ESTABLISHING A CGMP LABORATORY AUDIT SYSTEM A Practical Guide David M Bliesner Delphi Analytical Services, Inc Indian Rocks Beach, Florida ESTABLISHING A CGMP LABORATORY AUDIT SYSTEM ESTABLISHING A CGMP LABORATORY AUDIT SYSTEM A Practical Guide David M Bliesner Delphi Analytical Services, Inc Indian Rocks Beach, Florida Copyright © 2006 by John Wiley & Sons, Inc All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400, fax 978-750-4470, or 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consequential, or other damages For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at 877-762-2974, outside the United States at 317-572-3993 or fax 317-572-4002 Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products, visit our web site at www.wiley.com Library of Congress Cataloging-in-Publication Data: Bliesner, David M Establishing a CGMP laboratory audit system : a practical guide / David M Bliesner p cm Includes bibliographical references and index ISBN-13 978-0-471-73840-4 ISBN-10 0-471-73840-9 (cloth : alk paper) Pharmaceutical industry—Law and legislation—United States I Title [DNLM: Drug Industry—standards—United States Laboratories—standards— United States Management Audit—methods—United States Drug Industry—legislation & jurisprudence—United States Laboratories—legislation & jurisprudence—United States QV 736 B648c 2006] KF1879.B55 2006 343.7307Ј86151—dc22 2005024178 Printed in the United States of America 10 To my wife Kathy, and my children Nick, Sam and Erin for their love, support and patience CONTENTS PREFACE INTRODUCTION TO THE QUALITY SYSTEMS APPROACH TO CGMP COMPLIANCE xiii 1.1 1.2 Overview of Quality Systems / Quality Systems and Compliance with CGMPs: Reasons for Auditing Your Laboratory / 1.3 Goals of Auditing Your Laboratory / 1.4 Laboratory Audit Phases / 1.5 Integration with Existing Programs / 1.6 Modifiable and Scalable Approach / Reference / Bibliography / PREPARING FOR THE AUDIT 2.1 2.2 Procedure / Audit Tools and Templates / 2.2.1 Goals of the Audit / 14 2.2.2 Review of the Audit Process / 14 2.2.3 Laboratory Audit Form (LAF) Generation Process / 20 2.2.4 Subelement Audit Strategy Development / 20 vii CURRENT GOOD MANUFACTURING PRACTICE REGULATIONS 263 (d) Records required under this part may be retained either as original records or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records Where reduction techniques, such as microfilming, are used, suitable reader and photocopying equipment shall be readily available (e) Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures Written procedures shall be established and followed for such evaluations and shall include provisions for: (1) A review of a representative number of batches, whether approved or rejected, and, where applicable, records associated with the batch (2) A review of complaints, recalls, returned or salvaged drug products, and investigations conducted under Sec 211.192 for each drug product (f) Procedures shall be established to assure that the responsible officials of the firm, if they are not personally involved in or immediately aware of such actions, are notified in writing of any investigations conducted under Sec 211.198, 211.204, or 211.208 of these regulations, any recalls, reports of inspectional observations issued by the Food and Drug Administration, or any regulatory actions relating to good manufacturing practices brought by the Food and Drug Administration [43 FR 45077, Sept 29, 1978, as amended at 60 FR 4091, Jan 20, 1995] Sec 211.182 Equipment cleaning and use log A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed Entries in the log shall be in chronological order Sec 211.184 Component, drug product container, closure, and labeling records These records shall include the following: (a) The identity and quantity of each shipment of each lot of components, drug product containers, closures, and labeling; the name of the supplier; the supplier’s lot number(s) if known; the receiving code as specified in Sec 211.80; and the date of receipt The name and location of the prime manufacturer, if different from the supplier, shall be listed if known (b) The results of any test or examination performed (including those performed as required by Sec 211.82(a), Sec 211.84(d), or Sec 211.122(a) and the conclusions derived therefrom (c) An individual inventory record of each component, drug product container, and closure and, for each component, a reconciliation of the use of each lot of such component The inventory record shall contain sufficient information to allow determination of any batch or lot of drug product associated with the use of each component, drug product container, and closure 264 APPENDIX V (d) Documentation of the examination and review of labels and labeling for conformity with established specifications in accord with Sec 211.122(c) and 211.130(c) (e) The disposition of rejected components, drug product containers, closure, and labeling Sec 211.186 Master production and control records (a) To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed (b) Master production and control records shall include: (1) The name and strength of the product and a description of the dosage form; (2) The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unit; (3) A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic; (4) An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records; (5) A statement concerning any calculated excess of component; (6) A statement of theoretical weight or measure at appropriate phases of processing; (7) A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation according to Sec 211.192 is required; (8) A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling; (9) Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed Sec 211.188 Batch production and control records Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch These records shall include: (a) An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed; (b) Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including: (1) Dates; (2) Identity of individual major equipment and lines used; (3) Specific identification of each batch of component or in-process material used; (4) Weights and measures of components used in the course of processing; (5) In-process and laboratory control results; (6) Inspection of the packaging and labeling area before and after use; CURRENT GOOD MANUFACTURING PRACTICE REGULATIONS 265 (7) A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing; (8) Complete labeling control records, including specimens or copies of all labeling used; (9) Description of drug product containers and closures; (10) Any sampling performed; (11) Identification of the persons performing and directly supervising or checking each significant step in the operation; (12) Any investigation made according to Sec 211.192 (13) Results of examinations made in accordance with Sec 211.134 Sec 211.192 Production record review All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy A written record of the investigation shall be made and shall include the conclusions and follow-up Sec 211.194 Laboratory records (a) Laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays, as follows: (1) A description of the sample received for testing with identification of source (that is, location from where sample was obtained), quantity, lot number or other distinctive code, date sample was taken, and date sample was received for testing (2) A statement of each method used in the testing of the sample The statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested (If the method employed is in the current revision of the United States Pharmacopoeia, National Formulary, Association of Official Analytical Chemists, Book of Methods,\1\ or in other recognized standard references, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice) The suitability of all testing methods used shall be verified under actual conditions of use NOTE: Copies may be obtained from: Association of Official Analytical Chemists, 2200 Wilson Blvd., Suite 400, Arlington, VA 22201-3301 (3) A statement of the weight or measure of sample used for each test, where appropriate (4) A complete record of all data secured in the course of each test, including all graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific component, drug product container, closure, in-process material, or drug product, and lot tested 266 APPENDIX V (5) A record of all calculations performed in connection with the test, including units of measure, conversion factors, and equivalency factors (6) A statement of the results of tests and how the results compare with established standards of identity, strength, quality, and purity for the component, drug product container, closure, in-process material, or drug product tested (7) The initials or signature of the person who performs each test and the date(s) the tests were performed (8) The initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards (b) Complete records shall be maintained of any modification of an established method employed in testing Such records shall include the reason for the modification and data to verify that the modification produced results that are at least as accurate and reliable for the material being tested as the established method (c) Complete records shall be maintained of any testing and standardization of laboratory reference standards, reagents, and standard solutions (d) Complete records shall be maintained of the periodic calibration of laboratory instruments, apparatus, gauges, and recording devices required by Sec 211.160(b)(4) (e) Complete records shall be maintained of all stability testing performed in accordance with Sec 211.166 [43 FR 45077, Sept 29, 1978, as amended at 55 FR 11577, Mar 29, 1990; 65 FR 18889, Apr 10, 2000] Sec 211.196 Distribution records Distribution records shall contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped, and lot or control number of the drug product For compressed medical gas products, distribution records are not required to contain lot or control numbers (Approved by the Office of Management and Budget under control number 0910-0139) [49 FR 9865, Mar 16, 1984] Sec 211.198 Complaint files (a) Written procedures describing the handling of all written and oral complaints regarding a drug product shall be established and followed Such procedures shall include provisions for review by the quality control unit, of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with Sec 211.192 Such procedures shall include provisions for review to determine whether the complaint represents a serious and unexpected adverse drug experience which is required to be reported to the Food and Drug Administration in accordance with Sec 310.305 and 514.80 of this chapter (b) A written record of each complaint shall be maintained in a file designated for drug product complaints The file regarding such drug product complaints shall be maintained at the establishment where the drug product involved was manufactured, processed, or packed, or such file may be maintained at another facility if the written records in such files are readily available for inspection at that other facility Written records involving a drug product shall be maintained until at least year after the expiration date of the drug product, or CURRENT GOOD MANUFACTURING PRACTICE REGULATIONS 267 year after the date that the complaint was received, whichever is longer In the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under Sec 211.137, such written records shall be maintained for years after distribution of the drug product (1) The written record shall include the following information, where known: the name and strength of the drug product, lot number, name of complainant, nature of complaint, and reply to complainant (2) Where an investigation under Sec 211.192 is conducted, the written record shall include the findings of the investigation and follow-up The record or copy of the record of the investigation shall be maintained at the establishment where the investigation occurred in accordance with Sec 211.180(c) (3) Where an investigation under Sec 211.192 is not conducted, the written record shall include the reason that an investigation was found not to be necessary and the name of the responsible person making such a determination [43 FR 45077, Sept 29, 1978, as amended at 51 FR 24479, July 3, 1986; 68 FR 15364, Mar 31, 2003] Subpart K-Returned and Salvaged Drug Products Sec 211.204 Returned drug products Returned drug products shall be identified as such and held If the conditions under which returned drug products have been held, stored, or shipped before or during their return, or if the condition of the drug product, its container, carton, or labeling, as a result of storage or shipping, casts doubt on the safety, identity, strength, quality or purity of the drug product, the returned drug product shall be destroyed unless examination, testing, or other investigations prove the drug product meets appropriate standards of safety, identity, strength, quality, or purity A drug product may be reprocessed provided the subsequent drug product meets appropriate standards, specifications, and characteristics Records of returned drug products shall be maintained and shall include the name and label potency of the drug product dosage form, lot number (or control number or batch number), reason for the return, quantity returned, date of disposition, and ultimate disposition of the returned drug product If the reason for a drug product being returned implicates associated batches, an appropriate investigation shall be conducted in accordance with the requirements of Sec 211.192 Procedures for the holding, testing, and reprocessing of returned drug products shall be in writing and shall be followed Sec 211.208 Drug product salvaging Drug products that have been subjected to improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures shall not be salvaged and returned to the marketplace Whenever there is a question whether drug products have been subjected to such conditions, salvaging operations may be conducted only if there is (a) evidence from laboratory tests and assays (including animal feeding studies where applicable) that the drug products meet all applicable standards of identity, strength, quality, and purity and (b) evidence from inspection of the premises that the drug products and their associated packaging were not subjected to improper storage conditions as a result of the disaster or accident Organoleptic examinations shall be acceptable only as supplemental evidence that the drug products meet appropriate standards of identity, strength, quality, and purity Records including name, lot number, and disposition shall be maintained for drug products subject to this section INDEX Acceptance criteria, 200 Accountability-authority-responsibility (AAR) triangle, 93 Accuracy, 200 Action level/alert level, 200 Action owner: corrective action implementation, 74–75 corrective action support, 83 functions of, 76 nonverifiable actions revisions, 83 verification of corrective action, 76, 78, 83 Action team leader: corrective action plan implementation, 75 corrective action support, 83 reverification process, 83 verification of corrective action, 76–78 Active pharmaceutical ingredient (API), 201, 203–204, 209–210 Administrative systems, see Managerial and administrative systems Analytical methodology development, Analytical performance characteristics, 201 Annual record review, AOAC Book of Methods, 207 API, see Active pharmaceutical ingredient Approach, audit summary report, 49, 147–148, 150–152 Atypical results, 201 Audit and data capture phase, workflow: diagram, 40 explanation of steps, 41–44 procedures, 4, 39–44, 90 Audit checklists, see Checklists Audit Headquarters, 15 Audit notebook: data capture, 42 documentation quality, 36 Laboratory Audit Form, 32 monitoring phase documentation, 86 purpose of, 14–15, 18, 28–29, 49, 61–62 sampling plan development process, 37 Audit participants, roles and responsibilities matrix, 11, 17–19 Audit process, in-depth review, 11, 14–16 Audit start date, 10 Audit strategy: development, 12, 14–15, 20, 25–26 implementation of, 15 Audit summary report (ASR): approach, 49, 147–148, 150–152 background, 49, 147 completion of, 17 creation of, 46–47 defined, 201 269 270 INDEX Audit summary report (ASR) (Continued) draft of, 17 example template for, 146–199 format, 49–50, 148, 152 future work section, 51, 148–149, 154 header, 48–49, 147, 150 laboratory controls subelement sections, 52, 149, 155–199 presentation of, 46–48 publication of, 46, 48 purpose of, 34, 45–46 review of, 46–47, 55 summary of results, 50–51, 148, 152–154 Audit team leader: assignment of, 7–9 audit notebook review, 16 briefing of audit team members, 10 checklist review, 16 compliance upgrade compliance plans, 44 coordinates audit detail with management, 42 corrective action, see Corrective action team leader corrective action plan, 54, 57 debriefing session, 43–44 functional areas defined by, gap analyses, 43–44 Laboratory Audit Form compilation, 43 overview presentations, 7, 12–13 reporting phase role, 47–48 results presentation to senior management, 43 roles and responsibilities matrix, 17 supporting data compilation, 43 tools and template development, 6, 11 training audit team members, 10–12 Audit team members: assembly and briefing of, 7, 10 corrective action phase, 54 See also Corrective action team members introduction of, 10 reporting phase roles, 46–48 selection of, 7, 9–10 training/training agenda, 7, 10–12, 14 Audit workflow diagram, 11 Background section, audit summary report, 49, 147 Batch: compounding, defined, 210 record, 210 release, Bias, 34 Blank, 201 Briefing sessions, 58 Building and facilities, maintenance of, See also Facilities management Calendar(s): finalizing, 41 monthly, 16 weekly, 16 working, 11–12 Calibration See also Equipment qualification and calibration curve, 201–202 defined, 201 Capacity factor kЈ, 202 CBE 30 (change by effect, 30 days), 202 CGMP deficiencies, see Deficiencies Change control: change implementation, 92 importance of, procedure, 201 Change implementation, 92 Checklists: applications, 94–95 corrective action plan, 61 deficiencies/gaps, 28 Laboratory Audit Form, 30–32 Laboratory Documentation Practices and Standard Operating Procedures Subelement (OP), checklist, 106–116 Laboratory Equipment Qualification and Calibration (LE) Subelement checklist, 117–121 Laboratory Facilities (LF) Subelement checklist, 122–126 Laboratory Managerial Administration Systems (MS) Subelement checklist, 96–105 Methods Validation and Technology Transfer Subelement (MV) checklist, 127–146 review of, 14–15, 41 subelement, 28, 96–146 use of, 16 Check standard, 202 Chromatographic analysis, 210 Cleaning processes, validation of, Closures, Code of Federal Regulations (CFR): defined, 202–203 21 Code, Parts 210 and 211, CGMP Regulations, 236–267 Collaborations, 26 Commissioning document: content requirements, corrective action plan, 57–59 INDEX review of, 10, 12 senior management role in, 54, 57 Compendial tests methods, 202 Complaint, 202 Compliance: benefits of, 93 determination of, 16 level, 45 monitoring system, Component, defined, 202 Compounding, 202 Compressed gases, Computer software, tracking database, 87 Computer systems: applications, 3, 9–10, 147 sample audit summary report, 189–193 system establishment, 49, 89 Conflict resolution, 42 Consent decree, 202 Consultants, roles and responsibilities of, 8, 11, 19 Containers, Contract research organization (CRO), 203 Corrective action(s): audit summary report (ASR), 50 disclosure of, 18, 26 disclosure session agenda, 24 identification of, 85 Laboratory Audit Form, 33 management assignment of, 67–68 monthly status reports, 60 ownership, 92 phase in laboratory audit, 4, 46 plan development, see Corrective action plan development (CAPD) presentation of, 13 process, 12 verification of, see Verification plan Corrective action and preventive actions (CAPA): creation of, 61, 68 defined, 53 implementation of, 54, 60, 77 Laboratory Audit Form conversion to, 61–62, 66–68 Corrective action plan development (CAPD) See also Corrective action project plan (CAPP) corrective action plan, 61 Gantt chart format example, 65 LAF-to-CAPA workflow diagram, 61–62, 66–68 monthly status reports, 60 procedure, 43, 53 steps of, 55–60 work breakdown structure (WBS), 53–54, 59, 63–64, 68 workflow diagrams, 54, 61–62 271 Corrective action project plan (CAPP): creation of, 4, 33, 53, 68, 88 database, 29 defined, 203 implementation of, 54, 60, 85, 87 Laboratory Audit Form conversion to, 34–35 monitoring phase, 85, 88 updates to, 75 Corrective action team members: assembly of, 54 briefing, 54 design and implementation systems-based corrective actions, 75 selection of, 54, 58 team leader, functions of, 58, 60, 78 training, 54, 59 Corrective and preventive actions (CAPA) defined, 203 Critical deficiencies, 48 Critical gaps, 28, 50–51 See also Gap analyses Current good manufacturing practices (CGMPs), defined, 203 Customer identification, 26 Daily meetings, 18–19, 42–43 Database(s): of Laboratory Audit Forms (LAFs), 15 tracking software, 87 Data capture: audit workflow, 4, 39–44, 90 instruments, 28 procedures, 11–12, 27–34 Data collection, See also Data capture Data package, verification plan, 74 Debriefing session, 15, 19, 43–44 Deficiencies: correction documentation, 85–87 correction strategies, 48 corrective actions, 54, 61, 83 determination of, 56 direct, 26 disclosure of, 13, 18 documentation of, 11, 27–28 identification of, 13 presentation of, 48 remediation of, 43 severity of, 56–57 Degradation compounds, 213 Degradation product, 203 Detection limit (DL), 203 Development report, 203 Disclosure sessions: agenda, 13, 24–25 deficiencies, 18, 28 272 INDEX Disclosure sessions (Continued) preparation for, 17–18 presentations, 18 purpose of, 7, 12–13, 15 sample of, 20, 25 Dissolution, 213 Distribution controls, Document control system, 203 Documentation: using audit notebook, 28–29, 32 audit summary report, 49, 164–170 corrected deficiencies, 87 of deficiencies, 11, 27–29, 32–34 defined, 203 disclosure of/disclosure session agenda, 24, 26 good practices, 205 guidelines, Laboratory Audit Form generation, 42 modification phase, 86–87 monitoring, 18–19 practices, 3, requirements, 15 review of, 28, 32 system establishment, 89 Do-loop cycle, 83 Dosage form production, Drug product, 203 Drug storage, Drug substance, 204 Effective date, 204 End user(s): applicability to your facility, 90–91 audit as learning tool, 92 benefits of compliance, 93 potential compliance, 92 proven approach, 90 success factors, 92–93 systems-based solutions, value of, 91–92 Equipment calibration, see Equipment qualification and calibration Equipment qualification and calibration: components of, 2–3, 9, 147 disclosure session agenda, 25 documentation requirements, 29 sample audit summary report, 171–178 system establishment, 49, 89 Excipient(s), 204 Expiration date, 204 External audits, data collection, External department representative, Extra-site relationships, 26 Extraction efficiency, 204 Face-to-face meetings, 78 Facilities management: components of, 2–3, 9, 147 sample audit summary report, 179–182 system establishment, 49, 89 Federal Food, Drug, and Cosmetic Acts, xiii, Federal Register, 202 Filter study, 204 Finished pharmaceuticals, Code 211 of Federal Regulations, 242–257 Finished production controls, Finished product testing laboratories, 5-to-1 rule, 93 Flowchart diagrams, 91 Follow-up interviews, 16 Food and Drug Administration (FDA): Compliance Program Guidance Manual 7356.002, 215–235 corrective action plans, 57, 66–67 defined, 204 drug manufacturing regulation, xiii–xiv, Laboratory Control System (LCS) defined, 89 monitoring plan, 84 observations, 28–29 Preapproval Inspection (PAI), 14, 49 regulatory action, 90 Footer information, LAF, 33 Forced degradation studies, 204 Form 483 observation, 50, 56, 200 Format, audit summary report (ASR), 49–50, 148, 152 Formulation, 204 Functional area management: disclosure session agenda, 24–26 interim control plan, 57 Functional area managers, role of: audit and data capture phase, 43 corrective action plan, 54–55, 59 debriefing session, 43 overview of, 12, 17–18 preparation phase, 7, 12–13, 20, 25 verification phase, 74–75 Future work section, audit summary report (ASR), 51, 148–149, 154 Gantt chart, 68 Gap analyses, 4, 28, 43, 49–50, 56–57, 70–71 Gap analysis in sample audit summary report: computer systems, 191–193 documentation and standard operating procedures, 166–170 equipment qualification and calibration, 173–178 facilities, 181–182 INDEX investigations, 196–197 managerial and administrative systems, 158–163 methods validation and technology transfer, 186–188 Gap priority, 58 Glossary, 200–214 Goals of audit: review of, 11 team training agenda, 14 Good documentation practices, 205 Header, audit summary report (ASR), 48–49, 147, 150 High-performance liquid chromatography (HPLC), 210, 212–213 High priority assignment, 32, 56 HVAC, ICH, see Tripartite International Conference on Harmonization Identification tests, 205, 213 Immediate deficiencies, 57 Immediate priority assignment, 32, 56 In-process: control/test, 9, 205 sampling, testing, Installation operation and performance qualification (IQ/OQ/PQ), 205 Installing equipment, Interim controls: determination of, 57 development of, plan implementation, 54 In-use data, corrective and prevention action, 77–78 Intermediate, defined, 205 Intermediate precision, 208 Internal audit, 4, 205 Interview/interviewing: deficiency/gap analyses, 28 follow-up, 16 Laboratory Audit Form, 32 personnel selection, 15 schedules, 14, 20 by subject matter experts (SMEs), 18 training for, 20 Inventory and control processes, Investigation(s): components of, 3, 9, 62, 147 disclosure session agenda, 25 Laboratory Audit Form, 32 sample audit summary report, 196–197 system establishment, 49, 89 273 Label/labeling: claim, 205 examination and usage, storage and issuance, operations controls, Laboratory audit: effectiveness of, efficiency of, goals for, 3–4, 90 phases of, 4, 90 quality of, reasons for, Laboratory Audit Form (LAF): conversion to audit summary report (ASR), 34, 199 corrective action and, 59 to corrective action plan workflow diagram, 35 database entry, 43, 87 deficiencies, 47, 66 defined, 205 example of, 30–31 gap analyses, 29, 32–34 generation process, 14–15, 20, 85–86 link to system deficiencies, 67 preparation phase, 17–19 participants in, 17–19 purpose of, root causes of, 55 review of, 42 sample tracking database, 44 Laboratory controls subelement section: audit summary report (ASR), 52, 149, 155–199 purpose of, 2–3, 29, 56 Laboratory Documentation Practices and Standard Operating Procedures Subelement (OP), checklist, 106–116 Laboratory Equipment Qualification and Calibration (LE) Subelement checklist, 117–121 Laboratory Facilities (LF) Subelement checklist, 122–126 Laboratory information management system (LIMS), 205 Laboratory investigation report (LIR), 205 Laboratory Managerial Administration Systems (MS) Subelement checklist, 96–105 Laboratory qualification, 205 Laboratory trainer, hiring process, 77 LAF-to-corrective-and-preventive action: implementation, 59, 66 sample audit summary report, 199 Leadership, see specific types of team leaders 274 INDEX Limit of: detection (LOD), 203 quantitation (LOQ), 209 Linearity: defined, 206 of method, 209 Linkages, Laboratory Audit Form, 33 Lot, 206 Low priority assignment, 32, 56 Managerial and administrative systems See also Facilities management sample audit summary report, 147, 155–163 system establishment, 3, 9, 26, 28, 49, 57, 89 verification phase, 71 Mapping, 91 Master production record, 206 Material resource analysis, 92 Materials system, Matrix (sample matrix), 206 Maximum allowable residue, 206 Meeting(s): face-to-face, 78 room reservation, 15 verification plan development, 78 Method: development, 206 qualification, 206 transfer, 9, 207 verification, 207 Methods validation and technology transfer: components of, 3, 9, 147 methods validation defined, 207 sample audit summary report, 183–188 system establishment, 49, 89 Methods Validation and Technology Transfer Subelement (MV) checklist, 127–146 Model laboratories, characterized, 90 Modifiable approach, 5, 91 Monitoring changes, 92 Monitoring phase, of laboratory audit: long-term goal of, 84 procedure, 4, 11, 84, 90 workflow diagram, 85 steps of, 86–88 Monitoring team: assembly of, 85–86 Laboratory Audit Form generation, 85–86 schedule implementation, 85–86 training, 85–86 Monitoring team, corrected deficiencies documentation, 87 Monthly audit routine schedule: example of, 23 template, 11, 16 Non-CGMP deficiencies, 26 Nonchecklist gaps, 50 Noncompliance, identification of, 42 Noncritical gaps, 28, 50–51 Nonverifiable corrective actions, 76, 82–83 Note-taking, verification package development, 78 See also Audit notebook Open disclosure, 13 Operating equipment, See also Equipment qualification and calibration Organizational chart, 12, 20, 25, 41 Out-of-specification investigation (OOS result), 32, 207 Outsourcing, 26 Packaging and labeling system, See also Labels/labeling Percent relative standard deviation (Percent RSD or % RSD), 207 Personnel, see also specific types of teams disclosure session agenda, 24–25 management, 91–92 qualification, 207 Placebo: defined, 207 spiked, 211 Plan development and implementation process, 3–4, 43 Preapproval inspection (PAI), 207 Precision, 208 Preparation phase, of laboratory audit: audit process, 14, 16 audit tools and templates, 6, 8–13 defined, procedure, 6, 90 workflow diagram, 7, 14–15 Presentations, corrective action verification plan, 82 Preventative maintenance, Preventive action process, 12, 43 Preverification package: development of, 77 review of, 78 Previous audit, results of, 28 Priority assignment, LAF, 32 Priority list, 54, 58 Process impurity, 207 Process performance qualifications, Process validation, Product defect evaluations, Product efficacy, 48, 56 Production system, Product release testing, 36, 90 Product safety, 48, 56 INDEX Product stability testing laboratories, Prospective validation, 208 Protocol, 208 Purchasing guidelines, 92 Q, defined, 208 QA, see Quality assurance (QA) Qualification, 208 Quality assurance (QA): filed verification package, 74 monitoring phase, 85–88 representative, roles and responsibilities of, 8–11, 19, 57 unit defined, 208–209 verification plan development, 74 verification phase, 71, 75 Quality control (QC), 209 Quality management system self audit, 150–152 Quality systems: components of, 1–2 defined, 209 elements of, 33 goals of auditing, 3–4 integration with existing programs, laboratory audit phases, modifiable and scalable approach, 4–5 overview of, 1–3 reasons for auditing, Quality unit, 209 Quantitation limit (QL), 209 Quarantine, 209 Range, 209 Raw data, 209 Raw material, 9, 210 Reagents, disclosure session agenda, 25 Recidivism, monitoring phase, 84–85, 88 Recordkeeping, See also Documentation Reference standard: defined, 210 disclosure session agenda, 25 Related compounds, 210 Relational database, development of, 43 Relative response factor (RRF), 210 Relative retention time (RRT), 210 Repeat audits, 11 Repeatability, 208, 210 Reporting limit, 210 Reporting phase, of laboratory audit: components of, 4, 90 steps of, 47–48 workflow diagram, 46 Reporting procedures, 12 See also specific types of reports 275 Reprocessing, 1, 210 Reproducibility, 208 Resolution, 210 Response factor, 210 Results summary matrix, 51 See also Audit summary report (ASR) Retain sample, 210 Retraining, 92 Retrospective validation, 211 Returned and salvaged products, evaluation of, Revalidation, 211 Reverification, 82–83 Robustness, 211 Root cause analysis: determination of, 54–56, 58, 67, 91 verification report, 83 Root causes: analysis of, see Root cause analysis in gap analyses, 49 Laboratory Audit Form, 32 Routine priority assignment, 32, 56 Ruggedness, 211 Sampling plans, 14–15, 20, 25, 36–39 Scalable approach, 4–5, 91 Schedule/scheduling: adherence to, 18 audit interviews, 14–15, 20 audit start date, 10 development of, 17, 82 finalizing, 41 flexibility with, 41 monthly routine calendar, 16 time allocation, 8–10, 12–13, 47 weekly routine calendar, 16 workflow diagram, Selectivity, 211 Senior management roles: correction action phase, 54–55, 57 importance of, 9, 15, 17 results presentations, 43 verification role process, 75 Signal-to-noise, 211 Specification, 211 Specificity, 211–212 Spiked placebo, 211 Spiking, 211 Stability indicating methodology, 212 Stability program, Standard and sample solution stability, 212 Standard operating procedures (SOPs): audit summary report, 164–170 characterized, 3, 9, 36, 55, 62, 77 system establishment, 49, 89 Start dates, 60, 68 276 INDEX Statistical sampling: components of, 14, 20, 25, 41 random, 34, 36 Steam, Stop dates, 60, 68 Storage, Strategy development, 41 Stressed studies, see Degradation studies Subelement audit team: audit checklist review, 41 corrective action plan, 64 debriefing sessions, 44 disclosure document review, 41 documentation, obtaining, 41 final audit schedule, 41 interview candidate selection, 41–42 Laboratory Audit Form generation and review process, 42 meeting schedules, 41 roles and responsibilities of, 15, 18–19 sampling plan development, 41–42 strategy development, 41 strategy execution, 42 Subject matter expert (SME), 10, 18, 41, 212 Summary of results section, audit summary report (ASR), 50–51, 148, 152–154 Supervising changes, 92 Supervisors, role in preparation phase, 13 Supplies, disclosure session agenda, 25 Supporting data: importance of, 15, 18, 26, 28, 42, 61 Laboratory Audit Form, 33 monitoring phase, 86 verification process, 75 System deficieincy, 67, 71 See also Deficiencies Systems-based approach: corrective action, 75, 88 solutions, value of, 91–92 System suitability, 212 Tailing factor, 212 Technology transfer, 3, 9, 147, 213 Testing validation, Test method, 2, 213 Theoretical plates, 213 Time allocation: corrective action phase, 54 preparation phase, 8–10, 12–13 reporting phase, 47–48 reverification process, 82 Tools and templates: development of, 8–13 modification of, 11, 14 Tracking and trending report: data collection, 85 development of, 85 frequency of, 87 publication of, 87 review of, 88 Training, for audit team members: agenda for, 7, 10–12, 14 benefits of, 92 CGMP deficiency documentation, 27 components of, 10–12 data capture, 27 scheduling dates, 10 team leader roles, 11–12 Transcription accuracy verification (TAV), 213 Tripartite International Conference on Harmonization, 213 United States Pharamcopoeia (USP/NF), 202 USP Ͻ1225Ͼ Category I/II/III/IV, 213 Utilities, Validation See also Analytical performance characteristics defined, 214 phase, 56 protocol, 1–2, 214 report, 214 Value-added tasks, 91 Verifiable corrective action, 73, 78, 82–83 Verifiable pending in-use data, 78, 82 Verification defined, 214 Verification phase, of laboratory audit: components of, 4, 11, 54, 90 verification schedule, 72 workflow design, 70 Verification plan, development and implementation of: corrective action verification process, 69 example of, 79 generation process, 78 process, 69 workflow diagram, 70 steps of, 71–75 systems-based corrective actions, 75 Verification report: creation/generation of, 73, 77, 79 example of, 80–81 modifications to, 82–83 review of, 82 Verification review board (VRB), 71, 73–74, 76, 78, 82–83 Verification team, roles and responsibilities, 71, 77 INDEX Verification team leader: CAPP updates, 75 corrective action support, 81, 83 scheduling, 72, 76, 82–83 supportive data for verifiable corrective actions, 83 verification status report, 75 Verifiers: characteristics of, 78 review of preverification packages, 78 roles and functions in corrective action verification, 77–80, 82 verification report, 79–81 Violations, identification of, 43 Water systems, Weekly audit routine: example of, 21–22 template, 11, 16 Work breakdown structure (WBS): corrective action plan, 59–60, 63, 68 defined, 53 example of, 63–64 in workflow diagram, 54 Workflow See also Workflow diagram disclosure session agenda, 24–26 process analysis, 91 Workflow diagram: audit, 11 audit and data capture phase, 40 audit process sample, contents, 14 corrective action plan development, 54, 61–62 example of, 15 LAF-to-CAFA, 35, 61–62, 66–68 monitoring phase, 85 preparation phase, 7, 14–15 reporting phase, 46 sample audit summary report, 198 schedule/scheduling, verification phase, 70 work breakdown structure (WBS), 54 Working calendar, 11–12 Written procedures, 2, 26 See also Standard operating procedures (SOPs) 277 .. .ESTABLISHING A CGMP LABORATORY AUDIT SYSTEM A Practical Guide David M Bliesner Delphi Analytical Services, Inc Indian Rocks Beach, Florida ESTABLISHING A CGMP LABORATORY AUDIT SYSTEM ESTABLISHING. .. 1.0 Day Audit Team Leader Assigned Step 0.25 Day Audit Team Leader Defines Functional Areas to be Audited Step 1.0 Day Audit Team Leader and Functional Area Managers Give Familiarization and Overview... they are discovered Establishing a CGMP Laboratory Audit System: A Practical Guide is a systematic approach for auditing your laboratory to demonstrate to your xiii xiv PREFACE organization and,