A Biotech Cleaning Validation Worst-Case Soil Selection

April 22, 2013

Glass of clean water next to a glass of unclean water.

When conducting cleaning validation studies at large biologics or biotechnology facilities or perhaps even conducting a small cleaning validation study on a non-dedicated piece of equipment in the same industry; what soil do you choose as your worst case or challenge soiling solution?  Multiply that quandary by making all of the process solutions non-toxic and naturally occurring biologics.

Do you find yourself as a Validation professional in this predicament? As the biotechnology pipeline increases the dilemma of conducting cleaning validation runs on each and every process stream and all process equipment items becomes a daunting task.  This is no small undertaking and one that could take countless hours and threaten to break your budget.

This author has previously encountered this problem and employed a solubility matrix approach that estimated and compared the collective components of each media and buffer solution (“A Semi-Quantitative Matrix for Selecting an Appropriate Cleaning Validation ‘Worst-Case’ Challenge Soiling Solution” see Journal of Validation Technology November 2004 issue).  That article, while complete in its address of media and buffer solutions, does not address the biologic drug substance itself.  That information remained buried in the laboratory notebooks and toxicology reports of product and process development scientist who were generally not at the manufacturing site where the cleaning validation strategies, justifications, plans and protocols were being written.

I work in Validation at a manufacturing site, where do I find toxicology data anyway?

Fast forward to 2011 and the release of the U.S. Food and Drug Administration’s Guidance to Industry concerning Process Validation, General Principles and Practices; the transparency and accessibility of product and process information is now an expectation of that document’s lifecycle Stage 1, Process Design. For those conducting cleaning process validations, a benefit of the new Process Validation Guidance will be the great availability the product information therein required.  With solubility, toxicity and dosage information contained in those documents, the validation professional will have a wealth of information from which to determine safe levels of cleaning acceptance criteria.  That information will readily provide manufacturing technical operations groups with data from which to rationalize batch to batch carry-over and tolerances of endogenous protein drug substances.

There is so much equipment and so little time (and product to soil)!

With ever growing manufacturing facilities and expensive drug product, how does a Validation professional build an efficient, practical and compliant cleaning validation plan?  Strategies to consider are as follows; divide and conquer your equipment and soils, consider creating a challenge soiling solution that will last and double check your assumptions as you progress.

Divide and Conquer

The equipment and process solutions at your facility should already be cataloged in a master list.  Take that list and create a sortable spreadsheet for the following parameters; GMP and non-GMP equipment, product dedicated and non-dedicated product equipment, product contact and non-product contact equipment.  Certainly one could intuit that non-GMP, non-dedicated and non-product contact equipment should be eliminated from cleaning validation consideration and all other combinations will have varying levels of cleaning risk.  Similarly, very dilute and aqueous soluble non-product containing solutions versus highly concentrated or toxic drug substance materials pose the spectrum extremes in terms of cleaning risk levels.  By combining the later sort with the former, the validation professional should quickly find a few discrete grouping within which vastly different worst-case cleaning challenge soils and equipment can be identified.

Create your own Challenge

But what if your manufacturing facility is a pilot plant or a launch site where numerous new clinical entities are introduced and rapidly turned over?  In situations such as those, the validation professional should consider formulating their own worst-case challenge soil based on the manufacturing area and on historical and long range production plans.  It is possible to rationally craft a low solubility, high viscosity solution for either the media or buffer operations that would constitute a challenge greater than most standard process soils.  This “worst-case validation soiling solution” could be used to challenge cleaning-in-place (CIP) systems once upon initial cleaning validation studies and again at later dates to demonstrate the continued efficacy of the cleaning regimen used and validated on that equipment.

Constant Vigilance

The “worst-case validation soiling solution” strategy cannot be employed along without a cleaning monitoring program to verify that no unusual or unforeseen challenge is introduced into the facility thus compromising the previously effective and valid cleaning cycle.  This monitoring program, which harkens Stage 3 of the FDA’s Guidance on Process Validation, can be proceduralized in both bench scale cleanability assessments and by adding appropriate process analytical technologies (PAT) on every CIP skid.  By doing a screen for process solutions posing a soiling challenge above the level already validated, the manufacturing technical operations groups can rest assured in the knowledge that their process will not sustain a challenge beyond its capabilities.  Furthermore, the use of in-line conductivity and total organic carbon (TOC) analyzers (along with operator visual inspection) will provide full scale data that the levels of cleanliness are achieved with every use of the equipment.

In sum, choosing a worst-case challenge soiling solution in the biologics and biotechnology industry has often created much consternation among validation professionals.  This task will be made easier with the continued progress to more documented and accessible process design documents.  Moreover by categorizing equipment and process solutions, a validation professional should easily develop a compliant and efficient cleaning validation program that may serve the site’s needs for quite a while.  Of course, due attention and application of the US FDA’s guidance to industry concerning process validation will ensure continued process design and verification that the appropriate challenge and controls remain.


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