Wednesday, November 16, 2011

Process Wednesday: cleaning our your vessels

From the archives of Organic Process Research and Development, Valvis and Champion [1] talk about cleaning out your reactors:
Handling such compounds has presented manufacturing with special challenges, including “containment”, “cleaning”, and “decontamination”. Two classes of compounds in particular, anti-cancer and anti-thrombotic agents, are of the greatest concern due to their respective toxic or pharmacological potential. Due to their low-dose therapeutic profile, these classes of compounds can present serious risk of exposure to humans in a work environment and can lead to product cross-contamination in manufacturing. For this reason, great effort has been made by companies to acquire or develop the necessary technology for the cleaning and/or deactivation of such compounds. Since supporting such efforts can require significant resource commitment, the need for better understanding of this emerging challenge is great.
[snip] The following describes  the cleaning strategy and results obtained following the pilot scale manufacture of a potent anti-cancer substance having an AWEL of 0.2 microgram/m3 (chemical strucure not shown). The operation involved a number of 300-500 gal reactors, a filter-dryer, a number of centrifugal pumps, and a nutsche filter. The cleanliness requirements were established for the entire reactor setup ( 2500-gal capacity, including pumps) to be <10 ppm of active substance in 50 L of cleaning solution; the limits for the filter-dryer and the
nutsche filter were considered separately. Prior to obtaining the final sample, each of the reactors was sampled to ensure that individual activity levels did not exceed 2 ppm in 50 L of cleaning solution. The analytical (HPLC) limit of quantitation was set at 0.1 ppm, and no deactivating “kill” solution was available. During processing, an accidental spill of a significant amount of the (solid) drug substance took place inside a dryer room, adding to the complexity of the cleaning effort. 
Due to the potency of the substance, great emphasis was placed on the design of the cleaning protocol. Approval of the cleaning rationale required consensus of the principal development engineer, chemist, and operations personnel, while solubility data and placebo testing results played significant roles in the design of an effective cleaning protocol. To assess the potential effectiveness of boil-outs, a cleanability test was performed prior to the design effort, using a concentrated solution of lactose as the placebo contaminant. The solution was circulated through each of the reactors and associated piping and pumps. Cleaning included the initial disposal of the reactor contents, application of two water rinses to remove excess lactose, followed by a sequence of four water and four water-methanol boilouts. 
The final sample was obtained from a combined 100-gal rinse which was circulated through all reactors, pumps, and associated piping. When a minimum plateau at a concentration of 2 ppm was established, the cleaning effort was deemed complete. The choice of lactose as a placebo contaminant was thought to offer the benefits of a worst case cleaning scenario without the health hazard implications; however, its natural presence in the air of the work environment (i.e., interfering with background air-monitoring) pointed out its limitations. In retrospect, the use of acetaminophen is now thought to be a more appropriate option.
I think it's interesting how serious pharmaceutical manufacturing is about cleaning; it's obviously something that can carry terrible consequences if cross-contamination is involved (especially of highly potent compounds.) Think about that then next time you scrub out your flasks -- I know I do.

1. Valvis, I.I.; Champion, Jr.; W.L. Org. Process. Res. Dev. 1999, 3, 44-52.

1 comment:

  1. This remind of a time when I worked at a generic pharma company as a QC chemist. Three kilos of digoxin API went missing in manufacturing. The FDA absolutely nailed them when they came to audit and saw their abysmal effort in trying to locate it. Then they made us retest hundreds of lots of other products, manufactured during the same time period, to see if it had some how made it into other products. We probably prepped well over 1000 samples and never found it. This was only one of the reason the FDA shut manufacturing down and 2.5 years later, they are still under a consent decree and not manufacturing. Glad I'm out of there!


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