Yang Luyao,Dong Jiangping,Yang Yue

(School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China)

Abstract Objective To carry out an on-site inspection to promote the optimal allocation of inspection resources through the introduction of risk management theory in the process of inspection because inspection can prevent drug quality deterioration and ensure drug safety and efficacy.Methods The application of Food and Drug Administration(FDA) risk management plan in pre-registration and daily supervision was analyzed to study the construction of inspection model for production site based on risk management procedures.Results and Conclusion In order to improve regulatory efficiency,China can establish a risk-based drug inspection system from FDA risk management plan.

Keywords:establishing inspection;risk;monitor

Risk management is a scientific method to eliminate the bad consequences with lower cost through the identification,assessment and control of risks.Applying risk management to drug inspection can more accurately judge whether enterprises in the process of drug production conform to standards and predict their possible risks,thus taking corresponding measures to reduce the losses.

1 Background of FDA risk-based drug inspection program

1.1 Change of the production trend in pharmaceutical industry

In 1984 Hatch-Waxman Act was promulgated,prompting generics enterprises to seize the market shares rapidly by taking the legal advantage.Meanwhile,in order to make up for their market share,the original drug enterprises were forced to continue to increase cost of research and development(R&D) for new products.They had to reduce funds for clinical trials of the safety and efficacy of new compounds.As a result,the quality of products could not be guaranteed.Nearly 50% of new drugs were not approved due to lack of sufficient data to support their safety and efficacy in phase III[1,2].Therefore,in the context of products failing to comply with Current Good Manufacturing Practice (cGMP) requirements and the prolonged review time,FDA adopted a riskbased management approach,focusing resources on high-risk sites[3].

1.2 Limited inspection resources

21 CFR 360 (h) stipulated previously that drug companies registered in the United States should be inspected at least once by the FDA every two years.If this rule is still in use today,based on the statistics of the FDA in 2019,FDA should inspect more than 6 000 drug manufacturing sites that produce 97 000 finished products and 4 000 active pharmaceutical ingredients(APIs).Given the FDA’s human resources,it is not possible to inspect all the production sites regularly and indiscriminately.As a result,it is difficult for FDA to implement uniform and intensive good manufacturing practice (GMP) inspections at all sites[4].In 2012,the Food and Drug Administration Safety and Innovation Act (FDASIA) regulated that the frequency of supervision and inspection of production sites should be adjusted from the fixed frequency of at least once every two years to a risk-based inspection program,which means targeted selection and inspection of highrisk sites[5].

2 Application of risk principle in drug inspection

2.1 Application of risk principle in pre-approval inspection (PAI)

According to the FDA’s risk-based initiatives,in order to simplify PAI procedure,FDA updated the Compliance Program Guidance Manual of PAI(CPGM 7346.832) several times in 2003,2010 and 2019,deleting the list of narrow-therapy index drugs,specifying the information that was not required for registration,and reducing the categories of inspection project.At the same time,FDA requires enterprises to establish a risk-based quality management system,optimize production processes,and eliminate production projects with low value-added for drug safety and effectiveness[6].

2.2 Application of risk principle in daily supervision and inspection

2.2.1 Risk-based inspection method

FDA has introduced the risk principle in CPGM 7356.002,identifying six key areas of inspection:quality system,facility and equipment system,materials system,production system,packaging and labeling systems and laboratory control system.According to the principle of risk,at least one system will be selectively inspected or a comprehensive inspection will be carried out.The focus of the inspection is to determine whether the quality management system of the enterprise can maintain effective control,and to concentrate on deviations and corrective actions.FDA focuses its inspections on determining whether a company’s quality management system maintains effective controls.This principle is to inspect the deviations made by enterprises and their corrective measures.

2.2.2 Model of risk-based site inspection

In 2018,FDA issued the policy and procedure manual“MAPP 5014.1:Understanding CDER’s Risk-Based Site Selection Model”,promoting the risk-based site selection model (SSM) to prioritize the supervision and inspection of production sites and make inspection plans,i.e.Site Surveillance Inspection List (SSIL).

(1) Scope.Currently,SSM is applicable to sites in the inventory of Center for Drug Evaluation and Research (CDER) production sites that require routine supervision and inspection,including commercial production sites for intermediate products,finished drugs (preparations) and active pharmaceutical ingredients[7].

(2) Risk factors.Section the Federal Food,Drug and Cosmetic Act (FD&CA) 510 specifies the risk factors referred to by SSM,including:firstly,the compliance history of the drug site (the inspection record and recall history of FDA or other inspection agency);secondly,the inherent risks in product production (the complexity of API or process).

(3) Model of risk-based site selection.The experts in CDER and Office of Regulatory Affairs(ORA) who owe drug review,production control and inspection experience discuss to determine the factors that influence the production,such as the number of shipping lines and the inherent characteristics of the product.Through direct observation,FDA experts divided the list of risk factors into three categories:product,process and facilities.The risk score of each site,namely,the site risk potential (SRP),is the weighted function of each risk category.The assignment of weights or grades is based on empirical evidence or expert judgment or a combination of the two.FDA office of drug quality is responsible for formulating the site supervision SSIL of CDER,inputting the list of drug sites applied for inspection into SSM.Then SSM assigns and sorts the sites according to the score attached to the risk factors.The sites with high risk scores will be given to the office of regulatory affairs for inspection,and SSIL will be generated at the same time[8].

(4) Continuous improvement of site selection model.The selection of risk factors in the model mainly depends on the existing data in FDA database.With the improvement of data quality and the collection of new data,FDA constantly adjusts model through expert assessment and peer review according to the identified risk in the examination of the deviation,including reviewing methods of models,risk factors and weight.And then they evaluate the current version of the model and modify it to scientifically support the inspection[9].

3 Performance of FDA’s risk-based site inspection model

From 2014 to 2018,the number of inspections in drug and medical device production sites in the United States is shown in Table 2.The actual number of inspection sites is lower than the number of registered sites,which indicates that FDA has selected the onsite inspections through screening.The proportion of the actual inspection sites reduced gradually shows the continuous improvement of SSM.The number of high-risk sites on the SSIL list decreased,and FDA inspection coverage of production sites decreased as well,indicating that more and more production sites can meet cGMP standards.

Table 1 Quantity of FDA GMP on-site inspection of pharmaceutical and medical devices [10]

In 2018,the FDA spent about $200 million on GMP inspections of drugs and medical devices,according to the agency’s annual inspection report.Taking the $45 000 inspection fee for API sites in the United States in 2018 as an example,we can see that the cost is not sufficient to support the 34 466 domestic and foreign GMP inspections.Besides,other types of inspections,such as PAI,unannounced inspection and routine inspection were not included.Therefore,the risk-based inspection program will help the FDA save billions of dollars in costs and a lot of human resources[11].

4 The significance of FDA’s risk-based inspection program for China

On March 31,2020,China’s latest version of the Provisions for Drug Registration was released,which clearly stipulated that risk-based review,inspection and analysis model should be established.Based on product risk,PAI and pre-marketing GMP compliance inspection can be conducted simultaneously.Risk factors include the complexity of the variety and production process,site facilities,and prior inspection history etc.Learning from the risk management model of FDA,some suggestions for establishing and improving the risk-based drug inspection system are provided for China’s national conditions.

4.1 Revising and updating laws and regulations timely

In recent years,China’s drug regulatory system has been reformed rapidly and relevant documents and regulations have been issued by different institutions.At the same time,the rapid development of the pharmaceutical industry and the emergence of new regulatory ideas may be contradictory to laws and regulations.In order to ensure the timeliness of the law and the development of the pharmaceutical industry coordination,it is necessary to update and refine the ambiguities in laws and regulations timely and issue guidance documents[12].For example,Guiding Principle for Risk Evaluation During On-site Inspection of Pharmaceutical Production classifies the product risk as high risk and general risk.Most products are general risk products except for high risk ones.As products diversify,such a ‘one rule fits all’ approach may not work well.In order to avoid misjudgment,it is suggested to divide the products into high,medium and low risks according to the complexity of API and production process,and then corresponding supervision principles should be made according to the grade.Lastly,the revision period of drug regulatory laws and regulations should be clarified,and the revision time should be written into the regulations as well.It is recommended that relevant guidelines and quality management specifications be revised dynamically.This can change the status quo of long-time limit and unpredictable process of laws and regulations in China.Meanwhile,it will ensure the adaptability of laws and regulations and avoid the situation that the documents cannot keep up with the changes of laws and regulations[13].

4.2 Improving the risk-based inspection program

In order to concentrate limited resources on enterprises that need regulation most,the Center for Food and Drug Inspection (CFDI) should cooperate with the evaluation department to establish a risk-based inspection plan.The plan can describe the philosophy,methodology and procedures of risk management.At the same time,the plan should be continually reviewed and updated (at least annually),and should cover various inspections and other activities.

(1) Identifying risks in the inspection.The number of inspectors required for inspection,the time and scope of inspection shall be determined according to various kinds of risks.Risk may include product complexity,product type,process,compliance risk,inspection records,site complexity,and complaints and recall history,etc.Referring to the risk matrix model in Fig.2 and FDA risk-based SSM,industry experts are assembled to form a group to determine the risk level of the sites through brainstorming or group discussion and combined with field research and data research (low risk,general risk,high risk).

Fig.2 Risk matrix grid

(2) Risk-based inspection program and implementation.According to the risk level of the sites,the registration application is divided into:required inspection (high risk),random inspection(general risk),and exemption inspection (low risk).As to the necessary inspection of innovative products or newly established enterprises,the Center for Drug Evaluation (CDE) and CFDI should strengthen their cooperation to clarify the inspection points in the application so that they can carry out targeted inspections and reduce the mandatory inspection categories.For the random inspection,such as increasing product specifications,a certain proportion of random inspection shall be stipulated to ensure that the number of random checks accounts for a certain proportion of the total number of general risk applications.The proportion shall be continuously adjusted in real time according to the total amount of verification and the registration applications.For the exemption inspection,the supervision of postmarketing products should be strengthened.For instance,the frequency of routine GMP inspection should be increased.

4.3 Encouraging enterprises to apply risk-based methods and innovative technologies in quality control

Previously,due to the high cost of clinical trials,enterprises may avoid using some innovative quality control methods to reduce the assurance of product safety and effectiveness.For example,computers are used to simulate animal clinical trials to save the cost.In order to perfect in risk-based inspection method,regulators should strengthen communication and coordination with enterprises.Meanwhile,enterprises should be encouraged to apply risk management to the production quality control link based on the principle of quality by design.A risk-based quality system can be established by scientific approaches to integrate the organizational structure,process and production site of the enterprise.Deviations should be identified and corrected quickly,and site risks must be reduced continuously.The quality system of enterprise should be improved in real time to promote the transformation from research and development to production.

5 Conclusions

Drawing on the experience of FDA and combining it with China’s social conditions,riskbased inspection methods can be improved.Besides,regulators should optimize the mix of resources and focus on compliance of high-risk enterprises.Pharmaceutical industry can use the risk approach to deepen their understanding of the design control,key process and product attributes,and ultimately promote R&D innovation.Through the dual efforts of the industry and regulators,the quality and safety risks of products are controlled.