Bulk Drug Stability

In addition to the general physiochemical evaluation of the insoluble compounds, there are certain considerations that are product speciLc. These are brieLy discussed below. 

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During bulk drug stability and preformulation testing, preliminary formulations and processes are developed that are first stability tested on a shortterm, accelerated basis. Drug product intended for clinical use after IND approval must be stability... 

GMP bulk drug synthesis, including stability studies... 

The stability of material stored at elevated temperatures and increased relative humidities was also evaluated. No changes were evident after 3 months of storage at 80°C, or after 3 months of storage at 90% of relative humidity. When kept for 3 months under 2000 lux or 3 days under UV light, the bulk drug substance was unchanged and no degradants were observed. 

The stability... under the conditions of administration will in most cases be the stability of the article/carrier mixtures determined under 58.113(a)(2). If a drug is administered as a powder (e.g., by capsule), the stabihty of the bulk drug determined under 58,105(b) will be reported. 

Farmer, S., anderson, R, Burns, P. K., and Velagaleti, R. (2002, May), Forced degradation of ibuprofen in bulk drug and tablets and determination of specificity, selectivity, and the stability-indicating nature of the USP ibuprofen assay method, Pharm. Technol., 28-42. 

The application (or Type II DMF) should include a detailed description of the complete container closure system for the bulk drug substance as well as a description of the specific container, closure, all liners, inner seal, and desiccant (if any), and a description of the composition of each component. A reference to the appropriate indirect food additive regulation is typically considered sufficient to establish the safety of the materials of construction. The tests, methods, and criteria for the acceptance and release of each packaging component should be provided. Stability studies to establish a retest period for bulk drug substance in the proposed container closure system should be conducted with fillers or desiccant packs in place (if used). Smaller versions that simulate the actual container closure system may be used. 

A container closure system for the transportation of bulk drug products to contract packagers should be described in the application. The container closure system should be adequate to protect the dosage form, be constructed with materials that are compatible with product being stored, and be safe for the intended use. The protective properties of the shipping container are verified by the practice of including annual batches of the packaged product in postapproval stability studies. 

The development report has two main sections, one that addresses the dosage form and one that deals with the bulk drug substance The product development scientist compiles the experimental evidence to demonstrate bioequivalency for the first clinical trial lot through those lots that will be used for launch. The report further includes a description of the current process along with a description of the chemical/phys-ical characteristics, purity, related substances, specifications, and stability of the drug substance. 

Description of the bulk drug substance, including structural and molecular formula, process impurities or degradants, specifications, rationale for specifications, safety, approved supplier(s), test methods, validation, and stability. Include basic information on synthesis or derivation of the drug substance, or if applicable, reference supplier drug master file. 

For both the drug substance (bulk drug) and drug product (dosage form) stability information from accelerated and long-term testing should be provided on at least three batches with a minimum of 12 months duration at the time of submission. 

P. C. Dabas, H. Erguven, M. C. Vescina, and C. N. Carducci, Stability study of ethyl loflazepate in bulk drug, solution and dosage form by LC, J. Pharm. Biomed. Anal., 70 241 (1992). 

It is prudent to evaluate impurity peaks observed in a supplier s bulk substance and compare them with those observed in the drug product. The extent that the peaks differ may determine the need to obtain further information, including toxicity. Samples of impurities/degradation products methods should be appropriately validated by the ANDA sponsor for their sensitivities and specificities. It also is recommended that the sponsor of an ANDA set up and maintain a stability program for the bulk drug substance. 

Regarding laboratory controls, a review of laboratory notebooks and chromatograms should be done to check the reliability and authenticity of the supporting data in the methods development and testing of the clinical, bio, and stability batches. Reference standards used should be certified as standards. The FDA expects that, for bulk substances, the suitability of reference standards should be more extensive than that of bulk drug substance specifications. A comparison of analytical methods and specifications for lots of drug substance used in clinical batches and biobatches should be performed to see if any deletions or revisions to any specifications occurred. 

The most logical way to ensure adequate light stability during the manufacturing and packaging process is to control the levels of iron present in the excipients in the formulation. Currently, iron content is controlled only in the sodium chloride that is used in the formulation (as <2ppm). Iron is not controlled in citric acid, sodium citrate, and the bulk drug substance, nor in water. The addition of iron specification controls for the solid components in the formulation are analyzed in Table 9. 

As with the bulk drug substance, spedfications for both enantiopure and racemic chiral drug products should include both a stereochemically spedfic identity test and stereochemically selective assay method. The analytical method to be used should not be arbitrarily chosen to be the same as for the bulk drug but should be chosen on the basis of the composition, method of manufacture, and stability characteristics of the formulation. 

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