Out-of-specification results

The usual response to the apparently high and out-of-specification result is to correct the problem by increasing boiler blowdown. The net result is an unnecessary waste of BD water and the heat associated with it. Consequentially, there is an unnecessary increase in fuel consumption. 

Sample preparation (SP) is generally not given adequate attention in discussions of pharmaceutical analysis even though its proper execution is of paramount importance in achieving fast and accurate quantification (see Chapter 5). Non-robust SP procedures, poor techniques, or incomplete extraction are the major causes of out-of-trend and out-of-specification results. The common SP techniques have been reviewed with a strong focus on tablets or capsules, as they are the primary products of the pharmaceutical industry. Detailed descriptions of SP methods for assays and impurity testing are provided with selected case studies of single- and multi-component products. 

The sample must be soluble If it s not in solution, it cannot be analyzed by HPLC. Although this may seem obvious, solubility issues complicate real assays of low-solubility drugs and controlled-release formulations. Many situations encountered in pharmaceutical analysis, such as low recovery, lack of mass balance, and out-of-specification results, might stem from solubility problems in a sample preparation step, rather than the HPLC analysis itself. 

SOP (provide number) will be referred to for out-of-specification results. 

Instrument qualification is required to establish the functional capability and reliability of a system for its intended use in a suitable environment. Instrument qualification can be divided into three stages installation, operation, and performance qualifications. A qualification protocol that provides details about the system, the scope and constraints of the qualification, qualification tests, test procedures, and acceptance criteria should be available for review and approval before qualification begins. Sufficient time should be provided for review and approval. The protocol should also contain an exception log to record any out-of-specification results, investigation, and problem resolution. 

Analytical practitioners place great faith in the readings and outputs from their instruments. When unexpected or out of specification results occur, the initial suspicion often falls on the sample, the preparation technique or the analytical standard employed. Rarely is the equipment questioned. Indeed, the whole underpinning of method validation assumes that the analytical equipment used to acquire the experimental data is operating correctly and reliably. 

It defines anew term, OOS or out-of-specification result, which refers to a result obtained for the pharmaceutical material or drug product that does not comply with the regulatory specification for the particular test performed. Previously, FDA inspectors would prematurely term OOS laboratory results as product failures, which clearly was not established without proper laboratory and possibly more extensive investigational activities outside the laboratory environment. 

Out-of-specification laboratory results have been given additional emphasis by the FDA, particularly after the Barr v. FDA court case [55]. An out-of-specification result falls into three catogories laboratory error, non-process-related or operator error, and process-related or manufacturing process error. Retesting of the same sample is appropriate when the analyst error can documented. An outlier test on some chemical assays, particularily those involving extensive sample preparation and manipulation, is justifiable but is not a routine approach to rejecting results [56]. 

Samples submitted to a pharmaceutical laboratory for testing must be representative of the production lot or another bulk unit from which it was taken. This criterion helps to avoid a risk of obtaining out-of-specification results for a lot within specifications and vice versa. The Food and Drug Administration (FDA) requires that a description of a sampling plan be submitted to assure that the sample of the drug product obtained is representative of the batch [1). The plan should include both the sampling of production batches and the selection of subsamples for analytical testing. 

Upon completion of the process, samples are taken to establish that the batch meets the final product specifications defined for release. Predefined sampling plans are utilized to obtain representative samples of the entire batch, the prior validation effort having assured through an expanded sampling effort that the process provides a uniform product. End-product sampling often suffers from the inability to link an anomalous result with a specific portion/segment of the batch. If the validation is insufficiently rigorous, an out-of-specification result will ordinarily result in rejection of the batch and little opportunity to take effective corrective action. 

The notification requirements of out-of-specification results wiU vary depending on the criticality of the deviation. Some deviations may need immediate attention such as alerts identifying the loss of availability of I/O cards or peripheral devices. Other observations such as the above-recommended disk utilization will gather information to be used by periodic reviews. All parameter deviations should be diagnosed and any corrective action progressed through change control. 

Lack of process and computer validation. Out-of-specification results inadequately investigated. Failure to investigate injury complaints. Cross-contamination due to improper equipment cleaning, particularly with APIs. 

Two Unrelated Events. Proposed revision to U.S. CGMPs for drugs and biologies (21 CFR 210/ 211) adds detail for validation, blend uniformity, prevention of cross-contamination, and handling out-of-specification results. 

The procurement agency should have a procedure for investigating, handling and reporting out-of-specification results when these are obtained from laboratories. If a sample fails to meet the specifications, the procurement agency should investigate the problem and communicate the outcome to the manufacturer. 

Test attributes procedures and acceptance criteria selection of batches testing frequency storage containers, conditions, and period, as well as data evaluation are discussed in great detail. Data evaluation considers out-of-specification results. Documentation covers protocols and protocol amendments, deviation reports, out-of-specification reports, test results and raw data, and stability reports. 

Once the validation is complete, a final report summarizing the acceptability or unacceptability of the cleaning procedures must be written. It should include a summary of the swab, rinse, and air impinger data supporting the adherence to the MAC acceptance criteria and an explanation of any variances or out of specification results. The raw data should be attached to the final report. 

These analytical tests are critical to establish the stability profile of APIs and drug products. These tests require a level of expertise and attention to detail that an experienced analyst needs. A training program is critical to ensure that the analyst understands the tests as well as recognizes the atypical or out-of-specification results. Proper reporting of results is also crucial for these procedures as some of them are subjective. 

Management review of the quality management system (QMS) Out-of-tolerance calibrations Out-of-specification results Equipment failures Training issues Internal and external audits. 

Standard interfaces with analytical equipment Monitoring of out-of-specification results using user-programmed limits on a per sample basis Import/export of data to/from spreadsheets Statistical process control Status of materials Tracking of samples... 

The correctly designed, computer-based LIMS will offer a more robust and accurate means of identifying out-of-specification results than can be achieved by a human laboratory technician. With the additional ability to trend, collate and report results, the LIMS has become an important tool within the laboratory environment. The integrity of the data is frequently scrutinized by the regulatory authorities and is often found to be an area of weakness. 

The cells of reporting and communications, analytical decision-making, and organizational integration cover the functions whereby reports generated by the system are transmitted via the network, out-of-specification results are highlighted, and the cH-ents can have remote access for online query of the database. The aim of these first two cells is to transmit the report to the client effectively and highlight aberrant results this allows the client to focus immediately on problem areas. Some of the options available to implement this section are covered in more detail under Financial justification and risk assessment in the next section. 

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