How to Handle Pesky Surprises in API Manufacturing

Surprises are good when it comes to birthday parties, or winning the lottery, but not so much when it comes to developing and manufacturing critical Active Pharmaceutical Ingredients (APIs).

The fact of the matter is that even with the soundest of methods, processes and strategies, problems can occur in API manufacturing that are beyond a Contract Manufacturing Organization’s (CMO’s) control.

In this article we’ll address key surprises and how to address them.

Bad Raw Materials. Sourcing the highest quality raw materials whenever possible is a critical concern of CMOs, yet even with the most diligent sourcing and closest supplier alliances, there are many things that can go wrong. They can fail to meet the specifications set forth in the Drug Master File (DMF) or you could find foreign matter in the raw materials which could cause major damage to reactors and other equipment.  For whatever reason, a CMO would need to send back or destroy the material and thus seriously delay project timelines.

So how can CMOs ensure they are receiving the highest quality raw materials they can? The key is to properly vet your suppliers through on-site visits, references and audits; while also having a back-up supplier on hand. Additionally, once a CMO has a good, trustworthy supplier, it’s important to maintain a strong relationship and establish ongoing communication. CMOs also should realize that when it comes to raw materials, price should not be the primary focus, but quality, given the costs that can be incurred when they fail to meet specs.

Purification Strategy Producing Too Little Yield. Organic compounds are never too pure. When isolated from natural sources or created through organic reactions, they always contain other compounds. Before carrying out the qualitative and quantitative analysis of organic compounds that is needed to characterize them, it is very important to purify them as much as possible.

Purification is a critical step in drug manufacturing, helping to eliminate unwanted materials that can be hazardous or compromise drug efficacy.  While there will always be a certain amount of impurities in APIs, the goal of a current Good Manufacturing Processes (cGMP) facility is to minimize these impurities.

But what happens when the level of impurities is extremely high?  Any amount of impurities can be eliminated to reach the specifications you are aiming for, but the problem is that it can affect the yield. As you strive to eliminate many of the impurities, you can lose a good portion of the chemical you’re developing – you may be throwing the baby away with the bathwater, so to speak.

But, impurities can be controlled by understanding their formation, fate and purge during the manufacturing process. They also can be controlled by setting up appropriate controls at places where they either enter or form during the manufacturing process. The key here is to have seasoned chemists who are familiar with such impurities and yield challenges and thus apply best practices to minimize them.

Problems in Scale-Up. Manufacturing an API in a kilo lab and scaling up in the plant can produce very different results. When bringing a molecule to cGMP suites for first time, the process can take much longer, given the need for greater supervision, sign-offs and quality control. It’s often difficult to exactly simulate the cGMP suite in the lab so sometimes new impurities show up or material doesn’t crystallize properly.

Yet, while problems that occur in the GMP suite can be resolved over time, they can come at a cost much larger than when they’re found in the kilo lab where less raw materials are affected.

To reduce the risk of late-phase surprises, some experts recommend that additional screening efforts in early development can smooth the pathway in later development stages. CMOs and CDMOs must balance the need to better understand potential formulation challenges and the manufacturability of APIs, with the reality of time and budget constraints.

Analytical Challenges. When a manufacturer qualifies an analytical method, it is assessing that it is suitable for its intended purpose. It compares specific samples of the compound to a standard one to test its reproducibility. Many companies choose to conduct this process early in pre-clinical stages in order to determine the feasibility of the method for the API or generic compound. Analytical procedures in the early stages of method development are initially developed based on a combination of an understanding of the basic methodology and prior experience.

Yet, as surprises crop up in a molecule as it goes through the various stages of manufacture, changes must be made to the analytical method. As development timelines are altered because of issues that arise for various reasons, often, not enough consideration is given to analytical method development and validation. To handle this challenge, the analytical development team needs to closely work with the development team to anticipate the changes and actively participate in any relevant discussion regarding the timeline. It is also important for analytical development to educate and work with the project managers during the development process.

In the event of any surprises in the manufacturing process – which are often inevitable, the key is to have a strong line of communication with sponsors through regular meetings, project updates and mutual collaboration. Through experience, expertise and sound strategies, effective CMOs can weather the surprises and facilitate successful API outcomes.