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Focus on containment


As a change from the norm, this issue of

focus is given over to a single topic.

The protection of operators and the environment has always been a priority for the pharmaceutical industry. The production of active materials in smaller quantities with much higher potency is driving an increasing number of manufacturers of bulk drug substances and final dosage forms to examine their containment options. The increasingly risk-based regulatory framework and developments in containment technology are driving changes to the design and operation of containment devices. At Foster Wheeler we have gained considerable cutting-edge, practical experience in devising and supplying containment solutions, to the point where we have been selected as global containment consultants by one of our key multinational customers. As part of our ongoing quality improvement program we recently held an information exchange forum on containment to which we invited a number of clients, to share our joint experiences based on real-life case studies and a wide range of projects. The contents of this focus issue are based on that event, an idea that the participants actively encouraged us to repeat in other technical areas. Clive Mullins Global business director

Published by Foster Wheeler Shinfield Park Reading Berkshire RG2 9FW UK Managing Editors Carolyn Greenhalgh Director, Corporate Communications & Global Marketing T 0118 913 2494 E Jacqueline Hogarty Marketing Consultant T 0118 913 2167 E Produced by FW Graphics Group Foster Wheeler

The Containment Forum held in Milano was a very valuable experience. Bringing together industry expertise from both engineering and operating companies in an informal setting to share non-proprietary knowledge and experiences allowed for open discussion and debate as to good engineering practices relative to containment system design. I believe all involved gained some knowledge which will be applied to the improvement of future installations. Paul Richards Project & technology engineer Pfizer Global Research and Development

setting the scene


What is

Recent changes
Pharmaceutical companies tend to specialise in certain therapeutic areas, and the activity of their compounds reflects that. We see the need to handle increasingly active compounds. We also see new guidance, for example for cytotoxics, and the need to transfer techniques from other industries such as the nuclear industry. The pharmaceutical industry is now prepared to learn to SWIPE, (Steal With Integrity and PridE) from other industries. Huw Thomas describes what others are doing in dose form manufacture, page 10. David Ainsworth covers the need to treat the commissioning and qualification of facilities for nanogram containment differently on page 11. We are also seeing production of smaller quantities of materials, partly due to their activity, and partly due to demand. This is changing the associated method of containment and is addressed in Nanocontainment and Small Scale Manufacture by Marco Mascarenhas on page 3. We are seeing an increase in the need to contain not only powders but also aerosols potentially generated in liquid filling. Germana Molinari gives a review of fill-finish design on page 7, and David Ainsworth looks at a case study at a Janssen highly potent powder handling unit (Facility of the Year Finalist 2006) on page 8. Other changes involve increasing use of new solutions such as flexible plastic, and increased use of gloveboxes. Huw Thomas, page 6, and Emilio Moia, page 4, address these two areas respectively. The use of risk assessments in many areas of life has become an everyday subject. In the pharmaceutical industry they are embodied in much guidance, now reinforced by ICH Q9. Their use in containment occurs both at macro and micro levels and John Nichols discusses this in an article on hierarchy and risk-based approaches on page 2.

If an overall manufacturing facility consists of three components pharmaceutical material, personnel, and the environment surrounding them containment is the isolation of the first of these components from the other two. ISPE
Why is containment important?

When considering containment there are multiple drivers. The mix of critical factors will change application-by-application, and the solutions will vary accordingly. This leads to a very complex subject and Paul Richards of Pfizer addresses this range of solutions on page 9. Typically, drivers will include operational hygiene for operator protection, plant safety, product quality, reduced environmental impact, and operational improvement. The operational health impacts on the operator can be very serious. The use of personal protective equipment has been shown to be poorly effective in practice and its use for routine operations has been discouraged by regulation. All of this drives us to ensure better protection for the operator. Pam Davison, in describing GSKs forward strategy, addresses this area on page 5. Safety is, of course, dominant, for example in handling materials in an inert environment. The prime interest of the pharmaceutical product regulators is patient safety, via the quality of the medicinal product, and containment has to prevent contamination or cross-contamination of this product. As well as the internal plant environment we are interested in preventing material escaping to the external environment. For some compounds, operator health may not be an issue but potentially there could be significant external environmental impact.



John Nichols Global technology director

Successful containment requires an holistic approach: development of the correct strategy, selection of containment elements by their capability for typical operations and a risk assessment technique for ranking the exposure potential.
An holistic approach

The containment chapter of the draft ISPE BPC Baseline Guide, to be issued in 2007, recommends a similar holistic approach to that adopted for HSE, following the steps below in sequential order to alleviate an exposure potential wherever possible:

ISPE Baseline Approach: Hierarchy of Containment

Modify process to remove hazard Sealed equipment and connections Localized containment devices Contain in the facility Use of procedures

HSE Approach
Eliminate Reduce Isolate Contain PPE/Discipline

Selection of containment elements

Values for the containment obtainable under typical operating conditions for an average material with good operating practice (as illustrated on the enclosed reference card) can be used as guidance for potential protection. However, all factors should be taken into account in selecting equipment for a specific application. There is potential for improving the performance of standard equipment by adding additional layers of protection, such as illustrated on the card by a downflow booth with several typical upgrades.

Risk assessment

Risk assessment using a variety of tools is a widely-used technique. With the issue of ICH Q9, and the ISPE RiskMAPP initiative, its use in pharmaceutical containment has been reinforced. Ranking the exposure potential enables a better choice of an appropriate methodology for containment equipment selection, taking into account particular circumstances. Foster Wheeler has developed a method for assessing the risk from widely different operations and has used it for a number of projects to identify highest-risk operations and to prioritise upgrade work.




Marco Mascarenhas Manager, bulk pharmaceuticals

Two significant trends are impacting the manufacture of active drug substances. These trends are delivering some exciting innovations in glovebox isolators, plug and play concepts, process interlinking, secondary containment and control.

Firstly, the increasing activity or potency of active pharmaceutical ingredients for certain therapeutic areas has warranted some materials being given an occupational exposure level (OEL) of the order of 5-10 nanogram/m3 (plutonium is 0.1 nanogram/m3). Secondly, some compounds are being manufactured in everdecreasing quantities, with some annual production quantities of less than 1 kg, and we have even seen an instance of annual production of about 0.1 kg. These trends clearly impact on the design of pharmaceutical facilities and equipment, and especially containment. Established technology uses glovebox isolators with rapid transfer ports and measures to reduce the internal challenge to achieve the required containment. Glovebox isolators are the chosen solution for smallscale nanogram operation and some standard units are available from suppliers. Establishing the right technology is driven by analysis using risk assessment, and by custom and practice. A recent project executed by Foster Wheeler for a cytotoxic API involved the whole non-aseptic cytotoxic production - including weighing/dispensing, solution preparation, reaction, crystallization, filtering, drying and weighing/filling - taking place inside one five-chambered isolator. Achieving 1-10 nanogram/m3 is highly demanding, and it should be appreciated that the glovebox isolation technology for this level of containment is different from that required to achieve microgram containment. With continuing increased potency of pharmaceuticals, and the prospect of manufacture of smaller quantities for responder groups and so on, we see this type of facility becoming more common.



Emilio Moia Manager contamination control & containment

Continuous development, innovation and a stringent attention to detail in design and manufacture, maintains our product portfolio at the cutting edge of technology.
Steril, Foster Wheelers manufacturing division, designs and manufactures a comprehensive range of vertical and horizontal laminar flow benches, bio-safety cabinets and isolators for powder containment. This is done in strict compliance with the exacting standards and design guidance for containment which include: ISO 14644-7: ISO 10648-1: ISO 10648-2: AGS-G001-1998: EN 12469: Separative devices (clean air hoods, gloveboxes, isolators, etc) Containment enclosures Part 1: design principles Containment enclosures Part 2: classification Guideline for gloveboxes Performance criteria for microbiological safety cabinets

In addition, a continuous research and development programme maintains Sterils equipment at the forefront of LAF and containment technology. Results from this development programme include: An innovative isolator exhaust system that, in the event of an accident, has a zero transition time to safe operation. This development has been operating in a high potency drug facility in Italy since 2005. Containment solutions for gaseous decontamination involving products that are effective against biological agents but which can, after use, be rendered harmless.

Pharma i
Both of these developments were covered in more depth in the previous issue of focus which can be found at:




Pam Davison Technical director GlaxoSmithKline

Adverse health effects related to chemical agents can seriously affect a persons quality of life and in some cases be life-threatening. Of these, allergic and dermatitic reactions form a significant proportion of reportable occupational diseases. Clearly the industry has a duty of care to protect workers from exposure to such agents.

A study looking at ten pharmaceutical manufacturing sites owned by different companies, showed that of the 211 subjects tested, 145 (69%) had leaking respirators. The study also showed no correlation between the effectiveness of the respiratory protective equipment and the frequency of use, experience or training. In addition it can be shown that if a respirator is only effective, say, even 98% of the time, it can fail to meet the desired application requirements. GSK has set itself a challenge to have 80% of its unit operations respirator-free by 2010.

Further, when matching engineered control solutions to problems it is necessary to understand that it is not just a direct relationship to the Occupational Exposure Level (OEL). Factors such as scale, dustiness, process energy, and API content can alter the most applicable control strategy for a given OEL. GSKs integrated strategic approach includes documented established solutions, communities for engineers and hygienists, tracking performance, hygienist networking and training, a behaviours program, engineer training, and established partnerships with suppliers.



Huw Thomas Senior pharmaceutical engineer

Disposable systems can provide efficient, cost-effective containment in the right application. They are very adaptable and can accommodate a wide range of applications, but are not the best solution for all applications. Taking a wider viewpoint, using the layered approach is a good underlying principle for containment selection and design.
A recent project involved the specification of a containment upgrade to allow manufacture of a particular higher potency product in an existing small-scale tablet manufacturing facility with granulator capacity of 400 litres. The operator exposure limit for the compound being handled was 10g/m3, and we needed to implement short-term upgrades quickly before the next campaign, with minimum disruption to manufacturing operations. Flexible, disposable containment was the key to this project, and it had to be designed, made, tested, modified, installed and the operators trained in just thirty days! The results of personnel monitoring (outside air suits) showed exposure was reduced by up to 1000-fold by the use of flexible barrier containment. Although exposure was still affected by operator action, it was less so than with the use of personal protective equipment alone. In addition to the flexible glovebags, use was made of Spraylat floor covering to trap any potential surface contamination. There was a significant reduction in surface contamination, leading to a 20-fold reduction in room cleaning times. The disposable Spraylat floor was peeled up, thrown away, and the surface swabs were clean. Future use of disposable containment may include the design of granulator and fluid bed drying glovebags, modified and extended to the other granulation sites in the facility. Longer-term engineering improvements need to be made to areas not suitable for flexible containment, for example through-floor feeders, automated bin charging and discharging.

Some useful containment figures:

One sugar crystal One grain of sand 100 particles of pollen Household dust ~ ~ ~ ~ 1000 gm 100 gm 10 gm 1000 gm/m3

Typical airborne concentrations from open handling:

Dispensing Manual charging Granulation (scraping) Drying (open transfer) Compression 1,000 - 10,000 g/m3 10,000 - 50,000 g/m3 10,000 - 50,000 g/m3 5,000 - 100,000 g/m3 10 - 300 g/m3

Disposable / Flexible Containment Principles












Germana Molinari Senior finishing & formulation engineer

In the absence of a one size fits all solution to the containment of fill finish operations, a logical approach to the design of effective protection is required. Key to success is the correct combination of working area confinement and personnel gowning.
Three possible indicative decision trees are below:
Working area protection

Previous solutions often relied on personal protective equipment (PPE) together with contained rooms or departments to protect the environment. Now, more and more, the approach is to use primary containment at the very source of product exposure, using secondary containment as a back up solution and PPE as an emergency/short-term intervention protective device. The essential first step is identification of the critical operations, typically: Injectables Facility Dispensing Formulation Filling Lyos unloading Oral Solid Dosage Facility Dispensing Product transfer Tabletting/capsule filling Blistering/bottle filling

Low Standard Approach C-RABS
(only for cross-contamination)



High Y

(for personnel safety)

Very High

Containment Isolator

HP : no PPE use

Working area protection

(only for cross-contamination)


The range of containment devices applicable to the different operations is wide and includes: contained connection - split valve, high containment valve, rapid transfer port, continuous liner glovebox isolator closed restricted access barrier system (C-RABS)


Very powdery? Almost not powdery?


(for personnel safety)


Very High

Containment Isolator

HP : no PPE use

Crucial is the awareness that there are no universal solutions applicable to every situation. The selection of the proper containment solution should include an analysis of the key features of the operation to be contained, typically: product potency - low, medium, high product form - liquid or solid product diffusion capability - aerosol generation, powder spread activity duration - occasional or shift-based product exposure - open or closed activity aseptic processing requirements - meeting HSE and GMP requirements product potency issue or only crosscontamination prevention

Product Transfer

Open process allowed or Closed process with butterfly valves



Closed process with standard split valves


Tight closed process with high containment valves

Very High

Tight closed process with RTP parts and glove box

HP : no PPE use



David Ainsworth Principal consultant

Janssens major primary pharmaceutical manufacturing site at Geel in Belgium produces thousands of tonnes per year of active pharmaceuticals and intermediates. The site has almost 100 reactors and manufactures a wide range of materials of varying levels of potency. The most potent products OEL of less than 5 micrograms/m3 means very high containment requirements.
Recently, Foster Wheeler and local Belgian partner BnS worked together to deliver a high containment solids handling facility. The process involved delumping, milling, sieving, homogenizing and pack-off and all of these operations were designed to be undertaken within a series of bespoke gloveboxes. Glovebox design had to take full account of the processing needs and also enable full disassembly and cleaning of the solids processing equipment. Complex ergonomic mock-up models of the process equipment were developed to ensure that the design on paper was practical and enabled all of the required operations to be undertaken by an operator working via gloves. Heavy equipment was mounted either on hinges or slides, flexible connections were needed in the powder transport piping system and full nitrogen inertion was necessary to prevent explosions! The design containment level of 50 nanograms/m3 was achieved, the project was completed from concept to process start-up in two years and the degree of innovation achieved was recognized by the project being selected as a finalist in the prestigious Facility of the Year Awards in 2006.

Quality Award

Foster Wheeler is delighted to announce that the General Technical Services Department of Janssen Pharmaceutica NV has awarded its annual Quality Certificate to Foster Wheeler, in recognition of its contribution to the development of the concept study for the recently announced Chemical Development Pilot Plant (CDPP). Foster Wheeler scored the highest possible rating, AA, in this award, which is given to the best performing contractor at Janssens Geel and Beerse sites in Belgium. Foster Wheeler is continuing to support Janssen with the BOD-B (FEED) phase of the project.




Paul Richards Project & technology engineer Pfizer

There are many engineering control options for containment. What option is most suitable for your application? What is the range of performance expected with various containment solutions? Who are the primary vendors? And what are the budgetary costs? Question, questions .

But a useful starting point is: what are we trying to achieve? If we consider that 1 granule of sugar is about 3 milligrams, then a containment level of 3 g/m3 is like dispersing 1/1000th of 1 granule of sugar in 1m3 of air - pretty exacting stuff! In API plants, the movement of materials, supplies, tools, wastes, and recovery systems into and out of the contained environment is the key to successful containment. The performance of an isolator is only as good as the transfer devices on the isolator. There are many different transfer devices available on the market, each with its own pros and cons. A primary concern with split butterfly valves, for example, is material on the faces of the valves after undocking, and concerns with cleaning extraction rings. Some recommendations include: Contain at the source Avoid technique-dependent systems Many containment technologies are available and continue to evolve Transfer system selection is a key to successful containment Design below the operator exposure limit Consider ergonomics, cleaning, sampling, waste, material compatibility Provide redundancy/secondary containment Engineer out the reliance on personal protective equipment

And the golden rule is, there is no silverbullet containment solution!



Huw Thomas Senior pharmaceutical engineer

Foster Wheeler recently carried out a survey for the Global Containment Engineering Group of a multinational pharma company with a view to benchmarking its oral solid dosage (OSD) manufacturing of highly active products against current industry best practice. The results identified key learning points and lessons to incorporate.
Census Results


The pharma company currently has no OSD facility designed to handle actives of <10g/m3. Many of its facilities currently require the use of personal protective equipment (PPE) to process <100g/m3 actives. It has an increasing number of products in the pipeline that fall into the <10g/m3 and <100g/m3 categories and the companys future production plans will dictate smaller batches of higher potencies, requiring a more flexible facility.

The census results included analysis, key learning points, features, lessons to take forward, and these conclusions: All manufacturers surveyed are seeing an increased number of potent products and hence a need for manufacturing flexibility All manufacturers surveyed are committed to moving away from routine use of PPE to control exposures in new facilities There is general agreement on a range of containment equipment performances - backed up by occupational health monitoring There is increased use of clean-inplace (CIP) in facilities for <1g/m3 compared with 10-100g/m3 facilities . Use of CIP is becoming the norm for new facilities - accepting trade-off of containment benefits versus increased changeover down-time More dedicated facilities are found in those designed for <1g/m3 compared with 10-100g/m3. The decision between a multi-purpose versus a dedicated facility is based on commercial or cleanability/GMP reasons, not purely on potency All companies use risk assessment, and there was good agreement on the factors considered. All agree that engineering high containment is not sufficient by itself.

Cleaning Approaches for 10-100 g/m3

Census Aim

Split into two parts, the census surveyed 11 global manufacturers, covering 22 different facilities, and 9 equipment vendors. The census aim was to benchmark existing facilities to determine current best practice for OSD manufacturing facilities handling potent actives, including an overview of current and possible future changes in processing and containment equipment.

Cleaning Approaches for <1 g/m3




David Ainsworth Principal consultant

Bearing in mind that a required containment level of less than 5 nanograms/m3 is the equivalent of one grain of pollen in an average-sized living room, factory acceptance testing at such levels can be pretty exacting.
To demonstrate the performance of a number of high containment gloveboxes to be installed in an existing primary pharmaceutical manufacturing unit, Foster Wheeler went to extraordinary lengths. Testing of the units covered: ergonomics - operations, controls and sequences documentation - GA, P&ID and materials checks lighting and noise level checks surface finishes, cleanability and drainability airflows, operating pressure and inertion times accuracy of instrumentation connections to pressure systems leak performance - pressure and vacuum testing containment performance - surrogate material testing In particular the containment performance testing of each glovebox was stringent. A surrogate material, Sodium Naproxen, detectable at levels as low as 0.5 nanograms, was used to mimic the actual operations that would be conducted in each glovebox. The surrogate test material was kept in doublesealed containers inside a small storage room (actually a garden shed bought locally!). This was segregated from the rest of the factory by a temporary polythene sheeted antechamber to guard against inadvertently contaminating the glovebox test environment. Surrogate test material to be used in testing each glovebox was loaded into sealed containers in this storage room; the containers were then cleaned and passed out of the room for further cleaning outside the factory. Once the containers were thoroughly clean and free of any of the test material on the outside, the container was double-bagged and sealed and then brought back into the facility for use in the glovebox testing area. The container was docked onto the glovebox in the test area and the surrogate material introduced via rapid transfer port into the glovebox interior. Here a full cycle of the required operations was conducted. During this cycle of glovebox operations, both airborne and surface samples were collected from the surrounding environment. The entire operation was undertaken on three separate occasions to demonstrate the effectiveness of the glovebox. At Foster Wheeler, we really do roll up our sleeves and get on with the job!

Photos from l to r: Store, Test Enclosure, Preparing for Testing, Inside the Test Chamber.



We continue to secure significant new pharma business around the world, across the full range of technologies.

Category Key
Secondary General Infrastructure Validation API Biotech R&D Medical Devices

Elsewhere, our clients continue to value the quality of our teams and the facilities we design and build.
We are very pleased to work with Foster Wheeler again and have every confidence that our joint teams will work together to successfully complete this phase of the project on schedule. This will provide a firm foundation upon which to build for subsequent phases of the project. We have been working successfully with Foster Wheeler since 2001 we are pleased with Foster Wheelers professionalism, responsiveness to our needs and capability to mobilise highly qualified resources from its European offices... We have selected Foster Wheeler for this challenging project because of its ability to make available skilled resources from its various operations centers, under the management of Foster Wheeler Milan. The team has a very proactive approach and the team members are not afraid to roll up their sleeves. There are too many names to mention individually, but the whole Alliance team has made an outstanding contribution to achieving our business objectives.



Exhibitions Conferences
ISPE Congress, Vienna Society of Chemical Industry
At the SCIs Process Development Symposium in Cambridge, Mark Dickson, senior process engineer, presented on Continuous Technology... when, how and why we should change, highlighting the advantages of continuous processing over traditional batch operations for low tonnage products.

The Annual European Congress was attended by a large cross-section of technical specialists from across Europe and even beyond. John Nichols, our global technology director, co-chaired a well-attended session which explored how to introduce continuous processing into pharma facilities.


Come and meet us at: ISPE Tampa Conference, Florida

12-15 February

ISPE Copenhagen Classroom Training, Denmark

26 February - 1 March
Bob Adamson, our pharmaceutical compliance manager, will be discussing the Application of Commissioning and Qualification and Bob Davies, principal biopharma consultant, will be lecturing on Biopharmaceutical Process Development.

ISPE Annual Meeting

Once again, the ISPE Annual Meeting this year in Orlando, Florida attracted a large audience, as well as almost 300 table-top exhibitors. John Nichols was course organizer and chair for the seminar on Continuous Processing in the Real World. Our presence in the exhibit hall (and in the committee rooms), enabled us to make contact with a large number of key clients who were attending.

ISPE Brussels
The ISPE year ended at Brussels where Foster Wheeler had a significant presence. John Nichols participated in the session reporting on the latest update of the Bulk Pharmaceutical Chemicals Baseline Guide, speaking on containment and the activities of the API Community of Practice. Huw Thomas, senior pharmaceutical engineer, contributed to the Oral Solid Dosage session with a paper on containment.

ISPE Paris Conference, France

16-19 April
John Nichols will be chairing a session on nanotechnology, and Paul Frey, our principal facilities consultant, will be presenting a baseline approach to modification of a WFI system.

ISPE Appointment
John Nichols, pharmaceutical technology director, has been re-elected to the ISPE Board of Directors. This two-year appointment is Johns second, and is a significant achievement. John has contributed a great deal to ISPE. He works on a number of ISPE committees: the International and European Education Committees, Facility of the Year Committee, Body of Knowledge Task Team and API Community of Practice (CoP) and CoP Council. In 2003, John was a member of the ISPEs Facility of the Year Task Team which received the Committee of the Year award. He also regularly chairs and speaks at ISPE conferences promoting Innovation in the Industry.

Interphex, New York

24-26 April
Visit us at booth #143.

ISPE Washington Conference, Arlington, Virginia

4-7 June

ISPE Singapore Conference

10-12 June

focus 13

Technical consultancy Feasibility studies Concept design Site selection Site master planning Permitting Environmental consultancy Process simulation Basic design Detailed engineering Project management Procurement Construction management Commissioning Validation Plant operation Maintenance Site remediation

the right people with a can do attitude and the commitment to deliver