Contents:

Chapter 1: Executive Summary 1-1 Chapter 2: Introduction 2-1 The Assurance of Quality in Drug Research, Development, and Pre-Clinical Testing 2-1 Good Laboratory Practice and the Transfer of Technology2-3 The Cost of GLP Non-compliance 2-6 Chapter 3: International Regulations Governing GLP 3-1 Chronology and Current Regulations 3-1 United States of America 3-1 Europe 3-5 Canada3-5 Japan 3-6 Comparison of the Regulations 3-7 Chapter 4: Critical Compliance Issues4-1 Organization and Personnel (Subpart B, §§ 5829–35) 4-1 Matrix Organization 4-1 Personnel Qualifications, Training, and Behavior (see §§ 5829 & 5831) 4-2 Management Responsibilities (See § 5831) 4-6 Specific Appointments: The Study Director (see § 5833) 4-13 The Quality Assurance Unit (see § 5835) 4-15 Facilities (Subpart C, §§ 5841 – 51) 4-19 Containment Issues 4-20 Animal Unit Design 4-22 Equipment (Subpart D, §§5861–63) (OECD: “Apparatus”) 4-24 Testing Facilities Operation (Subpart E §§ 5881 –90) 4-28 Standard Operating Procedures (§ 5881) 4-28 Guide to SOP Writing 4-30 Reagents and Solutions (§ 5883) 4-35 Animal Care (§5890) 4-36 Test and Control Articles (Subpart F, §§ 58105–113) (OECD: “Test & Reference Items”) 4-38 Protocol for and Conduct of a Study (Subpart G, §§ 58120–130)4-41 The Study Protocol (§ 58120) (OECD “Study Plan”) 4-41 Conduct of the Study (§ 58130) 4-43 Recording of Data 4-44 Electronic Data Management 4-45 Records and Reports (Subpart J, §§ 58185–195) 4-46 The Final Report of the Study (§ 58185) 4-46 Archiving the Data (§ 58190) 4-48 Retention of Archived Records and Specimens (§ 58195) 4-49 Form of Retained Records (§ 58195 g) 4-49 Transfer of Records (§ 58195h) 4-50 Conclusions 4-50 Chapter 5: Submitting Pre-clinical Study Findings in Clinical Trial Applications 5-1 IND Contents According to FDA 5-1 The ICH Common Technical Document 5-3 Nonclinical Summaries and Tables 5-4 Order of Presentation of Information within Sections 5-5 Module 4—Nonclinical Data 5-11 Chapter 6: GLP Inspections and Study Audits 6-1 What Are Inspections and Audits? 6-1 Establishment Inspections 6-1 Key Inspection Points 6-3 Study Audits 6-4 Establishment Inspection Report (EIR) 6-6 Deviations which are not required to be notified by FDA 483 are: 6-6 How to Survive Inspections and Audits 6-7 Before—Preparing for the Inspection 6-7 During—Inspection Days 6-10 After—Dealing with the Report 6-12 How Others Fared—Excerpts from Form 483 6-13 Chapter 7: Conclusions 7-1 Chapter 8: References and Further Reading 8-1 Access to Regulatory Documents 8-1 Useful Publications 8-2 Associations and Information Web Sites 8-3 GLP Consultants 8-3 Chapter 9: Appendices 9-1 GLP Inspection Forms 9-1 Texts of GLP Regulations 9-29 Endnotes 9-71 Japan Ordinance 21 & PAB 424, 19979-107 TABLE OF EXHIBITS Exhibit 21 What is Quality Assurance?2 Exhibit 22 The Stages in Drug Development 4 Exhibit 31 Member Nations of OECD3 Exhibit 32 OECD Documents Concerning GLP and Compliance Monitoring 4 Exhibit 33 Comparison of Contents of GLP Regulations9 Exhibit 34 Definitions of Major Terms 12 Exhibit 41 Matrix Management Chart 2 Exhibit 42 Sample Ground Rules for Laboratory Operation4 Exhibit 43 Section of a Study Schedule GANTT Chart (“On Target” Software) 8 Exhibit 44 Certificate of Analysis 10 Exhibit 45 Suggested Layout for the Master SOP Manual 17 Exhibit 46 Study Monitoring Record 19 Exhibit 47 Critical Factors in Facility Compliance 21 Exhibit 48 Biohazard Laminar-Flow Cabinet, Class II Type B1 22 Exhibit 49 Animal Unit Layout 23 Exhibit 410 Typical Equipment Maintenance Record 26 Exhibit 411 Minimum List of SOPs Required (according to 21CFR5881) 29 Exhibit 412 Templates for SOP 32 Exhibit 413 Solution Label 35 Exhibit 414 Animal Cage Label 37 Exhibit 415 Sample Container Label 40 Exhibit 416 Sample Storage Box Label 41 Exhibit 417 Label for Specimen Container 44 Exhibit 418 Retention Times for Archived Materials 49 Exhibit 419 Other Records to be Maintained 50 Exhibit 51 Contents of the CTD3 Exhibit 52 TOC of Section 26 6 Exhibit 53 Example of Pharmacology Summary Table 8 Exhibit 54 Example of a Specific Pharmacokinetics Table9 Exhibit 55 Example of a Toxicology Summary Table 10 Exhibit 56 Example of a Toxicokinetics Summary Graph 11 Exhibit 57 Table of Contents of Module 4 12 Exhibit 61 Inspection Request Form 12

Summary:

New drug discovery and development becomes more difficult and more expensive every year. The larger pharmaceutical companies continue to seek new leads outside of their own research laboratories in order to control R&D costs, or to extend their portfolio. This is particularly true in the biopharmaceutical area, since most traditional pharmaceutical companies have had limited direct experience in this field and prefer to license-in such technology. Alternatively, the smaller biotechnology company may be acquired by the larger partner. In the same week in May, 2007, two major US companies both published their intent to invest further in biotechnology incubator companies (Pfizer, Inc.) or the purchase of biotechnology companies with late-stage products, especially vaccines (Merck & Co.). In all of these cases, the new product leads will be of increased value to the acquiring partner if the principles of Good Laboratory Practice (GLP) have been followed by the originating scientists. In any drug development program, but especially with the acquisition and further development of any new technology by a major industrial partner, the term “time to market” becomes allimportant, since each month lost in the laboratory is a month when the product is not earning revenue to pay back the ever-increasing costs of development and testing. The drug development and testing timeline is being extended by more stringent regulatory requirements, especially in the pre-clinical testing stages. Time to market will be extended, with negative commercial impact, if critical early research work and drug testing has to be repeated under more strictly controlled conditions in order to comply with the GLP regulations. These regulations were introduced first in the USA in 1979 and revised in 1987. They were intended to assure the quality and integrity of any pre-clinical safety or efficacy data, especially animal testing data, which would be submitted in support of an application to start testing a drug in human subjects, or for approval to market the new drug on completion of the clinical trials. The regulations cover all key areas of pre-clinical laboratory work, including facilities and operations, personnel qualification and training, study design and execution, data recording and archiving and quality assurance procedures. The same requirements may apply in those laboratories which are testing samples derived from clinical studies—in some countries, the concept of Good Clinical Laboratory Practice has been introduced, as a supplement to GLP and to Good Clinical Practice regulations. University laboratories, spin-off companies and smaller drug development companies which therefore undertake to apply GLP to their work as soon as it is required, are those which can attract greater attention from potential industrial partners. Alternatively, if the smaller new companies prefer to proceed to further independent development before approaching “Big Pharma”, they can gain a more rapid acceptance of their experimental results by the regulatory bodies, leading to earlier qualification of the drug for clinical studies. Contract laboratories offering pre-clinical testing services will have to be able to demonstrate to their clients and the regulatory bodies that their operations are fully in GLP compliance. Companies planning to extend their work beyond the bounds of North America will benefit from a better understanding of the OECD principles of GLP and their practical application. This Guide examines the GLP regulations of the U.S.A. and other countries in detail and gives firm guidelines for compliance, using as a basis the GLP requirements published in the U.S.A. Code of Federal Regulations, Title 21, Part 58, 2006 Edition (21CFR58). The regulations laid down by other countries, especially the members of the European Community, are based upon guidelines developed by the Organization for Economic Development (OECD) in 1980. These are very similar to 21CFR58 and have been updated regularly. Guidelines on safety testing and analytical methods issued by the International Conference on Harmonization (ICH) are also reviewed. Those rules which are most commonly cited by FDA inspectors for non-compliance are highlighted. Since compliance is finally determined by official inspections of the laboratory organization and operations, and by audits of data and reports, special attention is paid to documentation and the preparations for internal and external inspections and audits. The recommendations presented in this Guide have been distilled from a large body of information and opinion. The most recent guidelines issued by the FDA and other regulatory authorities to industry and to their inspection staff have been accessed. Opinion and advice collected from other regulatory consultants, including ex-FDA personnel, has been reviewed. With this Guide, the task of GLP compliance is made easier to understand and to achieve.