Proving It’s Clean with Analytics

Validating the effectiveness of the cleaning of pharmaceutical manufacturing and process equipment is part of good manufacturing practices (GMPs) (1,2). Regulators expect manufacturers to be able to show that their cleaning process is sound. Analytical methods and tools assist in assuring that equipment is clean and ready for use. “An analytical method provides an independent assessment that the equipment [being used] for a client’s product is clean,” according to Wayne Goodwin, director, Quality Operations at BIOVECTRA.

Preventing cross contamination between manufacture of different products is of primary concern. Residue from a previous product must be reduced to acceptable levels before equipment can be used to manufacture a new product, remarks Goodwin. Regulators, and clients, need to be assured that this has been done. “[Regulators and clients] want the entire cleaning package, including work instructions for cleaning the equipment and results of rinse and swab testing. They routinely review the method validation reports which support the analytical methods,” he says. “[Manufacturers] also must show that [the] cleaning acceptance criteria are appropriate as [they] clean from Product A to go into Product B. The justification typically includes an acceptable daily exposure (ADE) limit for the outgoing product and also incorporates factors such as shared equipment surface areas and the rinse and swab recovery factors for the
outgoing product.”

Analytical procedures can be used to quantitate if residuals of a drug product or cleaning agent remain on equipment after it has been cleaned, asserts Shailesh Vengurlekar, senior vice president of Quality and Regulatory Affairs, LGM Pharma. “Determining or quantitating the left-over residues helps reduce the risk of cross contamination or adulteration of products,” he says.

Analytical method development

When creating an analytical method to ensure cleaning validation, the type of residue being measured, the sampling method, and the residue acceptance limit (RAL) in the sample should all be considered, according to Vengurlekar. “The selection of an analytical method depends on the chemical nature of target residues and analytical limits established for those residues. A key element in the selection of an appropriate analytical method is that the method produces a result that has a logical, scientific link with the target residue,” he says. The method or procedure should confirm residue has been removed from the equipment during cleaning. “The analytical procedure is first developed and validated to ensure that the drug substance can be recovered/detected using that methodology,” says Vengurlekar. “The validation of a cleaning validation analytical method for product residue must be based on the RAL calculated for that material as defined in a cleaning validation plan. The method may be considered valid for any RAL within the validated RAL recovery range. If the RAL is outside this recovery range, the method must be revalidated with respect to the affected parameters/characteristics.”

According to Goodwin, an appropriate analytical method for cleaning validation includes limit of detection, quantitation of the method, specificity, and recovery studies from both the rinse and swab samples. “Data from the cleaning validation exercise demonstrate that the method is suitable for use,” he states. “If a product goes into [the] GMP equipment, then a cleaning method validation [is needed] regardless of the lifecycle status of the previous product.”

Analytical procedures should be meticulously designed, stresses Goodwin, to detect impurities and confirm cleanliness. “A ‘non-detect’ result may arise if our testing methods lack sensitivity for the target analyte,” he says. A method should attain the necessary specifications. “For cases when the preferred method for a particular product isn’t sensitive enough to detect low levels, we’re obligated to find an alternative method with sufficient sensitivity,” Goodwin confirms.

The method should also fit the needs of the production facility, Goodwin continues. “For example, our preferred method might use HPLC [high-performance liquid chromatography] with methanol as the diluting solvent. However, if that area of the production facility is not rated for flammable solvents, manufacturing teams cannot use solvent in the cleaning and cannot provide the QC [quality control] team with methanol samples,” he specifies. “Other factors such as material cost and reagent toxicity must also be considered.”

Analytical methods should meet detection limit requirements. “Regardless of what the cleaning is, we perform a product-specific validation of the analytical methods, such as TOC [total organic carbon], HPLC, or UV [ultraviolet]. This [product-specific validation] provides the data for the overall process cleaning validation,” continues Goodwin.

Goodwin also points out that analytics ensure cleaning process consistency. “The work instructions are coupled with automation and process analytical technology (PAT) to demonstrate that we are able to remove the previous product from the equipment consistently every time,” he says.

Analytical tools for the job

Analytical tools used in cleaning validation include HPLC (limit and quantitate test), gas chromatography (GC), spectrophotometry, TOC, microbial analysis, total protein analysis, and visual inspection. However, the analytical tool used for cleaning validation depends on the product used on the equipment, according to Vengurlekar.

Pre-approved test methods developed for a cleaning activity for a specific product should be compared for every quality control release, Goodwin agrees. “A one-size-fits-all approach is not feasible at BioVectra given the varied product mix,”
says Goodwin.

“For complex chemistry and small molecules, product-specific analytical methods, like HPLC or GC, [are typically used] to detect trace amounts of the intact API. Often this means adapting the release assay method to detect 1000–10,000-fold lower concentrations in the cleaning samples, at levels approaching 1 µg/mL in solution,” says Goodwin. “For biologics, nonspecific methods, such as TOC and conductivity, [are generally applied], which are more appropriate to these sample matrices.”

Cleaning validation and data

Data collected from analytical laboratory testing can provide information on method sensitivity and determine recovery for rinse and swab samples, according to Goodwin. Cleaning solvent volumes, temperatures, contact time, and stir rate data can be obtained from production data. Coverage testing on equipment that uses spray balls can determine if there are dead spots, he says.

“The information collected on a given cleaning validation can certainly be used to inform subsequent cleaning activities for other products, though it is important that the development work is sound prior to putting any new product into manufacturing equipment,” Goodwin stresses.

Analytics can be used to develop a cleaning validation procedure and evaluate critical process parameters such as solubility, porosity and roughness, concentration of cleaning agents, water temperature and flow, contact time, and cleaning times, confirms Vengurlekar. “The level of drug product and cleaning agents detected through analytical methods after cleaning can be used to improve the cleaning procedure to ensure residuals/carryover to the next product are within allowable limits and prevent risk to consumers,” he summarizes.

References

1. 21CFR211.67
2. ICH. 12.7 Cleaning Validation. Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (ICH, Nov. 10, 2000) ICH.org.

About the author

Susan Haigney is managing editor of Pharmaceutical Technology®.

Article details

Pharmaceutical Technology
Vol. 48, No. 1
January 2024
Pages: 26–27

Citation

When referring to this article, please cite it as Haigney, S. Proving It’s Clean with Analytics. Pharmaceutical Technology 2024 48 (1).