By Marty Vanderlaan
When I started working for Genentech 20 years ago, one of the first projects I worked on was the anti-CD20 monoclonal antibody (Mab) Rituxan for B-cell cancers. Overall, I spent my career dealing with quality issues related to biopharmaceutical development and then retired in the autumn of 2015. That December, I was hospitalized for lung infection and pulmonary hemorrhage, was diagnosed with a form of non-Hodgkin’s lymphoma, and soon became a Rituxan patient. Over the next four months I received six cycles of Rituxan in combination with Velcade, a combination cyclophosphamide and dexamethasone.
Becoming a patient, and receiving a drug I had helped to develop, gives me a unique perspective and chance to reflect on what is important about medicines. Rituxan is given by intravenous infusion over a period of hours, and as I sat in the infusion chair thinking, I concluded there were two things that were important: the availability of Rituxan, and the quality of the product.
That the drug exists at all, and is available to me as a therapy, is a great tribute to the long sequence of events starting from the initial idea of an anti-CD20 therapy at Stanford and its commercialization by Idec in partnership with Genentech and Roche; the scale-up of manufacturing by the process development team, clinical trials, Food and Drug Administration (FDA) and European Medicines Agency review, and finally licensure. Rituxan was the first Mab approved as an oncology therapy, and the first produced in CHO cultures at the 12,000L scale. Much of what was done to bring it to market was done for the first time not only by Genentech staff as the manufacturer but by FDA as reviewers. The Rituxan preapproval inspection by FDA was the first I directly participated in.
Since then, the ongoing successful manufacture has involved transfer of the process to new manufacturing facilities worldwide; to facilities in Vacaville, California; Penzberg, Germany; and most recently to Samsung in Korea. Staff in my lab at Genentech ran the tests that demonstrated the comparability of Rituxan manufactured at each of these facilities. Beyond the manufacture of bulk is the whole infrastructure associated with supply chain logistics, raw materials, fill-finish, and shipping. So my thanks and appreciation to all those that have a hand in delivering the drug to my vein.
The concept of quality is more amorphous and a philosophical, but infusions allow time for this kind of reflection. What is meant by “quality” from a patient’s perspective? I decided quality is fundamentally connected to the issue of “sameness.” Is the lot of Rituxan that I am about to receive “the same product” that I got three weeks ago, and are both tolerated well and benefited from? Is it “the same” as that given to tens of thousands of other patients over past decades? Is it “the same” as the material used in the clinical trials, establishing safety and efficacy? The sameness concept also applies to the development of biosimilars and the quality that is expected of them.
Unlike small molecules, biopharmaceuticals are populations of molecules and the population varies from lot-to-lot. There will be “acceptable” variations in many biochemical and biophysical properties. At the time of licensure, experts at the company and the health authorities set limits on the acceptable variation in the Critical Quality Attributes of the biopharmaceutical. So how much variation is acceptable and still meets the patient’s quality requirement of “sameness”? Set the specifications too tight, and lots will fail, potentially infringing on drug availability. But set the specifications too wide, and one fails to guarantee “sameness” to the patient. It really comes down to manufacturing capability—is the process robust enough that the manufacturer can regularly meet specifications that are as tight as possible to ensure both drug availability and product sameness? These are some of the questions I asked while contemplating the wonder of being treated by a therapy that went from my bench to my bedside.
Ultimately, my journey is an unfinished one. With more awareness of Waldenstrom macroglobulinemia and amyloid disease, the more interest generated for new therapies. I’m proud of the work that my team did on Rituxan, and I look forward to finding out what other life-changing therapies will become available in the future.