Laboratory Self-Audits

Transcription

1 P e e r R e v i e w e d : A u d i t 101 Laboratory Self-Audits Paul L. Pluta and Jerry Lanese Audit 101 provides useful and practical information that addresses various topics associated with audits. Common-sense suggestions with application to all audits internal and external, regulatory and non-regulatory, domestic and international are provided. Examples of actual occurrences are described whenever possible. Audit 101 has previously discussed the following First Impressions -- The Plant Tour (1) Preparation, Preparation, and More Preparation (2). Reader comments, questions, suggestions for discussion topics, and actual audit experiences are needed to help us fulfill the column objective. Please send your comments and suggestions to column coordinator Paul Pluta at paul.pluta@comcast.net. Every laboratory must become comfortable with being audited. A self-audit conducted internally is an excellent tool for the lab to prepare itself for any audit, identify problems, test execution, and simulate an actual audit experience. Conducting a rigorous self-audit that simulates an actual audit also helps to establish a culture that supports an on-going state of preparedness in the laboratory. Successful laboratories operate in this state at all times. This discussion provides a guide to the self-audit of a laboratory. Laboratory systems independent of an actual test result are reviewed beginning with the laboratory organizational structure through sample collection, analytical testing, and record retention. Areas of interest are identified including specific function, procedures, practices, records, and staff compliance with procedures. Topics discussed include the laboratory audit process, relevant audit documents and references, laboratory procedure availability, document requests by auditors, and audit training for personnel. An approach to gap identification, analysis, and prioritization of mitigation projects is presented. A case study is given describing an actual regulatory audit of an analytical quality control (QC) laboratory and its supporting research and development (R&D) laboratory. INTRODUCTION Every organization must become comfortable with being audited. Regulatory audits by global agencies, International Organization for Standardization (ISO) Registrar certification audits, external customer audits, and internal quality assurance (QA) audits happen frequently. Some may come at a moment s notice while others are planned weeks in advance. The key to a success is to make sure your area is always prepared for an audit. A functioning laboratory must function in a state of readiness on a daily basis. However, audits and inspections of the laboratory are often not anticipated. Audits that start in a distant site s conference room usually lead to the manufacturing floor and ultimately involve one or more laboratories at the site. Organizations often have a designated internal function whose sole purpose is to conduct internal audits. These may be very rigorous audits; the personnel conducting such audits are usually very well experienced. These audits are stressful events for the lab since the results may be communicated to high-level personnel in the organization. To prepare for these internal audits as well as the aforementioned regulatory, ISO, and other audits, self-audits conducted by the laboratory personnel Summer 2012 Volume 16 Number 3 71

2 P e e r R e v i e w e d : A u d i t are recommended. This is an excellent tool for the lab to prepare itself for any audit, identify problems, test execution, and simulate the actual audit experience. Conducting a rigorous self-audit or that simulates an actual audit also helps to establish a culture that supports an ongoing state of preparedness in the laboratory. The following discussion provides a guide to the self-audit of a laboratory. Audits may be conducted in different ways. This approach addresses the laboratory systems independent of an actual test result. It begins by identifying the major elements of a laboratory operation listed according to a typical sequence of activities. It then identifies areas to assess to determine the readiness of the laboratory for an outside audit. The elements of a laboratory operation are listed below beginning with the laboratory organizational structure through the sample collection, testing, and record retention: Laboratory overview Sample collection Sample receipt in the lab Sample handling and storage in advance before testing Sample testing Instrument qualification Instrument maintenance and calibration Test method and sampling procedure development Test method validation Laboratory technical training Data treatment Results verification, review and approval Results reporting Investigations Record compilation. Record storage, retention and retrieval Topics including the laboratory audit process, relevant audit documents and references, laboratory procedures, document requests by auditors, and audit training for personnel are also discussed. When self-audits of laboratory operations are completed and gaps are identified, risks are evaluated. The remedial actions required to mitigate these risks are then prioritized and addressed. A case study demonstrating an alternate approach to the laboratory audit is also presented. This case study follows an actual test result backwards through the lab, starting with the result. Either of these approaches, (incoming sample receipt through final results or final result through incoming sample), may be utilized in a self-audit. A combination of methods, or use of both approaches at different times, may serve to best uncover area weaknesses. Approach to the Self-Audit Areas of interest are identified within each of the elements of the laboratory operation. The auditor should investigate the following in each area and respective activities: Function of the specific element or activity Appropriate procedures are in place Procedures accurately reflect the practice Records are complete, accurate, and maintained Staff is compliant with procedures LABORATORY OVERVIEW An overview of the laboratory operation is the first area for review in the self-audit. Areas for review in this element address the general goals and objectives, operations, function, and management of the laboratory. This type of information is requested when the auditor first arrives at the laboratory. Information regarding the type of testing conducted, qualifications of personnel and management, organizational chart, responsibilities, and other descriptive information must be readily available. Documentation and records must be provided when requested. The areas to assess here are: Type of testing conducted in the laboratory Areas and units that submit samples to the laboratory Organization of the laboratory, including responsibilities and accountabilities Qualifications of laboratory personnel Qualification of laboratory management 72 Journal of GXP Compliance

3 P a u l L. P l u t a a n d J e r r y L a n e s e Education, training and experience of laboratory management Processes which monitor laboratory performance Laboratory work outsourced to other areas within the company or outsourced to an outside laboratory Prior audit or inspection observations SAMPLE COLLECTION The areas for review in this element address the source of samples for testing. What areas submit samples, how are samples collected, required special training for sampling personnel, etc. Samples may be submitted from various areas in the organization. Samples may also be submitted at various stages of manufacturing. Some samples may require immediate testing, while others may able to be staged within the specific response time for laboratory efficiency. Each of these considerations may lead to a specific line of questions including specific requirements, specific handling, and so on. The sampling activity is often not within the control of the laboratory. If the laboratory cannot assure the quality and integrity of the samples received for testing, testing results will be suspect because the sampling process lacks appropriate controls. The specific areas to assess are: Areas or units that submit samples to the lab for testing Qualifications of individuals who actually remove the samples from the manufacturing process, stability area, or other source of samples Specialized personnel training required for sampling Specialized equipment or facilities required for sampling The qualifications of individuals who deliver samples to the laboratory The technical input by the laboratory into proper sampling, packaging, and labeling of the samples Sample labels Procedures for sampling, packaging, and labeling, and submission of samples to the laboratory SAMPLE RECEIPT IN THE LAB The areas for review in this element address specific activities associated with the receipt of samples by the laboratory from the sample delivery person. Are all samples simply dropped into a receipt box or are there specific receipt procedures under laboratory control? Important areas to evaluate are: Sampling receiving area s security and integrity Sample receiving process Sample receiving records Storage of samples immediately upon receipt and environmental controls Security of receipt area Qualification of the sample receiving area Examination and evaluation of samples upon receipt, including records of the activity Process for logging samples into a laboratory information management system (LIMS) computer system for tracking Validation of the LIMS system SAMPLE HANDLING AND STORAGE IN ADVANCE OF TESTING The areas for review in this element address the handling and storage of samples before they are actually tested by the laboratory. These areas are: Sample storage while samples are awaiting testing Provisions for special storage conditions such as refrigeration, light protection, or other requirements Qualification of sample storage area Identification and prioritization of samples that require immediate testing Security of storage area Specific goals for completion of testing Procedures for sample handling and storage in the laboratory SAMPLE TESTING The areas for review and assessment in this element address the actual testing of samples: Reference standard program and controls Reagent controls Control of chromatographic columns Summer 2012 Volume 16 Number 3 73

4 P e e r R e v i e w e d : A u d i t Preparation control of stock reagents System suitability requirements for test methods Procedures for handling deviations to analytical methods or other laboratory procedures Procedures for handling changes to test methods or other laboratory procedures Test procedures Test-specific work sheets Qualification of analysts to perform tests The performance of required tests INSTRUMENT QUALIFICATION The areas for review in this element address the capability and readiness of laboratory instrumentation for testing. All instruments and equipment must be qualified according to their United States Pharmacopeia (USP) (or equivalent) instrument categorization (3). Laboratory management must be mindful of the intended use of the instruments as well as the instrument manufacturer s recommendations regarding the equipment use. Changes to laboratory instruments should be evaluated through a change control system: Procedures related to instrument qualification Responsibility for instrument and equipment qualification Status of laboratory instrument and equipment qualification Change control as it applies to instruments and equipment INSTRUMENT MAINTENANCE AND CALIBRATION The areas for review in this element address maintenance and calibration activities associated with instruments and other equipment. Instrument calibration is significant routine maintenance activity for analytical instruments. Instruments must be calibrated or user standardized for actual use. The following must be assessed: Instrument maintenance procedures Laboratory instrument calibration program Instrument calibration procedures Calibration records Instrument logbooks TEST METHOD AND SAMPLING PROCEDURE DEVELOPMENT The areas for review in this element address the development of test methods by Analytical research and design (R&D) or other technical support functions: Responsibilities for the development of test methods, including sampling used in the laboratory Evidence that specific samples for testing are representative of the material received Availability of method development reports in the lab when needed for problem solving Transfer of methods from other labs to this laboratory Procedures defining test method and sampling procedure development TEST METHOD VALIDATION The areas for review in this element address test method validation and associated activities. Test method validation is a key area in the laboratory audit. Industry and regulators focus on analytical method validation. Any type of test method (physical, biological, microbiological, chemical) must have documented evidence that demonstrates the test performs as intended. Test methods must be appropriately validated if they are used for any testing required by the good manufacturing practices (GMPs). Changes to validated test methods must be evaluated through a change control system. The following aspects of the test method validation must be evaluated: Responsibilities for test method validation The test method validation process Status of the validation of all test methods Evidence that test methods perform as intended The system for changing test methods The involvement of development subject matter experts in evaluation of changes Location and availability of test method validation documentation LABORATORY TECHNICAL TRAINING The training of laboratory personnel and associated training records are always requested in an audit. 74 Journal of GXP Compliance

5 P a u l L. P l u t a a n d J e r r y L a n e s e Areas that should be reviewed include: The laboratory technical training program Process for determination of appropriate training for each analyst Evidence of analyst qualifications Retraining Maintenance of training records and responsibility, and current records DATA TREATMENT The areas for review in this element address raw data recording, calculations, and other treatment of data to determine test results. The laboratory analysts who perform the analytical testing record all data, calculations, and compile instrument documentation and associated information. Calculations may be done with calculators, spreadsheets, or other computer software. If computer systems and software are involved, these must be validated. The specific areas of data treatment to be reviewed are: Procedures for recording data in worksheets or notebooks, labeling of instrument printouts, entry into computer systems, calculation, and result reporting Procedures covering averaging and significant figures Procedures for good recordkeeping practices (good documentation practices) Software and spreadsheets used to perform calculations, spreadsheet development standards, evidence of validation Change control RESULTS VERIFICATION AND APPROVAL The areas for review in this element address the final review and approval of raw data, calculations, data treatment, and other associated activities by supervision prior to release of results to the appropriate organizations. Laboratory records are signed and dated by the analyst to affirm performance of the testing. They are then reviewed and approved by laboratory supervision. All records are signed and dated by laboratory supervision affirming performance of the testing, approval of the test results, and compliance with internal procedures and regulations. Througout this process, there should be heightened emphasis on the assemente of: Responsibilities of analysts and reviewers Procedures covering verification, approval and release of raw data, calculations, final reports to appropriate areas, and signature/date requirements for analysts and supervisors Responsibilities for approval of all data and calculations prior to reporting results RESULTS REPORTING The areas for review in this element address the report of approved results to the sample originator or the unit using the data. Sites may have electronic systems into which test results are entered and are ultimately transferred for final lot disposition. Other sites may have paper systems that accomplish the same objective. Sites may also have mixed systems, (e.g., electronic systems) for certain samples and paper systems for special samples. Specifically, in results reporting, the following should be reviewed: The process for reporting results to quality or sample originators Validation of any computerized system used in the sample reporting process Timeliness of results measured against laboratory turnaround goals Procedures for reporting of results Assurance of appropriate testing and complete testing INVESTIGATIONS The areas for review in this element address performance of investigations when aberrant test results are generated. Test data may fail specifications or may vary significantly from historical norms. This data requires investigation by the laboratory to determine the causes for the aberrant laboratory results. There should be focus on the reviewing the following: Procedures for handling and investigating out-of-specification or out-of-trend laboratory results Procedures for laboratory investigations Summer 2012 Volume 16 Number 3 75

6 P e e r R e v i e w e d : A u d i t Evidence of typical laboratory investigations Retention of laboratory investigation reports Corrective and preventive actions resulting from laboratory investigations RECORD COMPILATION After testing is completed, data verified, results calculated, reviewed, and approved; and results reported to quality or the originator, all records are compiled in a standardized format. Areas for review in this element include: Procedures covering the format for completed laboratory records Procedures for compilation of records Evidence of completed records RECORD STORAGE AND RETRIEVAL The areas for review in this element address the storage and retrieval of laboratory data. Data and test documentation may be stored electronically or in hardcopy depending on the organization. Storage must be secure. Access to test records must be restricted to qualified personnel. If storage is by electronic systems, these systems must be validated. Data and test information must be quickly and easily retrievable. Reviewing the following is a necessity: Procedures for record storage, retention and retrieval Security and environment of the record storage areas Qualifications of individuals responsible for record storage THE LABORATORY AUDIT PROCESS Actual laboratory audits may be conducted in various ways. The above elements outline a start to finish approach to the audit structured according to the business process of the lab. It establishs the laboratory organization infrastructure through the testing to the storage and maintenance of the records. Audits may also be conducted in the reverse order, (i.e., following a test result from finish to start. ). In this approach, the audit follows a reported test result from the laboratory report to data generation. The audit then follows to testing through sample receipt and original sampling by the sample originator. The attached case study is an example of this latter approach and represents a realistic audit experience. Use of both approaches at different times will challenge the laboratory system and expose personnel to a variety of audit circumstances. Other documents that may be used as the basis for internal audits include the US Food and Drug Association Compliance Program Guidance Manual # (4), FDA Compliance Program Guidance Manual # (5), and PIC/S Aide Memoire: Inspection of Pharmaceutical Quality Control Laboratories (6) and periodic review of FDA Warning Letters (7) are also helpful. FDA observations provide insight into current regulatory emphases and ideas for additional areas or questions in a self-audit. FDA Compliance Program Guidance Manual # This document was written to provide Center for Drug Evaluation and Research (CDER) investigators an overview of areas to be reviewed during a drug manufacturing inspection. It identifies the six basic systems within a quality system including the laboratory control system. This guidance identifies areas within each system which the investigators should review. It also directs that the firm should have written and approved procedures for each of the areas and records of these procedure results. The investigators are also directed to verify that personnel are following the procedures. The areas listed for the laboratory control system are: Training/qualification of personnel Adequacy of staffing for laboratory operations Adequacy of equipment and facility for intended use Calibration and maintenance programs for analytical instruments and equipment Validation and security of computerized or automated processes Reference standards source, purity and assay, and tests to establish equivalency to current official reference standards as appropriate System suitability checks on chromatographic 76 Journal of GXP Compliance

7 P a u l L. P l u t a a n d J e r r y L a n e s e systems such as gas chromotography or high performance liquid chromotography Specifications, standards, and representative sampling plans Adherence to written methods of analysis Validation/verification of analytical methods Control system for implementing changes in laboratory operations Required testing performed on the correct samples Documented investigation into any unexpected discrepancy Complete analytical records from all tests and summaries of results Quality and retention of raw data such as chromatograms and spectra Correlation of result summaries to raw data; presence of unused data Adherence to an adequate out of specification (OOS) procedure which includes timely completion of the investigation Adequate reserve samples; documentation of reserve sample examination Stability testing program, including demonstration of stability indicating capability of test methods The guidance also identifies example laboratory and control system problems. These include the following: Pattern of failure to establish/follow a control system for implementing changes in the laboratory operations Pattern of failure to document investigation of discrepancies Lack of validation of computerized and/or automated processes Pattern of inadequate sampling practices Lack of validated analytical methods Pattern of failure to follow approved analytical procedures Pattern of failure to follow an adequate OOS procedure Pattern of failure to retain raw data Lack of stability-indicating methods Pattern of failure to follow stability programs FDA Compliance Program Guidance Manual # This document provides Center of Biologics Evaluation and Research (CBER) investigators an overview of areas to be reviewed during a biological manufacturing inspection. It identifies the same six basic systems within a quality system and critical elements. Standard operating procedures (SOPs) and training records are highlighted. It also identifies areas within the laboratory control system that should be reviewed, as well as observations that could be reported. These are similar to the areas identified in and include: Written procedures and control system for laboratory operations Calibration and maintenance programs for analytical instruments and equipment Adherence, validation/verification to the written methods of analysis Testing and release for distribution Specifications, standards, and representative sampling plans Stability testing program, including demonstration of stability indicating capability of the test methods Special testing requirements Adequate reserve samples and documentation of reserve sample examination Required testing is performed on the correct samples Laboratory records PIC/S Aide-Memoire This document provides guidance for GMP inspectors for training and preparation of inspections. It contains nine tables addressing general subjects and items to be investigated during GMP inspections. The general subjects addressed in this document include the following: General information Quality assurance system Documentation system Personnel Premises and equipment Summer 2012 Volume 16 Number 3 77

8 P e e r R e v i e w e d : A u d i t Materials and supplies Sampling and samples Testing Results and release of test results An extensive list of specific questions for each of the above sections is listed in PIC/S Aide-Memoire. The above provides a different approach to a laboratory audit with different focus. Supplements addressing GMP inspection of chemical, physical, and microbiological testing laboratories are also provided, also including an extensive list of very specific questions. The quality assurance system section of this document asks the following questions regarding self inspection : How is it, and by whom performed? How is it reported? How are corrective measures implemented? Is the schedule available and adhered to? OTHER CONSIDERATIONS Documents Requested by Auditors Whenever documentation is requested by an auditor, it must be quickly retrieved within a reasonable time (for example, 30 minutes). If R&D reports or other documents or records generated by another unit are not readily available through an electronic report system, hardcopies or relevant reports should be obtained from the originating unit and stored within the laboratory area to facilitate timely retrieval. Excessive time delays in retrieval of documents are not acceptable. Laboratory Procedures Auditors always request the approved laboratory procedures and test methods. These are usually available through an electronic system. In the normal operation of the laboratory, analysts may print a copy for their immediate personal use. This introduces the potential for using an outdated procedure when revisions have occurred. Laboratory personnel must be trained to always access the current procedure when a procedure is needed. There should be a system that prevents the holding and extended use of printed copies. If printed copies are used in performing testing, they should be destroyed after completion of the activity. Audit Training for Personnel Aside from the technical training for personnel on laboratory and testing procedures for the actual performance of sample testing, laboratory personnel should also be trained on proper interactions with auditors. This includes topics such as audit protocol, listening carefully to questions, asking for clarification if requests are unclear, being calm, and phrases to avoid. Internal audits should include analyst interaction to provide practice for handling audits and responding to auditor questions. Laboratory analysts will be nervous when dealing with external auditors. Practice will help to minimize their anxiety and fears. RISK EVALUATION OF IDENTIFIED GAPS Gaps in procedures, processes, records, and performance will be identified after conducting a rigorous self-audit. These gaps must then be evaluated and corrective actions initiated. Highest risk gaps must be prioritized for rapid response. Tables I, II, and III illustrate the results of a representative self-audit using the activity format discussed. Table I provides a representative list of audit observations from a selfaudit using the format of the above discussion. Table II demonstrates a risk evaluation of observations. Table II provides a prioritized list of project assignments addressing gaps with target dates and personnel responsibilities. CASE STUDY: LABORATORY AUDIT A regulatory auditor team was conducting a new tablet product pre-approval inspection at the product manufacturing site. The audit was being conducted in the designated conference room in the manufacturing plant. The regulatory agency auditor, site compliance officer, and QA manager were present in the conference room. 78 Journal of GXP Compliance

9 P a u l L. P l u t a a n d J e r r y L a n e s e TABLE I: Laboratory self-audit LABORATORY OVERVIEW 1 All laboratory equipment not identified in equipment list SAMPLE COLLECTION 2 Sample collection by manufacturing area not well controlled SAMPLE RECEIPT IN LAB 3 Refrigerated samples transport not controlled 4 Refrigerated sample not immediately stored in lab SAMPLE HANDLING AND STORAGE ANALYTICAL METHOD DEVELOPMENT EQUIPMENT VALIDATION / QUALIFICATION 5 All laboratory equipment not appropriately qualified EQUIPMENT MAINTENANCE 6 No maintenance on unidentified equipment ANALYTICAL METHOD VALIDATION SAMPLE TESTING 7 Current procedures not always used for testing DATA TREATMENT RESULTS VERIFICATION AND APPROVAL RESULTS REPORTING INVESTIGATIONS 8 Deficiencies in investigation procedure DOCUMENT COMPILATION DOCUMENT STORAGE AND RETRIEVAL LABORATORY TRAINING 9 Complex procedures do not have sufficient training AUDIT TRAINING 10 Audit training needed for new employees Summer 2012 Volume 16 Number 3 79

10 P e e r R e v i e w e d : A u d i t TABLE II: Risk evaluationof identified gaps # OBSERVATION RISK EVALUATION HIGH MEDIUM LOW LABORATORY OVERVIEW 1 All laboratory equipment not identified in equipment list X SAMPLE COLLECTION 2 Sample collection by manufacturing area not well controlled X SAMPLE RECEIPT IN LAB 3 Refrigerated samples transport not controlled X 4 Refrigerated sample not immediately stored in lab X EQUIPMENT VALIDATION / QUALIFICATION 5 All laboratory equipment not appropriately validated X EQUIPMENT MAINTENANCE 6 No maintenance on unidentified equipment X SAMPLE TESTING 7 Current procedures not always used for testing X INVESTIGATIONS 8 Deficiencies in investigation procedure X LABORATORY TRAINING 9 Complex procedures do not have sufficient training X AUDIT TRAINING 10 Audit training needed for new employees X The process validation report for the new product was requested by the auditors. The process validation report was retrieved from the validation library. The auditors reviewed the report. The auditor then selected the content uniformity test results in the validation report. The report provided the sampling, test procedure, test lab location, acceptance criteria, table of results, description of data treatment, and a statement that the data met acceptance criteria requirements. The auditors then requested to visit the laboratory where test data were generated. The testing laboratory was approximately 30 minutes away from the manufacturing plant. The laboratory supervisor was immediately contacted and informed that the auditors would be visiting his lab in approximately 30 minutes to review content uniformity testing from the process validation. The regulatory audit team, compliance officer, and QA manager then departed for the lab with the process validation report. After arriving at the laboratory and brief introductions of personnel, the lead auditor selected a single test result reported in the process validation report. The specified result was determined by an HPLC test method. He asked to see the following laboratory documentation associated with the test result: 80 Journal of GXP Compliance

11 P a u l L. P l u t a a n d J e r r y L a n e s e TABLE III: Risk mitigation goals, responsibilites, and target dates Sample Collection 1. Obtain sampling collection procedures from respective operations areas and from stability area. Review procedures. Note procedures for refrigerated samples. 2. If needed, propose modification of sample collection procedure to responsible area. Follow up to assure training on new procedure. 3. Review transportation procedures for samples. Note process for refrigerated samples. 4. If needed, propose modification of transportation procedures to responsible areas. Follow up to assure training on new procedure 5. Review sample receipt procedures for lab. Note process for refrigerated samples. 6. If needed, modify sample receipt procedures. Conduct training for laboratory personnel. Laboratory Technical Training 1. Review laboratory procedures. Identify complex procedures. Review training methods associated with complex procedures. Initiate demonstration training requirements for complex procedures as needed. GMP 1. Investigations Procedure. Review Investigations procedure. Modify as needed. Responsibility: Target date: 2. Department GMP Meeting. Remind all personnel to destroy printed procedures and use new copies of procedure from electronic system Responsibility: Target date: Laboratory equipment 1. Verify accuracy of department list of equipment and instrumentation. Add overlooked equipment to list as needed. 2. Initiate appropriate validation/qualification of newly identified equipment. Responsibility: Target date 3. Initiate log book for new identified equipment. Responsibility: Target date 4. Initiate maintenance program for new identified equipment. Audit Training 1. Conduct audit training for all personnel. Summer 2012 Volume 16 Number 3 81

12 P e e r R e v i e w e d : A u d i t The analytical test method procedure associated with the sample The analytical method validation report The analytical method development report After the above review, the auditors then focused on the specific test result. They requested the following: HPLC chromatogram associated with the sample Sample preparatory equipment associated with the test method Actual equipment on which sample was tested Standard used in the test procedure Standard storage, handling, and source of supply Reagents used in the test procedures Reagent preparation procedures including expiration dating Instrument qualification report Calibration procedure Calibration history Name of laboratory analyst Resume of laboratory analyst Training records of laboratory analyst Name of supervisor who approved data and calculations Resume of supervisor Training records of supervisor Procedure for sample receipt and storage Sample receipt area Sample receipt record Sample storage area Procedure for data treatment Procedure for data and report storage Data and report storage facility Procedure describing report security area All laboratory documentation requested was retrieved and reviewed. Results were consistent with the results reported in the process validation report. After looking at the analytical method development report which was written by an analytical R&D scientist, the auditors requested to visit the R&D lab where analytical method development work was conducted. The R&D area was contacted. The R&D manager was informed that the auditors would be visiting the laboratory in connection with the content uniformity method development for the new product. After approximately a fifteen minute walk between site buildings, the audit team arrived at the analytical R&D lab. The following were then requested from the R&D lab manager: General overview of R&D laboratory function Organizational chart for laboratory Analytical R&D report for the content uniform test method Raw data for testing reported in the analytical R&D report (This data was recorded in a laboratory notebook. Consistency between the raw data and the analytical R&D report for representative data was verified.) Procedure describing R&D documentation practices Data security and storage policy Equipment and instrumentation used in the development process, including Instrument maintenance and calibration logs Standards and reagents used in the development process, including expiration dating of materials. Resume and qualifications for R&D scientist who developed the test method Resume and qualifications for R&D manager All auditor questions were successfully answered and requested documents provided. No inconsistencies between reports and original data was found. This case describes a typical progression of a regulatory audit. The audit started with a reported test result. This result was then tracked to laboratory raw data. Activities associated with the test result were then reviewed. These included laboratory test procedures, supporting equipment and instrument information, miscellaneous laboratory systems, and review of training of personnel associated with the original test result. The audit then continued to the R&D area the developed the test method of interest. R&D reports were reviewed, equipment was reviewed, calibration records were checked, reagent 82 Journal of GXP Compliance

13 P a u l L. P l u t a a n d J e r r y L a n e s e dating was checked, personnel training was reviewed, etc. All questions and requests from by the auditor were successfully answered. All documents were quickly retrieved. The audit of the quality control (QC) and R&D laboratories required one full day of review. No deficiencies were cited by the auditor. The auditors then returned to the manufacturing area to continue the audit. FINAL THOUGHTS Successful laboratories operate in a constant state of compliance to internal procedures and regulations and they are continually prepared for an audit. There is no getting ready for an audit. Successful laboratories are always ready. In reality, regulatory auditors may arrive unannounced at a firm at any time and proceed to initiate an audit. Successful laboratories understand this reality and operate appropriately. Conducting self-audits on a regular basis is a good way to assess laboratory performance, improve readiness for an audit, and expose personnel to an audit experience. Using different approaches and styles as described above and in the case study is desirable. Knowledge of regulatory requirements, recommendations, and expectations as described in official documentation is mandatory. Periodic review of regulatory FDA Warning Letters is also helpful. Audits are a way of life. A good laboratory and its personnel are always prepared. REFERENCES 1. Pluta, Paul L., editor. Audit 101. First Impressions -- The Plant Tour. Journal of GXP Compliance, Volume 15 # 1, Winter, Graham, Ballard, Richard Poska, Robert Ertmann, and Paul L. Pluta. Audit 101. Preparation, Preparation, and More Preparation. Journal of GXP Compliance, Volume 15, #4, Autumn USP <1058> Analytical Instrument Qualification. www. usp.org. 4. FDA. Compliance Program Guidance Manual: Program, # Implementation date FDA Compliance Program Guidance Manual: Program Implementation date PIC/S. Aide-Memoire. Inspection of Pharmaceutical Quality Control Laboratories. September 25, FDA. ABOUT THE AUTHORS Paul L. Pluta, PhD, is Column Coordinator and Editor-in-Chief, Journal of GXP Compliance and Journal of Validation Technology. Contact Dr. Pluta with comments or questions on this discussion at paul.pluta@comcast.net. Jerry Lanese, PhD, is an independent consultant specializing in quality systems and laboratory controls. He is a member of the Editorial Board of Journal of GXP Compliance. Contact Dr. Lanese at jerry@lanesegroup.com Summer 2012 Volume 16 Number 3 83