KiloMentor Process Development Strategy Reviewed

 

KiloMentor | revised 6th  January 2009 republished February 17/2017 and March 22nd 2025

This is a revision of one of the earliest articles from the KiloMentor archives. The original was written in 2007.  It restates for new readers the core idea of the KiloMentor process development philosophy and teaches an approach that KiloMentor thinks leads consistently to valuable ideas. for improving process throughput.

In synthesis, we talk about assembling, building, or constructing a molecular structure. This is a misleading metaphor because we are comparing an activity in the nano-world to an activity in the macro-world. Operating in the macroscopic world, for example in building a house, we handle the pieces, we position the pieces, and we join the pieces.

In chemical synthesis, we do none of these. The substructures we are endeavoring to unite are atomic in scale: too small to touch, to align, or even to see. 

In chemical synthesis, the chemist adjusts macroscopic conditions: solvent ratios, stoichiometry, stirring, temperature, duration of exposure, etc. Then the chemist presents the proposed reaction partners, to each other under the orchestrated conditions and they interact, as their nature dictates; but, hopefully, this is also as we have planned.  How is this perspective different from the conventional one?  Chemical process development is simply making these parameter choices that cause nature’s choice to comply with what we want the outcome to be, efficient. Nature to be commanded must be obeyed.

According to the academic synthetic chemistry tradition, synthetic accomplishments are scored based on the number of synthetic steps, the yield per step, and the overall yield for the combination of steps. High yields are good. A short sequence is good. The combination is elegant. According to this traditional perspective, the focus is on the reactants, the plan for reactant transformation, and the overall yield output from that plan. Separation of unreacted starting materials, by-products, co-products, catalysts, solvents, salts, and other excipients and processing chemicals are in the background (the attitude is that work-up/purification can be done and will be done BUT these are not important criteria to evaluate the quality of the synthesis).  The give-away phrase of those who harbor this philosophy is “the product was isolated in the usual way.”

From the KiloMentor perspective, in this age of online substructure searching, coming up with creative transformations with strong literature analogies is no longer the domain of the synthetic genius but has come within the scope of good synthetic chemists. We do not have to depend upon our neuronal computers alone anymore. Now it is creative ideas for separation and purification that are not easy to search for and have become the greater artist skill of the project. The deconstruction of the chemical soup and the fishing out of the desired product in an adequate state of purity is paramount. 

Is there any particular value in this way of looking at processes that surpasses the traditional way which focuses on the series of chemical reactions while taking the separation of intermediates as an obvious technical work? My perspective emphasizes: 

• The work involved in setting up and controlling the necessary reaction conditions. 
• The work involved quenching the reaction condition/then working up the reaction and finally isolating and purifying the desired product. 

The value in this perspective is that in chemical synthesis, the money, manpower, and resources consumed during the reaction step phase, ie. while A & B are reacting with each other, is minuscule compared to the money, manpower, and resources expended preparing for the reaction and recovering pure product from the reaction. 

The clash of these perspectives leads to the question, “Which would I rather do- a four-step synthesis in which every conversion has many parameters that must be rigorously controlled and from which each intermediate must be isolated by gradient column chromatography and evaporated to a foam OR an eight-step synthesis which is rugged and forgiving of process deviations and from which each intermediate can be cleanly extracted in a separatory funnel or crystallized or distilled to give an adequate practical purity intermediate."

People have personal preferences and this is as it should be in a pluralistic society BUT I pick the second sequence and as the need for larger quantities and higher quality intensifies, I increasingly prefer the second route. 

Please note- I am not saying the number of chemical steps doesn’t matter. I am not saying that the overall yield does not matter. I am saying that elegance also encompasses simplicity, ruggedness, time economy, and scalability. 

OK, so what. How does this insight change our behavior in the synthetic laboratory, office, or library? Based on an examination of what really goes on in a chemical process step a method of rating the difficulties of the separation is proposed as a quantitative tool to rank the challenges of a process scale-up.

We should evaluate or rate synthetic schemes using more criteria:

1. Number of Chemical Steps
2. Isolated overall Yield
3. Yields of the Individual Steps.
4. Difficulty Rating for Each Reaction Mixture Separation

The fourth point comprises the new insight. How could we execute this new difficulty rating? We could classify work-ups:

A. The product can be separated practically pure by simply liquid-liquid extraction (ie acid-base pH or other phase switching)

B. Product can be separated by crystallization of precipitation as a filterable solid.

C. Product can be separated by atmospheric or vacuum distillation based on a projected difference in boiling points (based on molecular weights)

D. Product can be separated based on chemical reactivity (formation of reversible simply separable derivative, or destruction of contaminant by reaction)

E. The product seems likely only to be separable in practical purity by chromatography.

Clearly, as process chemists, we want to face more A-C separations and fewer D-E type separations.

The KiloMentor blog will highlight methods to augment isolations and purifications so chemists can improve their ability to assign these ratings and take them into account when designing synthetic chemical processes that can be readily and ruggedly scaled up into the plant.

The Portfolio Method of Chemical Process Development

More efficient chemical process development is possible but it requires the addition to the team of someone with an unusual combination of bench experience, book learning, creativity, electronic search skills, and communication. This person acts as an assembler of the initial literature folio.

The method would work as follows:

As soon as a Process Development Project has been accepted all the client’s pertinent information is provided to the folio assembler. The longer the period between project acceptance and the planned start of the bench-work the better. The shorter the period, the more critical the assembler’s timeline becomes. The folio assembler works with the senior research chemist for the project. It is the folio assembler’s job to provide a stack of pertinent literature to the senior research chemist as quickly as possible of such a quality that after reading through it the senior research chemist will say, “The solution is obvious.” 

The early bench work of junior team members should concentrate on the development of ‘in situ’ assays for product and starting materials and sometimes known impurities. 

The senior research chemist, the folio assembler, and often other senior scientists conceive and rank possible synthetic routes.

 By the time the actual process work begins at the bench, the senior research chemist has read a wide variety of articles pertinent to the various critical aspects of the process problem. Thus the early work period is not spent just keeping junior people busy or making mistakes that could have been avoided with basic literature familiarity. Once new pertinent literature examples become difficult to unearth, the folio assembler moves on to a different priority. Searching becomes more focussed once bench results start coming in and the Senior Research Chemist should decide what new information will address the problem.

This methodology will work efficiently because:

• Reliable chemical data is pains-taking to acquire at the bench.

• It is much faster to learn methodology from a publication than de novo.

• A comprehensive set of pertinent references would be useful as close to the beginning of the process development experiments as possible.

• Early experiments are usually poorly chosen and waste time

• It takes more time to find a key paper than to read it.

Models for Ideal Chemical Processes

Any process has the possibility of continual incremental improvement but practically a point will be reached when it is not worth further effort and one’s time and talents are better expended elsewhere. 

 In process development how does one judge the good and the better?  A good process meets its quality and quantity requirements. The better process does this and goes further. The better process must be rugged. In a rugged process, if human error, mechanical failure, or equipment inadequacy creates some small deviations from the prescribed procedure, the result does not suffer seriously either in quality or quantity.

We judge a process by its costs and these include the labor expended, the time utilized in the special equipment, the price of the starting materials, and the price of waste disposal or recycling. A costing not only provides an indication of the efficiency with which inputs are used but it also provides a running assessment on the specific shortcomings that contribute most to the overall expense. A preliminary costing is an important tool in developing any process because it ranks areas where one might invest whatever limited time one has to achieve improvement.  

Trost has philosophized that the ideal process would be a single step and that there should be no co-product. That is, all the atoms in the reacting substances are retained in the products. Nothing then is thrown away. This is an interesting idea to contemplate.  It dramatically highlights that atom economy, as he calls it. It has the benefit of high weight throughput and low waste disposal but it is far from reality in terms of what can be actually practiced.  Every process is indeed ideally only a single transformation but the problem is starting materials for this ideal process are not commercially available- and because of this, the process creator must move retro-synthetically one step at a time until we do reach such commercial precursors.

Another useful idealized conception of a process is a sequence of chemical steps in which the reaction mixture from each step is simply treated over and over again with the reagents for the next transformation until the material which is the synthetic goal is present in the mixture; then, in one isolation operation, this product is separated pure from the complete complex mixture containing all the by-products and co-products of all the prior steps. This model dramatizes that it is most important to eliminate isolations because it is isolations that usually consume the most time and resources in a process.   In practice, of course, there are very valid reasons for performing isolations before the final isolation.

Valid reasons for isolation are:

1. To remove non-productive mass (ballast)
2. To change solvent for reaction optimization
3. To achieve needed purification through phase shifting
4. To correct stoichiometry and so save reagents
5. To provide convenient stopping points for campaign processing
6. To provide rework opportunities for rugged processing

Advanced Manufacturing Ideas Can Be Applied to Fine Chemicals/ Pharmaceuticals

 

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."