The Effect of a Source Change for an Active Pharmaceutical Ingredient (API) or Excipient on the Finished Drug Product

Abstract

The global cost of health care is increasing year after year, and one of the ways governments and health care providers are looking to reduce cost is by reducing the cost of drug products. The generic industry is under tremendous pressure to remain competitive in the market place by reducing the cost of their product, with the main cost factor being the active pharmaceutical ingredient and some of the excipients used in the manufacture of the drug product. These companies are expected to follow the required guidelines set out by the international regulatory authorities and more specifically of the countries they intent to market their product in if they are planning to change the source of the material. These regulatory guidelines are general in nature with a focus on safety and efficacy and the evaluation of an alternate source of material by pharmaceutical companies varies greatly from company to company. The evaluation is conducted mainly on the basis of chemical and physical data from the Certificate of Analysis comparing the current and alternate source to determine equivalency. Differences in process and critical processing parameters of the material can have significant impact on the behavior of the chemical, which may not be detectable through evaluation of the Certificates of Analysis. It is, therefore, critical to study properties that are not captured on the Certificate of Analysis, such as polymorphism, melting point, solubility, particle shape, packing tendencies among other aspects of the material that are important for the performance of the material in the drug product formulation and manufacturing process. The differences in these properties can have significant impact on the unit operations during the manufacturing process as well as the critical quality attributes and the stability of the drug product. The evaluation is conducted by utilizing various tools of analytical and process testing to determine the physical performance, physicochemical evaluation, chemical evaluation and functional performance evaluation for the active pharmaceutical ingredient and excipient. The evaluation of the Certificate of Analysis will also need to be more in depth, and go beyond the alternate source meeting the specifications as there can be significant differences with the results obtained even though they meet specification. It is important to identify these differences earlier in the evaluation stage and to assess the impact, if any, on the manufacturing process and the drug product prior to introducing the change. This study was conducted with active pharmaceutical ingredients selected based on the processing unit operations, such as direct compression process (metformin HCl), dry compaction (gabapentin), and hot-melt process (fenofibrate). The selection of the excipients was based on their functional properties, such as binders (copovidone NF/EP) and super disintegrant (croscarmellose Sodium NF/EP), allowing for evaluation with respect to differences in functionality if any, from the different sources. Additionally, the copovidone NF/EP is the binder in the gabapentin USP tablet formulation while the croscarmellose Sodium NF/EP is the super disintegrant in the fenofibrate EP/BP tablet formulation. An example of this challenge is that the evaluation of Certificate of Analysis for the materials supplied from two companies and two sources revealed differences in tests required for the two materials and a significant difference in some of the results obtained; however, both materials met their respective Certificate of Analysis specifications. Several tests beyond the Certificate of Analysis were performed and significant differences were also observed in many of these as well. The two sources were evaluated with respect to the compression process and the alternate source of material did show significant challenges during the tablet compression process and did not meet some of the in-process critical quality attributes test. The in-vitro performance for both sources were comparable, however, the recommendation will be not to proceed with the alternate source. There were many differences between the sources of all the materials evaluated including differences in particle size, morphology, moisture, manufacturing process and residual solvents among others. The impact on the manufacturing unit operation varies from no impact for the fenofibrate EP/BP materials, to not meeting the critical quality attributes for metformin HCl tablets with the new source of the active pharmaceutical ingredients. This study indicates the importance of a systematic evaluation of a material from an alternate source with respect to the performance of the manufacturing process, drug product, and their critical quality attributes; understanding the impact of these changes to the material and having the ability to correlate these to potential issues with the manufacturing process and drug product critical quality attributes prior to introducing an alternate source of material is critical.