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Feliza Mirasol is the science editor for BioPharm International.
Fill/finish inspection for vaccine vials and syringes must remain GMP-compliant while aiming for fast, efficient methods.
The global race to produce COVID-19 vaccines under the Operation Warp Speed initiative adds pressure to vaccine manufacturers to have product ready while conforming to US-based current good manufacturing practices (CGMP) and other countries’ regulations. The speed and efficiency with which vials and/or syringes are inspected during fill/finish are crucial for meeting these goals.
Visual inspection methods are common, but visual inspection is not necessarily simple, notes Andy Polywacz, vice-president of Quality Assurance at West Pharmaceutical Services. Polywacz explains that in-line vision systems are highly capable at evaluating a number of product attributes, such as detecting particulate, the presence of the vial stopper, the presence and position of the vial seal, the color of the cap on the seal, the fill level of the vial, and cracks and/or deformations in the glass. Meanwhile, the speed of inspection should be based on the capability of the vision system. “Some systems are engineered for high-speed processing and, as such, can effectively inspect vials/syringes at a relatively high speed without compromising the quality of the product,” Polywacz says.
Multiple COVID-19 vaccine candidates are currently in development today that are following different development strategies, and they can likely pose two different scenarios: one in which the vaccines will be in a light suspension, with low turbidity, and another scenario in which the vaccines will be in a suspension that is more difficult to inspect, says Raffaele Pace, engineering head of Operations at Stevanato Group, a producer of glass primary packaging and provider of integrated capabilities for drug delivery systems.
“In the first case, a ‘traditional’ inspection method based on cameras could work efficiently. To increase the foreign particle detection rate, Stevanato Group relies on motion detection using advanced trajectory algorithms, as the particles behave in a statistically measurable way,” Pace states. “Should one or more approved vaccines be a thicker suspension, or even an emulsion, line scan cameras would be the best-suited option.”
The most crucial element in global vaccination programs, once a successful vaccine candidate moves into the manufacturing phase, is the supply of billions of doses of vaccines, Pace continues. “The inspection phase will keep up the pace and match this high-volume production,” he says. “It is assumed, therefore, that the vials and syringes will be inspected at an average speed between 400 and 600 units per minute, depending on the inspection method used, counting up to 36,000 inspected items per hour.”
Darryl Peterson, business development manager for Antares Vision North America, a provider of inspection equipment and traceability solutions, points out that the inspection process should, at least, equal the line speed, which is generally determined by the “slowest common denominator” on a filling line (i.e., the machine with the lowest throughput rate). “Some experts believe that about 15 billion doses of a COVID-19 vaccine would be necessary to immunize the global population; the worldwide combined capacity within an acceptable timeframe is not even half this amount. This means that the industry will need to innovate and upgrade to meet unprecedented vaccine demand in a condensed, emergency-level period. Inspection will play a mission-critical role in this expedition process,” he states.
Peterson observes that the highest rate possible for fill/finish inspection, in this vaccine niche, is in the vicinity of 500 items per minute, in line with Pace’s evaluation (400–600 units per minute). This pace of inspection slows slightly should vacuum leak detection be needed. “There are a significant proportion of companies converting existing fill/finish lines with speeds in the 100–150 item per minute range, with desires to get to [a speed of] over 200 items per minute,” Peterson says.
Ensuring container closure integrity (CCI) as part of the fill/finish inspection process is also important, emphasizes Oliver Stauffer, CEO, PTI Inspection Systems, a global provider of package testing equipment, specifically non-destructive inspection and leak testing technologies for high risk packaging applications. “Failure of CCI poses a significant risk to patients, and visual inspection does not identify the lion’s share of CCI defects posing a risk to patients,” he says. “Vacuum decay and high voltage leak detection (HVLD) are two fundamental technologies that can be deployed to inspect containers for CCI.” PTI’s technologies can detect defects below 1 micron in size on liquid fill parenteral products and can be performed with cycle times under 10 seconds.
Moreover, CCI plays an important role in maintaining the sterility and stability of sterile injectable products, adds Derek Duncan, PhD, director, Product Line Europe, Lighthouse Instruments. Duncan explains that defects that cause a leak in a sterile vial are not necessarily defects that will be detected by a visual inspection process. “Examples of such defects are defects that are hidden by the crimp, microscopic cracks, and scratches in the glass, or temporary defects, such as stopper pop-up that result in temporary container leakage,” he says.
Duncan also notes that scientific CCI studies should be conducted earlier in the product life cycle to justify a CCI testing strategy in manufacturing. “In other words, there is an implicit requirement on packaging and process development to generate robust scientific CCI data in support of manufacturing’s efforts to be compliant. If CCI studies generate data showing a high-risk package or process, then a more robust CCI testing strategy could be implemented in manufacturing and vice versa,” he states.
Meeting the goals set for COVID-19 vaccine development under Operation Warp Speed will have logistical impacts on fill/finish operations.
“First and foremost, pharma companies are reconfiguring vaccine lines dedicated for other medicines for COVID-19 treatments and vaccines. This can require a significant amount of rework,” says Peterson. “Some are also adding entirely new lines to increase capacity exponentially; here, opportunities exist to ‘start fresh’ with modernized filling lines with the latest and greatest in automatic inspection capabilities.”
Peterson also recognizes the importance of temperature control for most vaccines and suggests that companies take note of this detail. Maintaining proper temperature control means that speed of production must be paramount to get the filled vials/syringes immediately into cold storage. “From there, that vaccine needs to be shipped in cold storage in a verifiable fashion, so that end users are assured of highest-possible efficacy,” he asserts.
Polywacz points out, however, that COVID-19 vaccines will more than likely follow the same basic filling process as other vaccines, including the inspection process. “The capacity for filling and the line speed is the question, not the ability to inspect the product. In-line vision inspection is a capability that allows an integrated approach to filling and inspection and, as such, the key is overall line speed,” he states.
“It is advisable to develop the vision recipes for the automatic inspection machines immediately, using multifunctional analysis equipment and, thus, anticipating any unknown issue,” interjects Pace.
Pace also suggests using multifunctional manual equipment to generate the “vision recipe”, highlighting the importance of collecting samples of product during Phase III studies, even if the candidate vaccine is not stored in the final primary container that will be marketed. He further notes that leveraging the extensive database of existing vaccines currently on the market would be helpful in establishing inspection methodology for potential COVID-19 vaccines. “Artificial Intelligence could support the fast realization of an inspection recipe for the COVID-19 candidate vaccines,” he adds.
Duncan, meanwhile, says that because the time during the COVID-19 vaccine development process is limited, more emphasis could be put on inspection/testing practices in manufacturing, as an extra precaution to guarantee product quality in terms of CCI. “After validation of the fundamental closure system, data needs to be generated to understand if the process introduces risk to CCI. To gain statistical confidence in the process, it would be necessary to perform testing on statistical sample sets. This in turn will require the use of non-destructive deterministic test methods because the probabilistic legacy test methods (blue dye and microbial ingress testing) have limited throughput capability.”
“Any pharmaceutical technology needs to adhere to the highest quality standards,” adds Stauffer. “Container quality is just one aspect of assuring drug quality and safety and ultimately patient safety.”
“Simply put, there are a lot of challenges here,” Peterson confirms, stating that “CGMP is typically non-negotiable; they are and should be mandatory for FDA acceptance. Evidenced by the greenlighting of mass production even while Stage III trials are ongoing, Operation Warp Speed may be a slight exception to full GMP compliance, as several companies are producing vaccine in ‘at risk’ quantity, signifying that they may come with some potential for diminished efficacy—whether that means the inability to verify cold chain perpetuity or fully fail-safe inspection practices.”
Peterson also says that the logistics of manufacturing a vaccine at “warp speed” is stretching the limits of global pharma capabilities. “The extraordinary demand—literally twice the global population—makes meeting the highest GMP standards while achieving desired capacity exceptionally challenging,” he states.
A solution to the challenge of meeting Operation Warp Speed goals is the use of automatic inspection machines that can inspect for all crucial parameters, including the presence of foreign particles, fill volume (also referred to as fill height), discoloration, and closure orientation, while also incorporating vacuum-driven leak detection, Peterson says. Automated inspection machines help companies inspect pre-filled vials and syringes—with either liquid or lyophilized (freeze-dried) product—for foreign particles, proper fill volume/height, color, cosmetic aspects (i.e., cracks or other defects), and the integrity of the aluminum crimp seal as well as the cap, if applicable, he adds.
“The overarching point is that flexible, comprehensive automatic inspection will be needed to achieve the mission laid out by Operation Warp Speed. Meeting these needs with basic manual inspection would be nearly impossible,” Peterson adds.
“There are no corners being cut in the pharmaceutical response to COVID-19. While the focus is speed to market, no steps are being skipped, and it simply means streamlining decision processes and always driving the process forward,” says Stauffer. “Warp speed simply means all hands on deck all the time. The pharmaceutical industry knows there is a lot at stake in this mission and quality will not be compromised.”
The primary needs for supporting the pharmaceutical industry’s mission is project execution, which requires effective cross functional teams, financial resources, ability to make decisions in deploying those resources, and ultimately having suppliers that can rise to the challenge, according to Stauffer.
Polywacz also asserts that manufacturers of approved vaccines will follow the established CGMPs, stating that “the filling and inspection process is not something new for the industry and, as such, can be conducted in a complaint manner.”
“Manufacturers will operate their lines within the validated parameters to achieve a filled, compliant vaccine. Speed and compliance can co-exist as the two concepts are not mutually exclusive—it all goes back to the capability of the overall proces,” says Polywacz.
“In my opinion what is needed is speed and scale,” Polywacz adds. “The challenge is having enough open capacity to produce and fill the vaccine in a timely manner. All other drug products need to continue to be produced, so it is not as if manufacturers can stop making other products and focus on the vaccine—they need to do both. The available capacity will be dependent upon the overall line speed for manufacturing, filling, and inspection. If a manufacturer needs to produce hundreds of millions of vials of vaccine in a relatively short time, then more than likely they will need to look at high speed lines and/or additional capacity to achieve the output needed to supply the market.”
“To keep up a ‘speedy’ pace to meet Operation Warp Speed goals while still remaining CGMP compliant will require implementation of CCI inspection/test methods that are conducive to generating a significant amount of science-based CCI data in a short amount of time. Methods that are non-destructive, rapid, and analytical will be preferred, and the implementation of these methods will accelerate trends that have already started in the industry,” concludes Duncan.
Feliza Mirasol is the science editor for BioPharm International.
Vol. 33, No. 10
When referring to this article, please cite it as F. Mirasol, “Reconfiguring Fill/Finish Inspection to Meet COVID-19 Vaccine Goals,” BioPharm International 33 (10) 2020.