	Continuous manufacturing for solid-dosage drugs has made significant strides over the past few years and commercial activity is increasing, as was evident at Interphex 2015 in presentations and exhibitions. Industry experts agree that continuous processing offers potential economic benefits, including reduced costs due to lower inventory and significantly increased flexibility of scale. The use of continuous processing is on the upswing because manufacturers are recognizing these economic benefits; research efforts and an increased academic focus have solved many of the initial technology concerns; and there is now greater availability of equipment, said Christine Moore, acting director in the Office of Process and Facilities at FDA's Center for Drug Evaluation and Research (CDER), in 

	Continuous processing has long received support from FDA, which has been interacting with the European Medicines Agency, academia, and industry for more than six years to advance the technology, noted Moore in a presentation at Interphex. Continuous processing aligns well with FDA's process analytical technology (PAT) and process validation guidance. Modeling and system monitoring, using PAT for example, allow for greater control, resulting in greater assurance of quality, noted Moore. There are no real regulatory hurdles to continuous manufacturing, but experience is limited, said Moore in the presentation. Experience is growing, however, and "FDA is staffed, trained, and ready to discuss," she said, noting that companies should meet early with FDA to ask questions and discuss their plans for continuous processes.

	Significant differences between batch and continuous processing are the way material flows and the measurement and control of the system, noted Moore. In continuous processing, unit operations are connected and interactions can be coupled, thus the control strategy is often different from that of batch processes. It is also important to understand the system dynamics, including how the material mixes and how it can be traced through the system, she explained. Continuous processes are typically plug flow, in which the material is mostly 'first in first out'. A disturbance in feed for a batch mixer is readily evened out during mixing, but mitigation of such disturbances in a plug flow system should be understood and modeled. "You should be measuring at an appropriate measurement frequency so you can detect fluctuations in quality and then have controls in place to make sure you have assurance of quality throughout the entire run," explained Moore in an interview.

	Process modeling is a tool that can be used to answer questions such as how material mixes. Because continuous processes are integrated, an integrated model is needed to describe the system, explained Doug Hausner, associate director at the Engineering Research Center for Structured Organic Particulate Systems (CSOPS) at Rutgers, the State University of New Jersey, in a presentation at Interphex. Flowsheet modeling tools can be used to help define a batch and validate that definition, by tracing how the material flows through the system and describing the residence-time distribution in the system. A model can also be used to do process sensitivity analysis and to optimize parameters such as output. Using models for risk assessment is key. "Models allow you to look at variations, such as perturbations in the system, and assess risk for a given product," Hausner added in 

. Modeling saves money and time by evaluating processes in a computer-modeling environment, which can then be verified in the laboratory, he concluded.

	A Pfizer, GEA Pharma Systems, and G-CON Manufacturing collaboration on a PCMM (portable, continuous, miniature, and modular) system was being promoted at Interphex. Pfizer brought the pre-assembled and prevalidated pieces of a prototype PCMM system to its facility in Groton, CT and is now getting the system up and running, said Phil Nixon, executive director for drug product technology and innovation lead for pharmaceutical sciences at Pfizer, in an interview with 

. The prototype system is designed to produce uncoated tablets, but could be modified to add other unit operations, such as coating. The concept could even be used for API synthesis or biologics, added Nixon. "An objective of this project was to make the technology broadly available to the industry," he explained. "The vendors (GEA and G-CON) are offering the equipment commercially, and Pfizer hopes that more companies will use it because that will help advance continuous processing technology." 

	Two weeks after Interphex, at a CSOPS workshop, "The Future of Advanced Pharmaceutical Manufacturing," held on May 7, 2015, representatives from pharmaceutical manufacturing, academia, and FDA gathered to discuss how to further advance continuous manufacturing in the pharmaceutical industry. A strong academic base is important for innovation, noted Janet Woodcock, director for CDER, in the keynote address. "FDA's vision for what needs to be done next to advance continuous manufacturing is closely aligned with the vision at CSOPS," commented Hausner in discussing the workshop with 

. "This vision includes a focus on process modeling and a greater scientific understanding of the process, for example." One of the next steps for CSOPS, which was spurred on by an invitation from Woodcock at the workshop, will be to put together a document to serve as input for a draft guidance on continuous manufacturing. 

Articles

Production Trends

Economic benefits, equipment availability, research results, and FDA support are driving progress in continuous processing.

Advancing Continuous Solid-Dosage Manufacturing

	Demand remains high for quality-control technology, driven by high-profile recalls, revised guidelines like the 

 General Chapter <1207> Sterile Product-Integrity Evaluation, the expanding population of biologic products, serialization requirements, and the evolution of a worldwide supply chain. One way to experience many quality-control systems in a short period of time is at the annual INTERPHEX trade show. As always, exhibitors at this year’s show (held Apr. 21–23, 2015, at the Javits Center in New York) displayed a full array of quality-control technologies, including optical inspectors.

	Packaging quality is crucial to drug-product quality. Optical inspection is an important piece of quality control, but building quality in begins with primary container production. For parenteral products, reducing or eliminating particulate contamination is imperative. To meet this need, West Pharmaceutical Services has developed ways to minimize particulate generation from the packaging components it supplies, such as ready-to-sterilize containers.


	Product quality may be supported by standalone or in-line optical inspection systems. In-line systems can integrate multiple inspection functions or be built into a packaging machine. The Cremer CFS-622*4 tablet counter from NJM Packaging, for example, features an integrated CountSafe inspection and automatic ejection system from Optel Vision. The camera/strobe system is compatible with any electronic counter. When it identifies tablets with a wrong shape, color, or size; broken product; or rogue product, a vacuum device sends rejects to a closed bin.

	Another integrated system, the HSAjet PV650 carton printer/inspection system from HSA USA, confirms print quality and correctness. A camera and optical character recognition and optical character verification software check alphanumeric information. The system also verifies Datamatrix and linear bar codes.

	Optical inspection is commonly used to check vials and other parenteral packaging formats for surface flaws and particulate contamination. The latest model from Brevetti CEA, the BL-S300 inspection system, is a highly configurable, camera-based machine designed to perform a three-part inspection (particle, fill level, and cosmetic) of vials and large volume parenterals ranging in size from 100 to 1000 mL.

	Two tabletop systems for visual inspection, the Maschinpex Visomat IV-T model from Driam USA and the DI-100 LT machine from Dabrico, handle vials, ampules, cartridges, and syringes in a wide range of sizes and liquid or lyophilized product. Designed for small batch sizes and laboratory applications, the semiautomatic units feature easy changeover. Speed depends on operator experience, product, and scope of inspection. Dabrico’s servo-driven DI-100 LT machine controls all functions from the operator interface.

	A linescan camera is the basis of an optical inspection system from Innoscan that converts a three-dimensional (3D) surface to a single, high-resolution two-dimensional image. Originally developed for insulin syringes, the rotary system with integrated high-voltage leak detection detects particles, cosmetic defects, and package integrity problems at up to 660 containers/min. Redundant particulate and cosmetic defect inspection stations minimize false rejects. If both paired stations don’t pass or fail a container, the system recirculates for another cycle. After the second pass, if the stations still don’t agree, the container is rejected.

	The GF Bag Control machine from ACIC inspects intravenous bags against a black or white background and prevents printing on the bags from causing false rejects. Color cameras and different wavelengths of light ensure identification of black, white, and translucent particles. An integrated load cell checks seal integrity by detecting changes in pressure during compression.

	To overcome problems traditional vision systems experience with opaque and non-round containers, Rommelag has developed a two-station, eight-camera unit that puts containers in a horizontal position. Cameras capture images from above and below as containers are vibrated. Although currently limited to inspecting blow-fill-seal containers, the technology is suitable for detecting flaws in other difficult-to-inspect containers.  

	For solid-dosage forms, the camera-based Teonys vision sorter from Proditec checks for cosmetic defects, rogue tablets or capsules, and off-specification dimensions. Modular design enables top or top-and-bottom surface inspection. An optional laser head measures thickness to detect doses that contain too much or not enough active ingredient.  

	Upgraded software helps Scanware Lynx-Spectra systems from Pharmaworks inspect printed tablets and capsules. This task can be challenging because the print message often is not the same on the top and bottom of the dose. In addition, the print may be the same color as the background or look like a contaminant.

	A tablet and capsule inspection service from Visionspect provides on-site operators and equipment from Daiichi Jitsugyo Viswill. The 3D inspection systems feature LED lighting, color cameras, more sophisticated inspection algorithms, easy cleanability, fewer changeparts, and a simpler operator interface.

					Visionspect provides tablet and capsule inspection equipment from Daiichi Jitsugyo Viswill. Image courtesy of Hallie Forcinio. 

	Optical inspection systems also document optimum performance and assist in troubleshooting packaging machines. The Hindsight 20/20CAM portable, washdown-compatible, high-speed video system from Monitoring Technology captures and stores images of machine operation in the cloud for easy sharing of video, which can be examined frame-by-frame if necessary. The system fits in a suitcase and accompanying backpack and consists of a monochrome or color camera head, image processor, laptop, remote control or manual lens, lighting, power cords and adjustable mounting gear. Options include an aseptic camera head and lens cover, wireless operation for recording inside clean rooms and a caster-equipped stainless-steel cart for multiple camera applications. 

	Look for more news on quality control equipment in July’s Equipment & Processing Report; an article will describe checkweighers, metal detectors, x-ray inspection systems, leak detectors, and headspace analyzers on display at INTERPHEX 2015. 

Packaging

Optical inspection equipment for packaging was displayed at INTERPHEX 2015.

Quality Control Solutions at INTERPHEX: Optical Inspection

	Tablet compression is a science and an art, and a host of factors contribute to a successful product run. Some of the most troublesome problems that manufacturers encounter, including insufficient tablet hardness, inconsistent tablet weight, incorrect flow of formulation through the feed system, and tool damage, can often be corrected by making adjustments to the tablet press or its systems. This article will discuss potential problems and how to adjust for them.


	Although many common tableting problems may be solved by making adjustments to the press, it is just as important to select the proper machine components, such as fill cams and feeder paddles. Choosing the correct fill cam is crucial to clean press operation and consistent tablet weight. Rotary tablet presses operate on the overfill principle, in which more powder is filled into the die bores than required, and the lower punch is then raised to eject the excess by the weight/dosing cam. This procedure is essential to obtaining consistent tablet weight. If the fill cam is too shallow, weight variation may occur due to insufficient die-bore overfill. If the fill cam is too deep, excess material will be ejected onto the die table or reintroduced into the feeder, depending on the type of press. If material is ejected back onto the die table, it will collect around the neck of the turret and then be forced outwards due to centrifugal force. The dies may then be refilled after passing over the weight/dosing cam, resulting in weight variation. In presses where the excess material is reintroduced to the feeder, it may undergo shear forces in the paddle feeder, resulting in particle-size reduction or densification, which affects tablet quality.


	A frequent problem with feeding material into the tablet press is bridging of material in the hopper, which results in feeder starvation (i.e., no material in the feeder) and/or overfill of the feeder, because the weight of the powder can cause compaction. A lack of freely flowing powder can result in variation in tablet weight. Material bridging can be identified by visual inspection through the sight window in the hopper or feeder. If the press is not equipped with these, problems can be observed by monitoring the progress of powder flow in the hopper from above. Most commonly, bridging and other flow problems are due to formulation issues such as cohesive formulation components, excessive moisture, or irregular particle shapes.

	Feeder paddle configuration also plays an important role in tablet consistency, because it affects die bore fill and tablet weight, which correlate directly to proper API dosage and are therefore crucial. One simple, yet effective, feeder paddle option is implementing paddles with a 45-degree angle on the leading edge of the paddle blades (see 

). This configuration is particularly helpful with light or “fluffy” formulations where consistent die bore fill is problematic. The angled blades direct powder down rather than just pass it over the die bores. This configuration has also improved die fill with good flowing formulations, resulting in standard tablet weight deviation being reduced by as much as 75%.

	Most modern presses are equipped with human-machine-interface-controlled operating systems. Tablet weight control is automatically adjusted by statistical process control based on compression force. Theoretically, this would eliminate the need for the operator to make manual adjustments, but these systems are not 100% reliable due to worn parts, improper calibration, or software issues. An “old school” experienced operater can sense weight variation by listening to, or touching, a press while it is in operation and, based on the harmonics of the press sound and vibration, can make manual adjustments to maintain proper tablet weight.

	One way to correct flow issues is to adjust the formulation. If the formulation cannot be changed, then the hopper will need to be modified, possibly by fabricating a new hopper with an optimal wall angle to allow proper flow. Results of powder rheology testing can predict the hopper angle needed for acceptable flow or indicate the need to add a glidant to assist with powder flow.

	Another method that can be used to encourage flow is to insert a vibratory rod into the hopper transition to agitate the formulation. Mounting a vibrator directly on the hopper may exacerbate the problem by causing product separation.


	Several adjustments can be made to the tablet press to improve tablet hardness and ensure proper die-bore fill and tablet weight. Proper rotation speed (i.e., RPM) of the feeder and turret as well as proper setting of upper punch penetration and precompression are all crucial to achieving tablet hardness.

 Correct feeder RPM can affect tablet hardness by ensuring proper filling of die bores. In addition, high RPM may induce particle attrition, thus leading to compaction issues.  The mating surfaces of the die table and feed frame(s) must be properly aligned and adjusted for a press to run cleanly. Lack of press cleanliness is one of the most common causes of press and tooling failure. It is important to perform a visual inspection for wear or damage when setting up the tablet press. These surfaces must be in good condition or formulation leaks may occur, again affecting tablet weight.

	Proper turret RPM can significantly affect tablet hardness. Sometimes it may be necessary to slow the press down to increase dwell time to achieve proper tablet hardness.

 It is generally better to run minimal upper-punch penetration (to help prevent air entrapment) and to reduce tablet ejection travel in the die bore. This practice also reduces lower punch movement, which generates heat. Heat is the enemy, because it increases sticking and picking issues. Increasing upper punch penetration, however, may aid in achieving tablet hardness. Because the punch heads will make contact with the upper roller at an earlier point, compression time will be increased. This parameter is not to be confused with dwell time, which is when the punch head flats are passing between the rollers. 

 shows how the compression time is affected by the upper punch penetration.

	Correct tool configuration can also affect dwell time. A "D" punch has a larger head flat than a "B" punch, and the larger head flat generally results in a harder tablet due to increased dwell time. When necessary, specialty or custom tooling with larger head flats can be manufactured to increase dwell time.

 Precompression is probably one of the most improperly used adjustments on a tablet press. Precompression is often set using a percentage of final compression, but in the author's opinion, this method is not a good practice because the operator does not truly know what is happening to the formulation prior to final compression. If insufficient precompression is used, there may be increased air entrapment, resulting in capping and/or laminating. If too much precompression is used, a tablet can become fractured. Often mistaken for soft tablets, fractured tablets are analogous to a safety glass window that has been hit with a rock; it may remain in its original form, but it won’t have any strength due to all of the cracks that have formed.  A tablet hardness tester will not be able to distinguish between soft and fractured tablets. By setting pre-compression manually an operator can observe the effect of compression force applied. With all main compression force backed off and turning the turret manually, tablets should be formed at the ejection point but should be weak enough to break apart when handled or ejected down the tablet chute. Minor increased or decreased pressure adjustments may be required after start up, but this is an effective beginning point.


	Regular inspection and maintenance of the tablet press and its parts is mandatory for successful tableting operations. In addition to proper cleaning and lubrication, the press should be visually inspected as often as possible

 Metal parts should be checked for fretting wear (see 

). Fretting on machine parts is often misinterpreted as rust, but it is actually microwelding of two mating parts that results from cyclic motion, due to increased clearances created by wear. Fretting is most commonly observed on dies that have cracked, which indicates worn die pockets. It appears at the top of the die as depicted in 

. The top of the die pocket suffers the most damage due to improper die installation. Fretting can also be observed on punches, but does not appear as clearly as it does on the dies or other press parts. Because punches are in motion in their guides, residual microwelded material is worn off.

	The turret is the heart of the tablet press; for successful tableting it is crucial that the turret remains within specification. Use inspection gauges to confirm turret wear. These gauges check the alignment between upper and lower sections, punch guide/die-pocket wear, and punch-tip to die-bore concentricity. If these areas become worn, tooling may be damaged resulting in poor table quality. Worn turrets need to be refurbished or replaced.

	Tablet presses are designed to allow for many automated and manual adjustments. If press operators are not trained properly, however, these adjustments can be useless. Operators must understand why the adjustments are being made, and what impact they will have on the tablets. Nothing can replace well-trained, experienced operators in ensuring product quality and meeting production schedules.


	Doug Kirsch is technical service manager of the Tablet Press Division for Natoli Engineering Company.

	Please cite this article as: D. Kirsch, "Fixing Tableting Problems," 

Troubleshooting

Adjusting the tablet press and its systems can prevent manufacturing and product quality problems.

Equipment and Processing Report-05-20-2015

Advancing Continuous Solid-Dosage Manufacturing

Quality Control Solutions at INTERPHEX: Optical Inspection

Press Adjustments Help Prevent Tableting Problems