On Wednesday, 22 April 2015, Susan Dexter (principal consultant at Latham BioPharm Group) chaired a midday roundtable titled, “Fill and Finish Manufacturing Strategies: Better or Just New?” She brought together three industry experts to provide mixed perspectives:
- Joseph Figlio (senior project officer for the manufacturing facilities and engineering division of the Biomedical Advanced Research and Development Authority, BARDA, in the US Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response)
- Victor Lee (vice president of contract manufacturing operations at BioTechnique)
- Debashis Sahoo (engineering director at MedInstill).
Susan Dexter, Latham BioPharm
Fill–finish (FF) is the last manufacturing step and the most critical to maintaining product quality before patient use. That’s an important aspect of what regulatory authorities assess when they inspect FF facilities. Washing, depyrogenating, and filling– capping processes are complicated systems involving many moving parts. The US Food and Drug Administration (FDA) is interested in novel technologies and new ways of doing things to “derisk” the GMP envelope around these processes. Disposable technologies, which have derisked the GMP validation space around bioprocessing of drug substances, may be able to do the same for drug products.
Joe Figlio (BARDA)
Figlio monitors and reviews infrastructure-related contracts supporting domestic vaccine manufacture for pandemics at two centers for innovation and a manufacturing network. He previously worked for Merck and Metos Technologies. He presented the government’s approach. In 2010, it was discovered that the United States lacked domestic manufacturing capacity to rapidly produce and package a pandemic vaccine. That pushed BARDA to increase the nation’s capacity to produce more vaccines in bulk. A few years later, FF operations are still working to catch up.
Along with a clinical and nonclinical network, BARDA’s centers for innovation in advance development and manufacturing are set up to mirror a pharmaceutical company. That includes a fill–finish network that was established in 2013. Its goals are to support the FDA as well as the BARDA project with existing, prequalified facilities contracted to fill and finish vaccines for the government. “We want companies that have done this before,” Figlio emphasized. Expertise in formulation, filling, and finishing (labeling, packaging) of vials and syringes should include check transfers, regulatory support, analytical development, and clinical trial management. Contract manufacturing organizations (CMOs) were not the only companies to be considered, but BARDA wanted proven, US-based filling capacity because borders can be closed during pandemics.
Network companies had to produce documented evidence of their experience with licensed and approved products. They needed to present a capability statement explaining how and where the work would be done and whether additional resources or facility modifications would be necessary. The maximum time frame would be 12 weeks for filling and finishing a bulk vaccine. Technology transfer and an influenza vaccine would be provided by its manufacturer within the first three years of a project award. Figlio pointed to Ebola projects in progress as just one example.
BARDA made offers to four companies: Cook Pharmica in Indiana (partnering with GlaxoSmithKline), which is now starting tech transfer process; Patheon in North Carolina (still working to establish an influenza partner); Nanotherapeutics in Florida (partnering with Baxter), currently working in the tech transfer stage; and PAR in Michigan (currently working on an agreement with an influenza manufacturer). After confirming a partner and transferring technology, the companies will establish their surge capacity through staffing or other means. Then they will be available to support emerging disease projects that arise.
Live-virus capabilities and sterile-bag technologies are fairly limited, and some product shortages have arisen. BARDA is seeking to fill those gaps either through the network or outside it. Figlio explained that new technologies are not part of this effort because BARDA wants to rely on proven capabilities that exist in current capacity. “We didn’t want to have all this bulk vaccine lying around that we could not fill and get to the public.”
Victor Lee (BioTechnique)
Lee overviewed his company’s sterile liquid-filling processes and technologies and “shrinking the fill zone.” He focused on product considerations, container–closures, technical aspects, the filling environment, and its regulatory impact.
It all begins with the product, he explained, and its unique characteristics (e.g., liquid or lyophilized) and requirements (e.g., temperature, oxygen, shear, and material sensitivities). The next consideration is the container and its closure. Many options are available, from vials and ampules to prefilled syringes, flexible bags, and bottles, all in glass or plastic form. Closures may be stoppers, overseals, end ports, and so on. These choices define a FF process and drive its equipment and validation needs. Once you understand what kind of container–closure your product requires, you can consider different filling technologies, keeping in mind cost, regulatory impact, and available technology.
Lee called positive-displacement pumps and mechanisms the “tried and true technology” for liquid filling. It moves liquid from one area to another by means of a rotary piston, rolling diaphragm, peristaltic pump, and pressure. “There really is not a lot of room for improvement,” Lee said.
Other aspects of the process could be improved, however, and Lee pointed to aseptic processing itself. “People are the number-one source of contamination in any FF operation,” he asserted. So companies take measures to exclude sources of microbial and nonviable contamination. In the past, they have used class 100 cleanrooms with gowned operators and continuous monitoring. New components and equipment would be introduced through autoclaves and pass-throughs for aseptic assembly.
Lee said companies need to mitigate risk in aseptic liquid filling, where product is inevitably exposed to its environment as it moves from a bulk-storage vessel to its container awaiting closure. Overall sterility assurance is only as good as the robustness of the operation with the highest risk, Lee pointed out.
Risk mitigation begins with isolating people from high-risk operations. As Lee put it, “you shrink the environmental envelope and immediate surrounding filling operation.” Rather than controlling an entire class 100 cleanroom, you could tighten that control to an even higher level in a smaller space. The industry is creating physical barriers between filling operations and their operators using isolators, restricted-access barrier systems (RABs), transfer isolators, rapid transfer ports, and air locks.
In-process monitoring for FF operations includes inline fill-volume weight checks, oxygen level measurements, and stopper detection. They help companies maximize yield and minimize line loss for high-cost products. Lee pointed to automation as a way of improving these aspects of FF to further mitigate risk.
He went on to talk about cytotoxic, highly potent products (e.g., antibody–drug conjugates, ADCs) and live vaccines or biological agents. Here, not only must a company prevent contamination, but it also needs to prevent operator exposure and stop products from getting out into the environment. Aseptic and containment strategies, Lee said, are synergistic. Single-use, disposable components for direct product contact can play an important role here. They eliminate the need for cleaning and steaming in place (CIP and SIP) and autoclaving, as well as associated validation and qualification. Components arrive presterilized and ready to use. And they are less capital-intensive than reusable stainless-steel equipment. This makes them popular with regulators.
As a CMO cytotoxic manufacturer, Biotechnique has an integrated Bosch filling line with an inline weighing- check lane system and disposable product-contact parts. Drug substance moves from a supply vessel all the way to the filling needle through single-use components. At the end of a batch, those are discarded and the company starts with another set for the next run. Closed-vial filling may make it possible to shrink that envelope even further. A gamma-irradiated vial, in essence, becomes an isolator itself: a fill needle penetrates a septum on the vial to fill it, then is extracted so the hole can be laser sealed.
From a regulatory standpoint, such an approach enhances sterility assurance, mitigates contamination risk, improves operator and environmental safety, and increases process ease and control. Lee said that single-use technology is key to achieving these goals.
When asked about validation, Lee said it would be streamlined. To ensure that a process validated for one facility works in another, a company need not go through full-blown qualification testing. Historical data can guide such activities.
Debashis Sahoo (MedInstill)
Sahoo presented some disruptive technology with evidence that it could transform the FF business. Close INTACT Transfer technology is essentially a closed-system transfer method with applications in filling and multiple-dose dispensing, as well as sterile transfer and connections.
MedInstill’s closed-vial filling technology was licensed to GlaxoSmithKline in the early 2000s and qualified by the Parenteral Drug Association using media fills. A presterilized, closed vial is introduced into filling equipment and filled from an open-eyed needle, the environment around which is classified and controlled. It has been applied to dispensing and the food industry and used for a vaccine that has been approved in Europe. Recently the company has developed a means of filling a closed vial through a closed needle, which opens only when it is inside the vial to transfer the drug product. Thus, at no point does the product come into contact with its environment. The technology can also connect a formulation vessel to filling equipment.
“Currently we have set up two lines in India for a CMO,” said Sahoo. His company is also working with the FDA to validate the system for the food and pharmaceutical industries. MedInstill seeks to use this technology to ensure safer products for people around the world. Not everyone can currently afford the highest safety standards. The technology also could be used to prevent hospital-associated infections such as those associated with catheters. “CDC data currently state that we have about 33,000 deaths in the US every year because of this,” Sahoo said. And finally, his company hopes to aid in pandemic prevention. “It is possible to fill and to protect three-billion people in 20 days.”
Risk analysis comparing exposure with open-vial and closed-vial filling has shown the latter to allow a trillion times less exposure. It costs 10–20 times less than standard aseptic lines. In a 2004 meeting with the FDA, the company received no objection to file an abbreviated new drug application (ANDA) for pandemics. Sahoo said the equipment could deliver 15 million doses per day.
After extensive audience questioning about the technology, Dexter (Latham Biopharm Group) recalled the introduction of disposable technologies in drug-substance bioprocessing. Early on, many questions were asked and many experiments were needed to produce enough evidence that SUT was a viable option. But when 50 million doses are needed in 12 weeks during a pandemic outbreak, current capacity would be inadequate, so disruptive technologies and novel approaches like these will be needed.
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