FDA Warning Letters (Extracts)

Issues Related to Validation........................................................................................................1

Issues Related to Cleaning Validation.........................................................................................2

Issues Related to Validation

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Failure to test each lot of over-the-counter (OTC) pharmaceutical finished product for identity
and strength of each active ingredient prior to release. [21 CFR 211.165(a)].

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Failure to clean and maintain equipment at appropriate intervals to prevent malfunctions or

contamination. [21 CFR 211.671]. Layers of chemical powders were observed covering the
lids of mixing tanks and equipment. Cleaning procedures have not been validated to assure
the adequacy in preventing contamination.

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Failure to ensure that the cleaning methods used to clean equipment and utensils are adequate
to prevent malfunctions or contamination that would alter the safety, identity, strength, quality,
or purity of the drug product beyond established requirements, as required by 21 CFR 211.67.

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Failure to assure that the acceptance criteria for the sampling and testing conducted by the
quality cqntrol unit is adequate to assure that batches of drug products meet each appropriate
specification and appropriate statistical quality control criteria as a condition for their
approval and release, as required by 21 CFR 211.165(d).

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Contrary to the requirements of 21 CFR Part 211.65(b), there was no documentation to

demonstrate that the- Metal Detectors were qualified for their intended use and that
substances required for operation, such as lubricants, would not alter the quality of the drug
products.

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Records are not kept of the cleaning, sanitizing, and inspection of equipment, as required by
21 C.F.R. 5 211.67(c).

Alfa Laval Pharma Seminar, October 2005 1

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Qualification of major equipment has not been documented, the equipment is not properly
identified as to status, nor have written procedures been established for this [21 CFR 211.63,
1051.

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Process validations and equipment cleaning validations have not been done, nor have written
procedures been established [21 CFR 211.110, 671.

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Contrary to the requirements of 21 CFR 211.67, your firm has not demonstrated that the
cleaning procedures for removing product residuals and detergents from non-dedicated
packaging equipment are effective.

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Our Investigation also found that a change to the process (i.e., was not evaluated as to impact
on material stability and other aspects on material quality to ensure consistent, acceptable
results. We acknowledge your written response to update your DMF accordingly and to
validate this reprocessing step (you expect to need to use this processins0 step on occasion to
stabilize an intermediate). When implementing process changes it is good practice to
generally include one or more batches from the changed process in your stability program.

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Alfa Laval Pharma Seminar, October 2005 2

 Issues Related to Cleaning Validation
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Written procedures are not adequately established for the cleaning and maintenance of
equipment, including utensils, used in the manufacture, processing, packing or holding of a
drug product [21 CFR 211.67(b)]. Specifically, the “Artificial Tears Process Equipment
Cleaning Validation Protocol” was deficient in that there was no specified evaluation for
microbial contamination of product contact surfaces. In addition, the protocol failed to
identify and require residue sampling of difficult to clean locations (i.e. nozzles, filter
housings).

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Your cleaning procedure for product contact equipment surfaces has not been shown capable
of reducing microbial and endotoxin contamination to acceptable levels. And this procedure,
SOP $101, General Sanitation Procedure, lacks sufficient detail to ensure that cleaning is
performed consistently and acceptably from batch-to-batch. Specifically, the procedure lacks
minimum time limits for cleaning agent contact, method of wash and rinse, and volume of
cleaning agent(s) to be used. A sanitation cleaning procedure should include such information
to ensure adequacy and reproducibility of cleaning. As an example, while your letter of March
27, 2002 (item 3B) points out that endotoxin removal can be effected with a “hard flush” of
surfaces your procedure does not, in fact, specifically require a “hard flush.” We acknowledge
your commitment to validate the effectiveness of this procedure contained in your March 27
letter.

Alfa Laval Pharma Seminar, October 2005 3