Validation Master Plan(VMP)

Bethesda 1 April 2009 Pharmaceutical Development Section Validation Master Plan First Draft For review 1 April 2009 Begin NIH Review2 April 2009 Signature Adoption Effective Date Pharmacy Department 10 Center Drive Room 1N257 Bethesda Maryland 20892 1196 This Page Intentionally Left Blank National Institutes of Health Inc Pharmaceutical Development Section Signature Page Document Validation Master Plan Revision Identification OriginalOrigination 1 Apr 2009 Facility National Institutes of Health Department of Pharmacy Pharmaceutical Development Section Location Pharmacy Department 10 Center Drive Room 1N257 Bethesda Maryland 20892 1196 This Revision Date Complete Title Validation Master Plan Objective The objective of this Validation Master Plan is to define the Facility Equipment and Process Validation requirements methodologies and acceptance criteria for qualification of the Pharmacy PDS liquid and solid dose manufacturing area Document Written By Narlin Beaty Title Contractor Qualification Process Solutions LLC Signature Date Document Approved By Title Signature Date Document Approved By Title Signature Date Document Approved By Title Signature Date This Page Intentionally Left Blank TABLE OF CONTENTS BY SECTIONS 1 INTRODUCTION POLICY AND SCOPE 8 2 CONCEPT OF QUALIFICATION VALIDATION 12 3 ORGANIZATIONAL RESPONSIBILITIES FOR VALIDATION 28 5 CALIBRATION PROGRAM 44 6 PREVENTATIVE MAINTENANCE PROGRAM 50 7 KEY STANDARD OPERATING PROCEDURES REQUIRING VALIDATION 54 8 GUIDELINES FOR SPECIFIC EQUIPMENT AND SYSTEMS 60 9 PROCESS VALIDATIONS 88 10 ENVIRONMENTAL MONITORING PROGRAM I PHYSICAL TESTS 126 11 MICROBIOLOGICAL TESTING 145 This Page Intentionally Left Blank NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 1 Page 7 of 163 Contents 1 Introduction Policy and Scope 2 1 1 Project Description 2 1 2 Scope 2 1 3 Definition of the Term Validation 4 1 4 Living Document 4 NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 1 Page 8 of 163 1 Introduction Policy and Scope 1 1 Project Description The objective of this Validation Master Plan is to define the Facility Equipment and Process Validation requirements methodologies and acceptance criteria for qualification of the Pharmacy located at the National Institutes of Health Pharmacy Department NIH PHAR 9000 Rockville Pike Building 10 Pharmacy Bethesda MD 20892 Where appropriate this document makes reference to suitable internal policies and procedures identified by document number Every attempt is made to generate a consistent uniform policy however due to the revision lag that occurs when this document is updated conflicts may occur from time to time such as in issuing updated SOPs to reflect new policy Where conflicts exist the most recent document that has undergone signature review must prevail 1 2 Scope The Validation Master Plan VMP covers all of the FDA regulated cGMP items that need to be validated in order to comply with Part 21 211 of the Code of Federal Regulations The VMP is not intended to be an exact prescription for the validation of processes or equipment Instead it serves as an internal guidance document that lays out the policies of NIH PHAR as they apply to validation This Master Plan is limited to the NIH PHAR and its Drug Manufacturing Operations its manufacturing equipment and dedicated or shared utility systems The following systems equipment processes are addressed by this plan Equipment NumberEquipment Name 201HPLC Unit s 202Mass Spectrometer 203Polarimeter 204 DSC differential scanning calorimeter 205 CZE capillary zone electrophoresis 206IR infra red spectrophotometer 207Dissolution Testing Apparatus 208 UV ultra violet spectrophotometer NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 1 Page 9 of 163 401Vial Washer 402Autoclave 403Depyrogenation Oven 404Pass Thru 405Lyophilizer 406Bio Safety Cabinet 407Laminar Flow Hood 408Dishwasher 409Glatt fluid bed dryer 410Bio Safety Cabinet 411Dishwasher 412Capsule Machine 413 V Blender 414Tablet Press HVAC WFI Pure Steam RODI Compressed Air Nitrogen Chilled Water In addition to the IQ OQ PQ of equipment the plan includes processes that must be validated These are processes that are performed by NIH PHAR personnel and for which the validation is proving not only the process but especially that specific personnel can conduct the process Products used for process validation should be manufactured using the same production equipment methods and procedures that will be used in routine production Some of the Processes Covered by the VMP are listed in the following table Section 9Title 1Fill Volume Qualification 2Thawing of Frozen Product pre fill 3Filter Sterilization 4Product Sterile Sampling 5Media Fills 6Visual Inspection 7Product Lyophilization 8Holding Period for Clean Items Prior to Use NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 1 Page 10 of 163 9Holding Period for Sterile Items Prior to Use 10General Hold Time Studies 11Gowning Procedure Validation 12Sterile Filter Integrity Testing 13Washing of components other than vials 14Sterilization of Loads Steam or Dry Heat other than vials 15Facility Cleaning and Sanitization 16Environmental Monitoring non viable 17Environmental Monitoring viable 1 3 Definition of the Term Validation Validation is a system of inter related practices and procedures which in combination with routine production methods and quality control techniques provides a high degree of assurance that a system is performing as intended and will consistently produce a product meeting its pre determined specifications and quality systems 1 4 Living Document To be of any use the VMP must be reviewed regularly and changed as needed It should serve as an organizational history and all changes should be included in an appendix with an explanation of what changed and why In the beginning it is expected that many fundamental changes may occur as the organization evolves CFR 21 compliance Later the primary changes may include additions of equipment and processes Section 3 Organizational Responsibilities for Validation lays out the specific responsibilities of three groups These include the Validation Department the Operations Department and the Quality Control Personnel The assigned responsibilities for these groups facilitates keeping the document and keeping it as a living document NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 2 Page 11 of 163 Contents 2 Concept of Qualification Validation 2 2 1 Definitions 2 2 2 Validation Life Cycle Demonstrate that controlling monitoring and or measuring equipment and instrumentation are capable of operating within the parameters prescribed for the process equipment Perform replicate cycles runs representing the required operational range of the equipment to demonstrate that the processes have been operated within the prescribed parameters for the process and that the output or product consistently meets predetermined specifications for quality and function and Monitor the validated process during routine operation As needed re qualify and recertify the equipment 2 1 Definitions Installation Qualification Installation Qualification IQ is the process that ensures that all equipment used in the manufacturing process meets the specified requirements and is constructed placed and installed in accordance with pre approved specifications to facilitate maintenance adjustment cleaning and use The Installation Qualification includes the verification of the installation requirements the verification of the equipment specifications and the verification of the installation Operational Qualification Operational Qualification OQ is the process that establishes confidence through testing that the equipment used in the manufacturing process is capable of functioning within the anticipated range NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 2 Page 13 of 163 of operations The Operational Qualification is normally conducted following the successful completion of the Installation Qualification Performance Qualification Performance Qualification PQ is the process that establishes through appropriate testing that the equipment or system can consistently perform as specified The Performance Qualification is normally conducted following the successful completion of the Operational Qualification Process Validation The process that establishes confidence through appropriate testing that the manufacturing process inclusive of all related equipment personnel and practices will produce a product meeting all the pre determined requirements for functionality and safety Validation Protocol The protocol will be a written and approved plan stating how the validation will be conducted including test parameters product characteristics production equipment and decision points in what constitutes acceptable results Prospective Validation The validation process conducted prior to the distribution of either a new product or a product made under a revised manufacturing process where revision may affect the product s characteristics Static Operation Operational state wherein normal cleaning sanitization and maintenance are conducted but no manufacturing processes are operating Dynamic Operation Normal operating conditions with manufacturing or simulated manufacturing in progress with the normal number of personnel present CIP Clean In Place Cleaning of fixed equipment by use of an automated cleaning system COP Clean Out of Place Cleaning of non fixed equipment by use of a semi automated COP tank Manual Cleaning Cleaning performed by individuals per codified procedure using manual methods e g using wipes brushes etc Process By Product NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 2 Page 14 of 163 Products produced by the manufacturing process that are not the desired product Also included are products that have been altered modified or denatured by the cleaning process Direct Product Contact Equipment Such equipment will be defined as any surface in direct contact with the product either fluids or solid components or in direct contact with product contact components equipment Indirect Product Contact Equipment Defined as any surface NOT in direct contact with product fluids solids e g in the product transport path but having the potential to become soiled and when grossly soiled have the possibility to contaminate the manufactured product e g formulation areas isolators where residual particulate matter could contaminate direct contact surfaces Dedicated Equipment Relative to cleaning validation defined as product contact equipment that is used in the manufacturing of a single Product or Product Family e g multiple strengths of the same active using the same excipients Dedicated Equipment is appropriately labeled and is stored and controlled procedurally such that use with other products is precluded Multi Use Equipment For purposes of cleaning validation is defined as any product contact equipment used for more than one Product or Product Family Equipment used for both Product manufacture and Media Fills is considered Multi use Visually Clean For purpose of cleaning validation is defined as visually free of particulates and soils when carefully examined under normal lighting conditions Pyrogens Endotoxins Bacterial components typically lipopolysaccharides that can deleteriously elevate body temperature when introduced into the bloodstream are called Pyrogens Endotoxins are lipopolysaccharides that behave as Pyrogens 2 2 Validation Life Cycle however periodic validation may not be adequate More NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 2 Page 15 of 163 important is appropriate monitoring so that if problems develop or changes are made the need for immediate revalidation is considered 2 3 System Impact Assessment What processes must be validated Where process results cannot be fully verified during routine production by inspection and test the process must be validated according to established procedures In the case of equipment used in the manufacture of a drug product the process must be validated for reproducibility regardless of its obvious or not state of operation When any of the conditions listed below exist process validation is the only practical means for assuring that processes will consistently produce products that meet their predetermined specifications Routine end product tests have insufficient sensitivity to verify the desired safety and efficacy of the finished products Clinical or destructive testing would be required to show that the manufacturing process has produced the desired result or product Routine end product tests do not reveal all variations in safety and efficacy that may occur in the finished products The process capability is unknown or it is suspected that the process is barely capable of meeting the drug specifications Specific cGMP regulations require validation for example CFR 21 211 68 2 4 Elements of a Process Validation Protocol Careful planning of a validation study is essential to ensure that the process is adequately validated The plan should include design reviews The plan for the validation study is documented in the validation protocol Planning for the validation should include the following elements as well as any other relevant issues that must be addressed to conduct the validation study Protocol Approval Identification of the process to be validated Identification of all personnel participating in the validation Identification of the use of any equipment or process in manufacturing Criteria for a successful study Length and duration of the study Assumptions shifts operators equipment components Identification of equipment to be used in the process Identification of utilities for the process equipment and quality of the utilities Complete description of the process may be done by reference to another document Relevant specifications including those for the product components manufacturing materials the environment etc NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 2 Page 16 of 163 Any special controls or conditions to be placed on preceding processes during the validation Process parameters to be controlled and monitored and methods for controlling and monitoring Product characteristics to be monitored and method for monitoring Any subjective criteria used to evaluate the product may require a discussion of how the subjective criteria are to be evaluated Definition of what constitutes nonconformance for both measurable and subjective criteria Statistical methods for data collection and analysis Consideration of maintenance and repairs Statement of conditions that may indicate that the process should be revalidated Stages of the study where design review is required A place to record deviations from the protocol 2 5 Elements of an Equipment Validation Protocol The equipment validation is called a qualification and will be carry one of several adjectives At NIH the types of equipment qualifications that will be performed include only installation qualification and operational qualification Performance qualifications fall into the broad category of process validations and were discussed above After process equipment is designed or selected it should be installed reviewed calibrated challenged and evaluated to ensure that it is capable of operating within established limits and tolerances as well as throughout all anticipated operating ranges Installation and operation qualification studies establish confidence that all equipment used in the manufacturing process meets specified requirements and is appropriately designed constructed placed and installed to facilitate maintenance adjustment cleaning and use The installation and operation qualification phases of process validation include examining equipment design and supplied documentation determining installation requirements establishing any needed environmental controls and procedures assuring that the work area has sufficient space to perform the processing and associated activities installing the equipment verifying correct installation establishing manufacturing procedures for the monitoring operation and control of the equipment including the minimum number of operators determining calibration cleaning maintenance adjustment and expected repair requirements identifying important elements of the equipment that could affect the output or finished device verifying that the system or subsystem performs as intended throughout all anticipated operating ranges and documenting the above information NATIONAL INSTITUTES OF HEALTH Title Validation Master Plan for Drug Manufacturing Operations Document Number Effective Date Supersedes Date Section 2 Page 17 of 163 2 5 1 User Requirement Statement User Requirement Specifications URS may exist for major equipment or other installations When such documents exist they can be used as a guide in drafting equipment validation protocols 2 5 2 Start Up Start up of equipment and facilities means to turn it on apply power start it up and otherwise operate it for the first time Start up may be performed by the vendor the custo