Contorting Convention

Modern aseptic performance demands new flexibility in both mindset and technology

By Karen Langhauser, Chief Content Director

There’s a quote I once saw framed in the lobby of a pharmaceutical company: “Be stubborn about your goals, and flexible about your methods.”

The pressing need to take advantage of new technologies and explore new ways of addressing process control and efficiency is ubiquitous to all areas of pharmaceutical manufacturing.

However, today’s modern therapies - new, targeted approaches to treatment that are resulting in small-batch aseptic products, proving more difficult to sterilize and handle, and requiring faster speeds to market - add further emphasis to this industry-wide need.

“If you look at where we are today with the effects of genomics-based tools and genetics understanding, that’s all having an effect on making much more specific and smaller patient population therapies. And the effect is that we are not all going to take a blockbuster - we are going to take a very specific therapy for our condition, which will most likely be a smaller batch injectable with a higher price tag,” says Chris Procyshyn, aseptic subject matter expert and CEO at Vanrx, a company at the cutting-edge of aseptic filling.

This shift in market demand means that manufacturers are now able to recognize previously unattainable value in small-volume aseptic processing. With this shift not only comes the opportunity, but the need to refocus on available technologies.

“Traditional methods and approaches to aseptic design and process control that were geared toward mass production may not be optimal, or in some case even feasible, with some of the new therapies we are seeing,” says Hal Baseman, chief operations officer, ValSource. “Rather than take needs of these new therapies and try to fit them into the ideas and approaches that have worked for large-scale manufacturing, maybe we should be looking at this a different way, instead asking what are the new approaches that we should be considering that would better fit these new therapies.”

THE DEMANDS OF SMALLER BATCHES
Smaller batch sizes mean that manufacturers are looking at facilities very differently, and re-assessing capex spending.

“The industry is starting to see a lot more products being manufactured in each facility, and a lot more specific process requirements. This is a different scenario for drug manufacturing - one that is really demanding a rethink on how facilities are put together and where priorities are placed,” says Procyshyn.

Drug manufacturing of the past required heavy investments in large manufacturing facilities and equipment, but this may not be the case with modern aseptic processing. Some biologics manufacturers are even using their clinical manufacturing facilities to launch, enabling them to determine how well the product performs before making bigger investments into manufacturing technology, points out Barry Starkman, a 30-year veteran in biopharma facility design and principal consultant, parenteral manufacturing, for DPS Engineering.

Speed to market is also more important than ever before, which means facilities of the future need to be operational a lot faster than facilities of the past. Equipment standardization is a great enabler when it comes to bringing products to market quickly. Conventional, custom-built fill-finish lines are expensive and time-consuming to build and offer limited flexibility. Equipment leaders, such as Vanrx, are recognizing this new challenge.

“We are talking about an equipment market where ‘custom’ used to be the rule. But today’s drug manufacturers don’t have time to be the guinea pigs for what’s never been tested before. Customers are looking for something that is predictable. At Vanrx, we build very consistent, standardized offerings, and consequently we can develop and refine and test at a very deep level,” says Procyshyn.

Standardization needs aren’t limited to filling lines. Aseptic component designs also can benefit from standardization.

“The machine is just a vector for the components to flow through. Standardizing component offerings would be an important move forward for the industry. If you get too many different component designs it becomes difficult to design machines that can be everything to everybody. If the goal is maximizing flexibility while minimizing costs, the implementation of standardized, ready-to-use components allows for more flexible facilities, capable of handling a wide variety of products in a single facility,” says Starkman.

EMBRACING EMERGING TECHNOLOGY
The U.S. FDA defines emerging technologies as, “Technology with the potential to modernize the body of knowledge associated with pharmaceutical development to support more robust, predictable, and/or cost-effective processes or novel products and with which the FDA has limited review or inspection experiences, due to its relative novelty.”

The industry’s migration away from standard cleanroom filling in favor of isolators (close to 30 years ago) brought with it dramatically improved product safety and environmental compliance. This, according to Starkman, helped open the industry’s eyes to the incredible benefits of emerging technologies. “There was an increase in willingness to look at the data and make changes accordingly,” notes Starkman. “And I’m hoping this continues, because acceptance of new technologies is the only way the industry is going to move forward.”
Recent emerging technologies in aseptic processing, such as advanced isolators, robotics and increased automation, have indeed changed the industry and markedly reduced contamination risks for sterile products.

“Equipment manufacturers are definitely moving in the right direction and end-users are getting better at defining what they want, but ultimately there needs to be a lot more consorting and collaboration between equipment manufacturers, end-users and regulators. We are getting there, but there is still a ways to go,” says Starkman.

An often-used reason for the drug industry’s reticence when it comes to the use of new, emerging technologies in the drug manufacturing process is regulatory hurdles. And yet, most experts agree that regulatory agencies are no longer impeding progress when it comes to technology.
“We are in a really interesting time. Global health authorities are recognizing that these new therapies don’t quite fit large-scale manufacturing methods, and consequently, I believe they are open to considering changes,” says Baseman. Baseman is also the committee co-chair of PDA’s Manufacturing Science and Operations Program, which, among numerous goals, seeks to identify and encourage use of new manufacturing technology and methods.

In late 2015, CDER’s Office of Pharmaceutical Quality (OPQ) established its Emerging Technology Team (ETT) to serve as a primary point of contact for companies that are interested in implementing emerging manufacturing technology in the manufacture of their drug products. The group is focused on establishing open communication between the FDA and drug companies who want to introduce modernizing technologies. Participating in this program will grant a drug company a face-to-face meeting with the FDA as well as an onsite meeting at the participant’s plant in order to show the Agency the technology in action.

Encouragingly, the Agency noted last year that aseptic innovations were one of the dominating submission types for participation in the FDA emerging technology program.

Vanrx, who has met with the ETT to discuss the company’s gloveless isolator technology, reports that the team is very positive and ready to work with industry.

“Ultimately, regulators have the obligation to make sure there is a supply of safe and effective medication. They are pushing for technology advancements. Keep in mind that they see everyone’s filing and everyone’s plant, so they know what best-in-class looks like. Consequently, they push for advances once they see what’s possible,” notes Procyshyn.

RISE OF RISK-BASED APPROACH
Regulator’s shifting attitude in terms of emerging technologies can partially be attributed to the adoption of a risk-based approach to manufacturing.

Adoption of a true risk-based approach to process design and process control involves drug manufacturers defining the quality attributes of their products, and how to best assure those quality attributes are established and maintained. As a result of this reverse engineering approach, manufacturers can look at each step along the way and determine the risk of failure.

Taking a risk-based approach means pharma can better articulate its processes to regulators. Having good data and analyzing that data means manufacturers can better understand - and articulate - the risk of failure.

“The idea of the risk-based approach has really driven regulators to look at things differently. With manufacturers now able to demonstrate that they understand the critical quality attributes of their products and what drives them in terms of critical process parameters, it is much easier for regulators to say with confidence that manufacturers truly understand their process,” says Starkman.

Additionally, a risk-based approach encourages a more proactive view of emerging technologies, enabling drug manufacturers to take a hard look at the needs of a particular process and design technologies that meet those specific needs.

“Adoption of a true risk-based approach means manufacturers can ask themselves what equipment they really need to establish process control and then design technologies around that need - as opposed to designing a process around technologies that happen to be available,” notes Baseman.

Another added bonus that could potentially come of a more risk-based approach is the introduction of new industry guidance in the area of aseptic processing.

“The guidances we have are geared toward larger scale aseptic production. There needs to be some work put into changing guidances or adding new guidances and approaches. It’s important to consider that maybe the tried and true, traditional approaches aren’t fitting as well with the manufacturing needs of new therapies,” says Baseman.

If you were to view guidances as a compilation of best practices in the industry, it would follow that if the industry’s approach to best-practice in aseptic processing was to shift, new guidance highlighting these changes should follow.

THE NEED FOR CHANGING MINDSETS
In addition to next-generation technologies, next-generation aseptic processing requires next-generation thinking. It can be said that the pharmaceutical industry is dominated by a generation of people who don’t necessarily have a lot of experience managing industry-wide change. “There is a very different level of technical understanding necessary for managing change,” notes Procyshyn.

“If you step backward, one of the challenges with our industry is that it’s a lot slower and more glacial than people might think - but even if you look at glaciers these days, they change too. It may be a slow wave that goes through industry, but every sign is there that major changes are well underway,” continues Procyshyn.

In addition, most experts in aseptic processing gained the bulk of their experience in large-scale processing, and are now being challenged to apply that knowledge to aseptic processing on a much smaller scale, notes Baseman.

“Manufacturers are going to hit this fork in the road where they either make the process fit what they know from large-scale manufacturing, or they take a fresh look. They can take the easier way, or they can take a way that will have more long-term benefits. Taking an honest, risk-based thinking approach will create a process that can give the industry high levels of assurance that is unquestioned by regulators and will allow new levels of production efficiencies,” concludes Baseman.

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