Pharma API Manufacturing Process: Challenges and Achievements

Behind the prosperity of China's API industry, there are many challenges, which make its development encounter difficulties.

Objectively speaking, China is currently the world leader in API, and the market is still expanding. Data show that China is the largest producer and exporter of API, capable of producing more than 1,500 API and intermediates, accounting for 27.7% of the global market share of generic API commodities. In 2017, the export of API reached 8.961,500 tons, a record high, with a year-on-year growth of 8.33%. Average export prices bottomed out, up 4.96% year on year.

From the data, China's API industry is booming, both in terms of overall market share and export, showing a rising trend. But this kind of leading, in fact is only the leading quantity, the real added value of the product is still behind; This rise, which also hidden a series of challenges, or even difficult.

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, 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 Pilot 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, 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.

Solutions Continuous manufacturing (CM) presents a feasible solution to these issues by providing a resource to facilitate production of the final dosage form in a single nonstop process with no equipment downtime. In CM, the material moves nonstop within the same facility, eliminating any hold time between steps. Because a small number of people are involved in CM, the risk of human error is significantly reduced. The operating cost is also reduced as less product handling is required during the process. Additionally, the Food and Drug Administration (FDA) estimates that some drugs that take three to four weeks to produce in a conventional batch method can be produced in a day with CM. Also, when it comes to day-to-day expenditures like water and electricity, CM, being a closed-circuit method, requires lower utility expenditures. With no holds and less human error, the continuous method is more reliable and safer.

FDA has also recently awarded a $4.4 million contract to Continous Pharmaceuticals to develop a science- and risk-based approach to monitor and improve drug quality through integrated CM. The Continous team is developing a fully automated, end-to-end, integrated continous pilot plant, expected to be fully functional soon, that will test relevant regulatory principles.