Emerging Technologies and Solutions for the Pharmaceutical Industry

By Matthew Bundenthal
URS and Technical Writer
Fette America

In recent years, the pharmaceutical industry has seen a growing number of products that pose potential health risks to those working with them. Airborne dust, in particular, can put the equipment operator at risk, when a formulation containing a high percentage of a potent, active drug substance is used. Adverse effects related to the handling of dangerous compounds can be respiratory, dermatological or reproductive. Complicating the issue further is the fact that some of these effects can go unnoticed in the short-term, and only develop over time, after prolonged exposure. Pharmaceutical products are typically administered for a specific purpose, at a very limited, controlled dosage. Therefore, it is important for workers exposed to such products during the manufacturing process to avoid uncontrolled exposure, especially over a long period of time.

Historically, the handling of many potent compounds necessitated the use of positive-pressure respirators, "moonsuits," and various other types of personal protective equipment (PPE). While the use of such equipment can help reduce exposure levels they are by no means foolproof. Filters must be replaced diligently and batteries must be re-charged often. There is no guarantee of proper fit, which can undermine the original design of the PPE manufacturer. Maintenance and replacement costs are substantial and the repeated replacement of certain components (i.e. filters) can also lead to compromised effectiveness and protection.
Occupational Exposure Limits

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The aforementioned issues and their relation to worker safety have led to the development of Occupational Exposure Limits (OELs). Toxicology studies determine what levels of exposure to a given substance can lead to adverse health reactions. Specific OELs are often established only by the company producing a given product, and can therefore vary from manufacturer to manufacturer. Additionally, it is sometimes difficult to establish an OEL early in a product's life cycle, due to minimal available pharmacological data. OELs are generally created with the assumption that they apply to healthy adults, over an 8-hour work day. The units of measurement used for OELs are micrograms per cubic meter (m3). The average sugar crystal weighs approximately 3 milligrams. One microgram would be represented by a quantity of 3,000 times less than that one crystal! The following pyramid diagram depicts various OEL categories, with the more dangerous or potent levels being represented at the top, as OEL5.

Some manufacturing processes and products require even tighter containment levels, with OELs being measured in nanograms, rather than micrograms. A packet of sweetener that one might put in a cup of coffee generally weighs 1 gram. One nanogram is what you would be left with if the same packet were cut up - one billion times!
OEL Hazard Categories
Products are classified according to hazard levels that correspond to these five OEL levels, as shown in the chart below.

CategoryHazard Description
OEL 1Harmful, and/or low pharmacological activity
OEL 2Harmful, and/or moderate pharmacological activity
OEL 3Moderately toxic and/or high pharmacological activity
OEL 4Toxic and/or very high pharmacological activity
OEL 5Extremely toxic and/or extremely high pharmacological activity
Emerging Technologies and Solutions
Surrogate Test Results

Fette America recently underwent rigorous surrogate testing with their WIP/Containment equipment and related systems. On May 27, 2004, a highly structured and closely monitored surrogate test was performed at Fette America's facility in Rockaway, New Jersey. The test was monitored, and the subsequent results were recorded, by Broadspire/Natlsco, a third party consultant with expertise in this field. The primary equipment utilized for the test was the Fette 2090i WIP tablet press and two Carlisle Barrier Systems isolators, housing a Fette Gratex De-Duster, a Safeline Metalcheck Unit, and a Schleuniger AT-4 Tablet Testing Unit. The surrogate material utilized for the test was Naproxen Sodium, and a target OEL of 60 nanograms per cubic meter TWA (the equivalent of exposure over a hypothetical 8-hour work shift) was identified as the maximum allowable exposure limit for three key measurable parameters:

• A primary operator, who would only occasionally enter the test lab during the manufacturing process to make brief observations
• A secondary operator, who stayed in the test lab throughout the manufacturing/test operations
• A post-operation / WIP compression zone

The final reported exposure levels for the aforementioned operators and equipment were as follows:

ParameterMeasured Exposure Level
Primary Operator< 1 ng/m3
Secondary Operator< 33 ng/m3
Post operation / WIP compression zone< 10 ng/m3

The results indicated that the equipment tested would offer a level of protection that greatly surpasses an already stringent requirement. Despite this, Fette has continued to optimize and refine their WIP / Containment technology, including the manufacture of their own isolators, which offer even greater control over the manufacturing of potent compounds.

A second surrogate test was performed at Fette's factory in Schwarzenbek, Germany, again with a 2090i WIP Tablet Press, and now with isolators manufactured by Fette themselves. The test was again overseen by a third party consultant firm. Based on equipment availability at the time of the test, OEL levels were measured at the press and isolators only. The isolators contained an uphill de-duster, a metalcheck, and a washable CheckMaster weight/thickness/hardness tester. No high-containment bulk container (IBC) or split-valves were utilized.

The final results indicated that the OEL at the press and isolators during manufacturing and cleaning (vacuum and wet washing) was below the detection limit of < 1 ng/m3 TWA.
All of these issues led to a need for specifically-engineered manufacturing equipment and systems that would offer far greater protection to individuals regularly working with potent compounds. Good Manufacturing Practices (GMP) mandate that it is important not only to protect the operator from dangerous substances, but also to provide thorough cleaning of the manufacturing equipment between batches of different products to ensure no cross-contamination. When it came to tablet press technology these two important developing requirements resulted in the need for a highly-contained system that also has integrated wash capabilities. Only by marrying the two systems can an operator:

• be assured of protection from potentially dangerous airborne particulate matter
• interact with and manipulate the tablet press while a batch is being manufactured
• clean the press very rapidly with minimal hands-on time, and with no risk of exposure to dangerous compounds
• clean the press in place, without risk of contaminating adjoining/adjacent rooms, pathways, or equipment
• have the press ready for acceptance of the next product in the shortest time possible

It is imperative that pharmaceutical manufacturers remain diligent about the needs for containment and operator safety, especially in cases where potent compounds are used. Equipment vendors must be equally diligent, and willing to sit down with a client early on in a project and clearly identify the needs for engineering, special handling, containment, processing and cleaning.
Wash-in-Place vs. Clean-in-Place
Since the advent of projects necessitating tablet presses that clean themselves and make use of high containment features, there have been two schools of thought: Wash-in-Place (WIP) and Clean-in-Place (CIP). The basic premise behind a WIP design is quite simple and, more importantly, effective in real-world settings. Following the processing of a batch, the machine utilizes a cleaning system that effectively binds any airborne particulate matter to water, which is then drained from the machine before any access door is opened. Following the automated cleaning process there is no longer any remaining risk of inhaling airborne matter and the machine can therefore undergo its final manual cleaning with no risk to the user. Given the fact that it is clearly understood there will always be a final check made by the user, a WIP system can be reliably and easily validated. CIP, on the other hand, can prove to be extremely difficult to validate. Many CIP systems use components or tools that vary greatly from widely accepted industry standards, and can prove to be very, very expensive. Certain sub-systems on such equipment can be virtually impossible to clean properly, leading to protracted validation endeavors.
WIP vs. Compartmentalized Design

Surrogate testing of Fette 2090i WIP tablet press, Carlisle isolators, and related equipment at Fette America on May 27, 2004
There are alternative methods for protecting the operator from potent compounds on modern tablet presses. There are WIP designs that intentionally allow water and cleaning agents to reach all surfaces within the compression zone following a batch, and there are compartmentalized designs, that purportedly allow the user to contain product within a certain compartment and then move the entire compartment to another area for cleaning. The safety-related implications associated with running potent compounds on these types of presses warrant a deeper analysis of these alternative designs.

Equipment as tested in Germany
The WIP tablet press offers numerous advantages that are derived directly from real-world directives put forth by pharmaceutical companies involved with the manufacturing of potent compounds. It is imperative that the compound in question remain isolated from the operator and adjacent areas not only during the processing phase, but during all phases of cleaning as well. By washing in place, the user ensures that the product stays in one localized area, with little risk of contaminating other equipment, hallways, or rooms. A compartmentalized design necessitates the eventual movement of the compartment from the processing room to a cleaning room. This transport of the compartment, especially in the absence of controlled negative pressure, can potentially lead to unintended contamination of other areas and migration of the compound from the compartment. The WIP design operates under constant negative pressure through all phases of processing, thereby greatly reducing the concern of contamination or product migration. When the cleaning cycle is complete, the user can simply and safely open the press for final cleaning, with no risk and without a need for moving large components to other areas or rooms. Compartmentalized designs currently necessitate the use of bags for closing off potential sources of product egress, such as discharge ports, product inlets, etc., thereby further increasing the risk of contamination, to the user and/or work space.
In-Process Manipulation

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OEL results from the surrogate test in Germany
(x axis = time, y axis = OEL in ng/m3)
Through the use of several key features a WIP design allows the user to interact with the tablet press and isolators (if so equipped) while a batch is being processed. The ability to do this is absolutely critical, as there are always events leading to the need for operator intervention. Examples of this need can be a broken punch, a particularly sticky product, or the need to change a fill cam. The WIP design makes use of strategically placed glove ports that allow the user, once the press stops moving, to reach into the machine and make necessary changes or adjustments, without compromising containment. Each glove port is microswitch-controlled, ensuring that a user cannot inadvertently make use of the glove ports while the turret is still rotating. Making things easier still is the use of a Rapid Transfer Port (RTP), also strategically located, that allows for the introduction or removal of small components into or from the press. The key, once again, is being able to easily and safely manipulate the machine and/or isolator without compromising containment integrity.

During the past few years, the industry has indicated a preference for as much single-sourcing as possible, including totally integrated systems with great attention to detail in all aspects of complete system containment, cleaning and process electronic control.

This industry mandated attention to detail has led to the development of the following:

• WiP Center for washing the entire system including all ancillary equipment. This includes a common nozzle system, sparging ball system, manual spray in compression compartment, manual dust extraction.

• Single-sided discharge for double-sided press thus eliminating costly duplication of dedusters, metal check, loading drums and extra isolators to contain same, as well as reducing space requirements.

• GMP cleaning features, such as smooth surfaces, pitched stainless steel casting for central drain, product specific wash cycle, product specific washing agents, stainless steel components including stainless steel segmented turret, special door seals, special tablet chute assembly, vertical seals for leak proof considerations.