Author name: Robert Packard

Selecting and Changing the European Authorized Representative

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This article explains the roles and responsibilities of a European Authorized Representative for CE Marking of medical devices. The article also provides advice on selecting and changing the European Authorized Representative.

How to Select or Change Your European Authorized Representative Selecting and Changing the European Authorized Representative

European Authorized Representatives are the legal representative of non-European manufacturers for medical devices sold in Europe. If a company already has offices located in Europe, an Authorized Representative is not needed. However, if you don’t have offices in Europe, you must have a legal agreement with an Authorized Representative that is physically located in Europe to be your primary contact for receipt of customer complaints. The Authorized Representative can also act as your liaison between the Competent Authority in Europe and your company.

Why your distributor is not the right choice

Many manufacturers located outside of Europe choose their distributor as an Authorized Representative. Distributors often want to do this, because then their name is required to appear by law on the labeling and the IFU. Unfortunately, your distributor has a conflict of interest. The distributor does not want adverse event reporting, recalls, or even complaints. Therefore, can you be sure that the distributor will notify you immediately of all potential complaints?

In January 2012, the European Commission released a guidance document explaining the roles and responsibilities of European Authorized Representatives: MEDDEV 2.5/10. Distributors rarely have the regulatory expertise to act as an Authorized Representative.

Competent Authorities occasionally audit Authorized Representatives to ensure that the legal requirements are being met. When this happens, clients often ask me to recommend a European Authorized Representative to switch to.

Primary Responsibilities

The EU Authorized Representative has two primary responsibilities:

  1. Complaint handling
  2. Registration of CE Marked devices

The complaint handling function is the reason why the name and address of the European Authorized Representative must appear on the product labeling and IFU. Your distributor may still become aware of potential complaints, and therefore, distributors should still be trained on the importance of forwarding any potential complaints to your company immediately. The registration function is critical for Class I devices that are non-sterile and do not have a measuring function, because those devices do not have a Notified Body involved. It is often valuable to have an Authorized Representative located in one of the Member States where you intend to sell a larger percentage of the product because the labeling will include a physical address in that Member State.

Other ways an Authorized Representative Can Help

Some manufacturers complain that they are paying $3,000-$5,000 each year for a competent authority to do very little. However, Authorized Representatives are required to review your procedures before CE Marking, and anytime you notify them of an update. This additional review of procedures is equivalent to hiring a consultant to review your procedures.

European Authorized Representatives can be helpful at other times too. For example, if your company and your Notified Body do not agree on the classification of a device, the Authorized Representative may be able to assist you in the same way that an experienced regulatory consultant can. If you receive communication from a Competent Authority, the Authorized Representative can act as your liaison. Most important of all, the Authorized Representative can help you determine when complaints require vigilance reporting and provide support if a recall or advisory notice must be initiated.

How to Select an Authorized Representative

I recommend a three-step approach to selecting your Authorized Representative. First, visit the EAARMED website. One of the 15 members of this association should be your starting point because these are the most experienced Authorized Representatives. Next, you should determine which of the 15 members is located in a country that matches the country you intend to sell in. For example, if 100% of your sales are through a distributor located in Italy, Donawa would be a better choice than a German Authorized Representative. Finally, you should obtain quotes and interview more than one Authorized Representative. You want to make sure that the Authorized Representative is responsive and easy to communicate with. It’s surprising how much we learn about responsiveness and communication during the quoting process.

If you need any additional help preparing for the CE Marking product in Europe, please email Rob Packard.

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5 Alternatives When You Can’t Find a Predicate Device

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This article summarizes five alternatives that medical device manufacturers have for regulatory approval in the US when a 510k submission predicate device cannot be identified.

success and failure choices 5 Alternatives When You Can’t Find a Predicate Device
Choosing the best 510k submission predicate device is critical to success or failure.

The premise behind the FDA 510k regulation is that your new device is substantially equivalent to another device (i.e., predicate device) that is already on the market. Therefore, you only need to submit a premarket notification to the FDA instead of a premarket approval (PMA) submission. Most 510k submissions reference a similar device manufactured by a competitor, but what do you do when you can’t find a predicate device?

Your 5 Options if you cannot identify a 510(k) predicate device

  1. Conduct a Clinical Study and Prepare a PMA Submission = $$$ + 2 years min.
  2. Prepare a De Novo Submission = avg. review time was 307 days in 2019
  3. Submit a 510k with Your Best, Poor Choice & Expect One of Two Responses: Refusal to Accept (RTA) or Not Substantially Equivalent (NSE)
  4. Request a Pre-Sub Meeting with the FDA = 60-day Delay at the front of Project
  5. Submit a 513(g) Request to the FDA = $ + 60-day Delay at Front of Project

Option 1 – Clinical Study & PMA preparation

If you cannot identify a predicate device, you may need to conduct a clinical study to demonstrate that your new device is safe and efficient. Some devices even require an investigational device exemption (IDE) approval from the FDA if the risks of the device are significant. If your device presents significant risks, likely, the De Novo process (Option #2 below) will not be an option, and the device will be considered a Class III device by the FDA. In this case, the fastest pathway to regulatory approval is a modular PMA submission. The minimum timeline for this type of submission is typically two years, and the FDA user fee for a PMA submission is very high–unless you are a start-up company and this is your first product. The following FDA webpage summarizes the process for a modular PMA.

Option 2 – De Novo Classification Request if there is no predicate device

Originally the De Novo process was created with IVD products in mind where the technological characteristics are nearly identical between the two devices. Still, the intended use is different (i.e., the device is used to diagnose a different disease). The problem with the original process is that you had to submit a 510k and have it rejected before you were allowed to submit a De Novo application. Now the De Novo process allows two pathways. A company can submit a 510k, have it rejected with a “not substantially equivalent” (NSE) letter, and then submit a De Novo application. The new option allows a company to skip the initial 510k submission and submit a De Novo application first. This extends the decision time from 90 days to 120 days, but the previous option took even longer. We recorded a webinar on the De Novo Classification Request Process in 2019. The FDA also recently updated the De Novo webpage to summarize the regulations related to the De Novo new final rule. The following FDA webpage summarizes all the De Novo Classification Requests recently granted.

Option 3 – Submit a 510k with whatever device you found

This is probably not your best approach, but sometimes it’s worth a shot to see what the FDA will say instead of waiting to schedule a pre-submission meeting, and this approach doesn’t eliminate option #2. There are two likely outcomes from this approach. First, the reviewer screening your 510k submission during the 15-day, refusal to accept (RTA) process will determine that you have not selected a suitable predicate device, and you will receive an RTA letter. In this case, you have an answer in just 15 days. You should never accept your first RTA letter. You should make the requested changes the reviewer indicates and re-submit. The FDA’s goal is to have all submissions make it through the RTA process on the second try. Therefore, you might have more success on the second try with another predicate or just by fixing other problems the reviewer identified.

The other possible outcome of this approach is that you will make it through the RTA process, but your submission will be determined to be NSE. In this case, you will receive an NSE letter from the FDA, and it will suggest options–typically a PMA or a De Novo submission. If a De Novo submission is a good option, it will be stated in the letter.

Option 4 – Request a pre-sub meeting to discuss a potential predicate device

If you are not able to identify a suitable predicate, you might consider preparing a classification rationale and selecting a potential predicate. Then this information can be summarized in a pre-submission meeting request to the FDA. The FDA will respond within 75-90 days from your submission. If you are still developing your device and you have not started any performance testing, then this option may be your best approach. I recently recorded a webinar on pre-submission meeting requests.

The webinar includes specific dos and don’ts for pre-submission meetings. There is also final guidance for the pre-submission program that was released last year on February 18, 2014. The FDA pre-submission guidance document was updated again on January 6, 2021, and we recorded a webinar on pre-submission meeting requests.

Option 5 – Submit a 513(g) application to identify the regulatory pathway

When a company has difficulty identifying a 510k submission predicate device, the FDA recommendation is to submit a 513(g) application. As I indicated in a past blog, the 513(g) process may not be your best choice for two reasons. First, the 513(g) process takes 60 days before the FDA responds. Second, the 513(g) process has a user fee that is higher than hiring a consultant to do the same research. Since the FDA 513(g) response is “non-binding,” the FDA’s opinion doesn’t necessarily hold any more weight than an experienced consultant. Therefore, paying a consultant to do the research and then requesting a pre-sub meeting is probably a better approach, but the timeline for a 513(g) submission is slightly shorter.

Do you still have questions about 510(k) predicates?

Rob Packard recorded an updated webinar on the topic of predicate selection. If you are interested in this topic, please register for the webinar. The updated webinar was recorded on March 28, 2022.

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Combining a 510k Submission with CE Marking: 9 Sections that are Duplicated

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This article explains how to reduce your workload by at least 35% if you integrate your two project plans for a 510k submission and CE Marking into one comprehensive regulatory plan.

510k submission and CE Marking Combining a 510k Submission with CE Marking: 9 Sections that are Duplicated

My first medical device regulatory submission was for CE Marking, while my second regulatory submission was for a 510k submission of the same product. This is a very common path for medical device regulatory submissions, but it is also an inefficient path. If you know that you will be submitting both types of documents, then you should plan for this from the start and reduce your workload by at least 35%.

The reason why you can quickly reduce your workload is that there are nine key sections in both submissions that are very similar. Therefore, you can write the content for those nine sections in such a way that the material can be used for your 510k submission and CE Marking.

9 Sections are Duplicates

Here are the nine key sections that the two types of regulatory submissions have in common:

  1. Device Description
  2. Labeling
  3. Sterilization & Shelf-Life
  4. Biocompatibility
  5. Software
  6. EMC/Electrical Safety
  7. Bench Testing
  8. Animal Testing
  9. Clinical Testing

There are 20 sections required by the FDA for a Traditional 510k submission, but often some of the sections are boiler plating, and other sections do not apply to the device being submitted. A few sections are unique to a 510k submission, such as:

  • Substantial Equivalence
  • 510(k) Summary
  • User Fee Cover Sheet Form 3601 & Submission Cover Sheet Form 3514
  • Declarations of Conformity on Form 3654
  • Table of Contents

Technical Files for CE Marking also have a few unique sections, such as:

  • Essential Requirements Checklist
  • Classification Rationale
  • CE Marking Application to Notified Body
  • Declaration of Conformity
  • Table of Contents

How to Construct Your Plan

In one of my previous blogs, I explained how I use the 510k Table of Contents as a project management tool for a 510k submission. You can do the same when you are constructing a combined plan for a 510k submission and CE Marking. The first step is to create the same kind of project management tool I use for a 510k submission (i.e., a Table of Contents) to manage your CE Marking Technical File. I recommend preparing your Technical File in accordance with the GHTF guidance document released by study group 1: N011:2008. This guidance mirrors the format that will be required in Annex III of the new European Medical Device Regulations that should be released next spring. I do not recommend using the NB-MED 2.5.1/rec 5 guidance document. Even though the content is similar to the GHTF guidance, the format is quite different. After I have two separate project plans organized in accordance with the Table of Contents, then I merge the two plans on a spreadsheet and consolidate the duplicate sections.

Scheduling Tasks & Project Management

If you are going to outsource sections of either submission, these nine sections should be written and reviewed by someone familiar with both types of submissions. The headers and footers will be unique to the type of submission, but I write the text in Google Docs without formating for ease of sharing and so I can use my Chromebook.

If you have an in-house team that prepares your 510k submissions and Technical Files, you might consider training the people responsible for each section on the requirements for each type of submission. This eliminates rewriting and reformatting later. I like to assign who is writing each section in a separate column of my Table of Contents planning tool. Then I will sort the sections by the expected date of completion. All the safety and performance testing, and any sections requiring validation, will typically be finished at the end of the project. Therefore, it is important to dedicate unique resources to those sections rather than asking one person to write several of those sections. You also will want to make sure any supporting documentation they need is completed early so that the project’s critical path doesn’t change. I typically use a Chromebook spreadsheet for all of this, because 20+ sections are just too few tasks to warrant the use of Microsoft Project or some other Gantt Chart planning tool. If you keep it simple, more of your team will read it and update it frequently.

RA Consulting Tip

I have several PCs (laptops and desktops of various vintages), but nothing is faster for writing plain text than a Chromebook. Then I export documents to Word format and work on tables and formatting of the information as needed. I can also jump on any computer with an internet connection and work on my documents. This enables me to travel very light when I need to. If you are a tablet user, there are some other solutions I prefer–such as Evernote.

Additional 510k Training

The new 510k book, “How to Prepare Your 510k in 100 Days,” ships on Monday, February 6th, 2017. There is also an on-line 510k course series consisting of 24 webinars. Please visit my webinar page to purchase individual webinars. We also have live 510k workshops.

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Status of the European Medical Device Regulations?

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This article describes the status of the new European Medical Device Regulations, and it provides some advice for what you should be doing to prepare for the changes.

MudI 600x334 Status of the European Medical Device Regulations?

The picture above is not a picture of people on their way to the local maple sugar shack, trying to get a car unstuck during mud season in Vermont. It’s actually a photo of paid actors reenacting the European negotiations for new medical device regulation. The European Parliament is in the overcoat on the left. The four men on the right represent the various presidents–Greek, Italian, Latvian, and Luxembourg. The Dutch President is driving the horse team in the front in the hopes of getting unstuck in time for next Spring.

Yes, in a word, the negotiations are “stuck”!

My friend Erik Vollebregt did a wonderful job of summarizing the status of negotiations on April 30, in his blog posting. The best guess anyone has is that we might have a final version released next year in Spring 2016. It’s only two years later than I was expecting. I guess they encountered more mud than expected.

There are a number of issues that the member states appear to be stuck on:

  • Ingested products
  • Non-medical devices
  • Companion diagnostics
  • Non-viable human tissues and cells
  • Viable biologic substances
  • Reprocessing single-use devices
  • Genetic testing
  • Implant cards
  • Eudamed & UDI
  • Summary of safety & performance
  • Notified Bodies
  • Pre-market approval
  • Clinical investigations
  • Post-market surveillance
  • Market surveillance & vigilance
  • Reference laboratories
  • Hazardous chemicals
  • Classification rules
  • Governance & oversight

I’m not quite sure whether the remaining list of issues the member states agree upon is shorter than this or longer. Still, this list includes a number of fundamental principles that could dramatically change the nature of medical device regulation in Europe. We expect that many of these issues will be resolved with a compromise of some sort. Still, I suspect every medical device manufacturer with a CE Mark will be extremely busy from 2016-2019 revising their procedures, technical documentation, and training personnel on the new European Medical Device Regulations.

 What Should You Be Doing to Prepare?

  1. Update Your Quality System to ISO 13485:2015 Early – The second Draft International Standard (DIS2) for ISO 13485 was released in February, and the final version is expected to be published this Fall. The changes to ISO 13485 are minor, but audits by your Notified Body will be far less complicated if you upgrade your quality system to the new revision before you attempt to address the new European Medical Device Regulations.
  2. Strengthen Your Internal Auditing & CAPA Processes – Companies with strong internal audit programs and CAPA processes have fewer findings resulting from Notified Bodies. When you have multiple outcomes from a previous audit to close, your annual surveillance audits and recertification audits become longer and more complex. These findings must also be closed before a manufacturer may transfer a quality system or CE Certificate from one Notified Body to another. Therefore, strengthening your internal audit and CAPA processes will result in a shorter Notified Body audit, and you will find it much easier to transfer from one Notified Body to another–if your current Notified Body is no longer able to issue a CE Certificate for one or more of your products.
  3. Update Your Technical Files – Companies that have a Design Dossier are required to submit all changes to their Design Dossier for approval before implementation. Still, companies with a Technical File for a lower risk device have their technical documentation sampled periodically. A sampling of technical documentation allows companies to fall behind in their documentation of changes. Re-issue of new CE Certificates will require a more thorough review of these Technical Files that may not have been sampled in several years. Therefore, I recommend that companies allocate resources to updating technical documentation now so that there is less work to update the technical documentation for the new European Medical Device Regulations.
  4. Review Your Product Portfolio and Prune It – The more mature product lines become, the more likely it is that you have products you are maintaining that just aren’t selling. The cost of maintaining your technical documentation and updating everything for compliance with the new European Medical Device Regulations will be expensive. Therefore, you can save some money now and a larger amount of money later by eliminating any products from your CE Certificate that is not selling well. If you have customers that are still buying an older version of the product, now is the time to persuade them to transition to the current version of your product. You don’t want to maintain your Technical File for two versions of the same product.

Regardless of what compromises are made, the new European Medical Device Regulations are guaranteed to be the most substantial change in regulatory requirements that the medical device industry has endured since 2003–much more dramatic than the 2007/47/EC amendment to the Medical Device Directive (MDD).  

Will someone please buy the negotiators a pair of Bogs and a Subaru Crosstrek?

Subaru XTrek 300x199 Status of the European Medical Device Regulations?

Bogs Status of the European Medical Device Regulations?

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HDE Application and 510k Submissions

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This explains the differences between the regulatory pathways for a Humanitarian Use Device (HUD) or HDE and 510k submissions.

HUD Designation 300x229 HDE Application and 510k Submissions

HDE Application

In September 2019, the FDA released a final guidance document explaining the regulatory process for a Humanitarian Device Exemption (HDE) Application. HUD designation is for a product that affects less than 8,000 patients per year in the United States. The limitation of 8,000 There are three steps required before a HUD may be used at a user facility:

  1. HUD Designation Request to Office of Orphan Products Development (OOPD)
  2. HDE Application to Center for Devices and Radiological Health (CDRH)
  3. Investigational Review Board (IRB) approval of using the HUD

Note: The above regulatory pathway may not apply to combination products. In the case of combination products, you should contact the Office of Combination Products (OCP).

Major Differences between the HDE Application and a 510k submission

  • Unlike the 510k process, HDE approval is device approval rather than “clearance” for marketing and distribution.
  • If another equivalent (an actual term used is “comparable”) device is already being legally marketed, then the FDA may not approve an HDE application. In contrast, the first requirement for the determination of substantial equivalence of a subject device for a 510k submission is that the predicate device must be a legally marketed device that is equivalent.
  • There are no user fees, while 510k submissions generally are subject to FDA user fees; pediatric-only products are an exception to the requirement for 510k user fees.
  • There is no requirement to demonstrate the effectiveness of devices in an HDE application. Instead, devices approved for HDE must provide an acceptable benefit/risk analysis.
  • HDE-approved devices are not generally eligible to make a profit. Any device that a manufacturer intends to sell for more than $250 requires a report issued by an independent public accountant.
  • IRB approval for the use of HUD-approved marketing is required, but IRB approval is not for a clinical study, and IRB approval is not required in the case of an emergency.

The FDA guidance document also explains how HDE approval is different from pre-market approval (PMA).

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CE Marking Approval of a Medical Device (Case Study)

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This article explains the process for CE Marking approval of a medical device. For this case study, I selected the same hypothetical client that I chose for my case study on Canadian Medical Device Licensing and a 510k submission to the US FDA. The product is a cyanoacrylate adhesive sold by the makers of Krazy Glue®. This hypothetical client wants to expand its target market to include the healthcare industry by repackaging and marketing the product as a topical adhesive in Europe.

CE marking case study CE Marking Approval of a Medical Device (Case Study)

My client called to ask if I could help obtain CE Marking approval. In Europe, cyanoacrylate is a medical device when it is used as a topical adhesive. My first step is to determine the device classification as per Annex IX in the Medical Device Directive (93/42/EEC as modified by 2007/47/EC). Instead of relying solely upon the Directive, I use guidance documents published on the Europa website–specifically MEDDEV 2.4/1 rev 9 (the following link explains the European MEDDEV guidance documents – http://bit.ly/Whats-a-MEDDEV).

I identified three potential device classifications: 1) Class 1 as per Rule 4 (a non-invasive device which comes into contact with injured skin, if the device is intended to be used as a mechanical barrier, for compression or absorption of exudates); 2) Class 2a as per Rule 7 (a surgically invasive device intended for short-term use [i.e., < 30 days] are in Class 2a; and 3) Class 2b as per Rule 8 (an implantable device). These three applications match the three possible indications that I identified when I was reviewing classifications for Canadian Medical Device Licensing for this product.

If this device were not required to be “sterile,” then a Class 1 device could use the Annex VII route of conformity (i.e., self-declaration). However, even generic bandages are sold as sterile devices. Therefore, whether the device is a sterile Class 1 device or a Class 2a device, obtaining CE Marking approval will still require a Notified Body’s review and approval. The most common route would be the Annex V route of conformity. If my client were to launch their product as a “glue” for internal use, then the device would require an Annex II.3 Full Quality System Certificate or the combination of an Annex V Certificate and a Type Examination Certificate (i.e., Annex III).

STOP!

The previous paragraph was hard to understand, but the source of this jargon is Article 11 of the Medical Device Directive. This one section is the best practices in European legalese. If you want to make something almost unintelligible, copy Article 11. If you’re going to understand this stuff, a flow chart of the various routes to conformity is as good as it gets (still hard to understand, but fewer words). The following simplified table is what I use in my CE Marking webinar:

Classification Routes for CE Marking CE Marking Approval of a Medical Device (Case Study)

What you need to know…

My client only has one product family, and they are currently selling the product in Canada for external use by healthcare professionals—not as an implant. Therefore, the device is a Class 2a device requiring an Annex V certificate. My client will need to do the following:

  1. Select a Notified Body
  2. Submit a Technical File for review and approval
  3. Select a European Authorized Representative, because my client does not have a physical presence in Europe

Fortunately, my client already obtained an ISO 13485:2003 certificate with CMDCAS from their current registrar as part of the Canadian Licensing process. Therefore, the changes required for the Quality System consist of adding a few work instructions to meet European-specific requirements, such as vigilance reporting, creating a technical file, and performing clinical evaluations. My client also needs to add the European Requirements as an applicable regulatory requirement in the Quality Manual.

The more significant challenge is an assembly of a Technical File for submission. Since the product is already on the market in Canada, all of the technical requirements have been met. The documentation of these requirements now needs to be converted into a format acceptable to a Notified Body. There are three recommended strategies:

  1. Whatever the Notified Body prefers. Some of the Notified Bodies have a checklist of requirements for a Technical File. If such a list exists, the client should organize the Technical File in the same order.
  2. The GHTF STED format (GHTF/SG1/N011:2008). The Global Harmonization Task Force (http://bit.ly/GHTFSTEDGuidance) published this guidance document to standardize the format for submission of regulatory submissions. This is the format required for Class III and IV Canadian medical device license applications. This is also the format specified in the proposed EU Medical Device Regulations that is expected to be released in 2015.
  3. The NB-MED recommended format (NB-MED 2.5.1/rec 5). This document was created by the “Big 5” Notified Bodies. It provides a template in a two-part format for submissions. This was the format I used most often for auditing files and for creating new files. However, the proposed EU Regulations that are anticipated for release in 2015 are closer to the format of the GHTF guidance. Therefore, I no longer recommend this format.

My client chose option 3 for organizing their Technical File because they have full reports for each of the verification and validation tests that were performed, but creating summaries for each report would take longer than assembling a Technical File with copies of each of these full reports.

In all, I estimate that the overall timescale for completing this project is about 60 days–not including review by the Notified Body. Therefore, I suggested that the client obtain a quotation from their registrar for an Annex V Certificate. In addition, I suggested hiring a consultant from Medical Device Academy to help them with the preparation of a Clinical Evaluation. Before 2010, Clinical Evaluations were only required for high-risk devices. As part of the new MDD, clinical evaluations are now needed for all devices. Since the use of and risks associated with cyanoacrylates is well characterized in published literature, my client may use a literature search method for preparing a Clinical Evaluation as per MEDDEV 2.7/1 rev 3.

My client hired an Authorized Representative to handle European registration, receive customer complaints, and to act as a liaison with the Competent Authority in the event of an adverse event. An Authorized Representative Agreement was signed, and the Authorized Representative recommended a few corrections to procedures they reviewed as part of entering the contract with a new client.

The company also hired another clinical consultant from our firm to complete a literature search and write a Clinical Evaluation in four weeks. The complete Technical File was assembled and submitted to the Notified Body electronically with seven weeks of starting the project. The Notified Body’s first round of questions was received within six weeks. The client and I prepared responses to the questions in a week and submitted them to the Notified Body. Fortunately, the responses were thorough, and the Technical File was well-organized from the start. The Notified completed their final review and recommended the product for CE Marking within three more weeks. The Notified Body conducted two-panel reviews to verify the technical, regulatory, and risk aspects of the submission. Finally, the Annex V certificate was received 12 weeks after the initial submission of the Technical File.

If you are interested in additional training or assistance with CE Marking of medical devices, please email Rob Packard (mail to: rob@13485cert.com). We have standardized procedures to meet each of the requirements in the European Regulations and a couple of webinar recordings that explain both the Medical Device Directive and how to create a technical file or design dossier.

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Indications for Use Case Study

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This indications for use case study illustrates 510k requirements using the example of a spinal pedicle screw.

PASS LP Spinal System Indications for Use Case Study

Indications for Use Case Study

A hypothetical new client asked me if I could help them with a 510k submission for a new pedicle screw design. The company’s device utilizes a lower-profile version of a traditional pedicle screw that is pre-packaged with rods, hooks, clamps, and nuts. The pre-packaged system is gamma-irradiated, and the product is specially designed for pediatric patients. Unfortunately, the company was only able to find similar designs of pedicle screws that were for adult patients.

Identifying the FDA Regulation – Indications for Use Case Study

The applicable FDA regulation for a pedicle screw product is 21 CFR 888.3070 – pedicle screw spinal system. However, the only indication stated in this regulation is specific to “skeletally mature patients.” Therefore, the indications portion of the regulation does not apply to the subject device for my hypothetical client.

Case Study Product Classification

If you type in “pediatric” as a keyword into the product classification database, 12 different product classification codes result from that search. The applicable product classification code for this product is “OSH”—“Pedicle Screw Spinal System, Adolescent Idiopathic Scoliosis.” The definition for this product classification is: “Intended to stabilize the thoracolumbar spine as an adjunct to fusion using allograft and/or autograft to treat adolescent idiopathic scoliosis.” This is the desired indication because it is specific to pediatric patients. This product classification code also references “pedicle screw spinal system” as the regulation description, and there is a link provided for the 888.3070 regulation number.

Identifying a Predicate Device

97 establishment registration and listing entries are under the “OSH” product classification code. Medicrea Technologies, located in France, submitted one of the most recent 510k submissions (K150049) referencing this product code. Many other possible predicate devices could be used for this 510k submission. However, a recent 510k submission with the same indications for use is usually a good choice. The description of the potential predicate device in the 510k Summary indicates that the predicate is also pre-sterilized. Still, the predicate device description does not specify that it is a low-profile version. Additional research on the company’s website revealed that the PASS LP Spinal System is a low-profile polyaxial spine system. For a 510k submission, it is more important to select a predicate with the same indications rather than a predicate with all the same technological characteristics. However, This particular predicate device appears to have most of the same technological characteristics. The minor differences between the “Pass LP Spinal System” and the subject device are insignificant, and the K150049 was selected as a predicate device submission.

FDA Form 3881

The form has four sections to complete:

  1. The 510k number is assigned by the FDA to each premarket notification submission (usually not assigned yet).
  2. The device name is the subject of your 510k submission.
  3. The indications for use should match the indications for the use of the predicate device, and it should be similar to the indications for use as written in the regulations for the product classification.
  4. The type of device—prescription-only and/or over-the-counter use.

The form is completed using Adobe Acrobat Pro. The Form used to be a stand-alone document that would be included in Section 4 of the FDA eCopy, but now FDA Form 3881 is incorporated into the FDA eSTAR and PreSTAR templates. The FDA includes this page as part of the 510k Summary published on the FDA website for all 510k-cleared devices. For this case study, the 510k number is unknown. The name of the subject device is the “Miniflex Pedicle Screw Spinal System.” The indications for use are: “The Miniflex Pedicle Screw Spinal System is used for posterior non-cervical pedicle screw fixation in pediatric patients. The spinal implants are indicated as an adjunct to fusion to treat adolescent idiopathic scoliosis. The spinal implants are intended to be used with allograft and/or autograft. Pediatric pedicle screw fixation is limited to a posterior approach.” The device type is for “Prescription Use” only.

Writing Your Indications for Use

When writing an Indications for Use statement, the most straightforward approach is substituting your subject device’s name for the predicate device’s name. Ideally, you have chosen a predicate device that matches your subject device for the indications for use and the technical characteristics. However, it is possible to have a subject device with a narrower indication. For example, the predicate device may be indicated for both adult and pediatric patients, while your subject device may be specifically designed to fit pediatric patients better. For our case study, only the last paragraph of the predicate’s IFU applied to the subject device because the device was limited to pediatric use. Therefore, the last paragraph was copied, and the subject device name was substituted for the predicate device name.

Indications for Use Case Study – Broader Indications

The first step of the 510k review process is verification that the subject device has the same indications for use as the primary predicate device. Therefore, if broader indications for use are claimed for the subject device, then the 510k submission will likely be rejected as not substantially equivalent (NSE). In this case, you have a few options. One alternative for submissions that require a broader indication for use is to perform a clinical study to provide safety and efficacy for the broader indication. A second alternative is to submit a De Novo application.

You should request a pre-submission meeting with the FDA before pursuing either option. In the case of a clinical study, you should plan to provide the FDA with a clinical study synopsis that includes a benefit/risk analysis. The clinical study synopsis should also include a rationale for why the broader indication for use presents a non-significant risk if you plan to conduct the clinical study under good clinical practices (GCPs) instead of applying for an investigational device exemption (IDE). Suppose you plan to submit a De Novo application. In that case, it is recommended that you prepare a special controls guidance document before the pre-submission meeting to obtain feedback from the FDA. For novel devices of medium risk, your company may need to conduct a clinical study and submit a De Novo application.

Your Next 510k Submission

Most companies have plans for subsequent submissions to expand the functionality of the subject device. In this case, often, the subject device is the best choice of a predicate device for subsequent 510k submissions. In this case, you should attempt to make the initial application as broad as possible concerning indications for use. This will enable you to narrow the indications for use in future submissions without the device being NSE to your predicate device.

If you are interested in watching a webinar on the topic of indications for use, please visit the webinar page.

Additional 510k Training

The 510k book, “How to Prepare Your 510k in 100 Days,” is available as an eBook only with the purchase of our on-line 510k course series. Please visit the webinar page to purchase individual webinars.

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Re-validation of EO Sterilization – When is re-validation required?

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This article reviews some of the factors to consider when you are evaluating the need for EO sterilization re-validation.

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EO Sterilization Cycle Re validation of EO Sterilization When is re validation required?

ISO 11135-1:2014 is the international standard for sterilization validation for Ethylene Oxide (EO or EtO) sterilizers. The standard describes multiple methods of sterilization validation: 1) overkill approach, 2) single lot release, and 3) parametric release. The overkill approach is the most common method for validation of your EO sterilization process. If you are using a contract sterilizer, the sterilizer will already have completed an Installation Qualification (IQ) and an Operational Qualification (OQ). You will need to complete a Performance Qualification (PQ) for your product. A typical PQ for initial process validation consists of the following:

  1. Process Challenge Device (PCD) validation
  2. Bioburden measurement
  3. EO residual measurement (as per ISO 10993-7:2008/R2012)
  4. Fractional Cycle (at least one)
  5. 3 Half Cycles
  6. 3 Full Cycles (or 1 Full Cycle, if performed in parallel with the three half-cycles)

Most contract sterilizers already have one or more Process Challenge Devices (PCDs) that they have developed, and they may evaluate multiple PCDs in your fractional cycle to determine which PCDs are more challenging to kill than an internal biological indicator (BI). In addition to the above “typical” PQ, you might also choose to validate partial loads and/or re-sterilization of product in the case of rework.

In the ISO 11135 standard, #4 and #5 are referred to as the microbial performance qualification (MPQ), while #6 is referred to as the physical performance qualification (PPQ). For a successful MPQ, at least some of the PCDs must be non-sterile after a fractional cycle to demonstrate the ability to recover the BI challenge organism. After a half-cycle, however, all biological indicators should be sterile.

Ethylene oxide sterilization is typically outsourced to a contract sterilizer due to the environmental and safety requirements of working with EO. Usually, the contract sterilizer will provide a standard validation protocol for full validation that is compliant with ISO 11135-1. However, the ISO 11135-1 standard requires that manufacturers perform annual process reviews to evaluate the need for re-validation of the sterilization process. Assuming there have been no problems, and no changes to the product or process, then re-validation is not required at the end of the first year. However, companies are expected to re-validate the process after two years–even if there have been no changes. So why do some companies perform re-validation after three years or more?

Longer Re-Validation Cycles

If there have been no changes to the sterilization process, the product, or the biological indicators, then the manufacturer can use this as a justification for waiting until two years have elapsed before re-validating the ethylene oxide sterilization process. Also, there should be no evidence of sterilization failures or other problems with the validated process. However, that alone is not necessarily enough to justify extending the duration between validations beyond two years. Companies that can justify intervals of three or more years have multiple products that are using the same sterilization process.

In this case, the manufacturer may alternate annually between three, four, or even five different product families that are using the same sterilization process. In this case, one of the product families is being re-validated each year or every two years, but the interval between validations for any one product family is longer. If the products are made of similar materials and using the same sterilization process, then this approach is valid. If you only have one product, then you need to re-validate the sterilization process once every two years to verify the process remains active.

Minimum Re-Validation Requirements

When you determine that it is time to re-validate your ethylene oxide sterilization process, you need to perform the following tests to meet the minimum requirements of ISO 11135-1:

  1. Re-validation of PCD
  2. Bioburden measurement
  3. EO residual measurement
  4. 1 Half Cycle
  5. 1 Full cycle (to verify the EO residuals are acceptable)

The purpose of #1 is to verify that the resistance of internal BIs used in the half-cycle is more resistant than the product bioburden. The purpose of #2 is to verify that bioburden levels have not changed, and the type of organisms has not changed. In practice, most companies monitor bioburden quarterly, and therefore this step should be routine. Step 3, EO residual measurement, should be performed to verify that there have not been minor changes to the product or process that would increase the concentration of EO, Ethylene Chlorohydrin (ECH), or Ethylene Glycol (EG) beyond the Tolerable Contact Limit (TCL). The purpose of this third test is to prevent localized irritation caused by residual chemicals from the ethylene oxide sterilization process.

Step 4 of the re-validation is intended to verify that a full injection of EO is more than required to kill the bioburden present for the number of injections required for a half-cycle.

The final step is to perform a full cycle. The product from the full cycle is typically used for EO residual testing. Any product from the full cycle that is not used for testing can be sold after sterility testing is complete.

Partial Loads & Rework

If you occasionally sterilize loads that are less than “full loads,” then you need to ensure that you have validated a minimum load or a specific partial load (e.g., half-pallet, instead of a full pallet). In the case of a partial or minimum load, you may identify different locations in your load that is considered “worst-case.” These are the locations that had PCDs that were not sterile in a fractional cycle.

Most companies do not have concerns about the cost of the actual sterilization runs during re-validation, and biological indicators are typically less expensive than boxes of product. The primary cost concern for re-validation is any product that must be scrapped. Therefore, many companies will accumulate dunnage (i.e., empty packaging or scrap product) over time to fill a sterilizer. This dunnage may be used to ensure that every load is a full load, or it may only be used for re-validation.

Another alternative to using dunnage for re-validation is to validate a rework process. Any product that is exposed to a fractional cycle or half-cycle can be resterilized in a full cycle. To justify the commercial use of that product, a company needs to validate that the product will not be damaged by exposure to two full cycles. One of the key acceptance criteria for rework is the EO residual levels in the product. However, the manufacturer also needs to determine if there has been any deterioration of the product by a second exposure to EO that would affect performance.

Other Considerations

Many companies do a poor job of reviewing the potential impact of changes to a product, packaging, and biological indicators. Ideally, initial validation involves different lots of product, packaging, and biological indicators to assess lot-to-lot variability. However, many times, the packaging and biological indicators consist of only one lot during validation. Minor changes to the tolerances may reduce the amount of ethylene oxide that is absorbed by the product or change the resistance o the biological indicator to the sterilization process. Therefore, these minor changes should trigger a re-validation.

Changes in suppliers with the same specification can also be difficult to evaluate. If a component is made of a material that absorbs EO, then it may be recommended to re-validate sterilization for any changes to suppliers of those components. Re-validation in these cases may consist of only a fractional cycle, half cycle, or a full-cycle to evaluate risks associated with the change.

Who Should Be Making Evaluations

The evaluation of the need for re-validation should include the input of three types: 1) microbiological, 2) materials, and 3) performance. To make these assessments, typically, a cross-functional team is needed. Someone with responsibility for design and development can assess the performance impact of changes. A materials engineer is generally needed for assessment of the interaction between components and EO. Finally, a microbiologist is needed to confirm that there is no impact related to biological indicators or bioburden.

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EO Sterilization Cycle 1 150x150 Re validation of EO Sterilization When is re validation required?
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Bioburden Failure Analysis Webinar Re validation of EO Sterilization When is re validation required?Medical Device Academy also released a new webinar recording on the topic of Bioburden Failure Analysis last week – Read More…

If you need assistance with sterilization validation or bioburden failure analysis, please contact me by email at rob@13485cert.com or call me at +1.802.281.4381.

 

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510k Submission, Section 14-Sterilization Validation and Shelf-life

Leave a Comment / 510(k) / By / , , , ,

This article explains the process for preparing the sterilization validation and shelf-life section of a 510k submission.

sterilization validation 510k Submission, Section 14 Sterilization Validation and Shelf lifeSterilization validation and shelf-life, Section 14, is typically one of the last sections of a 510k submission to be completed. However, most of the work in preparing this section of your 510k submission should be completed more than a month before actually completing the associated testing. The reason why you can write this section, before receiving the results, is that your results are 99% predictable. If you are unlucky enough to be part of the 1% that have surprising results during sterilization validation, then you will need to make changes and repeat your testing.

Design Planning Aspects Related to Sterilization Validation

During your design and development process, sterilization validation testing is part of design verification testing—not design validation. This testing is verification, rather than validation because you are testing in accordance with recognized standards (i.e., design inputs) to ensure that the sterilization process parameters are adequate to consistently meet the sterility specification (i.e., design output). In your design plan, it is critical to understand which of the following three categories your sterilization process falls under:

  1. Traditional Sterilization (e.g., ethylene oxide)
  2. Non-traditional Sterilization (e.g., Hydrogen Peroxide)
  3. Novel, Non-traditional Sterilization (e.g., Chlorine Dioxide)

You must identify which category your sterilization process falls into because the review process used by the FDA for each category of the sterilization process is different. Traditional sterilization processes have recognized standards that a reviewer can easily compare your validation methods with.

Non-traditional sterilization methods are becoming more popular for products that are sensitive to degradation caused by high temperature, or exposure to radiation or ethylene oxide. However, the FDA has identified non-traditional sterilization processes as being a priority for inspection. Therefore, after your product receives 510k clearance, you can expect an FDA inspection sooner than products that use traditional sterilization methods (i.e., 6-12 months instead of 12-24 months). 

The novel, Non-Traditional Sterilization

The novel, non-traditional sterilization methods require a different 510k clearance process, because the FDA requires an internal consultation from the Infection Control Devices Branch (INCB) before issuing 510k clearance. A consultation is needed for evaluation of the sterilization process because reviewers lack sufficient expertise in the field of microbiology and Sterilization to evaluate novel sterilization processes. The INCB can also provide a consult for non-traditional sterilization processes, but this is not typically needed if the process is following established ISO Standards for sterilization validation. 

For the novel, non-traditional sterilization processes, and INCB consult is required, and it is recommended to consult with the FDA early regarding the use of this type of sterilization process. Part of the reason for this early consultation is that a pre-clearance priority inspection is required before issuing the 510k. The FDA published draft guidance on this topic in 2008 that can be found on the following webpage – Click Here.

The image below shows where the INCB is located within the hierarchy of the FDA’s organization.

incb 510k Submission, Section 14 Sterilization Validation and Shelf life

Creating Summary Technical Documentation (STED)

The sterilization validation and shelf-life section of a 510k submission may be copied from the summary technical documentation (STED) that you prepare for CE Marking applications or a Canadian Medical Device License Application. Instead of including all of the protocols and testing reports from your validations, the regulators only require a summary of the validation activities and results. If the STED is thorough and well-organized, the reviewer should not request validation reports. However, if the STED is incomplete, then the reviewer is likely to request a copy of the validation reports.

Any STED should include the following elements:

  1. Identification of the validation dates
  2. Identification of the organization(s) that performed the validation
  3. Reference to the ISO standard or other recognized standard that was used
  4. Identification of any deviations from the referenced standard
  5. Number of lots and samples per lot tested
  6. Description of the testing performed—including testing parameters
  7. Identification of the document control numbers and revisions for protocols and reports
  8. Acceptance criteria for the validation
  9. Summary of the results

For your STED specific to sterilization validation and shelf-life, you will also need to ensure you include a description of the packaging used to maintain the device’s sterility (primary packaging) and a description of the packaging used to protect the primary packaging (i.e., secondary packaging).

For a 510k submission, you will only need to make a few modifications to the STED that you use for European CE Marking and Canadian licensing. First, you need to ensure you are referencing standards recognized by the FDA. If you followed a different method, the differences need to be documented in Section 9 of your submission on FDA Form 3654 for each Standard.

Second, you will need to include a reference to Ethylene Oxide (EO) residual testing summarized in Section 15 for biocompatibility (not applicable to non-EO methods of Sterilization). EO residual testing must be performed in accordance with ISO 10993-7. You should also include an outline of the validation methods that were used in your comparison of substantial equivalence in Section 12 of your submission. Finally, you should reference the methods used briefly in your executive summary (i.e., Section 10) and the 510k summary (i.e., Section 5)—assuming that you did not use a 510k statement.

If you are writing your first STED for sterilization validation and shelf-life, I recommend reviewing the RTA checklist in advance.

You may want to organize your STED with headlines that address each of the questions outlined in the RTA checklist.

You should also be aware that although the FDA references the 2002 guidance document K90-1 for the format and content of the sterilization validation section, there is a 2008 draft guidance the represents the FDA’s current thinking on the topic of sterilization validation. That draft guidance document is also identified as a priority for the FDA to release as a final guidance in FY 2015 (i.e., before October 1, 2015).

Additional 510k Training

The new 510k book, “How to Prepare Your 510k in 100 Days,” ships on Monday, February 6th, 2017. There is also an on-line 510k course series consisting of 24 webinars. Please visit my webinar page to purchase individual webinars. We also have live 510k workshops

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Validating Bioburden Limits

18 Comments / Validation / By / , ,

This article explains the process for setting and validating bioburden limits, and you will learn when investigations are needed. 

Last week, I was in Europe reviewing product specifications with a potential contract manufacturer for a medical device implant. Due to the raw materials that the contract manufacturer currently is using for a similar product, bioburden levels are higher than we can accept. The company uses an ISO Class 7 cleanroom for assembly and packaging, which is clean enough for these implants, but the molded components used for the assembly are not clean enough.

Validating Bioburden Limits Validating Bioburden Limits

The average bioburden is 220 CFU/device (i.e., colony-forming units/device), and the maximum observed bioburden exceeded 500 CFU/device. We want to use a lower dose range of gamma radiation to prevent the deterioration of bioabsorbable plastics, but a lower dose range requires that the average bioburden never exceed 100 CFU/device.

There are quite a few Clauses in ISO 13485 that differ from ISO 9001. One example is Clause 6.4–Work Environment. Subsection 6.4(b) states, “If work environment conditions can have an adverse effect on product quality, the organization shall establish documented requirements for the work environment conditions and documented procedures or work instructions to monitor and control these work environment conditions.” This is the applicable clause of ISO 13485 related to setting bioburden limits. Unfortunately, this vague requirement does not explain how to establish or validate bioburden limits.

Rule of Thumb for Setting Limits

One of my microbiologist friends recommends using the following “rule of thumb”: +2 sigma for alert limits and +3 sigma for action limits. This rule of thumb assumes that you are performing data analysis of bioburden and that you have calculated a “sigma” value for the standard deviation. There are a few problems with the “rule of thumb” approach.

First, this method assumes a normal distribution and a controlled process–which bioburden seldom is. Second, the cleanliness you need for your product and the cleanliness your controlled environment is capable of are not always appropriately matched. In my example, we need the finished device to have a bioburden of <100 CFU/device before gamma sterilization. Molded parts are essentially bioburden free due to the hot temperatures of the parts ejected from the mold. Unfortunately, molded components attract dust like a magnet. Therefore, how you handle and store molded parts is important to the bioburden of the molded parts.

Which factors affect bioburden?

For this example, we have three aspects critical to the final bioburden limit of the finished medical devices.

  1. How are the molded parts handled and stored?
  2. Are molded parts cleaned before assembly?
  3. What is the cleanliness of the work environment where the device is assembled?

The cleanliness of the molding environment matters, but parts can fall into a container that keeps the parts clean. It also matters how molding machine operators handle the parts. Gloves should be used, and typically the container the parts are in will be placed in an outer bag for storage. It is possible to clean molded parts with ultrasonic cleaning before assembly, but if the parts are kept clean after molding, this is unnecessary.

For your assembly operation, you need an environment with suitable cleanliness. Sometimes a controlled environment is sufficient. Other times a certified cleanroom is more appropriate. In either case, it is important to control the bioburden in the assembly area to a level that meets the needs of the most critical product assembled in that area. Cleanroom procedures, the design of the cleanroom, and your cleaning/sterilization processes should match the needs of the product. Fortunately, cleanroom procedures and bioburden limits for cleanrooms are well established in ISO 14644-1 (e.g., for an ISO Class 7 cleanroom, particles ≥ 0.5 microns must be fewer than 352,000). If you have devices of different types in the same manufacturing area, you must plan according to the most critical needs.

Validating Bioburden Limits

After establishing your bioburden limits, you need to validate these limits. Once again, cleanroom validation has established ISO Standards to follow. The more challenging validation is a validation of the bioburden of parts and the final assembly. It’s important to validate the component levels first to reduce the variability of inputs to the final assembly process. Typically the first step is to perform data analysis of other molded parts produced in the same molding area by the same operators. If this data meets your needs for cleanliness, then further measures for controlling bioburden may not be needed. However, if you need to reduce bioburden (i.e., bioburden failure), you might consider measuring parts at critical control points. The goal is to identify where the bioburden is being introduced. This analysis is typical of the type of root cause investigation performed when bioburden increases for unexplained reasons.

Once the sources of bioburden are identified and quantified, process controls should be implemented to reduce bioburden. Gloves, double-bagging of product, and keeping containers covered during the molding operation are typical risk controls that may be implemented. To validate the effectiveness of these measures, you should write a bioburden validation protocol that evaluates each of the following aspects:

  1. lot variability of component bioburden
  2. operator variability for assembly
  3. variability in the cleanliness of the assembly area
  4. number of operators in the assembly area
  5. duration of the manufacturing lots

After you have validated the bioburden limits for the components, then the same process should be conducted for the final assembly of the product. A sampling of bioburden after transfer to the assembly area and before assembly begins should be done. This is important because often, improper storage of components and/or failure to remove and clean outer packaging will contaminate the parts and your assembly area.

process validation webinar Validating Bioburden LimitsIf you are interested in learning more about process validation, please download the process validation webinar. We also published a blog on sterilization and shelf-life validation for 510k submissions.

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