	The recent milestone of FDA approval of two solid-dosage formulations produced through continuous manufacturing has brought attention to the merits of continuous manufacturing to the entire global pharmaceutical community. As this industry continues to investigate and use continuous manufacturing practices, the roles of loss-in-weight (LIW) feeders and the subsequent accurate and consistent refill of these feeders are critical. The importance of the method of refill, refill control algorithm, reaction time of the refill device, and also the size of the refill hopper are all critical variables that often get overlooked when designing a continuous manufacturing system. This article outlines a number of important considerations in refill operations and investigates their influences not only on LIW feeder accuracy, but on the overall continuous manufacturing process.

	A typical LIW feeder achieves rate control by weighing the entire feeder, hopper, and the material contained in it (see 

). The speed of the metering device is controlled to result in a per-unit-time loss of system weight equal to the feed rate. As an integral part of loss-in-weight feeding, the weighed hopper must be resupplied with material. Several pharmaceutical operations are dependent upon this refill of feed principle. These operations include continuous extrusion (both hot-melt and wet-granulation extrusion), continuous direct compression, and continuous wet granulation.

The feeder hopper can be refilled with either a manual method or an automatic method. The manual method implies that a quantity of bulk solids is tossed into the feeder hopper by the plant operator, and the process continues. The automatic method implies that dosing machinery under control of the feed system will add material to the feeder hopper from an upstream supply. 

	In the past, the traditional method of maintaining feed was to simply use a constant metering speed throughout the refill phase-a speed corresponding to the metering speed associated with gravimetric control just prior to entering the refill phase. If, for example, the metering speed averaged 60 RPM just prior to the system sensing the need to refill the supply hopper, the screw speed would be maintained at that 60 RPM for the duration of the refill operation. After refill is completed, material has settled, and the feeder senses an appropriately declining system weight, the feeder is returned to gravimetric operation where metering speed once again becomes the parameter of control.

	There are two problems associated with this technique. First, during refill, the feeder only acts as a volumetric feeder. Second, upon re-entry to true LIW control, abrupt changes in feeder speed can occur, resulting in a sometimes extended period of off-spec mass flow until the feeder settles into the new proper speed.

 plots the hopper weight versus time and shows the declining weight signal, the slope of which is the feed rate (change in system weight per unit time). Note that the hopper does not empty completely before the refill phase is triggered, primarily to assure an ever-present supply of material at the metering device so feeding may proceed without interruption. Additionally, if a sufficiently large material heel is not present, the increasing pressure applied by the impact of the incoming and possibly aerated material during refill may cause uncontrolled flooding through the feeder.

	Even with an insulating heel of material in place, density within the metering zone will rise somewhat as the hopper fills. Given a constant metering speed during refill, this increase in density causes aggressive degradation (overfeeding) in feeding accuracy as more and more material enters the hopper and compacts the material into the hopper’s lower regions. 

	How severe is this accuracy? The answer hinges on hopper size/geometry in addition to the compactability of the material itself. Laboratory tests and field experience involving many hundreds of materials show that, in practical terms, headload-related LIW overfeeding may range between +/- 1% for relatively constant-density materials. For powders and other materials whose density can vary substantially, however, this variation can be as high as +/- 10–15%. When dealing with compressible pharmaceutical powders in continuous operations, this variation can significantly affect accuracy. 

 A controlled method of storing and trending the weight-to-speed relationship was developed to avoid these problems. This method, referred to as Smart Refill Technology (SRT), discards the approach of maintaining a constant metering speed. Instead, during automatic refill, the feeder control system switches to volumetric control, relying on the trending data obtained while the hopper was emptying of product. As the hopper is emptied, the corresponding speed of the motor is trended.  When the refill is occurring, this same speed is used for the corresponding hopper weight (see 

	SRT enables metering speed to be gradually lowered during refill to precisely counterbalance the effects of increasing material density occurring within the metering zone as the hopper weight increases. In this way, gravimetric feeding accuracy during the brief refill may be maintained.

 illustrates the Smart Refill Technology (SRT) approach. The graph at the top plots net hopper weight versus time.  Beginning with a full hopper (where net hopper weight equals refill complete weight) gravimetric operation is in effect, and the feeder operates normally. As net hopper weight declines, the controller also determines and stores a set of up to 100 feed factors, each of which is the index of the average density of material discharged at the hopper weight associated with the feed factor. A low feed factor indicates that a higher number of screw revolutions were required to discharge a given weight, implying a reduced material density. Conversely, a higher feed factor reflects higher density because fewer revolutions were required to deliver the same material weight.

					The middle plot of Sidebar Figure 1 shows motor speed versus time. During the early portion of the gravimetric feeding phase, motor speed is relatively constant because density within the metering zone of the feeder, while higher than at later times in the feeding cycle, does not vary substantially. This is because material in the upper portion of a typical hopper is largely supported by the material below, and, in turn, the tapering walls of the lower portion of the hopper. As feeding proceeds and hopper level declines, headload in the metering zone begins to lessen, resulting in a reduction in density and a corresponding increase in motor speed required to maintain feed rate. When hopper weight reaches the refill request threshold, the refill phase begins. During refill, SRT begins with the motor speed that was in effect at the time of the refill request, and then modifies that speed by applying the corresponding feed factor as each hopper weight “slice” is encountered. 

					By taking this more sophisticated approach, it is possible to smoothly exit the refill phase and return to true gravimetric operation. Additionally, by controlling feeder speed during refill based upon the most recent performance history, reverting to volumetric performance is avoided and gravimetric accuracy is essentially preserved.

	As a rule, the refill period should be approximately 6–10 seconds. This duration ensures positive control over the incoming material but is so short that minor flow variations should not perturb the downstream processes. For many pharmaceutical operations, however, the refill window can be much smaller, due to the shorter overall time span of the operation. Because it is important to keep the feeder in gravimetric control over the majority of the continuous operation, often more frequent and shorter refills are used, typically using approximately 60–80% of the refill hopper volume. This refill window can be crucial to the overall operation of the feeder and must be evaluated for the material being fed and its properties.

	For this reason, it is imperative to study the bulk solid properties such as bulk density, particle size, compressibility, angle of repose, gas permeability, particle morphology, and angle of friction when dealing with any type of material feeding operations, including refill. Each of these material characteristics will greatly affect not only the flow out of the hopper to the feeder but also how quickly the hopper is refilled. For example, if the bulk material has a high gas permeability (i.e., if gas can escape rapidly from the solid), the refill can occur as rapidly as is feasible. On the other hand, if the bulk material has a low permeability rate (i.e., the gas expands the bulk material and doesn’t quickly escape to return the solid to its resting condition), care must be taken during refill, for often these materials become floodable in this condition or at least suffer significant bulk density changes.

	For example, if flooding of the bulk solid begins during refill, the product could easily flush out of the LIW feeder. At a minimum, air entrainment effects resulting in underfeed conditions during and immediately after refill can significantly alter bulk density, because the control system is using control data from earlier in the run, when the product density was much higher. Air entrainment comes from rapidly refilling the feed hopper, such that air, being unable to quickly escape, passes through the incoming material to the region of lower pressure in the refill hopper. Venting of the weighed hopper can minimize the problem, but now dust collection and, in the case of active materials, filtration, must be arranged. Adequate venting will assist in material settling and aid in a quicker return to true gravimetric operation.

	There are several choices of refill devices used above the feeder hopper. Options include modulating butterfly valves or, in the case where extreme control is required, the use of alternate metered devices, such as volumetric screw feeders. In addition, the use of pneumatic loaders above the butterfly valve is often employed to transfer the material to a receiver above the feeder hopper. 

	It should be noted that problems may arise when the refill system does not take into consideration the capacity of the feeder hopper, the flow properties of the bulk sold, and the distance and potential storage volume of the bulk solids that can occur between them. For example, in refilling a feeder hopper from an intermediate bulk container (IBC), the volume of the product in these vessels will often exceed the volume of the feeder hopper. Clearly, it is impossible to control the refill without overfilling the feeder hopper, unless a time window is established for the opening and closing cycle of the refill valve. This time window can be calculated based upon bulk density of the material, the angle of repose (which dictates the settling level in the feeder hopper), and the flow rate through the refill device. When discharging from bins or IBCs, which may be equipped with flow aid devices (e.g., vibrators or live bottom bins), special care must be made to isolate the vibration of these devices from the feeder hopper to ensure that there is no interference on the LIW feeder weight-measuring device.

	As stated previously, the flow rate from the refill device must be sufficient to avoid exceeding the refill time limit. Additionally, the flow cutoff action of the selected device must be quick. A slow tapering off of the refill flow needlessly lengthens refill time; any leakage of the refill device may cause an unavoidable measurable weight disturbance, but will always result in a flow error in the positive direction.

Pneumatic vacuum receivers as refill devices.

 Pneumatic receivers, which operate under a dilute-phase vacuum transfer principle, are often used as refill devices, particularly for continuous operations. The pneumatic receiver can have a butterfly valve at its outlet, or it can be part of the volumetric feeder, which includes a valve at the outlet. The pneumatic system uses negative pressure to draw the material into a separately mounted and supported vacuum receiver. The receiver is filled to a determined level and then holds this material charge until the feeder below requests a refill. The level of fill in the receiver is determined by level sensors. At the point of the refill request by the feeder, the discharge valve opens and the receiver contents are discharged into the feeder hopper. At the same time of this release, a gas pulse is sent through the filter housed in the vacuum receiver to release any entrained particulate or material that may have settled on the filter. Filter material options include a laminated membrane-type material for quick release and easy-clean properties. 

	After dumping the material into the feeder hopper below, the valve is shut again and the receiver vacuum cycle immediately begins, so that the pneumatic receiver will be instantly ready for the next refill request. The use of pneumatic receivers as refill devices allows for an uninterrupted source of refill from a bulk container.

	A pneumatic receiver avoids possibly overfilling the feeder hopper. It should be noted, however, that in some cases, refill by gravity (not pneumatic transfer) is preferred. Gravity refill typically uses an IBC above the feeder hopper, and this system should use a modulating control valve tied directly to the required feeder refill levels to avoid overfill, as previously discussed.

	The refill method of the LIW feeder and the control of the refill algorithm are important processes in the optimal performance and design of a highly accurate continuous manufacturing system. Through careful evaluation of the feeding process, system layout, and material characteristics, a continuous feed and refill system can be optimized.

	Sharon Nowak is global business development manager, Food and Pharmaceuticals at Coperion K-Tron, www.coperionktron.com, 

	When referring to this article, please cite it as S. Nowak, "Improving Feeder Performance in Continuous Pharmaceutical Operations," 

Articles

Designing loss-in-weight feeders for accurate and consistent refill is crucial to a continuous solid-dosage process.

Improving Feeder Performance in Continuous Pharmaceutical Operations

	Pharmaceutical manufacturers are expected to have a continuous improvement program in place to monitor the performance of their operations, detect any underlying issues, and make the necessary corrections. This usually involves the collection of data and statistical analysis of the data.

	For years, FDA has been advocating the adoption of modern quality systems and risk management approaches in pharmaceutical manufacturing, noted Prabir Basu, consultant, Mt. Prospect, IL, US, and Professor Thomas Friedli from the Institute of Technology Management, University of St. Gallen, Switzerland in the 

. The idea is to establish management controls to support and maintain a company’s cGMP compliance status, as recommended in FDA’s guidance documents.

 of a pharmaceutical quality system (PQS) and how to measure the performance of the PQS while defining quality systems for drugs. According to FDA, 

“The requirements of good manufacturing practice are underpinned by a central objective: to create a system of programs, policies, processes, and facilities that prevent errors and defects. A PQS is successful when it assures an ongoing state of control. In a healthy PQS, managers establish a vigilant quality culture in which timely action is taken to prevent risks to quality. Lifecycle adaptations are made to address manufacturing weaknesses and continually improve systems. An effective process performance and product quality monitoring program provides early warning of emerging quality issues. Systemic solutions are implemented rather than ineffective shortcuts. A firm will also habitually attend to the seemingly small problems that quality experts remind us later would accumulate into costly, complex problems. An effective PQS will ultimately support stable processes, and predictable quality and supply.”

	Managing quality of pharmaceutical operations requires a systems approach, said Basu and Friedli. They stressed that the choice of metrics used to measure the performance of a pharmaceutical operation are crucial. Instead of using lagging indicators that measure the symptoms such as batch failure rate, metrics should be systems oriented.

	Given that continuous improvement is the goal, measurements must be linked to processes and reflect process performance. There has to be a feedback loop where an action is attached to the measurement result such that depending on the measurement, some actions are taken to adjust, correct, or improve the processes.

, Basu and Friedli also reviewed a new systems based approach to quality metrics-following the University of St. Gallen receiving a grant from FDA to undertake this project. They recommend a measurement system based on an operational excellence (OPEX) model, developed by the University of St. Gallen.

	The important components of a true OPEX program, as noted by Basu and Friedli, are continuous improvement, management commitment, and employee involvement. In principle, there is an excellent match of the key components of OPEX and those of an ideal quality system, they said. According to them, it makes sense to develop and integrate the metrics for OPEX implementation with appropriate metrics for “Quality” for pharmaceutical manufacturing operations.

Production Trends

Metrics used to measure the performance of a pharmaceutical operation should be systems oriented and based on an operational excellence model.

Choosing Quality Metrics

	Issues with glass (the traditional material for parenteral containers) and the complex needs of the rapidly growing biologics market are spurring developments in parenteral packaging. “Ease-of-use for the patient is another concern due to an increasing trend toward self-medication,” says Christopher Cassidy, vice-president of sales and marketing, North America for Schott Pharmaceutical Packaging.

	Quality continues to be imperative. “ … the main and most important concern of the pharmaceutical packaging market has always been the integrity of the drug and how to avoid any interaction between the glass and the drug,” says Paolo Golfetto, director of technical and business external relations at Ompi. He reports, “In recent years, with several recalls spurred by container or closure defects (… loss of sterility) or particle contamination, attention has intensified.”

	Dr. Nicolas Brandes, director, Market Development at West Pharmaceutical Services, agrees. He says, “From a regulatory perspective, we are seeing increased scrutiny on quality. It’s essential to build in quality from the start.” 

	The steady rise in biologics poses additional challenges. “Biologics often require specialized containers,” notes Brandes. Products often are highly concentrated, more viscous, and sensitive to packaging materials such as glass, polymers, elastomeric stoppers, coatings (such as silicon oil), and the traces of tungsten left behind during the syringe manufacturing process.

	The higher viscosity and higher volume of many biologics that will be entering the market may not be compatible with some formats, especially auto-injectors and prefilled syringes. Steven Kaufman, global business development lead at Bespak, explains: “In the past, a fill volume of 0.2 mL to 1 mL, using a 1-mL prefilled syringe with a 27-gauge needle was typical. That’s changed. In addition to the 1-mL prefilled syringe, primary containers have grown to include the 2.25-mL prefilled syringe, and needle gauges have diminished in size to 29 gauge. This combination poses a big challenge for injection time and, more importantly, for ensuring completeness of injection. With high viscosity comes concern about the force placed on a glass syringe to achieve a target injection time and guarantee conpleteness of injection. Glide force also must be considered, along with injection time and the risk of breakage. Major suppliers have addressed these needs with biotech-ready prefilled syringes, which offer better dimensional control and siliconization. Many pen systems have difficulty handling formulations above 10 centipoise (cp), but Bespak’s VapourSoft-based auto-injectors and our latest amplification system can easily handle several 100 cp with minimal risk of glass breakage.” In addition, Kaufman says, “Shipping testing and transport are critical parts of any device manufacturer’s program. When delivering high-value biologics, the appropriate level of robustness must be built into the device itself. ISO standards must be followed and tested against to ensure there’s no variability and that key specifications are met.  Now, more than ever, the importance of auto-injectors and similar devices such as wearables is increasingly clear.”

	Glass, a well-established material for vials, syringes, cartridges, and ampuls, has experienced quality issues such as particulate contamination, interaction with high pH products, and subsequent delamination. Glass also has the potential to break and may not be compatible with the cold temperatures some biologics and other novel applications, such  as cell therapy, require. “Extremely cold temperatures pose a challenge to container closure integrity,” explains Brandes.

	Suppliers of glass containers for parenterals have improved manufacturing processes to reduce chances of delamination and particulate generation and upgraded testing to provide earlier detection of problems. Ompi, for example, has “completely redesigned manufacturing equipment and introduced new process steps to drastically reduce … particles,” Golfetto reports. He adds, “We operate with a continuous improvement mindset, with a special focus on manufacturing process capability and product quality.” In fact, the company’s quality targets have moved from an acceptable quality level approach to a more stringent parts-per-million defect level.

	Cassidy emphasizes the importance of making process improvements within existing validation frameworks. For example, he says, “With Vials DC, we have optimized an established production process [to minimize chances of delamination].” Produced from high-quality Fiolax glass tubing, Vials DC containers undergo an optimized hot-forming process. The result is vials with highly homogeneous inner surfaces. Tests based on 

 <1660> showed no delamination or pre-indicators for delamination. He recommends, however, “performing screening studies for each individual case.”

	Measures are also being taken during manufacture, fill/finish, and final packaging to minimize glass-to-glass and glass-to-machine contact, which can flaw a container or cause breakage. The expanding use of ready-to-use nested vials, now available from multiple suppliers, prevents containers from coming into contact with each other or the equipment. Nested vials also streamline the fill/finish process. “Ready-to-fill packaging eliminates the need for washing and sterilization by the pharmaceutical company or third-party filler,” says Brandes. Users can load tubs directly onto filling lines. The streamlined, contact-preventing process reduces reject rates and preserves the cosmetic quality of the vials.

	Nested vials are not the only recent innovation in glass packaging for parenteral products. Double Chamber cartridges from Schott combine liquids with liquids or liquids with lyophilized drugs to provide stable storage, reliable reconstitution, and convenient and safe administration versus the traditional, multi-step dual vial (drug, diluent) and syringe administration process. “The risk of error, such as a possible contamination of the substances, increases with the number of steps,” observes Cassidy. “In addition, there is the risk that the patient could miss the right mixing ratio or inject the wrong dosage. A Double Chamber cartridge solves this problem because it carries out mixing and application in one go.”

The dual-chamber design addresses approximately 25% of new injectable drugs, vaccines, and biologics that are freeze-dried and have to be reconstituted prior to injection. The Double Chamber cartridge stores drug and diluent in consecutive chambers separated by a plunger (see 

). A bypass in the glass barrel allows the contents to mix before the drug is injected. Turning the pen lock pushes the plunger, leveling it to the bypass and forcing the diluting liquid through a 0.1-mm opening and into the second chamber; the liquid then reconstitutes the drug. Now, the exact dosage of the drug can be injected without risking contamination.

	Medical professionals and patients favor dual-chamber cartridges because they’re simple to operate. Plus, high dosage accuracy makes the system safe and convenient for patients, especially if a highly concentrated drug is involved. The cartridges are compatible with common pen systems and can be customized. Several major pharma/biotech firms have already adopted the format for a variety of products including human growth hormone.

	Although glass continues to dominate parenteral packaging, it’s not suitable for all products. In those situations, polymeric options are being specified. The most common materials, cyclic olefin copolymer (COC) and cyclic olefin polymer (COP), are tungsten-free and do not leach alkali-ions such as sodium, which can cause the pH-value of the drug to shift. “In severe cases this pH shift may affect the stability of the drug,” notes a Gerresheimer spokesperson.

	“COP reduces the risk of breakage and is proven for low temperatures,” says Brandes of West, which offers Daikyo Crystal Zenith COP vials. West licenses this technology from Daikyo Seiko. A clean material, Daikyo Crystal Zenith systems provide very low extractables. As a result, he adds, COPs “help reduce chemical interactions, delamination, protein absorption, and aggregation.” He notes that the material can be formed in custom shapes and designs, which are not possible with glass. “In a crowded market, there’s a need to differentiate products. Custom containment and delivery systems could deliver that differentiation.”

	Gerresheimer has offered a range of ready-to-fill COP syringes manufactured by its longstanding partner, Taisei Medical, in Japan. In collaboration with Taisei, Gerresheimer has expanded its ready-to-fill COP syringe portfolio and production capacity by beginning to manufacture the Gx RTF ClearJect syringe at its Gerresheimer Medical Systems plant in Germany. The first Gx RTF ClearJect product to be manufactured is the 1-mL long syringe with staked-in needle. “The Gx RTF ClearJect syringe … allows the use of standard components like plunger stoppers, backstops, and plunger rods,” says a Gerresheimer spokesperson. Under development for approximately 18 months and now in a prelaunch phase, the Gx RTF ClearJect syringe will be available in 2018.

	Schott offers a prefillable COC syringe for sensitive drugs. The Schott TopPac SD syringe with pure elastomer components features a reduced extractables and leachables profile. Careful component selection and an optimized processing method result in a significantly reduced level of impurities and decrease the chance of drug/container interaction. Cross-linked silicone for barrel lubrication reduces the amount of subvisible particles while providing optimal functionality. Sterilization with ethylene oxide instead of irradiation further reduces extractables and leachables.

	Polymeric containers may also be multilayer. The Gerresheimer MultiShell COP/polyamide/COP vial combines excellent barrier properties and glass-like transparency to protect contents from oxidation and water vapor and increase shelf life. A commercial production line manufactures vial sizes from 2 mL to 100 mL. An automated packaging line packages ready-to-use vials or bulkware. Applications include oncology drug products, monoclonal antibodies, osteoporosis treatments, and specialty injection solutions with high pH-value and significant sensitivity to oxygen.

	Another multilayer polymer-based container, Wheaton’s DualFusion vial, addresses delamination and leachate concerns. “There are two Fusion layers. The first layer is what we call a ‘protective layer,’ which is an inert organosilicate layer that protects against high or low pH products that can cause delamination via a silicon network hydrolysis,” explains Wayne Brinster, president and CEO of Wheaton. “The second layer is the ‘barrier layer,’ which is a silica layer that is covalently bonded to the COP shell via a plasma-enhanced chemical vapor deposition technology. These layers are less than 500 nm in thickness, so they are not seen with the human eye. When these two Fusion layers are combined with a COP shell it is known as a new material called a ‘Fusion material.’” The outer COP shell provides mechanical strength, protects against breakage, and can withstand a temperature range of -196 C to 121 C without cracking. The inner layer prevents permeation of water vapor, oxygen, and other gases; protects against delamination; and eliminates concerns over leaching of metal ions. Since the lining is so thin, transitioning to the new container would be reportable, but would not require new trials. “It would be a drop-in replacement,” says Brinster.

	The base of each ready-to-use, ready-to-sterilize DualFusion vial is laser-etched with a unique DataMatrix barcode for rapid and easy traceability. “This is extremely important when combating the ongoing concern of counterfeit drugs,” says Brinster. In addition, batches can be matched to run size.

	Applications include highly toxic drugs like chemotherapy doses where breakage would result in hazardous conditions and an arduous cleanup. Brinster reports, “We are already seeing a shift toward the DualFusion vial in the pharmaceutical industry, specifically in the biological segment. ... There is always a concern with leachates when packaging large protein molecules. For example, if a chemical molecule migrates from the primary packaging component into the end product, it can cause the protein to fold and change its form; this occurrence would result in a drug efficacy [concern]. For example, the folding of the protein will cause the end product to become less potent or even cause it to become dangerous to the patient.” The organosilicate inner lining of the DualFusion vial reduces the concern for leachates because of the high purity of the material. “We are also seeing a shift toward the DualFusion vial in the traditional chemical-synthesized segment due to its protection against delamination. ... The inert organosilicate layer ... protects against delamination from silicon network hydrolysis, which is common for drug products that are in a pH range of 3 to 11,” he concludes.

					According to Gerresheimer, the shift to ready-to-use vials depends on:

					According to Ompi, the benefits of ready-to-use vials include:

	When referring to this article, please cite it as H. Forcinio, "Protecting Parenterals in Primary Packaging," 

Packaging

Primary packaging and manufacturing technologies minimize product/package interaction, protect quality, support safe travel through the supply chain, and enhance performance at point of use.

Equipment and Processing Report-10-19-2016

Improving Feeder Performance in Continuous Pharmaceutical Operations

Choosing Quality Metrics

Protecting Parenterals in Primary Packaging