Product, Process, People
When official rules or regulations are updated, changes can often be summarised in headlines or distilled into key takeaways.
Such a task was arguably not possible when the revised EU GMP Annex 1 came into force on 25th August 2023. Rather than subtly tweaking the rules governing the manufacture of sterile medicinal products in the European Union, EU GMP Annex 1 effectively reset standards in this area for pharmaceutical companies across the globe.
The holistic nature of the updated regulations places emphasis on a range of areas that in themselves are already comprehensive in scope. This includes the role of primary packaging components, where attention has been given to an in-depth understanding of container closure integrity (CCI), and the wider requirement for a comprehensive, evidence-based contamination control strategy (CCS). Both of these are focused on reducing contamination, such as particulates, microbes, and pyrogens throughout the whole sterile manufacturing process.
The expected benefit is fewer deviations in manufacturing, as illustrated in Figure 1, and improved supply chain integrity. A operational level, this means there must be a collective and concerted commitment to limiting contamination at every step of a sterile drug product’s lifecycle to meet the overarching goal of enhancing patient safety.
Figure 1: Particulate contamination and lack of sterility cause most U.S. product recalls attributable to primary packaging1
Suppliers of primary packaging materials are expected to develop their own CCS in anticipation of the demands set out by EU GMP Annex 1. A combined global approach with site-level implementation ensures strategic ambitions are delivered locally on the ground. This is manifested through an enterprise-wide master CCS that defines the overarching objectives and requirements for EU GMP Annex 1 compliance in a single-source document as illustrated in Figure 2.
Figure 2: Example of manufacturing controls for primary packaging elastomer, including individual and collective effectiveness of the controls measured through the product process flow.
The enterprise master CCS is complemented by an individual Contamination Control Plan (CCP) at each supplier production site, the latter of which provides location-specific details on compliance with global requirements while enabling cross-site sharing of best practices.
This 'top-down, bottom-up' approach ensures contamination is controlled consistently at all levels across the organisation, both operationally and culturally. To satisfy both the suppliers' own ambitions and regulatory expectations for continual improvement, a lifecycle management approach should be established, ensuring sustained compliance as regulations evolve. This relies on continual internal and external benchmarking as part of an ongoing 'Plan Do Check Adjust' (PDCA) methodology. Such measures are not, however, designed exclusively to satisfy internal requirements. Rather, the ambition to complement a customer's own CCS, plugging the best-practice approach into wider contamination control efforts as a trusted supply chain partner. An example of a CCS development process flow is shown below (Figure 3).
Figure 3: CCS journey development process flow: from global development to site implementation.
A critical aspect to be considered in the journey to align a manufacturing site with EU GMP Annex 1 is the development of a Change Management Communication Strategy. This should underline the importance of ongoing efforts to control contamination in a very human way, helping inform and educate team members as per the demand for personnel to have a “specific focus on the principles involved in the protection of sterile product during the manufacturing, packaging and distribution processes” as set out in EU GMP Annex 1. With the ultimate goal of reinforcing a mindset shift towards the notion of continual improvement with regard to contamination risk, using the fact that every product produced has a patient’s name on it as a motivating factor.
At the point of initial engagement with a customer to assess primary packaging components, in light of EU GMP Annex 1 requirements, the focus should be placed on the four areas of product, process, protection and proof, see Figure 4.
Figure 4: Key considerations when assessing primary packaging components for EU GMP Annex 1 readiness.
Product considers the quality levels of current components and whether they are sufficient to meet a sterile injectable manufacturer's contamination control objectives.
Process considers any potential changes to processing that might be required, taking into account whether components are sterilized in-house or supplied in ready-to-use form, whether they will be introduced into restricted access barrier systems (RABS) or isolator fill-finish lines, and the context within which vial crimping takes place.
Protection considers the various factors that can have an impact on CCI and how it is managed throughout a product's lifetime. Finally, proof considers the importance of suppliers evidencing their own CCS so that it can be incorporated into a customer's wider holistic plan.
It is these individual components that can be regarded as being at the core of maintaining sterility for parenterally administered drug products. From a physical and chemical perspective, packaging components must adhere to the highest quality standards if they are to deliver on the requirements set out by the revised EU GMP Annex 1. Elastomer raw materials, dimensional tolerance, coating performance, extractables and leachables profile, and integration with production environments are all factors that must be controlled to avoid introducing risks.
To ensure primary packaging elastomer components meet this demanding level of component quality, controls need to be implemented at each manufacturing step to eliminate possible sources of risk. In the early stages, this includes segregation of materials, isolation of utensils and line clearance procedures, supported by exhaust systems and filters, as well as low particulate environments molded/formed components are then washed, vision inspected, packed, and sterilised with validated processes before being shipped.
Together, these controls all conspire to optimize conditions so that particle generation is restricted to the subvisible range.
Figure 5: Illustration of manufacturing steps and respective controls for elastomeric closures.
An example in the market are elastomeric components that specify both subvisible and visible particles ranges.
Pharmaceutical companies rely on automated vision inspection systems to help ensure product safety. Ideally, primary packaging elastomer components should also have vision inspection systems implemented in their manufacturing line, with the goal of reducing the end-of-line reject rate via the detection of visible particulate matter and other defects. The vision inspection system and tight manufacturing controls enable a higher acceptable quality level (AQL).
Another area of focus introduced in the revised EU GMP Annex 1 is in the form of extractables and leachables. The guidance calls for “an assessment of leachable profile studies, including safety concerns” that reflects processing conditions and is rooted in a scientific rationale to evaluate the risk of impurities in the drug product. Ensuring that a drug product is safe and effective means selecting an elastomer closure system that will not significantly interact with the drug nor adversely affect the patient. That can be achieved via carefully selecting and characterising the elastomer closure raw material ingredients and processing steps to reduce the risk associated with leachables and using a barrier film applied in the elastomer closure surface facing the drug product. (Figure 6).
Figure 6: Depiction of closures with a laminated barrier film applied to the closures surface. The blue color indicates the area of the barrier film coverage and is for illustration purposes only.
Clinical examples demonstrating the effectiveness of a protective barrier properties include: Eprex® packaged using laminated stoppers reduced the incidence of pure red cell aplasia (PRCA) by creating a barrier to a rubber accelerator leaching from the elastomer closure; and metal ion induced degradation of epinephrine in lidocaine-epinephrine injection resulting in lidocaine ineffectiveness was mitigated with laminated closures.2
As well as protecting the integrity of the drug product within the primary container, EU GMP Annex 1 also places clear emphasis on CCI as a means of maintaining drug product sterility and quality. Drug manufacturers are referred to USP to demonstrate a container closure system can maintain CCI, where integrity is defined in relation to a drug product's maximum allowable leakage limit (MALL). The selection of the test method will depend on multiple factors including, but not limited to, the drug product itself and corresponding storage conditions. It is noted that one single test method may not be sufficient, and that the leak test(s) chosen should be capable of demonstrating the ability of the specific container closure integrity to meet the MALL for the product of interest. The CCI should also be built into the overall process via a holistic approach considering all CCI aspects and elements of a control strategy, starting with the right elastomer component selection at the product design, to address all risks and how to prevent and control them.3
Primary packaging components can therefore be seen to answer the most demanding questions in relation to contamination control, demonstrating alignment with the requirements set out in EU GMP Annex 1. However, suppliers should be cognisant of the fact that components are rarely considered in isolation and must also appreciate how they integrate within cleanroom environments if they are to truly support a seamless, end-to-end approach to minimising the risk of microbial contamination in Grade A and Grade B areas. For example, the provision of flexible secondary packaging options ensures facilities with isolators and RABS (as advocated in EU GMP Annex 1) can support the use of rapid transfer ports to allow components to be introduced without the use of glove ports and in a way that reduces turbulent airflow.
But even with the most streamlined processes and the highest specification components, sterile manufacture must also continue to address the human factor if contamination control is to be managed in a truly holistic way. As discussed above, people should represent a vital pillar in supplier journey not just to comply with EU GMP Annex 1 but to implement continuous improvement when it comes to contamination control. The belief is that these elements must all come together in a multi-faceted approach, with component quality, production principles and personnel all aligned on the critical responsibility of bringing ever safer products to market.
About the Authors
Dr Ana Kuschel ... is a Principal Scientific Affairs at West Pharmaceutical Services and an active member of the ISO TC 76 and PDA Packaging Science groups.
Niamh Bissett is a Director of Business Transformation at West Pharmaceutical Services and has over 20 years of experience in quality compliance and program management
Notes:
1 https://www.fda.gov/drugs/drug-safety-and-availability/drug-recalls and https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/recalls-biologics (Accessed February 2, 2024)
2 Boven, K, et.al., The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes, Kidney Int. 67(2005) 2346-2353. Milano E.A. et.al., Aluminum Catalysis of Epinephrine Degradation in Lidocaine Hydrochloride with Epinephrine Solutions. J Parenter Sci Technol. 36 (1982) 232-236.
3 Wuchner, K. et. al., Industry perspective on a holistic container closure integrity approach to parenteral combination products, European Journal of Pharmaceutics and Biopharmaceutics 194 (2024) 20–35.
NovaPure and FluroTec are registered trademark of West Pharmaceutical Services, Inc., in the United States and other jurisdictions.
