System Suitability Acceptance Criteria

[Sallybeetle]

Is there a generally accepted pharmaceutical cGMP industry standard for the limits on system suitability criteria? For example, how high can tailing factor and %RSD criteria be set and a HPLC method still be deemed acceptable? I do not find this mentioned in any compendial source, e.g. the USP.

[tom jupille]

The FDA's "Guidance for Reviewers" of HPLC methods suggests that the tailing factor should be < 2.

The RSD is something of a can of worms. In very broad terms, the uncertainty in a measurement should be significantly smaller than the tolerance in the process or product to be measured. Statisticians will give the rule of thumb that the "Precision/tolerance ratio" should be ≤ 10% (see, for example: http://tinyurl.com/279wmr). So a rational starting point is to ask "how tightly do you want to control the product/process?" and go from there.

That said, most people seem to settle on about 1% RSD. When probed as to "why", the consensus answer seems to be "because we can".

[DR]

<Generic Pharma analytical support person...

2% RSD for assay (Uniformity, Composite) is still pretty common
5% RSD for trace level quantities (impurity standards within stability assays or very low level drug release quantities) is also commonly accepted.

Of course, lower is preferable, but nobody is interested in painting themselves into a corner and it's always easier to tighten a specification than to loosen it as the regulatory process goes forward.

[unmgvar]

i do not have my copies of the EP or USP as i write this in front of me but each of them as some criteria on the matter.
i remember that in EP a peak's tail should fall between 0.8 to 1.5 unless specifically mentionned in the method.

[Bruce Hamilton]

The Current EP 6.0 guidance is defined in Section 2.2.46

[ Could be copyright issue, but here's the relevant part of that section ]

SYSTEM SUITABILITY

The system suitability tests represent an integral part of the method and are used to ensure adequate performance of the chromatographic system. Apparent efficiency, mass distribution ratio, resolution, relative retention and the symmetry factor are the parameters which are usually employed in assessing the performance of the column.

Factors which may affect the chromatographic behaviour include the composition, ionic strength, temperature and apparent pH of the mobile phase, flow rate, column length, temperature and pressure, and stationary phase characteristics including porosity, particle size, type of particles, specific surface area and, in the case of reverse-phase supports, the extent of chemical modification (as expressed by end-capping, carbon loading etc.).

The various components of the equipment employed must be qualified and be capable of achieving the precision required to conduct the test or assay.

The following requirements are to be fulfilled unless otherwise stated in the monograph.

— The symmetry factor of the principal peak is to be between 0.8 and 1.5 unless otherwise stated in the monograph. This requirement has general applicability to tests or assays described in the monographs.

— Maximal permitted relative standard deviation for replicate injections of the prescribed reference solution do not exceed the values given in Table 2.2.46.-1. This requirement is applicable to assays for content only and does not apply to the test for related substances.

— The limit of detection of the peak (corresponding to a signal-to-noise ratio of 3) is below the disregard limit of the test for related substances.

— The limit of quantitation of the peak (corresponding to a signal-to-noise ratio of 10) is equal to or less than the disregard limit of the test for related substances.

Table 2.2.46.-1. — Repeatability requirements

- Number of individual injections = 3 4 5 6
B (per cent) - Maximal permitted relative standard deviation
2.0 - 0.41 0.59 0.73 0.85
2.5 - 0.52 0.74 0.92 1.06
3.0 - 0.62 0.89 1.10 1.27

ADJUSTMENT OF CHROMATOGRAPHIC CONDITIONS

The extent to which the various parameters of a chromatographic test may be adjusted to satisfy the system suitability criteria without fundamentally modifying the methods are listed below for information.

The chromatographic conditions described have been validated during the elaboration of the monograph. The system suitability tests are included to ensure the separation required for satisfactory performance of the test or assay.

Nonetheless, since the stationary phases are described in a general way and there is such a variety available commercially, with differences in chromatographic behaviour, some adjustments of the chromatographic conditions may be necessary to achieve the prescribed system suitability requirements.

With reverse-phase liquid chromatographic methods, in particular, adjustment of the various parameters will not always result in satisfactory chromatography. In that case, it may be necessary to replace the column with another of the same type (e.g. octadecylsilyl silica gel) which exhibits the desired chromatographic behaviour.

For critical parameters the adjustments are defined clearly in the monograph to ensure the system suitability.

Multiple adjustments which may have a cumulative effect in the performance of the system are to be avoided.

Liquid chromatography

Composition of the mobile phase: the amount of the minor solvent component may be adjusted by ± 30 per cent relative or ± 2 per cent absolute, whichever is the larger (see example above). No other component is altered by more than 10 per cent absolute.

pH of the aqueous component of the mobile phase: ± 0.2 pH, unless otherwise stated in the monograph, or ± 1.0 pH when neutral substances are to be examined.

Concentration of salts in the buffer component of a mobile phase: ± 10 per cent.

Detector wavelength: no adjustment permitted.

Stationary phase:
— column length: ± 70 per cent,
— column internal diameter: ± 25 per cent,
— particle size: maximal reduction of 50 per cent, no increase permitted.

Flow rate: ± 50 per cent. When in a monograph the retention time of the principal peak is indicated, the flow rate has to be adjusted if the column internal diameter has been changed. No decrease of flow rate is permitted if the monograph uses apparent number of theoretical plates in the qualification section.

Temperature: ± 10 per cent, to a maximum of 60 °C.

Injection volume: may be decreased, provided detection and repeatability of the peak(s) to be determined are satisfactory.

Gradient elution: the configuration of the equipment employed may significantly alter the resolution, retention time and relative retentions described in the method. Should this occur, it may be due to excessive dwell volume which is the volume between the point at which the 2 eluants meet and the top of the column.

[ End extract ]

Please keep having fun,

Bruce Hamilton