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Introduction
Activities in a GMP Development and Process Laboratory manufacture non-sterile and controlled bioburden preparations: bulk intermediates, bulk drug substances, and finished products in final containers. These batches encompass a range of activities from development projects and stability sample preparation, to material for toxicology studies, through Phase II clinical material for a range of non-sterile dosage forms. The type of dosage form may vary from batch to batch, as does the nature of the product. A GMP Clinical Manufacturing Area is for the manufacture of sterile, non-sterile, and controlled bioburden preparations, as well as bulk intermediates, bulk drug substances, and finished product in final containers. As a multi-product operation with a wide range of products in various stages of development, LTI relies on Total Organic Carbon (TOC) as a superior method for detecting very low levels of any residual organic chemical entity. TOC is a highly sensitive, flexible, non-product specific assay with a level of detection to parts per billion (PPB) resolution.
Why TOC?
The processed materials vary batch to batch and often lack validated product-specific assays that could be used for cleaning verification or conducting a cleaning validation study. While product contact surfaces are disposable or product dedicated, some shared equipment exists. This equipment includes lyophilizers, vial trays and rings, filling machine parts, lyophilizer shelf spacers, and balances. It is important to note that shared equipment is non-product contact. Even though the product is not in direct contact with the interior surfaces of the lyophilizer, it is possible that a contaminant can infiltrate into the product since the product container is not completely sealed during processing in the lyophilizer. Consequently, it is necessary to verify the absence of any residual chemical entity on such shared equipment after cleaning has occurred. This verification is part of the batch closure and also part of preparation for a subsequent batch. A procedure describing this approach to “Cleaning Verification of Shared Processing Equipment” is an effective way in providing guidance.
Sampling Technique
A direct method to sample equipment is to swab the surfaces of interest to collect contaminants that may adhere to surfaces even after thorough cleaning. The swab technique involves moistening a polyester swab with Purified Water, USP meeting USP Water for Injection specifications, including TOC. The swab is then used to wipe a measured area of 100 cm2 in a controlled and systematic manner. The swabs are then placed in a 40 mL TOC vial with Purified Water, USP. Each time swabs are submitted for TOC testing, the Point of Use utilized to fill the TOC vial with Purified Water, USP is also sampled and submitted as a negative control. The vials, swabs, and vial lids are a commercially available kit. These cleaning verification kits are specifically designed for TOC swabbing purposes and should be purchased only from a qualified vendor.
Testing Equipment
A TOC Analyzer with an Autosampler provides analysis of multiple samples without the direct involvement of an analyst to run the instrument. The instrument should be designed to measure the concentration of total organic carbon (TOC), total inorganic carbon (TIC), and total carbon (TC) in water samples. The relationship of the results is expressed in the common equation TC = TOC + TIC.
A common type of analyzer oxidizes organic compounds to form carbon dioxide using UV radiation and ammonium persulfate as a chemical oxidizing agent. Flow rates of the sample need to be established for TOC vial samples filled with Purified Water, USP. If samples have unknown TOC, are highly variable, or the TOC is > 1ppm, the use of the auto-reagent function is required. This function will determine the flow rates for each individual sample independently. Carbon dioxide can be measured using a selective membrane-based conductometric detection technique. For each TOC measurement, the concentration of inorganic carbon species is determined and after oxidation of organic compounds, the total carbon content is measured. The concentration of the organic compounds is then calculated from the difference between total carbon and total inorganic carbon.
The TOC analyzer needs to be installed and qualified, with Installation, Operation, and Performance qualification executed prior to using the analyzer. Preventative maintenance is required semiannually. Multi-point calibration is conducted annually. Per USP <643> Total Organic Carbon, system suitability must be performed, however, the frequency is not defined in the chapter. System suitability is performed monthly utilizing purchased standards from the instrument manufacturer.
TOC Limits, Action Level
Beginning a monitoring program presents challenges, whereas managing a routine program can be based upon historical trends using Control Charts. Initially, sample results can be recorded without subtracting the results from the Purified Water USP, negative control. The acceptance criteria of <500 ppb can be assigned as it is the USP Purified Water specification, <643> Total Organic Carbon, and allows for the inclusion of the blank water within the sample. If samples exceed 500 ppb, the equipment sampled should be cleaned and sampled again.
With sufficient time and enough samples available, a historical review of data from the TOC analyzer can be completed to establish a historical trend. The data must cover a nominal 3-month interval. With a historical trend available, it is then reasonable to subtract the negative control of the Purified Water, USP from the sample results. The negative control helps identify any actual contaminant recovered and yields greater accuracy in analysis of the data. From this data and abiding by ICH Q10 guidance on continual improvement, a new TOC Action Level can be established and readily justified.
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