Stability protocols standard

Annual reports should include new or updated stability data generated in accordance with the approved stability protocol. These data may include accelerated and long-term studies for each product to satisfy the standard stability commitment made in the original or supplemental application, including the annual batch or batches, and to support postapproval changes. The data should be presented in an organized, comprehensive, and cumulative format. 

Potency studies should be performed at appropriate intervals as defined in the stability protocol, and the results should be reported in units of biological activity calibrated, whenever possible, against nationally or internationally recognized standards. Where no national or international reference standards exist, the assay results may be reported in in-house derived units using a characterized reference material. 

Impurity analysis/identification/synthesis Reference standard characterization Change control documentation Stability protocols... 

To ensure consistency and quality of the stability program, many companies institute standard stability protocols. These are pre-approved protocols based on the phase of development for certain dosage forms. 

A study protocol will be drafted by the appropriate organizational unit and must be reviewed and approved by the quality unit. Therefore, it would be time-saving if a company could establish a set of standard stability protocols. These standard protocols should include any specifications, standards, sampling plans, test procedures, and the time points needed for stability studies at different stages of development. 

Many procedures for the formation of carboxylic acid amides are known in the literature. The most widely practiced method employs carboxylic acid chlorides as the electrophiles which react with the amine in the presence of an acid scavenger. Despite its wide scope, this protocol suffers from several drawbacks. Most notable are the limited stability of many acid chlorides and the need for hazardous reagents for their preparation (thionyl chloride, oxalyl chloride, phosgene etc.) which release corrosive and volatile by-products. Moreover, almost any other functional group in either reaction partner needs to be protected to ensure chemoselective amide formation.2 The procedure outlined above presents a convenient and catalytic alternative to this standard protocol. 

Using standard references and protocol, we find the three reactions are respectively endothermic by ca 2, 8 and 6 kJmol-1, or ca 2, 4 and 3 kJmol-1 once one remembers to divide by 2 the last two numbers because the allene is dialkylated. So doing, from equations 10 and 11 we find an average ca 3 kJmol-1 (per alkyl group) lessened stability for alkylated allenes than the correspondingly alkylated alkenes. This is a small difference that fits most naturally in the study of substituted cumulenes such as ketenes and ketenimines, i.e. not in this chapter. But it is also a guideline for the understanding of polyenes with more cumulated double bonds. 

The thermolytic preparation by De Shong et al. (74) of azomethine ylides from aziridines and their intermolecular reactions are the first examples of singly stabilized ylides of this type. However, the protocol has been further extended to include intramolecular processes. Aziridines tethered to both activated and unactivated alkenes were subjected to flash vacuum thermolysis generating cycloadducts in moderate-to-excellent yields. While previously singly activated alkenes had furnished low material yields via an intermolecular process, the intramolecular analogue represents a major improvement. Typically, treatment of 222 under standard conditions led to the formation of 223 in 80% yield as a single cis isomer. Similarly, the cis precursor furnished adduct 224 in 52% yield, although as a 1 1 diastereomeric mixture (Scheme 3.77). 

The first antibody-catalyzed asymmetric 1,3-dipolar cycloaddition was reported recently by Janda and co-workers (382). The reaction of the relatively stable nitrile oxide 280 and dimethyl acrylamide 281 was catalyzed by antibody 29G12 having turnover numbers >50, and the product 282 was obtained in up to >98% ee (Scheme 12.89). The antibody 29G12 was formed for hapten 283 and coupled to a carrier protein by standard protocols. The hapten 283 contains no chiral center and therefore the immune system elicited a stereochemical environment capable of stabilizing the enantiomeric transition state leading to 282. 

The so-called storage stability test is a standard test that is used across many different fields—e.g., the pharmaceutical, cosmetic, and food industries. The test is popular because it yields precise information about the long-term shelf life of emulsions. In this test, emulsions are stored under conditions that are applicable to those encountered in the actual production/consumption situation. It should be noted that the presented test protocol is time consuming and requires sampling over an extended period of time. In the... 

Nucera E, Schiavino D, D Ambrosio C, Stabile A, Rumi C, Gasbarrini G, Patriarca G Immunological aspects of oral desensitization in food allergy. Dig Dis Sci 2000 45 637-641. Patriarca G, Schiavino D, Nucera E, Schinco G, Milani A, Gasbarrini GB, et al Food allergy in children Results of a standardized protocol for oral desensitization. Hepatogastroenterology 1998 45/19 52-58. 

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