Since the FDA released its current good manufacturing practices (cGMPs) and 21st century initiative that includes promoting industry modernization, the majority of industries—including pharma—have gotten onboard the digitalization and Industry 4.0 train. Though cost and documentation hold some companies back, this has resulted in improvements such as robotics and biometrics initiatives in drug product manufacturing being implemented as well as the adoption of modern, robust aseptic processing technologies that afford tangible safety benefits to sterile products. Three industry panelists and a U.S. FDA regulatory expert presented on these subjects at the 2021 PDA/FDA Joint Regulatory Conference:
James C. Weber, advisor IT, digital manufacturing, Eli Lilly and Company
Carl-Helmut Coulon, PhD, head of future manufacturing concepts, Invite GmbH
David Wolton, engineering technology lead, Takeda
Nicholas A. Violand, investigator/drug national expert, ORA, U.S. FDA
Modern tech: cleaner, faster, safer
Benefits of adopting modern technology emphasized between the four panelists’ presentations included improved cleanroom capabilities, time efficiency, and product and worker safety. Weber explained that Eli Lilly and Company (Eli Lilly) jumped on the opportunity to seize these benefits through developing a Global Robotics Program and integrating biometric solutions, both of which furthered the company’s digital plant aspirations.
“There definitely is an industry opportunity for robotics,” said Weber. “That’s demonstrated by the fact that most players in pharma are pursuing some type of robotics program. There are a lot of both ergonomic and economic drivers that make it attractive and in terms of regulatory or interaction with the FDA, from where I sit as an engineer, as a practitioner, most of the challenges are very tactical and they come down to risk-based design, validation decisions, and creation procedures to mitigate risks.”
Efforts began in 2017 when the cost of robotics technology started decreasing as the market increased, along with the physical and digital capabilities of the robots. Eli Lilly established central staffing and funding for its new program and used site experts to network and establish partnerships for opportunity identification, prioritization, design, and deployment. These experts focused on projects with the most potential value that could be replicated throughout the company. Eli Lilly’s standard sets of equipment, platforms, automation, and IT landscapes allowed it to create a lab for simulating activities across most locations and sites in order to develop solutions.
Weber said the company’s solutions ranged from logistics operations with automated warehouse and automated guided vehicles; to drug production manufacturing through loading and unloading of cartridges and vials on production lines, automated cleaning, and flexible aseptic filling; to flexible device assembly and flexible drug product packaging; as well as parts identification, in-process checks, and packaged product unloading, palletizing, and transport.
A specific robotic solution brought up by Wolton and Coulon was autonomous mobile robots (AMRs) which are experiencing increased demand. AMRs work 24/7, do not host viruses or bacteria like humans, are cleaner as they do not shed skin, and are ideal for repetitive or manual tasks. These robots are commonly used for the delivery and removal of items, such as waste, consumables, gowning materials, spare parts, and reagents for QC labs, and the newest type of AMR that comes with a manipulator can do more complicated and complex tasks, such as repetitive tasks in environmental monitoring, water sampling, and product sampling.
Adopting robotic technology further opens up next level opportunities to go “deeper” and “broader” than initially expected, allowing the focus to be on processes instead of individual activities. Digital data trail benefits become apparent through the ability to track the chain of custody of a product, its time out of refrigeration, etc. The same thought process can be applied to labs and creating a robotic logistics flow with the digital chain of custody for samples as they’re withdrawn for production and sent to the lab, stored and crated in an automated way, or tested in an automated way.
“By deeper, I mean capitalize on the integration of robots with the process equipment,” said Weber. “For example, sensor technology integration so they’re not just moving material but they’re also verifying materials, verifying batch identities, maybe even using vision technology to verify undamaged materials.”
Eli Lilly saw similar benefits with biometrics. Previously, the tedious task of operators entering their credentials in the form of signature entries made up of usernames and passwords was an ergonomic risk and needed to be done whenever an operator interacted with a machine. The company used manufacturing execution systems (MES), which have an especially high demand for user entries to support electronic batch records and related documents.
The company ran initial pilots in drug substance manufacturing “control room” settings using fingerprint and iris scanning biometric devices, then introduced biometric bracelets as options for operator mobility. Operators were given the opportunity to continue using the traditional signature method, yet three months in, data showed 80% of signatures being done with biometrics and 56 of 60 users opting to use the biometric bracelets, which data proved saved a minimum six seconds per signature.
Similar to robotics, Eli Lilly saw opportunities to go “deeper” and “broader” with a wider-administration process for user enrollment and using the biometric devices for access control and tracking people within operations on the shop floor or production offices. Further abilities the company is pursuing are general-purpose wearables to enable additional capabilities such as alerts and alarms from machines and systems; standard communication to notify maintenance and supervision; safe operations applications, including “operator down”; social distance monitoring; and contact tracing.
Room to improve
Though robotics can prove very beneficial to operations, there is still much to be done to make robotic solutions more efficient. In the case of AMRs, though more sanitary than humans, they are highly expensive assets, often resulting in a company having just one AMR, which will likely traverse all parts of the facility including air locks. Getting through air locks is the biggest challenge keeping the use of AMRs from becoming widespread.
Grade D air locks, in particular, require a specific type of cleaning with IPA wipes, which are difficult for AMRs to use for a number of reasons, so validating the cleaning process is very challenging. A potential solution brought up by Wolton is to automate air locks, having different automation solutions per grade. These solutions would need to disinfect quickly and be retrofittable, cost-effective, and flexible. But between companies, and even within a company, a solution cannot be agreed on.
Suggestions that have been explored include robots from the semiconductor industry, which have similar requirements to GMP cleanroom class A, as well as cleanable robots, for their compact cleanroom design, powder coating, seals to protect against particle emission, extremely smooth surfaces, and hydrogen peroxide-resistance. But the issue of humans needing to clean these robots keeps arising and Coulon asserted that current requirements for cleaning methods do not reflect automated cleaning but rely on human intelligence and vision.
He concluded that a concept for validating automated cleaning of complex equipment taking into account environmental, equipment, and substance features needs to be developed and to do so, engineers and pharmacists must be connected—in other words people, science, and regulation need to be connected.
Wolton agreed, adding that next steps should include defining specifications for what air locks need to achieve in terms of air quality and surface disinfection—especially if using ultra violet (UV) disinfection—as well as a discussion around the issues of visually clean. Wolton said, “What we’d like to ask for is a working group to actually debate this topic, but also then recommend a path forward. Now, we believe this will need a collaboration between PDA, ISPE, and BPOG and maybe other organizations as well. But at least if we can agree on what specifications are required, we can actually look into achieving it through automated means.”
Common cause of observations
Another important sector, highlighted by Violand, where modern technology applications can have a significant impact is aseptic processing. Violand stated that one of the primary contributors to contamination in drug manufacturing is the personnel. He asserted, “The greater the level of separation between personnel and operation the greater level of sterility assurance.”
Microbiological contamination of drug products purporting to be sterile has continued to be a top 20 observed citation in the drug realm over the last decade according to FDA research, and a solution not as widespread as the FDA expected is the use of isolator technology. This contamination is mainly due to operators not following sanitation guidelines around sterile drug products. Violand explained that isolators, however, create that needed distance between personnel and operation as they don’t allow space for operator hands and heads to enter sterile areas, such as under the laminar flow hood, instead using automated disinfecting systems, such as vaporized hydrogen peroxide (VHP).
Typical advantages of the closed isolator design listed by Violand include:
- Fully closed, with personnel completely separated from aseptic operations
- Positive pressure, and no interventions requiring open doors permitted
- Surrounding room can often have lower classification than in traditional aseptic processing
- Increased automation in lines is typical, further reducing opportunities for human error
- Transfer of materials inside is controlled (e.g., rapid transfer ports or transfer chambers)
- Disinfection processes can be more tightly controlled (e.g., VHP)
- Decontamination occurs after initial line setup and any necessary open-door activities
The FDA’s Guidance for Industry, Sterile Drug Products by Aseptic Processing – Current Good Manufacturing Practice, 2004 states that “aseptic processing using isolation systems separates the external cleanroom environment from the aseptic processing line and minimizes its exposure to personnel. A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control, offers tangible advantages over traditional aseptic processing, including fewer opportunities for microbial contamination during processing.”
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