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Cross contamination in Pharmaceuticals - by Jitendra J Jagtap
- 1. Your logo Click toadd title CROSS CONTAMINATION IN PHARMACEUTICALS Jitendra J. Jagtap (M.Pharm)
- 2. THE MANUFACTURING ENVIRONMENT ISCRITICAL FOR PRODUCT QUALITY 1. Light 2. Temperature 3. Humidity 4. Air movement 5. Microbial contamination 6. Particulate contamination 7. Uncontrolled environment can lead to product degradation product contamination loss of product and profit Jitendra J. Jagtap (M.Pharm)
- 3. CROSS-CONTAMINATION What is Cross-Contamination? Definition of Cross-Contamination: “Contamination of a starting material, intermediate product, or finished product with another starting material or product during production.” (WHO) Jitendra J. Jagtap (M.Pharm)
- 4. CROSS-CONTAMINATION From where doesCross-Contamination originate? 1. Poorly designed air handling systems and dust extraction systems 2. Poorly operated and maintained air handling systems and dust extraction systems 3. Inadequate procedures for personnel and equipment 4. Insufficiently cleaned equipment Jitendra J. Jagtap (M.Pharm)
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- 6. CROSS - CONTAMINATION JitendraJ. Jagtap (M.Pharm)
- 7. CROSS - CONTAMINATION JitendraJ. Jagtap (M.Pharm)
- 8. CROSS CONTAMINATION -RISK Jitendra J. Jagtap (M.Pharm)
- 9. CROSS CONTAMINATION –CHEMICAL ANALYSIS Jitendra J. Jagtap (M.Pharm)
- 10. CROSS- CONTAMINATION Cross-contamination canbe minimized by: 1. Personnel procedures (Skilled Manpower, Technical Awareness) 2. Adequate premises (Proper Lay out, Area Classification) 3. Use of closed production systems (Man & Material movement) 4. Adequate, validated cleaning procedures 5. Appropriate levels of protection of product 6. Correct air pressure cascade (HVAC design & Air Distribution) Jitendra J. Jagtap (M.Pharm)
- 11. 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” Jitendra J. Jagtap (M.Pharm)
- 12. HOW ARE CONTAMINANTSREMOVED? By efficient filtration of supply air By dilution of contaminants or flushing contaminants by supplying adequate air quantities to the room Jitendra J. Jagtap (M.Pharm)
- 13. WHERE DO CONTAMINANTSCOME 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 e.g. paint off equipment, dust from belt drives, etc Jitendra J. Jagtap (M.Pharm)
- 14. WHY ALL THECONCERN ABOUT DUST? Typical size relationship between dust, bacteria and viruses Virus (0,006µm to 0,03µm Dust Particle (0,5µm to 500µm) Bacteria (0,2µm to 2µm) Dust Is a Bacteria Carrier Jitendra J. Jagtap (M.Pharm)
- 15. Particle sizes AIRBORNE CONTAMINANTS JitendraJ. Jagtap (M.Pharm)
- 16. REMOVAL OF BACTERIA Asdust 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 Jitendra J. Jagtap (M.Pharm)
- 17. DEFINING THE ENVIRONMENT Whatis the manufacturing environment ? How does the manufacturing environment effect contamination and cross-contamination ? Clean room concept Jitendra J. Jagtap (M.Pharm)
- 18. WHAT IS ACLEANROOM ? A clean room is an environment where the particulate contamination & bacterial contamination are limited to prescribed levels. Jitendra J. Jagtap (M.Pharm)
- 19. HOW ARE CLEANROOMSCLASSIFIED ? Jitendra J. Jagtap (M.Pharm)
- 20. CONTROLLED ENVIRONMENT STANDARDS - - - •=Uni-directional (Laminar Flow) ** = Maximum number of viable microorganisms permitted per m³ 200 Jitendra J. Jagtap (M.Pharm)
- 21. FACILITY PARAMETERS THATNEED TO BE CONTROLLED Temperature Humidity Air Cleanliness Room Pressure Air movement Lighting Jitendra J. Jagtap (M.Pharm)
- 22. HOW CLEAN SHOULDIT BE? Level of Protection Concept Defines environmental requirements Working to defined environments helps prevent contamination and cross-contamination Allows production under optimal hygiene conditions Takes into account - product sensitivity to contamination - therapeutic risk Jitendra J. Jagtap (M.Pharm)
- 23. MANY DIFFERENT STANDARDSIN USE Levels of Protection & Clean room 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. Jitendra J. Jagtap (M.Pharm)
- 24. Therapeutic risks Manufacturing Environmentrequirements CleanroomClassA/B CleanroomClassC Cleanrm.ClassD Others CLEANROOM CLASSREQUIRED IS DEPENDANT ON MANUFACTURING PROCESS BEING CARRIED OUT ! Jitendra J. Jagtap (M.Pharm)
- 25. LEVELS OF PROTECTION PARAMETERSTO BE DEFINED: Air cleanliness requirements (filter type and position, air changes, air flow patterns, pressure differentials, contamination levels by particulate matter and micro-organisms) Personnel and material transfer methods Permitted operations Building design & finishes Jitendra J. Jagtap (M.Pharm)
- 26. Based on theClean room Class Requirements, various Levels of Protection have to be created, including: 1. Correlation between process operations and Cleanroom classes 2. Type of operation permitted in each Level of Protection zone 3. Definition of Clean room class (Contaminant parameters, building materials, room requirements, air handling systems ) 4. Requirements for personnel and material in the different classes (clothing, training, type of materials, etc. ) 5. Requirements on entry conditions for personnel and material (change & clean-down procedures ) LEVELS OF PROTECTION Jitendra J. Jagtap (M.Pharm)
- 27. PARAMETERS INFLUENCING THELEVEL OF PROTECTION Air Handling System Production Room With Defined Requirements Supply Air Outlet Air How does an Air Handling System influence the Clean room Class or Level of Protection ? Jitendra J. Jagtap (M.Pharm)
- 28. 1 Number ofparticles in the air 2 Number of micro-organisms in the air or on surfaces 3 Number of air changes for each room 4 Air velocity 5 Air flow pattern 6 Filters ( type, position ) 7 Air Pressure differentials between rooms 8 Temperature, humidity PARAMETERS INFLUENCING THE LEVEL OF PROTECTION Jitendra J. Jagtap (M.Pharm)
- 29. Cleanroom Class defined by CriticalParameters Air Handling System Additional Measures PARAMETERS INFLUENCING THE LEVEL OF PROTECTION Jitendra J. Jagtap (M.Pharm)
- 30. Air handling systems: arethe 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 PARAMETERS INFLUENCING THE LEVEL OF PROTECTION Jitendra J. Jagtap (M.Pharm)
- 31. Jitendra J. Jagtap(M.Pharm)
Editor's Notes
- #3 Some environmental factors have a direct influence on a product: Light, for light sensitive products (photo-degradation) Temperature, for temperature sensitive products (many injectables, vaccines) Humidity, often for capsules and always for effervescent tablets Air movement, affecting contamination and 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 and profit Cross contamination can lead to sensitization or allergic reactions. In the case of highly potent drugs, it can lead to grave accidents.
- #4 Definition of Cross-Contamination: According to WHO, cross-contamination is “Contamination of a starting material, intermediate product, or finished product with another starting material or product during production”. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992 (WHO Technical Report Series, No. 823). Annex 1: Good manufacturing practices for pharmaceutical products. 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.
- #5 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
- #6 Contamination can be air-borne: particles, micro-organisms. Contamination can also come from equipment: leaching of plastic components, metal parts (broken sieves in granulators), brittle gaskets, oil, chips of paint, etc. Contamination can be brought by operators (objects falling into the product, skin particles, dandruff, fibres from uniforms). Likewise, cross-contamination can be either airborne or physically transferred: by bringing traces of a product through ventilation systems by transfer of contaminants from one room to another due to poor pressure cascade through clothing into another product through badly cleaned equipment retaining traces of a product and contaminating another product.
- #11 There are different ways to prevent or reduce the effect of cross-contamination. Personnel procedures: Clean clothing, and for clean rooms (C, B, A) non-linting clothing, to be washed in special laundries; Personal hygiene on entering a pharmaceutical area. Adequate premises: Minimisation of possibility of accumulation of dust; Premises with good ventilation and dedusting system. Closed production systems: Closed systems, in which product is transferred from one piece of equipment to another one, without being exposed to the atmosphere. Validated cleaning procedures: Manual cleaning procedures may not be reproducible. Level of Protection concept 2: A good hygiene, or Level of Protection concept, specifying requirements for environmental conditions; entry procedures for personnel and material is fundamental for keeping cross-contamination under control. Maintaining the correct air pressure differential between rooms helps prevent cross-contamination. The module on HVAC deals precisely with the last of these ways, namely a good air handling system.
- #12 What are contaminants? 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. 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 the product manufactured (e.g. 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.
- #14 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
- #15 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.
- #16 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!
- #18 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…
- #19 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.
- #20 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.
- #21 Give origin of Class 100 etc. (imperial) Be sure to specify full criteria i.e. “as-built’, “at rest” or “operational” You need this 2 nd 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
- #22 An automated Building Management System is a great help in monitoring these conditions and establishing trends.
- #23 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.
- #24 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.
- #25 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.
- #26 All the above aspects need to be present to achieve a balanced facility.
- #27 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 .