Pharmaceutical Processing July 2011

INTERPHEX 2012™Official Media Sponsor of

NEW TECHNOLOGY FOR THE BIOPHARM/PHARMACEUTICAL PROFESSIONAL JULY 2011

VOLUME 26, NUMBER 6WWW.PHARMPRO.COM

UNDER ONE ROOF Acceleron Pharma Relies on Single-Use and Suppliers to Control Their Destiny

COOL TECHNOLOGY Freeze Dryers Adapt to Changing Market Demands

SOLID DOSAGE PROCESSING Can a Continuous Process Increase Efficiency and Reduce Waste?

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INNOVATIONS■ WEIGHING■ VIAL & SYRINGE PROCESSING■ COATING EQUIPMENT

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■ IN THIS ISSUE

■ P H A R M P R O . C O M

■ 4 JULY 2011 | PHARMACEUTICAL PROCESSING

12 Cool Technology Freeze dryers adapt to changing products and

market demands.

14 Continuous Solid Oral Dosage Processing

Converting from a batch to a continuuous process leads to more efficiency and less waste.

20 Recall Remediation How to successfully manage a recall and

prevent future problems.

26 Steam Trap Tips The right steam trap saves money and increases

uptime in SIP applications.

28 Brainstorm Have sponsor requirements for qualification as

a preferred vendor become more strict?

30 Delivering Process Improvements

By leveraging single-use operations and lean strategies companies can deliver real value and reduce costs.

■ COVER STORY

8 Under One Roof Acceleron Pharma leverages single-use technology

and capable suppliers to meet their goals.

page 14

page 24

page 19

■ DEPARTMENTS

6 From The Editor

18 What’s Hot

INNOVATIONS22 Weighing24 Vial and Syringe Processing29 Coating Equipment

On the Cover: In order for Acceleron Pharma to manufacture their products in-house they have relied heavily on single-use technologies.

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II’ve been thinking a lot lately about packaging. We all know how important packaging is to our lives and how

packaging has, for the most part, made our modern, high-tech lives possible.

But what happens when you look past the big picture – and get down to the real nitty-gritty of packaging – down to the individual consumer level – and how they interact with packaging on a daily basis. For this survey of modern packaging I took a look at my own experiences with packaging.

For starters, there are some winners and, to be chari-table, some non-winners.

Let’s start with a standout.Due to more than his fair share of sports-related broken

bones, my son was drinking a very popular nutrition supplement high in calcium. This product, marketed primarily to older people worried about osteoporosis and other age-related bone diseases, has an ingenious cap that with just a few easy twirls is open. The packaging designers clearly had their target consumer in mind when designing this easy open container.

Moving on to some less than stellar examples of packaging – I have to say that I have had some issues with modern blisterpackaging products. I know there are many benefits to blisterpackaging, and I don’t have the space here to go into them but they are well known. However, some forms of blisterpackaging, particularly the type where you have to peel a layer off before you can push out the product can be maddening, especially when you can’t get the corner started to start the peel. And, more often than not, only half of the film peels off, leaving you to try and squeeze the pill through the opening.

And finally, does anyone ever get the little tab at the top of the cereal box to stay in the slot on the other flap? I rarely get it to stay in place, especially after I’ve mangled the top trying to open it up.

Do you have any packaging winner or losers? I would love to hear about them.

■ FROM THE EDITOR


Packaging Points

Have a comment or question about Pharmaceutical Processing? My E-mail is: [email protected]

When it comes to packaging there are

some winners, and let's just say, some

that don't quite make the cut…

■ Michael Auerbach, Editor in Chief

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Above: The large cell culture production area.Left: The small cell culture suite.

Acceleron made a decision to internalize protein production. The initial production and purification of the proteins was done by the company’s own personnel in development labs.

This initial facility was a simple, 1600 ft2 facility which was designed and constructed in a relatively short period of time, minimizing capital and validation costs, and allowed the company to adopt a ”pay as you go” approach to the costs associated with pre-clinical and clinical production.

As the company got closer to the need for making preclini-cal and clinical material for its first product, the question of whether to outsource its product or do it internally resurfaced. Again a number of CMOs were contacted and asked for quotes for the work to make the initial development candidate. As the quotes came back the company realized that the cost of out-sourced production would limit the number of projects which they could pursue into Phase I clinical studies. In addition, given the aggressive timelines critical to creating value for existing investors by showing the utility of these molecules in the clinic, company management had a strong desire to have better control of the timelines for production. Bob Steininger, SVP Manufacturing at Acceleron Pharma explains the compa-ny’s thought process at the time, “My goal here was to figure out a way to get a small company to control their destiny, which is really tough and frustrating when you have a great idea and you can’t act on it fast enough and you can’t learn

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The old adage, “If you want something done right, you should do it yourself” can be applied to many situations. Perhaps nowhere is it more appropriate, at least in the pharmaceutical indus-

try, is at Acceleron Pharma in Cambridge, Massachusetts. Acceleron was established in 2004 to focus on growth

and differentiation factors in the TGF beta super family. The company’s main purpose is to develop biologics that modu-late the growth of bone, muscle, fat, and the vasculature in order to treat patients with diseases with high unmet medi-cal needs – many of which are know as “orphan diseases” for which there are no other available treatments. As the bi-ology is complicated, a substantial number of novel proteins are required as tools for in vivo experiments. Due to the complex biology, Acceleron has developed numerous protein antagonists as tools to understand the biology initially and has developed similar molecules as therapeutics.

DOING IT ALL IN-HOUSE Early in the company’s history, management compared

production at Contract Manufacturing Organizations (CMOs) to “in-house” protein production. Based on several factors in-cluding the difficulty of expressing these proteins, the internal knowledge and insight of the properties of the members of this protein family, and the more favorable economics for the internal production of many reagents projected to be needed,

Under One Roof Acceleron Pharma leverages single-use technology and capable suppliers to meet their goals ■ By Mike Auerbach, Editor-In-Chief


■ P H A R M P R O . C O M■ COVER STORY

■

pp1107_coverstory_acceleron.indd8 8pp1107_coverstory_acceleron.indd8 8 7/1/2011 11:09:27 AM7/1/2011 11:09:27 AM

Above and left: Acceleron Pharma's facility is located in the heart of Cambridge, Masssachusetts.Right: Diagragm of the facility layout.

along the way.” He continues, "we are making relatively complicated molecules. It is more difficult for an outside firm to deal with these. We had the expertise in house. Whenever it was sent out it took longer and more times to do the process, and it wasn’t clear when we would get into a CMO. For a small company like ours, for us to get data as quickly as possible, it

was necessary to have control of the timeline.”Based on the first facility's success and the company’s desire

to control their destiny and costs – the decision was made to build a larger, second generation facility. The result is a 12,000 ft2 facility with approximately 4500 ft2 of processing space.

SINGLE-USE In order for Acceleron to make the facility as cost-effec-

tive and as nimble as possible, the company relies heavily on single-use technologies. The heavy reliance on what many might consider a “new” technology, was actually based on years of experience, as Steininger explains, “I was previously at Millenium, and technology was being devel-oped to use single use – and I accepted that technology and made it work for a process that we had. It appeared to be reasonable. We probably did the first Phase 1 material made in bags. We put together a facility very quickly and made material – everything was delivered and made in single-use bags – which is very similar to what we do here.’

He adds, “The facility here and our whole effort; develop-ment, production, pilot production and GMP production has been based on the use of single-use technology from the get-go. It has really helped us by enabling us to make mate-rial quickly, particularly the complicated material we make.”

ADDITION BY SUBTRACTION W hile many companies are exploring single-use technolo-

gies and realizing the benefits that this technology provides, Acceleron needed to push the envelope a bit more with their new facility. As the facility is based in a rather crowded ur-ban environmen t with little space to expand, and considering the company’s desire to contain costs as much as possible,

the company came up with the revolutionary idea to elimi-nate in-house production of water and steam.

Steininger explains how they accomplished this, “In order to do this you have to be very confident that your media and buffer suppliers have a very good system to provide wa-ter and buffers appropriately.”

“Its very much like the Japanese auto industry – a very close relationship with your suppliers. All the parts have to fit together and fit together well with the appropriate tolerances. That’s not any different from what we are doing here. The companies that supply us with media and buffers have to do that well and as accurately as possible. That’s a dependence that most people have not taken a risk with, but it can be done given that there are a number of com-panies that will supply you liquid and plastic, etc."

And Acceleron has found those suppliers. “There are three reputable suppliers of buffers and there are lots of people who will supply you with media,” says Steininger. “Our media comes from California and our buffer comes mostly from Maryland. We are transporting water over a dis-tance which doesn’t seem to be a limiting factor.” FACILITY DESIGN INPUT

As mentioned, Acceleron sought to keep the process, and perhaps more importantly, the process knowledge as much

PHARMACEUTICAL PROCESSING | JULY 2011 9 ■


■ COVER STORY

■ The initial pilot\phase 1 facility at Acceleron was based on the following design principals:■ Focused limited development\production

personnel on the process, not support.

■ Simple facility design focused on con-trolled areas using one HVAC.

■ “One product at a time” facility.

■ The facility has no water system. All pro-cess solutions delivered in sterile containers

■ The facility has no steam. All material is delivered sterilely unless cleaned as part of in-process sanitization (column cleaning).

■ All process equipment is mobile, to facili-tate its movement at a future time.

■ The processes are based on a platform, where equipment and number of process steps are substantially the same among different product candidates.


■ P H A R M P R O . C O M■ COVER STORY


as possible, in-house. This knowledge, which isn’t stored on a computer, is found in the experience and talent of their personnel. “To a certain extent, we have called them manufac-turing (personnel) but they are in fact scien-tists,” says Steininger. “In this early phase, you really want people who can understand how the process works, how it can translate into a larger scale, and how to adapt equipment from a vendor to what we are doing. That is in fact, I think what Acceleron has tried. We have manu-facturing scientists who can adapt the single-use technology, the connectors, etc. and make it work. Many of these people worked in our first facility, they then transferred that technol-ogy into our new facility and made it run. That has worked well for us.” A SMALL-SCALE FLEXIBLE FUTURE

With the success of Acceleron's facility, the question that needs to be asked is this the wave of the future? Are small-scale, flexible facilities, using predominantly single-use technologies the nail in the cof-fin for older facilities and technologies? “I think it is certainly one of the ways,” says Steininger. “One of the aspects that have come clear over the last few years is that there hasn’t been a lot of big stainless steel facilities built recently. This is because ex-pression levels have gone up and there are

more than enough plants in the area. You are seeing a lot of old and new companies using this technology. (In our case we used it) to see how we can minimize our capital costs and maximize the utility of what we have and if we need to add more (capacity) lets use this technology (single-use) rather than another way. It is enabling us to use capital more effectively – especially on the

smaller scale. For a small company, it’s a very big advantage. ”

FACILITY HIGHLIGHTS Steininger and the folks at Acceleron

have designed, built and are operating a very unique facility and one which they are rightly very proud of, “I think the ability to set it up where you actually made a facility that could depend upon, at least initially, other people supplying all your liquid and designing a gray space in a way that helps keep a lot of the "junk" out of the process (is what I’m most proud of)," says Steininger. “This design also allows us to think about the future - to build out our facility so we can make our own water and buffers.”

THE FUTURE With their facility operating the way they

want it to, Acceleron is planning for the fu-ture, as Steininger explains, “We have four drugs that will be in the clinic from Phase 1 – 2b in the next few years. Depending on how the trials go some we will make our-selves, some we might use a CMO. If it has to be done real fast we will make it here. If it gets too big, too fast, we will transfer it. We will have to focus on how we can make clinical supplies and make sure our prod-ucts move through the clinical process. We will expand if need be depending on the clinical data.” ■

■ The additional capabilities of the new facility were accomplished through the following design features:■ A separate, independent area for cell

culture which can be used for cell bank production.

■ Space for at least 2X 1000L single use reac-tors (potentially 2000L) and inoculum train.

■ Two larger, more integrated purification areas.

■ Extensive use of grey space and pass-thrus to enhance movement of solutions into the facility from the warehouse, and from one processing area to another.

■ Use of same systems of grey space and pass-thrus to facilitate the removal of waste from the facility

■ Juxapositioning QC and Warehouse func-tion to the production area

■ Creation of a clear path of movement of raw materials (particularly liquids) from loading dock, through QC sampling, and into the facility

■ Separate air handling systems for each of the four processing areas, and a separate entry to each process area entering from a common clean corridor

Top: Large purification production area.Bottom: Small purification production area.

Top: Grey space for solution delivery.Bottom: Miniature pass-thru.

■ T he following companies contributed to the success of Acceleron Pharma's facility:Advanced ScientificFinesseGE HealthCareHyclone Laboratories, Inc.MilliporePall FlowstarSartorius North America, IncSpectrum Laboratories, Inc.VWR International, Inc.W.L. Gore & Associates (Amesil)


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A t its most basic – freeze drying or lyophilization is a process in which water is removed from a per-ishable material first by freezing the material and then reducing the surrounding pressure to allow

the frozen water in the material to shift directly from a solid, frozen state to a gas state. The greatest benefit of freeze drying to the pharmaceutical industry is the creation of a product that can now be maintained at room temperature without the need for further storage costs.

To get an update on the latest freeze drying trends and tech-nologies affecting the pharmaceutical industry, Pharmaceutical Processing spoke to several freeze drying experts.

NEW PRODUCTS – NEW EQUIPMENT DESIGNS Developing new products is important to every industry,

but perhaps none more important than the pharmaceutical industry. With millions spent on R&D, the industry has a lot riding on new products. We asked our experts if the devel-opment of new types of drugs have had an influence on the design of freeze dryers.

“Definitely,” says Mark Shon from SP Scientific, “You are seeing cytotoxic type drugs, you are seeing more demand for barrier interface and for auto loading capability – even on some of the small pilot units. Even on the small units we are getting requests for CIP capability. You may have to de-velop a freeze dryer where historically you never had any of that and now the user wants to freeze dry cytotoxic drugs

with some type of barrier isolation along with ability to wash out anything inside.”

“New types of products have influenced the design of freeze dryers,” says Millrock’s T.N. Thompson. “Many new products are more potent and more expensive, requiring changes to the freeze dryer design. It is very common to have 2ml vials in use which require a higher stoppering pressure. The higher value of product being freeze dried also requires the highest reli-ability components to be used and more sophisticated control systems to monitor and control the process.”

“I do see that there are a lot new product formats, notes Cook Pharmica’s Zach Yim. “You have vaccines, monoclonal antibodies, liposomes, and small molecules that all require different approaches to stabilize them via lyophilzation. They all have different requirements.” NEW PRODUCTS – NEW CONTAINERS

Traditionally, freeze dried products have been processed in glass vials – with new products being developed we asked our experts if glass was still the preferred container material or if other types of material are being tested and used.

“Within glass there are a variety of different developments to improve the flatness of the glass and therefore reproducibility of manufacturing, because how flat vials sit on the shelf is a

fairly large determinant regarding the quality and time of the freeze drying, says SP’s Shon. “There are some

plastic vials that have come into the market – that’s a little trickier

A Cool Technology Freeze dryers adapt to changing market and product demands ■ By Mike Auerbach, Editor In Chief


■ P H A R M P R O . C O M ■

■FREEZE DRYING

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Freeze dryers are available in many sizes and capacities. One of the newest features is "con-trolled nucleation". Controlled nucleation allows all of the vials to be nucleated at the same time - allowing for better product quality and faster processing.

pp1107_feature_freezedrying.indd12 12pp1107_feature_freezedrying.indd12 12 7/7/2011 9:14:50 AM7/7/2011 9:14:50 AM


■ S L U G■ P H A R M P R O . C O M

■FREEZE DRYING

– because of the thermal characteristics of the heat transfer into a plas-tic vial. You also have some development work in the closure. There is a new closure that does the stoppering and capping in one step. If you can take out a step and make things easier – that’s a good thing.”

“One company has introduced plastic vials and another has come out with a coating that prevents collapse during lyophilization and is also hydrophobic, so you can completely retrieve liquids. Of course, nothing is perfect, people need to test these new products first,” adds Cook’s Yim. MORE THAN JUST A “FREEZE DRYER”

Many pharmaceutical companies in the present economic climate are looking for all the assistance they can get. Are pharmaceutical companies looking to equipment vendors for more than just a piece of processing equipment? Are they looking for integrated lines along with the engineering and validation support to get the lines up and running as quickly as possible?

Millrock’s T.N. Thompson offers his views, “Pharma companies first look for the right solution to their problem, rather than a single vendor to supply all their equipment. Freeze dryers are made-to-or-der and vary greatly, so the vendor and the customer need to work through the details of the equipment to get the right solution for their application. The area where a single vendor would provide a complete line would be in an automated loading application, which might also include the fill and capping equipment."

"Validation and training have become a large part of the freeze dry-ing equipment business. FDA regulations require a significant amount of documentation and performance testing to verify the equipment performs to the requirements.” CONTROLLED NUCLEATION

All of our experts agree that controlled nucleation is one of the big-gest advancements to come along for freeze dryers in a long time. So what, exactly, is controlled nucleation?

"Controlled nucleation was introduced because vials freeze at dif-ferent and random temperatures,” says SP’s Shon. “This created a problem, as now each vial is different. They each have a different thermal history. So the time for drying is also changed. Controlled nucleation technology allows the user to instantly nucleate all of the vials at the same time – so they all will behave the same – and allows you to shorten your cycle time and improves the consistency of your batch. This is probably the biggest advancement in freeze drying”.

Cook’s Yim agrees, “The most exciting development in freeze dry-ing is controlled nucleation. It used to be nucleation was random and not controlled. This (controlled nucleation) can provide better uniformity, and accelerate the primary drying process by 20%. Also the product quality is better.”

“Controlled nucleation is a very important trend,” adds Millrock’s Thompson. “By controlling the nucleation process the crystal struc-ture of the material can be more uniform resulting in shorter pri-mary drying cycles.”

FUTURE TRENDS With controlled nucleation grabbing much of the freeze drying

“headlines” are there any other trends or technologies we can look

to in the coming years?Cook Pharmica’s Yim offers several to look for “The use of wire-

less temperature probes which allow you to map the sublimation rates and to compare temperatures from the front to back and side to side will allow people to design their cycles better.”

He continues. “There is also the non-destructive determination of moisture in vials so you can inspect vials 100% for moisture content and loss of vacuum due loss of closure integrity. These are very ex-citing things that people can use to improve their product.”

And finally, Yim states, “People are also beginning to realize they need an intermediate size freeze dryer for small batch size clinical materials. This would facilitate further scale – up. This would elimi-nate partial loading of larger freeze dryers for small, clinical batch work and make it more efficient and eliminate bottlenecks in larger freeze dryers.” ■


P H A R M I C A DEVELOPMENT CLINICAL COMMERCIAL DRUG SUBSTANCE DRUG PRODUCT

Syringe line under barrier isolation

Simplify your contract manufacturing with process development, cell-culture manufacturing, formulation development and vial/syringe fi lling and fi nishing all inone location. Accelerate the delivery of your life-enhancing products to patients, and work with one point of contact and one set of business practices.

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Processing individual ingredients toward a more useful end is as old as humankind. Witness the magnificent cave paintings of our ancestors as an expression of their daily lives that became

possible by mixing common ingredients to manufacture pig-ments. Of course, manufacturing efficiency has very little influence when much of your day is given to collecting nutri-ents and avoiding predators, so providing a pigment batch at irregular intervals is sufficient to the purpose.

Fast forward to our current century where most process manufacturing is still being accomplished one batch at a time. Pharmaceutical manufacturing in particular is biased toward batch operations for various reasons. Some reasons are due to prior regulatory environments that favored batch validation and general stasis of the manufacturing situation. One may ar-gue that the unique relationship pharmaceutical manufacturing has to human health abets the batch inertia. However, the reg-ulatory environment has significantly changed in recent years with renewed emphasis on deep process understanding.(1,2). In addition, other industries have been involved with continuous manufacturing and they enjoy high success rates.

In these industries, there are examples of formulation ana-logues to solid oral dosage formulations that utilize continuous

techniques to manufacture their products. One application involves cross-linking polyethylene (PE) pel-lets with organic peroxides. The organic peroxide may be thought of as the active ingredient in liquid form and thereby requires fine control of its addition to maintain the functionality of the extruded wire coating. The PE pellets are similar to a phar-maceutical unit dosage and each pellet must have the proper amount of peroxide applied. The components exit as effluent in a real time release scenario to an extruder. Inconsistencies in content uniformity may be reflected in poor extruder per-formance or more importantly in a coating failure in the field. Considering that some of these wire coatings are undersea ap-plications, one can see the impact of such a failure.

A second application with analogies to pharmaceutical manufacturing, particularly with regard to formulation con-stituents, is processing detergents. These formulations contain builders that are analogous to pharmaceutical diluents, clean-ing agents analogous to the active pharmaceutical ingredient (API) and flow aids analogous to silicon dioxide. They also contain a striking analogue to the lubrication step. The for-mulation contains a chlorinated component that will degrade under the aggressive agitation necessary to mix the main for-mulation constituents and thus requires a secondary, gentle tumble mixing step. This, of course, mimics the requirements of lubrication addition in solid oral dosage formulations.

Each of the above operations is processed at several thousand kilograms per hour (kg/hr) with good content uni-formity and high yields.

AMENABLE PROCESSING OPERATIONS Many manufacturing applications are transferable from

batch to continuous processing. The continuous processes often maintain similar abilities on the ultimate result be-cause the basic unit operation remains the same. An influ-ential criterion for choosing between batch and continuous processing is the throughput requirement. Continuous oper-ations generate substantial amounts of product and several tons per hour are common rates. These high rates are inap-propriate for solid oral dosage manufacturing but vendors now offer pharmaceutical-ready, low throughput devices that have much lower throughputs; often a 5 kg/hr and less.

Continuous Solid Oral Dosage ProcessingConverting processes from batch to continuous leads to more efficiency and less waste


■ P H A R M P R O . C O M■ SOLID DOSAGE

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pp1107_feature_continuousprocess14 14pp1107_feature_continuousprocess14 14 7/7/2011 10:34:40 AM7/7/2011 10:34:40 AM

Figure 2. 1500 liter batch mixer.

A non-exhaustive list of operations that transfer well to continuous may include tumble powder blending, high intensity powder mixing, wet granula-tion of various varieties, drying and hot melt extrusion. Because of its ubiquity in general process schemes, the continu-ous mixing application will be dealt with in some detail in the succeeding para-graphs that detail the positive and nega-tive aspects of continuous processing. To make the contrast more effective, we will assume a continuous operation de-livering 100 kg/hr (figure 1) versus a sin-

gular batch operation utilizing a 1500 liter vessel (figure 2). In both examples, an 8

hour production run will yield about 800 kg of drug product.

POSITIVE ASPECTS OF CONTINUOUS PROCESSING It is difficult to overstate the extensive advantages of con-

tinuous processing.These systems are built to operate on a 24 hour per day

and 7 day per week work cycle resulting in impressive utiliza-tion efficiencies. By contrast, the batch unit operation encom-passes only a small portion of the production day. A typical mixing time for a 1500 liter vessel would be on the order of about 30 minutes. Substantial additional time would be en-countered in ancillary duties including staging the raw mate-rials, loading the materials, sampling, discharging, and clean-ing the vessel in preparation for a subsequent process run.

Cleaning downtime may be minimized with continuous pro-cessing as these systems are offered with the ability for a quick changeover of the vessel and agitator bar. A single drive station is capable of accepting several sizes of the continuous vessels, allowing wide process ranges that are typically between 5 and 200 kg/hr. The attachment point to the drive station is similar to the familiar multi-vessel processing stations seen with batch offerings. Consequently, the vessel and agitator bar may be quickly removed (< 15 minutes) and replaced by a fresh system as the previous system is sent off for cleaning.

Analytical processing is simplified within continuous applica-tions. When assessing batch uniformity, a small group of sam-ples is collected to represent the entire batch. This sampling, of-ten done with a sampling thief, has its own inherent drawbacks that include drawing down surface material to the sample site as the thief enters the powder bed, preferential filling of the thief cavity by better-flowing formulation constituents and entrap-ment of smaller particles in the annular space of the thief’s tube within a tube design. The analysis requires high value employ-ees for evaluation and the samples themselves may languish for several weeks in the analytical queue. Continuous applications are ideal for on-line analysis with technologies like near infrared spectroscopy (NIR) that provide the analytical assessment very quickly, do not require sample preparation and are suitable to remote sampling via fiber optic probes. There is an initial

method development phase where NIR, a secondary technique, must be established versus a primary method, but once this is accomplished the continuous analysis may be monitored within software-developed, standard operating procedures that are quite easily adapted to the operator level.

The other advantage of this type of analysis is the reduc-tion of in-process inventory, as immediate release is now feasible. Perhaps even more important is the pervasiveness of sampling available. A large portion of the effluent stream is monitored continuously and a much broader profile of the system is available. Consequently any uniformity issues can be reconciled quickly. The actual at-risk mass is very small and is generally a kilogram or less as represented in the hold-up volume of the mixer. Novel statistical techniques have been proposed to deal with the larger sample size (3).

There are a few other more esoteric advantages within continuous applications. Scale-up becomes much less com-plex. With batch applications, similarity criteria (generally geometric, kinematic and dynamic) are established in the pilot scale vessel. These criteria are promoted to the larger vessel, with varying degrees of success, as the scale-up factor. Continuous scale-up is time related and based on a common period of residence among the vessel sizes. A re-tention time of 180 seconds in a 5 kilogram per hour opera-tion can easily be replicated to a 100 kilogram per hour op-eration by increasing the hold-up volume, which, in effect, is merely placing a larger vessel on the common drive station.

Another advantage is the simplicity within which continu-ous fits into efficient experimental design, especially when real time analysis with NIR has already been established versus a primary method. A factorial sequence with replicates that evaluates machine factors such as agitator bar tip speed, ves-sel tip speed and vessel slope with respect to a critical quality attribute such as mix uniformity, thereby proving a proven acceptable range, may be accomplished in one day of testing. Contrast that with the time that would be necessary to a com-plete a similar factorial sequence in a small batch vessel as thief samples are drawn for analysis by the laboratory.

Finally, the space utilization difference of batch versus continuous is another profound advantage. A general ar-rangement for the continuous scenario of delivering 100 kg/hr will fit on a table top while the batch scenario of utilizing a single 1500 liter batch requires a large processing suite.

DRAWBACKS TO CONTINUOUS PROCESSING There are disadvantages to continuous processing but

many of them may be reconciled through judicious planning. For example, if the continuous process is not well-character-ized and controlled in the experimental stage, it is possible to have substantial material manufactured before one is aware of any problem. The batch unit may also contain significant material but the only at-risk portion is what is contained in the blender and the possibility exists to re-work this material.

Manufacturing complex formulations with multiple ingredi-ents may also be a limiting factor for continuous processing.



■ SOLID DOSAGE


It is fairly easy to stage 2 or 3 feeders at the input end of the continuous process but if the formulation contains 6 or more ingredients, staging this many feeders may be impossible or economically prohibitive considering the cost of additional feeders. A second issue related to the complexity of the formulation is the addition of the lubricant. The main for-mulation components with a low dosage API require a high speed mixing environment to achieve uniformity. However, the functionality of the lubricant would degrade under such an environment and the lubricant must be blended in a gentle tumble mixing situation. In a batch process, it is simple to utilize the agitator bar for the high energy step, then add the lubricant and continue the process without the agitator and achieve a simple tumble blend. In a continuous process, this may involve two mixers in sequence; one for the high speed portion and the second for lu-bricant addition. There are continuous mixing technologies that overcome the problem by dividing a single continuous mixer into sec-tions that are capable of high speed mixing followed by gentle tumbling.

A final issue is related to environmental

control. In the batch unit, dust-free transfer of the raw materials and subsequent dust-free transfer of the finished formulation to a receiving container is well-established. The continuous may also achieve an environ-mentally clean transfer but with the multi-plicity of feeders and the outflow transfer to a tablet press, environmental control be-comes more problematic and sophisticated.

UNDERSTANDING FIRST PRINCIPLES AND THE GRAND ALGORITHM

The ultimate advantage of continuous processing is the potential to build into a grand algorithm for efficient process control. Experimental design can readily establish proven acceptable ranges for critical process inputs like agitator bar tip speed, vessel tip speed and agitator bar design as these inputs relate to critical quality attributes like blend uniformity and particle size. Available technol-ogy can constantly monitor the critical qual-ity attributes in near real time and then make adjustments of the critical process inputs according to the process algorithm developed in the experimental phase. Sophisticated feed-back loops are possible within many common

PAT software packages. (4,5) REFERENCES 1. Pharmaceutical cGMPs for the 21st

Century-A Risk-Based Approach: Second Progress Report and Implementation Plan, Department of Health and Human Services, US FDA, September, 2004.

2. Guidance for Industry PAT- A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance. US Department of Health and Human Services, US FDA, Center for Drug Evaluation and Research, Center for Veterinary Medicine, Office of Regulatory Affairs, Pharmaceutical cGMPs, September, 2004.

3. “Continuous Verification-Providing an Alternative Approach to Process Validation,” R. Kettlewell et al. Pharmaceutical Engineering, Jan/Feb 2011.

4. “Process Analytical Technology(PAT)-PAT and Batch Recipe Execution,” Emerson Process Management White Paper, Life Sciences, May 2010.

5. “SIPAT The Software Heart of PAT,” Siemens Product Brochure, Siemens NV, Belgium, November, 2007. ■

■ P H A R M P R O . C O M■ SOLID DOSAGE

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� Tablet Press Offers Improved Productivity And Flexibility The FE55 tablet press is clad in easily detachable, FDA-

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increases production output up to 50%, as well as the ability to produce single-layer and double-layer tablets and direct pressing. It is additionally characterized by a dust-tight, through-the-column discharge assembly

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and direct-compression tablet production, and it is equipped to handle approximately 90% of the most common tablet formats. When config-

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■ W H AT ' S H OT

WHAT’S HOT


■ 18 JULY 2011 | PHARMACEUTICAL PROCESSING P

� Solid Dosage Packaging Machine Features Fast Changeovers With no micro-stops, no ramp-up time and the ability to quickly complete changeovers, the

IBC-120 reliably packages diverse small- to medium-sized batches at a rate of up to 150 bottles (or 24,000 tablets or capsules) per minute. The machine processes round, rectangular and oval bottles 45 to 200

millimeters in height and 25 to 125 millimeters in diameter. In be-tween batches, it can be reset to a different bottle diameter in just 6 minutes - it is fully automatic so there is no need for format parts and tools. The machine is streamlined and compact: at barely 5

meters in length, its monoblock design combines all the essential func-tions for the packaging of solid dose products in bottles and makes it, on average, 20% more efficient than line solutions composed of sepa-rate components. The integrated packaging stations are controlled by

a central touchscreen user interface, meaning the machine adjusts to new bottle heights at the touch of a button. ■ Uhlmann Packaging Systems, L.P., Towaco,

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� Mixers for Improved Efficiency High Viscosity “HV” blades feature a precisely angled helical contour which generates a unique vertical mixing action: the sweeping curve firmly pushes the batch material forward and downward, keeping it within the mixing zone at all times. Enhanced control over batch level can significantly improve mixing efficiency and shorten cycle time, while ensuring easier clean-up and product purity. HV blades also extend the viscosity range of the double planetary mix-er to approximately six million cP. Other clean design features include highly-polished stainless steel 316 wetted parts, labyrinth style gearbox sealing arrangement, and double lip seals on each stirrer shaft, dust shield. ■ Charles Ross & Son Co., Hauppauge NY 11788. www.mixers.com or call 631-234-0500

pp1107_whatshot.indd 18pp1107_whatshot.indd 18 7/1/2011 11:30:52 AM7/1/2011 11:30:52 AM

■ P H A R M P R O .C O M■ W H AT ' S H OT

WHAT’S HOT


Single-Use Tubing and Filter Assemblies � BioFlex™ fluid path assemblies are designed for secure fluid transfer in critical biophar-maceutical processing applications. These single-use tubing and filter/tubing assemblies offer maximum convenience and flexibility in single-use systems. They can also be used in conventional or hybrid facilities to connect single-use and stainless steel processing equipment. BioFlex™ assemblies can be cus-tomized with end-user’s requirements for con-nections, tubing material and various other com-ponents to create a secure fluid path. The assemblies can also be integrated with sterilizing-grade filter capsules in a choice of STyLUX® PES, EverLUX® PES, or SteriLUX® PVDF membranes, or with depth media for clarification requirements. BioFlex™ tubing and filter/tub-ing assemblies are supplied gamma-irradiated for sterility assurance. ■ Meissner Filtration Products, Inc., Camarillo, CA 93012. www.meissner.com or call 805-388-991 1

� Bioreactor System with Compact Footprint The IKA® BR 10 Bioreactor features an inter-face that controls all of the photosynthetic variables of lighting, motion, pH value, and temperature. The unit takes up less than half the space and is priced at about half the price of a traditional bioreactor. Yet, with advanced features and a sleek design, it ensures optimal cell growth of phototrophic organisms such as algae, moss plants, and even many species of bacteria. Used for ap-plications including fermentation, medical research, biodiesel, nutraceuticals, pharma-ceuticals, cosmetics, food, and more, this 10-liter model is versatile in the lab. The interior of the fully jacketed vessel is chemically inert with no exposure to metals. It is specifically designed for temperature-sensitive samples. The vessel is surrounded by a lamp shield with six removable and compact double-fluo-rescent lamps, enabling the photosynthetic process to take place. The digitally controlled PTFE overhead stirrer with two 4-blade ad-justable propellers gently agitates contents to assist in oxygen transfer - yet preserves frag-ile cells. The variable-speed peristaltic pump provides a 120 to 450 mL/min flow rate. As a 10-liter system, the lighting can be disabled and the unit can be used as a lab reactor. ■

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Expanded Biological Safety Cabinet Line � Company has expanded the 1300 Series A2 biologi-cal safety cabinets. In addition to the existing four- and six-foot cabinets, the 1300 Series A2 line is now available in three- and five-foot widths, maxi-mizing internal work space while minimizing the external footprint. The 1300 Series A2 biological safety cabinets also feature the new NSF-approved SmartPort, providing a clean, easy and safe access port for routing vacuum tubing and cables through the side wall of the biological safety cabinet. The 1300 Series A2 biological safety cabinets are avail-able with choices of stainless steel or SmartCoat interiors and eight-inch or ten-inch work apertures. Featuring SmartFlow technology, the supply and ex-haust blowers adapt in real time to provide the cor-rect airflow parameters and maintain a safe working environment. The Digital Airflow Verification (DAVe) system increases safety by monitoring the pressure difference within the exhaust and downflow plenums and sounding an alarm if it varies by more than 20 percent. Reducing the laboratory energy profile is an important consid-eration both economically and ecologically, so the blowers use brushless DC motors to reduce energy consumption and heat output and, for added benefit, reduce noise as well. ■ Thermo Fisher Scientific, Waltham, MA 02454. www.thermoscientific.com or call 781-622-1000

pp1107_whatshot.indd 19pp1107_whatshot.indd 19 7/1/2011 11:31:12 AM7/1/2011 11:31:12 AM

A t one time or another everyone has heard the mantra, “The customer is always right!” When a company is in the midst of a regulatory recall and its new “best friend” is the FDA, the company must

clearly understand that the FDA is their customer AND it is imperative to get the recall “right.”

Over the past year there have been a number of highly vis-ible recalls that have laid waste to companies who did not meet FDA standards. What a company does both publicly and with the regulatory agencies is critical to an organization's ability to survive and thrive. This is a true test of resilience as the FDA is not the only concern. People who buy the company’s products could be the ones to decide their fate.

The FDA and other regulatory agencies have entered a phase of intense regulatory scrutiny of companies who do

not decisively address audit findings. The result has been not only closer scrutiny of the company subjected to the recalls, but to other sites or business units as well. These actions on the part of the FDA make it very clear that they mean business.

However, all is not lost. There are effective courses of action an organization can take to successfully manage cur-rent recall status and prevent future recalls.

ASSESSMENT OF KEY PERFORMANCE INDICATORS (KPIS)

A company scorecard of metrics for investigations and Corrective Action Preventative Action (CAPA) is the start-ing point for the remediation efforts. Each company does this in different ways and to varying levels of sophistica-tion. In order to assess the scale and scope of the recall, an organization needs to review the measures, metrics,

and trends from the past two years to determine the extent of the recall. Some of the data points

needed include:• Number of open investigations and CAPAs• Reportable vs. non-reportable incidents

(counted by level)• Time to close investigations and CAPAs• Resources required to close investigations

and CAPAs• First-time fix rates

• Mean time to resolution (tracked by person-hours)

In order to launch a remediation effort, this information must be quickly accessible and available to all involved in the remediation effort. This is crucial for proper analysis of KPIs.

Next, current workflows that impact the recalled product need to be reviewed. These should include troubleshooting methodology, performance environment and performance sup-port work flows as well as the standard operating procedures (SOPs) for investigations, CAPAs and investigation training. This information, along with the metric information above, will serve as a basis for verifying the improvements recommended at the conclusion of the project.

INVESTIGATION ASSESSMENT Consistency, stability and capability of business processes

are necessary to reduce variations caused either by common causes or by incursion of external factors or special causes. Analysis of the current business and investigation processes regarding the use and implementation of CAPA methods - and root cause analysis (RCA) tools - will identify a framework to address quality events in a holistic fashion. This will reduce the time required to complete investigations and provide a blue-print for future CAPAs to be transparent and traceable and can be adopted at other sites throughout the company.

To achieve this, a company should start with a structured re-view of the organization’s SOPs against past investigations in a “should vs. actual” analysis to judge outcomes. This structured review includes analyzing the SOPs as compared to the written investigations, as well as reviewing the actions of the employ-ees involved. By this approach, the gaps and shortcomings not found in typical audits can be identified and addressed.

CAPA ASSESSMENT To continue with the recall remediation, it is important to as-

sess the company’s CAPAs. That process begins with a review of the SOPs. Once this is complete, a company should meet with its CAPA approval team to identify the gaps between the SOPs and the actual work flows that drive CAPAs as described by the CAPA approval team. This meeting will yield valuable data that will help a company zero in on the “sweet spot” for improving their CAPAs. It is important to note that there typi-cally is a gray area associated with how to choose the most effective and efficient corrective action, among the many that are available. For these decisions, companies should consider working with outside vendors, who can look at these potential actions with an objective mindset, thus removing any emo-tional elements.

RCA TOOL ASSESSMENT Integrity of the RCA tools used in investigations is essential

for achieving scalability, repeatability, improved hit rate, and


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By Michael Curran-Hays , Senior Partner, Life Science, Kepner-Tregoe, Inc

pp1107_feature_Kepner.indd 20pp1107_feature_Kepner.indd 20 7/7/2011 10:51:58 AM7/7/2011 10:51:58 AM


■ R E G U L AT O R Y


ensuring the use of the least amount of re-sources. Consequently, a review of current RCA tools and the training programs that uti-lize these tools will help identify weaknesses and/or limitations that can hinder the level of results. This is essential to keep problems from reoccurring.

Often times, companies use multiple tools to assess RCA, which can result in experts racing down parallel paths towards the same goal - determining the root cause. However, these experts are separated by “virtual walls” because they typically work in different func-tional areas of the company, and the effect of separation results in redundant work and little synergy. One solution to this remediation problem is to establish a companywide RCA tool chest where employees receive train-ing and have access to the basic set of RCA tools, such as “5 Whys,” Fishbone and Kepner-Tregoe (KT) Problem Analysis. Then, as inves-tigations unfold and possibly become more complex, experts of particular RCA tools get assigned to the investigation team so they can apply the more complex set of tools.

In the remediation effort, looking at the interaction between quality investigations and manufacturing production will greatly increase the probability of effectively address-ing issues. Finally, continuous improvement in the use of RCA tools and methods will only guarantee a reduction in recalls if the current RCA tools are in line with training programs. A review of training manuals and seminars is a key element in any remediation effort.

ASSESSMENT OF ROLES AND RESPONSIBILITIES

Understanding the people performance and the dynamics of team performance in cur-rent investigations and CAPAs is THE most overlooked area during remediation efforts. Our work with companies indicates this is often overlooked in standard audits. Yet, when performing a review and remediation of a company’s Investigation/CAPA processes, this is where most of the time is spent.

All meetings associated with investigations and CAPAs, such as CAPA In-Process Status Reviews, Investigation Reviews, Disposition Meetings and Problem-Solving, should be re-corded in order to obtain a summary picture. Once this is achieved, interviews should be conducted with operators, quality control analysts, supervisors and quality assurance

personnel, to get a better understanding of why people are not getting the appropriate performance during investigations.

The results and trends from those inter-views should be explored and clarified with focus groups. Once completed, a full, and comprehensive picture may begin to emerge regarding the rewards and consequences the workplace and the quality or the lack of qual-ity of feedback given to employees. It may also reveal the encouraging consequences man-agement offers the organization to get to root cause and close out CAPAs effectively.

The Performance Environment is an area where the majority of systemic failures can be found. Looked at another way, perfor-mance systems, if designed correctly, and with individual levers pulled appropriately, are the most significant area that WILL ensure a reduction in the likelihood of recalls AND drive dramatic improvements in a company’s “in-process” investigations. Effective perfor-mance systems are the silver bullet for recall remediation. These need to be in place at both leadership and operational levels.

CONCLUSION In the end, recall remediation is hard work.

Somewhere, in all those previous audits, were the nuggets of information and “ah ha” mo-ments that, if exposed earlier would have kept the recall from happening. Somewhere during your past efforts, the blinders were left on and issues were looked at through rose-colored glasses. Now, things have gone sideways in the worst possible way for the company. All pro-cedures, processes and SOPs need to be seen through a new set of eyes with renewed pas-sion to get to the bottom of what is happening. Unfortunately, in a recall those new eyes are now many pairs of eyes, some within the com-pany and many outside of the company. The rush to judgment by many will be uninformed and very damaging, unless the company takes the time to start over and drive the remedia-tion effort across all aspects of the business. ■ ABOUT THE AUTHOR: Michael Curran-Hays coordinates Life Science operations for Kepner-Tregoe (KT) globally with a focus on pharmaceutical, medical device, biotechnology, generic and the health-care provider industries. His area of expertise extends to business process and operational improvement as well as strategy formulation.

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� Weigh Feeders Offer A Small Footprint For Space Constrained Areas Model 407 Series "Weight-Loss" weigh feeders feature

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versatile and are available with a variety of different metering mechanisms which are capable of feeding a broad range of even the most difficult-handling dry sol-

ids materials. The feeders incorporate a robust design and feature a high-resolution, non-load cell based weigh-ing mechanism that never requires field calibration or adjustment. Additionally, the feeding equipment is specifically designed for the industrial environ-ment. The weighing system, including its associated

electronics, is unconditionally guaranteed for five full years. ■ Acrison Inc., Moonachie, NJ 07074. www.acrison.com or call 201-440-8300

Checkweigher Eliminates Steps in Production � Designed for speeds up to 250 pieces per minute, the new HC-MEDIUM (HC-M) features the same control concept as the high-end checkweigher, HC-A, making cross training between various controllers unneces-sary. The new model features a modular sub-frame for cost-effec-tive scaling to various applications and individualized integration with metal detectors, cameras, etc. Additionally, it can be outfitted with a range of reject devices to discharge products of an incorrect weight without disturbing the ongoing flow of production. ■ OCS Checkweighers, Inc., Snellville, GA 30039. www.ocs-cw.com or call 678-344-8300

■ INNOVAT IONS

WEIGHING



EQUIPMENT

� Weighbelt Feeders for Sanitary Wash-Down Applications Designed for pharmaceutical and other sanitary processing environments, the open frame weighbelt feeder is designed to handle high pressure wash-down settings. The design of the weighfeeder makes it easy to clean and maintain. A cam-operated lever lets users remove the belt virtually in seconds, and special

clean-out ports and sanitary grade bearings enable the weighbelt to be pres-sure washed to remove any material or debris build up. The stainless steel DEA open frame weighbelt feeder utilizes a direct drive system that reduces

the use of grease, belts, and chains. Hermetically sealed stainless steel strain gage load cells and a design that incorporates watershed angles optimize drainage

and simplify cleaning. The feeder can be custom built in 12-inch (300 mm) or 24-inch (600 mm) widths. Feed rates up to 1,680 cubic feet per hour are achievable. ■ Schenck AccuRate, Whitewater, WI 53190. www.accuratefeeders.com or call 800-558-0184

� Weighing and Transporting Device The Ergo-1000-OBS-BC is a simple-to-use drum transporting device that allows the operator to handle steel, plastic, or fiber drums. The series uses a manual foot pump to lift and lower each drum vertically up to 20 inches (32 inch optional lift heights also available). The drum is lifted using the com-pany’s exclusive “Parrot-Beak®” clamping sys-tem. The “OBS” model offers a digital readout of each drum’s weight (registered in pounds or kg.). This weighing device allows for sim-ple product weight verifications as well as formal weight management. Accuracy is with-in one pound or 0.25 percent for up to 1,000 pounds in weight. Available options include power lift, spark resistance, wheel choices for varying floor conditions and a printing feature. ■ Liftomatic Material Handling, Inc., Buffalo Grove, IL 60089. www.liftomatic.com or call 800-837-6540

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Leak Tester with Particle and Cosmetic Inspection Capabilities � The PK V Vis Combi is a fully automatic leak tester and visual inspection machine for ampules and vials. This leak testing method follows the ASTM and is fully validated. Because it is equipped with cameras, the machine is able to perform particle, level and cosmetic inspection. When the container is inserted in an airtight chamber, it is tested by applying vacuum. Once testing is completed, the same container is spun and stopped, and several photos are taken. Container is checked for any particles in the product or cracks, and fill levels are also tested. ■ Bonfiglioli Engineering S.p.a., 44049 Vigarano, Pieve (Fe), Italy. www.bonfiglioliengineering.com or call 39 0532 715631

� High-Output Filling and Closing Machine The SFM5110 fills and closes ready-to-fill syringes, vials, and cartridges that are supplied in nests. The intermittent-motion machine achieves a maximum output of 11,300 containers per hour. Depending on the required capacity, the SFM5110 is available for processing 2 or 5 posi-tions at each machine cycle. The compact design and the streamlined work area enhance the effect of a laminar air flow. The filling process can be carried out by means of rotary piston pumps, peristaltic pumps, or a time-pressure dosing system. In order to prevent air from becom-ing trapped in the tip of the syringe, the filler/closer can be equipped with a vacuum-assisted dosing station. Immediately after filling, the containers are closed by precisely positioning a stopper in the syringe. The stopper insertion is carried out by means of a vent tube or under vacuum. A fully-automatic in-process control (IPC) system allows for controlling the automatic dose adjustment optimization process when starting up the machine, and for performing regular weight checks during production. ■ Bausch + Stroebel Machine Company, Inc., North Branford, CT 0647. www.bausch-stroebel.com or call 866-512-2637

■ INNOVAT IONS

VIAL&SYRINGE



PROCESSING

Automatic Ampule Filler and Sealer � The Ampulmatic®-10 speeds and automates filling and sealing of glass ampules at rates of up to 10 per minute. The gas and liquid filling units have been redesigned for increased service life and ease of maintenance. The optional ampule filling unit can be configured to fill each ampule automatically with an inert gas or a precisely measured of liquid. This new feature will be available in the second half of 2011. The base unit automatically indexes each ampule on a carousel rack, available in 1, 2, 5, 10, 20 and 50 ml standard sizes, for a consistent hemispherical flame seal. The filler and sealer can be operated on natural gas, MAPP or propane, with technical grade oxygen at 10 to 20 psi. Supply voltages can range from 110 or 240 VAC and power consumption is 100 watts. ■ Bioscience, Inc., Allentown, PA 18109. www.bioscienceinc.com or call 800-627-3069

� Bench-Top Dual Syringe Filler The Model 1100 is a highly precise dual syringe filling system designed to fill two syringes simultaneously in as little as two seconds. Dispense cycles on each

syringe remain independent, making it possible to fill syringes with separate materials. This bench-top system is ideal for down packing or filling syringes with a wide

variety of materials including pharmaceuticals, creams, cosmetics, and dental products. The model’s precision is attrib-

uted to its unique, nozzle-end filling method and individual, automatic shut-off sensors. Materials are filled through the tip of the syringe allowing the syringes to be filled with pre-inserted plungers, which increases accuracy of fill by eliminating air pockets and material stringing. ■ DYMAX Corp., Torrington, CT 06790. www.tridak.com or call 877-396-2988

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t

t

t

vtt

Fig 1: Example of an SIP process

Pharmaceutical and biochemical plant owners must adhere to regulatory standards that govern the cleaning and sterilization of pipes, valves, tanks and reactors. These standards assure the integ-

rity of the process and the batches produced. The hygienic processes associated are very demanding on the controls and equipment, and can be quite expensive.

Sterilization-in-place (SIP) and cleaning-in-place (CIP) provide an economical method of meeting the goals of batch integrity and regulatory compliance at a fraction of the cost of breaking down a process to clean it. The goal of SIP and CIP is to oper-ate plants efficiently with reduced down time and maximum re-liability. Selecting the correct steam traps is crucial to ensuring the stability of the process, as well as maintaining the required cleaning schedules. However, these valves are not always given the attention they deserve and thus customers can miss an op-portunity to maximize cost savings.

The first step in the overall process is CIP. The process liquid is drained, and water and acid are forced through the entire system to clean out contaminants such as dirt and viruses. This process allows for cleaning and disinfect-ing without having to break down or reassemble the process com-ponents, promoting uptime and process availability. With a CIP pro-cess, parameters such as tempera-ture, speed, concentration of the cleaning medium, and the cleaning duration must be considered.

Once the CIP process is com-

pleted, the subsequent SIP process focuses on killing microor-ganisms by heating the entire system, without disassembling it. Depending on the kind of organisms, the system is heated up to 150°C. The SIP process uses saturated steam from a clean steam generator. This is the only type of steam with a combination of temperature and moisture that offers a suitable medium for dependable sterilization. The success of the sterilization proce-dure then depends on whether the temperature in the system remains constant. Following sterilization, the system must be cooled down; this is done by purging it with sterile air.

The SIP process is regulated at a constant temperature by selecting the correct pressure for the saturated steam. Any condensate that is produced will reduce the temperature. An im-portant process step is therefore to detect the physical state of the medium and to achieve an adequate response time for the steam trap. Plant components that are difficult to reach - as well as the endpoints of the system - are especially critical. These sensitive positions are monitored by temperature sensors and provide the basis for validation of the production plant.

SUITABLE STEAM TRAP PROPERTIES All internal components in contact with the fluid should

be made of stainless steel type 316L. There is a fundamental principle that special requirements are best served by a more precise definition of the desired specifications, since a variety of materials in this “material group” may be used, depending on the manufacturer. Body gaskets are usually made of polytetrafluoroethylene (PTFE), ethylene propylene diene monomer (EPDM) or fluoroelastomer (FPM). All meet the requirements of the FDA.

With regard to the surface roughness (Ra) of the interior surfaces, a roughness value of Ra �0.8 µm (32 microinch) has become standard. The goal is to prevent active ingredients from the batch to embed in the pores of the process com-ponents. Some manufacturers offer values down to < 0.4 µm (16 microinch). In some cases, electropolished surfaces are requested, with a view to preventing batch material active in-gredient deposits and contamination from the very start. The most important functional unit of the steam trap is its control component. Thermostatic steam traps are offered in a choice of bimetallic, membrane and bellows types (Fig. 3).

With bimetallic regulators, the opening and closing opera-tions are controlled by the interaction of the temperature sensor (consisting of bimetallic plates) and the stage nozzle. Because of its propensity to trap dirt and potential for contaminating the process, it is generally not suitable for use in pharmaceutical

Steam Trap Tips The right steam trap saves money and increases uptime in SIP applications n By Alexander Hofmann, Key Account Manager Pharmaceutical Industry, Steam Traps And Valves, Flowserve Corporation


■ P H A R M P R O . C O M ■

■ C L E A N I N G■

Fig 2: Condensate produced in a ¾” pipe of stainless steel during sterilization with saturated steam at 43.5 psi/291.2°F

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plants. The same applies to the bellows regulator, although this type is very similar in function to the membrane regulator.

In contrast, the membrane regulator offers a decisive advantage over bimetallic and bellows regulators for phar-maceutical applications. Because of its small surface area, it responds quickly to changes in temperature and other oper-ating conditions. When condensate flows through the trap, the control medium in the capsule is completely liquid, as a result of the low ambient temperature. This gives operators the ability to drain air and cold condensate during the start-up process, minimizing start-up time.

When the pressure within the capsule is lower than the sur-rounding pressure (surface pressure), the membrane with the valve disc is pushed open (Fig. 4, left). When the condensate temperature rises, the liquid starts to evaporate. When the in-ternal pressure of the capsule rises, the membrane is pressed in the closing direction (Fig. 4, right). The function is not af-fected by a fluctuating upstream pressure or by back pressure.

Since the membrane regulator detects the change of the medium’s physical state from steam to condensate and

Fig 5: Structure of the Flowserve Gestra steam trap type SMK 22-81

Fig 6: Functional test of the FlowserveGestra capsule 5HiUpstream pressure = 46,4 psi / TS = 293 °F25.8 lb/h condensatePractically constant plant temperature T2 with minimal banking of condensate through use of a capsule when sterilizing a 32.8 yard section of pipe with the nominal size ¾”.

Fig 4: Functional principle of the Flowserve thermostatic capsule

-


■ C L E A N I N G

quickly discharges the condensate, downtime is reduced and a stable batch process is maintained. Membrane regula-tors also have an advantage in their structural design. Since they have almost no crevices, the risk of process contami-nation is reduced dramatically. This permits a long service life and a reliable, safe SIP process.

Outages and maintenance downtime can be reduced to a minimum. Nevertheless, it is necessary to take steps during the planning phase to ensure good accessibility to these valves. In order to minimize the need for gaskets, orbital welding ends are frequently used for the connections to pipework. There are also body versions which allow a rapid and easy exchange of the regulator (i.e. the functional unit). Only two gaskets are re-quired in this case (Fig. 6).

With the correct selection and sizing of the steam trap sys-tem, sterilization-in-place is a safe, reliable and cost-saving pro-cess. Temperature fluctuations, and hence the risk of unwanted contaminants entering the process, need not jeopardize ef-ficient production, high system availability, and profitable operation of the plant. ■



Fig 3: The various types of thermo-static steam trap regulators. From left to right: bimetallic regulator, bellows regulator, membrane regulator.

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■ B R A I N S T O R M



Terry Novak, President, Norwich PharmaceuticalsRequirements to qualify as a preferred service provider have become

stricter and sponsors now hold preferred providers to higher standards than in recent years. The key requirements haven’t changed, how-ever, I see greater scrutiny being focused towards security of sup-ply and financial stability. While regulatory compliance will remain the cornerstone of a successful due diligence process for service providers, sponsors are increasing demand for on-time delivery, re-questing historical performance metrics and including accountabil-ity measures within contracts that guarantee performance. As large companies continue to consolidate and outsource more services, the greatest difference now occurring is centered upon financial

stability to ensure that service providers will be financially viable partners for the long term. RFI’s are now much more detailed regarding the financial information needed to become a preferred provider. Driving the focus on fi-nancial stability is the increasing number of financially troubled service pro-viders that can't meet the rapidly expanding technical needs of the industry.

Have sponsor requirements for qualification as a preferred service vendor become stricter? If so, can you explain what the drivers are behind this change?

Veda Walcott, Vice President of Qual-ity, Cook Pharmica

I am not sure I would describe our client’s qualification requirements as more strict; however, the process has definitely become more complicated. An increasing number of biopharm companies are forming one or more strategic partnerships, which is adding to the complexity of the process. As a result, becoming a qualified vendor requires partner due diligence visits and at times multiple quality system audits to support a single client relationship. In addition, with the goal being successful integration of multiple quality systems, qual-ity agreement negotiations with our clients necessitates consideration of the partner(s) requirements. All of these factors can influence our qualification status as a preferred vendor, but it also it provides us the opportu-nity to demonstrate our flexibility and responsiveness.

IMA ACTIVE Division [email protected] • www.ima.itIMA NORTH AMERICA, [email protected]

IMA perforated and solid wall coating pans: always the best solution for your requirements

The new Perfima perforated pan

guarantees the best results in coating

processes.

Having the same shape, and with the mixing

baffles in the same position as the established

IMA GS coating pans ensures perfect mixing,

uniform coating and high flexibility allowing

a wide range of batches to be processed

in the same drum.

The drying of cores is carried out using

a minimum quantity of air, thereby

saving energy.

PERFIMA the perfect perforated solution

H A N D L I N G • G R A N U L AT I O N • TA B L E T I N G • C A P S U L E F I L L I N G A N D B A N D I N G • W E I G H T C H E C K I N G • COAT I N G • WA S H I N G

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Fluid Bed Dryer-Granulator-Coater �

The 3-in-1 fluid beds allow drying, granulating and coating on the same machine using one single product bowl with no need for insert, Wurster column, or rotor. The product’s unique features include a discjet bottom plate which distributes the drying air from the bottom of the fluid bed at the same 45-degree angle as the nozzles deliver the coating liquid, as well as a Hüttlin 3-fluid nozzle design which includes a compressed air supply for ‘microclimate air’. The 3-fluid nozzle blows a protective ring of air around the tip of the nozzle to prevent any block-age and ensure that the coating of the particles happens at the correct distance from the nozzle. ■ OYSTAR USA Process Division, Edison, NJ 08837. www.oystarusa.com or call 732-346-7600

Self-Contained, Portable Coaters � The LDCS-Pro system is an extension of the highly successful LDCS Hi-Coater product line that utilizes multiple interchange-able fully perforated pans.The coater is a self-contained and portable system for pilot scale and small production, aqueous, solvent and sugar coating applications. Five interchangeable pans are available to provide maximum batch size processing flexibility. Pan volume capacities are 20, 40, 55, 110 and 150 liters and each pan has the capability to process as low as 25 percent of the rated volume capacity. System features include a touch screen recipe-driven control system with manual and auto-matic operation modes, an integrated solution pump system, anti-bearding spray guns, and anti-marking mirror-finished coating pans along with removable anti-slide and mixing baffles. ■ Vector Corporation, Marion, IA 52302. www.vectorcorporation.com or call 319-377-8263

� Perforated Pan for Tablet Coating The PERFIMA is a highly flexible and reliable perforated pan for tablet coating. The shape of the pan and the mixing baffles’ position ensure a perfect mixing of the cores and a uniform distribution of the coating mate-rial. The machine can work a wide range of batches, from 25 to 100% of the pan capacity, maintaining mixing capability when work-ing with a minimum or a maximum quantity of product. Position and dimensions of the outlet air duct allow for uniform drying of the product, thus saving energy. The spray guns fitted on a sliding support arm can be positioned and adjusted from outside. Automatic product loading and discharge are available on request. Complete isolation of all the parts in contact with the product is obtained with special seals, allowing full containment installations and a completely automatic clean-in-place system. A “through the wall” installation is also available. The front and side doors fitted on the machine provide excellent accessibility. PERFIMA is available in four models: 200, 500, 800 litres and Perfima Lab for R&D purposes. ■ IMA North America, Inc., Leominster, MA 01453. www.ima.it or call 978-537-8534

� Tablet Coater Reduces Processing Times Tablet coater reduces processing times up to 35% compared to conventional tablet coating systems, yielding significant cost savings and improved cam-paign efficiency while maintaining cGMP standards. The company’s patented air flow bed technology eliminates spray drying, thereby reducing waste while lengthening campaigns between cleaning. It also promotes uniform tablet coating with a high-quality, defect-free film coat. The tablet coater’s elongated coating pan provides a larger tablet spraying surface accom-modating up to 10 spray nozzles, which delivers more suspension solution

and reduces overall coating time. The unit’s integrated mixing baffles are double-helix shaped to ensure thorough tablet mixing with gentle handling. The

baffle design provides 100% tablet discharge, increasing campaign efficiency. ■ L.B. Bohle LLC, Warminster, PA 18974. www.bohle-tablet-coater.com or call 215-957-1240

■ INNOVAT IONS

EQUIPMENT



COATING

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Intense pressure to demonstrate increased productiv-ity and a robust return on R&D investment is leading the pharmaceutical industry to focus aggressively on cost control and process improvement. To address

these challenges, drug developers are increasingly leveraging lean manufacturing initiatives. Based on principles largely developed by Toyota, lean manufacturing seeks to identify and eliminate waste in order to reduce the cost of bringing a product to market. Centered on creating more value with less work, lean manufacturing generally focuses on reducing eight specified wastes to improve overall customer value (Table 1).

In parallel with this focus on lean process improvement, the industry is actively evaluating and leveraging single-use products and systems to reduce costs, increase productivity, and speed time to market. The move to single-use solutions, either alone or in conjunction with stainless steel, is likely to continue growing in an effort to address these imperatives.

When managed properly, implementation of single-use sys-tems can deliver key benefits as defined in the principles of lean manufacturing: • Improved quality

• Reduced waste• Increased productivity• Optimized resource utilization

This article will highlight industry trends that are driving adoption of single-use systems and describe the implementa-tion of single-use filtration to deliver lean process improve-ment efficiencies and drive waste out from the manufacturing workflow.

A MARKET IN TRANSITION The biopharmaceutical industry is undergoing a number of

changes that are having a significant impact on manufactur-ing (Table 2).

Where once a few major drug companies were the industry leaders and had little competition, contract manufacturing or-ganizations (CMOs) and generic manufacturers are now play-ing an increasing role in bringing drugs to the market. Adding to this new reality is the need to evolve from a focus on large batches manufactured at a single facility to production of numerous, low volume, high variability batch runs at multiple facilities around the world.

Delivering Process Improvements By leveraging single-use operations and lean strategies companies can deliver real value and reduce costs■ By Vikas Gupta, EMD Millipore, Group Product Manager, Mobius ® Single-Use Products and Services


■ P H A R M P R O . C O M■ S I N G L E - U S E

v

t

■

EMD Millipore has the capability to mimic a customer’s pilot manufacturing setup in their Biomanufacturing Sciences and Training Center.

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One of the most challenging trends is the shift of drug development phases (research and development, pilot scale, commercial scale manufacturing) from single, vertically inte-grated facilities to separate locations around the world. While use of multiple sites across multiple countries can bring great value into the system, the practice puts increased demands on technology transfer processes.

Different manufacturing equipment, materials, and design may be used in each phase, presenting significant process optimization and validation challenges due to inconsistencies among bioprocess equipment across scales. Rapid and seam-less technology transfer processes are thus essential to main-tain consistency across all scales.

In an effort to address these challenges, many manufactur-ers are turning to single-use manufacturing solutions. The benefits of single-use products in manufacturing are widely known and well-documented. When implemented properly,



■ S I N G L E - U S E

Table 1. Eight Types of Wastes Targeted by Lean Process Initiatives

TYPE OF WASTE WHAT IT IS

Overproduction Processing too soon or more than is required. Product(s) are made just-in-case and not just-in-time, which results in excess orders, high inventory, high scrap and unnecessary labor.

Defects Product defect is the most easily identified waste and has a direct impact on customer satisfaction.

Inventory Lack of balance between inventory and process flow can result in excess inventory being created.

Overprocessing Having a complex tool or product design can cause unwanted activity, resulting in unnecessary labor, overdesigned functionality, and is often a result of legacy processes.

Transportation Moving product unrelated to processing such as moving equipment to meet layout constraints, long distances between process setups, fixed capital equipment results in difficulty in moving assembly manifolds and lack of modularity.

Waiting Unnecessary waiting for the next production stop, without adding value, such as waiting for approvals, shared resources, sub-optimal workflow, insufficient labor, results in long vendor lead times and long assembly set-up time.

Motion The unnecessary movement of people beyond the minimum required can be caused by sub-optimal SOPs, poor process design and/or poor work area layout.

Underutilized People Perhaps due to a lack of open communication or lack of integration among employees, employee creativity can be overlooked.

Table 2 – Evolution of Biopharmaceutical Manufacturing

PAST FUTURE

Large drug companies maintained leadership position with no major competition

Increasing competition from CMOs and generic manufacturers

Single product facilities Multi-site, multi-product facilities

Large-scale batches Small to large scale batches with a lot of variability

High volume-low variety formulations Low volume-high variety formulations

All stainless steel equipment Mix of stainless steel and single-use or all single-use equipment

Less focus on cost control and process improvement Focus on lean process improvement and bottom line impact

Vertically integrated with minimal need for technology transfer Increasingly complex technology and knowledge transfer between R&D, pilot, and commercial manufacturing sites

Table 3 – Sources of Process Inefficiencies with Single-Use Systems

Multiple single-use components from multiple vendors

Long vendor lead times

Excessive item number set-ups, costly maintenance of multiple item numbers in material master

High inventory and scrap levels

Inefficient use of warehouse storage space

Inefficient use of operator time, EHS issues

Complicated assembly design and long set-up periods

Difficulties in handling single-use assemblies


■ P H A R M P R O . C O M■ S I N G L E - U S E


single-use systems can accelerate produc-tion, improve flexibility, reduce costs and waste – benefits that are well-aligned with lean process initiatives.

What can prevent a company from fully realizing these benefits, however, is the manner in which single-use systems are sometimes employed – on an ad hoc basis without a cohesive plan for applying the technology across all process scales. Lack of an overarching single-use strategy can actu-ally increase process inefficiencies (Table 3).

When single-use assemblies are sourced from different vendors, inefficiencies can be amplified as operators must become famil-iar with multiple systems, and components are likely to have different expiration dates and lack compatibility. Further, a smooth and seamless technology transfer process may be much more challenging when differ-ent materials are used at various manufac-turing scales.

Consideration of the principles of lean process improvement during implementation of single-use systems can help ensure that maximum value is achieved.

DELIVERING VALUE WITH SINGLE-USE FILTRATION

In order to deliver lean process benefits, single-use systems must be able to speed production processes, reduce the risk of deviations, maintain consistency, and have an immediate and favorable impact on the bottom line through improved efficiency. Assemblies must effectively keep pace with

changing product, scale and site require-ments via a modular structure that is repli-cable and scalable across geographies.

To fully support lean initiatives, the single-use filtration system should offer fully optimized, customized and integrated assem-blies, and reduce waste.

Single-use storage and filtration systems based on Mobius® Flexible Filtration ap-proach (EMD Millipore) are designed to target the wastes identified by lean process initiatives: overproduction, defects, excess inventory, overprocessing, unnecessary transportation and motion, waiting, and un-derutilized talent (Table 4).

Most critical to the successful implemen-tation of single-use systems and delivery of the full array of benefits, however, is the applications support process. This prac-tice brings together users, applications engineers and lean process improvement experts. Through observation of existing process and direct interface with operators, performance gaps and opportunities for im-provement are identified.

The team then works in a collaborative fashion to develop the new process designed on Flexible Filtration principles.

REDUCING PROCESS PRODUCTION TIME

We have found that single-use filration as-semblies can reduce processing time by as much as 50% through decreased preparation and set-up time. A number of innovative ele-ments are the drivers of this reduction. A

modular manifold design allows a manifold to be built on site, to scale as needed. The easy filling bag design eliminates the need for operator handling during bag filling. A universal bag design and scalable sterile filtration assemblies facilitate technology transfer between early development, late development and commercial manufacturing. Unique disconnection technology reduces the time required for sterile disconnection to less than a minute as compared to five to ten minutes required by a tube sealer.

IMPROVING PROCESS CONSISTENCY As with any lean process initiative, the

ability of single-use technologies to con-sistently deliver the full range of expected benefits depends on a thorough assessment of the current processes, opportunities for improvement, and a clear definition of ob-jectives.

To this end, EMD Millipore mimics the customer’s pilot manufacturing setup in our Biomanufacturing Sciences and Training Center (BSTC, Figure 1). The center enables prototyping of solutions and performance testing in a laboratory setting before the definitive solution is finalized and delivered. Consultants review process parameters such as flow rate and pressure drop re-quirements, and recommend appropriate filter membrane and size when designing filtration sub-assemblies.

As many as ten to fifteen operators can gather at the training center to see, touch, and use the prototypes in the training center. Hands-on testing gives operators a greater degree of confidence than a typi-cal new processing setup might foster. In addition, operators can provide real-time feedback, allowing the solution to be better adapted to their actual process.

FACILITATING TECH TRANSFER The effectiveness of the technology trans-

fer process is critical to maintaining product quality and speeding time-to-market. Use of different systems from different vendors can impede an efficient and accurate transfer and force processes developed at one scale to be recreated and re-optimized at other scales.

Use of replicable, modular single-use sys-tems help facilitate cost-effective and timely

Table 3 – Sources of Process Inefficiencies with Single-Use Systems

Multiple single-use components from multiple vendors

Long vendor lead times

Excessive item number set-ups, costly maintenance of multiple item numbers in material master

High inventory and scrap levels

Inefficient use of warehouse storage space

Inefficient use of operator time, EHS issues

Complicated assembly design and long set-up periods

Difficulties in handling single-use assemblies

P


Table 4. Reduction of Waste Using Mobius Flexible Filtration

TYPE OF WASTE BENEFITS OF SINGLE-USE SYSTEM

Overproduction Based on the manufacturing requirements of the day, the operators can develop a Flexible Filtration-based solution by choosing the right-size and right quantity of modular components such as a storage bag sub-assembly and a filtration sub-assembly and connect them using a sterile connector sub-assembly, thereby preventing over-use of single-use components.

Defects A limited, yet prudent selection of modular components that can be easily connected to each other reduces the risk of excessive handling related product defects, a very common occurrence with complex and custom designed single-use solutions.

Inventory Flexible Filtration-based solutions can result in as much as 75% reduction in single-use catalog numbers with the added benefit of product consistency from a single vendor. This significantly reduces warehouse storage space, produces far less scrap, and results in shorter ordering lead times. Item master maintenance is reduced and synchronized expirations dates are ensured. A smaller set of catalog numbers and increased standardization also helps ensure security of supply.

Overprocessing A modular approach reduces unnecessary handling of supplies as well as time needed for data input and recordkeeping tasks.

Transportation The risk of damage associated with transporting assemblies, as well as the difficulty in moving complex assembly manifolds, is reduced with modular solutions.

Waiting Flexible Filtration based modular solutions can result in as much as 50% reduction in single-use assembly set-up and handling time. Easy connection of modular components using Lynx S2S sterile connector devices and easy filling bag designs requiring minimal operator intervention during filling contribute to significant time savings and improve operator productivity.

Motion The traditionally designed custom single-use assembly manifolds can result in excessive motion related waste. Operators are not only forced to design jury rigged hardware systems to support “spaghetti-like” assembly manifolds, they also have to spend a lot of wasted effort and deal with EHS issues while maneuvering and using these assemblies. Flexible Filtration-based modular solu-tions address this problem and make the assembly set-up and use a really simple step in the manufacturing process.

Underutilized People Flexible Filtration-based single-use systems incorporate extensive collaboration with and input from users. This process creates engaged stakeholders with a clear understanding of how the system and processes work.

technology transfer across multiple sites and different scales.

IMPACTING THE BOTTOM LINE Table 4 summarizes the reduction in waste that can be achieved

through proper incorporation of single-use systems. Properly estab-lished single-use systems can deliver as much as a 20% reduction in materials usage.

In addition to significant reductions in processing time and waste, Flexible Filtration based single-use systems can significantly reduce the number of part numbers needed to be maintained. One customer has reported to us a 70% reduction in material master maintenance when the number of single-use vendors was consolidated; with each new catalog number requiring an investment of up to $1200 to main-tain it annually in an ERP system, this reduction represents an im-pressive cost savings.

PERSPECTIVE Drug developers are actively exploring and leveraging single-use

operations to deliver lean process improvements. When incorporated as part of an overall strategy to reduce waste and process time, im-prove process consistency, and facilitate technology transfer, single-use systems designed with lean process improvement principles can deliver measureable benefits to the bottom line.

Critical success factors include consolidation of single-use vendors and equipment to minimize variability and create consistency across processes, and a collaborative approach with applications support engineers and lean process improvement experts to assess current process and identify opportunities for improvement. ■


■ S I N G L E - U S E



■ MARKETPLACE


The Advertisers Index is provided as a reader service. Although every attempt has been made to make this index as complete as possible, the accuracy of all listings cannot be guaranteed.■ ADVERTISERS INDEX


Advanced Scientifi cs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21

Cook Pharmica LLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

Heinkel Filtering Systems Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34

IMA North America Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28, 35

Mettler-Toledo Safeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Mettler-Toledo Hi-Speed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Millrock Technology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

Natoli Engineering Company Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1, 7

OCS Checkweighers Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23

Pall Life Sciences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Reed Exhibition Companies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Ropack Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

Ross, Charles & Son Company . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34

Scilog Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

Sensient Pharmaceutical Coating Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Veltek Associates Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Western States Machine Co. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33

TUMBLEBLENDERS IN STOCK

“V”AND DOUBLE CONE DESIGNS• Sanitary construction• Many sizes available

LOWEST PRICES!

1-800-243-ROSSwww.tumbleblenders.com

For information or to

reserve space contact

MIKE KELLY E-mail:

[email protected]

Phone: 973-920-7751

Fax: 973-607-5678

CENTRIFUGESHorizontal Peeler Centrifuges

Vertical Basket Centrifuges

856-467-3399www.heinkelusa.com

Inverting Filter Centrifuges

Comber Nutsche Filter-Dryers

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INSPIRED BY EXCELLENCE.

THE IMA LIFE NEW RANGE OF ISOLATORS.

Th is is the refrain that always drives us to further innovate.

Combining essential features and the simplicity of proven technology

with widely appreciated high standards of quality and reliability

the new line of ISOLATORS is the ultimate innovation

in the IMA Life range.

V I A L LOA D I N G • WA S H I N G • D E P Y R O G E N AT I N G • F I L L I N G • F R E E Z E D RY I N G • S TO P P E R I N G • C A P P I N G

Life should be treated with kid gloves

IMA LIFE S.r.l. • [email protected] • www.ima.it

IMA LIFE NORTH AMERICA, INC. • [email protected]


845-339-5700 millrocktech.com

®

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Pharmaceutical Processing July 2011

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