Quality from the start: Assessing risk to support success in early phase development
During the early phase development of active pharmaceutical ingredients (APIs), pharmaceutical and biotechnology organisations are not only considering imminent project requirements but also implications down the line as a project scales. While organisations typically aim to minimise investment during their projects’ earliest stages, until they come closer to ensuring their products’ success, they must also consider potential challenges that could delay filing or drug substance preparation.
Early phase risk assessment aims to systematically identify and mitigate potential challenges related to safety, quality, purity and other key factors, often before a product has advanced to clinical trials. It allows scientists to identify factors that can impact product and project quality or safety, then systematically monitor them throughout development to ensure they are resolved. By harnessing this more proactive approach, organisations can maximise efficiency while circumventing potential challenges and setbacks.
In this whitepaper, we’ll explore the importance of early phase risk assessment, then outline an actionable approach for defining factors that can impact product quality and mitigate risks in development.
A look at the process: A template for early phase risk assessment
A pragmatic approach to early phase risk assessment allows chemists to prioritise risks according to impact and define actionable ways to mitigate them throughout development. Below, we outline an approach that scientists can leverage to identify and mitigate risks.
Scientists should begin by understanding the measurable properties that are integral to product quality, efficacy, and safety, such as purity, reaction completion, and stability. Each property can be impacted by variables like temperature, concentration, flow rates and pH levels. They should pinpoint the objectives and impacting factors that are most relevant to the project, then set target ranges or limits for each based on experimental data and analysis.
Click here for some examples.
Next, scientists should identify tools and techniques that will be used to evaluate risk, along with the objective of each of these methods. Accounting for perspectives from engineering, hazard evaluation and other teams that will be involved over the course of a project means that scientists can more proactively consider long-term implications. These considerations might include what may work at lab scale but not plant scale, safety hazards and quality risks that might surface as a project scales, and more.
Begin with identifying the risks that might result from failure to achieve each given objective. For example, temperature control, mixing time, and other parameters can impact purity. If any of these fall outside of the specified range, it risks unwanted impurities in the final product. Scientists should score each risk based on severity and likelihood, and prioritise them accordingly. By using analytical techniques like HPLC, GC, and NMR, scientists can quantify the impact of each risk and take more effective measures to remove or reduce them.
Then scientists should put together a detailed plan that outlines risks and controls, and align on this plan with the customer. This should consider things like at what point certain reagents will be introduced, whether they will use closed or open charges, and whether any substances introduced will fit properly with the equipment used. This allows scientists to readily determine any other potential hurdles that may arise and take appropriate action.
Once risks have been identified and scored, scientists should outline strategies to control risk as the process scales. Following the purity example, chemists can leverage analytical methods like HPLC, GC, mass spectrometry and NMR to quantify and characterise impurities. It is important to monitor primary objectives and impacting factors on an ongoing basis to ensure everything remains within range, and make adjustments as the project scales, if necessary.
Early phase risk assessment in action: A scenario
Now that we’ve outlined a strategy for early phase risk assessment, we will explore what this would look like in action. For example, consider a process that produces hydrogen gas as a side product, using the methodology previously outlined.
Objective: Minimise hydrogen gas concentration. Hydrogen gas can be explosive at concentrations over 4%. In addition to posing a significant safety risk that can impact operators on plant, strong exotherms may generate impurities that can affect product safety and quality.
Impacting factors: Temperature, pressure, rate of gas production.
Assessing risk would require understanding exotherms present in the reaction, identifying how they might affect quality, and evaluating the manufacturing suite for safety and suitability.
In this scenario, if the hydrogen concentration falls outside of the specified range, the associated risks are explosion and impurities. Due to its significant safety and purity impact, this is a high-priority risk that must be carefully addressed.
To contain the exotherm and help ensure product purity, scientists should work to limit hydrogen gas concentration as much as possible. In addition, scientists should carefully evaluate the manufacturing suite to identify where risks are present, such as electrical equipment that could cause sparks.
Scientists can mitigate risk by limiting hydrogen gas formation as much as possible, which might involve alternative reaction conditions or reactants. In addition, scientists should ensure they have the necessary controls in place for the level of risk present. These might include removing electrical equipment within the suite to prevent the risk of sparks, using an air pump instead of an electrical one, implementing remote monitoring to keep operators away from the suite and continually monitoring exotherms and reaction conditions.
Methods for evaluating risk
Since risk can surface in various forms, it must also be evaluated using a range of tools and methodologies. Some common methodologies for early phase risk assessment, depending on the risk, include:
Stability and impurities: analytical testing like HPLC, GC, and NMR aid in analysing stability and surfacing potential impurities.
Impurities: when impurities surface, scientists must quantify and characterise them using methods like HPLC and GC, and assess whether concentrations fall within ICH guidelines.
Formulation: polymorphs and particle size can have a significant impact on formulation down the line. Both X-ray diffraction analysis (XRD) and thermogravimetric analysis (TGA) can aid in providing initial solid form data.
Physical hazards: testing such as differential scanning calorimetry, reaction calorimetry, thermogravimetric analysis, minimum ignition energy testing and others can be applied to measure heat release, ignition points and other possible hazards that can affect both quality and safety.
Proactively mitigating risk with the right partner
In addition to enabling safe operations, early risk identification affects almost every indicator of success in pharmaceutical processes, from product quality, to yield, costs, timelines, safety and more. When organisations take a reactive approach to risk mitigation, it not only poses a safety risk, but also neglects a critical opportunity to improve the efficiency and effectiveness of their programme as a whole. In contrast, when organisations take a proactive approach, they can realise transformative advantages in their programme and mitigate setbacks down the line. ... Read more
At Sterling, our experience spanning the full product lifecycle provides us with a deep understanding of long-term project implications from the earliest stages of development. Closely collaborating across departments enables us to consider hazard evaluation, engineering requirements, solid form implications and others from the early stages of a project. In addition, we serve as true scientific partners to our customers, providing full transparency and offering continued guidance to maximise success in their projects’ early phases and beyond.Read less
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