Keeping up with USP <467>

Peter K. Kang, PhD
Development Manager, and
David Hildreth, Senior Development Engineer
Anticon Products by Milliken

In the pharmaceutical cleanroom environment, controlling bacteria is, and probably always will be, the big issue. But as regulations evolve and new rules are added, other contamination sources emerge to share the spotlight.

One such regulation, made official in 2007, is USP <467>. Its tougher standards for residues in pharmaceutical products have caused an industry-wide reaction, and a shift in validation protocols.
Residues now under Regulation
Contamination from nasty bugs such as P. aeruginosa, A. niger and the potentially deadly S. aureus can reduce yields and jeopardize compliance with FDA regulations. Total particle count is also a factor - the number and size of particle contamination should be under control to produce safe products and meet standards. But the United States Pharmacopeia (USP) compendium's newly modified regulation, USP <467>, adds an additional metric to the mix: residue level control.

Certain drugs were previously subject to residue monitoring, and suggested guidelines were in place for all manufacturers for a considerable time. But after July 1, 2007, all products, not just those for which the monograph specifies, are subject to residue monitoring. Residue reduction is now required, not merely suggested.

Residues, or organic non-volatile impurities, occur when even minute amounts of the substances used to kill bacteria remain in the finished product. The standards are adjusted depending on the relative toxicity of the antibacterial substance, but even the least toxic residues apply to this new standard.
More Consider Process Analytical Technology
To address changing regulations, the industry is increasingly willing to adopt process analytical technology to better monitor contamination compliance. Though the FDA's initiative to promote the measurement technique began over five years ago, and some in the industry began to use the procedures even before then, industry-wide adoption is still developing.

Process analytical technology (PAT) allows real-time, on-location measurement of quality control factors. Metrics range from the simple, such as pH or temperature, to more complex metrics such as near-infrared spectroscopy (NIR) or Raman mapping.

Imagine catching production problems in-process, and fixing them before an entire batch is produced and contaminated. PAT can minimize damage from contamination issues by identifying them as they happen. Because testing is performed in-process and not after production is completed, the technique can also dramatically reduce the lag-time between ingredient manufacturing and the delivery of pharmaceutical products.

It can be difficult to develop PAT procedures, since they can be complex and must be highly customized to a particular manufacturing environment. But when it comes to getting products to the shelf faster, and compliance with ever-tougher standards, many in the industry agree PAT is the way to go. Companies are finding the benefits sometimes far outweigh the difficulties.
Battle Residues with Next-Generation Consumables
In addition to an increased focus on PAT, manufacturers are relying on new developments in the cleanroom supplier's arsenal. In response to tightening regulations, industry suppliers have released next-generation solutions to the residue problem, including hydrogen peroxide vapor and new versions of the sterile wiper.

Hydrogen peroxide vapors, when properly controlled, can disinfect without leaving the residues sometimes associated with liquid disinfectants.

Unlike formaldehyde, hydrogen peroxide doesn't leave a toxic residue after cleaning. In addition to the substance's lower toxicity, hydrogen peroxide vapor has the added benefit of the gaseous state's quicker dissipation. Air quality must be carefully controlled and leaks sealed to protect employees returning to the environment after cleaning, but hydrogen peroxide vapor is proven an effective disinfectant.

For other disinfectant solutions, the newest sterile wipers allow cleanroom operators to reduce residues and remove particles in one step. Squirt bottles can prove difficult to control, and operators may not be able to feel their way to the proper amount of liquid through thick cleanroom gloves. Pre-wetted wipers, on the other hand, can be an easily adopted solution to reducing residues in pharmaceutical production. Wipers can further ensure sterilization by removing dead bacteria from the environment.

For ultimate particle control, and to reduce recontamination risks in a disinfected environment, engineered cleanroom wipers can be an appropriate choice. New engineered wipers with particle attraction technology can be an incredibly effective solution to particle removal, and can safeguard a sterilized environment. Wipers with this particle-grabbing property can remove dead bacteria and retain it, preventing the contaminant from dropping off and returning to the cleaned surface.
Remember the Basics
A proper balance of new technologies and attention to basic validation truths is the perfect formula for contamination control. New regulations call for a reevaluation of cleanroom validation practices. But while contamination control is an ever-evolving problem, and new innovations can certainly help in the fight, these basic remedies are also vital to the contamination control cause.

1. Train and retrain. When problems in contamination control occur, check to make sure employees on the floor are following the validation engineers' prescribed programs. Regular training can go a long way in consistent compliance - consider checking in on a regular basis to head off contamination issues at the pass.

2. There's a right way. Even the most sterile cleanroom wipers and mops are ineffective without proper wiping technique. Make sure your employees are versed in the proper techniques and are comfortable with all cleaning materials.

3. Consider the season, consider the source. Bacterial contamination can vary with the seasons; for example, mold is more prevalent in the spring and fall than any other time of year. Change protocols to allow for known seasonal changes, and the unique bacterial environment of your location. Customization is vital.

4. Seek outside training. To keep up with ever-changing regulations, training and other external sources can be a key to success. Your current vendors can be a great source for training, or choose a well-known consultant to help in the design of validation protocols.
Between yearly editions of the USP-NF manual and bi-annual revisions, pharmaceutical regulations are ever-changing, and sometimes challenging to meet. The result, however, is higher standards, accountability industry-wide and improved quality for customers.

To meet regulations, utilize the resources available in the marketplace, from engineered supplies to consultants and training. And train employees well to use new technologies to best effect. With proper training and the latest materials, reducing contamination due to residues is certainly within reach.

About the authors:
Peter K. Kang, Ph.D., is a development manager for Anticon Products by Milliken. Kang holds a doctorate in chemical engineering from the University of Florida. He has authored ten journal articles and conference proceedings and holds four U.S. Patents. (864) 237-3724,,

David Hildreth is a senior development engineer for Anticon Products by Milliken. Hildreth has 16 years of experience in textile product development, has authored two journal articles and holds three U.S. Patents. He holds a bachelor's degree in textile chemistry from Clemson University. (706) 302-3989,,