SPECIFIC REQUIREMENTS FOR MANUFACTURE OF STERILE PRODUCTS, PARENTERAL PREPARATIONS (SMALL VOLUME INJECTABLES & LARGE VOLUME PARENTERALS) AND STERILE OPHTHALMIC PREPARATIONS
Sterile products are very critical and sensitive in nature need very high degree of precautions, prevention and preparations and needed. Dampness, dirt and darkness are to be avoided to ensure aseptic conditions in all areas. There shall be strict compliance in the prescribed standards especially in the matter of supply of water, air, active materials and in the maintenance of hygienic environment.
A. Building and Civil Works. –
(1). The building shall be built on proper foundation with standardized materials to avoid cracks in critical areas like aseptic solution preparation, filling and Sealing rooms.
(2). Location of services like water, steam, gases etc. shall be adjusted such that their servicing or repair shall not pose any threat to the integrity of the facility. Water lines shall not pose any threat of leakage to aseptic area.
(3). The manufacturing areas shall be clearly separated into support areas (e.g. washing and component preparation areas, storage areas etc.), preparation areas (e.g. bulk manufacturing area, non-aseptic blending areas etc.) changing areas and aseptic areas. Operations like removal of outer cardboard wrappings of primary packaging materials should be performed in the de-cartoning areas which are segregated from the washing areas. Wooden pallets, fiberboard drugs, cardboard and other particle shedding materials shall not be taken inside the preparation areas.
(4). In aseptic areas:-
Walls, floors and ceiling should be impervious, non-shedding, non- flaking and non-cracking. Flooring should be unbroken.
Walls shall be flat, and ledges and recesses shall be avoided.
Ceiling shall be solid and joints shall be sealed.
There shall be no sinks and drains in Grade A and Grade B areas.
Doors shall be made of non-shedding material. These may be made preferably of Aluminium or Steel material. Wooden doors shall not be used.
Windows shall be made of similar material as the doors, preferably with double panel and shall be flush with the walls. If fire escapes are to be provided, these shall be suitably fastened to the walls without any gaps
The furniture used shall be smooth, washable and made of stainless steel or any other appropriate material other than wood.
(5). The manufacturing and support areas shall have the same quality of civil structure described above for aseptic areas, except the environmental standards which may vary in the critical areas.
(6). Change rooms with entrance in the form of air-locks shall be provided before entry into the sterile product manufacturing areas and then to the aseptic area. Separate exit space from the aseptic areas is advisable. The sink and its drain in the un-classified (first) change rooms may be kept clean all the time. The specially designed drain shall be periodically monitored to avoid presence of pathogenic microorganisms. Change room doors shall not be opened simultaneously. An appropriate inter-locking system and a visual and/or audible warning system may be installed to prevent the opening of more than one door at a time.
(7). For communication between aseptic areas and non-aseptic areas, intercom telephones or speak-phones shall be used.
(8). Material transfer between aseptic areas and outside shall be through suitable airlocks or pass-boxes. Doors of such airlocks and pass-boxes shall have suitable interlocking arrangements.
(9). Animal houses shall be away from the sterile product manufacturing area and shall not share a common entrance or air handling system with the manufacturing area.
B. Air Handling System (Central Air-Conditioning):-
(1). Air Handling Units for sterile product manufacturing areas shall be different from those for other areas. Critical areas, such as the aseptic filling area, sterilized components unloading area and change room conforming to Grades B, C and D respectively shall have separate air handling units.
(2). For products which are filled aseptically, the filling room shall meet Grade B conditions at rest unmanned. This condition shall also be obtained within a period of about 30 minutes of the personnel leaving the room after completion of operations.
(3). The filling operations shall take place under Grade A conditions which shall be demonstrated under working of simulated conditions which shall be achieved by providing laminar air flow work stations with suitable HEPA filters or isolator technology.
(4). For products, which are terminally sterilized, the filling room shall meet Grade C conditions at rest. This condition shall be obtainable within a period of about 30 minutes of the personnel leaving the room after completion of operations.
(5). Manufacturing and component preparation areas shall meet Grade C conditions.
(6). After completion of preparation, washed components and vessels shall be protected with Grade C background and if necessary, under laminar air flow work station.
(7). The minimum air changes for Grade B and Grade C areas shall not be less than 20 air changes per hour in a room with good air flow pattern and appropriate HEPA filters. For Grade A laminar air flow work stations, the air flow rate shall be 0.3 meter per second ± 20% (for vertical flows) and 0.45 meter per second ± 20% (for horizontal flows).
(8). Differential pressure between areas of different environmental standards shall be at least 15 Pascal (0.06 inches or 1.5mm water gauge). Suitable manometers or gauges shall be installed to measure and verify pressure differential.
(9). The final change room shall have the same class or air as specified for the aseptic area.
(10). Unless there are product specific requirements, temperature and humidity in the aseptic areas shall not exceed 27 degree centigrade and relative humidity 55%, respectively.
TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR ASEPTIC PREPARATIONS AND TERMINALLY STERILIZED PRODUCTS.
GRADE ASEPTIC PREPARATION STERILIZED PRODUCTS
I. Aseptic preparation and filling Filling of products, which are usually at risk
II. Background room conditions for activities requiring Grade A
III. Preparation of solution to be filtered Placement of filling and sealing machines, preparation of solutions when usually at risk. Filling of product when unusually at risk.
D Handling of components after washing Moulding, blowing (pre-forming) operations of plastic containers, preparations of solutions and components for subsequent filling
C. Environmental Monitoring:
All environmental parameters listed under para B (1 to 10) shall be verified and established at the time of installation and thereafter monitored at periodic intervals. The recommended frequencies of periodic monitoring shall be as follows:-
Particulate monitoring in air – 6 monthly.
HEPA filter integrity testing (smoke testing) –Yearly.
Air change rates- 6 Monthly
Air pressure differentials –Daily
Temperature and humidity – Daily
Microbiological monitoring by settle plates and/or swabs in aseptic areas – daily, and at decreased frequency in other areas
Note: The above frequencies of monitoring shall be changed as per the requirements and load in individual cases.
(1). This section covers garments required for use by personnel working only in aseptic area. Outdoor clothing shall not be brought into the sterile areas.
(2). The garments shall be made of non-shedding and tight weave material. Cotton garments shall not be used. The garments shall shed virtually no fibers or particulate matter.
(3). The clothing and its quality shall be adopted to the process and the work place and worn in such a way as to protect the product from contamination. Garments shall be single piece with fastenings at cuffs, neck and at legs to ensure close fit. Trouser legs shall be tucked inside the cover boots. Suitable design of garments shall either include a hood (head-cover) or a separate hood which can be tucked inside the over-all. Pockets, pleats and belts shall be avoided in garments. Zips (if any) shall be of plastic material. Garments with damaged zips shall not be used.
(4). Only clean, sterilized and protective garments shall be used at each work session where aseptic filtration and filling operations are undertaken and at each work shift for products intended to be sterilized, post-filling. The mask and gloves shall be changed at every work session in both instances.
(5). Gloves shall be made of latex or other suitable plastic materials and shall be powder-free. These shall be long enough to cover wrists completely and allow the over-all cuff to be tucked in.
(6). The footwear shall be of suitable plastic or rubber material and shall be daily cleaned with a bactericide.
(7). Safety goggles or numbered glasses with side extension shall be used inside aseptic areas. These shall be sanitized by a suitable method.
(8). Garment changing procedures shall be documented and operators trained in this respect. A full size mirror shall be provided in the final change room for the operator to verify that he is appropriately attired in the garments. Periodic inspection of the garments shall be done by responsible staff.
(1). There shall be written procedures for the sanitation of sterile processing facilities. Employees carrying out sanitation of aseptic areas shall be trained specifically for this purpose.
(2). Different sanitizing agent shall be used in rotation and the concentrations of the same shall be as per the recommendations of the manufacturer. Records of rotational use of sanitizing agents shall be maintained.
(3). Distilled water freshly collected directly from the distilled water plant or water maintained above 70 degree centigrade from the re-circulation loop shall be used for dilution of disinfectants. Alternatively, distilled water sterilized by autoclaving or membrane filtration shall be used.
(4). Where alcohol or isopropyl alcohol is used for dilution of disinfectants for use as hand sprays, the preparation of the same shall be done in the bulk preparation area and diluted solution membrane filtered into suitable sterile containers held in aseptic area.
(5). Formaldehyde or any other equally effective fumigant is recommended for the fumigation of aseptic areas or after major civil modifications. There shall be Standard Operating Procedures for this purpose. Its use for routine purpose shall be discouraged and an equally effective surface cleaning regime shall be followed.
(6). Cleaning of sterile processing facilities shall be undertaken with air suction devices or with non-lining sponges or clothes.
(7). Air particulate quality shall be evaluated on a regular basis and record maintained.
(1). The special equipment required for manufacturing sterile products includes component washing machines, steam sterilizers, dry heat sterilizers, membrane filter assemblies, manufacturing vessels, blenders, liquid filling machines, powder filling machines, sealing and labeling machines, vacuum testing chambers, inspection machines, lyophilizers, pressure vessels etc. suitable and fully integrated washing sterilizing filling lines may be provided, depending upon the type and volume of activity.
(2). Unit-sterilizers shall be double-ended with suitable inter-locking arrangements between the doors. The effectiveness of the sterilization process shall be established initially by biological inactivation studies using microbial spore indicators and then at least once a year by carrying out thermal mapping of the chamber. Various sterilization parameters shall be established based on these studies and documented. For membrane filters used for filtration, appropriate filter integrity tests that ensure sterilization shall be carried out before and after filtration.
(3). Filling machines shall be challenged initially and then at periodic intervals by simulation trials including sterile media fill. Standard Operating Procedures and acceptance criteria for media fills shall be established, justified and documented. Special simulation trial procedures shall be developed, validated and documented for special products like ophthalmic ointments.
(4). The construction material used for the parts which are in direct contact with products and the manufacturing vessels may be stainless steel 316 or Boro-silicate glass (if glass containers) and the tubing shall be capable of being washed and autoclaved.
(5). On procurement, installation qualification of each of the equipment shall be done by engineers with the support of production and quality assurance personnel. Equipment for critical processes like aseptic filling and sterilizers shall be suitably validated according to a written program before putting them to use.
(6). Standard Operating Procedures shall be available for ALL equipments for its calibration and operation and cleaning. Gauges and other measuring devices attached to equipment shall be calibrated at suitable intervals against a written program. Calibration status of equipment gauges shall be adequately documented and displayed.
G. Water and Steam Systems:
(1). Potable water meeting microbiological specification of not more than 500 cfu/ml and indicating absence of individual pathogenic microorganisms like- Escherichia coli, Salmonella, Staphylococcus aureus and Pseudomonas aeruginosa per 100 ml sample shall be used for the preparation of purified water.
(2). Purified water prepared by de-mineralization shall meet the microbiological specification of not more than 100 cfu per ml and indicate absence of pathogenic micro-organisms in 100 ml. Purified water shall also meet IP specification for chemical quality. Purified water shall be used for hand washing in change rooms. Containers, closures and machine parts may be washed with potable water followed by suitably filtered purified water. Purified water shall be stored in stainless steel tanks or plastic tanks.
(3). Water for Injection (hereinafter as WFI) shall be prepared from potable water or purified water meeting the above specifications by distillation. Water for Injection shall meet microbiological specification of not more than 10 cfu per 100 ml. WFI shall also met IP specification for Water for Injection and shall have an Endotoxin level of not more than 0.25 EU/Ml. Bulk solutions of liquid Parenterals shall be made in WFI. Final rinse of product containers and machine parts shall be done with WFI. Disinfectant solutions for use in aseptic areas shall be prepared in WFI.
(4). Water for Injection for the manufacture of liquid Injectable shall be freshly collected from the distillation plant or from a storage or circulation loop where the water has been kept at above 70 degree centigrade. At the point of collection, water may be cooled using suitable heat exchanger.
(5). Water for Non-Injectable sterile products like eye drops shall meet IP specifications for purified water. In addition, microbiological specification of not more than 10 cfu per 100ml and absence of Pseudomonas aeruginosa and Enterobacter coli in 100 m shall also be met.
(6). Water for Injection shall be stored in steam jacketed stainless steel tanks of suitable size and the tanks shall have hydrophobic bacterial retention with 0.2 µ vent filters. The filters shall be suitably sterilized at periodic intervals. The distribution lines for purified water and distilled water shall be of stainless steel 316 constructions and shall not shed particles.
(7). There shall be a written procedure and program for the sanitation of different water systems including storage tanks, distribution lines, pumps and other related equipment. Records of sanitation shall be maintained.
(8). There shall be written microbiological monitoring program for different types of water. The results shall justify the frequency of sampling and testing. Investigation shall be carried out and corrective action taken in case of deviation from prescribed limits.
(9). Steam coming in contact with the product, primary containers and other product contact surfaces shall be sterile and pyrogens free. The steam condensate shall meet microbiological specification of not more than 10 cfu per 100ml. The condensate shall also meet IP specification for Water for Injection and shall have an Endotoxin level of not more than 0.25 EU/ml. There shall be a suitable schedule for the monitoring of steam quality.
H. Manufacturing Process :
(1). Manufacture of sterile products shall be carried out only in areas under defined conditions.
(2). Bulk raw materials shall be monitored for bio-burden periodically. Bioburden of bulk solution prior to membrane filtration shall be monitored periodically and a limit of not more than 100 cfu per ml is recommended.
(3). The time between the start of the preparation of the solution and its sterilization or filtration through a micro-organism retaining filter shall be minimized. There shall be a set maximum permissible time for each product that takes into account its composition and method of storage mentioned in the Master formula record.
(4). Gases coming in contact with the sterile product shall be filtered through two 0.22 µ hydrophobic filters connected in-series. These filters shall be tested for integrity. Gas cylinders shall not be taken inside aseptic areas.
(5). Washed containers shall be sterilized immediately before use. Sterilized containers, if not used within an established time, shall be rinsed with distilled or filtered purified water and re-sterilized.
(6). Each lot of finished product shall be filled in one continuous operation. In each case, where one batch is filled in using more than one operation, each lot shall be tested separately for sterility and held separately till sterility test results are known.
(7). Special care shall be exercised while filling products in powder form so as not to contaminate the environment during transfer of powder to filling machine-hopper.
I. Form-Fill-Seal Technology or Blow, Fill-Seal Technology:-
(1). Form-Fill-Seal units are specially built automated machines in which through one continuous operation, containers are formed from thermoplastic granules, filled and then sealed. Blow, fill-seal units are machines in which containers are moulded / blown (pre-formed) in separate clean rooms, by non-continuous operations.
(2). Form-Fill-Seal/Blow, Fill-Seal machines used for the manufacture of products for terminal sterilization shall be installed in at least Grade C environment and the filling zone within the machine shall fulfill Grade A requirements.
(3). Preparation of solutions, which are to be sterilized by filtration, shall be done in Grade C environment, and if not to be filtered, the preparation of materials and products shall be in a Grade A environment with Grade B in background.
(4). Filtration (membrane).-
Solutions for Large Volume Parenterals shall be filtered through non-fibre releasing, sterilizing grade cartridge/membrane filter of nominal pore size of 0.22 µ for aseptic filling whereas 0.45 µ porosity shall be used for terminally sterilized products.
A second filtration using another 0.22 µ sterilizing grade cartridge / membrane filter shall be performed immediately prior to filling. Process specifications shall indicate the maximum time during which a filtration system may be used with a view to precluding microbial build-up to levels that may affect the microbiological quality of the Large Volume Parenterals.
The integrity of the sterilized filter shall be verified and confirmed immediately after use by an appropriate method such as Bubble Point, Diffusive Flow or Pressure Hold Test.
(5). Sterilization (Autoclaving).
(6). Sterilization (by dry heat): The process used for sterilization by dry heat shall include air circulation within the chamber and the maintenance of a positive pressure to prevent the entry of non-sterile air. Air inlets and outlets should be provided with micro-organism retaining filters. Where this process of sterilization by dry heat is also intended to remove pyrogens, challenge tests using Endotoxin would be required as part of the validation process.
(7). Sterilization (by moist heat):
The items to be sterilized, other than products in sealed containers, shall be wrapped in a material which allows removal of air and penetration of steam but which prevents re- contamination after sterilization. All parts of the load shall be in contact with the sterilizing agent at the required temperature of the required time.
No Large Volume Parenterals shall be subjected to steam sterilization cycle until it has been filled and sealed.
Care shall be taken to ensure that the steam used for sterilization is of a suitable quality and does not contain additives at a level which could cause contamination of the product or equipment.
J. Completion/finalization of sterile products:
(1). All unit operations and processes in the manufacture of a batch shall have a minimum time specified and the shortest validated time shall be used from the start of a batch to its ultimate release for distribution.
(2). Containers shall be closed by appropriately validated methods. Containers closed by fusion e.g. glass or plastic ampoules shall be subjected to 100% integrity testing. Samples of other containers shall be checked for integrity according to appropriate procedures.
(3). Containers sealed under vacuum shall be tested for required vacuum conditions.
(4). Filled containers Parenterals products shall be inspected individually for extraneous contamination or other defects. When inspection is done visually, it shall be done under suitably controlled conditions of illumination and background. Operators doing the inspection shall pass regular eye-sight checks with spectacles, if worn, and be allowed frequent rest from inspection. Where other methods of inspection are used, the process shall be validated and the performance of the equipment checked at suitable intervals. Results shall be recorded.
K. Product Containers and Closures:
(1). All containers and closures intended for use shall comply with the Pharmacopoeial and other specified requirements. Suitable samples sizes, specifications, test methods, cleaning procedures and sterilization procedures, shall be used to assure that containers, closures and other component parts of drug packages are suitable and are not reactive, additive, adsorptive or leachable or presents the risk of toxicity to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used.
(2). Plastic granules shall also comply with the Pharmacopoeial requirements including physico-chemical and biological tests.
(3). All containers and closures shall be rinsed prior to sterilization with Water for Injection according to written procedure.
(4). The design of closures, containers and stoppers shall be such as to make cleaning, easy and also to make airtight seal when fitted to the bottles.
(5). It shall be ensured that containers and closures chosen for a particular product are such that when coming into contact they are not absorbed into the product and they do not affect the product adversely. The closures and stoppers should be of such quality substances as not to affect the quality of the product and avoid the risk of toxicity.
(6). Whenever glass bottles are used, the written schedule of cleaning shall be laid down and followed. Where bottles are not dried after washing, these shall be finally rinsed with distilled water or pyrogens free water, as the case may be, according to written procedure.
(7). Individual containers of Parenterals preparations, ophthalmic preparations shall be examined against black/white background fitted with diffused light after filling so as to ensure freedom from foreign matters.
(8). Glass Bottles: Shape and design of the glass bottle shall be rational and standardized. Glass bottles made of USP Type-I and USP Type-II glass shall only be used. Glass bottles shall not be reused. Before use, USP Type-II bottles shall be validated for the absence of particulate matter generated over a period of the shelf life of the product and shall be regularly monitored after the production, following statistical sampling methods. USP Type-III glass containers may be used for Non-Parenterals sterile products such as Optic Solutions.
(9). Plastic Containers: Pre-formed plastic containers intended to be used for packing of Large Volume Parenterals shall be moulded in-house by one-continuous operation through an automatic machine.
(10). Rubber Stoppers:- The tuber stoppers used for Large Volume Parenterals shall comply with specifications prescribed in the current edition of the Indian Pharmacopoeia.
(1). Products shall be released only after complete filling and testing.
(2). Result of the tests relating to sterility, pyrogens, and Bacterial Endotoxin shall be maintained in the analytical records.
(3). Validation details and simulation trail records shall be maintained separately.
(4). Records of environmental monitoring like temperature, humidity, microbiological data, etc. shall be maintained. Records of periodic servicing of HEPA filters, sterilizers and other periodic maintenance of facilities and equipment carried out also be maintained.
(5). Separate facilities shall be provided for filling-cum-sealing of Small Volume Parenterals in glass containers and/or plastic containers.
(6). It is advisable to provide separate facilities for manufacture of Large Volume Parenterals in glass containers and / or plastic containers.
(7). For manufacture of Large Volume Parenterals in plastic containers, it is advisable to install automatic (with all operations) Form–Fill-Seal machines having one continuous operation.
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