The first zodiac sign in the Chinese zodiac cycle. According to the Chinese zodiac story, in the competition held by the Jade Emperor to decide the zodiac animals, the quick-witted rat asked the diligent ox to take him on a ride to cross the river and jumped down before the ox crossed the finish line, so the rat won the race and became the first of the zodiac animals.
Rats are quick-witted, resourceful, and smart. With rich imaginations and sharp observations, they can take advantage of various opportunities well.
In Chinese culture, rats represent working diligently and thriftiness. With good insight and a sharp perspective, Rats have good judgment in what they do, which enables them to prevent unnecessary problems. Rats are cautious and meticulous, so they tend to show a serious attitude toward their work.
Incorporation of phase appropriate development strategies is becoming increasingly essential to manage the balance between speed, cost and completeness during development. The possibilities for both Chemistry Manufacturing and Control (CMC) development and filing approaches range from the minimalist style to a continuously supported style.
The minimalist style is preparing only the things necessary for the next filing to save money and time. The continuously supported style is keeping a development program up-to-date and fully current, so filings are ready to go.
There are pros and cons to both styles, and while there is no right answer, there probably is a “best answer” to suit each company’s culture, funding runway, and the ultimate goal for the project.
Timelines are very crunched, especially now with FDA’s accelerated approvals. It’s essential that drug developers think through any process, go through it step by step and unit operation by unit operation to determine risk and predict where issues will show up during scaleup or technology transfer.
FDA’s accelerated review process, part of the 501(b)(2) approval pathway, may have made it more tempting to take shortcuts. This is reflected in the growing number of Complete Response Letters (CRLs) that FDA has issued to manufacturers. CRLs put a temporary stop on a drug’s approval until specific issues are addressed. For the past few years, as the complexity of drug formulations has increased, FDA reviewers have issued more CRLs that directly cite CMC deficiencies.
Given the complexity of CMC, the best way to develop a clear approach is to develop a regulatory strategy, you need an understanding, not only of the of CMC data, but how that fits into the regulatory plan.
Every compound and every development program will be different. It’s a matter of understanding what information is needed and when. You can adjust that strategy as you go so that you can make good decisions on whether to move forward at each step.
The biggest problems typically; most fail to anticipate problems based on the data that have been generated, they haven’t generated the right data, they haven’t thought through all the potential problems, or in many cases they don’t have adequate expertise in the CMC area.
Another misstep that companies can make is failing to talk with FDA. Reviewers should be part of the team so invite them to the table early on. Small emerging pharma at some point also requires at least one person, supplemented with consultants where needed, to manage the CMC issues of getting ready for the milestone meetings, managing CMO relationships (Get as much information as possible on potential CMOs and visit them!) and the eventual NDA or BLA submission.
All too often, Module 3 is poorly written late in the game, and crucial information is missing or is buried somewhere in a development report that cannot be found. It’s important to spend time on writing the CMC portion of the NDA starting from in Phase 1. A submission needs to tell a story, and it should be a coherent one, with information that is readable, clear, and as concise as it can be.
CMC is the most underappreciated aspect of the whole drug development process, but it can make or break development, we have witnessed firsthand over the past fourteen years. Smaller innovative emerging companies do not always understand the importance of having a clear CMC strategy. Many small emerging biotech’s take the approach of ‘Let’s run as fast as we can with whatever works, and if there’s a problem, we’ll deal with it later.
Performing extensive due diligence on CMC is also crucial before an asset is acquired. It is possible for companies to buy a process that cannot be scaled up; has dozens of impurities that were previously undetected by the seller’s CMC quality-control group; may not have sufficient stability; or that may have been created with an uncharacterized cell bank.
Big pharma is unlikely to make mistakes due to the resources invested early in program management. They generally have much more experienced personnel and turn to consultants primarily to supplement their staff when timelines accelerate.
Smaller emerging biotech do not have the same number of experienced people on staff or too few staffers with the specific experience required for the drug that they are developing. Companies with limited budgets and experience may force short development timelines that compromise assay qualification and validation, as well as supplier and material qualification; facility and equipment qualification; storage conditions; tech transfer; and process validation.
New drug development is challenging and it’s hard to blame manufacturers for seeking shortcuts. But one area that cannot be taken lightly is the CMC strategy, which offers a blueprint for taking a drug from clinical stages and through to commercial manufacturing.