Meeting the Regulations and Validation Rules is an Important Task for the Pharmaceutical Industry.
In order to be compliant with the regulations and meet the required quality and safety, the pharmaceutical industry must develop economical and competitive production and cleaning methods, which in turn will help the industry develop appropriate operational methods.1
Compliance with the regulations must be maintained within the pharmaceutical industry and throughout the different processes. Within the pharmaceutical industry, the processes can be grouped under three general categories: preparation (includes processing and innovation), production ,and waste discharge (Figure 1). Throughout such processes, it is required to use pharmaceutical quality water, monitor the pharmaceutical water used, and achieve the required cleaning level to avoid any cross contamination. During the process of monitoring the pharmaceutical water and maintaining the required quality and safety to meet the regulations, the FDA does not recommend any one specific analytical technique for the analysis. On the other hand, the FDA states that any specific or non-specific analytical technique can be used, as long as the technique provides results that prove its ability to detect any contaminants that affect the quality of the water used.1
Several specific and non-specific analytical techniques may help the industry monitor the pharmaceutical water used and also help in achieving the required cleaning validation. A “specific” technique is defined as an analytical technique that identifies the concentration of a specific chemical within the analyzed sample. A “non-specific” technique, relates to analytical techniques that identify the presence of all the chemicals present in the analyzed sample, i.e., a cumulative representation of the effect of all the chemicals present within the sample. During the cleaning processes, pharmaceutical water and different cleaning agents are used. Based on the cleaning agents used during the cleaning process, the drug residue under concern, and the excipients, different analytical methods can be used to Also, based on whether a specific chemical within the residue must be monitored or a cumulative study of all of the chemicals within the residue should be monitored, either a specific or non-specific analytical method will be used. Table 1 presents some of the available techniques that can be used as specific and non-specific analytical techniques.
Total organic carbon (TOC) analysis is a non-specific analytical method. TOC is not only used in the cleaning validation process, but is also is used to monitor the pharmaceutical water used within the cleaning process and for the preparation of the drugs. TOC can measure the active compounds, excipients, cleaning agents and water system organics within the sample. As a result, TOC is a non-specific tool that provides an accurate result that represents all of the chemicals under study within the sample, in a few minutes (Table 2). According to the FDA, TOC analysis is an acceptable method for evaluating cleaning effectiveness, as several studies published since the publication of Inspection Guide on Cleaning Validation in 1993 indicated.2
Purified water (PW) and water for injection (WFI) are two types of pharmaceutical water. PW is water used for the cleaning process and in the preparation of drugs that do not enter into the blood stream.3 As a result, PW must be maintained under certain chemical purity levels, but need not be biologically ultra-pure. The TOC-acceptable level for PW should be less than or equal to 500 ppb. WFI, on the other hand, is used in intravenous drugs, i.e. drugs that enter the blood stream and also is used in the cleaning validation process of specific systems.3 WFI must be maintained under the same chemical and biological purity levels of the PW. In addition, WFI, must undergo other tests such as bacteria count and endotoxin content to achieve a more stringent biological purity level. WFI’s TOC level must be maintained at 500 ppb or less.
TOC analysis for either the cleaning validation processes or monitoring of pharmaceutical water can be measured using different organic carbon analyzers (Figure 2). TOC can be measured for both liquid and solid samples, using the organic carbon analyzer, i.e., whether it is a residue swabbed directly from the vat, or if it was a solution in which the residue collected on a swab was desorbed in it. The organic carbon analyzer identifies the carbon level within the samples contributed from all chemicals present in the sample. The organic carbon analyzer identifies the carbon levels present in the sample, by oxidizing the carbon present to carbon dioxide, and consecutively detecting the carbon dioxide produced.5 Results for TOC can be either reported as TOC or NPOC (non-purgeable organic carbon).5,6 TOC within a sample consists of purgeable organic carbon (POC), volatile carbon, and NPOC (hard to volatilize carbon). According to the USP, “the amount of POC in pharmaceutical water is negligible and can be discounted,” therefore, TOC can be reported as NPOC and vice versa.6
Several oxidation and detection methods exist on the market that can be used in conjunction to accomplish the carbon analysis (Table 3). Use of any of the combined oxidation/detection methods, depends on the preference of the user, required detection levels, oxidation and detection method, matrix of the sample, characteristics of the sample, and/or sample type (solid or liquid). ■
References:
Weitzel, S. Critical Process Cleaning and Cleaning Validation, CFPA 2006
FDA. http://www.fda.org/cder/guidance/cGMPs/equipment.htm
USP 29, > USP/NF The Official Compendia of Standards. U.S. Pharmacopeia. Webcom Limited: Toronto, Canada.
Shimadzu Scientific Instruments, Inc. www.shimadzu.com
TOC-V CPH/CPN & TOC-Control V Software User Manual. Shimadzu Corporation: Process & Environmental Instrumentation Division. Japan, Kyoto, 2001.
USP 29 >. USP/NF The Official Compendia of Standards. U.S. Pharmacopeia. Webcom Limited: Toronto, Canada.
Mohamed Abouleish, PhD is product coordinator and R. H. Clifford, PhD is marketing manager for Shimadzu Scientific Instruments, Inc. (Columbia, Md.) Reach Dr. Abouleish at 410-381-1227, ext. 1343, or mzabouleish@shimadzu.com. Dr. Clifford can be reached at 410-381-1227, ext. 1375, or rhclifford@shimadzu.com.
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