1. Parenteral Preparations

2. Parenteral is derived from two words ‘‘para’’ and ‘‘enteron’’ meaning to avoid the intestine.
Parenteral articles are defined according to the USP 24/NF19 ‘‘as those preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active substances they contain are administered using gravity or force directly into a blood vessel, organ, tissue, or lesion.

3. Parenteral products are prepared scrupulously by methods designed to ensure that they meet pharmacopeial requirements for sterility, pyrogens, particulate matter, and other contaminants, and, where appropriate, contain inhibitors of growth of microorganisms. The first historical references to the parenteral administration of a compound was in the late 15th century when a blood transfusion from three young boys was given to Pope Innocent VIII, resulting in the death of all four individuals.

4. It was not until the 17th century that studies on the parenteral administration of compounds was first studied in animals. The development of the hypodermic needle and the use of parenterally injected drugs in humans is first reported in the mid-19th century. By the end of this century, there was an increased interest in the use of intravenous administration of glucose and normal saline solutions. Baxter produced the first commercially prepared intravenous solutions in However, parenteral products and their administration became acceptable and a mainstay in the treatment of patients in the mid 20th century.

5. Advantages
Useful for patients who cannot take drugs orally
Useful for drugs that require a rapid onset of action (primarily intravenous administration)
Useful for emergency situations
Useful for providing sustained drug delivery (implants, intramuscular depot injections)
Can be used for self-delivery of drugs (subcutaneous)
Useful for drugs that are inactivated in the gastrointestinal tract or susceptible to first-pass metabolism by the liver
Useful for injection of drugs directly into a tissue (targeted drug delivery)
Useful for delivering fluids, electrolytes, or nutrients (total parenteral nutrition to patients)
Useful for providing precise drug delivery by intravenous injection or infusion utilizing pharmacokinetic techniques
Can be done in hospitals, ambulatory infusion centers, and in home health care

6. Disadvantages
More expensive and costly to produce
Potential for infection at site of injection
Potential for sepsis
Potential for thrombophlebitis
Potential for fluid overload
Potential for air embolism
Potential for extravasation
Psychological distress by the patient
Require specialized equipment, devices, and techniques to prepare and administer drugs
Potential for pain upon injection
Potential for tissue damage upon injection
Risk of needle stick injuries and exposure to blood-borne pathogens by health care worker
Increased morbidity associated with long-term vascular access devices Disposal of needles, syringes, and other infusion devices requires special consideration

7. The most commonly used routes of administration for parenteral products:
intraperitoneal; (B) intravenous; (C) intramuscular; (D) subcutaneous;
(E) intradermal.

8. TYPES OF PARENTERAL PRODUCTS
Other Routes
Intra-abdominal
Intra-arterial,
Intraarticular,
Intracardiac,
Intracisternal,
Intradermal,
intraocular,
Intrapleural,
Intrathecal,
Intrauterine,
Intraventricular
TYPES OF PARENTERAL PRODUCTS
Parenteral products can be divided into two general classes according to the volume of the product.
Small-volume parenterals (SVP) or injections are 100 ml or less and can be provided as a single- or multidose product.
Large-volume parenterals (LVP) are intended to be used intravenously as a single-dose injection and contain more than 100 ml of solution.
SVPs and LVPs are often combined during the extemporaneous preparation of
intravenous admixtures.

9. On the Basis of Number of doses
Single Dose
Multiple Dose
On the basis of Dosage Form
Wet Injections:
Sterile Solution for Injection
Sterile Suspension for Injection
Sterile Emulsion for Injection
2. Dry Injections:
Sterile Powder for Solution
Sterile powder for Suspension

10. Parenterals Products must be sterile and free from pyrogens and foreign particulate matter. These three major characteristics distinguish sterile dosage forms from any other pharmaceutical product.
Sterility
Sterility is a state of absolute freedom from microbial contamination. Interestingly, the word sterile on the label of a sterile product has had a historic meaning that a sample of the product lot passed the compendial test for sterility. Today, to claim that a product is sterile involves much more than passing a sterility test. Achievement of sterility involves the combination and coordination of a wide range of activities and processes such as:
Cleaning and sanitization of all facilities and equipment
Cleaning and sterilization of equipment, packaging, and all other items to be in contact with the sterile product

11. 3. Installation and certification of laminar air flow areas where sterile air is provide via high-efficiency particulate air (HEPA) filters
Environmental monitoring of the facility, equipment, water, and personnel for strict microbiological and particulate control
Appropriate gowning and training of personnel in aseptic techniques
Validation of sterilization processes
Validation of the filter system
Integrity testing of the filter system before and after filtration
Integrity testing of the container-closure system to maintain sterility of the product
10.Conductance of the sterility test initially for all lots and at the end of the shelf-life expiration dating period for the product lot under stability testing

12. Freedom from Pyrogens
Pyrogens are metabolic byproducts of microbial growth. Injected in sufficient amounts in humans (infact, in any mammal), pyrogens can react with the hypothalamus of the brain to raise the body temperature. In addition, they can cause a number of other adverse physiological effects, including death.
The serious problems with sepsis are a result of high levels of endotoxins, endotoxins being a major type of pyrogen. Pyrogens are very small, water-soluble, heat-resistant lipopolysaccharides that cannot be destroyed by typical
steam-sterilization cycles or removed by 0.2 µ membrane filters. Prevention rather than elimination is the key for pyrogen removal. The primary source of pyrogenic contamination in parenteral products is water.

13. Fortunately, pyrogens are destroyed by distillation
Fortunately, pyrogens are destroyed by distillation. Water used to clean containers and closures can also be a source of pyrogens. However, glass is sterilized by dry heat at temperatures hot enough (usually >250C to destroy pyrogens). Rubber closures are steam-sterilized, which does not destroy pyrogens. Closures are depyrogenated by the cleaning and rinsing process using pyrogen free water. If the parenteral product is contaminated with pyrogens, there is no practical way to remove or destroy them.
Pyrogenic contamination is detected using two tests. In the older method, rabbits are injected with product samples, and rectal temperature is measured.
The newer method involves a relatively simple in vitro technique called the Limulus Amebocyte Lysate (LAL) test. It is based on the high sensitivity of amebocytes of the horseshoe crab (Limulus) to the lipopolysaccharide component of endotoxins.

14. Freedom from Particulate Matter
Particulate matter is viewed as unacceptable contamination in parenteral solutions. It is recognized that subvisible particulate matter will exist in certain amounts, but the USP now has limits for acceptable levels of particulate matter for Parenteral (no more than 6000 particles per container >0.5µ, no more than 600 particles per container >25 µ). Parenteral solutions with visible particulate matter should not be used.
Stability
Drugs in Parenteral are generally unstable. Many drugs are so unstable that they cannot be marketed as ready to use solutions. Drugs with sufficient solution stability will still require certain formulation, packaging, and storage conditions to maintain stability during shelf life storage and use. The primary pathways of drug degradation involves oxidation (reaction with molecular oxygen catalyzed by various factors including high temperature, high pH level, heavy metals, light, and peroxide contaminants) and hydrolysis (reaction with water catalyzed by high temperature and extremes in pH).

15. For protein pharmaceuticals, aggregation of the protein, resulting in a loss of potency, can be a major degradation pathway. Drugs can also react with packaging and formulation components, resulting in physical and chemical degradation.
Many SVP products are packaged in light protective packaging, require storage at controlled room or lower (refrigeration) temperatures, are formulated at low pH, contain antioxidants and/or metal chelating agents, and are processed in ‘‘oxygen free’’ conditions where water is saturated with an inert gas, and, before to sealing the container, the product is overlayed with an inert gas to remove oxygen from the headspace of the container.
Many drugs in liquid Parenteral will react with water and form hydrolytic degradation products. Hydrolysis and decomposition occur as solution pH may change and are catalyzed by resulting hydrogen and/or hydroxyl ions.

16. Buffers play an important role in certain injectable products to achieve tight control of solution pH. Hydrolysis of solid-state injectables can occur with moisture from the headspace in the container, moisture remaining in the solid product, and/or moisture originating from or through the rubber closure. Control of residual moisture during and after processing and the use of effective container-closure systems to minimize moisture ingress are very important to protect dried powders from hydrolytic degradation.
Isotonicity
Parenteral should be isotonic with blood, tears, spinal fluid, and other biological fluids into which the product is injected or instilled. This means that the injected or instilled solution contains the same ‘‘number’’ of solute ‘‘particles’’ in solution as is contained in the biological cell. Isotonicity means that the ‘‘tone’’ of the cell will not be disturbed, either by the ingress of water from the injected solution (if the solution is hypotonic) or egress of water from the cell (if the solution is hypertonic). Solution tonicity can be ascertained by measurement of a colligative property such as osmotic pressure or freezing-point depression.

17. FORMULATION INGREDIENTS
Parenteral are simple formulations compared with other pharmaceutical dosage forms. Solution Parenteral contain water, the active ingredient, and a minimal number of inactive added ingredients. Solid Parenteral contain the active ingredient and usually one or two added ingredients.
Solvent
The most widely used solvent for Parenteral is water for injection (WFI), USP. As a solvent, WFI is used in preparing the bulk solution (compounding) and as a final
rinse for equipment and packaging preparation. WFI is prepared by distillation or reverse osmosis (200 to 400 psi), although only distillation is permitted for sterile water for injection,

18. USP. Sterile water for injection is used as a vehicle for reconstitution of sterile solid products before administration and is terminally sterilized by autoclaving. Bacteriostatic water for injection, USP, is commercially available as a reconstitution vehicle for solid products intended for multiple-dose use. Benzyl alcohol is a common antimicrobial preservative used in bacteriostatic water for injection.
Sesame oil, cottonseed oil, fractionated coconut oil, arachis oil and other vegetable oils are used as vehicles for water insoluble drugs such as corticosteroids and oil-soluble vitamins. Oily solutions can be administered only by intramuscular injection.

19. Solubilizers
Solubilizers are used to enhance and maintain the aqueous solubility of poorly water soluble drugs. Examples of solubilizing agents used in sterile products
include:
Liquid co solvents: glycerin, polyethylene glycol (300, 400, 3350), propylene alcohol, and ethanol, Cremophor EL, sorbitol.
2. Surface active agents: polysorbate 80 (polyoxyethylene sorbitan monooleate), polysorbate 20, Pluronic 68, lecithin.
3.Complexing agents: b-Cyclodextrins, Captisol, polyvinylpyrrolidone, carboxymethylcellulose sodium.
Liquid solubilizers act by reducing the dielectric constant properties of the solvent system, thereby reducing the electrical conductance capabilities of the solvent and increasing the solubility of hydrophobic or non-polar drugs.

20. Surface active agents increase the dispersability and water solubility of poorly soluble drugs owing to their unique chemical properties of possessing both hydrophilic and hydrophobic functional groups in the same molecule (the same is true of b-cyclodextrins, addressed below). The hydrophobic groups adsorb to surface molecules of the drug, whereas the hydrophilic groups interact with the water-solvent molecules. Therefore, the drug molecules locate within the hydrophobic core of the surface active agent (sometimes called a micelle) while the polar molecules of the surface active agent are oriented with water, and the drug is solubilized within the surface active agent dissolved in water.
Complexing agents act by forming soluble inclusion complexes in aqueous solution. These molecules, as with surface active agents, are amphiphilic.

21. Antimicrobial Preservative Agents
Antimicrobial preservatives serve to maintain the sterility of the product during its shelf life and use. They are required in preparations intended for multiple dosing
from the same container because of the finite probability of accidental contamination during repeated use. They also are included, although this is quite controversial,
in some single-dose products that are aseptically manufactured to provide additional assurance of product sterility. The combination of antimicrobial preservative agents and adjunctive heat treatment (usually temperatures below 110 oC) also is used to
increase assurance of sterility for products that cannot be terminally sterilized. Very few antimicrobial preservative agents are acceptable. Most substances with antimicrobial activity are irritating and toxic at relatively low concentrations and usually have stability limitations.

22. Antimicrobial preservative agents in small-volume parenterals
They can be incompatible with the drug and formulation ingredients and can interact adversely with packaging components. Most commonly used parenteral antimicrobial preservatives are alcoholic or phenolic chemicals.
Antimicrobial preservative agents in small-volume parenterals
Agent Concentration range (%)
Phenol –0.5
m-Cresol –0.3
Methylparaben –0.18
Propylparaben –0.035
Chlorobutanol –0.55
Benzyl alcohol –2.0
Benzalkonium chloride –0.025
Thimerosal –0.01

23. Common buffer systems used in small-volume parenteral products
Buffers are used to maintain the pH level of a solution in the range that provides either maximum stability of the drug against hydrolytic degradation or maximum or optimal solubility of the drug in solution. The appropriate choice of buffer depends on the pH range in which the drug in question is most stable (or most soluble) that matches the pKa (dissociation constant) of the buffer species. For example, if a pH of 4.5 is most desirable, the correct choice of buffer would be an acetate buffer because the pKa of acetic acid is At pH 4.76, acetic acid exists 50% as the acid (un-ionized form) and 50% as the salt (ionized form).
Common buffer systems used in small-volume parenteral products
pH Buffer system Concentration (%)
3.5–5.7 Acetic acid–acetate 1–2
2.5–6.0 Citric acid–citrate 1–5
6.0–8.2 Phosphoric acid–phosphate 0.8–2
8.2–10.2 Glutamic acid–glutamate 1–2

24. Antioxidants
Antioxidants function by reacting preferentially with molecular oxygen and minimizing or terminating the free radical auto-oxidation reaction. Many drugs are sensitive to the presence of oxygen and will degrade very rapidly in the absence of protection. In addition to the use of antioxidants, other precautions must be taken. These include protection from light, heat, heavy metal and peroxide contamination, and excessive exposure to air. Formulating the product at low pH is preferable if the product is stable and soluble at low pH.
The most widely used agent is sodium bisulfite because its oxidation-reduction potential lies in the range at which it does not preferentially oxidize too slowly or too rapidly. Other sulfurous acid salts also are effective antioxidants, as are ascorbic acid and sodium ascorbate. Sometimes, combinations of antioxidants strengthen oxidative drug protection as well as the combination of an antioxidant and a chelating agent. The most common chelating agent used in parenterals is disodium ethylenediaminetetraacetic acid (DSEDTA).

25. Antioxidants commonly used in small-volume parenterals
Antioxidant Concentration range (%)
Water soluble
Sulfurous acid salts
Sodium bisulfite –1.0
Sodium sulfite –0.2
Sodium metabisulfite –0.1
Sodium thiosulfate –0.5
Sodium formaldehyde sulfoxylate –0.15
Ascorbic acid isomers
L- and D-Ascorbic acid –1.0
Thiol derivatives
Acetylcysteine –0.5
Cysteine –0.5
Thioglycerol –0.5
Thioglycolic acid, Thiolactic acid,Thiourea –0.05
Oil soluble
Propyl gallate –0.1
Butylated hydroxyanisole –0.02
Butylated hydroxytoluene –0.02
Ascorbyl palmitate –0.02
Nordihydroguaiaretic acid –0.05
a-Tocopherol –0.075

26. Tonicity Adjusters
A variety of agents are used in sterile products to adjust tonicity. Most common are simple electrolytes such as sodium chloride or other sodium salts and non-electrolytes such as glycerin and lactose. Tonicity adjusters are usually the last ingredient added to the formulation after other ingredients in the formulation are established and the osmolality of the formulation measured. If the formulation is still hypotonic (i.e.<280 mOsm/kg as measured by a commonly used osmometer instrument), tonicity adjusting agents are added until the formulation is isotonic. If the formulation is hypertonic, the degree of hypertonicity and the intended route of drug administration need to be considered. For intravenous administration, hypertonicity values up to approximately 360 mOsm/kg are not considered harmful. However, for other routes of administration, efforts should be made to make the final product isotonic before administration. This can be accomplished either by reducing concentrations of ingredients, if acceptable, or by diluting the product before administration.

27. Other Ingredients
Bulking agents are used in freeze-dried preparations to increase the solid content of the ‘‘plug’’ in the container after the sublimation process during the freeze drying cycle. Bulking agents not only serve to enhance the elegance of the product but also can serve as stabilizers in adsorbing excess moisture during shelf life. Suspending agents keep the drug suspended in the solvent after shaking and allow homogeneous dosing of the suspended drug from the container. Emulsifying agents lower the interfacial tension of an oil and water interface to allow the two immiscible solvents to mix and form a stable emulsion dosage form. Examples of these different additives are:
Bulking agents: mannitol, lactose, sucrose, dextran.
2.Suspending agents: carboxymethylcellulose, methylcellulose, gelatin, sorbitol.
3. Emulsifying agents: lecithin, polysorbate 80.

28. STERILE PRODUCT MANUFACTURING
The manufacture of sterile products is universally acknowledged to be the most difficult of all pharmaceutical production activities to execute. The production of sterile products requires fastidious design, operation, and maintenance of facilities and equipment. It also requires attention to detail in process development and validation to ensure success.
FACILITY DESIGN
To have microbial, pyrogen, and particles controls over the production environment are essential. The facility concerns encompass the entire building, but the most relevant components are those in which production materials are exposed to the environment.

29. Ware House
Environmental protection of materials commences upon receipt where samples for release are taken from the bulk containers. Protection of the bulk materials is accomplished by the use of ISO 7 classified environments for sampling. All samples should be taken aseptically (sterile material).
Preparation Area
The materials utilized for production of sterile processes move toward the filling area through a series of progressively cleaner environments. Typically, the first step is transfer into an ISO 8 [Class 100,000, European Union (EU) Grade D] environment
in which the pre-sterilization preparation steps are performed. Wooden pallets and corrugated materials should always be excluded from this zone. Preparation areas provide protection to materials and components for a variety of activities: component washing (glass, rubber, and other package components), cleaning of equipment and preassembly/wrapping.

30. The preparations area typically includes storage areas where clean and wrapped change parts, components, and vessels can be held until required for use in the fill or compounding areas. The preparations area is ordinarily located between the warehouse and the filling/compounding areas and connected to each of those by air locks.
Preparation areas are supplied with high - efficiency particulate air (HEPA) filters. The common design requirement is more than 20 air changes per hour, turbulent airflow and temperature and relative humidity controlled for personnel comfort. As in any clean room area designed for total particulate control, the air returns should be low mounted.
Wall and ceiling surfaces should be smooth, easily cleaned, and tolerant of localized high humidity. Floors should be typically monolithic with integral drains to prevent standing water. Common utilities are water for injection, deionized water, compressed air, and clean/plant steam.

31. Ordinarily, present within the preparation area are localized areas of ISO 5 unidirectional airflow (Class 100) utilized to protect washed components prior to sterilization and/or de-pyrogenation. They are designed to reduce/eliminate the potential for particle contamination of unwrapped washed materials.
Operators in the preparations area are typically garbed in low particle uniforms with shoe, hair, and beard covers. The use of latex or other gloves is required when contacting washed components. Equipment within the preparations area can include manual or ultrasonic wash/rinse sinks, single or double door automated parts washers, batch or continuous glass washers, stopper washers for closure components, equipment wrap areas and staging areas for incoming (pre-wash) components, dirty equipment, and cleaned components/equipment. The preparations area may include the loading areas for both sterilizers and ovens.

32. Compounding Area
The manufacture of parenteral solutions is ordinarily performed in ISO 7 (Class 10,000, EU Grade C) controlled environments in which localized ISO 5 unidirectional flow hoods are utilized to provide greater environmental control during material addition. These areas are designed to minimize the microbial, pyrogen, and particle contributions to the formulation prior to sterilization. Depending upon the scale of manufacture, the vessels can range from small containers (up to 50 L) to portable tanks (up to 600 L) to large fixed vessel (10,000 L or more have been used) in which the ingredients are formulated using mixing, heating, cooling, or other unit operations.
Compounding areas often include equipment for measuring mass and volume of liquid and solid materials including, for example, graduated cylinders, and scales of various ranges, transfer and metering pumps, homogenizers, pre-filters, and a variety of other liquid/powder handling equipment.

33. Because parenteral formulations can include aqueous and non-aqueous vehicles, suspensions, emulsions, and other liquids, the capabilities of the compounding area may vary. Agitators can be propeller, turbine, high shear. Walls and ceiling materials are selected to be impervious to liquids and chemical spills and are easy to clean. Floors in these areas are monolithic and should be sloped to drains with appropriate design elements and control procedures to eliminate backflow potential. Compounding areas are supplied with HEPA filters (ceiling - mounted terminal HEPAs are more common). The common design requirement is more than 50 – 60 air changes per hour, turbulent airflow, with temperature and relative humidity for personnel comfort. Air returns may be at or near floor level, with localized extraction provided as necessary to minimize dusting of powder materials.
Common utilities are water for injection, de-ionized water, nitrogen, compressed air, clean/plant steam, and heating and cooling media for the fixed and portable tanks. Cleaning of the fixed vessels and portable tanks is accomplished using either manual sequenced cleaning procedures or more commonly with a CIP system.

34. Personnel working in the compounding area typically wear a coverall (which may be sterilized for contamination control as required), with head/beard covers, as well as dust masks and sterile gloves. Additional personnel protective equipment may be necessary for some of the materials being processed. A fresh gown should be donned upon each entry into the compounding area. Separate gowning/de-gowning rooms should be provided to minimize cross - contamination potential for personnel working with different materials.
Aseptic Filling Rooms and Aseptic Processing Area
The filling of aseptic formulations (and many terminally sterilized products as well, by reason of their lesser number) is performed in an ISO 5 (Class 100) environment, which is accessed from an ISO 6/7 background environment in which personnel are present. Some measure of physical separation is provided between the ISO 5 and ISO 6/7 environments as a means of environmental protection as well as a reminder to personnel to restrict their exposure to ISO 5.

35. aseptic processing areas (APAs) are built to the same design standards: smooth, impervious ceilings, walls and floors, flush - mounted windows, clean room door designs, coved corners, finishes capable of withstanding the aggressive chemicals utilized for cleaning and sanitization. Air returns throughout the APA are located at or near floor level.
Unidirectional airflow is provided over all exposed sterile materials, that is, fill zone, sterilizer/oven/tunnel unload areas, and anywhere else sterile materials are exposed to the environment. Air changes in these ISO 5 environments can approach 600 per hour, though lesser values have proven successful. Air changes in the background
environment vary from 60 to 120 per hour.
Non-sterilized items should not be allowed to enter the ISO 5 portion of the fill zone, and sanitization is essential for all non-product surfaces in the fill zone, as well as the surrounding background environment.
Discharge of sealed containers can be accomplished via a exit port or “ mouse hole ” that allows for the passage of the containers from the APA to the surrounding environment. Proper design of the mouse hole system ensures protection of the

36. classified fill area from contamination fl owing against the flow of the containers. In many instances the discharge is into a non-classified inspection area that may lead directly to the secondary labeling/packaging area.Personnel working in aseptic compounding wear full aseptic garb i.e. sterile gown, hood, face mask, goggles, foot covers, and gloves.

37. Capping and Crimp Sealing Areas
The application of aluminum seals over rubber stoppers is essential to secure them properly. In many older facilities this was accomplished outside the aseptic processing area in an unclassified environment. Current practice requires that air supplied to this activity meet ISO 5 under static conditions. crimps should be applied in a separate crimping room accessible from the filling room maintained at a negative pressure differential relative to the filling environment.

38. Sterilizer Unload (Cool-down) Rooms
Sterilizers/ovens are unloaded and items staged prior to transfer to the individual fill rooms. ISO 5 air is provided over the discharge area of ovens (and autoclaves if items are sterilized unwrapped) to provide protection until the items are ready for transfer.
Air Locks and Pass - Throughs
Air locks serve as transition points between one environment and another. Ordinarily, they are designed to separate environments of different classification i.e. ISO 6 from ISO 7.

39. When this is the case, they are designed to achieve the higher of the two air quality levels in operation. If they are utilized for decontamination purposes for materials/equipment that cannot be sterilized, but must be introduced into the higher air quality environment, they may be fitted with ultraviolet (UV) lights, spray systems, vapor phase hydrogen peroxide generators, or other devices that may be effectively utilized for decontamination of materials. The doors at each end can be automatically interlocked or managed by standard operating procedure. In some instances a demarcation line is used to delineate the extent to which individuals from one side should access the air lock.

40. A smaller scale system with comparable capabilities is the pass - through. This differs from the air lock primarily in dimension, as items are typically placed into the pass - through by personnel, whereas the air lock is customary for pallet, portable tanks, and larger items In general pass - throughs should be supplied with HEPA filters and should be designed to meet the air quality level of the higher air quality classification room served.
Air locks and pass - throughs are bidirectional and can be used for movement in either direction.

43. Gowning Rooms
The gowning area used for personnel entry/exit presents some unique problems. Gowning facilities must be designed to the standards of the aseptic processing area, yet personnel upon entry are certainly not gowned. Because un-gowned staff will release higher concentrations of contaminants into the environment, gown rooms must be designed with sufficient air exchange so that this contamination is effectively and promptly removed.
In general, the contamination load within a gowning environment will require air exchange rates. Gowning areas are separated into well defined zones where personnel can progress through the various stages of the gowning process.

44. The most common approach in industry is a three - stage gowning area design in which three linked rooms with increasing air quality levels are utilized to efficiently and safely affect clothing change. Staff should enter the first state of the gowning room wearing plant uniforms. No articles of outerwear worn outside the facility should be worn to the gowning area. Therefore, a pre-gowning room equipped with lockers is required so that operators can change into dedicated plant clothing prior to moving to the gowning area. Generally, the pre-gowning locker area is not classified, although entry is controlled and temperature and humidity are maintained at 20 – 24 ° C and 50% + 10%.

45. The pre-gown area should have extensive hand washing facilities equipped with antibacterial soap, warm water, and brushes for cleaning finger nails. Soap and water dispensing should be automatic and hands should be air rather than towel dried.
Upon entry into the first stage gowning room, which is generally designed to an ISO 7 air quality level, the operators put off the plant uniform and shoes. Upon entry to the 2nd stage operator don a hair cover, body cover, surgical mask, sterilized shoes and shoe covers and then sterilized gloves.

46. In the second and third stages of the gowning area room classification is typically ISO 6 or ISO 6 followed by ISO 5 at the exit point. A dry glove decontamination point utilizing disinfectant foam is generally provided prior to exiting the gowning area. In some facilities air showers, which provide a high intensity blast of HEPA air for a predetermined length of time, are employed after gowning is completed. Side by side gowning of personnel should be avoided to preclude adventitious contamination. Similarly, personnel exiting the aseptic area should use a separate de-gowning area.

47. Inspection, Labeling, and Packaging
These activities are performed on finished product containers in unclassified environments. The primary design requirements are straightforward i.e. separation of products to prevent mix up, adequate lighting for the processes, and control over labeling materials.

48. UTILITY REQUIREMENTS
Water for injection (WFI)
The most important utility in sterile manufacturing is WFI. Not only is it a major component in many formulations, it is also utilized as a final rinse of process equipment, product contact parts, utensils, and components.
The WFI may be produced by either distillation (multiple effect or vapor compression) or reverse osmosis (generally in conjunction with deionization) and is ordinarily stored and recirculated at an elevated temperature greater than 70 ° C to prevent microbial growth.
Clean (Pure) Steam
Sterilizers and SIP systems in the facility are supplied with steam which upon condensation meets WFI quality requirements. It is generally produced by boilers or steam generators.

49. Process Gases
Air or nitrogen used in product contact is often supplied in stainless steel piping and ordinarily equipped with point of use filters.
Compressed air is typically provided by oil free compressors to minimize potential contaminants and is often treated with a drier to obviate the possibility of condensation within the lines which could be a source of contamination. Nitrogen is supplied as a bulk cryogenic liquid. Argon and carbon dioxide have also been utilized as inert gases, while propane or natural gas may be needed for sealing of ampoules.

50. Clean Room
(a) Federal Standard 209 Definition
"A Clean Room is an enclosed area employing control over the particulate matter in air with temperature, humidity and pressure control as required. To meet the requirements of a 'Clean Room' as defined by this standard, all Clean Rooms must not exceed a particulate count as specified in the air cleanliness class."
(b) BS 5295 Definition
"A Clean Room is a room with environmental control of particulate contamination, temperature and humidity, constructed and used in such a way as to minimize the introduction, generation and retention of particles inside the room."

51. Federal Standard 209D Class Limits

52. Federal Standard 209E Airborne Particulate Cleanliness Classes

53. BR 525  Environmental Cleanliness Classes

54. Selected ISO 209 airborne particulate cleanliness classes for clean rooms and clean zones.

55. EU

58. HEPA Filter Components

59. HEPA Filter Media - Typically a micro fine fiberglass media, synthetic fibers, expanded film such as Polytetrafluorethylene (PTFE) that can be pleated back and forth to form a compact element. Close pleating is necessary to fit all the required media into the desired space, because the paper has a high resistance to airflow and the media velocity is usually in the range of 6 feet per minute.
HEPA Filter Separators - These devices support the HEPA media pleats, and provide channels through which the air can flow to reach the media in a laminar flow pattern.
HEPA Filter Pack - This is the term used to describe the combined HEPA media and separator unit.
HEPA Filter Sealant - This is an adhesive, commonly urethane or silicone, used to create a leak-proof seal between the HEPA filter pack and its supporting frame. Sealant may also be used to patch any small leaks that are found in the HEPA filter during in-situ leak testing.
HEPA Filter Seal - This is the seal on a HEPA filter frame that prevents air bypass around the filter. In most instances it is either a closed cell neoprene gasket attached to the face of the filter frame, or a groove in the frame to allow a knife-edge to penetrate a non-Newtonian gel (a gel that will not be influenced to fall out due to the forces of gravity)

60. Dry Injection Lay Out

61. Wet Injection Lay Out