Cochlear implants have made it possible for deaf people to hear for the first time, and implanted defibrillators can give at-risk individuals ongoing protection against sudden cardiac arrest. Newer types of implants allow the treatment of epilepsy, depression, and obstructive sleep apnoea, and can dramatically improve survival rates and quality of life for patients with advanced heart failure until a donor heart can be found.
Besides the noble aim of giving people hope and improving their quality of life, active implants are a very attractive and stable market for device and component manufacturers. The annual growth rate exceeds 10%, and the market is several billion dollars in size and allows high margins.
If an implanted device fails, however, the effects are dramatic. In the best case, the implant can be replaced, but this requires surgery. In the worst case, the failure may cause disability or even death. The manufacturer may need to recall the product, or its manufacturing may be shut down by regulatory bodies; and it may be faced with costly lawsuits and punitive damages. In a recent instance, an implant manufacturer set aside an outstanding-claims reserve of close to $200 million.
The quest to minimise risk
Active implants are considered high-risk devices, meaning they are subject to rigorous standards and approval processes before they can reach global markets.
As a consequence, time to market is quite long, and the costs involved are extensive. In the US, for example, it is usual for 18-30 months to pass between submission to the US FDA and approval being granted – and this is provided that the submitted documents are complete and meet the requirements of regulatory bodies.
For manufacturers of finished devices, an adequate quality system is therefore a key prerequisite to reduce risk, minimise time to market and prove that the products are safe, effective, and consistently meeting applicable requirements and specifications. In the US, this is regulated by current good manufacturing practices (CGMP: 21 CFR part 820) that require companies to use technologies and systems that are up to date.
Although this regulation does not apply to manufacturers of components or parts of finished devices, and the actual work may be delegated, the responsibility for continuously meeting (and having objective evidence of meeting) these requirements stays with the manufacturer of the finished devices. This manufacturer must therefore ensure that its suppliers of components and parts have adequate systems in place, and can continuously and demonstrably meet all requirements.
Printed circuit boards
In an active implantable device, one of the more complex and critical components is the printed circuit board (PCB). A PCB is not a standard component but is different in each product, and design specifications are usually provided to the board manufacturer by the customer. The production itself consists of multiple mutually dependent manufacturing steps such as galvanic and chemical processes, laser drilling and routing, and pressing under vacuum and high temperature. In PCB manufacturing, yields are commonly well below 100%. In addition, PCBs are subject to substantial thermal stress during the assembly process. This makes PCBs a point of concern deserving special attention.
It is therefore of the utmost importance that only PCBs of good quality and meeting specifications are delivered to the customer. A thorough failure mode and effects analysis (FMEA) is a good method to identify and prevent process or product errors before they occur, and to identify critical-to-quality characteristics. The analysis will show that good process control is important for the manufacturing of high-quality PCBs but that the effectiveness of test steps is the real key to ensuring reliable parts.
The simplest way to increase the confidence level of tests is to change sample size from AQL-level to 100% testing. A further increase of the certitude that test equipment is functioning correctly can be achieved by running a test board immediately prior to and after the actual test is performed. Typically, PCBs are subject to electrical testing for the detection of short circuits and opens – with automated optical inspection, microsections, X-ray fluorescence measurement and final inspection under a microscope.
More refined testing methods include ionic contamination and temperature cycling tests. Contaminants on the board – from the fabrication process or environmental exposure – can cause electrochemical migration and dendritic growth, potentially leading to failure in the product’s lifecycle. With an ionic tester, it can be determined if the level of contamination is below an acceptable level. The interconnect stress test (IST) is an IPC-approved accelerated temperature cycling test that makes it possible to measure the integrity of vias of various types, inner layer connections or microvias to capture pad interconnects. Specific IST coupons located in the production panel are subject to subsequent heating and cooling cycles, whereas the resistance in the sense circuit of the test coupons is measured. The gradient of the resistance increase in relation to the number of temperature cycles correlates to the quality of the entire interconnect structure and allows a quantitative assessment of the robustness of the PCB. For meaningful measurement results, adequate and calibrated measurement tools must be used. Suitability of a measurement system for its intended use must be proven by gage repeatability and reproducibility studies.
Quality assurance
Another essential element of quality assurance for the manufacturing of implants is the demonstrably proper qualification of production and test equipment. Installation qualification (IQ) ensures that equipment is received as designed and specified, and correctly installed; operational qualification (OQ) demonstrates that it will function according to its operational specifications; and performance qualification (PQ) demonstrates the consistent performance according to specification over a period of time. This also requires equipment to be maintained and, where applicable, calibrated in regular intervals on a planned schedule.
All this is meaningless, however, if the workforce does not understand these requirements and operations are not executed properly. Employees therefore need adequate education, regular training and experience. It must be ensured that only properly qualified personnel are involved in the manufacturing and testing of PCBs intended to be used in implants.
For manufacturers of finished devices, it is essential that the manufacturing of PCBs is controlled, and that no changes to the product, materials used, methods and processes are made without proper prior authorisation. A quality assurance agreement is usually concluded for this purpose.
The device manufacturer is required by regulatory authorities to ensure that PCB manufacturers consistently comply with quality requirements. This is only possible if the producer of the boards is able to provide adequate records proving that requirements have been met. These records must be readily available for review and copying: for device manufacturers, the US FDA defines the record retention period to be equivalent to the design and expected lifetime of the device. In the case of cochlear implants implanted in young children, for instance, this period can be 70 years or more.
PCBs for implants are not simply components: they need to reliably and demonstrably fulfil specifications and quality expectations. This is not only to meet requirements of regulatory bodies, but also to minimise the substantial risks involved in the sale of active implantable devices. Ideally, it should be possible for each individual PCB to be traced back to its date of manufacture, the lot numbers of the materials used, every production step, the machines used (including proof that the machines were properly qualified and maintained), the process parameters, the name of the employee performing the manufacturing steps (including evidence of adequate training, results of tests and photos of microsections with
all relevant dimensions).
