Contents:

Chapter 1: Executive Summary 1-1 Chapter 2: Introduction2-1 Validation in Research, Development, and Manufacturing 2-1 The Regulatory Environment 2-2 Types of Validation 2-5 Corporate Implications of Non-compliance with GVP 2-8 Chapter 3: The Validation Master Plan 3-1 Introduction 3-1 Validation Master Plan Contents 3-1 Responsibilities 3-4 What is to be Validated? 3-4 Facilities 3-4 Systems3-5 Processes 3-5 Analytical Methods 3-6 Implementing the Plan 3-7 Design, Installation, and Operational Qualification3-7 Performance Qualification and Validation 3-8 Documentation 3-9 Change Control 3-11 Chapter 4: Facilities, Services, and Systems4-1 Facilities 4-1 Design and Construction4-1 Utilities 4-2 Validation of Special Systems 4-4 Water Systems: Purified and WFI 4-5 Sterilization Systems and Clean Steam Systems 4-8 Clean Rooms—Aseptic Work Areas 4-13 Computerized Systems 4-17 Chapter 5: Process Equipment and Pipe-work 5-1 Introduction 5-1 Design and DQ of Equipment and Piped Systems 5-2 Installation, Operation, and Performance Qualification 5-3 Validation of Cleaning Procedures 5-5 Validation of Sterilization-In-Place Procedures 5-6 Chapter 6: Manufacturing Processes 6-1 General Principles of Process Validation6-1 Guide to the Performance of Validations 6-8 Special Processes—Validation Challenges 6-9 Glassware Washing Machines 6-10 Fermentor and Bioreactor Control 6-11 Chromatographic Separation 6-13 Transverse-flow Micro- and Ultrafiltration 6-16 Sterilizing Filtration 6-18 Virus Removal Processes6-21 Aseptic Filling Operations 6-23 Lyophilizer (Freezedryer) Operation 6-27 Chapter 7: Analytical Methods for In-process and Final Quality Control 7-1 Regulatory Requirements and Guidelines7-1 Qualification of Analytical Instruments and Equipment 7-2 Test Method Validation 7-5 Types of Analytical Procedures to be Validated 7-6 Test “Verification”, “Qualification” versus “Validation” 7-8 Physical and Chemical Analyses 7-9 Biological Assays 7-11 Chapter 8: Sample Checklists and Forms 8-1 Check Lists for Plans and Protocols 8-1 Equipment Qualification Report Forms 8-5 Chapter 9: References and Further Reading 9-1 Access to Regulations on the Internet 9-1 Validation and GMP Compliance Guidelines 9-2 Canada 9-2 European Union 9-3 International Conference on Harmonization (ICH) 9-3 Associations, Consultants and Publications 9-3 Chapter 10: Abstracts from International GLP/GMP/GCP Regulations 10-1 Good Laboratory Practice 10-1 OECD PRINCIPLES OF GOOD LABORATORY PRACTICE* 10-1 (as revised in 1997) 10-1 USA Code of Federal Regulations 10-2 CANADA – “Guidelines for Good Manufacturing Practice” 10-3 JAPAN MHW Ordinance 16, March 123, 1999, Amended by MHW Ordinance #95, May 20, 2003 10-8 Chapter 11: Text of Key Validation Guidelines 11-1 Process Validation Guidelines11-1 TABLE OF EXHIBITS Exhibit 21 Definitions of “Process Validation” 2-2 Exhibit 22 The Drug Development Cycle 2-3 Exhibit 23 International "Practice" Regulations 2-4 Exhibit 24 Regulations Specifically Concerning Validation 2-4 Exhibit 25 Process Validation and the Product Development Cycle 2-6 Exhibit 31 Typical “System Definition” Table for a VMP 3-3 Exhibit 32 Derivation of Validation Plans/Protocols 3-8 Exhibit 33 Validation Protocol Contents List 3-10 Exhibit 41 Factors Determining User Requirements Specifications 4-2 Exhibit 42 Standards for Pharmaceutical Water Grades 4-5 Exhibit 43 Schematic of WFI System 4-7 Exhibit 44 Clean Room Classes According to FS 209E4-14 Exhibit 45 EUDRA Clean Room Specifications4-15 Exhibit 46 ISO 14644-1 Standard 4-16 Exhibit 47 EU Microbiological Monitoring of Clean Areas 4-16 Exhibit 61 Validation and Product Development 6-3 Exhibit 62 Process Validation Life Cycle 6-5 Exhibit 63 Terminology of Process Validation 6-6 Exhibit 64 Calculation of Process Capability 6-7 Exhibit 65 Washer Qualification Plan 6-11 Exhibit 66 Control of a Cell Culture Bioreactor6-13 Exhibit 67 Typical Flow/Pressure Graphs for TFF Membranes 6-17 Exhibit 68 Parameters Affecting Sterilizing Filter Performance6-20 Exhibit 69 Viruses Commonly Used in Clearance Studies 6-23 Exhibit 71 Basis of Questionnaire for Vendor Qualification 7-3 Exhibit 72 The Characteristics of a Calibration Curve 7-6 Exhibit 73 Parameters Applicable to Different Analytical Procedures7-7 Exhibit 74 Analytical Methods Applied to Biological Products 7-8 Exhibit 75 Calculation of Intra-assay and Inter-assay Precision7-13 Exhibit 76 Three-dimensional Factorial Test Validation Plan7-15 Exhibit 111 FDA Guideline on General Principles of Process Validation 11-2 Exhibit 112 EU European Commission 11-16 Exhibit 113 ORA Compliance Policy Guide11-26 Exhibit 114 Guidance to 21CFR11 11-31 Exhibit 115 FDA/ICH Analytical Method Validation Q2A & B 11-43 Exhibit 116 FDA Bioanalytical Method Validation 11-59

Summary:

The major emphasis in drug product development in these competitive times is on the reduction of “time to market”. It follows that delays to clinical trial initiation or product approval resulting, for example, from validation non-compliance, will adversely affect the company’s cash flow and competitive position. They will make the return on the high development and clinical testing costs that much more difficult. In addition, the failure to provide satisfactory documentation of processes involved in the production and testing of a marketed product can result in product recalls and even legal action against the company by the regulatory authorities. Moreover, the regulatory authorities are placing increasing emphasis on adequate validation documentation in new drug applications. This is being applied to the submissions from drug manufacturers for permission to proceed to clinical trial (e.g. USA IND), as well as those to market the product (NDA),. This documentation must demonstrate that all critical activities that may affect the safety, purity or efficacy of the product are properly defined, controlled and reproducible in performance. Validation requirements may be applied to the manufacturing facility, its critical services and systems, the manufacturing processes, and all analytical test methods used to demonstrate the conformation of the product with its pre-set specifications. Although regulatory agencies in North America and Europe have issued guidelines on validation methods, the means whereby validation may be achieved in particular cases, especially in the production of biopharmaceuticals, are not always clear. The Process Validation Guideline from 1987 is being revised by the FDA and a new draft is expected soon. The revision will be based upon the concepts of the revised Compliance Policy Guide 7132c.08 Sec. 490.100: “Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients subject to Pre- Market Approval”, issued in March 2004. Validation is now considered not to be a one-time event in the development and finalization of a particular process or analytical method. A proper program for validation, especially of processes, must include a “life cycle” approach. The ongoing monitoring of manufacturing processes is a key element in this process. Priorities in validation must be based upon an accepted risk evaluation process, with those processes posing the greatest potential for risk to the integrity of the product being given the highest priority. This will involve the application of the concept of Quality by Design, emphasized in new guidances on Quality Management Systems and Process Analytical Technology. Life-cycle validation will be achieved by gathering complete product/process knowledge, establishing a “continuous quality verification system” and a successful monitoring/assessment program to address effective process control and continuous improvement as the key factors for reducing the risk to the product quality. For these reasons, this guide is devoted to considering in greater detail the ways of complying with validation requirements at all stages of drug research, development and manufacture. The particular problems associated with the newer biopharmaceutical products are given special consideration. The definitions currently accepted for the validation process may be summarized by stating that “validation provides documentary evidence that the operation of a system, process, or analytical test method produces the required result reliably and reproducibly, and that this fact can be well documented as a result of testing the performance”. The problems associated with validation often revolve around the tests that must be performed in order to demonstrate this reliability, and the interpretation of the results. The problems are highlighted by the fact that “failure to validate” is a term often encountered in the FDA Form 483 reports which are written at the end of the inspection of a regulated facility. In fact, a recent report lists this problem as number 3 in the top 10 subjects for 483 citations. Three types of validation procedures are generally recognized. Their application is most often based upon the validation of production processes according to the stage of development of the drug product, but a similar approach may be taken to analytical test method validation. Prospective Validation is the most valuable procedure. It is performed during the development of the product, before GMP manufacture commences. The validation plan is derived by performing an analysis of the potential for failure and risk to the product inherent in each proposed production process. Each individual production step is evaluated on the basis of past experience and knowledge of the engineering and science involved. Concurrent validation is performed during routine production, usually in the start-up phase. This method is acceptable if the development process has yielded a full understanding of all the production steps. At least three consecutive production-scale batches are monitored as comprehensively as possible. Retrospective Validation involves the examination of past experiences of production. It assumes that, during the period under examination, the materials, processes, and equipment involved have remained unchanged. This is in itself a dangerous assumption, unless the process has been extremely thoroughly documented and all batch records are absolutely reliable. Revalidation should be performed if any change capable of affecting product quality is introduced. Such changes may include those in raw materials, manufacturing processes, packaging components (especially containers and closures), equipment, in-process controls, or manufacturing areas and the specialized systems therein, such as purified water and filtered air supplies. An integral part of quality assurance is therefore the maintenance of an effective change control procedure. Planning is the most important part of validation. The Validation Master Plan (VMP) provides a framework and operating procedures for the qualification of the facility’s utilities and systems, the process and test equipment, the computer systems which may control the equipment, and the information management systems for laboratories and production facilities. It will specify the risk evaluation methods to be used. Or, if this has already been done, it will use the evaluation to place the systems, processes, and tests in some form of validation priority. Although the Good Practice regulations do not specifically require a VMP, the FDA usually expects to see one in place, as evidence of the company’s overall commitment to compliance and of a rational, well-controlled approach to the validation task, with realistic time frames. The specifications, designs, materials, and mode of operation of most pharmaceutical and biological manufacturing plants and their environmental control systems can be expected to affect areas or procedures involved in the quality of the product. As a result, validation will start with these. The systematic approach to this task is detailed in the following chapters. Emphasis is also placed on the validation of the cleaning and sanitization/sterilization of installed pipework. This is an area often given special attention by regulatory inspectors. The most common requirement for validation procedures is that applied to the manufacturing processes. All GMP regulations and guidelines are directed towards assuring that every critical process affecting the integrity of the product is validated. This is particularly the case for biologicals and biopharmaceuticals, where final testing of the product is not sufficient to guarantee compliance with product specifications. Process validation must be based upon full understanding of the scientific and engineering principles involved in the process. This understanding is developed during the product development and process scale-up stages. At this stage in the development process, scaled-down models can be used to examine the effect of various process parameters and to define the control limits. It must be shown, however, that the results of scaled-down experiments can be reliably applied to full-scale operations. By the time a process is to be validated, the process control parameters should have been defined and the process fixed. The scientific rationale for the validation protocol and acceptance criteria must be documented. A key objective of the validation should be to ensure that the process does not operate too close to the failure limits of any critical parameter. The requirement to ensure adequate validation of analytical methods is a more recent addition to the North American and international GMP regulations. The accuracy, sensitivity, specificity, and reproducibility of test methods used by a manufacturer are now required to be validated and documented. And, the suitability of all testing methods used must be verified under actual conditions of use. The ICH guidelines and two new FDA guidances on the validation of analytical procedures have been used as the basis for the advice on method validation which is given in this guide. All successful validation processes depend upon adequate documentation of the original plans, the validation protocols, the data obtained during the validation runs and the conclusions drawn from the analysis of these data This dependency is recognized in every section of this work and sample forms and check-lists are provided to assist in the task of assembling the documents which will be generated To complete this comprehensive guide to validation and its problems, full texts are provided of the major guidelines issued by National and International regulatory authorities, along with the relevant abstracts from the GLP, GMP, and GCP regulations Other references include web sites for the retrieval of the text of regulations and guidelines, a list of useful publications, and of some well-known firms specializing in validation consulting