Liquid Silicone Rubber

2019 & Beyond - What the LSR Material Market is Predicting

What is LSR?

Liquid Silicone Rubber (LSR) is aplatinum-cured elastomer that can be injected into a mold cavity to manufacture a part. LSR starts out as a 2-part liquid that cures into a solid form when mixed together. LSR is a versatile rubber in the elastomer industry and has a wide range of end-uses from medical devices to consumer goods to electronics to automotive. For example, LSR can be found in catheters, stents, windshield wiper blades, LED headlights, adhesives, microwaves, seals, and grommets.

There are several types of LSR that can be manufactured such as medical, self-lubricating, conductive, flame-retardant, and radio opaque. The type of LSR produced is determined by the additives incorporated during the manufacturing process. Additionally, LSR is available in different grades, namely medical, food, and industrial.

LSR has many attractive properties such as durability, low viscosity, chemical and temperature resistance, and flexibility, but its biocompatibility is outstanding. LSR has demonstrated superb compatibility with human tissue and body fluids, and is resistant to bacteria growth. Medical grades of LSR are temperature resistance and can easily sterilize, which makes them compatible with various medical devices and accessories such as implantable devices, liquid feeding bottles, dialysis filters, and oxygen mask instruments.

LSR MarketPredictions through 2026

The LSR market is forecasted to steadily grow over the next 5-10 years and some sources estimate the global market for LSR will reach a valuation of US$ 7.9 billion by 2026. Additionally, the global LSR market is forecasted to have a Compound Annual Growth Rate, or CAGR, of 4.5% through 2026 which is considered moderate growth. (Note: CAGR is considered a good measure of an investment’s return over time compared to annual return figures that do not account for compounding).

This growth is attributed to several factors. First, enhancements to the physical properties of LSR is expected to allow LSR to continue to replace traditional rubber materials in various applications. Additionally, injection molding of LSR produces consistent parts, cycle to cycle, and is a low-cost option for part manufacturing; for these reasons, LSR injection molding continues to expand into new markets, driving the continued demand for LSR.

LSR growth is also attributed to several societal factors such as growing demand for LSR in equipment and surgical tools necessary to treat the rising geriatric population and the growing awareness about health concerns, accelerated demand within the electronics industry due to continued innovation and technology advancements, as well as global urbanization and standard of living increases.  The industries that are expected to demonstrate the highest demand for LSR are medical and automotive.

Among the various grades of LSR, medical grade is expected to continue to hold the largest global market share. Moreover, stricter regulations and compliances of many specifications for use in medical products are further projected to drive the overall market growth. In addition, replacement of latex with LSR in impactable devices is expected to provide new opportunities for LSR applications.

The LSR market is segmented across five regions: Asia Pacific, North America, Europe, Latin America, and the Middle East & Africa (MEA). Among these, Asia Pacific is expected to continue as the largest marketplace for LSR, estimated at 35% of global market share, due to demand for the product in electrical & electronics and medical applications. Other factors contributing to the market growth are the easy access to raw material and favorable government policies. China and India are the strongest country-based markets in the Asia-Pacific region since distribution networks are well established and many LSR players have a strong presence in these countries.

The North America market, the United States in particular, is also forecasted to grow due to increasing usage of LSR in the electronics industry as well asincreased expenditures on, and technological advances of, medical devices. Europe is also forecasted to grow LSR demand due to growing demand for lightweight material in the automobile sector. Additionally, multinational companies are focusing on collaboration,and perhaps even joint ventures, with distributors to achieve sustainable growth. The Latin America and MEA regions are also expected to observe LSR market growth due to increasing demand for growing usage of LSR in consumer goods and healthcare industries.

The LSR market faces a couple key challenges including minimization of the carbon footprint associated with LSR production, and improvement of LSR’s reusability and disposability. But even with these challenges, the LSR market is forecasted to have moderate growth across all 5 regions as LSR usage expands to even more markets.

Contact ProMed today at 763-331-3800 to find a solution to your medical molding needs.

silicon injection molding

The Future of 3D Printing with Medical Biomaterials Such as Silicone

3D printing, also referred to as “additive manufacturing”, is not only a game-changing innovation for rapid prototyping, but is also poised to transform many industries in the years to come, healthcare and medical devices included.

As 3D printing continues to advance and mature, novel materials, processes, and applications applicable to medical biomaterials such as silicone will continue to deliver better patient outcomes for existing treatments, while opening the doors to entirely new ones.

New Medical 3D Printing Materials

From diagnostics to growing tissues for research, recent research in new 3D printing materials illustrate the promise of this technology.

For instance, engineers at the University of Illinois have designed a 3D printer which can make structures out of isomalt, the same sugar alcohol throat lozenges are made of. The fact that isomalt dissolves in water makes it a great material out of which to fabricate scaffolding for growing tissues, providing researchers the ability to study them in three dimensions.

Another innovation, from engineers at Rutgers University-New Brunswick, involves movement rather than stationary structures. A team there has produced a smart gel which can be 3D printed into shapes which move and grab objects in salt water when an electric field is applied. Potential applications for this hydrogel-based material range from providing the “muscle” for artificial hearts to drug delivery.

Even living cells—bacterial ones, at least—can now be 3D printed. A group of MIT engineers have created an ink containing genetically programmed bacterial cells and figured out a way to 3D print it. Like the smart gel from Rutgers, this living ink is based on hydrogel, which provides the bacteria an aqueous environment they can live in. The live bacteria cells are genetically programmed to react to different stimuli, such as the presence of specific substances. The MIT team demonstrated their innovation by creating a “living tattoo”: a patch made of this new ink whose different segments are programmed to detect a different chemical and change color.

Meanwhile, silicone continues to gain adoption for medical 3D printing. The additive manufacturer Carbon recently announced the release of a biocompatible silicone resin. In addition to being biocompatible, this new silicone resin is soft and tear-resistant as well—perfect for medical wearables.

Novel Biomaterial 3D Printing Processes

Hydrogels also play an important role in the development of new biomaterial 3D printing processes. One recent example of this is a novel stereolithography 3D printing method developed at UCLA, which currently uses four different bio-inks. Up to now, biomaterial stereolithography has been limited to just a single material. Central to this new technique is a custom mircofluidics chip with multiple inlets, one for each biomaterial to be printed.

For practical medical applications, 3D printing of medical biomaterials requires the purity and cleanliness required of all other fabrication technologies used for medical devices. Recent material and process 3D printing breakthroughs in the lab are great, but patients require (and deserve) additive manufacturing solutions which reliably produce devices which are free from contamination, something currently not possible with many existing 3D printing systems.

One startup looking to change that is Kumovis, which has recently developed a 3D printer for the engineering-grade polymer PEEK (a popular choice for high-strength implants). Kumovis effectively designed a miniature cleanroom into their 3D printer, protecting the implants from being contaminated with foreign particles during printing.

Biomaterial 3D Printing Applications

Ultimately, clinical applications are the end goal of all this material research and invention of new additive manufacturing techniques. Additive manufacturing is already having a positive impact in patients’ lives, and as more advances cross over from laboratories to clinical trials and regulatory approval, biomaterial 3D printing will become even more commonplace.

Additive manufacturing is a great process for producing small batches of custom parts. When medical 3D printing is combined with imaging technologies such as CT scans, implants and other medical devices can be custom made for a patient, leading to better device performance and lower risks of complications.

A recent study involving heart valves shows how CT scanning, digital modeling, and 3D printing can work together to reduce mortality rates for patients who have a high risk of developing a paravavular leak (PVL) after a transcatheter aortic valve replacement (TAVR). The lead author of the study, Dr. Sergey Gurevich remarked on the how this technology successfully prevented PVLs, “We are very encouraged to see such positive outcomes for the feasibility of 3D printing in patients with heart valve disease. These patients are at a high risk of developing a leak after TAVR, and anything we can do to identify and prevent these leaks from happening is certainly helpful.”

Presently, 3D printing of medical biomaterials is a hotbed of experimentation and advances in printing materials and processes. Regardless of what breakthroughs actually break through to clinical use, medical device OEMs can remain confident that ProMed will stay on the leading edge of biomaterial 3D printing.

Medical Grade Silicones

The Use of Medical Grade Silicones for Prosthetics

From restoring mobility to re-enabling everyday tasks, prosthetics elevate a patient’s quality of life. Whether they take the form of artificial limbs or simpler, more cosmetic devices, prosthesis place many demands on the materials used to make them.

For instance, by their nature, prosthetics must be in contact with at least some part of the patient’s body for prolonged periods. This in turn requires that those areas of the prosthetic in contact with the patient be made of a highly biocompatible material. Likewise, the liner sections of prosthetic limbs which must fit against the residual limb must be able to absorb the shocks of regular use, including the dynamic forces of activities such as running.

Silicones possess many properties which are needed for prosthetics: a vast selection of available duromers (from soft to stiff), chemical inertness, biocompatibility, durability, the ability to bind to various substrates (often without a primer), and a wide useful temperature range. These are all reasons why liners for artificial limbs are commonly made from silicone.

Medical grade silicones have the added advantage of the exceptional purity and cleanliness needed for safe long-term contact with the patient’s body, allowing them to be used in a multitude of prosthetic applications.

For almost any prosthetic application, there is a silicone type or fabrication method that can meet the need. The low viscosity of Liquid Silicone Rubber (LSR) is perfect for quickly filling injection molds. On the other hand, High Consistency Rubber (HCR) can be a great choice for parts made by transfer molding, compression molding, or extrusion. Medical grade Room Temperature Vulcanizing (RTV) silicone rubbers are also utilized in prosthetics.

Prosthetics and the Medical Grade Silicone Market

The size and growth of prosthetic segment of the medical grade silicone market will continue to employ all these forms of medical grade silicones. According to a market report published last year, prosthetic applications of medical grade silicone accounted for almost $121 million, which the report attributes to “diversified segmentation, including orthopedic implants, cardiovascular implants, stents, structural cardiac implants, spinal implants, neurostimulators, ophthalmic implants, dental implants, and face and breast implants.” That same report projects that number to grow too due to “innovative technological innovations and increasing FDA approvals” for clinical trials, among other factors.

This growth can already be seen in the continued release of new medical grade silicones for prosthetic and orthopedic applications. Wacker’s new medical grade RTV silicones are just one example. The new low temperature curing medical grade LSRs released by Dow Corning are another. The release of materials like these enable prosthetic designers and manufactures to produce prosthetics which are more durable, higher performing, dependable, comfortable, and safer.

The quality, purity, and cleanliness of medical grade silicones set them apart from other silicone grades, and make them uniquely suitable for prosthetics, as we explained above. Increasing commercial availability and competition among silicone suppliers should make these medial grade materials more affordable.

New Uses

More affordable material choices will be key in opening the door to new prosthetic options, and ultimately better patient outcomes. This is just as true for temporary prosthesis as it is for permanent prosthesis like artificial limbs. For example, high temperature vulcanizing medical grade silicone is already being used for temporary cranial prosthesis. Among the benefits of using this medical grade silicone over acrylic and metal are:

  • Improved cosmetic appearance
  • time saved during cranioplasty surgery
  • Adequate bone closure due to the silicone’s flexibility

Medical grade silicone’s purity, sterility, biocompatibility, lack of magnetism, durability, transparency to x-rays, and low thermal conductivity make it an excellent material for cranial prosthesis, and prosthetic devices in general.

Medical grade silicones are widely used for prosthetics, and that as new applications emerge, their usage will only grow. No matter how the industry unfolds, ProMed has you covered—from injection molding LSR to compression molding HCR, from artificial limbs to implants.

Medical-Grade Liquid Silicone Rubber

The Importance of Medical-Grade Liquid Silicone Rubber

Medical-grade Liquid Silicone Rubber (LSR) is becoming increasingly crucial to the medical device industry, as the combination of the general benefits of medical-grade silicones combine with LSR’s unique advantages for medical device OEMs. As new medical-grade LSR materials become commercially available, more reliable, better performing, and more affordable medical devices will be within reach of patients.

Medical-Grade Silicones

Silicone has long been a popular material for medical device manufacturers due to its durability, ease of molding by many methods, wide useful temperature range, chemical inertness, high tensile strength, vast range of available durometers, biocompatibility, and compatibility with many sterilization methods.

Medical-grade silicones add the benefits of stringent purity and biocompatibility testing, making them suitable for use in long-term implants.

One application where medical-grade silicones really shine is drug-eluting implantable devices. Before molding, silicones can be compounded with active pharmaceutical ingredients (APIs) such as cancer drugs or hormones which can can then be steadily released into a targeted area of the patient’s body over time once that molded implant is inserted.

Drug-eluting implants are able to maintain the desired level of the API in the patient much more consistently and over a longer period of time than both pills and injections. Also, since the implant can usually be inserted near the targeted organ or tissue, lower total amounts of API are needed because that API doesn’t need to spread throughout the entire body before reaching the targeted area.

As a result, the level of the API in the patient’s body remains inside the therapeutic window (the range of concentrations between too low to be effective and high enough to be toxic) for a much longer duration.

As we’ll see shortly, medical-grade LSR is a great material for making drug-eluting implants, due to its processing advantages.

The Advantages of LSR

LSR is a type of silicone material which starts out as two separate liquid components which are then precisely mixed together before injection into a heated mold, where the silicone elastomer becomes solid (i.e. vulcanizes).

The low viscosity of LSR makes it a great silicone material for making parts via injection molding, since the LSR can easily flow into and completely fill molds with relatively low injection pressures, even those with intricate and small features.

LSR’s inherent compatibility with injection molding results in the cost-effective, repeatable, and scalable manufacture of silicone parts—including medical devices and their components.

Furthermore, the temperatures needed to vulcanize LSR are usually low enough that significant degradation of compounded substances like APIs can be avoided. Thus, medical-grade LSR an excellent material for drug-eluting implants.

Implantables aren’t the only medical device application suitable for medical-grade LSR. Wearables (such as heart rate and activity monitors), respiratory products, linings for prosthetic limbs, and other devices which must stay in prolonged physical contact with a patient all benefit from medical-grade LSR’s outstanding biocompatibility and purity.

The Future of Medical-Grade LSRs

New and improved medical devices originate from innovations in both design and materials. As new medical-grade LSRs continue to be released on the market, the medical device industry as a whole will make steady advances and improve the length and quality of life of patients around the world.

Dow Corning’s release earlier this year of two new LSRs is a prime example. These new LSR materials cure quickly at low temperatures, don’t require a primer for binding to many substrates (including polyester), need low injection pressures, and boast broad process windows.

These are all significant features for the medical device industry for the following reasons:

  • Fast cure times at low vulcanizing temperatures enable silicone injection molders to shorten the total molding cycle time (which in turn can greatly reduce the cost per molded part), and consume less energy for each silicone part since the mold will not need to heated as much as other LSRs may require. Both of these result in reduce production costs for medical-grade LSR products, and consequently, lower costs for the patients and insurance companies to purchase these products.
  • The lower injection pressures of these LSRs will allow silicone medical device manufacturers to utilize more economical, lower tonnage injection presses. These LSRs’ broad process windows can enable lower defect and scrap rates, due to a more forgiving molding process.

New medical-grade LSRs, like these from Dow Corning, will help the whole medical device supply chain ramp up production capacity to meet global demand.

At ProMed, we combine industry-leading medical-grade LSR expertise with the latest developments in silicone materials and technology. From helping OEMs incorporate the latest medical-grade LSR formulations into their designs to delivering rapid silicone prototypes, we serve as a premier silicone molding contract manufacturer for medical device OEMs. Contact us to find out how we can help you.

Silicone Molded Components

4 Steps for Confirming Bond the Strength in Silicone Overmolded Medical Devices

While silicone is great for making medical devices and their parts, the material is also a great choice for areas of those parts or devices which need the properties that only a silicone can provide, whether it’s excellent compression set, softness, or chemical inertness. Overmolding provides medical device designers the flexibility of incorporating silicone’s advantages where they’d have the most benefit. From handles and grips to gaskets and catheters, silicone overmolding is used for many medical device applications.

A strong bond between the overmolded silicone and the base material (called the substrate), is crucial to the finished device’s performance and safety. When the silicone and substrate fail to adequately jointogether, the two materials can become detached, resulting in premature failure of the device. Frequently for medical devices, this bond not only must withstand the stresses of normal use, but also the temperatures, chemical agents, and radiation used for sterilization.

Tips for Good Overmolding Bonds

Because silicone overmolding has been used extensively for medical devices, the industry has learned several tips to help ensure a good bond between the silicone and substrate.

Keep the surface of the substrate clean and dry. Contaminants such as oils and mold release agents can thwart both the chemical and mechanical bonding of the silicone to the base metal or plastic. Some contaminants can even hinder the curing of the silicone.

Design features into the substrate for mechanical bonding. Loops and other such features in the substrate allow the silicone to flow into the substrate and mechanically lock into it. This is especially true if Liquid Silicone Rubber (LSR) is used to overmold.

When necessary, treat the substrate’s surface with primers or plasma. Sometimes the silicone and substrate are incompatible when it comes to chemical bonding. Care should be taken with using primers for medical devices, since the primer can impact the biocompatibility of the finished device. That’s why plasma surface treatment is preferred, as that process doesn’t introduce new substances.

How to Confirm Bond Strength

The above tips and other industry best practices provide great guidance, but testing is what ultimately reveals the true bond strength of an overmolded part. The regulatory requirements for medical devices require such testing to provide the proof required for FDA approval, not to mention the continued testing of production samples for ongoing Quality Assurance (QA).

Medical device OEMs should follow these steps in order to verify that their chosen combination of substrate, silicone material, surface treatment (if any), and molding process can produce adequate bond strengths:

  1) Have the molder create sample plaques with your substrate material, surface treatment (or primer), and silicone material. This should be done early in the development process, before a final material selection has been made and molds have been machined. An OEM may need to experiment with several different silicone formulations or substrate surface treatments before one is found which not only delivers the required bond strength, but also meets all the other design requirements (e.g. durometer and biocompatibility).

 2) Perform thorough destructive testing on the sample plaques. The best way to measure the strength of a bond between two different materials is to measure the amount and type of stress needed to make that bond fail. Thus, destructive testing covering tensile strength, lap shear, cyclic fatigue, compression, and torsion is a must. Many OEMs may find it helpful to consult the ASTM D429 standard, which covers methods for testing the adhesion of rubber to rigid substrates.

The resulting test data will definitely guide an OEM toward making the best material and surface treatment decisions for the medical device.

3) Produce device prototypes and subject them to the same destructive testing as well. This can be done both on early stage prototypes and on production equivalent parts.

4) Once production has started, incorporate bond strength testing. This can be done in a number of ways, from quick and simple hand stripping or peeling tests to much more quantified testing using machines. Either way, bond strength testing should only be performed on a subset of parts, due to the destructive nature of the testing.

At ProMed, our passion and expertise is silicone molding for medical devices—and that includes overmolding. From selecting the best silicone formulation for a substrate to optimizing molding parameters for a strong, durable bond, we produce exceptional overmolding results for medical device OEMs. Contact us and let us know how we can help you.

Wearable Medical Product

The Wearable Medical Product Market & the Benefits of LSR for Speed-to-Market

The global market for wearable medical products is rapidly growing, driven by both demographics and maturing technology. Fortunately for the industry, the liquid silicone rubber (LSR) market is uniquely positioned to grow right along with the increasing demand for these devices. LSR’s advantages will also help wearable medical devices clear the regulatory, technological, and economic hurdles presently holding back their adoption.

Demographics, Diabetes, and Global Demand

According to one recent forecast, the global market for wearable medical devices is projected to increase at a Compound Annual Growth Rate (CAGR) of 18% over the period from 2017 to 2023. In terms of dollars, this market was worth $2 billion in 2016, with the forecast predicting triple that number by 2023.

Wearable medical devices are used to monitor health parameters including blood pressure, heart rate, and blood glucose level. Those last two items are a major driver of the adoption of medical wearables, as an aging global population and other trends are increasing the prevalence of diabetes. In fact, the International Diabetes Federation notes that incidence of diabetes in the global adult population is growing at an annual rate of 8.4%, with 625 million diabetic adults worldwide by 2040. In the US, over 29 million people are diabetic according to the CDC, which in turn is propelling the demand in North America of wearable diabetes care products.

Shrinking Components

As the worldwide demand for wearable medical devices grows, the technology needed for them has continued to shrink. Computing chips, sensors, and wireless components continue to miniaturize, and this has opened the door to constant clinical monitoring at the health care facility, at home, or even outdoors.

Potential Shackles Impacting Medical Wearables

Despite these technological and global health trends, there are several factors hindering the increased adoption of wearable medical devices. Two of the most central are:

Proving the reliability of wearable medical products. The bar for wearable medical devices when it comes to dependable operation is significantly higher than it is for consumer wearables like FitBits. As Mike Bolduc, C&K’s the Global Marketing Manager for Industrial and Medical Segments explained last year for Medical Product Outsourcing, “Whereas consumer fitness trackers can help users stay in shape, medical wearables can detect life-threatening conditions, collect biometric data to help with patient diagnoses, and even administer medicine to alleviate pain. Thus, consumer wearables can be considered a superfluous indulgence while medical wearables are more mission-critical”.

With the wearable medical device industry still relatively young, there a lot of either clinical data or industry experience to confidently conclude medical wearables are as dependable as they will need to be.

Regulatory and compliance hurdles. In that same article, Bolduc also points out that medical devices must meet “meet stringent safety and accuracy standards” and that wearable medical products need to “be validated by U.S. Food and Drug Administration and ISO standards”. Wearable medical products used clinically to monitor blood glucose levels or measure irregular heartbeats will be given the same regulatory scrutiny as other diagnostic devices. Likewise, a wearable which administers a pharmaceutical agent will have to meet the same quality standards as other drug delivery products.

How LSR Can Benefit Wearable Medical Products

LSR can help the wearable medical device industry clear these two key hurdles and shorten the time to market for new medical wearables, which will be necessary to meet the projected global demand for these devices.

Medical-grade silicone is an excellent material for wearable medical product components. It boasts excellent biocompatibility, durability, availability in a wide selection of durometers, and compatibility with a vast range of sterilization and disinfection methods. All of these features make it a great choice for wearables which must be in prolonged contact with the patient, and durable enough to operate reliably wherever the patient goes. That proven durability can benefit the reliability of a whole wearable device, and thus help that device pass the required reliability testing.

High-quality precision LSR prototypes can be made economically and quickly when choosing LSR as a material.  This expediency results in more rapid design iterations, more thorough evaluation and testing of the design, and earlier completion of product development phases.

There is another way LSR can increase the speed-to-market of wearable medical products. LSR is compatible with injection molding, wearable medical product OEMs who incorporate it will more quickly ramp up production inventory to levels needed for meeting the worldwide demand expected in the upcoming years.

Besides accelerating the market debut of new medical wearables, LSR opens entirely new doors for them. For instance, the advent of electrically-conductive medical-grade LSRs makes possible wearable medical devices which provide external stimulation to nerves or muscles—a potentially huge untapped market. Such therapeutic devices which combine conductive silicones with wearable medical devices can deliver safe and non-invasive treatment for millions of patients.

Finally, medical-grade LSR is widely available and has a proven track record of safe, reliable, use in a plethora of medical devices, including long-term implantables. The medical device industry’s—not to mention that of regulators—experience with LSR means one less material in an OEMs’ supply chain to worry about meeting the stringent FDA requirements for clinical use.

As medical device companies rush to address the global need for medical wearables, LSR can provide the solutions OEMs need to satisfy the regulatory and other hurdles this new and rapidly expanding market is up against.

As a silicone-focused contract manufacturer of medical devices, ProMed has the LSR design and molding expertise needed to launch help these companies find those solutions. Contact us today and find out how we can help you.

Top 3 Qualities to Look for When Choosing a Contract Manufacturer

When OEMs are looking to outsource production to a contract manufacturer (CM), they need to accomplish several goals:

  • Ensure a smooth transfer of production operations, including documentation, raw material, parts, and fixtures.
  • Achieve a shorter time to market than can be achieved by keeping procurement, inventory management, assembly, testing, packaging, and distribution in-house.
  • Continue to provide the technical assistance needed to help resolve any production or supply chain issues.

To those ends, OEMs should focus on a few key aspects of any potential CM partner as they whittle down all the competing firms in their search. Just as there are many different types of OEMs and original device manufacturers (ODMs), there are plenty of CMs. . .but not all of them are a good fit for your product, size, or industry. We’ve compiled a short list of the most important qualities OEMs should look for in order to select the best CM for them.

Expertise in the Materials and Processes Most Applicable to Your Product and Industry

A CM’s expertise is valuable for more than design for manufacturing (DFM) reviews during prototyping and before high-volume production. Production execution also requires automation, materials, and process knowledge, even if the best fabrication method or material grade is chosen.

A prime example of this is the choice of materials in silicone molded medical devices. Liquid silicone rubber (LSR) has been displacing high consistency rubber (HCR) as the preferred material for years. HCR, however may still be an OEM’s best choice in some cases, as the cost and performance tradeoffs between the two materials vary depending on the specific requirements of the product design. OEMs must face similar choices when it comes to deciding between medical-grade silicone rubbers and thermoplastic resins.

A CM which specializes in silicone molding can provide both general guidance and specific recommendations—backed by engineering data and lessons learned from previous projects.

The value of a CM’s expertise extends beyond material selection. Manufacturing is about much more than “what” (i.e. the materials) is used to make a product. The processes that make that product—the “how” –is just as important.

For injection molding production lines which must pass process validation for regulatory approval and which must remain under control, the scientific injection molding process is vital for determining the optimal molding process parameters. Besides helping to satisfy regulatory requirements, scientific injection molding also increases production efficiency and thereby lowers the cost per part.

And now to “where”. Medical devices are also increasingly manufactured in cleanroom facilities. Medical device OEMs therefore need CMs with cleanroom manufacturing facilities and the associated gowning procedures, material control, and air handling infrastructure in place.

Finally, we cannot mention medical device manufacturing without discussing the training, documentation, testing, inspection, validation and other processes necessary to achieve regulatory approval. A medical device CM must have a quality management system (QMS) which is compliant with at least FDA medical device requirements (and usually also ISO 13485). Just as important as satisfying current regulations is keeping in step with new ones, given how the FDA is attempting to keep up with new advances in the industry.

Necessary Production Capacity

To avoid the inconvenience of selecting, qualifying, and investing in a CM only to have to repeat the process all over again when production requirements outgrow the CM’s capacity, OEMs need to have a realistic estimate of the expected demand for their product over its lifetime, and they also need to verify if a potential CM can match that expected demand before that CM is chosen.

Here are some questions OEMs should ask:

  • How much floor space does your manufacturing facility have?
  • How many facilities will be involved in this project?
  • What is the staffing level at your facility (i.e. how many employees)?
  • How much warehouse space do you have for parts and finished goods inventory?
  • Do you have the shop floor space available for another production line if necessary?
  • Does your proposed production line or automated workcell have any reserve capacity to accommodate drastically increased production requirements in the future?

By asking the right questions, OEMs can avoid the costly mistake of outgrowing their CM.

Location That Aligns with Your Logistics Needs

With the emergence of “full-service” CMs, logistical concerns are becoming almost as important as production ones. Take location, for instance: the central United States is good for linking domestic suppliers, production, and customers in a tight, responsive supply chain. As an added bonus, there are no delays at customs or tariffs to worry about. The same cannot be said for supposedly cheaper overseas factories.

Another location advantage that a given CM can bring to the table is proximity to multiple transportation hubs (e.g. shipping ports, rail lines, highways, and major airports). From expediting urgent shipments via next-day air to facilitating continent-wide distribution, location can be almost as vital in logistics as it is in real estate.

As a premier contract manufacturer of molded medical devices, ProMed’s focus, expertise and passion lies in silicone molding, particularly LSR injection molding. With our large manufacturing facilities based in Minnesota and a talented team who can take a new design from concept to completion, ProMed continues to win the business and accolades of medical device OEMs.

What can we mold for you?

Prototype Advancements for Innovative Medical Device Designs. ProMed Molding

Prototype Advancements for Innovative Medical Device Designs

Prototyping new product designs will always be necessary in the medical device industry.

Computer simulation of a device’s mechanical performance has come a long way, but simulation doesn’t reveal everything. For starters, users need a physical prototype in order to give feedback. They must physically hold or interact with device in order to provide the subjective (but nonetheless invaluable) insights which are useful for refining the appearance or even the function of a new medical device. Prototypes are also necessary for validating the manufacturing capabilities of a production line—a regulatory requirement. Lastly, making, testing, and examining prototypes can help an OEM identify unknown issues that weren’t caught in the digital model of the design.

Prototyping then plays a pivotal role in moving innovative medical device concepts from the idea stage to the marketplace. Those innovative concepts in turn require modernizations in prototyping technology and materials. Let’s explore a few of these innovations.

Smart polymers

One material advance that medical device prototypes are incorporating is smart polymers. What makes these polymers “smart” is their ability to change their shape, electrical conductivity, size, or other characteristic in response to stimuli like light, pH change, or temperature. Currently, the use of smart polymers is limited to targeted drug delivery, but future medical devices like wearables could leverage them as sensors for personalized and preventive healthcare.

Online Quotes and Ordering

Advances in CAD/CAM software are largely responsible for a recent process innovation when it comes to prototyping: rapid prototype price quoting and ordering. By uploading the digital files and material requirements of a new design, OEMs can hand off all the information that the CM engineer needs, to quickly review the requirements and estimate a price.

The speed and ease of this process for OEMs allows them to submit prototype designs for quote to many CMs, enabling them to “shop around” in a completely digital way. Besides helping them find the best price, the material, dimensional, and surface capabilities of multiple prototyping vendors can all be compared, helping the OEM make an informed decision quickly. In turn, the total turnaround time for an OEM to receive those prototype parts also drastically shortens, leading to faster design iterations and a better final design before high volume production begins.

Additive Manufacturing (3D Printing)

Additive manufacturing (better known as 3D printing) refers to a slew of different fabrication technologies well-suited for low-volume manufacturing, including producing prototypes. Due to the fact that the 3D printing of medical device prototypes is still relatively new, there is a lot of research and development activity in new materials, processes, and process improvements. Medical devices pile on their own challenges: biocompatibility, more stringent safety requirements, and in some cases the need to withstand repeated sterilization.

Despite these challenges and often conflicting requirements, the medical device 3D printing market’s value was estimated to be $750 million in 2016 and is expected to grow 17.5% from 2017 to 2025. As existing heavyweights in the general 3D printing industry continue to market their offerings even more into the medical device industry, the unique benefits of 3D printed prototypes will continue to unlock novel, innovative products and therapies. From 3D printed jawbones to titanium spinal implants, additive manufacturing already is a key enabler of medical device innovation.

The key 3D printing technologies to keep an eye on are:

  • FDM (Fused Deposition Modeling): A molten material (usually thermoplastic resin) is extruded into a very fine thread which is then laid down in successive layers, building up the part.
  • Stereolithography: Short wavelength (e.g. blue or UV) light selectively illuminates a pool of photopolymerizing resin from the bottom, causing each layer of the part to solidify as it is drawn up and out of tank.
  • Metal Laser Sintering: A very intense laser beam is directed at a bed of metal powder. The high power of the beam rapidly heats the powder, causing the metal grains to fuse. By fusing layers and layers of metal powder, a complete 3D object is fabricated.

One hurdle FDM, stereolithography, and other additive manufacturing technologies will have to clear is reliably making parts out of silicone rubber—a dominant material in medical devices, especially implantables. Current elastomeric materials commercially available for 3D printing don’t match true silicone rubber’s mechanical properties. This is a major reason why ProMed’s rapid prototyping service uses aluminum injection molds and real, production-grade liquid silicone rubber (LSR) –the close match between the performance of the prototypes and that of production parts adds tremendous value to engineers developing their next new design.

The materials and methods used to create prototypes of tomorrow’s medical devices are advancing rapidly and in many directions. These advances push medicine and healthcare forward by providing a steady stream of new solutions for the problems patients face.

By keeping up with the latest medical device prototyping and production innovations, ProMed is able to remain the leader in medical silicone molding.

Our rapid tooling capabilities and quick quote turnaround time save both the time and money of our customers, helping them launch new medical innovations into the marketplace faster. What breakthrough are you trying to bring to the market?

Manufacturing Combination Components

The Challenges of Manufacturing Combination Components Part 2


ProMed Molded Products was founded in 1989 and grew to become an industry-recognized leader in the manufacture of silicone molded implantable components for many of the industry’s largest Medical Device companies. In 2006, we expanded our market offerings and embarked on a journey to manufacture devices containing active pharmaceutical ingredients. Today, we know these devices as “Combination Products.” In our first whitepaper on the subject, we wrote about the challenges of implementing a Pharma Quality Management System (QMS), a Pharma facility’s design requirements, and resource challenges. In Part 2 we take a closer look at how we interpret and comply with 21 CFR Part 4, cGMP Regulation of Combination Products.

Combination Product Regulations (21 CFR Part 4)

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.

Table 1
Section Description
Section 211.84 Testing and approval or rejection of components, drug product containers, and closures.
Section 211.103 Calculation of Yield
Section 211.132 Tamper-evident packaging
Section 211.137 Expiration Dating
Section 211.165 Testing and Release for Distribution
Section 211.166 Stability Testing
Section 211.167 Special Testing Requirements
Section 211.170 Reserve Samples

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.


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.

Manufacturing Combination Components

The Challenges of Manufacturing Combination Components Part 1


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.

ProMed Pharma. Medical molding solutions

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.

ProMed Medical Molding cleanroom

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.

Facility Qualification and Validation Clean room at ProMed

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.

ProMed ISO 13485 certified Medical Device Quality SystemTo 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.

Batch Processing. ProMed Medical MoldingIn 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.

ProMed Pharma Medical Molding SolutionsTo 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.


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 Please contact our Business Development group at for more information.

The Challenges of Manufacturing Combination Components Part 2