Regulatory GMP focus explained at BPSA conference
The third important single-use conference of the summer was the BPSA International Single-Use Summit, which was held in Washington,
DC on 27–29 July. 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 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 recognised as:
- Reduced need for cleaning and sterilisation systems and validation
- Reduced risk of crosscontamination
- Improved containment
- Potentially greater control over aseptic operations (as facilitated with sterile connectors/disconnectors and tube welders/sealers).
Doleski's talk included 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 (i.e., materials or design), certificates of analyses,
and flow path testing for endotoxin, particulates and bioburden (where necessary). With regards to sanitisation (e.g., irradiation
for microbial control) or sterilisation, bioprocessers should note where sterilisation is performed (i.e., contract irradiator)
and provide documentation on the sterilisation validation method, sterilisation records, impact on materials (supplier validation
data) and repeated sterilisation 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). When 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 (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 impact 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 (i.e., handling training),
improper operation parameters (i.e., tube welding) and exposure to extreme temperature.
Doleski summarised his talk by saying that the FDA recognises 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.