The third series of multi product common line risk management and control strategy

In order to achieve reliable quality objectives, production enterprises should pay proper attention to and control the factors of cross contamination in production sites or facilities It is unrealistic and scientifically impossible to achieve zero cross contamination risk between products in the production of multi product co production plants In the normal GXP range, the degree of cross contamination control should be appropriate to the determined patient risk level As mentioned in the previous article of multi product co production management, special facilities are required for the production of drugs when they have the following risks ? 1 The risk cannot be fully controlled through operation and / or technical measures? 2 The scientific data from toxicology evaluation does not support the controllable risk (such as possible allergic reactions of highly sensitized materials, such as β - lactam antibiotics)? 3 The validated analytical instruments cannot satisfactorily determine the relevant residual limit obtained from toxicology In addition, as long as adequate control is provided, adequate control measures to prevent pollution are established, and the risk of cross pollution is kept below the acceptable level, common facilities can be used for production When an enterprise decides to adopt multi product co production, it needs to develop a reasonable and perfect risk management system for it, and the purpose of the implementation strategy is to inspect whether the control measures of the risk management system are sufficient, and the second is to make decisions on whether special facilities / equipment are used for some process steps of the co production process Strategy description the establishment of strategy needs to be considered from two aspects, one is GMP / regulatory factors, the other is occupational health factors, both of which are equally important In addition, two important parameters need to be defined before strategy formulation, one is PDE of GMP / regulatory factors, the other is OEL of occupational health factors （1） The strategy based on GMP / supervision needs to define the PDE of products in the strategy formulation of GMP / supervision PDE involves many strategies formulation in GMP / supervision factors These strategies provide sufficient help in reducing cross pollution, such as the formulation of cleaning residue limit, the development and confirmation of analysis methods related to cleaning residue limit, etc The guidance for PDE requirements from the perspective of regulations and guidelines is as follows: the implementation question and answer issued by EMA on risk-based prevention of cross contamination in drug production and "health-based exposure limit setting guidelines for risk identification of different drug production in shared facilities" (EMA / CHMP / CVMP / SWP / 169430 / 2012) It is proposed that pharmaceutical enterprises should establish hbel (hbel = PDE) for all drugs The toxicity or pharmaceutical data on which hbel calculations rely need to be reassessed periodically over the product life cycle In combination with ISPE benchmark guide 7, risk-based pharmaceutical product production (MAPP) provides a risk level model corresponding to different PDE values, and requires enterprises to establish corresponding risk control measures for different levels of PDE values In the model diagram, the PDE value of the product is 10000 μ g / day, which is low PDE should be determined by personnel with sufficient expertise and toxicology / pharmaceutical experience, familiarity with drugs, and health-based exposure limit determination experience such as occupational exposure level (OEL) or PDE The scientific basis for health exposure limits should be summarized in a formal and written form The calculation of hbel, or daily allowable exposure (PDE), is still a challenge for enterprises In EMA common facility guidelines, this method is used to calculate product raw material residues The calculation formula is as follows: the search and determination of NOAEL in the above formula will be the first difficulty At present, pharmaceutical companies may not have enough time and energy to explore the NOAEL value of each API, and the retrieval of NOAEL should be based on scientific and risk-based methods and develop corresponding strategies Retrieval strategy, retrieval records and results should be recorded and reviewed by relevant subject matter experts (SMEs), so the accuracy judgment of NOAEL will be very important In addition to PDE, strategy development in GMP / regulatory factors also includes risk-based strategies to prevent confusion, which are mainly considered from the following two activities: process activity process and exposure: review potential exposure factors generated in the process The process of product production may have many characteristics, all of which may have more or less influence on the risk of cross contamination of one or more paths The main factors considered in the production process include: the degree of material open operation (e.g manual dispensing) and energy internalized in the process in the form of speed, pressure and temperature, which may form a transmissible aerosol, such as: milling transfer: repeated loading and unloading through fragile connectors in unit operation, providing a possible way for material release The more transfers are needed, the more potential risks are exposed The more frequent a process is running, the higher the risk of material release or continuous release is Personnel behavior or compliance with SOP: systems that are highly dependent on operator technology or systems that allow operators to perform a wide range of changes are more likely to fail Non process activities can include the following: waste disposal The risk assessment of planned and unplanned maintenance to identify cross contamination should consider the path of all potential cross contamination under all operating conditions in a systematic and detailed way Conduct assessment review: in the design stage of new or modified facilities / equipment, when introducing new products, processes or equipment changes, as part of the relevant change control as part of the regular risk management review, the following are some possible examples, when the probability of failure or error is high, and these should also be part of the assessment: Manual process has always been unstable process or equipment process specific elements (batch change, shift change, maintenance) new employees, untrained employees, or replacement of other employees (two) based on the strategy of industrial health multi product line production should not only consider product quality, but also consider the exposure risk of operators Occupational exposure limit (OEL): the concentration of large airborne particles of a pollutant at which almost all workers can repeatedly contact the pollutant day by day without adverse reactions It is usually expressed as a time weighted average of eight hours per day The data calculated by OEL are from toxicology or clinical data The following questions are combined to evaluate industrial health: who will be exposed? Online workers, maintenance personnel, general personnel in the area, or QA when facing sampling? What are the factors that affect exposure? Dusty powder? Liquid? Closed or open process? How do we train our employees? A program or frequent task? What is the way to expose it? Inhaled, ingested, or absorbed through the skin? What is the frequency of exposure? Do employees need to sample directly in the process? After the interruption of the production process, is it cleaning or the termination of production activities? It is very important to summarize the strategies of assessment and control to solve the problems of cross contamination and confusion Any control strategy used to maintain an established acceptable risk level should not add another new risk.