Applying Stability Data in Sterile Compounding

Michelle C. Simpson; Eric G. Schaefer; Rachel V. Marini; Marissa A. Davis

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Applying Stability Data in Sterile Compounding

in Extended Stability for Parenteral Drugs

Authors:

Michelle C. Simpson

Eric G. Schaefer

Rachel V. Marini

, and

Marissa A. Davis

DOI:: https://doi.org/10.37573/9781585286720.PT1001

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INTRODUCTION

In order to apply stability data in sterile compounding, storage times shown in the drug monographs of this book represent chemical and physical studies of drug stability, container material, and storage conditions. Before the official publication of the United States Pharmacopeia (USP) Chapter <797>, Pharmaceutical Compounding – Sterile Preparations, which set enforceable standards related to compounding sterile preparations, beyond-use dates were based primarily on chemical and physical stability, with pharmacies labeling compounded medications for use over several weeks or months. The USP recognizes the risks of microbial contamination as a contributor to patient safety and sets limits on the length of time a compounded sterile preparation (CSP) may be stored before that actual time that clinical administration to the patient starts. Pharmacists responsible for compounding and dispensing parenteral drugs must assign a date to each CSP that represents the date beyond which the preparation should not be stored or used. Assigning an appropriate beyond-use date (BUD) incorporates both chemical and physical factors, plus maintaining a level of quality assurance through the compounding facility’s design, equipment, personnel, and procedures.¹ Compiling extended stability information supports pharmacy operations within healthcare organizations by minimizing waste, maximizing product utilization, and managing medication shortages. Additionally, extended stability information allows for the compounding of enough medication to cover a shift at a hospital or a weekly delivery for a home infusion patient.

FACTORS AFFECTING EXTENDED DRUG STABILITY

The stability monographs in the Drug Monographs section of this book show data from studies where at least 90% of the drug is measurable in the container specified under the conditions listed, with the exception of factor products which are required to retain at least 80% activity. Stability involves chemical integrity, physical properties such as appearance and dissolution, as well as microbiological stability by maintaining sterility of the final dosage form. Environmental factors can reduce stability through light exposure or storage temperatures that are higher or lower than recommended. Stability considerations related to the dosage form include particle size, pH, and container material.² For more information, refer to Table 1: Conditions Affecting Drug Stability.

TABLE 1:

Conditions Affecting Drug Stability

Stability/Influence	Description	Outcome
*Chemical Changes*	Active ingredient must remain within labeled amount for the duration of storage and use.²^,⁸	Sub-therapeutic response or toxicity.
*Physical Changes*	Alteration of the appearance²^,⁸	CSPs with visible changes (eg, color, dissolution, uniformity, turbidity, particles) fail the visual inspection and should not be administered. Exception: If data are available to support that a visible change (eg, color) does not relate to or affect the stability of the CSP, then the CSP can pass the visual inspection.
*Microbiological Contamination*	Microbial contamination risk¹	Variables affecting microbial risk: Environment (eg, engineering controls) Aseptic processing (eg, personnel aseptic technique) Storage conditions (eg, refrigeration, room temperature) Sterile starting components Sterility testing (eg, air sampling, personnel evaluation) Controlling these variables *decreases* the risk of contaminated CSPs being administered to patients.
*Storage Temperature*	Heat²	Temperature fluctuations affect chemical reactivity, primarily hydrolysis and oxidation. Heat *increases* the rate of hydrolysis. A fluctuation of 10°C can change the rate of reaction.
Freezing²	Freezing may either break emulsions or cause a large *increase* in the droplet size of emulsions. Freezing temperatures can denature proteins or cause crystallization or precipitation.
*Container*	Fluid evaporation⁴	Evaporation of water through the container material can lead to changes in the concentration of the CSP’s active ingredient(s).
*Container*	Sorption⁴^,⁵	Adsorption followed by absorption into the plastic material causing a loss of pharmaceutical activity.
Leaching⁴^,⁵	DEHP leaching of lipophilic medications and PVC. Glass containers have: Relatively *low* levels of leachables at pH 4-8. Relatively *high* levels of leachables at pH > 9.
*Light Exposure*	Ultraviolet light (UV)²	Exposure to UV light may cause oxidation. In susceptible compounds, photochemical energy creates free radicals. Accelerated chemical degradation reactions.
pH	High and low pH extremes²	High and low pH extremes *increase* the rate of hydrolysis and oxidation. Drugs in solution are directly affected by changes in pH. Small fluctuations can decrease stability by factors of 10. *Higher* pH values catalyze and oxidize. *Lower* pH values destabilize emulsions and other two-phase systems.
*Handling & Transport*	Mechanical stress⁶	Caused by shipping, manipulations, pneumatic tube systems, etc. Agitation and shearing can affect stability of protein-based or large molecule medications.
*Handling & Transport*	Packing¹	Fragile items should be carefully packaged (eg, surrounded by bubble wrap) for delivery and storage.
Temperature¹^,²	The delivery process (eg, containers, insulating and packing materials, courier, environmental conditions) should be validated to ensure that the contents of the shipment are maintained at a temperature within established stability parameters. The pharmacy should be aware of storage and shipping limitations and should take extra precautions when extreme temperature conditions exist (eg, summer heat, winter freezing temperatures) to ensure that preparation stability is not affected throughout the entire shipping process.

When the usage timeframe in the manufacturer product labeling is limited or omitted, published stability studies can potentially support extending the BUD assigned to a CSP. If a referenced study does not match the conditions of a specific CSP’s formulation or conditions, assess the individual components based on the diluent used, concentration, container type, storage temperature, and exposure to light to determine if the available stability data may be extrapolated. Predictions of any area of stability impart an element of risk, and the degree of accuracy depends on the extent of the difference between the CSP characteristics.⁷

Extrapolation between diluents is discouraged. For example, stability in sodium chloride 0.9% is not applicable to stability in dextrose 5% in water. When several concentrations of a drug are studied with similar stability results, it is reasonable to expect the stability to be the same for concentrations falling within the ones tested.³ In the absence of stability studies in a specific container, the pharmacist should consider the available container materials and compare them to the materials studied. Comparing data between different containers should consider both the drug degradation mechanism and physical properties of the container.³ For more information on container material comparison, refer to Table 3:  Comparison of Plastics for Compounding and Storage of Parenteral Drugs. Temperature excursion comparisons may widen the options if a medication is studied as stable in another concentration or container at two temperatures. If not explicitly studied, room temperature storage stability data should not be applied to refrigerated storage conditions, and refrigerated storage stability data should not be applied to room temperature storage conditions. Studies performed while the preparation was protected from light cannot be extrapolated to light-exposed conditions. However, stability studies of light-exposed drugs can be extrapolated to light-protected conditions. Time periods reported can only be shortened, not lengthened. For more information, refer to Table 2: Extrapolating Stability Data.

TABLE 2:

Extrapolating Stability Data

Comparison of CSP to Studied Conditions	Considerations	Conclusions
*Container*	Bag	Compare available container materials to those studied. When stability data are available in a wide range of container types, consider documented stability of the drug and diluent in the desired container.¹^,³^,⁸^,⁹
	Syringe
	Glass
Elastomeric	Stability information from Easypump^® also applies to SMARTeZ^® pumps with reported equivalent drug reservoir and fluid path composition.⁹
*Manufacturer*	Manufacturer product studied differs from inventory³	Drugs that are generically and chemically identical are expected to have the same results as those studied. If there are differences in salt form, excipients, or solubilizing agents, the studied stability data may not be applicable.
*Concentration*	Several concentrations studied with similar stability results³	Prediction of similar stability for a concentration falling within the range of studied concentrations is reasonable. If there are data available in a container type and diluent with documented stability at two concentrations, concentrations falling within the two data points is acceptable. Extrapolating stability outside the studied concentrations is not recommended due to increased risk of instability of the final solution. Drug concentrations studied in differing container types may widen the stability range to specific containers needed for an individualized CSP.
*Diluent*	Diluent studied is *different* in composition to diluent ordered	Extrapolation of studied stability between diluents with different properties (eg, NS to D5W) is not expected to have similar results and should be avoided.¹^,³
Diluent studied is *similar* in composition to diluent ordered	Diluents with similar properties (eg, ¼NS to ½NS) are expected to have similar stability to those studied.¹^,³
*Temperature*	Studied at two temperatures and stable at both vs. studied at only one temperature	Temperatures should not be extrapolated without studying the drug at the temperature desired.⁸
*Light*	Light-protected compared to light-exposed	Do not extrapolate light-protected study results to light-exposed CSPs.⁸
Light-exposed compared to light-protected	Stability studies of light-exposed drugs can be extrapolated to light- protected CSPs.
*Sterility*	Sterility tests from CSP to CSP	Do not extrapolate sterility studies.¹
*Premix/Ready to Use (RTU)*	RTU manufacturer expiration to compounded CSP	Do not extrapolate RTU manufacturer expiration dates to beyond-use dates for compounded CSPs.

TABLE 3:

Comparison of Plastics for Compounding and Storage of Parenteral Drugs

Characteristic	Ethylene Vinyl Acetate (EVA)	Multilayer EVA	Ethylene Propylene Copolymer	Polyethylene (PE)
*Brand Names / Examples*	Bag EcoFLX^TM DME²⁵ EcoFLX^TM DMP²⁶ Exactamix^®²³	Bag Baxa^® Multilayer²⁴	Bag Excel^®⁶² PAB^®⁶³^,¹⁴⁶	Bag Ecoflac^® Plus¹⁶^,⁶²
*Inert / Nonreactive*	Inert⁴^,²⁰	Inert⁴	Inert⁶²^,⁶³^,¹⁴⁶	Inert¹⁰
*Evaporation*	Minimally water permeable⁴	Prevents water loss⁴	Prevents water loss⁶³^,¹⁴⁶	Prevents water loss²⁰
*Permeation*	Oxygen permeable⁴^,¹⁴^,²⁰	Decreases oxidation¹⁴	Prevents permeation⁶³^,¹⁴⁶	Prevents permeation⁴^,²⁰
*Sorption*	Not affected⁴	Not affected²⁰	Not affected⁶²^,⁶³^,¹⁴⁶	Not affected⁴
*Leaching*	No plasticizer⁴^,¹⁴^,¹⁵	No plasticizer¹⁴^,¹⁵	No plasticizer⁶²^,⁶³^,¹⁴⁶	No plasticizer⁴^,¹⁰
*Visibility*	Transparent⁴	Clearly visible⁴	Clearly visible	Clearly visible⁴
Characteristic	Multilayer PE	Polypropylene	Polyolefin^a	Polyvinyl Chloride (PVC)
*Brand Names / Examples*	Bag Nexcel^®²²	Bag AVIVA^™¹⁸ Fleboflex^®²⁸ Freeflex^®¹⁹ Inerta^®²⁷ IntraCon²⁹ Syringe BD Plastipak^™¹⁴⁵ Monoject^™¹⁴⁴	Bag AVIVA^™¹⁸ Excel^®¹⁶^,⁶² Intravia^™¹⁸ PAB^®⁶³^,¹⁴⁶ Viaflo^®²¹ VisIV^™¹²	Bag Lifecare^®³⁰ Viaflex^™¹⁸ Cassette CADD^® Cassette¹¹
*Inert / Nonreactive*	Inert¹⁰	Inert⁴^,²⁰	Inert¹²	Reactive with surfactants & oils⁵^,¹³^,²⁰
*Evaporation*	Prevents water loss²⁰	Prevents water loss²⁰	Prevents water loss²⁰	Water permeable⁴
*Permeation*	Decreases oxidation²⁰	Prevents permeation⁴	Prevents permeation²⁰	Water and oxygen permeable⁴^,²⁰
*Sorption*	Not affected²⁰	Not affected⁴	Not affected¹²	Sorption occurs with proteins & susceptible medication⁴^,⁵
*Leaching*	No plasticizer¹⁰	May leach additives from syringe plunger¹⁷	No plasticizer⁴^,¹²	Plasticizer leaching⁴^,⁵^,¹⁷
*Visibility*	Clearly visible⁴	Transparent⁴	Clearly visible⁴	Transparent⁵

Polyolefin is a category of polymers made with mixtures of low-density polyethylene, high-density polyethylene, polypropylene, and ethylene vinyl acetate.⁴

PREPARATION STERILITY AND QUALITY ASSURANCE

Individual organizations have to determine their own specific standard operating procedures (SOPs). In order to ensure consistent practices and reproducible results, there should be SOPs for all compounding and related processes. SOPs define the sequence of steps and conditions necessary for compounding CSPs. Consistency in compounding compliance using standardized SOPs can reduce variation among CSPs and decrease the chances of preventable errors occurring. SOPs should be based on applicable laws, regulations, and accreditation standards, and they should be further individualized for the types of compounding performed and equipment used at each facility.¹

If compounding in batches for more than one patient, a master formulation record provides specific compounding instructions and describes how the CSP was prepared.⁵⁷^-⁵⁹ When standardizing compounding records and master formulation records, the names, descriptions, and identifiers of CSPs should be consistent.⁵⁹^,⁶⁰ Master formulation records and compounding records should contain sufficient detail to be used on their own without additional verbal explanation.⁵⁸

When CSPs are stored before use, a visual inspection of each CSP should be documented at every stage. A visual inspection should occur during compounding, checking, labeling, dispensing, and before clinical administration to a patient by each individual who handles the CSP. Any visible changes to a CSP should be reported to the pharmacist.¹

An environmental monitoring program decreases the potential for contamination of CSPs and gives assurance the BUD assigned is appropriate. Maintaining a state of control of the compounding personnel, environment, and equipment is required for quality assurance of sterile preparations. For more information on quality assurance, refer to Table 4: Quality Assurance of Sterile Compounding.

TABLE 4:

Quality Assurance of Sterile Compounding¹^,³¹

Quality Components	Monitoring and Competency	Compliance
*Personnel*	Garbing, material handling, staging, cleaning	Incorporated into aseptic technique testing
	Gloved fingertip sampling
	Media fill testing	Proper technique, effective cleaning
Surface sampling to measure work practices
*Environment*	Sampling plan customized for each facility	Create a diagram of locations to be sampled
*Environment*	Document the number of people in the room during sampling
Include surfaces of carts, counters, pass-through windows/doors	Proper technique, effective cleaning
*Equipment*	Viable air sampling to test the engineering controls	Certification is performed on a schedule by third party
Automatic compounding devices	Cleaning, calibration, maintenance

ASSIGNING BEYOND-USE DATES TO COMPOUNDED STERILE PREPARATIONS

Assigning a beyond-use date or BUD to a CSP is performed as part of the compounding process and is distinctly different from expiration dates assigned to products during manufacturing. A BUD encompasses the time period starting at the date and time of compounding through the date and time after which the start of clinical administration should not occur. Assigning an appropriate BUD requires the consideration of many factors such as chemical stability, physical properties, component compatibility, sterility, component concentrations, container type, personnel factors, environmental factors, and equipment utilized during the compounding process. BUDs of CSPs are determined using a risk-based approach. The USP limits maximum BUDs to decrease risks posed to patients by requiring a labeled BUD that represents a time span before it is a risk for physical or chemical degradation, microbial contamination and proliferation, and diminished integrity of the container. For more information on container influence on stability, see Table 5: Stability Influence of Containers for Compounding Parenteral Drugs. The date takes into consideration the specific conditions where the CSP was made, the probability for microbial growth, and the time period within which it should be used. In unclassified spaces (eg, home, bedside), shorter BUDs are applied.¹ Extended stability BUDs require aseptic processing, sterile starting components or end sterilization method, sterility testing, and controlled storage conditions. The BUD of a CSP prepared in a small volume container, as defined in USP Chapter <659>, Packaging and Storage Requirements, that was packaged by the manufacturer in overwrap should not exceed the BUD of the container after removal from its overwrap unless data on stability and sterility exists for the CSP following guidance provided in USP Chapter <71>, Sterility Tests. For more information on dating related to overwrap removal, see Table 7: Manufacturer Storage of Commercial IV Solution Containers after Removal from Protective Overwrap. The BUD of a CSP prepared from another CSP (eg, stock solution, aliquot container) cannot exceed the shortest BUD of the individual starting components.⁵⁸

TABLE 5:

Stability Influence of Containers for Compounding Parenteral Drugs

Container	Characteristics
*Polyvinyl Chloride (PVC)*5,32	Permeability of fluid out of the package: Evaporation leads to *increased* concentration of the drug(s) in solution. Small volume containers are most susceptible to permeation. Drug reactivity to PVC: May cause leaching of plasticizers and chemicals. Sorption of the drug with the container surface may result in *decreased* concentration of the drug(s) in solution.
*Polyolefins*20	May be any of the following types: Low-density polyethylene High-density polyethylene Polypropylene Ethylene
*Ethylene Vinyl Acetate (EVA)*17	EVA containers are made of a flexible plastic that does not require phthalate plasticizers, such as di(2-ethylhexyl) phthalate (DEHP), in the manufacturing process. EVA containers can serve as a DEHP-free alternative for preparation of medications when that choice is appropriate for the patient or therapy.
*Syringe*4,33,34	Plastic syringes are composed of plastic polymers; common types include: Polypropylene Polyethylene Polycarbonate PVC Medications compounded in a syringe for administration are associated with accuracy, safety, and simplicity. Premeasured doses prepared in syringes reduce medication errors. Siliconization of rubber closures and lubricants may interact with medication stored in syringes.^a
*Glass*4	Used for clarity, inert composition, moisture, and gas barrier. Storage of drugs with high pH (>9), proteins, and peptides may lead to delamination of the interior surface and contamination of the CSP.
*Elastomeric*	It has been determined that stability information for Easypump^® also applies to SMARTeZ^® pumps.⁹
*Ambulatory Infusion System*	CADD^® Cassette reservoirs are composed of PVC.¹¹
*Commercially Prepared Solutions*	Always consult the most current prescribing information/package insert for stability dating of commercially available premixed solutions. Frozen and post-thaw stability data for each premixed drug applies only to that specific commercial product. Practitioners must not extrapolate stability data from premixed commercial preparations of drugs in solution to extemporaneously compounded preparations.

In 2015, the FDA provided notice that there were reports of interactions with the rubber stoppers of BD syringes that could cause some drugs stored in them to lose potency when not used immediately. On January 12, 2018, the FDA provided an update related to actions taken by BD. BD informed the FDA that they were no longer using the rubber stopper material that was associated with loss of drug potency in their general use syringes, and that they returned to a rubber stopper they had used previously in syringes.¹¹³^,¹⁴³

TABLE 6:

Temperature Excursion Stability Data for Refrigerated Intact Vials Stored at Room Temperature

Medication	BUD AFTER Removal from Refrigeration
Alprostadil *(Prostin VR^®* )**⁹⁰	120 days
Alprostadil (Caverject^® ) (40 mcg/mL vial; Lyophilized Powder)⁷⁴^,⁸⁴	3 months
Alteplase *(CathFlo)*⁶⁴	4 months
Ascorbic Acid *(Ascor^®* )**⁸³	10 days
Atracurium *(Tracrium^TM* )**⁶⁴	14 days
Bacitracin⁶⁵	14 days
Belimumab *(Benlysta^®* )**⁹³	21 days ^PFL
Botulinum Toxin⁶⁴	5 days
Bupivacaine Liposome *(Exparel^®)*⁷¹	30 days ^DNR
Calcitonin *(Miacalcin^®* )**⁶⁴	14 days
Carbaprost Tromethamine *(Hemabate^®* )**⁸⁷	15 days
Cisatracurium *(Nimbex^®* )**⁶⁴^,⁷⁵	21 days ^PFL
Clevidipine *(Cleviprex^®* )**⁶⁷	60 days ^{PFL, DNR}
Dacarbazine *(DTIC-Dome^®* )**⁶⁴	3 months
Daptomycin *(Cubicin^®* )**⁶⁴	1 year
Darbepoetin Alfa *(Aranesp^®* )**⁶⁴	7 days
Desmopressin⁸⁴	21 days
Digoxin Immune fab (Ovine) *(Digibind^®* )**⁶⁴	30 days
Diltiazem⁷²^,⁷³	1 month ^DNR
Diphtheria, Tetanus Toxoids & Acellular Pertussis Vaccine *(Infanrix^®* )**¹⁰¹	7 days
Diphtheria, Tetanus Toxoids, Acellular Pertussis, Hepatitis B (Recombinant) & Inactivated Poliovirus Vaccine *(Pediarix^®* )**¹⁰⁵	72 hours
Diphtheria, Tetanus Toxoids, Acellular Pertussis & Inactivated Poliovirus Vaccine *(Kinrix^®* )**¹⁰²	72 hours
Diphtheria, Tetanus Toxoids, Acellular Pertussis, Inactivated Poliovirus and Haemophilus B Conjugate (Tetanus Toxoid Conjugate) Vaccine Kit *(Pentacel^®* )**¹²³	≤72 hours ^CM (>8° − ≤25°C)
Epoetin Alfa (Procrit^® ) (multi-dose vial)⁶⁴^,⁸⁴	7 days
Epoetin Alfa (Procrit^® ) (single-dose vial)⁶⁴^,⁸⁴	14 days
Epoetin Alfa *(RETACRIT^TM* )**⁹¹	30 days
Eptifibatide *(Integrilin^®* )**⁶⁴	60 days
Estrogens, Conjugated *(Premarin^® Intravenous)*⁸⁸	1,095 days
Etanercept *(Enbrel^®* )**⁶⁴	7 days
Etanercept (Enbrel^® ) (prefilled syringe)⁶⁴	4 days
Exenatide (Byetta^® ) (vial or prefilled syringe)⁸⁴	30 days
Famotidine *(Pepcid^®* )**⁶⁴	90 days
Filgrastim (Neupogen^® ) (vial or prefilled syringe)⁶⁴	7 days
Fosphenytoin Sodium *(Cerebyx^®* )**⁶⁴	48 hours
Gemcitabine⁸⁶	30 days
Glatiramer Acetate *(Copaxone^®* )**⁸⁴^,¹¹⁰	1 month
Haemophilus B Conjugate Vaccine (Tetanus Toxoid Conjugate) (Hiberix^® ) (Lyophilized Powder)¹⁰⁰	7 days
Hepatitis A Vaccine *(Havrix^®* )**⁹⁹	72 hours
Hepatitis A Vaccine *(VAQTA^®* )**⁶⁴	1 year
Hepatitis A & Hepatitis B Vaccine (Recombinant) *(Twinrix^®* )**¹⁰⁷	7 days
Hepatitis B Vaccine (Recombinant) *(Engerix-B^®* )**⁹⁶	7 days
Hepatitis B Vaccine (Recombinant) *(Recombivax HB^®* )**¹²⁴	72 hours
Human Papillomavirus 9-valent Vaccine *(Gardasil^®* )**¹⁰⁸	130 months
Hyaluronic Acid *(Healon)*⁶⁴	14 days
Hyaluronidase (Recombinant) *(Hylenex^®* )**¹⁰⁹	1 year
Influenza Vaccine (Quadrivalent) *(Fluarix^® Quadrivalent)*⁹⁷	72 hours
Influenza Vaccine (Quadrivalent) *(FluLaval^® Quadrivalent)*⁹⁸	72 hours
Influenza Vaccine (Quadrivalent), Live *(FluMist^® Quadrivalent)*¹¹²	12 hours ^SE
Insulin, Aspart (U-100) (Novolog^® ) (vial or prefilled syringe)¹³⁰	28 days
Insulin, Aspart Protamine and Insulin, Aspart (U-100) (Novolog^® Mix 70/30) (vial)¹⁴²	28 days ^PFL
Insulin, Aspart Protamine and Insulin, Aspart (U-100) (Novolog^® Mix 70/30) (prefilled syringe)¹⁴²	14 days ^PFL
Insulin, Degludec (U-100 or U-200) (Tresiba^® ) (vial or prefilled syringe)¹²⁵	8 weeks ^PFL
Insulin, Detemir (U-100) (Levemir^® ) (vial or prefilled syringe)¹³⁷	6 weeks ^PFL
Insulin, Glargine (U-100) (Lantus^® ) (vial or prefilled syringe)¹³⁶	28 days ^PFL
Insulin, Glargine (U-300) (Toujeo^® ) (prefilled syringe)¹⁴³	8 weeks ^PFL
Insulin, Glulisine (U-100) (Apidra^® ) (vial or prefilled syringe)¹³¹	28 days
Insulin, Isophane (U-100) (Humulin^® N) (vial)¹³⁵	31 days ^PFL
Insulin, Isophane (U-100) (Humulin^® N) (prefilled syringe)¹³⁵	14 days ^PFL
Insulin, Isophane (U-100) (Novolin^® N) (vial)¹⁴⁰	6 weeks
Insulin, Isophane (U-100) (Novolin^® N) (prefilled syringe)¹⁴⁰	28 days
Insulin, Isophane and Insulin, Regular (U-100) (Humulin^® 70/30) (vial)¹³⁴	31 days ^PFL
Insulin, Isophane and Insulin, Regular (U-100) (Humulin^® 70/30) (prefilled syringe)¹³⁴	10 days ^PFL
Insulin, Isophane and Insulin, Regular (U-100) (Novolin^® 70/30) (vial)¹³⁹	6 weeks
Insulin, Isophane and Insulin, Regular (U-100) (Novolin^® 70/30) (prefilled syringe)¹³⁹	28 days
Insulin, Lispro-aabc (U-100 or U-200) (Lyumjev^TM ) (vial or prefilled syringe)¹³⁸	28 days
Insulin, Lispro Protamine and Insulin, Lispro (U-100) (Humalog^® Mix) (vial)¹³²^,¹³³	28 days ^PFL
Insulin, Lispro Protamine and Insulin, Lispro (U-100) (Humalog^® Mix) (prefilled syringe)¹³²^,¹³³	10 days ^PFL
Insulin, Regular (U-100) (Humulin^® R) (vial)⁶⁹	31 days
Insulin, Regular (U-100) (Novolin^® R) (vial)¹⁴¹	6 weeks ^PFL
Insulin, Regular (U-100) (Novolin^® R) (prefilled syringe)¹⁴¹	28 days ^PFL
Insulin, Regular (U-500) (Humulin^® R U-500) (vial)¹²⁹	40 days
Insulin, Regular (U-500) (Humulin^® R U-500) (prefilled syringe)¹²⁹	28 days
Interferon Beta-1a (Avonex^® ) (vial) (Lyophilized Powder)⁸⁴	30 days
Interferon Beta-1a (Avonex^® ) (prefilled syringe)⁸⁴	7 days
Interferon Beta-1a (Rebif^® ) (prefilled syringe)⁸⁴	30 days
Interferon Gamma-1b *(Actimmune^®* )**⁸⁴	12 hours ^{CM, DNR}
Japanese Encephalitis Inactivated, Adsorbed *(IXIARO^®* )**¹²⁶	72 hours
Lorazepam⁸²	90 days
Meningococcal Groups A, C, Y and W-135 Oligosaccharide Diphtheria CRM₁₉₇ Conjugate Vaccine (Menveo^® ) (Lyophilized Powder)¹⁰³	2 years
Meningococcal Group B Vaccine *(Bexsero^®* )**⁹⁴	48 hours
Meningococcal Group B Vaccine *(TRUMENBA^®* )**⁹²	7 days
Mepolizumab (Nucala^® ) (autoinjector or prefilled syringe)¹⁰⁴	30 days ^{PFL, CM}
Methylergonovine Maleate *(Methergine^®* )**⁶⁴	14 days
Octreotide⁷⁹	14 days ^PFL
Palivizumab *(Synagis^®* )**⁶⁴^,⁸⁴	14 days
Pancuronium *(Pavulon^®* )**⁶⁴^,⁷⁶	6 months
Peg-interferon Alfa-2a (Pegasys^® ) (vial)⁶⁴	14 days
Penicillin G Benzathine, Penicillin G Procaine *(BICILLIN^® C-R)*⁸⁵	180 days
Pneumococcal 13-Valent Conjugate Vaccine *(PREVNAR^® 13)*⁸⁹	7 days
Pramlintide Acetate (Symlin^® ) (prefilled syringe)⁸⁴	30 days
Rabies Immune Globulin (Human) *(KEDRAB^®* )**¹¹¹	1 month
Rocuronium⁶⁴^,⁷⁷^,⁷⁸	60 days
Succinylcholine⁷⁰^,⁸⁰^,⁸¹^,¹²¹	90 days
Tetanus Toxoid, Reduced Diphtheria Toxoid & Acellular Pertussis Vaccine *(Boostrix)*⁹⁵	7 days
Vasopressin *(Vasostrict^®* )**⁶⁸	1 year
Zoster Vaccine (Recombinant, Adjuvanted) (Shingrix^TM ) (Lyophilized Powder)¹⁰⁶	72 hours ^PFL

PFL

Protect from Light, ^SE Single Excursion, ^CM Cumulative, ^DNR Do Not Return to Refrigeration

TABLE 7:

Manufacturer Storage of Commercial IV Solution Containers after Removal from Protective Overwrap

Brand Name (Manufacturer)	Volume	Maximum Storage Time (Room Temperature)
*LifeCare™ (HOS) and  ADD-Vantage^® (PF)PVC containers***⁶⁶	25 mL	21 d
>25 mL	30 d
*Viaflex™ (BA) PVC containers*⁶⁶	≤50 mL	15 d
*Viaflex™ (BA) PVC containers*⁶⁶	≥100 mL	30 d
>250 mL	30 d
*EXCEL^® (BRN) Ethylene  propylene copolymer*47	250 mL	30 d

Labels that specify the storage conditions and BUD of compounded preparations are placed on each parenteral dosage unit. Documentation of the preparation date should be part of the labeling and include the time of compounding, if applicable. If preparation stability varies under different temperature conditions, list the BUD for each anticipated storage condition on the label. If the preparation needs to be warmed to room temperature prior to administration, the label and ancillary instruction material should describe it. If preparations are stable for less than 24 hours at room temperature, the label should be specific about the end-use time. Individuals administering CSPs should be trained to check preparations for current BUDs prior to usage. Practitioners should establish a standardized approach to labeling that is clear, concise, and meets all licensure and regulatory requirements, including USP Chapter <797> general labeling guidelines.³¹

PROFESSIONAL, REGULATORY, AND ACCREDITATION EXPECTATIONS

Pharmacists have professional and legal responsibilities related to all aspects of the medication compounding and dispensing process. In addition to any issues unique to each state’s pharmacy practice act, professional standards of practice set the expectations for practitioners in all care settings where pharmaceutical services are provided. Pharmacists should be aware of these expectations, including requirements applicable to their specific practice setting(s).

Professional Associations, Organizations, Standards,  and Guidelines

American Society of Health-System Pharmacists (ASHP) Guidelines on Compounding Sterile Preparations assist pharmacists in establishing quality assurance procedures for sterile drug preparations based on the risk level associated with the process and preparation.³¹ These professional guidelines should be used in conjunction with other best practice resources that address the procedures and quality assurance for compounding sterile preparations.

ASHP Guidelines on Home Infusion Pharmacy Services outline the requirements for the operation and management of pharmaceutical services provided by home care pharmacies.³⁶ These guidelines affirm the pharmacist’s responsibility for sterile preparation quality and integrity, including assignment of reliable beyond-use dating.

The Board of Pharmacy Specialties has established a certification for sterile compounding. Board Certified Sterile Compounding Pharmacists (BCSCP) validate their advanced knowledge and experience related to sterile compounding. They specialize in ensuring that compounded sterile preparations meet patients’ unique clinical needs while satisfying all quality, safety, and environmental control requirements set by legislative, regulatory, and accreditation bodies. The BCSCP has responsibility in all phases of preparation, storage, transportation, and administration of CSPs and maintain compliance with established standards, regulations, professional guidance, and best practices.³⁵

The National Association of Boards of Pharmacy (NABP) is a professional organization that focuses on protecting public health by supporting state boards of pharmacy. The NABP was initially founded in 1904 and had a consultative role in the Drug Quality and Security Act that US Congress enacted in November 2013. The NABP defined the terms compounding and manufacturing in its Model State Pharmacy Practice Act, which helped distinguish these terms and their differences related to sterile compounding practices.¹¹⁹

Regulatory Bodies, Standards,  and Guidelines

The United States Pharmacopeia (USP) is an independent, scientific non-profit organization that has set public quality standards for over 200 years. Through rigorous science, USP focuses on setting standards that help build public trust in the supply of safe, quality medications.¹¹⁸ The standards set by USP are utilized by more than 140 countries around the world. Since the late 1980s, USP has had increased focus on the processes and practices related to CSPs. USP Chapters have been developed to provide guidance for almost all aspects related to sterile and non-sterile compounding. All USP-NF chapters numbered under 1,000 are enforceable by state boards of pharmacy, the FDA, and accreditation organizations.¹¹⁹ Some of the key USP chapters that relate to the assignment of BUDs utilizing extended stability data are summarized below.

USP General Chapter <71>, Sterility Tests, outlines the standards and procedures required to validate sterilization processes or verify that batched products were aseptically compounded. It provides guidance related to culture media selection and use, incubation temperatures, sterility testing methods, method suitability testing, and the quantities that require testing based on batch characteristics (eg, solid vs. liquid, final preparation container volume, parenteral vs. ophthalmic or noninjectable, antibiotic).¹¹⁴ USP Chapter <71> has become an important part of compounding for facilities that utilize automated compounding devices (ACDs) to compound larger medication batches with extended stability dating applied to prevent waste.
USP Chapter <659>, Packaging and Storage Require- ments, provides definitions related to packaging, auxiliary packaging information, and definitions for storage conditions pertinent to the storage and distribution of medications. USP Chapter <659> defines small-volume and large-volume injections, single-dose and multi-dose containers, and light-resistant containers. It also defines temperature ranges that are important for storing compounded sterile products (eg, controlled room temperature, refrigerator, freezer).¹¹⁵
USP Chapter <797>, Pharmaceutical Compounding – Sterile Preparations, outlines the standards and minimum required practices related to CSPs in the United States. It provides the organizational structure, procedures, processes, and resources necessary to ensure predefined quality measures are met by facilities that compound sterile products.¹
USP Chapter <800>, Hazardous Drugs – Handling in Healthcare Settings, outlines standards and minimum required practices related to handling hazardous drugs. It was developed to ensure that hazardous drugs used within a healthcare setting are handled in a manner that keeps both patients and staff safe while attempting to mitigate any possible negative impacts on the environment. USP Chapter <800> applies to all healthcare personnel who could potentially be exposed to hazardous drugs at any type of healthcare facility that stores, prepares, transports, or administers hazardous drugs. It applies to facilities that treat humans as well as facilities that treat animals. Each facility must ensure that USP Chapter <800> requirements are met for any medication that they store, prepare, transport, or administer that is listed on the National Institute for Occupational Safety and Health’s (NIOSH) list of antineoplastic and other hazardous drugs used in healthcare.¹¹⁶
USP Chapter <1163>, Quality Assurance in Pharmaceu- tical Compounding, reinforces the importance of quality assurance systems being implemented by any healthcare facility that prepares compounded preparations, both sterile and nonsterile. It further describes critical components that should be incorporated into quality assurance programs to ensure that compounded preparations are produced with quality attributes appropriate to meet the needs of patients and healthcare professionals. USP Chapter <1163> outlines requirements related to personnel training, standard operating procedures (eg, components, review), compounding documentation and record-keeping, and quality-related testing (eg, analytical, microbial) throughout the entire compounding process as well as the finished products.¹¹⁷
USP Chapter <1191>, Stability Considerations in Dispen- sing Practice, describes different aspects of drug product stability that pharmacists should be concerned with throughout the preparation and dispensing process for medications. Criteria for acceptable levels of stability (eg, chemical, physical, microbiological, therapeutic, toxicological) describe the conditions that must be maintained throughout a drug product’s shelf life. Information related to different factors that can affect product stability (eg, hydrolysis, oxidation, photochemical decomposition, pH, temperature) is provided to ensure that healthcare providers have an understanding of reactions that can occur within a dosage form that lead to loss of active drug despite the lack of obvious visual or olfactory evidence of their occurrence.²

Accreditation Bodies, Standards,  and Guidelines

Accreditation standards are applied to home infusion and hospital pharmacies to ensure that the organization undergoes peer-review and operates using a set of best practices to safeguard patients.³⁶

The Centers for Medicare and Medicaid Services (CMS) requires the inclusion of processes related to compounding sterile products in the survey and review process of acute care facilities.³⁷ Acute care facilities must meet CMS Conditions of Participation to receive reimbursement for services provided to Medicare and Medicaid patients. Surveying and accreditation are generally conducted by CMS-approved accrediting bodies (eg, deeming agencies), which include The Joint Commission (TJC), Accreditation Commission for Health Care (ACHC), The American Osteopathic Association’s Healthcare Facilities Accreditation Program (HFAP), Det Norske Veritas (DNV) GL-Healthcare, and the Center for Improvement in Healthcare Quality (CIHQ), that are deemed to have authority by CMS. State agencies confirm that deeming agencies perform to CMS standards by conducting surveys of acute care facilities following the guidance outlined in the interpretive guidelines that CMS maintains.¹¹⁹^,¹⁴⁸

ACHC is a non-profit accreditation organization considered a deeming agency for CMS with authority for home infusion therapy, infusion pharmacy, home health, hospice, renal dialysis, durable medical equipment, prosthetics, orthotics, and supplies. ACHC Infusion Pharmacy Accreditation (IRX) surveys the processes and practices related to the compounding of sterile preparations in compliance with USP Chapters <797> and <800>, and includes standards for dispensing medications, equipment, and supplies to patients receiving home infusion therapy. In addition to accreditation authority, ACHC has distinctions for hazardous drug handling, specialty pharmacy, nutrition support, oncology, infectious diseases, and rare diseases. By achieving ACHC accreditation, pharmacies are able to demonstrate their commitment to providing the highest quality service through compliance with national regulations and industry best practices.¹⁴⁸

TJC is a non-profit, independent organization considered a deeming agency for CMS. In addition to accreditation of acute care facilities, TJC reviews the processes and practices related to the compounding of sterile products at ambulatory care locations, including ambulatory centers, outpatient surgery centers, physician offices where office-based surgeries are conducted, imaging centers, and urgent care centers. TJC standards exist that connect directly to compliance with USP Chapter <797> and USP Chapter <800>.  TJC standards related to sterile compounding span many areas, including human resources (eg, personnel training), medication management, infection control (eg, cleaning and disinfecting, gowning/garbing), environment of care (eg, compounding equipment, hazardous medications), and patient care (eg, patient education).¹¹⁹

APPLYING STABILITY DATA USING COMMERCIAL PRODUCTS

Extended stability data does not just apply to preparations manipulated or prepared by an individual healthcare facility. Data are available for intact commercial products stored in a manner that differs from how the product was received from the manufacturer or for products exposed to temperature excursions that differ from the manufacturer’s storage requirements as outlined in the official product information. The ability to extend intact commercial products can allow healthcare facilities to utilize medication stock to the greatest extent possible and reduce healthcare spending caused by medication waste.

Commercial Intact Vials and  Parenteral Diluents

Many drugs require refrigeration from the time of manufacturing until the time of compounding or administration. Maintaining a controlled refrigerated temperature throughout the supply chain process can pose many challenges due to reliance on a multitude of factors (eg, refrigeration equipment, outside temperature, extreme exposure during transit). Challenges also exist when medications must be stored under refrigeration until use but may be needed urgently in a care location where installation of a refrigerator may not be possible or reasonable (eg, ambulance, operating room). When storage temperature excursions occur, data may be available to support storage outside of the manufacturer’s recommendations and provide a BUD for the drug at alternative storage temperatures. See Table 6 for information on BUDs for intact vials stored at room temperature after removal from refrigeration.

Manufacturers of parenteral products packaged in PVC and other non-rigid plastic containers recommend maximum usage times after removal from the overwrap. Table 7  summarizes maximum out-of-overwrap storage times for solution container storage at room temperature. Once additives are placed in these containers, the BUD changes to the shortest date for any of the components, which could be either the drug stability dating or the solution manufacturer’s maximum recommended time for use after removal from the overwrap and storage.

Manufacturers of commercial intravenous solutions place a small amount of excess diluent into each container during the manufacturing process, referred to as overfill. This overfill amount is required by USP Chapter <1151>, Pharmaceutical Dosage Forms. The specifically required volume of excess diluent is based on the labeled size of the solution container and the solution’s properties (eg, mobile liquids, viscous liquids). A specifically required volume is noted for labeled container sizes of 0.5 mL, 1 mL,  2 mL, 5 mL, 10 mL, 20 mL, and 30 mL. For any solution with a labeled container size of ≥50 mL, the manufacturer is required to add an additional 2% for mobile liquids or 3% for viscous liquids to the container.¹²⁰ Overfill volume of a diluent solution container is essential to consider when preparing CSPs. Suppose the volume of overfill is not considered, and a large amount of drug solution is added to the diluent container. In that case, the final concentration of the CSP may not be the same as the concentration stated on the label. Generally, if the volume of a drug solution that needs to be added to a diluent container is ≥10% of the labeled container size, an equal amount of diluent should be removed from the container before injection of the drug. This “10% rule” helps to ensure that the concentration of the final CSP is as accurate as possible without requiring the exact amount of diluent to be physically measured and transferred to an empty container before injection of the drug. Table 8 provides overfill volumes for select manufacturers of intravenous solutions.

TABLE 8:

Overfill Volumes of Commercial IV Solution Containers

Solution	Container Type	Container Size	Average /  Target Fill	Fill Range, Minimum	Fill Range, Maximum
*Baxter*¹²⁷
Various	Viaflex^TM	25 mL	31 mL	28 mL	34 mL
		50 mL	58 mL	53 mL	63 mL
		100 mL	110 mL	105 mL	115 mL
		250 mL	275 mL	265 mL	285 mL
		500 mL	547.5 mL	530 mL	565 mL
		1,000 mL	1,050 mL	1,030 mL	1,070 mL
2,000 mL	2,080 mL	2,055 mL	2,105 mL
*B. Braun*⁴⁶^,⁶³^,¹⁴⁷
NS	E3^®	1,000 mL	1,027 mL	1,022 mL	1,032 mL
D5W; D10W; LR; ½NS; NS	Excel^®	250 mL	270 mL	263 mL	276 mL
D5W; D10W; LR; ½NS; NS	Excel^®	500 mL	532 mL	523 mL	550 mL
1,000 mL	1,058 mL	1,043 mL	1,088 mL
D5W; NS	PAB^®	25 mL	29.5 mL	25.5 mL	33.5 mL
D5W; NS	PAB^®	50 mL	57 mL	53 mL	61 mL
100 mL	109 mL	105 mL	113 mL
*Fresenius Kabi*¹²⁸
D5W	Freeflex^®	100 mL	114.5 mL	108 mL	121 mL
		250 mL	270 mL	264 mL	277 mL
		500 mL	529 mL	522 mL	535 mL
1,000 mL	1,030 mL	1,024 mL	1,035 mL
D10W	Freeflex^®	250 mL	-	260 mL	272 mL
D10W	Freeflex^®	500 mL	-	519 mL	535 mL
1,000 mL	-	1,023 mL	1,041 mL
LR	Freeflex^®	250 mL	270 mL	264 mL	277 mL
LR	Freeflex^®	500 mL	529 mL	522 mL	535 mL
1,000 mL	-	1,024 mL	1,037 mL
½NS; NS	Freeflex^®	50 mL	-	57 mL	64 mL
		100 mL	114.5 mL	108 mL	121 mL
		250 mL	-	260 mL	272 mL
		500 mL	-	519 mL	535 mL
1,000 mL	-	1,023 mL	1,041 mL
*ICU Medical*¹²²
D5W; NS	Small volume flexible containers	25 mL	29 mL	26 mL	32 mL
D5W; ½NS; NS	50 mL	56 mL	52 mL	62 mL
D5W	Large volume flexible containers	100 mL	107 mL	102 mL	112 mL
½NS; NS		100 mL	107 mL	103 mL	113 mL
D5W; NS		150 mL	175 mL	160 mL	200 mL
D5W; D5¼NS; D5½NS; D10W; M20; LR; ½NS; NS		250 mL	280 mL	260 mL	300 mL
500 mL		540 mL	520 mL	560 mL
D51/3NS; D5NS		500 mL	540 mL	520 mL	560 mL
D5W; D5¼NS; D51/3NS; D5½NS; D5NS; D10W; LR; ½NS; NS; SWFI	1,000 mL	1,040 mL	1,025 mL	1,055 mL
D5W; NS	VisIV^TM	50 mL	59 mL	56 mL	62 mL
100 mL	VisIV^TM	111 mL	107 mL	115 mL
D5W; ½NS; NS	250 mL	272 mL	268 mL	276 mL

Vial-Bag Connectors

Specialized point-of-care activated devices and containers allow for the connection of a vial of medication to a small volume infusion container. Generally, the connection of the vial to the bag is made under aseptic conditions. The actual mixing of the medication with the IV fluid (activation) takes place immediately prior to administration. The bags with attached vials may be stored prior to administration in automated dispensing cabinets or alternate sites to expedite patient access. The pharmacy must consider the specific device manufacturer’s guidelines for storage of connected but not activated devices. Table 9 summarizes the manufacturers’ BUDs for these devices after assembly in ISO Class 5 PECs and prior to activation.

TABLE 9:

Beyond-Use Dates for Point-of-Care Activated Devices after Assembly

Device	Manufacturer	BUD	Products
*ADD-Vantage^™*	Pfizer	30 d from date diluent removed from overwrap	50 and 100 mL containers³¹
*Mini-Bag Plus^™*	Baxter	15 d from date diluent removed from overwrap	50 and 100 mL containers³¹
30 d from date diluent removed from overwrap	100 mL containers attached to the following: Aztreonam 1 gm Cefazolin 1gm Ceftriaxone 1 gm Cefuroxime 750 mg Piperacillin and tazobactam 3.375 gm
*Add-EASE^™*	Braun	70 d	When connected to 50 or 100 mL PAB^® containers⁴⁷
30 d	When connected to Excel^® 250 mL containers⁴⁶^,⁴⁷

VASCULAR ACCESS DEVICES AND CATHETERS USED IN MEDICATION ADMINISTRATION

Vascular access devices are flexible catheters inserted into a vein to deliver infusion therapy. Selection criteria for the type of vascular access device (VAD) used should incorporate the length of infusion therapy and physical properties of the medication. The most common types of VADs are peripheral catheter, midline catheter, peripherally inserted central catheter (PICC), central venous catheter (CVC), and implanted port.³⁸ See Figure 1: Common Types of Vascular Access Devices.

FIGURE 1:

Common Types of Vascular Access Devices (VADs)

Peripheral catheters are usually 1-1.5 inches in length, with the tip terminating in a peripheral vein. This type of catheter should not be used for continuous infusions of vesicants, parenteral nutrition, or infusates >900 mOsm/L. The anticipated duration of therapy is generally less than 6 days when using a peripheral catheter.³⁸

Midline catheters are longer than peripheral catheters, measuring 3-8 inches, with the tip terminating in veins located between the elbow and shoulder.³⁸ It is inserted similar to a peripherally inserted central catheter (PICC) yet terminates in the periphery. Since it is not a central venous catheter, it does not lead to central line-associated bloodstream infections (CLABSI). Hospitals may turn to midlines to avoid CLABSI and related financial penalties.³⁹ Midline catheter duration of therapy is typically 1 to 4 weeks.³⁸ This type of catheter is an alternative to PICCs for certain indications, expected length of infusion therapy, and intravenous solutions appropriate for administration into the peripheral vasculature.³⁹

The utilization of midlines is increasing in hospitals to improve the rate of appropriate use of PICCs and traditional central venous catheters (CVCs). Studies show that midlines are suited for short-term therapy over 6-14 days.³⁹^,⁴⁰ Properties of the infusion solution should be within the parameters appropriate for peripheral catheters, particularly the osmolarity, irritant, and vesicant characteristics. Each CSP should be assessed for its irritant or vesicant properties prior to administration into the peripheral vasculature, paying attention to excipients added to medications, and verifying the solution is well tolerated by peripheral veins.³⁸

A central venous access device (CVAD) is a catheter whose tip terminates in the lower segment of the superior vena cava. CVADs may be utilized for the administration of any type of infusion therapy. The large diameter and high blood flow of the superior vena cava permit administration of medications with high osmolality, concentration and/or viscosity, parenteral nutrition, chemotherapy, blood products, and medications with vesicant properties. CVADs may be valved or open-ended. Valved catheters are designed to maintain line patency without the use of an anticoagulant flush.

There are two basic types of CVADs, tunneled and non-tunneled.

Tunneled CVADs are anchored by tunneling in tissue prior to the insertion into the large blood vessel. They are generally used for permanent or long-term venous access.

An implanted port is a type of tunneled CVAD that is implanted under skin and tissue with no portion of the catheter externally exposed. Ports must be accessed using a special non-coring needle.

Non-tunneled CVADs are placed via a percutaneous stick into the blood vessel and advanced within the blood vessel. They are not permanently placed.

A PICC is a type of non-tunneled CVAD that is inserted in the antecubital space into the basilic, brachial, or cephalic veins and advanced within the blood vessel to achieve central placement.

Vascular Access Device Complications VAD complications related to the drug concentration, osmolality, and direct contact of irritants include:

Infiltration (leakage of infusate into tissue surrounding a vascular access device) can occur when the VAD tip no longer resides in the blood vessel.
Extravasation (infiltration of vesicant or irritating agents into tissue surrounding a vascular access device) can result in tissue and/or nerve damage.
Chemical phlebitis is an inflammation of the inside of the blood vessel caused by direct contact with an irritant infusate.
Catheter occlusion can cause a complete or partial blockage of the VAD due to incompatibility, resulting in a precipitant in the line.

VASCULAR ACCESS DEVICE FLUSHING AND LOCKING

Flushing with sodium chloride 0.9% (NS) is performed to assess catheter function prior to each infusion and again after each infusion to clear any residual medication from the catheter lumen. Locking of the catheter is a final step to prevent occlusion or infection. Often the two terms are used interchangeably when they are not equal in function and purpose. Nursing standards define the volume of a flush as an amount sufficient to clear the medication from the lumen and lock as the minimum volume equal to the internal volume of the catheter and any add-on devices, plus 20%. The catheter lumen volume and add-on devices plus 20% for peripheral and midline catheters are in the range of 1-1.5 mL, and for PICCs and other CVCs, are in the range of 1.5-2.5 mL.⁴¹ These volumes are smaller than the generalized guidance from the nursing standards to administer flushing and locking solutions of 5 mL for peripheral catheters and 10 mL for central catheters.³⁸ Flushing with unmedicated NS uses a larger volume for the purpose of clearing the catheter. Considerations for specific flush volumes include the size of the catheter and the type of infusion solution. Viscous solutions, parenteral nutrition, or blood products require a larger volume to remove all of the residual drug.³⁸^,⁴² When studied with protein-based medication administration, 10 mL of flush did not remove all the proteins from the lumen walls of the catheter, suggesting a larger volume of NS flush for clearing protein-based medications. The method of flushing using a pulsatile push/pause was better at catheter clearance than a single bolus flush.⁴¹^,⁴³

Locking of the VAD using a medicated flush solution is performed to prevent occlusion, maintain patency, and reduce infection risk.⁴³ Heparin is the most common choice for a catheter lock. It should be administered as a final step after flushing and instilled at the lowest dose for the indication. Based on the internal catheter volume plus add-on device estimations, even though 5-10 mL may be ordered, 50% to 90% of the dose is administered into the patient, and only a small amount remains in the catheter.⁴⁴ For information on VAD lumen volumes, refer to Table 10. If the patient is using an antibiotic or ethanol lock, smaller volumes ordered may reflect the internal lumen volume plus a small amount of overfill to account for spillage into the system.

TABLE 10:

Vascular Access Device Lumen Volumes⁴⁴

Catheter Type	Lumen Volume
*Peripheral catheter*	0.03 mL
*Midline catheter*	0.4 mL
*CVAD (4F SL)*	0.6 mL
*PICC (4F SL)*	0.7 mL
*Tunneled (small bore)*	0.7 mL
*Tunneled (large bore)*	1.5 mL
*Port*	1.3 mL

If heparin is contraindicated as a catheter locking medication, there is an option for sodium citrate 4% solution, which had similar efficacy to heparin and fewer incidences of CLABSI.⁴³ Studies have indicated that sodium chloride 0.9% may be used as a primary agent for maintaining the patency of peripheral catheters in the acute care setting.⁶¹ If locking of the catheter is not feasible, elastomeric infusion devices are available to administer a continuous slow rate of sodium chloride 0.9% to maintain catheter patency in neonates and patients in alternate sites of care.⁴⁵^,⁶¹

INFUSATE PROPERTIES

Osmolarity is an additive figure for all of the chemical ingredients of a solution, including the diluent. A central VAD is used to administer solutions with high osmolarity  (>900 mOsm/L).³⁸

TABLE 11:

Osmolarity and pH of Commercial Infusion Solutions

Solution	Osmolarity (mOsm/L)	pH
*Sterile Water for Injection, USP*	0	5.5 (5.0-7.0)
*Dextrose 5% in Water*	252 (calculated)	4.3 (3.2-6.5)
*Sodium Chloride 0.9%*	308 (calculated)	5.6 (4.5-7.0)
*Sodium Chloride 0.45%*	154 (calculated)	5.6 (4.5-7.0)
*Dextrose 10% in Water*	505 (calculated)	4.3 (3.2-6.5)
*Dextrose 5% in Lactated Ringers*	530 (calculated)	5.0 (4.5-6.0)

Source: accessdata.fda.gov. and dailymed.nlm.nih.gov. Accessed February 2021.

ETHANOL AND ANTIBIOTIC  LOCK THERAPY

Catheter-related bloodstream infections (CRBSI) and central line-associated bloodstream infections (CLABSI) are complications associated with vascular access devices. Best practice for the management of these infections includes adequate source control (eg, line removal); however, ethanol lock therapy (ELT) and antibiotic lock therapy (ALT) are increasingly used to prevent or manage CRBSIs and CLABSIs. Guidelines recommend line lock therapy for intravenous catheter salvage therapy (Grade B-II recommendation) where line replacement or removal is not feasible.⁴⁸ Practitioners must consider the pathogen(s) of interest, available stability data of lock solutions, and catheter compatibility information when utilizing these specialized forms of access device care.⁴⁹ The preferred solution and concentration of ELT and ALT have yet to be defined.

Line Lock Therapy Considerations

There are many aspects to consider when selecting a line lock therapy solution, including the antimicrobial spectrum of activity, patient allergies, catheter compatibility, the addition of an anticoagulant, the concentration of the solution, the volume of the solution, dwell time, and the duration of therapy.

The Infectious Diseases Society of America (IDSA) guidelines recommend ELT should be limited to prevention of CRBSIs and CLABSIs⁴⁸; however, additional literature is available describing the use of ELT for treatment.⁵⁰^-⁵³ Central venous catheter (CVC) removal or replacement is preferred if Staphylococcus aureus or Candida spp. are isolated.⁴⁸ Antifungal lock therapy has been described in the literature for extenuating circumstances, but line removal remains the preferred management in this setting.⁵⁴^,⁵⁵

ALT includes a high concentration of antibiotic, usually at least 1,000-times higher than the pathogen minimum inhibitory concentration, as a means to penetrate or disrupt biofilms and eradicate or prevent the growth of bacteria.⁴⁸^,⁴⁹ Although the concentration of antibiotic is high at the site of action within the catheter lumen, the concentration of the CSP compounded into a syringe may be low compared to systemic dosages. Extrapolation of concentrations shown in medication monographs may not be applicable to concentrations compounded for ALT. Antibiotic selection for ALT should include an agent with activity against the pathogen(s) of concern and an agent with minimal toxicity concern for the patient (including allergies). Products prepared for lock therapy should be clearly labeled “for line lock therapy” to decrease the risk of inadvertent systemic administration.

Many studies have assessed the stability of various concentrations and drug combinations, but standard recommendations have yet to be defined. ALT and ELT solutions that dwell in the line may be exposed to varying temperatures, including body temperature. When determining BUDs for line lock therapies, professional judgment should be utilized when analyzing stability data of an available product.

Dwell time is the time the ELT or ALT solution sits in the CVC line and lumen. Studies suggest a minimum of 8 hours⁴⁹ and should not exceed 48 hours for most scenarios.⁴⁸ Dwell time is dependent upon the administration schedule of concomitantly prescribed intravenous medications and available intravenous access. For hemodialysis catheters, ALT dwell time is commonly defined by the time between hemodialysis sessions.

Determining Volume of Line Lock Therapy Solution

Determining the volume of line lock solution can pose a challenge. While there are standard volumes of CVC, patient-specific catheters may be manipulated during placement on a case-by-case basis (eg, lines may need to be shortened, thus decreasing volume for locking). If the volume of a line lumen is unknown, the following procedure can be utilized to determine the volume; this process should be completed for each lumen of the CVC.⁵⁶

Prepare the cap of the catheter using aseptic technique.
Flush the lumen with 5-10 mL of normal saline.
Attach a syringe to the lumen cap and draw back until the blood returns to the inlet of the syringe. The volume in the syringe at this point is the final volume.
Re-flush the catheter lumen with 5-10 mL of normal saline.

Most CVCs have multiple lumens, and coordination of locking therapy and administration of intravenous medications/fluids should be completed on a patient-specific basis. If patients do not have alternative intravenous access, coordination with scheduled intravenous medication(s) or fluid administrations should be analyzed. Utilizing separate orders for each lumen to be locked is considered best  practice—orders should note the lumen color to be locked for differentiation and include the specific volume of that lumen (lumen volumes on the same line may differ).

SUMMARY

Pharmacists are responsible for dispensing CSPs that meet patients’ unique clinical needs while satisfying all quality, safety, and environmental control requirements set by legislative, regulatory, and accreditation bodies. They direct and evaluate all phases of preparation, storage, transportation, and administration of CSPs and maintain compliance with established standards, regulations, professional guidance, and best practices.

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Table of Contents

Applying Stability Data in Sterile Compounding

INTRODUCTION

FACTORS AFFECTING EXTENDED DRUG STABILITY

Conditions Affecting Drug Stability

Extrapolating Stability Data

Comparison of Plastics for Compounding and Storage of Parenteral Drugs

PREPARATION STERILITY AND QUALITY ASSURANCE

Quality Assurance of Sterile Compounding1,31

ASSIGNING BEYOND-USE DATES TO COMPOUNDED STERILE PREPARATIONS

Stability Influence of Containers for Compounding Parenteral Drugs

Temperature Excursion Stability Data for Refrigerated Intact Vials Stored at Room Temperature

Manufacturer Storage of Commercial IV Solution Containers after Removal from Protective Overwrap

PROFESSIONAL, REGULATORY, AND ACCREDITATION EXPECTATIONS

Professional Associations, Organizations, Standards, and Guidelines

Regulatory Bodies, Standards, and Guidelines

Accreditation Bodies, Standards, and Guidelines

APPLYING STABILITY DATA USING COMMERCIAL PRODUCTS

Commercial Intact Vials and Parenteral Diluents

Overfill Volumes of Commercial IV Solution Containers

Vial-Bag Connectors

Beyond-Use Dates for Point-of-Care Activated Devices after Assembly

VASCULAR ACCESS DEVICES AND CATHETERS USED IN MEDICATION ADMINISTRATION

Common Types of Vascular Access Devices (VADs)

VASCULAR ACCESS DEVICE FLUSHING AND LOCKING

Vascular Access Device Lumen Volumes44

INFUSATE PROPERTIES

Osmolarity and pH of Commercial Infusion Solutions

ETHANOL AND ANTIBIOTIC LOCK THERAPY

Line Lock Therapy Considerations

Determining Volume of Line Lock Therapy Solution

SUMMARY

REFERENCES

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Quality Assurance of Sterile Compounding¹^,³¹

Professional Associations, Organizations, Standards,  and Guidelines

Regulatory Bodies, Standards,  and Guidelines

Accreditation Bodies, Standards,  and Guidelines

Commercial Intact Vials and  Parenteral Diluents

Vascular Access Device Lumen Volumes⁴⁴

ETHANOL AND ANTIBIOTIC  LOCK THERAPY