Emerging Biotherapies and Their Manufacturing Challenges

A BPI Theater Roundtable at the 2016 BIO Convention

On Tuesday, 7 June 2016, Patricia Seymour (senior consultant in process development at Bio Process Technology Consultants) chaired a lunchtime roundtable titled, “Emerging Bio-Therapies and Their Manufacturing Challenges.” She brought together a panel of three industry experts:

Mark Angelino (BlueBird Biotechnology)
BlueBird is a six-year-old company specializing in gene therapy. It uses a viral vector and patients’ own cells. After processing, the patients receive their modified cells back as a curative therapy. BlueBird currently has four products in clinical trials and is providing treatments for central nervous system (CNS) disorders, thalassemia, sickle-cell disease, and cancers. The company also added a gene editing platform four years ago.

Andreas Weiler (Lonza)
Lonza has capabilities across the breadth of emerging technologies including antibodies and cell/gene therapies. The company has been in biotechnology for 30 years, and a decade ago it moved into cell therapy and built an antibody–drug conjugate (ADC) manufacturing facility to bring biologic and small-molecule components together. To move into gene therapies Lonza recently acquired Evanta in Texas.

Chris Chen (WuXiBiologics)
WuXi Biologics has a wealth and depth of expertise in multiple platforms for manufacturing ADCs, antibodies, and gene therapies.

Discussion

The biopharmaceutical industry is approaching the next frontier of emerging therapies. This session began with an overview of the topic. There are two basic types of cell therapy: autologous (patient-derived) and allogeneic (from donors or immortalized cell lines). Each involves different concerns regarding manufacturability. Gene therapies include viral vectors and gene editing. And although ADCs have been around for some time, in many ways they are yet to fully emerge. ADCs involve a host of manufacturing issues such as a complex supply chain, control issues, and quality issues.

It can be hard to find contract manufacturing organizations (CMOs) that are willing to handle these molecules. Cell therapies often require miniature manufacturing environments and harvesting cells from patients. Many technologies currently used are open, fairly manual, small in scale, and use research-grade materials. To manufacture cell/gene therapies on a commercial scale, they need robust processes that work at a larger, good manufacturing practice (GMP) scale. But it’s uncertain whether companies can make such products less expensively with different technology and still achieve the same therapeutic ends.

Next, the moderator posed a series of questions to her panel of experts.

What are the patient demands and needs for these new therapies? The limitations of traditional drugs are driving development of these new therapies. Some CNS diseases affect 50–100 new patients each year. Thalassemia affects an order of magnitude more, sickle-cell disease another magnitude more. Oncology indications involve thousands to tens of thousands of patients every year. One strategy is to work on rarer diseases first and learn the development process before moving into major disease treatments.

Chemotherapy doesn’t fight only the disease, but also a patient’s whole body. With targeted approaches such as ADCs, patients can have a better quality of life with fewer side effects. In principle, you could enable a patient’s own immune system to recognize the cancer and destroy it. Globally, the capacity to produce the necessary ADCs is not close. Whereas cell and gene therapies are patient-specific and low-volume products, a successful ADC could be a blockbuster drug needed on a massive scale. How to manufacture, store and deliver such products are questions that still need to be answered.

Will gene therapy products indeed be curative, and what does that mean from a product, manufacturing, and reimbursement perspective? If a drug cures all affected patients, then it conceivably makes itself obsolete. We are seeing some gene therapies with which a single treatment solves the problem and doesn’t have to be reapplied. You could see peaks and troughs in the prevalence of diseases as patients are treated. With some diseases, companies might have to forecast when those peaks and troughs in demand will occur.

How would a CMO build infrastructure around that fluctuation in demands? About 1,100 products are in the clinical pipeline right now. Fewer than a dozen of those therapies are currently marketed. Many were developed by small biotechnology companies. CMOs need to examine the development pipeline and take some risks. They also should look deeply into manufacturing processes because intellectual property (IP) lies not only in the products, but also in their associated processes. A CMO faces much lower risk in managing capacity than a product-development company does because many products can and do fail. One panel member described the current ADC supply chain as “a nightmare.” Ideally, everything should be located within 100 miles: supplies and facilities for conjugating, manufacturing, and fill– finish.

Are we going back to the old model where the process does define the product? Biomanufacturing can be centralized or decentralized, with manufacturing occurring right in hospitals. In patient-centric models, cells are collected by a blood draw and taken elsewhere for development into patient-specific treatments, then sent back to be injected into the same patients. The future could bring small, automated manufacturing areas in hospitals and develop such treatments at the hospital more quickly.

Regulations would need to catch up to this concept. How do you then define a batch? The conservative approach in which nothing changes will no longer work. Regulatory agencies want companies to evolve their technologies along with the related science. With multiple laboratories in multiple locations making small batches, you will need a great deal of control. You must ensure that work is being done properly and to the same high standard at every location.

Are these platforms amenable to quality by design (QbD) from the beginning, or do they develop more organically to proof-of-concept and then tighten up in later phases of development? What if you have micro-facilities or even regional facilities? For smaller situations — as with rare-disease treatments — companies might not be able to apply QbD from the start. Beginning early for a larger application makes more sense. When you think of cell therapies, you think of huge facilities involving a great deal of manual processing. To move forward, companies will need to show comparability: that cells made in a small batch are the same as those made in a large bioreactor. “We are making progress in this area,” said one panelist.

CMOs provide QbD processing. What are some other business demands and services on offer? A CMO should allow companies to bring a drug as fast as possible to market and be ready to move forward on innovations. CMOs are now beginning to offer solutions and guidance: They can design and scale up processes and guide smaller companies through manufacturing drug substances and products. Some even offer discovery services related to creating ADCs and producing homogeneous solutions of them.

How can innovators and CMOs partner to develop techniques, drugs, and processes? Advances often address unmet needs, and companies have developed new processes in-house. The panelists all expect innovations and new technologies to come both from internal company resources and from partnerships. Processes will be adapted to each innovator’s needs. CMOs need to be part of new innovations or be left behind. But regulatory expectations will come with all new technologies.

What do you struggle with now? Many emerging therapies are being granted fast-track status because they address highly unmet medical needs and are found to be efficacious in small clinical trials. CMOs must be innovative and creative. They must work with regulatory agencies. Techniques currently being used in clinics with only 15 patients can be adapted to improve products. CMOs and regulatory agencies are learning that emerging products will change throughout their life cycle, which is different than the case with more familiar biologics such as monoclonal antibodies.

Agencies are receptive because they do want to get safe products to the market.

Another concern is forecasting: Early stage data can show high promise that isn’t repeated in larger trials. How do companies approach this and make decisions about building capacity? One strategy is to start small and then build up. For emerging biotherapies, however, companies might not need big facilities but just cleanrooms and single-use technologies. When they run multiple programs simultaneously, overall risk is lowered. If one product-development program doesn’t pan out, then another might.

What other bottlenecks (e.g., access to talent) do you see? The biotechnology market currently faces much competition for talent, especially in these emerging areas. Academia is a major source, of course. But companies must train their employees carefully. When you genetically modify patient’s cells and then introducing those cells back to the same patient, that is a “one-shot deal.” Staff members must be able to deliver high-quality results every time. Scale-up was the other bottleneck mentioned, but panelists expected that issue to be solved over the next few years.

Questions from the Audience

How bullish are you looking forward to gene and cell therapy? If it takes several years to develop ADCs, for example, how long will it be until such therapies are common? Now that we are seeing good results in patients, one panelist pointed out, “the rest will follow.” These are exciting products that help patients and have limited side effects. Even cancer patients can have a normal life. It is generally hoped that ADC products can be commercially available within a decade. One audience member mentioned that his company in Taiwan is working on a new ADC platform that solves certain homogeneity problems.

How soon should we bring in some processing experts to help us during development so that we can get this to clinical trials? Processing is key to ADC development, so the panelists said it is helpful to get such experts involved as early as possible. That will minimize problems occurring further along.

Biologics going through clinical trials always risk failure. Is the failure rate for these emerging therapies different from that of chemicals going through trials? For small molecules, about 10% will make it through development to market. The rest will fail because of efficacy limitations and/or toxicity-related side effects. The numbers are better for biologics, but they have different failure points. On average, one in eight biologic products succeeds. If a genetic treatment actually fixes a mutation, then it should have success. So far, cell therapy results have been excellent results between phase 1 and phase 2.

Alison Center is editorial assistant ([email protected]) for BioProcess International, PO Box 70, Dexter, OR 97431. Recordings of many of these full presentations are available online at www.bioprocessintl.com/ BIO2016.