SMALL VOLUME PARENTERALS
An injection that is packaged in containers labelled as containing 100ml or less. All the sterile products packaged in vials, ampoules, cartridges, syringes, bottles or any other container that is 100ml or less fall under the class of SVP.
The products come under SVP are biological products ophthalmic products diagnostic agents dental products.
- Quick on set of action
- Suitable for drugs which are not administered by oral route
- Useful for unconscious or vomiting patients
- Useful for patients who cannot take drugs orally
- Useful for the emergency situations
- Pain on injection
- Difficult to reverse an administered drugs effects.
- Requires strict control of sterility and non pyrogenicity than other formulation
- Only trained person is required. Require specialized equipment devices and techniques to prepare and administer drugs.
- More expensive and costly to produce
The production of sterile drug products by bringing together the product container and closure that have been subjected to different sterilization methods separately and assembled them in an extremely high quality environment by skilled personnel using the right tools
The methods which are used to prevent the access of microorganism during their preparation of parenteral products and their testing are called Aseptic Techniques.
The essential elements for the aseptic processing are as follows.
• Control and verification
• Finished product testing
Buildings and Facilities
The building layout and its construction are poor there is very little that an air conditioning system designer can do to satisfy the end-user of the sterile areas. Sterile zones are normally divided into three sub zones;
- Main sterile zone or white zone.
- Cooling zone which is also a white zone
- Set of three change rooms: black, grey and white in ascending order of cleanliness. In order to achieve a pressure gradient, it is imperative that zones are located such that the gradient is unidirectional, i.e. the room with the highest pressure should be located at one end and the room with the lowest pressure should be located near the opposite.
Entry for people to the main sterile room should be from a set of three change rooms: black, gray and white. Entry for equipment and material must be through airlocks. In case any wall of the sterile area is exposed to the outdoor, care should be taken that no glass is provided. Any glass window provided in an internal partition should be sealed.
- Sharp corners should be avoided between floors, walls and ceiling.
- Tile joints in the floor should be carefully sealed and epoxy painting should be carried out in these areas and special attention should be given to the type of ceiling.
In such cases the air conditioning system is required to be designed before slab construction is started in order to provide the following
a. Location and size of the cutouts for terminal filters.
b. Location and size of the cutouts for return air risers and inserts in the slab.
c. Provide floor drain locations for air handling units and sleeves for drain line and cabling should be provided in inverted beams.
In areas where air handling units are located water proofing must be carried out. Additional cutouts are required to be left for other services.
a. All cutouts should have curbing at the edge to prevent water seepage into the working area and mounting frames for terminal filters/terminal filter boxes should be grouted at the time of casting the slab.
b. Lighting layout and equipment should be matched with the cut-out location and size. The ceiling slab should have inverted beam construction in order to avoid projections into the clean rooms.
In the case of a false ceiling in the sterile area, the following points should be considered:
a. Inserts should be provided for false ceiling supports and mounting of filters.
b. To prevent fungus growth and eliminate air leakage, the false ceiling should be of non shedding variety, such as aluminium or PVC coated CRCA sheet. False ceiling members should be designed to support part of the weight of terminal filters and proper sealing must be provided between panels and between filters and panels to avoid air leakage.
Compounding and room design
The ante room or area can be achieved with something as simple as a strip curtain, preferably outside of the clean room. The ante room/area should be sized based on the number of technicians that will be working in the compounding room at any given time
Cleanrooms :- A cleanroom is a facility ordinarily utilized as a part of specialized industrial production or scientific research, including the manufacture of pharmaceutical items and microprocessors. Cleanrooms are designed to maintain extremely low levels of particulates, such as dust, airborne organisms, or vaporized particles. Cleanrooms typically have an cleanliness level quantified by the number of particles per cubic meter at a predetermined molecule measure. The ambient outdoor air in a typical urban area contains 35,000,000 particles for each cubic meter in the size range 0.5 μm and bigger in measurement, equivalent to an ISO 9 cleanroom, while by comparison an ISO 1 cleanroom permits no particles in that size range and just 12 particles for each cubic meter of 0.3 μm and smaller.
The clean room divides into; Critical Area and General Area.
The critical area is the area around the point of the production where contamination can gain direct access to the process. This area often protected by localized laminar flow clean benches and workstations.
The “General” area is the rest of the clean room where contamination will not gain direct entry into the product but should be kept clean because of the transfer of contamination into the critical area. It is necessary that the critical area be cleaned most often with the best cleaning ability without introducing contamination
Classification of Clean Rooms
The class is directly related to the number of particles per cubic foot of air equal to or greater than 0.5 micron.
(1) Class 100,000: Particle count not to exceed a total of 100,000 particles per cubic foot of a
size 0.5μ and larger or 700 particles per foot of size 5.0μ and larger.
(2) Class 10,000: Particle count not to exceed a total or 10,000 particles per cubic foot of a size
0.5μ and larger or 65-70 particles per cubic foot of a size 5.0μ and larger.
(3) Class 1,000: Particles count not to exceed a total of 1000 particles per cubic foot of a size
0.5μ and larger or 10 particles per cubic foot of a size 5.0μ and larger.
(4) Class 100: Particles count not to exceed a total of 100 particles per cubic foot of a size 0.5μ
For the manufacture of sterile medicinal products normally 4 grades can be distinguished.
GRADE “A”: The local zone for high risk operations. eg. Filling zone,stopper bowls,open ampules
GRADE “B”: In case of aseptic preparation and filling, the back ground environment for grade
GRADE “C” &”D”: Clean areas for carrying out less critical stages in the manufacture of sterile produce
Processing areas for sterile pharmaceutical products
Air Handling System Design While designing the air handling system the following points should be taken into consideration.
- Motors for supply air/return air fans should have two speeds, since during non-working hours even though air conditioning is not required it is necessary to have pressurisation in the clean room for all 24 hours in order to ensure sterility.
- Trend is to use VFD’s (Variable Frequency Drives) on AHU and run the AHU at lower speeds at night/ holidays. This helps as a energy saving measure as well.
- Cooling coil section should be provided with sandwich type of drain pan to collect condensate.
- In case of a heating coil, at least a 0.5 meter space should be kept between coils.
- Two sets of fresh air dampers should be provided, one for 10% to 20% and the second for 100% of fan capacity.
Air Flow Pattern
Air flow velocities of 0.36 m/s to 0.56 m/s (70 fpm to 110 fpm) are recommended as standard design for laminar flow clean room systems. Air is supplied at a much higher pressure than its surrounding area ensuring a higher velocity and pressure in the clean zone relative to the parameter. In pharmaceutical plants use of laminar flow work benches is quite common to obtain class 100 at the work place
Heating Ventilation and Air Conditioning (HVAC) Systems
HVAC systems are an internal part of environmental control system design. The primary purpose of an HVAC system is to provide a specific set of environmental conditions required for the manufacturing process. To properly design HVAC system it is importantly to define the required operational parameters. The parameters discussed in the following sections are to be determined prior to designing an effective HVAC system.
HVAC System Temperature and Humidity Control Temperature in the 68-74°F (19-23°C) range are considered acceptable. Lower temperature are normally selected in manufacturing environments used .Humidity control in most cases is also a comfort requirement. Comfort levels are in the 45-55% RH range. Humidity range 15-30% this is the case with many freeze dried substances. Normal humidity levels achieved with air conditioning systems
The main method for airborne contamination control in production areas is air filtration. The existence of various types of air filters, each with different design, construction and efficiency Air in controlled environment shall have
- A per-cubic-foot particle count of not more than 100,000 in a size range of 0.5 micron and larger when measured with automatic counters or 700 particles in a size range of 5.0 microns or larger when measured by a manual microscopic method.
- A temperature of 720F+_50 or 220C +30C and maximum relative humidity of 50 percent and a minimum of 30 percent.
- A positive pressure differential of at least 0.05 inch of water with all.
Entry and Exiting :-Entry and exit passage ways are also required for the transfer of personnel, equipment, and materials, locations of these rooms, sometimes referred to as “airlocks,” must satisfy the internal and external requirements for the flow of materials and personnel.
HEPA:- A High efficiency particulate air, or HEPA filter is a type of air filter that satisfies standards of United States Department of Energy (DOE).
Definition: A screen that filters out particles in the air by forcing them through microscopic pores. HEPA filters have different ratings for efficiency, which are generally posted on the filter itself. HEPA filter is so efficient that for every 10,000 particles that enter the filter within its filtering range, only 3 particles will get through.
Five classifications of HEPA filters exist
• Type A HEPA filters: Also referred to as industrial filters. An efficiency performance of 99.97 % retention of particulate matter 0.3 micrometers in size at an airflow of 85 L/minute.
• Type B HEPA filters Known as nuclear type are designed to handle nuclear containment. Filters are tested for pinhole leaks, as significant numbers of these leaks lead to an efficiency drop at slower air flows. The test checks for 99.97 % retention of particulate matter 0.3 micrometers in size, but at 20 % the normal airflow.
• Type C HEPA filters Called laminar flow filters due to their mostly exclusive use in biological laminar flow systems, filters are tested for particulate matter of larger sizes. filter has an efficiency of 99.99 % .• Type D HEPA filters Known as ultra-low penetration air. An efficiency rating of 99.999 % retention of particulate matter 0.3micrometers in size at airflow of 85 L/minute.
• Type E HEPA filters Referred to as biological filters. These filters are created with a focus on stopping toxic, nuclear, chemical and biological threats.
Laminar Flow Clean Air Benches:-Laminar flow clean air benches used in pharma labs, food (quality control) parenteral feeding. Tissue culture, horticulture, sterile testing, IVF, optics, micromechanics, Electronics industries. Laminar flow benches are specially designed for particulate and bacterial free sterile atmosphere to handle non hazardous non pathogenic samples, cell & tissue cultures, alimentation controls in microbiology
A well-designed, maintained, and operated aseptic process minimizes personnel intervention. As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases. To ensure maintenance of product sterility, it is critical for operators involved in aseptic activities to use aseptic technique at all times.
Appropriate training should be conducted before an individual is permitted to enter the aseptic manufacturing area. Fundamental training topics should include aseptic technique, cleanroom behavior, microbiology, hygiene, gowning, patient safety hazards posed by a nonsterile drug product, and the specific written procedures covering aseptic manufacturing area operations.
After initial training, personnel should participate regularly in an ongoing training program. Supervisory personnel should routinely evaluate each operator’s conformance to written procedures during actual operations. Similarly, the quality control unit should provide regular oversight of adherence to established, written procedures and aseptic technique during manufacturing operations.
Some of the techniques aimed at maintaining sterility of sterile items and surfaces include:
• Contact sterile materials only with sterile instruments Sterile instruments should always be used in the handling of sterilized materials. Between uses, sterile instruments should be held under Class 100 (ISO 5) conditions and maintained in a manner that prevents contamination (e.g., placed in sterilized containers). Instruments should be replaced as necessary throughout an operation.
After initial gowning, sterile gloves should be regularly sanitized or changed, as appropriate, to minimize the risk of contamination. Personnel should not directly contact sterile products, containers, closures, or critical surfaces with any part of their gown or gloves.
• Move slowly and deliberately Rapid movements can create unacceptable turbulence in a critical area. Such movements disrupt the unidirectional airflow, presenting a challenge beyond intended
clean room design and control parameters. The principle of slow, careful movement should be followed throughout the clean room.
Maintain Proper Gown Control Prior to and throughout aseptic operations, an operator should not engage in any activity that poses an unreasonable contamination risk to the gown.
Only personnel who are qualified and appropriately gowned should be permitted access to the aseptic manufacturing area. The gown should provide a barrier between the body and exposed
sterilized materials and prevent contamination from particles generated by, and microorganisms shed from, the body. The Agency recommends gowns that are sterilized and nonshedding, and cover the skin and hair (face-masks, hoods, beard/moustache covers, protective goggles, and elastic gloves are examples of common elements of gowns). Written procedures should detail the methods used to don each gown component in an aseptic manner.
An adequate barrier should be created by the overlapping of gown components (e.g., gloves overlapping sleeves). If an element of a gown is found to be torn or defective, it should be changed immediately. Gloves should be sanitized frequently.
There should be an established program to regularly assess or audit conformance of personnel
to relevant aseptic manufacturing requirements. An aseptic gowning qualification program should assess the ability of a cleanroom operator to maintain the quality of the gown after performance of gowning procedures. We recommend that this assessment include microbiological surface sampling of several locations on a gown (e.g., glove fingers, facemask, forearm, chest). Sampling sites should be justified. Following an initial assessment of gowning, periodic requalification will provide for the monitoring of various gowning locations over a suitable period to ensure consistent acceptability of aseptic gowning techniques. Annual requalification is normally sufficient for those automated operations where personnel involvement is minimized and monitoring data indicate environmental control. For any aseptic processing operation, if adverse conditions occur, additional or more frequent requalification could be indicated.
QUALIFICATION AND VALIDATION OF THE UTILITIES
Validation studies should be conducted to demonstrate the efficacy of the sterilization cycle. Requalification studies should also be performed on a periodic basis. The specific load configurations, as well as biological indicator and temperature sensor locations, should be documented in validation records. Batch production records should subsequently document adherence to the validated load patterns.
It is important to remove air from the autoclave chamber as part of a steam sterilization cycle. The insulating properties of air interfere with the ability of steam to transfer its energy to the load, achieving lower lethality than associated with saturated steam. It also should be noted that the resistance of microorganisms can vary widely depending on the material to be sterilized. For this reason, careful consideration should be given during sterilization validation to the nature or type of material chosen as the carrier of the biological indicator to ensure an appropriately representative study.
Potentially difficult to reach locations within the sterilizer load or equipment train (for SIP applications) should be evaluated. For example, filter installations in piping can cause a substantial pressure differential across the filter, resulting in a significant temperature drop on the downstream side. We recommend placing biological indicators at appropriate downstream locations of the filter.
Empty chamber studies evaluate numerous locations throughout a sterilizing unit (e.g., steam autoclave, dry heat oven) or equipment train (e.g., large tanks, immobile piping) to confirm uniformity of conditions (e.g., temperature, pressure). These uniformity or mapping studies should be conducted with calibrated measurement devices.
Heat penetration studies should be performed using the established sterilizer loads. Validation of the sterilization process with a loaded chamber demonstrates the effects of loading on thermal input to the items being sterilized and may identify difficult to heat or penetrate items where there could be insufficient lethality to attain sterility. The placement of biological indicators at numerous positions in the load, including the most difficult to sterilize places, is a direct means of confirming the efficacy of any sterilization procedure. In general, the biological indicator should be placed adjacent to the temperature sensor so as to assess the correlation between microbial lethality and predicted lethality based on thermal input. When determining which articles are difficult to sterilize, special attention should be given to the sterilization of filters, filling manifolds, and pumps. Some other examples include certain locations of tightly wrapped or densely packed supplies, securely fastened load articles, lengthy tubing, the sterile filter apparatus, hydrophobic filters, and stopper load. Ultimately, cycle specifications for such sterilization methods should be based on the delivery of adequate lethality to the slowest to heat locations. A sterility assurance level of 10-6 or better should be demonstrated for a sterilization process. For more information, please also refer to the FDA guidance entitled Guideline for the Submission of Documentation for Sterilization
CLEAN IN PLACE
To attain documented evidence, which provides a high degree of assurance that the Cleaning procedure can effectively remove residues of a product and a cleaning agent from the manufacturing equipment, to a level that does not raise patient safety concerns
• Assurance of quality & safety.
• Government regulations.
• Product integrity,
• Microbial integrity,
• Cross contamination integrity,
• Batch integrity,
• Equipment reuse,
• Reduction of quality costs.
• Making good business sense.
• Less down time, fewer batch failures and may operate / clean more efficiently.
Several basic mechanisms exist to remove residues from equipment, including Mechanical action refers to physical actions such as
• pressurized water to remove particulates.
STERILIZATION IN PLACE
A sterilization in place system is a sterilization method which is designed to sterilize an entire system of equipment in situ without disassembly of components or piping. The most common agent for SIP is saturated steam.
When equipments like tanks filling lines transfer line, filtration system, water for injection that cannot to be sterilized by autoclaving due to size or shape is subjected to SIP acceptance criteria for
SIP is sterility assurance level is less than or equal to 10 to the power of -6.
RECENT ADVANCES IN PROCESSING
An isolator is an arrangement of physical barriers that are integrated to the extent that the isolator can be sealed in order to carry out a routine leak test based on pressure to meet specified limits. Internally it provides a workspace, which is separated from the surrounding environment. Manipulations can be carried out within the space from the outside without compromising its integrity.
Pharmaceutical Isolator Types Include:
- Dispensing Isolators
- Transfer Isolators
- Sub-division and Weighing Isolators
- Cell Therapy – Cell Culture Isolators
- R&D Isolators and Class III Biosafety Cabinets
- Reactor and Charging Isolators
- Off-Loading Isolators
- Cytotoxic Compounding Containment Units
- Micronizing/Milling & Blending Isolators
An isolator is a totally enclosed and sealed stainless steel glove box type system. The isolator has an air handling system that provides HEPA filtered air to the interior in a unidirectional down flow pattern. The air handling system can be designed to provide the isolator interior with positive or negative pressure. A positive pressure isolator is used to protect the interior environment from ingress of any contaminants from the background cleanroom. Negative pressure isolators are used for containment of biological or chemical products that are highly toxic and hazardous to the operator. Since the interior of the isolator is sealed off from the background cleanroom, operator access to the interior is done through glove ports or half suits. Sterile containers, stopper components, and environmental monitoring materials are brought in to and out of the isolator through air locks, mouse holes, and devices known as Rapid Transfer Ports (RTPs). One of the major advantages that isolators have over RABS type systems is that the interior can be bio-decontaminated through a automated process commonly using hydrogen peroxide vapor (H2O2). This automated bio-decontamination process allows for a repeatable and consistent high-level biodecontamination of the interior, thus the Sterility Assurance Level (SAL) is improved significantly over conventional cleanroom manufacturing.
Advantages of isolators
- Highest product quality due to consequent technology
- Automatic validatable bio-decontamination syatem
- Fast and highly efficient bio-decontamination cycles
- Perfectly prepared for campaigning
2) RESTRICTED ACCESS BARRIER SYSTEMS
Restricted Access Barrier Systems (RABS) also offer a high level of product protection and contamination control. Unlike isolators they use a combination of physical and aerodynamic barriers to prevent ingress of contaminants into the interior environment. The physical barrier is similar to machine guarding having glass or polycarbonate doors with stainless steel walls that totally enclose the machinery with an air handler supplying HEPA filtered, unidirectional airflow providing an ISO 5 environment. RABS operate with a positive pressure and a high air exchange rate relative to the background cleanroom. RABS are typically unsealed barriers having the HEPA filtered air supplied to the RABS interior and exhausted through a gap between the RABS walls and the equipment. RABS that exhaust to the background environment are referred to as open RABS. An open active RABS has the air handler integrated into the barrier system. A passive open RABS is a barrier system that is built around equipment installed below air handlers in the background cleanroom, which provide the ISO 5 environment. Closed RABS offer another option and are by design sealed isolators that can be positive or negative pressure, but are manually cleaned and bio-decontaminated rather than utilizing an automated bio- decontamination process typical of isolators. Like isolators, introduction and exit of materials is done through mouse holes, Rapid Transfer Ports (RTPs) and pass throughs. Glove ports and half suits are also used to further separate an operator from the sterile interior of the RABS
RABS(RESTRICTED ACESS BARRIER )
• Open Passive RABs utilize existing clean room overhead air supply systems to deliver HEPA filtered air over a critical process before returning air back into the clean room without the need for additional fans or filters. The RABs enclosure is not sealed to the filling machine.
• Open Active RABS have an onboard fan/filtration units to supply HEPA Filtered air over a critical process before returning air back into the clean room. The RABs enclosure is not sealed to the filling machine.
Closed RABs is a positive pressure system with an onboard fan/filtration units to supply HEPA Filtered air over a critical process which then passes through exhaust filters before being recirculated. Airflow recirculates with the RABs enclosure. RABs typically are not decontaminated, unless the filling machine and all other openings can be sealed. All RABs can include glove ports, RTP systems, access doors with interlocks and EM systems as required. For existing equipment, a site visit is typically required to measure the equipment and develop a 3D model of the RABs.
3) BLOW FILL SEAL METHOD
Blow-fill-seal (BFS) technology is an automated process by which containers are formed, filled, and sealed in a continuous operation. This manufacturing technology includes economies in container closure processing and reduced human intervention and is often used for filling and packaging ophthalmics, respiratory care products, and, less frequently, injectables. This appendix discusses some of the critical control points of this technology. Except where otherwise noted below, the aseptic processing standards discussed elsewhere in this document should apply to blow-fill-seal technology.
Equipment Design and Air Quality Most BFS machines operate using the following steps.
• Heat a plastic polymer resin
• Extrude it to form a parison (a tubular form of the hot resin)
• Cut the parison with a high-temperature knife
• Move the parison under the blow-fill needle (mandrel)
• Inflate it to the shape of the mold walls
• Fill the formed container with the liquid product
• Remove the mandrel
THE ADVANTAGES OF THE RECENT TECHNOLOGIES
B/F/S technology offers several advantages for sterile packaging. Product contact surfaces are
cleaned and sterilized in place and sterile contact surfaces are protected from environmental
contamination with HEPA-filtered or equivalent air. In addition, machine designs create a
physical barrier, restricting personnel intervention during the container formation and filling
Microbiological contamination control. Operations personnel are the main source of microbiological contamination in the cleanroom and, therefore, represent a potential product contaminant. Automated, well-designed B/F/S operations minimize the need and opportunity for human intervention, thus reducing the risk of microbial contamination. In addition, B/F/S typically involves small container openings and short product exposure times, further lessening the likelihood of microbial ingress.
Reduced container defects. Product seal failures can result from defects in glass and other types of packaging components (e.g., closures). Damage or defects can occur to packaging components during transport and handling, before product filling, or due to variations in the component manufacturing process. Because B/F/S technology does not use supplier-made containers or (in most cases) closures, using B/F/S eliminates shipping and handling damage. In addition, container formation is controlled by the B/F/S product manufacturer as the container is formed immediately before the sterile product is filled and is not affected by flaws in vendor process control.
Easier process validation. B/F/S is a fully automated process that requires little operator
involvement, if any. Therefore, its operations are more predictable than manual operations, less variable, and less prone to error. More of the process is controlled by the product manufacturer
rather than by component suppliers. This can further reduce process variability, thus resulting in a process which is easier to validate.
Concerns with B/F/S technology
Despite these sound advantages, wider use of B/F/S has been limited by concerns such as:
• nonviable particulate levels in the environment surrounding the B/F/S machine
• exposure of product to the elevated temperature of the formed container
• gas and moisture barrier properties of container plastics.
Particulate control. Relatively high levels of nonviable particulates are generated by the plastic extrusion and cutting process. B/F/S machine manufacturers have taken steps to address the plastic particulate issues by designing better machine enclosures to isolate and protect the product contact surfaces from environmental conditions. Some B/F/S line designs place particle-generating equipment away from the filling zones and isolate with walls and barriers. For some products, closed-parison systems, in which the inside of the parison is continually bathed with sterile air and is not cut, can be used to further protect product contact surfaces.
Temperature effects. B/F/S containers remain at an elevated temperature of up to 60 oC for
several seconds after filling. It is speculated that other types of plastic with a lower
processing temperature can be used to reduce this temperature. To reduce the effect of exposure to elevated temperature container surfaces, filled product can be cooled soon after filling and sealing.
Oxygen and moisture effects. Plastics typically used for B/F/S containers provide a relatively low barrier to oxygen or moisture, especially as compared to traditional glass containers (i.e., vials and syringes). For oxygen sensitive products, filled units can be placed in foil pouches or other secondary packaging. Inert gases can be used in these secondary packages to lessen risk for oxygen permeation. Process development and product stability studies using products filled using the B/F/S process, container, and packaging can provide evidence of product compatibility. Companies considering the use of B/F/S should take steps to assure that the heat and permeation issues do not have an adverse effect on product quality.