In-use stability testing

Where antioxidants or antimicrobial preservatives are used, the finished product release specification will need to include identification tests and assays for these two types of excipient. The shelf life specification should also include a specification for assay for antimicrobial preservatives. Stability data will be required for both antioxidants and antimicrobial preservatives in the finished product, and in addition the preservative efficacy of the formulated product should be examined over its shelf life and by means of appropriate in-use stability tests. Preservative efficacy data should also be presented at the lower limit of the preservative assay. 

There are three documents that give guidance on the design and conduct of in-use stability tests the EMEA/CVMP/127/95 final (adopted March 1996), CPMP/QWP/2570/98 (a concept paper adopted in November 1998) and CPMP/QWP/2934/99 draft (released for comment in December 1999). The studies undertaken may be discussed in the development pharmaceutics or the stability section of the dossier. 

The application should state the rationale for the design of the in-use stability tests performed. The procedures used should be fully validated. One key factor is that the test should simulate the use of the product as far as practicable. This should include any reconstitution or dilution prior to use. Aliquots should be removed in an appropriate manner following, as far as possible, the usage pattern that will be encountered in practice. Physical (color, clarity, closure integrity, particulate matter, and particulates/particle size), chemical (assays for active ingredient, antioxidants and... 

EMEA/CVMP/127/95 final Note for guidance— In-use stability testing of veterinary medicinal products (March 1996)... 

CPMP/QWP/2570/98 Concept paper on the development of a CPMP note for guidance on in-use stability testing of non-sterile human medicinal products (November 1998) CPMP/QWP/2934/99 draft Note for guidance on in-use stability testing of human medicinal products (released for comment December 1999) CPMP/QWP/598/99 draft Note for guidance on process validation (released for comment September 1999, also issued under CVMP reference EMEA/CVMP/598/99 draft) CPMP/QWP/486/95 Note for guidance on manufacture of the finished dosage form (reissued April 1996)... 

EMEA - March 2001 Note for Guidance on In-Use Stability Testing of Human Medicinal Products The analytical procedures used in the [stability] study should be described and fuUy validated. Stability-indicating assays should be employed... 

EMEA CPMP (2001) Note for guidance on in-use stability testing of human medicinal products CPMP/QWP/2934/99. 

Note A PTX-4 compn, prepd by the addition of Haleite to 30/70 Pentolite, also offered promise, but because of borderline stability in accelerated stability tests, it was decided that PTX-4 must be proven by long term storage to be acceptable for use in standard ammo Refs 1) W.R. Tomlinson, Properties of Ternary Mixtures of High Explosives PATR 1414 (1944) 2) A.J. Phillips, The Manufacture of... 

The purpose of in-use stability studies is to establish the period for which a product intended to be used on more than one occasion may be used after reconstitution or dilution or the withdrawal of the first dose from the container without adversely affecting the integrity of the product and with the product retaining acceptable quality characteristics. This type of test can be applied to any multiple use product (e.g., sterile products in multiple-use containers, powders or granules including those used to produce oral solutions or suspensions) but is likely to be of particular importance in the case of products that are manufactured with an inert headspace gas, for products containing antioxidants to protect an active ingredient that is liable to oxidative decomposition, and for products that contain a volatile antimicrobial preservative. 

Duddu S, Weller K. Importance of glass transition temperature in accelerated stability testing of amorphous solids case study using a lyophilized aspirin formulation. J Pharm Sci 1996 85 345-347. 

In this stability test, which was proposed by Hansen in 1925, 8 samples of the material to be tested are heated up to 110 °C (230°F). Every hour one of the, samples is taken out of the oven, extracted with C02-free water, and the pH of the filtrate determined. Since the decomposition of propellants based on nitrates is usually accompanied by the liberation of C02, which interferes with the potentio-metric determination, the results obtained are unsatisfactory, and the test is now hardly ever used. 

A reference to the use of "Quinine actinometry as a method for calibrating ultraviolet radiation intensity in light stability testing of pharmaceuticals was added."... 

Piechocki J, Wolters R. Use of actinometry in light stability testing. Pharm Tech 1993 6 46-52. 

Brook et a . [ 16] summarized tlie widely-used stability tests in Table 122 (see also Vol. HI, p. 558). 

The specifications of the packaging of the product are identical to those used in the stability tests carried out by the licenser. 

Chromatographic methods are specific. They thus find a wide range of use especially in the field of pharmacy, where in particular stability tests require the separation of decomposition products. Grimm and Schepky 58) describe the in situ evaluation of thin-layer chromatograms as one of the most important methods of analysis in stability tests. 

In the opinion of this author, isothermal microcalorimetry can be useful for the studies of biological systems and in chemical stability testing, whereas it is certainly useful in solid-state characterization of materials. 

It is important to note that the alkenes produced in reaction (11.1) can eventually form particulates in the lubricant, a critical criterion used in oxidative stability tests to determine the capabilities of turbine lubricants. This is demonstrated by the oxidative stability test [7] used in the Defence Standards for UK MoD gas turbine lubricant grades OX-7 [8] and OX-26 [9]. 

---