The Development Pathway to a Sterile Drug Product IND
by Joe Page, Ph.D., President, Eurofins Advantar Laboratories
The sterile drug development pathway to an Investigational New Drug (IND) is best traveled with a partner who can guide you through the milestones. The route generally includes a determination of the physicochemical properties of the molecule. Based on these findings, a formulation is designed to stabilize the molecule. Method development, qualification, and characterization studies are then performed to validate the potency, purity, and identity of the drug product and its impurities. The staff at Eurofins Advantar has decades of experience guiding clients through these milestones.
An initial method, typically HPLC or UPLC, is needed for pre-formulation experiments with the drug substance. Project Directors, each with 15 to 30 years of development experience, and a laboratory equipped with 25 HPLCs and 10 UPLCs enable sensitive, high resolution methods to be quickly developed. It is essential to know the physical properties of the drug substance such as its pKa, pI, logP, MW, MP, and solubility. For a small molecule, the pKa can be determined in titration experiments, and for proteins or peptides, capillary isoelectric focusing (cIEF) can be used to determine the pI. For poorly soluble compounds, pH-solubility and pH-stability experiments are performed to determine the optimal pH where the molecule should be formulated. Screening of the molecule with a series of GRAS solvents will reveal co-solvents that may be needed to achieve target concentrations of the API. Additional physicochemical studies such as DSC and XRPD may be needed if a lyophilized formulation is needed for the molecule’s stability. These physical properties, along with the molecular structure, enable a formulation to be designed that achieves the clinical concentration requirements and guards against degradation reactions.
Achieving the targeted clinical concentration is often the first challenge in the formulation development as this concentration may approach the solubility limits of the API. For small molecules, this may require a specific pH range and the use of co-solvents. For proteins, an optimal pH range and ultrafiltration with stabilizing sugars may be needed. pH is controlled with parenterally acceptable buffers (acetate, citrate, phosphate, histidine, and Tris) at levels to provide buffering capacity over the shelf life of the drug. Many degradation pathways are pH dependent so this must be balanced with pH-concentration considerations. For example, protein deamidation can often be minimized by formulating the protein at neutral to low pH. Oxidation may be controlled by the use of antioxidants such as ascorbate, metabisulfite, methionine, or metal chelators. The rate of aggregation is often reduced by the use of polysorbates such and Tween 20 or Tween 80. Often the only defense against a hydrolysis labile molecule is to develop a lyophilized formulation. Multiple formulation candidates are designed and compounded based on above considerations and the clinical requirements. These formulations are screened in accelerated stability studies to select the most stable formulation.
The initial analytical methods are revised, optimized and qualified for the selected drug product formulation. The methods must achieve resolution of the known impurities and degradation products as determined in pre-formulation and formulation development. Orthogonal methods may be needed to achieve resolution of all impurities. The method needs a limit of quantitation of at least 0.1% for analysis of impurities. A collection of qualified methods are produced that cover: appearance, pH, potency, purity, impurities, particulate matter, sterility and endotoxins. Analysis of historical API or DP lots is often performed to ensure proposed specifications are in alignment with the stability of the molecule. Compatibility of the drug product with IV bags and line sets can be evaluated in “in-use” studies to ensure potency and stability of the API in the presence of these materials during administration. Impurity characterization with high resolution LCMS is often performed at this stage. The IND filing is supported with a formulation development report, qualified methods, validation reports, characterization and “in-use” studies.