Sterile Dosage Forms PDF

STERILE DOSAGE FORMS  OUTLINE i. Sterile Products: Overview ii. Parenterals (Injections, ROA, Official types of Injections) iii. Solvents and Vehicles for Injections iv. Methods of Sterilization v. General Guidance for Developing Formulations of Parenteral Drugs v. Parenteral Combinations vi. Gener...

STERILE DOSAGE FORMS  OUTLINE i. Sterile Products: Overview ii. Parenterals (Injections, ROA, Official types of Injections) iii. Solvents and Vehicles for Injections iv. Methods of Sterilization v. General Guidance for Developing Formulations of Parenteral Drugs v. Parenteral Combinations vi. General Considerations  OUTLINE vii. General Manufacturing Process viii. Components ix. Water for Injection x. Containers and Closures xi. Needles xii. Small and Large volume Parenterals xiii. Environmental issues xiv. Production Facilities  OUTLINE xv. Quality Control xvi. Packaging and Labeling xvii. Biologics xviii. Types of Immunity xix. Production of Biologics xx. Storage, Handling, and Shipping of Biologics xxi. Special Solutions and Suspensions xxii. Ophthalmic Drug Delivery and Pharmacologic Categories  OUTLINE xxiii. Pharmaceutical Requirements xxiv. Packaging and Administration of Ophthalmic Solutions and Suspensions xxv. Nasal Preparations xxvi. Otic Preparations  STERILE PRODUCTS these are dosage forms of therapeutic agents that are free of viable microorganisms include parenteral, ophthalmic, and irrigating solutions. Sterile products are most frequently solutions or suspensions, but may even be solid pellets for tissue implantation PARENTERAL DOSAGE FORMS Characteristics: must be sterile. must be free from pyrogenic (endotoxin) contamination. must be free from visible particulate matter. should be isotonic all products must be stable must be compatible  Injections Injections are sterile, pyrogen-free (endotoxin units [EU] limited) preparations intended to be administered parenterally Parenteral - injectable routes of administration Parenteral routes are used when rapid drug action is desired, as in emergencies Administered by physicians, and nurses Employed mostly in the hospital and at home less frequently Parenteral Routes of Administration Intravenous route Intraspinal Intramuscular route intrathecal Subcutaneous route Specialized access Intradermal route Intra-articular Intrasynovial Parenteral Routes of Administration  Official Types of Injection Injection - drug substances or solutions (e.g., Insulin Injection, USP) For Injection - Dry solids + suitable vehicles, (e.g., Cefuroxime for Injection, USP) Injectable emulsion - drug substance + suitable emulsion medium (e.g., Propofol, USP) Injectable suspension - solid suspended in a suitable liquid medium (e.g., Methylprednisolone Acetate Suspension, USP) For injectable suspension - Dry solid + suitable vehicle. (e.g., Imipenem and Cilastatin for Injectable Suspension, USP) Preparation of Solutions & Suspensions intended for injections Coloring agents is strictly prohibited Prepared in environmentally controlled areas Filled to a volume in slight excess of the labeled volume For solution or suspension immediately prior to injection are frequently packaged as lyophilized or freeze-dried powders Extemporaneously prepared parenteral preparations must be compounded in a USP compliant Solvents and Vehicles for Injections Water for Injection - most frequently used solvent in the large-scale manufacturer of injections. Purified by distillation or reverse osmosis. Sterile Water for Injection, USP - packaged in single dose containers not larger than 1 L. Solvents and Vehicles for Injections Bacteriostatic Water for Injection, USP - a sterile water for injection containing 1/ more suitable antimicrobial agents. Sodium Chloride Injection, USP - is a sterile isotonic solution of sodium chloride in water for injection. Bacteriostatic Sodium Chloride Injection, USP - is a sterile isotonic solution of sodium chloride in water for injection. It contains one or more suitable antimicrobial agents, which must be specified on the labeling.  Non-aqueous vehicles A nonaqueous solvent must be selected with great care for it must not be irritating, toxic, or sensitizing, and it must not exert an adverse effect on the ingreaients of the formulation. The screening of such a solvent must therefore include an evaluation of its physical properties, such as density, viscosity, miscibility and polarity, as well as its stability, solvent activity, and toxicity  Non-aqueous vehicles Solvents that are miscible with water, and that are usually used in combination with water as the vehicle, include dioxolanes, dimethylacetamide, N-(B-hydroxyethyl)- lactamide, butylene glycol, polyethylene glycol 400 and 600, propylene glycol, glycerin, and ethyl alcohol Water-immiscible solvents include fixed oils, ethyl oleate, isopropyl myristate, and benzyl benzoate. Most frequently used: PEG, propylene glycol, and fixed oils Solutes: Added Substances Enhance its stability are essential for almost every product Examples: solubilizers, antioxidants, chelating agents, buffers, tonicity contributors, antibacterial agents, antifungal agents, antifoaming agents Antibacterial agents in bacteriostatic concentration must be included in the formulation of products Benzyl alcohol, Butylparaben, Chlorobutanol Antioxidants to protect a therapeutic agent susceptible to oxidation, particularly under the accelerated conditions of thermal sterilization Ascorbic acid, Na bisulfite, Thiourea Buffers added to maintain the required pH for many products Acetates, citrates, and phosphates = principal buffer systems used Tonicity contributors Compounds contributing to the isotonicity of a product reduce the pain of injection in areas with nerve endings Glycerin, Lactose, Mannitol, Dextrose Chelating agents added to bind, in non-ionizable form, trace amounts of heavy metals, which if free , would catalyze degradative changes. Trisodium/ Calcium disodium salt of EDTA (0.05% w/v) Inert Gases used to displace oxygen from a solution and reduce possibility of oxidative changes Carbon dioxide  Methods of Sterilization Sterilization destruction of all living organisms and their spores or their complete removal from the preparation 5 General Methods to sterilize pharmaceutical products: 1. Steam 2. Dry heat 3. Filtration 4. Gas 5. Ionizing radiation  Methods of Sterilization Steam Sterilization conducted in an autoclave employs steam under pressure method of choice if the product can withstand it applicable to pharmaceutical preparations and materials that can withstand the required temperature and are penetrated but not adversely affected by moisture applicable to bulk solutions, glassware, surgical dressings, and instruments  Methods of Sterilization Steam Sterilization The usual steam pressures, the temperature obtainable under these pressures, and approximate length of time required for sterilization after the system reaches the indicated temp. are as follows: 10 lb pressure (115.5 C or 240 F) for 30 minutes 15 lb pressure (121.5 C or 250F) for 20 minutes 20 lb pressure (126.5 C or 260 F) for 15 minutes Most autoclaves routinely operate at 121 C (250 F) Methods of Sterilization Autoclaving of IV electrolyte solutions  Methods of Sterilization Dry Heat Sterilization usually carried out in ovens designed for this purpose ovens may be heated either by gas or electricity and generally thermostatically controlled higher temperatures and longer periods of exposure are required conducted at 150 C to 170 C for NLT 2 hours generally employed for substances that are not effectively sterilized by moist heat method of choice when dry apparatus or dry containers are required  Methods of Sterilization Sterilization by Filtration depends on the physical removal of microorganisms by adsorption on the filter medium or by sieving mechanism used for heat sensitive solutions medicinal preparations sterilized by this method must undergo extensive validation and monitoring higher temperatures and longer periods of exposure are required conducted at 150 C to 170 C for NLT 2 hours generally employed for substances that are not effectively sterilized by moist heat method of choice when dry apparatus or dry containers are required  Methods of Sterilization Sterilization by Filtration Millipore Filter thin plastic membrane of cellulosic esters with millions of pores per square inch. The pores are made to be extremely uniform in size and occupy approximately 80% of the membrane’s volume, the remaining 20% being the filter material.  Methods of Sterilization Gas Sterilization Ethylene oxide or propylene oxide exposure sterilized some heat- sensitive and moisture sensitive materials Ethylene oxide widely used gaseous sterilization agent, which kills by alkylation of the nucleic acid within the microorganism. The range of lethal concentration begins near 300 mg/L and extends to approximately 1200 mg/L as higher levels have not been shown to result in substantially shorter process times.  Methods of Sterilization Gas Sterilization requires specialized equipment resembling an autoclave, and many combination steam autoclaves and ethylene oxide sterilizers are commercially available. sterilization with gas is enhanced, exposure time required is reduced, by increasing the relative humidity of the system (about 60%) and by increasing the exposure temperature to 50-60C  Methods of Sterilization Sterilization by ionizing radiation sterilization of some types of pharmaceuticals by gamma rays and by cathode rays, but application of such techniques is limited because of the highly specialized equipment required and the effects of irradiation on the products and their containers. alteration of the chemicals within or supporting the microorganism to form deleterious new chemicals capable of destroying the cell. vital structures of the cell, such as the chromosomal nucleoprotein, are disoriented or destroyed.  General Guidance for developing formulations of parenteral drugs 1. Route of administration 2. Pharmacokinetics of the drug 3. Drug solubility 4. Drug stability 5. Compatibility of drug with potential formulation additives and packaging systems 6. The use of silicone to lubricate vial rubber closures, syringe rubber plungers, and cartridges 7. Desired type of packaging  Parenteral Combinations 1. Products in vials must be withdrawn into a syringe prior to injection and often combined with other products in infusion solutions prior to administration. Freeze-dried products, first, have to be reconstituted with a specific or non- specific diluent prior to being withdrawn from the vial. 2. Valid use in parenterals. Often, they are used as isotonic vehicles to which a drug may be added at the time of administration. 3. The additional osmotic effect of the drug may not be enough to produce any discomfort when administered. These vehicles include Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection.  Parenteral Combinations 4. Ideally, no parenteral combination should be administered, unless it has been studied thoroughly to determine its effect on the therapeutic value and safety of the combination. However, such an ideal situation may not exist. Nevertheless, it is the responsibility of the pharmacist to be as familiar as possible with the physical, chemical, and therapeutic aspects of parenteral combinations and to exercise the best possible judgment as to whether or not the specific combination extemporaneously prescribed is suitable for use in a patient General Considerations Types of Processes The preparation of parenteral products may be categorized as small- scale dispensing, usually one unit at a time, or large-scale manufacturing in which hundreds of thousands of units may constitute one lot of product. The former category illustrates the type of processing done in early clinical phase manufacturing or in institutions, such as hospital pharmacies. The latter category is typical of the processing done in the later clinical phase and commercial manufacturing in the pharmaceutical industry. General Considerations Types of Processes Parenteral products must be subjected to the same basic practices of GMPs and good aseptic processing essential for the preparation of a safe and effective sterile product of highest quality, however, the methods used must be modified appropriately for the scale of operation. The small-scale preparation and dispensing of parenteral products might use sterile components in their preparation. Therefore, the overall process focuses on maintaining, rather than achieving, sterility in the process steps.  General Manufacturing Process The preparation of a parenteral product may encompass four general areas: 1. Procurement and accumulation of all components in a warehouse area, until released to manufacturing; 2. Processing the dosage form in appropriately designed and operated facilities; 3. Packaging and labeling in a quarantine area, to ensure integrity and completion of the product; and 4. Controlling the quality of the product throughout the process.  Components Components of parenteral products include the: 1. active ingredient 2. formulation additives 3. vehicle(s) 4. primary container 5. closure Establishing specifications to ensure the quality of each of these components of an injection is essential.  Components Establishing specifications to ensure the quality of each of these components of an injection is essential. Secondary packaging is relevant more to marketing considerations, although some drug products might rely on secondary packaging for stability considerations, such as added protection from light exposure for light-sensitive drugs and antimicrobial preservatives. Containers and closures are in prolonged, intimate contact with the product and may release substances into, or remove ingredients from, the product.  Water for Injection (WFI) PREPARATION The source water can be expected to be contaminated with natural suspended mineral and organic substances, dissolved mineral salts, colloidal material, viable bacteria, bacterial endotoxins, industrial or agricultural chemicals, and other particulate matter. The degree of contamination varies with the source and will be markedly different, whether obtained from a well or from surface sources, such as a stream or lake.  Water for Injection (WFI) PREPARATION The source water must be pretreated by one or a combination of the following treatments: chemical softening, filtration, deionization, carbon adsorption, or reverse osmosis purification. Water for Injection can be prepared by distillation or by membrane technologies (i.e., reverse osmosis or ultrafiltration). The EP (European Pharmacopeia) only permits distillation as the process for producing WFI. The USP and JP (Japanese Pharmacopeia) allow all these technologies to be applied. Water for Injection (WFI)  Water for Injection (WFI) Distillation is a process of converting water from a liquid to its gaseous form (steam). There are two basic types of WFI distillation units—the vapor, compression still and the multiple effect still. Compression Distillation The vapor-compression still, primarily designed for the production of large volumes of high-purity distillate with low consumption of energy and water Water for Injection (WFI)  Water for Injection (WFI) Multiple Effect Still also designed to conserve energy and water usage. In principle, it is simply a series of single-effect stills or columns running at differing pressures where phase changes of water take place. Water for Injection (WFI) Water for Injection (WFI)  Water for Injection (WFI) Reverse osmosis the natural process of selective permeation of molecules through a semipermeable membrane separating two aqueous solutions of different concentrations is reversed. Pressure, usually between 200 and 400 psig, is applied to overcome osmotic pressure and force pure water to permeate through the membrane  Containers and Closures Injectable formulations are packaged into containers made of glass or plastic. Container systems include ampoules, vials, syringes, cartridges, bottles, and bags.  Containers and Closures Ampoules are all glass, whereas bags are all plastic. The other containers can be composed of glass or plastic and must include rubber materials, such as rubber stoppers for vials and bottles and rubber plungers and rubber seals for syringes and cartridges. Irrigation solutions are packaged in glass bottles with aluminum screw caps. Further, the integrity of the container/closure system depends on several characteristics, including container opening finish, closure modulus, durometer and compression set, and aluminum seal application force.  Containers and Closures Container Types GLASS Glass is employed as the container material of choice for most SVIs. It is composed, principally, of silicon dioxide, with varying amounts of other oxides, such as sodium, potassium, calcium, magnesium, aluminum, boron, and iron. Types: USP provides a classification of glass: Type I - Borosilicate glass Type II - soda-lime treated glass Type III - soda lime glass NP - a soda lime glass not suitable for containers for parenterals Containers and Closures  Containers and Closures The glass types are determined from the results of two USP tests: the Powdered Glass Test and the Water Attack Test. Leachable/Extractable - If the product is sensitive to the presence of ions, such as boron, sodium, potassium, calcium, iron, and magnesium, great care must be taken in selecting the appropriate glass container, as these ions may leach from the glass container and interact with the product, reducing chemical stability, inducing formation of particulate, or altering pH of solution. Delamination - or glass particulate formation, is caused by chemical attack on the glass matrix by the formulation solution, resulting in weakening of the glass and eventual dislodgement of flakes from the glass surface  Powdered Glass Test performed on powdered glass which exposes internal surfaces of the glass compound challenges the leaching potential of the interior structure of the glass Water Attack Test only for Type II glass performed on the whole container challenges only the intact surface of the container Powdered Glass Test Water Attack Test Standard Limits given in USP  Containers and Closures Adsorption - Adsorption of drug to solution contact surfaces and consequent loss of potency of delivered solution is a primary concern of container/solution compatibility and must be rigorously and formally evaluated during solution/container evaluation and stability studies. Cracks and Scratches - Small cracks and scratches on glass containers can best be minimized by implementation of quality agreements between parenteral product manufacturers and glass container manufacturers.  Containers and Closures RUBBER CLOSURES To permit introduction of a needle from a hypodermic syringe into a multiple-dose vial and provide for resealing as soon as the needle is withdrawn, each vial is sealed with a rubber closure held in place by an aluminum cap Rubber closures are composed of multiple ingredients plasticized and mixed together at an elevated temperature on milling machines. The elastomer primarily used in rubber closures, plungers, and other rubber items used in parenteral packaging and delivery systems is synthetic butyl or halobutyl rubber. Natural rubber is also used, but, if it is natural rubber latex, then the product label must include a warning statement, due to the potential for allergic reactions from latex exposure. Containers and Closures  Containers and Closures PLASTIC Thermoplastic polymers have been established as packaging materials for sterile preparations, such as large-volume parenterals, ophthalmic solutions, and, increasingly, small- volume parenterals. Three principal problem areas exist in using these materials: 1. Permeation of vapors and other molecules in either direction through the wall of the plastic container; 2. Leaching of constituents from the plastic into the product; and 3. Sorption (absorption and/or adsorption) of drug molecules or ions on the plastic material.  Containers and Closures NEEDLES Stainless steel needles have been used to penetrate the skin and introduce a parenteral product inside the body. The advent of needleless injection systems has obviated the need for needles for some injections (e.g., vaccines) and is gaining in popularity over the conventional syringe and needle system. Needles are hollow devices composed of stainless steel or plastic. Needles are available in a wide variety of lengths, sizes, and shapes. Needle lengths range from ¼ inch to 6 inches  Containers and Closures NEEDLES Stainless steel needles have been used to penetrate the skin and introduce a parenteral product inside the body. The advent of needleless injection systems has obviated the need for needles for some injections (e.g., vaccines) and is gaining in popularity over the conventional syringe and needle system. Needles are hollow devices composed of stainless steel or plastic. Needles are available in a wide variety of lengths, sizes, and shapes. Needle lengths range from ¼ inch to 6 inches  Containers and Closures NEEDLES Needle size is referred to as its gauge (G), or the outside diameter (OD) of the needle shaft. Gauge ranges are 11 to 32 G, with the largest gauge for injection usually being no greater than 16 G. 16 G needles have an OD of 0.065 inches (1.65 mm), whereas 32 G have an OD of 0.009 inches (0.20 mm). Intravenous injections use 1–2 inch 15–25 G needles. Intramuscular injections use 1–2 inch 19–22 G needles. Subcutaneous injections use ¼– 5/8 inch 24–25 G needles. Needle gauge for children rarely is larger than 22 G, usually 25–27G. Winged needles are used for intermittent heparin therapy.  Small Volume parenterals The USP designation small-volume injection applies to an injection packaged in containers labeled as containing 100 mL or less. Some of these injections are solutions, and others are suspensions. Commonly used in Antidiabetic drug such as Insulin, Human Insulin, Insulin Lispro, Insulin Aspart, Insulin Detemir, Insulin Pens, Insulin Gargline etc.  Small Volume parenterals Advantages: 1. Require little or no manipulation to make them patient specific 2. Extended stability dating & reduced wastage Disadvantage: 1. Do not offer flexibility in changing the volume or concentration 2. Some manufacturers premixed products require thawing poses stability problems. (E.g. Cefazolin)  Small Volume parenterals 3. The traditional method for preparing small-volume parenteral therapy from a partial-fill drug vial into a minibag can be labor intensive and costly in materials  Large Volume parenterals The USP designation large-volume IV solution applies to a single- dose injection intended for IV use and is packaged in containers labeled as containing more than 100 mL. Characteristics: — They should not contain bacteriostatic agents or other pharmaceutical additives. — They are packaged in large single dose containers.  Large Volume parenterals They are employed for the following purposes: 1. Maintenance therapy – for patient who are unconscious , for patients entering or recovering from surgery; or for patients who cannot take oral nutrition 2. Replacement therapy – for patients who have suffered heavy loss of water and electrolytes like they experience vomiting or diarrhea. Others: 3. Water requirements 4. Electrolyte requirements 5. Parenteral Nutrition Environmental Issues Some health care facilities are planning to phase out the use of PVC/DEHP products in future years. A concern, especially for male neonate patients, is that PVC bags can leach DEHP into the fluid of the container. Another concern is the amount of plastic waste generated by PVC/DEHP containers. In the past, the problems associated with PVC/DEHP resulted in IV admixtures still needing preparation in glass containers. While glass containers are more expensive to prepare than PVC/DEHP containers, PVC/DEHP containers are more costly to manufacture than the non- PVC/DEHP plastic bags. Production Facilities The production facility and its associated equipment must be designed, constructed, and operated properly for the manufacture of a sterile product to be achieved at the quality level required for safety and effectiveness Materials of construction for sterile product production facilities must be ‘smooth, cleanable, and impervious to moisture and other damage’. the processes used must meet cGMP standards. Since the majority of SVIs are aseptically processed (finished product not terminally sterilized), strict adherence to cGMP standards with respect to sterility assurance Production Facilities To achieve the goal of a manufactured sterile product of exceptionally high quality, many functional production areas are involved: warehousing or procurement; compounding (formulation); materials (containers, closures, equipment) preparation; filtration and sterile receiving; aseptic filling; stoppering; lyophilization (if warranted); and packaging, labeling, and quarantine. FLOW PLAN - In general, the components for a parenteral product flow from the warehouse, after release, to either the compounding area, as for ingredients of the formula, or the materials support area, as for containers and equipment. Production Facilities Clean Room Classified Areas - Due to the extremely high standards of cleanliness and purity that must be met by parenteral products, it has become standard practice to prescribe specifications for the environments (clean rooms) in which these products are manufactured. For the sake of convenience, the remainder of this chapter uses Class X (e.g., 100, 1,000, 10,000, 100,000) designations, although it is recognized that the use of Grades or ISO numbers are more contemporary:  Production Facilities 1. Air cleaning 2. Laminar-flow enclosures 3. Materials support area 4. Compounding area 5. Aseptic area 6. Isolation (Barrier) Technology MAINTENANCE OF CLEAN ROOMS Maintaining the clean and sanitized conditions of clean rooms, particularly the aseptic areas, requires diligence and dedication of expertly trained custodians.  Production Facilities Maintaining the clean and sanitized conditions of clean rooms, particularly the aseptic areas, requires diligence and dedication of expertly trained custodians. Liquid disinfectants (sanitizing agents) should be selected carefully, due to data showing their reliable activity against inherent environmental micro-organisms. PERSONNEL Personnel selected to work on the preparation of a parenteral product must be neat, orderly, and reliable. They should be in good health and free from dermatological conditions that might increase the microbial load.  Production Facilities CLEANING CONTAINERS AND EQUIPMENT Containers and equipment coming in contact with parenteral preparations must be cleaned meticulously. It should be obvious that even new, unused containers and equipment are contaminated with such debris as dust, fibers, chemical films, and other materials arising from such sources as the atmosphere, cartons, the manufacturing process, and human hands. All equipment should be disassembled as much as possible to provide access to internal structures.  Production Facilities EQUIPMENT: Filtration - After a product has been compounded, it must be filtered, if it is a solution. The primary objective of filtration is to clarify a solution. Membrane Filter  Production Facilities EQUIPMENT: Filling - During the filling of containers with a product, the most stringent requirements must be exercised to prevent contamination, particularly if the product has been sterilized by filtration and will not be sterilized in the final container. Syringe filling machine Vial Filling Machine  Production Facilities Perry Accofil Sterile Powder Filling Machine  Production Facilities EQUIPMENT: Sealing - Filled containers should be sealed as soon as possible, to prevent the contents from being contaminated by the environment. Ampoules are sealed by melting a portion of the glass neck. Two types of seals are employed normally: tip-seals (bead-seals) or pull-seals. Automatic monoblock closed ampule filling and sealing machine  Production Facilities EQUIPMENT: Sterilization - the parenteral product should be sterilized, after being sealed in its final container (terminal sterilization) and within as short a time as possible after filling and sealing are completed. Modern autoclave for sterilization  Production Facilities EQUIPMENT: Freeze-Drying - Many parenteral drugs, particularly biopharmaceuticals, are too unstable in solution to be available as ready-to-use liquid dosage forms. Professional Freeze Dryer Machine  Quality Control USP Chapter Pharmaceutical Compounding-Sterile Preparations, became official Three risk levels of CSPs are described: low-risk level, medium-risk level, and high-risk level. Risk levels are based on the potential of contaminating a low- risk-level or medium-risk-level CSP or failure to sterilize a high-risk-level CSP, which can cause harm to the patient, including death  Quality Control USP also includes sections on establishing beyond-use dates, compounding radiopharmaceuticals and allergen extracts, characteristics of a quality assurance program, verification of compounding accuracy and sterility, finished preparation release checks and test, and elements of quality control.  Quality Control QC embodies the carrying out of these plans during production and includes all of the tests and evaluations performed to ensure quality exists in a specific lot of product. Sterility test: All lots of injectables in their final containers must be tested for sterility, except products that are allowed to apply parametric release (i.e., terminally sterilized by a well-defined, fully validated sterilization process, has a sterility assurance level sufficient to omit the sterility test for release).  Quality Control Pyrogen test: The USP evaluates the presence of pyrogens in parenteral preparations by a qualitative fever response test in rabbits, the Pyrogen Test (Section ), and by the Bacterial Endotoxins Test (Section ). These two USP tests are described in Chapter 25 (Sterilization Processes and Sterility Assurance).  Quality Control Pyrogen test: The Bacterial Endotoxins Test (BET) is an in vitro test based on the formation of a gel or the development of color in the presence of bacterial endotoxins and the lysate of the amebocytes of the horseshoe crab (Limulus polyphemus). The Limulus Amebocyte Lysate (LAL) test, as it also is called, is a biochemical test performed in a test tube and is simpler, more rapid, and of greater sensitivity than the rabbit test.  Quality Control Particulate matter evaluation: The USP has identified two test methods in , Particulate Matter in Injections. All LVIs for single-dose infusion and those SVIs for which the monograph specifies a limit (primarily those commonly added to infusion solutions) are subject to the specified limits given. Container/Closure Integrity Test: This test is usually performed by producing a negative pressure within an incompletely sealed ampoule, while the ampoule is submerged entirely in a deeply colored dye solution. Most often, approximately 1% methylene blue solution is employed  Packaging and Labeling Packaging The USP includes certain requirements for the packaging and storage of injections: 1. The volume of injection in single-dose containers is defined as that which is specified for parenteral administration at one time and is limited to a volume of 1 L. 2. Parenterals intended for intraspinal, intracisternal, or peridural administration are packaged only in single-dose containers. 3. Unless an individual monograph specifies otherwise, no multiple-dose container shall contain a volume of injection more than sufficient to permit the withdrawal and administration of 30 mL.  Packaging and Labeling Packaging 4. Injections packaged for use as irrigation solutions or for hemofiltration or dialysis or for parenteral nutrition are exempt from the foregoing requirements relating to packaging. Containers for injections packaged for use as hemofiltration or irrigation solutions may be designed to empty rapidly and may contain a volume in excess of 1 L. 5. Injections intended for veterinary use are exempt from the packaging and storage requirements concerning the limitation to single-dose containers and to volume of multiple-dose containers.  Packaging and Labeling Labeling The label states the name of the preparation, the percentage content of drug of a liquid preparation, the amount of active ingredient of a dry preparation, the volume of liquid to be added to prepare an injection or suspension from a dry preparation, the route of administration, a statement of storage conditions, and an expiration date. The label must state the name of the vehicle and the proportions of each constituent, if it is a mixture, and the names and proportions of all substances added to increase stability or usefulness. Also, the label must indicate the name of the manufacturer or distributor and carry an identifying lot number. The lot number is capable of providing access to the complete manufacturing history of the specific package including each single manufacturing step. The container label is so arranged that a sufficient area of the container remains uncovered for its full length or circumference to permit inspection of the contents.  Biologics Definition : Therapeutic products derived from living organisms or their components. Example: 1. Vaccines 2. Blood Products 3. Proteins & Peptides 4. Cell & Gene Therapies 5. Recombinant DNA Product  Biologics Biologics for Active Immunity Bacterial Vaccines Another way to create a vaccine is to employ purified antigen subunits produced with use of recombinant DNA. With subunit vaccines, the genes that code for the desired antigen are introduced into the nonpathogenic organisms.  Biologics Biologics for Active Immunity Bacterial Vaccines A vaccine is a suspension of attenuated (live) or inactivated (killed) microorganisms or fractions thereof that are administered to induce immunity and prevent disease. A live attenuated vaccine can also be produced by genetic alteration of the pathogenic organisms. This allows the organism to survive and multiply but not produce the disease.  Types of Immunity There are two main categories of immunity: natural and acquired. Natural Immunity: natural, innate, or native immunity depends on factors that are inborn and can be classified as species immunity, racial immunity, and individual immunity. Acquired Immunity Acquired immunity is a specific immunity that may be active or passive.  Types of Immunity Species Immunity In general, cold-blooded animals are not susceptible to diseases common to warmblooded animals. Humans are not all susceptible to certain diseases of lower animals, such as chicken cholera. However, a number of infections that occur primarily in animals can be transmitted to humans  Types of Immunity Racial Immunity Human races differ in susceptibility to common infections. Factors that determine racial immunity are elusive and not well known. Racial immunity should not be used synonymously or confused with environmental immunity. Environmental immunity may be the result of resistance to infection among individuals in a community resulting from the degree of acquired immunity and other factors  Types of Immunity Individual Immunity Apart from any specific immunity to a particular infectious agent, individuals vary in the ability to resist common microbiologic diseases. Some individuals have little capacity to resist skin disorders, the common cold, and other familiar diseases.  Types of Immunity Active Immunity Develops in response to antigenic substances in the body. This may occur by natural means, as by infection, in which case it is termed naturally acquired active immunity, or it may develop in response to administration of a specific vaccine or toxoid, in which case it is artificially acquired active immunity. In either case, the body builds up its own defense in response to the antigen.  Types of Immunity Passive Immunity Occurs by introduction of the immunoglobulins produced in another individual (human or animal) into the host, who is not involved in their production. In similar fashion to active acquired immunity, passive acquired immunity can be classified as natural or artificial  Production of Biologics Biologics are produced by manufacturers licensed to do so in accordance with the terms of the federal Public Health Service Act (58 Stat. 682) approved on July 1, 1944, and each product must meet specified standards as administered by the Center for Biologics Evaluation and Research of the FDA  Production of Biologics Each lot of a licensed biologic is approved for distribution when it has been determined that the lot meets the specific control requirements for that product. Generally, each lot of a biologic product must pass rigid control requirements before it may be distributed for general use. Provisions generally applicable to biologic products include tests for potency, general safety, sterility, purity, water (residual moisture), pyrogens, identity, and constituent materials.  Production of Biologics Additional safety tests on live vaccines and certain other items are also required. Biologics to be administered by injection are packaged and labeled in the same manner as other injections. In addition, the label of a biologic product must include the title or proper name (the name under which the product is licensed under the Public Health Service Act); the name, address, and license number of the manufacturer; the lot number; the expiration date; and the recommended individual dose for multiple-dose containers.  Production of Biologics With few exceptions, most biologics are stored in a refrigerator (2°C to 8°C, or 35°F to 46°F), and freezing is avoided. The expiration date for biologic products varies with the product and the storage temperatures. Most biologic products have an expiration date of a year or longer after the date of manufacture or issue. Storage, Handling, and Shipping of Biologics CONTAINERS: Containers are in intimate contact with the product. No container presently available is totally non-reactive, particularly with aqueous solutions. Both the chemical and physical characteristics affect the stability of the product, but the physical characteristics are given primary consideration in the selection of a protective container. Storage, Handling, and Shipping of Biologics Glass is still the preferred material for containers for injectable products. Glass is composed principally of the silicon dioxide tetrahedron, modified physicochemically by such oxides as those of sodium, potassium, calcium, magnesium, aluminum, boron, and iron. Storage, Handling, and Shipping of Biologics Glass containers traditionally have been used for sterile products, many of which Glass amplues Glass vials are closed with rubber stoppers. Interest in plastic containers for parentherals is increasing, and such containers are being used for commercial ophthalmic preparations and IV solutions Glass bottles Storage, Handling, and Shipping of Biologics Container use Considerations The size of single-dose containers is limited to 1000 ml by the USP and multiple-dose containers to 30 ml, unless permitted otherwise. Storage, Handling, and Shipping of Biologics Container use Considerations Single-dose containers are intended to provide sufficient drug for just one dose, the integrity of the container being destroyed when opened so that it cannot be reclosed and used again. Storage, Handling, and Shipping of Biologics Container use Considerations The size limitation for multiple-dose vials is intended to limit the number of entries for withdrawing a portion of the contents of the vial with the accompanying risk of microbial contamination of the remaining contents. The particular advantage of these containers is flexibility of dosage offered to the physician Storage, Handling, and Shipping of Biologics Rubber Closures are used to seal the openings of cartridges, vials, and bottles, providing a material soft and elastic enough to permit entry and withdrawal of a hypodermic needle without loss of the integrity of the sealed container. Storage, Handling, and Shipping of Biologics Further packaging requirements for injections are given by the USP essentially as follows: The volume of an injection in single-dose containers should provide the amount specified for administration at one time and in no case is more than one liter. This requirement is intended to minimize the likelihood of someone attempting to use at a later time, a residue in a container after exposure to contamination from the environment. Preparations intended for intraspinal, intracisternal, or peridural administration should be packaged only in single- dose containers because of the sensitivity of nerve tissue to irritation from added substances such as antibacterial agents. Storage, Handling, and Shipping of Biologics Further packaging requirements for injections are given by the USP essentially as follows: The volume of an injection in single-dose containers should provide the amount specified for administration at one time and in no case is more than one liter. This requirement is intended to minimize the likelihood of someone attempting to use at a later time, a residue in a container after exposure to contamination from the environment. Storage, Handling, and Shipping of Biologics Further packaging requirements for injections are given by the USP essentially as follows: Preparations intended for intraspinal, intracisternal, or peridural administration should be packaged only in single- dose containers because of the sensitivity of nerve tissue to irritation from added substances such as antibacterial agents. Storage, Handling, and Shipping of Biologics Further packaging requirements for injections are given by the USP essentially as follows: Normally, no multiple-dose container shall contain a volume of injection more than is sufficient to permit the withdrawal of 30 ml, because larger volumes would provide for the withdrawal of more doses, thereby increasing the potential for contamination. Storage, Handling, and Shipping of Biologics Sterilization of Product A product must be sterilized by the most reliable method possible. The methods of sterilization, their application, and the bases for their selection have been discussed in Storage, Handling, and Shipping of Biologics Sterilization of Product: Freeze drying (lyophilization) is a drying process applicable to the manufacture of certain pharmaceuticals and biologicals that are thermolabile or otherwise unstable in aqueous solution for prolonged storage periods, but are stable in the dry state. Storage, Handling, and Shipping of Biologics Freeze drying A product to be freeze-dried is prepared and handled as an aqueous solution or suspension in the same manner as for an aseptic fill. The aqueous preparation is frozen rapidly and cooled to an experimentally determined temperature below its eutectic point. Most commonly, it would be frozen by a mechanical refrigeration device, often the refrigerated shelves in the freeze-drying chamber, at a temperature of −50°C or lower. Storage, Handling, and Shipping of Biologics Freeze drying When the product is completely frozen and properly cooled, the chamber is sealed and evacuated. The ice in the frozen product gradually sublimes from the frozen surface and is collected in a refrigerated condenser chamber or on plates within the chamber containing the product. Storage, Handling, and Shipping of Biologics Freeze drying As the ice leaves the product, the drying residue maintains essentially its original volume and becomes porous, owing to the loss of ice molecules. This porous structure usually increases the subsequent rate of solution of the product as compared to the original material Storage, Handling, and Shipping of Biologics Freeze drying The rate of drying depends largely on the thermal conductance of the frozen product, rate at which the vapour can diffuse through the progressively thicker layer of dried porous material, and the rate of transfer of the vapour through the system to the condenser surface. It has been said that the drying rate can be estimated as approximately one hour for each millimeter of depth of the product. Storage, Handling, and Shipping of Biologics Freeze drying In production, large freeze-driers are usually operated by an automatic control system. Professional Freeze Dryer Machine Storage, Handling, and Shipping of Biologics Freeze drying In production, large freeze-driers are usually operated by an automatic control system. Professional Freeze Dryer Machine Storage, Handling, and Shipping of Biologics Leak Test Ampoules are intended to provide a hermetically sealed container for a single dose of a product, thereby completely barring any interchange between the contents of the sealed ampoule and its environment. Should capillary pores or tiny cracks be present, microorganisms or other dangerous contaminants may enter the ampoule, or the contents may leak to the outside and spoil the appearance of the package. Storage, Handling, and Shipping of Biologics Leak Test Changes in temperature during storage cause expansion and contraction of the ampoule and contents, thereby accentuating interchange if an opening exists. Storage, Handling, and Shipping of Biologics Leak Test The leak test is intended to detect incompletely-sealed ampoules so that they may be discarded. Tip-sealed ampoules are more likely to be incompletely sealed than are those that have been pull-sealed. In addition, small cracks may occur around the seal or at the base of the ampoule as a result of improper handling. Storage, Handling, and Shipping of Biologics Clarity Test Clarity is a relative term, the meaning of which is markedly affected by the subjective evaluation of the observer. Unquestionably, a clean solution having a high polish conveys to the observer that the product is of exceptional quality and purity. It is practically impossible, however, to prepare a lot of a sterile product so that every unit of that lot is perfectly free from visible particulate matter, i.e. is, from particles that are 30 to 40 μm and larger in size. Storage, Handling, and Shipping of Biologics Clarity Test Consequently, it is the responsibility of the quality control department to detect and discard individual containers of a product that the ultimate user would consider to be unclean. Further, the USP states that good pharmaceutical practice requires that all containers be visually inspected and that any with visible particles be discarded. Storage, Handling, and Shipping of Biologics Pyrogens and Pyrogen Test Pyrogens Water used in parenteral and irrigating solutions should be free of pyrogens. To achieve this, proper controls must be maintained in the preparation and storage of water. Pyrogens are products of metabolism of microorganisms. Most bacteria and many molds and viruses have been reported as producing pyrogens. The gram-negative bacteria produce the most potent pyrogenic substances as endotoxins. Storage, Handling, and Shipping of Biologics Pyrogens and Pyrogen Test Pyrogens Water is free from pyrogens if it has been distilled so that the condensed molecules have gone through the vapour state protected from inadvertent contamination, and if the distillate has been collected and stored in a sterile condition. To be pyrogen-free, solutes must be prepared from vehicles free from pyrogens, and must be stored in a manner designed to prevent subsequent contamination. Storage, Handling, and Shipping of Biologics Pyrogens and Pyrogen Test Pyrogens Pyrogens sometimes can be removed from solutions by adsorption on the surface of select adsorbants, but the often concurrent phenomenon of adsorption of solute ions or molecules may prevent the use of such a method. Selective solvent extraction methods are useful in the production of antibiotics where heavy pyrogen contamination results from the fermentation process Storage, Handling, and Shipping of Biologics Sterility Test All products labeled “sterile” must pass the sterility test, having been subjected to an effective process of sterilization. The test for sterility is intended for detecting the presence of viable form of microbes in pharmacopoeial preparations. Storage, Handling, and Shipping of Biologics Sterility Test Sterility testing of the products is carried out either by the Membrane Filtration method (Method A) or by the Direct Inoculation method (Method B). Storage, Handling, and Shipping of Biologics Sterility Test The technique of membrane filtration is used whenever the nature of the product permits; that is, for filterable preparations, for alcoholic or oily preparations, and for preparations miscible with, or soluble in, aqueous or oily solvents, provided these solvents do not have an antimicrobial effect in the conditions of the test. Storage, Handling, and Shipping of Biologics Sterility Test The test for sterility is carried out under aseptic conditions with precautions taken to avoid contamination. The working conditions in which the tests are performed are monitored regularly by appropriate sampling of the working area and by carrying out appropriate controls. Storage, Handling, and Shipping of Biologics Pharmaceutical Aspects of Temperature Temperature control is an important consideration in the manufacture, shipping, and storage of pharmaceutical products. Excessive temperature can result in chemical or physical instability of a therapeutic agent or its dosage form. For this reason, the labeling of pharmaceutical products contains information on the appropriate temperature range under which the product should be maintained. Storage, Handling, and Shipping of Biologics The United States Pharmacopeia provides the following definitions for the storage of pharmaceuticals. Freezer – between – 25°C and – 10°C Cold – not exceeding 8°C Refrigerator – between 2°C and 8°C Cool – between 8°Cand 15°C Warm – between 30°Cand 40°C Excessive Heat – above 40°C Controlled Room Temperature – between 20°C and 25°C  Special Solutions and Suspensions Pharmaceutical dosage forms and drug delivery systems applied topically to the eye, nose, or ear can include solutions, suspensions, gels, ointments, and drug-impregnated inserts. Ophthalmic Drug Delivery and Pharmacologic Categories Pharmaceutical preparations are applied topically to the eye to treat surface or intraocular conditions, including bacterial, fungal, and viral infections of the eye or eyelids; allergic or infectious conjunctivitis or inflammation; elevated intraocular pressure and glaucoma; and dry eye due to inadequate production of fluids bathing the eye. Ophthalmic Drug Delivery and Pharmacologic Categories Pharmacologic categories: Anesthetics B-adrenergic blocking Antibiotics agents Anitfungals Miotics Anti-inflammatory Mydriatics Antivirals Protectants Astringents Vasoconstrictors  Pharmaceutical Requirements Sterility and Preservation - must be sterilized for safe use. Isotonicity value Buffering Viscosity and Thickening agents Ocular Bioavailability Additional considerations  Packaging and Administration of Ophthalmic Solutions and Suspensions Packaged in small glass bottles with separate glass or plastic droppers, most are packaged in soft plastic containers with a fixed built-in dropper Ophthalmic solutions and suspensions are commonly packaged in containers holding 2, 2.5, 5, 10, 15, and 30 mL of product. Ophthalmic solutions used as eyewashes are generally packaged with an eye cup, which should be cleaned and dried thoroughly before and after each use.  Nasal Preparations Preparations intended for intranasal use contain adrenergic agents and are employed for their decongestant activity on the nasal mucosa.  Nasal Preparations Most of these preparations are in solution form and are administered as nose drops or sprays; however, a few are available as jellies.  Nasal Preparations Nasal Decongestant Solutions Most nasal decongestant solutions are aqueous, rendered isotonic to nasal fluids (approximately equivalent to 0.9% sodium chloride), buffered to maintain drug stability while approximating the normal pH range of the nasal fluids (pH 5.5 to 6.5), and stabilized and preserved as required.  Nasal Preparations Nasal Decongestant Solutions Nasal decongestant solutions are employed in the treatment of rhinitis of the common cold, for vasomotor and allergic rhinitis including hay fever, and for sinusitis. Frequent or prolonged use may lead to chronic edema of the nasal mucosa, that is, rhinitis medicamentosa, aggravating the symptom that they are intended to relieve.  Nasal Preparations Nasal Decongestant Solutions Thus, they are best used for short periods, and the patient should be advised not to exceed the recommended dosage and frequency of use. The easiest but least comfortable approach to treat rebound congestion is complete withdrawal of the topical vasoconstrictor. Unfortunately, this approach will promptly result in bilateral vasodilation with almost total nasal obstruction.  Nasal Preparations Inhalation Solutions Inhalations are sterile drugs or sterile solutions of drugs administered by the nasal or oral respiratory route. The drugs may be administered for local action on the bronchial tree or for systemic effects through absorption from the lungs. Certain gases, such as oxygen and ether, are administered by inhalation, as are finely powdered drug substances and solutions of drugs administered as fine mists.  Nasal Preparations Inhalation Solutions Inhalations are sterile drugs or sterile solutions of drugs administered by the nasal or oral respiratory route. The drugs may be administered for local action on the bronchial tree or for systemic effects through absorption from the lungs. Certain gases, such as oxygen and ether, are administered by inhalation, as are finely powdered drug substances and solutions of drugs administered as fine mists.  Nasal Preparations Inhalation Solutions A widely used instrument capable of producing fine particles for inhalation therapy is the nebulizer.  Nasal Preparations Inhalation Solutions Inhalants are drugs or combinations of drugs that by virtue of their high vapor pressure can be carried by an air current into the nasal passage, where they exert their effect. The device that holds the drug or drugs and from which they are administered is an inhaler. Certain nasal decongestants are in the form of inhalants. For instance, propylhexedrine is a liquid that volatilizes slowly at room temperature.  Nasal Preparations Inhalation Solutions Amyl Nitrite Inhalant is a clear yellowish volatile liquid that acts as a vasodilator when inhaled. It is prepared in sealed glass vials that are covered with a protective gauze cloth. Upon use, the glass vial is broken in the fingertips, and the cloth soaks up the liquid, from which the vapors are inhaled.  Nasal Preparations Proper Administration and Use of Nasal Drops and Sprays To minimize the possibility of contamination, the pharmacist should point out to the patient that the nasal product should be used by one person only and kept out of the reach of children. If the nasal product is intended for a child, the directions for use should be clear to the child if old enough to understand, the parent, or the caregiver  Otic Preparations Otic preparations are sometimes referred to as ear or aural preparations. Solutions are most frequently used in the ear, with suspensions and ointments also finding some application. Ear preparations are usually placed in the ear canal by drops in small amounts for removal of excessive cerumen (earwax) or for treatment of ear infections, inflammation, or pain.  Otic Preparations Cerumen-Removing Solutions Through the years, light mineral oil, vegetable oils, and hydrogen peroxide have been commonly used agents to soften impacted cerumen for its removal. Recently, solutions of synthetic surfactants have been developed for their ability to remove earwax.  Otic Preparations Cerumen-Removing Solutions One commercial product uses carbamide peroxide in glycerin and propylene glycol (Debrox drops, GSK). On contact with the cerumen, the carbamide peroxide releases oxygen, which disrupts the integrity of the impacted wax, allowing its easy removal.  Otic Preparations Anti-Infective, Anti-Inflammatory, and Analgesic Ear Preparations Drugs used topically in the ear for their anti-infective activity include such agents as ciprofloxacin, colistin sulfate, neomycin, ofloxacin, polymyxin B sulfate, and nystatin, the latter agent used to combat fungal infections. These agents are formulated into eardrops (solutions or suspensions) in a vehicle of anhydrous glycerin or propylene glycol  Otic Preparations Anti-Infective, Anti-Inflammatory, and Analgesic Ear Preparations These viscous vehicles permit maximum contact time between the medication and the tissues of the ear. In addition, their hygroscopicity causes them to draw moisture from the tissues, reducing inflammation and diminishing the moisture available for the life process of the microorganisms. otic preparations also contain analgesic agents, such as antipyrine, and local anesthetics, such as pramoxine hydrochloride and benzocaine  Otic Preparations Proper Administration and Use of Otic Drops When eardrops are prescribed, it is important for the pharmacist to determine how the drops are to be used. For example, earwax removal drops should be instilled and then removed with an ear syringe. Drops intended to treat external otitis infection are intended to be instilled and left in the ear. The pharmacist should make sure the child, parent, or caregiver understands that administration is intended for the ear and the frequency of application.  References Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems Lachman/Lieberman's The Theory and Practice of Industrial Pharmacy Remington’s Essentials of Pharmaceutics