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3 Keys to Demystifying WHEN and HOW to Incorporate the Standards and Requirements Provided by Regulatory Bodies.
Think back to when your parents required you to complete household chores. Generally, you were provided with some sort of guidance regarding which chores to do, the expectations for chore completion, and the consequences for not sufficiently meeting those expectations. Sometimes you were given explicit step-by-step instructions, while other times it was just a general task (e.g., take out the trash, wash the car, etc.). When given clear instructions for the task you had the choice to: (1) ignore their instructions and complete the task how you wanted, (2) complete the work to meet the bare minimum of what they asked, or (3) take the initiative to complete the task to the best of your ability, aiming to exceed your parents expectations.
Inevitably, in most of our young lives, we did not always follow instructions to a tee when the consequences for disobedience were insignificant in our estimation. And, when we didn’t follow instructions, we may have found that our parents had a reason for giving specific instructions – that their experience gave them insight into some best practices that would better ensure a job well done. Now, as an adult, in your personal life you may be experiencing a similar scenario in the role of parent teaching your child. In your professional life, you may be connecting to this scenario because you recognize the parallels of other rule structures in regulated markets. In these, parental authority has been relplaced by governing bodies such as the United States (US) Food and Drug Administration (FDA) and in the EU, Notified Bodies and the European Comission. As with doing chores, the same general findings apply to following regulatory instructions. You feel most confident in a job well done when you complete a task per specified instructions; but you may find better ways to successfully complete the task if you want to take a different route. In those cases, you may have had to figure out what your boundaries for compliance were. You may also have figured out that it was best to review your decision with your parents before proceeding!
Organizations such as the FDA, International Electrotechnical Commission (IEC), Association for the Advancement of Medical Instrumentation (AAMI), American National Standards Institute (ANSI), and International Organization for Standardization (ISO) produce requirements, standards, guidance or recommendations to help inform the design of medical devices. These documents (e.g., IEC 62366, ISO 13485, ANSI/AAMI HE75, ISO 14971, etc.) are updated periodically in an effort to foster continuous improvement and to keep up with advancements in medical technology and its use.
Just like when you did chores around your parents’ house, as you assess any regulatory body’s instructions, it is important to understand the expectation of those instructions before you decide the best way to proceed.
Design vs. Test vs. Process Focus
The question to ask yourself here is, “Is this instruction telling WHAT needs to be done or HOW it is to be done?”. Think back to when your parent(s) started teaching you how to cook or bake. They will show you the different materials (i.e., bowls, knives, etc.) that are required to prepare the food and the recipe that you will be following. Recipes typically provide the quantity of ingredients used, the instructions for mixing the ingredients, and an estimate of how many servings the current unaltered recipe provides. When you are first learning to cook you make every effort to follow EXACTLY what the recipe says. For example, if it’s your first time baking chocolate chip cookies and the recipe states lists out the steps as: (1) Add 1 cup flour, (2) Add ¾ cup sugar, (3) Add 1 tsp vanilla extract, and (4) Add ½ cup Chocolate chips (yes there are steps missing…after all we are not pastry chefs), chances are you would follow those exact steps in that exact order. However, as your experience grows, you develop enough understanding to know where you can make adjustments in either the amount of ingredients or the process and still make a great cookie. That being said, there are instances even with cooking and baking where the exact steps listed in the recipe need to be followed precisely if you want to be successful. Just as recipes provide structure in the kitchen, regulatory compliance documentation specifies process requirements that provide structure for your quality system, design requirements, test requirements, or any combination of the three.
There is a differentiation between how each type of documentation may be applied to a specific product or system.
REGULATORY COMPLIANCE DOCUMENTATION
Regulatory compliance documentation that specify development process, such as the FDA 21 CFR 820, European Union (EU) Medical Device Regulation (MDR) 2017/745, ISO 14971:2019, or IEC 62366-1:2015, are examples where regulators expect compliance. The aforementioned documents among others represent horizontal standards because they are applicable to multiple product types. Documents that define process, such as the 62366-1:2015 which outlines the process for applying human factors/usability engineering to medical devices, provide requirements without much detail, so the manufacturer can define an implementation that is appropriate to their environment. However, for some of these documents, there are follow up documents that give the manufacturer less leeway to define their own plan: like ISO 62366-2:2016, which provides additional information to as ISO 62366-1:2015.
DESIGN & PRODUCT TESTING REQUIREMENTS DOCUMENTATION
In contrast, other standards such as ISO 11608-1 that define design requirements and product tests, expect a level of manufacturer-determined paths to execution. These documents may provide highly specific information regarding a specific class of device. These types of documents tend to include design-specific information related to testing, class definitions, and terminology. The downside to these documents, also referred to as vertical standards, is that they are applicable to multiple products within the same product family and therefore cannot be universally applicable to all products, including yours. As a result, the challenge that manufacturers face is determining how the regulatory guidance documents apply to their product.
REGULATORY GUIDANCE DOCUMENTATION
The regulatory guidance documentation provides insights into product designs and processes. However, in guidance documentation, just because the process or design has been specified does not eliminate the option for appropriate substitutions. When baking cookies, it is possible to swap out ingredients (chocolate chips for white chocolate chunks) or add in additional ingredients (when your mom adds walnuts) and still come to the same result – a delicious cookie. When it comes to medical devices, manufacturers can substitute design components or add/remove components if a scientific justification can be provided by the manufacturer. In addition to providing enough detail for the justification, it is important for the manufacturers to maintain all of the supporting documentation.
Requirements vs. Recommendations & Meeting the Intent
Sometimes when we were kids and our parents gave us instructions for completing a task we were able to find a new way to accomplish the task with the same result that was asked of us by our parents. It may not be the same way that our parents would have done it, but it still got the job done. If the evidence presented was sufficient enough to generate a compelling argument your parents would probably evaluate the work and see that it still met, or even better, exceeded their original expectations. However, if the evidence is not sufficient to support your decision, your parents may reject your argument and you may have to deal with the consequences.
The same can be said for submitting devices for approval by regulators. For some products, it is possible to provide enough evidence through telling the story of your reasoning for not following regulatory guidance materials. However, for other products, it may not be possible for you to be able to present sufficient evidence for deviating from the regulatory guidance documentation. Similarly, to deviating from your parents’ instructions, if your reasoning is not accepted you may have to deal with the consequences (e.g., project delays, resubmissions, etc.). Therefore, it is important to complete an analysis of the risks compared to the benefits for your argument to be sure you can generate sufficient evidence prior to any deviations.
Knowing how to navigate whether to follow or not follow recommendations is a challenge for many manufacturers, because there are times that the regulatory compliance documentation will make suggestions for the design and testing of certain devices that may not be accurate or appropriate for your device. Just like different parents vary in their strictness for various rules, regulators differ on how strictly they expect manufacturer compliance. While the FDA does not require products already on the market to conform with newly updated standards, the EU expects that manufacturers either comply (i.e., make design updates) with every updated change to the standards or provide justification for why they are not complying with certain (or all) updated standards based on the risk assessment for your product. A regulatory agency will review your submission and determine whether they agree with your conclusion to not follow certain recommendations. These are items that are appropriate for discussion during FDA Type C, Pre-IND, or Q-Submission meetings. This allows you to discuss the topic in more detail and have an extra review of your approach to approval. A way to ask “Mom or Dad” for permission instead of forgiveness.
We can’t stress enough:
If you are going to indicate that you will not follow a particular standard that a regulator has recognized or harmonized, then you must make sure to make a strong argument for why that is the case. Many product launches have been delayed because a strong rationale was not explicitly stated by the manufacturer of record.
Manufacturers must always apply good engineering judgment with strong justifications, including which parts of the standard are applied and which parts are not. It is possible that a specific guidance or standard is generally applicable to your product while it specifies certain details that may not be applicable to you or your device. In addition, there may be circumstances in which it can be argued that a standard is not followed, with good justification!
They may also only provide a base level for compliance. However, meeting the baseline standard compliance is not a replacement for following sound engineering best-practices. Just as when we were kids completing our chores, manufacturers should be wary of the assumption that just because you passed the minimum standard does not mean that the work was done properly. Meeting the bare minimum of compliance does not guarantee that the product will be approved. Autoinjectors or other needle injection systems, when designed appropriately, deliver a range of emergent (e.g., epinephrine) to heath sustaining (e.g., Humira) medication to patients in need. Manufacturers owe it to their consumers to reach for the highest form of excellence in every phase of the device design process to progress towards reducing adverse patient or clinician safety events stemming from flawed devices.
The Detail of Information & Assessing the Purpose in Context
When we are growing up, our parents give us chores that vary in the amount of risk if the task is not completed as required. Some, such as taking out the trash, are not high in risk as compared to completing car maintenance, such as changing the brakes, which are much higher in risk. To take out the trash your parents only need to provide a generic instruction such as “Please take out the trash” and the goal is easily comprehensible. However, if your parents ask you to change the brakes on the family car (highly irregular chore for a child, we know), they will need to provide either more detailed instructions and/or some level of supervision for the task to be completed safely and successfully. A mistake made while changing the brakes has the potential to result in significant consequences or possibly death, but a mistake (e.g., having the trash bag break or dropping the bag) while taking out the trash is recoverable.
Regulatory compliance documentation comes with a different level of detail depending on the topic it addresses. ISO 14971:2019 specifies the process for risk management. Corporations often take the examples in the appendices as the standard for to implement their systems, but there are many methods that meet the requirements for this standard. While the examples provided often follow a Failure Modes and Effects Analysis (FMEA) risk management approach, other risk management tools such as Hazard Analysis or Fault Tree Analysis are equally acceptable methods when applied correctly. The more information that is provided by the standard, typically, is positively correlated to the amount of risk that exists by using the device. Just like more information is needed to correctly change the breaks on the car, more information is required when designing a complicated (i.e., life sustaining) device with many intricate device components (e.g., defibrillator or pacemaker) compared to a device (e.g., syringe) with fewer components. Just as instructions and supervision are provided to a child to facilitate the highest potential for successful task completion, the regulatory bodies provide device manufacturers with the tools necessary to achieve approval for their devices. Ultimately, the device manufacturer must make the most informed decision for the best methods to approach the risk related to the use of their device while striving to maintain the regulatory guidance documentation.
Some products may not have a “perfect match” within the standards but may still use those standards as guidance for defining product test. If a product feature is required to sustain a person’s life, such as a pacemaker or implantable cardiac defibrillator, a test sample of one would not be justified within a risk-based sampling approach. This would be because of the level of risk associated with a pacemaker if the device were to fail. A more strongly powered test, and perhaps even 100%-line test, may be more appropriate. For example, it would not be appropriate to follow the same sample size for a syringe as for a pacemaker. In these cases, a “best match” scenario will need to be uncovered based on analysis of similar product options.
Understanding the intent of the documentation allows for organizations to incorporate the requirements and recommendations most effectively to their designs and processes. The documents need to provide information that allows for key concepts to be generalizable across device types (e.g., Class I to Class III) while providing enough structure when needed to prevent manufacturers from sacrificing safety during their product’s design development process. And, while the purpose of these documents is to provide manufacturers with the information to optimize the safety and effectiveness of medical device designs, the wide range of medical devices presents its own challenge when it comes to disseminating the appropriate information.
Manufacturers should use their best judgment when interpreting the application of these documents to their device. Regardless of the differences between medical devices and regulatory requirements/recommendations, manufacturers should always make every effort possible to optimize the safety and effectiveness of their unique devices. One way to validate the safety and effectiveness of the design is through the inclusion of human factors/usability engineering (HF/UE) throughout the design development process. Human factors activities can begin with the earliest prototypes and continue through the validation of the device during summative usability testing.
Here at Suttons Creek, we use our wealth of knowledge and experience to guide you through the labyrinth of global regulatory processes. With over 550 years of combined device experience, we have worked on 50+ drug and biologic delivery devices. Regardless of the product you are working on, odds are we have seen it before with another client and we will have the best practices knowledge to lead you to the quickest regulatory approval success possible. If, after reading this article, you feel that you may need support confirming that your company, and your product system, including packaging and labeling, meets all the regulatory body requirements, our team of specialists is just a phone call away.
Steve Badelt, PhD – Steve is a seasoned expert with over 20 years of experience in combination products, engineering management, systems engineering, and business development. He founded consulting firm Suttons Creek, Inc. in 2012, which has served as the device team for pharma on over 50 combination product programs. Steve values helping others learn and grow, and when he is not consulting on behalf of Suttons Creek, he is advising startups, sitting on industry boards, speaking nationally on combination product and connectivity issues and serving as a Graduate Professor at Loyola Marymount University. LinkedIn: Steve Badelt
Matthew Nare, Consultant – Matthew Nare is a junior consultant on the human factors team for Suttons Creek, Inc. His previous work as a physical therapy aide provided an opportunity to gain clinical experience in inpatient and outpatient rehabilitative care settings. He came to Suttons Creek, Inc. following an internship completing clinical observational research with MedStar Health’s National Center for Human Factors in Healthcare. Additionally, he spent over a year completing accessibility evaluations at Cal State Long Beach’s Center for Usability in Design and Accessibility. This combination of work experience and his educational background provides him with a unique perspective on how the medical devices and their users function. LinkedIn: Matthew Nare