Regulatory Guidance for TOC Measurement in Pharma Water
Today, pharmaceutical companies face two key challenges: the broad globalization of the pharmaceutical market and the needs of many government regulators. Organizations such as the European Medicines Administration (EMA), US Food and Drug Administration (FDA), China State Food and Drug Administration (SFDA), Japan Drug and Medical Device Administration (PMDA) and relevant global pharmacopoeia have different requirements for analytical parameters and their applications. This situation further complicated the decision process of determining parameter control protocols. In order to prevent setting too many restrictions on users, the language used in these regulations is further troubling to users in understanding these requirements: the purpose is to enable manufacturers to fully consider their own specific applications, risk assessments, and use cases.
While the International Coordinating Council (ICH) is not a regulatory body, it is committed to providing uniform guidance to the EMA, FDA, SFDA and PMDA. However, ICH information may cause confusion, and when the material is removed from the regulatory requirements directly specified in the Pharmacopoeia, additional steps are considered necessary to determine the measurement.
In fact, this interpretation is supported by the purpose of the ICH statement: "To propose to achieve greater coordination in the interpretation and application of technical guidelines and requirements for drug registration and the maintenance of such registration". In contrast, if specific guidance is provided, then users do not need to take further verification steps to meet the regulatory requirements.
The stepwise method of selecting the instrument
A simple four-step approach is recommended when determining which regulatory requirements must be met and which non-regulatory guidelines may facilitate the implementation of a specific measurement or analytical instrument (see Table 1). The most basic relevant regulatory requirements must first be considered, and then further clarified by adding regulatory requirements related to the parameters. Finally, clearer and specific requirements are obtained by considering the guidelines outside the regulations. This allows a complete and robust set of measurement requirements specifications to be developed. With this process, it is easier to evaluate the available measurement options and determine the most suitable measurement cases.
Table 1. Methods
|1. General regulatory requirements||USP monograph|
|2. Regulatory requirements related to the parameters||USP<643>、<1231>，ChP<0682>、EP2.2.44、JP2.59|
|3. Resources outside the regulations||ASTMI E2656|
|4. Instrument selection||Corresponding speed, continuous measurement, and ISM technique|
Regulatory guidance for TOC measurements in pharmaceutical water
Water is the most commonly used as excipients in the pharmaceutical industry. It is an ingredient, cleaner, reagent, solvent, and product. Therefore, the production and control of pharmaceutical water use is a common challenge for almost all pharmaceutical manufacturing processes. To assist in the management of the regulations defining the requirements of pharmaceutical manufacturers, the above is recommended to determine an instrument suitable for monitoring and control of TOC in pharmaceutical water.
Table 2 Global criteria for TOC in pharmaceutical water
|Pharmacopeia||Reference documentation||TOC standard|
|U.S.P USP||Chapter <643>||0.5mg/L|
|chinese pharmacopoeia ChP||ChP 2015 Chapter <0682>||0.5mg/L|
|European Pharmacopoeia EP||2.2.44||0.5mg/L and 0.3 mg/L,
which was used for the control
|Japanese Pharmacopoeia JP||Water for JP 2.59 and G8 quality control||0.5mg/L|
1. General regulatory requirements
Start by determining what basic regulations are available to regulate the products, materials, or processes involved. The applicable regulatory guidance should also be considered as required by the country where the product is sold. Regarding the production of pharmaceutical water, all global pharmacopoas define the basic regulations on water production and monitoring. These monographs are official documents proposing standard pharmacopodial procedures with clear requirements, serving as the basis for all monitoring and control water purification projects. In these monographs, specific limits for measuring, monitoring and reporting parameters of TOC, conductivity and microorganisms for pure water (PW), as well as endotoxin for injection (WFI) and pure steam. These requirements are largely (but not entirely) accepted by the major global pharmacopoeia.
2. Regulatory requirements related to the parameters
Each pharmacopoeia gives clear guidance and defines that TOC measurements should be validated to be used for identifying water for different intended uses. Detailed description of the requirements for pharmaceutical and injection water can be found in USP <643>, and other pharmacopoeas (see Table 1). In conclusion, the TOC measurement method must meet the following requirements:
- The carbon detection limit of the instrument was 0.05 mg / L or lower
- The instrument must be calibrated
- The instrument must be able to distinguish between inorganic carbon and organic carbon
- The instrument must pass the system suitability test: the method of comparing two known solutions (USP 1,4-benzoquinone solution, USP sucrose solution)
3. Best guidance outside of the regulations
For compendial compliance requirements, there is no need to add steps to confirm and verify measurements beyond the steps specified by the relevant regulatory authorities. Therefore, users should carefully consider the recommendations provided in any outside-regulatory references and how they can be applied to a particular environment to weigh the value of any additional work done against specific application requirements. There are a lot of TOC related test methods, guidelines, and standard practices covering a variety of water purity measurements and market applications. The user needs to determine if these additional resources are useful for their own specific needs.
4. Instrument selection
Once the continuous online TOC measurement for real-time release of pharmaceutical water meets the regulatory requirements, users can obtain more guidance on the operation and control of water systems through recommendations and practical experience from third-party organizations and professional journals. These resources can contribute to the development of different strategies and helping to ensure the safety of the final product. In these strategies is a detailed understanding of how each process application works throughout the manufacturing process.
In order to strictly follow the regulations and guidelines on ensuring the safety of the final product, the continuous measurement response of TOC and conductivity should be as fast as possible to achieve the most complete, fastest, and most reliable trend, change, or disturbance indication within the water system. Full mastery of changes in the water system will give the highest degree of confidence in maintaining process control and final product quality. Combined with continuous analysis, advanced features such as hourly TOC change, peak, mean, and minimum TOC levels provide a data-rich system that enables completely rapid and easy assessment of the health status of the water system. This allows users to predict trends and respond positively to changes.
However, several currently available online TOC instruments still use batch measurement techniques. In contrast to the continuous analysis, the batch method provides only a single TOC measurement that remains on the instrument display and any digital or analog signal output until the next measurement cycle that may be completed in a few minutes.
During routine, stable, standard water system operations, several minutes of delay may not have a large limiting impact on reliable process control. However, in the offset of the water system, only continuous measurements will provide a complete picture of the event, including the specific time of the event, the speed, duration, and water flow disturbance, so as to fully understand the nature of the disturbance.
By clearly providing a detailed view of the offset, continuous measurements are able to better characterize the events themselves and thus better find possible causes. Furthermore, the rapid measurement response provided by many continuous analytical instruments quickly indicates that the event has occurred to allow for immediate corrective action.
Over the course of a few minutes, the batch instrument provides only a single delay measurement. Therefore, when disturbed, these instruments have a high risk of losing valuable diagnostic information that facilitates the analysis of system failures, limiting the ability to quickly and accurately identify the cause. For example, short-term events such as backflow contamination from the point of use may be completely overlooked.
In designing and verifying process control and monitoring systems, the global pharmaceutical industry gives a range of regulatory requirements that need to be evaluated by pharmaceutical companies. By using a structured, hierarchical approach to understand the regulations, a simple list of applicable regulatory requirements can be prepared. By taking into account guidelines outside of regulations, regulatory requirements can be expanded for specific applications of monitored parameters and manufacturers.
Due to the TOC and conductivity involved, regulation and best guidance often focus on effective process monitoring and timely response to changes in water system behaviour. With a continuous real-time measurement system equipped with advanced functions, users can be able to quickly assess the change and health status of the water system. Therefore, Optosky's TOC-1700 online measuring instrument can be perfectly qualified for the needs of pharmaceutical companies.
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