Brabender Pharma
     Tabletop twin-screw extruder features easy cleaning.

Brabender Pharma’s PTSE 12/36 EC tabletop, 12-mm pharmaceutical twin-screw extruder is suitable for hot-melt extrusion (HME), early formulation development, and preparation of samples for clinical studies. The more compact addition to the company’s product line enhances the ability to address the challenges of HME in feasibility studies. The extruder has a removable barrel liner and a horizontally split barrel to allow quick access and ease of cleaning and sterilization. Two additional openings can be used as downstream feeding or venting ports. Segmented screws can be configured to customer specifications and optional ports can be added on request. 

K-Tron 
 Micro-ingredient feeder has high accuracy for low feedrates.

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Equipment from Brabender Pharma and K-Tron

June 2013 Editor's Picks: Products from Brabender Pharma and K-Tron

Model-predictive design—used to define, predict, and control a process—is well established in many industries and is beginning to take hold in pharmaceutical process-development and manufacturing. Modeling offers a way to improve process understanding and control and to speed development. In response to this trend, software tools that have improved capabilities and increased user-friendliness are being designed to meet the needs of pharmaceutical-industry users. Although modeling is relatively established in API-production processes, modeling of solid-dosage processes is less mature; software tools for modeling solids behavior are at the cutting edge. A wide range of tools can be used to model solids behavior, including computational fluid dynamics, population-balance models, and discrete-element modeling (DEM).

DEM discretizes a granular domain into elements and computes the interaction forces between the elements, which results in a detailed description of solid material movement, explains Richard LaRoche, PhD, vice-president of Engineering at DEM Solutions. DEM is being used to model solid-dosage unit operations including mixing, coating, powder feeding, granulation, and compaction. "A well-calibrated model can provide useful process information that is difficult or impossible to measure experimentally. For example, simulation and analysis can show shear inside a mixer, real-time forces in a tablet coater, segregation within a feed frame, and change in flow properties as the material is mixed or operated upon by devices (e.g., mills)," says LaRoche. DEM Solutions recently made available a searchable 

 containing over 3000 abstracts of papers involving DEM modeling, including many topics relevant to pharmaceutical solid-dose production. 

As with any new tool, there are challenges in adapting DEM to the needs of the pharmaceutical industry. One challenge is for the industry to better accept modeling in general and to understand the power, scalability, and adaptability of DEM, says LaRoche, who adds that he does see, however, an increasing acceptance of DEM-based modeling methods within the pharmaceutical industry. 

Another challenge is that modeling has traditionally been the tool of chemical engineers rather than chemists (who make up a large segment of the pharmaceutical industry). New modeling software interfaces, however, are more straightforward and incorporate online training that is designed to make the software more user-friendly for a wider range of users, notes Jonathan Kadane, director of product marketing for Pharmaceuticals/Life Sciences at AspenTech. Other improvements include a special search tool in the software that allows users to efficiently find and access models and data and a feature that allows users to identify ways to change designs to reduce energy or capital cost. Most recently, the company added a web-based user interface for its aspenONE software, which empowers more users to work with the software without specialized training using touch-enabled devices (i.e., through simple touch and swipe gestures on a tablet).   

For further discussion on modeling that includes additional comments from AspenTech and DEM Solutions as well as input from other modeling software providers, such as Accelrys and CD-adapco, and pharmaceutical industry members, see "

Using Model-Predictive Design in Solid-Dosage Manufacturing Processes

Model-Predictive Design, Control, and Optimization

,” written by members of the Engineering Research Center for Structured Organic Particulate Systems at Rutgers, the State University of New Jersey, which describes application of model-predictive methods and a continuous process-control framework to a continuous tablet-manufacturing process.  

Production Trends

Model-predictive design is applied to solid-dosage processes.

Developments in Pharmaceutical Process Modeling

Packaging machines displayed at INTERPHEX (April 23-25, 2013, at the Javits Center in New York, NY) rely on advanced technology to handle solid-dosage forms or parenteral products. 

Packaging equipment for solid-dosage forms tends to be integrated. BellatRx, for example, displayed a compact Packaging Cell designed to handle batches of less than 50,000 units. The flexible system consists of a container infeed turntable, infeed conveyor, counter, desiccant inserter, cotton inserter, and capper. A low-level vibratory bowl presents caps to the capper and can be equipped with an elevator for replenishment (see Figure 1). The Packaging Cell also may include an induction sealer, retorquer, bander, labeler, inspection modules and outfeed turntable. Rated at 60 bottles per minute, the cell can run up to 100 bottles per minute with the addition of a feedscrew. It also can be configured to handle liquids or powders. 

Expanded functionality also is commonplace as demonstrated by the US introduction of the MV-11 Outsert System from G&K–Vijuk International. A patented, three-knife process increases insert size to 266 panels in response to regulatory requirements for more product and patient information. Operating at 14,000 cycles per hour, the unit folds printed sheets measuring 40 x 20 inches into 1 1/8 x 1 1/8-inch outserts. 

  Compact, integrated systems also rule parenteral-product packaging. One example, the Da Vinci Loading/Unloading System from IMA Life North America, moves groups of vials in and out of lyophilization chambers using a battery-powered gear box and caterpillar drive system that recharges when parked (see Figure 2). An aluminum track and belt made of a material with a low coefficient of friction minimizes wear and particulate generation, enabling the unit to function in a Grade A (Class 100) cleanroom environment and move up to 600 vials per minute. Eliminating the actuating mechanisms usually found on the front and back of the machine shrinks the space required for loading and unloading and improves operator access. Patent-pending wireless communication eliminates cables between battery and programmable logic controller and further simplifies the design of the machine. Laser technology precisely controls positioning.  

Many aseptic filling lines begin with washing. The GW24 Batch Washer from Cozzoli Machine cleans ampules and vials ranging from 1 to 500 mL with 180 

F water for injection (WFI) and jets of air. A programmable logic controller stores nine wash recipes with up to 18 steps each. 

For low-volume and start-up applications, the RW-250 Vial Washer from PennTech Machinery operates the same way as its rotary RW-500 except the operator pushes vials into the cassette manually. Containers ranging from 1 to 100 mL are inverted to clean with WFI and sterile air and reoriented to exit the machine. Dwell times can be set as needed, and maximum output is 100 vials per minute. 

A compact monoblock system from Chase-Logeman includes modules to fill, insert droppers, torque, label, and apply date and lot codes. The rotary, 12-station unit fills containers ranging from microtubes to 4-ounce bottles at rates of up to 60 per minute. A checkweighing option tares the container and weighs it again after filling. Peristaltic pump or other filling technologies can be specified. Other options include a disposable fluid pathway and disposable filling needles. 

The all-electric ASEP-TECH Model 628 machine from Weiler Engineering blows, fills, and seals containers ranging from 0.5 to 500 mL. Standard features include a patented, electronically controlled fill system, automatic sterilization system with integral data collection, and filter integrity test system. A HEPA air shower maintains a Class 100 environment in the nozzle shroud area. A two-piece stepped base simplifies maintenance and product discharge.  

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Packaging

Solid-dosage forms and parenteral products benefit from next-generation packaging machines.

INTERPHEX Showcases Machine Innovations

While many factors contribute to the recent surge in glass delamination recalls, it is important to remember that no recalls, clinical, or laboratory studies to date have shown any evidence of harm to the patient from “glass flakes or lamellae”, and only a small fraction of drug products/container systems have a propensity for generating glass flakes. If one searches the literature, numerous examples of drug-product/glass-packaging interaction can be found in each of the past seven decades. The main reasons for increased glass delamination incidences in recent years are increasing inspection sensitivity for particles, high profile and costly recalls, and increased complexity of the formulations and, therefore, unknown criticality for corrosive attack of the containers. If glass delamination is observed, numerous types of alternate containers already exist in the market for packaging, and fast, reliable test methods are readily available for screening containers to evaluate the delamination risk for each drug-container combination.


  A delamination screening package developed by SCHOTT is aligned with USP 1660 guidance (1) and can be used to evaluate a drug-product/container system. The containers to be tested can be drawn from real-time stability samples or generated under accelerated aging temperatures to determine the amount of chemical attack from drug products on containers and assess the risk of glass delamination occurrence through the shelf-life of the drug product. For most drug-product solutions, the rate of attack can be assumed reasonably through use of the Arrhenius rate law. A combination of tests investigating the drug solution itself and the morphology and composition of the near surface area of the container are required to determine the risk of glass delamination for a scientifically justifiable selection of an alternative container. Test methods consist of optical inspection for visible flakes and video-camera inspection for subvisible flakes (15–50 microns). If flakes are not observed, three other tests are then usually run in sequence.


First, the solution is removed from the container and examined by inductively coupled plasma optical-emission spectroscopy/mass spectrometry (ICP-OES/MS) for concentration of typical “glass” elements to determine the total amount of dissolution or leaching into solution at a given time point. This test also measures the ratio of glass elements to get evidence for the mechanism of attack. 
 

The container is then assessed by a stereomicroscope method to look for light scattering and color bands in the container. Light-scattering regions indicate increased surface roughness, and color bands indicate an altered layer of material with a different index of refraction from the bulk glass of the container. Observation of either light scattering or color bands is followed up with cross-section scanning electron microscopy (SEM) to determine the extent of chemical attack on the surface and into the surface (i.e., depth-of-reaction zone). If a reaction zone is observed that grows with time, then there is an increasing risk of delamination with increasing storage time. 

To get a better understanding of the delamination mechanism, secondary ion mass spectrometry (SIMS) depth profiling is conducted to determine the chemical composition of any reaction zones found. If flakes are observed in solution, then the flakes can be separated from solution by filtration and analyzed by SEM energy-dispersive spectroscopy (SEM-EDS) to determine their morphology and chemical composition. These results are compared to the findings from the SIMS- and SEM-analyses from the interior container wall. The testing methods above, with the exception of the stereomicroscope method, have been incorporated into the USP 1660 guidance chapter on testing of containers for chemical durability. 

Delamination is usually seen after months or years of stability storage; tests must be much faster. 

Optical inspection gives a yes/no answer and relies partly on chance; complementary analytical tools are needed to see early indicators.

Delamination risk depends on the drug; tests need to use the drug or a placebo.

Responding to predicted container delamination


If delamination or significant evidence for chemical attack of the container has been observed and the mechanism determined, several alternative solutions exist before considering the need to change the formulation. A first approach would be to use the same glass type (i.e., Type 1A, Type 1B, molded Type 1) but from a different container manufacturer to eliminate the contribution to glass delamination from the container manufacturing process. A second approach would be to switch to a different Type 1 glass, either with the same or different container manufacturer. A third approach would be to use a Type 1 glass with a coating, such as the SCHOTT Type 1 plus container with a plasma-impulse deposited silicon dioxide coating. A fourth approach would be to switch from glass to a high-performance plastic such as cyclic olefin copolymer (COC, SCHOTT TopPac) provided there are no concerns regarding increased moisture or oxygen permeability. If none of those approaches work, the last approach would be to modify the drug formulation.

General Chapter <1660>, “Evaluation of the Inner Surface Durability of Glass Containers,” (US Pharmacopeial Convention, Rockville, MD, 2012). 

Dr. Dan Haines is scientific advisor, SCHOTT Pharmaceutical Services, 

daniel.haines@us.schott.com, tel: 570.457.7485 x653

Troubleshooting

A screening method predicts delamination in primary packaging.

Equipment and Processing Report-06-19-2013

June 2013 Editor's Picks: Products from Brabender Pharma and K-Tron

Developments in Pharmaceutical Process Modeling

INTERPHEX Showcases Machine Innovations

Evaluating Parenteral Packaging for Glass Delamination