The traditional goal of pharmaceutical cleaning processes is to remove or reduce active pharmaceutical ingredients (APIs), degradation products, excipients, residual cleaning agents, etc., to ensure the complete efficacy of drugs and patient safety.

With the application of new lifecycle methods to process validation, the traditional approach of measuring a single specific API using proprietary methods is no longer the best method recommended by the FDA, as traditional proprietary methods cannot help users gain a deeper understanding and mastery of the process. Total Organic Carbon (TOC) analysis is a non specific method used to measure the overall carbon content in products and process residues. TOC analysis can provide effective feedback information for the continuous evaluation of the validation status of cleaning processes, thus complying with FDA's best practice guidelines.

A key issue in the cleaning validation process isHow to establish practical, achievable, verifiable, and scientifically based acceptable standard limits

This article provides an overviewHow to establish acceptable standard limits using TOC analysis method，andMake acceptable standard limitsCompliant with FDA's Clean Validation Lifecycle ActofBest Operating Guide

One of the many challenges faced by production plants when implementing clean validation processes is that each production process isa kind ofThere are many factors that affect the cleaning process, including raw materials, process flow, production procedures, operating rates, Minimum Batch Size (MBS), and the sequence of operating steps. The cleaning processes and measurement methods of different production plants pose varying degrees of challenges to the implementation of cleaning validation processes. This article does not explore the factors that affect the cleaning process, but production plants must fully understand these influencing factors before calculating the Maximum Allowable Residue (MAC) for cleaning validation.

When the production plant converts products in the production facility, it must first determine the maximum allowable residual amount (MAC) of the relevant products. As the name suggests, product conversion refers to emptying a production container of one product (Product A) and then filling it with another product (Product B), as shown in Figure 1. The MAC value represents the amount of product A that can safely exist in product B without posing any safety risks to the patient.

Figure 1: Conversion from Product A to Product B, i.e. the amount of product A that can be transferred to Product B

Before calculating MAC, the clinical reference values of relevant products should be determined, including but not limited to: therapeutic daily dose (TDD), acceptable daily intake (ADI), lethal dose for 50% (LD50), and permissible daily exposure (PDE). You can search for clinical reference values in literature or online, such as by consulting the "PubChem DSSTox FDA Maximum Daily Dose Database" (DSSTox FDAMDD Maximum Daily Dose Database)²Regardless of where the starting reference value you use in the calculation comes from, there must be strict scientific basis. The starting reference value used in this article is derived from DSSTox FDAMDD.

The MAC value alone is not enough to put the cleaning equipment into practical use. After determining the MAC value, it must be converted to the actual product limit value (in ppm). The product limit should take into account the sampling method of MAC value.

Exclusive product limits cannot be directly used for non exclusive TOC methods. According to the sampling method, the specific product limit can be converted to TOC limit by multiplying it by the relative mass percentage of carbon in the product chemical formula.

If the specific method limit has been calculated previously, the specific clean validation method (such as HPLC, i.e. high-performance liquid chromatography) can be converted to a non specific method (such as TOC) using the carbon percentage in the product chemical formula. For example, if the API limit of HPLC is 10 ppm and the carbon percentage is 50%, then the TOC limit is 5 ppm.

The above example calculates the MAC value of adrenaline in diazepam as 1.46 mg/dm using the correct clinical reference value²When using the TOC method for cleaning validation, based on the MAC value and sampling method, the TOC limit for adrenaline in diazepam was determined to be 21.5 ppm.

According to the latest practice guidelines from the FDA, when conducting cleaning validation,The lifecycle approach should be considered as the best methodThe lifecycle approach requires continuous monitoring and updating of the design, qualification, and confirmation of clean validation processes. When selecting analytical methods to evaluate the effectiveness of clean validation processes, please note that proprietary methods for specific single active pharmaceutical ingredients (APIs) are no longer the best approach recommended by the FDA, as proprietary methods cannot detect concentration changes of other unquantified pollutants.

Non specific methods such as TOC can measure all pollutants in the cleaning process rather than specific active pharmaceutical ingredients, making it the best approach. For example, pollutants such as degradation products, excipients, and residual cleaning agents cannot be detected by specific methods (such as HPLC), but can be detected by non specific methods (such as TOC).

This application literature shows that using the correct clinical reference values can easily calculate and demonstrate the acceptable standard limit of TOC for clean validation processes. This application literature, as well as the US FDA's Best Methods Guidelines for Cleanliness Validation, list many reasons why TOC analysis is widely used in the industry for cleanliness validation today.

3. “Guidance on Aspects of Cleaning Validation in PharmaceuticalIngredient Plants. ” APIC Publications, APIC.cefic.org,

Visit period: September 10, 2017