Environmental Characterization of Controlled Rooms

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Environmental Characterization of Controlled Rooms

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Environmental Characterization of Controlled Rooms

  1. 1. Angel L. Salaman PhD
  2. 2. Objectives  Definitions  Regulation and Standards  Clean Rooms design requirements  Clean Rooms qualification  Environmental Monitoring
  3. 3. Introduction  Several changes have occurred within the last years with regard to non-viable particulate monitoring, specifically the new Food & Drug Administration’s (FDA) Guideline on Aseptic Manufacture, September 2004 and the revision of the EU GMP Annex 1, September 2003.  In both, the focus on proving control over the manufacturing environment has been increased.
  4. 4. Clean Rooms and Clean Zones  “A room which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation, and retention of particles inside the room and in which other relevant parameters, e.g. temperature, humidity, and pressure, are controlled as necessary”.  ISO 14644  Suites consist of different cleanrooms, where are made several steps of production.  It is continued until one reaches the moment of product filling, closing and sealing.  Less environmental conditions are required when a sealed product coming for labeling and inspection.
  5. 5. Standards in the design process.  The history of cleanroom standards started in the USA.  By order of American Air Force first standard was made in March 1961. It was called Technical Manual 00-25- 203. There was description of entering, designing and cleaning. Also it involves airborne particle requirements.  In 1963 was published Federal Standard 209.  It was entitled "Clean Room and Work Station Requirements, Controlled Environments".  There was determined measured size of particle more than 0.5μm. It was so, because there was not better equipment to measure smaller particles at those days.
  6. 6. Today there are 2 Standards  ISO 14644 - standard for Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones.  ISO 14698, Cleanrooms and associated controlled environments – Biocontamination control.
  7. 7. US FDA Guideline on Sterile Drug Products Produced by Aseptic Processing.  This document was published in 1987 by USFDA and revised on September 2004  Critical Area  Controlled Area
  8. 8. Critical Area: “one in which the sterilized dosage form, containers, and closures are exposed to the environment. Activities that are conducted in this area include manipulations of these sterilized materials/product prior to and during filling/closing operations.” US FDA
  9. 9.  Not more than (NMT) 100 particles of 0.5µm per cubic foot  Measured NMT 1 foot away from work site  Upstream of the air flow  Air must be supplied a the point of use as HEPA filtered laminar air flow.  Velocity 90 ± 20 feet per minute  NMT 1 colony forming unit per 10 cubic feet  Must have positive pressure differential relative to adjacent less clean areas  A pressure differential of 0.05 inch of water is acceptable. Critical Area
  10. 10. Controlled Area: “An area in which it is important to control the environment, is the area where un-sterilized product, in-process materials, and container/ closures are prepared. This includes areas where components are compounded, and where components, in-process materials, drug products and drug product contact surfaces of equipment, containers, and closures, after final rinse of such surfaces, are exposed to the plant environment.” US FDA
  11. 11. Controlled Area  NMT 10,0000 particles of 0.5µm per cubic foot.  NMT 25 colony forming units per 10 cubic feet.  Sufficient air flow.  Positive pressure differential relative to adjacent uncontrolled areas.  20 air changes per hour  Pressure differential of at least 0.05 inch of water  When doors are open, outward airflow should be sufficient to minimize ingress of contamination.
  12. 12. Clean room Zones  A – local zone. For operations that affords high risk for product quality, e.g. filling, closing, ampoule and vial opening zones. Usually in such zones is used laminar air flow which provides similar velocity 0.36-0.54 m/s.  B – zone, which is circled A-zone, is used for an aseptic preparation  C and D – zones for less critical stages of manufacturing.
  13. 13. Class limits for Federal 209D and ISO Standards
  14. 14. Air particle classification system
  15. 15. Non-Viable Air Particles Sampling  A non-viable particle is a particle that does not contain a living microorganism but acts as transportation for viable particles.  Non-viable particles are monitored using particle counters which do not distinguish between viable and non-viable particles, but are much more technically advanced than air samplers.
  16. 16. Viable Air Particles Sampling  Microbial (Viable) Air Samplers collect a predetermined volume of air and impact microorganisms against agar- based growth medium. Once that sample has been collected and the medium incubated, the results are expressed in colony forming units per cubic meter.  For sampling viable particles in the air use, R2STM (Remote Slit Sampler), Matson/Garvin, SASTM (Surface Air System), SMATM (Sterilizable Microbial Atrium), RCS(Reuter Centrifugal sampler), or other qualified air sampler units will be used.  For this sampling, sterile (irradiated or sterile filled) TSA plates, or media strips must be used.
  17. 17. Sample Air Volume ISO 14644-1 defines the minimum sample volume as “that volume whereby a minimum number of 20 particles would be detected if the particle concentration for the largest particle size were at the class limit for the designated ISO Class”. The formula is as follows: Vs = 20/Cn,m x 1000 Where…… Vs : the minimum single sample volume per location in liters Cn,m : the class limit (number of particles per cubic meter) for the largest considered particle size (n) specified for the class limit(m).
  18. 18. Calculate Sample Size ISO 5 Assembly area (ISO Class 5) C0.5,5 = 3 520 Assembly area minimum sample volume per location  Vs = 20/3520 x 1000  Vs = 5.68 Liters  Vs = 5.68 Liters at 2.83 Liters per minute requires a nominal sample time of 2.0 minutes per location  Assembly area (ISO Class 5) 3 x 1 minute per sample
  19. 19. Gowning area (ISO Class 7) C0.5,7 = 352 000 Gowning area minimum sample volume per location Vs = 20/3520000 x 1000 Vs = 0.0568 Liters Vs = 0.0568 Liters at 2.83 Liters per minute requires a sample time of 0.02 minutes per location. Gowning area (ISO Class 7) 3 x 1 minute per sample Note that in the case of the Gowning area, 1 minute minimum sample period specified by ISO 14644-1 applies Calculate Sample Size ISO 7
  20. 20. • Particle counters have four distinct components; a high intensity light source, (e.g. helium-neon laser), solid state laser diode; a photo detection electronics, sample flow system and counting electronics. • Briefly, particles pass through the optical chamber of the particle counter, they are sized and counted in real-time, giving immediate information relating to contaminant levels.
  21. 21. ISO 5 (A)  For Aseptic Filling operations these areas are considered ”Critical” environments wherein drug product, stopper bowls , vials and closures are exposed to environmental conditions.  This is an aseptic area (eg, Room, Laminar Flow Hood (LFH), Biological Safety Cabinet (BSC), Isolator) where the environmental control is intended to maintain the sterility of drug product, containers and closures .  Activities conducted in these areas include critical aseptic manipulations (eg, making aseptic connections, sterile ingredient additions, sterile filling and closing operations).
  22. 22. ISO 6 (B)  Room or Zone that is the immediate background for ISO 5 Zone.  Zones where production in-process steps are performed.  These environments “are designed” (actually this is NOT TRUE) to consistently ensure and significantly limit total particulate contamination.  ISO 6 Room/Zone that is not the background for an ISO 5 Room/Zone and is not used for production activities. Examples of ISO 6 Support rooms/zones include airlocks, equipment/material storage, gowning rooms and other support areas.
  23. 23. ISO 7 (C)  For some facilities, ISO 7 is the immediate background for ISO 5. There the production in- process steps are performed.  Ensure limited exposure of materials to microbial and total particulate contamination.  Also serve as zones where nonsterile components, formulated product, in-process material, equipment and container-closure are prepared, held or transferred.
  24. 24.  Herein processes are performed primarily in closed systems. These systems are designed to exclude the penetration of environmental microorganisms (eg, bioreactors purification equipment trains).  ISO 7 Room/Zone that is not the background for ISO 5 and is not used for production activities (e.g. airlocks, equipment / material storage, gowning rooms and other support areas.) ISO 7 (C) cont.
  25. 25. ISO 8 (D)  These areas are the zones where the processes are performed primarily in closed systems.  The environmental control in these areas minimizes the contribution or buildup of the level of total particulate contaminants of articles and components that are subsequently sterilized.  These systems are designed to exclude the penetration of environmental microorganisms (eg, bioreactors and purification equipment trains).
  26. 26.  Rooms or areas used for bulk production operations.  For some facilities these areas serve as zones where nonsterile components, in-process material are prepared, held or transferred. Examples of additional operations in ISO 8 Production areas include rooms or zones where Cell Culture, Buffer Preparation and Purification operations occur.  ISO 8 areas not in use for production activities (e.g. ingress/egress gowning rooms, equipment/material movement/storage, facility cleaning, corridors, production control/work rooms . ISO 8 (D) cont.
  27. 27. Controlled Non-classifed Areas  Non-classified areas or zones that are part of the facility layout with defined environmental controls (ie, gowning, cleaning process, etc.) to reduce the introduction, generation and retention of contaminants within controlled classified areas.
  28. 28.  After washing, components should be handled in at least a grade D environment.  The preparation of solutions which are to be sterile filtered is performed in a grade C environment; if not filtered, the preparation of materials and products must be done in a grade A environment with a grade B background.  The handling and filling of aseptically prepared products is performed in a grade A environment with a grade B background.  The preparation and filling of sterile ointments, creams, suspensions and emulsions is performed in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered. Aseptic Operations
  29. 29. Recommended limits for microbial contamination in the operation (a) Individual settle plates may be exposed for less than 4 hours. CFU – colony-forming unit. Limitation of warning and action for contamination by particles and microorganisms depends on results of controlling. Also you should provide for corrective action in case of exceeding these limits
  30. 30.  Cleanroom standards and GMP guidelines require that rooms are maintained at different pressures to guarantee different conditions that held in each cleanroom.  It is possible to reduce contamination transfer to prevent an unacceptable flow of air from a lower area to a higher area.  Sensible relative room pressure level and its later support offers main design, commissioning and operational problems. Contamination Controls
  31. 31. Cleanroom Contamination Classification
  32. 32.  The standards say that the room pressure difference between cleanrooms should be 10-15 Pa.  These values can be quickly reached, easy to control and appears to prevent contamination transfer.  It is good to understand that cleanroom requirements may define a pressure difference of 10 or 15 Pa but this guideline is only a means to an end.  The pressure difference is lesser important when there is no adverse air flow between the rooms in the suite (this statement can not be clear). Pressure difference between cleanrooms
  33. 33.  The same situation may happen with isolators. But, in this case due to controlled environment is small, the displacement effect of gloves is important and must be taken into account when selecting and finding pressure differences.  Ordinary pressure differences for isolators are 15-60 Pa. Pressure difference between cleanrooms
  34. 34.  The exhaust of the cleanroom can be in an outside neighboring corridor coming through an airlock or changing area and can be in area where pressure is in two levels lower than the room.  Surplus of pressure difference of over 30 Pa can cause “whistling” through the door cracks and it can be difficult to open and close swing doors. Pressure difference between cleanrooms
  35. 35.  It can be presented in a tunnel process where a component is washed, sterilized, and filled as it passes from a component preparation area into an aseptic filling room.  The pressure difference will cause air to flow between the two areas connected by the tunnel.  This air flow can change the heating descriptions of the hot air oven and can bring hot spots and damage the tunnel.  Fluctuation of pressure difference will cause changes in the volume of air flow.  This can bring changes in efficiency and difficulty in validating the system. Pressure difference between cleanrooms
  36. 36.  It is important to guarantee that the rooms are built in an air-tight way to minimize the air flow out of the room's envelope.  But, it is impossible to prevent air flow through the door cracks from an area of high pressure to one of low pressure.  Using the following formula we can calculate the amount of air leakage through small gaps and holes.  Q = A×a Dp where Q – air volume (m3/s),  A – area of air leakage (m2),  p – pressure difference (Pa), and  α – coefficient of discharge (0.85) Pressure difference between cleanrooms
  37. 37.  An estimation of door leakage can be calculated if the detailed sizes of the door are given but the total leakage will depend on the quality of building detailing.  This data can not be known until the commissioning of the room (e.g. balancing) is made.  So it is necessary to guarantee that the air handling system has enough capacity to accommodate more leakage than is expected. Pressure difference between cleanrooms
  38. 38. Air flow (m3/s) through suite with doors closed
  39. 39.  The isolator technology minimizes human influence on processing zones.  In aseptic manufacturing it can considerably decrease the risk of microbial contamination of product from environment.  Transferring materials inside and outside of an insulator is the main potential source of pollution.  The environment should be controlled and corresponds to aseptic manufacture, at least, to zone D. Isolators Technology
  40. 40. http://www.bioquell.com/applications/isolators / http://www.pharmaceutical- int.com/article/isolator-technology.html
  41. 41. "blowing - filling - hermetic sealing  Packages which are filled with a product and sealed are formed during one continuous work cycle.  All these operations are spent within one automatic complex.  The equipment "blowing - filling - hermetic sealing", used in aseptic manufacture zone A with an effective air flow, can be established in a zone C if personnel will wear clothes applied in zones A and B.  The "blowing - filling – hermetic sealing" equipment, which is used in manufacturing of the products which sterilized, should be established, at least, in zone D.
  42. 42. http://machinedesign.com/content/advanced-blow-fill-seal-0908 "blowing - filling - hermetic sealing
  43. 43. The design of a pharmaceutical cleanroom suite, must include the following features :  Exclusion of the environment external to the suite of cleanrooms  Removal or dilution of contamination arising from the manufacturing process  Removal or dilution of contamination arising from personnel working in the area  Containment of hazards arising from the product  Control of product-to-product cross- contamination
  44. 44.  Protection of personnel  Control and management of the flow of material through the process steps by means of layout and configuration  Control and management of personnel movement by optimizing the arrangement and connection of individual rooms  Overall security of the operation by control of the entry and egress of personnel and materials The design of a pharmaceutical cleanroom suite, must include the following features :
  45. 45.  Optimum comfort conditions for personnel  Special environmental conditions for products, e.g. low RH for powder filling  Accommodation of process plant and equipment to ensure safe and easy use, as well as good access for maintenance.  Effective monitoring of the conditions of the room. The design of a pharmaceutical cleanroom suite, must include the following features :
  46. 46. Phase Plan:  Analyze production stages  Prepare process flow diagrams  Define activities associated with rooms  Define environmental quality requirements  Quantify production, process and space requirements  Prepare room association diagrams
  47. 47.  Define the accommodation needs  Develop layouts and schemes  Prepare designs and specification  Undertake the detailed design and construction process Phase Plan:
  48. 48. Layout of cleanroom suite for terminally sterilized injectables
  49. 49. Process Flow  The staff who works in this manufacture would enter the suite of cleanrooms through the 'clean changing area'.  In this room clothes are removed, hands washed, and appropriate cleanroom clothes put on.  Raw materials and components, such as containers, would enter through their corresponding entry airlocks.  In these airlocks procedures are used to decrease the contamination which may come from outside to the cleanrooms.  Solutions are prepared in the “solution preparation” room for transfer, directly or indirectly, by pipes or mobile containers, to the filling operation in the “clean filling” room.
  50. 50.  Primary containers and closures would be prepared and washed in the “component preparation” room and manually transferred to the filling stage or by using a conveyor system.  Containers are filled and packed under the unidirectional flow clean zone in the “clean filling” room.  Filled and packed, containers of product leave the cleanroom suite through the terminal sterilization autoclave.  At the ending of a work period, personnel would leave the suite through the changing room where cleanroom protective suite would be removed. Process Flow
  51. 51. Layout of cleanroom suite for aseptic filling
  52. 52. The differences in the process requirements refer to the following key variations:  Rooms are separated into clean and aseptic rooms.  The barriers between them are created by the oven, autoclave and transfer hatch for items entering the aseptic suite, and through the separation of the “solution preparation” and “aseptic filling” rooms.  Separate and more exact changing room control is provided for the aseptic suite, due to the differences between environmental control of the clean and aseptic suites.  Also the isolator can be used in place of the unidirectional flow workstation.
  53. 53. The most difficult requirement to achieve correct level of cleanliness of the internal environment usually is caused by:  The amount of contamination released in the room.  The quality of the air supplied to the room.  The quantity and method of supply of room air, i.e. conventional/turbulent ventilation or unidirectional flow, or a combination of both.  The amount of incoming contamination from areas adjacent to the room. When isolators are used, many of the same considerations are required, but generally the ingress of contamination from outside the isolated volume is minimized.
  54. 54. Nonunidirectional Airflow Zone  An area in which the filtered air entering the zone or passing through the work zone is characterized by non-uniform velocity or turbulent flow. Such rooms exhibit non-uniform, random airflow pattern throughout the enclosure
  55. 55. Turbulent flow air distribution
  56. 56. Unidirectional Airflow Zone  An area in which the filtered air entering the zone makes a single pass through the work area in a parallel- flow pattern, with a minimum of turbulent flow areas. Unidirectional airflow rooms typically have HEPA or ULPA filter coverage of 80% or more of the ceiling (vertical flow) or one wall (horizontal flow).
  57. 57. Unidirectional downflow air distribution
  58. 58. Obstruction caused turbulence in a laminar flow cleanroom
  59. 59. Filtration and supply air The use of high-efficiency particle stopper (HEPA) filters including pleated packs of high-density glass fibre paper with aluminium or craft paper separators, sealed into a timber or metal frame with urethane, influenced by cleanroom technology. In pharmaceutical industry it is required to install HEPA and ULPA filters of H14 – U17 classes. The most penetrable particle size in below classification (Table 7) is more than 0.1μm but less than 0.3μm.
  60. 60. Impact of Human activities in the cleanroom
  61. 61. Qualification / Characterization  is the process by which classified rooms/zones are verified to meet established microbial and total particulate environmental standard requirements upon sampling testing protocols.
  62. 62. General Requirements  Risk assessments documentation containing the rationale for sampling sites, sampling frequency, and use of settling plates (for filling only).  Programs must provide data to make effective decisions about the level of the environmental control necessary to maintain the required levels of microbial and total particulate cleanliness.  Contamination control procedures.
  63. 63. Contamination control procedures:  Access and flow of personnel and materials within the facility  Facility shut-down/start-up and requalification requirements  Facility sanitization, including disinfectant effectiveness and rotation  Personnel gowning, including training/certification, results from sampling(s) and good cleanroom practices  Facility monitoring (eg, temperature, humidity, differential pressure, and baseline performance)  Initial and routine facility HEPA Certification (eg, airflow, air velocity, particulate levels,).
  64. 64. Risk analysis  A documented risk analysis is suggested to select the monitoring sites during characterization. The risk analysis must document the rationale for site selection and shall be based on the needs of the process and classified area .
  65. 65. Sample site selection  Real or potential microbial and particulate contamination associated with the specific process performed therein.  The site selection must be challenged under “as-built”, “at rest” and “in use” conditions.  The sites selected shall be qualified to demonstrate their suitability to demonstrate control and microbial cleanliness in air and on surfaces.  The analysis must include the identification of product contact sources and potential microbial contamination that are most likely to have an adverse effect on product quality.
  66. 66.  Sites having greater opportunity for contributing bioburden to the product should be sampled more frequently.  Sampling locations must include those locations which may have an impact on the product and must be sampled more often.  In addition to wall and floor surfaces, representative surface samples must be taken where human activity occurred.  Sampling must not be intrusive to the process to avoid the probability of product contamination. Sample site selection
  67. 67. Sample sites number Sample sites for Total Particulate monitoring by room can be determined using the following:  Where:  NL represents the minimum number of samples  A is the surface area of room in m² • The calculation result that is not an integer is to be rounded up to the next whole number
  68. 68.  Airflow velocity, volume & uniformity tests  HEPA/ULPA filter installation leak tests  Air generated aerosol challenge & aerosol photometer filter scan test method  Alternative source aerosol particle challenge & discrete particle counter filter scan test method  Airborne particle count test  Room pressurization test  Airflow parallelism test  Temperature/RH tests Cleanroom tests
  69. 69. Cleanroom tests (cont.)  Lighting level test  Sound Pressure (Noise) level Test  Flooring Resistance Test  Point to Point Test  Point to Ground Test  Testing of Swing / Balance voltage and decay time of ionizers (Electrostatics / Air Ionizer Performance
  70. 70. Sampling plan must include the followings:  Room classification  Room configuration  Criticality of operations in this room  Process and material flow  Sample sites with greatest potential for particulate contamination  Gowning requirements  Cleaning and sanitation procedures
  71. 71.  Personnel quantity per room  Personnel traffic patterns  Equipment  HVAC system (e.g. airflow patterns/design)  Duration of campaign/manufacturing process  Process / engineering controls  In-process monitoring  Historical data, if available Sampling plan must include the followings:
  72. 72. Non Viable Particles Sampling  Take three (3) one-minute, one-CFM (28.3 liters) samples per location for better statistical reliability.  Test Laminar Flow work stations and Barrier isolators the same way.  Testing must be performed after any repairs, or renovations.  When sampling, test for viable organism at the same time.
  73. 73. Viable Surface Sampling Sites The number of sites for air and surface may be established using the following information:  Dimension of the room in m2  formula NL= √A,  Room classification As stated before, the number of sites for Viable and Non- Viable Total particle counts may be established using the dimension of the room and the formula above mentioned
  74. 74. There is no industry guidance that defines required number of surface sample sites. A preliminary number of surface viable sample sites (foot, walls and ancilliary surface) may be determined by dividing each classified area by a “key” as follows: Viable Surface Sampling Sites Room Classification key m2 NL NL / key A Filling Line 1 200 14 14 A surroundings filling line 2 200 14 7 B 3 200 14 5 C 4 200 14 4 D 5 200 14 3
  75. 75. Rationale for Sample Site selection For routine monitoring must be based on the results of the testing performed during qualification activities plus the following factors:  The location must be based on the process needs and environmental conditions necessary for the manufacturing process.  Equipment surface samples must be included every time possible.  Additional sample sites for the filling line, and other critical production areas (eg, open processing), must be included when may have a direct impact on the product as compared to surrounding areas.
  76. 76. The clean room performance is tested studies under the following stages:  ”As built”, a test used to establish that the cleanroom constructor has met his contractual obligations.  “At rest”, a test taken with the room fully equipped ready for production but with no equipment running and personnel absent.  “In use”, a test taken with the room fully operational. Clean room performance testing
  77. 77. As Built Monitoring  This operational mode or phase refers to a facility that is complete and ready for operation with all services connected and functional, but without equipment or operating personnel in the facility.  As Built monitoring is performed when manufacturing related activity is not taking place. In addition, such monitoring is appropriate for data gathering during facility qualifications, to demonstrate baseline data, or other validation activities.  As Built monitoring may be used to demonstrate the state of the environmental control in the manufacturing facility before cleaning and prior to the start of manufacturing operations.  As Built monitoring includes total and viable particulate monitoring of the ambient environment, and surface microbial monitoring.  Is performed once.
  78. 78. Static Monitoring  This operational phase refers to a facility that is complete, with all services functioning and with equipment installed and operable or operating, on specified, but without operating personnel in the facility.  Static monitoring is performed when manufacturing related activity is not taking place. In addition, such monitoring is appropriate for data gathering during facility qualifications, to demonstrate baseline data, or other validation activities.  Static monitoring is used to demonstrate the state of the environmental control in the manufacturing facility after cleaning and prior to the start of manufacturing operations.  Static monitoring includes total and viable particulate monitoring of the ambient environment, and surface microbial monitoring.  Three (3) sampling is performed after 24hrs of the cleaning process
  79. 79. In Use Monitoring  This phase refers to a facility in normal operation, with all services functioning and with equipment and personnel, if applicable, present and performing their normal work functions in the facility.  “In Use” monitoring is performed to demonstrate the level of environmental control during production and support operations in the production environment.  Routine monitoring should be performed during dynamic conditions when possible.  Dynamic monitoring will include total and viable particulate monitoring of the ambient environment, as well as surface microbial monitoring.  Three (3) sampling is performed after 24hrs of the cleaning process.
  80. 80. Sampling Frequency The frequency of monitoring may vary from one plant to another depending of:  Sample site selection  Type of facility  Seasonal variations  Room design  Manufacturing process  Human activity and interventions  Claning and Sanitization procedures  Gowning requirements  Historical data
  81. 81. Critical Areas Monitoring  The EU Annex 1 says, “A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended in the surrounding grade B areas”.  The FDA says, “Regular monitoring should be performed during each production shift. We recommend conducting nonviable particle monitoring with a remote counting system. These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters”.
  82. 82. Grade A Critical Environments If we look at a filling line the locations that must be monitored are identified as:  Sterilisation tunnel - where the sterile vials exit from  The fill area - location where product is filled into vial or syringes  The stopper area - where stoppers are placed onto vial  The capping area - where the crimping or capping occurs
  83. 83. EM program requirements  for each facility must be outlined in site level procedures which describe the following:  Sampling and testing methods  Monitoring frequency  Classification and Identification of the areas to be monitored and sites to be sampled  Alert and action levels  Excursion response/investigation, including re-sampling requirements  Organism identification  Length of tubing for sampling and the radii of any bends in tubing
  84. 84. Sampling Frequency for Routing Monitoring for C and D Classes TEST MINIMUM FREQUENCY Air Particle Monitoring Three Months HEPA Filter Integrity Testing Yearly Air Change Rate Calculation 6 Months Air Pressure Differentials Daily Temperature and Humidity Daily Microbial Monitoring Once a month / During manufacturing process
  85. 85. Viable Particle Monitoring during Critical in process activities.  Air, Surfaces and Personnel Monitoring Should be done During Aseptic Operations  Product Contact Surfaces Should be Monitored at the End of the Aseptic Operation.
  86. 86. Sampling frequency reduction A reduction in or the number of sites for routine monitoring can be performed. Such an approach would require the following:  A risk analysis and evaluation of historic data collected from environmental surface sites and air sites, to assess the potential impact on the overall environmental cleanliness.  An analysis of adverse trends must be conducted to demonstrate that current and proposed sampling frequencies and sites are adequate for assuring the overall state of control.
  87. 87.  A review of the validated cleaning and sanitizing procedures and facility control (HVAC) program to ensure they have not changed significantly during the period under review.  Documentation of the analysis performed.  Approval of the reduction plan by site Quality Head, or designee.  Periodic review of the environmental data to determine if the reduced sampling frequency and number of sites remains appropriate. Sampling frequency reduction (cont.)
  88. 88. Last Remarks  A well designed and executed monitoring plan is a must.  The monitoring plan has to be designed using good Judgment so that it can be defended during a compliance audit.
  89. 89. References  FDA Guidance for Industry- Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Process  http://www.particlecounters.org/  ISO 13408 Aseptic Processing of Health Care Products  ISO 14644-1 Cleanrooms & associated controlled environments – Part 1 : Classification of air cleanliness  ISO 14698, Cleanrooms and associated controlled environments – Biocontamination control.  PIC/S Recommendation on the Validation of Aseptic Processes  USP 35 <1116> “"Microbiological Evaluation of Clean Rooms and Other Controlled Environments".  USP 35 <797> “Pharmaceutical Compounding—Sterile Preparations”

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