OR WAIT null SECS
To overcome the challenges of the widening range and scope of products that require aseptic processing and the evolving regulatory landscape in this field, companies should deepen their knowledge base on best practices.
Parenteral drug delivery is a common and useful option for drug developers and manufacturers when dealing with substances that have poor bioavailability, low solubility, or a narrow therapeutic index. According to research, the proportion of parenterally administered drugs in the pipeline is rising, which is mostly attributed to the growth in biologics (1).
Any drug product that is to be introduced to the patient via a parenteral route must be sterile as the patient’s natural defense system is bypassed, so any contaminant can have a severely adverse impact on the patient’s health. However, terminal sterilization methods involving heat are not always applicable or suitable, as such methods can have a negative impact on the potency/purity of thermolabile drug products. In these instances, aseptic processes are employed.
“Aseptic manufacturing is needed for dosage routes that are more targeted than oral ingestion,” specifies Waiken Wong, manager, Product Development Engineering, Woodstock Sterile Solutions. “Those entry points are more vulnerable to microbial intrusion, so maintaining sterility of those drug products through aseptic manufacturing is critically important for patient safety.”
“Sterile products need to be manufactured with considerable robustness and assurance of sterility,” continues Tim Sandle, head of GxP compliance and sterility assurance at Bio Products Laboratory (BPL) in Elstree, United Kingdom. “With the types of sterile products, aseptic processing presents the highest risk area of pharmaceutical manufacturing because the drug product in the final container cannot be subjected to any additional sterilization treatment (as any additional processing would damage the product). This designation includes many complex drug products, including ophthalmic suspensions, sterile injectables, reconstituted lyophilized powders for injection, and aqueous-based aerosols for inhalation. Therefore, considerable attention needs to be paid to the design and control of the filling and dispensing process.”
There are multiple points at which contamination can infiltrate a drug product and, hence, put the drug product’s integrity at risk. The importance of aseptic formulation and manufacturing begins with sterile filtration, points out Sandle, in which companies must ensure the filtration controls are in place to protect the filter integrity and control the filtration process within its validated state. Then, careful sterilization of containers and the maintenance of a filling environment that meets relevant regulatory requirements is critical, he adds.
“The filling environment is at a particular risk from microbial contamination, and the product needs to be protected by barrier technology (ideally through an isolator subjected to a decontamination cycle) and by the maintenance of unidirectional airflow,” Sandle says. “Any incursion into the filling zone is a considerable risk, along with any activity that disturbs ‘first air’ (such as the use of gloveports on an isolator) and, therefore, these activities need to be understood and risk assessed.”
Additionally, there is a preference within industry to work with larger batch sizes, which can lead to certain sterility complications. “An important control element is time, and this can affect everything from the validation of sterile filtration to the length of the filling period, which will require qualifying through media fills. In designing media fills (or ‘aseptic simulations’), it is important that all worst-case conditions have been evaluated, including the different types of interventions and the frequency at which they are conducted,” Sandle states.
“Companies that have a well-developed infrastructure for formulation and manufacturing can easily scale operations to meet the needs of complex drug products and larger batch sizes,” remarks Wong.
Regulatory bodies have set out numerous guidance documents on the matter of aseptic processing, to help chaperone industry toward best practices. Recently, the European Union’s good manufacturing practice (GMP) Annex 1 guidance was revised to improve clarity and extend the scope of the products included within the guidelines (2).
“When addressing any changes to regulatory guidance, the first point must be to clearly understand the intent of the changes, and more specifically what has actually been changed,” emphasizes Andy Whittard, managing director, Cherwell. “This is where easy-to-use comparisons between old and new can be informative in focusing on those elements that could have the biggest impact to manufacturers’ processes and facilities.”
For Helen Sauter, director Quality Assurance, Vetter, to ensure compliance, pharmaceutical and biotech companies, along with contract development and manufacturing organizations (CDMOs), need to view the aseptic process as a collection of interdisciplinary tasks. “Enhanced process understanding is a key element of the revised Annex 1,” she says. “Therefore, risks must be well understood, and it is important to talk to all relevant subject matter experts about the requirements, any gaps, or needs prior to a successful implementation.”
Generally speaking, there are key challenges for pharma and biotech companies described in the revised Annex 1 guidance, Sauter continues. “A major requirement is the implementation of a contamination control strategy (CCS),” she states. “The Annex 1 document says to implement a CCS across the facility, which can pose a major obstacle for some companies. Although this requirement is not new, it is now more formal and detailed, leaving less room for interpretation and expecting all companies to have their CCS in place.”
The greater focus on a broader level of risk assessment and strategy is considered critical to the Annex 1 revisions by Whittard. “The establishment of a CCS that takes a holistic approach will be the foundation from which all decisions will be driven,” he specifies.
“Overall, it is beneficial to call for multiple viewpoints, such as insights from external conferences and authorities to navigate and best interpret the regulations,” confirms Sauter. “A variety of perspectives gives a more comprehensive evaluation of what the revised Annex 1 guidance requires.”
Sandle points out that the changes to Annex 1 were extensive. “One important aspect is with harnessing the best available technologies to exclude personnel from any direct interaction with the product,” he says. “Other important sections relate to sterilization methods, cleanroom classification and control, and cleaning and disinfection.”
As a result of the revised Annex 1 guidance, CDMOs are under greater pressure to increase their inspection compliance, notes Brian Korson, director of Finishing, Grand River Aseptic Manufacturing. “New inspection equipment and technology increases inspection capabilities and quality results, while decreasing time out of refrigeration, which is a big win for pharma manufacturing,” he adds. “It is imperative that CDMOs take the steps to have the right processes and equipment in place to supply patients with safe and effective products.”
“There are several technologies available for use in development and aseptic production,” explains Stefan Kuehnhold, director Pharmaceutical Production, Langenargen Site, Vetter. “These options include the classic isolator technology, which is a closed system, as well as the restricted access barrier system (RABS). Every system has its advantages, and it is up to each company to choose the right technology for its specific purpose.”
Deciding between RABS and isolators is the first choice, according to Sandle. “Here, RABS is the minimum standard; although, within the RABS paradigm, there are ‘closed’ and ‘open’ variants (with the ‘closed’ versions being superior as the risk of surrounding room air ingress is lowered),” he says.
“Isolators are superior because they provide a complete barrier, and they can be subject to biodecontamination through an automated disinfection process,” Sandle continues. “A complexity remains in that product contact parts need to be subjected to a separate sterilization process (including filling needles and stopper bowls).”
However, both RABS and isolators have a weakness with potential air leakage—a risk that is particularly high with the gloveport gauntlets, Sandle explains. “Systems that can be fully automated and do away with gauntlets entirely (that is robotic systems) are optimal,” he affirms.
Focusing on inspection technologies, Korson reveals that there are a variety of options available that can help to support increased compliance in aseptic manufacturing. “Fully automated inspection solutions use innovative inspection algorithms to ensure high particle detection rates, plus voltage leak detection to detect very small cracks,” he says. “This technology brings a unique opportunity for throughput of up to 400 vials per minute.”
“Innovations in pharma inspection systems are helping FDA-regulated timelines while achieving high standards of quality and maintaining product stability,” Korson asserts. “Companies should decide on the most appropriate technology solutions by evaluating the latest regulatory guidelines. Staying ahead of compliance will ensure your technology investments payoff for the future.”
Rapid real-time methods have been gaining interest for some time within pharma environmental monitoring, adds Whittard. “These viable particle counters can deliver continuous monitoring and potentially speed up release of product,” he says. Recently, Cherwell launched a rapid, viable detection system—MicronView BioAerosol Monitoring System (BAMS)—which allows for rapid, real-time, continuous monitoring of airborne microbes, supporting Annex 1 requirements, Whittard explains.
For Wong, blow-fill-seal (BFS) technology stands out as an excellent platform for aseptic products. “Containers are formed, filled, and sealed within a very compact sterile environment within the BFS machine itself. This eliminates the need to maintain entire rooms and suites under sterile conditions and reduces the container componentry to just the resin needed to make the units,” he says. “BFS containers are also customizable in shape and size, and more robust when it comes to handling and use.”
The difficult nature of aseptic needs within the pharmaceutical industry, and the evolving demands that are being placed upon companies and individuals working within the field mean that improvements in understanding of the process is imperative. Attending conferences and events on aseptic processes is beneficial to companies and individuals seeking to improve their understanding of aseptic needs, notes Whittard. “These [events] not only provide the opportunity to learn from talks and presentations, but to also share and discuss good practice with fellow delegates,” he asserts. “Engaging with companies and suppliers who specialize in the pharma space is also key.”
“When considering how companies can improve their understanding of aseptic needs, it is important to address both internal and external improvements,” adds Kuehnhold. So, while externally speaking, it is beneficial to attend conferences and events, learn from representatives of industry and authorities, and exchange with suppliers or customers on specific aspects of aseptic processes, it is also important to promote cross-functional communication internally.
“Integrating a holistic understanding of GMP within the workplace culture promotes a sense of motivation to consider and adhere to aseptic requirements for the sake of the patients at the other end of the line,” Kuehnhold emphasizes. “This [integration] is done through constant communication and well-established training programs to support employees’ gaining knowledge.”
“One department alone cannot cover all aspects in the complex aseptic environment,” confirms Sauter. “Only working within interdisciplinary teams provides processes that drive quality.”
It is imperative to assure compliance across every facet of the aseptic chain, from facility design to manufacturing controls and risk management, Wong stresses. “Maintaining a strong foundation of quality-driven practices allows companies to respond quickly and nimbly to evolving guidance,” he says.
“The aseptic filling process is continually being challenged, not least because the range and scope of products that need to be filled aseptically shows no sign of slowing down,” asserts Sandle. “Spending time investing in a robust training package is important, from upper management to operators, so they are aware of microbial concerns and good aseptic practices. Each member of staff should have a basic understanding of microbiology, hygiene, cleanrooms, contamination control, aseptic techniques, product protection, and patient safety.”
Kuehnhold emphasizes that the world of injectables is niche, meaning that not many pharma and biotech companies have the deep experience that they need to get their drug products to market successfully. “The more knowledge that can be gained on best practices, the better suited a company will be to advance,” he concludes.
1. Fact.MR. Parenteral Drug Market. Market Report, March 2022.
2. EC. Annex 1 Manufacture of Sterile Medicinal Products, EUDRALEX Volume 4, August 2022.
Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.
Vol. 47, No. 7
When referring to this article, please cite it as Thomas, F. Gaining a Deeper Understanding of Aseptic Needs. Pharmaceutical Technology, 2023, 47 (7) 16–19.