Compounding Sterile Preparations, 4Th Edition Chapter 4

Chapter 4

Sterile Preparation Formulation Mark G. Klang

Introduction This chapter will provide insight into the issues of formulation when applied to compounding sterile preparations. The majority of options discussed in this chapter will involve high-risk compounding as defined by USP Chapter <797> Pharmaceutical Compounding—Sterile Preparations.1 Also, sterile compounding that requires specialized formulations may be designated difficult to compound by the newly created U.S. Food and Drug Administration (FDA) Task Force. This group examines specialized formulations and the resources available to pharmacists to safely conduct such procedures. This group then decides which modality or therapy is outside the scope of compounding. The Pharmacy Compounding Advisory Committee has met several times to evaluate what drug products are exempt from compounding under both Sections 503A and 503B of the Federal Food, Drug and Cosmetic Act. In June 2015, the FDA advisory group met to consider adding four more drugs to the list: aprotinin, ondansetron, bromocriptine, and acetaminophen. The compounder would be prohibited from any form of compounding that includes one of the banned active ingredients.2 Please refer to Chapter 21 for the stability and incompatibility of drugs, Chapter 15 for labeling compounded preparations, Chapter 16 for documentation, Chapter 17 for sterilization methods, and Chapter 18 for finished preparation release checks and tests.

Federal Regulations

New Compounding Drug Regulations The following is an excerpt of an FDA release pertinent to compounding sterile preparations: On November 27, 2013, President Obama signed the Drug Quality and Security Act (DQSA), legislation that contains important provisions relating to the oversight of compounding of human drugs.

Note: The author acknowledges E. Clyde Buchanan who authored this chapter in the previous edition.

51 52 Compounding Sterile Preparations

Title I of this new law, the Compounding regarded as safe and effective for the intended use.”5 Quality Act, removes certain provisions If the pharmacy fills each prescription as received, from section 503A of the Federal Food, clearance under the “new drug” provisions is not Drug, and Cosmetic Act (FDCA) that required.5 were found to be unconstitutional by the Compounding Phase 1 investigational U.S. Supreme Court in 2002.Section drugs does not require full compliance with 503A describes the conditions under which CGMPs because of the low volume of patients.6 certain compounded human drug products Compounding medications for Phase II and III are exempt from three sections of the FDCA trials requires complete adherence to CGMPs requiring: and products prepared for Phase I cannot be used • Compliance with current good manu- for the subsequent phases if not prepared under facturing practices (CGMPs) (section full CGMPs. 501(a)(2)(B); If a pharmacist compounds finished drugs from • Labeling with adequate directions for use bulk active ingredients that are not obtained from (section 502(f)(1); and an FDA-approved facility or are not compliant with compendial standards (i.e., The United States • FDA approval prior to marketing (sec- Pharmacopeia and The National Formulary [USP– tion 505). NF]), these finished preparations must be covered The new law creates also a new section by a new drug application.7 In other words, bulk 503B in the FDCA. Under section 503B, compounded preparations must conform to USP a compounder can become an outsourcing Chapter <795> Pharmaceutical Compounding— facility. An outsourcing facility will be able Nonsterile Preparations and USP Chapter <797>; to qualify for exemptions from the FDA otherwise, FDA requires that a new drug applica- approval requirements and the requirement tion be filed and accepted for the bulk compounded to label products with adequate directions preparation.1 for use, but not the exemption from CGMP If a pharmacist changes the strength, dosage requirements. Outsourcing facilities: form, or components of a commercially available preparation in a compounded prescription, good • Must comply with CGMP requirements, compounding procedures should be used.7 Pharma- • Will be inspected by FDA according to a cists are responsible for compounding and dispens- risk-based schedule, and ing finished preparations pursuant to prescribed • Must meet certain other conditions, such therapy, and for compounding and preparing those as reporting adverse events and providing preparations in compliance with established boards FDA with certain information about the of pharmacy and other regulatory agencies. These 3 products they compound. requirements vary from state to state. When formulating and compounding sterile preparations, pharmacists must follow both state laws and FDA regulations. State pharmacy practice Professional Standards acts and board of pharmacy regulations cover these Formulating, compounding, and sterilizing a activities. The FDA also regulates formulation and pharmaceutical from nonsterile ingredients or in compounding under adulteration, misbranding, nonsterile containers is the most difficult and is and new drug provisions of the FDA.4 considered a high-risk procedure.1 The chemical Since 1980, in their Field Regulatory Guidance, purity and content strength of ingredients must “Hospital Pharmacies Status as Drug Manufacturer,” meet their original or compendial specifications in FDA Guide 7132.06 states that “a physician may unopened or in opened packages of bulk ingredients prescribe an unusual preparation that requires in compliance with the Ingredient Section of USP compounding by a pharmacist from drugs readily Chapter <795>.8 Batch master worksheets should available for other uses and which is not generally include comparisons of actual with anticipated Chapter 4 Sterile Preparation Formulation 53 yields, sterilization methods, and quality control be accompanied by certificates of analysis from and validation of procedures used. Presterilized their suppliers to aid compounding personnel sealed containers should be used when feasible. in judging the identify, quality, and purity in Final containers must be sterile and capable of relation to the intended use in a particular CSP.10 maintaining product integrity through the beyond- Bulk or unformulated drug substances and added use date (BUD). The sterilization method must be substances, or excipients, must be stored in tightly based on the preparation’s properties. Whatever closed containers under temperature, humidity, method of sterilization is used, a sterility test is and lighting conditions, which are either indicated still required to ensure safety of the contents. The by official monographs or approved by suppliers. sterility test must be validated to determine if a Also, the date of receipt in the compounding contamination could be isolated if one were present facility must be clearly and indelibly marked on as well as to determine the sensitivity of the assay each package of ingredient. Careful consideration (USP Chapter <71> Sterility Test). See Table 4-1 for a review of the different types of terminal steril- and evaluation of nonsterile ingredient sources is ization, their advantages, and their disadvantages. especially warranted when the CSP will be admin- See reference 9 for a review of the FDA perspective istered into the vascular, central nervous system, on terminal sterilization.9 and eyes. Upon receipt of each lot of the bulk drug USP Chapter <797> specifies that nonsterile substance or excipient, the individual compound- active ingredients and added substances, or excipi- ing the preparation performs a visual inspection of ents, for compounded sterile preparations (CSPs) the lot for evidence of deterioration, other types of should preferably be officialUSP–NF articles.1 unacceptable quality and mislabeling, as described When unofficial ingredients are used, they must in a written protocol.

Table 4-1. Terminal Sterilizationa Sterilization Method Specifications Advantages Disadvantages Dry heat 180 °C for 30 min or Destroys pyrogens Heat sensitivity 170 °C for 1 hr 160 °C for 2 hr

Moist eat Pressure: 15 lb/sq inch Uses biological indica- Heat/moisture Temperature: 121 °C tor to verify sufficient sensitivity heat/pressure Autoclave, gravity sterilizer Time: 15 min

Filtration 0.2 μm Filter integrity test, Filter must be certified verifies filter did not for volume and filtrate rupture load Numerous fiber/size and load specifications

Gamma irradiation ~25 kGy; requires very Containers and pack- Not good for some high radiation to be aging may remain heat sensitive effective intact

Ethylene oxide/nitrous Depending on gas Less invasive, good for Requires tight wrap to oxide, hydrogen per- used different satura- heat sensitive but has avoid leaks, contami- oxide fog tion and permeation compatibility issues nates adjacent areas

aSee Chapter 17 for a more detailed review. 54 Compounding Sterile Preparations

Written Procedures The pharmacist ensures that the sterile components under their supervision meet acceptable The compounder of sterile preparations should criteria of stability and sterility by the following14: develop and comply with the following written procedures (Chapters 16, 22, and 31): • Observing expiration dates and dispensing the oldest stock first. The expiration date of a com- • There must be a specifically designated and pounded preparation’s ingredients should exceed adequate area for the orderly placement of equip- the expiration date set for the final product. Not ment and materials to be used in compounding. all chemicals used in pharmaceuticals have been CSPs should be prepared in a separate and dis- assigned an expiration date. The pharmacist tinct area from nonsterile compounding.1 should use good judgment to ensure the purity of any additive. A shelf-life of no longer than • USP Chapter <797> requires that presteriliza- 3 years after the container has been opened is tion procedures for high-risk level CSPs, such as considered a good maximum. weighing and mixing, be completed in at least an International Organization for Standardization • Storing components under the environmental Class 8 environment. conditions stated in the individual monographs and labeling. • For hazardous material, the storage should be in an environment of negative pressure to • Visual observation is an ineffective measure of ensure safety of the compounder according to instability. Most chemical changes fail to dem- National Institute for Occupational Safety and onstrate a visible change. A certified laboratory Health and USP Chapter <800> Hazardous must compile a stability indicating analysis that Drugs—Handling in Healthcare Settings (will will ensure safety through use of validated proce- 15 become official July, 2018).11 This new chapter dures to identify degradants. If a component has supersedes the section on Hazardous Drug han- undergone a physical change not explained in the labeling, such an ingredient should never to dling outlined in USP Chapter <797> earlier. be dispensed. Visual checks are of limited value • Special attention should be made to handling in this setting as the best observations will detect bulk agents, which would be expected when 20–50 µm diameters. Although a microscope will formulating a sterile compound that contains a enhance the size of the particles, the volume hazardous material. needed to be tested is quite large according to • Careful selection of respiratory and personal USP Chapter <788> Particulate Matter in In- 16 protective wear is crucial as is appropriate engi- jections. Light obscuration particle sizer is the neering controls to ensure safety of staff. ideal as it can detect fine precipitates that may occlude small blood vessels (4–9 µm in diameter) • Liquid preparations are especially hazardous as the vapor easily will pass through filtration-based • Testing sterility using validated procedures transfer systems, rendering them ineffective for as outlined in USP Chapter <71>. Sufficient exposure control.12 numbers of test samples are required for adequate strength of the analysis. Sterility test by mem- • Biological-based pharmaceuticals should be brane filtration is the ideal methodology, but vis- handled in accordance with the Biosafety Level cous liquids cannot pass the 0.4–μm filters used. designation as outlined by the Centers for Dis- For those samples that cannot be filtered, an ease Control and Prevention (CDC): The CDC inoculation test may be used, but it has a much operates an excellent “Quick Learn Lesson,” lower capacity to catch microbial contamina- which outlines the appropriate precautions and tion.17 Visual observations are not an effective identifications of biological risks level.13 measure of sterility. Evidence that the integrity • When USP–NF compendial monographs are of the seal has been violated should make the not available, another high-quality ingredient component suspect of microbial contamination. source may be acceptable (e.g., certified analyti- • Properly handling and labeling preparations cal reagent) certified by the American Chemical that are repackaged, diluted, or mixed with Society or Food Chemicals Codex grade. other products. Chapter 4 Sterile Preparation Formulation 55

• Dispensing in the proper container with the for injection USP is sterilized and packaged in proper closure. single-dose containers. Bacteriostatic water for • Using sterile compounding equipment that is injection is sterilized and contains one or more appropriate in design, size, and composition so bacteriostatic agents. that surfaces contacting components are not Sterile water for inhalation is sterilized and reactive, additive, or absorptive. These surfaces packaged in single-dose containers that are labeled should not alter the required safety, identity, with the full name. As implied, this component strength, quality, and purity of the components.1 cannot be used to prepare parenterals. Sterile water Prescription balances and volume-measurement for irrigation is sterilized and packaged in single- devices should meet USP specifications.18 dose containers with no added substances. • Inspecting and approving or rejecting all formu- Sterile water for injection is not intend- las, calculations, substances, containers, closures, and in-process materials. There should be a writ- ed for direct injection. The low tonicity will ten standard operating procedure in the event cause hemolysis of the cells and may be fatal. of nonconformance of bulk chemicals or com- Purified water may be used for enteral medication pounded preparations to quality assurance tests.19 compounding but cannot be used for compounding sterile preparations. See a detailed review of water Pharmacists who compound batches of parenteral for pharmaceutical purposes in USP.23 preparations must follow a master formula sheet to reproduce preparations that consistently meet all Aqueous Isotonic Vehicles purported norms. For more information about this, readers are referred to USP Chapter <1163> Quality Aqueous isotonic vehicles are often used in Assurance in Pharmaceutical Compounding.20 sterile preparations. A common vehicle is sodium chloride injection, a 0.9% solution (also known as normal saline) that is sterilized and packaged in Components single-dose containers no larger than 1,000 mL. Components are any ingredients used in compound- Bacteriostatic sodium chloride injection is a 0.9% ing, whether or not they appear in the final prepa- sodium chloride injection that contains one or ration (i.e., intermediate ingredients). Commer- more bacteriostatic agents in a container no larger cially sterile components should be used whenever than 30 mL. Sodium chloride irrigation also is a available. These ingredients should be made in an 0.9% solution. It has no preservatives and may FDA-approved facility and meet official compen- be packaged in a container larger than 1,000 mL. dial requirements.10 If these requirements cannot Other isotonic vehicles include Ringer’s injec- be met, pharmacists should determine if alternative tion, dextrose injection 5%, and lactated Ringer’s substances should be procured.19 injection. None of these components is available in containers larger than 1,000 mL.

Vehicles Water-Miscible Solvents Vehicles for most liquid sterile preparations should Several water-miscible solvents are used as a portion have no therapeutic activity or toxicity. Rather, of the vehicle in sterile preparations (i.e., as cosol- they serve as solvents or mediums for the admin- vents). These solvents (e.g., ethyl alcohol, liquid istration of therapeutically active ingredients. For polyethylene glycol, propylene glycol) dissolve drugs parenteral preparations, the most common vehicle with low water solubility. Preparations compounded is water. Vehicles must meet USP requirements for with these components are usually administered the pyrogen or bacterial endotoxin tests.21,22 intramuscularly or require significant dilution for parenteral administration.24 Examples of drugs in Water for Injection cosolvent formulations include some vitamins, Water for injection is purified by distillation or antihistamines, and cardiac glycosides. When reverse osmosis and is free of pyrogens. Water the solvent has toxic properties or produces toxic 56 Compounding Sterile Preparations

decomposition preparations (e.g., Cremophor), the effects and compatibility issues. Cyclodextrins are formulation requires extra caution (e.g., limiting the linked sugars that enhance water solubility but can final cosolvent concentrations). Administration of cause nephrotoxicity at higher concentrations.28 A these viscous liquids as an undiluted intravenous pharmacist must consider the total formulation of (IV) injection has resulted in complications.25 active ingredients and added substances; moreover, no coloring agent should be added to a sterile Nonaqueous Vehicles preparation solely to color it. Nonaqueous vehicles such as fixed oils can be used Antimicrobial Preservatives to formulate parenteral preparations. USP specifies that fixed oils must be vegetable (metabolizable) Antimicrobial preservatives may be added up to in origin and odorless (or nearly so) and also have a concentration that is considered bacteriostatic no rancid odor or taste.26 Examples include peanut, or fungistatic. Some preservatives, however, have cottonseed, corn, and sesame oils. Some vitamins innate toxicity within these concentrations (e.g., and hormones can only be solubilized in these phenylmercuric nitrate 0.01%, benzalkonium oils. Moreover, oil-based parenterals can only be chloride 0.01%, and phenol 0.5%). Because of given intramuscularly. However, emulsified oils their toxicity, these preservatives are used mostly in (e.g., soybean and safflower) prepared as liposomes, ophthalmics and with multidose injectables intend- mimic the natural chylomicrons which circulate ed for intramuscular or subcutaneous injections in the bloodstream. Liposomes may be used as Benzyl alcohol (usually 0.9%) and the parabens vehicles for lipid-based drugs such as propofol and (methyl 0.18% combined with propyl 0.02%) amphotericin, or as a source of essential fatty acids are commonly used in injectables. In oleaginous in nutrition support. preparations, no antimicrobial is highly effective. Sterile compounding of total parenteral nutri- However, hexylresorcinol 0.5% and phenylmercu- tion (TPN) often includes lipids along with ric benzoate 0.1% are reported to be moderately 29 the amino acids and dextrose. These combined bacteriocidal. Mercurial-based preservatives have products are called 3-in-1 or total nutrient admix- fallen into disfavor as they are associated with tures. Special handling is necessary for these formu- mercury contaminants such as those found in some lations as they are easily contaminated (Chapter fish. Although there is no such relationship, many 5). Special limitations on compatibility are also manufacturers have avoided their use. required as the destabilized emulsions can lead An antimicrobial agent may be effective in to pulmonary and immunological consequences. one formula of ingredients but not in another. Review USP Chapter <729> Globule Size in Lipid For example, large molecule components such as Emulsions for a detailed method to evaluate stabil- polysorbate 80, polyvinylpyrrolidone, and polyeth- ity of IV lipid emulsions.27 ylene glycol form complexes that inactivate the parabens. To select a preservative, an appropriate reference should be consulted and its effectiveness Solutes should be verified.30 USP provides a test for the Solute chemicals dissolved in vehicles should be efficacy of antimicrobial preservatives.31 Antimi- USP grade or better because their contaminants, crobial effectiveness is limited to 28 days (USP especially metals such as aluminum can alter solubil- Chapter <797 >). ity and compatibility of other solutes, cause catalytic Allergen extracts for multidose sterile injectables chemical reactions, or cause toxicity to patients. require antimicrobial preservatives like phenol or Added substances can increase stability or glycerin (Chapter 9). Compoundingtoday.com has usefulness. Some additives are used although they a database of commonly used preservatives and have limited effectiveness or have a narrow range of antioxidants.32 Note that simply adding a preserva- usefulness before producing complications. Solubi- tive to a CSP does not automatically extend the lizers prepared from castor oil have been used for BUD unless the compounder has a robust sterility many injectables despite a high incidence of side testing program in place. Chapter 4 Sterile Preparation Formulation 57

Preservatives should be avoided with prepara- acetone metabisulfite, ascorbic acid, and cysteine tions for neonates and premature infants. Surfac- hydrochloride. tant-based preservatives are toxic to neurological tissue and must be avoided in injectable for intra- Chelating Agents thecal administration. Chelating agents enhance the effectiveness of antioxidants. They form complexes with trace pH buffers amounts of heavy metals, thereby eliminating the Buffering agents stabilize an aqueous solution of catalytic activity of metals during oxidation. The a chemical against degradation. Limit the use of most commonly used chelating agent is edetate sodium bicarbonate to neutralize acid in an injection disodium. as it can form gas as a reactant and precipitate salts. Buffer systems are formulated at the lowest Tonicity Agents concentration needed for stability so that the Some injectable preparation monographs require body’s physiologic pH is not disturbed. Acid that the osmolar concentration appear on the salts such as citrates, acetates, and phosphates preparation’s label. Ideally, parenteral prepara- are commonly used as buffers. For an in-depth tions are formulated to be isotonic by use of an review of parenteral buffering systems, readers isotonic vehicle (e.g., normal saline). When the should consult reference 33. Cysteine is added desired concentration of the active ingredient in pediatric and neonatal parenteral nutrition is hypertonic, the drug must be administered by compounding solutions. It acts to reduce pH and slowing the rate of injection or by infusion into enhances solubility of the calcium and phosphate, a large vein (e.g., administration of TPN into which would normally form a precipitate (Chapter subclavian vein).24 In peripheral parenteral nutri- 5). Tables are available to predict the limits of tion (PPN), the solution is administered through calcium and phosphate in solutions of varying one of the smaller veins. PPN requires that the amino acid concentrations. It must be noted that overall osmolarity of the combined ingredients these are probability tables that do not consider below 900 mOsm/L to maintain the integrity of other additives that may contribute to precipitate the vein (Chapter 5). formation (e.g., dextrose). The consequences of a lack of understanding of this phenomenon have Solubilizers resulted in patient complications.34 Despite the use of solubilization enhancers, a filter should always Pharmacists must know the solubility charac- be used with parenteral nutrition solutions as the teristics of new drug substances (especially in potential for precipitation can be significantly aqueous systems) because they must possess some reduced, but it cannot be eliminated. aqueous solubility to elicit a therapeutic response. To maintain some drugs in solution, pharmacists Antioxidants may have to include either a miscible cosolvent or a chemical solubilizer (Table 4-2). Polyethylene Antioxidants help to prevent oxidation of the glycols 300 and 400, propylene glycol, glycerin, active drug. The most common antioxidants are and ethyl alcohol frequently are used. However, the sodium and potassium salts of metabisulfite toxic levels of these solvents must be avoided as and sulfite ions.35 However, the choice of salt well as amounts that make the preparation too depends on the pH of the system to be stabilized. viscous for parenteral use. Metabisulfite is used for low pH values, bisulfite for intermediate pH values, and sulfite for high Emulsifiers pH ranges. The administration of large amounts (500 mg/L) of sodium bisulfite in peritoneal dialysis Some drugs are minimally soluble in water. fluids causes toxicity with large volumes (10–40 L/ Emulsifiers are used to suspend tiny oil globules day). Allergic reactions have been noted with the in water to create an emulsion that contains a use of this preservative. Other antioxidants include uniform concentration of the active drug through- 58 Compounding Sterile Preparations

Table 4-2. Modalities to Improve Solubility of Parenteral Formulations Intervention Issues Advantages Lyophilization Requires a sugar to structure crys- Has stability against hydrolysis tal formation Enhances speed of dissolution of reconstituted powders

Cyclodextrin B-cyclodextrins is associated with α, β,and γ types contain 6, 7, and 8 nephrotoxicity glucopyranose units

Surfactants Castor oil-based has higher inci- Allows lipophilic drugs to have dence side effects aqueous solubility

Liposomal (emulsions) Limits on droplet size, USP <729> Can target droplets for immune clearance: amphotericin PFAT5 Or can be designed for “stealth” mode and avoid immune clearance: doxorubicin

PFAT5 = percentage of fat residing in globules larger than 5 µm.

out the volume of the liquid. Emulsions may Single or Multiple Dose serve as a caloric source in parenteral nutrition. Sterile, single-dose containers are intended One example is soybean oil and water emulsion for parenteral, inhalation, irrigation, otic, and manufactured with egg yolk phospholipids 1.2% ophthalmic administration. Examples are prefilled and glycerol 1.7% as emulsifiers. An example syringes, cartridges, ampuls, and vials (when of an active drug is propofol that is dissolved in labeled as single-use). soybean oil which is emulsified at a concentration of 100 mg/mL in water with glycerol (22.5 mg/ Multiple-dose containers permit withdrawal mL) and egg lecithin (12 mg/mL) as emulsifiers. of successive portions of their contents without Lipids are also used to encapsulate the active changing the strength, quality, or purity of the pharmaceutical. remaining portion. Sterile, multiple-dose containers are available for preserved parenterals, ophthalmics, and otics.37 Containers Containers are defined as “that which holds the Glass article and is or may be in direct contact with the Glass is the most popular material for sterile prepa- 36 article. The closure is part of the container.” All ration containers. USP classifies glass as Type I containers for sterile preparations must be sterile (borosilicate glass), Type II (soda-lime-treated and free of both particulate matter and pyrogens. glass), Type III (soda-lime glass), or NP (soda- These containers should not interact physically or lime glass unsuitable for parenteral containers).38 chemically with formulations to alter their required Different glass types vary in their resistance to strength, quality, or purity. Containers also must attack by water and chemicals. For pharmaceuti- 26 permit inspection of their contents. cal containers, glass must meet the USP test for Container volumes are specified by USP chemical resistance.39 Because most pharmacists standards. Each container of an injection is filled do not have the time or facilities to perform glass with liquid, slightly in excess of the labeled size or chemical interaction studies, they should use volume that is to be withdrawn. USP provides a only Type I glass to minimize sterile preparation guide showing recommended excess volumes for incompatibilities.40 both mobile and viscous liquids.26 Chapter 4 Sterile Preparation Formulation 59

Syringes • Zinc oxide or stearic acid as an activator Polypropylene syringes are not considered a approved • Carbon, kaolin, or barium sulfate as a filler long-term storage for compounded medications.41 • Dibutyl phthalate or stearic acid as a plasticizer Although the concept of packaging the medication • Aromatic amines as antioxidants in a syringe enhances the ready-to-use concept to improve patients care, packaging in a syringe is only Latex closures have been implicated as a risk factor for short-term use. The syringe allows air exposure, for patients with latex allergies (Chapter 29). higher contamination risks, and, in some cases, Removal of the stopper does not alter the latex reactions have been noted with the rubber plunger exposure. Despite the prevalence of latex aller- leading to reduced drug effectiveness. Two-part gies, there has not been a single documented case syringes are available (without lubricant and rubber of anaphylaxis due to exposure of a latex sensitive plunger) but do not resolve sterility issues. patient to a drug prepared from a container with latex stopper Thus, the rubber sealing of a vial or the plug in a Plastic syringe is a complex material that can interact with Plastic polymers can be used as sterile preparation the ingredients of a formula. Rubber closures also containers but present three problems: are subject to coring. Therefore, pharmacists should consult compendial or literature standards when 1. Permeation of vapors and other molecules in selecting a rubber closure for sterile preparations. either direction through the container 2. Leaching of constituents from the plastic into the preparation Parenteral Preparations 3. Adsorption of drug molecules onto the plastic Parenteral preparations are classified into six Plastics must meet USP specifications for biologi- general categories24: cal reactivity and physicochemicals.26 Most plastic 1. Solutions ready for injection containers do not permit ready inspection of their contents because they are not clear. Most 2. Dry, soluble preparations ready to be combined plastics also melt under heat sterilization.24 Rice with a solvent before use and Markel reviewed parenteral medications that 3. Suspensions ready for injection require selected containers because of adsorption to 4. Dry, insoluble preparations ready to be combined or leaching of plasticizers from polyvinyl chloride with a vehicle before use 42 (PVC) plastic bags. Lipophilic drugs can leach 5. Emulsions the plasticizer from the container into the patient. Avoid lipids and lipophilic drugs when using PVC 6. Liquid concentrates ready for dilution prior to administration containers. PVC containers also allow for evapo- ration of fluid over time and should not be stored Most CSPs are aqueous solutions (first category). outside protective overwrap for extended periods. Other categories usually require the equipment and expertise of a licensed pharmaceutical manufacturer. In addition to using the appropriate vehicle, Closures solvent, and container, the pharmacist must ensure Rubber closures must be rendered sterile and free that the final aqueous solution maintains the from pyrogens and surface particles. To meet these appropriate physiologic and physical norms. specifications, multiple washings and autoclav- ings are required. Closures are made of natural, Physiologic Norms neoprene, or butyl rubber. In addition, rubber contains the following43: When injectable solutions are formulated, every effort should be made to mimic the body’s normal • Sulfur as a vulcanizing agent serum values for pH and tonicity and to create a • Guanidines or sulfide compounds as accelerators pyrogen-free preparation. 60 Compounding Sterile Preparations pH • Containers and closures Normal human serum pH, a logarithmic measure • Chemicals used as solutes of the hydronium ion concentration in solution, • Human touch is 7.4. Drugs that are acids or bases or their salts If sterile water for injection USP is the vehicle, the sometimes must be buffered to a pH near normal (e.g., 3–8) to prevent pain or tissue damage. As risk of pyrogens in water is eliminated. Equipment, mentioned previously, acid salts are commonly containers, and closures can be decontaminated used as buffers. Stranz and Kastango have provided by dry heat or by washing or soaking with acids a good review of pH considerations in parenteral or bases. Dry heat depyrogenation must be used products.44 to render glassware or containers such as vials free from pyrogens as well as viable microbes. USP Chapter <797> requires that the description of Tonicity the dry heat depyrogenation cycle and duration Any chemical dissolved in water exerts a certain for specific load items shall be included in written osmotic pressure (i.e., a solute concentration relat- documentation in the compounding facility. The ed to the number of dissolved particles—un-ionized effectiveness of the dry heat depyrogenation cycle molecules, ions, macromolecules, and aggregates must be verified using endotoxin challenge vials 45 per unit volume). Blood has an osmotic pressure (ECVs).21,22 The bacterial endotoxin test should corresponding to sodium chloride 0.9%; thus, its be performed on the ECVs to verify that the common name is normal saline. Normal saline is cycle is capable of achieving a 3-log reduction in said to be iso-osmotic with blood and other physi- endotoxin. ologic fluids. Bulk supplies of chemicals may be specified In the medical setting, the term isotonic is as pyrogen free, although they usually are not. used synonymously with iso-osmotic. A solution Therefore, sterile preparations made from bulk is isotonic with a living cell if no net gain or loss chemicals must undergo a USP pyrogen test.21 of water is experienced by the cell and no other Touch contamination is most easily prevented with change is present when the cell contacts that proper aseptic technique. The maximum limit of solution. Very hypotonic IV preparations can endotoxin in a drug product labeled for intrathecal cause hemolysis of red blood cells. Very hypertonic use is set at 0.2 USP endotoxin units/kg/hr. Thus, injections can damage tissue and cause pain on to prepare high-risk intrathecal dosage forms, the injection or crenation of red blood cells. Paren- compounding pharmacist must be much more criti- teral solutions usually exert an osmotic pressure cal during the procedural protocol than during that of 150–900 mOsm/kg compared to a physiologic for IV administered preparations.22 norm of 282–288 mOsm/kg for blood. The greater the volume of solution to be injected, the closer the parenteral preparation should be to isotonicity. Physical Norms

Pyrogenicity Particulates Pyrogens are fever-producing endotoxins from Parenteral solutions must be free of particulate bacterial metabolism. They are contaminants that matter—mobile, undissolved solids not intended are unacceptable in final CSPs. As large proteins, for sterile preparations. Examples include lint, pyrogens are not removed by normal sterilization cellulose and cotton fibers, glass, rubber, metals, procedures and can exist for years in aqueous plastics, undissolved chemicals, rust, diatoms, and solution or dried form. dandruff. To determine levels of particulates, USP sets limits and provides tests.16 The following are sources of pyrogens in sterile preparations: However, a careful choice of components, containers, and closures can minimize particulate • Aqueous vehicles contamination. Moreover, filtration can remove • Equipment particles and bacteria from sterile preparations.46 Chapter 4 Sterile Preparation Formulation 61

The USP Chapter <788> states that visual • ASHP. Handbook on injectable drugs. 19th ed. checks for particles are unreliable method of Bethesda, MD: ASHP; 2016. evaluation only capable of reliably noting particles 150-µm in diameter. It is possible to detect smaller Impurities with enhanced techniques but nothing smaller FDA requires that large volume parenterals used than 20 µm. The USP sets limits on the number in TPN limit the aluminum content to 25 µg/L.48 of allowable 10- and 25-µm particles that can be Aluminum may reach toxic levels with prolonged detected using a microscope or a light obscura- parenteral administration if kidney function is tion device. The automated device has the higher impaired. Premature neonates are particularly at reliability. Pulmonary blood vessels have a 4–9-µm risk because their kidneys are immature, and they diameter and will occlude if the only quality assur- require large amounts of calcium and phosphate ance for undissolved particles is a visual check.34 solutions, which contain aluminum.49 The FDA requires that small volume parenterals used to Stability compound TPN show on the product container the Stability of parenteral preparations must be maximum concentration of aluminum at expiry or ensured so that patients receive the intended dose. state that the product contains no more than 25 Hydrolytic and oxidative drug degradations are µg/L of aluminum. Renal-impaired patients who the most common forms of instability but rarely receive parenteral aluminum at >5 µg/kg/day may show as cloudiness, precipitates, or color changes. accumulate aluminum at levels associated with The rate of hydrolysis may be affected by storage central nervous system and bone toxicity.49 When temperature or pH of the solution. Oxidation is formulating TPN, pharmacists should measure and affected by temperature, pH, exposure to light, calculate the soluble aluminum load that a patient oxygen concentration of the solution, impurities will receive and notify the patient’s physician if 48 (e.g., heavy metals), and concentration of the the FDA limit will be exceeded. The physician oxidizable drug. Other types of degradation (e.g., is responsible for making a clinical decision as to racemization, polymerization, isomerization, and patient risk for aluminum exposure versus the risk deamination) also can occur in solution. of a reduced or different treatment. The method chosen for stability should have the Heavy metals (e.g., lead and mercury) are also to capacity to view the breakdown products as well be minimized in sterile preparations. Heavy metals as the original entity. Attempts should be made to can be toxic and can catalyze the degradation of force degradation and determine the changes to active ingredients and preservatives. Introduction the original entity. To determine stability, it must of these impurities is most likely when nonsterile, be known what instability looks like.47 raw materials are used in compounding. This is why the pedigree of a chemical source is necessary Because many factors affect the stability of drug either by meeting USP–NF standards or by written molecules, pharmacists who compound parenter- manufacturer certification of analysis and purity. als from bulk chemicals should use a short BUD Of particular concern for formulators of TPN or know from the literature that longer stability are the relative concentrations of calcium salts and exists. Antioxidant and chelation additive systems phosphate salts. If either is too high, an insoluble should be reserved for formulas that are verified calcium phosphate precipitate results and has led in the literature as stable for a given period. The to deaths.50 Although some pharmacists rely on a choice of packaging also is important for parenteral “magic sum” of calcium and phosphorus to prevent drug stability. ASHP publishes the following guides calcium phosphate precipitates, this practice is that include information about sterile preparation unsafe because many variables affect the likelihood stability and compatibility: of precipitation, such as the type of calcium salt • Bing CD, Nowabilski-Vasilios A. Extended sta- (chloride or gluconate) or amount of proteins (as bility for parenteral drugs. 5th ed. Bethesda, MD: amino acids). A widely used guide to resolving the ASHP; 2013. calcium–phosphate problem is available.51 62 Compounding Sterile Preparations

Parenteral Formulas Tonicity The American Pharmacists Association (APhA) Lacrimal fluid has an osmotic pressure or tonicity has published a collection of 168 formulas, some similar to aqueous sodium chloride 0.9% solution. of which are parenteral, organized by therapeu- Eye tissue can tolerate tonicities of 0.5–1.8% 56 tic category, including analgesics, antiemetics, sodium chloride without much discomfort. anti-infective agents, and anti-inflammatory However, the tonicity of eyewashes is more agents.52 The International Journal of Pharmaceutical important than drops because a larger volume of Compounding (IJPC) maintains a website (www. solution contacts the eye. The tonicity of intra- ijpc.com) that lists formulas for many parenteral ocular solutions also should be as close as possible products, including some products that have been to physiologic. discontinued by pharmaceutical manufacturers.53 When formulating ophthalmic solutions, The IJPC website lists files for purchase that pharmacists should adjust the tonicity to approxi- contain articles and formulations from back issues mate lacrimal fluid by adding a substance such as of the journal, including sterile product compound- sodium chloride. Several methods can be used to ing, stability, and compatibility studies. calculate the amount of sodium chloride needed. The following example uses the colligative property, freezing-point depression. Lacrimal fluid lowers Ophthalmic Formulations the freezing point of water by 0.52 °C. To make a Ophthalmic preparations share many of the same boric acid 1% solution isotonic, sodium chloride properties as parenteral preparations but present crystals are added. Boric acid 1% lowers the freez- additional concerns. For example, ophthalmic ing point by 0.29 °C; therefore, sodium chloride formulations may use different added substances must be added to lower the freezing point further (e.g., buffers, antimicrobial preservatives, tonic- by 0.23 °C. ity-adjusting chemicals, and thickening agents). Furthermore, ophthalmic preparations include To use a proportion: solutions (eye drops or washes), suspensions, and 0.52 °C 0.23 °C ointments. Because pharmacists rarely compound = 09.% X sterile suspensions or ointments, this discussion is limited to solutions. Therefore, X = 0.4%. Thus, sodium chloride is added to a boric acid 1% solution to make it a Physiologic Norms sodium chloride 0.4% solution.57 Another easy method of calculation is to add Buffers and pH the sodium chloride equivalent. See Chapter Lacrimal fluid has a pH of approximately 7.4 and 31, Appendix A, of Remington’s The Science and limited buffering capacity. Ophthalmic solutions Practice of Pharmacy for the sodium chloride equiva- of weak bases (e.g., alkaloids), for which thera- lents, freezing-point depressions, and hemolytic peutic efficacy depends on the bioavailability of effects of nearly 400 medicinal chemicals.58 the alkaloid base, are buffered to acidity but as near pH 7.4 as possible while keeping the alkaloid Viscosity in solution after instillation.54 The buffer system (e.g., phosphate or acetate) should maintain pH Viscosity is important in ophthalmic preparations. within the drug’s solubility range for the duration Viscosity sometimes is increased to extend contact of expiration dating.47 A moderately acidic solution between the solution and eye. Moreover, water- does not cause discomfort on instillation unless dispersible polymers (e.g., methylcellulose, carboxy- the buffer system overcomes the buffer capacity of methylcellulose, hydroxypropyl cellulose, and lacrimal fluid. Nonisotonic ophthalmic solutions polyvinyl alcohol) are used as thickening agents. below pH 6.6 or above pH 9.0 have been associated A good review of viscosity agents, including their with irritation, reflex tears, and blinking.55 maximum concentrations, may be found in IJPC.59 Chapter 4 Sterile Preparation Formulation 63

Although USP discusses use of cellulose deriva- filtration; therefore, nonshedding filters, contain- tives, precautions are necessary. Cellulose derivative ers, and closures must be used. solutions cannot be filtered. When autoclaved, the Stability depends on the chemical nature of derivative precipitates from solution because of the drug, preparation pH, preparation method decreased water solubility at high temperatures but (especially temperature), solution additives, and redissolves at room temperature.60 packaging. If oxidation is a problem, sodium When a heat-labile drug is formulated with a bisulfite (up to 0.3%), ascorbic acid, or acetylcys- cellulose derivative, all components must be steril- teine can be added. Surfactants are used in low ized separately and then recombined aseptically. concentrations to achieve solution or suspension The drug in solution is sterilized by filtration, and of active ingredients. the cellulose derivative is sterilized by autoclav- ing.60 Viscosity of 25–50 centipoises improves Ophthalmic Formulas contact time with the eye, whereas higher viscosity offers no contact advantage but usually leaves a APhA has published a handbook that contains residue on eyelid margins.59 some ophthalmic formulas along with their stability information.59 IJPC has published an issue Sterility containing formulas for 15 ophthalmic prepara- tions60: To ensure sterility of ophthalmic solutions, pharmacists must prepare them in a sterile environ- 1. Acetylcysteine 15% ophthalmic solution ment in single-dose containers or use antimicrobial 2. Amphotericin B 2 mg/mL ophthalmic solution preservatives in multiple-dose containers. The microbe that causes great concern is Pseudomonas 3. Ascorbic acid 10% ophthalmic solution aeruginosa; however, no preservative is 100% effec- 4. Calcium gluconate 1% ophthalmic irrigation tive against all strains of it. solution The most common preservative is benzalkonium 5. Cyclosporin 2% ophthalmic solution chloride (0.004–0.02%), but high concentrations 6. Dexamethasone sodium phosphate 0.05% oph- of it irritate the eye. This preservative is incom- thalmic ointment patible with large anions (e.g., soaps) as well as 7. Fluconazole 0.2% ophthalmic solution with nitrates and salicylates. Other preservatives include phenylmercuric acetate and nitrate (0.001– 8. Fortified gentamicin ophthalmic solution 0.01%), phenyl-ethanol (0.5%), parabens (0.1%), 9. Glucose 40% ophthalmic ointment and chlorobutanol (0.5%). Because chlorobutanol 10. Idoxuridine 0.5% ophthalmic ointment is stable only near pH 5–6, it is used only with 11. Idoxuridine 0.1% ophthalmic solution solutions within this pH range. 12. Lissamine Green 0.5% ophthalmic solution Remington’s Chapter 43 discusses different ophthalmic preservatives.54 The properties of 13. Ophthalmic lubricant various ophthalmic preservatives have been 14. Rose Bengal 1% ophthalmic solution discussed above. Some ophthalmologists prefer 15. Vancomycin 25 mg/mL ophthalmic solution nonpreserved solutions because of allergic reactions to common preservatives. This is particu- These formulas are accompanied by the method of larly true for ophthalmic solutions injected during preparation, packaging, labeling, stability, discus- cataract surgery.61 sion, and references. ASHP has published extemporaneous formulations from The Children’s Hospital of Philadelphia Physical Norms for ophthalmics, including the following56: Required physical characteristics of ophthalmics include clarity, stability, and compatibility. • Bacitracin ophthalmic solution 10,000 units/mL Ophthalmics are made clear or particle free by • Cefazolin ophthalmic solution 33 mg/mL 64 Compounding Sterile Preparations

• Cidofovir intravitreous solution 0.2 mg/mL drug manufacturer. www.fda.gov/iceci/compli- ancemanuals/compliancepolicyguidancemanual/ • Gentamicin ophthalmic solution 13.6 mg/mL ucm074397.htm (accessed 2017 May 8). (fortified) 6. U.S. Food and Drug Administration (FDA), Cen- • LET (lidocaine 4%/epinephrine 0.1%/tetracaine ter for Drug Evaluation and Research. Guidance 0.5%) gel for industry, CGMP for phase 1 investigational drugs. Washington, DC: FDA; 2008 Jul. • Tobramycin ophthalmic solution 13.6 mg/mL 7. National Association of Boards of Pharmacy. (fortified) Appendix J: good compounding practices ap- • Tobramycin ophthalmic solution 15 mg/mL plicable to state licensed pharmacies. In: Model • Vancomycin ophthalmic solution 31 mg/mL state pharmacy act and model rules of the National Association of Boards of Pharmacy. Mount Prospect, IL: National Association of Boards of Pharmacy; 2012 Aug. Summary 8. U.S. Pharmacopeial Convention. USP chapter In many cases, no commercial preparation is <795> pharmaceutical compounding—sterile available for a final sterile preparation. Legally, preparations. In: USP 39–NF 34. Rockville, MD: pharmacists may compound these preparations U.S. Pharmacopeial Convention; 2016. 9. U.S. Food and Drug Administration (FDA). FDA under the FDCA regulations. However, various guidance: guidance for industry and FDA staff; sterile components (e.g., vehicles, buffers, and submission and review of sterility information solubilizers) are required. It is the pharmacist’s in premarket notification (510(k)) submissions responsibility to ensure that they meet the appro- for devices labeled as sterile. Washington, DC: priate compendial requirements. FDA; 2008. When formulating either parenteral or ophthal- 10. Anon. Standard operating procedure: certificates of analysis of materials used for pharmaceutical mic preparations, a pharmacist should use compo- compounding. Internat J Pharma Compound. nents so that the final sterile preparation achieves 2001; 5:147. both physiologic and physical norms. 11. U.S. Pharmacopeial Convention. USP chapter <800> hazardous drugs—handling in healthcare settings. In: USP 39–NF 34. Rockville, MD: U.S. References Pharmacopeial Convention; 2016. 12. Centers for Disease Control and Prevention 1. U.S. Pharmacopeial Convention. USP chapter (CDC). NIOSH A vapor containment per- <797> pharmaceutical compounding—sterile formance protocol for closed system transfer preparations. In: USP 37–NF 32. Rockville, MD: devices used during pharmacy compounding U.S. Pharmacopeial Convention; 2014. and administration of hazardous drugs (NIOSH 2. U.S. Food and Drug Administration, Science Board to the Food and Drug Administration. Ad- docket number 288, CDC-2015-0075). Atlanta, visory Committee; Notice of Meeting. Doc No. 80 GA: CDC; 2015. FR 67766. www.federalregister.gov/a/2015-27957 13. Centers for Disease Control and Prevention. (accessed 2017 May 8). Quick learn lesson. www.cdc.gov/training/Quick- 3. U.S. Food and Drug Administration. Compound- Learns/biosafety/ (accessed 2016 Mar 15). ing Quality Act Title I of the Drug Quality 14. U.S. Pharmacopeial Convention. USP chapter and Security Act of 2013. www.fda.gov/drugs/ <1191> stability considerations in dispensing guidancecomplianceregulatoryinformation/ practice. In: USP 39–NF 34. Rockville, MD: U.S. pharmacycompounding/default.htm (accessed Pharmacopeial Convention; 2016. 2016 Mar 15). 15. Tamizi E, Jouyban A. Forced degradation studies of 4. U.S. Food and Drug Administration (FDA), biopharmaceuticals: selection of stress conditions. Office of Enforcement, Division of Compliance Eur J Pharm Biopharm. 2016; 98:26-46. Policy. Manufacture, distribution, and promotion 16. U.S. Pharmacopeial Convention. USP chapter of adulterated, misbranded, or unapproved new <788> particulate matter in injections. In: USP drugs for human use by state-licensed pharmacies. 39–NF 34. Rockville, MD: U.S. Pharmacopeial FDA Guide 7132.16. Washington, DC: FDA; Convention; 2016. 2016 Mar. 17. U.S. Pharmacopeial Convention. USP chapter 5. U.S. Food and Drug Administration. FDA CPG <71> sterility test. In: USP 39–NF 34. Rockville, sec. 460.100 hospital pharmacies—status as MD: U.S. Pharmacopeial Convention; 2016. Chapter 4 Sterile Preparation Formulation 65

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