Release testing

An HPLC method for the estimation of potency and determination of degradation products is an integral part of release testing. The analytical method should be stability indicating and capable of separating the active ingredient peak from degradation product, process impurity, and excipient-related peaks (Fig. 1). 

In the analytical procedure, an accurately measured aliquot of the product is diluted Avith a diluent (normally the mobile phase) and the resulting sample solution is injected into the HPLC. Because the majority of injectable pharmaceuticals are clear solutions, typically a simple dilution step is all that is needed for sample preparation. However, if the parenteral product is an emulsion or a suspension, appropriate steps must be taken to dissolve the product to achieve a clear solution (ultrasonication, filtration, etc.). For the assay procedure, the sample concentration chosen should be such that the peak areas obtained from multiple injections from the same sample are reproducible with minimum variance ( 2% relative standard deviation). Peak shape and retention time also play important roles in the precision of the assay. A tailing factor less than 1.5 and a capacity factor less than 10 for the active peak are generally required for a good analytical method. A reference standard solution having the same concentration and using the same diluent as the sample solution is prepared. 

FIGURE I HPLC chromatogram of midazolam hydrochloride injection. (Benzyl alcohol and benzaldehyde are excipient-related peaks desfluoromidazolam is an In-process impurity peak.) 

Metabisulfite analysis can be performed by oxidation with a measured volume of 0.1 N iodine in acid solution and determination of excess of iodine by titration with sodium thiosulfate. The metabisulfite titration can be performed manually using a starch indicator or potentiometrically using an autotitrator. 

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The Ohio State University (OSU) calorimeter (12) differs from the Cone calorimeter ia that it is a tme adiabatic instmment which measures heat released dufing burning of polymers by measurement of the temperature of the exhaust gases. This test has been adopted by the Federal Aeronautics Administration (FAA) to test total and peak heat release of materials used ia the iateriors of commercial aircraft. The other principal heat release test ia use is the Factory Mutual flammabiHty apparatus (13,14). Unlike the Cone or OSU calorimeters this test allows the measurement of flame spread as weU as heat release and smoke. A unique feature is that it uses oxygen concentrations higher than ambient to simulate back radiation from the flames of a large-scale fire. 

Extraction tests are used primarily in Japan and Europe, a release test is used in the United States, and standard tests have been compared based on the sources of formaldehyde present in a finished fabric (76,78—80). Finished fabric may contain free formaldehyde, or formaldehyde released from unreacted /V-methy1o1 moieties. 

Linney (1990) summarized the liquid hydrogen release tests performed by A. D. Little Inc. in 1958, by Lockheed in 1956-1957, and by NASA in 1980. Both high- and low-pressure releases were studied. None of the tests resulted in a blast-producing explosion. 

For an example of a control chart see Fig. 1.31 and Sections 4.1 and 4.8. Control charts have a grave weakness the number of available data points must be relatively high in order to be able to claim statistical control . As is often the case in this age of increasingly shorter product life cyeles, decisions will have to be made on the basis of a few batch release measurements the link between them and the more numerous in-process controls is not necessarily straight-forward, especially if IPC uses simple tests (e.g. absorption, conductivity) and release tests are complex (e.g. HPLC, crystal size). 

Note that this case study was calculated on the basis of an old report in which all assay values were rounded to the 0.1% position if the raw data had still been accessible, the conclusions would probably have remained the same, but some specific numbers could have changed. This situation is very common if data trends over several years are investigated. It is not unusual that raw data from routine production QC release tests are destroyed a year or two after the expiration date of the product because local laws do not require longer retention. 

The determination and analysis of sensory properties plays an important role in the development of new consumer products. Particularly in the food industry sensory analysis has become an indispensable tool in research, development, marketing and quality control. The discipline of sensory analysis covers a wide spectrum of subjects physiology of sensory perception, psychology of human behaviour, flavour chemistry, physics of emulsion break-up and flavour release, testing methodology, consumer research, statistical data analysis. Not all of these aspects are of direct interest for the chemometrician. In this chapter we will cover a few topics in the analysis of sensory data. General introductory books are e.g. Refs. [1-3]. 

HPLC reverse phase procedures were established to follow the continuous release rates of a variety of agents from the two resins. Also a USP standard release test procedure (8) was used. Because of its ease of detection at the higher ultraviolet wave lengths, bovine insulin was used as the model delivery agent... 

Abrahamsson, B., Johansson, D., Torstensson, A., Wingstrand, K., Evaluation of solubilizers in the drug release testing of hydrophilic matrix extended-release tablets of felodipine, Pharm. Res. 1994, 2 2, 1093-1097. 

This secondary effect of materials is illustrated by the difficulties encountered, in a recent study [54], when attempts were made to correlate CO concentrations measured in small scale and full scale fire tests. The same small scale equipment (typically the cone calorimeter rate of heat release test) could predict adequately a number of very important full scale fire properties, including ignitability, rate of heat release, amount of heat release and smoke obscuration. It could not, however, be used to... 

In an ideal situation the parameters used to define furniture should be ignition resistance and the rate of generation of heat, smoke and toxic gases. Tests to do this with actual or mock-up full sized furniture are not yet available as final specifications but the Nordtest (28) and NBS furniture calorimeters (29) represent scientific methods while room/ corridor rigs, typically UK DOE PSA FR5 and 6 of 1976 (5) (6) were originally used but are less satisfactory from a scientific point of view. The Californian (30) and Boston tests (31) for public area furniture are essentially simple room tests and are similar in principle to DOE, PSA, FR5 and 6 although the latter do not have pass/fail criteria. Bench scale rate of heat release tests include the NBS cone (29) which, with a code of practice represent a possible alternative but the rate of burning of... 

Vertical Tray Fire Propagation and Smoke Release Test for Electrical and Optical Fiber... 

There are numerous types of TLC testing done in the pharmaceutical industry, which are quantitative in nature. Release testing or purity evaluation, stability testing, and LOD are the three that will be addressed here. 

An example of release testing by TLC is shown in Fig. 13.24. In this example, two more polar bands are observed, one that is quantitated at <0.1% and another at 0.3%. Quantitations are based on visual estimation using the standards on the plate. Alternatively, scanning densitometry can be utilized to obtain a more definitive quantitation of impurities. 

Release testing can be used to demonstrate the separation of components such as these in Fig. 13.25. 

The decision by the European Commission to impose an immediate ban on the sale of PVC toys and teethers containing phthalate plasticisers has drawn criticism from both within and outside of the plasticiser industry. The Commission says its decision was taken only after its scientific advisors reported that plasticiser release tests are unreliable for control purposes. 

Another use, now almost abandoned except for in natural product-derived chugs, is in quality control testing or batch release testing. The latter was once a mandated part of the standardization process for antibiotics, digoxin and insulin in the U.S. 

Due to the nature of the test method, quality by design is an important qualification aspect for in vitro disolution test equipment. The suitability of the apparatus for the dissolu-tion/drug-release testing depends on both the physical and chemical calibrations which qualifies the equipment for further analysis. Besides the geometrical and dimensional accuracy and precision, as described in USP 27 and Ph.Eur., any irregularities such as vibration or undesired agitation by mechanical imperfection are to be avoided. Temperature of the test medium, rotation speed/flow rate, volume, sampling probes, and procedures need to be monitored periodically. 

Siewert M, Dressman JB, Cynthia KB, Shah VP. FIP/AAPS guidelines for dissolution/in vitro release testing of novel/spe-cial dosage forms. Pharm Ind 2003 65(2) 129-134. 

Schauble T. A comparison of various sampling methods for tablet release tests using the stirrer method [USP apparatus 1 2], Dissolution Technol 1996 3(2) 11-15. 

USP 27 (2004) contains 185 capsule monographs representing 121 monographs with dissolution test and 15 other monographs with a drug-release test. Out of 527 tablet monographs, 346 contain a dissolution test while 21 cited a drug-release test (14). 

Going beyond the application of the in vitro-release test as a QC tool for special dosage forms to biowaivers and in vitro-in vivo correlations will require more research. 

Variation of temperature is usually not an issue for solid oral dosage forms, since experiments are always conducted at body temperature (37°C). For dosage forms applied on the skin, this can be a further consideration e.g., drug-release testing of transdermal products is typically performed at the average temperature of body surface 32°C (5). 

In general, if an IVIVC method has been established, the requirement for additional dissolution test conditions is waived in favor of multi-point dissolution testing according to the in vitro method with which the IVIVC has been established. For level 3 changes, multi-point dissolution testing according to application-release test conditions is required in addition to in vivo BE. If IVIVC is available, this requirement is reduced to comparison of dissolution profiles of... 

Table 1 outlines the current status of scientific development for the dissolution or release testing from various dosage forms and recommends, where possible, the dissolution apparatus of first choice (13). Refer also to Chapter 2 for further description of the USP apparatus. 

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