By Raghavendar Rao Morthala, Ph.D., General Manager – API R&D, and Rajesh Shenoy, Ph.D., VP R&D and Global Head of API, Piramal Enterprises Limited
Due to the increasingly competitive pharmaceutical1 industry, speed to market is essential in drug development. Medicinal chemists developing new compounds are faced with the probability that less than 10 percent of drug development programs successfully make it to market. Therefore, they strive to produce as many effective compounds as possible to increase the chances of commercialization. Nevertheless, in this rush to market, you should be aware of critical missteps that can occur during the early development phases, in order to avoid major challenges later during commercial scale-up.
1. Selecting a route that poses chemical and process challenges
Using intermediates in your synthetic route that are hazardous or unstable can create chemical and process challenges during large-scale manufacturing. For example, gas compounds present safe-handling risks due to their toxicities and large-scale handling issues; and liquid compounds are difficult to purify because they require high vacuum distillations, which complicates the separation of compounds/impurities. Instead, use solid compounds, as they provide more opportunities to enhance quality through techniques, such as crystallization, solvent extractions, precipitation, slurrying, filtering, and washing. Proper scouting and selection of your reaction scheme is critical in identifying and evaluating potential scale-up issues due to incompatible intermediates. If route selection is not evaluated properly, this may lead to route or process changes at a later stage, impacting regulatory filing and the timeline of the development program.
2. Using unsafe, not scalable, and/or expensive reagents
Because of the need for medicinal chemists to work quickly to make as many products as possible at a time, they often try to use reagents that are easily available. This can result in synthesis routes that contain effective but sometimes hazardous reagents. For example, lithium aluminum hydride does not pose a serious threat at a scale of 1 to 2 grams, but at a scale of 100 to 200 kilograms, it can create serious safe handling issues caused by its violent reactivity toward moisture/water while liberating hydrogen gas. When a reagent needs to be changed due to safety concerns, more time must be invested in establishing a new process to find a different reagent, validating the process in the laboratory, and then validating it again at the plant level. Some reagents may also be unavailable at commercial volumes, due to their manufacturing criticalities and niche technologies involved, or they may even be too expensive. Therefore, knowing their availability early prevents process changes later to avoid the cost and/or burden of refiling the reagents/process with regulators.
In addition, there are solvents and reagents, such as ethanol and acetic anhydride, that require permission from some countries’ local governments to use on a commercial scale. Providing justification and showing material consumption data to government agencies is a tedious and time-consuming process. Hence, it is critical to know the regulations around solvents and reagents for the countries you are targeting.
3. Not optimizing your processes during small-scale development
Oftentimes, when a medicinal chemist develops a process, it is fit for purpose only at that time. At that point, there is often no concern for yield or quality. As the compound makes its way through each phase of development, its manufacturing requirements begin to change. As a result, the original process can become less efficient and, ultimately, unscalable. That is why, after finalizing the route of synthesis for scale-up, the process must be optimized in such a way that it gives consistent yield and quality every time. To achieve this, process parameters, such as temperature, time, pressure, quantity of reagents, etc. need to be studied to identify the optimal conditions and reagent quantities. Optimization can also provide information on critical process parameters and critical quality and material attributes.
Understanding these parameters is not always easy for medicinal chemists to address or consider because speed is key for them, and defining those outcomes can be very time-consuming. Nevertheless, you must have a clear understanding of the parameters and the effects of making any changes. If you do not, you could face costly consequences, such as failed batches, the need to purchase special equipment, or additional time for optimization, which impact delivery timelines, risking a drug shortage for patients in need of the medication.
For example, if a chemist discovers they can achieve the desired reaction at 25 to 30 degrees Celsius, they should also collect data at other various temperatures, such as, for example, 20 to 25 degrees Celsius and 30 to 35 degrees Celsius, so they can record what could potentially go wrong at each temperature. This is critical, as the temperatures at which a manufacturing facility operates can sometimes be difficult to control in manually-operated plants. Any variabilities in temperature, pressure, or pH could impact the quality and/or yield of the product.
If impurities begin to generate when the temperature increases, for instance, five degrees, the correct temperature becomes a critical process parameter, and the production chemist can ensure the temperature stays within the required range. The chemist should understand and document what those impacts are in order to maintain consistency during scale-up. If they do not and the process is executed on a commercial scale without an understanding of the impact of the temperature on impurity formation, the company may face the risks of not just impurities but also lost batches because it cannot alter the temperature after filing is approved.
4. Filing unoptimized process parameters with regulators
When companies file unoptimized or semi-optimized processes, the outcomes can be costly, unsafe, and unscalable. This is especially problematic because, once the company arrives at Phase 3 or the commercial stage, it cannot change the process. Many customers do not anticipate scale-up challenges, which can be identified and addressed sooner if process optimization takes place prior to filing. By having a more thorough understanding of a product and its process parameters, an experienced chemist can build more flexibility into their regulatory dossier even without optimizing the process.
An example of a situation when building flexibility into the dossier would be helpful is related to the use of crystallization versus column chromatography to remove impurities. It is critical to leave this open-ended by listing both options in the dossier, as you can follow only the steps outlined in the dossier once it has been filed and approved. By doing so, you also improve the chances of selecting the optimal decision for scalability post-Phase 3. If a company specifies using chromatography in the dossier without listing the possibility of selecting crystallization, it risks being tied to a more costly option. Chromatography is not as easily scaled up for greater volumes, due to its higher costs, greater requirements for solvents, and added waste.
5. Not establishing process tolerance for scale up
Process tolerance requires the level of impurity formation and impurity purgeabilities to fall under acceptable boundaries. When there is any deviation in the process, impurity levels may increase, and the downstream process is not efficient enough to reduce the impurity to the desired specification levels. Process tolerance often varies when a process is taken from lab to plant scale. For example, the length of time a product is exposed to a specific temperature in the plant is not the same as how long it is exposed in the lab.
To establish process tolerance for scale-up, process engineers and chemists must work together to identify any potential operational challenges during process development. For example, small-scale experiments are typically conducted in round-bottom flasks. Because there will not be any geometric similarities used at a commercial scale, you should always perform experiments in cylindrical reaction vessels to mimic the plant conditions. Chemists and engineers can then predict the extent of impurity formation and process failures during scale-up, thus allowing process controls to be established and documented. These simulation experiments help manufacturers keep appropriate controls in their batch manufacturing records.
Overall, to establish a feasible and safe scale-up process and achieve right first time, it is essential to have a thorough understanding of your process from route selection through process validation and to commercial scale. By avoiding mistakes early, you can lay a stronger foundation for manufacturing and, ultimately, deliver a safer product with the highest level of quality and efficacy.
1 Biotechnology Innovation Organization (BIO), Clinical Development Success Rates 2006-2015 – https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf