Active pharmaceutical ingredient (API) manufacturing for new chemical entities (NCEs) is a lengthy undertaking involving many complex chemical processes, including the production of intermediates and purification and isolation steps. Optimizing the manufacturing process, through rational API process design and development, is the key to enabling fast, safe, reproducible, and cost-effective API production. And with the increasing pressure on accelerating drug development while staying within budget and meeting increasingly complex and stringent regulatory requirements, optimizing the API process development workflow has never been more crucial.
However, designing and executing an effective API process development strategy is no small or easy feat. From the early phases of drug development through to commercial manufacturing, the fine-tuning of many individual steps is required to optimize and de-risk API production. This blog outlines some of the key considerations involved in successfully designing and developing an optimal commercial API manufacturing process, including the selection of the synthetic route and regulatory starting materials, the development of a highly effective process control strategy, as well as risk management methodologies, and process safety considerations.
Synthetic route selection
When designing or selecting a synthetic route, it’s important that you get it right, as the use of suboptimal, inefficient routes can drain resources and substantially increase your time to market. Indeed, changing the synthetic route at the late development stage can prove very costly and time-consuming, not least due to the regulatory constraints being faced; in the worst-case scenario, such a change can even trigger the requirement for additional in vivo studies of the drug.
A key consideration for selecting the synthetic route for any type of chemical API is efficiency. Ideally, the chosen synthetic route requires the least number of steps and results in the shortest time to market.
In this regard, scalability is a critical aspect. All chosen materials, unit operations, processing equipment, and conditions should be suitable for scale-up to enable the manufacture of both clinical and commercial scale API batches. Building robustness into the synthetic route by selecting chemical transformations for ease of scalability will help maintain high levels of reproducibility, quality, and cost-effectiveness at increasing scales. This will ultimately ensure continuity in API supply by minimizing the time and costs involved in technology transfer activities.
Additional essential considerations in API synthetic route selection and optimization include those outlined by the SELECT principle: safety, environmental impact, legal requirements, economics, control, and throughput. These principles were first proposed in a 2006 consortium of pharmaceutical manufacturers, including AstraZeneca, GSK, and Pfizer, providing a good basis for selecting or designing a robust, commercially viable synthetic route.
Starting material selection
The selection and introduction of all processing materials, including raw materials, intermediates, solvents, and reagents, will depend on the chosen synthetic route and the API. However, all materials should have well-defined chemical properties, structures, and impurity profiles.
Additionally, a thorough understanding of the selection criteria for starting materials is essential, as outlined in global regulatory guidelines, including ICH Q7 ‘Good manufacturing practice for active pharmaceutical ingredients’. This requires a risk-based approach, which entails gaining a detailed understanding of how changes in the proposed API starting materials can influence the critical quality attributes (CQAs) of the drug substance, including its impurity profile, and the consequences this may have on the medicinal product’s quality.
All starting materials should also be evaluated for their security of supply, in addition to their quality, safety, and environmental impact. It is of particular importance to develop a robust supply chain strategy for custom-made starting materials, including the evaluation and qualification of reliable suppliers.
Developing a process control strategy (PCS)
Each process involved in API manufacturing requires the definition of a unique set of process parameters, such as mixing, temperature, pressure, and time. These parameters must be adequately monitored and tightly controlled to avoid the formation of impurities and prevent inconsistencies in output quality and yield. To develop an effective PCS, several considerations should be made, including the control of input materials, and the use of quality-by-design (QbD) principles to characterize the process and develop appropriate analytical methods to be implemented for quality control.
Quality-by-design (QbD)
QbD is a systematic, rigorous, data-driven approach that should be adopted to improve process and quality control in API manufacturing. QbD relies on predefined objectives to gain a thorough understanding of process control. This starts with determining the drug’s quality target product profile (QTPP), which consists of several design specifications that ensure the product is safe to use and has the desired therapeutic effect.
Based on the definition of the QTPP for the medicinal product, the API CQAs, i.e. the measurable properties of the compound that characterize its quality, including purity, potency, particle size, and stability, are identified. Once API CQAs are defined, the manufacturing process must be thoroughly studied and characterized to evaluate the critical process parameters (CPPs), which are the variables, such as temperature, pH, agitation, and processing time, that impact process performance and consequently product quality.
Essentially, QbD involves the consideration of all materials and processing parameters that could influence product quality. By gaining a sound scientific understanding of the processes through the execution of a rational experimental design, e.g. using a statistical design of experiments (DoE) methodology, this approach enables the elaboration of a more effective control strategy. As documented in the international pharmaceutical guidelines, ICH Q8, Q9, and Q10, the QbD methodology enhances drug development by helping to reduce the risk of batch failure and improving final product quality, safety, and consistency.
Learn more about the role of QbD in drug development
Analytical method development
QbD principles can also be extended to analytical method development. The API’s CQAs provide a good basis for selecting the most appropriate analytical methods and determining their parameters. Well-designed test methods are paramount to supporting the accurate and reliable monitoring of intermediates and product quality, in line with international quality standards and regulatory guidelines.
For in-process analysis, chromatographic methods, like high-performance liquid chromatography (HPLC) and gas chromatography (GC), are commonly preferred to monitor process execution due to their accuracy and reliability. More recently, the development of process analytical technology (PAT) based on the use of in-line spectroscopic methods, such as Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and focused beam reflectance measurement (FBRM), has helped to improve process control by enabling real-time process monitoring.
When choosing the best analytical method for each process, molecule type and stability arekey considerations. These attributes drive requirements for achieving the appropriate sensitivity and robustness of each assay, including the choice of detection method, range of detection, sample preparation procedure, and analysis time, in addition to cost and ease of routine implementation.
Implementing quality risk management
Risk of failures associated with the facilities, equipment, materials, personnel, processing, product testing, and storage are inherent to API manufacturing. Effective risk management strategies are required to prevent these risks from impacting the quality, efficacy and safety of the API, and from causing costly delays. Recognizing this, ICH guideline Q9 outlines a framework for quality risk management (QRM) applied to pharmaceutical products. This is a strategic approach that involves assessing, controlling, and continuously reviewing potential risks that could occur in API manufacturing, using the following steps:
- Risk assessment – this step considers the identification of hazards, the probability of them occurring, and the evaluation of the severity of their consequences.
- Risk control – this next step consists of the use of a decision-making tool to identify and implement control strategies designed to either eliminate or reduce the probability of occurrence, and lessen the severity of the impact down to a level that assures the quality, efficacy, and safety of the product.
- Risk review – this step is essential to maintaining the effectiveness of the quality risk management framework since it is designed to incorporate the risk assessment and control activities described above while reviewing the new data and knowledge generated throughout the product lifecycle activities.
Several risk management tools are available to aid quality risk management, including failure mode effects analysis (FMEA) and its extension, failure mode, effects, and criticality analysis (FMECA). FMECA is a critical risk analysis tool derived from FMEA and used to determine the potential sources of failure during the execution of the manufacturing process, evaluating the severity and likelihood of such failure, in addition to how it can be detected before it occurs.
Process safety
The development of API manufacturing processes requires particular attention to health and safety considerations to avoid serious and potentially fatal hazards. In addition to ensuring that operators are effectively protected from direct exposure to chemicals, particularly those with high potency, the process chemist also needs to ensure that the safety of the API manufacturing process is carefully assessed and established.
The first step to developing an effective process safety strategy consists of performing hazard assessments for each processing step. These require a detailed understanding of the chemical processes involved, in addition to several other components, including the use of material safety data sheets (MSDS) to take into account specific chemical risks associated with the starting materials and API, and the consideration of any requirement for specific operator training, worker exposure control measures, and compliance with regulatory standards. Although conducting thorough hazard assessments and using these to develop safe processes is time-consuming, it is essential to manage the operational risks associated with small molecule drug development.
Key considerations and future directions for API process development
In summary, a clear API process development strategy is essential to streamline and de-risk drug development, helping your drug reach the market in the most cost and time-effective way possible. Additionally, utilizing science- and risk-based methodologies in your strategy is essential for successful API production and for demonstrating a thorough understanding of the product and the process, including how any changes in the manufacturing process will affect the safety, efficacy, and quality of the final product.
Looking to the future, the adoption of innovative technologies, such as high-throughput experimentation (HTE) and predictive process modeling, will undoubtedly change the landscape of API process development. These methods can effortlessly generate large amounts of data, aiding the prediction of how processes will respond to varied reaction conditions and scale-up configurations. These data-driven techniques will further help to improve decision-making and design more efficient, robust, and scalable API manufacturing processes.
Head to our API capabilities webpage to find out more about how we can optimize your API process development strategy, and de-risk and accelerate your drug development program.