The USP-NF chapter <797> Pharmaceutical Compounding-Sterile Preparations makes the point that sterile compounding requires cleaner facilities, controlled environmental air quality, sterilization procedures, appropriate testing of both facilities and preparations, and an understanding of sterility and stability principles and practices. Sterile compounding also requires specific personnel training and testing, and the ability of personnel to carry out aseptic manipulations. In other words, proper sterile compounding includes everything from proper hand washing and gowning and proper inspection of sterile preparations, to understanding facilities design, testing, and maintenance.
In sterile compounding processes, there is a substantial challenge to maintain microbial control of the environment. This is because personnel, even those who use good aseptic techniques, shed enormous numbers of particles from themselves and their clothing and these particles are laden with microorganisms. It is estimated that more than 99% of all microorganisms detected in clean rooms are of human origin. Therefore, special techniques, precautions, and tests are necessary to ensure the microbiological burden is reduced enough to cause no harm to the patient.
|A person harbors an average of 150-200 classes of bacteria.|
|A person sheds 5 million squamous cells per day.|
|A person sitting motionless generates 100,000 particles (0.5 µm)/ft3/min.|
|A person sitting down or standing up generates 2,500,000 particles/ft3/min.|
|A person walking generates 10,000,000 particles/ft3/min.|
|Walking through the area will create a plume of turbulent air 30 feet behind.|
|It takes 8 minutes for 0.5 µm particles to settle to the floor from a height of 5 feet.|
|A person’s hands have 100,000 bacteria/mm2.|
Sterility is defined in USP-NF Chapter <1211> as complete absence of viable microorganisms. The absolute definition cannot be applied to all CSPs because it can only be practically demonstrated by destructive testing of all compounded preparations. So, sterility is defined in problematic terms where the likelihood of a contaminated preparation is remote. Sterility is considered one contaminated preparation in 1 million and is expressed as 10-6.
Pharmaceutical industries use a term “sterility assurance level” as a benchmark for acceptable sterility in aseptic manufacturing. Achieving that acceptable sterility assurance level during compounding in PECs is more difficult than in pharmaceutical manufacturing. There are several barriers to attaining more stringent sterility assurance levels reasons when compounding.
- Often times, components utilized in compounding preparations are nonsterile. Although the contents are considered to be sterile, the outside of the packages are not consistently decontaminated before being introduced into the ISO Class 5 preparation zone. Spraying and wiping techniques are not consistent or reproducible. Once the components are inside the ISO Class 5 environment, the packages are handled using the gloves that are used during the entire compounding procedure. The fact that the gloves can become contaminated increases the probability of contamination during preparation.
- Sterile preparations may become contaminated through other ingredients, process water, packaging components, process equipment, and compounders.
Working in a specified laminar airflow workstation or clean room (collectively known as primary engineering controls, PECs) does not ensure sterility of a compounded preparation. These PECs provide an ultraclean work area but do not provide sterility. So procedures need to be followed that will minimize the microbial burden as much as possible. For example, products that are placed in these PECs for assembly or compounding are sterilized beforehand or the completed preparation will be sterilized in a final step. Aseptic techniques are used to minimize potential contamination by microorganisms, particulate material, endotoxins, and pyrogens during these manipulations. Many of the procedures that are required in compounding CSPs are mandated by USP-NF, but some of the procedures are best practice extensions of the requirements of USP-NF. Each compounding facility will consider what is required and what is “better” in their individual operation.
Sterile compounding requires that the compounder adhere to additional rules and requirements. Those regulations describe additional facilities and specialized equipment needed for this level of compounding. Special clothing is required. This garb can consist of aprons, sleeves, gloves, hoods, shoe covers, coveralls, head coverings, lab coats, smocks, shirts/pants, hats/caps, face masks, and beard covers. The entire process of garbing is designed to reduce the particle shedding count from personnel.
The garb worn during aseptic compounding also provides some level of microbial containment, but complete containment is not possible. Personnel cleansing and hygiene also play an important role in reducing the microbial burden. Hands must be cleansed carefully and personnel protective equipment worn correctly in order to minimize the microbial contamination of CSPs. Infected skin (e.g., rashes, cuts, sunburn, and weeping sores) or people with active respiratory infections shed particles at higher rates. When individuals wear cosmetics or makeup, more particles are shed.
There is an appropriate order of garbing that can be remembered as covering or clothing from the “dirtiest” to the “cleanest” areas of a person’s outside clothing. This order is given in the table below:
Appropriate Order of Garbing
|Prior to entering buffer area or segregated compounding area||• Remove all personal outer garments
• Remove cosmetics
• Remove jewelry from hands, wrists, or any other visible body parts
• No artificial nails allowed
• Don PPE in the following order:
|Upon entering buffer area or segregated compounding area||• Antiseptic hand cleansing with surgical scrub
• Don sterile powder-free gloves
Hand hygiene, which is the most effective method of preventing the transmission of pathogens that cause infection in the community and in health-care settings, is an essential component of good compounding practices. Waterless, alcohol-based hand sanitizers that exhibit persistent activity (that is, effectiveness for six hours) and comply with guidelines and/or criteria from the USP, the FDA, and the Centers for Disease Control and Prevention (CDC), are among the most effective products that ensure an appropriate level of hand hygiene during compounding. In studies of antimicrobial-resistant organisms, alcohol-based products reduce the number of multidrug-resistant pathogens recovered from the hands of health-care workers more effectively than hand washing with soap and water.
Most alcohol-based hand antiseptics contain isopropanol, ethanol, N-propanol, or combination of two of those agents. The antimicrobial activity of alcohols results from their ability to denature proteins and disrupt bacterial and fungal cell membranes and viral capsids. The resulting cell lysis causes intercellular material to enter the cell and cause cell death. Alcohols solutions that contain 60% to 95% alcohol are most effective; the higher concentrations are less potent because proteins need water for the denaturation process.
Alcohols demonstrate excellent in-vitro germicidal activity against gram-positive and gram-negative bacteria, including multidrug resistant pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Mycobacterium tuberculosis, and various fungi. Some enveloped (lipophilic) viruses such as herpes simplex, human immunodeficiency, influenza, respiratory syncytial, and vaccinia have demonstrated susceptibility to alcohols when tested in-vitro. However alcohols exhibit very poor activity against protozoan oocysts, bacterial spores, and some non-enveloped (non-lipophilic) viruses. Alcohols are not effective against bacilli of the genus Clostridium, including those of Clostridium difficile.
A hand washing procedure is given in Appendix II of the USP-NF Chapter <797>. Below is a process validation check-off sheet that could be used alternatively.
|Removes all jewelry, watches, etc., up to elbow|
|Starts water and adjusts to appropriate temperature|
|Avoids unnecessary splashing during process|
|Uses sufficient antimicrobial cleanser and scrubs thoroughly for at least 30 seconds|
|Scrubs hands starting with fingernails first|
|Cleans all four surfaces of each finger|
|Cleans all surfaces of hands, wrists, and arms up to the elbows, using a circular motion|
|Does not touch sink, faucet, or other objects that may contaminate hands during the process|
|Rinses off all soap residue|
|Rinses hands holding them upright and allowing water to drip down to elbow|
|Does not turn off water until hands are completely dry|
|Turns off water with a clean, dry, lint-free paper towel|
|Does not touch faucet or sink while turning off water|
Guidelines recommend that Low Risk Level compounding be done in a ISO Class 5 environment such as a LAWF. The High Risk categories require that a laminar flow hood be located in a Class 100,000 (Category 1) or 10,000 (Category 2) controlled area. In any of these cases, however, working in a laminar flow hood is not sufficient to ensure sterility. The hood does not provide sterility – just an ultraclean work area.
Products will be placed in the hood for assembly or compounding that are either sterilized before hand or will be sterilized by filtration while in the hood. Personnel carrying out these procedures must use techniques to minimize the potential contamination (microorganisms, particulate material, pyrogens) possible during these manipulations. Aseptic Techniques can be defined as the sum total of methods and manipulations required to minimize the contamination of sterile compounded formulations.
The following are considered minimum requirements for good aseptic technique:
- Conduct all manipulations inside a properly maintained and certified laminar flow hood. Allow the laminar flow hood to operate for at least 30 minutes before use in order to produce a particle free environment. Maintain a designated “clean” area around the hood.
- Remove all jewelry and scrub hands and arms to the elbows with a suitable antibacterial agent. Sterile gloves are worn in addition to scrubbing.
- Wear lint-free clothing or clothing covers, head and facial hair covers, and a mask.
- Clean all flat surfaces of the hood with 70% isopropyl alcohol, or other antibacterial scrub such as benzalkonium chloride solution, working from top to bottom, then from back to front.
- Assemble all necessary supplies in the hood checking each for packaging damage, expiration dates, and particulate material. Use only pre-sterilized needles, syringes, and tubing for medication transfers.
- Remove the dust covering from supplies before placing them in the hood.
- Be sure there are no objects between the HEPA filter and the sterile surfaces, and that there is adequate space between objects. Place the smaller supplies closer to the HEPA filter and larger supplies farther away from the filter.
- Swab all surfaces that require entry (puncture) with 70% isopropyl alcohol or betadine solution. Avoid excess alcohol or lint that might be carried into the solution.
- Give close attention to hand position and the direction of air flow over injection ports or objects being manipulated. Minimize hand movements within the hood.
- To assemble needles and syringes, peel back the protective coverings and attach the needle and syringe, twisting to lock in place. When handling syringes and needles, be sure not to touch any surface that will come in contact with the sterile solution. Only the exterior of the syringe barrel, plunger tip and needle cap or sheath may be safely handled.
- Do all manipulations at least 6 inches inside the outer edge of the hood. Do not remove the hands from the hood until the compounding procedure is complete and the final inspection of the formulation has been made.
- Examine all formulations before removing them from the hood.
- Place all syringes and needles in puncture-proof containers and dispose of them according to institutional procedures.
Working in a specified laminar airflow workstation or clean room (collectively known as primary engineering controls, PECs) does not ensure sterility of a compounded preparation. These PECs provide an ultraclean work area but do not provide sterility. So procedures need to be followed that will minimize the microbial burden as much as possible. For example, products that are placed in these PECs for assembly or compounding are sterilized beforehand or the completed preparation will be sterilized in a final step. Aseptic techniques are used to minimize potential contamination by microorganisms, particulate material, endotoxins, and pyrogens during these manipulations. Many of the procedures that are required in compounding CSPs are mandated by USP–NF, but some of the procedures are best practice extensions of the requirements of USP–NF. Each compounding facility will consider what is required and what is “better” in their individual operation.
At a minimum, personnel should know how to transfer drugs in solution in vials or ampules into commonly utilized containers such as large volume parenterals (LVP) or small volume parenterals (SVP). Those techniques are highlighted in this section.
Aseptically Transferring Drug From a Vial
There are two types of parenteral vials that are used in making admixtures: (1) a vial that already has the drug in solution, and (2) a vial that requires a lyophilized powder be dissolved in a diluent to make a solution. In either case, a needle will be used to penetrate the rubber closure on the vial.
To prevent coring use the following technique:
- Place the vial on the work area surface and position the needle point on the surface of the rubber closure so that the bevel is facing upward and the needle is at about a 45 – 60 degree angle to the closure surface.
- Put downward pressure on the needle while gradually bringing the needle up to an upright position. Just before penetration is complete, the needle should be at a vertical (90 degree) angle.
If the drug is already in solution, then the aseptic transfer technique is as follows:
- Draw into the syringe a volume of air equal to the volume of drug solution to be withdrawn.
- Place the vial on the work area surface and penetrate the vial without coring.
- Invert the vial. Use one hand to hold the vial and the barrel of the syringe, and the other hand to hold the syringe barrel.
- Inject the air into the vial and withdraw the drug solution. It may be necessary to use successive small injections and withdrawals to exchange the air in the syringe with the solution in the vial.
- Fill the syringe to a slight excess of the drug solution. Remove all air bubbles from the syringe by tapping the syringe. Then fill the syringe to the correct volume once air bubbles have been removed.
- Withdraw the needle from the vial.
- Transfer the solution in the syringe into a final container, again minimizing coring.
If the drug is a lyophilized powder in a vial, it will need to be reconstituted before it can be withdrawn. First, determine the correct volume of suitable diluent to use. This information will be in the drug product information. Then the following steps can be followed:
- Perform steps 1 – 6 above to draw the correct volume of diluent into a syringe.
- Transfer the diluent into the vial containing the lyophilized powder.
- Once the diluent is added, remove a volume of air into the syringe equal to slightly more than the volume of diluent added. This will create a negative pressure in the vial and decrease the likelihood that aerosol droplets will be sprayed when the needle is withdrawn.
- Withdraw the needle.
- Swirl the vial until the drug is dissolved.
- Using a new needle and syringe, perform steps 1 – 6 again to withdraw the correct volume of reconstitute drug solution into the syringe.
- Transfer the reconstituted drug solution in the syringe into a final container, again minimizing coring.
Aseptically Transferring Drug From an Glass Ampule
Ampules have a colored stripe around the neck if they are pre-scored to indicate the neck has been weakened by the manufacturer to facilitate opening. Some ampules are not pre-scored by the manufacturer, and the neck must first be weakened (scored) with a fine file. The ampule is always broken open at the neck.
To open an ampule:
- Hold the ampule upright and tap the top to remove solution from the head space.
- Swab the neck of the ampule with an alcohol swab.
- Wrap the neck with an alcohol pad or gauze, and grasp the top with the thumb and index finger of one hand. With the other hand, grasp the bottom of the ampule.
- Quickly snap the ampule moving your hands away and out from you. Do not open the ampule toward the HEPA filter or any other sterile supplies in the hood. If the ampule does not snap easily, rotate it slightly and try again.
- Inspect the opened ampule for any particles of glass that might have fallen inside
To transfer the drug solution from an opened ampule:
- Hold the ampule at about a 20-degree down angle.
- Insert a needle/straw into the ampule taking care not to touch the ampule neck where it is broken.
- Position the needle in the shoulder area of the ampule beveled edge down. This will avoid pulling glass particles into the syringe.
- Withdraw solution but keep needle submerged to avoid withdrawing air into the syringe.
- Withdraw needle from ampule and remove all air bubbles from the syringe.
- Transfer the solution to the final container using a filter needle or membrane filter.
Aseptically Adding Drug Solution to Large Volume Parenterals (LVP) or Small Volume Parenterals (SVP)
Generally, LVP solutions are used as primary or continuous infusion solutions by administering them at a slow infusion rate. Drug additives can then be introduced directly into LVP with a syringe and needle. Drug additives can also be introduced into LVP at the Y-connection of the administration set. Drug additives are also put in minibags and used as a piggyback on the LVP.
All of these scenarios require a syringe and needle to transfer the drug additive solution into a plastic bag or administration set injection port. The needle must be at least 1/2 inch long and not less than 19 gauge to ensure that the inner diaphragm of the port will be penetrated and that the protective rubber cover will reseal.
To transfer a drug additive to a LVP or SVP container or an administration set with a needle and syringe:
- Remove the protective covering from the injection port.
- Assemble the needle and syringe and aseptically withdraw the necessary drug additive volume.
- Swab the injection port with an alcohol swab.
- Hold the injection port with one hand and insert the needle into the port with the other hand. Hold the port in such a way that the fingers are out of the way in case the needle punctures through the port. The injection port should be fully extended to minimize the chance of punctures through the port.
- Inject the drug additive solution.
- Remove the needle.
- Mix and inspect the admixture.
Discarded gloves, needles, syringes, ampules, vials, and prefilled syringes used in preparing sterile formulations pose a source of contamination and should be disposed of properly. Receptacles that are leak-proof, puncture proof, sealable, and easily identifiable should be used. Needles and syringes should be placed in “sharps” containers. They should not be clipped or recapped in order to prevent aerosolization or accidental needle sticks. Excess solutions should be returned to their original vial, an empty vial, or some other suitable closed container.
The compounded formulation should be inspected for:
- container integrity or leaks in flexible containers
- cracks or leaking stoppers in glass containers
- particulate material properties such as color, odor, fill volume, consistency, etc.
- unexpected precipitation, crystallization, or other physical property
Preparations in flexible containers should be squeezed to ensure the absence of unintended holes and slits. Glass bottles should be examined for cracks and leaking stoppers.
Visual inspection will show two of the six characteristics of parenteral solutions: (1) particulate material and (2) stability if such stability is physically characterized by precipitation or crystallization. The presence (or absence) of particulate material is best determined when the parenteral is held against an illuminated light/dark background.
Formulation properties should be known before hand and documented on the formulation record. The compounded product should be compared to these standards.
The pharmacist should also verify that the product was accurately prepared with respect to:
- ingredients (check used vials, ampules, diluents)
- quantities (check syringe volumes used)
- containers (check final solution container)
- instrumentation (check calibration and settings on repeat or automated dispensing devices)
During compounding, volumes of additives in syringes should be examined to confirm accurate measurements. The volumes of solutions remaining in vials and ampules should be determined to compare to the theoretical volumes required to make the formulation. A mass balance of materials should be evident. Also additive containers and syringes should be available (not discarded in the trash) until the product checks are completed. These inspections should be performed after each individual preparation is completed. Preparations that are not distributed promptly should be inspected again before leaving the pharmacy, the purpose of which is to check for defects such as precipitation, cloudiness, and leakage that may have developed during storage.
Formulations should be subjected to quality control tests as outlined in the formulation records and compounding records. These are generally the physical tests that can be conducted within the pharmacy and may involve weight variation, specific gravity, pH, filtration membrane integrity, etc.
A quality assessment review could involve the review of many items or steps, so it is important to focus on those items that may have significant impact on the entire compounding operation. Examples are:
- Evaluate the compounding operation with the GMPs.
- GMPs require information about “method suitability,” which assures that the test being conducted either in-process or at the completion of operations will provide a true outcome. For example, many compounded sterile preparations contain antibiotics and preservatives which could lead to false negative of a sterility test’s results.
- Evaluate the effectiveness of the current microbiological applications in the compounding operation to a compliant microbiological program that is in compliance with USP-NF General Chapter <1116> Microbiological Control and Monitoring of Aseptic Processing Environments.
- Preservatives such as antioxidants, antimicrobials, and antifungals often are added to the preparations to improve stability or to protect them from microbial contamination so evaluation of the effectiveness of the preservatives is important in those formulations.
Formulations that are not distributed promptly should be inspected again before leaving the pharmacy. The purpose of the pre-distribution inspection is to check for defects such as precipitation, cloudiness, and leakage which may have developed during storage.
In a general sense, validation is any mechanism that will establish a high degree of assurance that specific processes are achieving their objective. Its ultimate goal is to produce products that consistently meet predetermined specifications and quality attributes. Consistent quality (and improvement if possible) is a “must” for the health and well-being of the patient and should be an on-going process.
Several types of “quality control” can be developed for sterile compounding.
The Validation subsection of Section <1206> of the USP 24/NF19 describes an evaluation procedure commonly referred to as “media fills.” The evaluation involves an operator manipulating microbial growth media (usually soybean casein digest medium) according to a prescribed validation procedure. The procedure requires multiple aseptic transfers to multiple containers. It is recommended that the validation procedure by done at peak periods of fatigue, stress, and pacing demands (e.g., immediately after normal production activity).
The premise behind media fills is that the growth medium will support the growth of the contaminating microbe, and this growth can be detected. The other requirement of the validation is that the media must be manipulated using the same aseptic techniques actually being evaluated.
It is important to note that this validation is not intended to be a one time evaluation. The USP 24/NF19 recommends that competent operators be challenged quarterly. Other references suggest that 40 validation sample should be prepared for each 800 admixtures prepared, or that 10 validation samples be prepared each month. Regardless of the frequency, a competent sterile compounder will need to be evaluated on a regular and on-going basis.
There are several types of sterilization but the most appropriate method will depend on the physical and chemical properties of the preparation and its packaging. Typically, dry heat, filtration, and steam sterilization are used with compounded preparation.
Of the two general types of tests, one involves the use of culture medium and the other uses biological indicators. When using culture medium, the test sample can be introduced directly into the medium or the sample can be filtered and the filter transferred to the culture medium. There are several media that can be used in these tests, such as Soybean-Casein Digest Medium (SCDM), Fluid Thioglycollate medium (FTM), and dithionite-thioglycollate broth HS-T.
Biological indicator is usually the preferred method of verifying sterility. It is a preparation of a specific microorganism that is resistant to a particular sterilization process. The microorganisms are embedded either on paper or on plastic strips and are included with the materials being sterilized. USP-NF General Chapter <1035> Biological Indicators for Sterilization states that there are three types of biological indicators: 1) Type 1: a biological indicator that included spores that are added to a carrier and package to maintain the integrity and viability of the incubated carrier 2) Type 2: a spore suspension that is inoculated on or into representative units of the preparation to be sterilized. This represents an inoculated preparation; however, a simulated inoculated preparation may be used if it is not practical to inoculate the actual product 3) Type 3: a self-contained indicator. It is designed so that the primary package, intended for inoculation following sterilization processing, contains the growth medium for recovery of the process-exposed microorganism. This form of biological indicator, together with the self-contained growth media, can be considered a system.
Sterility Testing Failures
USP-NF Chapter <797> addresses the actions that should occur when a pharmacy encounters a sterility failure of a compounded sterile preparation. The chapter is not prescriptive on how to perform an investigation. However, there are certain basic points that should be covered and documented since the compounder may be asked to reproduce the information for future audits or inspections.
If the CSP has been dispensed before starting a failure investigation, a recall should be initiated by appropriate personnel, and patients and physicians should be immediately contacted. A recall should be followed and fully documented. If the CSP has not been dispensed, it should be quarantined until the investigation is complete.
The investigation should have a systemic procedure to review all of the items associated with the compounding of the CSP. Records of the compounding activity should be reviewed and other sterility failures or out of specification results examined for trends or consistent failure points. Further investigation may be needed and it has been suggested to conduct the investigation of the pharmacy operations using the acronym PEEMM, which represents people, environment, equipment, materials, and methods.
Depyrogenation and Endotoxin Testing
Pyrogens are organic compounds that are soluble in water and are not removed by filtration. They usually are endotoxins produced by gram-negative bacteria and are found in the cell wall. Endotoxins are at least 1000 times more potent than any other microbial agent and are stable over long periods of time. The endotoxins increase capillary permeability, and in small concentrations cause a variety of adverse effects such as fever, diarrhea, altered resistance to bacterial infections, complement activation, and leukopenia followed by leukocytosis. In greater concentrations, they cause septic shock that can lead to multiple organ failure and death.
The endotoxin test is the simplest test to perform in-house at the time of compounding. The test uses disposable Limulus Amebocyte Lysate (LAL) cartridges in a handheld spectrophotometer. During the testing procedure, kinetic chromogenic reagents and endotoxin controls are dried in the channels of the polystyrene cartridge. Diluted medication is pumped though the channels and mixed with reagents. The software monitors optical density changes in the solution, determined to reaction times, and interpolates the results against an archived endotoxin standard curve. The analysis is automatic, and the results can be read and interpreted in 15 minutes.
The types of preparations that should be screened for pyrogens include injectable preparations, intrathecal preparations, and all high-risk level sterile preparations made in batches of 25 or more. The decision to do endotoxin testing is often determined by the cost. When time is a factor and results are needed before a preparation is administered, an in-house endotoxin test kit is preferable to submitting a sample to an independent laboratory for testing. If contract laboratory testing is deemed preferable, then determining the reliability and accuracy of the endotoxin testing offered is essential.
- A process validation might involve sending formulations to contract analytical laboratories for testing. Analysis of drug content, sterility, and pyrogenicity can be routinely done using randomly selected samples.
- Process validation could be observing and testing formulation variables such as color, clarity, uniformity of dispersion, odor, consistency, pH, specific gravity, etc.
- The validation could also be documenting adherence to formulation records, policies and procedures, SOPs using compounding records, or techniques or procedures. Some example forms for Home Infusion Pharmacies have been published.
Routes of Administration Requiring Sterile Formulations
Some routes of administration demand that products do not bring microbial contamination with them into the body. This is required because some routes of administration by-pass the body’s natural defense mechanisms, or some tissues or organs are so sensitive and vital that such contamination could be serious.
All of these “sterility demanding” routes are parenteral routes.
NOTE: But not all parenteral routes are “sterility demanding” routes.
The term parenteral means next to or beside the enteral. Enteral refers to the alimentary tract, so parenteral means sites that are outside of or beside the alimentary tract. Since oral, sublingual, and rectal comprise the enteral routes of administration, any other route is considered a parenteral administration site. Topical administration is a parenteral route that does not require sterile formulations.
The parenteral routes of administration are used for various reasons.
- If a drug is poorly absorbed when orally administered or is degraded by stomach acid or the gastrointestinal enzymes, then a parenteral route would be indicated.
- The parenteral routes are also preferred when a rapid and predictable drug response is desired as in a emergency situation.
- Parenteral routes of administration are also useful when a patient is uncooperative, unconscious, or unable to take drug via an enteral route.
- Parenteral routes are used when localized drug therapy is desired.
- They provide a predictable and nearly complete bioavailability.
But there are major disadvantages.
- Most of these parenteral formulations are more expensive than enteral route formulations.
- Most these parenteral formulations must be sterile.
- Many formulations require that a skilled or trained person administer them.
- Once the drug is administered, it may be difficult to remove the dose is there if an adverse or toxic reaction.
The National Coordinating Committee on Large Volume Parenterals (NCCLVP) defines instability as “a phenomenon which occurs when an LVP or LVP drug product (IV admixture) is modified due to storage conditions (e.g. time, light, temperature, sorption).” An unsuitable product may be formed.
Incompatibility is defined as “a phenomenon which occurs when on drug is mixed with others and produces an unsuitable product by some physiochemical means.” The new product is unsuitable for administration because the “active” drug has been modified (e.g., increase in toxicity), or because some physical change (e.g., solubility) has occurred.
If the instability or incompatibility of a given preparation is not known, the pharmacist should consider the factors listed in this section to anticipate the likelihood of these problems.
The pharmacist may use the following suggestions to minimize incompatibilities and instability:
- Use only freshly prepared solutions.
- Follow an established order of mixing, and mix the preparation thoroughly after adding each ingredient.
- Do not shake preparations vigorously unless indicated in the labeling. Rotate or swirl preparations to minimize foaming and the formation of air bubbles.
- Use as few additives as possible.
- Dilute any problem additive.
- Develop an incompatibility table or file for frequently compounded preparations.
- If the preparation is to be filtered, ensure that any removed particulate matter is not the active drug.
If an incompatibility cannot be corrected or prevented, consider the following administration techniques:
- Administer the preparations separately at staggered times.
- Flush the administration line or set between preparation administrations, and use normal saline, not heparin.
- Use an alternative site of administration.
Chemical and Physical Properties of the Admixture
Fortunately, each of the structural functional groups can undergo only a limited number of possible reactions. The most significant among them seems to be hydrolysis (as in the case of esters, amides, and lactams) and oxidation (of catechols, phenols, and unsaturated compounds) as well as precipitation of weak electrolytes or neutral, hydrophobic compounds. These reaction and their rates may be pH dependent.
A product may be stable or soluble only at a pH that is not physiologically safe. When added to an infusion, a change in pH could take place and the chance for precipitation or accelerated chemical degradation increases. For example, Potassium Penicillin G contains a citrate buffer, and the injection is buffered at pH 6.5 when reconstituted. The solution is stable for 24 hours at such pH; however, it loses activity much faster at a lower pH.
In general, the following intravenous fluids are NOT recommended for any drug admixture. These infusions are unstable by nature and drug admixtures could trigger adverse reactions such as coagulation, coalescence or gas evolution, therefore rendering the IV infusion potentially hazardous, if not fatal.
- Blood, plasma, and other blood products
- Plasma substitutes
- Protein hydrolysates
- Amino acid solutions
- Sodium bicarbonate
- Fat emulsion
You should recall that the solubility of a weak acid or base may depend on pH: amines (dobutamine, dopamine, epinephrine, morphine) are basic and are generally soluble in acid media, whereas carboxylic and other acids (penicillins, cephalosporins, 5-fluorouracil) are generally soluble in basic media. Making the former basic or the latter acidic could induce precipitation.
Common LVP and Their pHs
|D5 Lactated Ringer’s||5.1|
Different manufacturers may have slightly different pHs.
Nonelectrolytes in Solution
Generally, nonelectrolyte or neutral drugs (such as digoxin, phenytoin, and the benzodiazepines) are dissolved in a nonaqueous or a cosolvent vehicle due to their poor solubility in water. If the drug is placed in an aqueous environment, it may form a precipitate, with concomitant loss of drug activity and/or danger to the patient. The solvents used in nonaqueous parenteral products are usually listed on the product’s label. Hence, if the drug is dissolved in a water miscible solvent and one administers it slowly, dilution of the vehicle results in cosolvent fractions that maintain the drug in solution. If a cosolvent system must be used, the fraction of cosolvent in the initial stock solution should be as high as possible, to decrease the probability of precipitation upon administration.
Non-polar, sparingly soluble drugs stored in plastic containers tend to partition into the plastic container wall. A classical example is nitroglycerin. Nitroglycerin has low water solubility, approximately 0.1%, which suggests that it has high non-polar solubility. Indeed, if nitroglycerin in aqueous solution is placed in a polyvinylchloride IV bag (non-polar medium) or is delivered through a polyvinylchloride IV set, there is little doubt that with time the drug will be lost by adsorption to the plastic. This seems to be true also for vitamin A acetate, warfarin, methohexital, terbutaline, lorazepam, and insulin. Since the dosing of nitroglycerin is critical, it should be dispensed in glass IV bottles and infused with a special, non-adsorbing infusion set.
Interaction with Antioxidants
Several parenteral products contain sulfites to prevent oxidative degradation. Sulfites, however, may chemically react with other drugs. For example, fluorouracil and thiamine hydrochloride react with bisulfites which can lead to inactive products. Fortunately, when such incompatibilities are discovered, they often find their way into the literature for the benefit of others.
With the increased use of large volume parenterals as electrolyte and nutritional supplements, an unlimited number of potential incompatibilities could result. In general monovalent cations are usually compatible. However, divalent cations like calcium and magnesium can be troublesome in the presence of bicarbonate, citrate, and phosphate, reacting to form insoluble complexes. When bicarbonate reacts, it will decompose to release CO2 gas, which can have devastating clinical effects. Calcium also forms complexes with tetracyclines resulting in an inactivated product.
Many injections have special storage requirements such as protect from light (PFL) or refrigeration. Using these solutions in intravenous fluids may produce conditions not favorable to the drug’s stability. Light sensitive drugs, when administered through an infusion, should be covered with aluminum foil, or other opaque materials, during administration to reduce photodecomposition.
Some Drugs Which Undergo Photodecomposition
|Fluorouracil (5-FU)||Vitamin B Complex|
Certain pharmaceutical preparations require special precautions in their preparation to minimize product contamination or environmental hazards. The following information may serve as a helpful guideline for a few of these classes of drugs.
Parenteral Nutrition Solutions
Because of their high risk for bacterial growth and their vast potential for drug incompatibilities, these products require special attention. Strict adherence to aseptic technique and frequent sterility testing are essential. Whenever feasible, it is desirable to maintain a separate hood for nutrition solutions to avoid cross contamination with other medicinal agents.
Cytotoxic Agents (Cancer Chemotherapy Agents)
These agents present an environmental hazard. It is now known that prolonged exposure to these agents may lead to the development of cancers. For this reason special precautions must be taken to minimize the exposure of pharmacy personnel to these agents. These agents should be prepared in a shielded vertical flow hood, so that materials are not blown into the operators face. When possible it is best to have the responsibility for preparing these agents rotated among pharmacy personnel to minimize any one individual’s exposure. It is desirable that pregnant women be exempted from preparation of these agents.
These agents also represent an environmental hazard and must be handled carefully. In addition to adhering to the guidelines set forth for cytotoxic agents, one may further reduce his exposure to these agents by working with them in protective lead vial shields. Special storage and disposal of these agents is required.
Due to the allerginicity of the penicillins, it is desirable to work with them in a shielded vertical flow hood to avoid environmental contamination. When working with any of the antibiotics, it is important to remember that prolonged exposure may lead to infections of exposed areas by nonsusceptible bacteria and fungi. It is recommended that anyone who must prepare large numbers of antibiotic doses wash their hands frequently to avoid infections of the hands and nail beds.