applicants shall provide the samples in 30 working days. Samples from on-site sampling must send to CDE in 10 working days. For application that are under priority review, samples must be provided within 5 working days after noticing. For emergencies which requires drugs that are launched in overseas, samples must be provided in 2 working days.
5 working days for documents review and samples receival. 60 working days for sample inspection. 90 working days for reassessment of the samples and standards. 30 days for submitting additional supplements.
8. Technical Requirements for Drug Registration Inspection
A. Documents Review
Inspection institutes shall justify the analytical data relating to the quality standard of the drug under registration. The research data shall include the following:
l Quality standard of the drug and the drafting instructions
l Materials on methodology verification (Including verifications on sterile and microbial limits tests)
l Drug Inspection Report
l Manufacturing Process
l Quality Control
l Stability Analysis
l Reference Standards
l Methodology Confirmation and/or transferred test items
l Critical points on inspection methods and standards review
B. Inspection of samples and standards review
(a) Sample Inspection. Inspection institutes shall complete experimental inspection and provide the inspection report. Samples will be assessed according to the materials submitted, the submitted drug quality standard and requirements from the inspection institutes.
(b) Standard Review. Inspection institutes will evaluate the test items in the drug quality standard in accordance to the Chinese Pharmacopeia (CP), guidelines from WHO, ICH and other international authorities, other pharmacopeias and other scientific data and results. Evaluation shall include the following:
(c) (i) Quantitative analysis: Method of analysis on major ingredients and impurities. It is necessary to
confirm the suitability, accuracy, precision and specificity of the methods.
(ii) Limit analysis: It is necessary to confirm if the limits are reasonable. Residual of solvents should be controlled as mentioned in Chinese Pharmacopeia. Method of analysis of impurities should confirm the limits. Purity analysis should confirm the specificity and precision. Impurity analysis with calibration factor should confirm the accuracy of the calibration factor. Other limit analyses shall confirm the specificity and limits.
(d) Qualitative analysis: Specificity confirmation is required.
(e) Requirements on writing the standard review comments
C. Reference standards used in Drug registration inspection
Reference standards used in drug registration inspection includes National drug reference standard and Overseas drug reference standard. National drug reference standard is prepared by the Chinese authorities.
(a) While applying for drug registration inspection, applicant shall declare the origin of the reference standard used. If National drug reference standard is used, inspection institutes will use the National drug reference standard for assessment. If Overseas drug reference standard is used, applicants should provide the relevant reference standards and research materials.
(b) For analysis using Overseas drug reference standard, applicants should provide the reference standards and relevant research materials before the market authorization approval. For using official reference standards from other countries, NO provision of standard is required. Instead, the relevant information of the standard must be submitted.