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John Ward, vice-president of Engineering at Patheon, discusses the potential for cross contamination in the manufacture of biopharmaceuticals.
BioPharm International spoke with John Ward, vice-president of Engineering at Patheon, about the potential for cross contamination in the manufacture of biopharmaceuticals. Ward discusses the common sources of cross contamination, how to prevent such contamination, and what companies should look for when working with contract manufacturing organizations (CMOs).
BioPharm: What type of drug product has the highest risk of exposure potential?
Ward: Closed systems generally have a lower risk of contamination. Open systems require higher levels of air quality and more restrictive gowning procedures to reduce contamination risk for the operations involved. Open systems’ greater reliance on procedures make them more prone to human error and can result in contaminations and mix-ups. If a process can be run under closed conditions, it is far more preferable. Stainless-steel systems are well known for their ability to be run in a validated closed manner. Single-use technology is advancing rapidly and eliminating many of the operating risks with new technology (i.e., closure systems).
BioPharm: Is product mix-up, retention (product residue), mechanical transfer, or airborne transfer typically the most common source of contamination?
Ward: Common contamination of biologic processes can be from improperly maintained or operated water systems, air, or heating, ventilation and air conditioning (HVAC) systems; inadequate equipment cleaning; or from personnel--typically from the skin. If the contamination is in the bioreactor, the chances of detection are fairly good, as the production parameters are usually affected. Product crossover is less frequent because, in most cases, very stringent protocols are in place. This is because the risk of product crossover is very high and the detectability is low.
BioPharm: What special precautions have to be taken for materials of an infectious nature, high pharmacological activity, or high toxicity?
Ward: When stainless-steel systems are used in a multi-product environment, crossover studies and cleaning validation are an absolute must. Highly active products are of particular concern. Some biological products have doses in the pico-gram/kg of body weight, while others have doses in the mg/kg. The pico-gram dose product must have assays that can test to very low levels of API concentration to ensure that no crossover is occurring between campaigns.
BioPharm: What is the best method for preventing spore contamination?
Ward: Heat pasteurization of media used in biologic processes is a very popular method of eliminating the risk of spore-forming bacteria. High temperature/short time (HTST) pasteurization is used in many facilities to address this risk.
BioPharm: How often should cleaning validation procedures occur?
Ward: Cleaning validation requires a risk-based approach. The finding of the risk assessment and the validation results should provide a guide for setting the revalidation of equipment cleaning validation. Different types of equipment carry different risks (i.e., buffer prep, media prep, cell culture, final bottling). One benefit of single-use is the more limited requirement for this type of validation versus stainless steel.
BioPharm: How have contamination concerns driven the facility design of CMO locations?
Ward: The concerns of contamination for a CMO can be viewed from many perspectives, including regulatory, client, and operational. These different views can place disparate requirements on a CMO. In a situation where contamination goes undetected, the result can be a drug recall or, even worse, cause potential harm to patients, and [that result] increases the requirement for preventative design controls. Different clients can place different requirements on a CMO, both from a design and operational view, given different views of risk and technology. Newer technologies can reduce the risk of contamination, but some clients will want or need to use more proven technologies, requiring greater design control. Some clients will develop their processes in stainless steel and will be hesitant to switch to single-use technologies. Single-use technologies have many benefits for a CMO, especially in the area of reducing product crossover risk. CMOs try to balance the various risks, costs, and technologies to maximize its ability to produce high-quality products, while still remaining competitive.
BioPharm: Is there a facility design that seems to be more prone to contamination (i.e., ballroom vs. closed room layouts)?
Ward: Contamination can come from several sources: the environment, personnel, product crossover, and more. This needs to be taken into consideration when designing the facility. Ballroom designs that are dedicated for single-product upstream and downstream processes will have a lower risk of product crossover contamination than one running multi-product by campaign. Segregation of unit operations into different suites can help reduce the risk level of contamination from a personnel and environmental perspective. Single-use product contact components typically do not require product crossover studies, and pose a lower risk versus similar stainless-steel components. New technologies that are being developed can help mitigate risks of contamination and cross contamination (i.e., new single-use sterile connectors).
BioPharm: Are there types of CMOs that are more prone to cross-contamination (i.e., those that produce multiple products for different sponsor)?
Ward: CMOs can have different risks, depending on the technology. Companies that use stainless steel have greater risk of product carry over, but can steam-sterilize the equipment, which reduces the risk of contamination. Single-use CMOs have a lower risk of product crossover risk, due to the nature of single-use processes. However, the ability to steam sterilize before use is limited, therefore creating a higher risk for contamination. Other precautions must be put into place to overcome this risk (i.e., production area room classification).
BioPharm: Are contamination events at CMOs ‘deal breakers’ for sponsors?
Ward: The record of a CMO’s operational performance in regards to contamination is of paramount importance to regulatory agencies, sponsors, and the CMO itself. While contaminations do happen, the CMO’s response to the contamination and the performance thereafter in many cases will be of greatest importance. Root cause analysis, continuous improvement, failure mode effects analysis, and other quality methods will help drive down the level of contaminations. Follow-on contaminations where the CMO does not have a good record of quality follow-up would be a deal breaker to many sponsors.
Vol. 29, No. 12
When referring to this article, please cite it as S. Haigney, "Cross Contamination in Biopharma," BioPharm International 29 (12) 2016.