What do the Lockheed Martin F-35 Lightning II fighter jet and an Oral Solid Dose (OSD) continuous manufacturing module like GEA’s CDC-50 have in common? Are any similarities apparent between Willys MB World War II Jeep and a 3D printer used to manufacture pharmaceutical drug products and devices? What about the Volkswagen Type 166 Schwimmwagen and G-CON cleanroom PODs? It turns out all six items listed offer the same benefit to their users: flexibility.
An F-35B fighter jet is probably best known for its short take off and vertical landing abilities, something that can be leveraged to significant advantage compared to conventional aircraft, especially when operating at sea. Similarly, the Schwimmwagen’s ability to maneuver on land and on water resulted in it being used extensively in World War II. The Willys MB’s 4x4 versatile on- and off -road capabilities led to it being called by Eisenhower “one of three decisive weapons the U.S. had during WWII”.5 All are very flexible in where they can operate successfully, something of the utmost importance in a battlefield where the circumstances change rapidly and there is little time to react. Thus, a premium is paid for vehicles that are multipurpose by design and are not limited to a narrow range of operating conditions. It can even be argued that in a battlefield, flexibility is the most important attribute for success.
By analogy, the pharmaceutical industry is becoming more like a battlefield, in that the rate of change is increasing, and the time to react is being challenged. Historically, small molecules and vaccines dominated, whereas today the breadth of medicines being developed has grown tremendously to also include antibodies, peptides, nucleotides, conjugate molecules, and many more. The markets being served are also increasing rapidly, and the patients, payers and providers of care are more diverse. Patients themselves span from the very young to the very old, often with customized dosing and delivery in each demographic. Suffice it to say, the era of one-size-fits-all medicines is no more. The pharmaceutical industry must become more flexible to keep up in the modern era.
Flexibility Explained
With high quality being a standard approach in the industry through the application of cGMPs and oversight from worldwide health authorities like FDA, the pharmaceutical industry has focused primarily on balancing the competing demands of cost and time, Figure 2(a). This can be seen across a wide range of application areas, from new products under development, to new manufacturing facilities. But as flexibility becomes an attribute worthy of independent consideration, Figure 2(b), a new balance comes into view: the flexibility-cost-time triad, Figure 2(c). No longer should cost and time be the only factors given weight, but rather all three factors must be considered simultaneously in any given project – only then is flexibility likely to survive as an attribute in the finished product.
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To consider flexibility alongside cost and time, it must be quantified in terms that are readily measured. Although the word flexibility is well understood generally, in the context of pharmaceutical manufacturing, it is beneficial to use a more technical definition. Chryssolouris defined the flexibility of a manufacturing system simply as its sensitivity to change.6 Further, he proposed that the flexibility be measured by a term called the penalty of change (POC), equal to the product of the probabilities of each potential change and the cost of each respective change, summed up over all potential changes.
In his work and more recent reviews such as that by Jain et al.,7 the different types of potential changes, corresponding flexibility dimensions and their definitions are exhaustively listed. Adapting that list for pharmaceutical manufacturing, one arrives at Table 1.
Using Flexibility to Guide Decisions
Within an organization, there is likely to be a wide range of opinions as to what dimensions of flexibility are most important. For instance a production supervisor might care most about labor, process and product flexibility. Contrast that with a supply chain professional, who considers volume and routing flexibility the most important. However, the probability of a change in each of these fields is unequal, as is the cost, and thus the POC will vary by orders of magnitude across the various dimensions. This allows one to focus on the dimensions most likely to manifest during the time horizon of interest.
For illustration of the concept, consider a manufacturing plant with a granulation line asset nearing the end of its life. Two options for replacement are being considered:
Option 1 – Traditional high shear granulator and coupled fluid bed dryer with fixed, large batch sizes
Option 2 – Modern compact twin screw granulator and continuous dryer with highly flexible batch sizes
Which asset should be purchased? In the absence of additional information, traditional analysis would dictate that the lower cost asset should be procured, and most often, traditional technologies are cheaper.
But what about flexibility? Considering the flexibility-cost-time triad, it should be noted that Option 2 has inherent volume and product flexibility that can’t be found in Option 1. More specifically, Option 2 allows for volume flexibility by allowing batch size to be adjusted through the setting of production run time, and product flexibility by allowing more rapid changeover between different products due to the smaller footprint of continuous operations. If additional consideration reveals that multiple new products in the pipeline will need to share the asset in the future, and that these products have variable or uncertain production volumes, then the tradeoffs between the choices becomes more clear. In this case, the costs of both options need to be considered, as well as the penalty of change over the lifetime of the asset. The mathematics of the decision becomes more complex, but the analysis ensures that decisions are not made considering only short-term thinking like upfront cost. Factoring in flexibility across the most important dimensions ensures that the probable total lifetime cost drives the decision.
The Role of Emerging Technologies
As the world has changed, pharmaceutical manufacturing technologies have emerged where flexibility is a significant capability being offered. The options considered above discussed how continuous manufacturing offers volume and product flexibility when compared to similar batch operations, but demands higher upfront costs to install. Three-dimensional printing (3DP) offers operational, production and expansion flexibility, but at the expense of time required to produce. Cleanroom PODs offer the potential for significant expansion flexibility, with shorter timelines and a cost premium per square foot. Modern robots have the potential to offer labor flexibility. The list goes on and will continue to grow well into the future. While these emerging technologies will cost more upfront, and undoubtedly require additional time to develop, the flexibility being offered in the long run must be properly considered and valued if pharmaceutical manufacturing is going to keep pace in a fast-changing world. Lockheed’s F-35 has been more expensive to procure and taken longer to develop than more traditional military fighter jets, but the flexibility designed into the jet will reduce the penalty of change in situations where change is certain. Likewise, change is certain for pharmaceutical manufacturing, and flexible emerging technologies must be part of the solution.
Author Biographies
Robert Meyer received his BS and PhD degrees in Chemical Engineering from the University of Akron and the University of Pennsylvania, respectively. Since joining Merck & Co., Inc., Kenilworth, NJ, USA, in 2002, he has worked in many areas of drug product development, with a focus on emerging technologies such as hot melt extrusion, continuous manufacturing of oral solid doses, and process analytical technologies. As a principal scientist, he currently leads innovation and new technology development in the area of small molecule pharmaceutical commercialization.
Yash Kapoor is a Principal Scientist at Merck & Co., Inc., Kenilworth, NJ, USA. As a member of the Sterile Formulation Sciences, he is involved with parenteral drug product development. Yash’s areas of interest include sterile & oral formulation development, intradermal, transdermal, ocular drug delivery technologies, pharmacokinetics, controlled release from degradable & non-degradable polymeric systems along with impact of self-assembled particulate systems such as microemulsions/liposomes and 3D printing for medical use. Prior to joining Merck, Yash worked in the eye care industry (Alcon, A Novartis Company) developing novel contact lenses with controlled release properties along with tunable surface chemistries. Yash received his PhD degree in Chemical Engineering from University of Florida at Gainesville in Fall-2008.
References
- Defence Imagery - defenceimagery.mod.uk, OGL v1.0, https://commons.wikimedia.org/w/index.php?curid=50237699.
- BrokenSphere - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=3557261.
- Max Smith (self) - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2417483.
- Smith, D.M., Kapoor, Y., Klinzing, G.R., Procopio, A., 2018. Pharmaceutical 3D printing: Design and qualification of a single step print and fill capsule, International Journal of Pharmaceutics, 544 (1), pp. 21-30.
- “Vehicle Profi les: Jeep Willys”. The ClassicCars.com Journal. 2 July 2008. Retrieved 8 August 2019.
- Chryssolouris, G., 1996. Flexibility and its measurement. CIRP annals, 45(2), pp.581-587.
- Jain, A., Jain, P.K., Chan, F.T. and Singh, S., 2013. A review on manufacturing flexibility. International Journal of Production Research, 51(19), pp.5946-5970.