Clean vs sterile

Parenteral pharmaceuticals administered subcutaneously via injection or implantation require a greater amount of quality control throughout the entire product lifecycle to ensure the health and safety of the patient. Parenterals must meet the requirements set forth by the United States Pharmacopeia (USP), whose requirements apply not only to the product, but to the primary container in which the finished product resides. In order to comply with these requirements and others in the USP, it is necessary to properly understand the differences in meaning between the terms clean and sterile.

When evaluating a product against the standards outlined in USP <1788> Methods for the Determination of Particulate Matter in Injections and Ophthalmic Solutions, the state of being ‘clean’ or ‘essentially free’ of particulate matter is often difficult to define due to the large number of variables involved in detecting the particulate. Particulate matter includes, but is not limited to, extraneous undissolved particles, fibers, glass shards, metals, polymer fragments, and skin. Particulate matter contamination can originate from undissolved drug product, processing equipment, containers and their closures, the environment, and humans. It is helpful to have a sample of the known drug product to use as a reference.

This month's cover shows a drug reference sample, captured at 500× magnification using a digital camera (PAX-it PAXcam ARC™) attached to a polarized light microscope (Olympus BX51) with the polarizers fully crossed, using transmitted and coaxial illumination.

The methodology for determining the presence of particulate is contained in USP <788> Particulate Matter in Injections. Particulate matter is often generated at one or more points during the lifecycle of a parenteral pharmaceutical. There are several packaging and container types that parenteral pharmaceutical companies can choose for their product. Guidance can be found in USP <1177> Good Packaging Practices and General Notice 10.20 that states: ‘The container is that which holds the article and is or may be in direct contact with the article. The immediate container is that which is in direct contact with the article at all times. The closure is a part of the container. Before being filled, the container should be clean.’

Sterile is defined as having a complete absence of viable life that has the potential to reproduce. Particulate matter does not reproduce, so therefore can be present in products that have been tested only for microbial growth. It needs to be understood that when something is deemed sterile, it does not ensure that it is ‘clean’ or ‘essentially free’ of particulate matter. For example, rubber closures produced in an aseptic environment, which are then deemed sterile, are often packaged in a sterilized bag that may contain extraneous particulate matter, such as fibers, which could later show up in the finished product. Particulate matter testing needs to be conducted parallel to testing for microbial growth throughout the entire lifecycle of the product: for example, sterilized bags in which containers are stored and transported prior to filling should undergo testing for particulate matter. Experimental data suggest that humans are the only significant source for microbial contamination, unlike particulate matter, which can have numerous sources.

Good Manufacturing Practices (GMP) requires by regulation that manufacturers, processors, and packagers of parenteral drugs take the proper steps to ensure their products are safe, pure, and effective. Failure of companies to comply with GMP regulations can result in serious consequences.

Pharmaceutical and packaging companies can have their products tested for particulate matter contamination by sending their product to an independent analytical laboratory. USP <788> is just one example of a test that may be performed to determine the presence of particulate. Deviations to this test may be necessary if the items being tested are empty vials, bags, or closures.

In conclusion, the pharmaceutical industry has the challenge of maintaining the integrity of a product throughout its entire lifecycle by complying with the regulations and standards set forth by the USP and GMP. Unwanted particulate matter can be controlled by understanding the meaning of sterile and knowing that it does not mean particle free. Communication between manufacturers and packagers is critical in the delivery of components that are not only sterile, but also essentially particle free. Producing a parenteral product that is both sterile and essentially particle free will help to ensure the health and safety of the patient.