Optimization of manufacturing platforms is at the core of the intersection between the science of biology and engineering, bringing that science to reality to produce much needed human therapeutics. The biotechnology industry focus on the need for expanding the laboratory capabilities for cell expansion began in the 1930s with T-flasks and tubes with very small surface area and cell replication ability. The challenges of flexibility and scale-up moved Engineering in the 1970s into roller bottles and a new era of monoclonal antibody (Mab) manufacturing was introduced that was a giant leap towards commercialization of larger scale production capabilities.
The journey moved again in the 1980s, going into fed-batch, stirred tank capabilities where scale and risk increased exponentially. From small scale bioreactors to large-scale units exceeding 20,000L scale, the Industry need for capacity grew. At the same time, the science wasn’t standing still, and improved process titers and yields saw efficiencies reach 3x efficiency or higher. In the mid-2000s, the impact of single-use technology and its advancement in equipment design began to launch a seismic shift in how the Biotech Industry viewed the manufacture of Mabs.
Risk
Risk Mitigation is not Optional. With the launch of the FDA 21st Century Initiative, Quality Risk Management (QRM) became a core attribute of both compliance and manufacturing philosophy. The growing focus of QRM is clearly stated in the EudraLex Volume 4, chapter 1:
“The evaluation of the risk to quality is based on scientific knowledge, experience with the process, and ultimately links to the protection of the Patient.”
The manufacturing landscape of Mabs as stated, is very diverse in scale, equipment platform technology, and operational control strategy. The relationships between identified CQAs and CPPs will vary, depending on the platform technology. And today, there is a growing emphasis on the risks associated with contamination control with the implementation of the revised EU Annex 1 guidance issued in August of 2023.
For Mabs, the traditional fed-batch manufacturing model is still predominant, regardless of the scale or platform. In that platform, there are a number of risks, even with robust process and control strategies, that must be addressed. The key one is focused on contamination control and Patient safety.
In the article, “Data Analysis of Contamination Control Strategies for Production,” (Pharmaceutical Engineering, Vol 44, number 4, July/August 2024), a key concern for accurate risk assessment and mitigation is the impact of subjectivity. An over-reliance on “baseline” experience driven by “this is how we have always done it” or a focus on “rules-of-thumb” can introduce a bias into the process. It is also important to minimize favoritism to a particular technology or methodology when assessing data. To minimize the impact of this type of subjectivity in the development of a risk assessment focused on contamination control during manufacturing, it is important to use a systematic and objective approach to risk, addressing both intrinsic and extrinsic contamination sources and properly analyzing the data.
Contamination risk assessment requires a holistic review of contamination sources, identification of risks and control points, and interaction of these elements between all process and facility attributes. Mab operations are, by necessity, aseptic operations. Contamination of these processes with viable particulates most often results in a rejection or loss of the batch. This is not only a risk to Patient safety but also to business operations and even result in product shortages when batch size is small.
The core focus of contamination risk control is knowledge of the product, generated by the manufacturing process. The Mab process design is the baseline protection control layer. Risk to the product that are not, or cannot be controlled by the process must be addressed in the risk assessment by other means of protection; environment, materials, procedures, etc. It is bioburden control, often from product exposure to environmental conditions, that constitutes the most important contamination control risk.
Process closure is at the core of Mab manufacturing optimization, and risk control. A closed process system is one where the product-contact surfaces are limited by the defined process zone boundary, which is the space that is in direct contact with the product, process, or process intermediates being manufactured. The importance of this zone is easily seen in the regulatory language of ICH Q7, item 4.12:
“Where the equipment itself (e.g. closed or contained systems) provides adequate protection of the material, such equipment can be located outdoors.”
Closing the Mab process by default limits the process zone, reducing contamination risk. Mab production can be done in batch, fed-batch, semi-continuous, or continuous platforms.
Sustainability
Historically, Mab manufacturing facilities prioritized product quality and regulatory compliance above all else. Systems were often overdesigned to ensure consistent environmental conditions, relying on energy-intensive design solutions to achieve operational goals. While these measures were once considered effective in preventing cross-contamination, they also resulted in significant energy consumption. Applying a systems-based approach to Mab manufacturing facility design is key. Not only does it lower the cost of drug manufacturing, it improves quality by focusing energy on product knowledge and minimizing non-value-added activities. This lays the critical foundation for the implementation of sustainability-driven design solutions. The article “Optimizing Cost-of-Goods for Cell Therapy Manufacturing,” (Pharmaceutical Engineering, Vol 43, number 6, November/December 2023) provides some data and approaches that support the alignment of sustainability goals and reduced cost of goods.
Patient protection is the primary objective. A key component to patient safety ties to contamination control. Traditionally, this has relied heavily on facility environmental control, such as HVAC systems, which consume a significant amount of energy. However, a shift to implementing closed processing technologies is revolutionizing this landscape as we have seen. Closed process technology minimizes the reliance on traditional environmental control systems. This shift not only reduces energy consumption but enhances contamination control by minimizing the risk of exposure to the surrounding environment.
As the Mab-focused segment of the Industry strives for sustainability and energy efficiency, Engineers are implementing a wide range of design tools to reduce energy consumption while maintaining the focus on Patient safety. These proven principles include:
- Close the process and utilize microenvironments.
- Avoid blindly applying standards.
- Prioritize airflow effectiveness over air change rates.
- Reduce airflows when not in use.
- Consider all air filtration in calculations to produce desired conditions.
- Recirculate air whenever safe and feasible.
- Broaden temperature and RH limits within product and process constraints.
A risk-based approach is crucial for achieving sustainability goals. By defining wants vs. needs and focusing on well-reasoned, scientifically sound goals, significant energy savings can be realized in the production of Mab products.
Throughput
The highest level of manufacturing optimization in Mab production will be seen in continuous manufacturing platforms. In the article, “Opportunities in Continuous Manufacturing of Large Molecules,” (Pharmaceutical Engineering, Vol 41, Number 4, July/August 2021) the optimization of Mab manufacturing is discussed in terms of current and future potential.
Three separate studies (Study 1: Pollock, J., et al., Biotechnology & Bioengineering, Volume 110, 2013, 206-219; Study 2: Walther, J., et al., J of Biotechnology. Volume 213, 2015, 3-12; Study 3: Godawat, R., et al., J. Biotechnology. Volume 213, 2015, 13–19) provide an averaged range of optimized factors:
- Facility area reduction range of 50%
- USP productivity increase 7X
- Buffer usage reduction of 20%
- Production cost reductions:
- 50% CAPEX
- 20% OPEX
- 20% COGM
- Cell Count increase 7.5X
- Titer increase 33 – 45%
This translates to a simple result; the ability to produce more product faster while improving costs for direct labor, raw materials, energy consumption, equipment utilization, and maintenance.
