In their August 12th, 2023 issue pg. 63-64, the Economist magazine describes the advanced manufacturing of first, computer chips and then, cordless electric drills. Reading this brief report suggested to KiloMentor possible parallels with future advances in the scale-up for the manufacturing of complex organic chemicals.
The article points out that “chips are designed using software that directly links to the automated hardware which fabricates them.” The efficiencies that this unlocks derive from the consequence that “the constraints of the production line- even fiddly details like the positioning of screws— are encoded in their CAD (computer-aided design) programs.”
Well, how does this have any analog implications for chemical processes for making sophisticated chemicals? We don’t have automated production facilities and we don’t work out the details of process steps in computer programs.
The research laboratory functions as our design tool and the pilot plant functions as our automated fabrication hardware and our problem is too often that our designing is not sufficiently linked to our manufacturing. The problem is how do “even [these] fiddly details”, like the constraints of large-scale production get signalled back to the laboratory before valuable time is wasted?
In advanced manufacturing, these constraints are wired into computer-aided design programs. For our projects, there are two possibilities. Either our process design chemists must have these limitations wired into their chemical know-how or the whole company must adopt some form of what has been termed ‘full process vision’. I have written previously about this idea in the blog, Avoiding the Screw-up from Left Field with a Full Process Vision.
Since it is difficult to impossible to find this article I have reprinted it below.
"Some process chemists will find themselves as small cogs in large teams whose goal is to develop new specialty chemicals or pharmaceuticals. As a scientist whose contribution is to apply highly specialized knowledge, you may be bunkered in a rather isolated trench or silo within your organization. Your mission may be defined for you rather narrowly so your undoing may come from an irrefragable requirement that comes from outside your silo and that is imposed so late in your work plan that it really means starting over.
A powerful organizing structure for pharmaceutical product development is presented in an article by Pradir K. Basu, Ronald A Mack, and Jonathan M. Vinson, “Consider a New Approach to Pharmaceutical Process Development“ Chem. Eng. Prog., 95(8), 82 (1999). It seems intended to reduce the likelihood of the above misfortunes.
Process chemists, as knowledge managers, need to press at an early stage in their work for some mechanism within the wider team so that these must-have ‘requests’ from outside your core group reach you before your work is too far advanced.
Much of the referenced article presents no more than standard reminders of the importance of cost considerations throughout discovering a synthetic method, scaling it up, and putting it into production for a process to manufacture a new pharmaceutical. This is the pharmaceutical business with the marketing, selling, and regulatory functions stripped away. Its importance to corporate profitability does not engender much debate. The importance of the article is that their concern is broader.
The authors are concerned about the efficient execution of a plan that starts after identifying a candidate to be a commercial drug with a salutary effect on a biological target and proceeds to the validation of manufacture for that molecule at a commercial scale.
The enhanced approach that they propose identifies what they call ‘process vision’ as the core organizing principle. The definition and exemplification of the expanded concept of ‘process vision’ is the article’s significant accomplishment.
The authors help us understand different aspects of this 'process vision' at different points in the article. For me, I cannot say I adequately grasped what they were getting at until I drew particular phrases together from my notes. Some of these quotes, drawn from different parts of the essay are:
“The process vision satisfies all essential requirements, including those for safety, quality, waste minimization, cost, time, and operability”.
“The process vision is neither the process with maximum yield nor the one that gives maximum product purity…..it is neither a chemist’s vision nor an engineer’s vision; it is not even the vision of the chemists and engineers together.”
“It is a vision that all stakeholders in development, manufacturing, and marketing can share…..”
Reading between the lines and amplifying certain aspects, the process vision emerged as a policy statement that provided, as a starting point, standards by which team members coming from each stage of the organization's endeavor (laboratory process, kilo lab, pilot plant, and manufacturing facility) could satisfy downstream colleagues’ concerns from the outset of their own work. The authors' specific examples of the unique orientation and emphasis that players at the different stages have and which they want to see addressed from the very outset reinforce my interpretation.
This early overview, whose importance they emphasize, can be expected to show up inevitable cross purposes and improve the odds for early compromise and conflict resolution.
They write:
“Chemists think in terms of steps, reactions, yield, purity, and so on; engineers in terms of unit operations, physical properties, heat load, and the like; manufacturing personnel in terms of throughput, waste control issues, and plant modifications that may be required to run a process; and marketing people in terms of the net present value of the product, how much it can sell for, etc.”
“It is important ….to get stakeholders to develop….agreed-upon objectives of process development.”
“communication among….personnel is critical during process development.”
“We need to…. provid[e] development team members with systems or tools to facilitate communications among different disciplines.”
“Unless the manufacturing team is involved in the process development, they will not have confidence in the scale-up”.
“…manufacturing and commercial input at this stage [late stage discovery] are essential for choosing the optimum processing route”.
“Team members need to be involved in setting targets for cost, manufacturability, waste and emission loads, development time….”
“These alternatives must be evaluated based on….criteria agreed upon by all stakeholders….”
“If stakeholders are involved in planning experiments, it’s likely that more useful data could be collected from fewer experiments.”
For me, the management tool the authors recommend for achieving this widely held ‘process vision' is Panglossian.
The authors propose that even at the experimental program level one should try to bring together a diverse project team including representatives all the way out to marketing, frequently enough to work out priorities and make decisions. This is what they recommend.
This seems excessively optimistic as regards human nature. Instead, I suggest, one could establish a 'process vision' statement establishing some sort of median or normal starting-point performance criteria that would address recurring diverse concerns of process development, manufacturing, regulatory affairs, and marketing and that would chevvy the most common interests of the downstream project teams on the upstream collaborators. In this implementation, the process vision would be via a statement delivered with full corporate authority that would continuously challenge upstream groups with the standard core concerns of the downstream members.
The authors illustrate marvelously this challenging interaction throughout their article. What I interpret them to be saying is that the problem is not that different elements of the project team have concerns that inevitably seem to operate at cross purposes; but that the team members can reach solutions that satisfy all parties, so long as the areas of tension are discovered early enough.
KiloMentor has a strong preference for its alternative. The use of a process vision statement as a proxy for the perspectives and concerns of downstream project groups seems preferable to using large frequent group meetings to actually direct even the collection of particular data. For a company’s drug product projects to be successful and on time, any process’s strategy must not conflict too greatly with the psychological needs and private professional goals of the individual team members. The people downstream in the project, whether they be in late-stage process development, manufacturing, or marketing, simply will not give a project the attention it needs until it arrives at the phase where they are being held singly and personally responsible. They are too busy concentrating their attention on what is on their plate already and extinguishing the fat that is already on fire. This is human nature! Besides, pharmaceutical product projects can go on so long that some participants can realistically expect to no longer be involved when a late-stage discovery project limps into manufacturing or marketing. People may hope or plan to outrun the difficulties. Only unambiguous corporate endorsement can get everyone to give a thought to early-stage projects.
Equally problematically, the upstream professionals, working at a particular phase of the work on their own turf, would require an uncommon personal modestly to accept without rancor face-to-face demands that particular questions be answered on a priority basis.
A corporate ‘process vision’ statement takes the personalities and egos out. At the same time, the standards proposed by a process vision statement would command authority and yet not be carved in stone. They would exist to bring a persistent awareness of particular concerns. They would bring those different needs, which may be pulling at cross purposes to early attention, and they can be expected to bring the affected team members together as needed to create or negotiate a solution."