Sampling in Cleaning Validation in Pharmaceutical Industry

Sampling in cleaning validation in the pharmaceutical industry has been a topic of ever-increasing interest and scrutiny in recent Food and Drug Administration (FDA) inspections. The validation of procedures used to clean the equipment employed during the various steps of a manufacturing process is a clear requirement of current Good Manufacturing Practice (cGMP). Such as, FDA inspectors now expect to see a functioning cleaning validation program with appropriate documentation in place during their inspections.

The objectives of this article are to establish a broad basis for sampling in cleaning method validation policy and programs and to determine the requirements, procedures, acceptance limits, and working papers needed to support this vitally important activity.

Cleaning validation protocols should be developed, approved, and executed in accordance with the SOPs covering these activities in place at the time. A typical cleaning method validation protocol should consist of Objective, Sampling and Testing Methodologies, and Acceptance Criteria sections.

Let us have a step-by-step explanation of sampling techniques and requirements, as well as the specific analytical procedures to be used in the analysis of those samples. It should specify which laboratories are to be involved in the testing and any precautions to be taken throughout the validation exercise.

A visual check should be incorporated into the cleaning assessment. The sampling technique chosen to evaluate the effectiveness of the cleaning procedure should be swabbing with a swab, the fluid rinse of samples, or a combination of both methods. The following sampling methods provide various levels of assurance concerning cleaning:

Visual Inspection

Active product contact parts of the equipment are individually examined (wherever possible) for cleanliness. This visual inspection allows the early localization and identification of any inadequacies in the cleaning procedure.

Rinse water sampling and analysis

According to 2004 FDA “Guide to Inspections Validation of Cleaning Processes:” “Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated.”

1. Analysis can be quantitative, using pH, conductivity, particle count, microbial count, Total Organic Carbon (TOC) determination, spectrophotometry, bioassays, or limulus amebocyte lysate for pyrogens.

2. Recovery factor is uncertain; it involves dilution.

Surface sampling and analysis

1. Removes adherent materials.

2. Analysis can be quantitative.

3. The Precise definition of the area sampled is required.

Method Selection

Whenever possible, each piece of equipment should be dismantled into its individual components after cleaning and each part should be individually tested for cleanliness. In this manner, any inadequacies in the cleaning process will be more readily identified and localized.

It may not be practical or desirable to dismantle large or Clean–In–Place (CIP) equipment. Regardless, validation sampling and testing should commence as soon as possible after the cleaning process is complete to reduce the chance of contamination by outside sources. Equipment that has just been cleaned should be covered immediately by appropriate means to protect it from any contamination.

Solvents

Aqueous or organic solvents used in the cleaning procedure should be sufficient to remove residues, and at the same time, should be minimized to reduce the risk of reaction with or damage to the equipment, or the over-dilution of the residue and the resultant loss of analytical sensitivity.

Samples should be collected in clean or sterile containers. Sterile containers are suitable for this intended use. All validation samples must be properly labeled with complete information regarding the source of the sample, sampler’s name, sampling date, reference number, product name, and the part of equipment from which the sample has been collected.

A sample of the rinse or swabbing solvent should always be included with the actual test samples to serve as a reagent blank for any chemical or microbiological determination when required.

All types of samples, physical, chemical, or microbiological, should be collected according to a written procedure and using techniques, reagents, equipment, and containers appropriate to the type of testing to be performed. Only trained personnel should perform the collection of these samples.

The environmental effectiveness of cleaning procedures should be assessed by the surface sampling of non-product contact surfaces (e.g.: floors, walls, air ducts, exterior equipment surfaces, etc.). Samples should be collected and analyzed for potential contamination.

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