Quality Demands – Using Flexible Containment Can Resolve Quality Concerns

During involvement of FabOhio Inc. with the Pharmaceutical Industry since 1993 we have come to recognize the importance of input from Quality Organizations at both the site and corporate levels. We also recognize the indirect, but pronounced, impact that other activities conducted by site services such as Maintenance, Sensor and Instrument Calibration, Warehousing and Dispensing Operations, and Waste Management can have on Quality issues. This document encompasses several of these areas of impact.

While firmly established in containment practices in nuclear and general industry (since 1963), FabOhio Inc. was not originally positioned to address the evolving needs of the Pharmaceutical Industry. We broke through the frontier into the Pharmaceutical Industry in partnership with a site Operator and an Industrial Hygiene Chemist. At that time we had little appreciation of the potential growth within the industry. By providing well-conceived solutions to the handling issues surrounding potent compounds, and diligent documentation of performance at every step of the way, all involved parties at the user site were encouraged to view the technology as a useful and cost effective adjunct. In this way we gained recognition for the technology as a fast response alternative to the traditional approaches of rigid or airflow containment solutions.

More than most, we realize from the onset of every project that the solution must address Health and Safety demands – the initial reason for our involvement, but also show benefits to the Quality and Engineering arms of a company. Buy-in from the Quality Organization can facilitate approval of new remedial solutions.

FabOhio Inc. has long been the leader in collecting statistically valid performance data under a variety of operating conditions using placebo and Active Pharmaceutical Ingredients (API’s) of differing particle sizes and airborne characteristics. Outside the nuclear industry, FabOhio, Inc. was the sole developer of performance methodology and data records in the early years (1993 – 1997) in partnership with a pharmaceutical client. By adopting statistically robust data collection and interpretation gleaned from the years of Health Physics monitoring in the nuclear industry, and the more recent clearance monitoring strategies promulgated in the EPA’s Asbestos Hazard Emergency Response Act (AHERA), we assisted our clients in establishing repeatable and valid sampling protocols.

We recently provided technical advice and statistically valid sampling strategies in support of a site regulatory challenge. The use of a shared function facility, using flexible containment for dispensation of potent compounds, was at issue. By responding to the Agency challenge in this manner they were able to gain their Agency Inspectors acceptance. 

It is based on our leading efforts that the flexible containment industry has grown. The industry pioneers in the US, UK and Ireland relied solely on the credibility established through our performance. For several years, the newly created Irish and UK vendors relied on our financial and technical support as well as our rapid response to orders for product shipment until they became capable of establishing independence. Even the growth of pioneers in the US relied on the substantial efforts expended by FabOhio Inc. Without our effort to convince Engineers, Occupational Health Professionals, Quality Control Representatives, Project Managers, and the many Site Service Providers with substantive data, e.g. performance capabilities, cost advantages, waste minimization, short turnaround time, and the many other benefits, it is unlikely that flexible containment as an industry would have flourished until third party contract manufacturing grew to the extent that it has today. For third party manufacturing, the initial attribute is cost, however our ability to support production outcomes rapidly becomes an essential part of their business model.

Where not protected by a company’s confidentiality requirements, we share data and methodologies with our clients. Our representatives are active in working groups tasked with creating useful measurement strategies. Our latest input to a peer working group on containment leak-testing is due to be published shortly.

To benefit from such solutions requires us to view Flexible Containment as a completely different technology from both Rigid and Airflow controlled containment approaches which have been the traditional fallback. When this viewpoint is addressed it opens up an entirely new concept with benefits such as:

1. More than just for potent and sensitizing compound handling
2. Freedom from Personal Protective Equipment (PPE)
3. Enclosed environment
4. Environmental conditioning of small enclosed spaces
5. Mobile enclosed solutions
6. Site wide applicability
7. No connected utilities – except under special circumstances
8. Savings on utilities
9. Minimal space requirements
10. No cleaning requirements or cleaning validation efforts
11. Control of processing Suite Environment, waste minimization, and cost reduction
12. Eliminates need for pressure zones for controlling access
13. Clean workspace
14. Reduced operator training
15. Reduced requirements for operator qualification
16. Dedicated enclosed spaces – no entrance portals for operators
17. No special pass-through portals for containment devices
18. Facilitates operator shared usage of contained space
19. Shared enclosure can move to different locations
20. Handling and storage footprint is small – both horizontal and vertical
21. Flexibility allows for unusual siting and appropriate collapse of structure
22. A safe enclosed shipping and transport container
23. Capable of withstanding change in environment conditions when Material Of Construction (MOC) is carefully selected.
24. Elimination of environmental waste hook-ups means no backwash
25. Maintains integrity of environmental legacy
26. Already recognized as a viable technology by Regulatory Agencies
27. Small footprint leads to reduced performance validation effort
28. Ability to adapt easily to performance validation methodology expectations
29. Adoption of a unified site-wide training approach
30. Containment efficacy as low as <0.04 ng/m3 (Containment Factor of >2 X 10¹¹)
31. Frequently the most cost-effective solution
32. Materials Of Construction limitations
33. Sealed sterile conditioned enclosures can be provided
34. Particulate free environment
35. Waste minimization

While some of these issues do not appear to be the province of a Quality Organization, there is often a backlash affecting operational performance whenever another department adopts a new strategy. One of these having most indirect impact is the Environmental Controls facility within a site. In order to accomplish their environmental goals they may have recourse to influencing building operations. Many of their areas of impact are covered within this review. 

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Many of these bullet items deserve more explanation:

1. More than just for potent and sensitizing compound handling:
   
   Cross-contamination issues are always a foremost consideration for a Quality organization. Every materials handling step has to be considered a potential threat. Minimizing the need for handling along with effectively containing handling procedures can be accomplished using the mobile attributes of a flexible enclosure on either a supporting surface, a wheeled cart or a pallet lifter. The advantages apply to any materials – potent compounds, sensitizers, biologically active materials, process intermediates, inert dusts, nanoparticles – regardless of particle size, and test equipment The passive behavior of enclosure vent filters results in them performing effectively as diffusional barriers (>98% efficiency for particles both >0.2 and <0.2μm diameter), superior to the normal lower limit of HEPA filter performance under forced ventilation flow (typically >95% breakthrough for particles of <0.2μm diameter). Their performance as bi-directional diffusional barriers allows for effective containment of even the smallest of colloidal size materials regardless of their static charge.
   
2. Freedom from Personal Protective Equipment:
   
   Once steps are taken to ensure that all process handling of materials occurs within the confines of the equipment hardware and the flexible containment, the external surfaces are contaminant free. Regardless of the PPE requirements within the processing rooms, operators outside the containment zone are free to handle a flexible containment system without PPE. Further PPE is not required until the materials are transferred into a suitable materials handling zone. The cost savings on PPE and associated training, maintenance, inventory, and lost time in restocking a work area becomes substantial over a year.
   
3. Enclosed environment:
   
   The small volume within a flexible containment is isolated from the work area. Major cleaning of the work area is not required as long as all materials transfer connection integrity is maintained and the hardware is in a leak-free condition. This may mean placing localized, small, enclosures around piping flanges, valves and actuators, seal points, etc. This has often been planned during design of a potent compound handling suite with excellent results. One facility was maintained in a contaminant-free condition in areas where contamination is normally an operational expectation based on prior equipment maintenance records. This performance was based on data generated as part of a 24 hour continuous monitoring program over a 6 year period. While some areas of open handling were still at risk, the overall health of the building was maintained at the detection limit (<0.02μgcu.m) – 10 times lower than the company’s Operator Workplace Exposure Guideline (WEG).
   
4. Environmental conditioning of small enclosed spaces:
   
   The small volume of the enclosed space allows for rapid achievement of any special environmental requirements such as humidity, oxygen exclusion, and solvent purging, e.g. inert atmospheres for handling highly static or flammable materials. Purge times are minimized allowing the practitioner more rapid access to the process in hand. Additionally the utilities requirements to maintain such conditions are of proportionally lower demand than for a larger space.
   
5. Mobile enclosed solutions:
   
   Once conditioned for transport, the atmosphere within the enclosed space is isolated from the external environment by sealing the vent filters and the utilities access pass-through. The only limitation is due to the permeability of the MOC of the enclosure. Rapid redeployment of an enclosure and immediate restoration of conditions at the new location can mitigate this. Due to the small enclosure volume, stable conditions can be re-established rapidly. Timing becomes the critical factor for maintaining low oxygen and moisture levels.
   
6. Site wide applicability:
   
   Flexibility of design and the MOC allows an optimum shape for the enclosure of merit when dealing with poor access such as limited headroom or inconvenient placement of sample points. Any handling area can benefit from the technology, e.g. warehouses and piecing operations receiving raw and intermediate materials in bulk by enclosing both the piecing process, and transport to user locations. Laboratories gain from the same benefits when either materials or contaminated equipment needs to be transported among different laboratories through public spaces, i.e. hallways. The ability to adjust the shape of the enclosure when in use is a major attribute. This allows for the shape at the handling location to be reduced for storage – for which laboratories are normally stressed. The only requirement is a rigid support for the containment floor. Enclosures relying on inflation of the built-in framework are the easiest to maneuver. More rigid support systems can be substituted when volume reduction is a requirement. Restoration to size is simply the reverse , but usually more rapid.
   
   The speed with which a prototype design can be delivered to clients for testing under stress conditions allows for rapid turnaround of a workable production item – typically within <6 weeks from conceptual to final design.
   
7. No connected utilities – except under special circumstances:
   
   Unless environmental conditioning is required, no utilities hook-ups are needed. No blowers, lighting, etc. In Europe, enclosures require grounding during handling and transport. This is accomplished by designing grounding tabs into the heat seal of the enclosure.
   
8. Savings on utilities – discussed in item 7.
   
9. Minimal space requirements – discussed in items 3, 4, 5, and 6.
   
10. No cleaning requirements or cleaning validation efforts:
    
    The most effective use of flexible enclosures is dedication to a single entity. The economics of cleaning and validation are such that use as a disposable item is the most cost effective approach. Validation costs including methods development approach ~$40,000 for each new molecule. Materials and invested cost of design, prototype testing and final cost for each disposable containment are typically ~$1,000 per item. The cost burden is demonstrably reduced. Sustained laboratory support is mitigated and cleaning time is short even using conventional wet wipe down procedures (~ ½ – 1 hour). A newly introduced method developed by FabOhio, Inc. further reduces that time to minutes.
    
11. Processing Suite Environment, waste minimization, and cost reduction:
    
    Containing materials within the confined space of a flexible enclosure will achieve significant waste minimization:
    1. No room surfaces to wash-down – no liquid waste stream
    2. No PPE needed – reduces lost time, training, and cost
    3. No cleaning procedure deterioration
    4. No particulate dispersion
    5. Simplifies materials accountability/yield evaluation since all fugitive releases from the handling process are captured within the enclosure envelope
    6. Simplified tracking of waste to final disposition – no environmental legacy
    7. Normal waste manifest records keeping
    Once an enclosure is in a condition free from release of friable materials, collapse of the enclosure is achieved by removing the support frame, or deflation of the inflated frame, allowing the enclosed atmosphere to vent though the diffusional barriers. Once collapsed it can be rolled up and placed in a waste drum for shipment to an approved destruction site, i.e. an incinerator. In this way the contaminants are contained throughout shipping and destruction, leaving no environmental legacy.
    
12. Eliminates need for pressure zones for controlling access:
    
    Since materials handling is contained within the flexible enclosure or the hardware there is little risk of release to either the processing area or the surrounding environment. Based on testing in a dispensing warehouse area, the environment within the dispensing room and the outer shared spaces can be maintained below the limit of detection for a potent compound of <0.04ng/m³ (with a statistical significance of >95% Coefficient of Variation) with daily usage.
    
13. Clean workspace:
    
    With no release of contaminant, work areas remain contaminant free. No changes are needed to normal cleaning practices when contained materials handling is practiced. No special handling of waste materials.
    
14. Reduced operator training:
    
    Training in use of flexible containment is a simple and readily repeatable process. A standard training module can be developed and kept in an active file for Agency review along with training records.
    
15. Reduced requirements for operator qualification:
    
    Much time and cost is involved in qualifying an operator in the work practices for entering a conditioned work zone. Enclosed materials handling using flexible containment reduces this burden by preventing contact with a material. Additional value arises from qualification of operators who are unable to achieve clean room status.
    
16. Dedicated enclosed spaces:
    
    The strategy of dedicating an enclosure for single material handling as a standard practice is discussed in item 10.
    
17. No entrance portals for operators:
    
    Operators access the enclosure through a sealed glove sleeve. The operator never contacts the enclosed materials. While not a recommended practice, materials handling within an enclosure could be performed safely in a public access area. Since operators are not able to share contact with the enclosed materials, it is not necessary to provide restrictive access portals unless as a standard Quality Requirement for an area.
    
18. No special pass-through portals for containment devices:
    
    The exterior of an enclosure remains free from contaminant. This allows for transport through any pathway, given that the size of the transport method does not present limitations.
    
19. Facilitates operator shared usage of space:
    
    When using enclosures, nearby workers and processes are not at risk from contained materials migration. This has merit in shared spaces such as laboratories. Nearby workers can focus on their own projects devoid from concerns about extraneous materials migration. The same attribute also applies when enclosures are transported within and outside a facility.
    
20. Shared enclosure can move to different locations – discussed in 19.
    
21. Handling and storage footprint is small – both horizontal and vertical:
    
    The minimal enclosed space of a workable enclosure results in a small footprint. This merits attention when siting work. The light weight of an enclosure means that it can be hand carried when containing small amounts of material or equipment. The use of a small mobile cart is commonly used, e.g. an instrument technician can wheel instruments for calibration purposes from processing areas to shop areas as long as he follows departmental requirements for access. Larger enclosures with metal support frames can be transported within a facility and onto trucks using a pallet lifter.
    
22. Flexibility allows for unusual siting and appropriate collapse of structure – discussed in item 6.
    
23. A safe enclosed shipping and transport container:
    
    Appropriate selection of MOC allows for robust construction of an enclosure. Handling during transport requires a material which can be subjected to changes in environmental conditions, abrasion, pinching, and the many hazards encountered during handling. The ability to flex without loss of integrity is of paramount importance. External robust enclosures can be used, e.g. a shipping overpack sack for large and heavy loads. Such attention becomes of extreme importance when required by shipping codes.
    
24. Capable of withstanding significant environmental conditions when MOC is carefully selected:
    
    A primary consideration when planning for the use of a flexible enclosure. Alluded to in many of the preceding items.
    
25. Elimination of environmental waste hook-ups means no backwash:
    
    Eliminating cleaning means no drain connections. No connection – no back-flow.
    
26. Maintains integrity of environmental legacy:
    
    Spills can have a major impact on a site. Clean-up and remediation costs, i.e. owners of hazardous waste sites (either now or in the future) has devastating impact, both financially and on a company’s reputation. Also discussed from the viewpoint of disposal legacy and cross contamination control capability in items 11 and 12.
    
27. Already recognized as a viable technology by Regulatory Agencies:
    
    Flexible enclosures have been in increasing use since FabOhio, Inc. and their partners established their efficacy. Regulatory agencies have become accustomed to accepting them as a short-term solution for containing materials. Long-term use is best justified with performance data. Standardized performance testing for facilities is evolving. The sample data needs for Health and Safety purposes differ markedly from the need to show engineering performance capability to an Agency representative. FabOhio, Inc. has been an active participant in pursuing and demonstrating appropriates practices to satisfy Regulatory Agencies. In this manner the EMA was presented with statistically robust performance data to establish use of a shared dispensing facility for potent and endocrine entities as a long-term practice.
    
    Companies rarely publish their practices or findings. FabOhio, Inc. stands ready to share our expertise with any of our users.
    
28. Small footprint leads to reduced validation effort:
    
    The small footprint occupied by flexible containment lead to a reduced effort for performance evaluations.
    
29. Ability to adapt easily to performance validation methodology expectations:
    
    The volume of data developed within companies is increasing. Sporadic release of data at professional forums on special topics does occur. In the absence of published data and methodology it has fallen to vendors to fill the gap with their in-house experience.
    
30. Adoption of a unified site-wide training approach:
    
    Work practices for the use of flexible containment become a common entity. Whoever is required to use a flexible enclosure can be trained with minimal effort within <30 minutes, including hands-on demonstration of capability. It does not involve rocket science – no automation for actuating valves, timers, etc. This makes it a simple matter to create common training document and training records.
    
31. Containment efficacy as low as <0.04ng/m3 (Containment Factor of 2 X 10¹¹):
    
    Item 12 discloses the protocol resulting in this data. The interpretation as a Containment Factor (CF) can also be considered a measure of Barrier Efficiency. It is based on an evaluation of common operations that would give rise to a challenge release of 1 Kg of airborne dust within the containment. The concentrations of challenge materials are sampled in a formalized random manner around the enclosure during simulated or normal operation. This value, divided into the 1 Kg challenge concentration, results in the CF value. The strategy used for setting up a statistically robust study and for evaluating the data will be covered in a forthcoming Leak Testing Guideline.
    
32. Frequently the most cost-effective solution:
    
    After due consideration to the items discussed above it frequently becomes obvious that where a flexible enclosure can be adopted, the accumulated cost savings and convenience for this approach are significant. The low costs involved with design and purchase allows potential users to by-pass creation of a purchase order by using a company credit card.
    
    The speed with which a functional enclosure can be designed, approved, fabricated, shipped, performance tested, modified, and delivered as a production tool is a matter of weeks. This allows a user to evaluate the merits without major delay or budget impact when involved in both fast track and long-term projects.
    
33. Sealed sterile conditioned enclosures can be provided:
    
    Fabrication tested flexible enclosures are easily sealed and placed in multiple sealed overpack layers prior to radiation conditioning. The conditioned package can be shipped to the user for storage until needed. Dosage coupons remain visible on the exterior of the package. The multiple layers of conditioned overpack are progressively removed as the enclosure is introduced to the sterile work zone.
    
    Efficacy studies for the e-Beam conditioning were performed by a Nationally certified independent service and resulted in a zero count for a standard battery of test organisms. The test revealed a control factor of over 1,000,000.
    
34. Materials Of Construction limitations:
    
    MOC can become a tiebreaker when dealing with product contact issues. Regulatory agencies frequently issue guidance documents identifying acceptable materials for the film itself or additives used to modify behavior such as conductivity. They rarely address the mechanical strength of a film which is a critical issue when dealing with large amounts of material.
    
    Contact with material is subject only to site and national safety standards which target physical characteristics. This applies to transient contact where materials pass through a film, and enclosures where contacted materials become waste.
    
    Reliance on vendor guarantees and Agency criteria regarding film choice is foolhardy. This merit of this information is for guidance only. A film certified to meet all of an Agencies criteria for prolonged product contact, i.e. packaging and storage, does not assure its acceptability for your material. The only meaningful data is that developed by the user during accelerated and long-term storage tests with the material.
    
    A client encountered this situation during fast track development of a new drug. The drug was eventually released under patent with a delay of over 9 months while a new film material was tested and the New Drug Application (NDA) modified. In the urge for speed to market, development performed accelerated storage testing using a new film formulation claimed to have superior properties over the standard approach of Linear Low Density Polyethylene (LLDPE) – traditionally recognized as a reference material by the FDA. Subsequent testing showed that the film did meet the latest EMA criteria for incendivity and solvent contact (ca. 1995). The film was selected to advance the development of a radically new packaging and charging system.
    
    The problem arose because the stability testing was conducted using laboratory-retained samples from previous small-scale manufacturing (~20 liter reaction vessel and vacuum drying oven scale). Samples of material taken from the commercial dryer during pilot plant scale-up showed it to meet criteria, in this case purged free from solvent. In reality there was still a ppm trace of residual solvent.
    
    When packaged product was opened for sampling two months later the qualified ‘superior’ film had eroded and free material was in the outer liner. The material is both air and light sensitive. When packaged, extreme care had been taken to ensure that the clear white product was packaged in an inert-gas purged condition within a flexible film package heat-sealed inside a foil overpack. The material was now blue revealing gross deterioration.
    
    The client suffered:
    1. Increased development costs
    2. Radically changed scheduling of pilot plant production
    3. Delays in completion of phase 3 clinical trials
    4. Lost over 9 month of valuable patent protected life and market value
    5. Lost over 30 Kg of product with a use value in the $millions
       
35. Particulate free environment:
    
    The very process of blowing flexible film stock requires inflation of a large bubble of annealing film drawn from a heated reservoir. The volume and flow rate of air used precludes the use of sterile filtered air. All further handling of blown film is subject to this restraint.
    
    At FabOhio, Inc. fabrication is performed under clean conditions, but the film extrusion challenge remains. There is still potential for particulate deposited during the blowing process to remain on the interior surface of the enclosure.
    
    For clients requesting a particle free enclosure, our fabricated products are leak tested and then rigorously cleaned using commercial alcohol wipes before sealing in their overpack ready for radiation conditioning or shipment. Client quality representatives have reviewed and accepted all of our manufacturing and shipping practices during their regular audits.
    
    Once placed within a support structure ready for use the enclosed volume within the containment can be economically inflated, purged and vented with minimal utility clean purge-gas requirements.

Useful tools in assessing potential solutions using any form of materials containment are:

Review of the key findings of a comprehensive Process Hazard Review covering receipt of raw materials through final disposition of all wastes as the processing affects the plant site legacy and the impact on local communities.

Review of the conclusions of a Risk-MaPP assessment of a process.

These documents provide a comprehensive listing of potential problem areas in need of improvement or termination. The former is a regulatory compliance requirement and the latter is becoming a regulatory agency expectation, especially for third-party manufacturers. Both rely on in-house expertise to complete the documents. Cost benefits of performing a combined review for both purposes become obvious when realizing that the same analytical mind set regarding the process operations is explored in detail for both end results. Whether performed as a joint analysis or as separate events, both analyses can be used as a business tool for future priority and budget planning.

Many project planning efforts lead to cost reductions within a building. Unfortunately what is not completed within the building often falls on the site services groups. Since site services are rarely involved in the planning stage, they frequently find that they are under-budgeted for the new responsibilities they are expected to assume. The role of flexible containment solutions planned up front can become a significant factor in reducing the cost impact to all concerned parties.

Research and Development and Quality Laboratories, Pilot Plant Scale-Up, Final Production Buildings, and Site Services including Dispensing, Warehousing, and Environmental Management, can all benefit from the performance capabilities and mobile attributes of flexible containment solutions.

FabOhio Inc. remains the leading base of expertise in the area of conceptual design, implementation, and documentation. We deal with the various company cultures in many countries. Our archives are well stocked with functional and tested solutions to which we refer before creating a new design. In this way we minimize design cost to our clients.