Pharmaceutical NEWS - Spring 2010

Cleaning Validations: Alternatives for monitoring non-soluble compounds

by Dr. Thomas Lehman and Eric Lingenfelter, Method Development & Validation Department

With cleaning validations becoming more of a regulatory requirement across the pharmaceutical industry, many manufacturing companies are experiencing the pressure to ensure their equipment is being cleaned to a satisfactory level. This pressure, in combination to the economic state we are experiencing, is leading companies to develop and validate cleaning methodology at as low a cost as possible. One such approach to evaluate and monitor cleaning validations is to develop a nonspecific total organic carbon (TOC) cleaning validation method.

Advantages to using a TOC approach is that a TOC method is not specific. The instrumentation will measure all organic carbon in the sample solution whether the carbon is contributed by the active in the drug product, from cleaning agents, from other excipients, or even from contamination. Therefore, because we cannot determine the source of the carbon in sample, one must assume that all carbon measured in the solution is due to the compound of interest. This approach is beneficial when monitoring products that may degrade while being cleaned, because even though the original product may no longer be present, the total amount of carbon present doesn’t change. Another advantage to TOC methods are that they are easy to develop and relatively inexpensive to perform.

On the other hand, TOC has some disadvantages as well. For cleaning validations, even though TOC being non-specific is viewed as an advantage, it can also be viewed as a disadvantage. If it is critical to monitor an individual compound, whether it is an API or a residual cleaning agent, a TOC method cannot meet the method requirements. In addition, TOC samples are very susceptible to contamination. One has to be careful with how the glassware and equipment is cleaned and handled if a TOC method is going to be used. Organic solvents cannot be used as rinse solutions because they will drastically increase the amount of carbon on the equipment surfaces and thereby artificially bias sample results. Another disadvantage is that all compounds to be monitored by TOC need to be water soluble. Or do they?

Historically, if a compound was rendered by the Merck Index to be only slightly water soluble, everyone immediately ruled out the option of TOC. Lancaster Laboratories has developed methods utilizing TOC for compounds that are not fully water soluble. In order to be TOC compliant, compounds only need to be slightly soluble in water. For example, if a maximum contamination limit (MCL) is set to 10 ppm, the compound only needs to be soluble at 11 ppm in water to be measured in the range of interest. This is a very interesting concept that is growing in popularity across the industry.

Sensitivity is always a concern when dealing with only slightly soluble compounds. The typical concentration detection range for TOC analysis is approximately 100 ppb to 2000 ppb. However, if solubility is limited, the concentration range is usually restricted to an even smaller range of approximately 100 ppb to 500 ppb for performing appropriate spike recovery studies. One limitation that must be determined during method development: is the compound water soluble enough to accurately perform spike recovery studies and still maintain the sensitivity to be detected within the allowable range of the instrumentation? This question may not be answered until suitable laboratory work is performed.

Another consideration is that sufficient carbon needs to be present in the sample matrix. Many cleaning detergents on the market today do not contain any carbon, thereby eliminating the possibility of TOC detection. When deciding whether or not TOC is the right approach for detection during a cleaning validation, one needs to understand that swab and rinse procedures must have the ability to collect the residue of interest from a surface with only the assistance of water. Although water is preferred, sometimes greater surface recoveries are obtained for swab samples by using a weak base or a weak acid as swabbing solvents. When collecting swab samples with alternative solents, TOC instrumentation may require higher oxidizer and/ or acid rates to effectively analyze the sample. This methodology should be determined during method development.

In summary here are some key factors to evaluate when determining if TOC is the correct approach for a cleaning validation:

• Is the carbon content of the sample great enough to be detected once the sample is appropriately diluted?
• Is the compounds solubility in water above the concentration of the desired MCL?
• Does the method need to be compound specific?
• Can acceptable surface recoveries be achieved by rinsing with water or swabbing with water, a weak acid or base?

For more information, contact Pharmaceutical Business Development at 717-656-2300 or email pha@lancasterlabs.com.