Facility Equipment Introduction
Pharmacists have been providing sterile compounding services in institutions for decades.
These services have provided parenteral therapies, infusion services, and complex
infusion administration devices and supplies. However, in the past two decades,
compounding sterile formulations and providing administration services has expanded
beyond the institution. These additional areas include home care agencies, infusion
service agencies, outpatient clinics, and community pharmacies. Pharmacists
are also providing patient and caregiver assessments, education, and skills,
and are taking the responsibility for coordinating patient care through an interdisciplinary
Pharmacists will compound a wide variety of sterile formulations in these
different settings. These formulations will include products administered by
injection (IV, IM, SQ, ID, intrathecal, epidural) or via inhalation, intranasal,
or ophthalmic routes of administration. Sterile formulations for either institutional
or home care use have a number of special requirements such as:
- particulate material
- osmotic pressure
Sterility is the
freedom from bacteria and other microorganisms. Formulations must be sterile,
which is not a relative term; an item is either sterile or not sterile. It is not possible to have a compounded preparation (or manufactured product) to be 100% sterile or to check every manufactured or compounded dosage form for sterility since the results only apply to the actual samples tested. According to USP-NF General Chapter <71> Sterility Tests, there are several requirements for conducting sterility testing:
- cleaning and disinfection of the aseptic work area
- air quality and surface testing for microbial contamination
- glove imprint testing
- visual confirmation that personnel are properly donning protective garments
- certification of personnel knowledge and compounding dexterity
There are two official sterility testing methods. The minimum number of samples to be tested in relation to the number of CSP preparations compounded in a batch is given in Table 3 in General Chapter <71>. The number of samples to be tested depends on the size and type of CSP and the number of those items in the batch.
The first one filters a solution through a 0.45 micron filter to collect microbes on the filter. Then all or part of the filter is placed into containers with suitable media. The second method is a direct inoculation of the CSP sample on to the culture media.
The test results are based on the turbidity of the culture media. After 14 days, if the media remains clear, this indicates that there is no bacteria growth thus the preparation passes the sterility test. But if the media indicates microbial contamination, the test can be repeated using the same number of samples as the original testing. If the repeat test shows no growth, the preparation is judged to pass the sterility test.
General Chapter <797> Pharmaceutical Compounding-Sterile Preparations states that sterility testing outlined in Chapter <71> may be applied to low-risk level and medium-risk level CSPs. But for high-risk level preparations, a standard self-contained biological indicator should be added to non—dispensable specimens before terminal sterilization to determine whether the sterilization cycle was adequate.
If the sterile formulation is a solution, it must be free of all visible particulate
material. Particulate materials refer to the mobile, undissolved
substances unintentionally present in parenteral products. Examples of such
material are cellulose, glass, rubber cores from vials, cloth or cotton fibers,
metal, plastic, rust, diatoms, and dandruff.
It is not possible to have preparations 100% free of particulate matter, so General Chapter <788> Particulate Matter in Injections has defined two methods to count the number of particulates in injections. The light obscuration particle count method operates on the principle of light blockage and is calibrated with particles of 10 microns and 25 microns. The microscopic particle count method uses a microscope with an ocular micrometer at a magnification factor of 100.
Sterile suspensions and ointments may have particulate material, but these are usually the active drug or an ingredient, not contaminants. There, these dosage forms are generally exempt from the requirements of the chapter.
Particles measuring 50 microns or larger can be detected by visual inspection.
Specialized equipment is needed to detect particles less than 50 microns in
size. The USP 24/NF19 Section <788> sets limits on the number and size
of particulates that are permissible in parenteral formulations. For large volume
parenterals, the limit is not more than 12 particles/ml that are equal to or
larger than 10 microns, and not more than 2 particles/ml that are equal to or
larger than 25 microns. For small volume parenterals, the limit is 3000 particles/container
that are equal to or larger than 10 microns, and not more than 300/container
that are equal to or larger than 25 microns.
The potential sources of particular material are:
- The product itself
- Manufacturing and such variables as the environment, equipment, and personnel
- The packaging components
- The administration sets and devices used to administer the product
- The manipulations and environment of the product at the time of administration.
Sterile formulations must be pyrogen-free.
Pyrogens are metabolic by-products of living microorganisms. So if pyrogens
are detected in a sterile product, that means that bacteria have proliferated
somewhere along during the formulation process. In humans, pyrogens cause significant
discomfort but are rarely fatal. Symptoms include fever and chills, cutaneous
vasoconstriction, increased arterial blood pressure, increased heart workload,
pupillary dilation, piloerection, decreased respiration, nausea and malaise,
severe diarrhea, or pain in the back and legs.
The stability of drugs in sterile
formulations is an important consideration. In institutional settings, most
admixtures are prepared hours in advance of when they are to be administered,
and are generally utilized within a short period or time. In home health care
settings, admixtures are prepared days in advance of when they are to be administered,
and are generally utilized over longer periods of time compared to the clinical
setting. Therefore, the stability of a particular drug in a particular sterile
formulation must be known.
Physiological pH is about 7.4,
and an effort should be made to provide sterile formulations that do not vary
significantly from that normal pH. Of course, there are situations in which
this becomes a secondary consideration because acidic or alkaline solutions
may be needed to solubilize drugs or used as a therapeutic treatment themselves.
Osmotic pressure is a characteristic
of any solution that results from the number of dissolved particles in the solution.
Blood has an osmolarity of approximately 300 milliosmoles per litter (mOsmol/L),
and ideally any sterile solution would be formulated to have the same osmolarity.
The most commonly used large volume parenteral solutions have osmolarities similar
to that of blood; for example, 0.9% sodium chloride solution (308 mOsmol/L)
and 5% dextrose solution (252 mOsmol/L).
Intravenous solutions that have larger osmolarity values (hypertonic) or smaller
osmolarity values (hypotonic) may cause damage to red blood cells, pain, and
tissue irritation. However, there are some therapeutic situations where it may
be necessary to administer hypertonic or hypotonic solutions. In these cases,
the solutions are usually given slowly through large veins to minimize the reactions.