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As pharmaceutical companies face ceaseless pressure to expedite products to market, strategies for improving the drug development and manufacturing process gets critical. And all challenges related to drug development start with the synthesis of active pharmaceutical ingredient (API), which makes its products important in any development program. Late API delivery can often result in missing significant milestones like filing an investigational NDA, which can have serious financial implications.
Many steps have to be followed to ensure the successful development of an API that caters to regulations and compliance. Having a solid optimized API strategy not only enhances timelines and success rates, but also adds value to your product and process.
As an API moves from early clinical development through clinical trials and towards commercialization, the original synthetic route may sometimes turn out to be not so efficient, cost-effective or sustainable processes as the scale of manufacturing goes up. Additionally, hazardous or complicated chemistries, or exorbitant key intermediaries may not facilitate insourcing or outsourcing of production, or can even make the process excessively uneconomical, preventing the development programs to continue.
This paper provides an overview of the API development process, a few of the most important challenges, and how to raise your chances of success.
De-risking API Strategy
De-risking involves lessening the guesswork and eradicating as many unknowns as possible from an API strategy. Multiple options have to be considered while planning your project with regards to the best path to take based on present data and knowledge. The risks and assumptions for each of these routes should be evaluated and recorded so as to pre-confirm the path.
Here are some tips to help you get started.
Failure Mode Effects Analysis
The manufacturing of APIs is greatly complex. Planning beforehand and validating your route should help improve timelines and cut down associated expenses. Failure Mode Effects Analysis (FMEA) is an effective tool to relate process parameters and material/product features besides identifying and prioritizing product risks. The main points of FMEA process include inclusion of an interface which makes it easy to detect complicated process involved in research, identifying undesirable effects to indicate process defects, in addition to a quantitative estimate of all undesirable effected linked to efficiency and quality. It’s a robust tool for summarizing the important modes of failure, reasons behind these failures and the possible impacts of these failures.
When failure modes are established, risk reduction can be used to reduce, control, contain or eliminate the potential failures. FMEA depends on understanding of product and process. It methodically breaks down the examination of sophisticated processes into easily manageable steps.
FMEA can be applied to facilities and equipment and might be used to peruse a manufacturing operation and its effect on process or product. It identifies operations/elements within the system that render it vulnerable. The results/output of FMEA can be used as a benchmark for designing or in-depth analysis or even to pilot resource deployment.
Scalability of Raw Materials
As part of an ideal de-risking process, companies should first define how the production of their API will eventually scale-up throughout the drug discovery program. All raw materials aren’t scalable as there may be health or cost and safety implications. This indicates that when production of massive batches is required, the synthesis will not be scalable. It’s best to identify raw materials that are scalable and use these to build a strategy for the chosen route.
Normally, the grade choice for reagents is considered less in the nascent stages of drug development compared to other factors. That said, it’s very important that the materials you choose belong to the same grade as drawing correlations becomes easy. It also assists in ruling out material interactions and differences. Examining available batch data following every batch synthesis helps in identifying nuances and insights that can be of tremendous assistance when scaling production. The scale up gets easier if the tinier batch syntheses are performed rigorously and robustly.
De-risking an API strategy in the early phases can add a lot of value to a drug development program.
Enhancing the cost-efficiencies and reliability of API synthesis helps prevent unwanted delays and costs and adds value to your data package.
The long-term timeline of your development program will also witness a significant reduction, helping to lessen associated expenses and release funds if investment is based on meeting important milestones.
Are You Using The Appropriate Synthetic Route Phase?
Not all phases of a drug development program are the same. The synthetic route of an API, which was appropriate at the onset of your program, may look obsolete when conducting Phase III clinical trials or for commercialization purposes. An ideal API strategy has to evolve through the development phases and specifications for raw materials, API and intermediates have to be elaborated throughout the development phase as understanding/knowledge of the analytical procedures and process improves from Phase I to Phase III.
Manufactures should look for what they want from their synthetic routes for each phase. Give enough time to carefully assess the route to ensure you’ve everything you require when it comes to raw materials, equipment, time, data etc.
When the synthetic route you consider for a phase isn’t appropriate, you can fall into many common traps:
- The route is immature for a particular phase of the program
- The route needs reagents that cannot be accessed or/and are unsafe on an industrial level
- The route cannot be scaled
- Sometimes, the reagents become unavailable, making it futile to continue with the route.
Preventing Common Analytical Disasters
Not having the proper analytical method
There are many common pitfalls that take place during an API strategy-the most common being not having a proper analytical method to figure out the quality of the produced API. For instance, if you use screening methodologies based on the polarity of the compound, high-performance liquid chromatography (HPLC) will determine how pure your API is. However, you need to genuinely recognize all the identifiable and unidentifiable purities. It’s important to question the important peaks so that an impurity is not left hidden and retained as a result. If the impurity is polar, for instance, it’ll probably fly through the column in the liquid phase and not latch on to the solid phase. In such a case, a method has to be designed to be sure that all the unidentifiable impurities are resolved. This could possibly be de-risked by using various mobile columns and phases with unique selectivity and then comparing the generated chromatographs.
The methods of de-risking should also be appropriate to the phase of the drug development program. For example, Phase I screening and de-risking methods will be largely generic while those used in Phase III will be greatly specific.
Not having the right stressed method
An important aspect of testing the method is to break down a sample of the compound with the help of heated bases and acids and then injecting the degraded samples into a column connected to a UV detector. This ruptures the peaks into various reference spectra, which can easily show if an impurity is left unseen under a peak. In case of spectral differences, it indicates there are two or more compounds eluting in the chromatographic peak.
It’s essential to conduct a forced degradation examination to ensure that the analytical method is appropriate as it will be able to validate the method or to highlight regions of weaknesses that can immediately be rectified.
Using inappropriate instruments
This can be related to not having the right analytical method. Let’s consider a polar compound with minimum or no chromophore at all as an example. Analysis of this compound by HPCL technique will not yield the desired chromatogram. In such a case, a charged aerosol detector has to be used as it can measure a broad range of analytes. The detector is normally used with HPCL instrumentation to measure the analytes that remain unseen by UV and may not easily be identified with other techniques of detection, which includes molecules that don’t contain chromophores.
Avoiding and Overcoming These Disasters
The key lies in collaborating closely with the process development team involved with the program. If an impurity is identified by NMR (Nuclear Magnetic Resonance), report the data to your team. In case you’re outsourcing your API strategy, ensure to work closely with the CRO you are collaborating with, and then plan ahead. It’s important that the technique for API synthesis is relevant to the drug development team when conducting compatibility and uniformity testing. By working collaboratively, it minimizes risks as you develop an effective single method that manages drug product, API and clinical testing, eventually decreasing the risk of errors and building a transferable data package that will help overcome formulation and manufacturing issues in the imminent future.
How Innovation Can Optimize API Strategy
Innovation and the adoption of new technologies by a contract manufacturing organization (CMO) can keep the costs of API low. Also, cost-sharing approaches and collaborative risk between a CMO and customer can be beneficial to both the parties. Let’s now try to understand this further.
There are numerous opportunities in the marketplace where a CMO can enhance your API strategy. Even though potential reward may be humongous, these opportunities come with a high degree of commercial and technical risks. For this reason, perfect project selection as to which to commit resource and time is utterly critical. The main three selection criteria include technical assessment, market evaluation and customer interaction. Technical evaluation normally involves a detailed and exhaustive literature search along with a freedom to operate (FTO) analysis to ensure that any new process development doesn’t infringe. A cost simulation also has to be conducted for the existing manufacturing process and also the proposed innovative process to gauge the degree of likely cost savings.
The market can be assessed by accumulating information related to the target product and other competitive products in the pipeline, which may have a major influence on the market dynamics. Following this, the rewards and risks associated to each product are evaluated.
In case of projects involving a CMO manufacturing a product for a customer, open discussions with the customer are crucial. From the perspective of the customer, a cost-effective manufacturing route should be weighed up against the cost of change along with the regulatory consequences brought by the change.
After a suitable project has been identified, the next step is to undertake a proof of concept study, which normally focuses on the important step in the new process that has been proposed. Once this is successful, a proof of scalability study is the next step, provided the customer and market information has been reconfirmed. This is the time when the CMO will work to build a powerful and commercially ideal manufacturing process.
Some key elements to be considered while developing an innovative process are as follows:
- Knowledge of the patent landscape to ensure FTO
- Understanding of the cost of goods (CoG) for the competitive processes
- Understanding of the main cost drivers within the process
- Understanding of the availability and cost of raw materials
- Opportunities to improve the yield
- Opportunities to enhance processing times to condense the process whenever possible, eventually reducing the number of isolated intermediates
- Opportunities to develop reproducible and robust processes. This ensures that the specification is met each and every time
- Ensuring a manageable and limited waste stream
- Using standard equipment to prevent extra capital investment
- Recycling solvents within a regulatory framework
Drug discovery and development is one of the priciest ventures in modern science, with most candidates failing to make it to the market. Sometimes the process can seem overly daunting. However, an efficient and well-developed API strategy that parallels your drug discovery and development programs can have a massive positive impact.