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Guidelines on good clinical laboratory practice: Bridging operations between research and clinical research laboratories

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Abstract

A set of Good Clinical Laboratory Practice (GCLP) standards that embraces both the research and clinical aspects of GLP were developed utilizing a variety of collected regulatory and guidance material. We describe eleven core elements that constitute the GCLP standards with the objective of filling a gap for laboratory guidance, based on IND sponsor requirements, for conducting laboratory testing using specimens from human clinical trials. These GCLP standards provide guidance on implementing GLP requirements that are critical for laboratory operations, such as performance of protocol-mandated safety assays, peripheral blood mononuclear cell processing and immunological or endpoint assays from biological interventions on IND-registered clinical trials. The expectation is that compliance with the GCLP standards, monitored annually by external audits, will allow research and development laboratories to maintain data integrity and to provide immunogenicity, safety, and product efficacy data that is repeatable, reliable, auditable and that can be easily reconstructed in a research setting.

Introduction

The Good Clinical Laboratory Practices (GCLP) concept possesses a unique quality, as it embraces both the research and the clinical aspects of GLP. The development of GCLP standards encompasses applicable portions of 21 CFR part 58 (GLP) [1] and 42 CFR part 493 (Clinical Laboratory Improvement Amendments, CLIA) [2]. Due to the ambiguity of some parts of the CFR, the GCLP standards are described by merging guidance from regulatory authorities as well as other organizations and accrediting bodies, such as the College of American Pathologists (CAP), and the International Organization for Standardization 15189 (ISO) [3]. The British Association of Research Quality Assurance (BARQA) took a similar approach by combining Good Clinical Practice (GCP) and GLP in 2003 [4].

The GCLP standards were developed with the objective of providing a single, unified document that encompasses IND sponsor requirements to guide the conduct of laboratory testing for human clinical trials. Examples of these types of tests include protocol-mandated safety assays such as diagnosis of HIV-1 infection, blood processing to obtain high quality specimens routinely [5], and cellular and serological immunogenicity assays (e.g., enumeration of antigen-specific cells by ELISpot [6] or flow cytometry [7]), or enzyme-linked immunosorbent assays (ELISA) [8] to support clinical trials on a product licensure pathway. The intent of GCLP guidance is that when laboratories adhere to this process, it ensures the quality and integrity of data, allows accurate reconstruction of experiments, monitors data quality and allows comparison of test results regardless of performance location.

In this paper, we create a comprehensive description of GCLP utilizing GLP and CLIA as a foundation, augmented with specific guidance from organizations such as CAP and ISO. A comprehensive version of the GCLP standards with accompanying templates and examples is available at [http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/labs/GCLP.pdf] [9]. To illustrate the need for a single unified GCLP standards document, Table 1 compares major elements of US, UK and other international guidance documents, showing current gaps. The GCLP core elements described in this paper include: organization and personnel; laboratory equipment; testing facility operations; quality control program; verification of performance specifications; records and reports; physical facilities; specimen transport and management; personnel safety; laboratory information systems and quality management. By recognizing these standards as the minimum requirements for optimal laboratory operations, the expectation is that GCLP compliance will ensure that consistent, reproducible, auditable, and reliable laboratory results from clinical trials can be generated for clinical trials implemented at multiple sites. A corollary of this infrastructure is that the data will be produced in an environment conducive to study reconstruction, enable prioritization between candidate product regimens and guide rational decision making for moving products forward into advanced clinical trials.

Section snippets

Standards for organization and personnel

Appropriately trained and well-organized laboratory staff are key to the successful operation of a research facility. Systems are required to drive organizational structure, training and ongoing competency assessment to ensure appropriate accountability and communication during study conduct.

Standards for laboratory equipment

Proper maintenance of all laboratory equipment is necessary for assays to function within manufacturer's specifications. Internal preventative maintenance activities as well as vendor provided maintenance/repair for laboratory equipment is paramount in providing accurate and reliable results. The standards below provide direction on how to accomplish this.

Laboratory staff must conduct preventive maintenance and service per manufacturer specifications by following documented daily, weekly,

Standard operating procedures

Standard operating procedures (SOPs) are critical for maintaining consistent test performance. The laboratory must write SOPs for all laboratory activities to ensure the consistency, quality, and integrity of the generated data. Current SOPs must be readily available in the work areas and accessible to testing personnel [24].

The laboratory must write these SOPs in a manner and language that is appropriate to the laboratory personnel conducting the procedures. SOPs should also be written in a

Quality control program

The laboratory director or designee should be actively involved in the design, implementation, and oversight of a site-specific, written Quality Control (QC) program which defines procedures for monitoring analytic performance and consistent identification, documentation, and resolution of QC issues [11], [12]. This is so as to be able to detect immediate errors as well as changes that occur over time and hence assure the accuracy and reliability of test results, particularly if the data are

Standards for verification of performance specifications

Validation of manufacturer provided performance specifications, or the development of such specifications can be challenging. The assay development and approval status defines what parameters are required in a formal validation study. The standards below offer guidance on how to validate an assay.

Standards for records and reports

The laboratory must define and maintain a system to provide and retain all clinical trial data records and reports for a period of time to troubleshoot potential problems, or if it is necessary to reconstruct the study for auditing purposes. These records may include specimen tracking forms, laboratory requisitions, chain-of-custody documents, laboratory reports, equipment service and maintenance records, and instrument printouts [31].

Standards for physical facilities

The environment in which laboratory testing is performed must be conducive to efficient operations that do not compromise the safety of the staff or the quality of the pre-analytical, analytical and post-analytical processes.

Standards for specimen transport and management

The accuracy of all laboratory test results depends on the identity and integrity of the specimen submitted. The establishment of a sound specimen chain of custody from collection through to reporting of test results is paramount in ensuring quality data.

Standards for personnel safety

The safety of all laboratory staff is reliant upon the avoidance of avoid laboratory accidents that may pose a high risk of acquisition of infectious agents through handling of blood, as an example. Although exposure cannot always be avoided, every precaution must be taken to provide a safe work environment.

Standards for laboratory information systems (LIS)

An LIS is a powerful tool to manage complex processes, ensure regulatory compliance and promote collaborations between multiple laboratories. Usually an LIS is capable of consolidating disparate scientific processes into a single, compliant platform with comprehensive reporting, surveillance and networking capabilities. The result is vastly enhanced data management and data sharing-within the laboratory and across laboratories.

Standards for Quality Management

An overarching Quality Management (QM) Program is essential to ensure safety of study participants and maintenance of quality laboratory operations. The QM Program is a systematic approach to plan the achievement of quality objectives, comply with approved procedures, and assign specific functional responsibilities to laboratory staff. The QM Program should also include an External Quality Assurance (EQA) program, which is set up to externally evaluate the laboratory's analytical performance by

Conclusions

The GCLP standards were developed to bring together multiple guidance and regulatory information, as they apply to clinical research and to fill a void of a single GCLP reference for global clinical research laboratories with regard to laboratories that support clinical trials such as those that perform protocol-mandated safety assays, process blood, and perform immune monitoring assays for candidates on a product licensure pathway. To maintain a GCLP environment for a clinical trial it is

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