The Pharmaceutics and Compounding Laboratory
Sterile Compounding

Sterile Compounding Techniques

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.

Cleanliness Facts
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.

  1. 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.
  2. 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.