The Importance of Metal Detectors in Your Process:

A Comprehensive Review and Analysis

Today's manufacturers of pharmaceutical products have been undergoing a continuous process of automation aimed at increasing production volumes, raising quality and countering cost pressures. Even in a well-managed, thoroughly automated and mechanized facility, the possibility of the product becoming contaminated with metal at some point in the production process is very probable.

Frequently, metal particles enter the production process along with the primary products. No matter when or where metal contamination can or might take place, one absolutely essential requirement of good quality management is that no flawed product ever be allowed to reach the market. To prevent this from happening, metal detection and rejection systems are now essential in the process stream to reliably identify and separate out all metal-contaminated products including those in aluminum foil. (Fig 1.)

A Rationale for Using a Precision Metal Detector

Figure 1: A Rationale for Using a Precision Metal Detector.

A piece of metal in a finished product can cause serious injury to the person who consumes the contaminated piece. Therefore, consumer protection is of primary importance in this context. Consumer protection when analyzed a little more closely is related to and an important component of brand-name protection. Just suppose you happen to be reading a regional newspaper and stumble across the headline "Consumer gravely injured by chip of metal in a (name a pharmaceutical company's product)" – and the product in question is one of yours (lawsuits not withstanding)! Without wishing to disparage the consumer's injury, your first worry, of course, would be how much damage this is going to cause your company's reputation, much less its bottom line.

Another factor in the equation is machinery outage caused by even a tiny piece of metal wandering around in the production process. The result is lost time and money due to a production stoppage or even worse a plant shutdown. Therefore, to make a point, without belaboring the damage to a company's image- and health hazards aside – we can correctly assume that every manufacturer wants to produce high-quality products and keep their machinery functioning at their peak capabilities. Looking at the bigger picture and avoiding the nightmare scenario of a plant closing, finding the metal before it becomes a major problem should be the goal of every plant manager or supervisor.

As I already mentioned, if the plant is working under intense cost pressure, its production resources must be reliable and economically efficient. It is therefore prudent to install precise metal detection and rejection systems at various strategic points along the production line rather than risk a possible plant stoppage or shut down caused by the failure to detect the problem in the first case. Thus when metal is detected and eliminated from the process the cost of the detector becomes a non-issue in comparison to the peace of mind and bottom line of the manufacturer involved.

The Benefits of Metal Detection

The benefits of metal detection follow directly from the reasons for using metal detectors in the first place. By systematically exploiting the advantages of metal detection and rejection with state-of-the-art technology, a manufacturer can invest all its energy to refining its products and developing new ones. They won't have to worry about lawsuits for immaterial damages or about the company's image suffering because of negative headlines.

Modern metal detectors do much more than just sound the alarm on metal particles. They have also become a front line instrument of many manufacturer's quality management systems and SOP protocols. These advanced features include automatic check prompting and rejection monitoring that is now integrated into the production data as is quantity of pieces, number and time of metal-detected messages, detailed fault messages, beginning of recording and detection sensitivity settings. The accumulated data is then sent via an interface (provided with the metal detector by the manufacturer) to a central computer for evaluation.

Basic Design of Metal Detectors

When sensitivity requirements are particularly high, metal detectors with a tunnel like opening for the product to pass through are the preferred configuration (Fig. 2).

Figure 2: The housing of the metal detector is made of stainless steel with deference to hygienic requirements, particularly in wet areas.

The housing of the metal detector is made of stainless steel with deference to hygienic requirements, particularly in wet areas. The evaluating electronics unit is mounted either directly on the detector or at an operator's station situated a few meters/yards away. The measuring system itself is integrated into the detector and consists of three coils (Fig. 3).

The coil at the center is the transmitter. Driven by an oscillator, it sets up a more or less high frequency alternating field. We will take a closer look at the effects of frequency later on
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The transmitter is flanked by a pair of receiving coils situated equal distances away. The two receiving coils are wired up such that the voltages induced on either side by the transmitter cancel each other out. In the idle state the receiver voltage equates to zero and only changes if a piece of metal passes through the detector. The resulting signal is then amplified and processed electronically into a metal detected signal.

The size of the gate in a metal detector depends on the geometry of the product to be monitored: The smaller the gate, the better the base sensitivity.

Figure 3: The measuring system itself is integrated into the detector and consists of three coils.

Basically, there are two ways for metal to affect the magnetic field:

Field grouping

Ferromagnetic metals (those containing iron) and ferrites are most likely to cause concentration of the magnetic field lines (Fig. 4). Referred to as reactive, this effect is more or less pronounced, depending on the material's permeability, but will always be stronger than the other effect – field displacement – which we will go into next (see below).

Figure 4: Ferromagnetic metals (those containing iron) and ferrites are most likely to cause concentration of the magnetic field lines.

At the point where the metal is located within the search tunnel, the field lines are subject to localized concentration. The result in homogeneity of the transmitting field produces different induced voltages in the two receiving coils, and the difference amounts to a metal-detected signal that can be evaluated by the detector.

Field Displacement

Due to the permeability of diamagnetic and paramagnetic metals (stainless steel and nonferrous metals), they prevent concentration of the magnetic field. On the contrary, the alternating field set up by the transmitter induces a voltage in the metal. Depending on its electrical conductivity, this produces a current, i.e., an eddy-current that in turn generates its own magnetic field. In accordance with Lenz's Law, the magnetic field appearing in the particle of metal opposes the exciting field. The two fields repel each other, and the field around the particle of metal is displaced, or distorted (Fig. 5).

Figure 5: The two fields repel each other, and the field around the particle of metal is displaced, or distorted.

The inhomogeneous state of the receiving field resulting from that phenomenon produces a measurable voltage in the receiving coils that can be evaluated as a metal detection signal.

Eddy-current formation pulls energy out of the excitation system – so the effect is referred to as resistive.

Mixed Signals

In actual practice, both of these effects usually appear in combination. Depending on the transmitting frequency, a more or less pronounced eddy current will form on the surface of a ferromagnetic particle. This reduces the metal's permeability, perhaps to less than 1, depending on the size of the metal particle and on the working frequency. Outwardly, then, a piece of ferromagnetic metal acts as if it were diamagnetic.

Determining Factors of Metal Detection: Detectability of Various Metals as a Function of Transmitter Frequency - Basic Causality

Figure 6: spherical pieces of iron and of a nonferrous metal/stainless steel, each with a certain diameter.

As already mentioned, the effect responsible for the detection of metal changes with the frequency emitted by the metal detector and with the size of the metal fragment. Figure 6 illustrates this causality for spherical pieces of iron and of a nonferrous metal/stainless steel, each with a certain diameter. One product with a defined degree of conductivity (moisture) behaves like stainless steel (VA), but we will discuss that later on. As the curves clearly show, there is a certain optimal working frequency for the detection of various types of metal in combination with the product's own characteristics.

Phase Relations of Various Metals with Respect to the Transmitter Phase Angle

Each different kind of metal generates its own typical metal-detected signal specific to the transmitter voltage. It is useful to consider the metal-detected signal as a vector, with the phase angle representing the species of metal and the amplitude as the size of the particle.

Figure 7: the connection, i.e., it is a vectorial version of Figure 6 for a certain frequency.

Figure 7 illustrates the connection, i.e., it is a vectorial version of Figure 6 for a certain frequency.

The phase angles are subject to the same physical action mechanisms as those described before (3), and, as also already mentioned, the phase angle is function of the size of the metal fragment.

To begin with, the various species of metal – iron (Fe), nonferrous metals (aluminum, Al; brass, br; bronze, bz) and nonmagnetic stainless steel (VA, e.g., 1.4301, 1.4401) have distinctly differentiable phase angles. Magnetic varieties of stainless steel, e.g., 1.4043, behave like iron, which is detected by way of its pronounced ferromagnetic effect.

The Product Effect

Figure 8: Since its volume is significantly larger than that of a piece of metal, such a conductive product can also be expected to have a signal vector that is larger than that of the metal.

A product is said to have a product effect if it is electrically conductive, i.e., if it would commonly be referred to as somewhat moist. From the technical standpoint of metal detection, this kind of conductive product behaves like stainless steel or a nonferrous metal. Since its volume is significantly larger than that of a piece of metal, such a conductive product can also be expected to have a signal vector that is larger than that of the metal (Fig. 8). In order to detect and indicate a metal fragment in such a constellation, the detector must feature two-channel evaluation based on two different, independently adjustable sensitivity levels. Modern electronic equipment for metal detection should also be able to suppress the product effect. This suppression, or "learning", of the product effect is understood as the process of turning the product vector such that only the signal from the piece of metal to be detected is indicated in a given axis of evaluation (Fig. 9).

Since, as already mentioned, the various types of metal have different phase angles, it is difficult to identify each different metal species unless each evaluation axis has its own separate sensitivity adjustment - like some metal detectors have the capability to do. Any change in the product effect - normally a result of a change in its phase angle - will be "noticed" by the tracking function, so a counterbalance can be initiated and a loss of sensitivity avoided. Figure 8 - Vectorial addition of a product effect and a detected-metal signal (Fig. 9).

Monitoring Metal Detectors

Figure 9: This suppression, or "learning", of the product effect is understood as the process of turning the product vector such that only the signal from the piece of metal to be detected is indicated in a given axis of evaluation.

State-of-the-art metal detectors are equipped for automatic monitoring of their electronic functions. This keeps the appliance in good working order, but its product-specific detection sensitivity defies electronic checking, because it is not possible to simulate a product with a piece of metal embedded in it. Consequently, the product-specific sensitivity check must be performed with the aid of a test piece.

Test Pieces for Metal Detectors

As discussed above, the measurable vector sum (= resultant) is the compound of the product vector plus the metal vector. Consequently, for a product with a product effect, it is important that the sensitivity test be conducted on an appropriately prepared original product. The test piece should not be situated on top or below the product, but somewhere within the product.

If the metal-detector's threshold sensitivity is to be checked for different species of metal, the respective test pieces will have to be inserted into an appropriate number of different products. The test pieces must, of course, be selected such that their signals are always situated above the metal detector's threshold sensitivity setting. For reasons of operational reliability, that threshold in turn should be situated well above the product signal. The achievable sensitivity with the original product has been referred to as the operational sensitivity. By contrast, the base sensitivity describes an instrument's basic detection sensitivity. For products with no product effect, the operational sensitivity is equal to the base sensitivity.

Gate Sensitivity Profile

The sensitivity of a metal detector is not equal and constant across the entire tunnel-shaped opening, or gate. This is because of the field distribution within the gate. The field density declines in inverse proportion to the distance from the point of origin. Consequently, the least sensitive point in the cross section of the gate is situated at the center (Fig. 10), so the test piece should always be made to pass through the center of the search-coil gate.

Detectability of Wires as a Function of Their Gate-Passing Orientation

Figure 10: the least sensitive point in the cross section of the gate is situated at the center, so the test piece should always be made to pass through the center of the search-coil gate.

As already described previously, the metal detector's magnetic field is generated by a flow of electricity through its transmitter coil. The resultant magnetic field has a certain distribution and orientation with respect to the gate. Regarding the detectability of metals, the extent of field-symmetry disruption is the decisive factor. Differentiation must be made between the reactive effect of field concentration and the resistive effect of field displacement resulting from eddy-current formation. The transmitter's magnetic field is only able to induce voltage in particles of metal that do not have the same orientation as that of the magnetic field lines. The induced voltage is at its maximum, when the piece of metal comes through at right angles (90°) to the field plane. Thus, the instrument's sensitivity for wires is directional, and, of course, it is also dependent on the type of metal to be detected (Fig. 11 and Table 1).

Correlation Between Iron Pellets and Wires With Least-Favorable Orientation for Detection

Figure 11: The instrument's sensitivity for wires is directional, and, of course, it is also dependent on the type of metal to be detected.

For a medium working frequency, Table 2 illustrates the relationship between the detectability of an iron pellet and that of various wires. It is postulated that all of the wires are of homogeneous structure. The comparison is much more difficult for the kind of stainless-steel chips that are likely to be encountered in actual practice. With its inhomogeneous structure, the stainless-steel chip reacts even more weakly than a wire with the transmitter's magnetic field. In the interest of test-data reproducibility, it is therefore not advisable to make test pieces out of stainless-steel chips, since it is practically impossible to obtain two test pieces that show identical behavior within the magnetic field.

With a view to ridding the test of orientational dependences, pellets of a certain size and material species can be used as test pieces. Test pieces of certified conformity can be obtained from some manufacturers such as Sartorius Mechatronics Corp.

Determining Factors for Operational Sensitivity

As may be deduced from what has been said up to this point, metal-detection technology is a very complex subject, and the ultimate results of detection are determined by many different factors. The following list does not purport to completeness, and the order of mention is no indication of relative importance:

1. Size of gate

2. Product conductivity (product effect)

3. Mode of conveyance: continuous/ intermittent

4. Working frequency of search coil

5. Metal species

6. Shape of metal fragment

7. Limiting ambient conditions

Rule of Thumb for Approximating the Sensitivity for a Dry Product

The sensitivity threshold for a dry product is estimable. The following rule of thumb applies to rectangular gates and a working frequency of roughly 150 kHz:

Fe ø [mm] = height of gate [mm] 250 +0.5 VA ø [mm] = height of gate [mm] m 250 +1.0

For each doubling of the gate width, the sensitivity drops by 10 .. 20 %.

Sensitivity for Products With Product Effect

The threshold sensitivity of the metal detector for products with a product effect can only be estimated on the basis of empirical data or, for better results, by way of an original-product test.

Metal Free Zone

The metal detector's stainless steel housing ensures that most of the magnetic flux lines remain within the housing. Nevertheless, a few lines of flux emerge out of the gate and close around the metal detector. This effect can be minimized by special casing-design measures, but it can never be eliminated completely. Detectors with reduced metal-free zones are now state of the art. Any lines of magnetic flux penetrating outward can also be influenced outside of the detector, of course, so it is customary to provide a metal-free zone directly in front of the detector's gate.

Separation and Removal of Detected Metal Fragments

It is one thing to detect a piece of metal, but quite another to remove it, though the latter is at least as important as the former. Depending on the type of product involved, and on how it is being handled, there are different approaches available for systematically detecting and separating out pieces of metal (Fig. 12). If the metal-contaminated product is coarse or lumpy, the alternatives include:

* Blow-off devices

* Swivel arms

* Pushers

* Tilting conveyors

* Telescopic ejectors

In most cases, blow-off devices, swivel arms and pushers are used in combination with:

* Belt conveyors or

* Plastic chain-link belts

For material in bulk, the best option would be a reversing belt, a diverting slide, or product marking in combination with belt stoppage. Pneumatically conveyed products are amenable to the use of Airtect ejectors (specially engineered for that purpose). The rejecter must ensure that the delivery pressure is maintained despite the ejection of a piece of metal. Separators suitable for liquid products include:

* Pinch valves

* Ball valves

* Three-way valves

* Diverter valves/flaps

Which separator is ultimately opted for depends on the product and the prevailing boundary conditions, e.g., cleaning in place, sterile-state service, no dead space, etc. Free-flowing/fluid products for freefall monitoring call for either:

* Diverter valve

* Diverter funnel.

Summary

In order to provide adequate protection for consumers as well as for one's own machinery, no production line should be without a metal-detection system comprising a metal detector and an ejector, possibly in combination with a conveyor belt.

The detection of miniscule particles of metal is an extremely complicated affair that depends on numerous different parameters. In many cases, the sensitivity needs to be determined with the aid of an original product. In choosing the right metal-detection system for the right product, the aid of an experienced producer of metal detecting equipment should be considered

Recent Trends in Vial and Syringe Filling

Introduction

Recent developments in vial and syringe filling lines have been primarily evolutionary rather than revolutionary, with a few exceptions. Most of the new vendor offerings have focused on improving the flexibility, reliability, or efficiency of the filling and associated processes; on reducing product contamination risk; or on minimizing personnel exposure to potent compounds. Innovations introduced by one vendor have quickly been followed by similar offerings from its competitors.

Trends

Trends which have been identified through an evaluation of recent machine offerings, as well as discussions with key equipment suppliers, fall within the following categories:

* Flexible lines with more rapid changeover

* Improved filling techniques and process control

* Reduced customization

* Integrated and compact lines

* Enhanced integration with barrier isolators or RABS

* Higher grade vial capping

* Integration of external vial washing

Flexible Lines with More Rapid Changeover

According to Jeff Jackson, PHL Sales Director for Bosch Packaging Technology North America, and John Erdner, Director of Sales and Marketing for IMA North America, there has been a move towards filling of smaller batches of higher value drugs, requiring more accurate fills and faster line changeovers.

Pharmaceutical companies are driving vendors toward single use, disposable dosing systems in which the entire product path is discarded; for example, peristaltic pump systems which are further detailed below. Lengthy CIP/SIP of filling pumps and transfer piping (along with the required cleaning validation for each product) is replaced by simple mounting of a new presterilized tubing set and product tank. In addition, disposable product vessels, such as Stedim bags, are being combined with the dosing system for even greater disposability1.

Some vendors have improved their designs so that only one change part is needed for a vial diameter change, and others have designed vial carriers suitable for a wider range of diameters than ever before. This reduces spare parts cost and improves line efficiency by speeding changeover.

Several clients are now specifying fillers with more than one dosing system, to provide flexibility for filling a variety of products. Vendors have responded by supplying interchangeable, cart-based stations, and are looking into building a dual dosing system capability in a single station. The desired dosing system is then selected by the operator on the HMI.

Rapid changeover has now become more important than machine speed for many pharmaceutical companies. However, a number of clients still have high-volume products which demand a high-speed line. Varying customer demands have resulted in a wide range of machine offerings, from semi-automatic 1500/hr vial fillers to a fully automatic 48,000/hr vial line just introduced by Groninger. Vendors including Bausch & Stroebel and Optima (Inova) have recently gone from a 10-head nested syringe filler to a 16-head, raising processing rates of 1 ml long and 0.5 ml syringes to up to 60,000/hr.

Improved Filling Techniques and Process Control

Rotary piston pumps (volumetric): Still the most commonly used filling mechanism, this requires matched sets of piston and cylinder due to the tight clearances between the two, plus manual disassembly and cleaning after each use. While suitable for liquids of a wide range of viscosities and temperatures, use with shear- sensitive liquids and suspensions can be an issue. According to Matthias Poslovski, Director of Technical Sales at Optima Group Pharma GmbH, suspensions of particle size <10mcg may become trapped between the piston and cylinder, blocking it from cycling. Hard suspensions can degrade the surfaces of stainless steel pumps. CIP/SIP of rotary pumps can also be problematic.

Rolling diaphragm pumps: This is essentially a variant of a piston pump with a membrane joined to the piston and body to prevent product leakage. While typically fabricated of stainless steel, a new development from Bosch is a disposable system consisting of polycarbonate pump and needle bodies, with stainless steel retained for the needle tips in order to achieve the required tolerances.

Peristaltic pump systems: These systems were originally used for fluid transfer rather than high speed, accurate dosing. To improve their accuracy, machine suppliers have replaced the stepper motor controls with servo-drive controls, with the ability to control the motion and position of the rollers, and have integrated a feedback loop from a checkweighing sytem. Mechanical setup has been made more repeatable by changing the dynamics of how the elastomeric tubing is pinched on the unit. As noted above, this type of filling offers complete disposability, with virtually no chance of product cross-contamination, plus fill weight is temperature-independent. Disadvantages include a limited product viscosity range and a filling precision somewhat less than that of rotary pumps.

Time/pressure: These systems, incorporating a pressurized product tank and pinch valves to open and close silicone tubing between the tank and filling needles, have now become as accurate or in some cases more accurate than pump systems, due to improvements in tank headspace pressure control and process feedback control.

Other reasons for their increasing popularity include very low product shear and compatibility with CIP/SIP. Time/pressure systems do take more time to tune in at the start of a fill, and require control and/or compensation for product temperature as this affects product flow properties.

Mass-flow: This mass rather than volume-based technique utilizes the Coriolis effect created when fluid passes through a vibrating sensor pipe to control the opening and closing of a valve surrounding silicone tubing. The viscosity range is limited and fill accuracy at the lower end of the scale (of interest for injectables) is inferior to the other methods, so its use is currently limited to products such as ophthalmics.

Integrated Process Control (IPC) for vial fillers: Checkweighing with feedback for automatic adjustment of the metered quantity is especially valuable in that it reduces the overfill of expensive products and compensates for any fill weight drift over time. 100% checking can be supplied for low to intermediate output fillers, or can be used for the beginning and end of fill for high output machines, with a lower sampling rate employed throughout the rest of the fill. Weigh cells are isolated on a freestanding base to eliminate effects of machine vibration. While IPC systems have been available for several years on vial lines, the control algorithms have grown more sophisticated, and mechanical design has improved to the point that some new machines are capable of doing 100% testing at rates of up to 375/minute. Larger and larger proportions of fill lines are being purchased with these systems, with increasing sampling rates, notes Jorg Bengelsdorf, Director of Pharmaceutical Projects for Groninger USA.

IPC for nested syringe fillers: Syringe fillers have lacked an automated checkweighing feature until the last three to five years. As noted by Andreas Plank, Technical Sales Manager/Project Management for Bausch & Stroebel, the increasing number of products being prefilled in syringes and the high value of a subset of these, biotech products, have been an incentive for minimizing overfills. Furthermore, the double handling of syringes in and out of nests for tare weighing and then reweighing after filling require more complex design and space than for vials which are freestanding, taking more time to develop.

Non-contact checkweighing: Since BOC Edwards' 2005 integration of an NMR-based, in-line, noncontact check-weighing (NCCW) system on a filling line, only a couple of lines have been built with such a feature. The elegance of this approach is that it is rapid and does not require contact with or removal of the vial from the transport system, permitting 100% weighing at high speed, avoiding the introduction of cosmetic defects on the container, and simplifying mechanical design of the filler. Downsides limiting more widespread adoption include high cost and the need to calibrate or "train" the system for each product to be run on the line.

Reduced Customization

Faced with smaller internal engineering and validation staff handling multiple projects at multiple sites, and having had negative experiences in the past with highly customized equipment, a majority of pharmaceutical clients have adopted the mantra of wanting "standard" machines. Standardization has included the selection of vendors, machine models, PLC controls, HMIs, component transfer systems, filling method, and design of RABS or isolator enclosure. Recognized benefits have included faster line fabrication, shorter FATs, and reduced risk associated with startup, SAT, IQ, OQ, and PQ. Test protocols can be reused for several machines with only minor modification. Easier maintenance and a reduced spare parts requirement are added advantages.

Integrated and Compact Lines

Pharmaceutical firms are moving towards single-sourced, integrated lines, making one vendor responsible for functioning of the complete line. This has influenced several recent acquisitions and consolidations, including IMA's purchase of the BOC Edwards lyophilizer and loading systems business and Optima's similar purchase of the Klee business.

Requiring a single vendor to integrate and pre-test the entire line in a facility (and in some cases supply all pieces of the line) reduces risk during the official factory acceptance test, startup and overall line qualification. This is a key benefit considering the more and more limited internal engineering/validation staffs available at many clients and the importance of timely product launches.

The cost of building aseptic processing facilities has skyrocketed in recent years, as well as labor costs and the expense of product recalls and lawsuits. For low to intermediate production volumes, some vendors have been developing compact lines, including IMA's Modular Aseptic Compact System (MAC), a fully integrated line which replaces a separate vial washer, depyrogenation oven, and filler. Operator handling of components between process steps is eliminated, reducing the likelihood of introducing microbiological contamination and making the entire process more efficient. The floorspace required is also minimized, reducing facility capital investment and ongoing operating costs.

Enhanced Integration with Barrier Isolators or RABS

To optimize airflow, vaporized hydrogen peroxide (VHP) distribution, the ergonomics of gloveport access to all workstations for loading components, removing waste, and clearing jams, vendors have designed increasingly streamlined machines. This usually takes the form of a linear filler with a narrow profile. For example, the new IMA XTREMA F2000 filler has a width just larger than a standard HEPA filter.

Clients purchasing RABS-type fillers are tending to specify HEPA filters mounted directly on the guarding of the machine, as with an isolator design, rather than relying upon ceiling-mounted filters, thereby ensuring better airflow control at the point of filling.

For isolator-based fillers, vial transport systems have been improved to allow complete exposure to VHP, and features such as inflatable gasket seals have been added to depyrogenation tunnels to make them VHP-sterilizable.

Electron beam tunnels are now available from at least four different suppliers to carry out surface sterilization of tubs of presterilized syringes directly feeding a syringe filler, at rates of 6 tubs/minute and higher. Automated bag opening has been integrated upstream of these tunnels and automated tub lid removal downstream to provide greater separation of operators from the process and to minimize the opportunity for microbial contamination of the product.

Addressing the issue of limited reach in an isolator using gloveports, two-piece ergonomically designed pumps have been developed which can be assembled with a single hand through a gloveport, simplifying setup.

Higher Grade Vial Capping

Three general approaches have been taken to crimp caps: a spinning head with wheels, a fixed rail, and an idle roller. The latter two systems are preferred because they produce less particulate, but no system is without particulate generation issues. The latest trend, driven in part by the new EU GMP Annex 1 Guidelines2 calling for a Grade A air supply over capping, is to move from full HEPA coverage to providing a true RABS enclosure around the capper, targeting unidirectional downward airflow over the capping head, sorting bowl, and chute. Going forward, vendors are considering placing additional guarding between the main crimping operation and the bowl/chute assembly, as the sorting and feeding operations are now often the main sources of particulate.

In cases where capping and filling are installed on the same machine base, a vertical wall is often installed between the filler and capper with a small "mousehole" opening connecting the two to keep particles from entering the fill area.

Integration of External Vial Washing

To minimize personnel exposure to potent compounds and antibiotics, clients are purchasing external vial washers for the end of their filling lines, such as that manufactured by Seidenader Maschinenbau GmbH. Vials can be sprayed with warm water, followed by an active-neutralizing or detergent solution, and then a water rinse, or simply with multiple water rinses. The water nozzles are directed to keep the caps from getting wet. Non-heated, or in some cases heated, compressed air is used to blow the vials dry. Removal of external contaminants has the added advantage of decreasing cosmetic reject rates at downstream vision inspection.

Summary

In the last few years substantial progress has been made in the accuracy and control of filling processes, combined with increasingly flexible lines allowing for rapid changeover in an effort to be responsive to changing product demands. Lines have become more integrated to improve efficiency and pass greater responsibility to the equipment suppliers. Moreover, steady improvement has been made in suitability for barrier isolation, particulate control, and limiting product exposure in order to enhance sterility assurance and safety.

References

¹ "Disposable Technologies for Aseptic Filling," J.E. Zandbergen and M. Monge, BioProcess International, 4(6):S48-S51 (June 2006).

² Revision to EU GMP Annex 1, "Manufacture of Sterile Medicinal Products," (November 2008). Provisions on capping of vials expected to be implemented by March 1, 2010.

Process manufacturing

As the pharmaceutical industry has matured, concerns about the safe handling of drug compounds during the manufacturing process have increased. To meet exposure limits and protect batches from any kind of contamination, the industry’s need for improved containment has increased. Vendors have responded by providing glove boxes, better seals, more robust dust-collection systems and improved vessel design.

One such piece of equipment that incorporates many of these improvements is the agitated filter dryer, which Rosenmund Guedu, Liestal, Switzerland, invented in 1971. “The agitated filter dryer is a unique piece of processing equipment to separate solids from liquid in a single vessel,” says Todd Peterson, manager of filters and dryers for De Dietrich Process Systems Inc., Charlotte, N.C., which acquired Rosenmund in 1999.

The filter dryer typically is designed to provide a closed environment for separating, washing and drying in a single vessel, and is continually evolving to meet manufacturers’ needs. Vendors have taken various approaches to address contained powder discharge, including glove boxes, continuous liner technology and specially designed valves and scrapers, promising product recovery upward of 99%.

Although generally used for pharmaceutical applications, chemical producers such as Eastman Chemical Co., Kingsport, Tenn., also are making use of the technology. “It’s easier to justify the cost for pharmaceuticals,” says Bryan Suggs, business analyst for Eastman. “But we also use filter dryers for general chemicals production.”

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Machines that multi-task
Depending on the application, the agitated filter dryer might use either cloth (generally polyethylene or polypropylene) or metal mesh media; a manufacturer might even alternate between the two. The filter media can be held in place by bolts or clamps, and the metal mesh has the added option of being welded. Most advanced designs now use a boltless mechanism to secure the filter media by simply clamping it between the two halves of the filter dryer. This also provides a sterile design, says Chad Ranpuria, process manager for Powder Systems Ltd. (PSL), Liverpool, England. Cloth filter media is more likely to be used when processing specialty chemicals. Although many pharmaceutical manufacturers prefer metal mesh since product can more easily be recovered, cloth is ideal when used for single runs. The types and pore sizes of filter media that are available are continually expanding, while the cost is relatively stable, Ranpuria says.

Agitated filter dryer vessels separate into two pieces to allow access to the vessel internals, mainly for changing or repairing filter media. The two parts are generally sealed with an O-ring and can be held together with bolts, C-clamps or a bayonet closure (Figure 1); these last two are easier to assemble.

Once the vessel is charged with slurry, pressure is either applied from the top of the filter dryer using a gas, such as nitrogen or compressed air, or a vacuum is pulled from beneath the filter media, thereby forcing or pulling liquid through the cloth or mesh. Low pressures are generally used (1 barg to 2 barg) to keep the cake from becoming so compressed that the crystals fuse together. The liquid exits at the bottom of the vessel where it might be recycled or reused in another part of the process.

While the crystals are collecting on the filter media, the smooth edge of the agitator acts to smooth the surface of the cake so there are no crevices. The other edge of the agitator, which can rotate in both directions, might have teeth for digging into the cake to help break it up and remove it from the filter media (Figure 2). The cake might be broken up and washed several times to remove all trace solvents or impurities.

The powder is then dried by applying heat to the vessel. “Heating has become more sophisticated and efficient,” Ranpuria says. Not only are PSL’s filter dryer vessels fitted with jackets on the walls and top dome, but the agitator shaft and blades are also heated, providing direct contact with the powder. Several vendors’ designs also supply heat to the bottom filter plate.

Lewis Fabricius, P.E., manager of reactor systems for Pfaudler Inc., Rochester, N.Y., says the company’s design speeds drying by using an internal heating grid that directly conducts heat to the product. The company also offers an optional heated nitrogen distribution system, which can fluidize the cake, thereby reducing drying times.

Vendors now can provide programmable logic controllers (PLCs) that integrate with a site’s distributed control system (DCS), as well as an interlock system. “If the unit is under pressure or vacuum, you don’t want someone to open the side-discharge valve,” Ranpuria says. “So you add a pressure sensor and an interlock system so the valve can’t be opened until the vessel is at atmospheric pressure.”

Customized control systems can be used to set the nitrogen purge, temperature and pressure cycles, Ranpuria says. “It also makes it possible to dry to a specific end point which is a great benefit for processes that need to be repeatable.”
For smaller, lab-scale units, however, it probably doesn’t pay to automate units, says Lawrenzo Heit, New Brunswick, N.J.-based group leader for Bristol-Myers Squibb Co.

The final step is to remove the finished product from the filter dryer vessel.

PSL’s approach is to attach a glove box directly to the side of the vessel so no powder can escape. Operators then discharge the dried product using the agitator controls and transfer the loose powder from the vessel to containers, such as drums or bottles. Since the agitator is designed so that it can’t damage the filter media, there is always some product left on it, which is called the heel. This can be removed through the glove box with a specially designed rake, Ranpuria says.

De Dietrich’s Peterson says there are various methods to remove the heel; the best one depends on the customer’s needs, but that there is “no perfect solution at the moment.” Smaller units come equipped with a glove box and might also have a pusher port, which is mounted opposite the side-discharge valve, and allows powder to be manually pushed out of the vessel. Larger filter dryers use the agitator to push the powder out the side-discharge valve, and might combine a nitrogen purge to help sweep product off the filter plate. Vessels up to 4 m² (filter surface area) can also be tilted, which requires additional mechanical equipment in addition to flexible connections (Figure 3).

Pfaudler started offering filter dryers in 2003 after entering into a partnership with Delta Costruzioni Meccaniche (DCM), Misinto, Italy, which has been building filter dryers for 30 years. Fabricius says the company’s filter dryer can be equipped with any of three features to aid in heel removal: The vessel tilts and has retractable nitrogen side-sprayers in addition to the nitrogen distribution system. Contain yourself
An agitated filter dryer might supplant several different pieces of equipment on the plant floor: Eli Lilly and Co., Indianapolis, is gradually replacing several centrifuge/dryer combinations where appropriate, says Kumar Abhinava, Ph.D., engineering consultant for the company, whereas Eastman prefers the filter dryers to the open-top nutsche filter/dryers they used to have, Suggs says.

“In the past, the filtration and drying steps would have been carried out in separate pieces of process equipment -- typically a centrifuge and tray dryer combination,” Ranpuria says. “This required lengthy solids handling steps when transferring from centrifuge to tray dryers with all the associated containment and cleaning issues, together with any product losses due to the transfer step.”

This equipment is being taken offline not only to reduce the potential for employee exposure when material is manually transferred, but today’s agitated filter dryer provides a high degree of containment and also meets cGMP standards. As an added benefit, the filter dryer takes up less floor space than the equipment it replaces, Abhinava says.

In the past, pharmaceutical manufacturers might have had to meet occupational exposure limits (OELs) of 100 μg/m³ to protect personnel – now many OELs are as low as 1 μg/m³, and in some cases are less than 100 ng/m³. “Many drugs are becoming more and more potent,” Ranpuria says. “The efficacy is increasing, so manufacturers are producing less and they need higher containment.” Abhinava concurs, saying containment figures prominently when selecting technology and that filter dryers usually are chosen for products requiring a high level of containment.

“Some of these drugs are lethal,” De Detrich’s Peterson says. The degree of containment provided by the agitated filter dryer also reduces the costs associated with personal protective equipment (PPE) and can make it unnecessary to make certain drugs in cleanrooms, which are expensive to build and maintain, Peterson says.

To meet cGMP standards, vendors provide a clean-in-place (CIP) system, as well as a steam connection and drain so the vessel can be sterilized by steam-in-place (SIP). “The standards for GMP keep changing and becoming more rigorous,” says Bristol-Myers’ Heit. “The newer filter dryers have fewer problems meeting our cleaning standards.”

Many vendors now test the efficiency of the CIP system with riboflavin (vitamin B2), low levels of which will fluoresce in UV light. CIP systems generally consist of some arrangement of sprayers or a ring with nozzles. Vendors set the direction of the sprayers or nozzles so all of the internal parts are adequately cleaned, especially in places where material might get trapped, as proved by riboflavin testing.

When several batches are processed in a single campaign, the metal mesh filter media can become less efficient as particles become wedged between the fine wires. Ranpuria says PSL’s filter dryers are equipped with a reflux cleaning system. This allows manufacturers to heat and recirculate solvent or some other liquid at pressure or under vacuum. The bottom plate of the vessel is designed such that the amount of solvent needed to cover the filter media is minimized. After the procedure, the mesh is returned to like-new efficiency and a polishing filter recovers any product in the exiting liquid, Ranpuria says.
The high level of containment that can be achieved with the filter dryer certainly is one of its most attractive features. Another is the ability to filter and dry in the same vessel so operators don’t have to manually remove material from one vessel and transfer it to another. Processing the material in one vessel is safer and reduces potential loss of material. “You don’t want to handle material twice,” Ranpuria says. “Each time you lose product.”

Other benefits of using the filter dryer are reduced capital cost, including erection costs, and reduced maintenance, Abhinava says. The lower capital costs are a direct result of the smaller footprint of the filter dryers, whereas maintenance costs are diminished because “there are fewer things that can go wrong with one piece of equipment,” Abhinava says.

Another benefit to using an agitated filter dryer is that an entire lot can be processed at one time, whereas a lot likely has to be processed batch wise in a centrifuge, Abhinava says. “This is a ‘quality’ advantage that is important to pharmaceutical manufacturers.”

De Dietrich’s Peterson estimates about half of the filter dryers the company sells are a standard design, with the remaining being designed on a per-customer basis. PSL’s Ranpuria and Pfaudler’s Fabricius both say their companies sell more custom vessels than standard. The high percentage of custom design is due, in part, to the control and interlock systems that can be sold with the filter dryer.

Although more units are being sold, Peterson and Ranpuria say the average size of the vessels has decreased as drug compounds become more active. However, the need for control systems, containment and cleaning, for example, has increased.

Suit your application
The agitated filter dryer is not suitable for every application, however. “Amorphous products are hard to deal with in any filter,” Fabricius says.

Those who use the equipment also say it has a couple shortcomings. For the most part, they indicate they can get around such issues once they are identified.

Gary Hedden, Palo Alto, Calif.-based group leader of process development for Roche Pharmaceuticals, says there are two small filter dryers in his lab: a Rosenmund machine, purchased circa 1993, and another from PSL, vintage 1999. Both are used for developing pharmaceuticals and are rarely used to process the same thing twice. “After CIP, we always have to take the filter dryer apart to get the last bit of material that is stuck in the filter media and in the O-ring groove,” Hedden says.
Eastman’s Suggs says they used to have problems with material getting lodged around the O-ring at the side-discharge valve; he now specifies a higher-grade O-ring that provides a better seal to avoid such problems. Since 1998, Eastman has purchased four agitated filter dryers from Rosenmund/De Dietrich that range in size from 6 m² to 12 m²; these larger vessels do not have CIP systems. “Since we often process the same chemical for several runs, it’s sufficient to manually wash the bottom filter plate with a hose,” he says.

Bristol-Myers Squibb’s Heit and colleague Tom Mitchell, a senior research scientist, have seven filter dryers in their care. The company has six vessels from Rosenmund that range in size from 0.03 m² to 1.5 m², as well as a 0.28 m² unit from Pfaudler (another unit from the company is on the way). Heit says the vessels are used in the pilot plants for process development and producing drugs for clinical trials. Since the filter dryers are used for a different product every time, “we spend as much time cleaning as we do processing,” Heit says, even with the CIP systems.

“The filter dryer can become a bottleneck since you are combining two unit operations into one unit,” Lilly’s Abhinava says. “We usually use it when filtration and drying rates are sufficiently fast in order for the filter dryer not to be a bottleneck.”

Ranpuria says that although the filter dryer might limit throughput, “it is more cost effective as one single unit, thereby simplifying manufacture and removing complexity while minimizing product handling steps, reducing potential cross-contamination during handling, and saving analytical time.”

Heit and Mitchell say they would like for filter dryer vendors to offer a more complete package that includes glove boxes or other systems for removing the product, adding that PSL is leading in such offerings. “The mechanisms for getting material in and out, and for cleaning the vessel should be resolved at the vendor level, not onsite,” Heit says.

Fabricius says Pfaudler is making progress toward offering such a package: The company is working with outside vendors to provide isolators, such as gloveboxes, as well as other technologies to ease product handling.

Pharmaceutical and Medicine Manufacturing

Nature of the Industry
The pharmaceutical and medicine manufacturing industry has
produced a variety of medicinal and other health-related products
undreamed of by even the most imaginative apothecaries of
the past. These drugs save the lives of millions of people from
various diseases and permit many ill people to lead normal lives.
Thousands of medications are available today for diagnostic,
preventive, and therapeutic uses. In addition to aiding in the
treatment of infectious diseases such as pneumonia, tuberculosis,
malaria, influenza, and sexually transmitted diseases, these
medicines also help prevent and treat cardiovascular disease,
asthma, diabetes, hepatitis, cystic fibrosis, and cancer. For example,
antinausea drugs help cancer patients endure chemotherapy;
clot-buster drugs help stroke patients avoid brain damage;
and psychoactive drugs reduce the severity of mental illness
for many people. Antibiotics and vaccines have virtually
wiped out such diseases as diphtheria, syphilis, and whooping
cough. Discoveries in veterinary drugs have controlled various
diseases, some of which are transmissible to humans.
Advances in biotechnology and information technology are
transforming drug discovery and development. Within biotechnology,
scientists have learned a great deal about human genes,
but the real work—translating that knowledge into viable new
drugs—has only recently begun. So far, millions of people have
benefited from medicines and vaccines developed through biotechnology,
and several hundred new biotechnologically-derived
medicines are currently in the pipeline. These new medicines, all
of which are in human clinical trials or awaiting FDA approval,
include drugs for cancer, infectious diseases, autoimmune diseases,
neurologic disorders, and HIV/AIDS and related conditions.
Many new drugs are expected to be developed in the coming
years. Advances in technology and the knowledge of how
cells work will allow pharmaceutical and medicine manufacturing
makers to become more efficient in the drug discovery process.
New technology allows life scientists to test millions of drug
candidates far more rapidly than in the past. Other new technology,
such as regenerative therapy using stem cell research, also
will allow the natural healing process to work faster, or to enable
the regrowth of missing or damaged tissue.
There is a direct relationship between gene discovery and
identification of new drugs—the more genes identified, the more
paths available for drug discovery. Discovery of new genes also
can lead to new diagnostics for the early detection of disease.
Among other uses, new genetic technology is being explored to
develop vaccines to prevent or treat diseases that have eluded
traditional vaccines, such as AIDS, malaria, tuberculosis, and
cervical cancer.
The pharmaceutical and medicine manufacturing industry
consists of about 2,500 places of employment, located
throughout the country. These include establishments that make
pharmaceutical preparations or finished drugs; biological products,
such as serums and vaccines; bulk chemicals and botanicals
used in making finished drugs; and diagnostic substances
such as pregnancy and blood glucose kits.
The U.S. pharmaceutical industry has achieved worldwide
prominence through research and development (R&D) work on
new drugs, and spends a relatively high proportion of its funds
on R&D compared with other industries. Each year, pharmaceutical
industry testing involves tens of thousands of new substances,
yet may eventually yield fewer than 100 new prescription
medicines.
For the majority of firms in this industry, the actual manufacture
of drugs is the last stage in a lengthy process that begins
with scientific research to discover new products and to improve
or modify existing ones. The R&D departments in pharmaceutical
and medicine manufacturing firms start this process
by seeking and rapidly testing libraries of thousands to millions
of new chemical compounds with the potential to prevent, combat,
or alleviate symptoms of diseases or other health problems.
Scientists use sophisticated techniques, including computer simulation,
combinatorial chemistry, and high-through-put screening
(HTS), to hasten and simplify the discovery of potentially
useful new compounds.
Most firms devote a substantial portion of their R&D budgets
to applied research, using scientific knowledge to develop
a drug targeted to a specific use. For example, an R&D unit may
focus on developing a compound that will effectively slow the
advance of breast cancer. If the discovery phase yields promising
compounds, technical teams then attempt to develop a safe
and effective product based on the discoveries.
To test new products in development, a research method
called “screening” is used. To screen an antibiotic, for example,
a sample is first placed in a bacterial culture. If the antibiotic is
effective, it is next tested on infected laboratory animals. Laboratory
animals also are used to study the safety and efficacy of
the new drug. A new drug is selected for testing on humans only
if it promises to have therapeutic advantages over drugs already
in use, or is safer. Drug screening is an incredibly risky, laborious,
and costly process—only 1 in every 5,000 to 10,000 compounds
screened eventually becomes an approved drug.
After laboratory screening, firms conduct clinical investiga-
Pharmaceutical and Medicine Manufacturing
(NAICS 3254)
SIGNIFICANT POINTS
• This industry ranks among the fastest growing manufacturing industries.
• More than 6 out of 10 workers have a bachelor’s, master’s, professional, or Ph.D. degree—twice
the proportion for all industries combined.
• Fifty-nine percent of all jobs are in large establishments employing more than 500 workers.
• Earnings are much higher than in other manufacturing industries.
72
tions, or “trials,” of the drug on human patients. Human clinical
trials normally take place in three phases. First, medical scientists
administer the drug to a small group of healthy volunteers
to determine and adjust dosage levels, and monitor for side effects.
If a drug appears useful and safe, additional tests are
conducted in two more phases, each phase using a successively
larger group of volunteers or carefully selected patients, sometimes
upwards of 10,000 individuals.
After a drug successfully passes animal and clinical tests,
the U.S. Food and Drug Administration’s (FDA) Center for Drug
Evaluation and Research (CDER) must review the drug’s performance
on human patients before approving the substance for
commercial use. The entire process, from the first discovery of a
promising new compound to FDA approval, can take over a decade
and cost hundreds of millions of dollars.
After FDA approval, problems of production methods and
costs must be worked out before manufacturing begins. If the
original laboratory process of preparing and compounding the
ingredients is complex and too expensive, pharmacists, chemists,
chemical engineers, packaging engineers, and production
specialists are assigned to develop a manufacturing process economically
adaptable to mass production. After the drug is marketed,
new production methods may be developed to incorporate
new technology or to transfer the manufacturing operation
to a new production site.
In many production operations, pharmaceutical manufacturers
have developed a high degree of automation. Milling and
micronizing machines, which pulverize substances into extremely
fine particles, are used to reduce bulk chemicals to the required
size. These finished chemicals are combined and processed
further in mixing machines. The mixed ingredients may
then be mechanically capsulated, pressed into tablets, or made
into solutions. One type of machine, for example, automatically
fills, seals, and stamps capsules. Other machines fill bottles with
capsules, tablets, or liquids, and seal, label, and package the
bottles.
Quality control and quality assurance are vital in this industry.
Many production workers are assigned full time to quality
control and quality assurance functions, whereas other employees
may devote part of their time to these functions. For example,
although pharmaceutical company sales representatives,
often called detailers, work primarily in marketing, they engage
in quality control when they assist pharmacists in checking for
outdated products.
Working Conditions
Working conditions in pharmaceutical plants are better than
those in most other manufacturing plants. Much emphasis is
placed on keeping equipment and work areas clean because of
the danger of contamination. Plants usually are air-conditioned,
well lighted, and quiet. Ventilation systems protect workers from
dust, fumes, and disagreeable odors. Special precautions are
taken to protect the relatively small number of employees who
work with infectious cultures and poisonous chemicals. With
the exception of work performed by material handlers and maintenance
workers, most jobs require little physical effort. In 2003,
the incidence of work-related injury and illness was 2.8 cases per
100 full-time workers, compared with 6.8 per 100 for all manufacturing
industries and 5.0 per 100 for the entire private sector.
Only about 3 percent of the workers in the pharmaceutical
and medicine manufacturing industry are union members or are
covered by a union contract, compared with about 14 percent of
workers throughout private industry.
Employment
Pharmaceutical and medicine manufacturing provided 291,000
wage and salary jobs in 2004. Pharmaceutical and medicine manufacturing
establishments typically employ many workers. Nearly
60 percent of this industry’s jobs in 2004 were in establishments
that employed more than 500 workers (chart 1). Most jobs are in
California, Illinois, Texas, Indiana, New Jersey, New York, North
Carolina, and Pennsylvania.
Under the North American Industry Classification System
(NAICS), workers in research and development (R&D) establishments
that are not part of a manufacturing facility are included
in a separate industry—research and development in the physical,
engineering, and life sciences. However, due to the importance
of R&D work to the pharmaceutical and medicine manufacturing
industry, drug-related R&D is discussed in this statement
even though a large proportion of pharmaceutical industry-
related R&D workers are not included in the employment
data.
Occupations in the Industry
About 29 percent of all jobs in the pharmaceutical and medicine
manufacturing industry are in professional and related occupations,
mostly scientists and science technicians, about 18 percent
are in management occupations, another 12 percent are in
office and administrative support, and 3 percent are in sales and
related occupations. About 1 out of 4 jobs in the industry are in
production occupations, including both low skilled and high
skilled jobs (table 1).
Scientists, engineers, and technicians conduct research to
develop new drugs. Others work to streamline production methods
and improve environmental and quality control. Life scientists
are among the largest scientific occupations in this industry.
Most of these scientists are biological and medical scien73
tists who produce new drugs using biotechnology to recombine
the genetic material of animals or plants. Biological scientists
normally specialize in a particular area. Biologists and bacteriologists
study the effect of chemical agents on infected animals.
Biochemists study the action of drugs on body processes by
analyzing the chemical combination and reactions involved in
metabolism, reproduction, and heredity. Microbiologists grow
strains of microorganisms that produce antibiotics. Physiologists
investigate the effect of drugs on body functions and vital
processes. Pharmacologists and zoologists study the effects
of drugs on animals. Virologists grow viruses, and develop
vaccines and test them in animals. Botanists, with their special
knowledge of plant life, contribute to the discovery of botanical
ingredients for drugs. Other biological scientists include pathologists,
who study normal and abnormal cells or tissues, and
toxicologists, who are concerned with safety, dosage levels, and
the compatibility of different drugs. Medical scientists, who
also may be physicians, conduct clinical research, test products,
and oversee human clinical trials.
The work of physical scientists, particularly chemists, also
is important in the development of new drugs. Combinatorial
and computational chemists create molecules and test them rapidly
for desirable properties. Organic chemists, often using combinatorial
chemistry, then combine new compounds for biological
testing. Physical chemists separate and identify substances,
determine molecular structure, help create new compounds, and
improve manufacturing processes. Radiochemists trace the
course of drugs through body organs and tissues. Pharmaceutical
chemists set standards and specifications for the form of
products and for storage conditions; they also see that drug
labeling and literature meet the requirements of State and Federal
laws. Analytical chemists test raw and intermediate materials
and finished products for quality.
Science technicians, such as biological and chemical technicians,
play an important part in research and development of
new medicines. They set up, operate, and maintain laboratory
equipment, monitor experiments, analyze data, and record and
interpret results. Science technicians usually work under the
supervision of scientists or engineers.
Although engineers account for a small fraction of scientific
and technical workers, they make significant contributions
toward improving quality control and production efficiency.
Chemical engineers design equipment and devise manufacturing
processes. Bioprocess engineers, who are similar to chemical
engineers, design fermentation vats and various bioreactors
for microorganisms that will produce a given product. Industrial
engineers plan equipment layout and workflow to maintain
efficient use of plant facilities.
At the top of the managerial group are executives who make
policy decisions concerning matters of finance, marketing, and
research. Other managerial workers include natural sciences
managers and industrial production managers.
Office and administrative support employees include secretaries
and administrative assistants, general office clerks, and
others who keep records on personnel, payroll, raw materials,
sales, and shipments.
Sales representatives, wholesale and manufacturing, describe
their company’s products to physicians, pharmacists,
dentists, and health services administrators. These sales representatives
serve as lines of communication between their companies
and clients.
Table 1. Employment of wage and salary workers in pharmaceutical
and medicine manufacturing by occupation, 2004 and
projected change, 2004-14
(Employment in thousands)
Employment, Percent
2004 change,
Occupation Number Percent 2004-14
Total, all occupations ............................. 291 100.0 26.1
Management, business, and financial
occupations ............................................ 53 18.2 31.7
Top executives ........................................ 4 1.5 27.8
Marketing and sales managers ............... 4 1.3 34.1
Industrial production managers ............... 4 1.3 28.9
Natural sciences managers .................... 5 1.6 28.9
Managers, all other .................................. 5 1.6 28.9
Business operation specialists,
all other ................................................... 7 2.3 41.8
Accountants and auditors ...................... 3 1.0 28.9
Professional and related
occupations ............................................ 85 29.3 31.7
Computer systems analysts ................... 4 1.3 41.7
Industrial engineers, including
health and safety ................................... 3 1.0 28.4
Industrial engineering technicians .......... 3 0.9 29.1
Biochemists and biophysicists ................ 4 1.2 28.9
Microbiologists ......................................... 3 1.0 28.9
Medical scientists, except
epidemiologists ....................................... 10 3.5 41.8
Chemists .................................................. 14 5.0 23.6
Biological technicians .............................. 8 2.8 28.2
Chemical technicians ............................... 5 1.6 28.9
Sales and related occupations ............ 9 3.0 27.9
Sales representatives, wholesale and
manufacturing, technical and
scientific products .................................. 6 2.0 28.9
Office and administrative support
occupations ............................................ 34 11.6 14.5
Bookkeeping, accounting, and
auditing clerks ........................................ 2 0.8 16.0
Customer service representatives ......... 3 0.9 32.0
Production, planning, and expediting clerks 3 1.0 27.6
Shipping, receiving, and traffic clerks .... 3 1.1 16.7
Executive secretaries and administrative
assistants ............................................... 5 1.7 22.2
Secretaries, except legal, medical, and
executive ................................................ 5 1.7 8.5
Installation, maintenance, and repair
occupations ............................................ 13 4.5 28.8
Industrial machinery installation, repair,
and maintenance workers ..................... 10 3.5 28.9
Production occupations ........................ 79 27.0 21.6
First-line supervisors/managers of
production and operating workers ........ 7 2.5 28.9
Team assemblers .................................... 5 1.6 28.9
Chemical plant and system operators .... 3 1.0 28.9
Chemical equipment operators
and tenders ............................................ 8 2.6 28.9
Separating, filtering, clarifying,
precipitating, and still machine setters,
operators, and tenders .......................... 6 2.0 28.9
Mixing and blending machine setters,
operators, and tenders .......................... 8 2.7 28.9
Inspectors, testers, sorters, samplers,
and weighers ......................................... 8 2.7 16.3
Packaging and filling machine operators
and tenders ............................................ 22 7.6 9.8
Transportation and material moving
occupations ............................................ 13 4.4 20.2
Laborers and material movers, hand ...... 10 3.6 18.2
Note: May not add to totals due to omission of occupations with small
employment
74
Most plant workers fall into 1 of 2 occupational groups:
Production workers who operate drug-producing equipment, inspect
products, and install, maintain, and repair production equipment;
and transportation and material moving workers who package
and transport the drugs.
Workers among the larger of the production occupations,
assemblers and fabricators, perform all of the assembly tasks
assigned to their teams, rotating through the different tasks rather
than specializing in a single task. They also may decide how the
work is to be assigned and how different tasks are to be performed.
Other production workers specialize in one part of the production
process. Chemical processing machine setters, operators,
and tenders, such as pharmaceutical operators, control
machines that produce tablets, capsules, ointments, and medical
solutions. Included among these operators are mixing and blending
machine setters, operators, and tenders, who tend milling
and grinding machines that reduce mixtures to particles of designated
sizes. Extruding, forming, pressing, and compacting
machine setters, operators, and tenders tend tanks and kettles
in which solutions are mixed and compounded to make up creams,
ointments, liquid medications, and powders. Crushing, grinding,
polishing, mixing, and blending workers operate machines
that compress ingredients into tablets. Coating, painting, and
spraying machine setters, operators, and tenders, often called
capsule coaters, control a battery of machines that apply coatings
that flavor, color, preserve, or add medication to tablets, or
control disintegration time. Throughout the production process,
inspectors, testers, sorters, samplers, and weighers ensure
consistency and quality. For example, ampoule examiners inspect
ampoules for discoloration, foreign particles, and flaws in
the glass. Tablet testers inspect tablets for hardness, chipping,
and weight to assure conformity with specifications. After the
drug is prepared and inspected, it is bottled or otherwise packaged
by packaging and filling machine operators and tenders.
Plant workers who do not operate or maintain equipment
perform a variety of other tasks. Some drive industrial trucks or
tractors to move materials around the plant, load and unload
trucks and railroad cars, or package products and materials by
hand.
Training and Advancement
Training requirements for jobs in the pharmaceutical and medicine
manufacturing industry range from a few hours of on-thejob
training to years of formal education plus job experience.
More than 6 out of 10 of all workers have a bachelor’s, master’s,
professional, or Ph.D. degree—twice the proportion for all industries
combined. The industry places a heavy emphasis on
continuing education for employees, and many firms provide
classroom training in safety, environmental and quality control,
and technological advances.
For production occupations, manufacturers usually hire inexperienced
workers and train them on the job; high school graduates
generally are preferred. Beginners in production jobs assist
experienced workers and learn to operate processing equipment.
With experience, employees may advance to more skilled
jobs in their departments.
Many companies encourage production workers to take
courses related to their jobs at local schools and technical institutes
or to enroll in correspondence courses. College courses in
chemistry and related areas are particularly encouraged for highly
skilled production workers who operate sophisticated equipment.
Some companies reimburse workers for part, or all, of their
tuition. Skilled production workers with leadership ability may
advance to supervisory positions.
For science technician jobs in this industry, most companies
prefer to hire graduates of technical institutes or community
colleges or those who have completed college courses in chemistry,
biology, mathematics, or engineering. Some companies,
however, require science technicians to hold a bachelor’s degree
in a biological or chemical science. In many firms, newly hired
workers begin as laboratory helpers or aides, performing routine
jobs such as cleaning and arranging bottles, test tubes, and
other equipment.
The experience required for higher level technician jobs varies
from company to company. Usually, employees advance
over a number of years from assistant technician, to technician,
to senior technician, and then to technical associate, or supervisory
technician.
For most scientific and engineering jobs, a bachelor of science
degree is the minimum requirement. Scientists involved in
research and development usually have a master’s or doctoral
degree. A doctoral degree is generally the minimum requirement
for medical scientists, and those who administer drug or gene
therapy to patients in clinical trials must have a medical degree.
Because biotechnology is not one discipline, but the interaction
of several disciplines, the best preparation for work in biotechnology
is training in a traditional biological science, such as
genetics, molecular biology, biochemistry, virology, or biochemical
engineering. Individuals with a scientific background and
several years of industrial experience may eventually advance to
managerial positions. Some companies offer training programs
to help scientists and engineers keep abreast of new developments
in their fields and to develop administrative skills. These
programs may include meetings and seminars with consultants
from various fields. Many companies encourage scientists and
engineers to further their education; some companies provide
financial assistance or full reimbursement of expenses for this
purpose. Publication of scientific papers also is encouraged.
Pharmaceutical manufacturing companies prefer to hire college
graduates, particularly those with strong scientific backgrounds.
In addition to a 4-year degree, most newly employed
pharmaceutical sales representatives complete rigorous formal
training programs revolving around their company’s product lines.
Outlook
The number of wage and salary jobs in pharmaceutical and medicine
manufacturing is expected to increase by about 26 percent
over the 2004-14 period, compared with 14 percent for all industries
combined. Pharmaceutical and medicine manufacturing
ranks among the fastest growing manufacturing industries. Demand
for this industry’s products is expected to remain strong.
Even during fluctuating economic conditions, there will be a
market for over-the-counter and prescription drugs, including
the diagnostics used in hospitals, laboratories, and homes; the
vaccines used routinely on infants and children; analgesics and
other symptom-easing drugs; antibiotics and other drugs for
life-threatening diseases; and “lifestyle” drugs for the treatment
of nonlife-threatening conditions.
Although the use of drugs, particularly antibiotics and vaccines,
has helped to eradicate or limit a number of deadly diseases,
many others, such as cancer, Alzheimer’s, and heart disease,
75
continue to elude cures. Ongoing research and the manufacture
of new products to combat these diseases will continue to contribute
to employment growth.
Because so many of the pharmaceutical and medicine manufacturing
industry’s products are related to preventive or routine
healthcare, rather than just illness, demand is expected to
increase as the population expands. The growing number of
older people who will require more healthcare services will further
stimulate demand—along with the growth of both public
and private health insurance programs, which increasingly cover
the cost of drugs and medicines.
Another factor propelling demand is the increasing popularity
of “lifestyle” drugs that treat symptoms of chronic nonlifethreatening
conditions resulting from aging or genetic predisposition,
and can enhance one’s self-confidence or physical appearance.
Other factors expected to increase the demand for
drugs include greater personal income and the rising health consciousness
and expectations of the general public.
Despite the increasing demand for drugs, drug producers
and buyers are expected to place more emphasis on cost effectiveness,
due to concerns about the cost of healthcare, including
prescription drugs. Growing competition from the producers
of generic drugs also may exert cost pressures on many firms in
this industry, particularly as brand-name drug patents expire. In
addition, the average time for the FDA to review “nonpriority”
drug applications is becoming longer, further delaying the time a
drug comes to market. These factors, combined with continuing
improvements in manufacturing processes, are expected to result
in slower employment growth over the 2004-14 period than
occurred during the previous 10-year period.
Strong demand is anticipated for professional occupations—
especially for life and physical scientists engaged in R&D, the
backbone of the pharmaceutical and medicine manufacturing
industry. Much of the basic biological research done in recent
years has resulted in new knowledge, including the successful
identification of genes. Life and physical scientists will be needed
to take this knowledge to the next stage, which is to understand
how certain genes function so that gene therapies can be
developed to treat diseases. Computer specialists such as systems
analysts, biostatisticians, and computer support specialists
also will be in demand as disciplines such as biology, chemistry,
and electronics continue to converge and become more
interdisciplinary, creating demand in rapidly emerging fields such
as bioinformatics and nanotechnology. Strong demand also is
projected for production occupations. Employment of office
and administrative support workers is expected to grow more
slowly than the industry as a whole, as companies streamline
operations and increasingly rely on computers. In an effort to
curb research and technological development costs, many companies
have merged. As companies consolidate and grow in
size, so do their marketing and sales departments. Despite substantial
increases over the past decade, sales forces at pharmaceutical
and medicine manufacturing firms should continue to
experience strong growth as companies promote and sell their
products to doctors at hospitals and private clinics.
Unlike many other manufacturing industries, the pharmaceutical
and medicine manufacturing industry is not highly sensitive
to changes in economic conditions. Even during periods
of high unemployment, work is likely to be relatively stable in
this industry.
Earnings
Earnings of workers in the pharmaceutical and medicine manufacturing
industry are higher than the average for all manufacturing
industries. In May 2004, production or nonsupervisory
workers in this industry averaged $892 a week, while those in all
manufacturing industries averaged $659 a week. Earnings in
selected occupations in pharmaceutical and medicine manufacturing
appear in table 2.
Some employees work in plants that operate around the
clock—three shifts a day, 7 days a week. In most plants, workers
receive extra pay when assigned to the second or third shift.
Because drug production is subject to little seasonal variation,
work is steady.
Sources of Additional Information
For additional information about careers in pharmaceutical and
medicine manufacturing and the industry in general, write to the
personnel departments of individual pharmaceutical and medicine
manufacturing companies.
For information about careers in biotechnology, contact:
􀂾 Biotechnology Industry Organization, 1625 K St. NW., Suite
1100, Washington, DC 20006. Internet: http://www.bio.org
For information on careers in pharmaceutical and medicine
manufacturing, contact:
􀂾 Pharmaceutical Research and Manufacturers of America
(PHRMA), 1100 15th St. NW., Washington, DC 20005. Internet:
http://www.phrma.org
Information on these key pharmaceutical and medicine manufacturing
occupations may be found in the 2006-07 edition of
the Occupational Outlook Handbook.
• Assemblers and fabricators
• Biological scientists
• Computer scientists and database administrators
• Computer support specialists and systems administrators
• Computer systems analysts
• Chemists and material scientists
• Engineers
• Inspectors, testers, sorters, samplers, and weighers
• Medical scientists
• Sales representatives, wholesale and manufacturing
• Science technicians

SYNTHESIZED PHARMACEUTICAL MANUFACTURING PLANTS

SYNTHESIZED PHARMACEUTICAL MANUFACTURING PLANTS
A. PROCESS DESCRIPTION
The synthesis of medicinal chemicals may be done in a very small facility producing only one
chemical or in a large integrated facility producing many chemicals by various processes. Most
pharmaceutical manufacturing plants are relatively small. Organic chemicals are used as raw
materials and as solvents. Nearly all products are made using batch operations. In addition,
several different products or intermediates are likely to be made in the same equipment at
different times during the year; these products, then, are made in “campaigned” equipment.
Equipment dedicated to the manufacture of a single product is rare, unless the product is made
in large volume.
Production activities of the pharmaceutical industry can be divided into the following categories:
1. Chemical Synthesis - the manufacture of pharmaceutical products by chemical synthesis.
2. Fermentation - the production and separation of medicinal chemicals such as antibiotics
and vitamins from microorganisms.
3. Extraction - the manufacture of botanical and biological products by the extraction of
organic chemicals from vegetative materials or animal tissues.
4. Formulation and Packaging - the formulation of bulk pharmaceuticals into various
dosage forms such as tablets, capsules, injectable solutions, ointments, etc., that can be
taken by the patient immediately and in accurate amount.
Production of a synthesized drug consists of one or more chemical reactions followed by
a series of purifying operations. Production lines may contain reactors, filters, centrifuges,
stills, dryers, process tanks, and crystallizers piped together in a specific arrangement. Arrangements
can be varied in some instances to accommodate production of several compounds.
A very small plant may have only a few pieces of process equipment but a large plant
can contain literally hundreds of pieces.
Exhibit 1 shows a typical flow diagram for a batch synthesis operation. To begin a production
cycle, the reactor may be water washed and perhaps dried with a solvent. Air or nitrogen is
usually used to purge the tank after it is cleaned. Following cleaning, solid reactants and
solvent are charged to the glass batch reactor equipped with a condenser (which is usually
water-cooled). Other volatile compounds may be produced as product or by-products. Any
remaining unreacted volatile compounds are distilled off. After the reaction and solvent removal
are complete, the pharmaceutical product is transferred to a holding tank. After each batch is
placed in the holding tank, three to four washes of water or solvent may be used to remove any
remaining reactants and by-products. The solvent used to wash may also be evaporated from
the reaction product.
EXHIBIT 1: Typical Synthetic Organic Medicinal Chemical Process
The crude product may then be dissolved in another solvent and transferred to a crystallizer for
purification. After crystallization, the solid material is separated from the remaining solvent by
centrifugation. While in the centrifuge the product cake may be washed several times with
water or solvent. Tray, rotary, or fluid-bed dryers may then be employed for final product finishing.
B. SOURCES OF POLLUTION
Exhibit 2 identifies pollutants from a typical pharmaceutical process. Volatile organic compounds
may be emitted from a variety of sources within plants synthesizing pharmaceutical
products. The following process components have been identified as VOC sources and will be
discussed further: reactors, distillation units, dryers, crystallizers, filters, centrifuges, extractors,
and tanks.
1. Reactors
The typical batch reactor is glass lined or stainless steel and has a capacity of 2,000 to 11,000
liters (500-3000 gallons). For maximum utility the tanks are usually jacketed to permit temperature
control of reactions. Generally, each tank is equipped with a vent which may discharge
through a condenser. Batch reactors can be operated at atmospheric pressure, elevated
pressure, or under vacuum, and may be used in a variety of ways. Besides hosting chemical
reactions, they can act as mixers, heaters, holding tanks, crystallizers, and evaporators.
A typical reaction cycle takes place as follows. After the reactor is clean and dry, the appropriate
raw materials, usually including some solvent(s), are charged for the next product run.
Liquids are normally added first, then solid reactants are charged through the manhole. After
charging is complete, the vessel is closed and the temperature raised, if necessary, via reactor
jacket heating. The purpose of heating may be to increase the speed of reaction or to reflux the
contents for a period which may vary from 15 minutes to 24 hours. During refluxing, the liquid
phase may be “blanketed” by an inert gas, such as nitrogen, to prevent oxidation or other undesirable
side reactions. Upon completion of the reaction, the vessel may be used as a distillation
pot to vaporize the liquid phase (solvent), or the reaction products may be pumped out so the
vessel can
be cooled to begin the next cycle.
2. Distillation Operations
Distillation may be performed by either of two principal methods. In the first method, the liquid
mixture to be separated is boiled and vapors produced are condensed and prevented from
returning to the still. In the second method, part of the condensate is allowed to return to the
still so that the returning liquid is brought into intimate contact with the vapors on the way to the
condenser. Either of these methods may be conducted as a batch or continuous operation.
Exhibit 2: Major Pollutants From Solvent Use in Pharmaceutical Productiona
Pollutant
(Solvent) Ultimate Disposition (%)
Air Emissions Sewer Incineration Solid
Waste Product
Acetic anhydride 1 57 42
Acetone 14 22 38 719
Amyl alcohol 42 58
Benzene 29 37 16 810
Carbon tetrachloride 11 7 82
Dimethyl formamide 71 3 20 6
Ethanol 10 6 7 176
Ethyl acetate 30 47 20 3
Isopropanol 14 17 17 745
Methanol 31 45 14 64
Methylene chloride 53 5 20 22
Solvent B (hexanes) 29 2 69
Toluene 31 14 26 29
Xylene 6 19 70 5
a Numbers are based on a survey of 26 U.S. manufacturers
3. Separation Operations
Several separation mechanisms employed by the industry are extraction, centrifugation, filtration,
and crystallization.
Extraction is used to separate components of liquid mixtures or solutions. This process
utilizes differences in solubilities of the components rather than differences in volatilities (as in
distillation); i.e., solvent is used that will preferentially combine with one of the components.
The resulting mixture to be separated is made up of the extract which contains the preferentially
dissolved material and the raffinate which is the residual phase.
Centrifuges are used to remove intermediate or product solids from a liquid stream. Centerslung,
stainless steel basket centrifuges are most commonly used in the industry. To begin the
process, the centrifuge is started and the liquid slurry is pumped into it. An inert gas, such as
nitrogen, is sometimes introduced into the centrifuge to avoid the buildup of an explosive atmosphere.
The spinning centrifuge strains the liquid through small basket perforations. Solids
retained in the basket are then scraped from the sides of the basket and unloaded by scooping
them out from a hatch on the top of the centrifuge or by dropping them through the centrifuge
bottom into receiving carts.
Filtration is used to remove solids from a liquid; these solids may be product, process intermediates,
catalysts, or carbon particles (e.g., from a decoloring step). Pressure filters, such as
shell and leaf filters, cartridge filters, and plate and frame filters are usually used. Atmospheric
and vacuum filters have their applications too. The normal filtration procedure is simply to force
or draw the mother liquor through a filtering medium. Following filtration, the retained solids are
removed from the filter medium for further processing.
Crystallization is a means of separating an intermediate or final product from a liquid solution.
This is done by creating a supersaturated solution, one in which the desired compound will
form crystals. If performed properly and in the absence of competing crystals, crystallization
can produce a highly purified product.
4. Dryers
Dryers are used to remove most of the remaining solvent in a centrifuged or filtered product.
This is done by evaporating solvent until an acceptable level of “dryness” is reached. Evaporation
is accelerated by applying heat and/or vacuum to the solvent-laden product or by blowing
warm air around or through it. Because a product may degrade under severe drying conditions,
the amount of heat, vacuum, or warm air flow is carefully controlled. Several types of
dryers are used in synthetic drug manufacture. Some of the most widely used are tray dryers,
rotary dryers, and fluid bed dryers.
5. Storage and Transfer
Volatile organic compounds are stored in tank farms, 233-liter (55 gallon) drums, and sometimes
in process holding tanks. Storage tanks in tank farms range in size from about 2,000-
20,000 liters (500-5,000 gallons). In-plant transfer of VOCs is done mainly by pipeline, but
also may be done manually (e.g. loading or unloading drums). Raw materials are delivered to
the plant by tank truck, rail car, or in drums.
C. POLLUTANTS AND THEIR CONTROL
1. Air Emissions
Solvents constitute the predominant VOC emission from production. Plants differ in the
amount of organics used; this results in widely varying VOC emission rates. Therefore, some
plants may be negligible VOC sources while others are highly significant. In addition, all types
of equipment previously described have the potential to emit air pollutants.
a. Reactors
Reactor emissions stem from the following causes: (a) displacement of air containing VOC
during reactor charging, (b) solvent evaporation during the reaction cycle (often VOC’s are
emitted along with reaction by-product gases which act as carriers), © overhead condenser
venting uncondensed VOC during refluxing, (d) purging vaporized VOC remaining from a
solvent wash, and (e) opening reactors during a reaction cycle to take samples, determine
reaction end-points, etc.
Equipment options available to control emissions from reactors include surface condensers,
carbon adsorbers, liquid scrubbers, and vapor incinerators (under certain conditions). Condensers
are often included on reactor systems as normal process control equipment.
b. Distillation Operations
Volatile organic compounds may be emitted from the distillation condensers used to recover
evaporated solvents. The magnitude of emissions depends on the operating parameters of the
condenser, the type and quantity of organic being condensed, and the quantity of inerts entrained
in the organic.
Emissions from distillation condensers can be controlled through the use of aftercondensers,
scrubbers, and carbon adsorbers.
c. Separation Operations
1. Emissions from batch extraction stem mainly from displacement of vapor while pumping
solvent into the extractor and while purging or cleaning the vessel after extraction. Some VOCs
also may be emitted while the liquids are being agitated. A column extractor may emit VOCs
while the column is being filled, during extraction, or when it is emptied after extraction. Emissions
occur not only at the extractor itself, but also at associated surge tanks. These tanks
may emit significant amounts of solvent due to working losses as the tank is repeatedly filled
and emptied during the extraction process.
2. A large potential source of emissions is the open-type centrifuge which permits large
quantities of air to contact and evaporate solvents. The industry trend is toward completely
enclosed centrifuges and, in fact, many plants have no open-type centrifuges. If an inert gas
blanket is used, it can act as a transport vehicle for solvent vapor. This vapor may be vented
directly from the centrifuge or from a process tank receiving the mother liquor. However, this
emission source is likely to be small because the inert gas flow is only a few cubic feet per
minute.
3. If crystallization is done mainly through cooling of a solution, there will be little VOC
emission. In fact, the equipment may be completely enclosed. However, when the crystallization
is done by solvent evaporation, there is greater potential for emissions. Emissions will be
significant if evaporated solvent is vented directly to the atmosphere. It is more likely, however,
that the solvent will be passed through a condenser or from a vacuum jet (if the crystallization
is done under vacuum), thereby minimizing emissions.
Several add-on control technologies may be used on the separation equipment described
above. Condensers, which can be applied to individual systems, are effective and may be
the least costly option. Water scrubbers also have found wide usage in the industry. They
are versatile and capable of handling a variety of VOCs which have appreciable water
solubility. Scrubbers can be either small or quite large; thus, they can be designed to
handle emissions from a single source or from many sources (via a manifold system).
Carbon adsorbers can be and have been employed on vents from separation operations.
Several vents may be ducted to an adsorber because it is likely that emissions from a single
source would not warrant the expense of a carbon adsorption unit. Finally, in some instances,
incinerators may be applicable. They may not be a good choice, however, since
the expected variability from these emission sources might make continuous incinerator
operation difficult.
4. Enclosed pressure filters normally do not emit VOCs during a filtering operation. Emissions
can occur, however, when a filter is opened to remove collected solids. Emissions can
also occur if the filter is purged (possibly with nitrogen or steam) before cleaning. The purge
gas will entrain evaporated solvent and probably be vented through the receiving tank for the
filtered liquid. The largest VOC emissions are from vacuum drum filters which are operated by
pulling solvent through a precoated filter drum. Potential emissions are significant both at or
near the surface of the drum and from the ensuing waste stream. These filters can be
shrouded or enclosed for control purposes.
d. Dryers
Dryers are potentially large emission sources. Emission rates vary during a drying cycle and
are greatest at the beginning of the cycle and least at the end of the cycle. Drying cycle times
can range from several hours to several days. Control options used for dryers include condensation,
wet scrubbing, adsorption, and incineration.
1. Condensers are often the first control devices selected when dealing with air pollution from
vacuum dryers. They can also be used by themselves or in series with another device. Condensers
are not typically used on air dryers because the emissions are dilute.
2. Wet scrubbers have also been used to control many plant sources, including dryers. They
can also remove particulates generated during drying. For water soluble compounds, VOC
absorption efficiencies can be quite high (i.e. 98-99%).
3. Carbon adsorbers may also be used, especially following a condenser. Not only will overall
efficiency increase but a longer regeneration cycle can be used in the adsorber.
4. Vapor incinerators might be viable controls although varying VOC flows to the incinerator
may present operating problems.
e. Tanks
The vapor space in a tank will in time become saturated with the stored organics. During tank
filling vapors are displaced, causing an emission or a “working loss.” Some vapors are also
displaced as the temperature of the stored VOC rises, such as from solar radiation, or as
atmospheric pressure drops; these are “breathing losses.” The amount of loss depends on
type of VOC stored, size of tank, type of tank, diurnal temperature changes, and tank throughput.
Emissions from storage or process holding vessels may be reduced with varying efficacy
through the use of vapor balance systems, conservation vents, vent condensers, pressurized
tanks, and carbon adsorption.
2. Solid and Liquid Wastes H(21)
The manufacture of the following types of pharmaceutical products can generate hazardous
wastes:
• Organic medicinal chemicals
• Medicinals from animal glands
• Inorganic medicinal chemicals
• Antibiotics
• Biological products
• Botanicals
• Miscellaneous products
The largest quantities of hazardous waste are from the production of organic medicinal chemicals
and antibiotics. Exhibit 3 identifies potential hazardous wastes from pharmaceutical
production:
PH(23-28)
Exhibit 3: Potential Hazardous Wastes from Pharmaceutical Production
Product or Operation Potential Hazardous Wastes Estimated U.S. Generation
(dry metric tons/yr)1
Organic medicinal chemicals • Heavy metals
• Terpenes, steroids, vitamins, tranquilizers
• Ethylene dichloride
• Acetone, toluene, xylene, benzene isopropyl alcohol, methanol, acetonitrile
• Zinc, arsenic, chromium, copper, mercury 1,700
13,600
3,400
23,800
2,700
Inorganic medicinal chemicals • Selenium 200
Antibiotics • Amyl acetate, butanol, butyl acetate, MIK, acetone, ethylene glycol,
monomethyl ether 12,000
Botanicals • Ethylene dichloride, methylene chloride
• Methanol, acetone, ethanol, chloroform, heptane, naphtha, benzene
• Misc. organics 100
100
700
Medicinals from animal glands • Misc. organics 800
Biological products• Vaccines, toxoids, serum, etc.
• Ethanol 500
300
Misc. sources Misc. solvents 63,900
1Hazardous waste amounts are for 1973 estimated total U.S. generation.
D. REFERENCES
1. Control of Organic Emissions from the Manufacture of Synthesized Pharmaceutical
Products, Environmental Protection Agency, Research Triangle Park, NC, December 1978.
2. The Handbook of Hazardous Waste Management, Metry, Amir A., Ph.D., P.E.,
Technomic Publication, January, 1980.