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.