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Why Silicone Injection Molding is a Great Choice for Medical Manufacturing

When it comes to medical manufacturing, companies have a variety of methods to choose from ranging from molding to machining to 3D printing.  The following explains why silicone injection molding is a great choice for medical manufacturing – and why it may be the best option for your next project.

Why Medical Manufacturing Prefers Silicones

Silicones have long been a popular material for medical devices due to their durability, wide temperature range, chemical inertness, high tensile strength, vast range of available durometers, low toxicity, and compatibility with many sterilization methods. Furthermore, silicone has a unique molecular structure, namely its silicon-oxygen backbone, that results in several excellent properties that are desirable for medical manufacturing such as:

• Superior Biocompatibility: medical products often come in contact with the human body – either externally on a patient’s skin or internally as an implant that contacts tissue and fluids. Silicones are compatible with human tissue and body fluids, have a very low tissue response when implanted, and do not support bacteria growth. Additionally, medical-grade silicones, such as Liquid Silicone Rubber (LSR), have undergone stringent purity and biocompatibility testing that make them suitable for short and long-term usage. Simply put, silicones are unmatched in their biocompatibility, making them an excellent option for medical manufacturing.
• Withstands Sterilization: medical grade material must be able to withstand sterilization in order to minimize contaminants and the risk of infections. Devices and products made of medical grade silicone are easily sterilized and resist bacteria growth. In fact, medical grade silicones are often processed in special facilities called cleanrooms that reduce the potential for contamination. For example, all of ProMed’s manufacturing facilities are equipped with certified class 10,000 / ISO Class 7 cleanrooms, demonstrating a strong commitment to quality.
• Superb Stability: silicone is known for its resistance to UV, weather, and other environmental conditions that tend to age materials, leading to a high level of stability and long-life span for silicone products. These characteristics are critical for a number of medical devices such as implantables.
• Broad Temperature Range: compared to other materials, LSR and other silicones have excellent thermal stability. LSR blends are able to withstand high temperatures without deforming or melting. As for low temperatures, LSR maintains its flexibility and does not become brittle and vulnerable to breaking like thermoplastic elastomers.
• Low Viscosity: the low viscosity of LSR makes it a great material for making medical devices via silicone injection molding, since the LSR can easily flow into and completely fill molds with relatively low injection pressures, even those with small, complex, or high-tolerance features. A lower viscosity also makes it easier for manufacturers to mix in additives including colorants, desiccants, barium, and pharmaceuticals such as hormones or steroids. For these reasons, LSR is a great option for medical devices such as combination products.
• Quick Cure Rate: one of the benefits of silicones, like LSR, is that it cures faster than most other rubber materials – in some cases in only seconds. Additionally, due to the highly automated nature of silicone injection molding and the potential for 24/7 manufacturing, high volumes of medical products can be produced in a short period of time – adding to its popularity.

Looking for a reliable and proven partner for your next medical manufacturing project?
Contact ProMed to learn about the range of solutions and materials we offer as well as our decades of silicone injection molding experience.

Advantages of Silicone Injection Molding in Medical Manufacturing

For companies seeking high-quality and cost-effective products for the medical sector, silicone injection molding is an ideal solution.  Silicone injection molding has several benefits compared to other molding processes, and the following is why this method is a great choice for medical manufacturing. To learn more about ProMed’s medical injection molding and our commitment to quality, watch our short video.

• High Quality & Very Reproducible: silicone injection molding produces products that are virtually identical from part to part which provides excellent brand consistency and part reliability during high volume runs – this is especially crucial for devices used in the medical industry. High reproducibility also allows for production to be scaled up to very large volumes, resulting in low costs per unit once the upfront equipment set-up costs are paid.
• Excellent Versatility: silicone injection molding is able to manufacture a wide range of part sizes, materials, and colors. Additionally, this form of molding allows for the use of multiple materials simultaneously, allowing for a high degree of customization.
• Able to Produce Complex Parts: silicone injection molding is typically performed at high pressure which forces the silicone into small crevices in the mold (that other molding processes are unable to reach), enabling the production of intricate and complex parts.
• Efficient Production & Low Cost Per Unit: silicone injection molding is a very fast process that quickly generates high volumes compared to other molding methods, making injection molding a more efficient and cost-effective solution. Additionally, silicone injection molding is highly automated via the use of machines and robotics, requiring less oversight by operations personnel. Automation reduces labor costs which further decreases the manufacturing costs per unit, especially for high volume production.
• Low Waste Generation: silicone injection molding manufactures smooth products that have minimal finishing requirements after removal from the mold – resulting in less waste generation compared to other medical manufacturing techniques. In some cases, silicone injection molding waste is able to be reused, resulting in a more environmentally-friendly and lower cost process.

ProMed – Your Silicone Injection Molding Partner

ProMed was founded in 1989 to address an industry need for cleanroom manufacturing of silicone components, specifically those having a medical application. We have garnered a reputation as the world benchmark of implantable silicone components and assemblies – and are one of few companies in the world to provide contract manufacturing of drug-eluting products.

ProMed has expertise in working with the full spectrum of silicones covering a wide range of properties and characteristics. We will assist in your material selection to help ensure all design requirements are met. Our manufacturing facilities and equipment are designed for a single purpose—to mold medical and implantable silicone, combination components, and bio-material grade plastics with uncompromising quality and service. We currently have four divisions that are located within two manufacturing sites. All are certified class 10,000 / ISO Class 7 cleanrooms.

We can identify the right medical manufacturing solution for any project. We have extensive experience in a wide range of silicone injection molding techniques including:

• Automated Injection Molding
• Multi-cavity tooling
• Micro molds and micro molding
• Servo-controlled de-molding capabilities
• Insert molds, overmolds, and automation integration
• Transfer molding
• Compression molding

Click here to see why ProMed is your silicone injection molding partner. Contact ProMed today at 763-331-3800 to discuss your next medical manufacturing project.

Micro-Injection Molding 101

Medical products continue to shrink in size but grow in capability as the demand increases for more portable and functional devices such as implantables, wearable devices, hearing aids, and surgical instruments. Medical manufacturers must keep up with these advancements and be able to manufacture smaller, more complex devices without sacrificing quality.

The trend toward miniaturization of medical devices has resulted in an increase in micro-injection molding, a form of manufacturing that creates tiny and often complex parts. Below is more information on this form of injection molding and why it is gaining popularity across the healthcare sector. When it comes to selecting a micro-injection molding partner, OEMs must choose wisely as this form of manufacturing requires specialized equipment and skills that many injection molding companies do not possess. The team at ProMed have the know-how and state-of-the-art equipment to successfully perform a broad range of molding methods including micro-injection molding. Our team is focused on meeting the challenges that product miniaturization often present and we are positioned to assist with all of your injection molding needs

What is Micro-Injection Molding?

Micro-injection molding is a tight tolerance method of manufacturing that produces miniscule parts – often weighing significantly less than 1 gram with dimensions measured in millimeters. Many industries benefit from these tiny products including the medical market which has numerous applications for these devices. Healthcare providers as well as patients have pushed for less invasive procedures, thus, medical devices are meeting these demands by becoming smaller with more complex features.

While there are some variations between micro-injection molding methods, the main equipment and process are generally the same. The process begins when silicone is fed into a heated barrel. In the case of Liquid Silicone Rubber (LSR), manufacturing, the two liquid LSR components are stored in separate containers and then fed simultaneously into the barrel. Next, a screw is used to mix, heat, and transport the silicone toward to the mold. The melted material is then injected through a nozzle into the mold and travels via a gate and runner system into the tiny mold cavities; the proper design of the gate and runner system is essential to ensuring the mold is filled properly. As the silicone enters the mold, excess air can be released via vents. The pressure and temperature of the mold are maintained to allow the silicone to conform to the desired shape and harden quickly. Once the part is adequately cooled, the mold opens and the part is ejected, sometimes with the help of ejector pins. The mold is then ready to receive the next shot of silicone.

Micro-injection molding is one of the latest innovations within injection molding. Due to their size, these miniature products weigh significantly less than prior versions of medical devices. This is a significant advancement for medical manufacturing as weight has historically been a challenge for the healthcare sector. Smaller and lighter parts lead to less material usage and lower cost per part – a huge win for medical manufacturing, giving OEMs a competitive advantage.
Benefits of Using LSR for Micro-Injection Moldin

Silicones have long been a popular material for medical devices and medical device components due to their durability, ease of molding by many methods, wide temperature range, chemical inertness, high tensile strength, vast range of available durometers, low toxicity, and compatibility with many sterilization methods. Furthermore, silicone is compatible with human tissue and body fluids, has a very low tissue response when implanted, and does not support bacteria growth – making it a perfect option for implants. Additionally, medical-grade silicones, such as LSR, have undergone stringent purity and biocompatibility testing that make them suitable for short and long-term usage.

LSR has a lower viscosity than many other medical-grade silicones, meaning LSR is less viscous and more readily flows. Due to its lower viscosity, LSR is a good fit for micro-injection molding as it is able to fill the tiny micro spaces in the mold. Additionally, LSR’s desirable handling properties and lower shrink rate make it an excellent choice for manufacturing complex geometries and intricate micro-sized products. Due to the automated nature of injection molding, LSR can produce high volumes of components in a short period of time.

Looking for a reliable and proven partner for your next medical manufacturing project?
Contact ProMed to learn about the range of solutions and materials we offer as well as our decades of silicone injection molding experience.

Challenges of Micro-Injection Molding

While the micro-injection molding process is relatively similar to standard injection molding, there are some challenges that exist due to the scale of micro parts.

Micro-injection molding demands unparalleled precision. The weight and dimensional accuracy required in micro tooling and throughout the molding process is incredible – often measured in millimeters or milligrams. Tooling required for micro-injection molding is specialized and requires extreme attention to detail to ensure consistent alignment throughout the life cycle of the mold – which is often millions of micro parts.

Material dosing is more challenging when working with micro amounts. LSR is a 2-part liquid that cures into a solid form when mixed, which are often referred to as the A and B components. For micro-injection molding, feeding the precise dosage and ratio of A and B components of LSR is crucial to ensure the desired product quality and properties. Additionally, if additives, such as a color, are added the dosage must remain precise in order to achieve consistency from batch to batch.

Micro-injection molding requires a small shot of silicone material. Due to the small volume of material, operating conditions such as pressure and temperature throughout the molding process must be uniform and balanced to ensure proper filling and distribution of the material.

Due to their tiny size and weight, micro parts must be handled more carefully than standard injection molded products. Micro parts are often more fragile and susceptible to damage during handling and assembly. LSR parts are often tacky, further complicating the automated as well as manual handling process for micro parts. In addition, ensuring a thorough and comprehensive inspection of the miniature parts is often a challenge for micro molders.

In order to have a successful project, OEMs must partner with a micro-molder, like ProMed, that has the requisite experience with the equipment, materials, and potential pitfalls of micro-injection molding. Even the slightest deviation during micro-molding will result in parts that are unusable. OEMs must leverage the experience of their micro partner, especially during the part design and prototyping stages where many key decisions are made that will significantly impact the success of the final product.

What OEMs Should Look for in a Micro-Injection Molding Partner?

It is imperative that OEMs understand that not all injection molding companies are equipped for micro-injection molding. OEMs must look for certain characteristics when selecting a micro-molding partner such as quality control, state-of-the-art equipment, and tooling experience. At ProMed, we offer customers a broad range of silicone material and equipment offerings, including micro-injection molding, which enables us to provide support as your business grows over time.

Manufacturers that perform micro-injection molding must have ample experience and expertise with micro-molding equipment. Equipment that is able to manufacture small parts via injection molding is not necessarily able to create micro parts. As noted above, micro-molding operates at very tight tolerances and very small masses – requiring exacting and repeatability that is often not feasible with standard injection molding equipment. OEMs need a manufacturer, like ProMed, that has the necessary know-how and state-of-the-art tooling and equipment to successfully manufacture micro parts.

Similar to injection molding, OEMs must ensure micro-injection molding companies meet the requisite regulations and quality standards for the healthcare sector. Clean rooms are one method that medical manufacturers use to meet these requirements. At ProMed, our manufacturing facilities are equipped with certified class 10,000 / ISO Class 7 clean rooms, demonstrating our strong commitment to quality.

About ProMed

ProMed was founded in 1989 to address an industry need for cleanroom manufacturing of silicone components, specifically those having a medical application. Over time, we broadened our product offerings to include assembly, micro-molding of highly engineered plastics, and combination products. We have garnered a reputation as the world benchmark of implantable silicone components and assemblies – and are one of few companies in the world to provide contract manufacturing of drug-eluting products.

ProMed has expertise in working with the full spectrum of silicones covering a wide range of properties and characteristics. We will assist in your material selection to help ensure all design requirements are met. Our manufacturing facilities and equipment are designed for a single purpose—to mold medical and implantable silicone, combination components, and bio-material grade plastics with uncompromising quality and service. We currently have four divisions that are located within two manufacturing sites. All are certified class 10,000 / ISO Class 7 cleanrooms.

We can identify the right manufacturing solution for any project. We have extensive experience in a wide range of injection molding techniques including:

· Automated Injection Molding

· Multi-cavity tooling

· Micro molds and micro molding

· Servo-controlled de-molding capabilities

· Insert molds, overmolds, and automation integration

· Transfer molding

· Compression molding

Click here to see why ProMed is your silicone injection molding partner. Contact ProMed today at 763-331-3800 to discuss your next silicone injection molding project

Lean Manufacturing in the Medical Sector

The concept of lean manufacturing, or lean as it is sometimes called, has been around for decades and focuses on streamlining production to improve value and productivity while minimizing waste. From a lean perspective, waste is considered anything that does not add value. 

What are the Key Strategies of Lean Manufacturing?

Below is a summary of the 5 key principles of lean manufacturing. When implemented effectively, lean manufacturing results in significant efficiencies and productivity gains that lower production costs – providing the competitive edge companies are seeking. These concepts can be successfully applied to any sector including medical manufacturing.

1. Value – this principle is based on how the customer defines “value”. It is nearly impossible to streamline a manufacturing process if the value points are not clearly understood.
2. Value Stream – this step involves mapping out the processes that contribute to the value stream from beginning to end. It often starts with raw material acquisition and ends when the final product is delivered to the customer. This is a crucial aspect of lean manufacturing as the purpose is to identify potential waste areas and then work to reduce or eliminate the waste.
3. Flow – once the waste is removed, the manufacturing operations should run more smoothly and efficiently. Teams should revisit the value stream to ensure all waste has been removed where possible.
4. Pull – with the process running more smoothly, products can be manufactured and delivered “just in time”, reducing inventory requirements and costs. This also results in shorter time to market, further driving competitiveness.
5. Perfection – the final principle is about continuous improvement as lean manufacturing is intended to be an on-going assessment to avoid waste and inefficiencies from creeping back into the process. Companies with a lean culture ensure all personnel are empowered to participate in continuous improvement efforts.

Looking for an efficient and reliable partner for your medical manufacturing project?
Contact ProMed to learn about our lean manufacturing approach and the range of silicone injection molding solutions we offer.

How is Lean Manufacturing Applied to Medical Manufacturing?

Let us now discuss how lean principles can be applied to medical manufacturing. There are several types of waste that are often identified when a lean approach is used in medical manufacturing: surplus inventory, unnecessary motion (of personnel or equipment), waiting (personnel or machinery), over-processing or over-engineering a product, off-spec product or other quality issues, inefficient logistics and transportation – and various others.

When lean principles are applied, these sources of waste are reduced, or even eliminated, improving operations efficiency and product quality – adding significant value for customers. With shorter production times, medical manufacturers are more nimble and able to respond to customer needs and market conditions. Additionally, lean strategies can be applied to supply chain and product development processes, leading to quicker speed to market and a significant competitive edge.  

At ProMed, the main focus of our lean manufacturing techniques is maximizing customer value while minimizing waste – and we empower every employee to make a difference. Our team achieves these objectives through the application of Lean Six Sigma methodologies. Six Sigma and lean are both process improvement programs used in medical manufacturing, each focused on the same goal: eliminate waste in order to elevate production efficiency.  

The professionals at ProMed monitor product and process performance during the development and production phases of manufacturing by incorporating Lean Six Sigma quality management principles. As part of our commitment to quality, we have certified Lean Six Sigma Black Belts on our team and we use a Lean Six Sigma Green Belt certification program to train our personnel on lean manufacturing principles. These efforts ensure we reliably deliver the highest quality products to our customers.

ProMed – Your Silicone Injection Molding Partner

ProMed was founded in 1989 to address an industry need for cleanroom manufacturing of silicone components, specifically those having a medical application. We have garnered a reputation as the world benchmark of implantable silicone components and assemblies – and are one of few companies in the world to provide contract manufacturing of drug-eluting products.

ProMed has expertise in working with the full spectrum of silicones covering a wide range of properties and characteristics. We will assist in your material selection to help ensure all design requirements are met. Our manufacturing facilities and equipment are designed for a single purpose—to mold medical and implantable silicone, combination components, and bio-material grade plastics with uncompromising quality and service. We currently have four divisions that are located within two manufacturing sites. All are certified class 10,000 / ISO Class 7 cleanrooms.

We can identify the right manufacturing solution for any project. We have extensive experience in a wide range of injection molding techniques including:

• Automated Injection Molding
• Multi-cavity tooling
• Micro molds and micro molding
• Servo-controlled de-molding capabilities
• Insert molds, overmolds, and automation integration
• Transfer molding
• Compression molding

Click here to see why ProMed is your silicone injection molding partner. Contact ProMed today at 763-331-3800 to discuss your next silicone injection molding project.

Liquid Silicone Rubber vs High Consistency Rubber for Medical Device Components

Silicone elastomers have long been a popular material for medical devices and medical device components due to their durability, ease of molding by many methods, wide temperature range, chemical inertness, high tensile strength, vast range of available durometers, low toxicity, and compatibility with many sterilization methods. Furthermore, silicone is compatible with human tissue and body fluids, has a very low tissue response when implanted, and does not support bacteria growth – making it a perfect option for implants due to its excellent biocompatibility.

Silicone elastomers are available in two commercial forms: Liquid Silicone Rubber (LSR) and High Consistency Rubber (HCR). HCR is known for its gummy consistency and mostly comes in partially vulcanized sheets. LSR is a newer technology and starts out as a 2-part liquid that cures into a solid form when mixed. LSR generally comes in buckets and has a longer shelf life than HCR.

Medical device OEMs often face a tough decision: should we use HCR or LSR for our medical device component manufacturing? LSR and HCR are both used to manufacture medical device products; however, there are some key differences. The following compares LSR and HCR to shed some light on their differences and when each should be utilized.

Viscosity Difference Leads to Different LSR and HCR Manufacturing Techniques

The performance characteristics of HCR and LSR are relatively similar; however, viscosity is a key differentiator between LSR and HCR, and has a significant impact on the equipment and processes used to manufacture each of these elastomers.

Simply put, viscosity is a measure of a material’s ability to flow. A low viscosity indicates a material is less viscous and more readily flows where a high viscosity indicates a material is more viscous and less apt to flow well. For reference, water has a relatively low viscosity and easily flows whereas molasses has a higher viscosity and is more resistant to flow.

LSR has a lower viscosity than HCR. Due to the lower viscosity, LSR is most often processed via injection molding. LSR’s desirable handling properties and lower shrink rate make it an excellent choice for manufacturing highly complex geometries and intricate products. Additionally, due to the automated nature of injection molding, LSR can produce high volumes of components in a short period of time. For this reason, deciding whether HCR or LSR injection molding is the better choice for your project largely depends on the production volume required.

A lower viscosity makes it easier for manufacturers to mix additives into LSR. Additives that can readily be incorporated into a batch of LSR include colorants, desiccants, barium, and pharmaceuticals such as hormones or steroids. For these reasons, LSR is a great option for medical devices such as combination products. The low viscosity of LSR and the temperatures needed to vulcanize LSR are usually low enough that significant degradation of compounded substances, like Active Pharmaceutical Ingredients (APIs) that are used in combination products, can be avoided.

Due to its higher viscosity and more challenging handling properties, HCR is typically processed using compression and transfer molding methods, which are more labor-intensive. In some cases, HCR is used in injection molding projects.

OEMs Often Prefer LSR

For companies already using HCR to manufacture medical device components, it may make sense to continue using this elastomer especially since the initial capital equipment costs have already been made. For new product development, however, LSR is often the best choice given the lower capital costs and labor associated with processing this elastomer. Due to its lower manufacturing cost and versatility with formulations, companies often prefer LSR over HCR – but the decision is on a case-by-case basis.

ProMed’s Silicone Manufacturing Capabilities

At ProMed, we combine industry-leading medical-grade LSR and HCR expertise with the latest developments in silicone materials and technology. We have garnered a reputation as the world benchmark of implantable silicone components and assemblies. From helping OEMs incorporate the latest medical-grade silicone formulations into their designs to delivering rapid silicone prototypes, we serve as a premier silicone molding contract manufacturer for medical device OEMs.

ProMed has expertise in working with the full spectrum of silicones covering a wide range of properties and characteristics. Our wide range of materials include: Liquid Silicone Rubber (LSR) 5 to 80 Durometer, High-consistency Rubber (HCR): 20 to 80 Durometer, Room Temperature Vulcanizing silicone (RTV). We will assist in your material selection to help ensure all design requirements are met.

Our manufacturing facilities and equipment are designed for a single purpose—to mold medical and implantable silicone, combination components, and bio-material grade plastics with uncompromising quality and service. We currently have four divisions that are located within two manufacturing sites. All are certified class 10,000 / ISO Class 7 cleanrooms.

Contact ProMed today at 763-331-3800 to discuss your next medical device project.

The Challenges of Manufacturing Combination Components Part 2

Until recently, companies manufacturing Combination Device or Drug products were faced with the formidable task of deciding how to best comply with multiple, and sometimes overlapping, regulations for both devices and pharmaceutical products. When the FDA issued the final rule for 21 CFR Part 4, cGMP Regulation of Combination Products, on Jan. 22, 2013 and the Final Guidance for Industry on how to comply with these new requirements in Jan. 2017, much of the gray and conflicting areas were resolved and it became apparent that a either a Device based Quality System or a Pharma based Quality System, enhanced with policies and procedures to cover either the Pharma regulations or the Medical Device regulations, is the preferred route.

ProMed’s Combination Products QMS was derived from the existing ISO 13485 certified and 21 CFR 820 compliant device Quality System used in our molded products area. The key provisions of the Pharma regulations in 21 CFR 210 and 211 that are needed for us to manufacture devices with a drug constituent are identified in Table 1.

This whitepaper examines ProMed’s approach to implementing QMS elements that satisfy these requirements.

Drug Product Containers & Closures (21 CFR 211.84)

This regulation defines the requirements for the testing and approval (or rejection) of components, drug product containers, and closures.

ProMed’s device Quality System uses risk evaluations to categorize our suppliers. Those vendors deemed critical are evaluated through assessments, audits, or both depending upon the level of risk. Components from critical vendors are qualified as required to assure we use only those components that meet customer specifications.

To comply with the additional pharmaceutical requirements, we enhanced our Pharma QMS to ensure that Drug components and Drug product containers are received using approved in-house procedures and, where cleanliness is a requirement, we assure that we clean the containers and components and assure containers are closed and only opened in environmentally controlled areas to prevent the introduction of contaminants into the products or components.

Representative samples of each shipment of each lot are collected for testing. Certificates of Analysis (CofA) are reviewed for compliance to pre-established material specifications. If testing is required, the quantity of material and amount required for reserve samples is determined and sampled from incoming containers. Sampling is generally based upon the √N+1 rule for N number of containers unless a higher degree of scrutiny is required. Reserve samples are labeled as to origin (lot number, date received, and expiration date) and stored in a secure, environmentally controlled area.

Testing for compliance with specifications is performed by our in-house ISO 17025-accredited laboratory or an approved contract lab. In the event out-of-specification (OOS) results are found during analysis, we document and investigate through our non-conforming material procedures. Once analysis of the samples is complete, a review and release is performed by our Quality Assurance team.

Material suppliers and their past quality history is tightly monitored through our Supplier Quality program and quality events may result in a Supplier Corrective Action Request (SCAR).

Calculation of Yield (21 CFR 211.103)

This regulation defines the requirements for calculation of yield and requires the manufacturer to know and control how much of the drug product is present in each dosage unit.

Although many colorants and mix ratios of activators and resins are critical in silicone molding processes, traditional device manufacturing processes do not require calculation of yield. To comply with the Pharma calculation of yield requirements, ProMed implemented comprehensive batch records to calculate and document the theoretical yield and actual yield of drug in components that have drug constituent. The batch records are predefined through process development and process validation to assure the specified loading and elution targets are achieved. During manufacturing, calculations are generally performed by one person and independently verified by a second person; when the yield is calculated by automated equipment the result is independently verified by one person.

It is important to note that our combination products typically consist of a molded silicone structure impregnated with the drug substance or active pharmaceutical ingredient (API). Once an active pharmaceutical ingredient is fully encapsulated within a silicone matrix through our molding processes, the next step is to confirm the drugs elution profile and burst. In other words, we test and confirm how fast the drug substance elutes or discharges from the silicone. This complex analytical testing is performed in-house using validated methods or by an approved contract laboratory as appropriate. The results are used to confirm actual yield and that the drug elution profile meets specifications. Conforming product is released for final packaging or further processing by Quality Assurance.

Tamper-Evident Packaging (21 CFR 211.132)

ProMed does not currently engage in manufacturing Over-The-Counter (OTC) drug products and tamper evident packaging is not a requirement in our medical device component manufacturing process. However, in our combination products area, we do use non-resealable pouches and our labeling practices comply with tamper-evident packaging requirements. If those pouches are breached or the labeling is missing, a consumer can reasonably be expected to determine that tampering has occurred.

Expiration Dating (21 CFR 211.137)

Expiration dates for Combination Products with a drug constituent are established through the product development process while working closely with the customer. Expiration date testing and aging studies are established in accordance with the requirements of 21 CFR 211.166 to meet our customers’ requirements. This stability program is managed by ProMed, an approved lab, or our customers. Together, we work to assure the drug product meets applicable standards of identity, strength, quality, and purity at the time of use and label each individual unit for sale with an expiration date as determined by appropriate stability testing.

Testing and Release for Distribution (21 CFR 211.165)

ProMed samples and tests each batch of drug product for conformance to specifications, including the identity and strength of each active ingredient, prior to release. Samples are collected according test plans defined in approved batch records and include the method of sampling and the number of units per batch to be tested.

Samples are tested by our in-house ISO 17025 accredited laboratory or an approved contract lab as required. All test methods used to support conformance to specifications are validated and documented to assure accuracy, sensitivity, specificity and reproducibility where appropriate. For products required to meet microbiological specifications, methods suitability for the product is verified and samples from each lot are tested for compliance prior to release.

ProMed’s Quality Assurance team verifies that the test results conform to predefined acceptance criteria and that the samples and results statistically represent the entire batch prior to approval and release. Any batch failing to meet established standards, specifications, or any other relevant quality control criteria are rejected. Due to the nature of manufacturing molded combination devices, reprocessing is not usually possible, and therefore rejected batches are destroyed.

Stability Testing (21 CFR 211.166)

ProMed’s stability testing practices for Combination Products with a drug constituents are established during the product development process and are specified and managed by our customers.

Special Testing Requirements (21 CFR 211.167)

ProMed tests each batch of drug product purporting to be sterile and/or pyrogen-free using an approved contract laboratory to verify conformance to such requirements prior to product release. The test procedures are included in the approved batch records.

Although ProMed does not manufacture ophthalmic ointments, we do manufacture implantable, drug eluting ophthalmic devices. ProMed ensures that these products have predefined requirements regarding the presence of foreign particles and harsh or abrasive substances and that each batch of product is tested and confirmed to meet these specifications.

Because many molded combination devices are formulated for controlled or extended release, drug burst and elution profiles are critical to product performance. To confirm how fast the drug substance elutes or discharges from the matrix, analytical methods for dissolution and quantification are validated and performed in-house or by an approved contract laboratory.

Reserve Samples (21 CFR 211.170)

ProMed retains an appropriately identified reserve sample from each lot in each shipment of active ingredient or released product. The reserve sample consists of at least twice the quantity necessary for all tests required to determine whether it meets established specifications, except for sterility and pyrogen testing. Reserve samples are retained for all drug product samples and excipients for one year after the drug product expiration dates at ProMed Pharma or at customer site.

Reserve samples are stored in a product-suitable environment in a closed container. The reserve samples are scheduled through our PM system for visual examination at least once a year to ensure that the sample integrity is maintained.

Other Requirements

ProMed implemented a formal procedure for performing Annual Product Quality Reviews (APQR) for each drug product we manufacture at the end of the first year of a product’s commercial manufacturing and every year thereafter. All manufacturing process parameters, failed batches, OOS, non-conformances, complaints or other quality related events are evaluated for trends, systemic issues, or opportunities for improvement. As a contract manufacturer, the report is shared with the customer and any changes are evaluated, validated, and approved by the customer prior to implementation.

Drug products in high concentration areas, such as compounding areas, may pose a threat to our employees’ health and safety. ProMed implemented a program for assessing our personnel’s overall health and the protection and safety features required to keep them safe. To prevent exposure, we perform a risk analysis for each API and specify appropriate containment using appropriate isolators and closed systems. This equipment is then verified to provide appropriate containment as part of our validation program to assure that these safety features are effective to meet our safety standards.

Conclusions

Over the past several years, our Quality Management Systems and management team have matured as we engaged with many new and exciting customers. We have developed expertise in Combination Products including drug-eluting vaginal rings, glaucoma treatments, and diabetes monitoring systems. Our knowledge and experience has added great value to our customers; from the planning stages through regulatory submissions and sustainable manufacturing. ProMed Pharma is positioned to ease your burden and shorten the time required for market launch.

The Challenges of Manufacturing Combination Components Part 1

Introduction

In 2006, ProMed embarked on a journey to broaden our capabilities from the molding and assembly of components for medical devices to include the manufacturing of drug/device combination products. Differences in regulatory requirements between medical devices and pharmaceutical products presented unique challenges during this effort across the company to meet our customers’ and regulatory bodies’ stringent quality, safety, and compliance goals. This whitepaper discusses the challenges ProMed Pharma has confronted in three key areas: facility design, implementing the Pharma Quality System, and company culture for the enhanced scrutiny that accompanies these products. We also discuss the solutions that ProMed Pharma has enacted to meet these challenges.

Challenge 1: Facility Design

Prior to bringing a new manufacturing process online, it is essential to establish a close collaboration between the customer and the ProMed team to understand and define the intended flow of materials, personnel, and equipment in the facility. Once these are understood, the needs of the facility can be summarized in a mutually agreed upon User Requirements Specification (URS) describing the necessary features that must be designed into the facility and validated to ensure those needs are met. These requirements are then translated into specific designs addressing each requirement by implementing appropriate-sized production areas, layouts, equipment, utilities, and safety precautions. Each can then be validated appropriately to ensure that all the requirements established for the facility in the URS have been met.

Much of this approach is shared with ProMed’s molded components facilities, but several areas are of particular concern when designing facilities for combination products:

1) Receipt, Storage and Testing of Raw Materials

Drug substances and excipients must be received, quarantined, sampled, tested, and released prior to use. Additionally, to ensure personnel are properly protected from hazardous drug substances, each drug substance’s Occupational Health Toxicity/Potency Category, Safety Data Sheet, and other available information are evaluated and a mitigation plan determined. Appropriate personal protective equipment such as respirators and isolators are then used during receiving, sampling, and manufacturing.

Prior to receipt of raw materials, documents establishing the sampling required for these materials are written, reviewed, and released into the ProMed Pharma Quality System. Upon receipt of material, these documents are consulted to verify material certificates comply with pre-established specifications and what tests must be performed. Generally, identity testing, purity, strength, and quality must  be confirmed. Prior to release to the manufacturing floor, these records documenting the sampling, testing, and release are completed, verified to meet materials specifications, and reviewed. Please refer to our follow-on article, The Challenges of Manufacturing Combination Components Part 2 for further guidance.

Throughout this process, it is essential that incoming materials are segregated in quarantine away from released material that has already been verified as suitable for use. These quarantine areas must have appropriate temperature, light, and humidity conditions to assure continued quality during testing and release. To ensure that this is the case, ProMed established a series of labeled, segregated cages, coolers, and freezers with temperature control, monitoring, and qualification for their intended use beyond those already in place for storing materials for use in manufacturing. To help ensure that unreleased materials are never used, we formalized and expanded our existing system of color-coded materials labeling for each stage of receipt, quarantine, and acceptance to supplement physical segregation in our cages, coolers, and freezers.

2) Cleanroom space, utilities, and equipment for manufacturing

To ensure that all requirements established at the outset of a project are met to the satisfaction of our customers and regulatory bodies, it is essential that the equipment, air handling, process flow, cleanroom layout, and utilities are considered and established as new pharma production facilities.

Each product has very different requirements that require careful consideration during design of the manufacturing facility. For example, the facilities needed for manufacturing an ocular implant containing minute quantities of drug tend to be quite different from those for large scale manufacture of an intravaginal ring that consumes kilograms of potent hormone per batch. To ensure proper materials and personnel flow, each cleanroom is tailored to the needs of a particular customer and product.

Equipment and process requirements are evaluated for appropriate size, required utilities, materials of construction, monitoring instrumentation, pressure gauges, temperature gauges, and any other equipment particular to the product. While specifying equipment, the available utilities are compared to the actual daily consumption and demand for these items and what additional usage is expected when installed in the facility. When necessary, utilities are upgraded or modified to suit the needs of the specified equipment. In cases where the utility has a direct or indirect impact upon product quality, validation testing is performed to verify quality during this operation. For example, ProMed uses compressed air both to drive actuators and remove materials. In the former case, the validation is focused on maintaining pressure and variability within pre-established limits. In the latter case, the compressed air contacts product; as a result, validation is expanded to ensure that no oils, moisture, or microbial contaminants are present. Similarly, if a Purified Water System is used to wash components it therefore needs to be validated to ensure that the water meets USP requirements.

Careful specification and validation of air handling units (AHUs) is a major feature in the design of pharma production facilities. Proper air exchanges, pressure differentials between clean and dirty areas, minimization of operator exposure to drug substances, and maintenance of the proper humidity and temperature levels are all critical design criteria that must be handled by these units. To ensure our facilities continuously operate within specified conditions, an industry-leading electronic Building Automation System (BAS) was installed and validated. The BAS provides continuous remote monitoring and control of pressure differentials, temperature, and humidity to ensure that production areas remain within specified limits for each area.

ProMed’s typical pharma production facility is an ISO Class 7 cleanroom suite dedicated to a particular customer. We prefer to build our cleanroom suites with two air handler units, one that serves the main manufacturing areas and a dedicated unit for our mixing rooms. The dedicated unit helps to ensure drug particulates generated during the mix process are not recirculated into the main cleanroom. Additionally, we design our facilities so that the mix room has a negative pressure differential to adjacent rooms, so drug particulates generated during the mix process do not escape to the main manufacturing area or areas outside of the cleanroom suite. When appropriate, a series of pressure differentials can be maintained within the sub-rooms of a particular suite to ensure appropriate cleanliness and flow for each space.

3) Facility Qualification and Validation

As each new manufacturing facility is brought online, Design Qualification (DQ) is performed to ensure the cleanroom suite has been built to meet the specifications initially agreed upon in the URS. Validation of the suite includes Installation Qualification (IQ), Operation Qualification (OQ), and Performance Qualification (PQ) testing to ensure the cleanroom and Air Handler Units have been installed and operate as expected, proper air changes per hour are achieved, room balancing requirements have been met, all HEPA filters passed leak testing, and the room passed ISO 7 particle classification.

Once the facility has been initially qualified, the facility is placed into an environmental monitoring program. The new cleanroom suite is thoroughly cleaned in accordance with cleanroom cleaning and sanitization procedures. Once cleaning has been completed and documented, initial testing includes a three-consecutive-day period where no operators are present (static testing) followed by a three- consecutive-day period where operators are present (dynamic). The airborne viable microorganism, surface microorganism, and non-viable particulate levels from this initial testing are used to establish a baseline and the initial alert and action levels. The facility is then added to our routine Environmental Monitoring (EM) program and sampling is performed quarterly.

ProMed typically dedicates process and in-process test equipment to a particular drug substance. This helps to minimize subsequent cleaning validation requirements. All pieces of equipment used in the process are evaluated through a risk-based process for validation requirements. Where appropriate, equipment is IQ/OQ and PQ qualified before Process Validation (PV) and all operators working in the manufacturing operations are trained to the process.

Process Validation is performed by Process Operation Qualification (POQ) where at least three production runs are performed to confirm the upper and lower process limits. The POQ helps to establish process control schemes and guard banding. Once the POQ is satisfactorily complete, three consecutive Process Performance Qualification (PPQ) runs at the process center points are performed to verify process capability and the appropriateness of the established control schemes.

Challenge 2: Quality System

When ProMed embarked on manufacturing Combination Products nearly a decade ago, few specific combination product regulations existed. To develop a new combination device Quality System, our existing ISO 13485 certified Medical Device Quality System was used as a base augmented with the applicable drug requirements.

To create the Pharma Quality System, ProMed compared it’s existing system to available guidance, particularly FDA’s draft guidance “Good Manufacturing Practice for Combination Products” and Medical Devices Quality Management Systems – “Guidance on Application of ISO 13485.” This led to significant additions to the existing system, particularly with regard to training, documentation, testing, and record management. This new Pharma Quality System was then implemented as a separate, sister system for combination devices to the existing ProMed Quality system; in this way we have been able to ensure full compliance for each portion of the company while continuing to ensure rapid and cost-effective delivery of non-drug components.

Since the initial implementation of this system, we have continued to modify and update the Quality System to reflect current guidance. In the intervening years the FDA has recognized industry’s struggle with regulatory expectations and in January 2013 issued the final rule for 21 CFR Part 4, cGMP Regulation of Combination Products, and the Final Guidance for Industry on how to comply with these new requirements was published in January 2017. As it is commonly referred to today, Part 4 instructs those companies making Combination Products to fully comply with either a Device-based Quality System or a Pharma-based Quality Management System and augment it with the procedures necessary to support either a pharma product or a device product. ProMed’s approach to compliance in-depth is explored in a second article on The Challenges of Manufacturing Combination Components – Part 2.

Challenge 3: Standards and Culture

The cultural shift necessary to move from manufacturing molded components to successfully manufacturing combination products has been a major area of focus for ProMed Pharma. Some basic assumptions about how products are made, moved, and documented needed to be changed as part of this shift. Several of these are discussed below.

1) Batch Processing

In much of the medical device contract manufacturing industry, batch size for a particular lot corresponds with the number of components processed through the manufacturing environment. As parts pass through a particular operation, process and yield data are recorded for the entire lot.

In contrast, for combination device manufacturing, manufacturing often consists of a series of discrete processing steps where key characteristics (weight, yield) of individual units are tracked. Often these characteristics act as in process controls to assure the quality of the product through each step of manufacturing and assure the correct amount of drug is incorporated into the manufactured component. To implement this shift, ProMed adopted a manufacturing process where yield and processing steps can be addressed in a granular manner throughout manufacture of a particular batch. For some particularly demanding products, this tracking has been sufficiently careful to allow tracking of sub-batches as small as 8-16 parts made in a single injection cycle from thousands in a production lot, with each of these sub-batches tracked through the manufacturing process. By documenting and trending key measurements through each phase of manufacture we are able to assure continued product quality and rapidly diagnose the source of any potential out of specifications results quickly and thoroughly. This allows more precise tracking of yield through the manufacturing process and reconciliation of drug substance for each batch.

2) Documentation and Company Culture

ProMed’s experience in medical device contract manufacturing provided a thorough understanding of the importance of the accuracy of device history records and associated documentation. Moving into combination products, we were challenged to take on another level of diligence to assure that we properly document every aspect of our work. This required a concerted and ongoing training program to ensure that employees from the newest operator to senior management were indoctrinated in the necessity of the additional documentation, conversant in the additional requirements required, and capable of withstanding the higher level of scrutiny expected. To ensure our ability to meet these more stringent standards of documentation in parallel, we have steadily expanded our QA staff to help ensure progressive compliance and ensure the timely and complete review of our records.

This emphasis on high documentation standards has had a synergistic effect on ProMed’s molded products division. As we endeavor to build best practices and standards for ProMed Pharma, many of these policies and procedures have been implemented companywide, enhancing customer value and providing higher assurance of quality. The process is an ongoing one. As part of our document review and training programs, we continue to implement best practices and incorporate updated regulatory requirements to ensure the highest levels of quality and compliance.

3) Understanding Value

Due to the incorporation of higher-cost constituents including Active Pharmaceutical Ingredients (APIs) and the higher degree of control required for manufacturing, combination devices rapidly became among the highest value parts manufactured at ProMed. While these parts may at first glance seem similar to parts our operators make every day from more conventional materials, the additional value of these components required a shift in practices. To ensure that materials were used and tracked effectively, additional education was necessary so operators could more fully understand the scope and added value for these parts. In addition, more rigorous training was implemented on each step of manufacturing to ensure that operators could more effectively execute the process. As a result, scrap was reduced as yields and reconciliation values increased.

4) Employee Flexibility

ProMed initially chose to use its workforce from existing component manufacturing areas during our first forays into manufacturing Combination Products. This required that the operators move between quality systems, batch processing approaches, and working with variable parts from day to day. To make this possible, feedback systems were implemented to monitor the performance of the operators, the process, and quality.

To help operators adjust to the new requirements, a flexible work schedule was implemented where personnel could enter the new environment at a level suitable to their level of experience. Coupled with existing performance metrics this allowed for a combination of self-selection for this more demanding manufacturing environment and identification of those operators who most consistently met the more stringent requirements of combination components, which allowed ProMed Pharma to steadily build a versatile work force capable of successfully manufacturing combination products, understanding the importance of pharma quality requirements, and exercising the diligence and attention to detail needed when completing rigorous manufacturing, testing, inspection, and release documentation.

Conclusion

With a dedicated Quality System, purpose-build cleanroom facilities, and experienced, capable employees, ProMed Pharma has met the challenges associated with manufacturing Combination Products. In the process, ProMed Pharma has been proven capable of consistently supplying quality products to a range of pharmaceutical and device partners. This has required a dedicated and ongoing effort across several fronts discussed in this paper.

Today, ProMed Pharma is well-positioned to actively support new partners and shorten the time required for market launch. With expertise in Combination Products, including drug eluting vaginal rings, ophthalmological implants, and diabetes monitoring systems, combined with extensive medical device manufacturing knowledge and experience, has added great value to ProMed Pharma’s customers from the planning stage through regulatory submission to sustainable manufacturing.

About ProMed Pharma

ProMed is an industry-leading supplier of small silicone components for Class III long-term implants. Founded in 1989, ProMed has been successful in combining state of the art equipment and tooling to produce tightly toleranced parts for finished medical devices sold in the United States, Europe, and Asia. ProMed began molding silicone parts with a pharmaceutical constituent in 2005. ProMed Pharma LLC was founded in 2006 in Plymouth, MN and has been manufacturing Combination Products including controlled release drug eluting molded dosage forms for women’s health, ophthalmology, and diabetes monitoring. As a company committed to quality, excellence, and customer satisfaction, we invite you to visit our website at www.promedpharmallc.com. Please contact our Business Development group at info@promedpharmallc.com for more information.

The Challenges of Manufacturing Combination Components Part 2

Design for Manufacturing (DFM) Tips for Molding Components in Silicone

Introduction

Device functionality is usually the starting point when designing devices. Another element that needs to be considered when designing devices and their subsequent components: manufacturability. Part design should also be focused on the ease of manufacturing because it can help reduce cost and lead to a robust and reliable process. Several aspects should be considered regarding manufacturability: part geometry, location and shape of critical surfaces, size, and among others. These may seem like more obvious characteristics, but there are a few others that can be overlooked, but yet should be considered just as important. These are material selection, dimensioning/tolerancing, and the selection of critical dimensions. To better understand the impact, each characteristic will now be explained in detail.

Material selection

Choosing the correct material for your application is important and can have an impact on the performance and cost of the component.

There are a few things to consider when deciding on a silicone to use for manufacturing. These include type of silicone (liquid silicone rubber or high consistency rubber), durometer (hardness), and even color. Each of these can have an impact on manufacturability.

(LSR) Liquid Silicone Rubber vs. (HCR) High Consistency Rubber

Both LSR and HCR are available in a variety of durometers. Of the two, LSR is the preferred silicone for manufacturing. LSR can be molded faster due to a few factors. LSR has a lower viscosity than HCR, therefore it can be injected faster into the mold. This means that a manufacturing cycle for LSR can be significantly shorter than that of HCR. The majority of HCR parts also need a post cure, which is a secondary operation and can add cost to the price of a part.

When manufacturing a part with complex geometries, a material with a low viscosity is recommended so that detailed features are consistently and accurately captured. LSR’s low viscosity allows it to quickly and fully fill small and intricate features in a mold, and therefore makes it the more desirable material for these applications.

Useful information for designing with either silicone is the shrink rate. LSR has a typical shrink rate of 2.5% to 4.0% and HCR has a typical shrink rate of 1.5% to 3.0%. Some factors that can affect shrink rate are durometer, lot to lot variation in the material, additives/colorants, the manufacturing process, gate/vent size, and material flow. While shrink rates don’t typically affect the manufacturing process, these rates are used in mold design.

Durometer: Soft or Firm?

Silicones for manufacturing are available in durometers ranging from 5 to 80 Shore A. Durometer has a significant impact on manufacturability at all stages. Parts that are made with very soft or very firm silicones can be difficult to remove from the mold. Soft parts tend to stick to the mold surfaces more while parts made with firm silicone are more brittle and may tear or break during removal. For optimal manufacturability, we recommended using a silicone with a durometer between 30 and 70 Shore A.

Clear or Colored?

Colorants come in a wide variety of hues and can be mixed into LSR or HCR materials at very precise amounts. Adding color to your part can benefit component manufacturing and assembly in several ways:

• Similar, hard to distinguish parts can be colored differently, making them easier to tell apart visually.
• Coloring very small or micro-size parts can make them easier to see and handle, especially against a white background.
• Very small, fully encapsulated bubbles or incursions of foreign material in a thick wall area are more easily hidden in colored silicone than in clear silicone. This can reduce the quantity of parts rejected solely for these minor cosmetic defects.
• Colored silicone can improve the accuracy and repeatability of measurements obtained from non-contact (i.e. optical) measurement processes.

Dimensioning and Tolerances

The dimensioning and tolerances of a silicone part can make or break a new project. The application of dimensions, selection of critical dimensions, and size of tolerances are all key to manufacturing success.  The main things to keep in mind when dimensioning a silicone part are to apply dimensions to silicone (not to the spaces between silicone), and keep tolerances to a minimum of 2.5% of the dimension or  ±.003 inches, whichever is greater.

Application of Dimensions

Selection of Critical Dimensions

Conclusion

Successful silicone molded components must not only perform as intended, but must also be designed from the beginning to be manufacturable. By making the right material, color, durometer, dimension, and tolerance choices OEMs can develop molded devices and components that can be reliably manufactured in large volume—while minimizing scrap rates and their losses.

About ProMed Molding

ProMed is an industry-leading cleanroom manufacturer of silicone components, specifically those having a medical application. Founded in 1989, ProMed has been successful in combining state of the art equipment and tooling to produce tightly toleranced parts for finished medical devices sold in the United States, Europe, and Asia. ProMed has garnered a reputation as the world benchmark of implantable silicone components and assemblies – and is one of few companies in the world to provide contract manufacturing of drug-eluting products. ProMed Molding also offers assembly, micro-molding of highly engineered plastics, and combination products.

As a company committed to quality, excellence, and customer satisfaction, we invite you to visit our website at www.promedmolding.com. Please contact our Business Development group at info@promedmolding.com for more information.

The Growth of Biocompatible Silicone for Implantable Devices

For decades, silicone rubber has been the material of choice for implantable devices. Its high chemical inertness, durability, tensile strength, availability in a wide range of durometers, wide temperature range, and ease of molding by many methods has made the material a mainstay of medical devices of all types, but especially for long-term implants.

This tradition has been further reinforced by the growing supply of medical-grade silicone, which is extensively tested for purity and biocompatibility in order to meet the FDA’s requirements for products implanted in the human body for more than 29 days. Testing of the raw silicone however, is only part of the effort needed to guarantee the biocompatibility of the final product. This is why process controls at device manufacturers are also required in order to ensure a silicone device’s quality and safety.

As more suppliers are able to meet these requirements and offer wider portfolios of medical-grade silicone formulations, the number of possible applications and types of implantable devices made with silicone continues to grow, as does the medical grade silicone market.

Expanding Applications of Biocompatible Silicone

Take one current development as an example. Recently, medical silicone tubing with embedded reinforcements has hit the market, which augments silicone’s natural flexibility with additional stiffness and strength. Braided or spiral monofilaments of stiffer resins, or even stainless steel, are located in the wall of the tubing provided enhanced burst, kink, and wear resistance—all qualities necessary for tubing which needs to conform around organs and through existing passageways as it is inserted into the body. This new development can meet the current pressing need for more durable and smaller implantable medical devices.

Another advancement for silicone implantable devices, which has just been achieved in the laboratory, can drastically reduce the costs of implants that need to be custom made for optimal fit inside the patient. A university laboratory in Florida has developed a way to 3D print these implants out of soft silicone, skipping the time-consuming and expensive process of conventionally molding these custom parts, a process that can take weeks. The breakthrough in this case is the ability to 3D print parts by using oil-based microgels, a welcome achievement since that material’s flexibility and pliability makes it ideal for implants that are located in and around delicate internal organs. Although this technology is at an early stage in the development process, it does demonstrate how medical-grade silicone continues to be at the forefront of new implantable devices.

The Growing Medical-Grade Silicone Market

With more types of biocompatible silicones becoming available, and a growing number of applications for them, the market growth of medical-grade silicone rubbers is expanding at an increasing rate. According to one report released last August, the market size for these silicones is forecasted to hit $1.6 billion by 2022, expanding at a compounded annual growth rate (CAGR) of 6.1% from 2017 to 2022. Two factors driving this growth are rising demand in the Asia Pacific region for devices such as surgical implants, and a growing elderly population whose medical needs are often met by products fabricated out of medical-grade silicone (especially implantable devices).

Biocompatible silicone is a popular choice for implantable medical devices, particularly those that require flexibility and durability. More medical niches continue to be filled as the manufacturing and formulation choices become more plentiful. In an industry accustomed to innovation and evolving regulations, silicone’s presence in implants will only grow more rapidly.

ProMed works meticulously with OEM engineers to ensure new product designs for their silicone implantable devices reach the market before their competitors’ products.  We challenge ourselves daily and strive to be at the forefront of the latest advancements in biocompatible silicone materials, processing techniques, and applications. How can we turn your latest innovation into the next groundbreaking medical product?

Making (Electrical) Connections: Electrically Conductive Silicone in Medical Devices

“Shocking Development” – Electrically Conductive Silicone is now ready for Medical Device Applications

Silicone rubber has many physical properties which make it an attractive material for medical applications: excellent biocompatibility, flexibility, high chemical resistance, stability over a wide temperature range, and ease of manufacturing.  Pure silicone is naturally an electrical insulator, which is normally desired for medical device applications. New innovative medical applications which require a flexible and biocompatible, but electrically conductive rubber however, are now in the development pipeline. Enabling these advances is a new class of conductive silicones, which include additives that allow electrical current to flow through the silicone.

Electrically conductive silicones have been used in automotive and industrial applications such as radio frequency shielding and sealing. Until now, their use in medical devices has long been hampered by the purity, cost, and processing challenges of the two traditional additives used to make silicone electrically conductive: carbon black and silver coated glass spheres. A third option, carbon nanotubes, has none of the drawbacks of these old standbys is opening new applications for conductive silicones. Let’s explain why carbon nanotubes are such an advance over the previous additives.

Carbon Black: Economical but Dirty

Carbon black is the most common additive for non-medical applications, and consists of a fine carbon powder that is mixed into the raw silicone material and is held in suspension.  While it is both economical and readily available, it does present some challenges for medical device applications.  The first of which is purity. Carbon black is not manufactured in the type of environments required for medical device materials.  It looks and feels like coal dust…..because it is basically coal dust. In addition to purity challenges, it is a very “dirty” material that can leave a residue with anything it comes into contact with, effectively shutting this material out of applications which require contact with, or implantation in, the patient. Silicones containing carbon black have little hope of passing the USP Class VI testing that is often a critical requirement for using a material in medical applications.

Silver Coated Microspheres are Pricey and Delicate

Silver coated glass spheres have been introduced as an alternative to carbon black.  As the description implies, this additive is comprised of microspheres that have been coated with a thin layer of silver.  While this additive is much cleaner that carbon black, it has some unique challenges as well. Mixing and processing of this material must be done in a way which doesn’t crush the glass spheres.   Ensuring the spheres remain in suspension and in a homogeneous mix throughout processing and part fabrication is also a concern. When it comes to liquid injection molding, care has to be taken to ensure that the spheres do not get filtered by the mold’s gates or get pulled out of suspension by thinning the material too much. In fact, this is why some commercial grades of this kind of conductive silicone are gumstock (HCR) meant for compression or transfer molding.  The high cost of the coated spheres presents a further obstacle to using this additive for practical medical devices.

The Nano Advantage

The new additive on the block, carbon nanotubes, is the game changer which is now enabling silicone raw material manufacturers to offer electrically conductive silicones that are capable of meeting some of the basic material testing requirements (including USP Class VI) for medical devices. Due to their purity, size, and robustness, carbon nanotubes offer a pathway to success to many electrically conductive applications for medical devices.

The high purity of commercially available carbon nanotubes combined with their small size makes them an ideal additive for conductive silicone medical applications. Because they are so small (they are “nano” after all), a silicone material loaded with carbon nanotubes processes much like an unloaded material, eliminating the problems associated with silver coated microspheres.  Because nanotubes are consistently available in high purity grades, devices made with this additive are likely to pass biocompatibility testing. While more expensive than carbon black, the cost of the nanotube-loaded material is not prohibitive for medical device applications.

Carbon nanotubes are price competitive with silver coated microspheres, and are as durable and stable in suspension as carbon black, while being much more pure. All these advantages will make nanotubes the additive which enables innovative conductive medical device applications.

ProMed has partnered with several companies experimenting with conductive silicone medical products in the R&D stage.   Our team has processed more than 10 varieties of raw materials manufactured by 3 suppliers, and continues to work closely with our customers and raw material providers to explore applications and turn them into released products.

Silicone Molding Rapid Prototyping: What Are the Options?

Speed, cost, and approximation to the final part design (including material properties and dimensions) are key criteria when selecting a fabrication method for making a silicone prototype. For silicone parts, there are actually more options than there are for thermoplastics, which makes the product development process for silicone products a little more challenging. Available processes for making silicone prototypes include: RTV (room temperature vulcanization) molding, selective laser sintering (SLA) and fused deposition modeling (FDM), transfer press molding using high consistency rubber (HCR) materials, and injection molding solutions. As we discuss these options, please keep in mind the majority of new silicone products are manufactured from LSR (liquid silicone rubber), injection molded in a durometer range of 30-70 Shore A.

A Review of 4 Methods

RTV Molding – Industrial RTV silicone formulations are widely available—some can even be found at the corner hardware store. Making parts out of these materials requires a mold, which can be made of almost any metal or plastic material. Although by definition RTVs will cure at ambient temperatures, albeit over hours, ovens are often used to accelerate the curing of the material.

• Pros: The use of RTV is attractive because of the low capital equipment requirements and the availability of raw materials. RTVs can be a very close approximation to their LSR relatives. It is common that well equipped R&D labs have the ability to manufacture tools from plastic and/or soft metal materials in-house. Once the mold is made, making parts is a simple fill-and-wait process. A skilled technician can make the first part within a day.
• Cons: RTV molding is a slow process with cure times extending from 20 minutes to hours. Production rates and cost per piece are both largely determined by the processing time.

HCR – Transfer molding is used to make parts out of HCR, and is a simple manufacturing process 3D printing in silicone is now an option for prototypes an HCR (“gum stock”) material into a heated cavity to cure and form a part. HCR is a natural fit for transfer molding since gum stock is much more viscous than LSR.

• Pros: Simple tools.  Little or no process development.
• Cons: Complex geometries may not be possible. Longer cycle times than LSR.

LSR – Production equivalent injection molding press and production grade materials are molded in soft metal tooling.

• Pros: Tooling can be made quickly and the production of parts is fast. The resulting prototypes are very close approximations of production parts.
• Cons: Can result in a higher cost per part for small runs of parts, since the initial tool cost can’t be amortized over a large number of parts.

Silicone Rapid Prototyping Comparison

Example #1 – Sleeve

LSR Rapid Prototype, 3D printed

Solid Model

Example #2 – Membrane

Solid Model

3D printed, LSR Rapid Prototype

ProMed is a supplier that partners with customers through the entire development process. We offer RTV, transfer, and LSR molding. Our focus is on your final manufacturing method and our ability to quickly deliver a prototype manufactured using that method.

By partnering with ProMed, you will get access to design for manufacturing (DFM) expertise coupled with that fast prototype delivery that you need.

Implantable Drug Delivery Devices – An Overview

Introduction

Implantable devices are called upon to serve a variety of functions, from vascular stents that preserve blood flow to electrostimulation devices that regulate heart rhythm or block spurious signals in the brain, to orthopedic devices that mechanically reinforce the spine or restore range of motion of hips and knees. For over a decade there has been an increasing convergence between implantable devices and drug therapies, including devices that deliver drugs as a primary of action. This article reviews some representative applications that materials and processes device designers can leverage in developing new products for these growing markets.

Why implantable devices for drug delivery?

Implantable drug delivery devices offer several advantages over conventional oral or parenteral dosage forms. First, implantable devices allow site specific drug administration where the drug is most needed. Examples include implants used in the treatment of brain tumors (Gliadel® wafer) or prostate cancer (Lupron® depot). This may also allow for significantly lower doses of drug which can minimize potential side effects. Second, implantable devices allow for sustained release of a therapeutic agent, as highlighted in the accompanying illustration (Figure 1). The last and perhaps most important advantage is patient compliance, as the treatment regimen associated with an implantable device is generally less burdensome than pills or injections.

Figure 1: Idealized comparison of tissue drug levels for injections compared with an implantable drug delivery device. Clearance of the drug after an injection may result in significant time outside of the therapeutic window.

Types of drug delivery devices

Implantable drug pumps are used to deliver insulin in the treatment of diabetics and to administer pain medications directly to the spine (intrathecal pumps). These are typically programmable “active” devices which require regular resupply of the medication through an access port. Subcutaneous solid implants, conversely, provide long-term, “passive” release without the need for replenishment. Typically found as thin flexible rods or “matchsticks”, these delivery systems are particularly effective for the delivery of highly potent drugs such as hormones. Commercial examples include histrelin implants for the palliative treatment of prostate cancer and uterine fibroids(Vantas®), and early puberty in children(Supprelin®), levonorgestrel (Jadelle®) and etonogestrel (Implanon®) implants for family planning, and buprenorphine for the treatment of opioid addiction (pending FDA approval). Additional indications in development include subcutaneous implants for treatment of schizophrenia, breast cancer, photosensitivity, and Parkinson’s disease.

A number of promising solid implant applications can be found in ophthalmology for the treatment of macular edema and retinal vein occlusion using corticosteroids (Osurdex®), with products in development for the treatment of glaucoma (prostaglandins) and age-related macular degeneration (anti-VEGF).

Opportunities in women’s health

In addition to subcutaneous implants, novel drug delivery forms such as intrauterine devices (IUDs) and intravaginal rings (IVRs) and are finding increasing applications in the area of women’s health. For more than two decades after serious safety issues were encountered with the Dalkon shield, no IUDs were marketed in the US. In 2000 the FDA approved a levonorgestrel eluting IUD (Mirena®) providing contraception for up to 5 years of use. Later, use of the device was expanded to include an indication for severe menstrual bleeding and a smaller device (Skyla®) has been approved for women who have not had children. IVRs are commercially available for contraception (Nuvaring®), hormone replacement therapy (Estring®), and to improve the rate of in vitro fertilization (in development).

Contraceptive devices used made from silicone (IUD, left) or ethylene vinyl acetate (IVR, right)

Materials for drug delivery

As with all implantable devices, key materials considerations for use in drug delivery include biocompatibility, stability and durability (except in the case of biodegradable drug delivery systems), and the ability of the material to control release of the active pharmaceutical ingredient (API). Silicones have long been a material of choice for drug delivery given their extreme chemical inertness, range of stable mechanical properties, and ability to compound various APIs within the matrix. The rate of release is generally proportional to the loading of drug within the silicone, typically 5-50% by weight. Ethylene vinyl acetate (EVA) is also finding use in drug delivery application due to the additional ability to control release rate by varying the vinyl acetate content. Like silicone, EVA is processed at relatively low temperatures, typically 150-250oF, which helps to minimize risks associated with degradation of the API. Polyurethanes and acrylate hydrogels have also been utilized in select applications.

Another option is to use a biodegradable material such as poly(lactic-co-glycolic acid) or PLGA to controllable release the drug while essentially “dissolving away” by hydrolysis to produce lactic and glycolic acid. While clearly most developers exhibit a preference for materials with an established history of use in vivo, new materials for drug delivery remain an active field of research, including tyrosine-derived polycarbonates which have the added benefit of being inherently radiopaque.

Processing of drug delivery materials

All of the above materials lend themselves to manufacturing processes based on molding or extrusion. At ProMed, work has historically focused on molding silicone drug delivery devices using injection and compression molding techniques. Several factors must be considered in optimizing the material formulation and developing a robust molding or extrusion process. The material system (e.g. liquid silicone vs. high consistency rubber), mixing or compounding technique, API particulate size cure temperature, and pressure will all potentially affect the drug release consistency and drug content uniformity of a manufacturing lot. In some cases, co-extrusion or over molding of a thin, drug-free layer has been used to enable more uniform release of drug from the implant.

Prototype mold for production of subcutaneous implants

Site-specific, controlled release of therapeutic agents represents an attractive option for companies looking to enhance the efficacy of an existing drug product or provide additional benefit in conjunction with an implantable device. A small but well-established pallet of durable and biodegradable polymeric materials provides options for delivery of potent compounds such as hormones, opioids, antibiotics, and oncology drugs. Well-established silicone rubber and plastic forming processes can be leveraged to make commercial volumes of devices with excellent consistency and reproducibility.

This article was written by James Arps, Ph.D., Director, ProMed Pharma LLC