Preserving Process Integrity: The Importance of Equipment Cleaning

Given the fact that pharmaceutical products command a high value, not only financially for the developer but also to the patients that require treatments, it is unsurprising that potential contaminants that can impede the integrity of such products must be avoided at all costs. If insufficient care is taken, contaminants can enter a drug product supply chain at multiple points, leading to costly failures and potential product recalls.

A fundamental part of good manufacturing practice (GMP) is the cleaning of manufacturing equipment. “Effectively cleaning process equipment on direct or indirect product contact surfaces is crucial to prevent cross-contamination or processing degradants contamination from the previously produced product, and introducing it into the next batch,” explains Walid El Azab, senior manager Technical Services for the Life Sciences Division of Steris. “Such degradants may include microbial or chemical elements that would negatively impact the subsequently produced product.”

Contaminant considerations

There are multiple factors to consider when seeking to preserve the integrity of the manufacturing process. Manufacturers should bear in mind that contaminants can differ depending on the type of process, if a mono- or multi-product equipment train is being used, and the specified quality target product profile, El Azab remarks.

“In large campaigns, a shorter cleaning cycle (cleanup) may be employed between batches of the same product, aiming to prevent contaminants from exceeding acceptable limits and negatively affecting product manufacturing,” El Azab states. “The risk of cross-contamination within the same product is generally minimal to none unless there are special formulation-dependent concerns, such as a microbiological limit or chemical relic from the process that could adversely affect the next batch.”

Therefore, according to industry standard practices (1,2), when performing mono-product processes, visual inspection alone is considered to be adequate as part of the cleaning validation or verification, El Azab continues. However, for multi-product processes, there is a higher risk for cross-contamination, which means that for such operations, cleaning limits based on a scientific approach, such as the Health Based Exposure Limit (1,3,4,5,6), must be set and integrated into the shared equipment train, he specifies.

Additionally, there should be alignment of the level of control, including sampling and detection methods, with the product type and equipment visibility, El Azab adds (4,5). Further, the risk of contamination and patient safety must also be considered, he states (7).

“During both validation and routine processes, a combination of visual inspection and quantitative detection methods is typically required to confirm cleaning effectiveness in a multiple product setting,” El Azab explains. “However, in specific cases, scientifically justified, quantitative visual inspection alone may suffice.”

When dealing with sterile products, it is essential to put a robust contamination control strategy in place to show the effective prevention of product contamination, Azab confirms (8).“If this strategy confirms that the existing measures are sufficient to prevent contamination, the need for separate, dedicated equipment may not be necessary,” he says.

Best practices

“To ensure the effective cleaning of equipment between products, it is essential to follow a structured procedure,” stresses El Azab. The first step is to map the process, he continues, which allows for the identification of potential sources of contamination and any variables that may affect the cleaning effectiveness and performance.

After mapping the process, manufacturers should gain an understanding of the contamination risks and then establish the appropriate corrective measures and associated controls that will need to be put into place, El Azab states. Then, pre-trial tests on a laboratory scale should be conducted, before the validation process, so that the optimal cleaning cycle can be established and any worst-case products identified, he adds.

Prior to starting the formal validation process, a trial should be performed when possible, and then the validation or verification runs can be executed as planned, El Azab highlights. A comprehensive cleaning cycle and procedure should be developed, he notes, with particular attention paid to critical points aimed at preventing cleaning failures. “For instance, during visual inspection, a best practice is to provide the inspector (or operator performing the visual inspection) with a defined path to follow,” El Azab says.

Final practices that should be adhered to include ensuring that personnel operating and cleaning the equipment are adequately trained to be able to perform the relevant procedures, and continuously assessing and monitoring cleaning performance over time, improving procedures where necessary, El Azab states. “In some cases (e.g., API manufacturing), the monitoring may require direct sampling after a routine cleaning of the equipment between product change over (9), except if properly justified based on historical data and assurance of the measures and controls in place preventing possible cross-contamination,” he asserts.

Supporting sustainability

“Over the past few years, the [equipment cleaning] market has seen the emergence of various technologies aimed at supporting sustainable initiatives,” El Azab remarks. “These [technologies] include rotary jet heads and devices for cleaning the underside of tank agitators, and improved formulated chemistries that reduce the cleaning cycle, water, and electricity consumption.”

Such technologies can also improve productivity, El Azab points out. For example, rotary jet heads can help “prevent product cross-contamination and preserve product quality” while devices designed to clean the underside of tank agitators can “eliminate confined space entry, making cleaning easier and boosting overall tank productivity,” he says.

“Notably, some pharmaceutical companies have adopted the approach of treating and recycling wastewater to lower costs and meet sustainability goals,” El Azab reveals. By way of example, he highlights the method of vacuum evaporation that allowed a laboratory to recover more than 90% of the water for re-use (10), whereas other pharma manufacturers are using other solutions, such as oil water separators, ultrafiltration, and reverse osmosis.

“Ultimately,” El Azab summarizes, “implementing suitable cleaning practices and validation procedures is crucial to maintaining the integrity of the manufacturing process and ensuring the high quality of the final products.”

References

1. European Commission. Annex 15: Qualification and Validation. EudraLex Volume 4, March 30, 2015.
2. Parenteral Drug Association. Technical Report No. 49 (TR49): Points to Consider for Biotechnology Cleaning Validation. Technical Report, July 2010.
3. EMA. Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities, November 2014.
4. EMA. Questions and Answers on Implementation of Risk-Based Prevention of Cross-Contamination in Production and ‘Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities.’ EMA.europa.eu, April 2018.
5. ISPE. ISPE Risk-Based Manufacture of Pharmaceutical Products, second edition, Volume 7, July 2017.
6. PIC/S. Inspection of Health Based Exposure Limit (HBEL) Assessments and Use in Quality Risk Management. Aide-Memoire, June 2020.
7. ICH. Q9 (R1) Quality Risk Management, January 2023.
8. EC. Annex 1: Manufacture of Sterile Medicinal Products, EudraLex Volume 4, Aug. 22, 2022.
9. ICH. Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, November 2000.
10. PRAB. Pharmaceutical Research Laboratory Reduces Wastewater Volume and Disposal Costs with Vacuum Evaporation. PRAB.com, accessed Aug. 16, 2023.

About the author

Felicity Thomas is senior editor of Pharmaceutical Technology®.

Article details

Pharmaceutical Technology
Vol. 47, No. 9
September 2023
Pages: 22–26

Citation

When referring to this article, please cite it as Thomas, F. Preserving Process Integrity: The Importance of Equipment Cleaning. Pharmaceutical Technology 2023 47(9).