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Manufacturers must figure out how flexible they need to be to meet the numerous new requirements of the changing therapeutic and regulatory landscapes.
By the end of 2022, biologic-based drug approvals accounted for a slightly larger proportion of approvals than the number of small-molecule new molecular entity approvals (1). With this shift in focus for the industry toward more complex molecules that are prone to degradation comes an increased need for more careful manufacturing processes that can ensure contamination-free end products are made.
Largely driven by this exponential increase in demand for biopharmaceuticals, the aseptic pharmaceutical processing market is estimated to grow at a compound annual rate of 7.9% between 2021 and 2031 (2). “During the past few years, sterile drug development and production has grown significantly as a consequence of the type of products that are coming to the market—biological drugs, advanced therapies, and so forth,” concurs Rafael Beaus, global consultancy manager, Telstar.
For David Stevens, global chief commercial officer, Kindeva Drug Delivery, a combination of factors is impacting aseptic and sterile drug manufacturing. In response to the increased focus on more challenging molecules, innovators have been using more advanced formulation strategies, he explains.
“Additionally, the need to optimize production costs of medicine, including even the most innovative biologics, has been further heightened by recent global inflation, which has ratcheted up pressure on the pricing power of pharmaceutical marketers already being challenged by government downward pressure on drug reimbursement costs,” Stevens continues. “Even in the [United States], historically, the most amenable to pharma drug pricing—payors—have consolidated their buying power, and pharmaceutical companies and healthcare industry-wide are having to adjust to the reality of a more cost-conscious environment.”
As a result, Stevens notes, growth in more specialized, targeted, and precision treatments is being seen, as these types of therapies can provide options for previously untreatable conditions or offer payors more sustainable value for their therapeutic costs. “The implication for sterile drug product manufacturers is a growing shift toward products that require meaningfully smaller production batch sizes and more complex manufacturing processes,” he says.
In addition, the recent COVID-19 pandemic has hastened the uptake of patient self-management, leading innovators toward development of novel products that differentiate them from their competitors and allow patients to administer therapies at home with the same level of safety as in the clinical setting, Stevens remarks. “This [trend] has propelled growing interest and demand for pre-filled syringes and autoinjectors, which provide patients with the convenience and simplicity of user-friendly devices with pre-defined volumes and efficient low-waste doses outside of a clinical setting, which in turn offers reduced cost and differentiating proof points for patients and payors,” he states.
Looking at technology, Joerg Zimmermann, vice president Vetter Development Service, External Affairs, reveals that there is a clear trend toward more automation and the introduction of robots in aseptic manufacturing, along with digitalization of all processes via the Internet-of-Things or Pharma 4.0. “All this [change] is leading to even more robust and safe processes for manufacturing sterile drug products,” he says.
Keeping people, who are the main contamination source in aseptic manufacturing, out of the critical areas where a product is exposed is becoming a more pressing concern for industry, stresses Beaus. “This [demand] means that automation is being required more in aseptic processes, as well as the use of closed systems and engineering solutions to provide maximum safety to products,” he adds.
“Obviously within GMP [good manufacturing practice], there is a continuous pursuit of greater levels of patient safety, which, for injectable medicine, translates to pursuing even greater levels of sterility assurance that naturally leads to engineering innovations to minimize direct human intervention in the production process,” specifies Stevens. “Most notably, however, the EU [European Union] GMP Annex 1: Manufacture of Sterile Medicinal Products update, published in August 2022, clarified expectations for sterile products that reinforced contamination control requirements and emphasized the role of engineering out associated risks using technology where possible” (3).
The issuance of the revised Annex 1 guidance came after two long commenting phases and will be largely coming into effect in August 2023, Zimmermann reveals. “While some say that it is nothing new in terms of content, the regulation has become much more prescriptive, and this is currently raising the question of what the right interpretation is,” he says. “As Annex 1 is not only published by the EU, but also adapted almost identically by WHO [World Health Organization] and PIC/S [Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme], this will be the global standard going forward.”
Interpreting the revised Annex 1 guidance document will prove to be the biggest challenge for companies dealing with aseptic manufacturing in the near future, Zimmermann stresses. “While the consultations between regulators and members of the industry were successful on several issues, some paragraphs can be misunderstood. It is therefore of the utmost importance to understand the intent, and this is being worked on in conferences, seminars, and symposiums,” he states.
Beaus adds that, in light of the revised guidance, companies will need to improve their know-how of new facility design to ensure they are fully compliant moving forward. Furthermore, challenges will arise when existing facilities are upgraded to meet the new regulatory expectations while also maintaining sufficient production, he emphasizes.
“With greater regulatory compliance demands, including the wide-ranging aseptic processing and contamination control strategy implications of updated GMP Annex 1 guidance, pressure on older facilities with older lines will be appreciably felt, accelerating a shake-up of market players that is likely to increase pressure on already limited high-quality capacity,” agrees Stevens. In anticipation of the impact these regulatory changes will bring, pharma innovators have already started to demand the use of best-in-class fill/finish technology within internal and external manufacturing supply chains, particularly for innovative pipeline products, he confirms.
Another obstacle that has impeded the industry over the past few years, particularly during the pandemic, has been shortages of certain materials, such as single-use systems, bags, filters, and so forth, in the supply chain, notes Zimmermann. Although, this issue has mostly been resolved now, he states.
The shortage of gamma-sterilization capacity has also caused some difficulties, Zimmermann continues. “The combination of higher demand and the scarcity of cobalt-60 have led to a fundamental rethinking of the choice of sterilization methods. Alternatives are being introduced, with X-ray sterilization becoming a popular choice,” he says.
“While a lot of large-scale capacity was brought quickly into the market during the pandemic, there is a lack of capacity for smaller, more specialized products, particularly when looking at the rise of mRNA [messenger RNA] therapeutics and other newer modalities,” confirms Stevens.
Newer modalities, such as advanced therapeutic medicinal products (ATMPs), which include cell and gene therapies, pose unique challenges for manufacturers, Zimmermann points out. “Many [ATMPs] are autologous, meaning that patient-derived cells are being modified and reapplied to the patient. This is the so-called batch-size 1, and the processes are more comparable to microbiological lab processes than industrial processes,” he says.
“Finally, acute downward pressure on generic injectable medicines, as reflected in the drug shortage list, has created an imperative toward improving manufacturing efficiency, further amplifying the need to adopt high-throughput, faster lines that take advantage of automation and isolator technology,” Stevens emphasizes.
For new facilities, more importance is being placed on isolators and automatic processes, with many manual operations being replaced, Beaus remarks. “All-in-all, new facilities are being designed to allow visitors to view the main operations from the outside,” he says.
In the case of existing facilities, however, companies need to upgrade the existing equipment, revamp areas, and implement automated solutions to continue production that complies with new requirements, Beaus adds. “There’s room for increasing the automation level in existing facilities to be able to skip most of the current manual operations. The balance between investment needed and product safety is what is difficult, as automation is quite expensive, making it difficult to justify the return on investment,” he states.
As an example, Stevens highlights Kindeva Drug Delivery’s newly constructed aseptic manufacturing facility in Bridgeton, Mo., where the company has adopted isolator technology as standard to offer optimum aseptic operating principles for the manufacture of sterile injectables. “Single-use technology has also been a game-changer for multiuse/multi-product facilities in terms of room turnaround and the elimination of reliance on cleaning methods, assuring there is no carryover from product contact surfaces,” he specifies.
“There is a trend to move toward more automation of aseptic processes,” concurs Zimmermann. “Transfers between processing steps can be realized with robots or automatic transfer systems, and there is a clear recommendation in Annex 1 to automate the loading and unloading of lyophilizers.”
Decontamination of cleanrooms is another area where automated solutions are providing benefits, Zimmermann remarks. Using Vetter as an example, he highlights the Vetter Cleanroom Technology, V-CRT, which is a fully automated system designed to fully decontaminate conventional restricted access barrier systems grade A/B rooms, allowing for optimized contamination control in critical zones.
“While gloveless isolators were first introduced a decade ago, there are further developments being done to optimize the systems with even more automation, including robotized microbiological environmental monitoring and avoiding contact of H2O2 [hydrogen peroxide] with the packaging components,” Zimmermann continues.
In the future, manufacturers will face hurdles as a result of the growing number of small-batch targeted biologics entering the pipeline because most commercial capacity has been designed for larger, recurring volumes, Stevens specifies. “Additionally, the complex and expensive drug substance production processes required for high-value biologics, such as mRNA and viral vectors, will further drive the goals of maximizing sterility assurance to minimize risk of batch failures,” he says.
Although in agreement that personalized medicines, developed in small facilities close to or even inside hospitals, with significantly high-value products will be a certain trend requiring flexible facilities, Beaus also believes development will occur for more common products too. “There will be [highly] efficient specialized facilities, that are [significantly] automated, where most common aseptic and sterile products are produced as commodities, with maximum safety for product, but at the same time achieving low cost per every produced unit,” he says. “This trend may be applicable to vaccines, large volume parenterals, or some other general sterile products.”
“Further trends are definitely in the artificial intelligence space, particularly regarding automated visual inspection,” Zimmermann states. Currently, the naked eye remains a reference point within this area of the process, so digital camera systems will offer huge assets in the future, he notes.
“Manufacturers face the challenge of being flexible to stay in touch with evolving requirements for new drug-delivery approaches, be that in more complex formulations or in administration methods,” Stevens concludes. “For manufacturers, the task is figuring out how flexible they need to be to meet this trend.”
1. Senior, M. Fresh from the Biotech Pipeline: Fewer Approvals, but Biologics Gain Share. Nat. Biotechnol. 2023, 41 (2), 174–182.
2. Research and Markets. Aseptic Pharma Processing Market—Global and Regional Analysis: Focus on Product, Technology, Regional, and Country Analysis—Analysis and Forecast, 2021–2031. Market Report, December 2021.
3. EC. Annex 1: Manufacture of Sterile Products. EudraLex Volume 4, Guideline, Final Version, Aug. 22, 2022.
Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.
Vol. 47, No. 6
When referring to this article, please cite it as Thomas, F. Facing the Future of Aseptic Manufacturing. Pharmaceutical Technology, 2023, 47 (6) 21–23.