GMP compliance audit procedure

Pharmaceuticals Quality Assurance & Validation Procedures GMPSOP From: www.gmpsop.com Step by step pre-written standard operating procedures, forms, templates and manuals in the area of GMP (Good Manufacturing Practice), GLP, Production Operations, Quality Assurance Management, Quality Control & Microbiology Laboratory; Process – cleaning and methodology Validation, Regulatory auditing created for small and medium size pharmaceutical manufacturing environments. All manuals and procedures are written by area experts in example formats in order to comply with cGMP, GLP, GDP, GAMP and international regulatory agency’s requirements. Our goal is to provide a complete GMP & GLP models with a set of ready procedures and manuals which are easy to understand and readily applicable. All procedures are written with practical instructions and examples. Forms and templates are referenced in the SOPs where applicable. Procedures and manuals are grouped into categories found in a typical GMP environment and documents are prepared to guide you through establishing a regulatory compliant facility.

Content of our procedures are not only guidelines but detail know how instructions which will help you to build up your systems from scratch. Following is a list of manuals and procedures linked with sample pages. For full version of manuals and procedures please read more by clicking the “Join Us” page on the menu. 1.1 Validation Procedures 1.1.1 Process/Cleaning/Method Validation Procedures This procedure describes general validation concepts and practices, the way processes and systems must be qualified/validated and the confirmatory documentation required. Here you will find the philosophy of validation, responsibilities, validation approaches of design qualification, installation qualification, operational qualification, performance qualification, cleaning validation, method validation, computer validation, general and specific criteria of validation, validation documentation and change control, validation reporting, guidelines of validation acceptance criteria. This procedure contains step by step instruction on initiation of revalidation categories, changes that warrant revalidation programs, basic steps of revalidation procedure, revalidation activities and specific responsibilities, revalidation protocols, revalidation timing, equipment checklist, revalidation discrepancy procedure, release of revalidated equipment, preparation of the revalidation reporting file. This procedure provides a guideline for a validation Technician on the characteristics that must be considered during the validation of an analytical testing procedure. The procedures set out in this SOP apply to qualitative and quantitative analytical methods which are used to test finished goods, in- process material, excipients and raw materials in support of registration documentation and cleaning validations and management responsibilities towards completing those method validation tasks. This SOP describes the types of cleaning process and cleaning agents of process equipments and their validation, complete instruction on cleaning validation procedure, calculation of acceptance limits for rinse and swab samples, calculation of acceptance limits for swabs, analytical method validation for cleaning, cleaning validation test protocols and change control for revalidation. This procedure describes the validation practices for laboratory instrument/equipment to be validated or calibrated and the

confirmatory documentation required showing that the instrument/equipment is capable and operating effectively for its intended purpose. This procedure has practical instruction on Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ) to be performed by the qualified equipment service technician in the presence of the laboratory staff with reference to the instrument/equipment manual. This procedure describes in detail the procedures for the procurement of equipment, incorporating standardized demand specifications and Installation Qualification documentation, to ensure that equipment procured complies with in-house requirements and standards and conform to Good Engineering Practice, to detail the general procedure to be followed regarding the reporting of Factory and Site Acceptance Tests, to detail the manner by which the equipment Installation Qualification is documented. The purpose of this SOP is to define common procedures to follow when organizing Trials/Evaluation Studies for the purpose of process improvement, equipment capability and validation studies. It defines the responsibilities within the trial process and documents that need to be considered when preparing the Trial documentation to ensure that the trial meets GMP and where applicable validation requirements. This SOP defines the procedures for conducting in house stand-alone trials on systems, processes and equipment. There can be an overlap between a trial and validation in that Trial documentation may form part of a latter process validation, (i.e. concurrent and prospective validation) and qualifications (OQ, PQ). This SOP defines the procedure for cleaning, passivating and derouging the purified water system at a GMP site. The procedure may be performed after construction, following invasive repair or following maintenance. The various parts of this procedure are to be performed as necessary. Parts of this procedure may not always be executed at the same time (e.g., The storage tank for the purified water may be cleaned and passivated without cleaning and passivating the ringmain). The scope of this procedure includes the validation of 1. Sampling methods used to determine residues after cleaning of manufacturing and packaging equipment used for the production of commercial product. 2. Analytical methods to detect residue after cleaning of manufacturing and packaging equipment used for the production of commercial product. The objective of this Standard Operating Procedure is to describe the actions required to handle deviations encountered during validation studies. The Validation Master Plan is designed to provide a planned and systematic framework within which all validation activities will occur. This document will

also ensure that the manufacturing facilities comply with the local applicable GMP regulations and site requirements for validation. This policy applies to all production process used for manufacture of commercial drug products or in-process materials for commercial drug products. Excluded form this scope is filling of tablets and capsules and labelling and secondary packaging of all drug products. This validation guideline describes the approach and methods which will be used for the qualification of equipment at a GMP manufacturing site. The aim of this validation guideline is to provide a clear statement of the scope, validation approach and testing requirements for the validation of the equipment that is involved, directly or indirectly, in the manufacturing and testing processes. The plan pertains to the qualification of processes and laboratory equipment. The aim of this validation guideline is to provide a clear statement of the scope, validation approach and testing required for the validation of the facilities and utilities that are involved, directly or indirectly, in the manufacturing processes at a GMP site. This procedure is applicable to validation sampling and testing for all new product introductions, and when changes to manufacturing procedures, manufacturing equipment, or raw materials warrant process validation. Each situation will be assessed on an indivisual basis, and the appropriate sections of this document shall be applied. The purpose of this Standard Operating Procedure is to describe the evaluation process for a new, or a change of, source raw material used to manufacture Drug Products at the GMP manufacturing facility. The procedure will provide a documented means of assuring that the changes are identified, documented, authorised and implemented taking due account of quality, regulatory and validation factors as well as environmental and safety issues. To outline the requirements for preparation, review, approval and execution of process validation protocols and preparation, review and approval of process validation reports for semi solid and solid dose products manufactured at a GMP Manufacturing Site. The purpose of cleaning validation is to provide documented evidence that the cleaning process is effective in removing residues of a product, cleaning agent or microbial contamination to below a predetermined level. The objective of this guideline is to describe the approach and methods, which will be used to validate cleaning and sanitation procedures involved in GMP processes employed in GMP Site Manufacturing facilities. The purpose of the VPP is to, 1. Establish a plan for the overall validation effort and validation lifecycle to describe the extent of the validation effort

required to meet Site and regulatory requirements. 2. Define Validation Deliverables for the computer system. 3. Provide a standardized format for Validation Project Plans. This procedure serves as a guideline for the development of a User Requirement Specification (URS) document and Functional Requirement Specification (FRS) document for a computer system at a GMP manufacturing facility. This SOP is to provide guidelines to ensure that materials that are brought into the manufacturing plant for trial purposes and not recorded into Material database are still accompanied by documentation so that their usage is recorded and reconciled and equipment that they contact is also recorded. This SOP covers the validated Direct Impact Systems (including the facilities, utilities, equipment, process control systems, computer / automation systems) and Processes in production, storage and distribution of drug products in a GMP site. The purpose of this SOP is to define common procedures to be followed when organising Trials, including allocation of responsibility to coordinate the Trial and suggestion of what needs to be considered when preparing the Trial documentation. This standard operating procedure outlines the validation approach for autoclaves, autoclave loads and autoclave cycles a GMP site. This document describes the validation and re-validation approach to sterilisation activities conducted utilising autoclaves a GMP site. Using a Heat PenetrationStudy, demonstrate that each of the proposed cycles will, with a high degree of assurance, sterilise a defined load configuration for the worst-case load. Similarly, conduct a Heat Distribution Study simultaneously to determine the cold spots and uniformity of heating in the loaded autoclave chamber. This procedure details the standard methodology used to perform GMP/Quality Risk Assessments during Validation activities. The Risk Assessment shall be conducted to determine the level of inherit risk within a given process or product. The Risk assessment should be developed to suit the type of Validation undertaken and should be used to determine the level at which Validation is performed. These guidelines provide suggestions and considerations for the design and preparation of aseptic media fill validations protocols and reports. They are intended to be used as guidelines only, alternative approaches for validation may be appropriate and can be used provided that the principals of validation as outlined in the company Validation Master Plans are followed.

The purpose of this document is to instruct the user on the operations required in order to conduct a Maximum Safe Carry-Over Determination (MSCO) for a piece of equipment or product equipment grouping. The use of Biological Indicators (BI’s) for the validation and in-process monitoring of sterilisation cycles is becoming increasingly complex and highly regulated. Therefore, a defined approach to the use and control of biological indicator validation exercises is required. It is the responsibility of the Validation Department to assign a project number to the validation project and to ensure that the progress of the project is kept up to date in the Validation Database. It is the responsibility of individual personnel (from outside the Validation Department) in charge of a project which requires validation to work in collaboration with the Validation Department on the generation of validation documents. 1.1.2 Computer System Validation Procedures To overview the procedure to be followed for the Qualification/Validation of computerized systems. This procedure applies to all computer systems (including embedded systems) directly associated with, or supporting, regulatory compliance requirements for the development, testing, manufacture and distribution of medicinal products. The objective of this guideline is, 1. To describe the approach and methods, which will be used to validate Computer Systems involved in GXP processes employed in the GMP Manufacturing facility. 2. To provide a clear statement of the requirements to identify, validate, document, maintain and retire Computer Systems at the manufacturing sites. The purpose of this SOP is to provide a method of assessing and determining the validation requirements for computerized systems and controllers. The SOP identifies the typical qualification activities required for those systems having a Direct or Indirect impact on product/process quality and data integrity, should the system fail or malfunction. These activities are in addition to Good Engineering Practice (GEP), which is appropriate for all systems, and is also outlined. This SOP provides guidance on functional testing during the development or change of computerized systems which have GxP impact at a GMP manufacturing site. What constitutes a change to a computerized system is described in manufacturing change control procedure.

The purpose of this document is to provide guidelines on conducting Design Qualification (DQ) during the conceptual and detail design phase for the implementation of a GMP facility, process and equipment (including computerized systems) to ensure conformance to operational and regulatory expectations. The guideline will provide the basis for conducting and documenting Design Qualification to all projects involving the introduction of, or significant change to, any facility, system or equipment that potentially impacts on product quality and is suitable for its intended purpose. This SOP applies to records created, processed, used or stored by (or for) the GMP Manufacturing site, that are the output of a computerized system. It is of particular relevance to records that have a GMP role, i.e. supporting product quality, patient safety or regulatory compliance. The guideline may also be used for other computerized systems that are classified as business critical. The purpose of the VPP is to: 1. Establish a plan for the validation lifecycle and to describe the extent of the validation effort required to meet Site and regulatory requirements. 2. Define Validation Deliverables for the computer system. 3. Provide a standardized format for Validation Project Plans. A Risk Assessment may be applied to computerized systems to enable the targeting of the validation effort to those areas and functions that most require it. Validation of systems serves two purposes: 1. To avoid any intolerable risk to patient safety or to the business. 2. To maximize the business benefits to be derived from the new system. This procedure serves as a guideline for the development of a Functional Requirement Specification (FRS) document for a computer system at a GMP manufacturing facility. The purpose of this document is to: 1. Define what a system should do and which functions and facilities are to be provided based on the requirements of the User Requirement Specification (URS). 2. Provide traceability to specific requirements in the URS. The purpose of this Standard Operating Procedure is to provide instruction and practical guidelines for conducting a Electronic Record and Electronic Signature Assessment. The purpose of the Assessment Worksheet is to: 1. Specify the criteria under which computer systems are to be evaluated against 21 CFR Part 11. 2. Document the evaluation of computerized systems The purpose of this document is to provide guidelines for a suitable approach for the qualification of Excel spreadsheets used in direct, or in-direct, GxP related activities at all GMP facilities. The procedure applies to the initial qualification and re-qualification of Excel spreadsheets, designed and used for making quality based decisions in GxP environments at the GMP facility.

These areas include but are not limited to: Quality Operations, Manufacturing Operations, Development, Planning, Regulatory Affairs. The purpose of the Validation Plan will be to outline the principles and objectives of the Computer Validation Program for GMP site. Validation activities will be determined to be the sum of all activities that are conducted to ensure that the systems of manufacture are sufficient to produce products of a high quality that are safe for the intended user of the product. 1.1.3 Validation Templates 1.2 Quality Assurance and Compliance Procedures (SOPs) This SOP describes standard SOP format that you can create and use immediately for your quality procedures. This SOP has instructions on how to write a formal Operating Procedures for your systems which your people can follow everyday. In this SOP you will find all type of quality and Technical/Master file documents to build up a good quality management system for your manufacturing sites, definition of documents, their classification, approval requirements and retention requirements. This procedure has schematic diagrams for your understanding of how different types of documents are prepared and stored in a typical documentation database. This SOP describes how to generate new quality documents or change control of existing documents, review of quality documents, satellite file management, role of document author, approver, document control officer and satellite file administrator. In this SOP you will also find numbering systems of different quality documents like audit files, SOPs, forms, manuals, training files, QA agreements, project files etc and their effective archiving system. This SOP describes the principles to be followed in GMP documents, entry of data and information, signature requirements and correction technique of incorrectly entered data or information. In this SOP you will find mainly the role of document control officer during the initiation, creation, circulation and approval of new quality related documents. It also describes the procedure of modification and review of existing document using a documentation database. Management of existing and superseded documents is also a part of this procedure. You will see all the forms referred during the instruction are attached at the end of the procedure. This SOP particularly focused on the management of master file documents like specifications, control methods, raw materials, finished goods and

packaging specification and test reports, formulation, stability files etc required to generate during the product registration in the market. This SOP gives instruction on their creation, change control, numbering system, approval requirements and maintenance in a simple master file database. You will see all the forms referred during the instruction are attached at the end of the procedure. It is a regulatory requirement to capture all sorts of deviations evolves in your systems in order to maintain the continuous improvement of your processes and systems. This SOP describes how to categorize the deviations between production, audit, quality improvements, technical deviations, customer complaints and environmental, health and safety deviations. It describes the management responsibilities of initiating deviation, capture data, analysis, investigation, determination of assignable causes, generation of management report and initiatives to be taken on corrective and preventative actions. This SOP describes the procedure to be followed during the vendor assessment and vendor evaluation for purchasing of raw materials, critical and non critical packaging components, laboratory supplies, engineering supplies and imported finished goods from the vendor. These instructions are essential for approving prospective vendor. This procedure aims to describe the process by which a vendor may be certified to supply materials or services. This procedure applies to vendors that supply a material or service to be used at any stage of manufacture by operations. Here you will get the roles of each department in the process to certify an approved vendor. This procedure covers the receipt, logging, evaluation, investigation and reporting system of all complaints received from customers for the marketed products. This SOP contains step by step instruction to be followed in the customer complaint management like numbering of complaint, registration, evaluation of complaints, determination of assignable cause for the complaint deviation, implementation of corrective and preventative actions, trending of complaints and handling of counterfeit products. This procedure provides a guideline to annual product review which is required to be performed for each product produced for the commercial market to evaluate data, trends and to identify any preventative or corrective action that would lead to product quality improvements and report them to management. This SOP contains the step by step instruction to be followed when the rework of an in-process or completed finished good is required. This SOP covers the reworks of in-process manufactured goods where new batch number is

introduced for the reworked part and rework of manufactured finished good keeping the same batch number. This sop also describes how to create rework protocols for each inpidual case. The purpose of this SOP is to define the method used for the identification of all contributing materials that could affect product quality and to ensure their full traceability. Here you will find instruction on all the records and documents used for the identification and traceability of incoming raw materials and out going finished goods. This SOP describes the process of planning, performing, reporting and follow- up of different audits for your systems like Internal Quality audit, Vendor audit, Environmental Health and Safety (EHS) audit, EHS workplace inspection, Housekeeping audit. This SOP also describes the process to be followed by manufacturing personnel during an audit from a Regulatory authority. This SOP describes the identification of all documentation relevant to a production process in the form of “Batch Documentation Checklists” and to ensure their collection by completion of the checklists by Authorized Persons. This procedure is based on an example of tablet packaging process described in the ‘Manufacturing’ category. This procedure describes the process of collection, evaluation and record of batch related document generated during the production of a batch before an authorized person can release the batch for sale. This procedure is based on an example of tablet packaging process described in the ‘Manufacturing’ category. This SOP describes how to design and deliver GMP related trainings for your manufacturing staffs, training assessment design, recording of assessment and preparation of training reports. This simple SOP contains instructions on how to write training materials, identification of training requirements, available resources, preparation of training aid checklists for your manufacturing staffs. This SOP describes the requirements, checklists and reporting procedure on housekeeping audits. Inpidual checklist forms are attached at end of the procedure for different areas like process, laboratory, engineering stores, warehouses. This procedure also describes the handling of non-compliance found during the housekeeping audits. The procedure describes the management and control of contract work provided by the contractors for packaging and finished products for your

company as well as control of contract works done by your company on behalf of others. The purpose of this SOP is to describe the process for approval of an external vendor/manufacturer supplying products to your company. It covers raw materials (including bulk products for subsidiaries and contract manufacturers), critical packaging components in contact with product and imported finished goods. The SOP also references affiliated documentation detailing the scope of active materials used and the approved manufacturers of these materials. This procedure contains instruction to be followed when conducting Investigations and to raise and assess Deviation Report when an Investigation or Incident Investigation occurs. This procedure is to be used in conjunction with Deviation management, which covers the approval and follow-up activities associated with a Deviation Report. Here you will find collection of information for an incident or a deviation, steps to be followed for a cross functional investigation, reporting and implementing of the outcomes of investigation. This procedure provides a standardised procedure and framework for initiating, authorising, planning and implementing any change to a GMP system. Product Change Management requires that all planned permanent changes that have the potential to impact on regulatory filings or the quality of an active pharmaceutical ingredient or drug product must be evaluated, reviewed and approved. It also requires that the site procedure must include provision for effectively tracking all quality and regulatory changes and provide a mechanism for review and approval by the Site Quality Team for all changes. This procedure describes the guidelines for initiating, communicating, conducting and documenting Cross-Functional Investigations (CFI) related to process, system, product, material, facility and laboratory deviations. A Cross–Functional Investigation is an extended investigation conducted in order to identify a Root Cause Analysis. This SOP defines the approach to Quality Risk Management (QRM) of a GMP site and gives practical examples for tools which may be used to facilitate the process and to aid personnel performing the assessment. 1.2.3 Quality Assurance Templates 1.3 Quality Control Laboratory Procedures (SOP)

The purpose of this procedure is to describe how to run the expired stock report; to describe how to define the requirements for the retesting and assignment of storage periods for active ingredients, excipients and raw materials; to instruct retesting procedure and to determine the status of a finished goods batch with a shorter shelf life. This SOP describes the calibration policies of laboratory instruments/ equipments. It describes labeling and security requirements of laboratory instruments/ equipments. This SOP also describes the investigational steps to be required in the case of failed calibration. This procedure describes retention and disposal procedures of laboratory documentation, general laboratory documentation system that includes handling of rejected raw material and finished product reports, finished goods certificate of analysis, finished goods register, raw material certificate of analysis, raw material register, trend cards, procedure for long term document retention. This SOP describes the ordering, referencing, storing, coding, use and general register maintenance of primary and impurity reference substances, primary reagent reference solutions, secondary raw material reference substance, assay testing procedure of secondary raw material reference substance, use of secondary raw material reference substance in the laboratory routine analysis, determination of expiry date and re-test date of reference substances. This SOP describes types of laboratory workbooks, general and GMP requirements of using workbooks, analytical data entry in the workbook, formatting of laboratory workbooks for routine testing, experiments and trials, workbook retention policy, instruction on data entry for incomplete experiments and additional data. The purpose of this procedure is to define the content and format of a Certificate of Analysis (C/A) and Certificate of Manufacture (C/C) and to provide guidance for issuing a Certificate of Analysis or Certificate of Manufacture and to locate the appropriate data required for this task. This procedure identifies the need for all analytical reagents and solutions prepared from the reagents, to have an assigned expiry date and storage conditions recorded on the label. Here you will find the procedure for purchase and management of analytical reagents and laboratory prepared reagents. ▪Laboratory Waste Management

This simple procedure describes how to dispose off laboratory generated wastes of toxic, explosive, flammable, corrosive, oxidizing and biologically damaging natures. The purpose of this SOP is to describe the finished good and raw material sample retention procedures, products manufactured and/or received onsite and/or chemically tested by the Laboratory. This procedure describes the actions to be taken by an analyst in the event the result of a test does not conform to raw material/components or finished products specifications for physical and chemical tests. An out of specification (OOS) result does not necessarily mean the batch under investigation fails and shall be rejected. The OOS results shall be investigated and the findings of the investigation, including re-test results shall be interpreted to evaluate the batch and reach a decision regarding release or rejection. This SOP describes the procedure for sampling, location, pre-testing, testing and documentation of all raw materials and components subject to test, out of specification results, microbiological tests and release procedure for passed raw materials and components. This SOP describes the procedure for sampling, location, pre-testing, testing and documentation of all finished products subject to test, reagents and standards to be used for analysis, management of out of specification results, microbiological tests and release procedure for passed finished goods. This procedure describes the preparation and management of Stability Protocols for marketed products. This procedure is applicable to all protocols for stability studies on commercial products. The responsibility of the commercial Site Stability Manager for creating and maintaining protocols that are required for studies that came as a result of validation or process deviation. To describe the steps necessary to ensure the effective control of stability and trial testing programs of new and existing products. This procedure is focused on setting up of stability programs, testing, reporting, general sampling procedure for stability programs, data generation and analysis, annual maintenance of stability, new product stability procedure, procedure for in- house trials, reporting and interpretation of trials and conclusion of the trail program. This procedure describes the preparation and use of disinfectant solutions (70% IPA) in the Sterile Area and also outlines the procedure for Integrity testing of the 70% IPA Filter.

This procedure describes the process of collection, evaluation and record of batch related document generated during the production of a batch before an authorized person can release the batch for sale. This procedure is based on an example of tablet packaging process described in the ‘Manufacturing’ category. The purpose of this document is to describe the operational procedures to be followed when carrying out analytical analyses in the Quality Control Laboratory at a GMP site. This SOP outlines the system suitability (SST) and acceptance criteria for analysis by HPLC and UV-VIS Spectrophotometer; e.g. Composite Assay (Assay), Degradation Products / Related Substances / Impurities (Degradation), Content Uniformity (CU), and Dissolution tests for all Raw Materials, In-process, Finished Products and Stability Samples in the QC Laboratory. This SOP also covers the number of standard and samples to be weighed for HPLC and UV-VIS Spectrophotometers analyses. The validation of an analytical method is the process by which it is established that the performance characteristics of the method, such as Precision, Accuracy, Specificity, Linearity, Limit of Detection (LOD), Limit of Quantitation (LOQ) and Robustness meet the requirements for the intended applications. This SOP refers specifically to HPLC. However, the same principles may be applied to validations of other types of analytical procedures. Well- characterised reference materials with documented purity should be used to perform the validation. This purpose of this document is to outline the procedure to be followed for the receiving, scheduling, testing, reporting, reviewing, approval and release of In-process and Finished Products in the QC Laboratory at a GMP site. This document describes the requirements for receipt, labelling, handling, storage, standardization and review of laboratory chemical materials in the Quality Control (QC) Laboratory. The purpose of this procedure is to outline the general system and documentation required for the qualification of laboratory instruments. This procedure also outlines post service qualification requirements for HPLC systems. The purpose of this document is to outline the correct sampling technique for samples of Raw Materials, Blends, End of Run (EOR), Coated and Bulk Finished Products, and to ensure that samples are representative of the batch of materials or products from which they are taken. The SOP also defines to process to be followed in case a re-sample or a batch or lot is required. This document outlines the procedure to be followed for the management of the stability program in the Quality Control Laboratory.

The purpose of this procedure is to define the requirements for the Validation of Non-Compendial Analytical and Biological Test Methods, as well as for the Verification of Compendial Analytical and Biological Test Methods. The objective of the Validation / Verification is to demonstrate that the test methods are suitable for their intended purpose. 1.4 Microbiology (Sterile) Laboratory Procedures SOP This SOP outlines the gowning procedure that must be followed by each and every person who enters a Sterile Area. The procedure is designed to reduce the risk of contaminating product with bacteria and/or particles Aseptic gowning is the ability to complete the gowning procedure without compromising the sterility of the garment. This SOP outlines the sterile gowning validation procedure as required for the final sign off for the initial sterile training and the revalidation of currently trained Operators, Fitters, Electricians and Cleaners and all organization staff who are authorized to enter Sterile areas. To describe procedures for the recording of Microbiological data using the in- house hard copy and computerized recording system. All documents containing test results are legal documents and therefore it is imperative that all the information required is recorded accurately. Any changes/corrections to be made must be signed with that person’s initials and dated. To outline the procedure for the depyrogenation of glassware using the Microbiology Laboratory Qualtex Oven. To describe the procedures for the preparation of microbiological media for use in the Microbiology Laboratory. One of the requirements of cGMP is a periodic evaluation of all aseptic processes by filling media into the appropriate containers under normal production conditions. The media fill should reflect the sterility of the entire process from the Sterilizing filter to the filled primary container and should include all subsequent manufacturing steps. This SOP outlines the procedures for both Media Fills and Microbiological Leak Tests. For Validation purposes, a Microbiological Leak Test (Soup test) or a separate Protocol to verify the entire process from the ‘Bioburden Reduction Filter’ to the primary container may be required. Media Fills are designed to verify the entire process, equipment and staff. This process simulation should be performed as initial validation with three (3) consecutive satisfactory simulation tests per shift and repeated at defined 6

monthly intervals (twice per year per process per shift) and after any significant modification to the HVAC-system, equipment, process and number of shifts” for aseptically filled process. Soup test has to be conducted at least once per year per shift for terminally sterilised lines and non-sterile process. Validation and re-validation media fills are to assure the sterility of the entire process. This process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. The Media Fill should challenge the “worst case” situation and should include all the possible interventions of a normal production run. The duration of the media run should be at least 4 hours or half a production shift to allow for all routine interventions. Description for Microbiological testing of areas of the environment which may influence or affect product performance and/or quality-including, air, surfaces, personnel, clothing and disinfectants. Daily monitoring of sterile grade areas during production is to be conducted by trained production staff. The Microlab is to ensure that the necessary plates are delivered on a daily basis so monitoring can take place. Once a test has been completed, the responsible operator is to initial the plate and make sure that the batch number of the batch running at the time of the test is written on the plate. Plates will be labeled with prompts to ensure this isn’t forgotten. If no batch is running at the time of the test N/A should be put on the plate instead of a batch number. If an area of concern is noted during routine daily testing, inform Micro immediately so that further steps can be taken. ▪Microbial Limit Testing Procedure Using Laminar Flow Cabinets To describe the procedures to be followed in conducting Microbial Limit Tests in the Laminar flow Cabinets in the Microbiology Lab. In this SOP you will find Sampling Procedure for Bioburden and Endotoxin Samples, Bioburden Test Method and Results, Endotoxin Testing of WFI (Distilled Water), Bioburden and Bacterial Endotoxin Alert and Action Levels, Diagrammatic Representations of a typical purified Water Systems, Bioburden Waste Tank Water Sampling, Clean Steam Sampling & Testing, OOL/OOS Result Actions etc. This sop is to describe the procedure for sterility testing of aqueous, injectable and terminally sterilized non injectable products. To explain the correct interpretation of sterility results and to outline Stasis requirements for used sterility canisters. This SOP describes the method for calculating the Heat Resistance Factor, (D-value),of spore-forming organisms. D-Value is defined as the time required

for a population of a pure culture of microorganisms to be decreased by 90% when exposed to a fixed temperature, e.g. 121°C (+1°C). To describe the procedures for the preliminary identification of bacteria isolated from Plant Water, Environmental, Personnel, Product and Raw Material sources. Bacteria that will require identification (ID) to at least genus level include organisms isolated from the manufacturing environment, personnel, in-process and finished products, plant water and other miscellaneous sources. SOP’s detailing the microbiological testing procedures for each of these samples will indicate the required level of ID of recovered organisms. The following sections detail the procedures for the preliminary ID of micro-organisms. Further ID to species level is to be conducted for conformation. This SOP describes the procedures for Microbiological Evaluation of Bioburdens, non-sterile Products & raw materials. Bioburdens includes: Batches prior to membrane filtration, i.e. solutions; Batches prior to sterilization i.e. filled containers; Face masks; IPA. This procedure includes Equipment preparation for Non-sterile testing, Bulk Solution Bioburden (BSB) Sampling; Filled Container Bioburdens (FCB); Raw Material Bioburdens (RMB); Surgical Face Masks; Isopropyl Alcohol (70% IPA); Speciation Procedures for Organisms found in Non Sterile Products and Raw Materials; Out-of-Specification Procedures for Non Sterile Products and Raw Materials; Retest and Repeat Procedures for Non-Sterile Products and Raw Materials. To describe the procedure for conducting a Bacterial Endotoxin Test by the LAL Gel-Clot method. The gel-clot method for bacterial endotoxin testing described in this SOP is based on the fact that Limulus Amoebocyte Lysate (LAL) will form a firm gel in the presence of bacterial endotoxin. The purpose of this SOP is to outline the theory of Bacterial Endotoxin testing using Kinetic Chromogenic Analysis (KCA). And to outline the procedure for routine product testing, operator / reagent verification and product validation by KCA using the Bio Whittaker KQCL (brand) reader. This Procedure also describes the routine maintenance procedures for the Bio Whittaker KQCL (brand) reader. The objective of this SOP is: To describe the method for preparing and maintaining stock suspensions of vegetative microorganisms and spores used within the Microbiology Laboratory;. To explain the procedure for growth promotion and media verification requirements for all media used within the Laboratory; To outline requirements for Stasis testing on sterility canisters after sterility testing has been completed.

To detail the procedure for taking Microbiological samples for Sterility testing, Bacterial Endotoxin testing, Bioassay testing, Microbial Limit test and Micro status testing throughout Production. This procedure includes sterilization charts, Settle plates (Fallout plates) and Personnel monitoring. The gel clot validation method for Bacterial Endotoxin testing described in this SOP, is to determine the level of Inhibition/Enhancement of products on the LAL test for endotoxins within the allowable Maximum Valid Dilution (MVD) for each type of product. The Gel-Clot techniques detect or quantify endotoxins based on clotting of the LAL reagent in the presence of endotoxin. To be determined for each type of product, using the highest and lowest concentration of active. If either concentration shows inhibition or enhancement, then each remaining concentration must be tested. At least three (3) Production batches of each finished product should be tested for inhibition and enhancement. The purpose of this procedure is to provide guidance when investigating microbiology laboratory out of specification (OOS) results associated with raw material samples, in-process samples and finished product samples. This procedure describes the actions taken by Microbiology Laboratory staff in the event the result of a test does not conform to company specifications for microbiological release. This procedure will also provide guidance for retesting raw material samples, in-process samples and finished product samples when it has been decided through a laboratory investigation that retesting is justified. Retesting should be viewed as an investigational tool to aid in determination of the Root Cause Analysis of the discrepant laboratory result. To define the procedures to be followed and the responsibility for the operation, calibration and maintenance of the Sievers 820 TOC Analyser with Autosampler. ▪IPA Contamination Testing Procedure To describe the test sometimes used to check the purity of the IPA used in the factory as a disinfectant. This document details the writing, control, and distribution of Microbiological Test Methods (MTM) for use in the GMP Microbiology Lab. This procedure applies to Microbiological Test Methods that are controlled from beginning to end by the Microbiology Lab Manager. ▪Handling of Test Sample in Microbiology Laboratory This document details the handling of test samples (raw materials, bulk product and stability samples) processed for Microbial Limits Testing (MLT) in

the Microbiology Laboratory. This procedure applies to samples tested for Microbial Limits within the Quality Control Microbiology Laboratory. The procedure describes the process for accessing and using protocol templates for documentation of test method validation activities in the Microbiology laboratories. This procedure applies to Microbiology personnel responsible for the validation or verification of microbiological test methods. The procedure outlines the requirements for approval of method development protocols, validation/verification protocols and final validation summary reports. This document deals with the correct means of maintaining a culture collection with an emphasis on aseptic practices in the laboratory. This Standard Operating Procedure outlines the criteria and rationale of selection of sanitizing agents, their quality control and documentation required. Cleaning validation of the sanitizers with direct contact with equipment will be covered in the cleaning validation policy. To establish a procedure for the investigation of initial out-of-specification (OOS) or questionable results which have been generated for the product or material being tested in microbiology laboratory. This Standard Operating Procedure describes good laboratory practices employed in the QC microbiology and chemistry laboratories. Safety in laboratories is an inpidual, as well as management responsibility; however, it is the laboratory staff’s responsibility to carry out safe work practices. This document describes the general procedure for the receival, use and storage of all media, diluents and reagents in the Microbiology Laboratory at a GMP site. All Microbiological media, reagents and diluents must comply with specified documentation, preparation, storage and quality control requirements before permitting their use in the laboratory. All batches of agar prepared in the Microbiology Laboratory must be examined for their ability to support the formulation of colonies by organisms that they are designed to grow. 1.5 Standard Operating Procedure for Packaging Operation This SOP covers the clothing requirements needed in all Factory areas for your manufacturing site. The different levels of cleanliness must be maintained to minimize microbial and particle contamination. This procedure contains general rules and restriction to be followed by your manufacturing

employees, defining different environmentally graded areas and entry requirements for those areas. This SOP describes the cleaning procedures to be followed by all employees working in the manufacturing area in order to prevent contamination of product by foreign materials from another batch, or by dirty parts, which may contain bacteria. This SOP contains instruction on responsibility of cleaning, degree of cleaning to be done, popular cleaning aids and solutions permitted to use for cleaning, rubbish removal and outline of cleaning methods for different environmentally graded areas. This SOP defines the methods, frequency and the intensity of Factory Cleaning. The purpose of cleaning is to remove debris from within the plant in a sanitary and effective manner and to avoid contamination from dust or foreign materials. This procedure describes which popular cleaning aids and solutions are to be used to clean the floors, walls, sinks and windows in the Production areas, office areas, change rooms, workshops, laboratories, stores, canteens, plus the toilet facilities. This procedure also describes the scope and responsibility of contract cleaners. This SOP describes the responsibilities of all employees and pest control services, classification of pests, frequency of the pest control service and effective treatments against all types of pest. This procedure outlines the generation, maintenance and filing of Production logbooks. Production logbooks form part of the documentation system required by the Code of GMP to provide complete and up-to-date histories of all batches of product. The logbook provides a key link in the process of traceability. This SOP provides an alphabetically indexed diagram of shipper packing and pallet packing configurations for any packaging process. This procedure contains schematic diagrams of different packaging configurations and calculations of total unit to be packed per container which can be useable into your packing lines. ▪Checking of Components Prior to Use This SOP sets out a procedure to ensure that only components of correct code and batch number are issued for a batch and only issued components will be used in a finished product batch. This SOP also describes the procedure to be followed during returning of components to warehouse from the production lines. This SOP describes how to prevent the risk of personal injury or damage to equipment likely to be caused by operating or attempting to operate

machinery or equipment diagnosed as being unsafe, in need of repair or maintenance or formally removed from service. The SOP covers all isolation, condemning, repair or maintenance work that necessitates a device or machine to be taken out of service. This SOP applies to any situation where energy (either supplied to equipment, or stored within it) needs to be isolated to ensure the safety of any person working on or near equipment, processes or services – for any reason whatsoever. This SOP describes the procedure and order to be followed when performing a Line clearance, Line opening and Line cleaning for a batch production. The procedure has been established to prevent mix-ups of products, containers, components, labels and mistakes in documentations. Mix-ups and mistakes can occur when correct procedure and GMP are not followed. Particular care should be taken when starting a new operation, at the change of shift and when additional components are needed. In this procedure you will find example of line clearance, opening and cleaning checklist based on an example of tablet packing line. This simple SOP describes the concept of reconciliation, how to reconcile finished goods and determine the allowable discrepancies of components and products when reconciled. ▪Example of Intermediate Bulk Containers Operation and Cleaning To describe the operation and cleaning procedures that relate to the use of the Intermediate Bulk Containers (IBC’s) used to store bulk tablets on the process line. The procedure covers: Receiving of the bins from Dispensary, Movement to the process, Lifting and emptying the contents, Cleaning and returning the bins back to Dispensary. This SOP describes the procedure for sampling, location, pre-testing, testing and documentation of all finished products subject to test, reagents and standards to be used for analysis, management of out of specification results, microbiological tests and release procedure for passed finished goods. This procedure describes how to create a complete manufacturing instruction for your process line to be followed by your manufacturing employees. To make the instruction more practical and easy to understand, a sample instruction is added in the form of a protocol for a typical tablet packing process. All the related blank forms are attached at the end of the procedure for a better understanding. This procedure describes how to produce a monthly manufacturing schedule following an agreed 12 months plan, to provide a sequence of work that will

enable the scheduling of support groups (i.e. Quality, Technical and Warehousing), incorporate any planned engineering down time (i.e. project work, calibration and preventative maintenance), create and release batches according to the agreed weekly schedule, provide key dates for product supply to support Customer Service. ▪Vacuum Leak Testing Procedure for Finished Goods This SOP describes the set up and operation of a standard vacuum Leak Tester for the very popular vacuum leak testing used in a typical packing line. The purpose is to outline the procedures required for the checking/calibration and repair of balances, scales, check-weighers and load cells. The purpose of this SOP is to describe the set-up and operating procedures for the Check weigher in the packing lines. This procedure contains instructions that enable the production operators working in a typical packing line to carry out Start-Up and In-Process Tests required in order to produce quality products and to ensure in-process controls. A typical tablet packing process is used here as an example. This procedure describes the process of sampling manufactured finished good required to be taken by production personnel for the laboratory testing. A typical tablet packing process is used here as an example. This procedure describes the steps to be followed when there are packaging components to be returned to the warehouse after the packaging operation has been completed. 1.6 Warehouse Management Procedures SOP This procedure describes the steps to be followed by planning and procurement department to create purchase order for inventory items to be purchased from overseas and local suppliers. Material Purchasing Information Record. This simple procedure describes how to keep purchasing information for approved materials, vendors, manufacturers, standard and current pricing and third party agreements. This SOP contains step by step instruction on condition of accepting incoming goods in the warehouse, ‘booking In’ procedure of component and non component goods, how to complete movements of incoming goods into different storage locations within the warehouse maintaining full traceability. Here you will find generation and filing of documents related to Receipt of incoming goods.

This procedure describes quarantining, sampling, testing and releasing of incoming raw materials to Production. Here you will find the labeling requirement for component to be sampled, checking requirements of components, sampling and re-sampling of incoming goods for laboratory testing, generation of documentation during the movement of components in order to maintain complete traceability. This SOP contains step by step instruction on issue of tested and QC released components for batch production, documentation needed for capturing identification and traceability information during the picking, assembling and transferring of those components from warehouse to production. This procedure also has instruction to follow during the return and reject processing of raw materials and components from production to warehouse. This SOP contains instruction and documentation on movement of finished goods to quarantine until release for sale, dispatching procedure and documentation needed for transferring of finished goods from quarantine to warehouse store and subsequently to out side the manufacturing site maintaining a complete traceability of finished goods. In this procedure you will find a complete inventory management system by stock counting instruction, stock classification and reconciliation programs. Here you will find instruction on cycle counting by material code, counting by bin sheet information and reconciling/cross checking of those counts by physical counting of the stock, determination of material gain or loss and filing instruction. This SOP is designed to understand and draw an schematic diagram of ideal warehouse and production areas, identifying in-coming goods storage unit types and storage bin types, quarantines, reject cage, cool room, flammable storage, dispensary booths, production area, finished goods quarantine area and finished goods storage areas. This procedure defines how storage unit types and storage bins are numbered. This SOP is to be used as a guide to define the types of storage units and bins, movement direction within the warehouse and production areas. This simple SOP contains instruction and documentation on movement of finished goods from production to warehouse finished goods quarantine location until the samples are tested and released by the authorized persons. This procedure primarily concerned with risk associated with sampling, precaution to be followed when sampling, general sampling procedures for

raw materials, critical and non critical components, chemicals and secondary reference standards for laboratory. This procedure is an elaboration of SOP WAR-045 and mainly concerned with sampling plans and instructions of components and printed materials for quality testing before release for production use. This SOP outlines the measures to be taken to ensure the safety of all goods and personnel when using the storage racking system in order to avoid injury to staff or damage to property. This procedure concerned with the handling and storage of materials or products and to report any damage which may be occurred. This SOP particularly relates to the activities of the staff of the receiving and distribution warehouse. This SOP gives instructions on operation requirements and maintenance of forklifts used in the warehouse, safety precaution to be taken during the operation of forklift under load. This procedure is mainly concerned with dispensing plans and instructions of released raw materials for production use. An example of tablet dispensary procedure is prepared for better explanation and understandings of dispensing. You will be able to follow the instruction for dispensing of any raw materials in facility cleaning. 1.7 Environmental Health and Safety Procedures SOP This procedure describes the requirements for the management of: Approval for proposed new chemical substances. (excluding Contractor activities), Existing chemical substances that are classified as Hazardous Chemical Substances, Material Safety Data Sheets (MSDS). The purpose of this SOP is to: Describe the risk management process of identifying EHS hazards, assessing risk, designing appropriate controls and reviewing the controls, Describe the steps to take and the tool that shall be used to undertake preliminary risk assessments (PRA), Outline the procedure for using the DR To standardize the types of containers used for handling all types of waste, recycling material and waste from the Manufacturing facilities. This procedure defines the requirements for immediate action, investigation, and reporting, corrective action, follow-up and training associated with EHS incidents.

The purpose of this SOP is to formalize the role of the nominated site first aiders, and to provide a clear understanding of the first aiders responsibilities and provide first aiders with information relating to the delivery of first aid. This SOP provides information and guidelines for the management of blood and body fluid spills as a result of an accident. Under the relevant Occupational Health and Safety Laws and Regulations for each state, employers have a duty of care to protect their employees in the workplace This SOP provides information and guidelines for the management of exposure to blood borne pathogens in the workplace. Under the relevant Occupational Health and Safety Laws and Regulations for each state, employers have a duty of care to protect their employees in the workplace. This SOP provides an overview of the procedures used for the contract cleaning and sanitation of the GMP building, Engineering shed and Demountable buildings. The SOP defines the areas and responsibilities for the contract cleaners. This SOP details the Environmental Management System (EMS) that ensures the GMP plant complies with the in-house Environmental Guidelines and local, state and national government regulatory requirements and has an ongoing improvement plan for environmental performance. This procedure is an elaboration of SOP WAR-045 and mainly concerned with sampling plans and instructions of components and printed materials for quality testing before release for production use. This SOP details the procedure required to notify GMP site’s insurers of any intended impairment of the installed ‘Fire Equipment’ on site. This SOP applies to all buildings on the GMP site. The SOP lists the procedure to record the details and timeframes of the intended fire equipment impairment. This SOP covers all aspects of Hot Work activity at the GMP facility. Hot work refers to any type of work that produces or has the potential to produce, a spark or open flame, including oxy and electric welding. The purpose of this document is to define the procedure for identifying, investigating and reporting hazards, near misses and accidents. The outcome is to identify appropriate risk controls and corrective actions to prevent a recurrence of the event. The purpose of this document is to define the first-aid procedure for the GMP site. The first-aid procedure shall encompass the responsibilities and actions

required for first-aid treatment. The first-aid procedure promotes the site philosophy for an early intervention program. Sampling must be performed with a calibrated sampling pump. Calibrations must be performed before and after sampling, for each sampling pump, with the sampling media (filter cassette or sorbent tube) in line. Site Security Team ensures a high level of awareness for security measures implemented for general site access and for the manufacturing building amongst all staff is of critical importance not only for our customers and our integrity as a supplier of prescription medicines but also for continued compliance with the conditions of our licenses to manufacture, import and export Pharmaceutical products. The purpose of this procedure is to provide all existing and potential colleagues with the information they need to comply with the procedures for preventative occupational medical evaluation and control in compliance with local requirements and EHS guidelines. The Pest control procedure is designed to act as a control and preventative maintenance program against insect and rodent infestation to buildings at the GMP site. This policy provides information and guidelines for the supply and purchase of personal protective equipment (PPE). Under the relevant Occupational Health and Safety, employers must provide PPE to workers and visitors as a control method when work hazards are unable to be controlled by other methods. The requirements outlines in this procedure are to be completed by all colleagues at the GMP site. Where specifically stated, some of the requirements in this procedure are to be completed by all personnel on site. This SOP provides guidance and instruction on the management of chemical spills in a laboratory environment. This SOP applies only to the spills of liquid and solid chemical spills in a chemistry laboratory environment. Spills of microbiological agents are outside the scope of this SOP. The purpose of this procedure is to ensure that hazards which have the potential to cause acute catastrophic events, such as accidental chemical releases, fires and explosions are identified, assessed and adequately controlled. This SOP is to provide guidance on a uniform methodology for workplace sampling of personal exposures and engineering performance validation.

Assessment of Risks will be assessed in all work areas and for all tasks to identify the requirements for PPE. All personal protective equipment will be worn as directed and will comply with the relevant Australian Standards. In a GMP environment a risk-based approach has to be used to evaluate the hazards and controls used to mitigate them. Hence it is essential for Risk assessments to be performed to ensure that all hazards in a plant are identified and are controlled if the risk associated with them is unacceptable. To evaluate and control all risks, Risk Assessment Process has been developed and widely accepted by the industry. 2.0 GMP Audit Training Manuals Apply the auditing techniques referenced in this unit to an actual audit. Understand the reasons for using these techniques, understand and use the auditing components while performing a GMP Audit. Use a range of information tools in support of a GMP Audit. Develop and communicate a complete audit agenda (may also be referred to as audit plan) both to audit team members and the firm/area being audited. Effectively execute an audit agenda, use generally accepted auditing techniques to conduct the audit. Document and communicate audit findings in a clear, concise report that includes examples of identified deficiencies. Determine the appropriate Worldwide Regulatory GMP requirements for a site or product being audited. Identify which Regulatory Agencies govern specific regions of the world. Use a range of information tools in support of a manufactured product distributed and sold throughout the world. Recognize compliance or non-compliance of Worldwide Regulatory GMP requirements based upon the country or region audited. Explain what the relationships are among the Worldwide Regulatory GMP agencies. Perform an audit of a personnel and training system. Know and understand which of the worldwide requirements apply to personnel and training. Use a range of information tools, including the contents of this module in support of a personnel and training audit. Recognize compliance or non-compliance of regulations pertaining to personnel training requirements. Perform an audit of a deviation management system. Use a range of tools and information, including the contents of this unit to support the audit of a deviation management system. Understand and apply appropriate GMP standards/regulations and In-house standards to an audit of a deviation management system. Recognize compliance or non-compliance of deviation management systems to applicable regulations

Perform an audit of a validation system (excluding computer systems). Use a range of tools and information, including the contents of this unit to support the audit of a validation system. Understand and apply appropriate GMP standards/regulations to an audit of a validation system. Recognize compliance or non-compliance of a validation system to applicable regulations Perform an audit of a change management system. Use a range of tools and information, including the contents of this unit and the internet to support the audit of a change management system. Understand and apply appropriate GMP standards/regulations to an audit of a change management system. Recognize compliance or non-compliance of a change management system to applicable regulations. Perform an internal, supplier or contractor audit of a complaint system. Know and understand which of the worldwide requirements apply to managing complaints. Use a range of information tools, including the contents of this module and the Internet in support of a complaint audit. Recognize compliance or non-compliance to regulations pertaining to complaints. Perform an audit of a documentation system. Use a range of tools and information, including the contents of this unit to support the audit of a documentation system. Understand and apply appropriate GMP standards/regulations to an audit of a documentation system. Recognize compliance or non-compliance of documentation systems to applicable regulations. Perform an audit of a calibration, preventive maintenance and housekeeping system. Use a range of tools and information, including the contents of this unit and the internet to support the audit of a calibration, preventive maintenance and housekeeping system. Understand and apply appropriate GMP standards/regulations to an audit of a calibration, preventive maintenance and housekeeping system. Recognize compliance or non- compliance of calibration, preventive maintenance and housekeeping systems to applicable regulations. Identify computer systems with GMP implications within the scope of the GMP facility audit Include in the audit an assessment of the computerized systems used to support a GMP facility. Understand and apply applicable GMP requirements to the audit. Recognize compliance or non-compliance of GMP facilities to applicable regulations for computerized systems. Perform an audit of a site utilities system. Use a range of tools and information, including the contents of this unit and the Internet, in support of auditing a utilities system. Understand and apply applicable GMP standards to

an audit of a utilities system recognize compliance or non-compliance of a utility system to applicable regulations. Perform an audit of warehousing and distribution. Access and understand warehousing and distribution requirements, including licensing requirements. Use a range of tools and information, including the contents of this module and the Internet, in support of auditing warehousing and distribution. Understand and apply applicable GMP standards/regulations to an audit of warehousing and distribution. Recognize compliance or non-compliance of regulations pertaining to warehousing and distribution requirements. Perform an Environmental Monitoring Audit. Use a range of tools and information, including the contents of this unit and the Intranet, to support an Environmental Monitoring Audit. Apply worldwide regulatory agency requirements to Environmental Monitoring. Recognize compliance or non- compliance of regulations regarding Environmental Monitoring requirements. Understand what the GMP requirements are for microbiological and sterility testing laboratories. Identify which GMP regulations govern microbiological and sterility testing laboratories. Use a range of information tools, from the contents of this training module to the Intranet, in support of microbiological and sterility testing. Recognize compliance or non-compliance of a microbiological and sterility testing laboratories Understand what the GMP requirements are for the analytical quality laboratory and stability testing laboratory. Identify which GMP regulations govern the analytical quality laboratory. Use a range of information tools, from the contents of this training in support of analytical testing and stability testing auditing. Recognize compliance or non-compliance of analytical quality laboratory and stability testing. Perform an audit of a material handling system. Use a range of tools and information, including the contents of this unit to support the audit of a material handling system. Understand and apply appropriate GMP standards/regulations to an audit of a material handling system. Recognize compliance or non-compliance of material handling systems to applicable regulations. Perform an audit of an API manufacturer. Use a range of tools and information, including the contents of this module and the Internet in support of auditing an API module. Understand and apply applicable GMP standards to an audit of an API manufacturer. Recognize compliance or non-compliance of API manufacturers to applicable regulations.

Perform a packaging component supplier audit. Understand which worldwide requirements apply to packaging component suppliers. Use a range of information tools, including the contents of this module, in support of a packaging component supplier audit. Recognize compliance or non- compliance with regulations pertaining to packaging component supplier’s requirements. Perform a packaging and labeling audit. Know and understand which of the worldwide requirements apply to packaging and labeling operations. Use a range of information tools, including the contents of this module to the Intranet, in support of a packaging and labeling audit. Recognize compliance or non-compliance of regulations pertaining to packaging and labeling requirements. Perform an audit of an aseptic/sterile processing area. Access and understand aseptic/sterile manufacturing requirements. Understand worldwide regulatory agency requirements for aseptic/sterile processing. Use a range of information tools, from the contents of this module to the Intranet in support of an aseptic/sterile processing audit. Recognize compliance or non-compliance of areas to regulations pertaining to aseptic/sterile processing requirements. Perform an audit of an excipient vendor. Use a range of tools and information, including the contents of this unit and the Internet, in support of auditing an excipient vendor. Understand and apply applicable GMP standards and site standards to an audit of an excipient vendor. Recognize compliance or non- compliance of excipient vendors to applicable regulations. Apply the regulatory requirements related to oral dosage forms. Perform an audit of oral dosage forms. Use a range of information tools, from the contents of this unit to the Intranet in support of an audit of oral dosage forms. Recognize compliance or non-compliance of regulations pertaining to requirements for oral dosage forms. 3.0 Quality and Validation Manuals (same as QMS MANUAL- 003) This guideline is designed to assist decisions on how to appropriately accommodate the packing of solid dosage forms starting from bulk-packed tablet product through to the finished pack for shipping. The focus of this document is on the technical issues that must be addressed. (same as QMS MANUAL- 005)

The purpose of this procedure is to describe the minimum requirements for the retention of samples and documents under GMP and Medical Device regulations/legislation. Local legislative and regulatory requirements which may require retention of increased sample quantities or longer retention periods, take precedence over this procedure. (same as QMS MANUAL- 007) This guideline aims to define the processes for certification of materials provided by suppliers including the requirements for maintaining materials in a “certified“ status for use. (same as QMS MANUAL- 010) The purpose of this Guideline is to define the general requirements and provide guidance for Quality Agreements for the development, manufacture, testing, storage and distribution of intermediates, active pharmaceutical ingredients and investigational products destined for use in pre-clinical, clinical and other Research and Development studies. (same as QMS MANUAL- 011) The purpose of this Procedure is to describe the requirements for the quality management of contractors; to describe the role of contract giver sites in this context and to provide a model for the development of Quality Assurance Agreements with Contractors (same as QMS MANUAL- 017) To provide the minimum mandatory requirements for notification, conduct, reporting and follow-up action associated with inspections by regulatory authorities and also to outline recommendations on how to achieve compliance. (same as QMS MANUAL- 018) The purpose of this guideline is to define the concept of Quality and Compliance Auditing within the system of quality management and outline the roles and responsibilities for planning, performing, reporting and follow-up of audits. (same as QMS MANUAL- 014) To provide minimum mandatory requirements and outline best practice for ensuring that company auditors have a common baseline of training and experience in order to carry out GMP Quality and Compliance Audits of company suppliers and internal audits of their own sites.

(same as QMS MANUAL- 029) The purpose of this document is to provide some requirements as well as some recommendations for the development, content and management of Compliance Improvement Plans (CIPs). (same as QMS MANUAL- 030) The purpose of this document is to provide management and technical personnel with requirements as well as guidance on the archiving, records management and disposal of data and information. (same as QMS MANUAL- 044) The purpose of this procedure is to describe the process for Quality Assurance (QA) Agreement regarding the supply of active pharmaceutical ingredients, bulk formulated products, part finished packs and finished packs to be followed by a pharmaceutical operation. (same as QMS MANUAL- 045) This Procedure defines the procedure for performing Distribution Site audits and includes selecting, preparing for, conducting, reporting and documentation archiving of Distribution Site audits. (same as QMS MANUAL- 046) This manual is to provide guidance on assigning Lead Audit Team/Site responsibilities, establishing an external supplier’s audit program, and the high level principles involved inconducting supplier audits. (same as QMS MANUAL- 047) The purpose of this Guideline is to provide the regulatory requirements for the management of master GMP documents; issued, controlled and used to verify compliance with required codes of GMP and/or other relevant Quality and Compliance Standards. Recommendations are also included on how to achieve compliance (same as QMS MANUAL- 048) The purpose of this Guideline is to describe the way in which artworks and printed package components should be created and controlled. (same as QMS MANUAL- 049) The purpose of this guideline is to define the requirements for assessment of data and documentation prior to release.

(same as QMS MANUAL- 050) To define the requirements for the application of risk management principles to computerized systems. (same as QMS MANUAL- 056) The purpose of this procedure is to describe the accountabilities and single process for the batch confirmation, certification and release by a Qualified Person (QP) within the European Union (EU). (same as QMS MANUAL- 057) The purpose of this Guideline is to describe the process in place to ensure that drug products and drug substances are manufactured in a manner that minimizes patient risk through adulteration from products manufactured in the same manufacturing plant or facility cleaning. (same as QMS MANUAL- 062) The purpose of this guideline is to define the content of Batch Specific Documentation (BSD), the process by which BSD is produced and the use to which it is put. BSD in this context refers to the Certificate of Analysis, (CofA) and the Certificate of Manufacture (CofM). (same as QMS MANUAL- 022) The purpose of this Guideline is to provide requirements for the content, scope and procedures for developing Annual Product Reviews and Product Quality Reviews, and also to outline recommendations on how to achieve compliance. (same as QMS MANUAL- 024) The purpose of this Guideline is to provide guidance on the warehousing and distribution of commercial products. (same as QMS MANUAL- 033) The purpose of this Guideline is to provide guidance on the design and specification of utilities associated with the manufacture, quality control and storage of API, intermediates and investigational products within an R&D facility. (same as QMS MANUAL- 034) To provide requirements in addition to recommendations for the performance of investigations in response to an incident, problem or deviation that may

affect the safety, identity, strength, purity or quality of an active pharmaceutical ingredient (API) or drug product. (same as QMS MANUAL- 037) To provide requirements for management and documentation of training and also to outline recommendations on how the requirements can be met. (same as QMS MANUAL- 038) The purpose of this Guideline is to provide requirements in the definition and documentation of raw data and also to outline recommendations on how to achieve compliance. (same as QMS MANUAL- 041) The purpose of this document is to give guidance on a process for risk identification, assessment, control and review within the area of GxP regulated quality and compliance. (same as QMS MANUAL- 052) The purpose of this guideline is to outline the requirements for the reporting, investigation and handling of inpidual deviations, and to outline a systemati approach for the trending of deviations, to enable ongoing improvement in deviation performance. (same as QMS MANUAL- 053) To define the process to be used for the frequency and audit of critical phases within a non-clinical safety study. This procedure may be applicable for all R&D GLP QA staff and will be used in the compilation of a program to identify audits to be undertaken for non-clinical safety studies and study parts for which compliance with GLP is claimed. (same as QMS MANUAL- 060) The purpose of this guideline is to describe the process for generation, approval and management within R&D of specifications for release of materials used in clinical trials during drug development. It also gives guidance on the contents of such specifications for drug substance, several common types of investigational medicinal products and excipients. (same as QMS MANUAL- 064) The purpose of this International Procedure is to describe the process for the manufacture, packing and/or shipping material ahead of clearance. This

Procedure can be applicable to any manufacturing Operations sites that is using, packing and/or shipping materials ahead of clearance. (same as QMS MANUAL- 065) The purpose of this Procedure is to define the requirements for the retesting and assignment of storage periods for API’s, excipients, intermediates and raw materials. (same as MFG MANUAL – 003) This document provides guidelines for the way in which the commercial manufacture and packaging of Active Pharmaceutical Ingredients (API) and formulated drug products should be documented. (same as QMS MANUAL- 067) The purpose of this document is to provide an interpretation of FDA 21 CFR Part 11, Electronic Records; Electronic Signatures (ER/ES) and to provide guidance for acceptable practices in the use of electronic records and electronic signatures by any site. (same as VAL MANUAL- 001) This procedure covers the planning of validation activities related to the manufacturing and control of the registered stages of Drug Product or Active Pharmaceutical Ingredient (API) for clinical use, validation or sale. (same as VAL MANUAL- 005) The purpose of this document is to provide guidance on the validation of processes for the manufacture of bulk drug i.e. those synthetic stages from introduction of the defined API Starting Materials into the process up to and including the physical processing of the API (Active Pharmaceutical Ingredient). Validation should extend to those operations determined to be critical to the quality and purity of the API. The validation of stages prior to the API Starting Materials is not mandatory. A risk assessment may deem it necessary. (same as VAL MANUAL- 009) The purpose of this document is to provide minimum mandatory requirements in the validation of processes for the commercial manufacture of formulated products to demonstrate the effectiveness and reproducibility of a process and being suitable for the intended purpose. The purpose is also to outline recommendation on how to achieve compliance. (same as VAL MANUAL- 013)

The purpose of this guideline is: To define the requirements for cleaning plant and equipment used to manufacture active pharmaceutical ingredients (APIs) or their intermediates; To give guidance on how to assure appropriate cleaning of API plants and equipment; To describe when validation is applicable and what must be done to complete validation. (same as VAL MANUAL- 016) To provide guidelines for the validation of sterilization processes used in the manufacturing activities for drug products or active Pharmaceutical ingredients (API) and also to outline recommendations on how to achieve compliance. (same as VAL MANUAL- 019) The Purpose of this guideline is to define the minimum requirements for cleaning and validation of cleaning processes for formulated product. It also covers post validation monitoring of the effectiveness of cleaning processes. (same as VAL MANUAL- 024) The purpose of this guideline is to outline the content and approval process for analytical procedures, and to describe those activities that should be carried out to demonstrate that analytical procedures used in laboratories within R&D and manufacturing operations are suitable for their intended purpose. (same as VAL MANUAL- 028) The purpose of this guideline is to provide requirements for the Validation of Facilities and Systems and to outline recommendations on how to achieve compliance. (same as VAL MANUAL- 036) This Guideline provides guidance on the qualification requirements to be applied to the Information Technology infrastructure. The establishment and maintenance of a qualified infrastructure for any regulated company is fundamental to meeting current business and regulatory requirements in respect of systems stability, reliability and security. (same as VAL MANUAL- 040) The purpose of this Guideline is to define and provide guidance on the requirements for managing and documenting changes which take place

during the development, implementation or operation of a computerized system, including its supporting operating environment. (same as VAL MANUAL- 045) The purpose of this Guideline is to advise on the practices to be adopted when wishing or requested, to display or provide copies of electronic records to regulatory authorities, auditors and other similar third parties. ▪Technology Transfer of Established Medicine from One (same as VAL MANUAL- 031) To describe a process for the transfer of manufacture of an established drug product, from one established commercial manufacturing site to additional/alternative sites. This will include the associated quality control procedures and health safety and environmental information. 3.3 - Laboratory Operations Manuals (same as LAB MANUAL – 003) To describe the quality standards required for the production, distribution, use and testing of water used in the manufacture of manufactured materials. (same as LAB MANUAL – 005) The purpose of this Guideline is to provide a general guideline for sterility testing. This guideline should aid in assuring that the products manufactured at the company’s sites as well as by a contract manufacturers meet the appropriate regulatory and company requirements and that there is a harmonized, company-wide approach to the concept of sterility testing. (same as LAB MANUAL – 006) The purpose of this Guideline is to provide a general guideline for endotoxin testing. The guideline should aid in assuring that the products manufactured at any of the company sites as well as by a contract manufacturer meet the appropriate regulatory and company requirements and that there is a harmonized, company-wide approach to the concept of endotoxin testing. (same as LAB MANUAL – 007) The purpose of this document is to provide recommendations for performing and documenting stability studies within R&D. Deviations from the recommended practice may be made providing: The scientific rationale can be justified against regulatory requirements and expectations. There is no precedent that the scientific rationale will be unacceptable to regulatory

authorities. For formal stability studies, the deviations and scientific rationale justifying them, do not conflict with, or undermine the validity of stability studies on similar commercial product types, particularly those belonging to the same therapeutic area. (same as LAB MANUAL – 009) The purpose of this Guideline is to outline the requirements in the expiration dating of all analytical reagents and solutions prepared from these reagents. Recommendations are also included on how to achieve compliance. (same as LAB MANUAL – 010) The Purpose of this guideline is to define the minimum requirements for cleaning and validation of cleaning processes for formulated product. It also covers post validation monitoring of the effectiveness of cleaning processes. (same as LAB MANUAL – 012) The intent of this procedure is to provide the Active Pharmaceutical Ingredient (API) Manufacturing Sites with the principles of a stability program. (same as LAB MANUAL – 013) The purpose of this procedure is to describe how stability studies carried out at contractors shall be managed. (same as LAB MANUAL – 016) The purpose of this Guideline is to provide guidance for the microbiological testing of non-sterile products. This guideline should aid in assuring that the products manufactured at each of the gmp sites as well as by a contract manufacturer should meet the appropriate regulatory and company requirements and that there is a standardized, company-wide approach to the basic concept of microbiological quality control of non-sterile products. (same as LAB MANUAL – 017) The purpose of this guideline is to describe the requirements for the sampling and storage of reference and retention samples under GMP regulations/legislation. Local regulatory requirements that require the retention of additional samples, increased sample quantities or longer retention periods, take precedence over this guideline. (same as LAB MANUAL – 018)

The purpose of this Guideline is to provide guidance on qualification of laboratory equipment within R&D. (same as LAB MANUAL – 020) The purpose of this Guideline is to provide guidance on the manufacture and microbiological testing of sterile Investigational Medicinal Products (IMP) and Active Pharmaceutical Ingredients (API). (same as LAB MANUAL – 022) The intent of this procedure is to provide to manufacturing and primary packaging sites the principles of a stability program. (same as LAB MANUAL – 001) The purpose of this Guideline is to provide requirements for environmental monitoring. This guideline provides recommendations on how to achieve compliance with the requirements. This guideline will aid in assuring that the commercial and investigational medicinal products manufactured will meet the appropriate regulatory and company requirements. (same as LAB MANUAL – 024) The purpose of this international guideline is to outline minimum mandatory requirements as well as recommendations for the identification and reaction to trends found in stability data (same as LAB MANUAL- 027) The purpose of this guideline is to outline the content and approval process for analytical procedures and to describe those activities that should be carried out to demonstrate that analytical procedures used in GMP laboratories are suitable for their intended purpose. 3.4 - Manufacturing Operations Manuals (same as MFG MANUAL – 003) This document provides guidelines for the way in which the commercial manufacture and packaging of Active Pharmaceutical Ingredients (API) and formulated drug products should be documented. (same as MFG MANUAL – 007) The purpose of this guideline is to define the general requirements and to provide guidance for the calibration and maintenance of instruments, equipment, facilities, utilities/services and systems.

(same as MFG MANUAL – 014) The purpose of this guideline is to provide guidance regarding the reworking, reprocessing or recovery (salvaging) of formulated products, active pharmaceutical ingredients (API’s) and intermediates used in the processing of APIs. (same as MFG MANUAL – 018) The purpose of this International Guideline is to describe the requirements for in-process testing and sampling during manufacture and packing. (same as MFG MANUAL – 022) The purpose of this International Guideline is to describe the principle of handling the quality assessment and recovery of returned goods. (same as MFG MANUAL – 026) The purpose of this guideline is to describe the way that packaging operations should be conducted. (same as MFG MANUAL – 028) The purpose of this Guideline is to describe the requirements for meeting current Good Manufacturing Practice (cGMP) compliance requirements for new and upgraded facilities to be used for the manufacturing of any sterile and non sterile product. The Guideline also aims to provide recommendations on how to achieve compliance with the requirements. (same as MFG MANUAL – 031) The purpose of this Guideline is to provide guidance in the GMP requirements for the labeling and packaging of investigational materials at all stages of manufacturing and packaging (same as MFG MANUAL – 034) The purpose of this procedure is to define the principles for management of change within Operations. This document may applies to the Change Management process, to Regulatory Affairs, CMC and to all cGMP activities performed by an Operation sites. It applies to all facilities, processes, systems and procedures used during manufacture, testing and distribution that may directly or indirectly affect the quality of pharmaceuticals products 4.0 Good Manufacturing Practice

Practice 4.1: Good Practice on Facilities and Equipment Practice 4.2 : Good Practice on Material Management Practice 4.3: Good Practice on Labeling and Packaging Practice 4.4: Good Practice on Manufacturing Operations Practice 4.5: Good Practice on Laboratory Management Practice 4.6: Good Practice on Validation Requirements Practice 4.7: Good Practice on Quality Management Systems 5.0 Quality and Validation Guidance 5.1.1 - Method Validation These guidelines in combination provide guidance for the validation of analytical test methods. These analytical test methods include those tests which evaluate API, Raw Materials, In Process samples (e.g. reaction monitoring) and early intermediate materials (prior to the introduction of the first critical intermediate). This also include Risk Assessment and Prioritization, System Suitability, Precision and Accuracy, Quantitation and Detection Limit, Linearity, Range and Specificity, Robustness. 5.1.2 - Cleaning Validation (same as VAL MANUAL- 053) The Maximum Allowable Residue for Therapeutics (MART) and Residue Acceptability Limit for Therapeutic Dose (RALT) should be calculated based on each product that is to be processed in a specific equipment train and determined by the formulas and equations provided in Appendix A. A common default MART is not more than ten (10) ppm. (same as VAL MANUAL- 054) This document provides guidance in selecting the type of routine verification sampling method to use for particular types of API equipment and recommends locations for where to perform swab and / or visual inspection

conducted during cleaning validation and during subsequent routine verification. (same as VAL MANUAL- 055) The ability to group products or equipment for the purpose of reducing the amount of sampling and testing during cleaning validation is dependent on scientific, documented rationale. Similarly, scientific, documented rationale is also required when determining a worst-case product for the purposes of cleaning validation of API and DP manufacturing equipment. (same as VAL MANUAL- 056) The area to be swabbed must be defined, typical areas range from 5cm x 5cm to 4” x 4”. It shall include special requirements and/or calculations for specific areas or equipment. It should be constant and well defined at each site to ensure consistency. (same as VAL MANUAL- 057) If visual inspection is the only verification of a changeover cleaning process on minor equipment, the limit of detection using visual inspection techniques should be quantified in the laboratory or referenced from recognized literature. (same as VAL MANUAL- 037) Comparison of an unknown peak to the RAL determines if an investigation is initiated. There are multiple Safety Factors typically applied in the RAL calculations. Therefore, the risk of having an unknown peak present that is significant to toxicity or dose limits is relatively low considering the conservative approach chosen to calculate the RAL. (same as VAL MANUAL- 058) The cleaning program requires that cleaning is conducted and the cleaning activities documented following written instruction-records, or SOPs with attached checklists. (same as VAL MANUAL- 035) An understanding of the concept and relationship between normal operating range and proven acceptable range is necessary in establishing the range for a critical process parameter. Rationale for the determination of a parameter as critical must be documented. 5.1.3 - Other Validation Guidances (same as VAL MANUAL- 060)

Critical process parameters should be determined by a review of available historical data generated during development and/or manufacturing, or by experimentation. Each critical step is evaluated by observing the effect that potential critical process parameters have on quality attributes. (same as VAL MANUAL- 013) A Cleaning Evaluation should be conducted, documented, and approved by the Site Quality and Production Team. This evaluation may be a single report or several reports and may be equipment centric or process centric and document or reference the required information. (same as VAL MANUAL- 034) Demonstrating equivalence is needed in all API validations, but this guidance is applicable to APIs prepared by chemical synthesis. Additional analysis (not described here) may be needed to evaluate physical attributes of the API, where requirements are defined for the corresponding Drug Product. (same as VAL MANUAL- 003) A new or modified drug products should be demonstrated to be equivalent to previously produced product. Comparisons must be done as part of process validation studies for new product and significantly modified processes that require validation. (same as VAL MANUAL- 002) This guidance describes considerations and risks for determining if the establishment of clean equipment hold times for equipment producing drug product and Active Pharmaceutical Ingredients (API) are required (same as VAL MANUAL- 004) This guidance outlines considerations and risks associated with hold times between equipment use and cleaning. The recommendations to evaluate if the time between equipment use and cleaning needs to be established and controlled are described for Active Pharmaceutical Ingredients (APIs) and Drug Products. When they are determined to be critical, recommendations on how to establish and extend existing hold times are also described. (same as VAL MANUAL- 006) This guidance provides recommendations and examples for evaluating the process validation impact of changes to manufacturing processes used for manufacture of API, Drug Products and packaging processes. (same as VAL MANUAL- 020 & VAL MANUAL- 022)

This guidance addresses recommendations for good sampling practices. Validation sampling plans must be specified or referenced in the protocol. (same as VAL MANUAL- 007) This guidance provides recommendations related to the selection and application of swab sampling and visual inspection for various types of Drug Product equipment. (same as VAL MANUAL- 008) This Guidance sets out guidelines for the determination and validation of in- process and bulk product holding times. (same as VAL MANUAL- 010) This guidance provides information on demonstrating batch homogeneity of final APIs (small and large molecules) and critical intermediates.This procedure provides guidance for performing a homogeneity evaluation in support of API process validation. The following components of the evaluation are described: Materials to be tested, Selection of test methods for examining homogeneity, Sampling plan – when to collect samples, from what locations, and the number of samples, Selecting acceptance criteria for evaluating homogeneity test results. (same as VAL MANUAL- 011) This guidance provides an example of documentation to support the use of Continuous Quality Verification for demonstrating that a manufacturing process is in a validated state. (same as VAL MANUAL- 012) This guidance describes the documentation needed to support the use of Continuous Quality Verification to demonstrate that a drug product or active pharmaceutical ingredient process is in a validated state. It also describes some similarities and differences between Continuous Quality Verification and traditional process validation using three discrete lots. (same as VAL MANUAL- 015) This procedure provides examples and guidance on classification of defects for packaged non-sterile drug products. (same as LAB MANUAL – 019) This procedure provides guidance in the qualification of simple, moderate, and complex laboratory equipment that is used in an analytical laboratory in a

Good Manufacturing Practices (GMP) environment associated with products in or intended for the market place. (same as VAL MANUAL- 017) Bracketing and matrixing allow a ‘most appropriatechallenge’ condition to be defined for a process or drug product family (the same drug product with different dosage strengths). This risk-based approach can allow the validation to be focused on the most challenging circumstances, or “worst cases.” Use of this approach can provide a significant benefit to reduce the overall validation effort. (same as MFG MANUAL – 001) Examples of primary and secondary packaging validation, both manual and automated operations are provided in this guidance. This also provides guidance on aspects to consider for packaging validation. Explanations of factors to consider for acceptable packaging validation and lot size are provided with various practical examples. (same as VAL MANUAL – 035) This guidance is to address environmental control for existing, new, and modified non-sterile API processing areas used for the manufacture of commercial materials. This includes non-sterile API manufacturing areas where the API will subsequently be used to produce sterile Drug Product. (same as VAL MANUAL- 018) This Guidance provides a tabulation of potential critical process parameters and quality attributes of typical steps of primary solid drug product (i.e. dry products) packaging processes. It also includes packaging validation items such as evaluation of equipment, protocol and report contents, amount of data (e.g. number of runs) and if warranted, microbiological studies. (same as VAL MANUAL- 020) This guidance provides Process Validation Sampling guidelines for non-sterile liquid (solutions and suspensions) and semi-solid (ointments, creams, pastes, gels and lotions) drug product dosage forms. (same as VAL MANUAL- 022) This guidance provides Process Validation Sampling guidelines for non-sterile solid dose drug product dosage forms. The purpose of this guidance is to provide the general principles and approaches that should be considered for sampling non-sterile solid dosage forms.

(same as VAL MANUAL- 023) This guidance compares and contrasts Performance Qualification (PQ) to Process Validation (PV). This guidance describes the differences between PQ and PV. It clarifies how the PQ term is applied to systems and to processes. As applied to processes, PQ batches are used to demonstrate the robustness of a process and PV batches are intended to demonstrate the reproducibility of the process. As applied to systems, PQ testing is intended to verify that integrated systems function together as required (same as VAL MANUAL- 025) This guidance addresses the application of a risk-based approach to: Prioritize the systems and processes for periodic review (PR); Justify frequency and schedule of PR (if applicable); Routine revalidation of processes. (same as QMS MANUAL- 001) This guidance addresses considerations for commercial release of batches of product manufactured prior to completion of process validation (PV) activities, and considerations for release of batches associated with performance qualification (PQ) and PV activities. (same as VAL MANUAL- 059) This guidance discusses the term critical process parameter and considerations are described for identifying the term CPP that need validation. It is applicable to the manufacture of commercial intermediates, API, Drug Products and packaging. (same as VAL MANUAL- 026) This guidance provides an explanation of the semi-solid Drug Product dosage form and recommendations for analysis of the manufacturing process critical process parameters. Semi-solids come in a variety of dosage forms, yet significant steps and equipment used for the manufacturing processes share commonality. The critical process parameters will often be the same from process to process. (same as VAL MANUAL- 027) This guidance provides an overview of potential critical process parameters for the manufacturing of solid oral dosage forms. Solid oral drug products come in a variety of dosage forms frequently with common steps and equipment. The potential critical process parameters are often the same from

process to process. This guidance provides an overview of process steps and typical equipment involved in manufacturing of solid oral dosage products and notes what might be critical process parameters associated with these process steps and equipment. (same as VAL MANUAL- 029) This guidance provides an example of the documentation for validation of a solvent recovery process. Solvent recovery validation is needed in some situations such as where the recovered solvent is intended for general site wide reuse into suitable manufacturing processes, including other API manufacturing processes than those from which the used solvent originated (same as VAL MANUAL- 030) Out-of-specification (OOS) results and any other deviations that may impact the acceptability of the qualification/validation should be documented, investigated, root cause determined, corrective action taken and reported. Several examples are included. (same as VAL MANUAL- 031) This document provides guidance for qualification and validation activities that take place as a result of the Technology Transfer for approved commercial Active Pharmaceutical Ingredient (API) and Drug Product processes. Other aspects of Tech transfers such as regulatory changes, stability impact, etc must also be considered as described in relevant guidance, but these other activities are outside the scope of this guidance. (same as VAL MANUAL- 032) This document provides guidance to determine if validation of re-work and/or re-processing steps are required for Active Pharmaceutical Ingredient (API) processes. This guidance provides recommendations for evaluating the potential impact on product quality to determine if a given re-work or re- process step requires validation (same as VAL MANUAL- 033) This guidance provides recommendations for the content of the planning, testing and reporting types of validation documentation. (same as VAL MANUAL- 038) The risk of compromising bio-pharmaceutical materials in shipping is relatively high, as these materials are particularly vulnerable to degradation when

exposed to various environmental and handling conditions. The risks can be managed effectively through qualification of packaging, handling, and transport procedures. (same as VAL MANUAL- 039) This document explains how the Commissioning and Qualification System Level Impact Assessment template can be used for Information Systems. To classify Information Systems as Direct, Indirect or No impact systems, only one question is applicable for Information Systems. By means of three typical examples, this guidance explains how system classification could be performed, based on the use of the system and its data. (same as VAL MANUAL- 041) This document recommends sampling locations, frequencies and testing activities associated with the commissioning and qualification of new installations or major revisions of Clean/Pure Steam Systems (e.g. the addition of new subloops or other system wide retrofitting). This guidance defines the sampling location, frequency, and testing activities utilizing a risk based approach for supporting the commissioning and qualification for a clean/pure steam system. (same as VAL MANUAL- 042) The classification of Information System components as critical or non critical can be performed using a Component Level Impact Assessment in order to determine which components need qualification. This guidance also gives guidance on how to identify components in applications and includes examples of component level impact assessments for three typical software applications. (same as VAL MANUAL- 043) There are three elements to achieving successful validation of a freeze drying cycle: 1. A well defined and understood formulation, 2. A qualified freeze dryer and a freeze drying cycle that provides the link between a specific formulation and 3. A specific freeze dryer. (same as VAL MANUAL- 044) Test results should be documented in a manner permitting objective pass/fail decisions to be reached. The following represents the objectives of good test documentation practices. The degree to which these are achieved should be based on the criticality of the function being tested.

(same as VAL MANUAL- 046) This procedure provides guidance for allowing Vendor’s Material of Construction (MOC) documentation, such as Certificates of Analysis (C of A) and other record documents, to be accepted as confirmation that a specified material has been used for new systems or components that come into direct contact with product. (same as VAL MANUAL- 047) This document provides guidance on the transfer of documents during the activities that take place as a result of the Technology Transfer for approved commercial packaged Drug Product (DP) processes. (same as VAL MANUAL- 048) This guidance recommends sampling locations, frequencies and testing activities associated with the commissioning and qualification of Purified Water (PW) and Water for Injection (WFI) Systems. (same as VAL MANUAL- 049) This guidance provides recommendations when developing specifications for the design of Direct Impact Compressed Air, Pressure Swing Adsorption (PSA) and Cryogenic Nitrogen Systems used in the manufacture of Active Pharmaceutical Ingredients (APIs) and Drug Products (DPs). 5.2 - Quality Management Systems Guidances (same as QMS MANUAL- 002) This Complaint Handling guidance defines practices for establishing and maintaining a product quality complaint handling system, and for monitoring and reporting corrective actions based on the findings (same as QMS MANUAL- 004) Application of Quality Risk Management to Periodic Review of SOPs is intended to provide a tool for determining the optimal review frequency that will ensure those SOPs which relate to GMP systems or processes and therefore bear the greatest potential for impact on product quality are reviewed/revised in a timely and possibly more frequent manner than those which are determined to be less critical or reflect stable processes. (same as QMS MANUAL- 006)

The practice of using the √N+1 as a rule for sample size is common in the pharmaceutical industry. (same as QMS MANUAL- 008) This document offers a risk assessment approach to document a critical instrument calibration interval change request. (same as QMS MANUAL- 012) This document discusses considerations for a site Structured On-the-Job Training system including GMP tasks and knowledge necessary to perform those tasks. (same as QMS MANUAL- 013) This document discusses considerations for a robust training system for those working in or in support of a preparation for aseptic processing area. (same as QMS MANUAL- 016) This document provides guidance for the handling, collecting and disposing of waste materials. (same as QMS MANUAL- 019) This document provides guidance in the conduct of Quality Assurance Audits to verify and assure the effectiveness of on-going quality systems, practices and programs and to identify potential procedural gaps or system weaknesses at Manufacturing Production and logistic Sites. (same as QMS MANUAL- 020) This document provides guidance on status control of the following materials: Raw Materials (RM); Starting Materials; Packaging Materials including labeling; In-Process Materials; Drug Products; Intermediates; Medical Devices; Components; Active Pharmaceutical Ingredients (API); Returned Goods, including Recalled product; Materials determined to be Acceptable for Rework/Reclaim; Rejected Materials; and Materials with Direct or Potential Indirect Product Contact, including cleaning materials and other items. (same as QMS MANUAL- 021) This document provides guidance in the performance of annual product record reviews to evaluate data and trending to: Verify consistency of the process; Identify the need to modify specifications, and Identify any preventive or corrective actions that would lead to product quality improvements. (same as QMS MANUAL- 023)

GMP compliance audit procedure