Inspecting the Unexpected

By Dr. Andrea Sardella and Raffaele Pace, Stevanato Group | 11.17.20

Preparing quality control processes for COVID-19 vaccine candidates.

“These unprecedented times” have called for unprecedented measures. With the worst pandemic in a century continuing to take lives, cost jobs, disrupt education and complicate even mundane chores like grocery shopping, the devastating toll of COVID-19 has prompted the most ambitious race for a vaccine in modern history.

Only rarely have successful vaccines been developed in under five years.1 The mumps vaccine, which was introduced in 1967, is typically seen as the gold standard—and even that took two years of human trials before its public release. Now, we’re talking about the possibility of a vaccine within a year of a novel virus’ global outbreak. If accomplished, it would be among the most amazing feats in the history of medicine.

But a vaccine can only work its magic if it can be produced and made available to a critical mass of at-risk consumers which, in this case, means most of the world’s population of over seven billion people. Eradicating COVID-19, then, will require logistics advancements as well as medical ones.

While the R&D effort so far has been impressive by any measurement, the manufacturing, quality control and logistics side of the broader pharmaceutical industry must begin zeroing in and catching up. Much like a production line is only as efficient as its slowest common denominator, an effort this vast and ambitious can only be as comprehensive and effective as the weakest link along the supply chain. For vaccine developers, that means finding the fastest route to a safe, effective vaccine; for their industry partners, it means having the processes in place to distribute it to consumers both around the corner and around the world. 

One step in particular could be a COVID vaccine choke point: Inspection, which has long exemplified the push-pull between speed and quality. In the case of vaccines, which typically are produced in glass vials and syringes, the inspection process means carefully scrutinizing filled containers for proper fill volume, contaminants, cosmetic defects, closure seal and leakage. Mission-critical challenges abound, including monitoring the formation of foam or bubbles, distinguishing between acceptable protein aggregates or protein flakes and unacceptable foreign particles and, on the container, determining whether a defect is an acceptable scratch or an unacceptable crack, typically one generated via thermal shock during cold storage. Rubber stoppers, plungers and other closure mechanisms also must be verifiable as leak-free.  

Let’s examine the challenges inspection poses in developing and distributing medicines with the combination of quickness and quality necessary to combat diseases like COVID-19—an effort that may be called upon to inspect billions of doses in a dizzyingly short timeframe. With expeditiousness paramount, this has prompted Stevanato Group’s engineering teams to work diligently toward compressing the standard manufacturing time by 30%, to deliver equipment solutions capable of inspecting millions of doses apiece.

Inspection from Inception
Since any number of factors can affect product quality and production yield, moving from lab-scale production to commercialization requires an in-depth knowledge of critical parameters associated with successful scale-up. In the case of glass-bottled pharma products, like most vaccines, this includes an intricate understanding of inspection needs. 

Especially when capacity demands are high and speed to market is critical, inspection should be seen as a parallel product development track rather than a postscript to it. And just like a pharma product has lab-scale production in its early stages, so must its eventual inspection solution. For example, manual bench vision units can be set up featuring the same software and component design as production-scale automatic visual inspection equipment. This allows inspection parameters to be developed offline, which helps to ensure a smooth transition during ramp-up and increase overall throughput once big-batch production commences.

Every product has its own inspection recipe resulting from evaluating three elements: the drug’s unique features, the defects that require detection, and its container type. By ensuring equipment and software compatibility and consistency early on, the ramp up process is expedited and the risk of unforeseen disruptive factors significantly reduced.

As production expands, so should the process of perfecting inspection. Among other items, this includes collecting samples during Phase I and II clinical trials. Even if the candidate vaccine is not stored in the final, market-facing primary container, doing this can provide quality control troubleshooting and insight specific to the product itself. After all, vaccine inspection is a double-layered procedure in which both product and container must be comprehensively analyzed.   

Of course, this is also a matter of infrastructure. Successfully scaling up production also means having the right equipment and technologies. We currently find ourselves living through the ultimate example of a large-scale, limited time crunch: Vaccinating the population against COVID will require billions of doses produced and distributed as quickly as humanly and mechanically, and technologically, possible. For pharma companies and contract manufacturers, this will inevitably mean some combination of upgrading existing equipment and technologies, in addition to purchasing and incorporating new ones. 

Here, flexibility and scalability are key. From a versatility standpoint, inspection equipment must be able to handle containers with a wide variety of sizes, shapes and closure types, as well as drugs that may have prerequisite needs such as continuous rotation or pre-mixing. Otherwise, it may be too limited in its scope if, for example, a vaccine candidate does not gain approval and the machine must be transitioned to another product.

For inspection in particular, flexibility also means incorporating versatile technologies on automatic machines—ones capable of analyzing the full range of defect scenarios by shifting between typical-yet-disparate inspection formats such as camera inspection and high voltage leak detection. To promote seamless integration of both upstream and downstream production workflow, a wide catalogue of infeed and outfeed options like rotary tables and denester-renesters also is advisable. The point: since a product’s inspection needs can be highly customized, inspection machines need to be as adaptable as possible to be viable infrastructure investments.

Scalability means the pain-free ability to take a project from lab-scale to the broader, desired level of production-scale capacity. Here, it is worth reiterating the value of setting up manual bench vision units in the pre-market phases that feature the same software and component design as production-scale automatic visual inspection equipment. This is the safest bet to diminish scale-up time without sacrificing inspection quality.

Finally, the inspection machines that power the COVID vaccine push will be well-served to incorporate advanced vision software platforms capable of addressing the complexities of glass vial and syringe quality control. This includes the flexibility to easily generate new recipes, the precision to ensure exemplary detection rates while minimizing false rejects, and the retrofitability to add new technologies over time. A promising aspect of this are “future-proof” solutions utilizing artificial intelligence (AI) algorithms to self-learn and self-correct—an example of Pharma 4.0 technology addressing a notorious pain point for pharma QA/QC processes.

COVID Vaccine Candidates Exemplify Inspection Challenges
From a production and quality control perspective, the multiple coronavirus vaccine candidates currently in development fall into several distinct categories. Therefore, it is highly likely that two different delivery scenarios emerge. For example, one of the approved COVID-19 vaccines could be a light suspension with low turbidity, while other formats could comprise more difficult-to-inspect solutions.
In the first case—light suspension, low turbidity—a “traditional” camera-based inspection method may be adequate. To increase the foreign particle detection rate, manufacturers could rely on motion detection incorporating advanced trajectory algorithms, since particles typically behave in a statistically measurable way.

Should one or more approved vaccines be a thicker suspension or even an emulsion, however, line scan cameras would become the best-suited option. One such solution from Stevanato Group, involves a patented method featuring product homogenization, a high-speed spinning inspection technique, and advanced use of lights to increase contrast.

If the inspection process is optimized to the drug format, speed should generally not be a major issue. Modern automatic inspection machines can keep pace with high-volume vial and syringe production, which typically entails throughput between 400 and 600 units per minute. Whether or not this is indeed fast enough to satisfy the unprecedented and near-instantaneous demand a successful COVID vaccine would cause is, here, beside the point: The fact is that modern inspection machines will not, if employed properly, be the slowest common denominator, which is all that can really be asked of quality control modules.

The cold chain is another important factor to consider from an inspection perspective. The range and types of controls and production conditions, as well as their levels of complexity, will vary between vaccines, meaning tight controls will be needed to preserve efficacy for safe and effective patient delivery.

For example, if vaccines are kept at a low temperature but then sorted for the inspection process, a temperature change could lead to condensation formation; the best-suited technologies can confidently bypass this issue. Inspection for lyophilized formats—important particularly for emerging countries, where often the cold chain can’t be maintained—also must be considered, as this format presents its own unique challenges.

Looking Ahead
The pharmaceutical industry is moving toward more predictive methods, exploiting the advances in technology. Artificial intelligence has the potential to increase productivity and reduce production costs. Inspection should, could and must follow suit.

For instance, leveraging quality control experience gained from the extensive database of existing vaccines, AI could support the rapid realization of an inspection recipe for new treatments and vaccines, enhancing inspection precision while reducing time-to-market. AI-enabled deep learning also could dramatically cut parametrization timing, expediting setup processes for clearer, quicker pathways for full-scale production.

In the case of the race to eradicate COVID-19, necessity can truly be the mother of innovation, leading to more robust, efficient ways of finding inspection recipes that pair perfectly with the mission-critical medicines they are charged with safeguarding. 

References
  1. https://www.historyofvaccines.org/content/articles/vaccine-development-testing-and-regulation


Dr. Andrea Sardella is Pharma Vision Product Development Manager for Stevanato Group, a leading provider of inspection systems, glass primary packaging and integrated capabilities for drug delivery systems. Dr. Sardella has decades of experience designing optical and vision controls for industrial application, including automation and inspection machinery solutions. He has a degree in Physics and a Master’s in Nuclear Engineering.

Raffaele Pace is Engineering Vice President of Operations for Stevanato Group. A licensed engineer, Mr. Pace holds an MBA and a Master’s Degree in Mechanical Engineering, and has more than 15 years of experience developing complex equipment and line configurations.