The Latest on Active Implantable Devices – Forecasting Into 2025 and Beyond

What are Active Implantable Devices?

Medical implants are devices that are placed on the inside or surface of the body with the purpose of delivering medication, monitoring body conditions, or supporting organ health. There are different types of implantable devices, but most generally fall into two categories: static or active. Static devices are the least complex and do not have moving parts; stents implanted in a patient’s artery are a common example of a static implant.

Active Implantable Medical Devices, commonly referred to as AIMDs, are more intricate in nature and often perform more complex functions than static devices. One of the key differences between active and static implantables is that AIMDs typically require an artificial power source, such as a battery or other electrical supply. Active implantable medical devices can be found in many healthcare applications including cardiac pacemakers, defibrillators, cochlear and other hearing aids, neuro stimulators, and infusion pumps.

As you would expect, there are key material considerations for AIMDs such as biocompatibility, stability, and durability. Medical grade silicones have long been a material of choice for implantables, including AIMDs, given their range of available durometers, extreme chemical inertness and biocompatibility, and excellent tear and heat resistance that make them ideal for parts that need to remain in the human body for extended periods of time. As this field continues to grow and expand in future years, medical grade silicones are expected to continue to play a significant role in the manufacturing of active implantable devices due to their ability to produce high volumes at low prices while meeting tight dimensional tolerances.

It is no surprise that active implantable devices have very strict and high standards that must be met in order to ensure patient safety. Compared to other medical devices, AIMDs can be more difficult to manufacture due to their intricacy and size, requiring additional considerations to achieve the necessary product specifications and tolerances. For these reasons, it is imperative that OEMs select a molding partner, like ProMed, that has both design expertise and manufacturing experience with active implantable devices, as well as an outstanding quality assurance program!

Recent Advances in Active Implantable Devices

The field of active implantable devices continues to rapidly expand and is an area of significant research and development. Below are three recent advances that give a glimpse into the not-so-distant future of AIMDs.

  • One of the issues of active implantable devices is that the electronic components are typically rigid and not biocompatible. A team of engineers are taking on this challenge by developing flexible, bioelectronic devices. Once successful, these devices will allow active implantables to expand into new treatments!
  • Another current limitation of AIMDs is battery life. Once a battery dies, the patient must undergo a procedure to replace the battery. One study currently underway is looking at methods to recharge a battery in-situ via a technology called “active photonic power transfer”. This program has tremendous implications for AIMDs as many surgeries could be avoided if batteries could be recharged remotely and did not need to be replaced!
  • Lastly, even though implants have come a long way, their size is still a challenge. The housing necessary to enclose the electronics is still larger than desired. Fortunately, a team is developing an ultra-thin coating that will allow for further size reduction of implants. The coating will encapsulate the electronics to protect them from the body’s environment and reduce the need for the traditional, bulky housing. This is an exciting time in the AIMD sector, with rapid R&D advancements!

Forecasting the AIMD Market into 2025 and Beyond

A recent report by Data Bridge Market Research projected the worldwide AIMD market will reach nearly $39 billion by 2027 with a CAGR (Compound Annual Growth Rate) of 7.8% during the period. This is an excellent growth rate, forecasting continued demand for active implantable devices in the coming years.

There are several drivers for the projected market growth. One of the main factors is the aging population worldwide. The number of people 65 years or older is expected to be nearly 1.5 billion by 2050, making up over 15% of the global population! As patients age, their need for active implantable devices grows in order to maintain a good quality of life. Additionally, cardiovascular disease and neurological disorders are becoming more prevalent, especially in developed countries, resulting in more demand for AIMDs that treat these conditions. Lastly, as the medical community continues to research and develop AIMDs, the field continues to advance, resulting in opportunities for AIMDs to expand into new areas of the medical sector.

As previously noted, the rise in cardiovascular disease is one of the factors responsible for the continued demand for active implantables, so it is no surprise that cardio products, such as cardioverter defibrillators, are forecasted to hold the largest AIMD market share. In terms of geography, North America is expected to continue to lead other regions in the demand for AIMDs in the foreseeable future.

The AIMD market does have some challenges to growth. For example, one of the key hurdles that must be addressed are the many regulatory standards that must be met by AIMDs in order to ensure patient safety; these standards can be daunting and may prevent some manufacturers from entering the AIMD market or expanding their product line.

ProMed’s Capabilities

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

ProMed Pharma is a leading contract manufacturer of polymer-based drug releasing molded dosage forms and combination device components. Working with both established and early-stage medical device and pharmaceutical companies, ProMed develops robust manufacturing processes and platforms for extended drug release from a variety of materials, including silicones and thermoplastics. 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.

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


Best Practices for HCR Injection Molding

What is High-Consistency Rubber (HCR)?

Silicone elastomers have long been a popular material for medical parts and devices due to their highly desirable mechanical and physical properties. One of the most common elastomers for manufacturing is High-Consistency Rubber, or HCR. It should be noted that the terms HCR and HTV, which stands for High Temperature Vulcanization, are often used interchangeably and refer to the same silicone material; for the purpose of this article, we will use the acronym HCR.

HCR is a type of silicone elastomer comprised of long polymer chains with a very high molecular weight. It is cured at high temperatures with a platinum catalyst or peroxides. HCR is known for its gummy consistency that is similar to peanut butter. Due to its higher viscosity compared to other elastomers, HCR is typically processed using compression and transfer molding methods, but can also be utilized for injection molding projects. HCR has many desirable properties such as excellent aging resistance, thermal stability, electrical properties, mechanical strength, elongation, and hardness. For these reasons, HCR is a good material for a broad range of applications and HCR products are found across many industries including medical, automotive, consumer goods, aerospace, and electrical uses.

Best Practices for HCR Injection Molding

Injection molding offers many benefits over other production methods, making it a very attractive manufacturing option. At a high level, the injection molding process for HCR is the same as with other elastomers: the silicone rubber is fed into a heated barrel and injected under pressure into a mold where the material completely vulcanizes into the desired part shape. However, due to its properties HCR processing presents some challenges when compared to other elastomers. But do not be alarmed – high quality parts are achievable with HCR when attention to detail is given during the part design phase as well as during manufacturing! Below are some best practices to consider when using HCR for injection molding projects.

  • High-consistency rubber takes longer to cure than many other molding materials. A longer cure time results in a longer injection molding cycle time. In order to make the project economics attractive, HCR molds often have a large number of cavities in order to accommodate the longer cycles and still achieve the desired production volume for each cycle – resulting in more attractive project economics!
  • One best practice that is especially important for HCR is preheating the material prior to injection into the mold. Preheating has a couple benefits. It reduces the viscosity and allows the HCR to more quickly fill the mold as well as more uniformly – reducing the cycle time and improving the quality of the final product.
  • HCR injection molded parts are susceptible to tearing when removed from the mold; this is referred to as hot tear. Hot tear is directly related to the mold temperature – the higher the temperature the more vulnerable the part is to hot tear; however, lower operating temperatures result in longer cure times – so manufacturers must adjust the temperature to optimize cure times while minimizing the potential for hot tear.
  • When compared to other silicone elastomers, HCR has higher part shrinkage rates. For this reason, it is crucial that OEMs work with their molding partner to design for manufacturing by selecting the right size and type of mold for their specific HCR project.
  • It is crucial to ensure the right size of shot for HCR projects to prevent over packing of the mold. When a shot size is too large for a given mold, HCR will seep from the mold resulting in flash. To avoid this situation, manufacturers must gradually increase the shot size until the mold completely fills without any mold leakage or flash on the final product.
  • To avoid air entrapment, the mold needs to have sufficient air flow and channeling when HCR is injected into the mold. Air that remains in the mold creates air bubble imperfections and inconsistencies in the final product. OEMs must ensure air flow is accounted for in the design and take steps to improve flow properties during production such as preheating and possibly a higher operating temperature.
  • Similar to other injection molding projects, selection of the right design for the mold, runners and gate, press, and other equipment are critical to the success of the project – and HCR injection molding is no exception. It is important to work with your design team to ensure the right equipment set-up during the design phase to set production up for success! Additionally, it is important to ensure the molding equipment are properly maintained over time.

The decision on which material is best for your injection molding project should be determined on a case-by-case basis and depend on a variety of factors including the requirements of the part and the OEM’s preferences. This is why it is important to team up with an experienced partner, such as ProMed, who will guide you through the selection process to ensure the right material is chosen for your project!

ProMed’s HCR Processing Capabilities

At ProMed, we combine industry-leading medical-grade expertise with the latest developments in silicone materials and technology – including HCR. 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: High-consistency Rubber (HCR): 20 to 80 Durometer, Liquid Silicone Rubber (LSR) 5 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.


Combining the Power of Medical Devices and Drug-Eluting Products

In the medical industry, a “combination product” is a term used to describe a product that is composed of two or more of the following: drug, device, and biological product. In recent years there continues to be increasing overlap between devices and drug therapies, leading to combination devices that more effectively deliver drugs and treatments to patients. This article will focus on the powerful combination of drug-eluting products and medical devices!

A drug-eluting device is a product that gradually releases a medicinal treatment over time. Generally, drug-eluting products are implanted into the body but there are some examples of external products such as drug-eluting wound dressings. For drug-eluting implantables, the exterior of the device can be coated with the drug, or the drug can be impregnated within the device during manufacturing.

Benefits and Examples of Drug-Eluting Medical Devices

Drug-eluting medical devices perform a variety of functions. One of the most common is vascular stents used to preserve and maintain blood flow in the heart. The stent is implanted in the patient’s artery and the device slowly releases the desired drug over time to target the care exactly where it is needed! Other examples of drug-eluting products include electrostimulation devices that regulate heart rhythm or block spurious signals in the brain, catheters with antimicrobial coating to prevent infections, and orthopedic devices that mechanically reinforce the spine or restore range of motion of hips and knees.

Drug-eluting medical products provide a great benefit to patients over conventional dosage methods. As noted above, these devices provide site specific drug administration where it is most needed – this targeted treatment often allows for lower doses since the drug does not have to spread throughout the entire body – resulting in fewer and less severe side effects. Drug-eluting implants are able to maintain the desired level of the drug, often referred to as the Active Pharmaceutical Ingredient (API), in the patient much more consistently and over a longer period of time than both pills and injections. For these reasons, the level of the API in the patient’s body remains inside the therapeutic window for a much longer duration. Additionally, drug-eluting medical devices are less burdensome to the patient and there is no risk of the patient forgetting to take a dose!

Recent Advances in Drug-Eluting Devices

Combining the power of medical devices and drug-eluting products is an exciting opportunity, and this field continues to be a focus area for research and development. One recent advancement is using a novel drug-eluting coating to reduce infections. Infection is often problematic with implants and it is estimated that up to 15% of hospital infections may be caused by internal medical devices! Bacteria often collect on the surface of an implant and form what is called a biofilm layer that makes it very difficult to fully remove the bacteria; in fact, in many cases, the implant must be removed, the bacteria treated via anti-biotics, and the device reimplanted – which is definitely not an ideal treatment plan! A cutting edge drug-eluting medical device in the form of a special coating was recently developed and will slowly release a drug that will combat the formation of a biofilm layer by the bacteria. The result is expected to yield fewer patient infections due to an implant as well as fewer procedures required to remove and reinstall implants when an infection does occur!

Traditionally, the field of medical devices has focused on palliative treatments, which try to manage a condition by improving quality of life and preventing the given problem from getting worse. But with the combination of medical devices and drug-eluting treatments, there is an opportunity to think broader than palliative treatments and shift toward treatments that potentially erase the damage from a prior medical event, such as a heart attack or stroke. And thinking even broader, these combination devices can potentially treat Alzheimer’s, Parkinson’s, or other diseases that are impacted by tissue or organ breakdowns – seeking to repair the tissue or organ and restore the patient to his/her original health. The sky is the limit when medical devices and drug-eluting products are combined!

ProMed Pharma’s Capabilities

ProMed Pharma is a leading contract manufacturer of polymer-based drug releasing molded dosage forms and combination device components, such as drug-eluting products. Working with both established and early-stage medical device and pharmaceutical companies, we develop robust manufacturing processes and platforms for extended drug release from a variety of materials, including silicones and thermoplastics.

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 – including Liquid Silicone Rubber (LSR) that is an excellent option for drug-eluting medical products! 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 molding project.


The Development of Novel Sustained Release Drug Implants

Medical implants are devices that are placed on the inside or surface of the body with the purpose of delivering medication, monitoring body conditions, or supporting organ health. When most people think of implantables, they think of drug pumps used to deliver insulin in the treatment of diabetics. This form of implantables are typically programmable “active” devices which require regular resupply of the medication through an access port.

Another type of implant is a drug delivery device that, when placed inside the body, releases drugs at a defined rate and for a defined period. These technologies enable the sustained release of drugs through a small non-mechanical subcutaneous implant device, and provide long-term, “passive” release without the need for replenishment. Typically found as thin flexible rods, these delivery systems are particularly effective for the delivery of highly potent drugs such as hormones. Commercial examples include implants for contraception and the treatment of prostate cancer. One significant advance in recent years is the addition of sustained release drug implants that dissolve over time and do not require removal of the implant – reducing the number of procedures required and the potential for complications such as infections.

Benefits of Sustained Release Drug Implants

For over a decade there has been an increasing convergence between implantable devices and drug therapies, including devices that deliver drugs. Sustained release drug implants offer several advantages over conventional drug delivery options. First, implantable devices allow targeted, localized therapy where the drug is most needed. This may also allow for significantly lower doses of a drug which can minimize potential side effects and reduce the impact on the kidneys and liver. Second, implantable devices allow for sustained release of a therapeutic agent. Both pills and injections produce Active Pharmaceuticals Ingredient (API) concentrations that rapidly rise and then exponentially decay as the body dilutes, metabolizes, and/or excretes the pharmaceutical compounds. By contrast, sustained release drug implants can slowly and steadily release the API at a controllable, optimal rate within the therapeutic window. 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, and patients won’t forget to administer the medication. These implants offer prolonged delivery of treatment ranging from weeks to years.

Materials for Sustained Release Drug Implants

Injection molding, a manufacturing method used for making everything from car parts to kids’ toys, is also utilized to make life-saving medical devices, including those inserted or implanted into patients’ bodies.

As you would expect, there are key material considerations for products used in drug delivery such as biocompatibility, the ability of the material to control release of the API, stability, durability, and the ability to naturally degrade over time if necessary.

Medical grade silicones have long been a material of choice for drug delivery given their range of available durometers, extreme chemical inertness and biocompatibility, excellent tear and heat resistance make it ideal for parts that need to remain in the human body for extended periods of time. Ethylene vinyl acetate (EVA), 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. While new material development for drug delivery remains an active field of research, injection molding is expected to continue to play a significant role in the manufacturing of drug delivery devices due to its ability to produce high volumes at low prices while meeting tight dimensional tolerances.

Recent Innovations in Sustained Release Drug Delivery Devices

The development of novel sustained release drug implants is an area of significant research and advances in recent years. Below are a few notable innovations that give a glimpse into the future of this exciting and relatively new field.

  • Contraception has long been an area where implantable devices have been utilized. Recently, a grant was awarded to Inflammasome Therapeutics for the development of a long-term bioerodible birth control implant. After being implanted under the skin, the device will provide a constant and consistent low plasma level of the hormone levonorgestrel for a period of up to 2 years at which point it will fully dissolve and require no removal. This is a huge step as current contraception implantables require removal. This form of treatment is expected to be extended to other disease treatments sch as HIV and arthritis.
  • A huge area for research and development is nanomedicine, which entails targeted drug delivery in which particles attracted to disease cells directly treat those cells. For example, scientists at Houston Methodist Research Institute recently successfully delivered long-term medications via a nanochannel delivery system (nDS) implanted under the skin. The implant is remotely controlled using Bluetooth technology. Researchers are hopeful that these devices can allow for remote patient care and lower healthcare costs. Additionally, this technology would allow for patient treatment during off hours, such as at night, when some treatments are proven to be more effective.
  • Researchers recently created a new type of coating for drug delivery that can be activated externally, specifically with infrared radiation (IR). The coating is considered a hybrid stimulus-responsive system that will allow for more on-demand, localized treatment of a given area with sustained release drugs.

ProMed’s Implant Molding Capabilities

ProMed understands the importance of quality to your success, especially when it comes to implants. We have a history of manufacturing drug delivery products, which means we have the experience as well as robust systems and processes in place to handle your specific project needs! Our work has historically focused on molding silicone drug delivery devices using injection and compression molding techniques. 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.

We have a well-established pallet of durable and biodegradable polymeric materials that provide options for delivery of potent compounds such as hormones, opioids, antibiotics, and oncology drugs. 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 molding project.


Pharmaceutical Combination Products: Why Silicone is the Perfect Match

What is a Combination Product?

“Combination product” is a term used in the medical industry that refers to a product composed of two or more of the following: drug, device, and biological product. For over a decade there has been an increasing convergence between devices and drug therapies, leading to combination devices that more effectively deliver drugs and treatments to patients. Implantable medical devices are a common pharmaceutical combination product that provide 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. Other examples of combination products include inhalers and insulin pumps.

Pharmaceutical combination products, in particular implantables, provide a great benefit to patients over conventional dosage methods. For example, implantable devices provide site specific drug administration where the drug is most needed – this targeted treatment often allows for lower doses, reducing side effects. Additionally, this form of drug dosage is less burdensome to the patient. For these reasons, the trend toward combination products is expected to continue as demand grows for patient-centric drug delivery and self-administration of healthcare.

Silicone – the Perfect Match for Combination Products

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, low toxicity, and compatibility with many sterilization methods. But the key characteristic that makes silicone the perfect match for combination products is its biocompatibility. Silicone is compatible with human tissue and body fluids, has a very low tissue response when implanted, and does not support bacteria growth. Additionally, medical-grade silicones have undergone stringent purity and biocompatibility testing that make them suitable for use in long-term implants.

LSR is a specific type of silicone used in combination products. The low viscosity of LSR makes it a great silicone material for making medical devices 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. Furthermore, the temperatures needed to vulcanize LSR are usually low enough that significant degradation of compounded substances like Active Pharmaceutical Ingredients (APIs) can be avoided.

One application where medical-grade silicones, such as LSR, really shine is drug-eluting implantable devices. Before molding, silicones can be compounded with APIs such as cancer drugs or hormones which 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 for a much longer duration.

ProMed’s Combination Product Capabilities

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.

ProMed Pharma is a leading contract manufacturer of polymer-based drug releasing molded dosage forms and combination device components. Working with both established and early-stage medical device and pharmaceutical companies, ProMed develops robust manufacturing processes and platforms for extended drug release from a variety of materials, including silicones and thermoplastics. 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.

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


Why Consistency Matters Most in Medical Silicone Injection Molding

Consistency is defined as the achievement of a level of performance that does not vary greatly in quality over time. While there are many factors that OEMs should consider when partnering with a silicone injection molder – consistency is certainly at the top of the list! This is especially true for OEMs that supply medical parts and devices to the healthcare industry – you simply cannot afford to cut corners when it comes to consistency and quality as these products are often critical to the health of the individual using them.

Due to its chemical inertness, durability, stability, and low toxicity, medical grade silicone is an excellent material for implantable and other medical devices and its use throughout the healthcare sector continues to grow. The healthcare industry has high expectations for its devices – requiring compliance with tight tolerances and cleanliness requirements that offer little room for error. A molder that has a high level of quality and repeatability in its medical device production is able to deliver consistent products to customers – becoming a trusted partner! Meeting an OEM’s specifications and requirements for a given device must be the top priority for every injection molder. From both the supplier and OEM perspectives, inconsistency and poor quality can result in various negative outcomes such as slower time to market, customer complaints, tainted reputation, strained supplier-OEM relationship – and worst of all, customer loss or harm! For these reasons, consistency and quality matter most in medical silicone injection molding!

Before partnering with an injection molder, OEMs should have a firm understanding of their quality program – this is an area where excellent injection molders stand out from their competition. A silicone injection molder’s quality planning and assurance program is more than just meeting the requisite ISO and FDA requirements – it represents their proven way to ensure consistent quality of their injection molded parts. A sound quality program demonstrates that the molder monitors the effectiveness of their supply chain and demonstrates traceability related to regulations of materials and finished goods – enabling the production of medical products with consistency and repeatability.

ProMed’s Commitment to Quality

Partnering with an experienced injection molder like ProMed allows for the necessary production planning needed to meet all of the necessary regulatory, quality, and commercial standards. ProMed understands the importance of quality to your success. That is why quality is embraced every step of the way to create a product that will assure confidence in your products. Our work force is highly specialized in the manufacturing and quality requirements of medical products, much of which go into the long-term implantable market space. Every employee at ProMed is trained with the idea that quality is their most important responsibility.

Our equipment utilizes cost-effective, high-end molding technology to keep operating expenses down while producing parts with an extremely high level of precision and repeatability. Our tools are designed and manufactured to exacting tolerances. Expert toolmakers use high-tech design software and machining centers to produce molds that are durable and dimensionally repeatable from cavity-to-cavity, part-to-part!

We are an approved, certified supplier to many of the top medical device manufacturers in the world. All ProMed facilities go through routine audits by our ISO registrars and customers. Below is a sample of the standards we meet.

 

·      ISO:13485 – 2016 certified ·      ISO Class 7 Clean Room
·      ISO:17025 certified ·      REACH and ROHS compliant
·      FDA 21 CFR 820, 210/211 and part 4 compliant

ProMed’s Silicone Injection Molding Capabilities

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

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


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

Introduction

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.

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.


Manufacturing Combination Components

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.

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.

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