You can’t get very far into a discussion of the modern-day pharmaceutical landscape without hearing the word “flexibility.” Gone are the days where it was common to find companies relying on blockbuster stars, produced in large quantities in dedicated facilities. Many of today’s specialty medicines are produced in higher potencies and smaller quantities. While the price tag may be bigger than traditional drugs, the complexity and business risk of manufacturing is also greater.
Priorities have shifted, and pharma manufacturers are stepping up their focus on increasing efficiencies and maximizing utilization in facilities. Contract manufacturers, however, are veteran players in this department. The nature of their business means juggling multiple clients and products while simultaneously delivering impeccable quality on tight timelines. Flexible production capacity, fast campaign changeovers, and rapid production at different scales are all part of the business model. Combine those demands with tight margins, and efficiency becomes a matter of survival.
Whether it’s a business necessity or a chosen mindset — or a combination of both — contract manufacturers have flexibility coursing through their veins. Insight into the methodologies, technologies, and strategies that today’s contract manufacturers are prioritizing can benefit the entire pharmaceutical industry as it enters a new era where flexibility is king.
Client and project diversity means equipment needs to not only be of the highest quality, but also serve more than one purpose. At Avista Pharma Solutions, a contract development, manufacturing, and testing organization with three U.S. sites, this flexibility is prioritized during equipment selection.
“We make sure all our equipment has the ability to fulfill a wide spectrum of formulation capabilities – from easy simple blends all the way to coated multi-particulates, for example,” notes Rich Shook, associate director, Drug Product Operations at Avista.
This flexibility extends to validation as well. Per the FDA’s process validation guidance, an Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification is generally performed for each piece of manufacturing equipment. Completing these qualifications means that the equipment can then be used for GMP manufacture of multiple products. This serves to ease the transitions for customers looking to move from early formulation development to larger scale production.
Using the same equipment for multiple products also introduces safety issues for workers and, ultimately, patients. When it comes to selecting equipment, especially with the increased use of highly potent active pharmaceutical ingredients (HPAPI), contract manufacturers prioritize equipment that both provides containment — lessening the chance of employee and environmental exposure — and minimizes contamination risks.
In order to reduce the chance of contamination, establishing a cleaning validation process is critical, and these too must be flexible enough to cover the wide range of equipment used across various contract facilities. Most guidance documents encourage the use of a risk- and science-based approach to cleaning validation.
“Our analytical cleaning methods are validated to cover each of the materials of construction found at our facilities i.e., glass, hastelloy, stainless steel and PTFE. Swab and rinsate samples are tested at every product changeover with individual cleaning limits based on established allowable daily exposure calculations. This provides the analytics needed to rapidly move a product from one production area to another,” says Dave Rippon, manager, Project Management at Cambrex’s Charles City, Iowa facility. Cambrex is a global CDMO with API development and manufacturing facilities in the U.S., Sweden, Italy, Estonia and Germany.
Many contract manufacturers are reducing contamination risks by investing in single-use equipment. With clear advantages in terms of flexibility, reduced cleaning resources, and lower utilities costs, single-use equipment speeds changeover between products and batches and, in the context of a multi-product facility, can drastically lower the risk of cross contamination.
Just last year, Emergent BioSolutions, in partnership with the federal government, spent $80 million to double the size of its plant near Johns Hopkins Bayview Medical Center. Emergent is a global life sciences company that manufactures specialty products that address intentional and naturally occuring public health threats, as well as provides contract manufacturing services for both bulk drug substances and sterile injectable drug products. Emergent’s recent expansion included the purchase of an ABEC 4,000L Custom Single Run (CSR) bioreactor. This is the largest single-use bioreactor size available in the industry by a factor of two.
The use of single-use bioreactors (SUBs) in the commercial market is a relatively new concept, but Emergent BioSolutions believes it is going to be a major factor in the future of manufacturing.
“The use of SUBs saved us a significant amount money on upfront capital installation of cleaning systems and the ongoing operational burden of utilities, as well as enhanced overall flexibility of our facility. We can now turn over the facility in a matter of one week and have the speed and assurance of no contamination,” says Sean Kirk, senior vice president, Manufacturing Operations, Contract Manufacturing Business Unit Head at Emergent.
According to a 2017 Nice Insight Contract Development and Manufacturing Survey, the top driver for pharmaceutical outsourcing is “access to specialized technologies.” For contract manufacturers, this need, paired with an ongoing focus on flexibility and containment, often results in a push to select equipment that is best-in-class in the industry.
“To put it simply, we need to have what clients will need to quickly and safely accomplish their goals in a finished dosage form,” says Shook.
FOLLOWING A ROADMAP
On its own, even the best-in-class equipment is not enough to enable facilities to juggle multiple products at once. Implementing new equipment and technologies requires a well-thought-out plan.
Sridhar Krishnan, vice president of Business Analysis & Excellence, responsible for Operational Excellence at Catalent Pharma Solutions, a global provider of drug delivery technology and development solutions with more than 30 global locations, stresses the importance of following a roadmap and progressing in a sequential order.
“Without understanding the process capability and limitations, automating the process does not make any sense,” Krishnan explains.
Catalent employs a seven-step process when it comes to implementing new technology. They focus on understanding process capability and optimizing each process step. Rather than rush onboard with new technology trends, they instead lay the groundwork for future technology and expansion, which also assures that facility space doesn’t need to be re-engineered after the fact.
We are investing proactively in areas but doing so in a very sequential way,” says Krishnan.
For example, when it comes to continuous manufacturing — an approach that has been heavily discussed in the industry for years but still has few real-world examples — Catalent is taking a methodical approach.
“We are not jumping the gun and buying fancy equipment. Instead we are using lean principles, optimizing the processes, putting semi-automated technologies in place and building the framework for continuous manufacturing,” notes Krishnan.
While it’s tempting to always be the first one out of the gate with new ideas, smart contract manufacturers are recognizing that properly preparing facilities for the future lessens the risk of failure when it’s time to launch new technologies.
DESIGNING FOR FLEXIBILITY
Planning ahead doesn’t just apply to technology implementation. Contract manufacturers are also meticulous planners when it comes to facility and suite design. Open spaces, modular equipment, and equipment on wheels — enabling plant floor operators to put together a new process train without engineers and mechanics — are common.
“Because you don’t know all your customers’ needs upfront, you have to design with flexibility and the capability to service their needs, not only from a GMP and quality perspective, but from a business perspective,” says Ken Domagalski, general manager at Avista Pharma’s Longmont, Colo. facility.
“Not designing facilities correctly upfront can cause major infrastructure issues down the road if you try to realign existing facilities to meet requirements,” adds Shook.
Avista’s recent investment in suite upgrades and capacity expansion at its Longmont site involved upgrading three existing GMP drug substance manufacturing suites and adding a fourth. In addition, Avista has also completed an expansion of new drug product manufacturing facility containing four flexible manufacturing suites for tablet and capsule manufacturing. Flexibility and containment were designed into the suites from the start. The
uites have unidirectional air flow patterns — a single pass, single direction air flow of parallel streams — which enables air to flow past potential obstacles with no risk of contamination from outside the zone.
“Each suite can be utilized for a different client at the same time, giving us ultimate flexibility, as well as containment,” says Shook.
To ensure that processes and systems were not only flexible, but also designed with containment and safety in mind, Avista enlisted the help of Safebridge Consultants — safety, health and environmental consultants who focus specifically on the pharmaceutical industry. Safebridge has been involved since pre-construction and Avista works with them on an ongoing basis to integrate suggestions and upgrades.
Emergent BioSolutions is also no stranger to the need for design flexibility. The company’s newly expanded Center for Innovation in Advanced Development and Manufacturing (CIADM) at its Bayview Campus in Baltimore is designed to support the U.S. Department of Health and Human Services’ strategic imperative to have “nimble, flexible capacity to produce medical countermeasures rapidly in the face of any attack or threat.” Because of the government’s need to respond to biological and chemical threats, as well as emerging infectious diseases quickly and economically, the 112,000-square foot facility was designed to incorporate flexible, innovative manufacturing platforms that can be used to manufacture multiple products.
“We are working with ABEC to push the boundaries on single-use,” says Scott Battist, Emergent BioSolutions vice president, and general manager of the Bayview site. “Now, rather than incur the costs needed to ‘scale-out’ capacity with multiple 2,000-liter systems, single-use customers can achieve true economies of scale.”
“Ultimately, this has helped us to focus on agility and nimbleness and our ability to service a variety of customers with unique needs across multiple platforms,” adds Kirk.
EMPLOYEE SKILL & MINDSET
Of course, no facility can operate seamlessly without the right people. The business of contract manufacturing mandates that employees have a balance of technical skills and the right mindset.
Cambrex’s Charles City, Iowa, facility is home to a team of more than 350 employees who understand the specific requirements of multi-product facilities. “We operate our production areas and testing labs on a 24/7 basis. We are staffed with highly trained operations and QC/QA personnel who have extensive experience in rapid equipment changeover,” says Rippon.
In the contract world, experience counts. Rich Shook and Ken Domagalski had a collective 55 years of industry experience between them — mostly with large pharma manufacturing — prior to joining Avista Pharma.
During Shook’s 20 years of experience at Sandoz, he often found scheduling constraints and the inability to fulfill needs on a tight timeline to be the biggest frustrations in large pharma/contract manufacturing relationships.
“I feel their pain,” says Shook. “At Avista, we look to alleviate some of the frustrations we’ve had in the past, and this helps build a trust with our clients.”
A contract manufacturer’s strong commitment to clients requires a certain type of mindset.
“We hire people who are able to handle a 24/7 commitment, who can think outside the box. Training is obviously important but having experience and a willingness to be flexible is key,” says Domagalski.
At Catalent, a flexible mindset when it comes to adopting new technology is also important.
“We have reached a tipping point in the industry. With increasing scrutiny from regulators from a patient safety point of view, the industry needs to realize that if we don’t start eliminating manual steps, we will not be able to meet these requirements,” says Sridhar Krishnan. “CDMOs are now embarking on an automation journey and this requires buy-in from plant floor employees.”
Ultimately, it circles back to employees who can build relationships with clients.
“Clients will ask themselves, ‘Who am I signing up to work with and do I trust them to deliver?’” says Battist.
“The cornerstone of any successful CDMO is establishing trust — having clients know they can rely on us to help them accomplish their goals,” adds Shook.
As pharma manufacturers pursue success in a landscape that demands flexibility, taking cues from those whose business model relies on their ability to efficiently accommodate different products, on a wide range of delivery platforms, with a variety of batch sizes, can help refine the art of multi-product manufacturing.
Deciphering what it takes to become a multi-product master is “the million-dollar question contract manufacturers must address,” says Krishnan. And for contract manufacturers, it appears that continually working to find the right balance between a multitude of techniques and technologies — all with flexibility at their core — is paying off.