Written by: Mike Ludlow, Market Development Manager, Life Sciences; Element Materials Technology.
The growth in the development of biopharmaceuticals has impacted the study design required for the assessment of extractables and leachables deriving from polymeric components used for the storage and production of these products.
MAT WRIGHT
Mike Ludlow
The nature of these, aqueous based, product formulations has resulted in a shift towards ‘simulated use’ type extraction solvents rather than the exaggerated system used in the assessment of ’traditional’ small molecule drug applications.
There is a range of biopharmaceutical products. The production process for these products is typically based on recombinant DNA technology using living organisms or biological systems.
Single use systems (SUS) are commonly utilised in the production of biopharmaceuticals. The use of primarily plastic components provides a flexible and cost-effective platform, reducing the potential for cross-contamination and minimising the need for cleaning and additional validation between production campaigns.
Several standards and guidelines have been developed by various regulatory bodies and specialised industry groups to assess the use of SUS components and ensure that the potential to adversely impact patient safety and / or product efficacy is minimised.
Single Use Systems
SUS components used in the production of biopharmaceuticals including:
- Tubing and connectors
- Tank liners and mixing bags
- Sensors and valves
- Elastomeric components e.g., O-rings, gaskets
- Process filters, filtration cassettes and preparative chromatography columns
USP <665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products
The United States Pharmacopeia (USP) have developed general guidance documents which cover the assessment of plastic components for the production, storage, and delivery of drug products.
USP<665> details a risk-based approach which considers the potential contact of each SUS component with the drug during the production process. An initial paper-based assessment is used to determine the degree of chemical testing required, based on the assigned level of risk.
The standard contains limited information concerning extraction procedures (see Table 1) and some basic acceptance criteria for testing, however the analytical methodology for characterisation of the extractable profile is not included. These procedures are discussed in USP<1665>, which provides additional guidance on the risk assessment approach for the characterisation and qualification of SUS components, but this chapter is for informational purposes only and is therefore not considered to be mandatory. The responsibility for the justification and qualification of suitable test methods lies with the product owner.
Table 1 Overview of USP<1665> extraction solvents
USP <665> has been developed to complement the existing USP<661> monograph which details the procedure for the assessment of plastic packaging systems and their materials of construction.
BPOG Guidelines
The Biophorum Operations Group (BPOG) is an industry collaboration group which currently comprises over 90 biopharmaceutical manufacturers and suppliers. The group has several joint initiatives focused on the production of best practice approaches for the development and manufacture of biopharmaceutical drug products.
Established in 2004, BPOG has since published a series of standardised best practice protocols which detail recommendations for performing extractable studies and leachables evaluation for bioprocessing components and storage devices.
The protocols provide suggested methodologies which include; sampling, sample preparation, extraction conditions and reporting requirements, but as per the USP guidelines BPOG also accepts that individual study parameters may be amended providing valid justification is provided.
The protocols also include an extensive list of key considerations for performing extraction studies which are defined by the nature and intended use of the test item under consideration. Extraction conditions are selected based on the actual use of the individual product component – see Table 2.
The BPOG protocol specifies key method performance parameters for organic and inorganic assays, cross-referencing USP, EP, ASTM, and ISO guidelines, but again leaves the justification of final method parameters to the test laboratory.
Discussion and Conclusion
Despite the implementation of risk-based assessment becoming standard practice for the pharmaceutical industry there is still a significant lack of alignment between the various guidelines used for the assessment of SUS components – see Table 3.
Table 3 Comparison of test requirements from USP<665> and Biophorum (BPOG) based on risk evaluation.
The work of the Biophorum clearly shows the benefits of establishing a cross-industry dialogue to create practical and robust protocols for biopharmaceutical applications. Although there was some early reluctance within the E&L community to become involved with the BPOG initiative, the need for separate protocols specifically relating to these products is now accepted and has been widely implemented by the main regulatory bodies.
Following the original BPOG protocol in 2014, end-users reviewed a revised version in 2020 containing updates based on industry feedback. These included the following changes:
Removal of 5M sodium chloride and 1% polysorbate 80 as extraction solvents due to low unique extraction capability
Elimination of the time point zero interval as results were not deemed to be significant
Elimination of elemental analysis of 50% ethanol extracts
The timescale taken to implement the BPOG protocol, assess results and to agree and issue a revised version illustrates a level of agility that would not be possible with the traditional regulatory guidelines and is vital in an area that is developing as rapidly as biopharmaceuticals.
Although there are still gaps in terms of final testing and validation procedures, the establishment of a consistent approach to extraction studies based on exposure of SUS components to actual use conditions, significantly increases the quality and relevance of data submitted to the regulators. This helps to ensure that the key deliverables for E&L assessment are achieved and any potential safety risks to patients resulting from the use of SUS components are controlled during the production process.