Nonclinical Laboratory Studies Research Articles

An expert Delphi study to derive minimum reporting set of indices for herbal medicine samples in non-clinical laboratory studies

IntroductionThe purpose of this study was to establish minimum reporting sets (MRS) on the quality of herbal medicines used in non-clinical laboratory studies to secure the reliability and reproducibility, provididng basis for follow-up clinical studies and increasing scalability for industrialisation, in the long run. MethodsThe types of herbal medicines used in laboratory studies are classified into crude drugs, herbal extracts, and herbal medicine formulations. A modified Delphi survey was conducted on multi-disciplinary experts of traditional medicine in Korea. In the first round, a written survey was conducted to select candidates for MRS. In the second round, an expert meeting was held to discuss the items for MRS. The final agreement was reached in the third round to propose the determined MRS for non-clinical laboratory studies using herbal medicine. ResultsThe agreed MRS included component observation, identification, and origin (scientific names and their origins) for crude drugs and quantitative test results on key marker compounds for herbal extracts and herbal medicine formulations, respectively. It was also agreed that herbal Good Manufacturing Practice and Good Manufacturing Practice standard test results of herbal medicine samples can replace MRS. ConclusionThis study proposed a MRS items for herbal medicine samples used in non-clinical laboratory studies. Further studies on standards of quality for herbal medicine samples would be required in the future.

Fake anabolic androgenic steroids on the black market – a systematic review and meta-analysis on qualitative and quantitative analytical results found within the literature

ObjectiveSupraphysiologic doses of anabolic androgenic steroids (AAS) are widely used to improve body image and sport performance goals. These substances can easily be acquired over the internet, leading to a substantial black market. We reviewed literature that assessed the quality and quantity of AAS found on the black market.MethodsWe searched PubMed/Medline, Embase and Google Scholar for articles published before March 2022. Additional hand searches were conducted to obtain studies not found in the primary literature search. Studies were included if they report on qualitative and/or quantitative analytical findings of AAS from the black market. Primary outcomes were proportions of counterfeit or substandard AAS. Eligible articles were extracted; quality appraisal was done using the ToxRTool for in-vitro studies. We used random-effects models to calculate the overall mean estimates for outcomes. The review protocol has been published and registered in INPLASY.ResultsOverall, 19 studies, which in total comprised 5,413 anabolic samples, met the inclusion criteria, and passed the quality appraisal from two WHO world regions that reported findings, the Americas and Europe. Most studies were nonclinical laboratory studies (95%) and provided samples seized by authorities (74%). In 18 articles, proportions of counterfeit substances and in eight articles, proportions of substandard substances were presented. The overall mean estimate for counterfeit anabolic steroids found on the black market was 36% (95% CI = 29, 43). An additional 37% (95% CI = 17, 63) were of substandard quality. We also demonstrate that these drugs could contain no active ingredient, or in another amount than that labeled, a wrong active ingredient, as well as not all or more active ingredients than were labeled. High heterogeneity among all analyses and significant differences between geographical subgroups were found.ConclusionWith this systematic review and meta-analysis, we demonstrate that substantial mean proportions of black-market AAS are counterfeit and of substandard quality. These products pose a considerable individual and public health threat, and the very wide range in proportions of fake black-market AAS puts the user in a situation of unpredictable uncertainty. There is a great need for future prevention and harm-reduction programs to protect users from these substances.

Abstract No. 676 Evaluation of venous valve anatomy after ClotTriever treatment in an ovine model

The ClotTriever System (Inari Medical, Irvine, CA) is a mechanical thrombectomy system cleared for the non-surgical removal of soft thrombi and emboli from peripheral blood vessels. We herein aimed to evaluate the system in an acute ovine model to study its potential effect on vein wall morphology. Testing was performed by Absorption Systems California, LLC (ASC) (San Diego, CA) and pathological evaluations were performed by a DVM pathologist at HSRL Histo-Scientific Research Laboratories (Mount Jackson, VA) in a manner consistent with Good Laboratory Practice for Nonclinical Laboratory Studies. The catheter was studied in two male Rambouillet-Columbia cross sheep. Jugular veins were exposed to 8 passes of the ClotTriever Catheter System, while control veins remained untreated. During the procedure, venograms were performed and immediately post treatment both animals were euthanized, and the test and control veins were collected and placed in 10% Neutral Buffered Formalin. Tissues for both animals were embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Stained sections were evaluated, and microscopic findings were graded based on severity of possible morphological changes. Posttreatment venograms visually confirmed that passes with the ClotTriever catheter did not impair valve functionality. In addition, the morphologic appearance of sections from the jugular veins treated with the ClotTriever catheter were comparable to the untreated jugular veins from these two animals, and all microscopically assessed sections were graded as normal. In conclusion, veins of an animal model showed no discernable macroscopic or microscopic changes post treatment with the ClotTriever catheter.

A Cross-Disciplinary Training Program for the Advancement of Medical Countermeasures.

In September 2012, the United States Department of Health and Human Services Food and Drug Administration's (FDA) Office of Counterterrorism and Emerging Threats and the University of Texas Medical Branch at Galveston entered into a collaborative educational partnership for the academic development of a robust training program for good laboratory practices in high-biocontainment environments. The implementation of problem-based learning techniques encouraged researchers and regulators to cross-educate each other on the challenges related to the conduct of regulated studies in biological safety level 4 (BSL-4) laboratories and identified solutions that were acceptable from scientific and regulatory perspectives. The result was the development of a face-to-face course entitled Achieving Data Quality and Integrity in Maximum Containment Laboratories and an additional online companion course covering the FDA regulation, Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58). The course offers a unique opportunity for members of the regulatory and scientific communities to solve complex issues in an interactive educational environment, especially for the advancement of medical countermeasures (MCMs) via the FDA Animal Rule (21 CFR Parts 314 and 601 (2002)). The program occurs annually and is expanding in 2019 to include a course addressing data quality and integrity in clinical trials involving the evaluation of MCMs for high-consequence pathogens. To date, 311 individuals have attended the course. Based on attendance numbers, diversity of participation (by affiliation and area of expertise), and self-reported evaluation results, course attendees indicate that the training program addresses a knowledge gap and that they will implement knowledge gained.

Regulatory Forum Opinion Piece*: An Experienced Pathologist Should Be Present at Necropsy for Novel Medical Device Studies.

Necropsies conducted to support medical device development may be conducted in facilities that do not have the infrastructure in place to support Good Laboratory Practice for Nonclinical Laboratory Studies (GLP) studies and for a variety of reasons they may be conducted without a pathologist present at necropsy. However, when a novel medical device or one that is expected to significantly alter tissues is deployed, or when the surgical model confounds interpretation of device effects, it is the opinion of the authors that an experienced pathologist should be present at necropsy.

A Global GLP Approach to Formulation Analysis Method Validation and Sample Analysis

Nonclinical pharmacokinetic (PK) and toxicokinetic (TK) toxicology safety studies are performed using good laboratory practice (GLP) regulations to ensure the availability of safe medicines. International GLP regulations uniformly require that dose concentration, homogeneity/uniformity and stability be known prior to administration. However, the United States Food and Drug Administration (US FDA) and the Organisation for Economic Cooperation and Development (OECD) both confirmed that GLPs do not apply to validation of analytical methods used to determine the concentration of GLP test article in drug dosage forms. It is our assertion that the outcome of nonclinical toxicology safety studies is inherently dependent upon accurate and precise dose formulations. In this paper, we attempt to provide supporting evidence as to why formulation method validation and sample analysis for supporting nonclinical toxicology studies should be consistently conducted under the framework of GLP principles across the globe. GLP studies are planned, performed, monitored, recorded, reported and archived according to a protocol, study plan or standard operating procedure (SOP) which is authorized prior to performing the experiments. All applicable experimental parameters and associated acceptance criteria are pre-defined. The FDA asked for responses to the Advance Notice of Proposed Rulemaking for 21 CFR Part 58 GLPs for Nonclinical Laboratory Studies [Docket No. FDA–2010–N–0548] on December 21, 2010. Several comments were received stating that guidance regarding the validation of formulation analysis methods and subsequent use for supporting GLP toxicology study sample analysis is warranted at this time and should be conducted consistently. Adherence to GLP principles for method validation and sample analysis would inherently improve the quality of nonclinical safety studies. Furthermore, the recently published White Paper titled, “Nonclinical dose formulation analysis method validation and sample analysis” should be the keystone of this effort.

Carrageenan analysis. Part 2: Quantification in swine-adapted infant formula

An LC-MS/MS method was validated in accordance with 21CFR Part 58 Good Laboratory Practice for Non-clinical Laboratory Studies to measure the concentration of carrageenan in dose formulations used in a 28-day piglet dietary feeding study of swine-adapted infant formulations stabilised with carrageenan. Carrageenan concentrations in the test formulations were 0, 300, 1000 and 2250 mg kg–1 formula. The method for the measurement of carrageenan was LC-MS/MS coupled with ESI in negative-ion mode for detection. Linearity was established over the range 1.00–7.50 µg ml–1. Carrageenan dose formulation samples ranging from 0 to 2250 mg kg–1 of carrageenan were diluted to within the linearity range for measurement.

Good Laboratory Practice. Part 3. Implementing Good Laboratory Practice in the Analytical Lab

Laboratories submitting experimental results to the Food and Drug Administration (FDA) or the Environmental Protection Agency (EPA) in support of Good Laboratory Practice (GLP) nonclinical laboratory studies must conduct such work in compliance with the GLP regulations. To consistently meet these requirements, lab managers employ a “divide and conquer” strategy: they break up the laboratory operation into key unit functions. Next they consider the regulatory requirements that must be met by each key unit function. This is called the quality system approach for implementing GLP in the analytical laboratory and it is embraced by nearly every laboratory endeavoring to perform this kind of work.

Good Laboratory Practice. Part 1. An introduction

The Good Laboratory Practice (GLP) regulations were put into place in 1978. They establish a standard of practice to ensure that results from the nonclinical laboratory study reported to the U.S. Food and Drug Administration (FDA) are valid and that the study report accurately reflects the conduct of the study. While the GLP regulations promulgate standards of laboratory conduct, for example, use of qualified personnel, instrumentation, and analytical methods, they also create a need to properly and thoroughly document such conduct. When this is done, it is easy to reconstruct and audit the study at a later date. Ultimately, the laboratory conduct in any particular study is compared to the FDA’s expectations, which evolve over time within the framework of these regulations, thereby moving the entire pharmaceutical industry forward. Yet, few people learn about these GLP standards before entering the industry. It is simply a matter of time before American colleges and universities respond to a pharmaceutical industry need and introduce GLP to undergraduates.

Process inspections and the OECD GLP Principles

The Quality Assurance JournalVolume 11, Issue 2 p. 108-110 Response to Letter to the EditorFree Access Process inspections and the OECD GLP Principles Henry Li, Henry Li henry.li@talecris.com Search for more papers by this authorDominique Pifat, Dominique Pifat dominique.pifat@talecris.com Search for more papers by this authorGerald Klein, Gerald Klein gerald.klein@talecris.com Search for more papers by this authorSteve Petteway, Steve Petteway steve.petteway@talecris.com Talecris Biotherapeutics, United StatesSearch for more papers by this author Henry Li, Henry Li henry.li@talecris.com Search for more papers by this authorDominique Pifat, Dominique Pifat dominique.pifat@talecris.com Search for more papers by this authorGerald Klein, Gerald Klein gerald.klein@talecris.com Search for more papers by this authorSteve Petteway, Steve Petteway steve.petteway@talecris.com Talecris Biotherapeutics, United StatesSearch for more papers by this author First published: 29 January 2008 https://doi.org/10.1002/qaj.417AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Li H, Pifat D, Klein G, Petteway S. Strengthening GLP Compliance through Internal Audits, Qual Assur J 2006; 10(4): 255– 261. 2 OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring; Number 4 (Revised); Consensus Document, Quality Assurance and GLP; [ENV/JM/MONO(99)20] 3 FDA. Good Laboratory Practice for Nonclinical Laboratory Studies. 21 CFR Part 58. Available at: http://www.access.gpo.gov/nara/cfr/waisidx_04/21cfr58_04.html (last accessed: 30 October 2007) 4 Visschedijik M, Hendriks R, Nuyts K. How to set up and manage quality control and quality assurance. Qual Assur J 2005; 9(2): 95– 107. 5 Comparison Chart of FDA and EPA Good Laboratory Practice (GLP) Regulations and the OECD Principles of GLP. Document issued on: June 2004. Available at: http://www.fda.gov/ora/compliance_ref/bimo/comparison_chart/ (last accessed: 30 October 2007). 6 FDA. Good Laboratory Practice (GLP), Amendment, Final Rule, 9/4/1987. Available at: http://www.fda.gov/ora/compliance_ref/bimo/default.htm (last accessed: 1 November 2007). Volume11, Issue2June 2007Pages 108-110 ReferencesRelatedInformation

Good Laboratory Practice (GLP) Regulations: Interpretation Techniques and Review of Selected Compliance Issues

The Food and Drug Administration (FDA) good laboratory practice (GLP) inspections in fiscal year 2003 increased significantly at a level of 71% over the previous year. A review and analysis of recently issued FDA warning letters for nonclinical laboratory studies found that the two major GLP compliance deficiencies were study director responsibility and authority (21 CFR §58.33) and the quality assurance unit (21 CFR §58.35). This article reviews the background of the GLP regulations, the FDA GLP inspection program, the importance of interpreting the GLP regulations, the use of published FDA references to ensure the correct and effective interpretations of the regulations, and the specific interpretations of the GLP requirements for the study director and quality assurance unit.

GIQAR position paper on ‘Archiving and Good Laboratory Practice’

Archiving of documents and specimens generated during a non-clinical laboratory study is a basic Good Laboratory Practice (GLP) requirement. The records and materials that should be archived as well as the characteristics and the organisation of archive facilities are addressed in the OECD Series on Principles of Good Laboratory Practice No. 1 (OECD Principles of Good Laboratory Practice (as revised in 1997) [1]. However, in recent years, questions concerning archiving have been raised and the need for a more detailed guidance on this matter has become evident The aim of the Society for Applied Pharmacological Sciences/Italian Group of Quality Assurance in Research (SSFA/GIQAR) working group on ‘Archiving according to GLP’ was to issue a position paper, present it for discussion in an ad hoc round table with representatives of the Italian GLP monitoring authority to promote common standards and to provide additional recommendations on storage and retention of records. Copyright © 2005 John Wiley & Sons, Ltd.

Pathology raw data in nonclinical laboratory studies for the pharmaceutical industry: The pathologists' view

AbstractPost‐mortem pathology data from nonclinical laboratory studies contain critical information for characterizing a new drug's safety and are pivotal for gaining an appreciation of potential hazards to humans. An understanding of the historical regulatory and scientific perspective on the nature of pathology data is valuable for assuring appropriate and useful audits of pathology material within nonclinical studies. This discussion reviews the specialty of pathology, the process of medical diagnosis, the definitions of ‘raw data’ as they pertain to histopathology data, and the rationale behind the consensus decisions made by industry and the Food and Drug Administration (FDA) in interpreting good laboratory practice (GLP) regulations for this type of data. Copyright © 2004 John Wiley & Sons, Ltd.

Validation of the anthrax lethal toxin neutralization assay

A validation of the performance characteristics of a toxin neutralization assay is presented. This in vitro assay measures the functional ability of antisera, containing antibodies to anthrax lethal toxin, to specifically protect J774A.1 cells against Bacillus anthracis lethal toxin cytotoxicity. This colormetric assay is based upon the reduction of MTT by living cells. Human and rabbit antisera produced against anthrax vaccine absorbed (AVA) were used to validate the assay. Results showed a high level of repeatability and reproducibility, particularly for a bio-assay. Inter-assay variability in absorbance values was the most prominent negative finding however, an acceptable level was demonstrated with a ratio [neutralization ratio (NR)] of the test serum 50% effective dose (ED 50) to the reference standard ED 50. Accuracy was maintained, even in samples with minimal neutralizing capacity, and linearity was noted when sample dilutions resulted in accurate prediction of the Y maxand Y min. Specificity tests demonstrated that normal sera did not have an observable effect on the ability of the reference standard to neutralize toxin. The assay remained stable against time, temperature, and freeze/thaw effects on the reference standards, but not on the toxin. The assay also remained stable against media and solution storage effects. Cell passage number and cell plating density were two critical parameters identified during the robustness studies that may be responsible for inter-assay variability in absorbance values. The work was performed in accordance with the FDA's Bioanalytical Method Validation Guidance for Industry and the FDA's Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58).

History of FDA good laboratory practices

AbstractThe United States Food and Drug Administration (FDA) requires nonclinical studies of new drugs, food additives and chemicals to predict their safety and potential efficacy in humans. The significance of the information gained from these studies requires that they be conducted according to sound scientific principles and with strict attention to quality assurance and quality control. Human health and safety are dependent upon the decisions made from these studies. The discovery of the lack of companies' adherence to these principles led to the development of the good laboratory practice (GLP) regulations, the driving force behind the quality of nonclinical laboratory studies. As the 25th anniversary of the publication of the regulations approaches, a description of the events leading to the proposal of the GLP regulations provides understanding about their significance and the importance of their use in assuring the quality and integrity of nonclinical safety data. Copyright © 2003 John Wiley & Sons, Ltd.

GLPs and medical devices

AbstractApplying Good Laboratory Practice (GLP) regulations to studies of medical devices and combination products (drug/device products) presents some unique challenges. The complexity of medical devices – which may be internal, external, or composed of many intricate parts including software, hardware, or drugs to perform their intended task – requires interpretation of the regulations. Further, the dynamics of the conduct of non‐clinical laboratory studies for medical devices can be quite complex often involving a team of scientists, engineers, computer specialists, technicians, veterinarians, physicians, pathologists and equipment from both the test facility and sponsor. This article highlights areas of the GLP regulations and provides information and suggestions for GLP compliance for medical device studies. Copyright © 2002 John Wiley & Sons, Ltd.

Guidelines for Laboratory Quality Auditing.

Need for Quality Control and Quality Assurance in a Laboratory The Regulated Industries Goals of a Laboratory Quality Audit Working Knowledge and Audit Documents Parameters for Evaluation Laboratory Instrumentation: Calibration and Preventative Maintenance Closing Conference, Final Report, and Follow-Up Frequency of Audit Epilog Appendixes Comparison of Domestic Laboratory Standards (FDA, EPA, HCFA) Sample Document for Use in Performing a Laboratory Quality Audit The OECD Principles of Good Laboratory Practice EPA Rules for Environmental Laboratories (State of Illinois Rules and Regulations) Federal Register (FDA): Good Laboratory Practice Regulations for Nonclinical Laboratory Studies Proposed Revision of the Clinical Laboratory Regulations for Medicare, Medicaid, and Clinical Laboratories Improvement Act of 1967 Programs (HCFA)

FDA's good laboratory practice regulations and computerized data acquisition systems

Lepore, P.D., 1992. FDA's good laboratory practice regulations and computerized data acquisition systems. Chemometrics and Intelligent Laboratory Systems: Laboratory Information Management Systems, 17: 283–287. The Food and Drug Administration's good laboratory practice regulations apply to computerized systems that are used to collect and process data deriving from a non-clinical laboratory study. Such systems are considered to be ‘equipment’ and are regulated similarly to other equipment used in a laboratory. In this regard, computerized systems are to be of appropriate design and adequate capacity to accomplish protocol directions, and their fitness for use in a study is to be documented. Written, approved standard operating procedures are to cover system testing, calibration, standardization, inspection, and maintenance, and a historical file is to contain a listing of versions and dates of implementation. The system is to accommodate the identification of each individual responsible for direct data entry at the time of entry. Data entries may be changed but an audit trail must preserve the original entry and identify the person making the change, list the date of the change, and provide a reason for the change. In view of the forgoing, FDA's inspections of computerized systems are designed to determine whether the systems operated properly in the past, whether they are currently operating properly, and whether they will continue to operate properly in the future. A satisfactory outcome can best be achieved through the development, installation, use, and maintenance of systems comporting with high quality standards.

Application of good laboratory practice (GLP) to culture collections of microbial and cell cultures

Although the principles and the necessity for good laboratory practice (GLP) guidelines to confirm the credibility, integrity, and quality of non-clinical laboratory studies have been known for more than a decade, culture collection activities are not subject to them. Because of recent advances in biotechnology, culture collections face increased demands not only for quality cultures but also current information. When applied in culture collections, GLP guidelines prove to be an excellent management tool as well as a cost-effective system of providing authentic and reliable microbial and cell cultures and associated data.

A Toxicologist's Viewpoint of the Quality of Computer-Captured Data and Data Audits

As computers become more common in toxicology laboratories, the need of handwritten data decreases. The good laboratory practice standards taught the toxicology community to prepare adequate standard operating procedures and how to document all phases of a nonclinical laboratory study. Have computers helped us with our SOPs or documentation? Maybe. Computers have streamlined many of the mundane tasks in data collection. However, they have also opened up a whole list of problems: data security, data audits, computer-generated backups, technician training and periodic updates, system validation (software, hardware, and data), and “data thieves.” A system of checks and balances must be developed, implemented, and reviewed constantly to assure the quality of data collected. This cannot be the responsibility of one person or one department but requires input from many, the cooperation of all, and support from management, without which quality would suffer.