Stuart R. Gallant, MD, PhD
Any successful drug development program generates a massive amount of information. Just the NDA can run to more than 100,000 pages [1]. And of course, what goes in front of the regulators represents a tiny fraction of the data generated within the development program. In this two-part post, the topic of how to organize the data is addressed.
Caveat: these two posts focus on CMC knowledge as an example, but it should be relatively easy to extend these principles to non-clinical or clinical knowledge.
The Knowledge Gap
Imagine a typical drug development program which is approaching the close of Phase 2. The company is starting to look ahead to Phase 3. On company radar are the upcoming validation and manufacturing activities to support Phase 3. To address the increased workload, new personnel are being hired in technical operations (engineering, manufacturing, quality control) and in clinical affairs and regulatory affairs. Perhaps, some personnel are leaving to take other positions. The team starts to look for data to support manufacturing ranges, analytical method procedures, and the choices of raw materials. The old hands—folks who have been at the company since the beginning—are having trouble remembering how some decisions were made. And, it is difficult to put hands on some of the supporting data.
What usually happens in this situation is that the team does additional work to back-fill gaps in project knowledge. Then, the program moves onward, and everyone forgets that anxious period. Or at least, they forget until the next knowledge gap becomes evident.
The gap in question is between the amount and kind of knowledge that is required and the knowledge that the team can find and organize—the knowledge exists but the team can’t find it or doesn’t know it exists. Times when the need for knowledge increases are: at IND filing, during preparation for Phase 3 manufacturing, at NDA filing, and at the time of annual report filing. But, those aren’t the only times, here are a few more: when new personnel enter the program and need to come up to speed, during release of a drug substance or drug product lot, during review of stability data and extension of retest dates on drug product lots, and whenever there is an adverse event reported in the clinic.
The Solution: Knowledge Management and Knowledge Mapping
This feeling that a lack of knowledge is pulling the program down is a familiar one to scientists in pharmaceutical companies, and in truth, you can never know enough. Nevertheless, there are some simple ways of dealing with the problem of the knowledge gap. The solutions are knowledge management and knowledge mapping. For those who are interested, there are excellent resources which address the theory of knowledge management [2, 3]. This post is going to address some practical solutions to knowledge management and knowledge mapping in the context of early pharmaceutical development.
For the purposes of this post, I am defining the terms as:
- Knowledge Management: standard operating practices within a pharmaceutical company to capture, organize, analyze, and make available what has been learned during the drug lifecycle of the product molecule.
- Knowledge Mapping: the creation of documents available to the development team which facilitate the rapid uptake and understanding of project knowledge.
- Knowledge Event: an activity at a startup that generates a large amount of new knowledge (for example, technology transfer of manufacturing process to a new CMO, manufacture of a new lot of drug substance or drug product, occurrence of a manufacturing deviation which requires significant effort to resolve).
The Knowledge Base
Let’s assume that a new pharmaceutical company is being founded today. Assume that it is a leanly-resourced stand-alone startup. Further assume that it is a one-product company manufacturing a small-molecule parenteral drug. How would the company’s knowledge base be set up?
- Select a file hosting service: (I get no referral fee.) Dropbox.com is a reasonable choice—it allows control of access based on a user’s profile, has features to allow searching for files, and is fairly intuitive. Your IT department will need to create profiles for company employees and consultants and make some other choices about how the service will be set up.
- A directory structure is then set up to support the knowledge base. An example knowledge base structure for CMC activities is provided here as a PDF:
I have used directory structures like this to organized CMC documentation for this type of project (leanly-resourced, startup, small molecule). This type of document can serve as a knowledge map—letting everyone on the team know where the information is and where they should be putting their information as it accumulates.
For an early phase company, knowledge management begins with using a knowledge map like this one to coordinate and integrate knowledge within the company. In the second of these two posts on knowledge management, we will dig into the use of a tool like this one.
[1] Van Norman, G.A. “Drugs, Devices, and the FDA: Part 1—An Overview of Approval Processes for Drugs,” JACC: Basic to Translational Science, Volume 1, Issue 3, April 2016, Pages 170-179.
[2] Calnan, N., et al. A Lifecycle Approach to Knowledge Excellence in the Biopharmaceutical Industry, CRC Press (2018).
[3] ISPE. Good Practice Guide: Knowledge Management in the Pharmaceutical Industry (2021).
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