By Paul Thomas, Senior Editor
Argos Therapeutics believes that it has solved one of personalized medicine’s greatest challenges—automating the manufacturing process. Current processes for small-volume, marketed products (e.g., Provenge) are mostly manual and time-consuming. Argos’ Arcelis is a “personalized immunotherapy technology for cancer [which] captures the complete, unique genetic information of individual tumors, loads a patient's own dendritic cells with the total tumor RNA and uses these dendritic cells to trigger an appropriate immune response.” Arcelis then generates the immunotherapy customized to each patient's tumor. A single production run makes enough product to continuously treat the patient for several years, the company says. We talked with head of manufacturing Fred Miesowicz to find out more.
PhM: First a general question: From a manufacturing standpoint, what limits the development of personalized therapies (or immunotherapies, if you wish), and how does Arcelis overcome these limits?
F.M.: The processing of personalized therapies requires scale-out or throughput instead of traditional scale-up. Issues such as cross contamination and changeover of equipment are exacerbated when manufacturing personalized therapies. Batch testing and release become major factors as one indication could mean up to 50,000 batches to be manufactured and released per year. The automated platform we developed at Argos addresses these limitations by enabling the required traceability and robust processing of these products with electronic batch records streamlining release.
Manual processing for the scale-out has limitations that are difficult to overcome and daunting for large markets such as manpower, facility requirements and maintenance of consistent quality of every product produced. This all translates into a high cost of goods for the product and a much slower timing for increasing capacity to meet the market demands.
PhM: Give us a sense of what Arcelis looks like and is comprised of in terms of components. To what degree are you relying upon disposable technologies, and why?
F.M.: There are three main products obtained from each patient. The first is the tumor or viral sample that is the source of the antigen RNA for the product. The other two are obtained during a white blood cell collection performed on the patient. These are the white blood cells needed to generate the dendritic cells and the patient’s plasma, which is used to formulate the final product. All three of these patient samples need to be processed individually and combined to generate the final Arcelis product. Disposable technologies are the cornerstone of the automation platform. It is critical for the successful scale-out of manufacturing. It allows us to package multiple manual processing steps in a single closed disposable, ensures the sterility of the product and eliminates the possibility of cross-contamination.
PhM: What are the primary robotics involved?
F.M.: A 6-axis robotic arm is the key to the automated RNA processing unit. The other components of the automated units are integrated equipment/devices required to perform the necessary unit processes, e.g., a heat block to perform the necessary incubations required in the processing of RNA. Arcelis also has proprietary dispensing head that prevents any patient to patient contact with the samples. This allows for the rapid change from patient to patient with minimum changeover between subjects.
PhM: In theory, automating has obvious benefits in terms of product purity and consistency. How can you guarantee the safety and efficacy of each personalized product within a single production run? What kind of quality control is involved?
F.M.: Each personalized product is tested for safety (endotoxin, sterility, mycoplasma) for release. The intermediates generated throughout the process are tested to ensure the quantity or quality is as expected to move forward with processing. The final product is cryogenically stored. Testing is performed on the thawed product prior to release to ensure the viable cell count and cell viability is acceptable. In addition, the cells are analyzed using flow cytometry to ensure the identity and potency of the final product.
PhM: How long does a typical production run take? How quickly is the turnaround once you have the patient’s dendritic cells?
F.M.: With automated processing, the RNA manufacturing requires one to two days. If done manually, RNA processing would require a four-day period. The automated cellular processing occurs within hours; however, the generation of mature dendritic cells requires a week of culturing from the time of the patient’s white blood cell collection to generate final product. Following the manufacturing, final release testing requires up to two weeks. With automation, the product can be delivered within a month.
PhM: How are you able to produce, and preserve, up to five years worth of personalized product from just one run?
F.M.: The Arcelis dosing regimen consists of an induction phase in the first year with more frequent dosing and a maintenance phase with less frequent dosing in the second and subsequent years. We have performed process development to improve yield and product potency. Thus, the patient’s white blood cell collection typically provides enough cells to generate over 20 final product doses, sufficient for the induction phase and several years of maintenance. We can also produce sufficient amplified RNA to generate these 20 final product doses with intermediates stored throughout the process to enable any additional processing required. The cryopreserved doses are stable for years and can be shipped on demand to the site for dosing in contrast to cell therapies that are produced and shipped at four degrees Celsius (non-frozen). These doses need to be delivered to the patient within one day.
PhM: You’ve had some initial discussions FDA about your technology and your drugs in development. What have their questions and concerns centered around, and how have you addressed them?
F.M.: As expected, the validation of the disposable components and the equipment and demonstrating aseptic processing in these disposable components is critical. The most complex example is the disposable for the RNA manufacturing requires aseptic assembly with the patient sample and appropriate reagents. There was significant discussion on how to perform this assembly appropriately and demonstrate the developed methods ensure aseptic processing. The considerations raised in the discussion are being incorporated into the design of the barrier isolator for this assembly.
PhM: You have one product moving into Phase III trials. Should it eventually be approved, what would scale up to commercial operations look like? What are the main challenges?
F.M.: For personalized therapies, the key is scale-out instead of scale-up. The goal with automation is to design a modular facility where additional modules can be added when expansion is required as the patient population increases post commercialization. The automated processing equipment and modular facility can be replicated as needed.
The main challenge of personalized therapies is logistics. The patient’s tumor or viral sample needs to be obtained as the source of antigen, and the white blood cell collection needs to be obtained as the source of the dendritic cells and plasma to manufacture and formulate the final product. Managing the logistics of obtaining those samples, scheduling the processing, and shipping each individual dose of the final product back for administration to the patient is complex and challenging. Due to its extensive clinical trial experience over the past six years, the Argos team understands and has developed the expertise to effectively manage the unique logistics of personalized immunotherapies.
PhM: For a marketed therapy, you expect to have a cost of goods comparable to currently marketed biopharmaceutical products. What enables this?
F.M.: The automation using functionally closed disposable components enables the lower cost of goods primarily through the reduction in the cleaning, facility, and personnel costs. The functionally closed disposable components minimize the cleaning requirements between patient samples. The size of the facility is significantly reduced and automation enables a higher classification for the processing rooms resulting in lower operating costs. The required manufacturing personnel is one third of the requirements of the manual process. The main driver for the cost of goods becomes the reagents and disposable components.
PhM: You’re targeting immunotherapies, but what’s the potential for Arcelis (or modifications of the technology) to have broader applications for personalized medicine?
F.M.: Arcelis is an immunotherapy platform technology and can readily be applied to other indications in cancer as well as infectious and other diseases, since each indication differs only by the source of disease material. Argos’s immunotherapy designed for treatment of HIV, AGS-004, recently completed a Phase 2 study and is now in a randomized, double blinded, placebo controlled, Phase 2b study. Argos is evaluating potential Arcelis programs in additional forms of cancer, as well as other disease models.
