5/3/16-5/5/16 MFG4 EXPO
Donna Bibber and MES will be attending the MFG4 Expo in Hartford, CT.
Dry Powder Inhaler Technology Seeks Partner
February 6, 2015 News Release Maine-based DoseOne, LLC Seeks Pharma / Device Partner
An opportunity exists for a Device/ API/Pharmaceutical partner to bring to market a revolutionary new singe-dose powder inhaler. DoseOne™ has been prototyped, tested, benchmarked, and is ready for pilot production and the support of a qualified partner to realize market potential. DoseOne™ is simple, inexpensive, and can be brought to market quickly as it is already designed, injection molded, and geared for fast iteration for the incorporation of minor modifications for a multitude of drug/excipient molecule sizes.
DoseOne, LLC holds multiple patents and is prepared to partner the most innovative DPIs available today, the DoseOne™ Single Dose Powder Inhaler.
Development of the DoseOne™ single dose powder inhaler (US Patents #7,832,399 B2 and #8,360,057 B2) required a multi-disciplinary team approach, as any such drug delivery device needs to combine not just design skills, but also software and mechanical engineering capabilities, and expertise in analytical science and industrialization. From concept to creation, the DoseOne™ device was designed to be sympathetic to the requirements for mass manufacture and regulatory compliance.
The two patents associated with the DoseOne™ single dose powder inhaler cover the unique dosing mechanism of the device, and the ability to use the technology for dual-drug delivery. The DoseOne™ inhaler contains multiple, segregated air pathways, which keeps powder hold-up to a minimum, and makes device optimization for powder properties considerably easier. Using this technology which drives the DoseOne™ inhaler, designs have been developed and patented for dual drug delivery, the device allowing for simultaneous release of two different and separately contained drugs.
From a manufacturability point of view, the key advantage of the DoseOne™ is its simplicity and intuitive use (one motion and complete). Through the expeditious use of design and micro manufacturing expertise, DoseOne™ is an easy to manufacture and assemble 3-component device. The simplicity is of great importance as an inexpensive drug delivery option, costing $0.16 per device at full volume. The ultra-precise nature of the design and components also ensures that the device is small, which makes it easy to carry and package for mass drug distribution.
The inherent characteristics, size, and nature of the drug delivery technology make the DoseOne™ inhaler hugely advantageous for numerous end use applications. One obvious area of interest is in third world treatments of pandemics and epidemics, where there is an enormous emphasis on safety of drug delivery, simplicity of drug delivery, and ways to show compliance with dose administered. The DoseOne™ is equipped with a simple dose readiness indicator and a dose delivery indicator, and its size and ease of use (relying on patient inhalation rather than propellant technologies) make it well suited to environments where local health services are sub-optimal. In addition, for mass drug administration the low unit cost of the device is obviously hugely significant.
The DoseOne™ is extremely easy to validate, and is ideal for drop-shipping with all this implies in reduction of total inventory management and shipping costs, which can reduce the end use cost of the device.
The simplicity of the design also makes it easy to revise to accommodate specific formulations. Of especial importance, however, is the ability using the DoseOne™ inhaler to simultaneously pierce capsules containing different drugs, meaning that the drugs mix within the body, so there is no necessity to address drug interaction issues as would be the case if the drugs were mixed in one capsule.
DoseOne™ is a perfect example of what can be achieved if an innate understanding of micro manufacturing design and manufacturing is combined with an understanding of the regulatory environment that exists around drug delivery devices these days, and a realization of the potential for innovative solutions that cater for mass “self” administration of drugs in a cost-effective and safe way.
The Market for DPIs:
Powder inhalers deliver drugs in the form of dry powder directly to the lungs, and are typically used in the treatment of respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD), asthma, and emphysema. However, due to many of their innate characteristics and advantages as a drug delivery mechanism, there is burgeoning interest around the use of dry powder inhalers (DPIs) in the pharmaceutical and medical device sectors.
In many ways, DPIs have become more prevalent as they have been tailored for markets previously catered for by Metered Dose Inhalers (MDIs), which many patients find difficult to use, which rely on propellants that have come under more and more legislative scrutiny, and — from the device manufacturers and pharmaceutical company’s perspective — are often expensive to make. It is generally agreed that DPIs are easier to use as they simply rely on patient inspiration to deliver the drug, and are less likely to lead to side-effects such as irritation of the airways.
As with all families of drug delivery devices, the balance for drug companies is between affordability and functionality. Unit cost per device is obviously critical, as is the ability for the drug to be delivered in the correct dose, and for there to be minimum drug wastage.
The DoseOne™ Solution:
DoseOne™ is a single-use disposable DPI, and as such overcomes many of the problems associated with multi-use DPIs and MDIs. As a single dose device, for example, it minimizes dose-to-dose consistency risk, and also negates the requirement for priming needed by many devices, with all this implies in respect of drug wastage.
In addition, as DoseOne™ is a single use disposable device — and therefore a new device is used for each dose — it eliminates the frequent problem of powder caking and flaking which can affect dose volumes in multi-dose devices.
Also, as a single use device, the issue of, and problems associated with, dose counting — which preoccupies the FDA and other health organizations around the world — is made redundant. In its current state, DoseOne™ contains a simple dose readiness indicator as well as a dose delivery indicator in the form of a viewing window, therefore promoting patient compliance by confirming the dose is ready and has been completely administered.
As such, DoseOne™ satisfies the regulatory demands previously only achieved by complicated and expensive designs.
So for any pharma or device manufacturer looking to locate a novel, cost-effective, and efficient drug delivery option please call or email Donna Bibber at dbibber@doseone.com to discuss potential partnerships.
DoseOne, LLC
t. +1 (774) 230-3459
e. dbibber@doseone.com
DoseOne™
For full details of DoseOne™ see www.dose-one.com
10/14/14-10/15/14 OPPORTUNITIES IN DRUG DELIVERY CONFERENCE
Donna Bibber and MES will be at the PODD Conference in Boston, MA
5/14/13 SOCIETY OF PLASTICS ENGINEERS presents its Pioneer Valley Dinner Event
* * Due to bad weather the March 19th dinner meeting has been rescheduled to May 14, 2013 * *
May 14, 2013 6-9pm at the Holiday Inn and Suites 265 Lakeside Ave Marlboro, MA.
Donna Bibber will be the keynote speaker, her topic of discussion – Micro Molding Bio-Resorbable Polymers.
Cost of Dinner Meeting: $35 for SPE members, $40 for non-members, $15 for students.
10/10/13 – 10/11/13 Opportunities in Drug Delivery
Donna Bibber and MES will be at the Opportunities in Drug Delivery Conference in Boston, MA
4/16/13 – 4/17/13 SME Micro Manufacturing Conference
Donna Bibber will be a speaker at the SME Micro Manufacturing Conference in Minneapolis. This conference is being held at the Hilton Minneapolis 1001 Marquette Ave South in Minneapolis, MN.
Secrets of Success in Micro Molding
This is an article Donna Bibber wrote for Plastics Technology Issue March 2012:
Medical-device, electronics, and biopharmaceutical manufacturers need new micro-molded products to create tinier, less invasive, and/or space-saving micro devices. Medical-device, electronics, and biopharmaceutical manufacturers need new micro-molded products to create tinier, less invasive, and/or space-saving micro devices. Micro-molded components can be as small as dust specks and/or have features that small. State-of-the-art micro parts can have molded features such as dimples around 3 microns in depth and diameter—more than 80 million of them across a surface the size of a microscope slide. (see Fig. 1 ). The tiniest parts in an assembly are the ones most likely to be a challenge and are also usually the enabling component of the entire device’s form, fit, and function. Similarly, micro tooling created by micro machining is critical to these parts ever making it to validation.
Fig. 1: Microscopic features molded in LSR. (Electron microscope image magnified 350X.) There are 84 million discrete shapes on each chip, each 100 μ tall and 100 μ wide and with 3 x 3 μ “posts” on top.
Many new advances in micro-machining technology are enabling design and manufacturing of micro molds, which then enable micro injection molding in thermoplastic, silicone, and metal powder. This is leading to worldwide advances in less invasive medical and pharmaceutical micro devices. This article provides a view of the challenges and solutions to many of the major elements of success to molding micro devices and assemblies.
THE CHALLENGE
Most micro products start with some level of extreme challenge. It is rare that they are manufacturable as initially designed or napkin-sketched; often they are scaled-down versions of something similar on the market, just several magnitudes smaller and/or requiring an experimental material to accommodate a drug-releasing agent or other special characteristic.
Micro assemblies are getting more complex due to their need to fit into tiny and delicate arteries, pumps, catheters, or endoscopes with actual working micro components inside. These often have challenging geometry because they were once designed as two or more components but have been cost-reduced to one so that they do not have to be assembled under a microscope. In many cases, such as with powder inhalers, they were once more than 20 micro components redesigned to fewer than five parts.
These devices may require pharmaceutical drugs directly compounded with or added to polymers, metals, or membranes and have working gears, levers, and drive mechanisms to make the device function repeatedly and with robust longevity. With these functions in mind, and the fact that these devices may be directly implanted into the body, it is important that they be developed in a robust way and are well tested for form, fit, and function.
MICRO-FLOW ANALYSIS
Because micro molds and prototype parts can be costly in their development cycle, micro mold-flow analysis provides insurance that a particular design will fill with the intended material. An all too common assumption when comparing parts made by conventional molding to micro molding is that micro parts can be filled with the same software and same modeling methods.
For example, flow analysis involving a typical 0.020-in. (500-micron) gate is very different from modeling flow through a 0.003-in. (75-micron) equivalent gate. The difference is that the micro part with the micro gate sees much more shear-induced heating (Fig. 2) in pushing through that small orifice. As a result, the solid-model mesh (Fig. 3) must have extremely high resolution to determine what is happening in the gate and thin-wall areas. The mesh of a solid model used in a mold-flow simulation requires single-digit microns (0.0001-0.0002 in.) while a mesh of tens of microns (0.0005-0.001 in.) is required in the part.
Fig. 2: Flow simulation of a micro part with shear effects modeled for a 50 μ gate orifice.
Fig. 3: Micro molding mesh used in mold-filling simulation requires high resolution with very small elements.
Another important factor in a mold filling or cooling simulation is direct practical knowledge of injection molding and moldmaking. The most talented computer jockey in the world would struggle without knowledge of plastics engineering, micro mold design, gate location and sizing, and runner and sprue geometry.
Process-specific and material-specific knowledge are also essential. The gates of micro-molded components will have to be properly sized so as not to place undue heat stress on the material entering the cavity. For heat-sensitive materials such as bioresorbable and biopharmaceutical polymers, the residence time in the injection barrel, nozzle, and hot runner must be understood in relation to additional heat that may be imparted to the material during injection. At times, the material drives the process choice, and at other times the process drives the material choice. Some common materials for micro molding are PEEK, PLA, PGA, LSR, polyethylene, polypropylene, polycarbonate, LCP, PMMA, cyclic olefin copolymers (COCs), and stainless steel (metal injection molding).
TOOLING
When the design and material are nailed down to the point of spending capital to test the components, it’s time for a micro mold to be made. Whether the material is thermoplastic, silicone, or metal powder, the tooling is the most critical component to success. Micro machining is the enabling technology for creating hair-sized core pins and micro channels and cavities. Because the parts and molds are so small (Fig. 4), the tolerances get smaller and the tooling must still be made to 25% of part tolerance to provide a good processing window. With tolerances of ±0.0005 in. (±0.01mm), the steel tolerances must be ±0.0001 in. (±0.003mm) to achieve a good window. There are not many tooling suppliers in the world that will sign up for these tolerances, for two main reasons:
1. They can’t measure ±0.0001 in. (±0.003mm) and therefore cannot validate.
2. They lack the equipment or skill set to achieve these tolerances.
Fig. 4: Mold insert and molded part, a micro transdermal patch. (Right) Close-up of part with multiple tall needles (<0.050 in.). This part has been molded in LCP, PC, PMMA and COC.
•Runner/sprue: The runner and/or sprue (if one exists), can be our friend or foe in micro assembly. We could use it as a handle to hold onto a part in automated assembly operations or add special locating “jogs” in the runner to aid in positioning the piece in an assembly nest.
•Parting lines: Parting lines on the order of 0.0002-0.0003 in. (10 microns) are significant in relation to the size of micro parts. Those 10 microns can easily make or break your assembly and must be considered when the part will be assembled to other parts, as it can prevent proper fit if the part is not guided or moved through the assembly process properly.
•Draft: More is better but can be as small as 0.2° of taper. This taper, inside or outside a molded part, can be cumbersome to deal with. Having your micro part “ride” on a taper will provide an arbitrary or irregular surface that can position it improperly for assembly to other parts. Ways around this are to eliminate draft on a small portion of the part being positioned, draft the assembly station/fixture with the matching draft angle, or add a drafted feature to the part or runner that can be used and removed later on.
•Gate location: What is true of any injection molded part is all the more so in micro molding: It is critical to choose a gate location that will create uniform flow in the cavity. Without that, the part may not fill and could result in damage to delicate pins and cavities.
•Gate vestige: Most micro molded parts use an edge gate. If so, they need to be degated properly to avoid issues with small “picks” of material causing damage to an artery (in implanted devices) or causing issues with automation and assembly. These small picks can be addressed in the mold design by placing a dimple in the wall thickness (if the walls are thick enough) so the vestige will “sit” below the surface of a guide or a mating component in the assembly.
•Surface finish: Often overlooked, the surface finish of a molded part is important in “riding” or “guiding” features into other features during assembly. Some surface finishes are best achieved with vapor honing or roughening the surface to provide improved surface area for bonding, for example. Smooth surfaces can cause problems in ejection from the mold and a compromise may be required.
INJECTION MOLDING PROCESS
If tooling is the enabler, then there’s the micro injection molding process to get you the remaining 10-15% to the finish line. With micro molded parts and features in the single-digit micron range, there are several challenges to achieving good tool replication in the molded part. It is one thing to make nice sharp corners and cavities in steel (less than 1 micron radii) but quite another to fill those tiny spaces with polymer. Proper venting is required, sometimes with extremely thin laminates (puzzle pieces of steel) to achieve proper degassing and filling of sharp corners.
Typical injection pressures in micro molded parts are upwards of 30,000 to 50,000 psi, which requires a delicate balancing act to fill at adequate pressure without displacing tiny, hair-thin core pins. Dust-speck-size parts with extremely thin walls (0.001-0.0015 in.) require extreme cavity-to-core alignment across parting lines.
This allows balanced flow throughout the tool without freezing off. If the polymer freezes off in a non-fill condition, or if the part fills more on one side than another, it is likely that micro core-pin damage will occur. This challenge is overcome with fast fill at short injection times (typically < 0.1 sec) and high pressures. With these two variables, it is clear that the tool must be robust and highly precise to meet these challenges during fill.
There are around a dozen manufacturers of specialized injection machines tailored for micro molding. The range of choices has at least tripled since 2005. Micro molding machines must be able to inject very small shots and keep the residence time in the barrel to a minimum. This is especially important for bioresorbable polymers (PLA, PGA), which are highly shear and heat sensitive. Specialized screws, nozzles, and auxiliary equipment are also needed to provide the level of precision of filling, handling, degating, measuring, and assembling these tiny devices.
ASSEMBLY & HANDLING
The best way to handle microscopic parts is to not handle them at all. Combining geometries into the least number of parts for a micro assembly is design work well worth the effort because picking them up, registering them in nests, and joining them to other parts of like or unlike materials can be much more costly than spending the time upfront in the design stage.
•Two-shot micro molding/overmolding: Injecting two different materials into a mold at two different locations or in the same location with a rotating mold enables one setup of combination geometry and materials. For example, if a pump piston requires a seal or silicone gasket, it is easier to overmold a gasket into an o-ring groove in the same mold as the piston than it is to bowl-feed an o-ring onto a precision tracking mechanism, grip the o-ring with some scissor grippers, and place it over the piston. The o-ring would be subjected to stretching and shape distortion with the scissors, bowl feeding, and riding on a track of an assembly system.
•Laser welding: If 3D geometry can’t be combined through overmolding, and material strength allows for it, laser welding is a good method for joining micro components. Careful control of laser energy and power densities also can be used to selectively clean and strip materials such as wires quickly and non-destructively.
Laser beam sizes in the sub-micron and lower range and pinpoint accuracy of multiple laser welds are possible using a nano-positioning table or a multi-axis robot station mounted on a rotary table or shuttle system. Laser welding can use existing wall thickness or an extra “tab” designed into the component being welded, or a small amount of similar material can be introduced using wires, as is done in soldering electrical components.
•Ultrasonic welding: Ultrasonic welding is also effective to join thermoplastics as well as compatible metals. Specialized low-energy boosters and ultrasonic horns are required for micro components as the amount of energy required for a strong weld is extremely low.
•Spin welding: This is usually not a good option for micro parts, due to the very thin walls; however, a very tiny (100-200 μ) weld bead is sometimes possible.
•Solvent bonding: This is often used as a quick, low-capital-investment method for joining micro components. “Quick-and-dirty” fixtures can easily test the feasibility of bonding dissimilar materials using micro and nano pipettes to distribute the tiny amounts of solvents. Appropriate solvents must be compatible with the materials being bonded, especially if the assembly is to be used as an implant. Ramping up a high-volume assembly process with solvent bonding can be headache-ridden, as the method is not easily automated and repeatable, and it’s messy and difficult to validate on a high- volume scale.
•Staking: Micro staking is a very inexpensive method to join polymer and metal components. In battery cans, for example, crimping or staking is a very common practice to generate good seals for preventing caustic fluids from escaping the battery vessel. Inexpensive progressive stamping dies enable a moderately fast method for staking both polymers and metals to one another using a pressurized “folding” of one material into another. Material lot variations can be a drawback of this method.
TESTING
An important aspect of automated micro assembly systems is testing, such as for electrical conductivity, leakage or pressure decay, and burst strength. Some are destructive and some are nondestructive. The best way to determine if your final assembly or sub-assembly will function properly is to keep your process in control for each component that makes up the assembly.
Statistical validation of each component and revalidation of the assembly will prevent costly testing and inspection in an automated cell later; but sometimes they may be unavoidable, especially with implantable and critical drug-delivery applications.
Automatic, inline testing can be performed in cycles shorter than 2 sec for high-volume applications. It’s not unreasonable to test sub-assemblies both on their own and within a final assembly on the same piece of automation. The main reason to test sub-assemblies first is the cost of components that will be added to make the final assembly. For example, a catheter with two plastic components and a wire sub-assembled and leak tested will be far less costly to scrap (using a shuttle off to the side for that particular station) than it would be to test the final catheter with five plastic components, two metal ones, and a handle. Sub-assembly testing can be statistically reduced once the automation process and your incoming micro components are in control—both of which usually happen during validation and clinical trials as product volume ramps up.
Some tests may take longer than is affordable in a high-volume automated cell, and parts may have to be selected at statistical intervals and shuttled off onto a side track. For example, a pressure-decay test may take 3 to 4 sec. If the test is nondestructive, parts can be shuttled back into the production line.
INSPECTION METROLOGY
We’ve all heard that “you can’t make it if you can’t measure it.” In medical and pharmaceutical devices, where critical components can be a matter of life or death, this also means “you can’t make it if you can’t validate it.” Micro metrology should be avoidable if parts are manufactured consistently and validated. But any time we are asked, “Can you say without hesitation that this assembly will work in the application 100% of the time?” the answer must be in the negative until all components have run with several different lots of material, at different times of the year, at several different humidity and temperature levels, etc. Therefore inspection is inevitable at least until we can statistically prove all of the above over a long period of time. For critical implants, inspection is a certainty for the life of program.
There are many viewpoints when it comes to inspecting micro components and assemblies. Some can be inspected with high-resolution cameras just to verify a feature or surface finish. Some require 3D laser scanning to verify a number of critical dimensions. Some others require high-speed video cameras to show powder or picoliter liquid dispensing has been achieved to the correct dosage. Inspection is often overlooked and becomes an after-thought. But with micro components and assemblies, it is critical to consider during the prototyping stage, even to determine if the Cpk of the device and the stack-up tolerances of the components will fit within the functional range of the final assembly.
2/13/13 – 2/14/13 Pharmapack Europe Conference
Donna Bibber was a speaking at the Pharmapack Europe Conference in Paris, which took place at the Grande Hale de la Villette on 2/13/13-2/14/13. She spoke about microfluidic devices for drug delivery.
UMASS Lowell creates an exciting new building for the micro industry!
UMass Lowell officially opened it’s $80 million Emerging Technologies and Innovations Center earlier this month. “This center houses a range of advanced machines and gadgets that industries need to compete in the global market. From nanotech to life science and chemical engineering, researchers, manufacturers and investors can work together to get their jobs done”, states the Lowell Sun.
Donna Bibber graduated from UMass Lowell and was also invited to attend this grand unveiling. She was grateful to be a part of the opening and excited with the opportunity and potential this center offers! You can read more about the micro field opportunity here.
Micro Molding Needles and Sharps
Micro molded needles and sharps have their advantages like ease of use and cost effectiveness. They are used in applications like insulin delivery devices, drug delivery and patches. They are made from many different materials and processed using many different micro manufacturing methods. Donna Bibber wrote a paper about this for CMM International, you can read this full paper by clicking here: micro needles and sharps