FDA Initiatives Drive 21st Century Advanced Manufacturing Technologies

Our vision is “a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight.

— Dr. Janet Woodcock, Acting Commissioner, U.S. FDA

The COVID-19 pandemic has clearly demonstrated the grave consequences of inefficient manufacturing and unprecedented supply chain challenges. Will 2021 be the year that the pharmaceutical industry fully embraces new technologies to keep up with these changing times?

The culture in big pharma companies is conservative. Regulatory Affairs executives may be reluctant to authorize the change of processes for several reasons ranging from cost, time, regulatory concerns, etc. even when technologies are approved with long histories. This obstacle can be difficult to overcome when we live in a world of constant litigation. However, it is amazing how quickly we can alter our current thinking when there is a public health crisis.

Advanced manufacturing involves activities that use data driven science to understand the capabilities of these novel technologies. The goal is to use the appropriate technology to help improve quality and capacity of the product. Some general examples of these technologies are the application of automation, advanced on-line analytics, or even artificial intelligence.

What is the Emerging Technology Program?

The U.S. FDA developed Emerging Technology Program (ETP) in 2015 as an initiative to help support the industry’s efforts in advancing product quality and addressing drug shortages. Through the ETP, industry members can meet with the Emerging Technology Team (ETT). The ETT is a group of specialists from the Center for Drug Evaluation and Research (CBER) Office of Pharmaceutical Quality (OPQ) who organizes early discussions on the development and adoption of a new technology within an application.

While legacy guidances are well established and help many traditional manufacturing technologies, there is room for improvement, especially with augmenting novel technological approaches. ETT can help identify and resolve these types of challenges. This program also can accelerate the development of new standards that are more fitted to these new technologies. Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization: Guidance for Industry was finalized and published in September 2017. An emerging technology under this program can be either product manufacturing, or a manufacturing or testing process. All have the potential to lead to more adaptable, robust, and efficient manufacturing operations.

The Center for Biologics Evaluation and Research (CBER) launched their own plan to ensure that there are risk-based, patient-centered reviews of new technologies by forming the Advanced Technologies Team (CATT), in June 2019. CATT was also developed to encourage the industry to have early conversations so applications with new technology are approved in a timely manner.

FDA is making additional progress to advance pharma manufacturing in 2021 by forming a partnership with the National Institute of Standards and Technology (NIST) through a memorandum of understanding (MOU). This MOU will create a collaboration of subject matter experts who will apply the agency’s regulatory standards to the advanced capabilities of measurement and testing from NIST.

3D printing as an example

3D printing (3DP), also known as additive manufacturing, is the process of fabricating three-dimensional objects from digital designs. The first platforms were developed in the late 1980s and the first Inkjet printer was available in 1996. Before it was researched for oral solid dose manufacturing, 3D printing was successful for various medical devices including orthopedic implants, surgical instruments, dental restorations, and prosthetics. “Technical Considerations for Additive Manufactured Medical Devices Guidance for Industry and Food and Drug Administration Staff” was published in 2017 and includes design, manufacturing and testing considerations.

Aprecia Pharmaceuticals was the first company to gain FDA approval for the 3DP of its reformulated antiepileptic drug (Spritam®) in 2015. Many patients may experience difficulty swallowing high doses of oral-solid dosage tablets which makes it challenging for them to receive the appropriate dose. ZipDose®, Aprecia’s proprietary 3D printing technology allows for multiple, successive layers to be printed on a sheet so that a single tablet can hold over 1000 mg compared to a standard 200 mg. This dosage form can be completely dissolved with just a sip of water so the patient can easily stay compliant to the dosing regimen.

Another promising 3DP application is drug delivery devices such as implants and microneedles. A 3DP based implant can deliver multiple APIs in sophisticated release profiles in one device. Newly developed ‘patch’ implants could be extremely effective in treating chronic diseases like cancer. A biodegradable implant for pancreatic cancer was studied in a mice model and demonstrated high efficacy. Microneedles allow for transdermal drug delivery of biological molecules. While traditional manufacturing of microneedles has challenges with complex geometries, 3DP techniques can fabricate curved needle tips that are less than 10 µm in radius which may be suitable for vaccines.

Although there are current challenges around scaling and excipient limitations as well as additional regulatory guidance for multiple site approvals, 3DP for pharmaceutical applications is an innovation with great potential to be very disruptive for both drug dosage and drug delivery. Small changes to the base model permit a high level of flexibility for personalized medicine and on-demand manufacturing with the greatest amount of process control. The use of 3DP could also expedite clinical trials since it can execute change to formulations and produce small batches faster than conventional methods.

From Batch to Continuous

Traditional batch manufacturing has many interruptions and holds, resulting in total processing times of days or weeks to produce one lot of oral solid dose drugs. Finished product must also be tested off-line for at least API concentration and content uniformity by high-performance liquid chromatography. Continuous Manufacturing (CM) is uninterrupted with on-line monitoring and control so that each process step can be adjusted based on analytical measurements. All steps including blending, granulation, compression, and film coating operate continuously. One major consideration when developing CM is to define ‘batch’ which is simply the amount of product in a lot. Establishing a sampling strategy as well as validated analytical tools (NIR, Raman, etc.) with appropriate feed-back control to assess quality are also important to consider at the beginning of process development. The industry has been discussing Process Analytical Technology (PAT) since the early 2000s and is now a critical part of CM.

Critical manufacturing’s requirement for space is significantly smaller than batch processing so there will be lower capital and operating costs. These facilities can even be modular and portable with reduced energy consumption and waste for a more environmentally friendly production solution. One case study for CM involves the end-to-end solution for producing a highly potent drug. Isolators or glove boxes for containment applications have been the industry standard for over 20 years but the manufacturing steps were in batches. When the formulation of dangerous compounds is constant and contained, the safety risks to the operators are considerably lower.

Continuous manufacturing received its first and biggest investment from Novartis in 2007. More than $60 million was given to MIT over 10 years to research and develop disruptive technologies for integrated continuous processing of small molecule pharmaceuticals. CONTINUUS Pharmaceuticals was created as a spin-off of this collaboration in 2013 and Integrated Continuous Manufacturing (ICM) was born. On January 21, 2021, the US Department of Defense along with the Department of Health and Human Services awarded CONTINUUS $69.3 million to utilize ICM to produce three critical medicines. ICM has several noteworthy benefits and can help us make the medicines we need now as well as prepare us for what is required for the future.

Recent FDA Approvals for CM

Vertex Pharmaceuticals had no fear of CM and started construction of a $30 million facility in Boston even before receiving approval. Their cystic fibrosis drug, ORKAMBI^®, received the first CM FDA approval in July 2015. SYMDEKO^®, another treatment for cystic fibrosis, was also approved in 2018.

Shortly after Vertex’s approval, Janssen made the decision to move to CM after a 10-year collaboration with Rutgers University Engineering Research Center and University of Puerto Rico. Janssen has estimated that CM can decrease their operating costs by more than 50%. This 1st NDA supplement for switching from batch manufacturing to CM was granted for the HIV drug (Prezista) in 2016.

Eli Lilly made the switch to CM for their breast cancer drug, VERZENIO^® and received FDA approval in 2017. They also have made a $40 million dollar investment in Ireland to accommodate CM of APIs. They have stated that both operator ergonomics and speed are the biggest reasons for their commitment to CM.

CM has several benefits to advance pharmaceutical manufacturing into the 21^st century. Improved patient safety and product quality are the most important but one must also consider the business case. Lower costs for R&D, scale-up, and operating expenses can be significant compared to traditional batch manufacturing. Lastly, supply chain becomes robust and predictable.

New ETP example

The Process and Environmental Monitoring Methods (PEMM) working group consists of industry end users, instrument manufacturers and consultants who are focused on the use and implementation of real-time alternative methods for air and water monitoring. The new ETP guidance gives detailed information on how a company can initiate early discussions about the use of a new technology that will be included in an IND, NDA, ANDA, BLA, or an application associated DMF. It does not suggest that other meetings which are not associated with an application could be organized. The PEMM group reached out to ETP in early 2020 to request a meeting that would address some hot topics around validation and acceptance of Bio-fluorescent Particle Counting (BFPC) technology. BFPC systems have been commercially available for over 10 years but do not yet have FDA acceptance as a complete replacement for traditional growth-based methods. And only a handful of pharmaceutical companies are using for non-GMP applications such as for investigations.

Prior to the meeting, PEMM sent a list of questions to the Emerging Technology Team (ETT) so they could be well-prepared for the discussion. The main purpose of the meeting was to initiate a collaboration to support specific technical and regulatory challenges with BFPC.

PEMM posed several questions about validation studies, regulatory guidance, filing, and inspections. FDA recommended the use of USP <1223> Validation of Alternative Microbiological Methods as the appropriate guidance and the manufacturer should take “careful consideration of the intended use of the method when designing the validation studies and interpreting the results.” which may include side by side testing to demonstrate equivalence or better performance than existing methods. They also suggested that data from spiking studies should be submitted to prove specificity.

One major concern of rapid microbiology method adopters is how the technology and data will be reviewed by an inspector following approval. In traditional microbial monitoring, it is a regulatory expectation to conduct a thorough investigation so that an appropriate CAPA can be initiated. If the organism is not identified, it becomes particularly challenging to find the root cause. The PEMM group proposed that an initial characterization or identification be performed and then only repeated if there is a noteworthy shift or trend. However, FDA encouraged periodic re-characterization and following facility changes. They also emphasized the importance of doing a risk assessment to justify this frequency.

PEMM inquired about filing BFPC in a Site Master File (SMF) to mitigate the worries around inspectors who are not familiar with these systems. FDA agreed that using SMF is suitable for BFPC but would request that PEMM provide publications and other training material for both facility assessors and field investigators.

FDA and PEMM will continue to work together on best practices for validating BFPC technologies including statistical process control and differences based on the specific application (air versus water) as well as the development of a robust training program for inspectors.

Closing Thought

The first commercial flight occurred on January 1, 1914, less than 10 years after the Wright brothers took their historic flight. Neil Armstrong and Buss Aldrin landed on the moon on July 20, 1969. Let’s hope that flying cars and 3D printed food don’t become available before we are utilizing state of the art technology to advance public health and fight the next catastrophic infectious disease.

References

1. Cook, L. “3D Printing and Pancreatic Cancer,” www.3duniverse.org. June 11, 2015.
2. FDA. “Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization Guidance for Industry.” September, 2017.
3. Kopcha, M. “A FDA Perspective on Continuous Manufacturing in the Pharmaceutical Sector,” Presented at PDA/Joint Regulatory Conference, Washington DC, September 12-15, 2016.
4. Kuehn, S. “Janssen Embraces Continuous Manufacturing for Prezista.” www.pharmamanufacturing.com. October 8, 2015.
5. Palmer, E. “Vertex, J&J, GSK, Novartis all working on continuous manufacturing facilities.” www.fiercepharma.com. February 9, 2015.
6. Park, B.J., Choi, H.J., Moon, S.J. et al. “Pharmaceutical applications of 3D printing technology: current understanding and future perspectives.” J. Pharm. Investig. 49 (2019). 575–585.
7. Scott, A., Forng R., Russ M., et al. “A Discussion on Bio-fluorescent Particle Counters: Summary of the Process and Environmental Monitoring Methods Working Group Meeting with the FDA Emerging Technology Team.” PDA Journal of Pharm. Science and Tech. January 2021. https://doi.org/10.5731/pdajpst.2020.012419.
8. Shanley A. and Markarian J. “Addressing Continuous Manufacturing’s Growing Pains.” www.pharmtech.com. May 16, 2018.
9. Takizawa, B., Born, S., and Mascia, S. “Leveraging Integrated Continuous Manufacturing to Address Critical Issues in the US Military.” Military Medicine. 185 (2020). 656-662.