The challenge of scaling up
Quality by Design (QbD) principles
Regulatory compliance and validation
Efficiency and cost-effectiveness
Patient-centric manufacturing
References
Further reading
Process development is the exercise of creating new and improved manufacturing methods, optimizing them in terms of time and financial efficiency while maintaining regulatory compliance and product quality.
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The manufacture of drugs and biological products, such as protein therapeutics or custom cells intended for research, comes with stringent requirements in terms of Good Manufacturing Practice (GMP) and requires significant collaboration between machine operators, engineers, scientists, and other production workers to design and maintain operations as regulated.
Typically, a variety of manufacturing scenarios may be explored during process development, and possible solutions may be tested using prototypes and simulations. In particular, extensive process development is required when bringing novel products to market, having shown success in clinical trials and now being available to the broader population, requiring scaling-up of production facilities.
The challenge of scaling up
Many common drug compounds are produced by now well-understood synthetic routes that are fairly easily scaled up by typical chemical engineering methods, i.e., larger batches or faster continuous production methods. As the production scale increases, complex facilities are increasingly required to accommodate the reaction.
For example, the quick addition of a small quantity of reagent into the reaction is easily achieved in the lab but poses considerable challenges when hundreds of liters must be injected into the reaction vessel in the same short time frame at the manufacturing scale to ensure that an identical product is produced.
More novel compounds may require expensive reagents or catalysts, utilize dangerous steps, or require a great degree of manual labor performed by highly trained staff to produce, introducing a bottleneck to scaling up.
Many other production methods suitable for small-scale production in the laboratory falter at large scale. For example, centrifugation is employed to separate biological products for many specific purposes, such as collecting cells and separating proteins, and can be performed in detail by a manual operator working with moderate quantities.
Centrifugation solutions at the manufacturing scale, such as continuous centrifugation or depth filtration, impose very different shear forces on the biological product and can cause damage, leading to less harsh methods being forced to be utilized. In turn, biological products are less effectively separated, leading to issues with contamination and purity.
Quality by Design (QbD) principles
Quality by Design (QbD) is the idea that quality should be designed into a product from the earliest stages, avoiding potential issues with manufacture and the product life-cycle from the outset. The US Food and Drug Administration (FDA) emphasizes a risk-based approach to QbD principles in drug product process development. It recognizes that increased testing does not necessarily improve product quality.
Quality must be built into the product and its manufacturing process in order to ensure a sterile and pharmaceutically effective product. QbD is therefore concerned with process development and manufacturing efficiency, particularly the elimination of defects via process understanding and control.
A systematic approach relies on thorough data collection at each stage of the manufacturing process, from checking the condition of precursor compounds before use to continuous monitoring of temperature and chemical parameters within the reaction. Root cause analysis can, therefore, be performed should a batch not meet the expected quality standards from the established process, and proactive actions can be taken to prevent future reoccurrence.
Regulatory compliance and validation
Regulations set by various local, national, and international organizations are intended to ensure the safety, efficacy, and reliability of medical products. Experts in the field establish them based on QbD principles and years of practical manufacturing experience.
Large pharmaceutical companies may employ in-house quality control services or alternatively may employ the services of contracting laboratories with enhanced GMP experience and certification.
Detailed documentation must be kept by manufacturing facilities that allow the lifetime of the product to be tracked, and thus, the cause of any later issues uncovered. This includes information such as precursor purity and concentration, the full temperature history of sensitive components, transfer timing, sterilization schedule, etc.
It is important that pharmaceutical manufacturers meet and exceed these basic regulatory requirements to ensure product potency by the end user and that physicians can accurately administer the correct quantity of drug.
Efficiency and cost-effectiveness
Scaling up of production processes can improve efficiency, firstly regarding worker hours required to produce the final product, and secondly regarding materials cost and wastage. If the same synthetic steps are taken, a single batch should take the same amount of time to complete no matter the batch size, and can thus be monitored by the same number of employees.
Any profit gained from synthesis over the cost of the raw materials is therefore also amplified by producing larger batches. As discussed, some processes cannot simply be scaled up in the same manner and thus require process intensification in some manner other than scale, such as higher throughput speed or the installation of additional processing routes.
Patient-centric manufacturing
Patient-centric manufacturing, or patient-centric drug design, is the process of identifying the needs of the target patient and designing a pharmaceutical product to fit this specific need, providing the highest benefit-to-risk ratio possible for the duration of treatment.
For example, drugs intended to treat patients with impaired liver function should be designed with renal and hepatic clearance in mind, possibly by careful adjustment of their pharmacokinetic and pharmacodynamic profile. Mid-sized labs capable of custom synthesis of drugs and biological pharmaceuticals are becoming increasingly able to provide patients with extreme patient-centric manufacturing and may play a large role in the future of personalized medicine.
References
- Yu, L. X., Amidon, G., Khan, M. A., Hoag, S. W., Polli, J., Raju, G. K., & Woodcock, J. (2014). Understanding Pharmaceutical Quality by Design. The AAPS Journal, 16(4), 771–783. https://doi.org/10.1208/s12248-014-9598-3
- Muller, D. et al. (2022). Process intensification in the biopharma industry: Improving efficiency of protein manufacturing processes from development to production scale using synergistic approaches. Chem. Eng. and Pro. – Process Intensification, 171. https://doi.org/10.1016/j.cep.2021.108727
- Menditto, E., Orlando, V., De Rosa, G., Minghetti, P., Musazzi, U., Cahir, C., Kurczewska-Michalak, M., Kardas, P., Costa, E., Sousa Lobo, J., & Almeida, I. (2020). Patient Centric Pharmaceutical Drug Product Design—The Impact on Medication Adherence. Pharmaceutics, 12(1), 44. https://doi.org/10.3390/pharmaceutics12010044
Further Reading