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Environmental Control & Support Processes

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Presentation on theme: "Environmental Control & Support Processes"— Presentation transcript:

1 Environmental Control & Support Processes

2 Environment & Control Environment - the circumstances and conditions that surround an organism or a group of organisms Where product is being made Control - To maintain desired conditions in a area /process/system by adjusting selected variables.

3 Environmental Control cont.
Biology, Chemistry, Engineering, Law, Sociology, Political Science, History, Literature, Art, Religion, Math, Physics Nature, Culture and Society Human Environment Environmental Control – Control of environment or surroundings (which tend to influence the work place and products that are made there.

4 Environmental Control cont.
It involves the control of the levels of Toxins Chemical pollutants Microbial contaminants or other harmful substances at a workplace

5 Get Familiar with ACRONYMS
CFR: Code of Federal Regulations CFU: Colony Forming Unit cGMP: Current Good Manufacturing Practice EM: Environmental Monitoring FDA: (US) Food and Drug Administration ISO: International Organization for Standardization cGDP: current Good Documentation Practices RODAC: Replicate Organism Detection And Counting SWOT: Strength, Weakness, Opportunities, Threats USP: United States Pharmacopeia

6 AREAS RELATED TO ENVIRONMENT CONTROL
Air filters Air-pressure monitors and controls Airborne particle counters Ceiling filter modules Cleaning and disinfection equipment Cleanrooms Design and construction materials Design and construction services Doors, automatic and manual Ducts Environmental monitors Environmental sensors Exhaust systems and fans Facility monitoring systems Flooring/mats Fume hoods Furniture Gloves Humidity-control systems HVAC systems Isolators Keyboards and keypads Laminar-flow benches Laminar-flow filters and test equipment Laminar-flow units Lighting Maintenance services Meters, airflow, humidity, and temperature Microbial air samplers Particle-control equipment Swabs and wipers Vacuum systems Wall panels

7 Get familiar to ……………., What is a clean room?
A room or environment in which you move the air by way of supply and return locations to control the airborne particle levels and temperature and humidity. What is Federal Standard 209E? The Federal government's basic design and performance requirements for clean rooms. Some of the information sets minimum and maximum levels, but in general it gives recommended guidelines. What is a Class? Defines the limit or measurement that a room will perform to particles per cubic foot at 0.5 micron or larger.

8 HEPA Filter High Efficiency Particulate Air
Class of air filters which meet a minimum performance level of 99.97% on 0.3 microns efficiency. In the cleanroom market HEPA is normally rated at 99.99% An additional face scan test is performed to assure no pin holes or leaks are found.

9 Particulate Matter What is a particulate matter? What is Recovery?
Contamination found in the air or which is generated within a room from a process. What is Recovery? How quickly the room or area will clean up and return to normal?

10 World Health Organization
7 February, 2018 Specimens Air samples For Both viable & Non-viable & compressed air Surface swabs Floors, Walls, Equipment, etc.

11 For a known Quantity (1000L) of Air/cubic meter
Air Quality Air Sampling Passive Air Sampling (Plate Exposure) Open pre-incubated media plates (90mm) keep exposed for 4 hrs. Active Air Sampling (Volumetric) For a known Quantity (1000L) of Air/cubic meter

12 Clean Rooms Surface By contact plates By swab sampling (RODAC)
55 mm Plates to be fixed on a flat surface By swab sampling Swabs are rubbed over the test surface & tested for microbial contamination Swabs are used for the surfaces that are not flat

13 21 CFR 211.46 Ventilation, Air filtration, Air heating and Cooling:
Adequate control over microorganisms, dust, humidity and temperature Air filtration systems including pre-filters and particulate matter air filters for air supplies to production areas

14 Sample Sites Locations posing the most microbiological risk
Monitor critical area Based on contamination risk Easiness/difficulty in set up Length of processing time Impact of any interventions Monitor filling/closing area Air and surface samples near significant activity

15 Elements of SOP on Sampling
Frequency of sampling Time of sampling Duration of sampling Sample size - How much surface area? - How much air volume? - How many plates? Specific equipment & technique Alert & Action levels - Appropriate response to deviations

16 483 – Sample, Warning Letter
Regarding the increased non-routine surveillance monitoring performed to further evaluate the Bldg. 37 Flu manufacturing There was no plan in place specifying the locations to be tested Method of sampling Actions to be taken in case of microbial contamination Samples on CFU were evaluated for morphological characteristics Only Gram negatives were stained and identified

17 483 – Sample, Warning Letter cont.
The method as written and used for increased surveillance monitoring of the environment has not been QUALIFIED. A qualification study with more data On location Frequency # of sample sites was needed

18 Number of Sites International Organization for Standardization (ISO) Describes a method to determine the number of sampling sites for site qualification NL = √A Where NL is the minimum number of sampling locations (rounded up to a whole number) A is the area of the clean room or the zone in meters2 This works well for non-viable particulate measures

19 Classification of Clean Rooms - Federal Standard 209
Quality Control in Biomanufacturing Monday July 23rd, 2007 Classification of Clean Rooms - Federal Standard 209 ≥ 0.1µm Particles/ft3 ≥ 0.2µm Particles/ft3 ≥ 0.3µm Particles/ft3 ≥ 0.5µm Particles/ft3 ≥ 5.0µm Class 1 35 7.5 3 10 350 75 30 100 750 300 1000 1,000 7 10,000 70 100,000 700 BIOMAN Portsmouth NH 19

20 Selected Equivalent Classes
FS Classes Class 1 10 100 1,000 10,000 100,000 ISO Classes 3 4 5 6 7 8

21 Particle Detection The validation of a clean room is ongoing
The air quality of a clean room must be monitored An optical particle counter is used to monitor air quality “Real-time” test results 21

22 Types of Particle Counters
Facilities Maintenance System Portable Particle Counter

23 Active Air sampling Active sampling involves the collection of air to be evaluated through a sampling tube or probe using a pump. The compounds of interest accumulate on the sorbent material in the tube or the nutrient plate and are returned to the laboratory for analysis, giving a result as a “mass per tube”. (i.e., micrograms per tube) The volume of air passed through the sorbent or collection device is also accurately determined. (i.e. cubic meters) The “mass per tube” is then divided by the volume of air to give the airborne concentration. (i.e. micrograms per cubic meter).

24 Passive Air Sampling It is a frequently used measure of cleanroom (controlled zone) monitoring. Settle plates are exposed for specified time period. Advantages: Ability to remain in continuous exposure for at least 4 hours (Extended hours need to be validated) Not disruptive to the immediate environment Air sample are collected very near to product exposure Not prone to variation among different vendors Disadvantages: Handling, transport and lab contamination

25 Plates Before and After exposure
Settling Plate- Before Exposure Settling Plate; After Exposure & After Incubation

26 Inspection of Settle Plate and Count
Total microbial count Bacteria Mold The colonies are counted and reported as colony forming units (CFU) per cubic meter of air

27 Microbial Evaluation and Classification of Clean Rooms and Clean Zones
Establishment of Alert and Action limits Suggests limits for airborne, surface and personnel contaminant levels. Methods and equipment for sampling Identification of isolates Aseptic media fills

28 Action/Alert/Acceptable Levels
Action Level at 118 Alert Level at 88 Passing level at 4

29 Setting Alert and Action Limits
Action limits can be established in a variety of guidance documents Alert limits Lower than action limits Reflect actual historical results under normal processing conditions

30 Exceeding Limits 1/3 Alert limits are designed to provide some warning that environmental quality is approaching action limit and allow you time to correct. Exceeding alert limit triggers a warning response Exceeding multiple alerts - triggers action level response

31 Exceeding Limits 2/3 Action limit excursions require investigations
Speciation of organism(s) Review batch records from date of excursion Review other recent EM data (trends) Review cleaning records Interview personnel Product impact - must quarantine until determined

32 Exceeding Limits 3/3 Excursions from action limits require corrective actions that may include: More rigorous or additional monitoring More rigorous cleaning Retraining of personnel Procedural changes - change to or addition of disinfection procedures, for example HVAC maintenance

33 Water for Pharmaceutical Use
Water is the most widely used substance / raw material Used in production, processing, formulation, cleaning, quality control Different grades of water quality available

34 Water Quality Different Water System Water by Reverse Osmosis
Water for Injections (WFI) Potable water

35 Micro Contamination of water
Microorganisms Protozoa Cryptosporidium Giardia Bacteria Pseudomonas Gram negative, non-fermenting bacteria Escherichia coli and coliforms

36 Environmental Trending
Should trend monitoring results: (environmental and water) Periodic (quarterly or monthly) review by QA and others Re-evaluation of action and alert limits on an annual basis This trending information is generally included in the Annual Product Review

37 Insect and Rodent Control
Great number of illnesses are associated with animal and insect contact. Encephalitis Lyme Disease Rocky Mountain spotted fever Bubonic plague West Nile virus

38 Microbial Monitoring Devices
Slit-to-Agar (STA): Air taken in through a slit Below which is a slowly revolving plate Sieve impactor: Vacuum draws in air through perforated cover That is impacted onto petri dish That contains nutrient agar

39 Microbial Monitoring Devices cont.
Surface contaminant monitoring devices: Contact Plates – plates filled with nutrient agar; for regular surfaces Swabs – useful for hard to reach or irregular surfaces; swab placed in suitable diluent and inoculated onto microbiological plate

40 What is Bioburden Testing?
It is microbial testing performed on medical equipment and products. It measures the number of living organisms on a surface prior to final sterilization and use. Certain microbial levels are allowed during handling of a product, and Bioburden testing makes sure those limits are in force.

41 How is Bioburden Testing Regulated?
All Bioburden tests must conform to the procedure outlines in ISO (International Organization for Standardization) Tests must fit the basic FDA criteria which include testing for the following: Yeast Candida albicans Bacteria Escherichia coli Bacteria Pseudomonas aeruginosa Bacteria Staphylococcus aureus Fungus Aspergillus niger

42 How is Bioburden Testing Performed?
Swabs of the outside of a product are collected and grown in petri dishes. Once the samples have grown, they are tested for various bacteria, fungi, and other contaminants. Bioburden is measured in colony forming units (CFU) per gram of product. A sterilization procedure is determined.

43 Endotoxin Testing Which products are tested?
Injectable drugs and medical devices which will contact blood or spinal fluid Includes Raw materials Water In process materials 43

44 The Pyrogen Test conducted with rabbits
Two tests – USP The Pyrogen Test conducted with rabbits Bacterial Endotoxins Test Also called Limulus Amebocyte Lysate (LAL) Test.

45 Pyrogen Assay USP considers a solution to be pyrogenic when:
10 ml/kg is injected into a rabbit and there is a rise of temperature of 0.6 °C or more for any rabbit or a total rise of more than 1.4 °C for three rabbits in a three rabbit test group.

46 LAL Test Limulus Amebocyte Lysate test: Developed in 1960’s Faster
Based on clotting reaction of horseshoe crab (Limulus polyphemus) blood cell (Amebocyte) lysate to endotoxin Developed in 1960’s Drs. Bang and Levin Faster more economical more sensitive than rabbit Pyrogen test All methods accepted by the FDA, USP, EP,& JP 46

47 Types of LAL Tests Gel Clot Turbidimetric Colorimetric
All accepted by the FDA, USP, EP,& JP

48 LAL Method 1. Gel Clot: Original method The official “reference test”
The specimen is incubated with LAL of a known sensitivity. Formation of a gel clot is positive for endotoxin. 2. Turbid metric: In the presence of endotoxin, LAL becomes turbid

49 3. Chromogenic Method Endotoxin concentration is measured as a function of color intensity LAL contains enzymes that are activated in a series of reactions in the presence of endotoxin. The last enzyme activated in the cascade: Splits the chromophore, Para-nitro aniline (pNA), from the chromogenic substrate Producing a yellow color.

50 Documents vs. Records Documents Records Offer guidance or explain actions to be carried out Can be changed Provide verification of things that have happened Cannot be changed

51 Documents vs. Records cont.
Documents are materials that provide management directions: environmental policy internal standards and operating procedures process information organization charts emergency plans Records include training records incident reports product information complaints and responses audit results management review meeting minutes


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