USFDA-Cleaning validation

Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.

This guide is designed to establish inspection consistency and uniformity by discussing practices that have been found acceptable (or unacceptable). Simultaneously, one must recognize that for cleaning validation, as with validation of other processes, there may be more than one way to validate a process. In the end, the test of any validation process is whether scientific data shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.

This guide is intended to cover equipment cleaning for chemical residues only.

For FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shall be maintained in a clean and orderly manner ***." A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to prevent contamination or adulteration of drug products. Historically, FDA investigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipment and/or poor dust control systems. Also, historically speaking, FDA was more concerned about the contamination of nonpenicillin drug products with penicillins or the cross-contamination of drug products with potent steroids or hormones. A number of products have been recalled over the past decade due to actual or potential penicillin cross-contamination.

One event which increased FDA awareness of the potential for cross contamination due to inadequate procedures was the 1988 recall of a finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become contaminated with low levels of intermediates and degradants from the production of agricultural pesticides. The cross-contamination in that case is believed to have been due to the reuse of recovered solvents. The recovered solvents had been contaminated because of a lack of control over the reuse of solvent drums. Drums that had been used to store recovered solvents from a pesticide production process were later used to store recovered solvents used for the resin manufacturing process. The firm did not have adequate controls over these solvent drums, did not do adequate testing of drummed solvents, and did not have validated cleaning procedures for the drums.

Some shipments of this pesticide contaminated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility's fluid bed dryers with pesticide contamination. This in turn led to cross contamination of lots produced at that site, a site where no pesticides were normally produced.

FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical manufacturer which manufactured potent steroid products as well as non-steroidal products using common equipment. This firm was a multi-use bulk pharmaceutical facility. FDA considered the potential for cross-contamination to be significant and to pose a serious health risk to the public. The firm had only recently started a cleaning validation program at the time of the inspection and it was considered inadequate by FDA. One of the reasons it was considered inadequate was that the firm was only looking for evidence of the absence of the previous compound. The firm had evidence, from TLC tests on the rinse water, of the presence of residues of reaction byproducts and degradants from the previous process.

FDA expects firms to have written procedures (SOP's) detailing the cleaning processes used for various pieces of equipment. If firms have one cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, we expect the written procedures to address these different scenario. Similarly, if firms have one process for removing water soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is to be followed. Bulk pharmaceutical firms may decide to dedicate certain equipment for certain chemical manufacturing process steps that produce tarry or gummy residues that are difficult to remove from the equipment. Fluid bed dryer bags are another example of equipment that is difficult to clean and is often dedicated to a specific product. Any residues from the cleaning process itself (detergents, solvents, etc.) also have to be removed from the equipment.

FDA expects firms to have written general procedures on how cleaning processes will be validated.

FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.

FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.

FDA expects firms to conduct the validation studies in accordance with the protocols and to document the results of studies.

FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid. The data should support a conclusion that residues have been reduced to an "acceptable level."

The first step is to focus on the objective of the validation process, and we have seen that some companies have failed to develop such objectives. It is not unusual to see manufacturers use extensive sampling and testing programs following the cleaning process without ever really evaluating the effectiveness of the steps used to clean the equipment. Several questions need to be addressed when evaluating the cleaning process. For example, at what point does a piece of equipment or system become clean? Does it have to be scrubbed by hand? What is accomplished by hand scrubbing rather than just a solvent wash? How variable are manual cleaning processes from batch to batch and product to product? The answers to these questions are obviously important to the inspection and evaluation of the cleaning process since one must determine the overall effectiveness of the process. Answers to these questions may also identify steps that can be eliminated for more effective measures and result in resource savings for the company.

Determine the number of cleaning processes for each piece of equipment. Ideally, a piece of equipment or system will have one process for cleaning, however this will depend on the products being produced and whether the cleanup occurs between batches of the same product (as in a large campaign) or between batches of different products. When the cleaning process is used only between batches of the same product (or different lots of the same intermediate in a bulk process) the firm need only meet a criteria of, "visibly clean" for the equipment. Such between batch cleaning processes do not require validation.

FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries. The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge of the materials involved and be practical, achievable, and verifiable. It is important to define the sensitivity of the analytical methods in order to set reasonable limits. Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue.

Check the manner in which limits are established. Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from actives, inactives, detergents) bulk processes may have partial reactants and unwanted by-products which may never have been chemically identified. In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove. There are circumstances where TLC screening, in addition to chemical analyses, may be needed. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scientifically justifiable.