Out-of-Specification Results and the Quality System Approach to GMPs

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-09-01-2006, Volume 2006 Supplement, Issue 4

Implementing an electronic system to track out-of-specification results could help ensure compliance with current good manufacturing practices, but the system must be 21 CFR Part 11 compliant and easy to install, maintain, and use.

Efficient and effective quality systems that incorporate tracking tools are necessary components for compliance with current good manufacturing practices (CGMPs). Strict compliance with regulatory requirements when an out-of-specification (OOS) result is observed preserves the integrity of both the individual data points as well as the overall study. Documentation that is easy to follow, with traceable data entry, is essential to creating an efficient and effective quality system to handle OOS results. The system chosen must incorporate 21 CFR Part 11-compliant methods, be well-organized and amenable to user-friendly training, allow easy and flexible configuration changes and updates, and permit ongoing monitoring by quality assurance staff as well as project directors.

The difficulties of paper systems

A dependence on paper systems is often problematic. Documents stored in paper files are not quickly searchable. Cross-referencing the initial failure with follow-up corrective and preventive actions (CAPAs) is also difficult with reliance on paper systems. Dual systems may appear to be adequate, but paper documentation and electronic documentation may not be in agreement when capturing relevant data and information pertinent to the compliance failure at issue. Implementing an electronic system with no paper backup ensures that all relevant information is stored in one reliable system and eliminates the possibility of conflicting records. Electronic signature and date capture create traceability for quality assurance management when changes are made to documents in the system.

Where do we start?

A critical first step is the identification of a 21 CFR Part 11-capable and -compliant software package. The software package must meet all regulatory expectations as well as any additional requirements that customers or clients may request. Anticipating customer and client needs is difficult; therefore, a software program designed with flexible, validation-ready add-on modules is highly desirable.


The installation of the software program must be seamless. No changes in source code or company-specific programming should be necessary. The system must be able to manage multiple users simultaneously within the standard time frames expected for current software. Routine maintenance of the software should only require minimal down time and must be achievable during off hours. Revisions and updates should not require any special formatting for implementation. Updates must have been tested under the constraints of full validation of the software package. The installation of any revision or updates also should only require on-site information technology personnel. The involvement of the software vendor's personnel can be kept to a minimal amount of time for a well-documented upgrade for the system.

Compliance with 21 CFR Part 11 necessitates a fully validated system. Validation of the software is expected to occur using off-the-shelf modules prepared by the vendor. Little interaction with the source code is desirable. The vendor can be expected to supply training, support, and service, but validation must be achievable with staff at the work site. In addition, general maintenance and operation of the system should not require extraordinary measures or above-normal training.

Keep it simple

Compliant systems that are not user friendly create additional problems for the end user. Ease of use is often a difficult concept to assess, but it is necessary for efficiency. System users should not be expected to navigate through complex components to enter data, perform searches, or create reports. Searching for original deviations or cross-references to CAPAs, generating reports, and entering data must only require a few quick key strokes for the function to be performed.

User-friendliness is not only the responsibility of the software vendor, but documentation at the site in the form of well-written, clearly defined standard operating procedures (SOP) also is necessary for efficient usage of the tracking system. A well-defined, step-by-step procedure is crucial for user compliance. The SOP outlines the steps that must be met for initiation of an OOS or deviation. It also must state the parties responsible for data entry, review, and approval of the final document. As in the case of the OOS, customer involvement to resolve and close the deviation is necessary. The software system and SOP must include action items for customer notification, acknowledgement of the OOS status, and inclusion of documentation from the customer or client on the proposed plan.

Organization of the documentation should include descriptions and definitions of applicable choices, definitions of retest versus reanalysis, and requirements for supporting records. Prompts for sufficient details must be included to allow complete understanding of the event and subsequent resolution. Justification of retest versus reanalysis must be adequately provided. Forms within the software program used for data entry must be easy to understand. Including drop-down lists from which the user can choose the appropriate record would contribute to the overall efficiency of the system. Blank areas designed for including suitable comments allow for the addition of supplemental information to the record. During the final processing of initial documentation, the software must prompt the user when inadequate information is present and reject acceptance of the signature until all required information is entered. When supplemental data entry is required after the initial signature(s), audit trails must be in place to document any changes to the record.

Review by the project manager, project director, and quality assurance staff should occur sequentially. Any questions or observations that arise should be captured electronically. Responses to questions or approval by the project manager, project director, and quality assurance staff also are handled via audit trails that include signature, date, and time stamps.

Training on the acquired systems cannot be excessively lengthy for the average user. Training can occur either in a classroom session or via a Web-based program or both. Training can be linked to other software that is 21 CFR Part 11 compliant and houses a database of training records. Routine retraining may be accomplished through group classroom instruction or individual sessions through a compliant Web-based program. One benefit of compliant training software is the ease of routine scheduling of required training.

The benefits of adopting a new system

Analysts, project managers, and project directors can monitor processes for recurrent OOS or deviations. Project directors and quality assurance personnel may use these tools to determine if retraining on a method is necessary for a particular analyst or for all analysts. Tracking tools also can help identify trends that can be handled with advance predictions of the event.

In the case of cell-based assays, failure to meet acceptance criteria can be highly dependent on the state of the cells at the time of the assay. Differences among analysts have also contributed to variations within assays. Trend analysis can identify predictable events that would lead to assay failure. The use of these tools would allow the implementation of procedures to prevent reaching the failure point and allow uninterrupted manufacturing or testing. Proper documentation with trend analysis is a powerful tool. When used appropriately, OOS results and deviations can be minimized even in cell-based assays.

Compliant software is a necessity for the GMP environment. Meeting the recommendations and specifications within 21 CFR Part 11 will ensure that the software package selected will achieve expectations and requirements. Efficiency and effectiveness are at the root of any good quality system. Without these two components, the benefits of the software system will not be fully realized. A dual system incorporating electronic and paper components may appear to be a good concept in redundant systems; however, the loss in efficiency makes this choice less attractive. Proper training using either classroom-based sessions or compliant Web-based systems will ensure effectiveness of the process. Routine retraining can be accomplished efficiently through the use of group sessions or individual Web-based compliant software.

Documenting the transfer of knowledge about the SOP is best accomplished through a Web-based system that incorporates short quizzes as a prerequisite to receiving approval for training. Compliant systems to manage OOS results must not require additional programming or manipulation of source code for installation or validation. The use of these off-the-shelf systems will improve adherence to compliance requirements, provide easily traceable databases, and improve the efficiency of the overall quality-management system.

Gwendolyn M. Wise-Blackman, PhD, is senior manager of cellular technologies with Cardinal Health, 160 N. Cardinal Health Way, Morrisville, NC 27560, tel. 919.465.8522, fax. 919.481.4908, Gwendolyn.Wise-Blackman@Cardinal.com