Reliable and reproducible analytical methods are an essential part of the pharmaceutical drug development process. Applied throughout the development life-cycle from pre-clinical to commercial release, it is vital to approach method development in a robust but yet pragmatic manner in order to lay firm foundations and minimise the time to market.
Pharmaceutical Method Development
Keep method development simple
A ‘keep it simple’ approach is always advisable to maintain future robustness of the method and to encompass any changes that may occur with the dose and/or the type of presentation. For example, when an API assay and related substances method is being optimised to reduce the run time, it might seem sensible to have as short a run time as possible. However, removing too many portions of the redundant baseline leaves far less scope for synergy in the future: if/when the active pharmaceutical ingredient (API) is formulated into drug product (DP), the presence of multiple excipients could pose issues if the API method is refined too much.
So, incorporating flexibility/synergy in the analytical method will offer multiple cost savings throughout the drug development lifecycle, including lower overall costs for development and QC release (where a single method could be employed for both API and product), both of which will also reduce analyst training needs.
Sample preparation is crucial, and often underestimated, in building a platform for the overall method development process.
When preparing a sample solution, a decision needs to be made with regards to the number of dosage units to be incorporated. This is driven by the need to obtain a suitable sample solution concentration (within the solubility limits of the active/impurities), optimisation of analysis conditions to obtain a peak that is within linear range of the detector and to provide adequate sensitivity of related substances. It is also key that sufficient units are taken to allow for a representative sample.
Pharmaceutical Stability Characteristics
A method should not only be fit for successful validation and transfer, but also be able to robustly measure key stability characteristics to support API/DP shelf-life evaluation. Therefore, there are fundamental criteria that should be considered when carrying out this evaluation as this will essentially impact upon the overall robustness of the method.
All relevant factors have to be balanced with the need to take a representative number of dosage units: this is essential to achieving a robust method as it will reduce the impact of any fill weight bias that may skew assay results.
Again, simple is best. Where possible, sample preparations should avoid any lengthy dilution steps in order to minimise errors, maximise recovery and save analytical time.
Throughout the development of a method, all findings should be continually evaluated in order to identify which parameters are particularly susceptible to minor adjustment, and ensure that these are experimentally assessed prior to moving into the validation phase. Typically, areas such as linearity, extraction efficiency and method repeatability should all be well characterised ahead of planning the validation in order to reduce any risk to the future robustness of the method (and any significant unwanted time and cost).
Scrutiny of the above should also enable a validation protocol to be produced that is far more representative of the specific API/DP.
Of course, the method needs to be validated, but that is a topic worthy of longer discussion. Therefore, no further detail will be given here, other than to note that the requirements of validation need to be borne in mind throughout the method development process to ensure that validation is possible and meets the requirements of GMP compliance.
In summary, method development requires a robust and pragmatic approach. With the right strategy, an experienced team will be able to develop a solid method that will ultimately support a successful DP filing, accelerate (rather than delay) the time to market, and also prove to be reliable and robust in its future use.
To find out more about RSSL's method development and validation services please contact RSSL Customer services on +44(0)118 981 4076.