Guidelines for the rectification of defects in drug production supervision and inspection (trial) were issued

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The holders of drug marketing licenses and drug manufacturers may refer to this guideline for risk reminders or warnings made by the Liaoning Provincial Drug Administration based on supervision and inspection.

 

2.
Basic principles

 

When drug marketing license holders and drug manufacturers implement rectification, they should highlight the principles of pertinence, systematization, scientificity, and effectiveness, start with the defects found in supervision and inspection, use risk management concepts, and focus on product characteristics and control points.
, In-depth investigation and comprehensive analysis of the root causes of defects, scientifically assess the potential impact on drug quality, take appropriate risk control measures, formulate targeted corrective and preventive measures, draw inferences from one another, and make systematic rectification and corrective and preventive measures.
The implementation results and rectification effects are reviewed and evaluated.
Through regular risk reviews, we continue to confirm the effectiveness of corrective and preventive measures to achieve closed-loop risks and ensure the safety, effectiveness and quality controllability of listed drugs.

 

In the process of rectification and implementation of drug marketing permit holders and drug manufacturers, they must pay attention to the correlation between different defects, strengthen organization and coordination and communication and cooperation between departments; it is necessary to clarify and implement investigation and analysis, risk assessment, risk control, and The rectification responsibilities of each link, including rectification review, rectification effect evaluation, and rectification report writing, are checked by level by level.
The whole process of rectification and reform implementation must meet people, see issues, see responsibilities, see measures, and see results, and prevent rectification from being formalized, formalized, and justified.

 

3.
Rectification requirements

 

(1) Implementation of rectification responsibilities

 

1.
Legal representative or main person in charge

 

The holder of the drug marketing license, the legal representative or the main person in charge of the drug manufacturer, as the top manager of the drug production quality management system of the company, must effectively play a leading role and be fully responsible for the rectification of defects; and organize the rectification of defects.
Plan, provide necessary human resources and financial guarantees, ensure that the quality management department independently exercises supervision and evaluation responsibilities, strictly require close communication with relevant departments of defects, and efficiently implement the rectification requirements put forward by the quality management department to ensure the effective implementation of rectification of defects; through implementation of rectification, Systemically solve the actual problems existing in the production quality management of the enterprise.

 

2.
The person in charge of quality

 

The holders of drug marketing licenses and the persons in charge of the quality of drug manufacturers shall effectively perform quality management responsibilities and organize the quality management department to participate in the investigation and analysis of various defects, risk assessment, risk control, rectification review, rectification effect evaluation and other rectification processes; It is necessary to supervise the defect rectification department to fully implement the rectification requirements in accordance with the plan; to organize the quality management department to evaluate the rectification conclusions of the defect rectification department, and to propose improvement suggestions to ensure that the risk control measures adopted can effectively prevent and control risks; to organize quality management The department writes a rectification report and conducts review and approval.

 

　　3.
Responsible department for defect rectification

 

　　Responsible departments for drug marketing license holders and drug manufacturers’ defect rectification should take the initiative to implement rectification responsibilities, earnestly perform investigation and analysis, risk assessment, risk control, rectification implementation, rectification review and other responsibilities, and ensure that defect rectification is implemented as planned; In the process of defect rectification, it is necessary to trace the source to carry out investigation and evaluation, and actively cooperate with other departments to carry out relevance investigations, in-depth analysis of the causes of defects and their relevance factors, timely correction and prevention of systemic risk hazards, and guarantee the quality and effect of defect rectification.

 

　　(2) Defect rectification requirements

 

　　1.
Investigation and analysis

 

　　Drug marketing license holders and drug manufacturers should follow scientific and objective principles, combine corporate organization, product quality attributes and production quality management points, etc.
, and carry out root cause investigations on the basis of sufficient research verification and data analysis.
Check the causes and possible factors of defects.

 

　　2.
Risk assessment

 

　　Drug marketing license holders and drug manufacturers should base their investigation and analysis on personnel management, plant facilities, production equipment, material management, production management, quality management, etc.
, and combine product characteristics, indications, users, and market sales.
And other factors, comprehensively evaluate the possibility and severity of the damage caused by the defect, and evaluate its impact on a certain link of the quality management system, related links, and the entire quality management system.

 

　　3.
Risk control

 

　　(1 ) Clear risk control for hidden safety hazards

 

　　Based on the results of risk assessment, drug marketing license holders and drug manufacturers should take immediate action on the identified risks of pharmnet.
com.
cn/" target="_blank">compliance with laws pharmnet.
com.
cn/" target="_blank">and regulations , the safety, effectiveness, and quality controllability risks of listed drugs, and the risks of public opinion that may be triggered.
Risk control measures appropriate to the risk level (such as active recall, suspension of sales, suspension of production, etc.
), reasonably determine the scope of risk control, eliminate hazards in time, and reduce drug safety risks to a controllable and acceptable level.

 

　　(2 ) Improve the risk control of production quality management

 

　　Drug marketing license holders and drug manufacturers should formulate and implement corrective and preventive measures based on the results of risk assessment, the causes of defects and their potential impacts, timely and effectively control risks at different levels, continuously improve the quality management system, and enhance production quality management capabilities , To prevent similar defects from happening again.

 

　　① Corrective measures

 

　　The corrective measures implemented by drug marketing license holders and drug manufacturers must ensure that they are compatible with the causes of defects and the level of risks, to prevent further expansion of their adverse effects, implement them in accordance with the requirements of the rectification time limit, and implement the effectiveness of the corrective measures.
Evaluation and confirmation.

 

　　②Preventive measures

 

　　In order to avoid the recurrence of similar defects and avoid similar effects on the defects-related links and related products, drug marketing authorization holders and drug manufacturers should reasonably formulate preventive measures and organize their implementation.
At the same time, it is necessary to formulate a risk review plan to continuously confirm the effectiveness of corrective and preventive measures.

 

　　4.
Rectification review

 

　　After the defect rectification is completed, the person in charge of the defect rectification department shall review the rectification situation and form a rectification conclusion one by one.
If the rectification cannot be completed within the rectification time limit, such as verification, stability inspection, equipment change, workshop reconstruction and expansion, etc.
, the defect rectification department shall formulate a practical rectification plan, and carry out the possible continuing impact of the defect that has not been rectified.
Evaluate to ensure that the resulting risks are controllable and acceptable.
The rectification conclusion and rectification plan shall be subject to review and approval procedures, and the rectification plan shall specify the person responsible for follow-up and implementation.

 

　　5.
Evaluation of rectification effect

 

　　After the defect rectification department completes the rectification, the quality management department shall summarize the rectification situation, rectification conclusions, and rectification plan (if any) of each responsible department, and evaluate the effectiveness of the rectification measures item by item.
For the evaluation results that the rectification measures are insufficient and the rectification results are not in line with expectations, the relevant responsible department shall be required to take further rectification measures until the rectification is implemented.

 

　　(3) Writing of rectification report

 

　　After the quality management department confirms that all defects have been rectified in place, organize the writing of a rectification report.
The rectification report must ensure that the content is true and complete, the presentation is clear and accurate, and truthfully reflect the implementation of the rectification.
The rectification report should include at least the description of defects, defect investigation and analysis, risk assessment, risk control, rectification review, rectification effect evaluation, etc.
The risk control measures and implementation results shall be described item by item, and specific details shall be specified for the causes of defects and risk assessment.
Responsible department and responsible person.

 

　　After the quality management department completes the rectification report, it must perform the review and approval procedures, submit it to the person in charge of quality for approval, and summarize the documents, records and other supporting materials generated during the defect rectification process, and file it together with the rectification report for future reference.

 

　　(4) Submission of rectification report

 

　　When the drug marketing authorization holder and drug manufacturer submit a rectification report to the drug regulatory authority, the supervision and inspection shall be judged as serious defects, major defects, and relevant supporting materials related to the defects of plant facilities, production inspection conditions, and inspection and inspection results Submit it together with the rectification report and ensure its authenticity and consistency.
For those who cannot complete the rectification within the prescribed time limit, the drug marketing authorization holder and the drug manufacturer can include the rectification plan formulated as a stage corresponding to the defect in the rectification report, and explain the relevant impact assessment results and temporary measures Risk control measures.

 

　　After the rectification plan is fully completed, the drug marketing authorization holder and the drug manufacturer shall form a supplementary rectification report in accordance with the requirements of this guide, and submit it to the drug regulatory authority after approval by the person in charge of quality.

 

　　IV.
Examples of rectification reports

 

　　In order to help drug marketing license holders and drug manufacturers to understand and grasp the regulatory requirements of this guide for investigation and analysis, risk assessment, risk control, rectification review and other rectification links, they have been followed and referred to in the rectification implementation process, as follows: Explain in detail through a virtual case:

 

　　1.
Defect description

 

　　A company’s "Finished Product Review and Release Regulations" stipulates that the quality authorized person is responsible for the release of finished products, but the document and personnel job responsibilities do not clearly define the specific job responsibilities, work content and work requirements of all levels of personnel in the finished product review and release.
The on-site inspection found that during the review of the release of the finished product of A injection with batch numbers 20190803, 20190804, 20190805, 20190901, 20190902, personnel at all levels did not find any calculation errors for the relevant substances Single Miscellaneous I and Single Miscellaneous II, and the finished product was released.
The review process is out of control.
The company did not train the inspector B who was temporarily transferred, and the change management was inadequate.
In the inspection of related substances of the above-mentioned batch A injection, the self-control method was used to determine the single miscellaneous I, single miscellaneous II and other unknown impurities.
The relevant inspection records showed that the inspector B mistaken the single miscellaneous II during the calculation of the related substance inspection results.
The correction factor and peak area of ​​the single miscellaneous I are used for the calculation of the single miscellaneous I (the correction factors and standard limits of the single miscellaneous I and single miscellaneous II are different), resulting in the error of the test results of the single miscellaneous I and single miscellaneous II.
The above products have been released.
Among them, A injections with batch numbers 20190803 and 20190804 have been on the market.
The inspection team asked the company to expand the scope of investigation, assess the quality risks of products in stock and products already on the market, and take necessary risk control measures.

 

　　2.
Investigation and analysis

 

　　According to the job responsibilities, the quality authorized person, the QA person in charge, and the QC person in charge organize the investigation and analysis of this defect.

 

　　On **year**month**, our company organized an investigation and analysis meeting.
The quality authorized person, QA person in charge, batch record reviewer D, QC person in charge, QC inspector B, and inspection reviewer C attended the meeting.
Participants reviewed the inspection procedures for related substances of injection A and finished product inspection records.
The calculation of single miscellaneous I and single miscellaneous II uses the same calculation formula.
The correction factors of single miscellaneous I and single miscellaneous II in the records are all marked with f.
There is a risk of confusion in the calculation.
Inspector B is temporarily transferred from the inspection position of other products to the finished product inspection position of A injection.
The pre-job training is only carried out by the way of inspector B self-learning the post operation procedures.
The personnel changes have not fulfilled the change control procedures and are released during the finished product review.
The change is not reflected in the record.
The inspection reviewer C lacked the inspection experience of A injection, and the follow-up batch record reviewer did not pay much attention to this record, which caused the release of the finished product to be out of control.

 

　　The meeting required the QC department to immediately carry out a comprehensive self-inspection, and QA batch record reviewers participated and supervised the implementation.
Inspector B’s temporary transfer to undertake inspection of finished product inspection records for injection A shall be further traced, and inspector B’s finished product inspection records shall be re-examined by personnel with A injection inspection experience to confirm whether the inspection results meet national standards.
The QC department investigates whether there is a temporary change of inspection personnel in other product inspection positions, and re-examines the relevant inspection records.

 

　　The meeting decided to change the approved and released A injection products in the warehouse and other products with similar conditions to the pending state during the defect investigation and analysis and risk assessment period, and suspend the release and sales.

 

　　Responsible department for defect investigation and analysis: quality authorized person, quality assurance department, quality control department.

 

　　Responsible person for defect investigation and analysis: quality authorized person, QA person in charge, batch record reviewer D, QC person in charge, QC inspector B, inspection reviewer C.

 

　　Responsible department for defect rectification: quality authorized person, quality assurance department, quality control department.

 

　　Responsible person for defect rectification: quality authorized person, QA person in charge, batch record reviewer D, QC person in charge, QC inspector B, inspection reviewer C.

 

　　3.
Risk assessment

 

　　**Year**Month**, the legal representative of the company or the person in charge of the company, the person in charge of quality, the person in charge of quality, the person in charge of QA, the batch record reviewer D, the person in charge of QC, the QC inspector B, the inspection reviewer C And inspection record review personnel to participate in the risk assessment meeting.
Based on the results of the investigation and analysis and the re-review of the inspection records, the risk assessment of the relevant products that have been on the market is carried out, and the risk control and rectification opinions are put forward by classification.

 

　　After reviewing again, there were calculation errors in the inspection records of *** batch A injection, the ** batch has been put on the market, and the ** batch has been released but has not been put on the market, and no non-compliance with national standards was found.
However, it was found that *** batches were close to the national standard limit.
No calculation errors were found in other inspection personnel changes and inspection records.

 

　　Reviewing the continuous stability investigation data of A injection, the related substances of this product have a linear upward trend during the validity period.
After a comprehensive assessment, it was determined that the A injections with batch numbers of 20190802, 20190903, and 20190904 had the risk of the relevant substances exceeding the national standards within the validity period.
It was decided to initiate a recall of the A injections with batch numbers of 20190802 and 20190903 that have not been marketed.
The batch number of 20190904 A injection will not be released.

 

　　Risk Assessment Responsible Department: Quality Manager, Quality Authorized Person, Quality Assurance Department, Quality Control Department.

 

　　Responsible person for risk assessment: the legal representative or person in charge of the company, the person in charge of quality, the person in charge of quality, the person in charge of QA, the person in charge of QC, the person in charge of inspection record review.

 

　　4.
Risk control

 

　　Based on the results of the risk assessment, the Quality Assurance Department and the Quality Control Department formulate corresponding risk control measures, and organize the implementation according to the plan.

 

　　4.
1 Clear risk control for hidden safety hazards

 

　　For the 20190802 and 20190903 batches of A injections that have been on the market, they immediately initiated active recall measures, traced sales flow information, notified relevant drug companies, and suspended sales of related batches of products.
The unmarketed 20190904 batch of A injection products in the warehouse were adjusted to a pending state, strict control was implemented, sales were suspended, and the recall plan and recall evaluation report were reported to the Provincial Drug Administration Resident Inspection Office in a timely manner.

 

　　4.
2 Corrective actions

 

　　4.
2.
1 Investigate the relevant batches of products whose re-audit results are close to the limits of the national standards, focusing on the quality of the API, the storage conditions of the API, the operation and maintenance of the sterilization equipment, and the control of the production process (such as whether the production time exceeds the verification Examination and analysis will be conducted in terms of the scope, whether the temperature of the dosing solution is consistent with the process verification, whether the temperature and time of the final sterilization deviate), etc.
, and other batches of A injections produced with the same batch of APIs and the same sterilization at the same time period will be used.
Bacteria equipment is terminally sterilized and other batches of injection A are included in the scope of investigation.

 

　　After investigation, the aforementioned related substances are close to the relevant batches of products stipulated by the national standards.
They are all terminally sterilized using the sterilization equipment with equipment number SZZZ02, and this equipment has experienced a deviation during the production of injection A on **month** After the deviation occurred, the equipment department replaced the temperature control probe of the equipment, and the production time of the above batch of products was before the replacement of the temperature control probe, which had obvious relevance.
After evaluation, the deviation did not adversely affect the production of other batches of A injection, and the related risks have been effectively controlled.

 

　　4.
2.
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2.
3A，f1、f2I、II，，，。

 

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3

 

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　　5.

 

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　　Responsible departments for rectification and review: Quality Assurance Department, Quality Control Department, Production Department, Material Control Department, Sales Department.

 

　　Responsible person for rectification review: *** (Quality Assurance Department), *** (Quality Control Department), *** (Production Department), *** (Material Control Department), *** (Sales Department).

　　Medical Network, February 22, in order to thoroughly implement the "four most stringent" requirements, further promote the implementation of corporate responsibilities, guide and standardize the rectification of corporate supervision and inspection defects, achieve closed-loop management of risks, and prevent and resolve drug safety risks.
According to the "Chinese People The Drug Administration Law of the Republic, the Vaccine Administration Law of the People’s Republic of China, the Measures for the Supervision and Administration of Drug Production, the Good Manufacturing Practices of Drugs and other laws and regulations, combined with the actual supervision and management, our bureau has formulated the "Guidelines for Rectification of Defects in Drug Production Supervision and Inspection (Trial) ", hereby released.

 

　　announce.

 

　　Liaoning Provincial Drug Administration

 

　　February 10, 2021

 

　　Guidelines for Rectification of Defects in Drug Production Supervision and Inspection

 

　　(Trial)

 

　　1.
Scope of application

 

　　Liaoning province, marketing authorization holder, pharmaceutical manufacturing enterprises in Liaoning Province and Drug Administration licensing examination, routine inspection, supervision and rectification of defects due to inspection found during inspection conducted for this guide.

 

　　The drug marketing license holders and drug manufacturers can refine and improve the rectification process based on the deficiencies and the actual situation of the rectification, based on the general requirements set forth in this guide.

 

　　The holders of drug marketing licenses and drug manufacturers may refer to this guideline for risk reminders or warnings made by the Liaoning Provincial Drug Administration based on supervision and inspection.

 

　　2.
Basic principles

 

　　When drug marketing license holders and drug manufacturers implement rectification, they should highlight the principles of pertinence, systematization, scientificity, and effectiveness, start with the defects found in supervision and inspection, use risk management concepts, and focus on product characteristics and control points.
, In-depth investigation and comprehensive analysis of the root causes of defects, scientifically assess the potential impact on drug quality, take appropriate risk control measures, formulate targeted corrective and preventive measures, draw inferences from one another, and make systematic rectification and corrective and preventive measures.
The implementation results and rectification effects are reviewed and evaluated.
Through regular risk reviews, we continue to confirm the effectiveness of corrective and preventive measures to achieve closed-loop risks and ensure the safety, effectiveness and quality controllability of listed drugs.

 

　　In the process of rectification and implementation of drug marketing permit holders and drug manufacturers, they must pay attention to the correlation between different defects, strengthen organization and coordination and communication and cooperation between departments; it is necessary to clarify and implement investigation and analysis, risk assessment, risk control, and The rectification responsibilities of each link, including rectification review, rectification effect evaluation, and rectification report writing, are checked by level by level.
The whole process of rectification and reform implementation must meet people, see issues, see responsibilities, see measures, and see results, and prevent rectification from being formalized, formalized, and justified.

 

　　3.
Rectification requirements

 

　　(1) Implementation of rectification responsibilities

 

　　1.
Legal representative or main person in charge

 

　　The holder of the drug marketing license, the legal representative or the main person in charge of the drug manufacturer, as the top manager of the drug production quality management system of the company, must effectively play a leading role and be fully responsible for the rectification of defects; and organize the rectification of defects.
Plan, provide necessary human resources and financial guarantees, ensure that the quality management department independently exercises supervision and evaluation responsibilities, strictly require close communication with relevant departments of defects, and efficiently implement the rectification requirements put forward by the quality management department to ensure the effective implementation of rectification of defects; through implementation of rectification, Systemically solve the actual problems existing in the production quality management of the enterprise.

 

　　2.
The person in charge of quality

 

　　The holders of drug marketing licenses and the persons in charge of the quality of drug manufacturers shall effectively perform quality management responsibilities and organize the quality management department to participate in the investigation and analysis of various defects, risk assessment, risk control, rectification review, rectification effect evaluation and other rectification processes; It is necessary to supervise the defect rectification department to fully implement the rectification requirements in accordance with the plan; to organize the quality management department to evaluate the rectification conclusions of the defect rectification department, and to propose improvement suggestions to ensure that the risk control measures adopted can effectively prevent and control risks; to organize quality management The department writes a rectification report and conducts review and approval.

 

　　3.
Responsible department for defect rectification

 

　　Responsible departments for drug marketing license holders and drug manufacturers’ defect rectification should take the initiative to implement rectification responsibilities, earnestly perform investigation and analysis, risk assessment, risk control, rectification implementation, rectification review and other responsibilities, and ensure that defect rectification is implemented as planned; In the process of defect rectification, it is necessary to trace the source to carry out investigation and evaluation, and actively cooperate with other departments to carry out relevance investigations, in-depth analysis of the causes of defects and their relevance factors, timely correction and prevention of systemic risk hazards, and guarantee the quality and effect of defect rectification.

 

　　(2) Defect rectification requirements

 

　　1.
Investigation and analysis

 

　　Drug marketing license holders and drug manufacturers should follow scientific and objective principles, combine corporate organization, product quality attributes and production quality management points, etc.
, and carry out root cause investigations on the basis of sufficient research verification and data analysis.
Check the causes and possible factors of defects.

 

　　2.
Risk assessment

 

　　Drug marketing license holders and drug manufacturers should base their investigation and analysis on personnel management, plant facilities, production equipment, material management, production management, quality management, etc.
, and combine product characteristics, indications, users, and market sales.
And other factors, comprehensively evaluate the possibility and severity of the damage caused by the defect, and evaluate its impact on a certain link of the quality management system, related links, and the entire quality management system.

 

　　3.
Risk control

 

　　(1 ) Clear risk control for hidden safety hazards

 

　　Based on the results of risk assessment, drug marketing license holders and drug manufacturers should take immediate action on the identified risks of pharmnet.
com.
cn/" target="_blank">compliance with laws pharmnet.
com.
cn/" target="_blank">and regulations , the safety, effectiveness, and quality controllability risks of listed drugs, and the risks of public opinion that may be triggered.
Risk control measures appropriate to the risk level (such as active recall, suspension of sales, suspension of production, etc.
), reasonably determine the scope of risk control, eliminate hazards in time, and reduce drug safety risks to a controllable and acceptable level.

 

　　(2 ) Improve the risk control of production quality management

 

　　Drug marketing license holders and drug manufacturers should formulate and implement corrective and preventive measures based on the results of risk assessment, the causes of defects and their potential impacts, timely and effectively control risks at different levels, continuously improve the quality management system, and enhance production quality management capabilities , To prevent similar defects from happening again.

 

　　① Corrective measures

 

　　The corrective measures implemented by drug marketing license holders and drug manufacturers must ensure that they are compatible with the causes of defects and the level of risks, to prevent further expansion of their adverse effects, implement them in accordance with the requirements of the rectification time limit, and implement the effectiveness of the corrective measures.
Evaluation and confirmation.

 

　　②Preventive measures

 

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　　1.

 

　　A company’s "Finished Product Review and Release Regulations" stipulates that the quality authorized person is responsible for the release of finished products, but the document and personnel job responsibilities do not clearly define the specific job responsibilities, work content and work requirements of all levels of personnel in the finished product review and release.
The on-site inspection found that during the review of the release of the finished product of A injection with batch numbers 20190803, 20190804, 20190805, 20190901, 20190902, personnel at all levels did not find any calculation errors for the relevant substances Single Miscellaneous I and Single Miscellaneous II, and the finished product was released.
The review process is out of control.
The company did not train the inspector B who was temporarily transferred, and the change management was inadequate.
In the inspection of related substances of the above-mentioned batch A injection, the self-control method was used to determine the single miscellaneous I, single miscellaneous II and other unknown impurities.
The relevant inspection records showed that the inspector B mistaken the single miscellaneous II during the calculation of the related substance inspection results.
The correction factor and peak area of ​​the single miscellaneous I are used for the calculation of the single miscellaneous I (the correction factors and standard limits of the single miscellaneous I and single miscellaneous II are different), resulting in the error of the test results of the single miscellaneous I and single miscellaneous II.
The above products have been released.
Among them, A injections with batch numbers 20190803 and 20190804 have been on the market.
The inspection team asked the company to expand the scope of investigation, assess the quality risks of products in stock and products already on the market, and take necessary risk control measures.

 

　　2.
Investigation and analysis

 

　　According to the job responsibilities, the quality authorized person, the QA person in charge, and the QC person in charge organize the investigation and analysis of this defect.

 

　　On **year**month**, our company organized an investigation and analysis meeting.
The quality authorized person, QA person in charge, batch record reviewer D, QC person in charge, QC inspector B, and inspection reviewer C attended the meeting.
Participants reviewed the inspection procedures for related substances of injection A and finished product inspection records.
The calculation of single miscellaneous I and single miscellaneous II uses the same calculation formula.
The correction factors of single miscellaneous I and single miscellaneous II in the records are all marked with f.
There is a risk of confusion in the calculation.
Inspector B is temporarily transferred from the inspection position of other products to the finished product inspection position of A injection.
The pre-job training is only carried out by the way of inspector B self-learning the post operation procedures.
The personnel changes have not fulfilled the change control procedures and are released during the finished product review.
The change is not reflected in the record.
The inspection reviewer C lacked the inspection experience of A injection, and the follow-up batch record reviewer did not pay much attention to this record, which caused the release of the finished product to be out of control.

 

　　The meeting required the QC department to immediately carry out a comprehensive self-inspection, and QA batch record reviewers participated and supervised the implementation.
Inspector B’s temporary transfer to undertake inspection of finished product inspection records for injection A shall be further traced, and inspector B’s finished product inspection records shall be re-examined by personnel with A injection inspection experience to confirm whether the inspection results meet national standards.
The QC department investigates whether there is a temporary change of inspection personnel in other product inspection positions, and re-examines the relevant inspection records.

 

　　The meeting decided to change the approved and released A injection products in the warehouse and other products with similar conditions to the pending state during the defect investigation and analysis and risk assessment period, and suspend the release and sales.

 

　　Responsible department for defect investigation and analysis: quality authorized person, quality assurance department, quality control department.

 

　　Responsible person for defect investigation and analysis: quality authorized person, QA person in charge, batch record reviewer D, QC person in charge, QC inspector B, inspection reviewer C.

 

　　Responsible department for defect rectification: quality authorized person, quality assurance department, quality control department.

 

　　Responsible person for defect rectification: quality authorized person, QA person in charge, batch record reviewer D, QC person in charge, QC inspector B, inspection reviewer C.

 

　　3.
Risk assessment

 

　　**Year**Month**, the legal representative of the company or the person in charge of the company, the person in charge of quality, the person in charge of quality, the person in charge of QA, the batch record reviewer D, the person in charge of QC, the QC inspector B, the inspection reviewer C And inspection record review personnel to participate in the risk assessment meeting.
Based on the results of the investigation and analysis and the re-review of the inspection records, the risk assessment of the relevant products that have been on the market is carried out, and the risk control and rectification opinions are put forward by classification.

 

　　After reviewing again, there were calculation errors in the inspection records of *** batch A injection, the ** batch has been put on the market, and the ** batch has been released but has not been put on the market, and no non-compliance with national standards was found.
However, it was found that *** batches were close to the national standard limit.
No calculation errors were found in other inspection personnel changes and inspection records.

 

　　Reviewing the continuous stability investigation data of A injection, the related substances of this product have a linear upward trend during the validity period.
After a comprehensive assessment, it was determined that the A injections with batch numbers of 20190802, 20190903, and 20190904 had the risk of the relevant substances exceeding the national standards within the validity period.
It was decided to initiate a recall of the A injections with batch numbers of 20190802 and 20190903 that have not been marketed.
The batch number of 20190904 A injection will not be released.

 

　　Risk Assessment Responsible Department: Quality Manager, Quality Authorized Person, Quality Assurance Department, Quality Control Department.

 

　　Responsible person for risk assessment: the legal representative or person in charge of the company, the person in charge of quality, the person in charge of quality, the person in charge of QA, the person in charge of QC, the person in charge of inspection record review.

 

　　4.
Risk control

 

　　Based on the results of the risk assessment, the Quality Assurance Department and the Quality Control Department formulate corresponding risk control measures, and organize the implementation according to the plan.

 

　　4.
1 Clear risk control for hidden safety hazards

 

　　For the 20190802 and 20190903 batches of A injections that have been on the market, they immediately initiated active recall measures, traced sales flow information, notified relevant drug companies, and suspended sales of related batches of products.
The unmarketed 20190904 batch of A injection products in the warehouse were adjusted to a pending state, strict control was implemented, sales were suspended, and the recall plan and recall evaluation report were reported to the Provincial Drug Administration Resident Inspection Office in a timely manner.

 

　　4.
2 Corrective actions

 

　　4.
2.
1 Investigate the relevant batches of products whose re-audit results are close to the limits of the national standards, focusing on the quality of the API, the storage conditions of the API, the operation and maintenance of the sterilization equipment, and the control of the production process (such as whether the production time exceeds the verification Examination and analysis will be conducted in terms of the scope, whether the temperature of the dosing solution is consistent with the process verification, whether the temperature and time of the final sterilization deviate), etc.
, and other batches of A injections produced with the same batch of APIs and the same sterilization at the same time period will be used.
Bacteria equipment is terminally sterilized and other batches of injection A are included in the scope of investigation.

 

　　After investigation, the aforementioned related substances are close to the relevant batches of products stipulated by the national standards.
They are all terminally sterilized using the sterilization equipment with equipment number SZZZ02, and this equipment has experienced a deviation during the production of injection A on **month** After the deviation occurred, the equipment department replaced the temperature control probe of the equipment, and the production time of the above batch of products was before the replacement of the temperature control probe, which had obvious relevance.
After evaluation, the deviation did not adversely affect the production of other batches of A injection, and the related risks have been effectively controlled.

 

　　4.
2.
2 Revised the "Finished Product Audit Release Procedures", further clarified and refined the work responsibilities and audit content of all levels of personnel engaged in the audit release of materials, intermediate products, and finished products, stipulated audit requirements, and strengthened the quality responsibility awareness of relevant personnel , Improved the review and release management procedures.
Relevant personnel for finished product review and release and A injection product inspection personnel were trained on job responsibilities and job operating procedures, and the training effect was evaluated.

 

　　4.
2.
3 Revised the inspection record template for the finished product of A injection, using f1 and f2 to indicate the correction factors of single miscellaneous I and single miscellaneous II to avoid errors in the calculation process, and conduct targeted training for relevant personnel to monitor the training effect Evaluation.

 

　　Responsible departments for implementing corrective measures: Quality Assurance Department, Quality Control Department, Production Department, Material Control Department, Sales Department.

 

　　Responsible person for implementing corrective measures: legal representative or person in charge of the company, person in charge of quality, quality authorized person, *** (quality assurance department), *** (quality control department), *** (production department), *** (material control department), *** (sales department).

 

　　4.
3 Preventive measures

 

　　4.
3.
1 Incorporate changes in personnel related to drug production and inspection into change management, and review the change control situation, which should be reflected in the finished product review and release record when necessary.

 

　　4.
3.
2 Strengthen the training and assessment management for the adjustment of position operators, and clarify the qualifications of the position operators.

 

　　4.
3.
3 Improve the internal self-inspection mechanism of the enterprise and refine the content and requirements of the self-inspection to ensure the effective operation of the quality management system.

 

　　Responsible departments for implementing preventive measures: Quality Assurance Department, Quality Control Department, Production Department.

 

　　Persons responsible for implementing preventive measures: *** (Quality Assurance Department), *** (Quality Control Department), *** (Production Department).

 

　　5.
Rectification review

 

　　After the quality assurance department, quality control department, production department, material control department, and sales department have reviewed the implementation of risk control measures in this department, as of **year** month**, 20190802, 20190903 batch A injection has been recalled , Product quality risks are effectively controlled, relevant document records have been revised, approved, and distributed, relevant personnel have passed training and assessment, and various corrective and preventive measures have been effectively implemented.

 

　　The rectification of this defect has been completed, and the review opinions on the rectification of the defect have been reported to the Quality Assurance Department.

 

　　Responsible departments for rectification and review: Quality Assurance Department, Quality Control Department, Production Department, Material Control Department, Sales Department.

 

　　Responsible person for rectification review: *** (Quality Assurance Department), *** (Quality Control Department), *** (Production Department), *** (Material Control Department), *** (Sales Department).