Pharmaceutical Technology Editors

In part of the session "Continuous Manufacturing and Publication of ICH Q13" at the PDA/FDA Joint Regulatory Conference, Kelley Burridge, PhD, Product Quality Team Leader, OBP, OPQ, CDER, U.S. FDA, discusses the barriers to the development of continuous manufacturing processes after implementing ICH Q13.

 Perceived barriers to continuous manufacturing have been falling one by one. ICH Q13 facilitates adoption of continuous manufacturing. By providing common language and a framework of fundamentals of a continuous manufacturing. I see as an accelerator, rather than an endpoint, the evolution of pharmaceutical quality over the last several decades. With adoption of risk based approaches, process analytical Technology and Quality by design have set the stage for adoption of continuous manufacturing. The concepts of process dynamics and system integration from multiple connected human operations are newer for the pharmaceutical industry. However, while newer to the pharmaceutical industry, continuous manufacturing has been the norm and other industries, such as petroleum refining for over 100 years. The FDA encourages industry to adopt and implement continuous manufacturing. The FDA Emerging Technology Team, created in 2014 allows for additional engagement and interaction with the agency to help industry adopt new technologies such as continuous manufacturing. There are about 14 FDA approved drugs that include continuous manufacturing elements. The first drug approved with continuous manufacturing elements was in 2015, followed by the first approval for switch from batch to continuous manufacturing in 2016. The first biotechnology or protein therapeutic drug with continuous manufacturing LMS was approved in 2020. 2022 saw the publication of ICH Q13 and the internationally harmonized guidance on continuous manufacturing. That same year, there was an FDA publication, which showed that the approval times for products with continuous manufacturing elements was actually faster than that for similar products using batch manufacturing. In summary, guidance from the FDA and the ICH had been published. There have been approvals for both small and large molecule drugs. There are FDA programs such as the emergent technology program designed to foster early engagement and collaboration. And certainly not least, the analysis has shown that approval timelines for continuous manufacturing are not longer than those for similar products produced with the batch operation.

Videos

Kelley Burridge, PhD, Product Quality Team Leader, OBP, OPQ, CDER, U.S. FDA, discusses the barriers to the development of continuous manufacturing processes after implementing ICH Q13.

Barriers to the Development of Continuous Manufacturing and ICH Q13 (PDA/FDA Joint Regulatory Conference 2023)

In his part of the session "Transforming Medicine: Unleashing the Potential of Cell and Gene Therapies" at the PDA/FDA Joint Regulatory Conference 2023, Michel Sadelain, MD, PhD, Director, Center for Cell Engineering; Stephen and Barbara Friedman Chair, Memorial Sloan Kettering Cancer Center,

discusses CAR-T cells and living drugs for immunotherapy. 

 Really, hurdles stemmed from the fact that this was an untested and unproven technology in the clinical realm. And also in the pharmaceutical industry. The medicine here, the drug, is not a chemical or a small molecule. It's not even a protein. It's a cell. And on until recently, cells have never been approved as drugs. On top of that, these are not just cells, human cells, but they're genetically engineered cells. And as you may recall, back a few decades ago, there was a lot of concern, and even fear that genetic engineering could prove to be harmful in some ways. So this, so developing this approach did indeed go against the grain of many received ideas back in the 90s. But we now see that all that changed with the first approvals of CAR-T cells approvals by the US FDA, back in 2017. 

The term living drugs is a term I actually introduced in an interview to the New York Times a little over 10 years ago when explaining what a CAR-T cell is to the reporter. CAR-T cells make use of a synthetic receptor for antigen, which is what we named A chimeric antigen, sorry, which is what we named primerica antigen receptor or CAR. That instructs the T cell to recognize an antigen of our choosing, and to further have the T cell to do something about it, which means to kill the tumor cell. And not only that, it also tells the T cell to multiply. And so this is a medicine that multiplies that expands the numbers in the body of the patient. And it also makes use of viral vectors to introduce the gene coding for the synthetic receptor into those T cells. So in that context, it seemed like one way of summarizing it was to describe these as living drugs. 

 A round of CAR-T cells first, what we see today is the approval of already six different products for them for different refractory B cell malignancies, and two of them for refractory, multiple myeloma. As we all know, there hasn't yet been success and solid tumors. And many groups though, and many in academia and in industry, are currently pursuing the goal of adapting this very powerful technology to those solid tumors. What I think is equally interesting, though, is to see today CAR-T cells being investigated beyond cancer. And there have been very recent reports of remarkable early results in forms of autoimmune disorders, in particular, systemic lupus erythematosus. This makes use of the exact same CAR-T cells that have been developed for B cell malignancies targeting this antigen that we anti identified many years ago called CD19, but put to use in patients with autoimmunity. I think it's fair to say that this is triggering widespread enthusiasm today to explore CAR-T cells and a range of autoimmune disorders. And CAR-T cells could also be useful in intractable infections or different settings of transplantation. Now, beyond CAR-T cells, cell and gene therapies are today really coming of age. After a good three decades of exploring different vector systems, devising different manufacturing schemes, I think it's fair to say that a number of ex vivo and in vivo genetic engineering strategies are showing, are starting to show real results for patients. So I think we have to expect more and more of these coming to the fore.

Part of the session "Transforming Medicine: Unleashing the Potential of Cell and Gene Therapies," Sadelain discusses CAR-T cells for immunotherapy and the future of cell/gene therapies.

Living Drugs for Immunotherapy (PDA/FDA Joint Regulatory Conference 2023)

Waters Corporation’s XBridge Premier GTx BEH size exclusion chromatography (SEC) columns

Waters Corporation’s XBridge Premier GTx BEH size exclusion chromatography (SEC) columns are designed to improve analysis while lowering the cost of gene therapies, specifically for adeno-associated viral (AAV) vectors. SEC is a technique used for aggregate and fragment analysis in the research, development, and manufacturing of biotherapeutic proteins, such as insulin and monoclonal antibodies.

The columns aim to reduce the cost of gene therapies by using three to 10x less sample, generating faster results and offering more drug substance information. Additionally, a new multi-attribute quantification method is intended to double analytical speed, quadruple sensitivity, and increases resolution of target analytes by up to 50%.

The Xbridge columns are designed to take robust physicochemical characterization and quantitative measurements. Aiming to double the speed of measuring the potency and safety of AAVs, the SEC columns are intended for process development, formulation studies, regulatory filing support, ongoing process monitoring, and quality control.

Articles

Waters Corporation’s XBridge Premier GTx BEH size exclusion chromatography (SEC) columns are designed to improve analysis while lowering the cost of gene therapies.

Size Exclusion Chromatography Columns

Charles Ross & Son Company's Sanitary Double Planetary Mixer Model DPM-4S and Sanitary Discharge System Model DS-4S

The ROSS line of Double Planetary Mixers, which come in various configurations and sizes ranging from half of a pint to 750 gallons, are designed for mixing thick, sticky, or putty-like materials. The pictured Sanitary Double Planetary Mixer Model DPM-4S and Sanitary Discharge System Model DS-4S were fully customized and engineered for efficient processing of medical-grade silicone formulations in a portable workstation.

The four-gallon Double Planetary Mixer features two patented HV stirrer blades. Rotating on their own axes, the blades orbit the mix vessel on a common axis using a slicing motion that pushes product forward and downward, an ideal process for ultra-high viscosity materials. Designed for vacuum operation, the mixer is equipped with an electromechanical lift to raise and lower the vacuum hood, as well as a 50-psig heating/cooling jacket on the mix can. Multiple sets of mix can and vacuum hood can be supplied for convenient cleaning with minimal downtime.

The accompanying Discharge System is designed to maximize product yield while also simplifying clean-up. It consists of a platen that is lowered hydraulically into a mix vessel. As the platen pushes down on the batch, product is forced out through a valve on the side or center bottom of the vessel with minimal product left behind. The change-can design enables semi-continuous operation, which can significantly increase production.

The ROSS line of Double Planetary Mixers are fully customized and engineered for efficient processing of medical-grade silicone formulations in a portable workstation.

Mixing Systems for Ultra-High Viscosity Materials

Customized for shear-sensitive applications with low to medium viscosity, the ROSS Model CDA-200 features a two-wing anchor agitator and two medium-speed agitators, each fit with five rows of three-blade pitched turbines. The mixer was supplied with two portable stainless-steel mixing vessels and transport covers for semi-continuous operation, a four-gallon charging hopper for introducing ingredients to the batch, and a thermoprobe for accurate temperature readings.

All three agitators are driven independently by explosion-proof inverter-duty motors. The two-wing anchor includes Teflon scrapers that contact the jacketed sidewall and bottom surfaces. Double FlexiLip seals and silicone O-rings enable vacuum operation up to 29.5 Hg for creating air-free pastes, slurries, gels, and suspensions.

Designed for heavy-duty use, the ROSS line of Multi Shaft Mixers standardizes on precision bearings with large bearing spans that reduce agitator shaft deflection and vibration, contributing to the quality and longevity of these machines. With no bearings and seals in the product zone, ROSS Multi-Shaft Mixers are designed to offer better protection against contamination compared to other designs with bottom-entering agitators

The ROSS Model CDA-200 is fitted with multiple agitators for semi-continuous operation. 

ROSS Multi-Agitator Low-to-Medium Viscosity Mixer

Sphere Fluidics’ Cyto-Mine is an automated cell line platform that integrates single cell screening, sorting, dispensing, imaging, and clone verification into one solution. Intended for use in various research areas, including antibody discovery, cell-line development, cell engineering, and synthetic biology, the device uses a unique microfluidic picodroplet technology that is designed to enable screening of up to 40 million cells over the course of several hours.

Recent software updates to the Cyto-Mine have been made to ensure compliance with current good manufacturing practice regulations. These updates include 21 

 Part 11, FDA’s regulation for electronic documentation and electronic signatures, and a full installation qualification/operation qualification package, which is intended to support quick and easy equipment qualification.

Sphere Fluidics’ Cyto-Mine is an automated cell line platform that is designed to enable screening of up to 40 million cells over the course of several hours. 