Most pharmaceutical manufacturing teams are expected to be productive, well-oiled machines. In the case of Organogenesis’ Apligraf manufacturing team, there really is no choice. Apligraf is a living product—a circular matrix of skin and tissue cells (keratinocytes and fibroblasts) that is applied to chronic wounds to facilitate healing. The finished product ships overnight and has a 10-day shelf life; if the manufacturing team isn’t functioning properly, there simply won’t be product to deliver.
Pioneered at MIT, Apligraf holds the unique distinction of being the first FDA-approved, mass produced, living cell-based product. The Apligraf manufacturing process involves the production of the skin equivalent in a custom, plastic insert dish over the course of 20 days. The Apligraf technology is comprised of a contracted collagen gel matrix and living keratinocytes and fibroblast cells. Collagen is combined with fibroblasts to first form a dermal matrix, onto which keratinocytes are seeded to form an epidermal layer. Throughout the manufacturing process, a differentiated epidermis is formed that contains multiple layers, including the outer protective stratum corneum. Operators watch carefully over the entire process.
Apligraf team members Andrew Fulton and Laura Turner
These are the complexities that help define the manufacturing team. “Making a living product requires consistency and precision,” says Phil Nolan, Vice President of Manufacturing Operations. “We have to constantly be aware of what’s occurring within the process.” Process steps for Apligraf are very well defined, and rigorously adhered to, Nolan says. It’s no environment for the careless. “Our teams are very clear about the agreed-to objectives,” he says. “And they are committed to the high level of performance that is expected on a daily basis.”
“We’re tracking to see what our yields are for every lot because of the shelf life of the product,” says Production Director Cheryl McManamin-L’Heureux. “Unlike many products, there is not a large inventory of Apligraf that we can store on hand; if yields are down on one lot, production must immediately increase on another.”
The results of this commitment have been impressive:
- The team boasts an on-time delivery rate for the product of 99.8%. Guaranteeing supply availability and precise forecasting are just two areas in which the team has excelled.
- Over 200,000 applications of the product have been manufactured, which accounts for more than two-thirds of all patients treated in the world with living cells.
- With this extensive clinical experience, Apligraf has an excellent risk-benefit profile and safety history.
- Product sales have grown on average 30% annually for the past five years.
- Employee retention is very high, close to 90%, well above biotech industry norms and excellent for a very competitive Boston-area market.
Building from Within
Apligraf was approved by FDA in 1998 for use in the treatment of Venous Leg Ulcers, and again in 2000 for Diabetic Foot Ulcers. Even before then, the pieces were being put in place for a team that would be able to handle the complexity of the process. “We’re very careful about who we hire and how we build this team,” says Nolan. The team members typically have biology degrees, and have continued their work in other areas of the organization such as Quality, Research, Clinical or Process Development. The support received from functions across the company—including Process Development, Engineering, Quality, Logistics, Regulatory, Research, and Sales and Marketing—are critical to the company’s success.
Apligraf, a living product, requires delicate handling.
“We’re also selecting people who have a sense of mission and teamwork, and who have the skills and initiative help build our leadership team,” says McManamin-L’Heureux. “And by supporting our teams as they move cross-functionally throughout the organization, we have a continuous feedback mechanism that continues to drive our process forward.”
The team gets a sense of fulfillment from making a meaningful product—the sales team regularly shares stories of how Apligraf has made a difference in patients’ lives. The manufacturing team can then better appreciate the significance of their role in the production of Apligraf, says Nolan. “They see the effectiveness of it, the importance of it,” he says.
“We have a great deal of pride in the work that we do every day,” says David Bartorelli, Director of Facilities, Engineering and Maintenance. “We get a scorecard every day on our performance, and everybody on the team takes it very seriously.”
Some key performance metrics consist of morphological aspects, sterility testing, and visual inspection for both in-process and finished product release testing.
Because Apligraf involves such a unique manufacturing process, the team has had to define and maintain its own standards. The Apligraf team has borrowed principles of Lean and Six Sigma on an as-needed basis, and has successfully managed continuous improvement in its practices and processes. One of the areas of improvement has been in waste reduction. At one point, the team was seeing a trend toward contraction of the product within its insert, leading to product that was out of specification. “The product in the insert can have an effect where you see overcontraction, which is pulling away from the sides,” says McManamin-L’Heureux. “We had to review the materials used, the equipment, the environment, the personnel trained, and look at every single variable as an independent entity, and do some assessments against other lots that performed similarly or better to identify what the differences were.” Through a cross-functional investigation between manufacturing, quality, and engineering, the team identified the cause and the problem was immediately rectified.
“That was a great example of combined teamwork,” says Ginger Abraham-Freel, Director of Cell and Tissue Banks. “We got together, performed a root-cause analysis, and came to a resolution in an effective manner.”
Tweaking for Success
Safety is also a team mantra, as evidenced by the 200,000 statistic. “Safety can never be a concern for our patients,” says McManamin L’Heureux. “We use tools such as failure modes effects analysis and other methods to identify where the potential challenges could be in our process, so that either detection methods or process controls can be continually improved..”
Esin Yesilalan in the Organogenesis Lab
Apligraf, produced in a Class 100 aseptic environment, traditionally employed 13 sterility tests throughout the 21-day process. In order to further drive the safety profile of the product, two additional bioburden sampling time points—a shorter test than the standard sterility test—were added to provide additional means to detect potential product contamination. This process change required validation and FDA approval, which came quickly as the team was adding additional quality control tests.
In another example, earlier this year, Organogenesis developed an automated processing station for Apligraf, to ensure greater consistency and aseptic control in the process. “We reviewed our existing manufacturing process, and applied the principles to the equipment design to meet all of the challenges in standard processing,” says Ted Donahue, Manager of Process Automation, “This was a custom-built system, and in our application to the FDA we were able to communicate the design of the equipment, the intents of the equipment, and display that it was operating within manufacturing processing parameters.” The FDA approved the process change within 90 days and it is currently in the process of being implemented at Organogenesis.
All for One
Any operator who handles the product has the opportunity—rather, the obligation—to identify waste and ensure quality, says Bartorelli. “Whether it's the people in the shipping department, QC or the production folks, everybody's empowered to stop it, to speak out if they see something that might be a concern.”
“We handle every single unit with care, and every unit is 100% inspected,” says Abraham-Freel. “There are many steps of the process. And that's how we guarantee that we have a high-quality, safe product.”
What also distinguishes the Apligraf team is its communication. The group is always having meetings—sometimes scheduled, sometimes not, sometimes ad hoc within the process. It has been critical that every aspect of the manufacturing process be thoroughly defined and discussed. “I think that's really what stands apart from what happens at other companies,” says Nolan. “This team is very, very unique.”