The Biotech Industry: Cleanrooms and Compliance

By SUSAN ENGLISH

Union, NJ–Schering-Plough Corporation, a mid-size pharmaceutical firm with sales of $4.7 billion, recently dedicated two new, state-of-the-art biotechnology clinical production facilities–a 20,000-ft2, $30 million Biotechnology Clinical Production Facility in Union, NJ, and a 16,000-ft2, $20 million plant near Lucerne, Switzerland. The plants are part of the company`s plan to accelerate the development of its new, biologically-derived products for use in clinical studies (anti-cancer and anti-viral drugs), while complying with continually evolving FDA, GMP and other industry standards. Both facilities opened in March and feature cleanroom areas ranging from Class 100,000 to Class 100. Both plants are part of the Schering-Plough Research Institute. They will serve as multi-purpose fermentation/purification sites for bulk protein products.

Clean Designs and Finishes

Schering-Plough has incorporated into its Union facility high quality architectural designs and easily cleanable finishes able to withstand regular disinfection. Floors are either epoxy Terrazzo or trowelled-on epoxy. Walls were constructed of impermeable PVC covering on cement board with flush-mounted control panels and instruments, and stainless steel panels were used in wash areas. Doors are of stainless steel with flush-mounted frames and ceilings have an epoxy-painted finish and flush-mounted HEPA filters and lights.

Stringent industry standards for design, construction materials, fabrication techniques and inspection methods were also used in the fabrication of process equipment and piping. Wherever possible, closed process systems were used to prevent product exposure to the operating environment. Clean utility systems were installed to provide high purity air, water and steam for process areas and operations. An automated clean-in-place (CIP) system for reproducible and validatable cleaning of process equipment and piping was installed, and a distributed computer control system provides automated control, monitoring and reporting of key process and utility functions. Stainless steel piping finishes–316 L with a 30 Ra internal finish and automatic orbital welds with argon purge–are used for USP (U.S. Pharmacopeia) purified water, WFI (water for injection), clean steam, CIP and process systems. For stainless steel process tanks and valves, a 15 Ra, electropolished internal finish was selected.

Dr. Douglas S. Inloes, Senior Associate Director of Biotechnology Production at the Schering-Plough Research Institute, has responsibility for the latter stages of process development and scaleup of biotechnology products. Specifically, his group is responsible for fermentation and purification. Talking about the “clean” conditions essential at the various stages of processing and manufacturing, Inloes says, “As you get closer to the final purified bulk material, the emphasis by the FDA is to operate under much cleaner and cleaner conditions. We end up being forced to address a clean environment in a number of different ways.”

Those ways include application of the FDA`s Aseptic Processing Guidelines, environmental monitoring, and testing of product “bio-burden” and endotoxin levels. (Bio-burden refers to the number of microbial counts found in the product. Endotoxins are materials produced and released by certain bacteria, which may cause a pyrogenic response.) In the purification facility, all air supplied to processing areas is HEPA filtered. In the initial stages of processing, the plant normally operates under conditions that approximate Class 100,000. However, as material becomes more and more pure, the design criteria range from Class 10,000 for rooms to Class 100, where laminar flow hoods/areas create mini-environments for any open operations that could potentially expose the product to external sources of contamination. Most of the critical purification steps occur in a Class 10,000 “cold room,” where temperatures are kept between 2&#176C and 10&#176C to prevent the protein product from degrading and to control the growth of potential microbial contaminants.

Differential pressurizations of approximately 0.05 inches of water are maintained between process rooms and access corridors. Process rooms used in the final purification steps are maintained at higher pressurization than those used in the initial purification steps. An automated system was installed for the measurement of non-viable particulates to continuously monitor air quality.

Standards, Validation and Certification

After construction of the facility was completed in July of 1994, an extensive startup and equipment commissioning phase was begun concurrently with validation of the facility, a process mandated by the FDA for GMP manufacturing facilities. Facility validation was completed in March, 1995. Torcon, Inc. (Westfield, NJ) was construction manager for the project.

Discussing the “standards” issue, Inloes observes that in the last 10 years, the FDA has been pushing everybody in the industry to much tighter control. “The industry is finding it necessary to operate essentially in a cleanroom environment.” Schering-Plough has taken a “proactive” approach to compliance with FDA guidelines, and some of its manufacturing levels of cleanliness are considerably higher than those specified by the FDA.

According to Inloes, the FDA`s GMP guidelines are just that–guidelines: the FDA leaves the specific design details of the facility up to the individual manufacturer, although it can withhold approval of the establishment license if the facility design is found to be unacceptable during its subsequent review. The challenge is to develop a cost-effective design that provides proper environmental control over the longer term without creating unnecessary or unmanageable restrictions on the operations. The pharmaceutical industry tries to work closely with the FDA to define what are appropriate and acceptable design approaches. “When you design a facility like this, you know from your own experience and that of other people in the industry (what are acceptable design approaches)–and based on the kind of input you get from the FDA inspectors as to what their expectations are.”

For example, to arrive at an industry design “standard” for a purified water system capable of producing water that can be injected into humans, there are certain water quality attributes in terms of the presence of trace contaminants that are allowed–chemically as well as microbiologically. Through experience, the industry has found certain types of water system designs to be successful in meeting those particular water specs. The industry then “collapses” on those system designs they know will meet the water quality standards. n