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.
|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.
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.
In 2006, ProMed embarked on a journey to broaden our capabilities from the molding and assembly of components for medical devices to include the manufacturing of drug/device combination products. Differences in regulatory requirements between medical devices and pharmaceutical products presented unique challenges during this effort across the company to meet our customers’ and regulatory bodies’ stringent quality, safety, and compliance goals. This whitepaper discusses the challenges ProMed Pharma has confronted in three key areas: facility design, implementing the Pharma Quality System, and company culture for the enhanced scrutiny that accompanies these products. We also discuss the solutions that ProMed Pharma has enacted to meet these challenges.
Challenge 1: Facility Design
Prior to bringing a new manufacturing process online, it is essential to establish a close collaboration between the customer and the ProMed team to understand and define the intended flow of materials, personnel, and equipment in the facility. Once these are understood, the needs of the facility can be summarized in a mutually agreed upon User Requirements Specification (URS) describing the necessary features that must be designed into the facility and validated to ensure those needs are met. These requirements are then translated into specific designs addressing each requirement by implementing appropriate-sized production areas, layouts, equipment, utilities, and safety precautions. Each can then be validated appropriately to ensure that all the requirements established for the facility in the URS have been met.
Much of this approach is shared with ProMed’s molded components facilities, but several areas are of particular concern when designing facilities for combination products:
1) Receipt, Storage and Testing of Raw Materials
Drug substances and excipients must be received, quarantined, sampled, tested, and released prior to use. Additionally, to ensure personnel are properly protected from hazardous drug substances, each drug substance’s Occupational Health Toxicity/Potency Category, Safety Data Sheet, and other available information are evaluated and a mitigation plan determined. Appropriate personal protective equipment such as respirators and isolators are then used during receiving, sampling, and manufacturing.
Prior to receipt of raw materials, documents establishing the sampling required for these materials are written, reviewed, and released into the ProMed Pharma Quality System. Upon receipt of material, these documents are consulted to verify material certificates comply with pre-established specifications and what tests must be performed. Generally, identity testing, purity, strength, and quality must be confirmed. Prior to release to the manufacturing floor, these records documenting the sampling, testing, and release are completed, verified to meet materials specifications, and reviewed. Please refer to our follow-on article, The Challenges of Manufacturing Combination Components Part 2 for further guidance.
Throughout this process, it is essential that incoming materials are segregated in quarantine away from released material that has already been verified as suitable for use. These quarantine areas must have appropriate temperature, light, and humidity conditions to assure continued quality during testing and release. To ensure that this is the case, ProMed established a series of labeled, segregated cages, coolers, and freezers with temperature control, monitoring, and qualification for their intended use beyond those already in place for storing materials for use in manufacturing. To help ensure that unreleased materials are never used, we formalized and expanded our existing system of color-coded materials labeling for each stage of receipt, quarantine, and acceptance to supplement physical segregation in our cages, coolers, and freezers.
2) Cleanroom space, utilities, and equipment for manufacturing
To ensure that all requirements established at the outset of a project are met to the satisfaction of our customers and regulatory bodies, it is essential that the equipment, air handling, process flow, cleanroom layout, and utilities are considered and established as new pharma production facilities.
Each product has very different requirements that require careful consideration during design of the manufacturing facility. For example, the facilities needed for manufacturing an ocular implant containing minute quantities of drug tend to be quite different from those for large scale manufacture of an intravaginal ring that consumes kilograms of potent hormone per batch. To ensure proper materials and personnel flow, each cleanroom is tailored to the needs of a particular customer and product.
Equipment and process requirements are evaluated for appropriate size, required utilities, materials of construction, monitoring instrumentation, pressure gauges, temperature gauges, and any other equipment particular to the product. While specifying equipment, the available utilities are compared to the actual daily consumption and demand for these items and what additional usage is expected when installed in the facility. When necessary, utilities are upgraded or modified to suit the needs of the specified equipment. In cases where the utility has a direct or indirect impact upon product quality, validation testing is performed to verify quality during this operation. For example, ProMed uses compressed air both to drive actuators and remove materials. In the former case, the validation is focused on maintaining pressure and variability within pre-established limits. In the latter case, the compressed air contacts product; as a result, validation is expanded to ensure that no oils, moisture, or microbial contaminants are present. Similarly, if a Purified Water System is used to wash components it therefore needs to be validated to ensure that the water meets USP requirements.
Careful specification and validation of air handling units (AHUs) is a major feature in the design of pharma production facilities. Proper air exchanges, pressure differentials between clean and dirty areas, minimization of operator exposure to drug substances, and maintenance of the proper humidity and temperature levels are all critical design criteria that must be handled by these units. To ensure our facilities continuously operate within specified conditions, an industry-leading electronic Building Automation System (BAS) was installed and validated. The BAS provides continuous remote monitoring and control of pressure differentials, temperature, and humidity to ensure that production areas remain within specified limits for each area.
ProMed’s typical pharma production facility is an ISO Class 7 cleanroom suite dedicated to a particular customer. We prefer to build our cleanroom suites with two air handler units, one that serves the main manufacturing areas and a dedicated unit for our mixing rooms. The dedicated unit helps to ensure drug particulates generated during the mix process are not recirculated into the main cleanroom. Additionally, we design our facilities so that the mix room has a negative pressure differential to adjacent rooms, so drug particulates generated during the mix process do not escape to the main manufacturing area or areas outside of the cleanroom suite. When appropriate, a series of pressure differentials can be maintained within the sub-rooms of a particular suite to ensure appropriate cleanliness and flow for each space.
3) Facility Qualification and Validation
As each new manufacturing facility is brought online, Design Qualification (DQ) is performed to ensure the cleanroom suite has been built to meet the specifications initially agreed upon in the URS. Validation of the suite includes Installation Qualification (IQ), Operation Qualification (OQ), and Performance Qualification (PQ) testing to ensure the cleanroom and Air Handler Units have been installed and operate as expected, proper air changes per hour are achieved, room balancing requirements have been met, all HEPA filters passed leak testing, and the room passed ISO 7 particle classification.
Once the facility has been initially qualified, the facility is placed into an environmental monitoring program. The new cleanroom suite is thoroughly cleaned in accordance with cleanroom cleaning and sanitization procedures. Once cleaning has been completed and documented, initial testing includes a three-consecutive-day period where no operators are present (static testing) followed by a three- consecutive-day period where operators are present (dynamic). The airborne viable microorganism, surface microorganism, and non-viable particulate levels from this initial testing are used to establish a baseline and the initial alert and action levels. The facility is then added to our routine Environmental Monitoring (EM) program and sampling is performed quarterly.
ProMed typically dedicates process and in-process test equipment to a particular drug substance. This helps to minimize subsequent cleaning validation requirements. All pieces of equipment used in the process are evaluated through a risk-based process for validation requirements. Where appropriate, equipment is IQ/OQ and PQ qualified before Process Validation (PV) and all operators working in the manufacturing operations are trained to the process.
Process Validation is performed by Process Operation Qualification (POQ) where at least three production runs are performed to confirm the upper and lower process limits. The POQ helps to establish process control schemes and guard banding. Once the POQ is satisfactorily complete, three consecutive Process Performance Qualification (PPQ) runs at the process center points are performed to verify process capability and the appropriateness of the established control schemes.
Challenge 2: Quality System
When ProMed embarked on manufacturing Combination Products nearly a decade ago, few specific combination product regulations existed. To develop a new combination device Quality System, our existing ISO 13485 certified Medical Device Quality System was used as a base augmented with the applicable drug requirements.
To create the Pharma Quality System, ProMed compared it’s existing system to available guidance, particularly FDA’s draft guidance “Good Manufacturing Practice for Combination Products” and Medical Devices Quality Management Systems – “Guidance on Application of ISO 13485.” This led to significant additions to the existing system, particularly with regard to training, documentation, testing, and record management. This new Pharma Quality System was then implemented as a separate, sister system for combination devices to the existing ProMed Quality system; in this way we have been able to ensure full compliance for each portion of the company while continuing to ensure rapid and cost-effective delivery of non-drug components.
Since the initial implementation of this system, we have continued to modify and update the Quality System to reflect current guidance. In the intervening years the FDA has recognized industry’s struggle with regulatory expectations and in January 2013 issued the final rule for 21 CFR Part 4, cGMP Regulation of Combination Products, and the Final Guidance for Industry on how to comply with these new requirements was published in January 2017. As it is commonly referred to today, Part 4 instructs those companies making Combination Products to fully comply with either a Device-based Quality System or a Pharma-based Quality Management System and augment it with the procedures necessary to support either a pharma product or a device product. ProMed’s approach to compliance in-depth is explored in a second article on The Challenges of Manufacturing Combination Components – Part 2.
Challenge 3: Standards and Culture
The cultural shift necessary to move from manufacturing molded components to successfully manufacturing combination products has been a major area of focus for ProMed Pharma. Some basic assumptions about how products are made, moved, and documented needed to be changed as part of this shift. Several of these are discussed below.
1) Batch Processing
In much of the medical device contract manufacturing industry, batch size for a particular lot corresponds with the number of components processed through the manufacturing environment. As parts pass through a particular operation, process and yield data are recorded for the entire lot.
In contrast, for combination device manufacturing, manufacturing often consists of a series of discrete processing steps where key characteristics (weight, yield) of individual units are tracked. Often these characteristics act as in process controls to assure the quality of the product through each step of manufacturing and assure the correct amount of drug is incorporated into the manufactured component. To implement this shift, ProMed adopted a manufacturing process where yield and processing steps can be addressed in a granular manner throughout manufacture of a particular batch. For some particularly demanding products, this tracking has been sufficiently careful to allow tracking of sub-batches as small as 8-16 parts made in a single injection cycle from thousands in a production lot, with each of these sub-batches tracked through the manufacturing process. By documenting and trending key measurements through each phase of manufacture we are able to assure continued product quality and rapidly diagnose the source of any potential out of specifications results quickly and thoroughly. This allows more precise tracking of yield through the manufacturing process and reconciliation of drug substance for each batch.
2) Documentation and Company Culture
ProMed’s experience in medical device contract manufacturing provided a thorough understanding of the importance of the accuracy of device history records and associated documentation. Moving into combination products, we were challenged to take on another level of diligence to assure that we properly document every aspect of our work. This required a concerted and ongoing training program to ensure that employees from the newest operator to senior management were indoctrinated in the necessity of the additional documentation, conversant in the additional requirements required, and capable of withstanding the higher level of scrutiny expected. To ensure our ability to meet these more stringent standards of documentation in parallel, we have steadily expanded our QA staff to help ensure progressive compliance and ensure the timely and complete review of our records.
This emphasis on high documentation standards has had a synergistic effect on ProMed’s molded products division. As we endeavor to build best practices and standards for ProMed Pharma, many of these policies and procedures have been implemented companywide, enhancing customer value and providing higher assurance of quality. The process is an ongoing one. As part of our document review and training programs, we continue to implement best practices and incorporate updated regulatory requirements to ensure the highest levels of quality and compliance.
3) Understanding Value
Due to the incorporation of higher-cost constituents including Active Pharmaceutical Ingredients (APIs) and the higher degree of control required for manufacturing, combination devices rapidly became among the highest value parts manufactured at ProMed. While these parts may at first glance seem similar to parts our operators make every day from more conventional materials, the additional value of these components required a shift in practices. To ensure that materials were used and tracked effectively, additional education was necessary so operators could more fully understand the scope and added value for these parts. In addition, more rigorous training was implemented on each step of manufacturing to ensure that operators could more effectively execute the process. As a result, scrap was reduced as yields and reconciliation values increased.
4) Employee Flexibility
ProMed initially chose to use its workforce from existing component manufacturing areas during our first forays into manufacturing Combination Products. This required that the operators move between quality systems, batch processing approaches, and working with variable parts from day to day. To make this possible, feedback systems were implemented to monitor the performance of the operators, the process, and quality.
To help operators adjust to the new requirements, a flexible work schedule was implemented where personnel could enter the new environment at a level suitable to their level of experience. Coupled with existing performance metrics this allowed for a combination of self-selection for this more demanding manufacturing environment and identification of those operators who most consistently met the more stringent requirements of combination components, which allowed ProMed Pharma to steadily build a versatile work force capable of successfully manufacturing combination products, understanding the importance of pharma quality requirements, and exercising the diligence and attention to detail needed when completing rigorous manufacturing, testing, inspection, and release documentation.
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 email@example.com for more information.
Device functionality is usually the starting point when designing devices. Another element that needs to be considered when designing devices and their subsequent components: manufacturability. Part design should also be focused on the ease of manufacturing because it can help reduce cost and lead to a robust and reliable process. Several aspects should be considered regarding manufacturability: part geometry, location and shape of critical surfaces, size, and among others. These may seem like more obvious characteristics, but there are a few others that can be overlooked, but yet should be considered just as important. These are material selection, dimensioning/tolerancing, and the selection of critical dimensions. To better understand the impact, each characteristic will now be explained in detail.
Choosing the correct material for your application is important and can have an impact on the performance and cost of the component.
There are a few things to consider when deciding on a silicone to use for manufacturing. These include type of silicone (liquid silicone rubber or high consistency rubber), durometer (hardness), and even color. Each of these can have an impact on manufacturability.
(LSR) Liquid Silicone Rubber vs. (HCR) High Consistency Rubber
Both LSR and HCR are available in a variety of durometers. Of the two, LSR is the preferred silicone for manufacturing. LSR can be molded faster due to a few factors. LSR has a lower viscosity than HCR, therefore it can be injected faster into the mold. This means that a manufacturing cycle for LSR can be significantly shorter than that of HCR. The majority of HCR parts also need a post cure, which is a secondary operation and can add cost to the price of a part.
When manufacturing a part with complex geometries, a material with a low viscosity is recommended so that detailed features are consistently and accurately captured. LSR’s low viscosity allows it to quickly and fully fill small and intricate features in a mold, and therefore makes it the more desirable material for these applications.
Useful information for designing with either silicone is the shrink rate. LSR has a typical shrink rate of 2.5% to 4.0% and HCR has a typical shrink rate of 1.5% to 3.0%. Some factors that can affect shrink rate are durometer, lot to lot variation in the material, additives/colorants, the manufacturing process, gate/vent size, and material flow. While shrink rates don’t typically affect the manufacturing process, these rates are used in mold design.
Durometer: Soft or Firm?
Silicones for manufacturing are available in durometers ranging from 5 to 80 Shore A. Durometer has a significant impact on manufacturability at all stages. Parts that are made with very soft or very firm silicones can be difficult to remove from the mold. Soft parts tend to stick to the mold surfaces more while parts made with firm silicone are more brittle and may tear or break during removal. For optimal manufacturability, we recommended using a silicone with a durometer between 30 and 70 Shore A.
Clear or Colored?
Colorants come in a wide variety of hues and can be mixed into LSR or HCR materials at very precise amounts. Adding color to your part can benefit component manufacturing and assembly in several ways:
- Similar, hard to distinguish parts can be colored differently, making them easier to tell apart visually.
- Coloring very small or micro-size parts can make them easier to see and handle, especially against a white background.
- Very small, fully encapsulated bubbles or incursions of foreign material in a thick wall area are more easily hidden in colored silicone than in clear silicone. This can reduce the quantity of parts rejected solely for these minor cosmetic defects.
- Colored silicone can improve the accuracy and repeatability of measurements obtained from non-contact (i.e. optical) measurement processes.
Dimensioning and Tolerances
The dimensioning and tolerances of a silicone part can make or break a new project. The application of dimensions, selection of critical dimensions, and size of tolerances are all key to manufacturing success. The main things to keep in mind when dimensioning a silicone part are to apply dimensions to silicone (not to the spaces between silicone), and keep tolerances to a minimum of 2.5% of the dimension or ±.003 inches, whichever is greater.
Application of Dimensions
While anything can be dimensioned on paper, not everything may be practical or even possible to measure accurately and repeatably. Examples include:
- Radii that are less than 90° of a circle
- Angles that have reference surfaces of less than .010”
- Referencing to theoretical transitions, such as a transition point from a flat surface to a radius.
- Referencing theoretical planes/surfaces in the use of GD&T
If there is a situation when these types of dimensions need to be applied, it is a good practice to make them reference dimensions if possible. Although doing so voids the application of tolerances, the development of a project won’t be slowed when the inspection data doesn’t meet certain statistical standards.
Selection of Critical Dimensions
Critical features are typically those that will be measured in production as part of continued quality assurance. They must also meet higher statistical requirements than non-critical dimensions used during development. The success of a project can hinge on the selection of critical dimensions.
When selecting critical dimensions, there are some important things to consider.
A critical dimension located in a rigid area of a part will prove more likely to be measured within specification than one located in a more pliable region. Also, if a rigid feature is being measured, the methodology used to measure it will be easier to develop. Typically, simpler fixtures will be required, and both the measurement times and number of fixtures required will be decreased. Measuring rigid features will also yield more consistent data, which will be reflected in improved statistical results.
Successful silicone molded components must not only perform as intended, but must also be designed from the beginning to be manufacturable. By making the right material, color, durometer, dimension, and tolerance choices OEMs can develop molded devices and components that can be reliably manufactured in large volume—while minimizing scrap rates and their losses.
About ProMed Molding
ProMed is an industry-leading cleanroom manufacturer of silicone components, specifically those having a medical application. Founded in 1989, ProMed has been successful in combining state of the art equipment and tooling to produce tightly toleranced parts for finished medical devices sold in the United States, Europe, and Asia. ProMed has garnered a reputation as the world benchmark of implantable silicone components and assemblies – and is one of few companies in the world to provide contract manufacturing of drug-eluting products. ProMed Molding also offers assembly, micro-molding of highly engineered plastics, and combination products.
As a company committed to quality, excellence, and customer satisfaction, we invite you to visit our website at www.promedmolding.com. Please contact our Business Development group at firstname.lastname@example.org for more information.
For decades, silicone rubber has been the material of choice for implantable devices. Its high chemical inertness, durability, tensile strength, availability in a wide range of durometers, wide temperature range, and ease of molding by many methods has made the material a mainstay of medical devices of all types, but especially for long-term implants.
This tradition has been further reinforced by the growing supply of medical-grade silicone, which is extensively tested for purity and biocompatibility in order to meet the FDA’s requirements for products implanted in the human body for more than 29 days. Testing of the raw silicone however, is only part of the effort needed to guarantee the biocompatibility of the final product. This is why process controls at device manufacturers are also required in order to ensure a silicone device’s quality and safety.
As more suppliers are able to meet these requirements and offer wider portfolios of medical-grade silicone formulations, the number of possible applications and types of implantable devices made with silicone continues to grow, as does the medical grade silicone market.
Expanding Applications of Biocompatible Silicone
Take one current development as an example. Recently, medical silicone tubing with embedded reinforcements has hit the market, which augments silicone’s natural flexibility with additional stiffness and strength. Braided or spiral monofilaments of stiffer resins, or even stainless steel, are located in the wall of the tubing provided enhanced burst, kink, and wear resistance—all qualities necessary for tubing which needs to conform around organs and through existing passageways as it is inserted into the body. This new development can meet the current pressing need for more durable and smaller implantable medical devices.
Another advancement for silicone implantable devices, which has just been achieved in the laboratory, can drastically reduce the costs of implants that need to be custom made for optimal fit inside the patient. A university laboratory in Florida has developed a way to 3D print these implants out of soft silicone, skipping the time-consuming and expensive process of conventionally molding these custom parts, a process that can take weeks. The breakthrough in this case is the ability to 3D print parts by using oil-based microgels, a welcome achievement since that material’s flexibility and pliability makes it ideal for implants that are located in and around delicate internal organs. Although this technology is at an early stage in the development process, it does demonstrate how medical-grade silicone continues to be at the forefront of new implantable devices.
The Growing Medical-Grade Silicone Market
With more types of biocompatible silicones becoming available, and a growing number of applications for them, the market growth of medical-grade silicone rubbers is expanding at an increasing rate. According to one report released last August, the market size for these silicones is forecasted to hit $1.6 billion by 2022, expanding at a compounded annual growth rate (CAGR) of 6.1% from 2017 to 2022. Two factors driving this growth are rising demand in the Asia Pacific region for devices such as surgical implants, and a growing elderly population whose medical needs are often met by products fabricated out of medical-grade silicone (especially implantable devices).
Biocompatible silicone is a popular choice for implantable medical devices, particularly those that require flexibility and durability. More medical niches continue to be filled as the manufacturing and formulation choices become more plentiful. In an industry accustomed to innovation and evolving regulations, silicone’s presence in implants will only grow more rapidly.
ProMed works meticulously with OEM engineers to ensure new product designs for their silicone implantable devices reach the market before their competitors’ products. We challenge ourselves daily and strive to be at the forefront of the latest advancements in biocompatible silicone materials, processing techniques, and applications. How can we turn your latest innovation into the next groundbreaking medical product?
“Shocking Development” – Electrically Conductive Silicone is now ready for Medical Device Applications
Silicone rubber has many physical properties which make it an attractive material for medical applications: excellent biocompatibility, flexibility, high chemical resistance, stability over a wide temperature range, and ease of manufacturing. Pure silicone is naturally an electrical insulator, which is normally desired for medical device applications. New innovative medical applications which require a flexible and biocompatible, but electrically conductive rubber however, are now in the development pipeline. Enabling these advances is a new class of conductive silicones, which include additives that allow electrical current to flow through the silicone.
Electrically conductive silicones have been used in automotive and industrial applications such as radio frequency shielding and sealing. Until now, their use in medical devices has long been hampered by the purity, cost, and processing challenges of the two traditional additives used to make silicone electrically conductive: carbon black and silver coated glass spheres. A third option, carbon nanotubes, has none of the drawbacks of these old standbys is opening new applications for conductive silicones. Let’s explain why carbon nanotubes are such an advance over the previous additives.
Carbon Black: Economical but Dirty
Carbon black is the most common additive for non-medical applications, and consists of a fine carbon powder that is mixed into the raw silicone material and is held in suspension. While it is both economical and readily available, it does present some challenges for medical device applications. The first of which is purity. Carbon black is not manufactured in the type of environments required for medical device materials. It looks and feels like coal dust…..because it is basically coal dust. In addition to purity challenges, it is a very “dirty” material that can leave a residue with anything it comes into contact with, effectively shutting this material out of applications which require contact with, or implantation in, the patient. Silicones containing carbon black have little hope of passing the USP Class VI testing that is often a critical requirement for using a material in medical applications.
Silver Coated Microspheres are Pricey and Delicate
Silver coated glass spheres have been introduced as an alternative to carbon black. As the description implies, this additive is comprised of microspheres that have been coated with a thin layer of silver. While this additive is much cleaner that carbon black, it has some unique challenges as well. Mixing and processing of this material must be done in a way which doesn’t crush the glass spheres. Ensuring the spheres remain in suspension and in a homogeneous mix throughout processing and part fabrication is also a concern. When it comes to liquid injection molding, care has to be taken to ensure that the spheres do not get filtered by the mold’s gates or get pulled out of suspension by thinning the material too much. In fact, this is why some commercial grades of this kind of conductive silicone are gumstock (HCR) meant for compression or transfer molding. The high cost of the coated spheres presents a further obstacle to using this additive for practical medical devices.
The Nano Advantage
The new additive on the block, carbon nanotubes, is the game changer which is now enabling silicone raw material manufacturers to offer electrically conductive silicones that are capable of meeting some of the basic material testing requirements (including USP Class VI) for medical devices. Due to their purity, size, and robustness, carbon nanotubes offer a pathway to success to many electrically conductive applications for medical devices.
The high purity of commercially available carbon nanotubes combined with their small size makes them an ideal additive for conductive silicone medical applications. Because they are so small (they are “nano” after all), a silicone material loaded with carbon nanotubes processes much like an unloaded material, eliminating the problems associated with silver coated microspheres. Because nanotubes are consistently available in high purity grades, devices made with this additive are likely to pass biocompatibility testing. While more expensive than carbon black, the cost of the nanotube-loaded material is not prohibitive for medical device applications.
Carbon nanotubes are price competitive with silver coated microspheres, and are as durable and stable in suspension as carbon black, while being much more pure. All these advantages will make nanotubes the additive which enables innovative conductive medical device applications.
ProMed has partnered with several companies experimenting with conductive silicone medical products in the R&D stage. Our team has processed more than 10 varieties of raw materials manufactured by 3 suppliers, and continues to work closely with our customers and raw material providers to explore applications and turn them into released products.
Speed, cost, and approximation to the final part design (including material properties and dimensions) are key criteria when selecting a fabrication method for making a silicone prototype. For silicone parts, there are actually more options than there are for thermoplastics, which makes the product development process for silicone products a little more challenging. Available processes for making silicone prototypes include: RTV (room temperature vulcanization) molding, selective laser sintering (SLA) and fused deposition modeling (FDM), transfer press molding using high consistency rubber (HCR) materials, and injection molding solutions. As we discuss these options, please keep in mind the majority of new silicone products are manufactured from LSR (liquid silicone rubber), injection molded in a durometer range of 30-70 Shore A.
A Review of 4 Methods
RTV Molding – Industrial RTV silicone formulations are widely available—some can even be found at the corner hardware store. Making parts out of these materials requires a mold, which can be made of almost any metal or plastic material. Although by definition RTVs will cure at ambient temperatures, albeit over hours, ovens are often used to accelerate the curing of the material.
- Pros: The use of RTV is attractive because of the low capital equipment requirements and the availability of raw materials. RTVs can be a very close approximation to their LSR relatives. It is common that well equipped R&D labs have the ability to manufacture tools from plastic and/or soft metal materials in-house. Once the mold is made, making parts is a simple fill-and-wait process. A skilled technician can make the first part within a day.
- Cons: RTV molding is a slow process with cure times extending from 20 minutes to hours. Production rates and cost per piece are both largely determined by the processing time.
HCR – Transfer molding is used to make parts out of HCR, and is a simple manufacturing process 3D printing in silicone is now an option for prototypes an HCR (“gum stock”) material into a heated cavity to cure and form a part. HCR is a natural fit for transfer molding since gum stock is much more viscous than LSR.
- Pros: Simple tools. Little or no process development.
- Cons: Complex geometries may not be possible. Longer cycle times than LSR.
LSR – Production equivalent injection molding press and production grade materials are molded in soft metal tooling.
- Pros: Tooling can be made quickly and the production of parts is fast. The resulting prototypes are very close approximations of production parts.
- Cons: Can result in a higher cost per part for small runs of parts, since the initial tool cost can’t be amortized over a large number of parts.
Silicone Rapid Prototyping Comparison
|Method||Description||Speed||Cost||Approximation to production|
|RTV||Material is injected by hand at very low pressure; material cures at room temperature; many mold material choices||Tooling needs to be machined (or 3D printed) – days to weeks
1-25 parts – Multiple days
25+ parts – Multiple days/weeks due to very long cure times
|$1,500 to $2,500||Medium – Durometer and dimensional attributes are close, but manufacturing process can be much different|
|SLA/FDM (“3D printing”)||The part is formed layer by layer from raw material||No tooling required
1-25 parts – 1-2 days
25+ parts – Multiple days
|$20-$50 each||Low – Parts will have shape similar to finished part, but many limitations on material likeness. Typically a “cloudy” finish.|
|HCR||Transfer molding; mold materials limited to metals||Machined tools – fast
1-25 parts – 1-2 days
25+ parts – Multiple days
|Medium – Parts will be silicone and durometer will be accurate, but manufacturing process can be different|
|LSR||Injection molding; mold materials limited to metals||Tooling and parts
|High – Parts will be silicone, durometer will be accurate, manufacturing process is the same as production in most cases|
Example #1 – Sleeve
Example #2 – Membrane
ProMed is a supplier that partners with customers through the entire development process. We offer RTV, transfer, and LSR molding. Our focus is on your final manufacturing method and our ability to quickly deliver a prototype manufactured using that method.