Issue link: https://www.e-digitaleditions.com/i/1499609
10 Pharmaceutical Technology ® Trends in Manufacturing eBook May 2023 PharmTech.com Biologics ization methods, the regulations outline decision trees to determine which method is appropriate for the DP or container in question. In addition to sterilization, the scope of guidance extends to aspects relating to aseptic techniques, including: • Personnel qualification • Cleanroom design • Process design • Material control • Quality control • Environmental monitoring • Review of production records. The consequences of failing to prevent contam- ination of parenteral biologic products range from delays, denied approvals, recalls, safety risks, and remediation costs. Risks associated with sterilit y breaches and the potential financial costs involved in their rectification may be reduced by implementing robust strategies for preserving aseptic conditions. FDA issued more than 25,000 observation forms related to aseptic processing in 2021 alone (5). In 2022, FDA issued many high-profile warning letters to biopharma companies for their lack of adherence to aseptic processes (6,7). Although an FDA warning letter is informal and advisory, failure to implement necessary changes can lead to the letter being used as evidence in subsequent legal action (8). Aseptic processing essentials Aseptic processing is a methodology that maintains sterile conditions during manufacturing and protects against breaches that could place both patients and product batches at risk. The importance of aseptic processing necessitates stringent sterility checks and controls to deliver an aseptic environment throughout the manufacturing cycle. Developers must adhere to strict current good manufacturing practice (CGMP) standards and consider how sterility assurance can be monitored at different points of the aseptic process. Facilities also need to be monitored 24/7 for contami- nation breaches to guarantee sterility. A robust approach to aseptic processing is needed to maintain and safeguard a sterile environment. From formulation and filling to inspection, labeling, and packaging, biologics producers must scrutinize sterility and consider the following key factors when building a rigorous aseptic processing methodology. Prior contamination checks. Part of building a ro- bust approach to aseptic processing is ensuring any material received from other facilities are free from contamination. Lab-based assays can detect both DS viral contamination and the presence of mycoplasma, a common and difficult-to-detect bacterial contaminant. Mycoplasma presents a particular issue as it re- sists many antibiotics and poses a heightened risk to patients. Detection of mycoplasma is difficult as its small size (0.15 µm–0.3 µm) is not visible to the na ked eye or under mag n i f icat ion, un l i ke most other common microbia l contaminants. Reg ular mycoplasma-specific testing of batches is therefore needed to ensure sterility. Typically, mycoplasma de- tection will be done through culture-based methods and polymerase chain reaction-based methods. Filtration to reduce bioburden. Following DS for- mulation but before fill/finish, drug developers and manufacturers will typically thaw DS containers or bring them to equilibrium, making the containers ready for transfer to bioburden reduction filtration. After mixing and pumping the DS into a filling unit with a validated f low rate and/or pressure, a series of t wo 0.22 µm filters (sterilizing grade) removes bacterial or any other cellular matter from the final formulation. Following sterile filtration, the product will be filled in an aseptic environment into the final container and sealed, from which point the material is considered a drug product (DP). Master specification checkpoints Late-stage monitoring includes checkpoint require- ments to confirm the finished drug product meets the expected quality and performance requirements. The master specification will outline these check- point requirements. Alongside visual inspection, developers should perform container closure integrity testing (CCIT) to assess the fitting of stoppers and vials during the fill/ finish stage. CCIT determines whether a true seal has been made between the vial and stopper, preventing contamination from microbial organisms. A selec- tion of vials should be used for quality control testing following the DP specification to verify that vials are suitable for distribution and patient use. Environmental controls in aseptic processing To support the contribution of sanitation and ster- i lization steps in producing a safe product, dr ug developers and manufacturers can use several en- vironmental controls to further limit the contami- nation risk. Environmental controls will assess the air qualit y, humidit y, pressure, temperature, and A robust approach to aseptic processing is needed to maintain and safeguard a sterile environment.