Q&A with Paul Lopolito on ADC Cleaning Validation: A Risk-Based Approach to Highly Potent Drug Manufacturing

Paul Lopolito, director of Technical Services at STERIS participated in a panel discussion in April 2026 during INTERPHEX at which he discussed cleaning considerations for antibody-drug conjugates (ADCs). BioPharm International® spoke with Lopolito‚ whose background spans biopharmaceutical and biomedical device manufacturing‚ about the unique complexities of cleaning validation for highly potent ADC manufacturing equipment, including the critical role of degradation profiling and risk-based strategy design.

BioPharm: What are the unique challenges for cleaning equipment used to manufacture highly toxic drug products like ADCs?

Lopolito (STERIS): The unique challenges with ADC cleaning validation are a few things. One is a highly potent drug substance. The second is that the cleaning validation approach for one drug substance may not be the same for a second drug substance, and some of the things that can interfere with that are the degradation profile‚ which can impact the health-based exposure limit (HBEL).¹ The profile can impact wastewater management and can impact the analytical method used as part of the validation strategy.

The next challenge is that some multi-product facilities are manufacturing multiple drug substances within the ADC space, which can be challenging.² The last consideration is that some highly potent drugs use solvents that are not amenable to single-use technology, so they require reusable equipment, which in turn requires cleaning validation.

Why is a risk-based cleaning validation strategy crucial for ADC manufacturing?

A risk-based cleaning validation strategy is critical because of the high-potency nature of drug substances used in antibody-drug conjugates. That requires a thorough understanding of the analytical method as well as the HBEL that is used as part of the cleaning validation approach.^1,3

Why is understanding large- and small-molecule drug degradation profiles essential when designing effective cleaning processes for ADC manufacturing facilities?

Understanding a degradation profile is an important element in cleaning validation, and we have two different drug substances within an antibody-drug conjugate. We generally have a large molecular weight molecule, in which case degradation as a function of pH, alkalinity, and temperature of the cleaning process is generally preferred, because the goal is to break down that molecule and reduce‚ or potentially eliminate‚ its therapeutic effect. That approach supports clearance of the large molecule component.

With the small-molecule drug substance, we need to be thinking about whether or not the cleaning process degrades it into something that is potentially more toxic to the patient, and, also, whether the analytical method used to [validate that] the equipment is clean to an acceptable limit will still be valid.⁴ We may find that we want to keep the small-molecule drug substance intact during the cleaning process while degrading the large molecule. Having a risk-based strategy is going to be important as we look at cleaning an antibody-drug conjugate.

Based on your panel discussion at INTERPHEX, what is the take-home message for stakeholders in the ADC space?

The take-home message is that we have a long history of cleaning validation for small molecules, and we have a long history of cleaning validation for large molecules. This is an opportunity to combine the strategies for both of those drug substances in our approach to cleaning validation of the antibody-drug conjugate‚ which involves understanding the degradation of the molecule, understanding the analytical method that is used, and setting appropriate limits for safe, reliable manufactured products.^2,3

References

1. European Medicines Agency. Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. EMA/CHMP/CVMP/SWP/169430/2012. Published 2014. Accessed May 21, 2026. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-setting-health-based-exposure-limits-use-risk-identification-manufacture-different_en.pdf
2. Challener CA. Managing cleaning validation in multi-product biologics facilities. BioPharm Int. 2014;27(9). https://www.biopharminternational.com/view/managing-cleaning-validation-multi-product-biologics-facilities
3. World Health Organization. Points to consider when including Health-Based Exposure Limits (HBELs) in cleaning validation. WHO Technical Report Series No. 1033, Annex 2. Published 2021. Accessed May 21, 2026. https://cdn.who.int/media/docs/default-source/medicines/norms-and-standards/guidelines/inspections/trs1033-annex2-points-to-consider-when-incl-hbels-in-cleaning-validation.pdf
4. Hinrichs MJ, Dixit R. Antibody drug conjugates: nonclinical safety considerations. AAPS J. 2015;17(5):1055-1064. doi:10.1208/s12248-015-9790-0