White Papers

Summary, Containment Testing of Saf T Flow Chemical Fume Hoods

DR. ROBERT HAUGEN
Director of Product and Technology Development

Robert K Haugen  currently designs chemical laboratory containment equipment and develops new relevant technologies for Flow Sciences Inc.in Leland, North Carolina. He has also held positions at Kewaunee Scientific, Jamestown Metal Products, and St. Charles Manufacturing in similar capacities for 31 years. Previously, he did analytical chemical work at the University of Illinois (DNA, wastewater, and crop research) and Lawrence Livermore Labs in California (nuclear weapons research).

Dr. Haugen began his career as a curriculum writer for the Illinois Office of Education, developing texts on energy, urban management, and industrial pollution topics.

He received all his degrees from the University of Illinois in Urbana-Champaign, and is currently a member of the American Society of Heating, Refrigeration, and Air Conditioning Engineers, the American Chemical Society, and the National Fire Protection Association. He has participated in the development of both ASHRAE 110-1995 and the current 2016 update.

Over a period of time ranging from 11/6/2013 onward, the range of standard Saf T Flow Fume Hoods shown below were tested by Flow Sciences using the ASHRAE 110-1995 methodology.  Details of the individual tests are available separately from Flow Sciences; total results are summarized below:

ASHRAE 110-2016 Saf T Flow Test Data Summarized by Volumetrics, Hood Description, and Catalog #:

Procedures and Equipment:

In each test position, face velocities were established using a TSI thermal anemometer and a velocity grid specified in section 6.2 of the ASHRAE 110 standard.

The ASHRAE 110-2016 test procedure used employs a sulfur hexafluoride diffuser set at 30 PSI with a diffusion rate of 4 lpm. Tests were run with the mannequin in place for 5 minutes and SF6concentrations in the mannequin-breathing zone recorded.

An SME (sash movement effect) test was run for a total of two minutes and included opening and closing the vertical sash twice in 30-second intervals over the two minute run. Tests were run with the mannequin in place and SF6 concentrations in the mannequin-breathing zone recorded.

Relevant illustrations from the standard are shown below:

Approved ASHRAE Standard 110-2016 used as an overarching methodology

Ejector Assembly Used in ASHRAE110 and Human as Mannequin Tests

 

In each test position, face velocities were established using a TSI thermal anemometer and a velocity grid specified in section 6.2 of the standard.

The ASHRAE 110-2016 test procedure used employs a sulfur hexafluoride diffuser set at 30 PSI with a diffusion rate of 4 lpm. Tests were run with the mannequin in place for 5 minutes and SF6concentrations in the mannequin breathing zone recorded.

An SME (sash movement effect) test was run for a total of two minutes and included opening and closing the vertical sash twice in 30 second intervals over the two minute run.  Tests were run with the mannequin in place for and SF6 concentrations in the mannequin breathing zone recorded.

Relevant illustrations from the standard are shown below:


The HAM Containment Test

 

While comprehensive dynamic tests are not a part of ANSI/ASHRAE 110-1995, it is evident that the low face velocity fume hood vulnerabilities might go unmeasured unless kinetic challenges are systematically introduced into our Safe-T Flow evaluation program.

The researchers decided to “borrow” a kinetic challenge test rather than design a hood to pass the lone and rather perfunctory dynamic sash movement test (SME Test) already in the ASHRAE 110 standard.

The Human as Mannequin Test

Funded jointly by Lawrence Berkeley National Laboratory and the California Energy Commission in 2005, the ECT group investigated kinetic challenges to low velocity fume hoods by developing a special test that used a human with an air sampler in front of a fume hood manipulating equipment in a specifically defined manner.

For this adapted version of the HAM test, the researchers placed a breathing zone monitor on a tripod stand so it and the analysis equipment would not be jarred by the moving operator.  Final array is shown below in Photo #1.  The HAM tests involve conducting a series of choreographed activities using objects located within the hood. The objects consist of two 100 ml measuring cups, a 100 ml scoop, and a spatula.

The modified timed sequence of activities follows the layout shown in Photo # 1

  1. Stand at hood opening with arms to side.
  2. Insert and remove hands and arms
  3. Move objects #1 through #4 from six inch line to twelve inch line
  4. Exchange position of objects. (1 to 2, 2 to 3, 3 to 4, and 4 to 1)
  5. Transfer liquid from scoop #1 to scoop #2.
  6. Place spatula in empty cup.

Each sequence of activities is conducted over a period of approximately 70 seconds


Conclusion:

All Flow Sciences Saf T Flow fume hoods pass ASHRAE 110-1995, using criteria set forth in ANSI/AIHA Z 9.5, Section 6.3.7.  A containment level of 0.050 PPM must be achieved in each test to pass, using the pass-fail level of 0.050 PPM established in AIHA Z 9.5; all data from all tests are much lower than this!

ASHRAE 110-2016 Saf T Flow Test Data Summarized by Volumetrics, Hood Description, and Catalog #:

Photos of Hoods under Test



Thinking Outside the Box: 10 Considerations For Balance Stability

ABSTRACT:

Stability of your weighing balance is paramount when it comes to collecting reliable data for project. As the old adage goes, “Anything that can go wrong will go wrong.”. Depending on the problem, taking obvious action for a seemingly obvious solution may not result in success. 

The purpose of this paper is to inspire thought and dialogue regarding those “not so obvious” sources of balance stability issues. Below, you may find 10 prompt questions that will hopefully guide one in resolving those pesky head-scratchers: 


1 – Is the work surface causing instability? 

Placing leveling pads on the bottom of the legs of the workbench or table is a useful tactic to prevent inaccurate readings caused by wear-and-tear of the leg undersides. 

Additionally, the mass of the work surface affects the severity of data noise caused by vibration. The relationship between mass and vibration (kinetic vibration energy) can be illustrated by applying Newton’s law of Kinetic energy: 

Although a rare case and dependent on region, buildings sinking into the soil has the potential of being a problem. In regions near fault lines, there may be a slight change in elevation that could impact measurements at high sensitivities. 

2 – How is data reproducibility affected when weighing operations are conducted inside an enclosure or fume hood? 

Vibration interference caused by an enclosure fan is commonly-cited disturbance in the lab. What are some ways where the vibration can be reduced? 

3 – What can cause vibrational interference? 

Other than an enclosure fan, other equipment in the vicinity of your balance may be vibrating through the materials between them. Some pertinent examples are floor-mount grinders, tablet grinders, etc. 

At higher sensitivities, foot traffic near the operation could lead to error. Vibration may travel from the floor and through to the legs of the workbench or other work surface. The end result could be loss of powder or error due to disturbance of the powder. 

4 – How can the construction of the enclosure affect weight measurements? 

Depending on the construction of your work surface, you may experience measurement error caused by electrostatic interference. As the diameter of testing material continues to shrink, particulate is becoming increasingly susceptible to the electrical charge of the surrounding environment. 

Static dissipation is a critical consideration during the design of our products. Chlorosulfonated polyethylene (CSM) gloves are a component of our EHA (Hybrid Isolator Series) and Butyl gloves are a component of our END (Nitrogenema) Series. The base of the Hybrid Isolator Series is phenolic and the superstructure of the Nitrogenema Series is composed of static dissipative acrylic. 

5 – What are factors that contribute to static interference? What are some control methods you could employ for abatement? 

In the powder world, static electricity is more than just that annoying winter zap when you touch a doorknob. In the lab, employees’ clothing/personal protective equipment, laboratory furniture, and even the construction of the Heating, Ventilation, and Air Conditioning (HVAC) system servicing are some factors that could lead to product loss and erroneous measurements. 

We recommend that you keep the balance where it is upon sitting it on the work surface or inside the enclosure. Moving the base across a surface, especially if the surface is made of material different than the base, may cause enough static charge to interfere with your measurements. 

6 – How does organization of equipment inside the enclosure affect results? 

Depending on the type of enclosure and equipment you’re using, your balance may shift over time. Multiple uses of the balance over a long period of time may cause the balance to shift towards the enclosure face. In turn, air moving over the airfoil can blow some of the powder off the balance. At higher sensitivities, it could even bias measurements due to the force onto the weigh boat and/or the pan. Flow Sciences recommends that the balance be placed at least 6 inches behind the base airfoil. 

7 – How can the balance be oriented to achieve optimal data reproducibility? 

Organization of your equipment inside the enclosure can incur interference due to air currents moving around equipment. Just like a scale that is too close to the enclosure face, interference may be caused by air currents moving around other equipment. Vibration from other equipment, such as capsule machines, can cause vibrational interference. Flow Sciences recommends organizing your equipment such that these interferences do not occur. Don’t forget to consider putting your equipment at an angle; it just may work in a pinch. 

8 – What are the moisture-retaining properties of your powder? 

If you’re shrugging your shoulders over lousy regression lines, it may not be you or your equipment. It could be the powder itself absorbing moisture from the atmosphere. At higher sensitivities, hygroscopicity has a tendency to rear its ugly head. What could you do to prevent this kind of interference? 

Additionally, product purity is negatively impacted by its own hygroscopic properties. Flow Sciences recommends performing your operation in a closed, controlled environment purged of oxygen. For example, a contained environment enclosure with automated nitrogen purging cycles, such as Flow Sciences, Inc.’s Nitrogenema Glove Box. 

9 – Have you checked your certification results and calibration certificates recently? 

Sometimes, the solution to the problem is not where we have our “mental crosshairs” set. Lab managers place much trust on their lab equipment. But, have you checked your certification results recently? Have any calibration certificates expired? 

10 – Is there anything going on outside the lab building? 

Do you live near an airport? Just like dropping an object onto the exterior of the enclosure negatively affects balance measurements, that humming of the plane is a vibration itself. Is that annoying jackhammer actually sabotaging your weighing operation? 


CAMERON FAULCONER, IH-MESH
Industrial Hygienist / Product Manager

Cameron Faulconer is an Industrial Hygienist with a wide breadth of experience, spanning between commercial manufacturing, to home residences. His inspiration for his choice of career is communicating the value of preserving the health and safety of employees using the most effective and efficient means possible. Therefore, Mr. Faulconer found his place in the “Engineering Controls” rung of the hierarchy of hazard controls.

As a problem solver, Mr. Faulconer believes that the best safety solutions are created through consultative conversations with those who seek solutions. He believes communicating information derived from these conversations to be critical to the continued understanding of the toxicological impacts of the work environment.

His personal motto is “protecting the safety and health of employees from what can and cannot be seen with the naked eye”.


Red Lights and Green Lights - The Keys to Superior Containment in Compounding Applications



Abstract:

In a previous White Paper 2, we reviewed in detail how Flow Sciences vented balance enclosures can allow accurate measurement of samples in the range of 0.1 mg to 0.1 µg.

In this paper, we will review why very bad things happen when either quantity or purity of Highly Potent Active Pharmaceuticals is not properly maintained during the compounding process. Additionally, when highly potent active pharma ingredients are not effectively contained, workers may be adversely affected.


Why Compounding Applications Require Superior Containment

In the last fifteen years, the number of compounding labs has dramatically increased in the United States. Because there is an increasing demand for more high potency products and the number of different products being compounded in each facility is growing, there is an increasing need for quality control worldwide in these labs.

 

Dramatic situations have occurred worldwide since 2002. Consider Table 1 below:

Table 1: Issues With Contaminated Health Products
# Name Location? (Mfr.?) Date Impact Cause Footnote
1 Cefotaxime Germany 2002 Not reported Particluate Matter in Injectable 3
2 Cough Syrup Panama (Chinese Mfg) 2006 138 Killed Diethylene Glycol impurity 4
3 Teething syrup Nigeria 2009 84 child deaths Diethylene Glycol impurity 5
4 FDA Report (1990-2009) US 2009 34% of Compounded Drugs Failed Purity Tests Drug potency, impurities 6
5 Chemotherapy Drugs US NIOSH Lab Worker Study 2010 ~50%  More Mutations than Control Grp. Inadequate, improper containment equipment 7
6 Injectable epidural Steroid US (New England Compounding) 2012 753 Meningitis Cases; 64 dead Contaminated Injectable Drugs 8
7 Sterile Meds (Injectables) US, Texas (Specialty Compounding) 2013 17 Rhodococcus Equi infections; 2 died No GMP, many products, contaminated 9
8 Sterile Meds (Injectables) US, Texas; ( IV Specialty) 2015 Unknown, unproven Bad Containment, sanitation, and air flow 10
9 Marijuana, Medical Use US 2017 20 defective doses; 3 Deaths Marijuana had fungus spores 11

From insulin to various heart and cancer medications, highly accurate measurement is required during formulation of compound drugs. If compound purity and worker exposure issues are not resolved, modern compound pharmaceutical companies have the capacity to significantly harm both the patients and workers inside these labs.

 

Figuratively speaking, “red and green lights” in this process must be devised and obeyed. The author believes the following issues (red lights) with compounding equipment need attention (green lights):



Containment failure caused by poor internal airflow:

High potency powders must be contained within a designated space while being weighed or mixed with other ingredients. Active pharmaceuticals should never be in an environment where they can inadvertently spill or blow into the lab environment during the weighing or compounding procedures. Sometimes equipment design issues cause powder and fume containment to be compromised.

Also, compounding labs need to protect their constituent ingredients and blending processes from cross-contamination during processing. Escaped airborne trace pharmaceuticals are a significant contamination issue. If process protections break down, scenarios 4,5,6,7, and 8 from Table 1 could easily occur.

Solution:  

Smoother air flow always minimizes the effect of turbulence outside of the enclosure, working to stabilize interior containment. The Flow Sciences Class I BSC (biological safety cabinet) achieves low turbulence by using four (rather than one) airfoils surrounding the rectangular face opening paired with a slotted rear plenum.

The resultant aerodynamics creates proven particulate and vapor containment using ASHRAE 110-2016 and ISPE approved surrogate powder containment protocols. ASHRAE 110 containment is routinely found to be 0.05 PPM or better; surrogate powder testing results are routinely at or below 10 nanograms per cubic meter.



Reduced weighing accuracy caused by fan vibration transmitted to the work surface: 

It is crucial in analytical and compounding environments that precise weighing takes place inside the containment area. In modern measurement scenarios, lab balances are required to be accurate and reproducible with deviations ranging from +0.1 mg (milligrams) to +0.1µg (micrograms). Fan vibration in many units creates drifting tare weights. With unreliable weighing taking place, scenarios similar to 4 from Table 1 could occur.

Balance containment units from several manufacturers mount the fan belowthe filter housing and attach it directly to the containment cavity with sheet metal screws. This produces a direct contact pathway for motor vibration to be transmitted into the weighing area. Frequently in these units, fans must be turned off to get a stable balance reading.

Not good, particularly if the fan is located just above the work area where particles from the fan may contaminate the work area.

Solution:

Weighing stability is accomplished using the features highlighted below:

Little to no vibration in operating FSI balance enclosures means balance stability is achieved while the fan-driven containment system is running.



Functionality of equipment can be impaired by bad design:

Any containment system should support, not impede, effective science. If containment equipment cannot do this, precision is lost. All nine scenarios shown in Table 1 could occur with containment equipment of inferior design.

The Flow Sciences balance enclosures not only contain and protect Highly Active Pharmaceutical ingredients, they facilitate more straightforward compounding and sampling four different ways:

Ease of Cleaning assured with large slotted baffles:

Many balance enclosures have small holes or slots in their baffle assemblies which are very hard to clean. The sharp edges can cut skin or a glove and increase the chance for contamination. Flow Sciences uses straightforward large slotted baffles which can easily be cleaned.

Bag-In/Bag-Out filters can be replaced without threatening lab area contamination.

Many less expensive balance enclosures do not offer this option. An exposed filter is difficult to remove from a lab area without room contamination. Such contamination will create health issues and potentially contaminate other samples in the lab, destroying traceability. Photos show how bag-out process protects the room environment during filter change-outs.

Filter system configured to stop back-contamination when the fan is switched off.

Some less expensive balance enclosures actually place the fan below the filter.  This creates an area of positive pressure inside the fan housing and causes loose particles to fall down onto the surface inside the containment area when the fan is switched on or off. The Flow Sciences enclosure places the fan above the filter, keeping it and the fan housing completely clean of particles deposited on the fan blades trapped by the filter!

Thicker Filters mean longer life!

Flow Sciences balance enclosure filters are 4” thick to assure long life and infrequent motor RPM adjustments. Other manufacturers use thinner (2-3”) filters, which need to be replaced more frequently. Also fan adjustments must be made more often, and the fans usually produce more noise working against a clogging filter.



Conclusion:

All the above features allow Flow Sciences containment units to effectively contain fumes and powders, prevent cross-contamination, and be in compliance with the US Centers for Disease Control and Prevention Criteria for a Class 1 BSC (biological safety cabinet) with proven particulate and vapor containment.

When the safety of compounding workers and the general public are both at stake, no lower standard is acceptable!

DR. ROBERT HAUGEN
Director of Product and Technology Development

Robert K Haugen  currently designs chemical laboratory containment equipment and develops new relevant technologies for Flow Sciences Inc.in Leland, North Carolina. He has also held positions at Kewaunee Scientific, Jamestown Metal Products, and St. Charles Manufacturing in similar capacities for 31 years. Previously, he did analytical chemical work at the University of Illinois (DNA, wastewater, and crop research) and Lawrence Livermore Labs in California (nuclear weapons research).

Dr. Haugen began his career as a curriculum writer for the Illinois Office of Education, developing texts on energy, urban management, and industrial pollution topics.

He received all his degrees from the University of Illinois in Urbana-Champaign, and is currently a member of the American Society of Heating, Refrigeration, and Air Conditioning Engineers, the American Chemical Society, and the National Fire Protection Association. He has participated in the development of both ASHRAE 110-1995 and the current 2016 update.


10 Worst Containment Engineering Mistakes

Abstract

Engineering is a process to develop a design to solve a problem. In the world of containment engineering, careful premeditation is important to the completion of a successful engineering project. Flow Sciences aspires to inspire caution when making deductive decisions during the design of a containment engineering solution.


The following list of ten selected mistakes, fallacies, and biases are intended to provide the reader with insight throughout their containment engineering projects:

  1. Improper diagnoses of an issue resulting in an improper solution.

Occasionally, the scope of the actual problem is misdiagnosed. Once actions are taken in accordance with the perceived scope, the problem is likely left unresolved. This concept is explained in the visual Venn diagram below:

While the perceived scope may share aspects with the actual scope of the problem, the actions the engineer takes towards resolving the issue may partially solve the problem, not solve the problem at all, or exacerbate the issue.suds

2. Failure to understand financial limitations of the project.

If the engineer fails to understand the financial limitations of a project, he or she may design a solution that is cost-prohibitive or infeasible for the consumer to purchase and/or use.

3. Lack of awareness of the solution’s application.

To successfully engineer a solution for a complex process, one must have comprehensive understanding of the application for the solution that is being created. To start, try using the “Four Y’s and an H” approach: Who, What, When, Where, and How….from the start of the project all the way through to the end.

4. Lack of knowledge of the consumer’s support infrastructure.

For example; if an engineer were to design a containment solution which consumes a quantity of electrical energy exceeding the consumer’s energy budget allocation, the containment solution would likely be an irrational solution for the consumer.

When designing a containment solution for a consumer, it is critical for the designing entity to understand the limitations of the consuming entity’s resources. Ideally, the designing entity should produce a solution for the consumer which does not exhaust the consumer’s communication, labor, power, transport, or water resources at an inordinate rate. The engineering entity should ascertain the consumer’s average conditions of resource availability and apply it towards its design.

5. Lack of awareness of the potential impact of the materials that you are trying to contain (from storage to process to exhaust)

How do materials involved in the process interact with the surrounding environment, from “cradle” to “grave”? Does the material switch between phases of matter (e.g. gas to a liquid to a solid)?

6. Being unaware and disinterested in the time frame (from quote to delivery).

When the engineering entity is physically isolated from the consuming entity, communication is critical to achieving a successful transaction. If the designing fails to properly assess a project’s level of complexity prior to devoting time and resources towards it, the engineering entity may not complete the project on time or design/produce an insufficient solution.

Additionally, urgency for project completion may increase as time passes. If the engineering entity is unaware or disinterested in maintaining communication with consuming entity, the likelihood of customer dissatisfaction increases.

7. Unawareness of who/how many people will be operating the equipment that is being designed. 

In some scientific applications, it may appear possible that the process can be completed with a number of persons less than an amount of persons feasibly, efficiently, and successfully complete it. Operating under the assumption that your solution will be utilized by a consumer of average stature, height, and health could also be detrimental to your customer’s satisfaction

8. Lack of foresight and knowledge of how well the design will interface with other elements of their system. 

Another cognitive bias that could negatively impact your project is not considering the environment surrounding your solution’s final location. Without an idea of the room or area in which your solution is going to be used, you may receive an unexpected or catastrophic result. For example, designing a large product without the capability to collapse and move through a doorway shortly before installation on-site.

9. Not understanding ergonomics of design (e.g. easy to clean).

Designing a product for a specific application has a broader scope than simply just the application itself. It is a good engineering practice to account for inconveniences or impossibilities arriving from routine activities such as cleaning. For example, if the face opening of a containment enclosure is too narrow such that cleaning the rear of the enclosure is difficult, the operator may have a propensity to ignore that spot. The circumstances of this phenomenon presents the risk of product cross-contamination with the residue leftover from previous operations

10. Unfamiliarity with the regulatory requirements of the geographic area where the solution will be used. 

When designing a product for a company located in another country, especially a developing country, it is important to review all laws and regulations that impact your project. Be sure to read any documents that may be referenced or adopted by the authoritative agency. It is a recommended practice to consult subject matter experts for input on the interpretation of laws which imply the usage of professional discretion.


CAMERON FAULCONER, IH-MESH
Industrial Hygienist / Product Manager

Cameron Faulconer is an Industrial Hygienist with a wide breadth of experience, spanning between commercial manufacturing, to home residences. His inspiration for his choice of career is communicating the value of preserving the health and safety of employees using the most effective and efficient means possible. Therefore, Mr. Faulconer found his place in the “Engineering Controls” rung of the hierarchy of hazard controls.

As a problem solver, Mr. Faulconer believes that the best safety solutions are created through consultative conversations with those who seek solutions. He believes communicating information derived from these conversations to be critical to the continued understanding of the toxicological impacts of the work environment.

His personal motto is “protecting the safety and health of employees from what can and cannot be seen with the naked eye”.


Critical Considerations When Selecting a Vented Balance Enclosure

Robert K. Haugen, Ph.D.

Steve Janz

Ray Ryan

Flow Sciences, Inc. 

2025 Mercantile Drive

Leland, North Carolina 28451

5/17/2018

ABSTRACT: This paper discusses the primary benefits of the vented balance enclosure. Critical to the operation of laboratories are the safe and effective weighing of potent powder compounds, active pharmaceutical ingredients and nanomaterials. Parallel challenges for fast accurate weighing with proven safe containment for product and personnel protection create continued demand for an enclosure that meets both functionality and performance.

 

Flow Sciences’ first product was a vented balance enclosure. Three engineering principles guided the design of this unit:

1) Containment: The unit had to keep all powders inside the enclosure, preventing operator exposure. Personnel and/or product protection when working with harmful and toxic powders was the priority.

2) Weighing Accuracy: Air currents and fan vibration inside the enclosure could not interfere with the accuracy of the analytical scale or semi-micro balance. Under no circumstance could the enclosure be turned off to achieve a stable weighing environment.

3) Functionality: Air currents within the enclosure could not prevent manipulation of finely divided powders. Equipment maintenance such as filter replacement should never cause a breach in containment.

 

In the age of Active Pharmaceutical Ingredients (API’s) and High Potency Active Pharmaceutical Ingredients (HPAPI’s), the equipment challenges for vented balance enclosures are even more critical today. The same three overriding engineering principles still apply:

1) Containment:

High potency powders must be retained within the containment area and these materials should never be expelled during the weighing procedure. Turbulence outside of the enclosure becomes laminar inside by using four airfoils on all sides of the rectangular face opening as shown below paired with the slotted rear plenum.

 

The net result of these features is a Class 1 BSC 6 (biological safety cabinet) with proven particulate and vapor containment using ASHRAE 110-2016 and ISPE-approved surrogate powder containment protocols. ASHRAE containment is routinely found to be 0.05 PPM or better; surrogate powder testing results are routinely below 10 nanograms per cubic meter. 2, 4

2) Weighing Accuracy:

In modern measurement scenarios, lab balances are required to be accurate and reproducible with deviations ranging from +0.1 mg (milligrams) to +0.1 µg (micrograms).

 

It is crucial in analytical environments that precise weighing takes place inside the containment area. This is accomplished with the Flow Class I BSC in the following manner:

Little to no vibration in Flow Sciences balance enclosures means balance stability is achieved while the fan-driven containment system is running under negative pressure.

In contrast, many weighing units from other manufacturers mount the fan below the filter housing and attach it directly to the containment cavity with sheet metal screws. This produces a direct contact pathway for motor vibration to be transmitted into the weighing area. Frequently in these units, fans must be turned off to get a stable balance reading.

3) Functionality:

The containment system should support, not impede, effective science. The Flow Sciences balance enclosures do exactly this in five ways:

a) Filter system should not cause particle shedding or emission back into the containment area.

Some less expensive balance enclosures actually place the fan below the filter.  This creates an area of positive pressure inside the fan housing and causes loose particles to fall down onto the surface inside the containment area when the fan is switched on or off. The Flow Sciences enclosure places the fan above the filter, keeping it and the fan housing completely clean!

 b) Bag-In/Bag-Out filters can be replaced without threatening lab area contamination or sample cross contamination. 3

Many less expensive balance enclosures do not offer this option. An exposed filter is difficult to remove from a lab area without room contamination. Such cross-contamination will create health issues and potentially contaminate other samples in the lab, destroying traceability.

c) Ease of Cleaning

Many balance enclosures have small holes or slots in their baffle assemblies which are very hard to clean.  The sharp edges can cut skin or a glove and increase the chance for contamination. Flow Sciences uses straightforward large slotted baffles.

d) Thicker Filters mean longer life!

Flow Sciences balance enclosure filters are 4” thick to assure long life and infrequent motor RPM adjustments. Other manufacturers use thinner (2-3”) filters, which need to be replaced more frequently. Also, RPM adjustments must be made more often, and the fans produce more noise.

e) Vented Enclosure Naming Conventions:

The VE or vented enclosure is defined as an engineering control as described by NIOSH6. The National Institute for Occupational Safety and Health is the United States federal agency responsible for conducting research and making recommendations for the prevention of work-related injury and illness. The selection of the appropriate vented enclosure has created SOPs (standard operating protocols) for many pharmaceutical companies and industries that have adopted acronyms to describe the unit. The acronyms below comprise a list of commonly used terms.5

VBSE™ = Vented Balance Safety Enclosure (trademark of Flow Sciences, Inc.)

VBE= Vented Balance Enclosure

VSE= Vented Safety Enclosure

VE = Vented Enclosure

CVE = Contained Vented Enclosure

Summary:

Flow Sciences has focused on three key issues affecting the functionality of balance enclosures: containment, accuracy, and functionality.  We have shared with you the ways our engineering team has addressed these issues. As the sciences of measurement and containment move forward in this century, there will no doubt be more such challenges to our industry in the areas reviewed in this paper. Flow Sciences’ experienced Engineering Team will continue to develop industry leading improvements and engineering controls to address the safety and performance concerns in our industry.

 

 

  1. https://flowsciences.com/vibration-isolation-enclosures/
  2. https://flowsciences.com/designing-testing-containment-devices-used-high-potency-active-pharmaceutical-ingredients/
  3. BIBO FILTER CHANGE Rev 103117 (C-8832), 1/13/2018, Flow Sciences
  4. https://www.youtube.com/watch?v=T0FqPuzDgGk
  5. ISPE: Good Practice Guide: Assessing Particulate Containment
  6. US Centers for Disease Control and Prevention; Primary Containment for Biohazards: Selection, Installation, and Use of Biological safety Cabinets (PDF), 2000

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Designing and Testing Containment Systems for High Potency Active Pharmaceutical Ingredients (HPAPIs)

Designing and Testing Containment Systems for High Potency Active Pharmaceutical Ingredients (HPAPIs)

Dr. Robert K. Haugen, Director of Product and Technology Development

Flow Sciences, Inc. 

2025 Mercantile Drive

Leland, North Carolina 28451

V 1.4; 2/7/2018

Background:

Flow Sciences (FSI) designs, tests, and manufactures laboratory containment devices.

In the ongoing search for new therapeutic treatments, pharmaceutical companies are developing a new class of active ingredients known as High Potency Active Pharmaceutical Ingredients (HPAPI’s).  As the name suggests, these compounds are highly potent, requiring “solid dilution” into therapeutic doses. It is therefore critical to maintain very minimal exposure to such ingredients during compounding and other operations. Commonly associated with oncology and cardiology drugs, an increasing demand for HPAPI’s is predicted over the next five years. 1

Unlike better-known typical reactive chemicals, these Pharmaceutical Ingredients are designed to be biologically active in low concentrations. HPAPI’s can therefore harm researchers with adverse symptoms at very small exposure levels! Warfarin, for example, shares its chemical roots with rat poison! 2

CMOs (contract manufacturing organizations) are the key stakeholders in this market as a good proportion of HPAPI manufacturing and compounding is understandably outsourced due to stringent manufacturing protocols and safety requirements. During research on the US market, Flow Sciences identified 96 CMOs (with over 130 production facilities worldwide) that are focused in this area; approximately 40% of these facilities are dedicated to the manufacture of both HPAPI’s and cytotoxic drugs.

A Containment Testing Program Geared for HPAPI’s

In 2011, Flow Sciences, Inc. was tasked by a major pharmaceutical company with designing and constructing a hybrid isolator for the protection of its employees during tablet crushing operations.  The design of the isolator included a bag in / bag out (BIBO) assembly and a containment glove box enclosure.

After design and construction of the isolator, it was factory tested using a variety of recognized testing methods, including flow visualization, tracer gas testing, and surrogate powder testing.  In each of these tests the detectable levels for the agents used was far below the client’s exposure standards, and often below quantitative levels of detection.3   Examples of such devices are shown below.

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To test such devices for effective containment of the materials used within them, Flow Sciences uses a series of specific tests detailed below:

 1) ASHRAE 110-2016 Test 4

Sulfur hexafluoride gas (SF6) gas is released at a flow rate of 4L per minute inside the containment area using a diffuser. The presence of escaping sulfur hexafluoride, a tracer gas, is monitored in the mannequin breathing zone located at right, center, and left positions in front of the device’s sash opening.  An as-manufactured acceptance level of 0.05 ppm in the mannequin breathing zone is set as the maximum acceptable level (AIHA Z9.5). Results of this test found that the concentrations of sulfur hexafluoride outside of the hybrid isolator is typically far below this level.

 2) Human as Mannequin (HAM) test 5

A modified, non-standard, HAM test (Human as Mannequin) uses the ASHRAE 110 diffuser described above in the vicinity of manipulated small lab objects on the containment device’s work top. The formally published version of this test was commissioned by Lawrence Berkeley National Laboratory 5.

 

Results of this modified test generally show the concentrations of sulfur hexafluoride outside of the hybrid isolator is at or below 0.050 ppm.

3) Surrogate Powder Test 6

Generally speaking, these tests are highly specific to the types of operations and procedures used by the customer. Flow Sciences designs a custom enclosure, based on customer input and requirements, and performs a containment evaluation based on ergonomic parameters, safety requirements, and customer containment requirements.

 

Below, is an actual custom unit undergoing surrogate powder testing.   The enclosure design and processes carried out inside the unit dictated the sampling strategy.  For this study, two operations were performed – tablet crushing within the isolator and a procedure where powder was transferred.  Using ISPE guidelines, air samples were collected from twelve locations around the isolator focusing on key areas including operator breathing spaces and other areas, such as joints, where leakage can be experienced. The samples were collected on a suitable sample media, and the analysis for surrogate powder performed by a third party.  In such a setup, the customer defines an acceptance level, often in the nanogram per cubic meter level, which is then used as a pass-fail criterion for Flow Sciences’ tests.

 4) Other Tests at the Customer’s Discretion:

Many pharma labs have specific applications, operations, or logistics challenges requiring special test arrangements. For these situations, Flow Sciences individualizes custom procedures which may include any or all of the following:

a) Incorporating actual devices used by the CMO into Flow Sciences’ factory containment tests. (Grinders, shakers, etc.)

b) Building medium density fiberboard (MDF) aerodynamic models of equipment to simulate air flow challenges inside the containment area.

Multi-Disciplinary Containment Solutions

 

Testing equipment to scrupulously contain HPAPI’s is important.  As you might imagine, the high standards and diverse applications of these pharma customers leads to an overwhelming number of different containment products whose performance must be evaluated.

 

The need for hybrid isolators, bulk powder isolators, stainless steel enclosures, sieve enclosures, balance enclosures, nitrogen enclosures, etc. has given Flow Sciences an opportunity to showcase its unique design diversity on their company website. Flow Sciences has therefore operationally designated several respective markets and developed an online resource for each market.

 

For example, Flow Sciences has recently published an electronic booklet for the Contract Pharmaceutical Manufacturer, detailing containment technologies developed for this industry. 7

TaskMatch: Matching Containment to Your Application

 

Researching containment solutions has, historically, been an arduous adventure. This cumbersome search process has now been redefined to empower end users to optimize their containment solutions with ease.

 

TaskMatch is an intelligent search tool that combines containment categories, application specific enclosures, and uses key containment concepts to aid researchers in discovering products and solutions for tasks identified as key to their process using the full capabilities of the online search tool. Customers can access this search tool on the Flow Sciences website: flowsciences.com/taskmatch/ .

 

When I enter HPAPI into the application search box, data and photos for many existing products immediately come up:

[dt_fancy_separator][dt_products_masonry show_products=”categories_products” mode=”grid” layout=”btn_on_img_hover” bwb_columns=”desktop:3|h_tablet:3|v_tablet:2|phone:1″ dis_posts_total=”9″ product_rating=”n” category_ids=”1012″][dt_fancy_separator]

Notice this is a sophisticated search.  Search results reveal relevant products, even though some do not mention the term HPAPI in their descriptionThere are hundreds of enclosure types represented in this reference; scores of categories available to differentiate. Additionally, TaskMatch provides details about the specific enclosure, containment category information, videos, and a contact form to request a containment consultant to work with you on the details of your process and containment requirements.

 

Flow Sciences highly recommends customers contact them directly for guidance before choosing the best Flow Sciences product for their application. Remember, Flow Sciences containment products can be tested to existing test Standards or to customer-defined criteria which can be organized at Flow Sciences’ facility in Leland, North Carolina.

Summary

In the ongoing search for new therapeutic treatments, pharmaceutical companies are developing High Potency Active Pharmaceutical Ingredients (HPAPI’s) into completed products. For worker safety, it is critical to maintain very minimal exposure to such ingredients during compounding and other operations.

Flow Sciences designs such products and then rigorously tests them in their test facility to document their effectiveness and containment. This testing always involves input from customers to validate the safety of the overall containment strategy. Flow Sciences has experience in producing hundreds of different varieties of containment devices to achieve this purpose. Research labs, CMO’s, and government testing agencies who use such products may find product matches by using the Flow Sciences website which facilitates matching applications with appropriate Flow Sciences containment products.

Contact Flow Sciences

Footnotes:

  1. https://www.giiresearch.com/report/root310060-hpapis-cytotoxic-drugs-manufacturing-market.html
  2. https://en.wikipedia.org/wiki/4-Hydroxycoumarins
  3. Flow Sciences can share test results with any interested party.
  4. ASHRAE 110-2016, ASHRAE Standard Project Committee 110 Cognizant TC: 9.10, Laboratory Systems SPLS
  5. “Human as Mannequin” (HAM) Test Methodology, ECT, Inc. & Lawrence Berkeley National Laboratory (LBNL), 2005
  6. https://flowsciences.com/solutions/services/
  7. https://flowsciences.com/contract-manufacturing-contract-research-solutions-booklet/


Vibration Isolation for Enclosures - Anti-Vibration

 Vibration Isolation for Enclosures

 

Robert K. Haugen, Ph.D.

       Director of Product and Technology Development

      Flow Sciences, Inc.

Background:

It is crucial in analytical environments that precise weighing takes place inside containment where potent powders being weighed do not escape into the lab.  This is typically accomplished with a top-mount safety containment system such as the one shown below.

An effectively designed unit must have an exhaust fan and HEPA filter located at the top of the unit, and such a fan has an inherent vibration.  If undamped, this vibration can significantly affect the accuracy and stability of the balance.

Any top-mount safety containment system must therefore accomplish two objectives which are at cross purposes: use air movement and a fan to accomplish protective containment while maintaining a vibration-free weighing zone to assure balance accuracy.

Flow Sciences incorporates a low vibration fan subassembly in its design by using a balanced fan, thicker low static pressure filters which put less strain on the motor, and a soft gasket junction between the fan subassembly and the containment unit.

The purpose of this paper is to measure the effectiveness of these three vibration isolation strategies.

Procedure:

• Determine a reasonable base line of vibration inside our product test area.

Base line measurements are made using a sensitive 3-D vibration measurement sensor attached to a Rigol DSI 052E oscilloscope. The sensor is attached to a large block of granite on the test area floor and the resulting 3-D vibration is measured and results recorded over one second.  Vibration is measured in G-Force (M/sec/sec).

• Determine an un-dampened vibration level for the fan and its metal housing by placing the 3-D vibration measurement sensor on top of the housing while the fan is operating at a speed necessary to achieve the design face velocity in the containment unit of 70 FPM (0.35 m/s).

• Determine a normal damped vibration level inside the containment area by placing the sensor inside the hood on the work surface front of the containment area. The same fan operating conditions outlined in step 2 above are used during this test (70 FPM).

• Determine a maximized un-dampened vibration level for the fan and its metal housing by placing the 3-D vibration measurement sensor on top of the housing while the fan is operating at full speed (approx. 140 FPM).

• Determine a dampened vibration level for inside the containment area by placing the 3-D vibration measurement sensor inside the hood on the work surface near the front of the containment area while the fan is operating at full speed (approx. 140 FPM).

• Determine an un-dampened vibration level for an adjacent “noisy” piece of common apparatus by locating a Jaansun 300 Capsule Machine 1 foot away from the ETA482424AAA containment device and mounting the 3-D vibration detector on top of the unit. Fan on containment unit is left off.

• Determine a normal damped vibration level from the Jaansun inside the containment area by placing the sensor inside the hood on the work surface near the unit front face. Fan is off. Jaansun machine remains at 50% power.

• Determine a sudden impact vibration on the fan unit of the ETA482424AAA containment device by dropping a ½” steel ball of 8.35 g mass from a 2 foot distance on to the top of the steel fan unit. Impact vibration measured by sensor placed at fan centerline.  Fan is off.

• Determine a normal damped impact vibration inside the containment area by repeating the ball drop experiment in number 8 but placing the sensor inside the hood on the work top near the front of the containment area. Fan is off.

Observations:

 

Digital data was recorded in all three dimensions (amplitude vs. time) for all nine tests cited above.  All graphs have ~ 1 second sweep horizontally.

Conclusions:

 1. The ETA482424AAA weighing isolation device provides effective dampening from all vibrations investigated. The “full fan rpm” was the only instance where a slight increase from the baseline vibration value was noted inside the containment area.

We believe increased static pressure drop past our filter will increase fan “work” and subsequently vibration. With units that have a lesser fan or thinner filter would see this phenomenon appear to a much greater extent than the very slight vibration increase seen in this study.

 

2. The vibration dampening effect of our Weighing Containment Device is achieved using a series of sound insulating materials between the steel top-mounted fan housing and the containment superstructure and work top.

 

3. Room and fan impact vibrations are therefore effectively dampened even when the fan is not running because the material interfaces between the vibration sources and the balance inside the containment structure still exist. Both the table-mount Jaansun Capsule Machine and the ball drop had significant vibration as measured over the 1 second sampling time as measured on the machinery, but no effect whatsoever at the balance location.

The researcher concludes that the ETA482424AAA weighing isolation device’s insulated fan unit and separate work top provide an effective material interface system for vibration damping. Other causative factors, like sound diffraction through dissimilar surfaces could also be examined in future studies.

Contact Flow Sciences


Validation of a Glovebox Workstation


VIEW / DOWNLOAD THE WHITE PAPER

 

VALIDATION OF A GLOVEBOX WORKSTATION

Clinical researchers are creating ADC’s (antibody drug conjugates) that consist of an antibody, a linker, and a cytotoxic drug. By combining the unique targeting of monoclonal antibodies with the cancer killing ability of cytotoxic drugs, the use of this type of ADC allows sensitive discrimination between healthy and diseased tissue.  These anti-cancer drugs use high potency active pharmaceutical ingredients (HPAPI’s) to achieve targeted therapy for treatment of people with cancer.  Many of the HPAPI’s are novel compounds of unknown potency and toxicity.  Some cytotoxic agents are made of a combination of nanoparticles.  The establishment of limits of operator and patient exposure for nanoparticles are only recently being investigated. However, nanoparticles less than 10nm (nanometers) may be absorbed through the skin.  The greatest risk to the operator is the inhalation of the HPAPI’s.  The occupational exposure limit (OEL) is based on the toxicity of the drug.  The OEL is measured by the potency of the drug, the frequency of contact with the drug, the duration of contact with the drug, and the quantity of the drug. Unfortunately, much of this is unknown when researchers are working with nanoparticles and ADC’s.  Therefore, during the risk assessment personnel protection must predict protection in a worst-case environment.  The recommended containment solution specified is typically Occupational Exposure Band (OEB) 4 or 5.  This is a system for grouping compounds of similar toxicity and potency to guide the assessment of the engineering controls required to achieve safe manufacturing of ADC’s in research, development, and manufacturing work environments.

Many existing research labs, pharmaceutical and biopharmaceutical manufacturers, and contract manufacturing organizations (CMO’s) are not designed nor are they equipped with the engineering controls to safely handle the manufacture of ADC’s.  The safe manufacture of ADC’s requires more modern facilities, equipment, and engineering controls as well as programs, practices, and procedures to adequately protect the operators and the work environment.

The FDA mandates that any substance manufactured for human consumption must strictly comply with current good manufacturing practices (GMP).  Flow Sciences, Inc. (FSI) provides verified containment and control solutions per current GMP requirements for manufacturing ADC’s for clinical trials with the glovebox workstation to maintain exposures below acceptable limits. Therefore, the Flow Sciences, Inc. Glovebox Workstations used for the manufacture of ADC’s are fully validated.  A master device record (MDR) documents the entire validation process of the glovebox workstation from design, construction, quality control, and facility acceptance testing. The ISO 9001 based quality management system and lean manufacturing concepts allow the rapid construction of glovebox work stations.

DESIGN QUALIFICATION

During a meeting with a Flow Sciences containment expert, details of the user requirement specifications (URS) are documented. In the manufacture of ADC’s both personnel and product protection must be addressed. A risk assessment is performed to verify the degree of containment and other engineering controls that must exist to assure compliance with the specific OEL of the drug.

The purpose of the Glovebox Workstation is to provide negative pressure containment for applications using toxic HPAPI’s requiring isolation that meet or exceed ISO Class 5 clean processing.  The ISO Class 5 environment is created by the movement of air thru the HEPA filter inlet, which is 99.97% efficient at 0.3 micrometers, across the inside work surface of the glovebox in a horizontal, unidirectional flow and into the return bag-in/bag-out HEPA filter exhaust.  Airflow and containment is predicted using computational fluid dynamics.  Computational Fluid Dynamics (CFD) is the study of fluid dynamics using sophisticated computing technology. URS may require changes in the design of the glovebox.   FSI uses CFD in the design process to study the effects of changes in airflow in the enclosure design.  This assures the change in the design will maintain stable airflow that improves containments while also providing a low turbulent atmosphere that allows sensitive equipment to perform properly and minimize potential product loss.

The ADC’s may be sensitive to fluctuations of temperature or humidity.  Therefore, stabilization of temperature and humidity may be engineered into the design.  LED lighting provides the precise amount of light to perform the most detailed procedure.  The glove ports provide additional protection to the operator.  Additionally, pass through or waste chute attachments may be engineered per the user requirement specifications. The FSI Glovebox Workstation has been evaluated by third-party testing facilities that have confirmed containment levels less than or equal to 50ng/m3 and a balance stability to the 7th decimal place which exceeds the industry norm.

The design engineers at Flow Sciences, Inc. create a 3D animated model and can also build a full-scale mock-up.  When the URS documents are signed by representatives of the customer and Flow Sciences, Inc. the installation qualification and construction of the Glovebox Workstation begins.  Many companies elect to have several “copy exact” gloveboxes shipped to various locations.  This standardizes processes and procedures to assure reproducibility of product from more than one research or manufacturing site.

INSTALLATION QUALIFICATION

During the installation qualification, supply chain management assures the high quality and integrity of the product.  QC (quality control) verification of materials used in the manufacture of the glovebox are documented in the MDR.  All materials used in the assembly of the Glovebox Workstation are in stock at Flow Sciences, assuring on-time delivery of every unit.  Assembly of the Glovebox Workstation is per FSI standard operating procedures that include several quality checkpoints before progressing to the next step.  Each unit is assigned a unique serial number to provide traceability to all materials used in the manufacture of the glovebox.  When the assembly of the Glovebox Workstation is completed and all quality checks compliant with the user requirement specifications, the operation qualification begins.

OPERATION QUALIFICATION

The operation qualification consists of the Factory Acceptance Testing that is performed on the Glovebox Workstation to measure the performance, interior cleanliness and to determine the containment effectiveness during simulated operations. The testing is performed in the Flow Sciences laboratory under the direction of Lab Manager Allan Goodman, Ph.D.  The laboratory meets ISO Class 7 particle requirements and maintains positive pressure while allowing ten air changes per hour.

The general enclosure performance is measured using standard ASHRAE 110 and SEFA 9-2010 testing protocols.  Flow visualization testing is performed to visualize airflow into the glovebox and determine the effectiveness in drawing air away from the operator.  The large volume smoke test evaluates the containment capacity of the glovebox and the time required to clear the glovebox of contaminants.  The tracer gas test evaluates the effectiveness of the glovebox in containment of contaminants.  This confirms that the airflow inside the glovebox is as was designed using the computational fluid dynamics.

The HEPA Filter Efficiency Evaluation determines the efficiency of the HEPA filters and their housing to remove particles from the air. The performance of the inlet HEPA and bag-in/bag-out (BIBO) primary HEPA filters and housing are tested using the Institute of Environmental Sciences and Technology recommended practice IEST-RP-CC001, HEPA and ULPA Filters.  This test confirms the HEPA filter integrity and efficiency is as was determined by the supplier of the HEPA filters.  The air particle cleanliness level is determined per ISO 14644-1 Cleanrooms and Associated Controlled Environments – Classification of air cleanliness by particle concentration. This test determines the cleanliness of the air inside the glovebox by measuring the number of particles (0.3µm and greater) per cubic meter of air.  This test confirms the particle cleanliness inside the glovebox.

The Surrogate Powder Testing simulates the containment expected for compounds during typical work practices.  This test provides documented evidence that the containment system design and manufacturing of the glovebox meets the contracted Occupational Exposure Levels (OEL) as defined by client/facility protocol and/or user requirement specifications.  At FSI, this test is digitally recorded to provide documented evidence of correct execution of the test or to evaluate out of specification results.

All validation documentation includes serialized documentation including a Certificate of Calibration for all instrumentation used and Certificate of Analysis for all surrogate products used. Validation documentation, maintenance manuals and recommended usage guidelines are shipped with the glovebox from North Carolina to facilities around the world.

 

 

PERFORMANCE QUALIFICATION

When the client receives the glovebox, all documentation should be reviewed and filed for future reference. The external packaging is removed and the glovebox is thoroughly cleaned in place per industry recommended practices.  Cleaning solutions should be compatible with the components used in the manufacture of the glovebox.  It is recommended that Site Acceptance Testing (SAT) be performed before any manufacture of ADC’s by any operators.  This testing is the same test protocols and standards as used in the Factory Acceptance Testing at FSI.  It is recommended that the facility occupational health and safety team is included in the execution of the SAT and operators wear sufficient personnel protective equipment (PPE).  FSI recommends that the glovebox is serviced and certified annually by a third party certifying company.

The safe handling of ADC’s can be performed in the FSI Glovebox Workstation.  Ray Ryan, Founder and President of FSI states, “Flow Sciences is a solution based company. Sometimes we have the solution on our shelves, but most of the time we have to develop a solution to fulfill that industry need.”  The expertise and experience at FSI enables rapid manufacture of high quality containment solutions for the manufacturers of ADC’s per current FDA GMP’s.

 


Resources


Stainless Steel in Pharma

On June 21, 2017, Barry J. Cadden, the owner and head pharmacist at the New England Compounding Center (NECC) will face sentencing for a conviction on more than 50 counts of mail fraud and racketeering. The accusation is hardly indicative of the accusations levied against Mr. Cadden, who has long been considered primarily responsible for a fungal meningitis outbreak in 2012 that sickened 753 people and left 64 dead.

 

The fungal infection was spread through contaminated vials of methylprednisolone acetate (MPA), an injectable pain medicine that was distributed to some of the country’s most prestigious medical facilities, including affiliates of Harvard, Yale, and the Mayo Clinic.

 

Fungal meningitis is an extremely rare form of the disease that normally afflicts people already suffering from a weakened immune system. As fungal meningitis spreads through the blood stream and spinal chord, it causes a range of complications from hearing loss to seizures, paralysis, brain damage, and death. In a cruel twist of fate for the patients who were infected by the contaminated pain medication, those who survived the outbreak have spoken of being sentenced to living with a lifetime of pain.

 

The 2012 meningitis outbreak is an extreme case that nonetheless demonstrates the necessity of quality assurance and quality control in the production and distribution of pharmaceutical products.

 

 

PUBLIC SAFETY and LEGISTATIVE CHANGE

 

When Mr. Cadden was subpoenaed to appear before the House Energy and Commerce committee, the scope of the outbreak was not yet known. It had begun, like most outbreaks, with two deaths that were linked to steroid injections in the patients’ spinal cords. When Dr. April Pettit, an infectious disease specialist at Vanderbilt University, identified the “index case” associated with the growing outbreak, 14 infected patients was considered frightening. When the outbreak was fully understood, a total of 817 people had been infected across 20 states. The Center for Disease Control issued recalls to 76 facilities for the NECC’s vials of MPA. It was estimated that 13,000 people could have been injected with the contaminated drug.

 

Two days before the House Committee on Energy and Commerce was scheduled to hold a hearing on the 2012 meningitis outbreak, the FDA released a report detailing similar quality assurance concerns at Ameridose, a pharmaceutical drug supplier and the sister company of the NECC. Spokesperson Sarah Clark-Lynn, speaking for the FDA, related that “inspectors observed conditions and practices at Ameridose which demonstrated that the firm could not consistently assure their injectable products were sterile and safe for use by patients.” Though the FDA could not link safety practices at Ameridose with the NECC, the report nonetheless raised the specter of concern for a public already terrified by a national outbreak caused by product contamination.

 

The NECC has since surrendered its pharmacy license and Ameridose shut its doors not soon after, but the outbreak galvanized a nation-wide conversation about compounding pharmacies, regulations, and federal oversight. The federal government pressed for new legislation in response to the outbreak and as a result of testimony to the House Committee on Energy and Commerce suggesting that the FDA’s limited power was crippling their efforts to enforce safety standards. Conflicting court decisions and a lack of consensus over the definition of compounding had crippled the FDA’s authority. Then Governor of Massachusetts Deval Patrick directed pharmacies in the state to submit annual reports on production, volume, and distribution. He also directed the state pharmacy board to ramp up unannounced inspections.

 

COMPOUNDING PENDULUM

 

Inspection reports of the facility linked the outbreak to the compounding pharmacy’s own practices. The government contended that the NECC produced pharmaceutical products in unsanitary conditions and sold them to patients while fully aware of the risks. While the Food and Drug Administration (FDA) report did not amount to a formal indictment of the company, it cited air circulation and equipment sterility as the likely causes of the outbreak.

 

Speculation abounded in the wake of the meningitis outbreak. Multiple investigations were conducted by the FDA, the Justice Department, and the House Committee on Energy and Commerce. Congress heard testimony from experts, victims, and those purportedly responsible for the outbreak. No one appeared to disagree with the fact that the NECC with primarily culpable for the unsterile conditions that lead to the distribution of fungal-tainted MPA, but the agencies and experts involved also identified varied systemic causes.

 

The limited authority of the FDA to enforce safety standards and the lack of quality assurance and quality controls at the NECC were the two most frequently cited reasons for the outbreak. The rapid growth in compounding pharmacies since the 1990s meant that regulations and oversight had not kept pace with large-scale changes in the industry, creating confusion over the precise definition of compounding and how that differed from pharmaceutical manufacturing.

 

Key pieces of federal legislation had governed drug manufacturing up to the moment of the outbreak, but they did not anticipate that local pharmacies would position themselves to become all but manufacturers in name. This meant that the state pharmacy board—the entity primarily responsible for enforcing safety standards on local pharmacies—was placed in a position of policing one of its own. Mr. Cadden was, at the time, a member of the board and also on the committee tasked with rewriting rules governing compounding safety standards for the state.

 

Traditional compounding is limited in scope. In a report to Congress following the meningitis outbreak, the Congressional Research Service (CRS) defined compounding as “a process where a pharmacist or a physician combines, mixes, or alters ingredients to create a medication tailored to the needs of an individual patient.” What’s important to note about traditional compounding is that it is highly individualized and typically serves the specific needs of particular patients. A patient who has trouble swallowing pills may need a liquid version of a prescribed medicine. The role of a compounding pharmacy is to fill the prescription according to that specific patient’s needs.

 

In the 1990s, however, compounding expanded to include large-scale production, arguably as a response to drug shortages and as a result of hospital outsourcing. The NECC was one of the compounding pharmacies that became a veritable drug manufacturer during this time, producing drugs without individual prescriptions for mass distribution. They also made copies of commercially manufactured drugs to supply the nation-wide shortage.

 

The FDA began to scrutinize the growth in pharmacy compounding almost from the moment it recognized the trend. David Kessler, FDA commissioner during the early 1990s, issued prophetic warnings about the growth in pharmaceutical compounding. He worried that they would produce a “shadow industry” that could cause “serious adverse effects, even death.” Kessler’s concerns proved to be sound as a spate of patients took ill or died after consuming compounded drugs.

 

PHARMACEUTICAL PRODUCTION and QUALITY ASSURANCE

 

Citing Kessler’s concerns over the growth of pharmaceutical compounding is not meant to imply that quality assurance and quality control do not exist in the pharmaceutical compounding. In fact, compliance with federal guidelines was reported at 73.9% in 2011—just a year before the outbreak—which then increased to 81.3% in 2014. Though an overwhelming majority of pharmacies abide by the federal statutes embodied in USP Chapter <797> standards, at the time of the outbreak the federal government argued that a lack of information on and authority over pharmaceutical compounding had lead to the tragedy.

 

Governing bodies at the state and federal level thus refocused their attention on sterile compounding. States have written new regulations and conducted more rigorous inspections. In conjunction with the federal government’s expansion of USP <797> to include the more rigorous standards of USP <800>, states have also updated their standards to assure patients and health care providers of quality pharmaceutical production at the local compounding level.

 

Any assurance offered to the public with concern to pharmaceutical production primarily deals with quality, safety, and efficacy. Pharmaceutical drugs should effectively treat diseases with as few complications as possible, and they should be free from contamination so as not to harm patients. In the shifting sands of compounding, quality assurance demands self-policing which begins with a full knowledge of how to safely produce pharmaceutical drugs. For instance, USP <797> requires hazardous drugs to be stored under negative pressure, but only 55% of hospital pharmacies reported abiding by this standard. Over 1/5 of those same respondents cited a lack of competency, training, and resistance to change as the main reasons for failing to abide by industry standards.

 

In light of the FDA’s report on the NECC, which cited air filtration and equipment sterilization as causes for the contamination that resulted in the meningitis outbreak, we may argue that even though the NECC knew the probability of potential contamination that there is also a possibility that an understanding on proper handling could have prevented the outbreak. Because of the FDA’s limited authority, it them becomes the responsibility of industry experts to inform and train the public.

 

PARTNERING for PRODUCT ASSURANCE

 

Product assurance and quality control of compounded pharmaceutical drugs begins when raw APIs enter the laboratory and covers their storage, the act of compounding, drug administration, and ultimately drug disposal. Flow Science, Inc. has worked directly with compounding pharmacies to address these points of potential contamination in order to design laboratory solutions that meet industry wide quality assurance standards.

 

Flow Sciences’ team of industrial engineers design workstations and enclosures that reduce product contamination and maximize protection for professionals who work with toxic substances and uncertain risks. All of our products are engineered and manufactured at out corporate headquarters in Leland, NC and are backed by our sophisticated design process and award-winning excellence in engineering, including 11 U.S. Government patents. In addition to compounding pharmacies, we have worked with pharmaceutical companies, research and development laboratories, manufacturing, and production facilities for 30 years.  Our task-specific designs are dynamic solutions that are adaptable to our clients’ workflow and specific needs.

 

Flow Sciences was one of the first companies in the U.S. to use computational fluid dynamics (CFD) in drafting our enclosures to ensure optimum airflow. Our engineers use CFD algorithms to simulate fluid flows and interactions within contained spaces. This enables us to predict and control airflow through design, which we then test in our state-of-the-art laboratory. Working closely with our clients to mimic real-world applications, we develop testing protocols based on the intended use of our enclosures and measure them against industry-accepted standards to ensure proper containment. We have designed, manufactured, and tested over 13,000 enclosures, generating a wealth of data on situational flow dynamics, which allows us to control for consistency, safety, efficacy, and overall quality.

 

Because all of our hoods and enclosures are manufactured at our corporate headquarters in Leland, NC, we are able to control the entire production process, from sourcing raw materials to the installation of our containment solutions in your laboratory.

 

Ensuring safe pharmaceutical compounding and manufacturing requires a range of containment options for the entire scope of development from weighing and handling active pharmaceutical ingredients (APIs) to creating tailored solutions for patients without sacrificing quality. Flow Sciences offers bulk powder solutions, isolators, and gloveboxes for processing highly potent pharmaceutical drugs. Our systems are designed to protect against both product contamination and personnel exposure.

 

The Glovebox Workstation provides negative-pressure containment for toxic applications using highly potent active pharmaceutical ingredients (HPAPIs) that meets or exceeds ISO 5 clean processing. The Glovebox Workstation comes standard with a HEPA inlet that creates a clean environment ensuring product protection; it also uses horizontal laminar flow to reduce turbulent airflow and reproduce consistent, performance-based results. Laminar, or unidirectional airflow systems direct filtered air in a constant stream, reducing turbulence. Consistent airflow is necessary for reducing exposure and ensuring reproducilibity.

 

  • HEPA INLET exceeds ISO 5 requirements for cleanroom classification,
  • BAG-IN/BAG-OUT HEPA exhaust ensures safe recirculation of air in the room
  • LAMINAR AIRFLOW reduces turbulence and allows for consistent, performance-based results, and
  • BALANCE STABILITY to the 7th decimal place makes the Glovebox Workstation ideal for weighing and working with HPAPIs.

 

HEPA filtration, laminar airflow, and negative pressure containment are integral to creating a controlled environment for pharmaceutical drug manufacturing purposes. In order to demonstrate the superiority of these engineering controls, we have submitted the Glovebox Workstation for evaluation by third-party testing facilities that have confirmed containment levels at or below 50 ng/m3 with balance stability to the 7th decimal place. This ensures that while you are working within one of our containment devices, your products will be protected and your results will be reproducible.

 

MATERIALS of CONTROL

 

We have also begun manufacturing many of our standard units in stainless steel in order to respond to the industry’s increasing demand for cleaner processing. High-polished stainless steel is non-reactive, non-additive, non-absorptive, and non-corrosive. Low-carbon stainless steel also has a proven resistance to most “hostile” chemical compounds, and is used when products require maximum levels of containment against contamination, as in drug development or compounding.

 

The advantage of using stainless steel for pharmaceutical compounding is its inherent resistance to contamination, which is generalized as “corrosion” in the metals industry. Stainless steel is also a preferred material of construction because it can be easily cleaned and disinfected. Its smooth surface—which is a result of polishing—does not encourage bacterial growth. Coupled with proper ventilation and air circulation systems, a stainless steel unit will also prevent mold growth.

 

Stainless steel is also versatile because it is an alloyed metal. There are over 200 different grades of stainless steel with a range of properties to suit various manufacturing needs and product protection requirements. For pharmaceutical hygiene products, grades 304 and 316L are chosen for their corrosion-resistant properties.

 

The 300 series of austenitic stainless steel is most appropriate for pharmaceutical use. It is an iron-based, low-carbon alloy that is non-magnetic and owes its high-corrosive resistance to chromium. The basic structure of 300-series austenitic stainless steel is 18% chromium, 8% nickel alloy, and 0.10% carbon; it is commonly known as 18/8 steel.

 

Within the 300 series, 304 stainless steel is known as “surgical stainless steel.” It is used primarily in brewery, dairy, and pharmaceutical production equipment applications. 316 stainless steel contains molybdenum and a higher nickel content (10%) than 304. In conjunction with chromium, molybdenum provides superior resistance to attack by most chemicals and an increased resistance to chloride corrosion as compared to 304 stainless steel. 316 L is the most common type of stainless steel used in the pharmaceutical industry. Corrosion resistance is the same as standards 316, but the low carbon content is used to avoid possible sensitization corrosion in welding. 316 L stainless is also frequently specified in pharmaceutical installations in order to prevent excessive metallic contamination of pharmaceutical products.

 

Table 1: What’s in Stainless Steel

 

Carbon Iron is alloyed with carbon to make steel, which increases the hardness and strength of iron.
Manganese 2% manganese improves the working strength of stainless steel at high temperatures, more than 20% manganese improves tensile strength.
Silicon When added to steel alloys, Silicon increases strength and resistance against strong acids like sulfuric acid.
Phosphorus Added with sulfur, phosphorus improves machinability.
Sulfur In small amounts, Sulfur improves machinability much like Phosphorus.
Chromium At precise ratios, chromium makes steel’s surface resistant to corrosion and oxidation; it also adds tensile strength to the metal.
Nickel Improves resistance to hot and humid environmental conditions.
Molybdenum Improves resistance to pitting and crevice corrosion, especially in environments where chlorides and sufur are prevalent.
Nitrogen Yield strength is greatly improved when Nitrogen is added to steel as is resistance to pitting corrosion.

 

Grade 304 is an excellent general-purpose stainless steel option that is used in many domestic applications, but 316L is preferable, particularly within the pharmaceutical industry. With lower carbon and higher inclusion of molybdenum, 316L stainless has greater corrosive resistance. While grade 304 is used for “non-product” applications within the industry, 316L is used wherever pharmaceutical products are directly handled or manufactured. No matter what grade, sanitary, pharmaceutical grade stainless steel must exhibit good corrosion resistance and maintain its structural integrity so that it is not affected by heat or corrosive elements, like strong acids or bases.

 

Stainless steel does not release contaminants because the chromium content of the steel combines with oxygen in the atmosphere to form an invisible film of chrome-containing oxide, called the passive layer. The chromium oxide layer protects stainless steel when it encounters potential damage by machining or chemicals. If the metal is scratched and the passive film is disrupted, more oxide will form and recover the exposed surface, protecting it from oxidation corrosion. Though the protective layer is too thin to be visible, it is responsible for the glossy look of stainless steel.

 

Common types of corrosion in stainless steel:

 

  • Pitting corrosion happens when the passive layer on stainless steel is attacked by strong chemicals. Chloride ions are the most common cause of pitting corrosion and can be found in everyday materials, like salt and bleach. The probability of pitting corrosion can be calculated based on alloy content. (Pitting Resistance Equivalent Number)
  • Crevice corrosion happens when not enough oxygen reaches welded corners. Stainless steel requires oxygen to make sure that a passive layer of protective chromium oxide forms on the surface. Crevices do not always allow for chromium to interact with oxygen, which makes the steel vulnerable to corrosion. (mention coved corners)
  • General corrosion can occur with the use of concentrated chemicals—most notably with hydrochloric and sulfuric acids—which corrode stainless steel uniformly and distribute metal loss across the entire surface.
  • Stress corrosion cracking is a rare form of damage that is the result of low tensile strength, extreme temperature, and the presence of a concentrated corrosive chemical, often with chloride ions.
  • Intergranualar corrosion is another rare form of corrosion that occurs when the carbon level in steel is too high. Chromium can combine with carbon to create chromium carbide between 450–850° This type of corrosion is called sensitization and typically occurs during welding operations when the passive layer of chromium is reduced to the point where corrosion can occur. Intergranular corrosion can be avoided by choosing low-grade carbons or by using steel with titanium or niobium.

 

The addition of chromium is what adds to steel the properties most sought by the pharmaceutical industry, namely its excellent resistance to corrosion and strength at high temperatures and pressures. There are three main classes of stainless steel depending on the metallurgic structure, but not all of them are appropriate for pharmaceutical use.

 

Austenitic Ferritic Martensitic
16–20%  chromium 10.5–27%  chromium 11.5–18% chromium
Up to 35% nickel Nickel free 1.2% carbon with nickel sometimes added
Highest corrosion resistance Less critical anticorrosion Modest corrosion resistance
Aircraft and dairy/food processing Architectural and auto manufacturing Cutlery, surgical instruments, wrenches, and turbines

 

 

LESSONS LEARNED

 

If the meningitis outbreak of 2012 has taught us anything about industry safety, it is akin to the ancient Greek lesson that guards against limiting perspectives. We must constantly look to the broad and the specific in order to balance our actions. The growth of compounding pharmacies in the 1990s was a direct response to overall industry shortages of necessary drugs, but the inability of regulatory agencies to keep pace with these changes resulted in production oversight that cost people their lives. These tragedies, like the production and distribution of MPA by the NECC could have been prevented with access to proper information about airflow requirements and appropriate equipment for processing pharmaceutical drugs.

 

While states and federal government agencies eventually interceded, it was not without the cruel recognition that the technologies needed to prevent these kinds of tragedies are well within our reach. It is wise for companies to understand the options that they have when it comes to designing laboratories for production purposes. Stainless steel is not merely shiny; its high gloss is, rather, a sign of its resilience and its ability to resist corrosion, which means that you can produce more safe and effective drugs for patients in need.

 

Though it is resilient enough on its own, not even stainless steel can guard against all types of contamination, which is why it is also imperative that drug manufacturers use appropriate air filtration systems to guard against the type of mold that infected the vials of MPA that eventually caused the outbreak of 2012. Partnering with experts like the engineers at Flow Sciences is an assured way to guarantee the integrity of your production process. For over 30 years, we have specialized in helping compounding pharmacies design containment systems to establish and improve their quality assurance.

 

The FLOW SCIENCES ADVANTAGE

 

As a manufacturer of safety products, we are also intimately familiar with quality as a standard of production. We know how important it is to certify raw materials and establish chains of command and consistent quality controls across the entire production chain. We know how important details are to the ultimate function of safety systems, just like how the smallest differences in stainless steel are critical to its function. It is our job to know these details, and we also consider it our duty to share them with our customers in hopes that, together, we can build a safer pharmaceutical industry.

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Improving Lab Safety

Improving Lab Safety

 

We all remember watching Saturday morning cartoons as a kid that featured the mad scientist, a typically larger-than-life character with little sense of risk. He wore goggles and mixed beakers of chlorine and ammonia to disastrous effect and, oftentimes, laughter from the audience.

 

In reality, scientists are rarely naïve about the risks of experimentation. They work in laboratories where hazards are rigorously controlled and risks are managed by entire departments devoted to safety and compliance. Establishing good lab practices, internal controls, and standards reflect a concern for reducing user error.

 

Laboratories are also accountable to regulatory agencies and responsible for upholding standards of industrial hygiene to ensure worker and community health and safety. The body of organizations that effectively make and enforce laboratory safety standards is vast and includes the Federal Drug Administration (FDA); Occupational Safety and Health Administration (OSHA); and the American Society of Heating, Refrigeration and Air-Conditioning Engineers (ASHRAE), among others.

 

Far from an absence of concern for safety, the scientific community is flush with organizations dedicated to ensuring that the mad scientist remains an absurd cartoon character. User error may continue to be the most imminent threat to personal safety and responsible for 90% of laboratory accidents, but it’s wildly unreasonable to believe that these accidents result from recklessness. Poor safety training, fatigue, inattention, and haste are the main culprits.

 

One of the most important ways to prevent these types of laboratory accidents is to be prepared, well trained, and informed. But the reality about prevention is that it assumes hazards, which cannot always be eliminated. It is, therefore, extremely important to establish an effective safety culture and risk management systems. Risk is the difference between control and exposure. No matter how well trained, worker protection is paramount because we cannot eliminate hazards. We can only control exposure.

 

If effective lab ventilation systems and equipment are an employees first line of defense, then Personal Protective Equipment (PPE) is an employee’s last line of defense against hazards that can cause serious injury and illness. Gloves, sleeves, lab coats, safety glasses and shoes, and respirators are common types of PPE that laboratories provide employees. Airborne hazards require additional safety precautions. Toxic fumes and powders used in laboratories where the risk to employee safety is respiratory also require filtration systems that direct potentially contaminated air away from workspaces.

 

Flow Sciences team of industrial engineers design workstations and enclosures that reduce product contamination and maximize protection for professionals who work with toxic substances and uncertain risks. All of our products are backed by our sophisticated design process and award-winning excellence in engineering, including 11 U.S. Government patents. We have worked with pharmaceutical companies research and development laboratories, manufacturing and production facilities for 30 years. Our task-specific designs are dynamic solutions that are adaptable to our clients’ workflow and specific needs.

 

If you work with airborne hazards, we can design an airflow control system to reduce your exposure risk.

 

Purchasing a Flow Sciences enclosure is only the first step. Whether you’re working with solutions that create toxic fumes that require a fume hood or powder APIs that can be contained with isolators and gloveboxes, we can manufacture a solution for your laboratory.

 

Once you receive delivery, the next step in proper containment is hiring a 3rd-party certification company to ensure that all lab systems are operating as designed, conform to applicable safety standards, and comply with relevant regulations. Certifiers check filters and airflow rates, set fan speeds and alarms, repair your systems when they are not functioning properly. They are a resource for laboratory managers who are responsible for the overall safety of employees and the workplace.

 

Flow Sciences works with a national network of 3rd- party certification companies who are trained on the specific operational features of our products. They can effectively install and certify your hood and provide routine maintenance so that all lab systems remain in compliance with relevant safety standards.

 

An efficient laboratory protects their employees by providing effective equipment in a safe environment with the knowledge that hazards cannot be eliminated. Purchasing proper equipment is only the beginning.

 

For practical tips on how to work with certifiers, look for our next newsletter where we will cover the certification process.

 

Sources:

 

Borchardt, John K. “Running Your Lab Like a Business.” Lab Manager. July 21, 2008: 10–14.

 

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Toxic Treatments - Controlling Exposure Risks in ADC Manufacturing

This year marks the 80th Anniversary of the National Cancer Institute, established by President Franklin D. Roosevelt to support research on the causes, diagnosis, and treatment of cancer. Since the 1940s, cancer researchers have produced nothing short of astonishing science.

 

The development of antibody drug conjugates (ADCs) ranks among one of the most important advancements in cancer treatments in recent history. The ability to precisely target abnormal cells throughout the body and deliver highly toxic drugs to the center of tumors significantly improves upon the negative side effects of traditional chemotherapies that employ a total war approach to defeating cancer.

 

Anticancer drug development has not come without challenges for pharmaceutical companies that manufacture ADCs. The potency and effectiveness of ADCs are dependent upon engineered nanoparticles (ENPs) — the cytotoxic payload that destroys cancer cells — but little is known about the environmental and human health hazards posed by ENPs. Yet, the promise ENPs hold for patients is why we continue to wield them in the quest for a cure even without a full understanding of their key physical characteristics, chemical properties, and associated hazards.

 

The National Institute of Occupational Safety and Health (NIOSH) has been a primary champion of safe nanotechnology. Their research suggests that nanoparticle exposure can happen through skin contact or ingestion, but the risk is greatest when the material is airborn and potentially inhaled. As a result, NIOSH recommends that laboratories use high-efficiency particulate (HEPA) filters along with a well-designed exhaust ventilation system to reduce the risk of exposure.

 

A BRIEF HISTORY of ANTICANCER TREATMENTS

 

Traditional chemotherapies have always posed serious side effects for patients because they cannot specifically target cancer cells. In the 1960s, “poison” was the general term used for chemical anticancer therapies. The label reflected scientists’ skepticism of the “chemical cure” hypothesis first imagined by Paul Ehrlich at the turn of the century.

 

The advancement of cancer therapies has benefitted greatly from the early pioneers like Ehrlich. The development of cancer drug screening models by Murray Shear was the first to test an array of compounds for their effectiveness in treating specific cancers. The discovery of hormone therapy in the 1930s by Charles Huggins also expanded treatment options that are still used today in combination with other therapies.

 

These early contributions to cancer treatments were largely individual accomplishments because there was no general public support for research. That changed in the 1950s with the inauguration of the Cancer Chemotherapy National Service Center (CCNSC). Widely recognized as a turning point in anticancer drug development, the CCNSC was the precursor to the multi-billion dollar cancer pharmaceutical industry. Up until the 1990s, all new cancer therapies were developed by the CCNSC.

 

It wasn’t until the 1960s that scientists began to conceptualize a cure for cancer, which greatly advanced after Howard Skipper introduced the “Cell Kill” hypothesis. Skipper hypothesized that a given dose of medicine would only kill a consistent fraction of cancer cells, which encouraged a more aggressive use of chemotherapy and dramatically increased remission rates. Through the 1970s and 80s, scientists made even more incredible advancements in the fight against cancer and were officially recognized in 1973 with the establishment of medical oncology.

 

It is a testament to the dedication of oncologists that, starting in 1990, cancer mortality rates have consistently declined. In 2007, the decline doubled largely as a result of prevention, diagnosis, and advances in cancer treatment.

CHEMOTHERAPY and the ADVENT of ADCs

 

Chemotherapy is an imperfect treatment that has historically been combined with surgery and radiotherapy along with immune-, hormone, and biological therapies to achieve remission in patients. Of all the available cancer treatments, chemotherapy is the most toxic to cancerous and healthy cells alike causing acute side effects for patients and limited therapeutic results. The limitation of chemotherapy as a treatment option is directly related to the systemic nature of disease.

 

Cancer spreads throughout the body based on changes in the molecular biology of tumor cells. While advances in research have allowed us to track and anticipate the spread of cancer, traditional chemotherapy cannot precisely target systemic cancers. The chemical composition and size of chemotherapy drugs also make them insoluble and incapable of overcoming biological barriers to reach cancer cells in sufficient concentrations. As a result, chemotherapy can damage a patient’s immune system and other organs, which is compounded by the fact that many patients also experience drug resistance, resulting in reduced dosage and low survival rates.

 

The history of anticancer drug development has only recently included nanomaterials, but they have quickly shown promise for combating some of the most serious side effects of chemotherapy treatments. This new class of highly potent biopharmaceutical drugs are gaining weight with oncologists in the fight to defeat cancer for their demonstrated ability to target cancer cells, bypass biological barriers, and combat drug resistance.

 

The success of ADCs is a function of their unique structure that combines the selectivity of immunotherapy with the potency of chemotherapy to create a novel class of anticancer treatments. ADCs are made by connecting an antibody to a cytotoxic agent through a linker that controls the pharmacokinetics, therapeutic index, and efficacy of the drug. Without these three elements, ADCs would not be able to target and kill specific cancer cells. While it may sound simple, manufacturing ADCs is a tricky science. Cytotoxins and antibodies have to be combined in exact ratios, and linkers have to release drugs at precise times in order to achieve their desired results.

 

Developing targeted anticancer therapies that overcome the characteristic downfalls of traditional chemotherapies has been a main goal of pharmaceutical and biopharmaceutical manufacturers since the discovery of monoclonal antibody technologies in the 1970s. Though these ADCs have experienced their own clinical hurdles—low delivery efficiency, the omnipresence of target antigens, and tumor antigen heterogeneity—they largely hold more promise for eventually realizing Ehrlich’s goal of a chemical cure, which probably wouldn’t be possible without the advent of nanotechnology.

 

NEW TECH on a NANO SCALE

 

Nanotechnology is a science of the small. Nanoparticles are defined as materials that have at least one dimension measuring between 1 and 100 nanometers. The size, shape, and surface area of nanoparticles distinguish them from their macro-cousins and contribute to their high potency. The size of nanoparticles also influences their chemical properties. When combined, the size, toxicity, and solubility of nanoparticles represent the evolution of anticancer drug development.

 

Nanoscience research combines advancements in engineering and medicine to produce targeted therapies that can more effectively deliver drugs to patients suffering from intractable forms of cancer. Three ADCs have received market approval from the U.S. Food and Drug Administration (FDA). The first ADC to be approved in 2000, Mylotarg® was withdrawn from the market in 2010 after clinical studies had shown that it did not outperform traditional therapies. The initial setback in the development of Mylotarg® may have been more of a premature judgment than proven analysis. More recent studies have shown that using Mylotarg® in combination with other anticancer therapies significantly improves event-free and relapse-free survival in adults suffering from acute myeloid leukemia.

 

Adcentris® and Kadcyla® have also been approved by the FDA for treatment of two forms of blood cancer and HER-2+ metastatic breast cancer, respectively. Both drugs have demonstrated ability to positively affect survival and remission rates in cancer patients, leading oncologists and drug manufacturers alike to boast a new era of cancer treatment. In addition to targeted ADCs, scientists have also recently advanced bioaffinity nanoparticle probes for imaging and even nanodevices for early detection and screening.

 

EXPOSURE RISK

 

Nanoparticles are more effective at fighting tumors primarily because of their toxicity. The smaller-sized particles have more surface area than their larger, macro-cousins. When these potent cytotoxins are introduced into cancer cells, they are capable of delivering higher dos amounts because toxicity is inversely proportional to particle size. It is precisely their size makes them capable of fighting formerly untreatable cancers, but their size alters more than their potency. Nanoparticles also act differently than larger molecules with similar chemical compositions, which further expands the range of uncertainty and increases occupational exposure risks.

 

Nanotechnology is an emerging field. The side effects of exposure to nanoparticles has only been measured in animal studies; while these studies are not directly applicable to cases of human occupational exposure, they have proven that nanoparticles are more potent than their macro-cousins. We still do not know, and therefore cannot fully anticipate, all the risks associated with the production of engineered nanoparticles (ENPs) like those used in ADC manufacturing. However, we do know that exposure to hazardous materials is calculated based on dose size, which is expressed as particle surface area. This means that an equal weight of nanoparticles is potentially more harmful than larger, chemically similar molecules due to the increased surface area exposure alone. Taking into account that the size of nanoparticles alters their chemical characteristics, the near-atomic size of the particles could also pose more adverse health risks.

The small size of ENPs makes inhalation exposure the biggest threat to scientists and technicians who work with and develop ADCs. In addition to their heightened toxicity, nanomaterials can agglomerate into larger particles or longer fiber chains, affecting their properties, behavior, and the exposure risk for humans. Skin can also be exposed to nanoparticles. Our outer layer of skin is only 10 µm thick. While it is difficult for particles and compounds to pass through the outer layer of skin, contact with anthropomorphic substances during nanomaterial manufacturing is a risk that is not fully understood and, therefore, should be managed.

As the production of ENPs continues to grow in response to their successful use in cancer treatments, they will continue to pose hazards for the people who make them. It is acutely ironic that the characteristics of ENPs for which they are so useful—small dimension, large surface area, and high toxicity—also increase the occupational risks associated with their development. As researchers continue to learn more about the risks of occupational exposure to ENPs, we will be able to fine-tune our risk-based assessment guideline and regulatory decision-making. In the meantime, we can still minimize risks by applying the precautionary principle.

 

More research is needed to determine the key physical and chemical characteristics of nanoparticles and their associated hazards, but this lack of information is precisely why taking measures to minimize worker exposure is prudent. At the very least, when working with nanoparticles, employers must establish workplace-engineering controls and include effective source ventilation and capture protocol to minimize exposure risk. The National Institute for Occupational Safety and Health (NIOSH) recommends the use of local exhaust ventilation systems and high-efficiency particulate (HEPA) filtration for any workplace task that would increase risk of exposure to nanoparticles.

 

CONTAINMENT MATTERS™

 

ADC production requires a laboratory that can provide both product and personnel protection during the initial familiarization phase as well as conjugation, verification, purification, and scale-up. Flow Sciences has designed a comprehensive containment solution that covers the entire scope of ADC development and simplifies laboratory setup.

 

The Glovebox Workstation was designed specifically for ADC development with a HEPA filtration inlet and Bag-In/Bag-Out technology offering both product and personnel protection for antibody-drug development and conjugation. Our engineers have analyzed all phases of the manufacturing process and designed the Glovebox Workstation to specifically address all of the containment and exposure risks. They have also submitted the Glovebox Workstation to rigorous engineering and performance testing to ensure effective containment.

 

Manufacturing ADCs requires specialized equipment and careful handling. One of the largest challenge pharmaceutical companies face is the need to balance conflicting requirements for handling antibodies alongside highly potent active pharmaceutical ingredients—HPAPIs or cytotoxins. Maintaining a clean environment is absolutely necessary for successful antibody-drug conjugation just as reducing occupational risk is necessary for a successful laboratory. The Glovebox Workstation guarantees product protection by applying isolator design principles to prevent contamination. Personnel protection is also vital while weighing cytotoxins because they are designed to disrupt cell reproduction and damage DNA, posing significant risks to operators. The Glovebox Workstation provides personnel protection for working with HPAPIs by operating under negative pressure.

 

In order to meet the requirements for product and personnel protection while accommodating the unique process of ADC development, laboratories typically have to invest in both positive- and negative-pressure enclosures. The cost of equipping a laboratory for ADC production is oftentimes cost-prohibitive, leading some laboratories to shop out ADC production and cede process control to contract manufacturers. Instead of bearing the cost of purchasing multiple enclosures to encompass the complex process of ADC production, the Glovebox Workstation can be used for weighing HPAPIs as well as conjugation, purification, and filling.

 

Successful ADC manufacturing depends upon thorough control and tracking of molecular-level characteristics, including: drug-to-antibody ratio (DAR), monomer content, drug distribution, and cell killing activity or antigen recognition. It also depends upon designing a process that controls for successful experimental parameters within selected ranges so that the manufacturing of ADCs can be scaled up to grams. Purification techniques that are crucial in the manufacture of ADCs can only be performed on process solution volumes at the gram scale. As production continues to be scaled up for early clinical phases, the manufacturing process ultimately depends upon careful analysis and control during the earlier experimental phases. Turning over this process to contract manufacturers forces pharmaceutical companies to turn over control. The Glovebox Workstation allows companies to save money and keep ADC processing in house.

 

GLOVEBOX WORKSTATION

 

The Glovebox Workstation provides negative-pressure containment for toxic applications using HPAPIs requiring isolation that meets or exceeds ISO 5 clean processing. The Glovebox Workstation comes standard with a HEPA inlet that creates a clean environment ensuring product protection; it also uses horizontal laminar flow to reduce turbulent airflow and reproduce consistent, performance-based results. Laminar, or unidirectional, airflow systems direct filtered air in a constant stream, reducing turbulence. Consistent airflow is necessary for limiting exposure risk and ensuring reproducibility.

 

  • Designed to offer both product and personnel protection for an all-in-one approach to safe ADC manufacturing.
  • HEPA inlet exceeds ISO 5 requirements for cleanroom classification.
  • Bag-In/Bag-Out HEPA exhaust ensures safe recirculation of air in the room.
  • Laminar airflow reduces turbulence and allows for consistent, performance-based results.
  • Balance stability to the 7th decimal place makes the Glovebox Workstation ideal for weighing HPAPIs like those used in ADC manufacturing.

 

The Glovebox Workstation has been evaluated by third-party testing facilities that have confirmed containment levels at or below 50 ng/m3 with balance stability to the 7th decimal place. This makes the Glovebox Workstation ideal for antibody-drug conjugation that requires accurate methods and precise measuring.

 


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ENGINEERING and ADMINISTRATIVE CONTROLS

 

The foundation of any effective workplace safety program is establishing risk management programs that include the use of good work practices and appropriate personal protective equipment. Flow Sciences, Inc. has partnered with pharmaceutical companies and laboratories that manufacture ENPs and ADCs to design task-specific containment enclosures that minimize product loss and exposure to nanoparticles.

 

In addition to the applying the patented engineering controls developed by Flow Sciences engineers, both national and international experts on the risks of occupational nanoparticle exposure agree that laboratories can limit exposure levels by implementing a thorough risk management program. By using good work practices and appropriate personal protective equipment, laboratories can limit exposure to nanoparticles and reduce the risks associated with these hazardous materials.

 

Flow Sciences is committed to partnering with our customers to ensure that they have access to the most effective occupational risk assessments, education and training, and personal protective equipment (PPE).

 

There are no specific limits for airborne exposure to ENPs. While occupational exposure limits (OELs) have been set for micro- and macroparticles of similar chemical composition, these limits may be insufficient for recommending protection against exposure to nanoparticles. Applying the precautionary principle, there are a number of additional measures that employers and workers can take to reduce potential exposure to nanoparticles: good work practices like cleaning using HEPA vaccums and wet wiping method; preventing food consumption in the workplace; setting up hand-washing facilities for showering and changing clothes; and proper PPE.

 

THE FLOW SCIENCES ADVANTAGE

 

We are now closer than ever before to realizing a chemical cure for cancer, with engineered nanoparticles and targeted delivery systems that do not cause the same side effects as traditional chemotherapies. The advancements in anticancer drug research enabled by nanoscience raise exciting opportunities for personalized oncology. Scientists are already beginning to imagine using biomarkers to diagnose patients and develop individualized treatments. As researchers continue to bridge the data gap, it’s important to stay abreast of risk assessments and incorporate those into environmental and occupational health and safety plans.

Nanomaterials present new options for cancer patients who once had little hope, but they also bring with them new challenges that need to be addressed in order to fully realize their potential. Partnering with a company that understands the process and risks of ADC development is crucial for drug developers who are leveraging new technologies and need to manage exposure risks. Responsible development of any new material requires that laboratories managed risks to health and the environment. The engineers at Flow Sciences are experts in containment technology and have worked closely with companies that produce ADCs. You can rest assured that we understand the manufacturing process and the risks involved. We can help you overcome any challenge that stands in the way of developing life-saving new technology.

 

 

FLOW SCIENCES: WHO ARE WE?

 

Flow Sciences’ team of industrial engineers design workstations and enclosures that reduce product contamination and maximize protection for professionals who work with toxic substances and uncertain risks. All of our products are engineered and manufactured at our corporate headquarters in Leland, NC and are backed by our sophisticated design process and award-winning excellence in engineering, including 11 U.S. Government patents. We have worked with pharmaceutical companies, research and development laboratories, manufacturing, and production facilities for 30 years. Our task-specific designs are dynamic solutions that are adaptable to our clients’ workflow and specific needs.

 

Flow Sciences was one of the first companies in the U.S. to use computational fluid dynamics (CFD) in drafting our enclosures to ensure optimum airflow. Our engineers use CFD algorithms to simulate fluid flows and interactions within contained spaces. This enables us to predict and control airflow through design, which we then test in our state-of-the-art laboratory. Working closely with our clients to mimic real-world applications, we develop testing protocols based on the intended use of our enclosures and measure them against industry-accepted standards to ensure proper containment. We have designed, manufactured, and tested over 13,000 enclosures, generating a wealth of data on situational flow dynamics, which allows us to control for consistency, safety, efficacy, and overall quality.



Containing a Budding Industry - Cannabis Processing and Product Assurance

 

As the market for medicinal cannabis products grows in response to research that suggests it is effective for relieving the symptoms of chronic illnesses, the industry will need to respond to safety concerns surrounding the production of cannabis extracts. States like Oregon that have legalized cannabis for medicinal and recreational use have experienced a rise in the number of injuries from dangerous solvent explosions. In one 16-month period, 17 people were sent to a Portland burn unit with injuries from butane-fueled blasts. This experience has been replicated across states that have legalized or decriminalized the use of cannabis.

Even through many of these states also require licenses for producers, they still misunderstand the risks associated with using hydrocarbon solvents. Hydrocarbon gases like butane can quickly fill enclosed spaces where something as ordinary as static electricity or a pilot light can ignite the fumes, producing fireballs and explosions that destroy infrastructure and seriously injure people. With education and access to safety equipment, states and the industry as a whole can begin to better manage the hazards of a budding cannabis market.

 

THE MEDICINAL MARKETPLACE

The cannabis industry in the United States is rooted in growing flowers and buds that are ultimately smoked by consumers, but the market for cannabis extracts is expanding as researchers are beginning to uncover the palliative qualities of the cannabis plant. Cannabis is widely recognized as a treatment for symptoms of multiple sclerosis, Chron’s disease, and glaucoma. THC and CBD—two of the active ingredients in cannabis—are also used to counter nausea in cancer patients undergoing chemotherapy and poor appetite/weight loss caused by chronic illnesses such as nerve pain and HIV. Laboratories around the world have also discovered that cannabis acts as a neuroprotective compound in the brain. Patients who have experienced strokes, emotional or traumatic brain injuries can potentially benefit from cannabinoid treatments. Even as new discoveries emerge, most researchers agree that more studies are necessary to fully understand how cannabis affects bodily systems.

With mounting evidence in support of a wide array of medicinal benefits, the staunch resistance from the Drug Enforcement Administration (DEA) bewilders many in the industry. According to the DEA, cannabis remains a Schedule I controlled substance—with no medicinal use, a high potential for abuse, and a lack of accepted safety standards for use—though the federal government has begun to authorize research into its potential uses. Groups like the Marijuana Policy Project have been indispensible in pushing for reform that would open up the marketplace to more research initiative and better regulation to ensure a more robust safety culture for the cannabis community.

In all, 22 states and the District of Columbia have enacted medical cannabis laws that authorize and regulate its use, but the disconnect between state legalization/decriminalization efforts and continued federal criminalization has raised safety concerns amongst producers, consumers, and researchers. Cannabis extracts contain 40—80% THC and are drastically more potent than marijuana buds, but we are yet to fully understand the complex chemical composition of cannabis.

With this limited information, few states currently require dispensaries to provide health warnings, ratings for potency and certification that the product meets safety standards. The growth of laboratories that perform these services indicates that industry demand favors better safety options than are currently required. According to industry experts like Michael Bishop, Director of Applied Markets for Heidolph North America, “there are going to be increasing requirements for high purity and reproducibility” of extracts, both as a medical necessity and a market imperative. For cannabis extracts to become a more readily accepted and viable treatment option, it is imperative for the industry to adopt standards regulating the consistency, safety, and efficacy of extracts.

 

PARTNERING FOR PRODUCT ASSURANCE

Quality control and safe processing of cannabis begin with cultivation, the management of moisture levels, reducing contamination by pesticides, and it extends through the extraction process where working with volatile substances makes personnel protection paramount. While the most important control in the cultivation of cannabis is the employment of good agricultural practices—which provide the best methods for soil and water use to prevent biological and toxic contamination—the risk for contamination extends to handling and processing. This means that it is imperative for producers to ensure the purity of their product after it has been harvested and properly dried.

From cultivation to production and consumption, the continued viability of the cannabis industry depends upon adopting standards and methods for bringing new products to market with the assurance that they are free of residual solvents, pesticides and other biological contaminants, like mold or E. coli. Equipping growers and producers with the means to reduce contamination that occurs during the drying and extraction process is the goal of Flow Sciences’ new partnership with the cannabis industry. Safe processing of cannabis extracts also means ensuring proper ventilation systems are in place to reduce the risks associated with volatile solvents like butane.

Flow Sciences’ team of industrial engineers design workstations and enclosures that reduce product contamination and maximize protection for professionals who work with volatile substances like those used in cannabis processing. All of our products are engineered and manufactured at our corporate headquarters in Leland, NC and are backed by our sophisticated design process and award-winning excellence in engineering, including 11 U.S. Government patents. We have been working with pharmaceutical companies, research and development laboratories, manufacturing, and production facilities for 30 years. Our task-specific designs are dynamic solutions that are adaptable to our clients’ workflow and specific needs.

Flow Sciences was one of the first companies in the U.S. to use computational fluid dynamics (CFD) in drafting our enclosures to ensure optimum airflow. Our engineers use CFD algorithms to simulate fluid flows and interactions within contained spaces. This enables us to predict and control airflow through design, which we then test in our state-of-the-art laboratory. Working closely with our clients to mimic real-world applications, we develop testing protocols based on the intended use of our enclosures and measure them against industry-accepted standards to ensure proper containment. We have designed, manufactured, and tested over 13,000 enclosures, generating a wealth of data on situational flow dynamics, which allows us to control for consistency, safety, efficacy, and overall quality.

As the cannabis market grows and becomes simultaneously more regulated and competitive, third-party potency testing to meet state statues will intersect with the need to analyze products and develop cannabinoid profiles through formal sampling protocols. With three decades of experience and expertise in developing containment solutions for product and personnel protection, Flow Sciences is ideally positioned to partner with producers and third-party testing facilities in order to address issues of safety and quality in cannabis processing.

 

CONTAINMENT MATTERS™

The essential oils of cannabis plants are found in the trichomes—or, the crystalline structures on the outside of the marijuana buds. The goal of cannabis extraction is to preserve these trichomes because they house the medically valuable cannabinoids (THC, CBD) and terpenoids (Myrcene, Linalool). There are various methods of processing cannabis, including dry sieving, but the principle methods of extraction involve the use of CO2 or highly volatile, carbon-based solvents to isolate the plant’s active ingredients. While CO2 offers producers an organic means of extraction and a higher degree of control, it also takes longer and is more expensive than using butane—or propane, hexane, acetone, or ethanol—which produces higher volumes and finer grain results.

Because trichomes are lipid and alcohol soluble, extraction oftentimes involves the use combustible solvents and necessitates laboratory equipment like rotary evaporators (i.e., rotovaps) to isolate cannabinoids and therapeutic terpenoids from cannabis plants. Rotovaps work by coupling a low-heat distillation process with a vacuum system, enabling producers to control for both heat and pressure and extract different components at varying intervals. While the use of rotovaps enables the extraction process and the production of valuable medicinal products, the use of volatile carbon-based solvents increases the risk of fire and explosions if there is no care taken to properly ventilate the workspace.

SAF T FLOW™ FUME HOODS

Ensuring safe extraction methods oftentimes requires the use of fume hoods, like the Saf T Flow™ Fume Hood designed by Flow Sciences to specifically protect personnel from chemical vapors generated during processes like distillation. The Saf T Flow™ system is a ventilated enclosure that works by containing vapors and fumes and continuously channeling airflow away from personnel and the workspace before being directed through a house exhaust system. Saf T Flow™ systems can safely remove volatile fumes generated during cannabis extraction by controlling airflow through design.

Flow Sciences’ Saf T Flow™ Fume Hood is designed with an Overlapping Sash Bypass (OSB) system of overlapping front panels that allow for varied airflow options depending on whether the sash is fully raised, partially open, or closed. This ensures that the Saf T Flow™ Fume Hood consistently directs airflow away from personnel and to exhaust systems regardless of air volume. The Saf T Flow™ Fume Hood can effectively eliminate vapors from the cannabis extraction-distillation process and reduce the risk of fires and/or explosions associated with the use of solvents like butane.

Saf T Flow™ FEATURES

  • Saf T Flow™ Fume Hoods have been tested from 100 FPM down to 60 FPM—simulating the full range of sash options—with ASHRAE 110 containment equipment, and have proven Breathing Zone Containment at or below 0.005 ppm.
  • The Saf T Flow™ Fume Hood Series features a unified design structure to maximize simplicity in lab planning, layout, and HVAC coordination. Saf T Flow ™ hoods accommodate most low-flow exhaust options without requiring expensive retrofits.
  • Saf T Flow™ hoods are designed to reduce the volume of air necessary to maintain containment with an OSB system that reduces the energy costs associated with hoods that use constant, high-volume airflow.

 

LOCAL EXHAUST VENTILATION (LEV) ENCLOSURES

The risks associated with the use of solvents for the production of hash oil extend beyond their volatility alone. According to a recent study in the Journal of Toxicological Sciences, cannabis concentrate could carry toxic solvents as residue from the extraction process, which may have long-term effects on exposed consumers.

Pesticide use is regulated by the Environmental Protection Agency, which has yet to approve pesticides for use on cannabis. In the absence of further guidance from the United States Department of Agriculture and the Food and Drug Administration, states have begun to issue guidelines and propose regulations for the cultivation, extraction, and distribution of cannabis to control for potential biological and toxic contamination of cannabis products. Washington requires that solvent-based extracts using hydrocarbon gases must be of at least 99% purity, and the products must also undergo a residual solvents test. Post-production testing of cannabis extracts for residual solvents and other biological or toxic contamination is performed by third-party laboratories.

Guidelines governing the presence of contaminants vary, but states that have decriminalized medicinal cannabis have consistently moved towards requiring third-party analysis of cannabis products. For these third-party testing facilities, the scope of analysis broadly varies and is further complicated by a lack of exposure data and the limits of analytical chemistry labs that can only certify the absence of certain contaminants, like pesticides, down to a limit of quantification. As a result, cannabis screening requires testing for both the presence and, more importantly, the absence of pesticides in order to guarantee the accuracy and reproducibility of results.

The Oregon Health Authority (OHA) convened a Technical Expert Working Group in 2015 to qualify public risks that arise specifically during the cultivation and processing of cannabis for medicinal and recreational consumption. Based on their research, the OHA established action levels that would trigger state agencies to prohibit the sale and distribution of cannabis products that were found to exceed reasonably safe levels of contamination. In all, they identified a total of three biological agents, 59 pesticides, and 45 solvents that pose health risks to the general public, and they recently began to require testing for all medical cannabis.

These complex-testing processes can be handled by a combination of screening techniques. Due to their relative cost, the most commonly used screening technologies for insecticides, herbicides, and pesticides in the cannabis industry are immunoassays and broad spectrum field tests, but these non-standardized methodology are at a high risk of not detecting pesticide residues.

Gas chromatography (GC) remains the primary methodological technique used for federal regulatory purposes, which is now being adopted by emerging cannabis testing laboratories across the country. GC and its laboratory cousins—like liquid chromatography (LC)—rely on the vaporization of solvents in order to separate, identify, and quantify the components of any mixture. Laboratories are also adopting alternative methods of analysis that do not rely on heat in order to vaporize samples because heat changes the structure of acidic cannabinoids and certain pesticides, rendering them nearly impossible to detect. High-Performance Liquid Chromatography (HPLC) is emerging as a non-destructive alternative to GC and LC analysis methods because it ensures more precise analysis of the cannabinoid components of cannabis.

Though it is nondestructive, the chromatographic process uses methanol and chloroform to prepare extract samples for cannabis testing, and the process itself produces fumes that are harmful to laboratory/dispensary personnel. Whether GC, LC, or HPLC is used to analyze cannabis extracts, laboratories and dispensaries should ensure that they understand and employ proper containment techniques.

Local Exhaust Ventilation (LEV) Enclosures

Similar to fume hoods, Flow Sciences’ LEV enclosures work by directing airflow away from personnel and across the workspace through the use of front airfoils and rear plenums. The Benchmark LEV enclosure is engineered with the same attention to airflow control as our fume hoods because the most common risk in any laboratory that utilizes solvents is daily exposure to hazardous vapors. The Benchmark LEV goes through comprehensive assessment from CFD design control and ASHRAE testing to ensure that laboratory personnel are not inhaling potentially damaging vapors from cannabis testing.

LEV enclosures are also designed to be compatible with existing house exhaust systems, which allows laboratories to replace outdated or underperforming equipment without needing to remodel their workspace. LEVs are ideal for scalable operations. Laboratories can couple two or more LEV units in order to accommodate large-scale processes without unduly increasing air change rates. While fume hoods are the standard containment solution for cannabis extraction operations that utilize large rotovaps, a laboratory equipped with LEV enclosures can conduct multiple, separate experiments simultaneously.

Benchmark LEV Enclosure

  • Through the use of front airfoils and rear plenums, LEV Series enclosures provide ideal protection from chemical vapors generated by the use of rotary evaporators and analytical chromatography instruments.
  • The LEV Series is designed specifically for laboratory equipment with a dual-hinged front loading sash and side access doors. LEV enclosures also feature a lightweight structure that makes for easy movement in dynamic laboratory spaces, and they come in standard dimensions tailored to fit industry leading equipment.
  • LEV enclosures are the fume hood alternative, providing laboratories with the same, unparalleled protection from harmful fumes and vapors while accommodating small-scale operations.

Cannabis testing that utilizes volatile solvents like methanol also place laboratory personnel at risk for exposure to fires. With this in mind, Flow Sciences developed a Fire Safety LEV enclosure constructed with a flame-retardant polypropylene superstructure and glass viewing panels. The Fire Safety LEV can be equipped with a built-in Fire Suppression system to quickly and effectively extinguish potential fires directly at the source of ignition.

Fire Safety LEV Enclosure

  • Fire Safety LEVs are constructed from flame-retardant polypropylene and glass to ensure that potential laboratory fires are contained at the source.
  • Fire Suppression. Flow Sciences worked with fire protection specialists to design a fire trigger that detects and automatically extinguishes fires from inside the enclosure.
  • Fire Safety LEVs are designed to accommodate large-scale operations that require the superior safety of fume hood technology.

THE EXTRACT ELITE

As more states moving to legalize and decriminalize the use of cannabis, industry growth will fuel the start of more analytical laboratories committed to testing cannabis products for safety. Beyond testing cannabis for the presence of contaminants, laboratories will also heed the market imperative to develop advanced cannabinoid profiles so that physicians and consumers can make informed decisions about treatment options.

Laboratories and dispensaries that use CG or LC to identify the components of cannabis extracts can couple those methods with a conventional detector or mass spectrometry (MS) to develop more complete cannabinoid profiles. Coupling analytical processes goes beyond testing for the presence of contaminants and is more in line with a developing market mentality regarding cannabis packaging and quality assurance. These Extract Elite are on the forefront of an industry seeking to legitimize cannabis by creating complete profiles that grow the industry by creating informed stakeholders.

Cannabinoid profiles offer the most accurate data concerning the potency, THC-CBD ratio and purity of cannabis extracts, which are invaluable to physicians, patients, and dispensaries that need to make informed decisions about the prescription and use of therapeutic cannabis extracts. In an effort counter the cost of additional testing by increasing capacity, cannabis industry leaders are utilizing faster, more capable, and single-process solutions that use triple quadrupole and ultrafast mass spectrometers (UFMS). These highly efficient analytical tools still require the same safety precautions as their more traditional counterparts, which can also be contained with a Flow Sciences’ LEV Series enclosure.

Instead of simply assuring customers that extracts are free of contaminants, the Extract Elite are partnering with laboratory and containment experts, like the engineering team and Flow Sciences, to develop formal sampling protocol using the best analytical tools and containment solutions to guarantee safe consumption, potencies, and constituent concentrations that adhere to standards like those put out by the FDA concerning safety, consistency, and efficacy.

As the cannabis market continues to develop and become more competitive, the Extract Elite will emerge as providers of more than products. By expanding the boundaries of product assurance to include cannabis profiling, they will deepen the industry’s commitment to quality and allow stakeholders to make more informed decisions about the prescription and consumption of cannabis products.

 

THE FLOW SCIENCES ADVANTAGE

By partnering with Flow Sciences, the Extract Elite can create a safety climate that recognizes and responds to risks, and they can further encourage industry growth and vibrancy by establishing a level of quality assurance hat guarantees both product protection and analytical reproducibility. More than any other containment specialists, Flow Sciences offers our partners expertise that is rooted in a commitment to innovation. The advantage of seeking a Flow Sciences solution is our ability to anticipate industry needs by fostering a dedication to complete safety quality assurance, and excellent performance.


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Industry Trends: Contract Manufacturing and Safety

George Petroka, Director of BioPharma/EHS Services at IES Engineers, and Ray Ryan, Founder and President of Flow Sciences, Inc., sat down recently to talk about trends the two saw in the pharmaceutical production and manufacturing industry. The conversation quickly turned to contract manufacturers and the need for better controls and systems for employee safety and product quality.

 

Question: There’s a lot of pharmaceutical industry experience in the room today. What are some of the issues that are popping up that you two see coming up for customers shopping for isolators from Flow Sciences and lab solutions and for clients looking for consultation and certification from IES Engineers?

 

George Petroka: In pharma, definitely contract manufacturing.  It’s going to be more and more the trend moving forward. Five, six years ago, pharmaceutical heavyweights weren’t doing any of it, now I know of several companies moving to that model. I know of one looking at a 50 in 15 or 50 in 5 plan, meaning they want to have 50% of their manufacturing outsourced in 15 years or even 5 years.

Some contract manufacturers will have facilities and operations outside the U.S., some will be here. That leads into the idea of cross contamination and it leads to even though companies are going to contract manufacturing, they are setting standards they want to meet.

 

Q: So, with operations overseas and in the U.S., that means contract manufacturers have to follow the guidelines set out by the FDA and other oversight agencies?

 

George Petroka: Yes. The main driving [standard] is quality [as seen from] the FDA or oversight agency’s view. The other is environmental health and safety factor. Companies want to make sure that if a contract lab is making something potent or cytotoxic, [the lab is] handling it safely so they don’t have liability. Once you go out to a contractor, that contract firm has the potential to go sue the big pharma company they’ve contracted with because they’re not protected by workers comp as if they’re full time employees.

 

Ray Ryan: One of the things I’m seeing is that the contract manufacturers don’t have the expertise that the manufacturer routinely had. As a result, the need for education has increased dramatically as well. That’s one of the big things. The rush to get into the contract manufacturing has caused some other issues. We deal with contract manufacturers who call us up and have no idea about containment. The question that comes to my mind is how did this come about that these people, who aren’t bad people, they’re smart, they’re good at parts of their job, but they are clueless when it comes to containment.

 

George Petroka: They see a business opportunity and someone comes to them and says, “You’ve been making aspirin, can you now make something far more potent at a smaller dosage?” That’s obviously a big difference in potency and also a big difference in someone being exposed or a small amount of material being carried over.

 

Q: When you talk about the rush to manufacturing and some of the issues that come up with contract manufacturers, you talk about the increased need for education. What do you mean by that? Increased education on what side, a formal education, application or product specific education?

 

Ray Ryan: Here’s what’s going on. You have these companies who are down to virtually no manufacturing in the U.S., and almost no manufacturing in their own facilities. They outsource to contract manufacturers in the U.S. and China. What happened is they had a cadre that was well educated in the proper handling of Active Pharmaceutical Ingredients (APIs). Now they’re farming it out to companies who’ve never worked on the APIs. As George was saying, you have permissible exposure levels that are much lower and people who have no idea how to handle those things. So, you have an organization with a level of expertise who farms out manufacturing to a company without that experience or expertise and the number of problems can be quite significant.

 

George Petroka:  I will say that it’s gotten a lot better over the last 10 years. The companies are aware of the issues – sometimes as a result of big pharma workers going to these companies after retirement or downsizing. Or, they’re being driven by big pharma who are saying, “You can make it for us, but you have to meet these criteria.” And they’re saying, “What do we do? We don’t do that, so what do we do?” They need education and better engineering controls.

 

Jason Frye produced this story with the assistance of Flow Sciences Inc., which produces containment systems for laboratories, pilot plants and manufacturers. These products are designed to protect operators from exposure to hazardous particulates and vapors while performing delicate operations.

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Nanotechnology’s Need for Containment

As the exploration of analytical-scale and micro-scale applications has increased among organizations and universities, so has the ability to safely weigh, transfer and use nano-materials. Advances within the field of nanotechnology have introduced new materials and products to researchers and end-users in the medical, energy, aeronautics and environmental fields, to name a few. Despite the robustness of the research and development community and their continued dedication to safe workplace practices, there is little regulation governing personnel and environmental exposure risks.

 

Until such a time that safe handling standards come on line, Flow Sciences’ specialty low-flow containment hoods will help laboratories meet or exceed their own in-house safety benchmarks, which means a cleaner, safer work environment and reduced exposure risk to personnel.

 

For the last five years, Flow Sciences has found their customers increasingly concerned with the safe weighing and handling of micro- and nano-gram materials (often falling in the sub 100 parts per 1,000 m3 range) and have responded by studying the varying levels of toxicity, chemical and physical properties of nano-materials. From their research, they have developed low-flow containment hoods ideal for nano-applications on the research and development side.

 

“Because of the size of the particles personnel in nanotechnology are working with – we’re talking about the macro scale here – the need to protect their breathing zone is of particular concern,” says Steve Janz, Vice President of Marketing and Business Development.

 

Flow Sciences’ containment hoods use engineered solutions to contain potentially hazardous particles within the unit. A removable plenum and high-speed impeller fan create the ideal air pressure and speed within the hood, while extruded anodized aluminum airfoils smooth and direct the airflow. As air sweeps across the opening, it creates a curtain, forcing loose particles to stay contained within the hood, out of the laboratory and away from lab personnel.

 

Though many of Flow Sciences’ low-flow containment hoods have been used in nanotech applications in the medical and pharmaceutical world, industries across the spectrum are seeking solutions for their carbon nanotubes, lithium batteries, rare earth metal processing and other potent materials.

 

“Lately, aerospace organizations and researchers have been using the [nanotech] hoods to safely develop new carbon fiber applications,” Janz says. “There’s a huge need for these products within aerospace and carbon nanotube manufacturing.”

 

Recently, representatives from Flow Sciences presented at the National Institute of Occupational Safety and Health’s gathering of academic and industry experts on “Prevention Through Design,” specifically on safe nano-material handling. Their cutting edge experience with powders and innovative containment solutions matches well with the challenges of working with nano-materials in a variety of industries.

 

Jason Frye produced this story with the assistance of Flow Sciences Inc., which produces containment systems for laboratories, pilot plants and manufacturers. These products are designed to protect operators from exposure to hazardous particulates and vapors while performing delicate operations.

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Five Reasons to Reassess Your Safety Practices

By Jason Frye

According to the Occupational Safety and Health Administration, more than 500,000 workers are employed in laboratories in the United States alone.  That means a half-million workers are at risk of exposure to potentially hazardous active pharmaceutical ingredients (APIs), nano-materials, pathogens, rare earth metals and other materials on a daily basis. Whether your employees work with these materials in a lab or at some other point along the supply chain or production line, they’re at risk for exposure and environmental (and product) contamination as well.

 

Periodically reviewing your health and safety practices can help minimize exposure and contamination risks in your labs, product and raw material storage, transportation and at other stops along your production line. Here are five reasons to spend some time reassessing your safety practices.

 

1.      My company was just acquired by a larger company and our safety standards are changing. Groups like OSHA, the American National Standards Institute (ANSI) and others set safety benchmarks and establish safe occupational practices, and we all have our own internal standards, but what do you do when you’re company is acquired and new safety standards are on the horizon? Take a look at the new standards and practices and prepare yourself, your lab or work area, equipment and employees as best you can. By familiarizing yourself with the new standards and starting to work with them before the changes come, you’ll be ahead of the curve and will be able to make the transition into the new organization go more smoothly.

 

2.     My apparatus was built and spec’d for material A, now we’re making a new product and I need to use material B. Orders change, product formulation changes and even ingredients change. As the pharmaceutical industry continues to use higher potency APIs, and as other industries delve into the use of nano-materials, rare earth metals and other potentially hazardous, the risk of exposure for lab workers and other employees increase. Compound that with the increased potency, decreased size and other factors that come with new or reformulated ingredients and you soon have equipment that was good enough for the old recipe but not quite up to par on the new recipe. From filters that let the smallest of particles pass through to cleanout traps that don’t adequately hold the new materials to ventilation hoods that fall short in removing harmful vapors or dust, equipment can quickly become unsafe. When new or more potent materials enter the lab, take the time to ensure that your equipment is calibrated to contain these new materials and keep the lab and the workers in it, safe.

 

3.     My employees need help with organization and workstation hygiene. When lab workers or other employees are having difficulty in keeping their workstations and benchtops organized and clear of clutter, call a timeout. By providing a hood or enclosure around troubled equipment or areas, you can define the space for them. Once the space it defined, employees will take greater care to keep the spaces clean and organized. An added benefit to the new organization and equipment is that the pride in and integrity of work often increases.

 

4.     My technology is out of date. Sometimes new materials don’t present the hazard, but the Occupational Exposure Limits (OELs) change or your equipment just doesn’t perform as well. No matter if it’s old hoods or enclosures, new OELs or just revised internal standards, the introduction of new equipment and technology will often present the cure. Enclosures from seven years ago may not fit new lab equipment properly or may have inadequate filtration systems, but a new enclosure provides ample room around your equipment for easy work and maintenance and introduces new safeguards to cleanup and filter changing. Hoods may have lost some of their ability due to overuse and a new hood will save benchtop space (or even expand it) while providing the ventilation you need. Or maybe advancements in chemical-resistant materials and coatings will cause your old workstations to become hazards harboring hidden contaminants but new workstations with the advanced materials will introduce added safety, cleanup and maintenance measures.

 

5.     My employees need a refresher on the basics. We all get rusty after a while and your employees could use a quick refresher on the basics of lab safety. How many of you can tell what PASS or RACE have to do with fire safety? How many of your employees could answer correctly? PASS summarizes how to use a fire extinguisher: P – pull the pin. A – Aim the nozzle at the base of the fire. S – Squeeze the trigger. S – Sweep the extinguisher from side to side to cover the fire with spray. And RACE? It’s what to do in case of a fire. R – rescue or remove occupants. A – activate alarms. C – close doors and contain the fire. E – evacuate or extinguish. What internal safety practices could your employees (and you) brush up on? Taking the time to review, refresh and reteach the basics can keep you, your employees and your workplace safe.

 

Jason Frye produced this story with the assistance of Flow Sciences Inc., which produces containment systems for laboratories, pilot plants and manufacturers. These products are designed to protect operators from exposure to hazardous particulates and vapors while performing delicate operations. For more information, visit quiet-harmony.flywheelsites.com or call (800) 849-3429.

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Nitrogen and Containment

Keeping labs, production lines and other work areas safe and hazard free starts and ends with the right combination of proper workplace hygiene practices and containment solutions. The isolators, hoods and other enclosures Flow Sciences designs and produces help keep workers and workspaces clean and safe across a spectrum of industries, from pharmaceutical packaging and production to rare-earth metals refinement to Nano-material production.

 

Often, clients require a controlled atmosphere for testing, weighing, manufacturing, packaging and producing oxygen or humidity sensitive materials. The engineers at Flow Sciences have answers to those needs: sealed enclosures filled with nitrogen.

 

“You’ll see nitrogen in use in a variety of places. Most of the time it’s used to purge oxygen from a container, be it a bag of chips or a lab or production line container like Flow Sciences provides. In the case of Flow Sciences, they use nitrogen to create highly stable environments that allow only the reactions they, or rather, their customers, need to mix, batch, weigh or manufacture their specific products,” says Charles Metzler, Industrial/Military  Sales Manager at SouthTek Systems. SouthTek makes nitrogen-generators that supply Flow’s controlled-environment enclosures with on-demand nitrogen without the expense of using bottled gas.

 

SouthTek’s nitrogen generators provide 99.999% pure nitrogen, even nitrogen with less than five parts per million, then stores it for later use.

 

“Most people forget what they learned about the atmosphere in high-school science: it’s 78% nitrogen. That means our generators are always surrounded by a ready source of nitrogen and it also means we’re only half joking when we say we pull nitrogen out of thin air,” Metzler says.

 

Once air is pulled into SouthTek’s generators, it goes through a process of physical separation. A carbon molecular sieve attracts oxygen molecules and the purified nitrogen passes through to a tank for storage and use in the process. Oxygen is expelled as exhaust and the scientists and production line employees have the pure nitrogen they need to perform their jobs safely.

 

Metzler says that nitrogen has several benefits that chemical, API (active pharmaceutical ingredient) and Nano-material producers and handlers need. For starters, nitrogen isn’t flammable or combustible, and is often used as a fire suppressant, which greatly reduces the risk of fire in the enclosure, unlike lithium, which is pyrophoric and can spontaneously combust in the presence on H2O. Secondly, nitrogen-filled environments can be kept at incredibly low relative humidity levels with dew points in extreme negative numbers, which means moisture-sensitive products like delicate Nano-materials and APIs prone to clumping are clear for handling.

 

Nitrogen’s use in the agricultural industry also has applications with select sectors of Flow Sciences client base as well. By storing perishable goods, like apples, in nitrogen-rich or nearly nitrogen-exclusive environments, farmers and grocers can slow or even pause ripening and decay, effectively lengthening the storage shelf life of time sensitive goods (it’s how, he says, we can have fresh, crisp apples in the summer). Many APIs and chemical compounds have a limited lifespan, and by storing them in a nitrogen-sealed container, waste is eliminated and product life lengthened.

 

While a number of labs and production facilities rely on bottled gas, the nitrogen generators Flow Sciences incorporates from SouthTek provides both a cost-savings and a convenience benefit to end users. With an integrated nitrogen generator, users have a constant supply of gas without having to change bulky bottles, schedule tank deliveries or refills, or worry about monitoring flow and reserve levels. Given the expense of traditional bottled gas, an integrated nitrogen generator is nearly 90% cheaper per cubic foot of gas used, meaning that most units pay for themselves in savings in 12-16 months.

 

All of Flow Sciences’ containment solutions are designed with an eye on the limited real estate on bench tops, in labs and on production floors, and the SouthTek nitrogen generators are no exception. Nitrogen generators the size of tractor-trailers are available, but Flow Sciences and SouthTek found that the smaller, cabinet sized generators were more than adequate for most applications. These units are compact, making them ideal for single-enclosure use in one room, or an exterior setup to feed multiple enclosures their required nitrogen.

 

“Flow [Sciences] is introducing something to this industry that sounds, and is, so logical, but for some reason was ignored by a lot of folks who could use it. Utilizing nitrogen to stabilize environments is the next step and Flow is one of the few who have seen the benefit of combining containment and nitrogen.”

Jason Frye produced this story with the assistance of Flow Sciences Inc., which produces containment systems for laboratories, pilot plants and manufacturers. These products are designed to protect operators from exposure to hazardous particulates and vapors while performing delicate operations. For more information, visit quiet-harmony.flywheelsites.com or call (800) 849-3429.

 

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