Impurity profile changes

Changes to the synthesis or manufacture process that may affect the impurity profile... 

Figure 1.8. Schematic frequency distributions for some independent (reaction input or control) resp. dependent (reaction output) variables to show how non-Gaussian distributions can obtain for a large population of reactions (i.e., all batches of one product in 5 years), while approximate normal distributions are found for repeat measurements on one single batch. For example, the gray areas correspond to the process parameters for a given run, while the histograms give the distribution of repeat determinations on one (several) sample(s) from this run. Because of the huge costs associated with individual production batches, the number of data points measured under closely controlled conditions, i.e., validation runs, is miniscule. Distributions must be estimated from historical data, which typically suffers from ever-changing parameter combinations, such as reagent batches, operators, impurity profiles, etc.

During the course of chemical development, impurity profiles in drug substances may change due to changes in synthetic route and changes in the size of the batch. ICH guidelines for Impurities in New Drug Substances (ICH Q3A), require that impurity test results for... 

Similarly, impurity profiles may change when the formnlation is modified or a scale-up of a specific formulation is made. Pharmacentical formnlations are a complex physiochemical system that may resnlt in impnrities due to reactions between API and pharmacentical excipients and/or packaging materials. In some cases, degradants that were generated by multiple-step degradation pathways can still react with the API leading to the formation of degradants that can be difficult to identify. 

Various international pharmacopoeias help assure the quality of drugs worldwide. These pharmacopoeias constantly review and revise their monographs. A different impurity profile can be anticipated if a drug s production process is changed this results in the development of new analytical methods that need to be incorporated in the pharmacopoeias. In earlier editions, color reactions were performed for identification and purity evaluation purposes. 

In our development studies, Endeavor (5 mL) and Buchi (IL) reactor systems were used to screen catalysts and to evaluate the impurity profile under various process conditions. Elydrogenation kinetic studies were carried out using a 100 mL EZ-seal autoclave with an automatic data acquisition system to monitor the hydrogen uptake and to collect samples for HPLC analysis. Standard conditions of 5 g of aldehyde in 25 mL ethyl acetate and 25 mL methanol with 0.5 g of 5%Pd/C Engelhard Escat 142 were used in this investigation. For the Schiff s base formation and subsequent hydrogenation, inline FTTR was used to follow the kinetics of the Schiff s base formation under different conditions. Tables 1 and 2 show the changes in the substrate concentration under different conditions. Both experiments were carried without any limitations of gas-liquid mass transfer. 

A change in the excipient composition may change the product impurity profile. This change may make the method deficient in its specificity for the assay or impurity tests and may require redevelopment and revalidation. 

Changes in the synthesis or manufacture of the drug substance that may affect its impurity profile and/or the physical, chemical, or biological properties. 

Some excipients contain a certain amount of amorphous form such as spray-dried lactose,27 and others are hygroscopic, such as microcrystalline cellulose.28 These excipients will adsorb water, which causes a change in the micro-environment of the formulation. If the drug substance is moisture-sensitive, degradation may occur quickly. Therefore, consider both drug-excipient compatibility and excipient impurity profile in selecting excipients for low-dose drug products. 

For FCNs, specifications serve to ensure that the substance marketed by the manufacturer/supplier identified in the notification is the same as that subjected to the safety evaluation when the FCN became effective. Several specifications may be given in an FCN. Specifications are applicable only to the manufacturer/supplier identified in the FCN and are well known to them. Thus, they are generally not included in FCN letters. As noted above, the notifier is held to the specifications and use conditions identified in the FCN. Accordingly, changes in the manufacturing process that result in new impurity profiles may require communication with the FDA and, if warranted, new FCN submissions. 

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