Behind every good formulator is… well, are… a number of good analytical chemists. They play a critical role in everything from measuring solubility, potency, and dissolution to monitoring purity and stability. Every step in the formulation development process requires some sort of analysis. Enter, the analytical chemists. Below, we discuss some of the techniques and tools formulation services providers use to measure the success of formulation development efforts.
There is something of a gray area between preformulation and analytical services, but they are intertwined in early dosage form design. Preformulation involves extensive physical characterization of API and excipients. Techniques such as x-ray diffraction, differential scanning calorimetry and thermogravimetric analysis are frequently used and compared at this early stage of development for applications such as excipient compatibility, optimization of process parameters, detection of form impurities and crystal morphology of API. Solubility, a key parameter, can first be tested by visual inspection and later with more precise HPLC quantitation. Similarly, salt selection can be carried out “organic chemist-style” with small quantities of material in vials. As the selection narrows, choices must be verified and quantified with larger quantities and rigorous spectrometric and chromatographic measurements.
Excipient Compatibility is a Key Consideration for Pharma Formulations
Excipient compatibility is another key consideration and one that requires a range of important and time intensive analytics. Many excipients may be screened with the API. Short term and accelerated stability tests need to be carried out in order to gather data supporting the use of chosen excipients.
Typically, HPLC test methods already exist for API and the formulation services provider can use these as a starting point. However, methods must be optimized to give confident results with the mixtures of additives and excipients used in the formulation. Formal HPLC test method optimization requires not only an assessment of sensitivity, precision, and linearity but also spike-recovery experiments and demonstration of noninterference with additives and excipients. Forced degradation studies must be carried out to demonstrate a method as stability-indicating before use in formulation stability tests. Samples are subjected to stress conditions – heat, light, acid, base, and oxidation – until degradation products can be detected. Then the method is adjusted, as needed, to show noninterference between the active peak and impurities.
Stability Testing is of Paramount Importance
Stability testing is of paramount importance throughout the formulation development process. Early activities will include pH solubility and stability profiling of the API with arrayed samples tested using the HPLC test method at multiple short-term (hours to days) time points. During progression of formulation development, prototypes are tested with short-term (i.e. days to weeks), accelerated temperature and humidity stability studies.
Validation of analytical test methods for pharmaceutical products is codified by the ICH, as well as the FDA and USP. ICH Guidance Q2R1 describes principles for validation of specificity, linearity, range, accuracy, precision, detection and quantitation limits, robustness, and system suitability. Details for these parameters may vary depending upon the stage of development and other factors. In any case, as the selected formulation candidate(s) progress through process scale up and engineering batches, test methods are validated for compliance with GMPs and other regulations to support manufacturing and stability studies for clinical drug products.
The objective of this blog series has been to provide a birds-eye overview of formulation development services. The first part laid the groundwork for subsequent posts that covered preformulation, formulation development, and process scale up. This series concludes with the current post about required wraparound testing requirements.
Check out the first installment in this 4-part Pharma Formulation Blog Series, Solving a Problem.
Respect the Chemistry, the second installment in the Pharma Formulation Blog Series, contemplates API and physicochemical considerations.
The third blog in the Pharma Formulation series outlines Considerations for Scaling Up.
Our Unique Formulation Opportunities for Drug Manufacturers Whitepaper discusses drug formulation including novel drug delivery systems, the pros and cons of certain drug forms and the challenges of developing a NDDS.
Our featured blogger is Bob Plourde, Avomeen’s Senior Director of Business Development for the Western USA. Bob has been involved in many aspects of the biopharmaceutical industry for more than 20 years, including carrying out drug discovery and development, roles in project management, and most recently serving in business development roles for organizations that provide solutions for biopharmaceutical research and development.