Ensuring Sterility of Parenteral Products

Experts describe best practices for sterility assurance in parenteral drug manufacturing. This article contains bonus online-exclusive material.
Apr 01, 2013

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Sterility assurance is of paramount importance in parenteral drug manufacturing. These products are administered directly into the bloodstream, bypassing the body’s natural defenses. Contamination of parenteral drug products, therefore, can have serious consequences on the patient. To gain further insight into best practices for sterility assurance, Pharmaceutical Technology spoke to James Agalloco, president of Agalloco & Associates and member of Pharmaceutical Technology’s editorial advisory board; Tim Sandle, head of microbiology at Bio Products Laboratory; and Benoît Verjans, scientific advisor at Aseptic Technologies and member of Pharmaceutical Technology’s editorial advisory board.

PharmTech:What are the most common sources of contamination that can arise in sterile manufacturing or aseptic processing?

Agalloco (Agalloco & Associates): The most common source of contamination has been the operator. We’ve all known this for years and there’s been a steady progression of technology advances to reduce the problem that the presence of the worker presents. It started with curtains, and has progressed to closed restricted access barrier systems (RABS) and isolators. The next advancement in this area will be the use of robotics and automation to further reduce the impact of personnel.

Sandle (Bio Products Laboratory): Parenteral drug products are required to be free from three things—viable microorganisms, pyrogenic substances (which essentially means a low-level of bacterial endotoxin), and visible particulates.

There are different sources of microbiological contamination within clean environments. They can be divided into water, air, surfaces (both within the room and from equipment), and personnel. The main risk from water sources is to product formulation and the activities up to and including final sterilization. In my experience, the greatest concern comes from wet equipment, allowing water-borne bacteria such as Pseudomonads to grow.

Water is a double concern because it is a vector for contamination and a growth source for microorganisms. We cannot avoid water in cleanrooms. Water is a common feature in pharmaceutical processing (e.g., as an ingredient, a cleaning agent, a diluent for disinfectants, and steam supply).

Other sources that affect aseptic processing include improperly designed clean air devices and air-flows that can direct microbial-carrying particulate contamination towards the exposed product. Importantly, these microorganisms will come from people, who are the biggest contamination risk within cleanrooms. As with water, we cannot wholly exclude people from cleanrooms, although we can reduce their contact with critical zones through the use of barriers such as isolators.

People can also pose a risk through touching, such as moving a contaminated object from a less clean area to a cleaner one, or more directly via their gloved hands. This risk often arises through improperly sanitized hands, where hands are either not sprayed frequently enough or the hand-rubbing technique, once the glove alcohol has been sprayed on, is not carried out effectively. Another important area is training; especially on aseptic techniques, gowning, and cleanroom behaviors.

Verjans (Aseptic Technologies): There are two distinct categories of contamination of injectable drugs. Some contaminations are a result of bad practices and in this case, multiple containers are usually affected. These contaminations are identified through outbreak episodes that affect several patients. Recent examples include the contamination from a cracked glass container that affected eight newborn babies in the Mainz hospital in Germany, of which three died; and the contamination case involving approximately 700 people in the US due to corticosteroids infected with a fungus triggering meningitis (1, 2). For the second case, it is obvious that bad practices led to the production of heavily contaminated batches by the compounding pharmacy. The other group of contamination is more insidious because it affects one vial from time to time. The source of contamination is a living organism that managed to penetrate the container at a certain moment and, if not detected, may trigger disease episodes such as septic shock. Because it is a single event, this type of contamination is often classified in the group of nosocomial diseases. A rough estimate of outbreak analyses and nosocomial disease epidemiology suggests that one out of 100,000 containers has a contaminated drug, resulting in approximately 30,000 contamination accidents in the US due to contaminated drugs (3).

Contamination of drugs may come from various sources but in most cases, we can identify a human being behind the contamination. It can be due to multiple sources of mistakes such as gowning mistake, whereby living organisms are carried on the gowning; lack of maintenance of a protected environment; contamination of product contact parts during manufacturing; or disrespect of procedures during sanitization.