White Papers

Novel Techniques for Containment

Fig 1: Perkin Elmer Janus G-3 Liquid Handling System inside a Flow Sciences Custom HEPA Filtered Unit
Unit Mission: Patient Covid 19 Sample Processing

Dr. Robert Haugen
Flow Sciences, Inc.
6/24/20

Abstract:

Recently published scientific papers feature various aspects of pandemic “star” Coronavirus 19. This virus has significantly changed pharma research and production in a variety of unique ways.

This white paper will focus on how research/production efforts might fail under the threats of highly contagious disease viruses, bacteria, and highly active pharmaceutical ingredients. Performing contemporary research safely and producing highly active pharmaceuticals and vaccines will require material isolation and medical product purity. Once identified, contamination paths and bad production procedures will require correction and control.

We will outline possible contamination vulnerabilities in this paper. Flow Sciences and other manufacturers are developing containment options to neutralize such challenges and test methods to certify them. The author will discuss several current enhancements already used and new approaches we are all developing right now!  

Fig. 2: Mock-ups allow resolution of device interfacing issues prior to manufacture.

Where Containment May be Challenged in Today’s Environment:

1.)  Collision of Energy Conservation with Containment Challenges

ANSI/AIHA Z 9.5 sets acceptable control levels for chemical fume hoods at stricter levels today than twenty years ago, while stricter energy conservation requirements mandate historically lower exhaust rates for the same equipment in most new facility designs. Recommended containment control levels using ANSI Z 9.5 are now 0.050 ppm as installed1 or lower 2. Twenty years ago, this level was double this value at 0.10 PPM 3.

In spite of achieving mandated containment improvements, a variety of contamination vectors are still possible, particularly with recently reduced exhaust volume requirements established to conserve energy.

2.)  Researcher and operator aerosol contamination from Covid 19 carriers:

COVID-19 follows a person-to-person transmission pattern that occurs primarily via direct contact or through droplets spread by talking or coughing from an infected individual. One hundred eighty eight countries have confirmed Coronavirus cases so far 12. Even though transmission vectors are somewhat limited, they work very well for this virus. Not for us humans.

Mass-transportation has also become a vulnerable breeding facilitator13,14. The Diamond Princess Cruise ship harbored in Yokohama, Japan, Holland America’s MS Zaandam cruise ship 6, and various aircraft incidents show how people housed in close quarters can suffer widespread contagion through this limited contact mechanism compounded by a large number of elderly passengers.

Fig. 3, Suspected Forms of Covid 19 Virus Transmission

Similar to SARS, CoV2, and SARS CoV, the earliest Covid 19 Chinese field studies found active virus in the same rooms as Covid patients 4. In addition, other studies point to contagion in family units 5

As Covid 19 testing becomes more available, it will be easier to stop infectious people from contaminating lab areas or production facilities by testing, tracing, and isolation. It is also possible to use personal protective equipment (PPE) in particularly sensitive areas. 

 3.)  Measurement of toxic or contaminant leakage outward from a containment device due to poor airflow or electrostatic attraction is less straightforward. For years, the ANSI/ASHRAE 110 test has prescribed diffusion of SF6 gas into chemical fume hood interiors and evaluated quantities that escape containment using a mannequin with an attached air sampler that measured ppm amounts of SF6 in the mannequin-breathing zone.

While ASHRAE 110 is not designed to evaluate powder or biological containment, it is nonetheless frequently used for these applications in coordination with a variety of powder tests.

Electrostatically charged powders can stick to the hands of an operator and “hitch a ride” out of the containment area. Air currents may or may not be effective in containing materials exiting the area using this mechanism. Specific additional testing addresses this concern, and FSI has published results comparing ASHRAE 110 tracer gas testing against surrogate powder testing. Results of such tests are beginning to build a comparative record in which we can be confident!

Containment equipment manufacturers generally run ASHRAE 110 tests followed by particulate studies, which provide high-level verification of containment under field conditions. Covid 19 and highly potent pharmaceuticals have only increased the likelihood of using these approaches in tandem to assess containment.

While powder and biocontainment tests developed for pharmaceutical evaluations are today recognized and useful, their conditionality, complexity, and expense have thus far prevented establishment of a broad record of consistent test results from which to build a reference containment standard similar to ASHRAE 110. Unfortunately, it may be next to impossible to generalize powder testing as the industry has done with tracer gas testing as the additional electrostatic vectors of containment escape are so situational that simulated process containment testing (as-used) of particulate escape may be the only answer to confidently apply a given containment approach.

Conclusions:

We do not wish to leave this topic languishing in the swamp of pessimism. The current pandemic has given us several opportunities to use what we have learned containing powders in the related field of viral control.

1.)  Good news

  • “At the time of publication, no research was available showing that airborne, infective SARS-CoV-2 had been successfully recovered from an air sample in a clinical setting.10
    There appears to be no air-born individual viable virus transmission of Covid 19. This means a developmental containment focus in our field will probably be on very short-range particle transmission. Since manufacturers have good tools available for studying intermediate and room-wide particulate air-born transmission, this industry already has tools for validating product containment in useful and relevant terms using a combination of tracer gas and surrogate powders.
  • We present a relevant table of such tools below11:

FSI has used most of these tests on a regular basis and they all are relevant today and will probably remain so in the future. While a review of these tests is beyond the scope of this paper, a more thorough discussion is available in the cited reference.

We must never use any single test of containment to validate a research or manufacturing application.

2.)  Bad News

While we remain challenged short-term, long-term many elements of our planet lifestyle require remediative changes. Examples include transportation, recreation, entertainment, healthcare, and, of course, safety research itself!

Nevertheless, hiding in this bad news is the key to our own eventual success and improvement. Let us roll up our sleeves and do this work! The future starts yesterday!

Footnotes:

  1. ANSI/AIHA Z 9.5, Tracer Gas Containment Tests, 2012, P. 72, Section 6.1.2.7
  2. In most cases because of limitations of SF6 detection, lower containment numbers are attained by running the gas flow rate into the fume hood at 8 lpm rather than 4 lpm. Other steps are used to complicate the hood interior by adding cans and other obstructions (Merck Rahway spec section 115315)
  3. ANSI/AIHA Z 9.5, Commissioning Plan, 2003, Section 6.2.2
  4.  Aerosol and Surface Distribution of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospital Wards, Wuhan, China, 2020, Zhen-Dong Guo1, Zhong-Yi Wang1, Shou-Feng Zhang1, Xiao Li, Lin Li, Chao Li, Yan Cui, Rui-Bin Fu, Yun-Zhu Dong, Xiang-Yang Chi, Meng-Yao Zhang, Kun Liu, Cheng Cao, Bin Liu, Ke Zhang, Yu-Wei Gao, Bing Lu, and Wei Chen, Abstract 
  5. The characteristics of household transmission of COVID-19, 3/26/2020, Nature Magazine, 17 April 2020, Wei Li, Bo Zhang, Jianhua Lu, Shihua Liu, Zhiqiang Chang, Peng Cao, Xinhua Liu, Peng Zhang, Yan Ling, Kaixiong Tao
  6. What the cruise-ship outbreaks reveal about CIVUID-19, Nature Magazine, 3/26/2020,
    https://www.nature.com/articles/d41586-020-00885-w
  7. Novel COVID-19: A Comprehensive Review of Transmission, Manifestation, and Pathogenesis, 18 May, 2020, Hussain A, Kaler J, Tabrez E, et al.,
    https://www.cureus.com/articles/30692-novel-covid-19-a-comprehensive-review-of-transmission-manifestation-and-pathogenesis
  8. Assessing the Particulate Containment Performance of Pharmaceutical Equipment, International Society for Pharmaceutical Engineering, 2012, Chapters 1-8
  9. Using the ASHRAE 110 Test as a Tool to Improve Laboratory Fume Hood Performance, Hitchings and Maupins, 1997, p.23,
    https://www.semanticscholar.org/paper/Using-the-ASHRAE-110-test-as-a-TQM-tool-to-improve-Hitchings-Maupins/4e828cb00c3cc66738f03d9a17f1321637a994d2
  10. Draft Reference and Guidelines for Post Cleaning Validation of Structures Contaminated with SARS-CoV-2, Indoor Air Quality Association Australia, 6 May, 2020, Bird, Prezant, Green, et.al., section 4.1
  11. Five Tests for Containment, Flow Sciences, Robert Haugen, 2/27/20, https://flowsciences.com/five-tests-for-containment/
  12. COVID-19 Dashboard, Johns Hopkins University Coronavirus Resource Center, 23 July 2020, https://coronavirus.jhu.edu/map.html
  13. Protect Yourself when Using Transportation, Centers for Disease Control, 6/23/2020,
    https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/using-transportation.html
  14. How to Safely Travel on Mass Transit, Bloomberg City Lab, Simon Clark, Associate Professor of Microbiology at the University of Reading, 6/23/2020,
    https://www.bloomberg.com/news/articles/2020-05-27/trains-planes-and-buses-how-to-avoid-coronavirus

Laboratory Containment Trends – The Next Ten Years

Dr. Robert Haugen
Flow Sciences, Inc.
6/11/20

Abstract:

Today, we all find ourselves in a reflective mood!  Our business is, after all, containment. Covid 19 and we are therefore at cross-purposes! Many other more general trends in pharmacy and bioscience also cause us now to reflect on our future.

Where is the lab containment going in the next ten years? What contemporary extract products have a future?  How will this health crisis help us refine our methods and objectives? What meager portion of our inventive genius will remain after we encounter the value engineering committee?

Fig 1: Typical VE Session at Cawdor Castle

These are the questions explored in this paper. Researchers, lab safety experts, pharma production designers, architects, planners, and of course, purchasing agents all have their own takes on such topics and their own unique influences on what will eventually happen.

While the writer aims to take an impartial approach to this topic, he is aware that forecasts tend to be largely autobiographical!

 

The Present: Successes and Challenges:

From 2000 to 2019, many important changes have changed the laboratory design industry.

  • Successes:
    In the past decade, containment improvements in lab equipment at lower exhaust volumes has been a chief focus. For example, acceptable control levels on fume hood ASHRAE 110 tests in the field are now recommended by ANSI Z 9.5 as 0.050 ppm “as installed”1 and in some job specifications even lower 2. This level is dramatically lower than the basis of testing at the end of the 20th Century, which was 0.10 PPM 7.

These more rigorous control levels now apply to fume hoods exhausting much less air. While 100 FPM was the ‘acceptably safe’ flow in past decades, we now expect modern fume hoods to function effectively at anywhere from 60 FPM to 80 FPM. 6

The industry now evaluates portable and smaller exhaust hoods using ASHRAE 110 methodology, even though the test document does not include many of them by definition. We also frequently measure containment of filtered powder hoods with exhaust thimble connections, and many purpose-built pharmaceutical production containment units even though ASHRAE 110 does not include these either.

All such FSI units test out on ASHRAE 110 at < AM 0.05 ppm. Many of these units have also been field tested (AI). In short, product-demonstrated containment as expressed by ASHRAE 110 has historically gotten tighter, while units tested by ASHEAE 110 are many times not within the scope of the current standard.

Other containment tests that directly measure particles, not tracer gas, have also gained general recognition in the pharmaceutical field. Such rigorous performance standards are individualized and context-specific. Our customers routinely apply these standards in the field under operating conditions with face velocities in the 60 FPM to 80 FPM range.

ISPE 3 methodologies are good examples. These techniques use kinetic operational testing with a selected surrogate powder using filtered air samplers in the application area, on the research subject, and inside the lab hood. These samplers collect particles that have remained inside containment, or escaped containment over the length of the procedure. “Procedures” usually simulate activities done in the relevant pharma production or research setting. Grinding, sampling, weighing, and powder transfers are all activities typically incorporated into a surrogate procedure. The measured short-term exposure limit (STEL) must stay under a certain pass-fail level, generally in the fractional mg/m3 range. Flow Sciences has actually used pass/fail levels as low as 1.0 ng/m3! The possibility of achieving control levels in this range is good news for working area laboratory air quality and system sustainability! The challenge with these hyper-specific methodologies is that they are difficult to generalize from precisely because of their specificity.

  • Challenges of the present:
    Insistent rumblings for changes in containment requirements are already in the air! Pharmaceutical production of highly active drugs is increasing 4. Examples are genetically specific drugs with high potency, which require smaller containment devices with rigorously low short-term exposure limits. As such challenges face our industry, an increased demand for monitoring low levels of allowable background contamination, documenting maintenance, memorializing SOP’s, and requiring customer support by the manufacturer are all critically prominent! 

 

The Future; Directions for the Next Decade:

As the writer sees it, the next decade is pointing in several exciting and challenging directions for evaluating containment. The author has listed these in their perceived order of importance:

  • New containment requirements in pharmaceutical production will mandate much lower short-term exposure limits (STEL’s).

As mentioned previously, very low STEL’s are on the horizon for highly active pharmaceutical ingredients (HAPI). These low requirements, possibly in the ng/m3 range, will probably change the types of containment devices used to house manufacturing equipment involved in making these products. The containment devices will therefore most likely transition from access openings to gloved enclosures

  • The Covid 19 Pandemic will require rapid crisis development and dissemination of vaccines and medications aimed at disease treatment and elimination.

While the United States Pharmacopeia has written a “new” standard, USP 800, USP typically does not enforce this standard. Uncertainty about levels of enforcement has resulted in legal challenge to the standard. While USP 800 is technically active, it is essentially advisory, until the legal challenges are resolved.

This scenario may truncate many pharma SOPs in order to make Covid 19 medicine quickly. This resulting rush could degrade containment and product purity standards.

The author anticipates that the Occupational Safety and Health Administration, some state pharmacy boards, and some state laws will eventually mandate a yet-to-be-determined standard once production pressures subside. It is the author’s belief that USP 800, or a derivative, will probably become a regulatory standard within this decade. This will be welcome news for those workers charged with safely producing or testing pharmaceutically active ingredients on a daily basis.

The author anticipates such a resulting successor to the currently unrecognized USP 800 will require personal protective equipment in many contexts for administration of hazardous drugs to contagious patients. It may also mandate the use of protective medical equipment like closed-system transfer devices, needleless equipment, and plastic pouches for pill crushing. 5

For hospitals, pharmacies (particularly compounding pharmacies), and other institutions that compound, administer, or manufacture pharmaceuticals, this new standard may require many facilities to upgrade procedures and acquire additional containment equipment to support and improve current activities. Increased personal protection will also become mandatory for staff who mix various pharma products together to meet specialized prescriptions.

Sterile product evaluation will undoubtedly also become involved in these changes.

  • Lower exhaust rates for most containment will probably hit practical lower limits this decade.

Exhaust levels in laboratories will continue to decrease. Containment requirements in labs and production facilities will continue to increase. At some point, these two trends will create a collision or achieve some sort of negotiated equilibrium. We will probably wind up balancing sustainable extract levels against minimal building needs such as sensible heat loads or tolerable room air quality.

 

Conclusion:

Today, Covid 19 is a huge shaping factor for science, pharma, medicine, social planning,     architecture, religion, education, politics, media coverage, and transportation.

What have I forgotten? Entertainment, sports, retail purchasing, auto sales, travel, history, archeology, and paleontology.

Everything. Absolutely everything. In no particular order.

In such an environment, hope must focus on tools, time, and ideas:

Tools that are generally useful, time to support research, and ideas that require development and expression through experienced engineering. We are prepared to face this future with containment equipment ready to ship now (tools). Such equipment will help meet urgent needs and buy us time. Our highly skilled, degreed and published design engineers address new perceived needs and move forward with adaptive ideas and appropriate means to build products and test them.

 

TOOLS

TIME

NEW IDEAS

After the chaos subsides, and it will, we will need to be forward-looking but cognizant of new challenges that may lurk in our future. Challenges capable of Covid 19 repercussions.  Challenges waiting to reset all our expectations about our futures and convenient laws exposed as being irrelevant. Something waiting to provide opportunity for all of us to progress the human condition if we embrace it!

Footnotes:

  1. ANSI/AIHA Z 9.5, Tracer Gas Containment Tests, 2012, P. 72, Section 6.1.2.7
  2. In most cases because of limitations of SF6detection, lower containment numbers are attained by running the gas flow rate into the fume hood at 8 lpm rather than 4 lpm.. Other steps are used to complicate the hood interior by adding cans and other obstructions (Merck Rahway spec section 115315)
  3. Assessing the Particulate Containment Performance of Pharmaceutical Equipment, International Society for Pharmaceutical Engineering, 2012, Chapters 1-8
  4. FDA Perspective on Continuous Manufacturing, Sharmista Chatterjee, IFPAC Annual Meeting,Baltimore, 2012, p.2 https://www.fda.gov/files/about%20fda/published/FDA-Perspective-on-Continuous-Manufacturing--Sharmista-Chatterjee--Ph.D.--January-22--2012--IFPAC-Annual-Meeting.pdf
  5. Best practices for the safe handling of hazardous drugs — How to prepare for USP 800, McKesson Health Care Company,
  6. ANSI/AIHA Z 9.5, Tracer Gas Containment Tests, 2012, P. 23, Section 3.3.1
  7. Using the ASHRAE 110 Test as a Tool to Improve Laboratory Fume Hood Performance, Hitchings and Maupins, 1997, p.23, https://www.semanticscholar.org/paper/Using-the-ASHRAE-110-test-as-a-TQM-tool-to-improve-Hitchings-Maupins/4e828cb00c3cc66738f03d9a17f1321637a994d2

Evolving Containment in Pharma Manufacturing Facilities

Dr. Robert Haugen
Flow Sciences, Inc.
5/26/20

Abstract:

Pharmaceutical manufacturing is now undergoing significant transformation. COVID-19 and its pressure on nearly every aspect of human life has put a gigantic emphasis on rapid development of prescriptives, vaccines, and accelerated means for pharmaceutical mass-production.

Newer highly potent active pharmaceutical ingredients (HPAPI) hold great promise for the health of the planet, while posing manufacturing challenges for plant workers and their packaging and validating associates. As we design such facilities, we are likely to produce new equipment and containment strategies that look nothing like what we have today.

Flow Sciences’ role in this evolution must be to develop containment devices that complement the different and unique types of equipment we already know will be present. These changes must allow lightning fast research, valid conclusions, rapid development of production strategies, and increased facility efficiency and worker safety.

The writer will characterize the new production directions in pharmacy and describe flexible equipment to improve pharma efficiency, purity, and production safety in the coming decade.

Fig. 1: Technically Advanced Pharmaceutical Products Require Significant Engineering Efforts Up-Front 1

Discussion:

The design of modern pharmaceutical facilities follows a series of factors during its development 2. Ahmed Salah Abu Shoukka frankly details this structure as shown below:

Fig 2: Design Factors according to Shoukka 2

Shoukka includes four key components in his description of pharma manufacturing design: Product, Process, Regulations, and Cost. Based on the writer’s own experience, I have described below key elements of each of these four components.

  • Product (pharma management, facilities planners, and production managers)
    The product and demand for it in the pharma marketplace will determine the scale of production, size of the facility, and the type of machinery used in the drug’s manufacture. The most well-known of these new influences is COVID-19, whose pressure is so great on all our existing systems that production issues are being faced in tandem with developmental research. 6
  • Process (biologists, chemists, biological and chemical engineers, plant design engineers, health & safety officers)
    The biological and chemical processes used to manufacture the product will define the types of material containment required. As an artifact of this decision, batch or continuous manufacturing techniques will typically both be present in the production area.

    It is always challenging for a manufacturer like Flow Sciences to predict what shape such containment will take. Flow Sciences must therefore maintain a diverse line of basic engineered options to house new production equipment compatible with manufacturing objectives.  

FSI makes seven basic categories of equipment now:
Vented Balance Safety Enclosures
Local Exhaust Ventilation Hoods
Chemical Fume Hoods
Nitrogen Purge Gloveboxes
Compounding Hoods
Hybrid Isolators
Glovebox Workstations

In addition to these basic categories, we produce a significant number of larger transparent enclosures for process-specific applications.

 Fig. 3: Large Containment Cubicle Under Construction at FSI      
Fig. 4: Field Installation of Similar Unit
  • Regulations (compliance officers, environmental engineers, analytical scientists, and certification specialists)
    The purity requirements and toxicity of each manufactured product will determine cross-contamination and worker protection standards for any containment apparatus. Communities close to the facility will insist air and water effluents and solid waste products released during manufacture are low enough to meet state and federal environmental standards.

    Flow Sciences is used to these requirements. We frequently apply containment tests to measure and evaluate our containment devices 5. This equipment routinely passes less than 0.050 ppm of tracer gas under ASHREE 110 test conditions into the test environment, and surrogate powder releases are always between (1mg to 5ng) per cubic meter depending on the challenge presented by the application 4.

Figs 5-9: ASHRAE 110, ANSI-AIHA Z9.5, and surrogate powder methodologies frequently used at FSI Test Lab
  • Costs (production control, product flow, cost accounting)
    Particularly with more established drugs, lean production is critical. This means efficient use of space and movement of intermediate bulk containers (IBC’s) from one temporary resting place to another. Such steps will also boost purity by minimizing cross-contamination of intermediate byproducts and precursor transfer.

    The pandemic challenges we all now face will also put design pressure on companies supplying the pharma industry to control containment costs, which is an important factor in making new pharma products affordable worldwide.

    As mentioned earlier, speed in addressing such needs is also crucial. This speed requirement has already produced commitments in principle to begin later stages in production acquisition while basic pharma is still being alpha and beta tested.6 

ILLUSTRATION: How the Four Factors Cited Above interact with other!

The characteristics of oral solid dosage (OSD) manufacturing facilities can illustrate how these four factors interact.  Lockwood3 recommends minimizing redundant labor costs caused by intermediate products moving from one batch to the next. Up until now, batch production appears to be the archenemy of production efficiency.

When designing a pharmaceutical OSD manufacturing facility, the ways in which materials move from one stage of production to another should be considered from the very beginning. We discuss how materials handling processes can, and should, influence building design for lean productivity.

A single floor facility is the cheapest to build or lease, but ceiling height can impose constraints on materials handling solutions. However, even with small, single-floor buildings, intermediate bulk containers (IBCs) can be used to achieve full batch transfer from one process to another, thus reducing wasted product. Creative use of frameworks or mezzanines can enable the use of efficient gravity-fed vertical transfer systems, too.

Expensive, but with lots of available space, multiple-floor facilities are endlessly flexible. However, space can be wasted if due consideration is not given to the factory layout and overall production flow. IBCs can make the best possible use of height and space, while at the same time providing the opportunity to embrace new technologies to maximize the efficiency of each production area.

Several large corporations have founded subsidiaries that specialize in assisting pharma giants at layout efficiencies and production layout planning. Many will operate these facilities themselves in consort with the drug developer. Patheon (Thermo Fisher)7, Emerson Resources 8, and Recro 9 are all examples of businesses that have been commonly referred to as CDMO’s (Contract Development and Manufacturing Organizations)

 

Can Devices Used in Pharma Research / Manufacture be Successfully Housed?

Up to this point, we have reviewed factors that determine the process used in operating a pharma manufacturing facility. We have given an example showing how batch and continuous manufacturing can lead to effective results by considering the product, the processes, cost, and applicable regulations.

We have also suggested an ideal partner for providing separation, containment, and safety for such operations should be able to:

  • Provide quick solutions for standard applications with a wide variety of standard product:  
  • Have larger housing strategies for accommodating continuous flow situations:
  • Be prepared to combine existing technologies for more complicated processes:
  • Have engineering skills which enable specialized testing of such equipment:

Footnotes:

  1. Cell & Gene architecture services, Pharmaceutical Process Architecture Services, 2020,
    https://www.cellandgene.com/doc/pharmaceutical-process-architecture-services-0001
  2. Design of Modern Pharmaceutical Facilities, Advanced Techniques in Biology and Medicine, Ahmed Salah Abu shoukka, Copad Pharma, 2017, frame 2,
    https://www.longdom.org/open-access/design-of-modern-pharmaceutical-facilities-osd-2379-1764-1000202.pdf

  3. The Ideal Design of Pharmaceutical Manufacturing Plant steps, 2017, Matcon Blog, Richard Lockwood, Pharma Business Line Director, Matcon Limited, England, https://www.matconibc.com/blog/your-what-kind-of-building-do-i-need-the-ideal-design-of-pharmaceutical-manufacturing-plant

  4. Five tests for Containment, Dr. Robert Haugen, Flow Sciences, 2020, https://flowsciences.com/five-tests-for-containment/

  5. ANSI-ASHRAE 110-2016, Human as Mannequin test, ANSI-AIHA Z 9.5, EN 14175, Good Practice Guide: Assessing Particulate Containment Performance of Pharmaceutical Equipment,
    2nd Edition,
    2012

  6. The $1 billion bet: Pharma giant and U.S. government team up in all-out coronavirus vaccine push By Jon Cohen, Science Magazine, Mar. 31, 2020 , 5:50 PM
    We’re jointly investing in the R&D part of this, and that will bring us, hopefully, to approval. And then in parallel, we’re investing more in the manufacturing, so we are creating additional capacity. Of course, it’s step by step—it has to work—but there’s no hesitation now to do everything in parallel. When we have clinical data, we will have the capacity to scale up to very large quantities. That is the short and long story.
    https://www.sciencemag.org/news/2020/03/1-billion-bet-pharma-giant-and-us-government-team-all-out-coronavirus-vaccine-push
  7. https://patheon.com/logistics-services/ 

  8. https://emersonresources.com/?_vsrefdom=googleppc&gclid=EAIaIQobChMItNGn54XA6QIVxdSzCh1aUwLaEAAYAiAAEgJB4vD_BwE

  9. https://www.recrogainesville.com/?gclid=EAIaIQobChMItNGn54XA6QIVxdSzCh1aUwLaEAAYAyAAEgJEnvD_BwE

Bulk Powder Containment: Key Factors for High Potency Handling and Processing

Figures 1 & 2: The EHP Hybrid Powder Units by FSI under Factory Test
and Field Certification

Abstract:

Today, many Flow Sciences customers must safely handle powdery materials. The reasons for containing such material cover a robust range of applications:

  • Mixing, blending, and dilution of active pharmaceutical ingredients. (API’s)
  • Dispensing, weighing, and packaging dosing quantities of active pharmaceutical ingredients
  • Quality control sampling of incoming bulk quantities of solid fillers or API’s
  • Grinding, milling, or otherwise changing the texture of raw pharmaceutical ingredients

Recently, pharmaceutical facilities have seen an increase in new API’s. These newer powerful drug ingredients have reached a potency where containment equipment requirements have reached a much more demanding level 3.

Such containment devices usually include one or more of these attributes:

  • A drum access opening in the worktop
  • Some type of waste chute or other means for removal of contaminated materials from earlier procedures
  • A fan/filtration system, typically with bag-in bag-out HEPA filters
  • The containment capacity to keep room levels of materials being processed at or below 1mg - 50ng per cubic meter.
  • A highly trained worker, armed with carefully-written manuals and SOP’s

The writer will flesh out some of the applications for such units and highlight newer products available to face the new challenges of active pharmaceutical ingredients.

Fig 3: The Flow Sciences Hybrid Isolator features a removable glove panel, offering great open sash containment plus highly effective gloved operation for more potent materials.

Factors Needing Control in Powder Containment:

Working with powders can present unique containment challenges:

First, the need to bring kilogram quantities of compound into an environment with a microbalance places in close proximity objects that seldom see each in any other analytical context. We already know this “meeting” has to happen, particularly in weighing or compounding environments. The ultimate mandate is that this meeting must smooth the awkwardness of Goliath, while preserving the accuracy of David!

The correct powder containment device can accomplish this feat. Sufficient airflow keeps powders contained, while the non-turbulent flow isolates one process from other materials in the same workspace. While all this is happening, the device provides an environment with virtually no turbulence or vibration impact on balance accuracy.

Flow Sciences technologies for doing all this have a long history in lab design and the efficiencies of such systems continue to improve4.

Powders spread inside containment spaces not only because of air currents, but also due to the electrostatic properties of the powders themselves. Powders are typically charged in turbulent airflow. They “stick” to surfaces and adhere to the operator’s hands (figures 4 below).

Figures 4: UV Luminescent Powder Shows Possible Electrostatic Transport of Powder. Note operator’s gloves!

Researchers must be able to police the containment work area, leaving gloves and equipment behind as they withdraw their hands from a procedure. We should always preemptively collect and isolate such waste inside the device. Waste chutes, transfer ports, bagging, and the like are all ways to retain and control contamination inside devices which contain powders.

To process with high purity, intelligent airflow design, built-in solutions for debris collection and isolation, and worker training about SOP’s are all important. The following six examples of bulk powder devices illustrate how many new types of containment structures achieve very good results.  

 

Examples of Powder Applications and Successful Containment:

1) The EHP: A Hybrid Isolator with Many Available Options:

Fig 5: The EHP unit Shown with Removable Glove Panel
Fig.6: Improved Multi-Foil Airflow Design
Fan Operates while weighing!

Fig 7: EHP used to weigh powder; rubber seal around drum;
vibration-isolated fan, and stable scale environment

Fig 8: Assorted Features Available on the EHP unit.

In summary, the FSI EHP Hybrid Isolator can handle kilo-sized quantities of powder for weighing and compounding applications. The unit is also suitable for custom compounding pharmaceuticals or weighing quantities of unique materials into dose quantities. The standard EHP containment device can do all this with the proper accessories. It has all the supporting attributes set forth in the abstract and illustrated in Figures 5 through 8.FC

Such a device contains weighing operations. Batching and dosage may proceed with products then transferred to a port for removal. Mixing pre-weighed ingredients for pharmaceutical use is also possible with the EHP unit. The more complex the application, however, the larger the device may become, allowing more equipment and processes to be undertaken simultaneously.

2) The Glovebox Workstation for LFBC (Lateral Flow Bio Containment Isolator)

The LFBC Isolator permits handling and manipulation of API (Active Pharmaceutical Ingredients) and HPAPIs (Highly Potent Active Pharmaceutical Ingredients) where personnel protection and product purity are required.

Fig 9: Assorted Features Available on the EHP unit.     
Fig. 10: The LBFC offers very good containment, lateral flow, and no exhaust option.

The LBFC very effectively isolates highly potent pharmaceuticals from the room environment using a lateral flow shown in Fig, 11 below.  This unit can contain to nanogram levels and from OEB 3-5. Consult FSI about your application, as containment levels can vary based on application and quantity of material processed.

This cabinet is also a Class 1 Biosafety unit certified using ASHRAE 110-2016. Generally usable in BSL class 1, 2, or 3 environments. Provides personnel protection, not product protection.

3) Specialized Compounding, Liquid Dose Preparation from Bulk Powder:

 The custom bulk powder unit shown below represents a more complex customer application. Addition of a measured amount of dry powder to a liquid in a mixing vessel on the right hand side to produce a liquid suitable for IV use.

Designed for personal protection, this unit has added features to facilitate working with powders using a Mettler Toledo XPE-10015 balance and an IKA mixer stand with the vessel top penetrating through the port on the right side of the worktop. This table section contains a black under-counter cabinet with a multiple height slide-out shelf for different size mixing vessels. Viewing panels are transparent acrylic.

Other features include energy-efficient LED lighting, black phenolic base, left side powder drum cutout, top-mount fans, dual HEPA filters with bag- in bag-out filter system (BIBO), iris ports on both sides, minihelic static pressure gauge, and a table with lock-down casters.

Fig. 7: Powder / Liquid Compounding Pharmacy Enclosure

4) Sieving and Drug Compounding Bulk Powder Containment:

Fig. 8: Bulk Powder unit designed to house a sieving machine

This Bulk Powder Station has dual, Bag-In/Bag-Out fan/HEPA filtration systems. Designed to vent and filter small batch sieving machine dust, the enclosure is equipped with a stainless steel lift cart and fitted with 20” bulk powder cutout for loading drums through the work top access hole. Hinged front and lower doors allow for additional equipment and samples. Airfoils, rear plenums, and top-mounted fans maintain laminar airflow across the workspace ensuring minimal exposure to hazardous powder APIs. The polypropylene superstructure is fitted with acrylic panels and built-in LED lighting.

5) Very large quantity unit:

Figure 9: This Bulk Powder unit allows large container to be connected to the left side
of the unit horizontally.

This large quantity unit features three top-mounted HEPA filtration systems. Designed for personnel protection while working with powder substances, the unit also houses a related balance application. The superstructure is acrylic with hinged upper access doors. A waste chute is located on the right side wall.

6) Animal Waste Processing:

In some cases, the “powder” being processed is waste, not ultra-pure ingredients. The stainless steel exhaust hood shown below offers our customers an isolated environment where animal cages are cleaned. Crushed clay absorbent is disposed of down the circular chute into a waste container below.

The coved 300 series stainless steel liner is easy to disinfect after use. Containment testing demonstrated isolation of waste contaminants inside.

Fig. 10: A Bulk Waste Unit, ASHRAE 110 tested, handles cage cleaning byproducts!

7) Stainless Steel Bulk Powder Units

Customers who have a need for very clean interior surfaces or effective contamination removal frequently opt for 300 grade stainless steel interiors. The powder device shown below has been tested and validated per end user requirements before leaving the FSI manufacturing facility.

Fig. 11: Stainless steel units are frequently used with radioisotopes, where interior cleaning is critical!

Are Devices Like These Right for Your Application?

There are, as we have seen, many types of powder containment devices designed to house a variety of different processes. Containment (personal protection) depends upon good and useful airflow, which keeps powders away from workers in the lab space, but there is so much more!

Because of electrostatics, workers should follow guidelines for properly using the opening. They must never remove an un-bagged object from the containment area. Since gloved hands can inadvertently bring hazardous powders out of containment areas, gloves and expendables should be kept under containment inside the containment area and be disposed using a waste chute. Ultimately, the work area must be clean after the process is complete. Otherwise serious contamination will occur. If the bulk powder containment device has no waste chute or portal, cleanup is virtually impossible. Beware of poorly designed units that allow no disposal routes from inside the containment area.

Experience with such units has shown that process-specific testing is necessary to demonstrate containment using proper technique by end-users. For this reason, ASHRAE 110-2016 and surrogate powder testing reports using the ISPE APCPPE Guideline1 must be part of the equipment validation procedure. Flow Sciences standard and custom containment equipment always come with documentation similar to that shown here!

Figure 12: ASHRAE 110 containment reports with standard sash opening
Figure 13: Custom unit being tested in 2016 using surrogate powder procedure outlined in ISPE Methods

All Flow Sciences, standard products easily pass both tests. Custom bulk powder containment units are tested with ASHRAE 110-2016 and the ISPE APCPPE Surrogate Powder Guideline2 using the customers’ procedures inside the unit. One such published study showed great containment for a standard Flow Sciences chemical fume hood using both containment tests. Results for surrogate powder and solvent vapor containment showed undetectable powder levels in the lab work area after significant interior powder and solvent exposure was created during the test. 2

 In addition, manuals for all our bulk powder units contain complete instructions for coupling and decoupling large ingredient drums, along with more general techniques necessary for effective containment of materials within the work area.

Figure 14: Manuals for bulk powder units review all techniques necessary for product protection.

Conclusions:

  1. Powder units should allow direct access to large quantities of powdered pharmaceutical materials while providing superior personal protection. Lab containment equipment should not expose workers to mixing, weighing, grinding, sieving, compounding, or other processes within an inadequate containment device.
  2. We should test containment units against contamination release using both ASHRAE 110-2016 and surrogate powder testing using the ISPE APCPPE Guidelines and processes relevant to the specified application.
  3. Powders differ from gases in that they will typically stick to surfaces, including the researcher’s hands and lab coat! Any successful test report by a manufacturer of such equipment should also include a review of cleaning and housekeeping procedures designed to prevent static transmittance of the relevant materials.

Footnotes:

  1. Assessing the Particulate Containment Performance of Pharmaceutical Equipment, Second Edition, 2012, International Society for Pharmaceutical Engineering
  2. Evaluating a Fume Hood for Containment of Solids, Liquids, and Vapors Using ASHRAE 110, HAM, and ISPE Methods, Goodman and Haugen, 2019, available from Flow Sciences, Leland NC
  3. Cyto Solutions, Engineering controls for the Containment of Cytotoxic Materials, Flow Sciences 2019, https://flowsciences.com/containment-engineering-controls-for-cytotxic-hpapi-adc/
  4. Red Lights and Green Lights-The Keys to Superior Containment, Robert Haugen, 2018, Flow Sciences, https://flowsciences.com/the-keys-to-superior-containment-in-compounding-applications/

Collaborative Performance Validation

Collaborative Performance Validation

Collaborative Performance Validation – Safebridge Consultants, Inc. and Flow Sciences, Inc.

Employees of a pharmaceutical manufacturing facility were producing synthesized estrogen, a female reproductive hormone. Some male workers exhibited symptoms of exposure to female hormones. In response, four Syntax employees collaborated with four other pharmaceutical companies to develop standards to prevent and attenuate exposure to pharmaceutical substances with unknown health effects. The efforts of all parties involved became the predecessor to the control banding policies which are practiced by many pharmaceutical companies today. The business collaborative was also a prelude to the founding of Safebridge Consultants, Inc.  Flow Sciences, Inc. utilizes Safebridge’s Industrial Hygiene and Toxicological expertise for numerous purposes. A demonstrative example is the development of a Containment Performance Target (CPT) for substances with unknown health effects.

Containment Performance Target (CPT) – customer defined level of acceptance exposure to personnel from potentially harmful materials handled in the process

Flow Sciences uses the CPT as a reference metric when validating the performance of enclosure through in-house testing. The concentration results of air samples taken in locations surrounding the enclosure and in the breathing zone of the simulation operators are compared to the CPT, which leads to a determination on whether the tested enclosure will contain contaminants to a concentration below the CPT. For more information regarding Flow Sciences’ internal performance validation testing, please visit the Performance webpage.

During selected containment projects, Flow Sciences, Inc. contracts Safebridge personnel to perform a Site Acceptance Test (SAT). The SAT is similar to that of Flow Sciences’ in-house performance validation; however the SAT is conducted on-site under simulated conditions similar to those present during the real-world use of the enclosure. Controlled, prescribed tasks are performed by simulation operators in accordance with the customer’s standard operating procedures (SOPs). If worst-case scenario (or catastrophic condition) testing is advantageous to the customer, breathing zone and area air samples are collected and the laboratory results compared to the CPT and/or internal metrics at the customer’s discretion or prerogative.

Another Flow Sciences, Inc. and Safebridge Consultants, Inc. Collaboration.

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Continuous Pharmaceutical Manufacturing; Challenges to the Containment Industry

Abstract:

Methods and techniques used in pharmaceutical manufacturing are broadly reviewed. There are two basic models of pharma manufacturing: batch and continuous. Both approaches are defined. It is concluded that both approaches have elements of the other. Generally speaking, many pharma manufacturing procedures are transitioning from the batch to the continuous approach.

Based on this finding, it becomes self-evident that basic containment devices used in either manufacturing approach should be adaptable to the other.

Background:

Perhaps some of the most common pharma manufacturing techniques being used today are listed below 1:

1.) Solvent extraction:

Buchi Universal Extractor E-800

2.) Milling

Jet Pulverizer Mill

3.) Cooling

Mokon Central Chiller

4.) Powder feeding

Coperion K-Twin screw feeder

5.) Powder blending

Munson Vee Cone blender               
Gericke GCM 250 Tubular Blender

6.) Granulation

PTK Mixer-Granulator

7.) Encapsulating

Typical Genyond Encapsulator System

These techniques plus other methods have been used in the batch production of pharmaceutical products 2. A generic example using these techniques might be:

Step 1:
Starting raw materials purified, then dried, using solvent extraction. (Batch 1)

Step 2:
Batch 1 then milled for uniform particle size. (Batch 2)

Step 3:
Batch 2 then cooled to uniform, sustained temperature. (Batch 3)

Step 4:
Batch 3 fed and

Step5:
Blended and mixed with other products (Batch 4)

Step 6:
Encapsulate batch 4 medication using hot melt extrusion or other technology (Batch 5)

The number of steps is different from the number of batches. This discrepancy occurs during steps 4&5 where many components are mixed together. This step gives us a big clue to an important possible route to simpler fabrication of pharmaceuticals.

A way that has fewer steps, fewer intermediate products which must be temporarily set aside or moved elsewhere, less human handling or warehousing of possibly hazardous intermediate products. This method is called Continuous Manufacturing. It has attracted much attention lately as being a faster, cheaper, and safer way of manufacturing pharmaceuticals.

Many articles have been written about continuous manufacturing (CM). In a perfect CM world, there are no batches. Ingredients are added and processes undertaken with quantities produced by the previous step. The following diagram compares batch and continuous manufacturing 2:

Figure 1: Batch vs. Continuous Manufacturing

Batch manufacturing involves discrete steps. Typically, production comes to a halt while samples are tested for quality offline. During these hold times, the material may be stored or shipped to other facilities globally to complete the manufacturing process. This can greatly increase the time it takes to make drugs, adding weeks or months to the process. All this introduces risk to quality and the continuity of the supply chain. 2

 In contrast, pharmaceuticals that are made using CM are moved nonstop within the same facility, eliminating hold times between steps. Material is fed through an assembly line of fully integrated components. This method saves time, reduces the likelihood for human error, and can respond more nimbly to market changes. To account for higher demand, continuous manufacturing can run for a longer period of time, which may reduce the likelihood of drug shortages 3.

Clearly, the design of a CM approach involves much of the same physical equipment used in batch manufacturing, modified to directly take products from one phase and pass it through to the next.

We must, however, put up a rather large caution sign here. The differentiation between batch and continuous processing is not this clear-cut! Let us look at some relevant examples of drugs that have simple manufacturing sequences. In these examples, multiple batching is limited and the continuous process predominates, however batching still takes place:

1) The modern manufacture of human insulin:

Several techniques are cited in the literature for manufacturing insulin. All involve recombinant DNA techniques and a variety of host cells modified to express the desired product.4

In practice, great care needs to be taken securing quantities of the desired organism for replication.

A bioreactor can be used to express the molecule by using modified bacteria such as e coli, yeast, or other living microorganisms shown on Figure 2:

Figure 2: Percentage of Biopharmaceuticals Produced in Different Expression Systems (2014) 4

Now here is how this example becomes relevant. At both the beginning of this process (cell modification to engineer insulin production). And at the end of the end (harvesting and purification), separate batches must be carefully “manufactured” and, isolated as batches! See Fig. 3 below:

Figure 3: Even this “Pretty Continuous” process has lots of batches!

While the process is continuous in the middle, very careful genetic and purification steps must be separated. These key batching steps cannot be entirely eliminated. At least in this space-time continuum!

2) The modern manufacture of aspirin (acetylsalicylic acid):

Commercially, aspirin starts out requiring a related chemical, salicylic acid, which is made under 100 atmospheres pressure combining sodium phenolate and carbon dioxide. (The Kolbe-Schmitt reaction). 5

After suitable purification to pharma standards, salicylic acid is then reacted with acetic anhydride in an acetic environment (phosphoric or sulfuric acid) to produce a powdered form of acetylsalicylic acid6.  After purification, this product is mixed with corn starch, fillers, and water and pressed into tablets.

While the entire process is relatively simple, only the first and last steps shown in Fig. 4 are continuous. Batching is necessary after the salicylic and acetylsalicylic powder phases.

Figure 4: Same story here, except steps 1 and 4 are continuous while middle steps are “batch”

The author needs to emphasize two clarifying points to the above analyses.

First, these two drug examples are very common pharma products, therefore differing manufacturers may have differing methods for producing them. The author has referenced his sources, but even these sources acknowledge a variety of manufacturing methodologies and steps are used for both drugs.

 Second, while the author has chosen widely-used drugs with low cost because these examples should show CM, batching is still significantly involved in both products!

Most pharma manufacturing has steps relating to isolating synthesis organisms, feedstock quality control, dosing, purity, and product quality control which directly or indirectly require batching.

While continuous manufacturing can be seen as a spreading technology, while this strategy will grow in relevance and contribute to significant reduction in manufacturing costs and higher product quality in the future, there are inherent reasons why batching will not become extinct.

The Challenges Batching and Continuous Manufacturing Issues Bring to containment Product Design:

Fig. 6: Three Joined Continuous Process Units
Fig. 5: Two Filtered Units with center Computer Monitor   

 

 

 

 

 

 

 

 

As figures 5&6 above show, similar units may be oriented differently to accommodate batch manufacturing (Fig. 5) or continuous manufacturing (Fig 6). Flow Sciences has been designing custom linked units similar to Fig. 6 for years as we respond to the growing demand for continuous process equipment.

Additionally, many CM applications may not ever require linking containment devices physically, but may just need hoses or other pre-made conduits added. FSI’s new Hybrid Isolator comes with several ways to field-modify installed units to include connectivity with other processes.

This type of product development will continue into the future as advancing CM techniques require a variety of linkages between existing containment units. The future of this industrial segment will require all containment manufacturers can furnish containment products that support transitioning manufacturing requirements.

Check out what’s already happening at www.flowsciences.com. Here’s a preview of diverse solutions for lab and manufacturing streamlining! 

Fig. 7: Linked Glove Box Work Stations
Fig. 8: 3-Unit Array
Fig.9 Filtered exhaust unit to negative pressure unit
 
Fig. 10; Sliding sash hybrids to gloved unit with ventilated enclosure underneath
Fig. 11: Sliding door filtered unit to floor-mount open sash filtered unit with doors
Fig. 12: Pass- through from room to negative pressure recirculating glove box

Commercial break: call us!

Flow Sciences 1-800-849 3429.

Footnotes:

  1. Wikipedia, 2019, https://en.wikipedia.org/wiki/Pharmaceutical_manufacturing
  2. CEP Magazine, 2018, Pharmaceutical Manufacturing: Current Trends and What’s Next
  3. The Case for CM, 2018, FDA Report 2018, Sou LEE, Director of Office of Testing and Research
  4. Microbial Cell Factories, October 2,2014, Cell Factories fir Insulin Production, US National Library of Medicine, National Institutes of Health; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203937/
  5. Wikipedia, 2019, https://en.wikipedia.org/wiki/Salicylic_acid
  6. https://chempics.wordpress.com/2013/09/18/acetyl-salicylic-acid-aspirin/
  7. http://www.madehow.com/Volume-1/Aspirin.html

Five Tests for Containment

Abstract:

As active pharmaceutical ingredients increase in potency and become more hazardous to work with, pharmacological and chemical containment devices are required to meet containment performance targets through independent testing before use in laboratories can begin. Typically, we test containment equipment against some minimum performance standard. This is necessary to protect procedural integrity and the sensitive products undergoing processing.

As air sampling and measurement techniques improve and cumulative recorded data becomes more robust, containment testing has grown more refined—even if the tests themselves are more complicated.

There are many reasons why such changes have occurred and influenced the design and production of containment units and the means of evaluating them. Powders and liquids are dangerous to handle over long periods, and the manipulating process equipment is more substantial in both size and capability. Testing is not one-size-fits-all when it comes to containment performance—here we will analyze and explain the different methods, their reasons, and which would be most beneficial for your first (or next) containment device to ensure personnel protection.

Discussion:

Over the last century, the use of devices designed to contain toxic gases, volatile liquids, and powdered solids has grown substantially within most operating labs and pharmaceutical production facilities.

The writer has previously examined this issue1. The following table represents current containment standards used worldwide to evaluate various lab and powder containment equipment in multiple contexts:

ANSI/ASHRAE 110-2016

ASHRAE 110 clearly states the standard’s scope in Section 1. Purpose: “The purpose of this standard is to specify a quantitative and qualitative test method for evaluating fume containment of laboratory fume hoods.” In North America, ANSI/ASHRAE 110-2016 is the most frequently used fume hood containment test 5.

Since 1985 when this limited scope was crafted, application of the 110 test has steadily expanded from lab fume hoods to other types of exhaust ventilation units including small worktop units, 100% exhausted biosafety cabinets, and even filtered ductless units.

In the latter case, the filtered exhaust air must not re-enter the test area when expelled from the unit. Typically, such tests of ductless units are a contrivance used for the limited purpose of verifying contaminants are not leaving through the operating opening.

Beginning this calendar year, ASHRAE 110-2016 is undergoing periodic revision, which will probably include the formal addition of new tracer gases and a possible elimination of SF6 due to environmental considerations. Test scope is also a likely topic of discussion since it has never expanded past its limited, initial 1985 fume hood only scope.

European Standard EN 14175 Part 3, 2019

EN 14175 covers construction, installation, and containment of lab hoods. It has, therefore, a much broader scope than ASHRAE 110. Here, the writer will only review Part 3 which covers testing.

Updated in 2019, Part 3 focuses on hood performance and its measurement. Most of the complex containment equipment remains unchanged from the 2003 edition of Part 3. Based on the size and complexity of the apparatus, this test does not easily travel to an operating lab or job site.

Primary concerns with EN 14175-3 include an inability to differentiate performance in a meaningful way between tested units and significant issues applying the tests under field conditions. 

Human as Mannequin Test (HAM test)3:

This test uses ASHRAE 110 - specified equipment in a kinetic challenge to the containment cavity. Prescribed manipulation of lab equipment within inches of the operating gas diffuser are undertaken. Containment of tracer gas in the operator’s breathing zone is measured. This test rarely shows containment issues with larger fume hoods, but Flow Sciences also uses this test inside much smaller containment units with similar success. The writer views this test as an aggressive containment evaluation tool because of the programmed movement of objects around the actual tracer gas diffuser. In the writer’s opinion, the test has added an additional kinetic challenge to the tests included in ASHRAE 110.

Surrogate Powder Tests:

While the previous three tests evaluate containment of vapor, powder containment has now become a huge issue for pharmaceutical and agribusiness enterprises. Because powders have unique electrostatic properties and routinely undergo grinding, sieving, and filtration operations, additional test procedures are necessary to evaluate containment devices destined for powder application. Such testing procedures will vary widely based on the characteristics of the processes being contained.

The International Society for Pharmaceutical Engineering describes the general surrogate powder approach in Good Practice Guide: Assessing Particulate Containment Performance of Pharmaceutical Equipment, Second Edition4.

In this testing approach, researchers manipulate lactose, or other surrogates, in a fashion similar to an anticipated pharmaceutical active powder as a way of forecasting the expected particulate containment.  These operations may include such procedures as weighing, grinding, dissolution, and filtering.

Air pumps and filters collect room and containment area samples during the test procedure. Such pumps are located in the test lab, in the containment device, and on the experimental subjects themselves as in figures 15 and 16 below. 

Experimenters then analyze “Loaded” filters using a contract analytical laboratory accredited by the American Industrial Hygiene Association (AIHA).

Flow Sciences reports resulting data from such tests using mg/m3 or ng/m3 in the containment cavity, the lab, and near the worker breathing zone. Research or production staff can then look to these data as indicators of work area concentration, room air contamination, and worker breathing zone contamination. Such testing therefore addresses whether containment equipment is demonstrably safe within pre-determined safety levels.

NSF 49 6:

The National Sanitation Foundation (NSF) completed the NSF 49 standard for testing Class II biosafety cabinets in 1976. This standard evaluates a cabinet’s ability to contain biological contamination while also preventing the outside environment from contaminating samples within the cabinet.  Class II biosafety cabinetry should be capable of minimizing the hazards inherent in working with biosafety agents of levels 1, 2, 3, or 4.

NSF/ANSI 49 includes basic requirements for design, construction and performance to provide personnel, product and environmental protection; reliable operation; durability; cleanability; noise level and illumination control; vibration control; and electrical safety.

In addition, the standard includes detailed test procedures involving nebulized and sprayed Bacillus Subtilis Niger as a representative surrogate bacteria and open agar petri dishes as the detection mechanism. NSF has an internet informational site, including recommendations for installation, field certification tests and decontamination procedures. The NSF website contains a biosafety cabinet index for all approved units, describing all flow metrics that will produce the proper flow to shadow parameters used to certify the original cabinet design 7.

Conclusions and Predictions:

The writer again shows Table 1 below; it lists the five tests used to evaluate the containment devices we have discussed in this white paper. 

All these tests provide necessary data to research and pharma/manufacturing clients wishing to assess containment safety. The following section reviews these tests and points out where each one is most useful:

American labs and drug manufacturing facilities all use ASNS/ASHRAE 110-2016 to evaluate chemical fume hoods. Other smaller filtered and unfiltered containment devices frequently face these tests as part of a less formal but equally relevant battery of evaluations.

In Europe and other regions on our planet. EN 14175 definitively evaluates lab fume hoods, sharing the same scope with ASHRAE 110: fume hoods. However, the specific equipment prescribed in these tests makes it difficult to use this standard to evaluate smaller non-fume hood devices, while the complexity of the equipment makes field evaluations time-consuming and proceduraly difficult.

The Human-as-Mannequin (HAM) test is the most frequently used supplementary test when using ASHRAE 110. HAM specifies the same equipment and tracer gas as ASHRAE 110. While kinetic movement inside the work area described in HAM is relevant to containment performance, such a test is not present in ASHRAE 110. Therefore, this test adds a significant kinetic challenge to the ASHRAE 110 methodology.

Surrogate powder tests evaluate powder containment and should always be included in any test protocol where finely divided powders are present. Flow Sciences and our clients have insisted on this for years. Powders do not propagate in the same way as tracer gas. Electrostatics can promote containment issues if powders stick to hands and arms inside the containment area and then are withdrawn.

Manufacturing sites using highly potent pharma ingredients must have high confidence in the containment of large quantities of such products during manufacture. For this reason, Flow Sciences frequently runs surrogate powder tests at our facility with functioning equipment and personnel simulating production operations with surrogate powders.

For powder use, surrogate powder testing will continue to be the primary criterion for evaluating containment equipment manufactured by Flow Sciences.

We can break down all these tests two ways to better understand the scope they cover in containment testing:

Simple and portable vs. complex and awkward: ASHRAE 110 and HAM tests are simple and portable; EN14178, surrogate powders, and NSF 49 are much more complex and not amenable to field use. Using tracer gas (molecular) techniques has led to simple equipment (ASHRAE 110 diffuser), which leads to lots of comparable data. Complex equipment using gas diffuser arrays and moving rectangles on tracks are inherently less capable of generating comparable data from one device to another. Complex equipment also is very difficult to use in the field.

Molecular tracers vs. living tracers: ASHRAE 110, EN14175, and the Surrogate Powder tests all use molecular tracers; NSF 49 uses living tracers.

Overall, the author has set forth containment testing protocols used to evaluate a wide variety of containment devices. There are several impacts this study has upon what direction such testing might take in the future.

The following diagram plots all these tests into a distribution continuum.

Simple molecular tracer tests are so widely used that much performance data is available. We read, compare, and study such data and deduce trends from one containment device to another with some validity. Such deductions are the first step in formulating reliable pass/fail standards for such equipment. All of this is good.

Currently devices evaluated with surrogate living organisms (bacteria, virus, etc.) or molecular powders present a more problematic array. We may use different powders or organisms as tracing agents. We can undertake different kinetic challenges based on procedures and customer requirements. We may have greater or lesser containment goals based on the virility or toxicity of the material we aim to isolate. These inherent differences in procedures and containment goals mean each test becomes unique. While each containment test may have successful results, generalizations will always be difficult from such a success to yet untried applications. All of this robustness in procedures and tests leads to fewer universal truths. Tests with powders or biological tracers do not readily spawn generalizations.

This challenge does not reduce the usefulness of biological or surrogate testing, but it does increase the work necessary to validate each new product! Be sure to research your chosen containment unit thoroughly; have the people who built and installed it relevantly and thoroughly tested its performance?

 

Footnotes:

  1. The Galaxy of All Containment Devices, Flow Sciences White Paper, 2019, Flow Sciences Inc., Leland NC., p. 16
  2. Waldner Video, EN14175 Kinetic Test, https://www.youtube.com/watch?v=VpkDBAsgQpc
  3. Side-by-Side Fume Hood Tests Using ASHRAE-110 and Human-as-Mannequin Test Methodology, 2005, Exposure Control Technologies, Inc, Carey, NC.
  4. Good Practice Guide: Assessing Particulate Containment Performance of Pharmaceutical Equipment, 2nd Edition, 2012, International Society for Pharmaceutical Engineering.
  5. Two Well-Known Fume Hood Tests, Robert Haugen, 2018, Flow Sciences, Inc.,p.2, https://flowsciences.com/two-well-known-fume-hood-containment-tests-ashrae-110-en14175-a-comparison/
  6. https://www.nsf.org/services/by-industry/pharma-biotech/biosafety-cabinetry/nsf-ansi-49-biosafety-cabinetry-certification
  7. http://info.nsf.org/Certified/Biosafety/Listings.asp?
  8. Because of diverse standards and countless pass-fail criteria, glove boxes and isolators are not included in this review of containment standards.
  9. International Standard, ISO 14644-7, “Cleanrooms and Associated Controlled Environments” Part 7 Separative Devices (Clean Air Hoods, Gloveboxes, Isolators and Mini Environments) (2004). International Standard, ISO 14644-7, “Cleanrooms and Associated Controlled Environments” Part 7

Issues with Weighing in a Ventilated Enclosure

Dr. Robert Haugen, Flow Sciences Inc.

Abstract:

The use of weighing equipment in all chemical and pharmaceutical endeavors is critical. In chemical research, the accurate measurement of a reaction product may directly lead to its chemical formula. In pharmacy, dry weight of a drug becomes central to administering proper dosage. Examples of the criticality of weight measurement are virtually endless!

Because Flow Sciences produces containment equipment for chemical and pharmaceutical applications, the writer will examine the impacts of weighing errors within laboratory containment devices. A review of such errors reveals that most relate to faulty equipment, unanticipated environmental factors, and negligent balance operation.

Impediments to Accuracy:

Five key impediments to accurate weighing will be detailed in this paper.

1) Vibration Interference caused by grinders, pumps, or crushing equipment can cause balance values to cycle over some midpoint. Such cycling expands the uncertainty of measurement. Many successful versions of weighing tables can minimize this issue by increasing the mass of the surface upon which the balance is placed. Increasing the table mass means the vibration energy trying to wiggle the balance is absorbed by the extra mass of the table top. Such a phenomenon is frequently called dampening.

Such vibration is also common in poorly designed ventilated balance enclosures.1 Frequently, such enclosures have inexpensive fan motors poorly insulated from vibrating the weighing chamber work top. Some filtered weighing stations must be turned off before balances inside work properly. This technique is clearly not advocated by the author. The Flow Sciences weighing station pictured below features a balanced fan wheel and vibration isolation between the fan and weighing area 1.

2) Instability of Chemicals being weighed: When weighing a substance that is sensitive to relative humidity, the measurement may unexpectedly increase while on the balance.

In this scenario, airborne water vapor may begin to react with the substance while it is still on the scale.

A remarkable “weight gaining” example is the slow saturation of anhydrous Copper (II) Sulfate. If left on a scale in a humid environment, this white powder will gradually turn to blue while remaining crystalline. As it is turning blue, it is also gaining ~56% more weight by absorbing water vapor!

CuSO4 + 5 H2O  –>  CuSO4(H2O)5

While the illustrated molecular hydrated structure shown above is not pretty, when repeated thousands of times in 3-space, it is systematic enough to form regular crystals! If such crystals are heated, they will turn white as they lose their waters of hydration.

In general, many anhydrous compounds have some potential to hydrate in ways similar to the example above. Because water vapor is so plentiful in our atmosphere, the effect of humid air on weighing anhydrous powders is pernicious. If dehydration during weighing cannot be completely solved by dehumidification of the lab, water in the weighing environment can be essentially eliminated by replacing the air in our weighing environment with a pure, unreactive gas like nitrogen or argon. The Flow Sciences NitrogenemaTM Series shown below does this with great effectiveness. Such a non-reactive atmosphere can also be used to prevent oxidation of unstable metallic compounds.2 Weighing becomes much more stable in such an environment.

3) Air Currents: Any quick, brisk gust of air that rushes through a routinely opened sash can challenge balance stability. This type of air draft can interfere with balance measurements by blowing powdered product off the balance pan or by aerodynamically lifting, then dropping, the pan itself. This effect can be minimized by closing the door of an analytical balance, using a draft shield (photo 2 on title page), or by moving the entire weighing apparatus away from room drafts.

In the containment industry, these drafts in front of an enclosure are commonly referred to as “cross drafts”. Cross drafts higher than 15 linear feet per minute will cause some face velocity variations. These variations can induce weighing error, particularly with platform balances. While any properly built ventilated weighing device with stable interior velocity profiles can routinely produce stable weighing data, proximity of such an enclosure to doorways, walkways, fans, windows or make-up air vents should be avoided at all costs.

4) Temperature Variations: When samples are introduced into a microbalance environment, there may be a temperature difference between the sample and the air surrounding the sample. Such a difference can introduce convective air flow around the object being weighed. Particularly when nanogram accuracy is required, samples being weighed should be close to ambient temperature for stable and reproducible readings.

5) Ignoring sample spillage: Leaving sample residue inside a contained weighing area is a preventable way of introducing major errors into weighing. Particles smaller than 0.1 millimeters (mm) are difficult to see. Many Contract Manufacturing Organizations and Contract Research Organizations work with substances that are on the micrometer scale, which is one one- hundredth of the particle referenced above. For powders this fine, it is quite necessary to clean areas where weighing takes place even if no residue is visible! Frequent cleaning is the only way to prevent increasing measurement error in repetitive procedures. Even though what is being removed may be invisible, SOP’s should be developed to prevent balance build-up and contamination from previous procedures.

Conclusions:

As stated in our abstract, weighing errors are primarily caused by faulty equipment, unanticipated environmental factors, and negligent balance operation. Ventilated enclosures that house weighing devices should have balanced exhaust fans and a massive enough work top to yield low vibration levels necessary for stable measurements. Most manufacturers should have test data revealing this type of performance1. Remember also that balances should be recalibrated and the calibrations memorialized on a regular basis.

Several environmental factors can cause weighing inaccuracy, including humid air, dirty air, and large cross drafts. Areas with balance enclosures should always be in low traffic areas with clean air. In some cases, a chamber with a non-reactive atmosphere may be required.

Human behavior can be responsible for many measurement accuracy issues. The scale area should be kept scrupulously clean. With microgram or nanogram quantities, areas may need to be cleaned even if spillage is not visible. Flow Sciences has a video using ultra violet light that demonstrates this.

Good data keeping and memorialization are also critical and guarantee that there will always be a protected data record to back up your lab’s findings!


Footnotes:

  1. The Importance of Vibration Isolation for Proper Enclosure Functioning, 2016, Robert Haugen, Flow Sciences Publication
  2. Containment Using a Non-Reactive Atmosphere, 2019, Robert Haugen & Gary Dean, Flow Sciences Publication
  3. Surrogate Fume Hood Test, 2019, PowerPoint, Flow Sciences


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.



Fume Hood Sash Glass: What Do Standards and Specifications Require?

Robert Haugen, Ph.D., Flow Sciences

Abstract:

The most obvious barrier between a lab worker and a potential experimental accident is the fume hood sash. Ideally, we want such a sash to protect the researcher from eruptions, spatters, and other dangers present in typical reactive chemistry.

Like many other issues involving materials of construction, fume hood glazing comes in a variety of designs and specifications.

The writer will set forth the glass types available for fume hood construction and discuss standards typically used to help specify this glass in a useful manner. It will also be noted that some safety glass types now specified are neither preferred nor reliably defined.

These issues of vagueness lead to confusion among lab planners and specifiers attempting to describe fume hood glass that is appropriate for a given application.

Sash Glass Options Often Specified for Chemical Fume Hoods:

  • Annealed glass: While annealed glass is never used in fume hoods 23, its manufacturing process gives us a clue about various strengthening procedures we will later describe in detail.

Annealed glass is glass produced without internal stresses imparted by heat treatment, i.e., rapid cooling, or by toughening or heat strengthening. Glass becomes annealed if it is heated above a transition point then allowed to cool slowly, without being quenched. Glass is treated with heat in order to change its properties by the annealing process. Annealed glass is the most common glass used in windows. Annealed glass is also known as a standard sheet of float glass.”22

“Glass which has not been annealed is liable to crack or shatter when subjected to a relatively small temperature change or mechanical shock. Annealing glass is critical to its durability. If glass is not annealed, it will retain many of the thermal stresses caused by quenching and significantly decrease the overall strength of the glass.”22

So annealed glass, because of its method of manufacturing, is free of irregular internal stresses which can make glass fragile and more brittle. The product we start with in any strengthening procedure is therefore stress-free and capable “as is” of reliable use for many construction purposes.

1) Laminated Glass:

This form of safety glass is designed to hold together when shattered2. Laminated glass is typically constructed from annealed glass lites with a layer of some kind of plastic in the middle (interlayer). The interlayer is typically PVB (Polyvinyl butyral) or EVA (ethylene-vinyl acetate). Both interlayer types form a bonded interface with the glass, making a sandwich that is very difficult to penetrate or shatter. Either interlayer material type tends to hold the glass together when the panel becomes damaged through impact.

Most specifications sent to Flow Sciences for quotation call out a PVB interlayer and a total glass –interlayer-glass thickness of not less than 7/32”. Flow Sciences uses nominal ¼” glass as our standard.

2) Tempered Glass:

If we start with stress-free annealed glass, we can re-heat this glass and rapidly cool it in a manner that puts a regular and uniform stress pattern into the glass structure. “Glass of any shape that has been subjected to a thermal treatment process characterized by uniform heating followed by rapid uniform cooling to produce compressively stressed surface layers is called tempered glass.” See ASTM C1048 for additional information.7

As a result of its safety and strength, tempered glass is used in a variety of demanding applications, including passenger vehicle windows, shower doors, architectural glass doors and tables, refrigerator trays, mobile screen protectors, as a component of bulletproof glass, diving masks, and various types of plates and cookware. 4

In chemical fume hood applications, extreme heat would require tempered glass which does not fracture due to heat until about 450o F. Laminated safety glass may crack at or above 160o F. When tempered glass does break, the entire sheet winds up in tiny glass shards due to the uniform stressed structure that increases its resistance to impact.

At least one major fume hood manufacturer6 is currently using ¼” tempered glass fume hood sashes. Flow Sciences and most other North American manufacturers use laminated safety glass.

3) Laminated-tempered Glass:

“Laminated/Tempered glass is a hybrid of two strong types of glass: Laminated glass, which consists of two glass panes with a thin, clear vinyl layer in between that prevents the glass from shattering on impact, and tempered glass, which has been heat-treated to make it harder and more durable than standard glass.9

This type of glass appears occasionally in fume hood specifications. It creates several problems for companies seeking to provide fume hoods with this glass:

  1. Fume hood design requires glass parts of non-standard dimensions (sash, bypass panels, light lens, etc.). All glass lites to be used to make a piece of lami-temp must be first pre-cut into two sets of pieces from non-tempered glass. These lites are then tempered in an oven to create thin (~2 mm) tempered glass panels. Each matching pair of panels must then be laminated together using a PVB interlayer. Typically, this safety glass must have a total thickness of no more than ¼”. Unfortunately, one cannot start with a big sheet of lami-temp glass and cut it, because the cutting motion will cause the piece to shatter at the instant the surface is scratched. Therefore, one must start with pre-cut lites of annealed glass, temper them, and then laminate matching tempered pieces together.
  2. The method described above of manufacturing each piece of laminated-tempered glass is time and labor consuming. Lites this thin are difficult to temper and then laminate due to breakage and other issues. There is no alternate way to make custom cut pieces with any better efficiency. Most fume hood manufacturers find the cost and manufacturing risk of this product prohibitive for standard product, and only offer this option if specified by the customer.

4) Other types of glass occasionally used in fume hoods.

Infrequently, other types of fume hood sash glass have been specified:

  1. “Bullet proof” glass is usually a combination of polycarbonate (Lexan) and glass in layers. The illustration below shows a cross section of this product comprised of two glass layers and three layers of polycarbonate film.11

    This material is usually sold in thicknesses greater than ¼” The department of defense has specified this product be used in some marine fume hood applications. Again, the constituent glass parts must be made separately and then joined together for each piece as the product cannot be cut once fabricated.

  2. Fire-Rated Wired Glass is infrequently specified for laboratory hoods. Years ago, the researcher saw a fume hood similar to ones shown below at the University of Illinois with wired glass throughout. There can be serious problems with this product.

The presence of the wire mesh appears to be a strengthening component, as it is metallic, and conjures up the idea of rebar in reinforced concrete or other such examples. Despite this visual implication, wired glass is actually weaker than unwired glass due to the incursions of the wire into the structure of the glass. Wired glass often may cause heightened injury in comparison to unwired glass, as the wire amplifies the irregularity of any fractures. This has led to a decline in its use institutionally, particularly in schools.12

The Influence of Various Standards on Fume Hood Glazing:

1) ANSI / AIHA Z 9.513 is the over-arching standard for fume hoods and other lab containment equipment. It calls out other standards within its arc of proper lab outfitting including fume hood containment testing and materials, including glass. ANSI AIHA Z9.5 states that fume hood sash glass should be shatterproof (no standard referenced).

No other codification, identification or mention of sash glass material or other glazing practices in fume hoods is mentioned in this entire standard. Not much help here!

2) SEFA 1 14 is a different standard written by members of the Scientific Equipment and Furniture Association.

Section 4.1.8, 2016 States: “Most lights are fluorescent tubes housed outside the hood chamber and separated by a vapor resistant safety glass panel in the top of the hood. The standard does not specify what type of safety glass should be used and what standard should be applied. Not much help here either!”

3) ANSI Z97.1 – 2015 15 delineates the most comprehensive list of definitions and standards for various forms of safety glazing:

a) Laminated

b) Tempered

c) Organic coated

d) Plastic

It must be emphasized, however, that no definition of laminated-tempered glass is offered herein.18

ANSI AIHA Z97.1 offers separate methods for testing laminated and tempered glass, but says nothing about testing or certifying laminated-tempered glass, even though there are major differences in the cracking, initiating energy, and thermal behavior of these materials.

This section is reproduced below to show how the standard does not specifically address laminated-tempered safety glass:

Note: Even though the above text of Z97.1 reviews SEPARATE methods for “shot bag” testing laminated and tempered safety glass, by industry convention, any laminated glass made up of any kind of glass lites is regarded as laminated glass and is tested using column two criteria of the ANSI Z97.1 – 2015 standard. Flow Sciences obtained samples of lami-temp glass 8mm thick for testing and evaluation. Each sheet came with the permanent label shown in the photo below:

There is inherent confusion in this label. Note the “HS” in the expression TEMPERED/H.S. It turns out that tempered glass comes in several categories, including HS (heat-strengthened) and FT (fully tempered). Here is a definition from the literature of HS and FT grades:

“The most dramatic and important difference between heat strengthened and tempered glass is in the post breakage characteristics of the two products (i.e. break pattern). If heat strengthened glass (HS) should break, the pieces will be relatively large and tend to remain in the glazing system until removed. Tempered glass, on the other hand, is designed to break into innumerable small, roughly cubical pieces. In fact, it is this break pattern that qualifies tempered glass as a safety glazing material. However, because of the break pattern, tempered glass is much more likely to evacuate the glazing system immediately upon breakage. Responsible design professionals must consider the tendency of tempered glass to evacuate the opening upon breakage and the consequences must be acceptable. Responsible parties know that there is always a possibility of glass breakage. The glass construction must be designed with a low probability of breakage, typically less than 8 panels per 1000 panels, but if the glass does break, the glass design must be done in a manner so that the breakage consequences are acceptable.” 20

A more direct explanation is offered by Vitro Architectural glass22:

“There are two different types of heat-treated glasses, heat-strengthened and tempered. The similarities between the two include:

  • Production using the same processing equipment
  • Heating the glass to approximately 1,200 degrees Fahrenheit, then force-cooling it to create surface and edge compression

The differences between the two glasses are as follows:

  • With tempered glass, the cooling process is accelerated to create higher surface compression (the dimension of force or energy per unit area) and/or edge compression in the glass. It is the air-quench temperature, volume and other variables that create a surface compression of at least 10,000 pounds per square inch (psi). This is the process that makes the glass four to five times stronger and safer than annealed or untreated glass. As a result, tempered glass is less likely to experience a thermal break.
  • With heat-strengthened glass, the cooling process is slower, which means the compression strength is lower. In the end, heat-strengthened glass is approximately twice as strong as annealed, or untreated, glass.”

Heat-strengthened (HS) laminated-tempered glass shatters into relatively large pieces when cracked, held together by the plastic interlayer.

This breakage pattern is actually better in some applications than an FT laminated panel, which would totally fracture into tiny cubes held together by the interlayer. Such broken panels of FT lami-temp could drop or sail into a work area like a “wet blanket.” See photo below:

4) ASTM C1048-18 also describes various types of tempered and laminated glass.

The C1048-18 abstract states the following:

“This specification covers heat-treated flat glass – kind HS, kind FT coated and uncoated glass used in general building construction. Glass furnished under this specification shall be of the following conditions: condition A – uncoated surfaces, condition B – spandrel glass, one surface ceramic coated, and condition C – other coated glass. Flat glass furnished under this specification shall be of the following kinds: kind HS – heat-strengthened glass shall be flat glass, either transparent or patterned, in accordance with the applicable requirements, and kind FT – fully tempered glass shall be flat glass, either transparent or patterned in accordance with the applicable requirements. All fabrication, such as cutting to overall dimensions, edgework, drilled holes, notching, grinding, sandblasting, and etching, shall be performed before strengthening or tempering and shall be as specified….”

Note the last sentence above: once glass is tempered, it may not be cut. This material cannot be dimensionally field modified. Incidentally, nowhere in this standard is laminated-tempered glass mentioned.

5) 16 CFR 1201: This is part of the larger standard Code of Federal Regulations Title 16: Commercial Practices. Part 1201 is the Safety Standard for Architectural Glazing Materials. It contains the principal set of rules and regulations issued by federal agencies regarding commercial practices for glass.

Discussion: Where Are We left?

On the positive side, American manufacturers are given clear ways to label and classify laminated, tempered, or laminated-tempered safety glass. The operative standard here would be ANSI Z97.1. Additional information on classifying tempered safety glass is provided in ASTM C1048.

Below is the label marked on every sheet of standard laminated safety glass Flow Sciences receives, cuts, and then uses in the Saf T Flow fume hoods manufactured here in the United States. Among other standards, note ANSI Z97.1 is prominently referenced. Tempered, laminated, and lami temp glass are certifiable under the same standard using different pass-fail criteria.

On the negative side, customers occasionally want a different glass product than laminated or tempered. As contradictory as it sounds, the common practice is to test lami temp using the laminated test criterion, not the tempered criterion.

The tests and descriptions for lami-temp glass neglect to specify whether the “tempered” glass used is FT or HS. Several construction specifications call out laminated-tempered glass and say nothing about this issue. The following two examples demonstrate how these vaguely defined and poorly established distinctions can cause serious problems with fume hood glass specifications:

1) A major University requested laminated-tempered glass. It requires 91% transmission or better, Category II compliance under 16 CFR 1201, and a permanent marking from SGCC delineating compliance with listed standard. The specification says nothing about the degree the lites must be tempered.

There is another problem with the same specification: The specified requirement for testing using 16 CFR 1201 Category II criteria states Category II glass must be used in one of the following building components: shower doors, bathtub doors, sliding glass doors (patio type), storm doors or combination doors that contain any piece of glazing material greater than 9 square feet in surface area, doors that contain any piece of glazing material greater than 9 square feet.” CFR 1201 is therefore not applicable using this specification because none of the included Category II materials are fume hood sashes.

As stated earlier, the CFR 1201 Category II dimensional requirements come from the construction industry, where larger thin pieces of FT laminated-tempered glass, when stressed, turn into a one-piece “wet blanket” and may fall out of their frame on a building exterior and become a massive and dangerous falling object.17 The writer therefore believes the large-piece dimensional size requirements are designed to encourage thicker glass panels that will not fall out of their frames when they become shattered. Even though fume hoods are not one of the limited list of products specified in this standard, it is easy to see why CFR 1201 limits the use of laminated-tempered safety glass even in building and construction applications.

Flow Sciences has not wished to use lami-temp glass ¼” thick for fume hood sashes because either (or both) glass lites comprising a panel could easily crack and precipitate a collapse of the entire panel into a single mass of shards which will then potentially fall out of the sash frame in one piece.

2) A second specification for fume hood sash glass was found to call out lami-temp that would comply with ANSIZ97.1, grade B impact performance.

Grade B impact performance is clearly defined in the standard and easy to evaluate whether the two panels used in the structure are glass or tempered glass. As with most fume hood manufacturers, Flow Sciences has its laminated ¼” sash glass fully certified using ANSI Z97.1 to this procedure and will gain no improved impact performance going to lami-temp panels.

In summary, Flow Sciences has found limited advantage in the lami-temp product for many of the reasons cited above. If laminated-tempered glass must be used it should be grade HS since damaged panels have larger pieces less likely to fall out of the framing system. The remaining issue is fully tempered and heat strengthened are poorly differentiated in the standards.

FSI has found laminated glass serves most lab needs better than tempered or lami-tempered products. Laminated glass also has a well-established and regularly-applied standard which makes it useful for upholding our ISO 9001:15 consistency and standard compliance. Under present guidance from relevant standards, HS Lami-temp may not!

 

Conclusions:

1) The researcher found three types of glass most commonly used in fume hoods: Laminated, tempered, and laminated-tempered.

2) Two types of glass, bullet proof and wired glass, are of minor importance in today’s fume hood market.

3) Fume hoods customarily use laminated or tempered safety glass. Both are typically furnished in either 7/32” or ¼” thicknesses depending on the manufacturer. Both may be tested for compliance using separate criteria in ANSI Z97.1.

4) In distant third place, is the sometimes-specified laminated-tempered safety glass. While such glass has improved performance at high temperature and better impact resistance than laminated glass, it is very complicated to quickly supply or replace and impossible to certify using a standard relevant to fume hood applications. There is an understandably larger cost for the lami-temp manufacturing process which involves factory cutting and piecing together the tempered pieces into the final laminated product.

5) One final point needs to be made regarding fume hood glass standards. The origin of a standard is important when deciding how to apply it to a component of a manufactured product. Department of transportation standards should test products that transport things. The construction industry should use standards related to building products. The fume hood industry, through appropriate groups, should promote or develop glass standards relevant to glass component safety in fume hoods.

As a fume hood manufacturer, FSI must seriously consider glass standards specifically related to fume hoods and their unique safety challenges. This final consummate issue will be developed in a future white paper!


1. “Fume Hood Incident”, MIT 7/2017, https://ehs.mit.edu/site/fume-hood-incident-july-2017

MIT Environment, Health & Safety Office; 265Massachusetts Ave, N52-496Cambridge, MA 02139

2. “Laminated Glass”; https://en.wikipedia.org/wiki/Laminated_glass; 1/21/2019

3. Maryland Glass Doors and Window Repair; http://mdglassdoorsandwindowrepair.com/laminated-glass

4. “Tempered Glass”; https://en.wikipedia.org/wiki/Tempered_glass; 12/5/2018; italicized portion in the text is a direct quotation from this citation.

5. 55 Glass Supply; https://www.55glass.com/temperedglasslosangeles.php;

6. CampbellRhea Lab Shield Fume Hoods; https://www.iciscientific.com/category/labshield;

7. ANSI Z97.1-2015; American National Standard for Safety Glazing Materials Used in Buildings -Safety Performance Specifications and Methods of Test

8. http://www.build.com.au/laminated-glass

9. https://www.onedayglass.com,

10. https://www.youtube.com/watch?v=KvFoNG7pXdk

11. http://security.tssbulletproof.com/bullet-resistant-glass-vs-window-security-film

12. https://en.wikipedia.org/wiki/Safety_glass

13. ANSI/AIHA Z9.5 – 2012, NO REFERENCE REGARDING SAFETY GLASS IN ENTIRE STANDARD.

14. SEFA 1- 2017, p57 section 4.8.1

15. ANSI Z97.1 – 2015, Sections 4 and 5

16. Partial direct quotation from ABSTRACT of ASTM C1048-18

17. https://www.glassonweb.com/article/post-breakage-strength-testing-overhead-laminated-glass-applications

18. ANSI Z97.1-2015, Section C

19. https://ehs.berkeley.edu/lesson-learned-dry-scraping-causes-chemical-explosion

20. http://ravensbyglass.co.uk/wp-content/uploads/2015/04/Ravensby-Glass-Technical-Document.pdf, Ravensby Glass, UK

21. http://glassed.vitroglazings.com/topics/heat-strengthened-vs-tempered-glass

22. http://www.glazette.com/Glass-Knowledge-Bank-79/Annealed-Glass.html

23. Kewaunee, Jamestown, Hamilton, Mott, Flow Science, Labconco specifications all refer to either Laminated or Tempered safety glass for fume hood sashes.


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.



Containment Using a Non-Reactive Atmosphere

Dr. Bob Haugen
Director of Product and Technology Development

Gary Dean
Mechanical Designer

What happens when the air itself becomes a threat to whatever process is being undertaken?

Abstract:

There are frequent cases where the atmosphere we live in every day can become a laboratory hazard. The earth’s atmosphere contains Nitrogen (78%), Oxygen (21%), Argon (1%), and Carbon Dioxide (.04%)1,2.

Any chemist knows a 21% Oxygen atmosphere supports combustion. Our planet has many materials on its surface that are oxidized without remorse by Earth’s atmosphere: iron, copper, and to a much more dramatic extent, carbon-containing compounds including wood, coal, organic solvents, and human flesh.

In thoughtfully designed laboratories, the containment device atmosphere should never cause unintended and un-measured chemical reactions with the procedure under way.

Typically, lab containment devices use air flow to control fumes by “pushing back” vapors away from the device’s access opening. What happens when the air itself becomes a threat to whatever process is being undertaken?

In this paper, the author will detail how a Flow Sciences Nitrogenema (END) device works. Applications will be discussed. Advantages in safety, utility, and product purity will be reviewed. There are many potential uses for such devices; some examples will be discussed. 3

Discussion:

The Nitrogenema© (END product series) is a fanless unit designed for low moisture or low oxygen procedures. It utilizes a nitrogen feed system to replace oxygen and water vapor with an inert, less reactive atmosphere.

This family of enclosures is designed to offer protection of product and personnel from environmental components such as water vapor (humidity) and oxygen, both significant constituents of the air flow typically applied to contain chemical reactions. The standard END enclosure is constructed from static dissipative clear acrylic upper sections and a phenolic resin base. Since such an enclosure eliminates humidity by design, the static dissipation characteristics of the cabinet greatly reduce the likelihood of internal sparks inside this very dry environment.

These enclosures have a connection point for introducing minimally reactive gases, such as nitrogen or argon. Other attributes of this system include a pressure relief valve, a pressure gauge, integrated glove ports, and a pass-through for transferring products and equipment into and out of the enclosure. Optional components include a power outlet located inside the enclosure and a gas flow controller which uses feedback mechanisms to minimize unwanted gases like oxygen and water vapor by continually replacing these gases with dry nitrogen or other gases3. Figure 1 shows the key components of this system:

The nitrogen supply can come from a variety of sources. Flow Sciences can provide a nitrogen flow controller which has programmable logic that regulates the flow of inert gas into the enclosure using either relative humidity (RH) or oxygen concentration as defining parameters for control set points. This controller is shown in figure 2.

A relief valve is designed to bleed out the internal END atmosphere as additional dry gas is added by the controller when required. There is a slight overpressure inside the cavity of about 0.3 to 0.7 inches WC during this cycle. The gas exiting the END is HEPA-filtered before passing into a thimble connection to house exhaust. (While nitrogen is not toxic, exhaust containing large amounts of nitrogen discharged directly into the laboratory air could displace oxygen in the room air and cause issues)

The controller detailed above must perform three functions:

1) When the sensed environment has a widely different oxygen or humidity value from that desired, the inert gas is allowed to flow at maximum rate. This will not cause over-pressurization of the END because the relief valve and filter allows the exhausted gas to leave the END device.

2) When fine adjustment of the environment is needed, a low flow setting allows the inert gas to flow at a lower rate.

3) When the desired environment has been obtained, the flow of the inert gas into the enclosure is stopped until increased oxygen or humidity is again sensed, requiring automatic re-adjustment by more inert gas flow.

This passive replenished-flow system yields a very stable end point over a short time; see figure 3 below:

Additionally, once a control level is reached, an appropriate unreactive gas feed control system will produce a stable low oxygen/water vapor concentration inside the containment cavity. (figure 4)

Flow Sciences has supplied this product to customers with the following needs:

1) Manipulation of pyrophoric compounds which might oxidize or ignite in the presence of atmospheric oxygen.

2) Weighing or manipulation of Hygroscopic substances which can chemically combine with atmospheric water and not even allow precise weighing because of this characteristic. These products include pharmaceutical products which are dispensed into bottles with desiccant packages inside.

3) Dispensing pharmaceutical products into smaller packages with atmospheric integrity

4) Nanotube production and packaging

5) Testing food product packaging in its ability to protect foods susceptible to atmospheric oxygen attack (Wine, cheese, some fruit products)

Flow Sciences has even used these units with modified systems and materials of construction to accommodate special applications as shown below.

  • Different systems for water and oxygen level control.

  • Different Materials of construction and Antechambers for special applications.
    • a) Multi-stage unit with antechamber

    • b) Coved stainless steel and glass for easy cleaning

Conclusion:

The END Nitrogenema is an artificial atmosphere low-flow glove box with a variety of applications. All applications require the removal or suppression of oxygen, water vapor, or both. This is achieved by introducing a minimally reactive gas in quantities large enough to flush out atmospheric water vapor and oxygen.

This approach has been used in a variety of applications, materials of construction, and accessories. Flow sciences has found a rather substantial market for this unit and anticipate its wide application in years to come. Please contact Flow Sciences for more information if you foresee an application in your facility!

This unit comes in many sizes and materials of construction. The END provides ultimate product protection at an affordable cost. We will be happy to discuss your application. Any custom unit you specify will be tested per your application and we will ship it only when it meets customer specification. We do this all the time!


References:

  1. https://en.wikipedia.org/wiki/Atmosphere_of_Earth
  2. Plus several other gases in small quantities: https://en.wikipedia.org/wiki/Atmosphere_of_Earth
  3. Argon and possibly other non-reactive gases have also been used


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.



Flow Sciences Containment

Designing Engineering Controls for High Potency Containment

HPAPI Containment - Flow Sciences

As Potency Increases Across the Industry, the Need for Personnel and/or Product Protection Grows. Flow Sciences is the World Leader in Sophisticated Containment to Meet this Challenge with Engineered Solutions.

Engineering Controls are Necessary to Extract and Remove Toxins to Prevent Inhalation, Dermal, and Other Exposures as well as Cross Contamination of Samples.


CONTAINMENT CHALLENGE: RISK ASSESSMENT

 

Personnel and/or product protection is imperative for the safety of operators and the liability of companies that manufacture and manipulate toxic materials. Arriving at a solution requires careful consideration and expertise. Flow Sciences provides that recommendation based on these factors:

  1. CONTAINMENT – Performance Target is the defined level of acceptable exposure to personnel and/or product from potentially harmful materials during the process.
  2. PROCESS – What you are doing inside and outside of the containment enclosure that requires personnel and/or product protection.
  3. EQUIPMENT – The specific specifications and parameters of the operating machines, instruments, and hardware required to complete the process.
  4. SCOPE – Defining the expectations of all parties involved in the project pertaining to budget, lead time, and complexity of the containment challenge.
  5. FACILITY – The allowances and restrictions in the designated work space required for power, installation, and operation of the containment systems and accessories.
  6. SOLUTION – A recommendation is provided, and the engineering or production process begins.


Our Highest Quality Ensures Your Excellent Results. The Pharma and Biopharma markets continue to grow every year. For these projects, the ability to provide effective and efficient safety protocols continues to be in high demand. Safety and performance are of the utmost importance, as the pharmaceutical manufacturing companies rely on proper engineering controls to develop and produce consistent products and results, while keeping their personnel and/or product safe. At Flow Sciences, we pride ourselves in the ability to engineer solutions that contain applications properly while creating consistent results.

Flow Sciences Containment

Flow Sciences Containment

Flow Sciences has engineered and manufactured products for many applications and equipment needs. As the challenges of containment arrive in the industry, we have adapted and improved our capabilities to meet and exceed the requirements.

Throughout the process, we have learned that the product that is manufactured is the result of a challenge designed specifically for that application. Once the unit is tested and validated, we can use that solution for other clients that have the same application or containment need. This is how Flow Sciences has organically grown and developed thousands of solutions for customers around the world.

Flow Sciences Containment

As the industry grows, Flow Sciences grows with it. New designs and technologies are being engineered every day to deliver the most current controls and effective containment strategies to our customers. This includes expansions in materials of construction like stainless steel, as well as multi-task systems where units are joined together to complete a continuous process.

Strategic partners such as IsoTech Design, are working with us to provide solutions into sterile manufacturing as well, allowing Flow Sciences to deliver complete systems and strategies for labs and facilities in many areas of the industry.

Cultivating strategic relationships with third party industrial hygiene companies as well as other containment solution providers allow Flow Sciences to offer much more than just the system. Services such as factory acceptance testing and site acceptance testing using surrogate powder (naproxen sodium, lactose) give results of actual operators performing applications around equipment. These can be administered or monitored by third party IH in the testing lab at Flow Sciences’ facility in NC or at the customer site. Other services such as IQOQ, cleaning protocols, installation, and more are available as well.

The industry is changing; ingredients becoming more toxic, processes becoming more dangerous, equipment becoming more sophisticated. We recognize that the units and systems being engineered today will help to protect the innovators and innovations of the future. The scope of responsibility we face as a safety community is more important than ever before, and we at Flow Sciences will continue to adapt and progress to provide the best containment systems available.

For more information or questions, please contact us.



CONTACT US FOR MORE INFORMATION


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? 



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:

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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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