Interpretation of EMA's questions and answers on cross contamination of shared facilities and health-based exposure limit setting

The term explains the exposure limit value of OEL (occupational exposure limit) occupational harmful factors, which refers to the allowable exposure level of workers who repeatedly contact for a long time in occupational activities without causing acute or chronic harmful health to the body TTC (threshold ofoxylogical concern) all chemicals can determine a human exposure threshold As long as the human exposure level is lower than the threshold, the possibility of harm to human health is very low ADI (acceptable daily intake) is a term used by who and some national and international health organizations A dose of a certain chemical substance (food additive, pesticide, etc.) taken daily by human or animal without any known adverse effect on health, expressed in milligrams per kilogram of body weight, abbreviated as milligrams per kilogram of body weight PDE (permitted daily exposure) the daily average Zui large dose, in mg / day, in which an organic solvent is allowed to be ingested without toxicity ICH is used to define the acceptable intake of organic solvents in drugs to avoid confusion with ADI of the same substance LD50 (lethal dose, 50%) refers to the drug dose that can cause half of the death of the experimental animals, which is usually expressed by the logarithm of the lethal dose of the drug Q & A Interpretation on April 30, 2018, EMA released the revised Zui final version of its Q & a document, focusing on risk identification and health-based exposure limit setting in risk-based prevention of cross contamination For the guidance of ISPE Volume 7 (a guide to managing risks associated with cross containment), which focuses on risk identification and risk-based prevention of cross contamination, the guide provides an ICH Q9 (15.1, 28 A scientific risk-based approach to manage the risk of cross contamination has maintained an appropriate balance between product quality and operator safety In risk-based production, risk is a combination of the possibility and severity of injury "Risk" is the probability of injury at a given level of exposure and reflects the severity of the injury (e.g., consequences of failure) Caution should be exercised in subjective evaluation (Qualitative) and risk scoring Where possible, appropriate data should be used to assess risk If the data is not available, you may need a plan to get the data Since the hazard (including its severity) cannot be changed, the level of hazard exposure can be controlled to reduce the health risks of staff and patients caused by cross product pollution or environmental pollution Therefore, the possibility (or risk) of injury is the role of exposure level Therefore, Q & A mentioned that all drugs should establish health-based exposure limit (hbel = PDE) The toxicity or pharmaceutical data relied on by hbel calculation need to be reassessed in the product life cycle, so as to analyze the priority of risk and formulate the prevention of cross contamination corresponding to the risk level Control measures The description in Q & A is: after the health-based assessment is completed and PDE is confirmed, these data shall be used through the quality risk management process (qrmp) to determine which controls need to be developed, and assess whether the existing organizational and technical control measures are sufficient or need to be supplemented A generalized hypothetical model (source: ISPE Volume 7) can be considered to show the hazard level growth of products, and the control level corresponding to preventing potential cross contamination in shared facilities should also be increased The PDE value of 10000 μ g / day was Zui low The actual PDE value should be used in QRM studies to determine the actual required control For different PDE values, different strategies may be adopted in quality risk management to analyze and control risks The difference between PDE and OEL should also be considered in the process of internal evaluation PDE is usually used to evaluate the cross contamination health standards concerned by GMP OEL is often used to assess health standards for the use of airborne products in the workplace The description in Q & A is: PDE report shall be determined by personnel with sufficient professional knowledge and toxicology / pharmaceutical experience, familiar with drugs and experience in determining health exposure limit, such as occupational exposure level (OEL) or PDE ISPE Volume 7 also provides guidance on the need for clear strategies to assess the risks set by IH or cGMP, and to scientifically define the basic criteria to make decisions for managing risks Although the criteria used for both are derived from the same toxicological or clinical data, they differ in the way they are used to derive acceptable limits and adequate control strategies It is important to understand these differences and the possible consequences of confusing them In the process of cleaning validation, LD50 is not enough to be used as hbel to determine drugs It is necessary to establish cleaning purpose limit based on PDE value, but it should not be the same as PDE value For the existing products, the cleaning limit used in the history of the manufacturer shall be kept, and the warning limit provided according to the cleaning process capacity can be considered, so as to provide sufficient guarantee to prevent exceeding the PDE value In terms of cross contamination, it should be understood that the risk should always be controlled within ade / PDE In the APIC cleaning validation guide, LD50 is calculated as MACO, and it is mentioned that if other data (such as PDE, OEL, TDD equivalent) cannot be obtained, only half lethal dose data (such as chemical substances, intermediates, cleaning agents...) can be obtained , MACO can be calculated based on LD50 data The limit calculation of ISPE Volume 7 for LD50 is only for cleaning agents, that is, for equipment cleaning agents (such as detergents), it is recommended to use the median lethal dose (LD50) value to deduce the cleaning limit When LD50 is used to determine the residual limit of drugs for calculation, the use of LD50 as the starting point of risk analysis may lead to insufficient protection of health due to the expected long-term existence of side effects before death The manufacturer shall establish a threshold value for the visual residue of the product At this time, the ability of visual inspection equipment, such as lighting conditions and observation distance on site, can also be considered Visual inspection shall include all product contact surfaces that may be contaminated The visual inspection shall include non product contact surfaces where product residues are likely to fall or transfer to subsequent batches in the future The qualification of visual inspection during cleaning verification is still the basic and primary standard of cleaning verification Zui In addition to the active observation of the visually visible contact surface of the pharmaceutical production equipment with the product after each cleaning, and it must be determined that the equipment has no visible residue, the visual inspection of the non product contact surface of the possible residual product is also required, For example, dust cover set on the pulverizer for dust removal Therefore, the visual inspection should formulate corresponding documents and regulations, such as specifying the light and distance, carrying out relevant experiments on the low residue of Zui visible to the observer, training the visual inspection personnel according to the contents of the documents, and establishing the formality of the visual inspection confirmation procedure through the risk analysis of the site and products It can be seen from the interpretation of Q & A documents that visual inspection is still the primary and Zui low standard for cleaning validation However, the calculation of traditional limit standards, such as 10 ppm and 1 / 1000 Zui low treatment dose and LD50, is not scientific In this case, health-based limit and robust cleaning procedures are used to prevent handover through low residue Cross contamination risk and demonstrate as high a safety boundary as possible The formulation of cleaning residue limit should be based on PDE value, but it should not be equal to the value from PDE PDE value is used as the reference point to judge the risk level brought by residual data, calculate the residue limit from PDE, then collect residual data according to PDE value and conduct trend analysis, and establish "process control limit" based on statistics All rights reserved No reprint without permission If you need to reprint, please be sure to indicate the author and source of the article Aoxing pharmaceutical life cycle compliance consulting service department was established in 2000 It has many GXP experts from developed countries in the global pharmaceutical industry, well-known domestic GMP experts and international registered consultants, and cooperates with foreign consulting agencies The service department, based on the global Zui new regulations and guidelines, takes the pharmaceutical quality system as the center, and provides GXP compliance services in line with the requirements of FDA, EMA, CFDA, MHRA, PIC / s, who, etc for the pharmaceutical industry through a strong project management implementation team, experienced foreign consultants and experts, as well as a complete set of European and American advanced verification instruments So far, we have served hundreds of pharmaceutical enterprises Based on the concept of customer satisfaction as the center, Aoxing provides pharmaceutical industry with consulting services covering drug life cycle compliance from R & D quality system consulting, technology transfer consulting, verification consulting and testing, data reliability consulting, quality system consulting, operation consulting, registration and approval and training, etc To promote the 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