By Erich H. Bozenhardt and Herman F. Bozenhardt
One of the most intriguing experiences we have had in our business in the last 20 years is being faced with a seemingly simple water-soluble topical or device component fill and then being told it is an organic peroxide! When we in our nice, safe water-based business (leave out liposomes) are faced with the compounding fire/electrical/OSHA compliances along with our GMP issues, it starts to read like a 1940s detective mystery.
I was sitting in my office. The day was shaping up to be like any other at the filling lines, when the phone rang. The caller, in a panic, asked if I can get the line ready for a new product. I said, “Sure, I worked with many new aqueous products on my old lines; we can do anything.” The caller replied, “There is a problem, a bad problem, a bad actor in this; can you can help me?” (Organ music blares.) He paused. “Are you familiar with handling organic peroxides?” (More organ music.) The bad actor in this case was BPO, benzyl peroxide, a compound that has both a fuel source and oxygen (two legs of the fire triangle) built into it. In addition, it can exothermically degrade in the presence of certain contaminates, making handling of purified BPO handling interesting. Danger, intrigue, and the investigation commences.
Understand Your Potential Hazards
The first step in planning any tech transfer is to understand the materials and process. Hydrogen peroxide is a main ingredient in lens cleaning and various medical device sanitizing fluid systems. BPO is the active ingredient in acne topicals, and those end formulations are sufficiently dilute that they are non-hazardous. Each peroxide has a specific class (NFPA [National Fire Prevention Association] 400-2019 and IBC [International Building Code] Chapter 2) based upon the formulation’s reactivity, the rate of combustion, and the detonation potential. These industry codes provide the safety requirements in terms of handling, storage temperature, storage container size, etc. Often in the dilution (formulation) process, a Class I (very hazardous material) can be reduced to a Class V (non-hazardous), if done correctly. In other cases, a formulation/dilution of a bad actor will only see a slight reduction, in this case from a Class II of pure BPO to a Class III at formulation.
This particular formulation of BPO doesn’t start decomposition until it is above 35 degrees C. Determining the hazard class is the first step in designing for hazardous materials.
The IBC is the go-to guidance for dealing with hazardous materials in design. Most states adopt the IBC in whole, but you need to verify that your particular local authority doesn’t have any amendments to the IBC.
The requirements in the IBC and good building design practices drive the design of the buildings. In the development of an engineering solution, we need to consider the transition of all the materials in the building. The second point of designing for hazardous materials is to understand the material flows throughout the process:
- Where is it stored?
- What are the temperatures?
- How are they stored, at what quantity and what are they stored in?
- Are the storage vessels or containers vented or not?
- Exactly where is it processed?
- How much is present at each stage?
- How are transfers done?
- Is the processing closed?
- How is the equipment cleaned, and where does the residuals or disposal go?
- What are the other materials used for cleaning?
In the IBC, these factors play into Table 307.1(1), which is effectively a risk assessment based on how hazardous the material is, how likely it is to have a loss of control and at what point in the process and building, and the impact/quantity involved. The table stipulates a building classification (aka engineering controls) based on those factors. In other sections of the IBC, similar tables cover fire sprinkler density and electrical classification. Some of these are interrelated; for example, sprinkler protection can increase the allowable quantity without moving to a hazardous building classification.
When working these renovations and processes, one should ask what cleaning material is used. Often “USP IPA” is the reply when dealing with oxidizers. United States Pharmacopeia certified isopropyl alcohol adds another factor to address, because now you have a flammable hazard. There will also be additional hazards, as sporicidals and other disinfecting agents have peroxides, solvents, and surfactants that, when combined, could exacerbate the situation.
Special Considerations For Flammable Materials
The same steps of classifying and understanding the material movement in the process are required for flammables, but now electrical classifications factor into the design. NFPA 30 is the base document for electrical design when flammables are present in the U.S.
Often, we find that the fill pump selection for a typical aqueous operation requires additional considerations in order to be used with flammable fluids. For example, on piston pumps, the fluid itself is the lubrication between the cylinder and piston walls. Additional mitigations are needed when this path is open and the motor is not ATEX rated (Atmosphère Explosibles, the European directive 2014/34/EU on handling potential explosive areas). A European equipment supplier may be more comfortable in conforming to ATEX, but in most areas UL or NEMA certification will be required instead of ATEX. In these cases, one solution is to have the pump end of the unit segregated from the motor by a solid barrier that keeps it out of the filling area and maintaining the inside of the filling area under constant exhaust to keep the amount of flammables in the air below the lower flammability limit (LFL).
Classification and, subsequently, rating, is based on the probability of a flammable/explosive environment. If a process is open or routinely opened, it is likely a flammable mixture could exist; therefore, the space around the open process would be classified as Class 1 Div. 1, and an electrically rated device with a low probability of providing enough energy to ignite the mixture would have to be used. If the systems are designed for closed processing, the likelihood of a failure creating a flammable mixture at the same time as an electrical device produces enough energy to ignite the mixture is low, allowing classification as Class 1 Div. 2. In this space, electrically rated devices might not be needed, but other considerations, such as electrical outlet location/height and potential construction materials, must be taken into account. A normally hot device like a heat sealer would most likely not be able to be in the space and an evaluation of the operating temperature versus the ignition temperature of the particular mixture would need to be done. Often, instead of explosive-proof motors, pneumatically driven motors are used.
Determining the electrical classification and appropriate device is more than just an electrical engineering activity. A process engineer should be involved to assess the hazard of the chemical, such as assigning a group as an indication of the minimum energy needed for ignition. As an example, IPA is in Group D of the IBC/NFPA. Also, a mechanical engineer should be consulted as to the airflow dynamics in the room in order to help locate LFL sensors and design appropriate exhaust systems. It is key to remember that ACR (air change rate) alone cannot mitigate the hazard classification. In some cases, dilution is needed to reduce the concentration of the flammable material. High ACR provides a well-mixed system and exhaust/makeup airflow provides the reduction in concentration.
In the pharmaceutical industry, the airflows that are maintained in the filling zone typically prevent flammable mixtures from being produced. However, there are a few points to consider. A recirculated system may accumulate flammable vapors. The amount of makeup air needs to be sufficient to prevent a buildup above 25 percent of the LFL. An LFL sensor should be used to verify that the LFL stays below 25 percent and, if exceeded, take action (i.e., shut power to machine and/or increase exhaust). This type of engineered approach needs to be presented to the authorities having jurisdiction (local code official), as not all jurisdictions have adopted NFPA 497 and may force a more prescriptive classification based on distances. Another consideration is that any recirculated air should only be returned to the room it originated from; otherwise, flammable vapors could be spread throughout the building. This requires a calculation of processing and fugitive emissions. In most cases, once-through air is the safest approach within that processing suite.
Using Isolators To Mitigate Hazards
Isolated fill lines provide another opportunity to mitigate both flammables and oxidizers. The isolator can be operated under an inert atmosphere (e.g., nitrogen) and can serve as the closed system. Using the isolator as the closed system boundary will allow a reduced electrical rating in the room and increased quantity of material allowed before exceeding the control area.
For assessing this type of technology transfer, begin with understanding the materials and formulation. Then map out the material flows through the process. This map will reveal the building’s suitability for the process. If the material is flammable, then electrical classifications need to be determined. Typically, this leads to mitigations and a recheck of building suitability and electrical design. The details of exceeding the IBC control area limits and International Fire Code requirements associated handling these hazardous chemicals are not addressed in this article but must be considered.
About The Authors:
Herman Bozenhardt has 43 years of experience in pharmaceutical, biotechnology, and medical device manufacturing, engineering, and compliance. He is a recognized expert in the area of aseptic filling facilities and systems and has extensive experience in the manufacture of therapeutic biologicals and vaccines. His current consulting work focuses on the areas of aseptic systems, biological manufacturing, and automation/computer systems. He has a B.S. in chemical engineering and an M.S. in system engineering, both from the Polytechnic Institute of Brooklyn. He can be reached via email at email@example.com and on LinkedIn.
Erich Bozenhardt, PE, is the process manager for IPS-Integrated Project Services’ process group in Raleigh, NC. He has 13 years of experience in the biotechnology and aseptic processing business and has led several biological manufacturing projects, including cell therapies, mammalian cell culture, and novel delivery systems. He has a B.S. in chemical engineering and an MBA, both from the University of Delaware. He can be reached at via email at firstname.lastname@example.org and on LinkedIn.