The Pharmaceutics and Compounding Laboratory
Sterile Compounding

Guidelines, Equipment, and Supplies for Sterile Compounding



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 team.

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:

  • sterility
  • particulate material
  • pyrogen-free
  • stability
  • pH
  • 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.

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. Sterile suspensions and ointments may have particulate material, but these are usually the active drug or an ingredient, not contaminants.

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:

  1. The product itself
  2. Manufacturing and such variables as the environment, equipment, and personnel
  3. The packaging components
  4. The administration sets and devices used to administer the product
  5. 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.