Good Laboratory Practice – To GLP or not to GLP?

hello and welcome to the drug discovery world podcast a podcast covering topics around drug discovery and development pharma and biotech my name is Giles and I'm here to take you through this episode today's episode is taken from our winter 2018 19 issue and is titled good laboratory practice to GLP or not to GLP the article is written by Scott Hickman dr. Brian Ogilvie and Tim Patterson so now on to the main article good laboratory practice to GLP or not to LP good laboratory practice GLP are federal regulations that require implementation of a robust quality management system to ensure the validity integrity and reliability of non clinical safety data submitted for regulatory evaluation and approval US Food and Drug Administration FDA GLP regulations were first issued by the u.s. in 1978 and at that time safety data was mainly obtained from in vivo animal test systems since then researchers have continued to develop alternative ways to assess drug safety and now good laboratory practice regulations can be applied to all non clinical laboratory safety studies including in vitro and ex vivo test systems in short GLP compliance studies require documentation for example standard operating procedures and are overseen by Quality Assurance units that perform process facility and study based inspections in this episode we provide an overview of which studies require good laboratory practice GLP compliance which do not and why in some cases the choices aren't clear understanding the details of your prospective contract research organizations GLP compliance and non GLP compliant study conduct is key once you know exactly what to expect you can select the level of study you need to achieve your projects objectives and possibly depending upon the CRO save time and funds by choosing non GLP which studies require GLP with formal regulations in place you'd think the answer to this question would be simple it is and it isn't in summary the FDA guidelines for GLP compliance are as follows one evidence that their products are safe in research and/or marketing applications must be submitted by sponsors of non clinical laboratory studies to support the safety of food and color additives animal food additives animal drugs human drugs and biological products medical devices for human use and electronic products to non clinical laboratory studies that must comply with FDA GLP regulations include toxicity profiles observed no adverse effect levels risks of clinical studies involving humans or animals potential Tetra genic carcinogenic or other adverse effects and safe levels of use and three compliance with GLP regulations is not required for these studies discovery basic research screening and any other in vitro studies in which the safety of the product is not being assessed mixed mess drug interaction and reaction phenotyping while non GLP studies do not need to fulfill GOP requirements they must still produce high quality reviews and reliable data in particular multiple nations regulatory agencies and the pharma industry have singled out in vitro drug interaction studies such as cyp inhibition induction or reaction phenotyping data or transport inhibition or substrate potential has especially important in assessing drug safety even though these are technically non DLP studies moreover the pharmaceutical industry states that drug interaction studies must be performed with high quality and consistency particularly when the studies ultimately influence the design of clinical trials furthermore the US fda recommended that these studies be carried out in the spirit of GLP with the investigator taking necessary steps to assure the quality and integrity of the data in light of these statements sponsors often feel they must deliver the same level of data integrity and validity for in vitro drug interaction studies as they would for non clinical safety studies to achieve this when outsourcing they frequently request GLP compliance studies as a matter of course but his GLP truly the only way to be certain these non GLP studies meet the guidelines we just discussed depending upon the rigor of the non GLP study conduct perhaps not waste not want not scrutinize your options unnecessary GLP studies squander both time and money avoid aside on GLP or non GLP enzyme inhibition enzyme induction drug transport or drug metabolism studies analyze your proposed CRO study options for in vitro and ex vivo test systems once you consider the exact differences between the GLP and non GLP studies you'll be able to decide whether the CRO is non glb conduct will fulfill the research objectives of your particular project in the end you may decide on non GOP studies or those in compliance with US FTA glp regulations Japan MHL WJLB regulations or oacd GLP guidance considerations when evaluating how your prospective CRO applies JLP regulations to in vitro and ex vivo studies most elements of the GLP regulations are constant regardless of test system for in vitro studies though a few points require interpretation in view of intent and applicability it is useful to compare specific relevant GLP regulations from 21 CFR part 58 how the CRO interprets these regulations in FDA GLP compliant studies and how the CRO handles these regulations in non GLP studies in vitro and ex vivo drug metabolism and drug interaction studies are critical to evaluate the safety of existing drugs or drug candidates and to assess the risk of toxicity and adverse drug drug reactions in vivo nonetheless they are not considered safety studies in the end the sponsor must choose whether to conduct them in GLP compliant or non DLP compliant fashion the degree to which your chosen CRO conducts GLP and non GLP studies identically will affect the likelihood that you'll be able to utilize non GOP drug metabolism and interaction studies specific aspects of GLP versus non GLP study conduct you may want to compare will now list firstly personnel roles and functions including planning training performance monitoring documentation archiving and quality assurance laboratory space standard operating procedures protocol and study conducts and documentation equipment hardcopy and electronic record storage retrieval and retention and bio analytical method validation selecting a CRO that conducts GLP and non GLP studies similarly will enable you to find new efficiencies by choosing non be services for some of your drug interaction studies when in doubt seek technical assistance to help you decide the result may be significant savings a few definitions firstly in vitro non clinical laboratory study a test article is applied to tissue or tissue derived material such as subset of fractions in a test tube plate etc examples include enzyme induction studies and cultured human apat sites enzyme inhibition studies with human liver microsomes or recombinant enzymes and reaction phenotyping enzyme mapping with human about sites human liver microsomes and recombinant enzymes next ex vivo non clinical laboratory study a test article is administered to a laboratory animal in vivo after which organs or tissues are removed and analyzed in vitro for enzyme induction etc examples include enzyme induction studies in mice rats dogs or monkeys often conducted as part of a 14-day toxicity study the next definition control article any food additive color additive drug biological product electronic product medical device for human use or any article other than a test article feed or water that is administered to the test system in the course of a non clinical laboratory study for the purpose of establishing a basis for comparison with the test article note positive and negative controls used to show that the test system is responsive under the actual conditions of the assay may not necessarily be categorized as control articles per GLP regulations a next specimen any material derived from a test system for examination or analysis for example microsomes isolated from cultured about sites treated with the test or control article additional definitions and requirements for GLP studies organization and personnel specific responsibilities are assigned as per GLP regulations for non clinical studies to study personnel study director facility management Quality Assurance unit QA you and archivist these responsibilities are outlined in SOPs the study director facility management and archivist roles are equally applied to non JLP studies any corrective actions taken to protocols or SOPs and any GLP deviations must be documented one study director is responsible for the conduct of each GLP compliant or non GLP study and acts as the studies single point of control the Quality Assurance unit q8u monitors GLP studies reporting to management and the study director the QA you does not monitor all non GLP studies or records however the QA you does perform facility and process based inspections of all facility operations to ensure that no deviations were made without proper documentation and authorization the QA you also maintains copies of all GLP compliant and non JLP audited protocols and a master schedule sheet MSS of all GLP compliant and non GLP audited studies conducted at a facility next facilities as per GLP regulations adequate facilities must be provided for each study adequate procedure specific laboratory areas contain test article and control article receipt and storage test article and control article storage solution preparation micro zone preparation LC ms/ms analysis sterile and aseptic procedures and biohazard procedures on site facility archives should be maintained but specimen archives are not required are the close of a study specimens may be shipped to the sponsor or another designated storage location or they may be disposed of at the sponsors request these ages are the same for both GLP compliance and non GLP studies next standard operating procedures standard operating procedures SOPs covering laboratory operations as listed in the GLP regulations are maintained these procedures cover both in vitro and ex vivo studies additional SOPs cover experimental methods and procedures appropriate for specific studies ie drug metabolism and drug interaction studies management's must approve all new and revised SOPs an archive is maintained for all historical versions of SOPs and hard copies are available in laboratories and electronic SOPs are available at all workstations with a few exceptions the same SOPs support the conducts of both GLP compliance and non GLBT studies and next equipment study personnel may use the same laboratories and equipments for all contracted studies thus maintenance calibration testing and record-keeping can be equally applied to all studies in order to maintain the equipment in proper regulatory compliance appropriate equipment is maintained for in vitro and ex vivo study procedures a department of maintenance and metrology is recommended they inspect clean and maintain equipment and these activities are documented in equipment SOPs verification and calibration may be conducted in-house by study personnel or maintenance and metrology personnel or these tasks may be performed by equipment vendors or specialized contractors as necessary where applicable all equipment use is documented in instrument logbooks records of equipment inspection maintenance testing calibration and standardization are archived and retained next test and control articles full characterization of test and control articles is not required for non GLP studies test and control articles are assigned internal tracking numbers information on test article receipts and distribution are stored in a central location and archived as facility records copies are maintained in the study records retention of test and control article samples is not required as in life study segments dosing observation typically lasts less than four weeks test and control articles remaining after the studies end should be returned or destroyed as per the sponsors request test dosing solutions are analyzed for concentration and stability for GLP compliant studies this analysis is not required for non GLP studies a sponsor may provide information on the stability of test solutions however if the stabilities are known or has not been characterized a fresh solution is prepared daily protocol and study conduct contract studies are conducted according to the applicable jlpt regulations and the protocol pre-printed forms with selected data may be used but these must be verified prior to the conduct of any study the same documentation requirements are applied to both GLB compliance and non GLP studies next reporting a final reports summarizing study methods and results including applicable components listed in the GLP regulations and study protocol must be prepared in a GLP compliant study report a compliant statement stipulating the regulations followed in the conduct of the study and any GLP deviations that occurred is included protocol deviations are reported for both GLP compliant and non GLP studies Corrections or changes to a final report for both GLP compliance and non GLP studies are only made through amendments as described in the GLB regulations with prior approval from the sponsor alternatives to preparing completes final reports for a non GLP study can be offered such as data summary or other simplified version according to the sponsors requirements record storage retrieval and retention all study records must be maintained in a facility archived records are indexed and stored either at the test facility or transfer to an off-site commercial archive facility records from G P compliance studies should be stored in fire resistant cabinets within a restricted access archive room access to the archives is controlled and all access to the archive room and archived records is documented and pulped records from non GLP studies may be stored in the same archive room with controlled access as TLB studies but they may not necessarily be stored in fire resistant cabinets GLP studies require record retention from the time the sponsor applies for a permit or submits required documents the FDA sponsors may request a specific retention period for study records at the test facility or may request the records be transferred to them after a designated period of time otherwise standard record retention policies based on a specific SOP or default time periods are followed next electronic record and electronic signatures instruments software and networked environments generates electronic records and signatures relevant FDA 21 CFR part 11 regulations are applied differently in a GLP compliance vs. and non GLP study computerized systems used in GLP compliance studies must meet all part 11 requirements including validation and electronic signatures whereas computerized systems used in non GLP studies may not be validated or include electronic signatures a computerized system masterless identifying all systems and their validation status must be maintained individual system SOPs cover the use of electronic signatures and the maintenance of electronic records and finally bio analytical method validation specific SOPs define how FDA guidelines are applied in bio analytical methods validation all methods used in GLP compliant studies must be validated methods are tested for accuracy precision selectivity sensitivity reproducibility and stability routine sample analyses are conducted using quality controls to accept and reject runs for GLP studies or upon request non GLP studies may follow methods that not been validated typically the same methods validated for GLP compliant studies are used for non GLP studies however in non GLP studies QC s are not necessarily used to accept or reject each batch and there we have our additional definitions and requirements for GL PE studies this article was written by Scott Hickman dr. Brian Ogilvie and tim paterson score taekman MBA sexy wheezy no tech director of global marketing has managed the customer experience for innovative life science companies for more than 25 years dr. Brian Ogilvy sex ooh easy no tech vice presidents of scientific consulting is an author on numerous posters and publications and an invited speaker at many conferences tim paterson a SQ c QA c qm sexes Louisiana Tech Quality Assurance Manager has more than 20 years of experience working in GMP and GLP regulated environments if you've enjoyed this episode then you can subscribe to drug discovery world free of charge by visiting our website at de ja vu where you can also view all of our articles including references and images and download the original pdfs you can find the links in the show notes if you enjoying the podcast and do leave us a review and subscribe we massively appreciate it and you can also follow us on LinkedIn and Twitter thanks for listening and we'll hope to see you in the next episode you

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