Quality Risk Management Of Oral Solid Dosage Form GMP Management

Oral solid preparations of drugs are widely used clinically, and the attention paid to their quality and safety is lower than that of other dosage forms. The safety of oral solid preparations cannot be ignored. The 2010 version of drug GMP puts forward the concept of quality risk management. How to implement quality risk management of drug production has become the focus of attention from all walks of life. . This article systematically discusses the implementation and research status of drug quality risk management in China, analyzes the ways to implement production quality risk management of oral solid preparations, and provides reference for the effective implementation of production quality risk management of oral solid preparations.

Oral pharmaceutical preparations are stable in quality, convenient to take, easy to carry, store and transport, and their production quality and safety directly affect public health and life safety. Oral solid preparations account for a large proportion of OTC drugs in the national essential drug list. Judging from the current situation of quality sampling inspection, the quality and quality of injections are at greater risk. Oral solid preparations account for a large proportion of civilian medicines. The incident shows that there is a great risk in the quality and safety of oral solid preparations. The current focus on drug safety ignores the quality and safety of oral solid dosage forms. In 2011, the drug GMP released by SFDA introduced the idea of risk management for the first time, requiring drug manufacturers to implement quality risk management, which is the demand for the quality and safety of drugs themselves. At present, there are many problems in China’s drug quality risk management. Drug manufacturers have weak risk awareness and lack corresponding technical guidelines. Research on drug quality risk management in China mainly focuses on theoretical research, and there are few literatures on the application of drug quality risk management related to production risk management. Strengthening the research on the production quality risk management of pharmaceutical oral solid preparations has important practical significance for strengthening the production quality risk management of pharmaceuticals.

Part 1 Overview Of Pharmaceutical Manufacturing Quality Risk Management

Risk management is used to prevent the occurrence of risk accidents and plays an important role in various fields of social life. Risk management refers to the systematic use of quality management policies and methods for risk assessment and notification. Quality risk refers to the possibility of product quality hazards. Quality risk is a systematic process of product quality risk assessment and review throughout the life cycle. Drug quality risk is the probability of occurrence of hazards related to the quality of the drug life cycle. Drug production quality risk is the analysis of a series of factors related to drug production, the impact on drug quality, risk assessment and review of drug quality. The quality risk management is mainly to analyze a series of human, machine, physical, legal, environmental and other factors related to pharmaceutical manufacturing activities, and to evaluate, control and review the factors that affect the quality of pharmaceuticals.

The implementation of drug quality risk management should be based on scientific knowledge, with the strength and documentation of scientific and reasonable quality management procedures. Quality risk management includes risk identification, assessment and control. The quality risk management approach includes a basic and concise approach to risk identification.

Part 2 Research On Risk Management of Drug Quality In China

At present, the main means of monitoring drug quality and safety in China is ADR (Adverse Drug Reaction) monitoring. The number of ADR reports has increased year by year, and the relevant legal system has been continuously improved. Monitor the information of the center and realize the electronic report.

Through a series of laws and monitoring means, corresponding administrative measures are taken to control drug risks. For example, the risk control of oral solid preparations of huperzine A mainly controls risks by improving the safety information of its instructions. Pharmaceutical GMP supervises the quality of pharmaceuticals in the whole process of production. In the quality management of pharmaceutical production, pharmaceutical GMP is the basic principle that must be followed. The implementation of pharmaceutical GMP has effectively guaranteed the quality of pharmaceuticals produced, but there are still many problems in the actual production of enterprises.

The basic condition of each stage of pharmaceutical production is to be supervised by the pharmaceutical GMP management system, and the introduction of quality risk management into pharmaceutical GMP has become a part of the regulations. Integrate quality risk management into production quality management according to the requirements of drug GMP, clarify the responsibilities of each department, and actively carry out drug quality risk management. Implement quality risk management, increase the requirements for personnel qualifications, and increase the requirements for the confirmation and calibration of plant facilities and equipment. During the operation of the GMP system such as complaints and adverse reactions, deviations and OOS, change control, and product annual reports, the company promptly discovers Risk Factors Affecting Drug Quality Strengthen the link between drug production supervision and other links to improve the controllability of product quality risks. Pharmaceutical GMP emphasizes the requirements of pharmaceutical production and its consistency. Due to the late start of China’s drug quality risk management, there are certain problems in the implementation of legal construction and other aspects. At present, the “China Drug Administration Law” only stipulates post-marketing drug monitoring, lacking specific guidance measures, drug GMP only proposes basic requirements for quality risk management, and relevant regulations on drug risk management need to be improved.

Manufacturers lack technical support in terms of risk control measures, and there are no guiding technical documents for guidance. Manufacturers have weak research and development foundations, low production technology, and high drug quality risks. Lack of perfect and effective data support system to integrate monitoring data. In-depth analysis of the data cannot be performed.

The implementation of drug quality risk management requires a sound risk management organization system. Under a sound legal system, scientific risk management measures can be adopted to achieve better development.

Part 3 Characteristics And Risk Management Of Drug Oral Solid Formulations

Oral solid preparations mainly include dosage forms such as tablets, capsules, and granules. Oral solid preparations have many advantages that other preparations do not have.

Oral solid preparations are available in various varieties and are widely used. The main advantages are stable quality, accurate dosage and convenient administration. Due to its many advantages, oral solid preparations have become the main dosage form currently developed, occupying the first place in the number of manufacturers and the share of pharmaceutical dosage forms.

Oral solid preparations account for 51.1% of domestic chemical pharmaceuticals. There are 121,626 types of different chemicals in all pharmaceutical manufacturers in China, and 47,803 types of oral solid tablets. Oral solid preparations accounted for 76.8% of domestic traditional Chinese medicines. Oral solid preparations account for a relatively large proportion of OTC. According to relevant statistics collected in the SFDA data query system, there are 11,708 different health products produced by enterprises, and oral solid preparations account for 67.7% of the total.

In 2010, the National Adverse Drug Reaction Monitoring Center received 692,904 adverse drug reaction reports, oral preparations accounted for 37.0%, and serious adverse drug reaction reports were 109,991 cases, oral preparations accounted for 19.7%. Oral solid preparations have advantages that other preparations do not have, and have great advantages in production and clinical application. Through the safety analysis of the quality supervision and random inspection of oral solid preparations, the oral preparations are unqualified, indicating that oral preparations are risky. Pharmaceutical GMP clearly stipulates the basic requirements of quality risk management, and it is very necessary to implement production quality risk management for oral solid preparations.

Part 4 Drug Oral Solid Dosage Form Quality Risk Management Model

Carry out production quality risk management for pharmaceutical oral solid preparations, and take corresponding risk control measures for risk control according to the ICH risk management process. The RRF (residual renal function) method is used to manage the risk of the production quality of oral solid preparations, classify the risks, and implement corresponding management methods.

Risk assessment is the first step of risk management, including risk identification, analysis and evaluation. The analysis and identification mainly adopts the flow chart method, and analyzes the activities related to human, machine, method, ring and other links in each production process. After determining the production process flow, each sub-step is analyzed and the related activities on site are investigated. Combined with the flow chart, determine the risk factors that affect the quality of the drug, and plan to determine the main risks of the product.

Risk analysis is to analyze the identified risks, analyze the possibility of occurrence of each risk, describe the risks in depth, and analyze the production process of oral solid preparations. Risk assessment is to evaluate the severity of identified risks after analysis, and the division of risk levels can use qualitative descriptions such as high, medium and low.

For the quality risk management of oral solid preparations, commonly used risk control measures mainly include continuous improvement of hardware facilities and standard operating procedures (SOP) and organization of personnel training, etc. All measures must be subject to change control, confirmation and verification in accordance with the implementation requirements of the enterprise’s GMP management system wait. Risk review is to evaluate the effectiveness and applicability of risk management activities, and judge whether the effect of each implementation in the implementation of risk management has reached the predetermined goal. Regularly review risk events and continuously improve risk management level.

Part 5 Quality Risk Management Of Efavirenz Tablets Based On FMEA Risk Assessment Method

FMEA was used to implement production quality risk management for efavirenz tablets, mainly evaluating the active ingredients of the product, the cleaning effectiveness of collinear equipment and product quality risks.

Risk analysis is specific to FMEA, and failure factors may cause the occurrence of failure modes. Evaluate the consequences of failures in each production process of efavirenz tablets, and determine product quality and process operations based on risks. The production process of Efavirenz tablets is a common wet granulation process, which is mainly divided into ingredients, wet granulation, drying, blending, tablet compression, coating and plastic bottle packaging. Each step achieves the intended purpose according to the specified requirements.

The unique physical properties of the active ingredients of efavirenz tablets may lead to the risk of unqualified dissolution of the preparation. It is a low risk to reduce the risk of unqualified dissolution by controlling the physical indicators such as the particle size of its active ingredients, controlling the granulation process, and developing a granule dissolution measurement method to deeply study the influence of the process on the dissolution rate.

Inadequate cleaning of the internal surfaces of equipment that come into direct contact with pharmaceutical products may lead to the risk of product cross-contamination. The active ingredient of efavirenz tablets is insoluble in water. Using the equipment cleaning procedures established in the workshop, there are still visible residues on the surface of the equipment after cleaning, which cannot meet the expected acceptance standards. There may be a potential risk of cross-contamination to other collinear products . The cleaning reliability is poor, and this risk can be identified through routine visual identification and sampling inspection, which is a high risk. Therefore, it is necessary to develop new cleaning procedures based on product characteristics, such as adding cleaning solvents, refining cleaning steps and visual inspection requirements, etc., to carry out cleaning verification on the newly developed cleaning procedures to prove the effectiveness of the cleaning procedures, and to increase periodic cleaning monitoring , including the detection of the residual limit of cleaning agents, to control the risk of contamination and cross-contamination at a low risk level.

During the coating process, if the prepared coating slurry is not completely dissolved, it may lead to clogging of the coating nozzle and defects in the coating appearance. The root cause of the analysis is that some slurry tanks are not equipped with a stirring speed display, and the operator sets the stirring speed based on personal experience. , caused by not checking whether the slurry is completely dissolved before starting to spray. Through the transformation of the slurry mixing tank, adding the display of the slurry speed, and specifying the speed range, stirring time and slurry dissolution inspection before starting the spraying in the program, the reliability of the product quality elements is not affected or the detectability is less affected . The probability of occurrence of this risk is small. Belong to low risk. After risk analysis and implementation of control measures for efavirenz tablets, the RPN value decreased significantly. The risk assessment of efavirenz tablets was carried out by using the FMEA method, which effectively reduced the risk level. FMEA is a continuous dynamic process, which needs to be improved and optimized in constant changes to improve product quality and economic benefits of the enterprise.

Part 6 Conclusion

This study takes the production quality risk management of pharmaceutical oral solid preparations as the research object, discusses the production status of oral solid preparations, and uses different risk management tools to conduct municipal research on the quality risk management models of oral solid preparations. The implementation of production quality risk management is a requirement of pharmaceutical GMP. Building a scientific and applicable production quality risk management model is the guarantee for effective implementation of quality risk management.