Eshelman School of Pharmacy: Standard Operating Procedure for the CPAC Laboratory Policy Manual

This document is a standard operating procedure that gives a brief overview of the Clinical Pharmacology and Analytical Chemistry Laboratory policies and procedures used for Tier 3 bioanalytical studies (clinical studies for regulated submission and Therapeutic Drug Monitoring and Proficiency Testing analyses) using LC-MS/MS to ensure compliance with GCLP, CAP, and CLIA regulatory requirements.

Unit Procedure

Title

Eshelman School of Pharmacy: Standard Operating Procedure for the CPAC Laboratory Policy Manual

1. Introduction

As stated in the online references cited herein, the overarching goal of the Clinical Pharmacology and Analytical Chemistry (CPAC) Core is to facilitate the development of safe, effective strategies for HIV prevention, treatment, and cure. To achieve this goal, the CPAC Core provides expertise in small-molecule drug development to assist investigators in nearly all aspects of HIV pharmacology research. This full-spectrum support, unique to our Core facility, helps advance preclinical and clinical HIV research towards ending the HIV epidemic. Members of the CPAC Core work with investigators to identify and deliver services that best meet their research needs. Through highly interactive collaboration, the Core helps progress activities at each stage of HIV research, from study design and grant writing to bioanalysis and mass spectrometry imaging, to data modeling and simulation, to publication and future work. The Core's activities are augmented by institutional support from the Eshelman School of Pharmacy, which links the Core with faculty renowned for their expertise in specialized fields of pharmacology [1].

The CPAC Core supports the global community of HIV researchers through fundamental services in drug quantification. These services are performed within a College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA)-accredited environment using six redundant AB Sciex instruments for LC-MS/MS analysis and two IR-MALDESI systems for small-molecule imaging. Redundancy allows for rapid results for studies with large sample numbers, as well as simultaneous assay development and sample analysis activities performed on consistent platforms. The Core's bioanalytical capacity helps sustain collaborations within every inhabited continent and more information about the CPAC Core can be found on the University of North Carolina at Chapel Hill's ("UNC-Chapel HIll") Center for AIDS Research website [1]. More information regarding Core laboratories at UNC-Chapel Hill can be found online on the UNC-Chapel Hill School of Medicine's Office of Research website.

2. Purpose

This document is a standard operating procedure that gives a brief overview of the CPAC Laboratory policies and procedures used for Tier 3 bioanalytical studies (clinical studies for regulated submission and Therapeutic Drug Monitoring and Proficiency Testing analyses) using LC-MS/MS to ensure compliance with GCLP, CAP, and CLIA regulatory requirements. The CPAC Laboratory is not a Good Laboratory Practices (GLP) laboratory. However, our laboratory applies the principles of GLP, GCLP, and FDA guidelines. This provides a higher level of quality assurance and scientific support critical to the analyses. The CPAC Core's mission is to produce valuable data for the purpose of providing better quality medical care to HIV-infected patients.

3. Scope

This SOP applies to all CPAC laboratory personnel who perform quantitative analyses of analytes in biological matrices for CPAC Tier 3 studies.

4. Definitions and Abbreviations

5. Laboratory Safety Requirements

All CPAC laboratory personnel should be fully trained in SOP-0109 Laboratory Safety Requirements.

6. GCLP, GLP, CLIA and CAP Overview

A. Good Clinical Laboratory Practice (GCLP) and Good Laboratory Practice (GLP)

As stated in the online references cited herein, GCLP is a set of standards that provide guidance on implementing GLP and GCP principles to the analysis of samples from a clinical trial. GLP is a quality system that covers the organizational process and the conditions under which non-clinical laboratory studies are planned, performed, monitored, recorded, archived and reported. Compliance with this standard provides assurance that the data and reported results are credible and accurate, and that the rights, safety and confidentiality of trial subjects are protected [2].

As state in the online reference cited herein, 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) and 42 CFR Part 493 (CLIA). Due to the ambiguity of some parts of the CFR regulations, the GCLP standards are described by merging guidance from regulatory authorities as well as other organizations and accrediting bodies, such as CAP and ISO 15189 [3]. The GCLP Guidelines and related documents may be accessed on NIAID's website [4]. Within the GCLP Guidelines and reference section, web links are provided to access resources that the laboratory personnel may use. If used, they should be interpreted to accurately reflect the CPAC Laboratory's specific processes and/or protocol requirements [4]. The FDA's Bioanalytical Method Validation Guidance for Industry, found on the FDA's website, is also employed for LC-MS/MS analytical validation analysis in the CPAC laboratory to ensure compliance with FDA-regulated requirements.

B. Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathologists (CAP)

As stated in the online references cited herein, CLIA is a federal program, governed by the Centers for Medicare & Medicaid Services (CMS), whose purpose is to establish quality standards for clinical laboratory testing to ensure that patient test results are accurate and reliable [5]. CAP, the leading organization of board-certified pathologists, serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide [6].

7. Organization and Personnel

Appropriately trained and well-organized laboratory staff are key to the successful operation of the CPAC Laboratory. Systems are used to drive organizational structure, training, and ongoing competency assessment to ensure appropriate accountability and communication during studies.

Laboratory management must ensure that the organization complies with any applicable personnel licensure, certification, or registration requirements for personnel it employs. The specific requirements that the CPAC Laboratory employs in the laboratory follow the applicable requirements outlined in Section 1 of the GCLP guidelines. The following UNC-Chapel Hill website and CPAC SOP pertain to policies applicable to organization and personnel:

1. HR: UNC-Chapel Hill HR policies and procedures located on the UNC-Chapel Hill Office of Human Resources website.
2. Employee roles and responsibilities/Competency Assessment/Organizational Chart: CPAC SOP-0511 QM Program

8. Equipment

Proper maintenance of all laboratory equipment is necessary for assays to function within the manufacturer's specifications. Internal preventive maintenance and vendor-provided maintenance and repair of laboratory equipment are paramount to achieving accurate and reliable results.

The specific equipment requirements that the CPAC Laboratory employs in the laboratory follow the applicable requirements outlined in Section 2 of the GCLP guidelines. The following CPAC SOPs and documents pertain to equipment:

1. Equipment SOPs are located on the CPAC M drive at 100 SOPs: Equipment Operation, and for pertinent SOP reference:
   1. Use and maintenance of pipettes: CPAC SOP-0111
   2. Freezer/refrigerator/ambient temperature monitoring: CPAC SOP-0120
   3. Use and maintenance of LC-MS/MS systems: CPAC SOP-0130
2. Equipment calibration documentation: All equipment calibration documentation is stored on the CPAC M drive at Equipment Inventory: Calibration Records and is printed and stored in laboratory notebooks in the records room. Sciex mass spectrometer annual PM documentation is printed and stored in a notebook next to each respective mass spectrometer in the laboratory.
3. Equipment inventory log: All instrumentation is itemized in an excel spreadsheet and stored on the CPAC M drive at Current Kashuba Lab Equipment Inventory.xlsx
4. Instrument comparability testing procedures: CPAC SOP-0511 QM Program

9. Testing Facility Operation

Standard operating procedures (SOPs) are critical for maintaining consistent test performance. The CPAC Laboratory uses SOPs for all laboratory activities to ensure the consistency, quality, and integrity of the data generated.

The testing facility operation requirements employed in the CPAC Laboratory follow the applicable requirements outlined in Section 3 of the GCLP guidelines. The following CPAC SOPs and information pertain to these guidelines:

1. Laboratory procedure SOPs are located on the CPAC M drive at 300 SOPs: Laboratory Procedures and are available in work areas and accessible to all testing personnel.
2. Tracking of supplies and services is managed via the online system Quartzy.
3. Project management through lead generation to sample disposition is tracked via the online project management application Pipefy. Also see CPAC SOP-0357 for further details about Pipefy.

10. Test and Control

The laboratory director or designee should be actively involved in the design, implementation, and oversight of a site-specific, written quality control program that defines procedures for monitoring analytic performance and consistent identification, documentation, and resolution of QC issues.

The test and control requirements employed in the CPAC Laboratory follow the applicable requirements outlined in Section 4 of the GCLP guidelines. The following CPAC SOPs pertain to these guidelines:

1. Using CPAC Laboratory notebooks: CPAC SOP-0318
2. Guidelines for performing bioanalytical assays: CPAC SOP-0342
3. Receiving and handling of proficiency test samples: CPAC SOP-0303
4. Data reporting, review, retention, and archiving: CPAC SOP-0346
5. Water quality testing policy: SOP-0121
6. Quality management/corrective action policy: CPAC SOP-0511
7. CPAC's 3-tier system: CPAC SOP-0344

11. Test Method Validation and Verification

Validation of manufacturer-provided performance specifications, or the development of such specifications, can be challenging. The assay development and approval status define what parameters are required in a formal validation study. Some guidance on the standards of validating an assay are accuracy, precision, analytical sensitivity, analytical specificity, reportable range, reference intervals, and any other parameter required for test performance.

The test method validation and verification requirements employed in the CPAC Laboratory follow the applicable requirements outlined in Section 5 of the GCLP guidelines and bioanalytical validation requirements outlined in the FDA's Bioanalytical Method Validation Guidance for Industry. The following CPAC SOPs and information pertain to these guidelines:

1. Guidelines for validating bioanalytical methods: CPAC SOP-0343
2. Validated bioanalytical method SOPs: located on the CPAC M drive at 200 SOPs: Analytical Method SOP
3. Analytical validation reports: located on the CPAC M drive at 400 SOPs: Analytical Validations

12. Records and Reports

The CPAC Laboratory defines and maintains a system to provide and retain all data records and reports for a period of time to troubleshoot potential problems or 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.

Records and report procedures employed in the CPAC Laboratory follow the applicable requirements outlined in Section 6 of the GCLP guidelines. The following CPAC SOPs and information pertain to these guidelines:

1. After study completion, all CPAC studies are scanned and filed. The scanned copies of all study packets, electronic chain of custody documentation, and final data transferred (organized by CPAC number and year of sample receipt) are located on the secure M drive at CPAC Analytical Sample Receipt Log. The physical chain-of-custody documentation and login are maintained in a sample receipt notebook in the laboratory.
2. Use of laboratory notebooks: CPAC SOP-0318
3. Data reporting, review, retention and archiving: CPAC SOP-0346
4. Procedure for development, management, and use of standard operating procedures: SOP-0349

13. Physical Facilities and Personnel Safety

The environment in which CPAC Laboratory testing is performed is conducive to efficient operations without compromising staff safety or the quality of pre-analytical, analytical, and post-analytical processes. Although exposures and accidents cannot always be avoided, every precaution must be taken to provide a safe work environment for laboratory staff, including waste management policy, safety equipment, and general safety policies. The CPAC Laboratory is required to assign a Laboratory Safety Supervisor role to one employee to ensure compliance with all safety requirements and training, and serve as a point of contact for safety concerns.

The CPAC Laboratory follows the applicable requirements outlined in Sections 7 and 9 of the GCLP guidelines to ensure the laboratory is set up for a safe work environment. The following CPAC SOPs and information that pertain to these guidelines include:

1. Laboratory Safety Supervisor role assignment: CPAC SOP-0511
2. Laboratory safety procedures: CPAC SOP-0109
3. Disposal of biohazardous waste: CPAC SOP-0349
4. Procedure for work with HIV in the BSL2+ rooms: CPAC SOP-0337
5. Disaster planning and recovery procedures: SOP-0348
6. The laboratory safety plan can be found on the UNC-Chapel Hill Environment, Health and Safety (EHS) website, and a physical copy is in a binder in the laboratory for easy access.
7. EHS annual safety inspection reports are saved on the CPAC M drive at CPAC Operations\Lab Safety\Lab Safety Inspection Reports and stored in a binder in the CPAC records room (safety inspection reports prior to 2020 are not stored electronically in the link provided but can be found in the binder in the CPAC records room).
8. EHS safety manuals can be found on the EHS website.

14. Sample 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 reporting test results is paramount in ensuring quality data. The CPAC Laboratory has documented procedures for collecting, transporting, and receiving specimens because the accuracy of all laboratory tests depends on specimen quality.

Sample transport and management procedures employed in the CPAC Laboratory follow the applicable requirements outlined in Section 8 of the GCLP guidelines. The following CPAC SOPs and information pertain to these guidelines:

1. Collecting and shipping samples to the CPAC Laboratory: CPAC SOP-0360
2. Electronic chain of custody documentation (organized by CPAC number and year of sample receipt) is located on the secure M drive at CPAC Analytical Sample Receipt Log.
3. Therapeutic Drug Monitoring (TDM) sample collection and transport to the CPAC Laboratory: CPAC SOP-0510
4. Physical chain of custody documentation (except for TDM chain-of-custody documentation) and login are maintained in a sample receipt notebook in the laboratory.

15. Quality Management

The CPAC Laboratory uses a quality management (QM) program that is essential for ensuring study participants' privacy and maintaining quality laboratory operations. The QM program is a systematic approach to planning the achievement of quality objectives, complying with approved procedures, and assigning specific functional responsibilities to laboratory staff. The CPAC QM program also includes an External Quality Assurance (EQA) program, which is set up to externally evaluate the laboratory's analytical performance by comparing performance using coded reagent panels with peer laboratories.

The CPAC Laboratory follows the applicable requirements outlined in Section 11 of the GCLP guidelines for quality management. The following CPAC SOPs and information pertain to these guidelines:

1. QM policy: CPAC SOP-0511
2. TDM sample analysis procedures: CPAC SOP-0510
3. Proficiency testing policy (EQA/external lab testing): CPAC SOP-0303

16. References

[1] UNC Center for AIDS Research. Retrieved from https://www.med.unc.edu/cfar/core-areas/clinical-pharmacology-analytical-chemistry/

[2] The Global Health Network. (2014). Global Health Training Centre. Retrieved from https://globalhealthtrainingcentre.tghn.org/articles/understanding-principles-good-clinical-laboratory-practices-gclp/

[3] Ezzelle, J., Rodriguez-Chavez, I. R., Darden, J. M., Stirewalt, M., Kunwar, N., Hitchcock, R., Walter, T., & D'Souza, M.P. (2008). Guidelines on good clinical laboratory practice: Bridging operations between research and clinical research laboratories. Journal of Pharmaceutical and Biomedical Analysis, 46(1), 18-29. https://doi.org/10.1016/j.jpba.2007.10.010. Pre-publication version available from https://pmc.ncbi.nlm.nih.gov/articles/PMC2213906/

[4] National Institute of Allergy and Infectious Diseases. Division of AIDS (DAIDS) Clinical Research Policies: Laboratory and Specimens Management. Retrieved from https://www.niaid.nih.gov/research/daids-clinical-research-laboratory-specimens-management

[5] Centers for Medicare & Medicaid Services. Clinical Laboratory Improvement Amendments (CLIA). Retrieved from https://www.cms.gov/medicare/quality/clinical-laboratory-improvement-amendments

[6] College of American Pathologists. About the College of American Pathologists. Retrieved from https://www.cap.org/about-the-cap

17. Contact Information

Primary Contact

Name: Lisa Tarantino, PhD

Email: lisat@med.unc.edu

18. Publication Details

SOP #: CPAC-0363

Revision #: 1.0

Implementation Date: March 31, 2023

Effective Date: March 31, 2023

Approved by: Hannah Bryan (QA Manager), Mackenzie Cottrell (Laboratory Co-Director), and Angela Kashuba (Laboratory Director)