PHARMACEUTICALS
Analytical: Ensuring method suitability & control
In parallel with chemical process development, the analytical methods used to support manufacturing must undergo the same level of careful evaluation. It is essential that the methods used are able to detect all impurities and degradants present not just in the process intermediates and API but also in any raw material used in the process.
For the API, intermediates and key raw materials, bespoke methods usually need to be developed. For more general materials, such as solvents or reagents, standard compendial methods( for example, those listed in the USP) may be acceptable. However, these methods must still be assessed to confirm they are suitable for their intended use in the process.
The suitability of an analytical method will depend on the sensitivity required, which may be contingent upon how the raw material is used in the manufacturing process. Whilst a solvent may be commercially available at ≥99 % purity by GC, as it is typically used in a large excess compared to the starting material, the remaining < 1 % of impurities would be present at a much higher level in the overall reaction mixture and the product quality may be compromised.
The type of impurity also matters. For instance, N-methylpyrrolidone may contain trace amounts of methylamine, a reactive species that can interfere with certain reactions due to its nucleophilic and basic nature. To ensure reliability, all analytical methods used in the process must be validated according to ICH Q2 guidelines. This confirms that each method is accurate, precise, specific and suitable for its intended purpose. 1
Specifications: Establishing performance limits
Once the manufacturing process is well understood and the analytical methods have been proven suitable, specifications for process intermediates, in-process controls and the final API can be established. These specifications define the acceptable limits for purity, potency and other CQAs, ensuring that every batch meets consistent standards. The limits should be based on historical batch data, which provides evidence of typical process performance and is further justified through fate and purge studies that demonstrate how impurities are formed, transformed or removed throughout the process. This combination of practical experience and scientific evidence ensures that each specification is both realistic and defensible to regulators.
To provide further confidence that these specifications are appropriate, it is prudent to perform the optimised process on the scale and using the equipment planned for future manufacture. The success of this commissioning( or engineering) batch should help assuage any lingering doubts. However, if any issues do arise, it also allows for minor modifications to be made before the manufacturing process and quality criteria are finalised.
Process validation
With the final manufacturing process in hand, accompanied by effective analytical testing and well-defined specifications, the process is now ready for the final phase of evaluation: validation.
For this, a protocol is prepared that specifies how each step of the process will be performed and the key criteria to be measured. Although committing to such a rigid set of parameters and outcomes may seem daunting, the success of the commissioning batch and
Reference: 1: For a more detailed discussion of analytical method validation, see A Practical Guide to Forced Degradation and Stability Studies for Drug Substances. https:// onyxipca. com / news / a-practical-guide-to-forced-degradation-and-stability-studies-for-drug-substances /
the underlying attention to detail during process development and optimisation help set a solid foundation for success.
Each batch of this is campaign rigorously reviewed both during production by QA and, upon completion, by the relevant authority as part of a regulatory submission. The focus of both parties is to confirm that all batches followed the stipulated process and fulfilled all of the predefined quality requirements.
This confirms that the process is under control and capable of reproducible commercial manufacturing. Once validation is complete, continued process verification is typically performed with trend analysis used to identify problems early and ensure the process stays under control.
PV marks the point where science, control and experience converge. While preparing a manufacturing process for commercial production can be intimidating, a systematic and diligent approach across multiple disciplines can provide the necessary support for an API in its final steps towards its ultimate therapeutic goal. ●
Rebecca Matters
PROCESS DEVELOPMENT TEAM LEADER
ONYX SCIENTIFIC k + 44 191 516 6516 j www. onyxipca. com
22 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981