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  • Production environment is not just ECS – lots of aspects affect the air quality such as:
    Building and equipment finishes
    Staff discipline
    Building layout
    Production processes
  • All factors contributing to a quality medicine must be seen as interactive.It is not possible to neglect any of them, as they mutually influence each other.
    There are no independently operating systems.
  • We will be paying the most attention to Product Protection as this is the most important from an inspector’s point of view.
    We will only briefly look at Personnel Protection and Environment Protection
  • Some environmental factors have a direct influence on a product: (these factors also have practical operator considerations, such as light is required to see, etc.)
    Light, for light sensitive products (photo-degradation)
    Temperature, for temperature sensitive products (many injectables, vaccines)
    Humidity, often for capsules and always for effervescent tablets. The higher the temp & RH the greater the proliferation of bacteria.
    Air movement, affecting contamination & cross-contamination
    Microbial contamination can lead to the destruction of the product and to grave accidents in the case of injectables or sterile products
    Particulate contamination is critical in injectable forms
    These factors, if not properly controlled, can lead to:
    Product degradation
    Product contamination
    Loss of product & profit
    Cross contamination can lead to sensitisation or allergic reactions. In the case of highly potent drugs, it can lead to grave accidents.
    Temp, humidity and air movement will be discussed in more detail in later modules.
  • What are contaminants?
    Contaminants are in fact the presence of anything in the manufactured product which should not be there.
    Contaminants can be:
    Products or substances other than product manufactured (eg. products resulting from air pollution)
    Foreign products, such as metal parts from equipment, paint chips,etc.
    Particulate matter, especially dangerous in injectables
    Micro-organisms – a particular problem for sterile products.
    Endotoxins: Even if killed by thermal treatment, micro-organisms are degraded to endotoxins and can cause damage.
    Contaminants can originate from:
    Environment (particles, micro-organisms, dust containing other products)
    Equipment (residues of other products, oil, particles, rust, gaskets, metal) and can be brought into the product by air movements.
  • Definition of Cross-Contamination
    Definition according to the PIC/S Guide to GMP for Medicinal Products. (Yellow box at bottom of various slides will refer to the PIC/S guide)
    In other words, Cross-Contamination is the presence in a particular product of small, traceable quantities of other pharmaceutical products manufactured
    at the same time in the same premises
    previously on the same equipment or in the same premises
    Cross-Contamination is thus only concerned with the presence of traces of products manufactured in-house !
    Adequate analytical detection is important to detect traces of contamination:Validated analytical methods, especially developed for detection purposes, may be necessary to detect cross-contamination.
    An absence of cross-contamination being detected may just mean the absence of adequate analytical procedures.
  • Cross-contamination is a sure indication of bad practices, as it shows that there is insufficient control over
    Design of premises and systems quality
    Air handling and dust extraction systems
    Operation and maintenance of air handling and dust extraction systems
    Procedures for cleaning of equipment and for restriction of movement of personnel
    Procedures for cleaning of premises
  • Contamination is the introduction of foreign products into a drug, which does not come from another drug product.
  • Particles (squames) of 0,3 micron & greater are liberated at a rate varying between of 100 000 to 10 million per minute (depending on the level of activity & the garments worn)
    Patient contaminants – bone saw – trauma case patient
  • Dust carries bacteria, much like a dog carries fleas.
    Dust can be categorized into 3 groups:
    COARSE DUST (50-500 microns) – settles rapidly
    FINE DUST (1,0 – 50 microns) – settles slowly
    ULTRA FINE DUST (< 0,5 – 1 micron) – remains suspended.
  • The smallest particle visible with the human eye is about 10 micron in size
    Just because you cant see it does’nt mean the dust is not there!
  • Before proceeding further we need to look at how we define the Manufacturing Environment. What is the air quality required and how do we quantify this?
    Rather than refer to the Manufacturing Environment – we would like to use the more generic term of “cleanroom”, which could refer to the production area, sampling area, Q& A Labs. Etc…
  • In the next slide we will look at how the air cleanliness defined.
    People often mistakenly refer to a cleanroom classification by a filter efficiency.
  • Be sure that the air particle tests are correctly carried out. There are very specific procedures laid down for carrying out particle counts. Ask for Mapping points!
    It is possible to get a very good particle count by sampling the air directly below an air inlet, but this gives a totally false reading as it is not representative of the room condition.
    The next slide gives a comparison of various international cleanroom standards as well as well as recommended bacterial limits.
  • Give origin of Class 100 etc. (imperial)
    Be sure to specify full criteria i.e. “as-built’, “at rest” or “operational” You need this 2nd criteria. Without specifying this it is like saying your car does 150!! Is that m/s, furlongs/fortnight or km/h.
    Bacterial limits = max no of viable organisms permitted per m3
  • An automated Building Management System is a great help in monitoring these conditions and establishing trends.
  • We need to have a measure for defining different levels of cleanliness. For instance manufacture of open product must obviously be cleaner than Secondary Packing where product is closed – but how do we define this?
    Having the zones classified ensures that we operate in the correct environment to prevent contamination and cross-contamination.
  • There are may different standards in use today. The recommendation is to adopt the new ISO standards to define the Level of Protection or Cleanliness.
  • The illustation shows that the manufacturing environmental requirements, as defined in the definition of the cleanroom zones, increase with the therapeutic risk.
    The Level of Protection classes are classified as a function of the product sensitivity to contamination (e.g. aseptically filled products are handled in a higher class than terminally sterilised products) and to the therapeutic risk (stricter environment for injectables, as injectables enter directly into the bloodstream without the additional protection given by the stomach and intestinal barriers ).
    In order to obtain a constant and well-defined quality level, it is necessary to have well-defined requirements for the cleanroom zones.
    Level of Protection classes are referred to as Class A, B, C, etc. in the EC countries, whereas other countries may refer to Class 100, 1000, etc or ISO Class 5, 6, 7, etc. These different classes will be discussed later in this module.
  • All the above aspects need to be present to achieve a balanced facility.
  • ISO 5U refers to an ISO class 5 with uni-directional airflow (equates to an EU Class A). Uni-directional airflow is the term which is currently set to replace all reference to Laminar airflow in GMP guides.
    ISO 5T refers to Turbulent airflow (EU Class B or US Class 100 turbulent flow)
  • The manufacturers should have a Level of Protection Concept for their factories, stating:
    Correlation between process operations and Cleanroom classes, as shown in the table of the previous slide
    Type of operation permitted in each hygiene class
    Definition of Levels of Protection classes (parameters, building materials, room requirements, HVAC systems)
    Requirements for personnel and material in the different classes (clothing, training, type of materials allowed in the respective classes, etc.)
    Requirements on entry conditions for personnel and material (change procedures, when to change clothing, etc.)
    The Levels of Protection concept can be part of the Site Master File.
  • Gmp ppt

    1. 1. MCC PRESENTATION - GMP MANUFACTURING ENVIRONMENTS Module 1 Presented by : Deryck Smith Consulting Engineers 1
    2. 2. GMP MANUFACTURING ENVIRONMENTS Presentation Outline Module 1: Module 2: Module 3: Module 4: Module 5: Introduction to GMP Environments Air Conditioning System Components Types & Configurations of AC Systems Pressure Cascades & building Layouts Validation, Qualification & Maintenance 2
    3. 3. GMP MANUFACTURING ENVIRONMENTS • • • • Topics for this Module What makes up the manufacturing environment (not just Environmental Control System) Contamination & cross-contamination How cleanrooms are defined Levels of Protection ∆ 3
    4. 4. Module 1: Introduction to GMP Manufacturing Environments • The primary objective of manufacturing in an ideal GMP environment is that this should lead to a high quality product being produced. • Manufacturing in an ideal environment not only leads to better quality products but should also result in : * Improved production rates. * Operator comfort, satisfaction and safety. ∆ 4
    5. 5. Factors Contributing to Quality Products Personnel Validated processes Validated processes Procedures Raw Materials The most important! Equipment Equipment Packing Materials Premises Environment Environment 5
    6. 6. Design considerations for a manufacturing facility Three primary considerations to be addressed to ensure a safe and productive manufacturing facility GMP MANUFACTURING ENVIRONMENT PERSONNEL PROTECTION Prevent contact with dust PRODUCT PROTECTION Protect from product cross-contamination ENVIRONMENT PROTECTION Avoid dust discharge Prevent contact with fumes Protect from ambient contamination Avoid fume discharge Acceptable comfort conditions Prevent contamination of staff Avoid effluent discharge Correct temperature and humidity 6
    7. 7. The manufacturing environment is critical for product quality The environment comprises aspects such as: 1. Light 2. Temperature 3. Humidity 4. Air movement 5. Microbial contamination 6. Particulate contamination Uncontrolled environments can lead to: Product degradation & contamination Loss of Product & Profit ∆ PIC/S PH 1/97 (Rev.3) #3.3 & 3.12 7
    8. 8. What are Contaminants ? Contaminants are : 1. Products or substances other than product manufactured 2. Foreign products 3. Particulate matter 4. Micro-organisms 5. Endotoxins (degraded micro-organisms) Cross-contamination is a particular case of contamination ∆ 8
    9. 9. Cross – Contamination (1) What is CrossContamination ? Definition of Cross Contamination “Contamination of a starting material, or of a product with another starting material or product.” PIC/S PH 1/97 (Rev.3) Pg. 134 9
    10. 10. Cross – Contamination (2) From w here does Cross-Contamination originate? 1. Poorly designed air handling system s and dust extraction systems 2. Poorly operated and maintained air handling system s and dust extraction systems 3. Inadequate procedures for personnel and equipment 4. Insufficiently cleaned equipment ∆ PIC/S PH 1/97 (Rev.3) # 3.14 10
    11. 11. Cross-contamination (3) Contaminants from Environment & Operators Contamination Contaminants from Equipment Product from Environment & Operators Cross Contamination Product from Equipment PIC/S PH 1/97 # 5.10 11
    12. 12. Cross-Contamination (4) Cross-contamination can be minimized by 1. Personnel procedures 2. Adequate premises 3. Use of closed production systems 4. Adequate, validated cleaning procedures 5. Appropriate Levels of Protection of product 6. Correct air pressure cascade ∆ 12
    13. 13. How are Contaminants Removed? • By efficient filtration of supply air. • By dilution of contaminants or flushing contaminants by supplying adequate air quantities to the room. ∆ More about this later! 13
    14. 14. Where Do Contaminants Come From? • Outside air carries dust which is a contaminant • People generate contaminants:  We completely shed our outer skin every 24 hrs.  Particles of 0,3 micron & greater are liberated at a rate varying between of 100 000 to 10 million per minute  A person walking will liberate 5000 bacteria/minute and a single sneeze can produce up to 1 million bacteria. • The manufacturing process itself can generate contaminants eg paint off equipment, dust from belt drives, etc ∆ 14
    15. 15. Why All the Concern About Dust? Dust Is a Bacteria Carrier Virus (0,006µm to 0,03µm) Dust Particle Bacteria (0,5µm to 500µm) (0,2µm to 2µm) Typical size relationship between dust, bacteria and viruses 15
    16. 16. Airborne Contaminants Particle sizes 16
    17. 17. Removal of Bacteria • As dust is a carrier, dust must be controlled. • Ambient bacteria is removed by filtration. • Internal bacterial distribution can be controlled by directional air flow and air flushing or dilution. • Surface bacteria is controlled by adherence to strict cleaning sop’s. ∆ 17
    18. 18. Defining the Environment • What is the manufacturing environment ? • How does the manufacturing environment effect contamination and crosscontamination ? • Cleanroom concept ∆ 18
    19. 19. What Is a Cleanroom ? A cleanroom is an environment where the particulate contamination & bacterial contamination are limited to prescribed levels. 19
    20. 20. How Are Cleanrooms Classified ? 20
    21. 21. Controlled Environment Standards - 200 - •= Uni-directional (Laminar Flow) ** = Maximum number of viable microorganisms permitted per m³. Annex 1 # 3 CONTROLLED ENVIRONMENT STANDARDS BS EN ISO 1 4644-1: 1999, Federal Standard and Approximate Equivalents .   21
    22. 22. Facility Parameters That Need To Be Controlled  Temperature Humidity Air Cleanliness Room Pressure Air movement Lighting 22
    23. 23. How Clean Should It Be? Level of Protection Concept 1. Defines environmental requirements 2. Working to defined environments h elps prevent contamination and cross-contamination 3. Allows production under optimal hygiene conditions 4. Takes into account • product sensitivity to contamination • therapeutic risk ∆ 23
    24. 24. Many Different Standards In Use Levels of Protection & Cleanroom Class definitions currently in use. EC, PIC/S, TGA, WHO, etc. : A, B, C, D. US FDA : Critical and Controlled or Class 100, 1000, etc. ISPE : Level 1, 2 or 3 or Cleanroom class (ISO 5, 6, etc.). Companies : Various others such as White, Grey, Black, Green, etc. 24
    25. 25. Cleanroom Class Required Is Dependant on Manufacturing Process Being Carried Out ! Cleanroom Class A / B Cleanroom Class C Cleanrm. Class D Others Manufacturing Environment requirements Therapeutic risks 25
    26. 26. Levels of Protection Parameters to be defined : 1. Air cleanliness requirements (filter type and position, air changes, air flow patterns, pressure differentials, contamination levels by particulate matter and micro-organisms) 2. Personnel and material transfer methods 3. Permitted operations 4. Building design & finishes ∆ 26
    27. 27. Levels of Protection All operations within a pharmaceutical facilility must be correlated to well-defined Cleanroom classes. Example: ISO 14644-1 ISO 5U ISO 5T ISO 7 ISO 8 X Washing of Containers X Preparation of solution for terminal sterilization Preparation of solutions for aseptic filling X Depyrogenisation of containers X X X Filling for terminal sterilization Filling for aseptic process X X Etc. U = Uni-directional T = Turbulent Annex 1, # 3, Pg 41 27
    28. 28. Levels of Protection Based on the Cleanroom Class Requirements, various Levels of Protection have to be created, including : 1. 2. 3. 4. 5. Correlation between process operations and Cleanroom classes Type of operation permitted in each Level of Protection zone Definition of Cleanroom class (Contaminant parameters, building materials, room requirements, air handling systems ) Requirements for personnel and material in the different classes (clothing, training, type of materials, etc. ) Requirements on entry conditions for personnel and material (change & clean-down procedures ) ∆ 28
    29. 29. Parameters Influencing the Level of Protection (1) How does an Air Handling System influence the Cleanroom Class or Level of Protection ? Air Handling System Supply Air Production Room With Defined Requirements Outlet Air 29
    30. 30. Parameters Influencing the Level of Protection (2) 1 Number of particles in the air 2 Number of micro-organisms in the air or on 3 4 5 6 7 8 surfaces Number of air changes for each room Air velocity Air flow pattern Filters ( type, position ) Air Pressure differentials between rooms Temperature, humidity ∆ 30
    31. 31. Parameters Influencing the Level of Protection (3) Cleanroom Class defined by Critical Parameters Air Handling System Additional Measures 31
    32. 32. Parameters Influencing the Level of Protection (4) Air handling systems: • are the main tool for reaching required parameters • but are not sufficient as such Need for additional measures such as Appropriate gowning (type of clothing, proper changing rooms) Validated sanitation Adequate transfer procedures for materials and personnel ∆∆ Questions & Answers 32