Applicability of the “Threshold of Toxicological Concern” Concept to Residue Limits for Cleaning Validation
ASEPTIC
Destin A. LeBlanc Cleaning Validation Technologies
Introduction
Limits for residues following cleaning of pharmaceutical process equipment are usually established for validation of the
cleaning process. Limits have generally been established based on a formula originally proposed by scientists at Eli Lilly in 1993 [1]. Those calculations, or some variation of them, have been referred to in a variety of regulatory documents [2,3], and have been adopted widely by pharmaceutical manufacturers [4]. For finished drug manufacturing,
those limit calculations are based on establishing no more than 0.001 of the dose of an active of the cleaned product in a maximum dose of the next manufactured drug product.
Recently, several articles have appeared suggesting that it may be possible in certain circumstances to set limits for cleaning validation based on the principles of the "Threshold of Toxicological Concern" (TTC) [5,6]. The basic principle behind the TTC concept is that for chemicals with limited safety data, it may be possible to determine an Acceptable Daily Intake (ADI) value based on known data from chemicals where there is an established database of information on ADI values [7,8].
active下载This paper will discuss the application of TTC principles to cleaning validation, first by reviewing the TTC concept, then covering how limits have traditionally been calculated for actives in cleaning validation protocols, and finally discussing issues in the application of TTC to cleaning validation limits.
 
TTC Background
The TTC concept was originally developed for the food industry. One issue addressed by th
e FDA was how to deal with the variety of indirect food additives that might be present in foods due migration from packaging components. Essentially using a risk-based approach, the FDA established a limit of 1.5 μg per day as a maximum daily intake; if the food additive was present at a level to give a maximum daily intake of no more than 1.5 μg per day in a typical diet
(1.5 kg of solid food and 1.5 kg of liquid for a 60 kg person), then there were no testing or submission requirements for that food additive [8]. This was based on an analysis of known carcinogens, in terms of what was a de minimis risk of increased cancer cases. If 1.5 μg per day of a known carcinogen was acceptable, then that same 1.5 μg per day should be acceptable for a new chemical which may or may not be a carcinogen. In the original FDA presentation, this was called the "Threshold of Regulation", meaning that above that threshold value, data was required for regulatory approval.
The concept has been expanded to address other chemicals not thought to be carcinogens, with the ADI values being somewhat higher [8]. Part of this evaluation has been to been based on risk-based approaches, so that development and testing dollars are
spent on the chemicals with the greatest risk. A second concern has been the issue of reducing animal testing [7].
There are several things important to point out about the use of the TTC concept for food. First, most of the data and corresponding analysis has been for oral administration, which should be obvious where food is the major issue. Second, the basic principle was to apply the TTC concept to chemicals where there was limited safety data. With extensive safety data, it was expected that an ADI value could be calculated by well established practices. There were certain classes of compounds where TTC principles were not applicable. These included alfatoxin-like compounds, azoxy-compounds, nitroso-compounds, 2,3,7,8-bibenzo-p-dioxin and its analogs, and steroids. Also excluded were heavy metals because of accumulation in the body. Athird excluded category was proteins [8]. Afurther concept is that these residues should be reasonably avoided, either not used or limited to "as low as reasonably practical" (ALARP) [9].
The TTC concept has been further refined by adding various decision trees to address cert
ain issues. The International Life Sciences Institute (ILSI) has published a major monograph on TTC applied to food [8]. Recently the concept has been applied to pharmaceutical actives, and specifically to cleaning validation [5]. That concept involved a proposed staged classification system for chemicals with limited or no toxicity data. That scheme involved three ADI values:
1 μg per day for suspect carcinogens
10 μg per day for actives that are not carcinogens, but which are potent or highly toxic
100 μg per day for actives which were not potent and not highly toxic
This scheme was discussed in light of OEL values for pharmaceutical workers and for residues from cleaning processes.
This concept was not critiqued, but was utilized in another publication in comparing limits based on a visual limit, an adulteration limit (10 ppm in the next product), and a health-based limit (based on the TTC concept using 100 μg per day) [6]. This was done for a pilot plant application, where there is a reasonable expectation of limited toxicity information. Fo
r this application it was determined that a value of 4 μg cm2 was generally a worst case (along with the expectation that the equipment be visually clean). It should be noted that the standard dose-based calculation of 0.001 of a dose was not evaluated in this analysis.

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