The Effect of Sampling Cannula on In Vitro Dissolution Testing with USP Paddle Method

In vitro dissolution tests are widely used as quality control tools for drug products in development and manufacturing. Dissolution acceptance criteria are one of the important factors assessed during the regulatory review process. A recent publication by scientists from the US Food and Drug Administration (FDA) demonstrated dissolution results as one of the major product quality attributes to calculate a process performance index to evaluate the variability in manufacturing of drug products. (1) As a standard method, the repeatability and reproducibility of dissolution testing have always been a concern after the methods became official in the US Pharmacopeia (USP) in the early 1960s. Understanding potential sources of variability is critical for ensuring reliable results when using a standardized system for in vitro dissolution testing. FDA scientists have conducted extensive research since 1980 to gain insight into possible testing variables associated with compendial USP dissolution apparatuses. (2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17) These studies showed the importance of physical alignment of compendial dissolution apparatus (3, 4, 12, 16, 17), possible effects from dissolved air in dissolution medium (6, 10), and deviations that may be caused by random environmental vibrations (13,14,15). FDA scientists also conducted gage repeatability and reproducibility studies on the paddle dissolution method (USP apparatus 2) to examine contributions of variability from the apparatus assembly, operators, and tested samples. (11) Most testing variables show direct impacts on hydrodynamics of dissolution medium that can be responsible for the poor reproducibility and inconsistencies of the dissolution results. In the past twenty years, many investigations focused on determining the hydrodynamics of dissolution medium in standard USP vessels by experimental and computational methods such as particle image velocimetry (PIV) and computational fluid dynamics (CFD). (18,19,20,21,22,23) The results show that medium hydrodynamics is highly nonhomogeneous with directions and intensities of fluid velocities highly dependent on the location within the USP vessel, especially at the bottom of the vessel where the testing sample is usually located during the test. The advance of technology and knowledge of possible testing variables and their impacts on medium hydrodynamics became the foundation to support FDA Guidance for Industry and standardized methods (American Society for Testing and Materials – ASTM), which led to improved mechanical calibration procedure to assure the performance of USP basket and paddle methods. (24, 25)

Sampling cannulas are commonly used to withdraw sample aliquots from dissolution medium. An automated sampling procedure is useful in a QC environment, and when the method requires sample aliquots at multiple time points. Considering the sampling procedure for dissolution apparatus 1 and 2, USP general chapter < 711 > requires to withdraw a specimen (sample aliquot) from a zone midway between the surface of the dissolution medium and the top of the rotating basket or blade, not less than 1 cm from the vessel wall. (26) However, a requirement for the size (outer diameter, OD) of sampling cannula does not appear in this USP general chapter. As a recommendation, USP general chapter < 1092 > states that sampling probes (cannulas) or fiber-optic probes can disturb the hydrodynamics of the vessel; therefore, adequate validation should be performed to ensure that the probes are not causing a significant change in the dissolution rate. (27) The USP chapter provides no guidance on the OD of a sampling probe/cannula and whether a sampling probe/cannula may or may not remain in the vessel throughout the entire run. Additionally, “significant change” mentioned in the USP chapter is subjective, lacks statistical meaning, and is hard to apply during the assessment of methods.

The sampling cannula is potentially one of the essential testing factors that can contribute to variability in dissolution testing, even for a calibrated dissolution system. The effect of sampling cannula on dissolution testing attracted the attention of FDA scientists in early 1980s. (2, 5) They used the USP paddle method to test different sizes of sampling cannulas and found that dissolution rates for some formulations were consistently higher with large OD (6–8 mm) cannula. The change in rates was less evident with small OD (1.5 mm) cannula, and no difference in dissolution results was observed between automated and manual sampling. Another study compared various sampling methods with 50 mg Sotaxin tablet (drug name is as stated in the reference) using USP apparatus 1 and 2. (28) In this study, the comparative tests with or without a sampling cannula in the dissolution medium during the test showed markedly different release profiles. One research group also studied the effects of sampling cannula on the hydrodynamics of dissolution medium in USP apparatus 2 vessel by velocity measurements using PIV. (29) The study used one commercially available sampling cannula to compare variations in flow field between the testing system with and without permanently inserted sampling cannula. The results from the PIV measurements showed that the hydrodynamics in the dissolution vessel was slightly affected by the introduction of sampling cannula (3.14 mm OD); however, the dissolution results for non-disintegrating salicylic acid tablets did not show statistical difference in the presence or absence of studied sampling cannula.

Sampling cannulas in sizes from 1.6 to 3.6 mm (OD) are commercially available and commonly used, but some sampling systems require a filter at the end of each sampling cannula. The filters are commercially available in a common size of 9 mm OD by 100 mm in length and feature a large surface area to optimize sampling flow rate of dissolution medium containing particulates. The sampling cannula with filter at the end may be inserted into the sample zone of the dissolution medium when sampling (intermittent) or may remain in the sample zone permanently throughout the dissolution testing (stationary). With this large size of filter in the dissolution medium, no matter in either intermittent or stationary setting, the dissolution results may be varied by possible medium hydrodynamic disturbances.

Though early studies show possible impacts of large-sized sampling cannula on dissolution results, and USP recommends adequate validation to ensure that the cannulas are not causing a significant change in the dissolution rate, the current practice of selecting sampling cannula for dissolution testing lacks rigorous considerations. Some recommendations consider hydrodynamic disturbances when using “resident dwelling probes” (stationary setting) and suggest using a sampling manifold to lower the cannulas at sample times and to lift the cannulas between time points (intermittent setting).

The objective of this study was to investigate whether various size and setting of sampling cannula yield different dissolution results using USP apparatus 2. A wide range of sampling cannulas (OD between 1.6–9.0 mm) was used in dissolution testing with either intermittent or stationary setting to collect sample aliquots at multiple time points. The dissolution results at each time point were statistically analyzed for effects of both OD and setting of sampling cannula on drug release from 10 mg prednisone disintegrating tablet. Dissolution results indicated both size and setting of the sampling cannula may cause significant systematic errors, even though the dissolution apparatus has been calibrated. Details on sampling cannula should be documented in standard operating procedure (SOP) for dissolution testing during method development.

留言 (0)

沒有登入
gif