Strengthening GLP Compliance Through Internal Audits

Transcription

1 Strengthening GLP Compliance Through Internal Audits Henry Li*, Dominique Pifat, Gerald Klein and Steve Petteway Talecris Biotherapeutics, Research Triangle Park, NC, USA Summary The Quality Assurance (QA) strategy for assessing Good Laboratory Practice (GLP) compliance at different testing facilities varies from focusing on study data verification to taking a quality system approach. As a best practice and to ensure overall compliance with GLP regulations, the Quality Assurance Unit (QAU) should perform three types of internal audits: study-specific, process-based, and system inspection. These internal audits serve as a tool to ascertain whether a GLP compliance program is functioning correctly. Information gathered from these audits can also be used to provide assistance during the evolution of a new GLP compliance program. As the GLP compliance program matures, internal audits can be a useful mechanism to help maintain compliance and promote continued improvement. Copyright # 2006 John Wiley & Sons, Ltd. Key Words: internal audit; system audit; process-based audit; Good Laboratory Practice; GLP; Quality Assurance Introduction An effective Quality Assurance (QA) function is an essential component of a Good Laboratory Practice (GLP) compliance program. The objective of a QA Unit (QAU) is to give management and, eventually, regulatory agencies confidence that safety studies and other studies that are intended to be GLP compliant meet regulatory requirements and have the necessary quality and integrity. However, if a QA group only focuses on verification of the data at the end of a study, it may overlook the quality system that supports the study and affects data quality. *Correspondence to: Henry Li, Talecris Biotherapeutics, 79 TW Alexander Drive, 4101 Research Commons, Research Triangle Park, NC 27709, USA. henry. The responsibilities of a GLP QAU are outlined in 21 Code of Federal Regulations (CFR) Part 58, Good Laboratory Practice for Nonclinical Laboratory Studies. This document states that the QAU shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations [1]. Specifically, the QAU shall: (1) maintain a copy of master schedule sheet of all nonclinical laboratory studies conducted at the testing facility; (2) maintain copies of all protocols pertaining to all nonclinical laboratory studies for which the unit is responsible; (3) inspect each nonclinical study at adequate intervals to assure the integrity of the study and maintain written and properly signed records of each periodic inspection; (4) periodically submit to management and the Copyright r 2006 John Wiley & Sons, Ltd. Qual Assur J 2006; 10, Published online in Wiley InterScience (

2 256 H. Li et al. Study Director written status reports; and (5) review the final study report to assure that such report accurately describes the methods and Standard Operating Procedures (SOPs), and that reported results accurately reflect the raw data of the nonclinical laboratory study [1]. The regulations emphasize two key QA functions: (1) auditing to monitor studies, and (2) reporting to communicate with Study Directors and management. Auditing is an important tool for the QAU to ensure that a facility is in compliance because it is during internal audits that actual conditions are compared with the requirements [2]. To be effective, the audit results and findings should be reported in a timely manner to the Study Director and facility management. In this article, several types of internal GLP audits are discussed. The effective, strategic use of these internal audits to assist with the development and continued improvement of a GLP compliance program is also reviewed. Internal audit types To completely fulfill regulatory requirements, a QAU should conduct three types of internal audits: study-specific, process-based, and system-wide audits. The types of audits and their roles in ensuring the quality and integrity of study data are shown in Figures 1 and 2. Studyspecific audits, which typically include a study protocol review, one or more critical phase audits and a final report review, focus on the integrity of study-related conduct and validity of the data [1]. Process-based inspections are conducted to assess areas such as routine testing, methodological practices and procedures that are typically beyond the scope of study-specific audits. Facility or system-wide audits are comprehensive assessments of the level of compliance of the testing facility. Study-specific audit The essential task of a QAU is to monitor each study to ensure compliance with GLP regulations, the protocol, and applicable SOPs. These study-specific audits are conducted at different stages of a study, progressing from protocol preparation to finalization of the study report (Figure 1). * Study protocol review Although it is not required by US Food and Drug Administration (FDA) regulations, study protocol review by the QAU is currently typical industry practice [3,4]. Protocols are audited for internal consistency, compliance with company SOPs and the Principles of GLP regulations. This is good business practice INTERNAL AUDITS Study-specific audit Process-based audit System-wide audit Protocol review Critical phase audit Final report audit Typical work audit Audit of group-specific activities Audit of activities within a specific timeframe Figure 1. Internal audit types All quality system elements

3 Strengthening GLP compliance Through Internal Audits 257 Study-specific audit Processbased audit System-wide audit Figure 2. Schematic diagram of relationships between internal audits because it demonstrates that the facility is taking a proactive approach to compliance. A scientifically sound, compliant protocol lays a solid foundation for the study. The Organisation for Economic Co-operation and Development (OECD) Principles of GLP require a QAU to monitor compliance of the study plan with GLP and to assess the clarity and consistency of the study plan [5]. In today s collaborative research environment, a study can be conducted in different testing facilities, sometimes even in different countries. OECD GLP No.13 [6] states that the roles of the QAU at each test site should be carefully planned. Often, the responsibilities of each test site QAU are stipulated in the study plan/protocol. For these reasons, it is important that the QAU take a proactive role in developing a plan with respect to their responsibilities at each site. * Critical phase or in-life audits These audits are conducted to observe specific tasks within the actual conduct of the studies in order to verify whether experiments are executed according to the protocol and appropriate SOPs. For example, test article preparation and dosing of test system are often monitored for compliance with the protocol. Critical pieces of equipment used are often verified for proper calibration for the intended use in the study. In addition, it is imperative to verify that deviations are appropriately documented and communicated. The number and frequency of in-life audits will vary depending on the length and nature of the study. Usually critical phases are jointly identified by the QAU and the Study Director. If the QAU has sufficient experience and scientific expertise, it can sometimes determine which phases of a study are most critical to audit. * Final study report audits The data generated in a study are intended for inclusion in submissions to regulatory agencies, such as the US FDA, in support of Investigational New Drug (IND) applications and/or product licensure. The task of the QAU is to ensure that methods are accurately described and that the results accurately reflect the raw data [1]. OECD GLP Principles provide detailed requirements for a final report audit [5]. In practice, the QAU is often required to review large portions of the data in a relatively short period of time. It should be emphasized that in addition to a solid understanding of GLP regulations, the QAU auditors should have a thorough understanding of the science underlying each study in order to be effective. In many cases there are regulatory guidelines and other documents that provide important scientific and technical information regarding how specific studies should be conducted [4,7]. The QAU auditors should have a working knowledge of these requirements in order to perform truly valueadded audits, rather than focusing on minor discrepancies in documentation. Process-based audit A process audit is verification by evaluation of an operation or method against pre-determined instructions or standards, to measure conformance to these standards and the effectiveness of the instructions [2]. It appears that the process-based audit concept originates

4 258 H. Li et al. from manufacture-based quality systems [2]. In a manufacturing facility, a manufacturing process can be easily defined, for example, a plastics part molding step. For nonclinical studies conducted at a testing facility, processes may not be as clearly defined as in the manufacturing arena. However, processbased audit approaches can be effectively adapted for use in non-clinical laboratory studies and can serve as an effective tool for QAU auditors to assess the GLP compliance level of a testing facility. In general, process-based inspections are often conducted by a GLP QAU to assess the areas that are usually beyond the scope of studyspecific audits. Study-specific audits tend to focus on data and are often not sufficiently comprehensive to monitor other activities that support data collection, due to time constraints. If a process that supports a GLP study is not in compliance, it may affect or introduce doubt about the quality of study data. During a process-based audit, QAU auditors can concentrate on a specific area or a particular quality system [5,8]. The scope of a processbased audit can be flexible and the audit relatively less time-consuming than a studyspecific audit. If one process or group is identified as a weak area, the QAU can strategically target that area. However, because of this flexibility, it is not always easy to clearly identify the group responsible for the weakness. If several groups contribute to a defined process, the auditors may have to deal with the responsible heads of several groups and assign appropriate responsibility for corrective actions to each group. Process-based audits can be classified based on the type and scope of the audits: * Typical work audit Routine work, such as animal husbandry, sample handling, routine testing, etc., may not be within the scope of study-specific audits because it supports multiple studies. A typical work audit is therefore conducted to assess compliance level of routine work. To facilitate the establishment of a process-based audit program, a test facility can analyze all routine work conducted at the facility, including testing, procedures and practices. The process-based audit program should be designed in such a way that all routine processes are rotated for evaluation for a fixed duration, for example, every year. * Audit of group-specific activities Another way to define a process-based audit is to focus on operational units, such as Metrology, Assay Support, and Formulation, etc. The QAU can assess one group at a time for GLP compliance. This is an easy approach to designing a process-based GLP audit program. The head of the group to be audited is thus accountable for GLP compliance of the activities conducted by his or her group. * Audit of activities within a specific time frame During these audits, auditors can assess studyspecific and/or support activities during a specific time frame, for example, a day [9]. The advantage of this type of audit is that it is flexible and relatively easy to schedule. Several areas can be sampled during one audit. However, it requires auditors to be familiar with the facility operations and the studies to be covered. The QAU auditors should carefully plan this type of audit and familiarize themselves with procedures and study protocols to be audited. System-wide audit GLP is in essence a Quality Management System (QMS) for drug research and development. To assess the overall level of compliance of a testing facility, auditors must take a systematic approach to evaluate the QMS. All quality elements can be reviewed during one audit. Consequently, the auditors can obtain a whole picture of the quality system of the facility. Because of this, system-wide audits are often performed to prepare the test facility for possible regulatory inspection. However, due to the resources required and potential impact on studies and operations, system-wide audits are not frequently conducted. System-wide audits are usually conducted annually or even

5 Strengthening GLP compliance Through Internal Audits 259 semi-annually, depending on compliance needs and the development stage of a GLP compliance program. The areas or quality system elements audited should cover all quality elements outlined in 21 CFR Part 58 [1]. System-wide audits should include, but not be limited to, the following areas: * Organization and Personnel * Facilities * Equipment/Computerized Systems * Test and Control Articles * Protocol and Study Conduct * SOPs * Methods * Controls * Reports * Storage and Retrieval of Records Use of audits during development of a new GLP compliance program Internal audits serve as an essential tool for a QAU to verify GLP compliance of a facility. It is suggested that for a new QMS, the stage between the initial implementation and maturity tends to be a difficult time for an organization to establish procedures and policies [10]. Thus, it is important for a QAU to analyze and summarize internal audit results and to apply them to facilitate the growth of a new GLP compliance program. Improving SOPs Audit results can be used to fine tune SOPs [10]. When SOPs are first developed, they might not capture all critical steps or be consistent with actual experimental procedures. Verifying actual conduct with the SOPs helps ensure that the SOPs are compliant with GLP and provide clear instructions. The same approach can be applied to improve standard forms, for example, an equipment routine maintenance form, and templates, such as those for the protocol and final report. Identifying best practices The QAU auditor(s) have the advantage of evaluating practices of different groups or departments during internal audits. This unique position allows the auditors to compare and identify best practices. Those practices can then be recommended for implementation within the testing facility. When a GLP compliance program expands and new groups are brought into the program, it is often necessary to establish new procedures or modify existing procedures to accommodate the new groups. The QAU auditors are again in a unique position to advise the groups as to the appropriate practices and procedures. Enhancing a mature GLP compliance program It is important for the QAU to understand that GLP compliance is a continuous process. As a QMS, a GLP compliance program is dynamic. For example, new regulations, guidelines, studies, procedures, and industry practices relevant to GLP compliance are continually being introduced. When new employees join the company, they may have a different perspective toward GLP compliance. Within a facility, habitual deficiencies may exist. In mature GLP compliance programs, analyzing patterns of noncompliance, taking a risk-based approach to auditing, and following regulatory developments are all useful mechanisms that can help maintain compliance levels and facilitate continual improvement. Pattern and trend analysis Analyzing and trending patterns of noncompliance is a key quality system approach [2] to maintain continued improvement of a quality system. This approach facilitates: (1) identification of the system-wide issues, specifically the habitual deficiencies; (2) investigation of the root causes of noncompliance; and (3) development and verification of effective corrective and preventive action plans.

6 260 H. Li et al. Takingarisk-basedapproach Effective use of internal audits can strengthen drug development compliance risk management. A risk-based approach toward auditing should be applied during internal audits. The QAU should prioritize audits based on the potential risk of noncompliance to product development and concentrate efforts on areas in which noncompliance would have a significant impact on product development. When audits are completed, the auditors should focus on the correction of critical findings. Furthermore, auditors with a strong knowledge of the regulations and broad familiarity with the operations and scientific studies, for example, can identify and help eliminate or reduce documentation redundancy, which could result in improved operating efficiency. Following regulatory development In addition, it is very beneficial for auditors to remain abreast of new regulatory audit trends and apply that knowledge in designing audit strategies. This helps ensure that the GLP compliance program remains up to date and current regarding new regulatory requirements. There are many ways to obtain regulatory information. For instance, the US FDA website provides a wealth of information. At this site, one can easily access the latest guidance documents, warning letters and other compliance information. Quality Assurance professional society meetings also are a good place to learn new regulatory developments and current industry practices. Last, but not least, qualityrelated articles and publications are traditional sources for quality- and compliance-related information and ideas. Conclusion To meet regulatory requirements, a QAU should establish an effective internal audit program consisting of study-specific, process-based, and system-wide audits. These audits should be designed and conducted to assess the level of GLP compliance within a particular facility or study from multiple angles, and at different levels. This will allow the QAU to obtain sufficient information to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations [1]. Information gathered from internal audits can be further used to assist in the development of a new GLP compliance program and to facilitate the continued improvement of a mature GLP compliance program. References 1. FDA. Good Laboratory Practice for Nonclinical Laboratory Studies. 21 CFR Part 58. Available at: ref/bimo/glp/87 finalrule.htm. Last accessed: 7 August Russell JP (ed.). The ASQ Auditing Handbook (3rd edn). ASQ Quality Press: Milwaukee, Visschedijk M, Hendriks R, Nuyts K. How to set up and manage quality control and quality assurance. Qual Assur J 2005; 9: Li H, Sharp G, Pilkington P, Pifat D, Petteway S. GLP-compliant assay validation studies: considerations for implementation of regulations and audit of studies. Qual Assur J 2006; 10: OECD. OECD Principles of Good Laboratory Practice. OECD Environmental Health and Safety Publications: Series on Principles of GLP and Compliance Monitoring. No. 4 (revised). Quality Assurance and GLP. OECD: Paris, OECD. OECD Principles of Good Laboratory Practice. OECD Environmental Health and Safety Publications: Series on Principles of GLP and Compliance Monitoring. No. 13. The application of OECD Principles of GLP to the Organisation and Management of Multi-site Studies: Paris, ICH. Guidance for Industry S7A Safety Pharmacology Studies for Human Pharmaceuticals. FDA CDER and CBER. ICH, July Available at: fda.gov/cber/gdlns/ichs7a htm. Last accessed: 7 August 2006.

7 Strengthening GLP compliance Through Internal Audits Arter DR. Quality Audits for Improved Performance. (3rd edn). ASQ Quality Press: Milwaukee, Fruk LF. Implementing an Effective Process Inspection Program to Monitor GLP Compliance. CPT s National Forum on Strategic GLP Compliance Summit Philadelphia, April Hackett W. Why Won t My QMS Grow Up? Process Auditing in an Adolescent Quality Management System. ASQ Quality Audit Division 14th Annual Conference. St. Louis, March 2005.