Quality facilities hvac and water systems

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  • 1. Qualify Facilities, HVAC and Water Systems Jerry Lanese Ph.D. The Lanese Group, Inc. 1
  • 2. Credits : GAMAL AMER, PH. D. PRINCIPALPREMIER COMPLIANCE SERVICES, INC. 2
  • 3. Critical Utilities Qualification 1. Overview 2. HVAC Qualification3. Water System Qualification Presented by: Gamal Amer, Ph. D. Principal Premier Compliance Services, Inc. © All rights reserved. Do not copy without permission. 3
  • 4. Process Validation: General Principles and Practices•  Guidance to industry issued by the FDA in January 24, 2011.•  Outlines the life cycle approach to validation.•  Inline with the principles advanced in ICH Q8, ICH Q9, ICH Q10 and in ASTM E2500.•  Defines PROCESS VALIDATION as the collection and evaluation of data, from the process design stage throughout commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. © All rights reserved. Do not copy without permission. 4
  • 5. Three Times Is Not Even The Beginning Jerry Lanese Journal of Validation Technology Vol. 7, No. 2, February, 2001 Vol. 14, No 2, Winter 2008 5
  • 6. VALIDATIONThe accumulated, documented evidencethat a system performs as intended VALIDATION validationThe collection and evaluation of data, fromthe process design stage throughoutcommercial production, which establishesscientific evidence that a process is capableof consistently delivering quality products.
  • 7. ICH Q10 Pharmaceutical Quality System Pharmaceutical Technology Commercial Product Development Transfer Manufacturing Discontinuance Investigational Products GMP Management Responsibilities Process Performance and Product Quality Monitoring System PQS Corrective Action/Preventive Action (CAPA) SystemElements Change Management System Management Review Knowledge ManagementEnablers Quality Risk Management 7 ©2009 The Lanese Group
  • 8. FDA Guidance: Process Validation: General Principles and Practices•  Replaces the guidance issued in 1987•  Quality of the product cannot be assured by simply inspecting or testing in-process and finished products. It must be built into the product-process a-priori.•  Focusing exclusively on the qualification effort without understanding the process and ensuring the process is maintained in a state of control may not lead to adequate assurance of quality. 8 © 2012 The Lanese Group
  • 9. Pharmaceutical Technology Commercial Product Development Transfer Manufacturing Discontinuance FDA Guidance To Industry January 2011•  Three Stages of Process Validation –  Process Design Stage (process is defined based on development and scale-up) –  Process Qualification Stage (Design is confirmed as being capable of reproducible production) –  Continued Verification and improvement (Continuously gaining assurance the process remains in a state of control) 9 © 2012 The Lanese Group
  • 10. The Life Cycle Approach to Process Validation Planning & Design (ICH Q8) PAT ICH Q9 Continuous Implementation Verification & & Qualification Improvement ICH Q9, CAPA, PAT & Change Control ICH Q10 The Quality System © All rights reserved. Do not copy without permission. 10
  • 11. Pharmaceutical Technology Commercial Product Development Transfer Manufacturing Discontinuance The Design Stage•  Understanding the science•  Understanding the risk•  Building Quality into the process•  Establishing Control Strategy•  Proper design of the facility and utility serving the process. 11 © 2012 The Lanese Group
  • 12. Pharmaceutical Technology Commercial Product Development Transfer Manufacturing Discontinuance Implementation and Process Qualification•  Qualification of utilities and equipment (“… design of the facility and qualification of the equipment and utilities”)•  Performance qualification and PQ protocol (… PQ combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches.)•  Protocol execution and report 12 © 2012 The Lanese Group
  • 13. Pharmaceutical Technology Commercial Product Development Transfer Manufacturing Discontinuance Continued Process Verification•  Monitoring appropriate parameters to ensure process in a state of control, including the performance of the utilities (e.g. Environmental monitoring for HVAC and water system verification).•  Use CAPA, PAT and Change control as well as data collected in monitoring to continually improve the process.•  Proper maintenance of the facility, utilities, and process equipment 13 © 2012 The Lanese Group
  • 14. Science and Risk Based Compliance: An Overview Gamal Amer, Ph. D. Principal Premier Compliance Services, Inc. © All rights reserved. Do not copy without permission. 14
  • 15. Risk to What?•  In GMP Compliance: –  Risk to product quality –  Risk to the patients well being•  In Manufacturing –  Risk to personnel –  Risk to the environment•  In Business –  Financial risk to the company © All rights reserved. Do not copy without permission. 15
  • 16. Focus for this workshop•  Risk is always present•  You need to know what it is and how it manifests itself a-priori•  We will focus on risk to product quality during manufacturing and the patient’s wellbeing•  Thus we will focus on GMP issues © All rights reserved. Do not copy without permission. 16
  • 17. FDA Initiative August 2002Pharmaceutical CGMP for the 21st Century: A Risk-based Approach A science and risk-based approach to product quality regulation incorporating an integrated quality system approach © All rights reserved. Do not copy without permission. 17
  • 18. FDA Guidance August 2002•  Early adoption of new technology.•  Adoption of modern quality management techniques and implementation of the quality system approach.•  Focus on understanding the science & technology associated with what you are making.•  Priority to mitigating the highest risk elements of the manufacturing operation. © All rights reserved. Do not copy without permission. 18
  • 19. FDA Guidance August 2002•  Take home: –  You must understand what you are doing. –  You must focus on critical areas (highest risk to product quality) of your operation. –  You should utilize automation and data collection to reduce risk associated with the operation and allow for continuous improvement. –  You must build the quality into your operation. 19 © 2012 The Lanese Group
  • 20. Mitigating Risk and Allowing Continuous ImprovementFDA Progress Reports discusses QAsystems:1. Quality by Design (QbD)2. Process Analytical Technology (PAT)3. Corrective and Preventive Action (CAPA) © All rights reserved. Do not copy without permission. 20
  • 21. Quality by Design © All rights reserved. Do not copy without permission. 21
  • 22. ICH Q8 – Pharmaceutical Development•  Deals with product development and its manufacturing process.•  Defines the need for good Design Of Experiments (DOE).•  Defines the need for prior knowledge.•  Use data from product development studies to manage the risk associated with the product (quality cannot be tested in the product but rather built into it).•  Managing quality through out the product life cycle from initial development through discontinuation.•  Defines continuous process verification as an alternative to process validation.•  Define the knowledge space, the design space and the normal or control space. © All rights reserved. Do not copy without permission. 22
  • 23. Product Life Cycle Verification and Drug Discovery ValidationClinical Studies Product Development Manufacturing and Operation Decommissioning Process Development Operation Design & Product Construction Discontinuation 23 © 2012 The Lanese Group
  • 24. Knowledge, Design, and Control SpaceThe concept Knowledge space (KS) – Science Based Design Space (DS) – Based on Design and technological capability Control/Operating Space (CS) 24 © 2012 The Lanese Group
  • 25. ICH Q8 – Pharmaceutical Development•  Benefits: –  Improved knowledge –  Manufacturing improvement within DS are not changes –  Operational robustness –  Reduce post-approval submissions –  Real time release and reduced product testing –  Continuous process/product improvement © All rights reserved. Do not copy without permission. 25
  • 26. ICH Q8 (R1) – Pharmaceutical Development (Revision 1)•  Introduces the concept of Quality by Design (QbD)•  Emphasize use of design of experiments and prior knowledge to define the design space.•  Identifies Critical Quality Attributes (CQA) of the product and Critical Processing Parameters (CPP) that would affect it.•  Defining a control strategy based on CQA=f (CPP) © All rights reserved. Do not copy without permission. 26
  • 27. ICH Q8 (R1)Quality by Design (QbD):A systematic approach to developmentthat begins with predefined objectives andemphasizes product and processunderstanding and process control, basedon sound science and quality riskmanagement. © All rights reserved. Do not copy without permission. 27
  • 28. ICH Q8 (R1)Critical Quality Attribute (CQA):It is a physical, chemical, biological ormicrobiological property or characteristicthat should be within appropriate limit,range, or distribution to ensure the desiredproduct quality. CQAs are generallyassociated with the drug substance,excipient, intermediates, and drugproducts. 28 © 2012 The Lanese Group
  • 29. ICH Q8 (R1)Critical Processing Parameter (CPP): A process parameter whose variability has an impact on a Critical Quality Attribute (CQA) and therefore should be monitored, “alarmed”, and controlled to ensure the process produces the desired quality. 29 © 2012 The Lanese Group
  • 30. ICH Q9•  Outlines Quality Risk Management Principles for Product Lifecycle.•  Phases of QRM include risk assessment, risk control, and risk review.•  Defines Risk and How to Measure it.•  Outlines the principle of focusing on the critical aspects of the drug manufacturing based on the level of risk.•  Use of change management to reduce risk. © All rights reserved. Do not copy without permission. 30
  • 31. What Is Risk? The combination of the probability of occurrence of harm and the severity of that harm.**ICH Consensus Guideline; Q9 Quality Risk Management; June 2006 © All rights reserved. Do not copy without permission. 31
  • 32. Risk is Always Present:•  Risk to the patient/public (Drug Side Effects, Adulterated Drugs)•  Risk to the product (Contamination)•  Risk to the personnel (Potent Compounds)•  Risk to the neighbors and environment (Explosion, Release Objectionable to Atmosphere)•  Risk to the company (Regulatory Recalls) © All rights reserved. Do not copy without permission. 32
  • 33. Defining Level of RiskFunction of: –  Severity –  Frequency –  Detectability•  These three factors determine the numerical Risk Priority Number (RPN)•  Qualitative risk (low, medium, and high) © All rights reserved. Do not copy without permission. 33
  • 34. Mitigating RiskThe level and extent of actions to be takento eliminate or minimize actual or potentialrisk must be appropriate to the magnitudeof the problem and commensurate with thelevel of risk anticipated. (ICH Q9) © All rights reserved. Do not copy without permission. 34
  • 35. ICH Q10•  Defines and discusses concepts such as: –  Quality Manual –  Management Responsibilities –  Continual Improvement of Process & Product –  Continual improvement of the quality system © All rights reserved. Do not copy without permission. 35
  • 36. ASTM E-2500 Consensus Standard Published in August 2007 © All rights reserved. Do not copy without permission. 36
  • 37. ASTM Standard E2500•  What is it? –  A consensus standard developed with input from industry and FDA –  It is called “Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment” –  Applies to all elements of manufacturing systems of biopharmaceutical products including facility equipment, process equipment, utilities, controls, etc. © All rights reserved. Do not copy without permission. 37
  • 38. ASTM Standard E2500•  What is its intent? –  Describe a risk- and science-based approach to design, specification and verification of the manufacturing systems. –  Satisfy international as well as US regulatory expectations. –  Follows the concepts introduced in August 2002 in FDA Guidance “Pharmaceutical CGMP for the 21st Century: A Risk-based Approach” © All rights reserved. Do not copy without permission. 38
  • 39. ASTM Standard E2500•  Objective –  Insure that manufacturing systems are fit for the intended use and while reducing work duplication and cost of the required validation. –  Accomplish through building quality into the design, specification and construction of such systems. –  Verify and certify suitability. © All rights reserved. Do not copy without permission. 39
  • 40. ASTM Standard E2500•  Tools: –  Use of User Requirements Specification (URS). –  Use of Good Engineering Practice (GEP). –  Use Scientific and Technical knowledge and enlist Subject Matter Experts (SME). –  Relating Critical Quality Attributes (CQA) to Critical Processing Parameters (CPP). –  Addresses Manufacturing System Lifecycle © All rights reserved. Do not copy without permission. 40
  • 41. Manufacturing Lifecycle Construction Installation Design Verification & Validation CertificationSpecification & Acceptance Operation Planning & Maintenance Decommissioning 41 © 2012 The Lanese Group
  • 42. Overall Approach to Verify Manufacturing Systems•  Define user requirements•  Conduct risk- and science-based analysis to define critical aspects of the operation•  Ensure that quality was designed into the operation a-priori•  Ensure that Good Engineering Practices were used in the design, specification and construction of the operation. © All rights reserved. Do not copy without permission. 42
  • 43. Overall Approach to Verify Manufacturing Systems (cont.)•  Utilize subject matter experts (SME) to plan and define verification strategy.•  SME to define acceptance criteria and selection of appropriate test methods.•  SME to execute the tests and review the results.•  SME to review and accept the verification testing and certify the system is “Fit For Intended Use” © All rights reserved. Do not copy without permission. 43
  • 44. Overall Approach to Verify Manufacturing Systems (cont.)•  Utilize vendor documentation and testing information to support the verification effort. –  Confirm acceptable vendor quality system and technical capability•  Avoid duplication of effort/testing by using GEP commissioning data to support the verification. –  Confidence that info is accurate and suitable 44 © 2012 The Lanese Group
  • 45. The Process Good Engineering Practices Product Knowledge Specification & Requirements Acceptance & Verification Process Knowledge Operation & Continuous Release Design Improvement RegulatoryRequirements CompanyQuality Req. Risk Management Design Review Change Management 45 © 2012 The Lanese Group
  • 46. The Verification Approach Requirements Define Acceptance defined Criteria and CQA verification tests Define Science and risk Define Critical Systems/based analysis done verification requirements Quality is built Define Critical Process into the design Parameters Use vendor GEP confirmed documentation Perform test Manufacturing Review and Operation Certify 46 © 2012 The Lanese Group
  • 47. Qualify/Validate Verified System•  Provide documented evidence that the process will consistently produce product which meets predetermined characteristics and quality attributes. Ensure system remains in a validated state. © All rights reserved. Do not copy without permission. 47
  • 48. In Summary•  The facility and utilities are part and parcel of the process and its operation.•  You must understand how the utilities and facility interact with the process.•  Qualification of utilities is part of the process qualification.•  Monitoring and maintaining the utilities and facility are part of the process validation. of the facility•  Focus on high risk components of the facility and utilities. © All rights reserved. Do not copy without permission. 48
  • 49. Validation of Heating VentilationAir Conditioning (HVAC) System Gamal Amer, Ph.D. Principal Premier Compliance Services, Inc. © All rights reserved. Do not copy without permission. 49
  • 50. Heating Ventilation and Air Conditioning System•  HVAC or “aitch-vak” systems are mechanical arrangement that treat outside air to produced cleaned (from dust and microbes) and conditioned air (temp. & Humidity) for use in controlled and critical areas within the Pharmaceutical manufacturing space.•  The systems normally consist of filtration, heating, cooling, dehumidification, and humidification steps.•  It is the technology of indoor environmental control and/or comfort. © All rights reserved. Do not copy without permission. 50
  • 51. Heating Ventilation and Air Conditioning•  The most important utility in the manufacture of drug products.•  Controls the environmental conditions in the manufacturing space, which may affect product quality, safety, and Efficacy (temperature and Humidity).•  Control the cleanliness of the manufacturing space (Room classification-particulate number both viable and non viable).•  Prevent cross contamination (relative pressurization between spaces). © All rights reserved. Do not copy without permission. 51
  • 52. Regulatory Imperatives•  Control Temperature, Humidity , Pressure, Dust (Particulate), and Microbial load (21 CFR 211.46)•  The need to filter the air coming into manufacturing space (21 CFR 211.46)•  Protect product from extraneous contamination by microorganisms or their byproducts. Most intermediates and materials used in the industry are excellent promoters of microbial growth.•  The need to ensure that the product is not cross contaminated by other products being processed in adjacent space. © All rights reserved. Do not copy without permission. 52
  • 53. You also must ensure the system isvalidated and remains in avalidated state. The HVAC systemmust perform to meet the productrequirements and ensure that theconditions within the manufacturingspace are consistent. © All rights reserved. Do not copy without permission. 53
  • 54. Process Validation and HVAC SystemsAn HVAC system can be viewed as a processusing outside air as a raw material andproducing conditioned air. The conditioned aircomes into contact with the drug product andhence has a direct impact on the quality of thedrug product.Additionally, HVAC is a system that is a utilityand part of the facility in which production occursand as such must be qualified and maintainedas part of Stage2 of the proposed FDA guidanceon process validation. 54 © 2012 The Lanese Group
  • 55. HVAC System Consists of1.  Air Handling Unit (AHU) - Air filtration and conditioning. - Pump and meter the air into the distribution system.2.  Air Distribution System – Duct Work - Distribute the air to the various areas. - Temperature, humidity and smoke detection controls - Final filtration and heating if necessary. - Returning or exhausting the air.3.  Use Areas - Manufacturing spaces - Support spaces © All rights reserved. Do not copy without permission. 55
  • 56. Typical HVAC System for a Biotech Facility (Schematic) AHU Meter Humidifier Outside air Cooling Coil Pre-heat Filters Recycle? Reheat Coil Terminal HEPAReturn Corridor Buffer Prep Clean Corridor Fermentation Suite Class 100K Hood © All rights reserved. Do not copy without permission. 56
  • 57. Schematic of Biotech Facility (Air flow pattern for cleanliness and contamination control) Air Flow Soiled Clean Storage Wash Storage Return Corridor Buffer & Fermentation IsolationDegown Media Prep Purification Clean CorridorGown Packaging Finishing Storage & Staging © All rights reserved. Do not copy without permission. 57
  • 58. Schematic of Biotech Facility (Air flow pattern for cleanliness and contamination control)Typical Layout Air Flow/Relative Pressure Fill & Finish Class 100 Cold Room Packaging & Shipping Class 10,000 Purification Gown/Degown Class 100,000 RH 50% +/-10% Gown & Degown Corridor Class 100,000 Air Buffer & Media Prep Lock Isolation Wash room Class 100,000 Fermentation Class 100,000 © All rights reserved. Do not copy without permission. 58
  • 59. Design Stage; Stage-1•  User requirements•  Risk issues and assessment•  Functional specification•  Design control strategy and how to control conditions. © All rights reserved. Do not copy without permission. 59
  • 60. Design Stage•  User requirements: –  Defines, temperature, humidity, cleanliness requirements for the product as defined by the design organization and others.•  Risk assessment: –  Identifies issues associated with maintaining the user requirements such as required levels of cleanliness and air flow parameters. –  Relative importance of the various conditions and whether or not there is a need to control all of them. © All rights reserved. Do not copy without permission. 60
  • 61. Design Stage•  Functional specifications: –  Identify how conditions can be reached using the appropriate technology and technical knowledge.•  Design specifications: –  Defines the design specifications and the appropriate design space that would allow reaching the required conditions. Defines CQA and their relationship to the CPP.•  Control Strategy: –  How will the conditions be controlled and how will the CPP be manipulated to give the required CQA for the resulting air. © All rights reserved. Do not copy without permission. 61
  • 62. Design Stage•  Documents that would be needed to support the qualification effort: –  User requirements and design specifications to define the conditions within the space and the critical system components. –  Control strategy to define what controllers are used and where the monitoring takes place. –  Mechanical and architectural drawings. © All rights reserved. Do not copy without permission. 62
  • 63. Implementation and Qualification Stage; Stage-2•  In this stage the systems are installed and the installation as well as the operation of the system is verified and its performance qualified (PQ).•  Process Performance Qualification (PPQ) of the process (encompassing facility, utility, and equipment) is conducted, through: –  Protocol development and defining acceptance criteria –  Execution of the protocols and certification of the process as being suitable for the intended use and performs as expected. © All rights reserved. Do not copy without permission. 63
  • 64. What to Qualify?•  The mechanical system –  Its installation and operation –  The controls•  The air distribution system –  Installation –  Adequacy –  Safety issues•  The conditions prevailing in the room. –  Temperature and humidity –  Air Changes –  Relative pressurization –  Classification if applicable © All rights reserved. Do not copy without permission. 64
  • 65. Documents you need•  User requirements•  Engineering specifications•  Contractor’s submittals•  O&M Manuals•  Engineering drawings –  Mechanical drawings (M series) –  Architectural layout drawings (A series)•  Test And Balance (TAB) Report © All rights reserved. Do not copy without permission. 65
  • 66. Qualification Plan For Utilities (FDA guidance on Process validation)•  Qualification of utilities and equipment can be covered under individual plans or under an overall plan.•  Plan should consider requirements of use and risk management used to prioritize and define extent of activities.•  Plan should define: –  Studies and tests to be conducted –  The criteria to assess outcome of studies –  Timing for qualification –  Responsibilities for conducting the effort –  Procedure for documenting and approving the qualification•  Firm’s criteria for evaluating changes © All rights reserved. Do not copy without permission. 66
  • 67. Qualification of the HVAC System•  First step is to confirm that the system has been installed per the design and is capable of operating within the required parameters.•  Second is to verify that the system is capable of providing the needed conditions within the space and maintain them.•  Finally a report summarizing the effort and reaching the conclusion that the system is acceptable for the intended use has to be developed. © All rights reserved. Do not copy without permission. 67
  • 68. Installation & Operation Verification Tests and Acceptance Criteria © All rights reserved. Do not copy without permission. 68
  • 69. IOQ or Verification ProtocolNormally the protocol will have the following sections:•  Purpose•  Scope•  Responsibilities•  System description•  References•  Procedures•  Certification records•  Attachments•  Approvals © All rights reserved. Do not copy without permission. 69
  • 70. IOQ or Verification Protocol Defining Acceptance CriteriaHow to Define Acceptance Criteria•  Manufacturer/Vendor Specifications•  Engineering Design Specifications•  Specific Requirements of System (e.g Temperature homogeneity throughout the space)•  Regulatory Application Requirements (NDA)•  GMP and/or other Regulatory or Compendial Requirements•  Product/Intermediate Characteristics Requirements © All rights reserved. Do not copy without permission. 70
  • 71. Installation Verification1.  List maker, local representative, and maintenance contractor. Include addresses and phone numbers.2.  Confirm completeness of components as per specifications (Fans, Heaters, Humidifiers, Condensers, etc.).3.  Verify existence of Filters and compliance with design specification (Pre-, Terminal, etc.).4.  Document existence of Instrumentation at specified locations (Thermostats, Humidistat, Sensors, Safety devices, etc.) and indicate criticality and frequency of calibration.5.  Verify utilities and connections as per design (electric service to unit, Steam for humidification, Natural gas for heaters, etc.). 71 © 2012 The Lanese Group
  • 72. Installation Verification1.  Ensure control system is installed per the design and verify its components.2.  Confirm the existence of a spare parts list.3.  Confirm that documentation and drawings for the system exist and are accessible.4.  Ensure maintenance, operation, calibration, and training procedures are in place 72 © 2012 The Lanese Group
  • 73. Operation Verification1.  Document that all instruments which will be used in the qualification have valid calibration certificates.2.  Test controls, alarms, and interlocks to verify their proper operation. 1.  Start and stop of system 2.  Heating and cooling response 3.  Humidification response 4.  Smoke alarm response3.  Test, Adjust and Balance Report and Room Air Changes Verification © All rights reserved. Do not copy without permission. 73
  • 74. Performance Qualification and PQ Acceptance Criteria © All rights reserved. Do not copy without permission. 74
  • 75. What will the PQ confirm•  Ability of the system to maintain temperature and humidity within the space for extended periods.•  Ability of the system to properly function under normal operating (load) condition of the facility•  Ability of the system to maintain air flow and hence relative pressure between the various spaces.•  Ability of the system to maintain the particulate count levels within the space•  Ability of the system to maintain microbial count within the space © All rights reserved. Do not copy without permission. 75
  • 76. PQ Acceptance Criteria © All rights reserved. Do not copy without permission. 76
  • 77. Product Requirements are the Driving Force•  Temperature and Humidity in the space should not negatively impact the product.•  Temperature and humidity should meet the user requirements.•  If sterile space, room classification is 100 (M3.5; ISO 5 – Less than 100 particles of <0.5 micron/ft3)•  If critical space, the air should flow from it to less critical space.•  If user requirements are not clear, use engineering specifications, regulatory guidance, standards, or compendial values. © All rights reserved. Do not copy without permission. 77
  • 78. Particulate CountUSP 23 and FDA Guidance on Sterile Drug Products, 2004 Room Classification Particles/ft3* cfu/ft3 100 (M3.5; ISO 5) 100 <0.1 10,000 (M5.5; ISO 7) 10,000 <0.5 100,000 (M6.5; ISO 8) 100,000 <2.5 * Less than the indicated number of particles of diameter <0.5 micron/ft3 © All rights reserved. Do not copy without permission. 78
  • 79. Air ChangesBased on: ISO Standard 14644 and IEST-RP-CC012.1•  Room Classification •  Air Changes per hour –  100 (M3.5) –  500-700 –  10,000 (M5.5) –  60-90 –  100,000 (M6.5) –  12-40* Relative pressurization standard is 0.05” of water relativeto adjacent less clean areas. © All rights reserved. Do not copy without permission. 79
  • 80. Temperature Based on USP; 8th supplement, dated May 15, 1998* Room (Condition) Description Temperature Range Freezer -25° C to -10° C Cold 2° C to 8° C Cool 8° C to 15° C Controlled Room Temperature 20° C to 25° C (68-77 F) Warm 30° C to 40° C Excessive Heat over 40° C Always insure that material is not in cold or hot spots.* Relative Humidity 50% +/- 10% unless product requires differently. © All rights reserved. Do not copy without permission. 80
  • 81. Example PQ Acceptance Criteria for HVAC•  Maintain temperature at 72°F ± 5° (design).•  Maintain Relative Humidity at 50% ± 15% (design).•  Provide 12 (or 20) air changes per hour (design standard).•  Maintain a positive air pressure in the room with respect to the hallway (GMP-prevent cross contamination).•  Maintain class 100,000 (GMP requirement, Compendial requirement). © All rights reserved. Do not copy without permission. 81
  • 82. Instruments to Use•  Data Loggers for temperature and humidity monitoring (e.g. Hobo).•  Particle counters for particulate monitoring (e.g. Met One).•  Smoke sticks or magnahelic gauges for airflow/ relative pressurization.•  Active microbial sampling techniques•  Possibly use data from BAS and its instruments if calibrated and verified a-priori. © All rights reserved. Do not copy without permission. 82
  • 83. Example Procedure•  Verify the directional airflow between the production rooms and adjacent areas by performing a smoke profile around each door between the spaces. When performing the smoke test, verify that all other doors adjacent to the spaces are closed. © All rights reserved. Do not copy without permission. 83
  • 84. Example Data Sheet AttachmentExpected Airflow Actual Airflow Direction Pass Verified (P) /Fail By / DateDirection (F)Room 101 Air-Lock⇒ CorridorRoom 102 Air-Lock⇒ CorridorRoom 101 Air-Lock⇒ Room 101Room 102 Air-Lock⇒ Room 102 © All rights reserved. Do not copy without permission. 84
  • 85. Continued Verification Stage Stage-3 © All rights reserved. Do not copy without permission. 85
  • 86. Continued Process Verification•  Establish an environmental monitoring program:•  Collect data and ensure that no negative trends are observed•  Define alert and action levels (limits) a- priori © All rights reserved. Do not copy without permission. 86
  • 87. What Do We Mean By Environment?•  Defines the conditions which prevail within the controlled space of interest (temperature, humidity, particulate, pressure, and microbial).•  Defines the influences and stresses prevailing within the space of interest.•  It is associated with a space, normally controlled , where an activity of interest takes place. 87 © 2012 The Lanese Group
  • 88. What Do We Mean By Environment?•  Usually related to a sterile product or a drug product that maybe affected by the environmental conditions.•  For non-sterile product it is important to be aware of the environmental conditions within the manufacturing space and their potential effect on the drug product. 88 © 2012 The Lanese Group
  • 89. What is Environmental Monitoring?•  Documented program implemented through SOPs describing method for monitoring temperature, humidity, pressure, particulate, and microorganisms in controlled environment. Such a program should include definitions of: » 1. Sampling (what and where) » 2. Frequency of sampling » 3.Investigative action » 4.Corrective Action » 5. Alert and action (levels) limits » 6. Method for trend analysis © All rights reserved. Do not copy without permission. 89
  • 90. Why Monitor?•  It is the law (21 CFR 211.42-10(iv))•  Identify and correct potential environmental control equipment problems•  Complete the validation effort by collecting data which takes into account the seasonal variations•  Validate cleaning of environment / manufacturing area•  Establish alert and action levels (by establishing baseline conditions and identifying hot spots)•  Insure that the manufacturing space is always in a validate state and GMP compliant © All rights reserved. Do not copy without permission. 90
  • 91. Why Monitor? (continued):•  Insure conditions within the manufacturing space remain within the appropriate ranges required by the product a.  No biological contamination for sterile space b.  No cross contaminating particles from other manufacturing operations or due to re-circulation of air. c.  Appropriate temperature and humidity conditions.•  Use information collected from the monitoring program / system to control the operation of the HVAC system (BAS). © All rights reserved. Do not copy without permission. 91
  • 92. Where to Monitor?•  All Production Areas (including corridors and airlocks)•  Storage areas for product, intermediates, and raw materials (especially if affected by environmental conditions, especially in critical areas near doors, ceilings, etc.)•  Clean Rooms and Laminar Flow Hoods•  Critical Surfaces•  Environmentally Controlled Rooms/Chambers•  Freezers, Refrigerators, Incubators © All rights reserved. Do not copy without permission. 92
  • 93. What You Should Monitor?•  Temperature•  Humidity•  Pressure•  Particulate•  Microbial / Biological Load © All rights reserved. Do not copy without permission. 93
  • 94. Establishing Criteria & Frequency?•  Product requirements (temp sensitivity)•  Regulatory requirements (Microbial content for sterile areas)•  Compendial, engineering, and federal standard•  Literature and industry experience © All rights reserved. Do not copy without permission. 94
  • 95. How to Monitor?•  Temperature probes, thermocouples, chart recorders•  Humidity probes, chart recorders•  Temperature and humidity mapping devices and data loggers•  Magnahelic gauges•  Building Automation Systems (BAS) when several HVAC systems are used (T, RH, Pressure deferential)•  Particle counters•  Active microbial air sampling•  Settling plates* –  *Use appropriate media for organisms to be detected, e.g. TSA for bacteria, SDA for mold and yeast © All rights reserved. Do not copy without permission. 95
  • 96. Data from routine monitoring should conform to a random pattern, andshould be within the action limits to indicate that the environment is under control. Action Level *Function Alert Level * * * * * *Being * * * * * * * ** * * * *Monitored Alert Level Action Level Time © All rights reserved. Do not copy without permission. 96
  • 97. Defining Alert & Action Limits•  Use historical data for variable to calculate Standard Deviation•  One way is to use 3 Standard Deviations around the mean as Action Level and 2 Standard Deviations as Alert Level•  Usually Alert level is based on where you expect to operate and action levels are based on design/process capability values.•  Make certain the limits you chose do not adversely affect the product when reached•  Be mindful of any pattern or trends in your historical data © All rights reserved. Do not copy without permission. 97
  • 98. What to Look for?•  Data trends towards deviations; Do not overreact to individual events -FDA Guidance on Process Validation January 2011•  Repeat occurrences, which may indicate a certain problematic event•  Patterns in the data•  Any changes/differences from what you have been observing in the past © All rights reserved. Do not copy without permission. 98
  • 99. Validation of Pharmaceutical Water Systems Gamal Amer, Ph.D. Principal Premier Compliance Services, Inc. © All rights reserved. Do not copy without permission. 99
  • 100. Pharmaceutical Water System•  Water in the pharmaceutical industry must be treated prior to use. Treating the water ensures that it would have consistent quality and be free of contaminants that may negatively impact product quality, safety and/or efficacy.•  Water systems normally consist of filtration, deionization, microbial removal/reduction, conditioning of water, and distribution to use points. © All rights reserved. Do not copy without permission. 100
  • 101. Water In The Pharmaceutical Industry•  One of the most important if not the most important utility in the manufacture of drug products.•  Water systems control the quality of the water, which may affect product quality, safety, and efficacy (chemical content, solids content, microbial content, etc.). © All rights reserved. Do not copy without permission. 101
  • 102. Where is water used?•  In manufacture.•  In formulation.•  In cleaning of equipment•  In cleaning of the facility. © All rights reserved. Do not copy without permission. 102
  • 103. Problems with untreated water•  Chemical content•  Dissolved Gases and odor•  Microbial and endotoxin content•  Inconsistent quality•  Seasonal variation © All rights reserved. Do not copy without permission. 103
  • 104. Regulatory Imperatives•  The introduction of undesirable chemicals or other contaminants through the use of water in the manufacture of drugs would result in adulterated product.•  Water should be supplied in a fashion that would not contribute to contamination of drug(ICH Q7a) 104 © 2012 The Lanese Group
  • 105. Regulatory Imperatives•  Potable water (this should apply to any water supply) shall be supplied under continuous positive pressure in a plumbing system free of defects that could contribute contamination to any drug product. (21 CFR 211.48 (a))•  Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits. (ICH Q7a) 105 © 2012 The Lanese Group
  • 106. You also must ensure the system isvalidated and remains in a validated state.The water system must perform to meet theproduct requirements and ensure that thequality of the water used in the production ofdrug products is consistent. © All rights reserved. Do not copy without permission. 106
  • 107. Water Systems Consist of1.  Water Conditioning - Water Filtration and removal of inorganic. - Microbial control.2.  Water Treatment - Deionization. - Distillation - Microbial Control.3.  Water Distribution - Storage of treated water - Pump and meter to use points - Condition water at use point - Microbial control - Recycle the water © All rights reserved. Do not copy without permission. 107
  • 108. Types of Water Increased Quality, complexity and compliance issues•  Potable Water•  Deionized Water•  USP purified water (DI-RO)•  Water for Injection (WFI) © All rights reserved. Do not copy without permission. 108
  • 109. Water Properties•  Water Properties: –  Organic chemical content (TOC) –  Inorganic chemical content (Conductivity) –  Microbial and endotoxin content –  Dissolved gases•  Water System Variables –  Flow rate –  Pressure © All rights reserved. Do not copy without permission. 109
  • 110. Schematic diagram for purified water production in Biotech Facility (possible example) To WFI Production/Distribution Return Purified Distribution loop Water Ozone inject Storage RO/Final For distribution Filter (0.45 & in facility 0.2 µ) UV Ozone destruct UV Sterilizer Municipal Water Ion Exchange Beds Meter Resin Trap UV Sterilizer Carbon Filter Pre-filter Conditioning © All rights reserved. Do not copy without permission. 110
  • 111. Water For Injection (WFI) Schematic of WFI Production in a Biotech Facility DistributionUSP Water Still(s) Hot Cold Storage Storage Cold WFI Loop Or UF Tank Tank Hot WFI Loop HE Filter Use Points Use Points © All rights reserved. Do not copy without permission. 111
  • 112. Design Stage; Stage-1•  User requirements•  Risk issues and assessment•  Functional specification•  Design control strategy and how to control conditions. © All rights reserved. Do not copy without permission. 112
  • 113. Design Stage•  User requirements: –  Defines water quality and type of water requirements for the product as defined by the user. –  Defines quantities needed and where within the process.•  Risk assessment: –  Identifies issues associated with maintaining the user requirements such as required quality and its potential effect on the quality of the product. –  Where to use the various types of water within the process. –  Relative importance of the various requirements/ needs and whether or not there is a need to control all of them. © All rights reserved. Do not copy without permission. 113
  • 114. Design Stage•  Functional specifications: –  Identify how properties and quantities can be achieved using the appropriate technology and technical knowledge.•  Design specifications: –  Defines the design specifications and the appropriate design space that would allow reaching the required conditions. Defines CQA and their relationship to the CPP. –  Takes into consideration eventual cleaning and sanitization issues•  Control Strategy: –  How will the conditions be controlled and how will the CPP be manipulated to give the required CQA for the resulting water. reserved. Do not copy without permission. © All rights 114
  • 115. Design Stage•  Documents that would be needed to support the qualification effort: –  User requirements and design specifications to define the conditions within the space and the critical system components. –  Control strategy to define what controllers are used and where the monitoring takes place. –  Mechanical, piping, and architectural drawings. © All rights reserved. Do not copy without permission. 115
  • 116. Water System Design Issues•  Sanitary piping, valves and fittings requirements (design)•  Materials of construction and passivation requirements (design-SS vs. PVDF, PVC)•  Dead legs and loop design considerations (design)•  Regular cleaning and sanitization (Maintenance - design)•  Hot vs. Cold System (Energy Considerations, material of construction- Design)•  Purification methods to be used (design; DI-RO, DI only, etc.)•  Control of microbes and endotoxin (include UV, ozone generators, etc.)•  Operating procedure of the system (design and initial testing) © All rights reserved. Do not copy without permission. 116
  • 117. Implementation and Qualification Stage; Stage-2•  In this stage the systems are installed and the installation as well as the operation of the system is verified.•  Performance qualification of the system is conducted, through: –  Protocol development and defining acceptance criteria –  Execution of the protocols and certification of the system as being suitable for the intended use. © All rights reserved. Do not copy without permission. 117
  • 118. What to Qualify?•  The Treatment system –  Its installation and operation –  The controls•  The water distribution system –  Installation and operation of use points –  Adequacy –  Cleaning and sanitization issues•  Water quality at the use points –  Flow rate –  pH –  Chemical content –  Conductivity/Resistivety –  Microbial and endotoxin content © All rights reserved. Do not copy without permission. 118
  • 119. Documents you need•  User requirements•  Engineering specifications•  Contractor’s submittals•  O&M Manuals•  Engineering drawings and Documentation –  System Description –  Mechanical drawings showing mechanical components (M Series) –  Plumbing drawings showing sampling points (P series) –  Architectural layout drawings (A series) © All rights reserved. Do not copy without permission. 119
  • 120. Qualification Plan (FDA guidance on Process validation)•  Qualification of utilities and equipment can be covered under individual plans or under an overall plan.•  Plan should consider requirements of use and risk management used to prioritize and define extent of activities.•  Plan should define: –  Studies and tests to be conducted –  The criteria to assess outcome of studies –  Timing for qualification –  Responsibilities for conducting the effort –  Procedure for documenting and approving the qualification•  Firm’s criteria for evaluating changes © All rights reserved. Do not copy without permission. 120
  • 121. Qualification of the Water System•  First step is to confirm that the system has been installed per the design and is capable of operating within the required parameters.•  Second is to verify that the system is capable of producing water meeting the quality requirements and effectively distributing it to use points, when proper operating procedure used.•  Finally a report summarizing the effort and reaching the conclusion that the system is acceptable for the intended use has to be developed. © All rights reserved. Do not copy without permission. 121
  • 122. IOQ Verification Tests and Acceptance Criteria © All rights reserved. Do not copy without permission. 122
  • 123. Installation Verification1.  List maker, local representative, and maintenance contractor. Include addresses and phone numbers for all system components.2.  Confirm completeness of components as per specifications (Deionization Beds, UV Light Generators, Tanks, Pumps, etc.).3.  Verify existence of Filters and compliance with design specification (Pre-, Secondary, carbon, 0.2 µ, etc.).4.  Document existence of Instrumentation at specified locations (Flow meters, temperature, pressure, conductivity meters, etc.) and indicate criticality and frequency of calibration.5.  Verify utilities and connections as per design (Feed water, Steam for evaporators, Steam for sanitization, electric service to pumps, etc.).6.  Verify correct material of construction for piping and other water contact surfaces. Document correct installation of piping per design. © All rights reserved. Do not copy without permission. 123
  • 124. Installation Verification (cont.)7.  Ensure control system is installed per the design and verify its components.8.  Document the existence of use points and their location.9.  Confirm the existence of a spare parts list.10.  Confirm that documentation and drawings for the system exist and are accessible. Make sure all sampling points are shown on drawings.11.  Confirm the existence of certifications such as weld logs, leak tests, passivation certification, etc.12.  Ensure operation, maintenance, calibration, and training procedures are in place.13.  Confirm training Documentation. © All rights reserved. Do not copy without permission. 124
  • 125. Operation Verification1.  Document that all instruments which will be used in the qualification have valid calibration certificates.2.  Test controls, alarms, and interlocks to verify their proper operation. e.g. 1.  Start and stop of system components. 2.  RO interlock with de-chlorination system. 3.  Alarms for UV and Ozone generator failure. 4.  Additional system specific interlocks and alarms3.  Leak testing through out the system (pressurize and observe leaks)4.  Flow testing at use points © All rights reserved. Do not copy without permission. 125
  • 126. Performance Qualification and PQ Acceptance Criteria © All rights reserved. Do not copy without permission. 126
  • 127. What will the PQ confirm1.  Document that all instruments which will be used in the qualification have valid calibration certificates.2.  Ability of the system to maintain water quality at the various intermediate and use points. –  Conductivity (based on compendial requirements) –  pH –  Chemical content –  Microbial and endotoxin content3.  Ability of the system to maintain water flow at the use points.4.  Ability of the system to maintain the temperature (if applicable) at the use points.5.  Ability of the system to maintain required conditions and water property at use and intermediate points over time. © All rights reserved. Do not copy without permission. 127
  • 128. PQ Acceptance Criteria © All rights reserved. Do not copy without permission. 128
  • 129. Product Requirements are the Driving Force•  Water characteristics should not negatively impact the product.•  Chemical and microbial content of the water should meet the user requirements.•  If WFI then microbial content should be <0.1 CFU/ml and 0.25 USP Endotoxin unit per ml (action level/limits-no pass fail limits).•  DI Water should meet USP 23 criteria for conductivity for either stage 1, 2 or 3.•  DI water should meet USP 23 criteria for TOC (limit 500 ppb).•  Sample for two to four weeks to demonstrate consistency.•  If user requirements are not clear, use engineering specifications, regulatory guidance, standards, or compendial values. © All rights reserved. Do not copy without permission. 129
  • 130. Sampling Requirements•  Sample daily after each step in the process•  Continue sampling for a minimum of 2 to 4 weeks•  Samples at use points should reflect how the use point will be used (e.g. if hose to be used sample with hose in place) © All rights reserved. Do not copy without permission. 130
  • 131. Example Acceptance Criteria for Purified Water System•  Maintain Flow Rate at 7 GPM within the loop. (design).•  Confirm water conductivity at use point is ≤1.3 µS/cm at 25ºC. (Compendial).•  Maintain a total bacterial count of ≤100 cfu/mL (Compendial).•  Repeat testing over 28 days (may use 14 or anything in between) with all tests meeting the specified acceptance criteria. (FDA Guidance) © All rights reserved. Do not copy without permission. 131
  • 132. Instruments to Use•  Mass flow meters.•  Stop watches and graduated containers.•  Pressure meters.•  Temperature probes, pH meters, conductivity meters, etc.•  TOC Analyzers.•  Proper water sampling techniques and proper aseptic technique training. © All rights reserved. Do not copy without permission. 132
  • 133. Example Procedure•  For all use points obtain a sample of water and verify the conductivity of water at use point at 25ºC±1ºC is greater than 2.1 µS/cm (USP Stage 2 criteria). © All rights reserved. Do not copy without permission. 133
  • 134. Example Data Sheet AttachmentSTAGE 2: Measured conductivity not to be greater than 2.1 µS/cm.Use Point Location: __________ Use Point ID: _______Time: ______ AM/PM Date: _____________Item ResultTemperature of Sample @ 25° C ± 1 C° ? 0 YES 0 NOConductivity of SampleAcceptance Criteria Met 0 YES 0 NO © All rights reserved. Do not copy without permission. 134
  • 135. Continued Verification Stage Stage-3 © All rights reserved. Do not copy without permission. 135
  • 136. Stage-3 Components•  Update documentation (Update as-built drawings regularly)•  Maintenance of the system and equipment logs (no leaks which could lead to contamination, filter replacement)•  Regular sanitization of the system•  Quality system components (CAPA, Change Control, OOS Investigations, etc.)•  System monitoring © All rights reserved. Do not copy without permission. 136
  • 137. Continued Process Verification•  Establish a water monitoring program.•  Collect appropriate data and ensure that no negative trends are observed•  Define alert and action levels (limits) a- priori•  Ensure maintenance and regular sanitization. © All rights reserved. Do not copy without permission. 137
  • 138. Where to Monitor?•  Incoming feed water•  Water quality at all use points.•  Critical processing parameters (CPP) within the system (e.g. Temperature of the still, UV Intensity, etc.).•  Storage Tanks (e.g. temperature, microbial content, etc.).•  Filter integrity.•  Water quality at critical processing/purification points within the system. © All rights reserved. Do not copy without permission. 138
  • 139. What You Should Monitor?•  Chemical content (TOC, pH, Conductivity, etc.).•  Microbial / Biological Load.•  Endotoxin content.•  Flow.•  Dissolved gases (Chlorine- for RO protection).•  Solids, color, odor.•  CPP (temp, pressure, Ozone concentration, etc.)•  Other (e.g. failures, Deviations, Maintenance issues, OOS, etc.) © All rights reserved. Do not copy without permission. 139
  • 140. Establishing Criteria & Frequency?•  Product requirements (chemical content, microbial, etc.)•  Regulatory requirements and guidance (Microbial content for sterile production- Daily for WFI one use points with all points tested weekly )•  Compendial, engineering, and federal standard•  Literature and industry experience © All rights reserved. Do not copy without permission. 140
  • 141. How to Monitor?•  TOC analyzers (on-line and in the laboratory)•  Conductivity meters (Laboratory and on-line )•  pH Meters and mass flow meters•  Turbidity meters•  Temperature sensors and indicators•  In-line pressure and flow meters•  Sampling for microbial (plating) and endotoxin (LAL) content © All rights reserved. Do not copy without permission. 141
  • 142. Defining Alert & Action Limits Again,•  Use historical data for variable to calculate Standard Deviation•  One way is to use 3 Standard Deviations around the mean as Action Level and 2 Standard Deviations as Alert Level•  Usually Alert level is based on where you expect to operate and action levels are based on design/process capability values.•  Make certain the limits you chose do not adversely affect the product when reached•  Be mindful of any pattern or trends in your historical data © All rights reserved. Do not copy without permission. 142
  • 143. What to Look for? Again,•  Data trends towards deviations; Do not overreact to individual events -FDA Guidance on Process Validation January 2011•  Repeat occurrences, which may indicate a certain problematic event•  Patterns in the data•  Any changes/differences from what you have been observing in the past © All rights reserved. Do not copy without permission. 143
  • 144. Summary•  HVAC and water systems are the most important utilities in health product manufacturing operations.•  HVAC and water systems are critical and represents increased risk as the complexity and cleanliness of the operation increases.•  Qualification/validation of HVAC and water systems is necessary•  HVAC and water systems must be properly designed for the intended application, qualified, and their operation monitored continuously to complete their validation. © All rights reserved. Do not copy without permission. 144