Operating Costs in Development Spaces

Development areas may be treated as any other space from an engineering perspective. They need floor space, headroom clearance, people and equipment access, installed equipment, utilities, and an appropriate airflow. Engineers can calculate the airflow needed for general purpose ventilation and provide suitable supply and exhaust equipment fitted with appropriate air filtration. No problem!

The cost of small-scale equipment is as high as that of full scale processing equipment and with little demand in the marketplace. For this reason, small scale and pilot plant batch equipment, while validated, tends to be archaic from a materials containment perspective. Existing work procedures are rarely challenged until provoked by unacceptable emissions data. Maintaining the status quo for quality reasons is accepted – until it’s broke, don’t fix it. Change control is an arduous process fraught with many contradictions and requiring diligence to collect and destroy all but controlled archival copies of each workplace document.

Estimating where airflow dead spots exist is another matter entirely. Accepted airborne measuring methods for evaluating room conditions still depend on the stability of airflow across a workspace, e.g. particulate counting assuming a homogenous room environment. Add to this the complexity of most prototype processing requirements in terms of portable equipment, charging, milling, granulation, sampling, and process equipment obstructions. These factors along with the congestion typical in small localized pilot plant suites, plus the need for multiple people access beyond normal full scale processing conditions, results in processing conditions rife for cross-contamination potential caused by fugitive contaminant release and dispersion.

Many problems have emerged due to cleanup difficulties between lots and products in both development and scale-up. Surprises are often encountered when cleaning down a processing suite due to a legacy of residue hot spots that are only disturbed intermittently. These incidences used to go unnoticed until airborne monitoring for highly potent compounds was adopted as a necessity. When identified, these can often be tracked down by identifying the non-homogeneous microclimate environments existing within the processing suites. Microclimates are not reproducible across either a single process or a campaign. The problem lies in the fact that airborne particulate dispersion does not follow airflow expectations. Depending on size they can be treated using conventional Reynolds Number calculations. However, fugitive releases comprising sub-micron particulates can be visually seen to move counter to airflow currents when using techniques more common to laboratory based clinical trial studies with vertebrates. This is because the particles exist as a stable air suspension (colloid) subject to disturbances influenced by static charges on the particulates (Zeta Potential). This same charge contributes to our failure to collect particles of ˂0.2µm diameter on conventional sampling media.

There are simple, yet uncommon, techniques to evaluate the overall airflow patterns and potential particulate deposition pathways. The tools are not in the conventional toolbox of either engineering or health and safety professionals. Sadly they rely on pre-digital tools, which have yet to be replicated in our modern age. Using either a Betacam or VHS Camcorder of early design (with an opticon tube), advantage can be taken of the enhanced sensitivity to UV and visible light as well as image persistence of the sensor. By using a Cathode Ray Tube (CRT) video display for playback, advantage can be taken of the persistence of image on the screen, i.e. with a low refresh rate as compared with the latest freezing action of High Definition Screens at >240 Hz frame rate. A low output theatrical fog generator (or even a smoke tube) is used as a source. A statically charged fog of <0.5µm diameter represents the airflow pattern. Combining the two devices allows us to record an event with enhanced visual acuity to track the particulate flow profile. Using fast forward video replay enhances the profile even more (image tearing may occur depending on the playback machine characteristics, but not the image tearing observed with non-CRT devices).

In testing a mercury micro-droplet settling pattern, it proved possible to accurately predict deposition hotspots at distances >10 times that observed by conventional observations. Areas of mercury deposit pooling due to airflow dead spots matched the fog profile observed using this technique. Both turbulent and stagnant flow patterns were clearly visible. Similar measurements enabled tracking of potent compound deposition profiles in pilot plant and full-scale operations, with and without people flow. Caution: since the equipment may be used in a hot work area, building supervisor approval will be needed.

Add to this the use of a simple bubble generator used at ground level to simulate particulate entrainment and dispersal by the local airflow and you gain a broader knowledge of the procedural changes that may need to be introduced such as:

process line make-and-break connection – plugged lines, skillets, etc.

impact of in-process maintenance – hardware and sensors

modification of sampling procedures

overpack of equipment not currently in use or being transported

overpack of materials leaving the suite, including final products &/or intermediates

selection/use/removal/decontamination/disposal of Personal Protective Equipment (PPE)

people and equipment flow

focused cleaning protocols

localized equipment enclosures

The same techniques are also valuable when studying airflow profiles in large spaces such as potent compound and sensitizer drum handling, forklift movements, warehousing facilities, etc.

Knowing that fluorescent light is used to test cleaning, one client decided to use it to perform a walkthrough of a development suite. With no knowledge of the fluorescent characteristics of materials that had been handled in the suite over the previous 12 years, specific deposits on room surfaces were easily detected. During a cursory walk-through, three repeated, and multiple discrete, residue hotspots were observed with materials displaying blue, purple, yellow, green, and a vivid orange characteristic appearance. Stainless steel finishes were the main culprit but many other surfaces showed deposits. The traditional cleaning method had been water wash-downs using a pressure wash. That these materials had obviously accumulated over at least 12 years of operation was a startling discovery. No attempt was made to visit the central clean equipment storage area.

A pharmaceutical company performed multiple studies using such airflow profiling methods. They recognized the need for localized containment throughout their early stage small scale and pilot plant suites. Traditional methods using exhaust hood and snorkel configurations were not providing the containment levels needed for their potent compound work.

FabOhio Inc was introduced into their program early and after two years the typical pilot operation had two rigid containments (glove boxes) and >20 secondary flexible containment enclosures. The joint program was successful in changing their 2-year history of pilot plant working cycle:

supplied air PPE while performing pressure wash-down cleaning

<2 days of processing until a materials release occurrence

7 – 20 days of cleanup until clearance for normal PPE operations

resumption of operations until the next observed release event

final suites clean-downs of >4 weeks until equipment removal permitted

to one of semi-continuous processing in a shirtsleeve environment for an entire 9-month scale-up campaign and manufacture of clinical trials and launch materials.

Headspace monitoring of the wash water sump showed continuously decreasing levels of potent compounds after the secondary containment program was introduced. Levels before the containment project began were thousands of times above the companies established worker permissible exposure guideline (PEG). Within 3 years of contained processing the headspace concentrations had diminished to ~50 times the PEG. The improvement was primarily due to the absence of contaminant on processing suite surfaces. The latter measurements were a worse case than the first because the wash volume required was much lower. Reduced cleaning efforts (less releases) created less cleaning waste to be stored, transported, and treated.

The key to this operational state was:

All materials transfers were contained using a flexible barrier designed to enclose the release point – both intentional and known fugitive release points, plus unanticipated fugitive release points once identified.

Localized containment for every event as it occurred – including in-process equipment and in-line sensor calibration or replacement.

The suite was also provided with storage of replacement flexible containments and sleeves with HEPA filters for enclosing piping flanges, valves, and moving parts such as drive shafts and lifters.

These experiences were shared with other companies. Within three months, a major R&D based pharmaceutical company had designed flexible containment solutions for every feasible equipment enclosure, make-and-break connection, and materials pathway, for all equipment in their pilot plant.

Reordering replacement flexible containments was a simple matter of citing the companies design number as provided to the vendor. Fabrication and shipment occurred within days of ordering.

The most effective extent of permanent containment and direct airflow control is in appropriate operation of entry and exit isolation portals typical of clean room design. For immediate needs, temporary portals can be designed, fabricated, and delivered, using flexible containment concepts until more rigid footprint enclosures can be installed.

Downflow booth performance can be improved by placing a barrier film with several glovesleeves between the product containers and the worker, but remains both procedure and by-pass airflow dependent.

Rigid containment has a definite place in the development facility. Dispensing and formulations are performed successfully in rigid gloveboxes. With newer drive systems it is possible to fully enclose milling and sieving equipment. Frequent opening of equipment for sampling, e.g. granulators, microwave driers, ribbon blenders, reactors, etc. is still a challenge. Maintenance is an area not typically addressed by rigid containment; in fact it may present major barriers to in-process maintenance and equipment change out.

There are unmistakable challenges to using rigid containment for a fast track development project:

1. Availability and Cost

Unless a site has existing rigid containment spares in stock, it takes several months to acquire a new piece of rigid containment. There is little in the way of off-the-shelf equipment. Most rigid enclosures are built for a specific application. With a performance scope in hand, typical delivery times run from a minimum of three month to a more normal nine month delivery on site. Costs can run from ~$50,000 into the hundred of thousands for a simple containment solution. Lead times for a new design scope can be significantly reduced using flexible containment mock-ups to test the operational needs and gain operator support.

2. Cleaning

With one notable exception, most rigid containment vendors do not finished internal surfaces for effective cleaning. Cleaning waste volumes are in the multiple gallon range of waste liquids contaminated with compounds of interest.

Our previous Technical Bulletin (#10 Operating Costs – Installed, Rigid, and Flexible, Containments in the Laboratory) discussed some of these issues. Cleaning places demands on the waste-handling infrastructure. The question arises: how many workers and operations in other departments are affected by the processing of potent or sensitizing materials within the development suite footprint – how many need to be trained across a site, how much PPE and usage training is required, how are materials moved and shared outside the facility, etc.?

Waste materials are minimized because clean down is eliminated for most flexible enclosures. Large volumes of in-process liquid wastes can be discharged through an attached drainage pipe to a portable receiver. Solid wastes are safely bagged out. Once recoverable materials are unloaded, purging the enclosed air through the HEPA filters allows the enclosure to be collapsed. The collapsed enclosure can be folded and rolled-up and disposed of as a solid waste of small volume.

In addition to adaptability of flexible containment to multiple needs, the most notable gains are minimizing the number of workers affected and reduction of waste disposal costs – reduced suite cleaning demands, contained waste instead of dispersion, simple waste manifests, eliminating tracking of contaminants, i.e. site protection.

In most cases, the use of disposable containment, i.e. flexible containment, is a desirable benefit from both the convenience factor and overall cost savings.

Flexible containment, especially prototype models can be delivered within 3 weeks. Volume production can be delivered within 4 – 6 weeks depending on design complexity. Design is limited by materials of construction such as extended contact with hot surfaces, e.g. above >160°F, and with some solvents. – specifically some lower molecular weight, highly volatile solvents typified by methylene chloride analogs. Even these conditions have solutions, which can be easily adopted.

Flexible containment costs are conservative and purchases are frequently made using a credit card. Cumulative costs are typically lower than single entry use of PPE. Purchase orders are frequently used for large or extended orders. Many topics such as short-term use of flexible containment barriers including in-process modifications and feasibility have been addressed in our Technical Bulletins.

FabOhio Inc. can assist in design and rapid execution of containment enclosures, both rigid and flexible, for your development facilities. We have a large design database of existing applications, which have been tested in use with much of the processing equipment manufactured over the past thirty years.

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