By Jeong Jin-hyeok
To assure patient safety, biologics developers and manufacturers must carefully consider where contaminants could be introduced to the drug substances (DSs) or drug products (DPs) at all stages of the drug lifecycle. From the filling lines, containers, and stoppers to the air in the surrounding manufacturing space, biologics producers must understand the sources of risk, create a highly controlled environment, and constantly monitor for potential breaches.
In this article, I will outline strategies developers should employ to protect biologic DSs and DPs. I will also explore key monitoring tactics to help maintain a sterile environment.
A sanitary manufacturing process for producing therapeutics is crucial to ensure the safety of patients receiving all forms of treatment—especially those seen with biologics. Most biologics will be administered via injection, enabling delivery directly to the bloodstream.
As parenteral drugs bypass many of the body’s natural defenses, a greater risk of infection may arise if these products are not sterile as compared with other dosage forms. To protect patients from serious infectious diseases, such as meningitis and sepsis, sterility must be of utmost importance.1
Developers and manufacturers of parenteral therapeutics also aim to attain sterility to ensure compliance. Regulatory bodies, including the FDA and the EMA, have published stringent guidance documents and recommendations for the aseptic processing of sterile DPs.2,3
Failure to prevent contamination of parenteral biologic products could bring a number of consequences, including delays, safety risks, recalls, remediation costs, and denied approvals. The risks associated with sterility breaches and the potential financial costs involved in their rectification mean it is critical to implement robust strategies for preserving aseptic conditions.
Through careful sterility checks and controls, aseptic processing maintains sterile conditions during manufacturing and protects against breaches. Aseptic processing necessitates extensive training and experience from operators and handlers. From formulation to filling, and from inspection to labeling and packaging, developers must also adhere to current Good Manufacturing Process (cGMP) standards and consider how sterility assurance can be monitored at different points of the aseptic process.
Meeting sterility demands requires facilities capable of constantly monitoring for contamination breaches. Therefore, biologic drug developers need to implement a robust approach to maintain an aseptic process, which should include the following monitoring and testing steps.
Detecting prior contamination
An important initial step when receiving a DS from another facility is to ensure that the material is not already contaminated. In vitro assays can be used to assess DS viral contamination, and similar analyses can be carried out to detect the presence of mycoplasma.
As a common bacterial contaminant with resistance to many antibiotics, mycoplasma poses a high risk to patients. Accordingly, determining the presence of mycoplasma is critical. However, mycoplasmas are often difficult to detect without chemical tests, as mycoplasmas are apt to be smaller than other common bacterial contaminants.
Bioburden reduction filtration
For many pharmaceutical products, terminal sterilization processes, such as steam or irradiation, ensure the product is sterile in its final container. As these harsh conditions can damage the efficacy of the biologic, many biopharma developers will instead need to rely on sterile filtration and subsequent aseptic processes.
After the DS is formulated but before fill-finish, DS containers will either be thawed or brought to equilibrium for bioburden reduction filtration. The DS will be mixed and pumped into a filling unit with a validated flow rate, where a series of two 0.22-µm filters will ensure that bacterial or any other cellular matter is absent from the final formulation. After sterile filtration, the product should be filled in an aseptic environment into the final container and sealed, at which point the material is considered a DP.
Meeting the Master Specification
The final steps should follow the Master Specification, which outlines the requirements for meeting quality and performance outcomes in finished products. Besides conducting a visual inspection, developers should perform Container Closure Integrity Testing (CCIT) to assess the fitting of stoppers and vials during the fill-finish stage. CCIT will determine whether a true seal has been made between the vial and stopper, preventing contamination from microbial organisms. A selection of vials should be used for quality control testing following the DP specification to ensure that vials are suitable for distribution and patient use.
In addition to the necessary sterilization steps, a number of environmental controls can be utilized to further limit contamination risk. Environmental controls will assess the air quality and pressure, temperature, ventilation, and humidity, in addition to detecting the presence of external microbes. Well-established environmental controls are a must to comply with cGMP requirements.
One example of environmental control is the implementation of a Restricted Access Barrier System (RABS), which protects process materials from potential contaminants in the environment through a barrier and positive airflow. Air quality within the RABS filling unit can be monitored using both viable and nonviable particulate counters. Utilizing both counters enables real-time monitoring and reduces the need for aseptic interventions, making it easier to establish a cause of contamination if a breach were to occur.
Another appropriate environmental control is the use of contact plates within the RABS filling unit to detect the presence of bacteria. Personnel working within the filling room should be monitored by using contact plates.
Single-use systems within aseptic processing
Another way to reduce cross-contamination risk during DP production is through the use of single-use systems, including components like formulation bags and filling tubing pathways, which should be assessed as a part of the cross-contamination strategy.
When using equipment that is not single use, it is important to guarantee the effective cleaning of equipment. Remnants of previous products should not be left behind on contact surfaces. Validation of cleaning systems and the use of stainless steel or another easy-to-clean equivalent material within the filling systems will be needed to ensure cleaning protocols are consistently effective.
The burden of cleaning validation requirements means there is a trending preference in the industry toward using single-use systems to avoid the additional labor, higher costs, and longer timelines generally associated with reusable equipment.
The importance of expertise and experience in aseptic processing
As aseptic processes and systems may require adaptation depending on the unique needs of processes or molecules manufactured, there is a critical need for experience and expertise. When working with a contract development and manufacturing organization (CDMO), it is important to work in partnership to perform a complete technical analysis and a robust technology transfer process. Developers will also need to evaluate equipment and processes based on the critical process parameters (CPPs) and critical quality attributes (CQAs) of each product. The approach to selecting sterilization methods will be project specific and tailored to each molecule.
The comprehensive training for personnel and specialized facilities needed for aseptic processing mean that it is advantageous to seek support from CDMOs, rather than spending time and money expanding in-house capabilities. The benefits of using a CDMO are vast, including gaining the expertise and experience of seasoned scientists and immediate access to purpose-built facilities.
Contaminant breaches in biologics manufacturing are associated with many risks, from negative impacts on patient health to financial losses and reputational setbacks. Preventing contaminant risk means great care must be taken to ensure that the final product is sterile through the implementation of various checks, controls, and measures. With so many factors that must be considered throughout aseptic processing, biopharma developers can alleviate the burden by relying on CDMO partners with the necessary experience and expertise to minimize risk.
1. Virtanen S, Kapp K, Rautamo M, et al. Compounding Parenteral Products in Pediatric Wards-Effect of Environment and Aseptic Technique on Product Sterility. Healthcare (Basel) 2021; 9(8): 1025. DOI: 10.3390/healthcare9081025.
2. U.S. Food and Drug Administration. Guidance for Industry on Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice (September 2004). Updated May 4, 2020. Accessed January 10, 2023.
3. European Medicines Agency. Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container (March 6, 2019). Accessed January 10, 2023.
Jeong Jin-hyeok is lead engineer, drug products at Samsung Biologics.