Focus on Standardization, Quality by Design, and Regulatory GMP - In this quarter's column, highlights from the IBC Single-use Applications meeting, the PDA Single-use Workshop, and the BioProcess sys


Focus on Standardization, Quality by Design, and Regulatory GMP
In this quarter's column, highlights from the IBC Single-use Applications meeting, the PDA Single-use Workshop, and the BioProcess systems Alliance International Single-Use Summit are presented.

BioPharm International
Volume 24, Issue 11, pp. 23-26


The third important single-use conference of the summer was the BPSA International Single-use Summit, which was held in Washington, DC, on Jul. 27–29 2011. This inaugural conference for BPSA served as a forum for suppliers and users to highlight the business model for single-use. In addition to business leader speakers, the summit featured J. David Doleski, the consumer safety officer at FDA's Center for Drug Evaluation and Research. Doleski opened with a review of relevant FDA regulations that impact single-use manufacturing, including 21 CFR 211.65 on Equipment, 211.94 on Drug Containers, 600.3 on Biological Purity and 600.11 on Biological Control. Each of these has similar statements about assuring that process equipment and containers do not adversely affect the drug or biological product. Additional compendial standards noted were USP General Chapters <87> and <88> on Biological Reactivity, <661> on Plastics, and <381> on Elastomers, as well as relevant FDA guidances, including cGMP for Phase I Investigational Drugs (July 2008) and Container Closure Systems for Packaging Human Drugs and Biologics (May 1999).

Advantages of single-use manufacturing were recognized as:

  • Reduced need for cleaning and sterilization systems and validation
  • Reduced risk of cross-contamination
  • Improved containment
  • Potentially greater control over aseptic operations (as facilitated with sterile connectors/disconnectors and tube welders/sealers).

Doleski's talk continued with an excellent overview of topics that should be incorporated in process documentation and FDA filings. Initially highlighted were considerations for vendor partnerships and materials control, included establishment of manufacturing (quality) agreements, vendor audits, notifications of changes in product (materials or design), certificates of analyses, and flow path testing for endotoxin, particulates and bioburden (where necessary). With regard to sanitization (e.g., irradiation for microbial control) or sterilization, bioprocessers should note where sterilization is performed (i.e., contract irradiator) and provide documentation on the sterilization validation method, sterilization records, impact on materials (supplier validation data) and repeated sterilization where applied (note that single-use systems are generally not suitable for multiple irradiations at doses > 25 kGy).

Extractables and leachables studies are performed to assess the potential impact of leachables on product quality, efficacy, and safety. This can begin with compatibility and extractables data from the supplier, testing with additional model solvents under manufacturing process parameters (e.g., temperature, pH, pressure, and time) where needed, considering the cumulative effect of all manufacturing equipment and conducting further risk assessments to determine if a leachable study is necessary (e.g., for final product formulation).

Process-validation considerations should take into account the full range of the manufacturing process, and incorporate multiple unit operations and actual manufacturing parameters, such as mixing speed and duration of perfusion culture. Sterile-media simulations should be conducted for filling of sterile product (i.e., bulk or unit dosage). Where fluids are stored in single-use containers, validation should include the length of time and temperature range, with assessments of the impact of fluid on materials, and the impact of materials on product, buffers or media, and container integrity (i.e., leakage) after storage. Where bulk fluids are shipped, considerations should include the effect of pressure changes, such as altitude, effect of motion (i.e., acceleration or vibration) and the protection offered by external containers. Other environmental considerations can include light, chemicals, and other mechanical forces that may affect the contained fluid.

Despite commonly cited concerns, leak integrity issues with today's improved biocontainer designs are rare. However, possible issues should be qualified and noted, such as movement or shipping of storage containers, operator error (handling training), improper operation parameters (i.e., tube welding), and exposure to extreme temperature.

Doleski summarized his talk by saying that FDA recognizes the importance of the user's relationship with their single-use equipment suppliers and expects users to work with suppliers to develop knowledge of their single use equipment, understand their product and processes, consider potential issues, conduct a corresponding risk assessment, perform appropriate validation, and establish proper quality systems to maintain a state of control.

Jerold Martin is senior vice-president of global scientific affairs at Pall Life Sciences, Port Washington, NY, and chairman of the board and technology committee at Bio-Process Systems Alliance,

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