GLP Compliance Monitoring

GLP Compliance Monitoring Cindy Green BBS UNITED, ALEX HAYDEN/GETTY IMAGES GLP Topics addresses topics associated with good laboratory practice requirements. We intend this column to be a useful resource for daily work applications. The key objective for this column: Useful information. Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Suggestions for future discussion topics or questions to be addressed are requested. Please send your comments and suggestions to column coordinator Cindy Green at cindynwrs@seanet.com or to coordinating editor Susan Haigney at shaigney@advanstar.com. KEY POINTS The following key points are discussed in this article: The US Food and Drug Administration relies on documented adherence to good laboratory practice (GLP) requirements by nonclinical laboratories in judging the acceptability of safety data submitted to the agency The quality assurance unit (QAU) is designed to assure test facility management of compliance with the principles of GLP 21 CFR Part 58.35 requires that the QAU conduct audits of nonclinical laboratory studies to assure study integrity and to assure that the study is being conducted in compliance with the approved protocol and applicable standard operating procedures The QAU must maintain records of each periodic inspection The QAU must be entirely separate from and independent of the personnel engaged in the direction and conduct of the study it monitors A QAU inspection or audit should be viewed as a methodical evaluation of a nonclinical study to determine if a study is being performed according to GLP principles There are four types of GLP audits: study-specific audits, facility audits, process-based audits, and supplier audits All audits have common elements involving audit preparation, conducting the audit, and preparing the audit final report There are also specific considerations for study audits, facility audits, process audits, and supplier audits involving audit preparation A specific supplier audit close-out meeting should be conducted with management Autumn 2009 Volume 13 Number 4 31

GLP compliance monitoring is an essential step in assuring the integrity of data generated in support of regulatory submissions. INTRODUCTION From the US Food and Drug Administration Compliance Program Guidance Manual, Chapter 48, Bioresearch Monitoring, it is clear that FDA relies on documented adherence to GLP requirements by nonclinical laboratories in judging the acceptability of safety data submitted in support of research and/or marketing permits (1). To accomplish the compliance monitoring requirements set forth by FDA, testing facilities must establish a quality assurance unit (QAU). A QAU is a defined system, including personnel, independent of study conduct, which is designed to assure test facility management of compliance with the principles of GLP (2). In doing so, the QAU also provides FDA with documented evidence of adherence to GLP requirements. An overview of the composition, requirements, and responsibilities of the QAU is presented in a previous article entitled GLP Organization and Personnel (3). Here, a more detailed look at QAU audits is presented. Regulatory requirements for audits, an overview of the audit process, and commonalities of all audits are discussed. Study-specific audits, facility audits, processbased audits, and supplier audits are also discussed. REGULATORY REQUIREMENTS FDA regulation 21 CFR Part 58.35 requires that the QAU conduct audits of nonclinical laboratory studies at appropriate intervals to assure study integrity and to assure that the study is being conducted consistent with the approved protocol and applicable standard operating procedures (SOPs) (3). It also requires that the QAU maintain written and properly signed records of each periodic inspection, including the date of the inspection, the study inspected, the phase or segment of the study inspected, the person performing the inspection, findings and problems, actions recommended and taken to resolve the identified problems, and any scheduled date for re-inspection. Regulation 21 CFR Part 58.35 further stipulates that the QAU must be entirely separate from and independent of the personnel engaged in the direction and conduct of the study it monitors. However, it should be noted that the individuals assigned to the QAU are not required to be technical personnel; however, they must be able to clearly understand their assigned responsibilities (3). OVERVIEW OF THE AUDIT PROCESS A QAU inspection or audit should be viewed as a methodical evaluation of a nonclinical study. It should be performed in cooperation with the study personnel (e.g., for study and process audits) or facility personnel (e.g., for facility and supplier audits). Although audits and inspections may be and sometimes are performed unannounced, normally they are planned and scheduled with the personnel involved with the areas being inspected or audited. An audit or inspection should not be viewed by the auditor or those being audited as an inquisition or punishment but as a tool to determine if a study is being performed according to the principles of good laboratory practice. ELEMENTS COMMON TO AUDITS The QAU performs four basic types of audits and inspections: study specific audits, facility audits, process-based audits, and supplier audits. All four audits have much in common in regard to preparation prior to conducting an audit. With few exceptions, the conduct and the final report of all four types of audits are basically the same. Elements common to all four audits are listed as follows. Elements specific to each type of audit are presented under the article sections describing the specific type of audit. Preparing for an Audit The following preparations for an audit are common to the four types of audits: The process for conducting an inspection or audit and the preparation of the report must be described in SOPs The inspection or audit must be planned in 32 Journal of GXP Compliance

Cindy Green advance and sufficient time must be allowed to conduct the inspection or audit in order to cover all the areas identified for inspection Preparation includes notification of the study director, department head, or company management, as appropriate, of the intent to audit or inspect. The date, purpose, scope, and intent of the audit should be provided. A unique number to identify the audit and to ensure the accurate recording, tracking, and accounting of collected data should be assigned A list of questions or a checklist for the study, process, facility, or supplier being audited should be prepared in advance. Conducting an Audit The following elements for conducting an audit are common to the four types of audits: In conducting the audit or inspection, auditors should comply with safety requirements of the laboratory area(s) at all times during the audit. They should wear protective clothing and equipment to ensure that the quality of test and control articles and test systems is not compromised. The auditing process should not interfere with or disrupt the work being done Each question or item on the checklist should be discussed with appropriate personnel and any unusual or deficient condition should be noted If a deficiency is noted that can be corrected immediately, the responsible individual should be instructed to make the correction and document the action taken Deficiencies, if any, should be rated as either a severe, significant, or a minor finding as follows: Severe findings are deficiencies sufficient to potentially disqualify a study, facility, process, or supplier for consideration in a safety assessment or to result in the unacceptability of the study for its intended use Significant findings are deficiencies that, although unlikely to lead to a disqualified study, do require corrective action Minor findings are deviations from SOPs, protocols, or the GLPs that have relatively little or no effect upon the quality or integrity of the data, the interpretation of results, or the ability to reconstruct the study If significant problems that could adversely affect the study s integrity are observed, the study director or management, as appropriate to the type of audit being conducted, should be immediately notified. Final Report for an Audit The following actions should be taken after the audit is complete: When the audit is complete, review the findings and determine if any findings require corrective action Schedule a meeting to review and discuss the audit findings. Comments should be clear, specific, and constructive. Maintain a record of the meeting held to discuss findings, including minutes and an attendance sheet Prepare an audit report clearly marked Confidential If possible, propose a solution to each problem reported in the inspection report. Unless absolutely necessary, do not target people; instead target events and organization. Solicit agreement for corrective actions necessary to resolve deficiencies found during the audit Establish timetables for implementation and completion of corrective actions For findings recognized as severe or significant with accompanying corrective action, schedule a follow-up audit Conduct follow-up audit activities to verify and record the implementation and the effectiveness of corrective actions taken Document the response to the audit findings and the corrective action in the audit report. STUDY-SPECIFIC AUDITS The type of audit performed is dependent upon the nature of the phase of the study. The study-specific audit must be performed at key points during the Autumn 2009 Volume 13 Number 4 33

study. Periodic audits of the critical phases of a study are performed to assess compliance with GLPs and consistency between the protocol, the SOPs, and the actual conduct of the study. The principles of GLP require that each phase of a study must be inspected and the timing should be such that problems are revealed prior to data generation so data integrity is not adversely affected. The basic steps for conducting a study-specific audit and for preparing a final report are provided in the Elements Common to Audit section. Steps for preparing for a study-specific audit (in addition to those presented in the aforementioned section) are presented as follows. Preparing for the Study-Specific Audit The following are steps for preparing for a study audit: Prior to the inspection, become familiar with the protocol, applicable SOPs, and results from past inspections Schedule audits in accordance with the master schedule Identify those procedures performed during the study that are likely to have an impact on the quality and integrity of the results. Include procedures such as the following: Receipt and handling of test systems Receipt, handling, and storage of test and control articles Preparation and handling of reference standards Dosage formulation and analysis Test system dosing Sample preparation and analysis Gowning practices Safety regulations Prepare a list of questions or a checklist for the study to be inspected. Questions in the following areas may include the following: Study protocol. Has the protocol been approved prior to the start of the laboratory phase of the study? Are the amendments (if any) approved and are they maintained with the protocol? Are deviations from the approved protocol documented and is the rationale adequate? Are there any deviations that have not been reported? SOPs. Are the SOPs approved and readily available? Are significant changes to approved SOPs properly authorized and documented? Are deviations from the SOPs properly documented? Were any of the deviations serious enough to affect the outcome of the study? Are there any deviations that have not been reported? Have the SOPs been recently reviewed and updated? Personnel. Is the work performed by study personnel in compliance with GLP regulations and local government agencies? Are personnel following health and safety procedures so as not to adversely affect the study? Are study personnel trained and authorized to perform their assigned functions? Are study personnel performing their duties and responsibilities as assigned and in compliance with the study protocol and the SOPs? Facilities. Are the facilities used for the processing of test specimens adequate to prevent cross contamination and/or adverse effects on the sample integrity? Are the environmental controls required identified and monitored to established requirements? Are instruments used to monitor the environmental controls calibrated and included in the preventative maintenance program? Test systems. Are the test systems in use consistent with the protocol with regards to species, age, sex, weight, etc.? Is the test system appropriately identified with unique tracking numbers? Is the test system monitored consistent with the protocol? Equipment. Is equipment used in the study calibrated, qualified, and included in the equipment preventative maintenance program? Is the equipment appropriate for use in the study? Are calibration, preventative maintenance, and qualification records readily available? Are calibration and preventative maintenance procedures performed consistent 34 Journal of GXP Compliance

Cindy Green with the established frequency? Facilities used for test systems. Are the facilities used to house test systems appropriate for the species used in the study? Is there a designated quarantine area? Are records retained documenting the environmental conditions (e.g., temperature, humidity, light exposure)? Test and control articles. Have test and control articles been stored according to recommended storage conditions? Are the test and control articles properly identified? Are test and control articles linked to the test system in which they are used? Have test and control articles been characterized and have the characterization results been reviewed by the test facility management? Mixtures. Have mixtures been prepared consistent with the protocol? Has the preparation of mixtures been documented with the date of preparation, person responsible for the preparation, quantity and concentration of ingredients, quantity prepared, storage conditions, etc.? Data collection. Are all the study records complete? Are required data as specified in the protocol, SOPs, and GLPs actually recorded on appropriate data forms or in notebooks? Are all forms and notebooks cross-referenced with each page and signed and dated by the appropriate individual? Are there any missing study records? Are the study records accurate? Are corrections to a recorded observation made properly? Are the data recorded directly, promptly, and legibly in ink? Are there multiple transcription errors present? Can the sequence of events in the conduct of the study be reconstructed solely from the study records? Is the chain of custody for test articles documented? Computer operations. Have software programs been validated? Has hardware used in conjunction with software programs been qualified? When changes are made to either software or hardware are changes made consistent with an established change control process? Is an evaluation to determine the need for re-qualification and/or re-validation a requirement prior to implementing a change? FACILITY AUDITS Inspections that are conducted for a system or facility-based audit are performed independently of any specific study. Internal quality audits of a testing facility by the QAU provide a more in-depth inspection of the study process that a study-specific audit does not provide. The various departments involved in nonclinical laboratory studies are audited to assess compliance with established SOPs, GLP, and applicable requirements. Internal audits are scheduled at least once a year, unless otherwise noted, at appropriate intervals according to the importance and status of the activity or area being audited. The basic steps for conducting a facility audit and for preparing a final report are provided in the Elements Common to Audit section. Steps for preparing for a facility audit (in addition to those presented in the aforementioned section) are presented as follows. Preparing for the Facility Audit The following are steps that can be taken in preparation for a facility audit: Prior to the audit, review any previous audit reports for the area or item being audited and any applicable corrective actions. Include verification of effectivity for all corrective actions. Prepare a list of questions or a checklist to verify the quality elements required to be in place for the area or item being audited. Include questions covering the following areas, as applicable: Personnel records (qualifications and training). Are personnel qualified to perform assigned tasks? Is there a documented training program that specifies training requirements for new hires? Is there a documented re-training requirement? Are personnel assigned to the GLP studies adequately trained? Record, specimen, and test and control article retention. Are records and retains maintained consistent with regulatory and Autumn 2009 Volume 13 Number 4 35

sponsor requirements? Is there an established archiving policy? Is the area used for record, specimen, and test and control article retention adequately secure with limited access? Are electronic systems used for record archive validated and consistent with Part 11 requirements? Receipt and handling of test systems. Is there an established process for handling animal quarantine? Are animals examined for evidence of disease, mishandling, stress, etc. upon receipt? Are test systems traceable to the supplier and supplier screening records? Is each animal received traceable to documentation from the supplier, date of receipt, and specific shipment received? Facility cleaning. Are there established procedures for facility cleaning? Have agents used for cleaning been qualified? Are records maintained for each cleaning, including the day of cleaning, person responsible for the cleaning, cleaning agents used, and area cleaned? Has cleaning been performed by qualified and trained individuals? Waste handling and waste flow. Are there established procedures for waste handling? Are there designated areas for holding waste until disposal? Are there holding areas clearly marked with associated hazards, if any? Personnel hygiene, gowning, and flow. Are there established gowning procedures? Are personnel exposed to disease that may affect animals restricted from areas where test systems are housed? Are personnel that have been working in quarantine areas restricted from entering areas where healthy animals are housed? Equipment maintenance and calibration. Is all equipment used in the facility included on a calibration and maintenance program? Is equipment maintained according to the established maintenance schedule? Has equipment been qualified for its intended use? Animal food handling. Is food labeled with an expiration or use-by date? Is food stored in an area free from evidence of pests or vermin? Is food received with a certificate of analysis from a certified supplier? Purchasing controls. Are written agreements in place with contract laboratories? Are suppliers qualified in accordance with written procedures? Are there established procedures for the ongoing monitoring of suppliers? Controlled drug receipt, handling, and disposition. Are there established procedures for the ordering, handling, and storage of controlled drugs? Is access limited to only authorized individuals? Are controlled drugs secure from the point of receipt until stored in a secure location? Are records of accountability maintained from receipt until the quantity received is exhausted or disposed? Material receipt, handling, and labeling. Are there established procedures for the receipt and handling of material? Are materials received identified as to their delivery (e.g., date of receipt, quantity received, person logging receipt)? Are materials monitored to ensure materials are properly stored according to the recommended storage conditions and not used once expired? SOP initiation, revision, and control. Are there established procedures for change control? Do procedures specify who has the authorization to review and approve all types of changes? Is there an effective date assigned to new and revised documents? Is there adequate time between obtaining the approval signatures and implementing the procedure? Study protocols. Are there established procedures for preparing study protocols? Are changes to protocols documented with review and approval by the same individuals who originally approved the protocol? Do protocols include sufficient detail to allow the study to be repeated and are all required elements included? Reagents and solutions. Are reagents and solutions stored according to their recommended storage conditions? Are reagents and solutions 36 Journal of GXP Compliance

Cindy Green tested prior to use for GLP studies? Are records maintained documenting how each specific batch was prepared? Test and control article identification and storage. Are there established procedures for the receipt, handling, characterization, and storage of test and control articles? Are the test and control articles labeled in a manner that ensures traceability to the procedure used for their production? Are test and control articles stored in an area that minimizes the potential for mix-up, cross contamination, and exposure to adverse conditions? Data collection. Are there established procedures that assure data integrity? If computerized systems are used for data collection, are the computerized systems validated? Is there traceability for all changes made to data to include date of change, person making the change, and reason for the change? Computerized systems and computer operations and security. Are there established procedures for the validation of in-house developed software as well as validation of off-the-shelf software? Have computerized systems been validated? Have changes been made to computerized systems? If so, have the computerized systems been validated? Utilities supply (e.g., water, electricity, etc.). Have specifications been established for water quality? Is water quality regularly monitored? Are records maintained of the water monitoring? Is there regularly scheduled maintenance for the heating, ventilating, and air conditioning (HVAC) system? Are records maintained? Ensure that specific SOPs required for GLP compliance cover the following areas: Animal room preparation, animal care, and handling of moribund or dead animals Histopathology Receipt, identification, storage, mixing, and method of sampling test articles and control articles Test system observations Laboratory tests (methods) Identification of samples Data handling, storage, and retrieval Maintenance, use, and calibration of equipment Quality assurance activities. PROCESS-BASED AUDITS Process-based inspections are conducted independent of a specific study and are intended to review procedures or processes that are repeated frequently by the testing facility, such as sterilization, decontamination, and cleaning. Process-based inspections are conducted because it is often considered less efficient or inappropriate to perform study-based inspections routinely on repetitive phases. Process-based inspections may be assigned for the following (4): Receipt of test and control articles Controlled drug accountability Archiving of records Personnel training records Equipment calibration Sterilization Decontamination Cleaning. The basic steps for conducting a process-based audit and for preparing a final report are provided in the Elements Common to Audit section. Steps for preparing for a process-based audit (in addition to those presented in the aforementioned section) are presented as follows. Preparing for the Process-Based Audit The following are steps to follow in preparation for a process-based audit: Request and review all procedures associated with the process to be audited Identify the key tasks required by the procedures Prepare a checklist including a request for objective evidence that each key task is consistently completed Review the procedures for potential gaps between the procedure and higher-level policy documents, between procedures, and between the procedures and the applicable regulations. Autumn 2009 Volume 13 Number 4 37

SUPPLIER AUDITS The basic steps for conducting a supplier audit and for preparing a final report are provided in the Elements Common to Audit section. Steps for preparing for a supplier audit (in addition to those presented in the aforementioned section) are presented as follows. Preparing for a Supplier Audit The following steps should be taken in preparation for a supplier audit: Identify the material or service provided by the supplier Review previous audit results and corrective actions, performance history records, and contract and contract requirements Notify the supplier with a request to perform an on-site audit. Provide suggested dates, scope of planned audit, estimated duration, topics to be covered, and names and titles of auditors. Prepare a checklist of topics to be covered. Refer to the example questions under Facility Audits for suggestions of items to cover. Conduct the audit and document the procedures reviewed (e.g., title, document number, revision level), individuals interviewed (e.g., name, title, nature of interview), and records reviewed (e.g., title, date, type) Document all findings with sufficient detail to enable follow up by the supplier. Audit Close At the end of the audit, conduct a closeout meeting to review the findings with the supplier management. If clarification of the findings is required, this meeting should be used to accomplish the delivery of this clarification. Prepare a written audit report listing all findings. These findings must be consistent with the findings discussed with the supplier during the closing meeting. New findings not previously discussed with the supplier are not appropriate to include in the written audit report. Request a corrective action plan for each finding. Provide a reasonable amount of time for the response based on the criticality of the findings and anticipated effort required to adequately address the finding. CONCLUSION It is the responsibility of the sponsor to assure that GLP studies are conducted in compliance with regulatory requirements and to assure that the GLP studies conducted support the conclusions drawn on product safety. As summarized in this article there are many factors that may potentially impact the results of GLP studies. GLP compliance monitoring is an essential step in assuring that these factors do not adversely affect the data generated in support of product safety. REFERENCES 1. FDA, Compliance Program Guidance Manual, Good Laboratory Practice (Nonclinical Laboratories), CPGM 7348.808, implemented February 21, 2001. 2. OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring, Number 1, EMV/MC/Chem(98)17. 3. Green, Cindy, GLP Organization and Personnel, Journal of GXP Compliance, Vol. 13, No. 1. 4. Lysy, H., Conducting GLP Compliance Audits of Bioanalytical Laboratories, PPD, April 2008. GXP ARTICLE ACRONYM LISTING FDA US Food and Drug Administration GLP Good Laboratory Practice QAU Quality Assurance Unit SOPs Standard Operating Procedures ABOUT THE AUTHOR Cindy Green, RAC, has been working with regulated industry for nearly 35 years holding senior positions in regulatory, quality assurance, and quality control for several biotechnology and medical device companies. She has been president of her own consulting company for the past 16 years. Cindy can be reached by e-mail at cindynwrs@seanet.com. 38 Journal of GXP Compliance