. .pdf

Pharmaceutical factory layout and design according GMP Dr. Yousef Algaradi Dr. Yousef Algaradi Inustrial pharmacy  Good Manufacturing Practices  GMP:A set of principles and procedures which, when followed by manufacturers for therapeutic goods, helps ensure that the...

Pharmaceutical factory layout and design according GMP Dr. Yousef Algaradi Dr. Yousef Algaradi Inustrial pharmacy  Good Manufacturing Practices  GMP:A set of principles and procedures which, when followed by manufacturers for therapeutic goods, helps ensure that the products manufacture will have the required quality  It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product  Some of the main risks are:  Unexpected contamination of products, causing damage to health or even death.  Incorrect labels on containers, which could mean that patients receive the wrong medicine.  Insufficient or too much active ingredient, resulting in ineffective treatment or adverse effects. Dr. Yousef Algaradi Inustrial pharmacy  Important of GMPS 1) Government requirement 2) Ensure quality product 3) Reduce rejects, recalls 4) Satisfied customers 5) Maintain manufacturing consistency 6) Company image and reputation 7) Helps boost pharmaceutical export opportunities Dr. Yousef Algaradi Inustrial pharmacy  GMP Covers  All aspects of production: From the starting materials, premises and equipment to the training and personal hygiene of staff.  Detailed, written procedures: Essential for each process that could affect the quality of the finished product.  Systems to provide documented proof : That correct procedures are consistently followed at each step in the manufacturing process - every time a product is made. Dr. Yousef Algaradi Inustrial pharmacy  Principles of GMP 1) Design and construct the facilities and equipments properly 2) Follow written procedures and Instructions 3) Document work 4) Validate work 5) Monitor facilities and equipment 6) Write step by step operating procedures and work on instructions 7) Design ,develop and demonstrate job competence 8) Protect against contamination 9) Control components and product related processes 10)Conduct planned and periodic audits Dr. Yousef Algaradi Inustrial pharmacy  Good Manufacturing Practice categories 1.Quality assurance 2.Sanitation and hygiene 3.Qualification and validation 4.Complaints 5.Product recalls 6. Contract production and analysis 7.Self-inspection and quality audits 8. Personnel 9. Training 10.Personal hygiene 11.Premises 12.Equipment 13.Materials 14.Documentation 15.Good practices in production Dr. Yousef Algaradi Inustrial pharmacy 16.Good practices in quality control  Basic GMP categories 1) Premises  Location  Layout  Design 2) Sanitation 3)Equipment 4)Personnel Dr. Yousef Algaradi Inustrial pharmacy Plant location Dr. Yousef Algaradi Inustrial pharmacy  Plant location  Plant location means the establishment of an industry at a particular place.  The performance of an enterprise is affected by its location.  The selection of site for any enterprise mainly depends on its size and nature.  Sometimes, the nature of the product itself suggest some suitable location. Dr. Yousef Algaradi Inustrial pharmacy  Plant location  Small scale industry:  Mainly select the site where in accordance with its capacity, the local market for the product is available.  It can easily be shifted to other place, when there is any change in the market.  Large scale industries:  Huge amount of investment has already been done  The selection of proper site is very important. Dr. Yousef Algaradi Inustrial pharmacy  Importance of plant location  The selection of appropriate location is important due to the following reasons : 1) Location of plant partially determines operating and capital costs 2) Location fixes some of the physical factors of the overall plant designs Ex. heating and ventilation requirements , storage capacity 3) location mean a allocation of capacity to respective market area. 4) Government sometimes plays an important role in the choice of location keeping in view the national benefits. Dr. Yousef Algaradi Inustrial pharmacy  Factors affecting plant location choice 1) Availability of Raw material:  An ideal location is one where the main raw material required is adequately available.  This will ensure regular supply of the material and will reduce the transportation costs. 2) Nearness to the potential market:  Loctation near the market may help management to keep close touch with changes in market environment and formulate its production policies accordingly.  Transportation and other overhead expenses are reduced. 3) Location should be near to source of operating power:  In such situation, location of the plant near to the water power situation will provide cheap electricity. Dr. Yousef Algaradi Inustrial pharmacy Factors affecting plant location choice 4) Supply of labour:  Regular and cheap supply of labour, specifically the unskilled labour.  Adequate supply of local labour near the plant, will be available at cheaper rates. 5) Transport and communication facilities:  Transport is important for bringing raw materials, fuel from different places, marketing of finished products.  The region must be connected with rail, road, water and air transport system.  Regions with good communication system should be given priority for the selection of the sites.  Industries producing goods for exports may be located near ports or airports Dr. Yousef Algaradi Inustrial pharmacy Factors affecting plant location choice 6) Suitability of climate:  Climatic conditions ,humidity, temperature and other atmospheric conditions should be favourable for the plant.  Ex, humid atmosphere is not suitable for the formation of pharmaceuticals. 7) Integration with other group of companies:  When enterprise owned or operated by a single group of companies , it should be so located that its work can be integrated with the work of the associated establishments. Dr. Yousef Algaradi Inustrial pharmacy Factors affecting plant location choice 8) Availability of housing, other amenities and services:  Good housing facility, adequate shopping centers , restaurants, rail services etc..  Sufficient availability of gas, water supply, drainage, disposal of waste.  All that can easily attract good staff. 9) Local building and planning regulations:  Proposed location should not be infringe local regulations and laws.  Laws for the construction of buildings, local taxes etc. should be taken into consideration Dr. Yousef Algaradi Inustrial pharmacy Factors affecting plant location choice 10) Safety requirements:  Industries likely to cause pollution or processes explosives in nature should be located in remote areas. 11) Miscellaneous considerations:  Low interest on loans.  Low rentals.  Attitude of residents towards the industry, living standards etc. Dr. Yousef Algaradi Inustrial pharmacy  Selection of sites  Once an appropriate area is chosen for certain plant, next step is location analysis to choose suitable site in that area.  Points should be kept in mind in selection of the site: 1) Connection with rail, road and water transports. 2) Efficient sewage system for the disposal of water and waste materials. 3) The surroundings should be good and peaceful. 4) The sub-soil should be capable of bearing the load of the building plant and equipment. 5) Sufficient space for the parking of transport 6) Sufficient land to meet the future requirements of the plant. Dr. Yousef Algaradi Inustrial pharmacy  Selection of sites  Site can be selected both in urban or rural areas.  Urban area:  Can provide better transport and communication system with sufficient labour supply.  There can also be adequate security arrangements as well as other social services like medical, restaurants, educational etc.  But in urban area, cost of land and labour wages are likely to be on higher. Dr. Yousef Algaradi Inustrial pharmacy  Selection of sites  Rural area :  Can provide cheaper land and labour with scope for future expansion.  The local taxes and land cost is likely to be low.  Rural location is good for large plants  The main disadvantages of rural plant site in lack of skilled labour and other means of amenities. Dr. Yousef Algaradi Inustrial pharmacy Factory location Dr. Yousef Algaradi Inustrial pharmacy Dr. Yousef Algaradi Inustrial pharmacy Plant layout Dr. Yousef Algaradi Inustrial pharmacy  Plant layout  Efficiency and performance of machines and sturdy building depend to a great extent on the layout of a plant.  What is Plant layout??  Method of allocating machines and equipment, various production processes and other necessary service involved in transformation process of a product.  With the available space of the factory.  To perform various operations in the most efficient and convenient manner  providing output of high quality and minimum cost. Dr. Yousef Algaradi Inustrial pharmacy  Plant layout  Planning the layout of a plant is a continuous process as there are always chances of making improvements over the existing arrangement.  The disposition of the various parts of a plant along with all the equipment used is known as plant layout.  It should be so designed that the functioning of plant would become very efficient.  A good layout results in comforts, convenience, safety, efficiency, compactness and profits.  A poor layout results in congestion, waste, frustration and inefficiency. Dr. Yousef Algaradi Inustrial pharmacy  Plant layout  Features of good layout : 1) Sufficient space for the workers as well as for the equipment to perform their functions.  Ensure smooth and continuous flow of production process. 2) Provide adequate safety and security to workers against accidents or injury.  Ex, provision of fire fighting equipment, first aid boxes, etc. 3) The arrangement of machines and equipment should be such that minimum material handling  Necessary for low cost processing. 4) The store for in-process material should be such that minimum material handling  Necessary for low cost processing. Dr. Yousef Algaradi Inustrial pharmacy  Plant layout  Features of good layout : 5) Provide effectively and easily executed supervision, coordination and control of all the activities. 6) Sufficient scope for making adjustment and modifications whenever any need arises. Dr. Yousef Algaradi Inustrial pharmacy Plant layout Dr. Yousef Algaradi Inustrial pharmacy  Plant layout  Good cGMP design features Include:  Clear layouts  Appropriate detailing and finishes  Adequate room sizes and staging areas  Presentation drawings that illustrate flows for people, product and equipment.  Flexibility: -Able to adapt to different uses -Able to bring new services to the rooms -Ease of clean up -Modulations Dr. Yousef Algaradi Inustrial pharmacy  Plant layout  Advantages of good layout: To the worker: 1) lesser number of operations and material handling. 2) Reduction in length of hauls and motions between operations, which minimize production time as well as the activities of workers. 3) More labour productivity i.e. more output per man hour 4) More safety and security to workers from accidents. 5) Better working conditions resulting in improved efficiency. Dr. Yousef Algaradi Inustrial pharmacy  Plant layout  Advantages of good layout: In manufacturing costs: 1) Maintenance and replacement costs are reduced. 2) Loss due to waste and spoilage is minimized. 3) Improved quality of product with reduction in handling, time and cost. 4) Better cost control. Dr. Yousef Algaradi Inustrial pharmacy  Plant layout  Advantages of good layout: In production control and supervision: 1) provides more space for production operation. 2) Efficient arrangement for receipt, transportation, and delivery of raw material and finished goods. 3) The cost and efforts in the supervision of production are minimized. 4) Better and convenient storage facility. 5) Control and supervision for operations are provided at appropriate points Dr. Yousef Algaradi Inustrial pharmacy Plant layout Dr. Yousef Algaradi Inustrial pharmacy Plant layout Sample layout of tablet section Dr. Yousef Algaradi Inustrial pharmacy Premises design Dr. Yousef Algaradi Inustrial pharmacy  Premises design  Premises design consideration: 1) Suitable size and construction to facilitate proper operations, manufacturing , maintenance and cleaning. 2) Situated system or measures to avoid the risk of contamination from:  External environment including air , open sewage, drain and public lavatory  Any other factory producing disagreeable or harmful fumes, odour, dust and smoke, chemical or biological emission. 3) Hygienic condition should be considered in building design and construction 4) HVAC system should be there where it is required (For environmental monitoring). Dr. Yousef Algaradi Inustrial pharmacy  Premises design 5) Compatibility of the premises used for manufacturing, processing, warehousing, packaging, labelling and testing with manufacturing operations carried out in same area. 6) Adequate space for logical and orderly placement of equipment and free movement of staff to avoid the risk of cross contamination. 7) The premises should be designed and constructed to prevent the entry of insects, birds, rodents etc. 8) Proper drainage and waste disposal system.  Which designed to avoid the back- flow and entry of rodents and insects to the manufacturing areas. Dr. Yousef Algaradi Inustrial pharmacy  Premises design 9) Smooth and washable walls and floors to facilitate ease of cleaning in the areas and free from cracks to avoid dust accumulation. 10) Suitable maintenance system for premises.  Which ensured that repair and maintenance operations do not prevent any hazard to the quality of the products. 11) Suitable cleaning system for premises according to the written standard operating procedures. Dr. Yousef Algaradi Inustrial pharmacy  Premises design 12) Appropriate electric supply, lighting, temperature, humidity and ventilation and such that they do not adversely affect directly or indirectly:  Either the pharmaceutical product during their manufacturing  Or effect in the accurate functioning of the equipment. Dr. Yousef Algaradi Inustrial pharmacy  Premises design  Principle areas of premises: 1) Production area 2) Quality control area 3) Ancillary areas 4) Warehousing Areas Dr. Yousef Algaradi Inustrial pharmacy  Production Areas  General category products:  General category products manufactured in separate manufacturing facilities.  Antibiotics, cytotoxic and hormones, highly potent, or sensitive or live micro-organism etc. produced in separate areas to avoid cross contamination.  Materials flow and plant layout :  Premises should be designed to have logical flow of materials, well organized layout of plant and machinery and ease of cleaning, both equipment and facility.  Depending on the volumes of materials being handled, adequate space should be provided to avoid mix-ups. Dr. Yousef Algaradi Inustrial pharmacy  Production Areas  Appropriate HVAC system:  Production areas should be effectively ventilated with suitable designed HVAC system.  HVAC system appropriate to products being handled, the operations undertaken and the external environment.  Suitable monitoring system:  Production areas should be regularly monitored during production and non-production periods to ensure compliance with their design specifications.  Packaging Materials:  Premises for packaging of pharmaceuticals should be specifically designed and out so as to avoid mix-up and cross contamination Dr. Yousef Algaradi Inustrial pharmacy  Quality Control Areas  Q.C. laboratories should be separate from production areas.  Areas where biological, microbiological, or radio isotope test methods are employed to be separate from each other.  Q.C. laboratories designed to provide facilities for:  Chemical analysis  Instrumental analysis.  Microbiological and biological analysis etc.  Storage for control samples, chemicals, microbiological media books, documents etc Dr. Yousef Algaradi Inustrial pharmacy  Quality Control Areas  A separate room or area should be provided where highly sensitive instruments area handled to protect them from electrical interference, vibration, contact with excessive moisture, and other external factors Dr. Yousef Algaradi Inustrial pharmacy  Ancillary areas  Ancillary areas covers:  Rest and Refreshment rooms.  Toilets and Washrooms.  Clothes storage areas.  Changing rooms for employees.  Rest and Refreshment Rooms should be separate from other areas.  Facilities for Toilets should not communicate directly with production or storage areas.  Areas for change rooms and storage of clothes and for washing, and toilet purpose should be easily accessible and appropriate for the number of users. Dr. Yousef Algaradi Inustrial pharmacy  Warehousing Areas  Materials in storages :  Storage areas should have sufficient capacity to allow orderly storage of the various categories of materials and products like: 1) Raw materials. 2) Packaging Materials. 3) Intermediates. 4) Finished products. 5) Products in quarantine. 6) Released, returned, rejected and recalled products. Dr. Yousef Algaradi Inustrial pharmacy  Warehousing Areas  Environmental conditions:  Storage areas designed to meet the required environmental conditions like temperature and Humidity  Records of such environmental conditions monitoring should be maintained.  Sampling :  Separate sampling areas provided for active and raw materials.  Sampling cubicles may be designed with suitable size and also provided with cleaning, drying and storage for sampling tools.  Sampling of liquid materials, solvents, flammable materials or toxic, poisons or potent materials done in separate areas with taking all the necessary precautions for safety of people and materials both. Dr. Yousef Algaradi Inustrial pharmacy  Warehousing Areas  Returned, rejected and recalled materials :  All returned, rejected and recalled materials must be stored in lock and key and necessary precaution should Printed  Packaging materials:  packaging materials are considered critical to the conformity of the pharmaceutical product to its labelling  Special attention should be paid to the safe and secure storage these materials.  Dispensing areas :  Dispensing areas should be separate for active and raw materials. Dr. Yousef Algaradi Inustrial pharmacy  Sanitation  Sanitation: hygienic control on manufacturing processes, including personnel, premises, equipment and handling of materials [from SM to FP].  It is reduction of microbial contamination  Hygienie: conditions and practices that help to maintain health and prevent the spread of disease  Clean and sanitary condition is primary in premises used in the manufacture, processing, packing or holding a drug product Dr. Yousef Algaradi Inustrial pharmacy  Sanitation  Sanitation and premise design:  Ensure that the premise is neat and clean and is free of puddled water.  Floorings of the equipment washing rooms could be sloped to allow draining of water  Hand washing and well ventilated toilet facilities  Changing rooms provided for personnel at suitable locations.  Meal rooms should not have direct access to controlled areas (e.g. production area and warehouse).  No food and beverages in controlled areas  Facilities in such rooms must meet sanitary standards. Dr. Yousef Algaradi Inustrial pharmacy  Sanitation  Sanitation and production:  Operations have to be carried out in clean areas to avoid contamination.  Disinfection of areas and equipments are very important and have to be carried out regularly.  Considerations to maintain sanitation and cleaning: 1) Create and maintain safe working environment. 2) Remove dust and dirt which can affect product quality. 3) Minimize the risk of cross-contamination occurring between products. 4) reduce the levels of microbial contaminate Dr. Yousef Algaradi Inustrial pharmacy  Sanitation  Sanitation and records:  A written procedures assigning responsibility for sanitation is important.  This procedures describe in detail the cleaning schedules, methods, equipment and materials to be used in the cleaning the buildings and facilities  Such written procedures should be followed  Such written procedures designed to prevent the contamination of equipment, components, drug product container and closures, packaging labelling material or drug products. Dr. Yousef Algaradi Inustrial pharmacy  Sanitation  Rodents, birds, insects  All the premises must be free of infestation by rodents, birds, insects, and other vermin' (other than laboratory animals).  A written procedures for use of suitable Rodenticides, insecticides, fumigating agents and cleaning and sanitizing agents.  Rodenticides, insecticides, and fungicides should not be used unless registered and used in accordance with the Federal Insecticides, Fungicides and Rodenticide Act Dr. Yousef Algaradi Inustrial pharmacy  Sanitation  Waste material:  Waste material should not be allowed to accumulate.  It should be collected in suitable receptacles for removal to collection points outside the buildings and disposed of safely and in a sanitary manner at regular and frequent intervals.  Ensure that properly closed areas are used for storage of waste materials Dr. Yousef Algaradi Inustrial pharmacy  Equipment  Manufacturing equipment should be designed, located and maintained to suit its intended purpose.  Equipment should be installed in such a way as to prevent any risk of error or of contamination.  Repair and maintenance operations should not present any hazard to the quality of the products.  Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective  Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the direction of flow. Dr. Yousef Algaradi Inustrial pharmacy  Equipment  Equipment cleaning :  Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned.  It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition.  Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.  Sensitive and control equipment:  Sensitive as measuring, weighing and recording  It should be calibrated and checked at defined intervals by appropriate methods.  Adequate records of such tests should be maintained.  Equipment of an appropriate range and precision should be available for production and control operations. Dr. Yousef Algaradi Inustrial pharmacy  Equipment  Production equipment  Production equipment should not present any hazard to the products.  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. Dr. Yousef Algaradi Inustrial pharmacy  Maintenance  Any building, premises used in the manufacture, processing, packing or storage of a drug product must be in a good state of repair.  A detailed check list may be prepared for maintenance.  Facility maintenance includes maintenance of following: 1) Leakage from ceiling or other surfaces. 2) Leakages from pipe lines of waters, steam, gases etc. 3) Plumbing problems. 4) Loose or broken tiles. 5) Improper closing of doors, windows. 6) Improper electrical wiring 7) Improper electrical fixtures. Dr. Yousef Algaradi Inustrial pharmacy  Maintenance  Facility must always be maintained in a routine inspection  During routine inspection of the facilities the deficiencies should be identified and corrected immediately.  Deterioration of building and facilities represents poor image of facilities and it can affect product quality.  Cracks/ holes in walls, ceilings:  Provide access to the rodents, insects, microorganisms  Directly affect the quality of the product, sanitation and hygiene.  Roof leakage:  Affect the quality of materials  Cause damage to the equipments.  Hence all the facilities should be checked regularly and maintained and records related to it should be maintained. Dr. Yousef Algaradi Inustrial pharmacy Dr. Yousef Algaradi Inustrial pharmacy  Manufacturing Environment of pharmaceutical industry (Contamination prevention)  Introduction  The manufacture of medicinal products involves a series of processing steps using various equipment and ancillary systems within a facility.  Each step/equipment/system can pose a contamination risk.  Manufacturers are expected to:  Have processes in place to avoid contamination scenarios.  Provide documented evidence that activities to prevent contamination have been performed, as well as evidence that contamination has not occurred (e.g. from testing). Dr. Yousef Algaradi Inustrial pharmacy  Introduction  In the pharmaceutical industry, contamination is the undesired introduction of impurities of a physical, chemical, or microbiological nature into or onto a starting material, intermediate, or finished product  Contamination can occur at any stage of the manufacturing process, including but not limited to:  Production  Sampling  Packaging  Storage or transport. Dr. Yousef Algaradi Inustrial pharmacy  Introduction  Cross-contamination is the contamination of a starting material, intermediate, or finished product with another starting material or product.  Cross-contamination is a particular case of contamination  The root cause for contamination and cross-contamination can range from technical issues to quality system deficiencies, and common sources of contamination are identified in next figure. Dr. Yousef Algaradi Inustrial pharmacy  Introduction  Failure to prevent contamination and cross- contamination may result in serious consequences to the consumer as well as the company’s Sources of contamination reputation. Dr. Yousef Algaradi Inustrial pharmacy  Facility design The facility must:  Have smooth, impervious and unbroken surfaces.  To minimize shedding and accumulation of particles which are easily cleaned  Be of suitable size, construction and location  To facilitate suitable cleaning, maintenance and appropriate operations.  Have adequate space for placement of equipment as well as production and packaging materials  Consider the sequence of operation during the design phase  Paying particular attention Dr. Yousef Algaradi Inustrial pharmacy to the location of equipment  Facility design  Have an adequate internal temperature, ventilation and lighting.  Have adequate segregation of areas, materials, products, and components to further reduce the risk of cross-contamination Dr. Yousef Algaradi Inustrial pharmacy  Equipment design  All equipment should have smooth inert surfaces:  Which are not additive or adsorptive.  Be installed in an area that is easily cleaned.  If the equipment is difficult to clean, then consider using it for a dedicated purpose.  Pipes, ducts and doorways should be installed so they do not lead to be difficult to clean  All unnecessary equipment must be removed and stored appropriately. Dr. Yousef Algaradi Inustrial pharmacy  Effective airflow/extraction and HVAC design  Directional airflow within production or primary packing areas may be used to assist in preventing contamination.  Internal contaminants should be controlled by displacing the airflow.  The pressure differentials should be of sufficient magnitude to ensure containment and prevention of flow reversal without creating turbulence.  External contaminants should be removed by effective filtration of the supply air, to retain the required cleanroom classification. Dr. Yousef Algaradi Inustrial pharmacy Effective airflow/extraction and HVAC design  Where possible, ventilation dampers and filters should be designed and positioned to be accessible from outside the manufacturing areas for ease of maintenance Dr. Yousef Algaradi Inustrial pharmacy  Effective airflow/extraction and HVAC design Example:  Unidirectional (or laminar) airflow systems are effective in managing contamination.  Particularly in grade A areas, which have a low airborne particle limit.  This is achieved by passing air through HEPA filters located in celling and directing it downward in a constant stream towards filters (ventilation) located on walls near the cleanroom floor or through raised perforated floor panels, which is then recirculated (refer to next figure). Dr. Yousef Algaradi Inustrial pharmacy Effective airflow/extraction and HVAC design This is referred to as vertical laminar flow. Unidirectional airflow systems can also run horizontally from wall to wall. Dr. YousefVertical Algaradi Laminar Flow Inustrial pharmacy  Effective airflow/extraction and HVAC design  An air velocity of between 0.3 and 0.4 m/s is sufficient to:  Remove particles before they settle onto surfaces.  Overcome obstructions from equipment and people, and be uniform.  Notes:  Any disruption to unidirectional flow must be quickly restored and the contamination around the obstacles adequately diluted.  The air volumes supplied to laminar flow rooms are a lot greater than those supplied to a conventionally ventilated room, therefore they are much more expensive to operate Dr. Yousef Algaradi Inustrial pharmacy  HVAC system design  Air Handling System:  Components/Layout: A: Dampers B:Filters C:Cooling Coil D:Heating Coil E:Humidifier F:Supply Fan G:Diffusers H:Return Fan Dr. Yousef Algaradi Inustrial pharmacy  HVAC system design System Variations:  A system may have multiple sets of filters to remove different levels of impurities.  The arrangement of the cooling coil and heating coil may vary from unit to unit.  A system may utilize a bypass setup where the air can be diverted past the coil(s) if it does not need to be treated.  A cooling coil may not be present in every unit.  A heating coil may not be present in every unit. Dr. Yousef Algaradi Inustrial pharmacy  HVAC system design  Humidification tubes may not be present in every unit or may be farther down in the ductwork just before the diffusers.  A return fan may not be present on every unit if the supply fan creates enough of a draw to pull the air back through the space.  Refrigerant/Heating Supply:  The cooling coils are fed from a source of cooling, such as chillers, a cooling tower, or DX unit.  The heating coils are fed from a heat source such as a boiler or electricity. Dr. Yousef Algaradi Inustrial pharmacy  HVAC system design  Heating/Cooling System:  Components/Layout: A:Dampers B:Filters C:Heating Coil D:Cooling Coil E:Humidifier F:Supply Fan G:Return Fan  This type of unit is most common in environments where moisture removal from the air is not much of a concern. Dr. Yousef Algaradi Inustrial pharmacy  HVAC system design Preheat System:  Components/Layout: A:Dampers B:Filters C:Cooling Coil D:Heating Coil E: Humidifier F:Supply Fan G:Return Fan H:Preheat Coils Dr. Yousef Algaradi Inustrial pharmacy  HVAC system design  This system is a standard air handling unit that utilizes a preheat coil (H).  This coil should only operate during the winter months, if the outside air is below freezing.  The goal of this coil is to preheat the incoming outside or mixed air to prevent the cooling coil (C) from freezing.  These units are typically found in colder regions where there is greater risk of low winter temperatures. Dr. Yousef Algaradi Inustrial pharmacy  HVAC system design  Dual Duct Air Handling :  Unit Components/Layout: A:Filters B:Supply Fan C:Cooling Coil D:Heating Coil E:Humidifier F:Mixing Box G:Diffuser H:Outside Air I:Return Fan Dr. Yousef Algaradi Inustrial pharmacy  Manufacturing process  There are many chances for contamination of RM, intermediates or PM throughout the manufacturing process.  To minimize the risk of contamination and cross- contamination, the following should be considered: 1) Manufacture of a single formulation of the product as possible. 2) Manufacture products in a campaign.  With the qualified cleaning processes.  Checks performed in-between batches 3) Utilise a closed manufacturing system. Dr. Yousef Algaradi Inustrial pharmacy  Manufacturing process 4) Perform an area line clearance.  According to approved procedures following each cleaning process and between each batch/campaign 5) Use cleaning status labelling on all equipment and materials used within the manufacturing, 6) Zone the facility Dr. Yousef Algaradi Inustrial pharmacy  Personnel training and clothing Personnel training:  Training personnel is key in ensuring good practices in the facility  Every person should be made aware that they have personal responsibility when it comes to consumer health.  Each employee must understand their role and responsibilities, which should be clearly outlined in job descriptions.  Before, and during employment, all personnel should undergo the relevant GMP training, and be periodically assessed for competency. Dr. Yousef Algaradi Inustrial pharmacy  Personnel training and clothing Personnel clothing:  The importance of gowning and cleanliness should be implicit.  Competency in gowning/degowning procedures should be recorded.  Competency in gowning/degowning procedures routinely re-assessed and monitored, particularly in sterile situations via microbiological testing Dr. Yousef Algaradi Inustrial pharmacy  Personnel training and clothing  Personnel should wear clothing appropriate to the duties they perform and the environment they work in, including, but not limited to: 1) Personnel protective equipment (PPE) 2) Clean body coverings 3) Cleanroom clothing: - A appropriate for each cleanroom classification. -Can withstand repeated wear and laundering with minimal deterioration. 4) appropriate footwear. Dr. Yousef Algaradi Inustrial pharmacy  Personnel training and clothing  Important:  Street clothing and shoes must not be worn within GMP areas.  Wristwatches, makeup, and jewellery should not be worn in GMP areas.  Direct contact should be avoided between the operator and SM, primary PM and intermediate and FP. Dr. Yousef Algaradi Inustrial pharmacy Personnel training and clothing Basic GMP Gowning and Cleanroom Gowning Dr. Yousef Algaradi Inustrial pharmacy  Cleaning procedures  Insufficient or ineffective cleaning procedures could invariably cause cross-contamination between batches.  To minimize the risk of contamination and cross contamination, cleaning procedures must be :  Appropriately designed, taking into consideration: -The product formulation -The equipment design -Functionality of the system  Documented and not be open to interpretation  Validated to provide documented evidence: -Procedure utilized is capable of cleaning the equipment to the predetermined acceptance Dr. Yousef Algaradi criteria. Inustrial pharmacy  Cleaning procedures  Cleaning and housekeeping of all areas within a facility should be performed routinely.  This includes floors, ceilings, walls, and work surfaces.  Any spills must be cleaned immediately Equipment cleaning procedures:  Operators must be trained in the relevant cleaning procedures.  Utilities and services (such as steam and water) should be tested and monitored routinely for any microbial growth and cleanliness of supply. Dr. Yousef Algaradi Inustrial pharmacy  Equipment cleaning procedures  Compressed air and brushes should be used with care or avoided if possible, as they increase the risk of product contamination  Vacuum or wet cleaning methods are preferred.  Particle-shedding clothes may not be used for manual cleaning of equipment Dr. Yousef Algaradi Inustrial pharmacy  Equipment cleaning procedures  Equipment should be cleaned both inside and outside after use according to established procedures.  Any non-automated cleaning methods should be subject to more frequent microbiological testing.  Cleaning reagents (e.g. disinfectants and detergents) should be monitored for microbiological contamination and should only be stored for defined periods unless sterilized. Dr. Yousef Algaradi Inustrial pharmacy  Equipment cleaning procedures  Cleaned equipment should be kept or stored in a clean condition and identified with the status of cleaning, and checked for cleanliness prior to each use.  Labels should be attached to each piece of equipment to clearly state the cleaning status.  The cleaning status of each piece of equipment must be recorded in logbooks. Dr. Yousef Algaradi Inustrial pharmacy  Manufacturing Environment of pharmaceutical industry (Clean room)  Introduction  A clean room is an environment where the particulate contamination & microbial contamination are limited to prescribed levels.  A clean environment designed to reduce the contamination of processes and materials.  This is accomplished by removing or reducing contamination sources.  “Federal Standard 209E” defines a clean room as a room in which the concentration of airborne particles is controlled to specified limits.  Introduction  ISO defines a clean room as: A room in 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  That which other relevant parameters, eg temperature, humidity and pressure are controlled as necessary.  Principles of the clean room environment: 1- Air is highly (HEPA) filtered (99.97%) 2- Layout should minimize particle sources in filtered air stream 3- Air flow should remove most particles generated by process  Classifications of clean room  Classification: level of airborne particulate cleanliness, represents maximum allowable concentrations (in particles per cubic meter of air) for considered sizes of particles  The particulate cleanliness of air shall be defined in one or more of three occupancy states, viz. “as-built”, “at- rest”, or “operational”  Designation : The designation of airborne particulate cleanliness for clean rooms and clean zones shall include:  The classification number, expressed as “ISO Class N”;  The occupancy state  The considered particle size(s), and the concentration(s),  Classifications of clean rooms  ISO 14644-1 clean room standards: Dr. Yousef Algaradi Inustrial pharmacy  Classifications of clean rooms  GMP EU classification Dr. Yousef Algaradi Inustrial pharmacy  Role of the Cleanroom 1) Exclusion of the external environment. 2) Create the class of cleanliness and environmental conditions required for the process by dilution or displacement of the contamination generated.  To maintain ISO cleanliness Classes (1-9), or GMP Grades (A-D). 3) Containment of hazards arising from the process. 4) Control of Process-to-Process cross-contamination. 5) Control and management of Material & Personnel flows and procedures by way of planning and layout of the suite. Dr. Yousef Algaradi Inustrial pharmacy  Cleanroom HVAC systems  Cleanroom design encompasses much more than conventional temperature and humidity control.  Typical office building air contains from 500,000 to 1,000,000 particles (0.5 microns or larger) per cubic foot of air.  A Class 100 cleanroom is designed to never allow more than 100 particles (0.5 microns or larger) per cubic foot of air.  Class 1000 and Class 10,000 cleanrooms are designed to limit particles to 1000 and 10,000 respectively. Dr. Yousef Algaradi Inustrial pharmacy  Cleanroom HVAC systems  A cleanroom differs from a normal comfort air conditioned space, in the following ways: 1) Increased Air Supply:  Whereas comfort air conditioning would require about 2-10 air changes/hr, a typical cleanroom would typically require 20 - 60 air changes and could be as high as 600 for absolute cleanliness.  The large air supply is mainly provided to eliminate the settling of the particulate and dilute contamination produced in the room to an acceptable concentration level. Dr. Yousef Algaradi Inustrial pharmacy  Cleanroom HVAC systems 2) Use of high efficiency filters:  The use of high efficiency particulate air (HEPA) filters having filtration efficiency of 99.97% down to 0.3 microns is another distinguishing feature of cleanrooms.  The HEPA filters for stringent cleanrooms are normally located at the terminal end and in most cases provide 100% ceiling coverage. 3) Room pressurization:  The cleanroom is positively pressurized (to 0.05 in-wc) with respect to the adjacent areas.  This is done by supplying more air and extracting less air from the room than is supplied to it Dr. Yousef Algaradi Inustrial pharmacy  Cleanroom HVAC systems  There is much more into the design of cleanrooms in terms of details of technology of equipment, the type of filtration, efficiency, airflow distribution, amount of pressurization, redundancy, noise issues, energy conservation etc… Dr. Yousef Algaradi Inustrial pharmacy  Clean room parameters  Facility parameters that need to be controlled: 1) Temperature 2) Humidity 3) Air Cleanliness 4) Room Pressure 5) Air movement 6) Lighting  Clean room environment monitoring Test Frequency Particle Monitoring in air 6 monthly HEPA Filter Integrity Testing Yearly Air Changes Rate Calculation 6 Monthly Air Pressure Differentials Daily Temperature and Humidity Daily Microbiological monitoring by-settle Daily, and at decreased plates and / or swabs in other aseptic frequency in areas areas