GMP Laboratory Controls

 GMP Laboratory Controls

GENERAL REQUIREMENTS

(a)    The establishment of any specifications, standards, sampling plans, test procedures or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit. The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.
(b)    Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling and drug products conform to appropriate standards of identity, strength, quality and purity. Laboratory control shall include.
    (1)    Determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components, drug product, containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration.
    (2)    Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples shall be representative and properly identified.
    (3)    Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products. Such samples shall be representative and properly identified.
    (4)    The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.

ANALYTICAL VALIDATION

The subject of analytical validation has been covered in numerous publications over the years. However, this section will primarily focus on the approach resulting from the ICH review that was published in the Federal Register, March 1,1995.

    Four different analytical applications were reviewed- identification tests, quantification of impurities, limit tests for impurities, and assay of actives or other key components of drug products. It was acknowledged that there are other important analytical procedures, including dissolution testing for drug products and particle size characterization of materials, but they were not addressed at this time.

    Identification tests normally compare the sample under evaluation with a known reference sample standard.

    Impurity tests may be either quantitative or limit tests, and different validation requirements apply. For limit tests, specificity and detection limits only may be required. For quantification the requirements are similar to those for assay methods (including those used for dissolution and content uniformity) except that for assay methods, detection and quantification limits do not need to be established since the methods are operating well in excess of these limits.

Accuracy – defines the agreement between the true value and the value found in the testing.
Precision – defines the degree of variability in a series of measurements ally expressed as a standard deviation or coefficient of variation. Three levels of evaluation of precision are defined.

(a)    Repeatability – relating to testing performed ever a short time interval.
(b)    Intermediate precision – evaluations performed on different days with different analysts and possibly different equipment.
(c)    Reproducibility – relates to collaborative studies between laboratories. This evaluation is a measure of the robustness of the method since many variables are involved- different facilities, different equipment, different analysts, different reagents. This is a key element in analytical verification and confirmation that a new laboratory (e.g., QC laboratory) obtained equivalent results to the originator laboratory (e.g., R&D). 

Specificity – confirms the ability of the method to evaluate the desired analyte in the presence of known other components: degradants, impurities, potential contaminants, and excipients. Frequently this is assessed by comparing results from "normal" material with those from stressed samples (heat, light, moisture, acid and/or base).

Detection limit – particularly important for limit tests.

Quantitation limit – relates to the lowest level that can be determined quantitatively with adequate accuracy and precision.
Linearity – applies only to methods involving quantification and involves the demonstration of a linear response over the range being evaluated. For example, an assay method may be evaluated only over the range of 85-115% of the specification since any results outside of these values would be out of specification.

Range – defines the upper and lower levels that have suitable levels of precision and accuracy. This is sometimes omitted since the linearity provides equivalent information.

Reggedness – while not a specific requirement in the ICH approach, it is an additional measure of the reliability of the method when normal variabilities in the product or method are experienced. Product variables can include excipient levels, pH ranges for liquids, hardness of tablets (potential impact on dissolution). Analytical method variables could include extraction process, sample preparation, HPLC flow rate, wavelength, mobile phase composition. The potential impact of these variables may be examined using a matrix design approach.

    The validation and verification (technology transfer) protocols should include acceptance criteria and be approved. Any discrepancies from the agreed acceptance criteria need to be evaluated and explained.

    Validation and verification data must be reviewed and approved by responsible persons. In the case of new methods it is advisable to have sign off by both the me
thod development unit (R&D) and the method receiving unit (QC). This acknowledges that the method has been transferred effectively.

(f)    Drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant criteria.

    The analytical failure should be reported to the section supervisor or manager. The critical steps in the analytical procedure should be reviewed with the analyst and appropriate evaluation initiated. A typical decision path for such an evaluation is outlined below (and in figure) immediately following.

1.    Investigate laboratory and production records for an assignable cause.
2.    If an assignable laboratory cause is identified and there is sufficient sample preparation remaining, the initial analyst ("A") should repeat
      the analysis in duplicate.

      (a)    If both results pass, consider release.
     (b)    If one or both of the duplicate results fail, go to step 4 (assumes the possibility of analyst bias)
3.    If there is no assignable laboratory cause but there is a relevant production deviation, reject the batch (it may be acceptable for rework).
4.    If there is no assignable laboratory cause and no relevant product deviation or there is an assignable laboratory cause but no remaining
       sample preparation, retest in duplicate using two analysts ("A" and "B").
    (a)    If all results pass, consider release.
(b)    If one or both results from "A" fail but both results from "B" pass, go to step 5.
    (c)    If one or both results from "B" fail, reject.
5.    Retest in duplicate by another analyst ("C").
    (a)    If both results pass, consider release.
    (b)    If one or both results fail, reject.
6.    Additional samples and testing maybe necessary in order to resolve any problems that may be associated with analytical techniques,
     non-representative sampling, or inhomogeneous material. Retesting of reference samples or previously released batches may be of value.
7.    Where analyst bias or error is involved, retraining may be required.
8.    If at any point in the decision path process it can be demonstrated that the result was invalid because of a specific identifiable error, that
       result can be ignored and a repeat analysis performed. The failing result must be reported with the supporting explanation. In rare cases
      an individual result may be excluded from the decision path if it deviates significantly from the average of the remaining values. The use
      of the statistical outlier approach requires adequate scientific justification for FDA acceptance.
9.    Duplicate analysis results must agree with the limits of precision defied during validation.
10.    The final decision should not be a mechanistic application of the decision path. QC management must be involved and must apply its  
      experience and knowledge of product history. Persistent or frequent failures are indicative of inadequate analytical method validation or
       verification, inadequate training, or inadequate process validation.