According to – EU and TGA Code of GMP –
“Contamination of a starting material or of a product with another material or product”.
- Contamination of a starting material or of a product by another material or product must be avoided.
- The risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, vapors, sprays or organisms from materials and products in process, from residues on equipment, and from operators’ clothing.
- The significance of risk varies with the type of contaminant and of product being contaminated.
- Amongst the most hazardous contaminants are highly sensitizing materials, biological preparations containing living organisms, certain hormones, cytotoxics, and other highly active materials.
- Products in which contamination is likely to be most significant are those administered by injection, those given in large doses and/or over a long time.
- Personnel working in processing areas should be given appropriate training, especially where contamination is a hazard, e.g. cleanrooms, or areas where highly active, toxic, infectious or sensitising materials are handled, should be given specific training.
CROSS-CONTAMINATION
Prevention General Requirements
Premises
a) Should be situated in an environment which, when considered together with measures to protect the manufacture, presents minimal risk of causing contamination of materials or products.
b) Should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of They should be cleaned and, where applicable, disinfected according to detailed written procedures.
c) Should be designed and equipped so as to afford maximum protection against the entry of insects or other animals.
d) Steps should be taken in order to prevent the entry of unauthorised Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them.
e) The use of dedicated and self-contained facilities must be available for:
i)The production of particular medicinal products, such as highly sensitising materials (e.g. penicillins) or biological preparations (e.g. from live micro-organisms).
ii) The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products, should not be conducted in the same facilities. For those products, in exceptional cases, the principle of campaign working in same facilities can be considered.
f) Should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
g) The manufacture of sterile products should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for
h) The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimise the risk of confusion between different medicinal products or their components and to minimise the risk of omission or wrong application of any of the manufacturing or control steps.
i) Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection.
j) Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.
k) Weighing of starting materials usually should be carried out in a separate weighing room designed for that use.
l) Packaging areas for medicinal products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.
m) There should normally be a separate sampling area for starting materials. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.
n) The risk of cross-contamination between biological medicinal products, especially during those stages of the manufacturing process in which live organisms are used, may require additional precautions with respect to facilities and equipment, such as the use of dedicated facilities and equipment, production on a campaign basis and the use of closed systems. The nature of the product as well as the equipment used will determine the level of segregation needed to avoid cross-contamination.
i)Dedicated facilities should be used for the production of BCG vaccine and for the handling of live organisms used in production of tuberculin products.
ii) Dedicated facilities should be used for the handling of Bacillus anthracis, of Clostridium botulinum and of Clostridium tetani until the inactivation process is accomplished.
iii) Processing steps after harvesting may be carried out simultaneously in the same production area provided that adequate precautions are taken to prevent cross-contamination. For killed vaccines and toxoids, such parallel processing should only be performed after inactivation of the culture or after detoxification.
Equipment
a) Equipment should be installed in such a way as to prevent any risk of error or of contamination.
b) Equipment should not present any hazard to the The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.
c) Dedicated equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit).
d) Product and process water pipelines should have sanitary couplings and be sloped for drainage
e) Equipment should not create a hazard to product through leaking glands, lubricant drips, and the like.
f) Equipment should be kept in good repair and records of maintenance kept.
g) Cleaning equipment or materials that shed particles, raise dust, produce aerosols or otherwise generate contamination should be avoided. These include bristle brushes, fibre-shedding cloths and certain design floor scrubbing machines. Vacuum cleaners should be fitted with appropriate dust retaining filters.
Air systems
Nonsterile products :
a) Air intakes and exhausts, and associated pipework and trunking should be located so as to avoid any hazard to product and to avoid overloading air filters. In particular, intakes should not be sited near to wet drains, air exhausts or sources of dust. Provision should be made to clean dust filters and air conditioning filters away from the air handling system or production areas.
b) In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning.
c) Appropriately designed airlocks, pressure differentials, and air supply and extraction systems should be installed.
d) The risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air should be minimised.
e) In all rooms, air supply and extraction points should not be so close or so disposed as to restrict or negate the supply of clean air to worksites and/or the sweep of dust or contaminants away from worksites.
f) The air flow pattern, throughput rate and proportion of recirculated air should be selected to afford adequate protection to the product as well as operator safety.
Sterile products:
a) Cleanrooms should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency. cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled.
b) The various operations of component preparation, product preparation and filling should be carried out in separate cleanrooms within the clean area. Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages.
c) Cleanrooms should be effectively flushed with air supplied under positive pressure and delievered where air enters the processing environment. Air inlets should be remote from air outlets in order to achieve effective flushing of the room space and allow critical operations to be located in the least contaminated air stream. Air outlets should be at a low level.
d) Pass-through hatches and airlocks for the movement of materials, equipment and other goods in and out of the clean area should be arranged so that only one side may be opened at any one time. Sliding doors should be avoided.
Biological agents and antineoplastic products:
a) The level of cleanroom control exercised should reflect the nature of the organism or active material employed in the process. At a minimum, the area should be maintained at a pressure negative to the immediate external environment and allow for the efficient removal of small quantities of airborne contaminants.
b) Primary containment that involves the use of closed containers or biological safety cabinets along, plus secondary containment (i.e. air handling systems, airlocks etc.), which prevents the escape of a biological agent into the external environment or into other working areas, may be necessary. Negative pressure in specific areas at point of exposure of pathogens is acceptable.
c) Where negative pressure areas or safety cabinets are used for aseptic processing of pathogens, they should be surrounded by a positive pressure sterile zone.
Processing operations
a) Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation.
b) use of “closed system” in production
c) When setting up a programme for the packaging operations, particular attention should be given to minimising the risk of cross-contamination, mix-ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation.
c) Containers and closures used for materials awaiting processing, for in-process products, and/or bulk product, should be clean and of a nature and type which will prevent contamination.
d) As far as practicable, packaging materials should be removed from the wrappings and packaging or transport material in or which they are delivered in an area where product is exposed
e) Containers for filling should be clean before use. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles.
f) In-process controls may be carried out within the production area provided they do not carry any risk for the production.
g) using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is a common source of cross-contamination.
h) Direct contact should be avoided between the operator’s hands and the exposed product as well as with any part of the equipment that comes into contact with the products.
Clothing
a) Clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination.
b) Clothing should be cleaned and handled in such a way that it does not gather additional contaminants which can later be shed. Separate laundry facilities for clothing are desirable.
c) keep protective clothing inside areas where products with special risk of cross- contamination are processed.
d) Working garments should not have pockets above bench level where the contents could fall into product.
Utilities & services
- a) Water systems
Chemical and microbial limits should be appropriate to its intended use.
- b) Steam
Steam used should be free of additives. Clean steam generators may be used where appropriate.
c ) Compressed air (and other gases)
Should be passed through appropriate filters.