Synthetic Chemistry & GMP Bulk Production
Production of bulk drug begins with an evaluation of the available synthetic route and re-synthesis of small batches. The identity and purity of these small batches establishes the expected purity criteria for subsequent scale-up processes. In some cases, the isolation of a natural product is performed, for use as the bulk drug substance or as a semi-synthetic intermediate. The process is scaled up to medium size batches and final purification methods are established with the goal to deliver a material suitable for IND-directed toxicology and possibly Phase I clinical trials; this usually means an overall purity of 97% or greater with major impurities at a level of less than 1%. Review of the purity standards and ultimate release of bulk drug are performed by the Quality Control Committee of PRB. These bulk drug materials are routinely prepared under GMP conditions and the synthetic procedures are optimized for any further scale-up. Additional quantities of bulk drug (in quantities up to kilogram amounts) are prepared as needed to support ongoing clinical studies.
Studies related to analytical development are initiated as potential clinical candidates are selected. The elucidation of the molecular structure, including determination of stereochemistry where applicable, is performed using a variety of instrumental techniques, e.g., NMR, MS, IR, UV, DSC, and optical rotation. Specific methods for quantitation, such as HPLC, CE or GLC, are developed for the assessment of potency and impurity profiles. These analytical methods also provide the basis of related assays used in drug product production, stability, and GLP studies. They are refined and validated as the drug candidates progress toward IND filing. All major batches of bulk drug are analyzed and the results are reviewed by the Quality Control Committee prior to release. Acceptance specifications for each active pharmaceutical ingredient (API) are established to provide assurance for the quality and consistency of the material for use in clinical product. Stability profiles of the APIs are also developed, in accordance with ICH and FDA Guidelines.
The analytical profiles of NCI's active pharmaceutical ingredients, including physico-chemical data and validated methods, are compiled. This information is available in the NCI Investigational Drug: Chemical Information
Development of a suitable formulation is central to the mission of PRB. Since most of the antineoplastic agents are fairly potent and often accompanied by unpleasant side effects, the formulations are kept as simple as possible to minimize any vehicle related discomfort to the patients.
Preformulation work begins as soon as sufficient quantity of bulk material becomes available. In the preformulation stage, every compound selected for clinical development undergoes basic physico-chemical characterization. This includes: determination of pH solubility profile, pH stability profile, light and oxygen sensitivity studies, pKa determination, solubility profile in various water miscible solvents, crystallinity, partition coefficient, and others.
Once a potential formulation is identified, a small batch is produced by the formulation development contractor and it is placed on accelerated stability protocol. If the data indicate that the formulation is stable, then decision is made to proceed with manufacture of the clinical product.
Clinical Dosage Form Manufacturing
All the information generated at the preformulation/formulation development stage is useful at this stage along with analytical reports and validation packages of the bulk drug. After producing one or more pilot batches to establish the manufacturing procedure, a master batch record is written. All subsequent batches are manufactured according to the master batch record and the product is subjected to QC testing before it is released for packaging and labeling. After the batch is labeled and packaged, the batch record and quality control information is reviewed and approved by the manufacturer's QC/QA departments. The batch is then shipped to the NCI clinical repository and is placed under quarantine until PRB Quality Control Committee releases it for clinical use. The batch is then put on active inventory and distributed for clinical use by the Pharmaceutical Management Branch of CTEP. Required number of dosage units are randomly selected and placed on shelf-life assessment program according to ICH/FDA Guidelines.
A Pharmaceutical Data Sheet containing information on composition, how supplied, storage and stability, and solution preparation (if applicable) is prepared for each productand included in the Clinical Brochure. These data sheets are also published in the NCI Investigational Drug: Pharmaceutical Data.