Formulation development biopharmaceutics

Frokjaer, S. 2000. Pharmaceutical Formulation Development of Peptides and Proteins. Taylor and Francis. Grindley, J. and Ogden, J. 2000. Understanding Biopharmaceuticals. Manufacturing and Regulatory Issues. Interpharm Press. 

Key operating parameters that may change (or be optimized) throughout a product s development and approval cycle are dissolution sampling time points and dissolution limits or specifications by which the dissolution results should be evaluated. The results generated from the dissolution test need to be evaluated and interpreted based on the intended purpose of the test. If the test is used for batch-to-batch control, the results should be evaluated in regard to the established limits or specification value. If the test is being utilized as a characterization test (i.e., biopharmaceutical evaluations, formulation development studies, etc.) the results are usually evaluated by profile comparisons. 

For an extended-release dosage form, at least three test time points are chosen to characterize the in vitro drug-release profile for the routine batch-to-batch quality control for approved products. Additional sampling times may be required for formulation development studies, biopharmaceutical evaluations, and drug approval purposes. An early time... 

The MS techniques described previously for characterization of the final recombinant protein product can be applied at all stages during process development. MS might be used upstream to define clone selection, processing format, and purification steps, and downstream to characterize the final product, ascertain lotto-lot reproducibility, determine stability, and define the formulation of biopharmaceutical molecules. Presented here are some examples found either in the literature or from our own experience in which MS has been found to be a useful or necessary tool. Potential limitations of MS methods are discussed, and when appropriate, other analytical methods are mentioned that can be alternatives to MS and are also efficient tools for biopharmaceutical development. 

Abrahamsson, B. and Ungell, A.L., Biopharmaceutical support in formulation development, in Pharmaceutical Preformulation and Formulation, Gibson, M., Ed., CRC Press, Boca Raton, FL. 

Westlake, W.J. (1988) Bioavailability and bioequivalence of pharmaceutical formulations. In Biopharmaceutical Statistics for Drug Development, (ed. K.E. Peace), pp. 329-352. Marcel Dekker, New York. 

The seemingly endless variation of polypeptides makes them interesting as potential therapeutics, but it also makes them a challenge to develop into products. Each protein is unique, and just as variation from protein to protein affects biologic production and purification, so it is central to the formulation development process. Methods developed for one biopharmaceutical are not always directly applicable to others. Similarly, it is quite likely that a formulation developed for one biopharmaceutical may not provide the same level of stability for a different biopharmaceutical. 

A Clinical Summary is to start with a subsection on Biopharmaceutical Studies, and Associated Analytical and Bioanalytical Chemistry Methods conducted during the clinical development of a drug candidate. The background of the formulation development process is to be briefly provided and is to include information on in vitro and in vivo dosage form performance and the general approach and rationale for developing the bioavailability (BA), comparative BA, bioequivalence (BE), and in vitro dissolution profile database. Also to be included is a summary of the analytical and bioanalytical chemistry methods and the validation characteristics of these methods. 

The biopharmaceutical information gathered in the candidate drug selection process regarding the characteristics of the drug molecule (e.g., dissolution, solubility, stability in fluids at the site of administration, enzymatic stability, membrane transport and bioavailability) is also very useful as input to the subsequent formulation development. This information is important, for example,... 

For pharmaceutical development, risk may be associated with the technical challenges anticipated in developing a novel or complex drug delivery system or manufacturing process. Information from early preformulation and biopharmaceutics studies should indicate the potential problems for drug delivery, formulation development and manufacture. 

In order to achieve the potential clinical benefits that can be provided by a formulation, as exemplified in Table 7.1, biopharmaceutical input is needed from the start of preformulation, through formulation development, to documentation for regulatory applications. The main objective is to obtain and verify desirable drug delivery properties for a pharmaceutical formulation. The key activities are as follows ... 

Identification of the relevant biopharmaceutical targets and hurdles in formulation development... 

Definition of test methods/study designs needed to obtain the biopharmaceutical targets in the formulation development and correct interpretation of the study results obtained... 

The present chapter is limited to presentations and uses of different biopharmaceutical test methods in formulation development, such as... 

---