What Are "Critical Minutiae" In Drug Development … And How Can You Best Manage Them?

By Sue Wollowitz, Ph.D., president, Wollowitz Associates LLC

Anyone who has worked with me has heard me talk about critical minutiae. To the inexperienced, this is an oxymoron, but to anyone who has worked to get a complex project done on time, it describes a painful reality.

Every tech transfer, every clinical supply, every regulatory submission, is a bundle of stepwise activities that fragment into multiple lines of activities, some converging, rebranching, and ultimately coming together at the end into a single desirable outcome. Each transfer point from one step to the next requires some piece of information, some material, some result, some decision, and/or some signed document. Each one of these elements becomes a critical path in the linear scheme. And so our large and highly visible corporate goals are held captive by every one of the hundreds of seemingly small steps. From 30,000 feet, many of these appear as minutiae with no indication of the importance they may have, yet each is critical to the end goal. For project planners and strategists, each deserves the attention and respect we would give to a serious adversary.

Why does this “minutiae” become critical?

The complexity of each step is one cause of delays; any single missing element out of a hundred can hold things up and thus become critical. Manufacturing might not be able to start because some raw material is stuck on a dock across the ocean due to a strike, or an excipient is suddenly found to have expired, or because a change in a master batch record cannot be signed off by the fifth required signer, who is in a two-day training session. Product can’t get released because system suitability fails during assay, or a sample shipment to a contract lab didn’t make it out by Thursday afternoon, or a documentation error in the batch record was not properly described. Clinical supply is delayed because of disagreement about a label translation. These types of critical minutiae can be reduced by recognition of potential problem areas, by good communication, and by good documentation.

Critical Minutiae Candidates

If we could dedicate a person to shepherding around the material, the document, or the explanation of why we are doing something a certain way, we could keep much of this type of minutia from becoming critical, but we can’t manage everything reactively. Better to recognize vulnerable tasks in advance and target the most likely candidates for attention.

Vulnerable tasks are frequently those that require action by people who are not directly engaged in our project but who rather are multitasking on numerous projects. When another department or functional area is responsible for the task or for making a decision, it is easy to forget our responsibility to track and engage them. Sometimes they need more detail, help making a selection, or a priority clarification. In the absence of proactive engagement from us, our needs get buried in their to-do piles, or they spend a lot of time moving in the wrong direction.

Raw materials and shipping are areas that can be rife with bottlenecks, including everything from insufficient, unreleased, or back-ordered raw materials, to long transport times for hazardous materials, to having appropriate documentation for import or export of materials.

Review of raw material availability should be done long in advance of manufacture, and possible roadblocks and contingencies should be considered. Meaningful updates from purchasing and/or shipping should be provided in project meetings to alter priorities and quickly identify when additional resources are needed to resolve issues.

Closeout of any document that requires multiple signatures is on the list of areas where critical minutiae can be found. The more signatories required and the less those signatories are accountable for the activity you are trying to move forward, the more difficult the task becomes.

Label approvals for multicountry clinical studies is another area that is often frustrating, and getting final approval on wording or translations for one country that may or may not actually enroll patients can hold up getting your first shipment out to any country. There are often a number of people involved in label reviews, including regulatory, clinical operations, one or more CROs, translation companies, QA, and CMC.

Closing contract negotiations in a timely manner is often the most important thing a sponsor can do to impact a timeline. Sponsors’ and suppliers’ legal counsel (and project leads) often do not see eye to eye on liability, cancellation, and termination clauses, though no clause is immune to controversy. It is a necessary but ironic state that disagreements on how to terminate a contract if needed cause delays in starting a contract in the first place. But getting the attention of legal counsel or approvers, particularly at the sponsor, can be rate limiting to getting contract closure and project initiation.

Making decisions about who are primary reviewers and whose input will be considered, by whom, and in what time frame can help reduce cycle times for document closeout.

This is not to blame these multiproject multitaskers; we can easily find ourselves in that position on some projects.

Data Availability As Critical Minutiae

Finally, data and information availability directly affects the ability to carry out activities, make decisions, and assess risk. A master batch record, a supply strategy, an out-of-specification (OOS) investigation, a formulation study, or a budget consists of many small pieces of information: a weight to check, a document to reference, a result to compare, a cost to verify. How many incomplete documents in front of you today have “need to get ref” or “information requested from xxx” in the margins? Good documentation practices and an effective document management system are hedges against these roadblocks becoming critical. If one can easily look up the information or find that prior work has been compiled, the activity can be quickly closed out. An outsourced environment requires proactive transfer of information and results in enough detail (and capture by the other party) to avoid repeated cross-company queries.

None of this will stop the details from being required, but anticipation, communication, and documentation can keep critical minutiae off the critical path to project completion.

About The Author:

Sue Wollowitz, Ph.D., is a pharmaceutical development consultant and educator. She is interested in CMC tactics and strategies in small companies that increase operational quality and best support project goals. Previously, Wollowitz worked at Medivation, Cerus Corporation, and the Dow Chemical Co. She is the holder of 32 patents and author of over 20 publications. Wollowitz has a Ph.D. in organic chemistry from the University of Wisconsin-Madison and had further training at CNRS in France and at the University of Chicago. She can be contacted at sue@wollowitzassoc.com or on LinkedIn.