The article reviews FDA guidance documents released in the past few months, including the new Final FDA guidance on biocompatibility, published June 16.

For anyone responsible for monitoring new and revised regulatory requirements, the FDA guidance documents are something you probably check at least once every month. If you are not familiar with these FDA resources, here are the links for two of the medical device FDA guidance documents webpages:

• Recent Medical Device Final FDA Guidance Documents
• Recent Medical Device Draft FDA Guidance Documents

New Final FDA Guidance Documents

The last time I reviewed an FDA guidance document was in February for the new guidance document from the FDA related to usability engineering and human factors engineering. There was a new final FDA guidance document released by the office of device evaluation on June 16: “Use of ISO 10993-1”.This biocompatibility guidance was expected for release in December, but the release was delayed.

Use of ISO 10993-1

The new biocompatibility guidance that was published last month provides specific guidance about the application of certain tests required for demonstrating biocompatibility. For example, test article preparation and risk assessments for the applicability of specific tests is addressed. A revised test matrix is included in the guidance document. Special considerations are provided for each of the following biocompatiblity tests:

• cytotoxicity,
• sensitization,
• hemocompatibility,
• pyrogenicity,
• implantation,
• genotoxicity,
• carcinogenicity,
• reproductive and developmental toxicity, and
• degradation assessments

New Final Rule for Symbology

In addition to FDA guidance documents, the FDA also released a final rule on symbology that will modify 21 CFR Parts 600, 801, and 809. The FDA is finally changing its position on the acceptance of harmonized symbols in place of English text. The FDA is accepting ISO 15223-1 as a recognized standard and allowing manufacturers to use the symbols instead of English text to facilitate global harmonization of labeling. The FDA is only allowing the use of Rx-Only as to indicate that a product is a prescription only. The guidance even defines the acceptable process for creating new product-specific pictograms. The effective date of the new final rule will be September 13, 2016. 

New Draft FDA Guidance Documents

In addition to final FDA guidance documents, there have been several new draft guidance documents that were released recently:

1. List of Highest Priority Devices for Human Factors Review
2. Public Notification of Emerging Postmarket Medical Device Signals (“Emerging Signals”)
3. Characterization of UHMWPE for Orthopedic Devices
4. Technical Considerations for Devices for Additive Manufacturing

The second two FDA guidance documents focus on materials that are important for orthopedic manufacturers because UHMWPE is used as a wear surface for join implants, and many of the implants and instruments are now being manufactured using additive manufacturing instead of forging, casting or milling bar stock.

How to keep up on FDA Regulation Changes

If you are interested in keeping up on new and revised regulations from the FDA, I wrote a blog explaining four ways to identify new and updated FDA regulations. The blog identifies FDA webpages for the following four types of updates:

1. Guidance Documents
2. Recognized Consensus Standards
3. Device Classifications
4. Total Product Lifecycle (TPLC) Database

The ISO 15223-1 standard for medical device symbols has been released for several years, but the FDA did not recognize it until June 14, 2016. The recognition of the Standard is part of the implementation process for the new final rule regarding the use of symbology for medical device labeling. The timing of this new final rule coincides with the implementation of UDI labeling requirements for Class II devices. Also, the new European Medical Device Regulations now specify labeling requirements for the primary sterile packaging as part of the Essential Requirement (ER) 19.2:

• (a) an indication permitting the sterile packaging to be recognized as such,
• (b) a declaration that the device is in a sterile condition,
• (c) the method of sterilization,
• (d) the name and address  of the manufacturer,
• (e) a description of the device,
• (f) if the device is intended for clinical investigations, the words: ‘exclusively for clinical investigations’,
• (g) if the device is custom-made, the words’ custom-made device’,
• (h) the month and year of manufacture,
• (i) an indication of the time limit for using or implanting the device safely,
• (j) an instruction to check the Instructions For Use for what to do if the sterile packaging is damaged etc.

These new requirements will require many manufacturers to redesign labeling for sterile packaging, and the ability to use symbology will assist in creating globally harmonized labeling.

This article presents a Pareto Analysis of FDA 483 inspection observations from FY 2015. It compares the trends observed with a similar Pareto analysis that was performed a couple of years ago on FY 2013 data.

Method of Data Analysis for FDA 483 Inspection Observations

The FDA posts Excel spreadsheets on the website to download data for FDA 483 Inspection Observations. These spreadsheets include inspection results for all the divisions of the FDA. To perform data analysis for FY 2015 results, I deleted the sheets that were not specific to medical device manufacturer inspections (i.e., only used data from CDRH). I sorted the data by the regulation that was referenced. For example, all the sub-clauses for 21 CFR 803 were combined into one category for the Pareto analysis. The combined categories were then sorted from the most frequent 483 inspection observations to the least frequent 483 inspection observations. The data was then added to the graph that I produced in February 2014 using FY 2013 results as a second data set. The resulting graph is shown above.

Comparison of FDA 483 Inspection Observations between FY 2013 and FY 2015

For MDR Compliance (i.e., 21 CFR 803), there was a slight increase in the number of 483 observations issued from FY 2013 to FY 2015. However, the difference was only a 1% increase from 6.2% to 7.2% of the total number of 483s issued. There was an even smaller increase in the number of findings related to purchasing controls (i.e., 5.6% increased to 6.1%). I noticed a slight drop in the number of findings related to design controls, CAPA, and complaint handling. However, the overall trend for FY 2013 and FY 2015 is essentially the same.

There are two other categories where an increase was observed: 1) process validation increased by 0.7% from 4.8% to 5.5%, and 2) control of nonconforming product increased 0.8% from 4.3% to 5.1%. These areas are important. Control of nonconforming product is one of the major sources of CAPAs and often results in design changes. Therefore, FDA inspectors are reviewing your data for a nonconforming product during inspections to help them identify potential CAPAs and design changes that may have been made. The typical sequence is 1) nonconformity, 2) investigate nonconformity as part of a CAPA, and 3) initiate a design change as a corrective action.

Process validation is a completely different area that is separate from CAPA, complaint handling, and MDRs. However, inadequate process validation is a common root cause of nonconformities. Therefore, inspectors often follow an audit trail from a nonconforming product record back to a process change that was implemented but inadequately validated. Thus, an increased focus on nonconformities may be the reason for an increase in FDA 483 inspection observations related to process validation.

So what’s the big deal?

This proves that the FDA inspectors continue to be predictable. The “playbook” for FDA inspections is the QSIT Manual. It hasn’t changed since 1996. Yet, companies continue to be shocked and amazed by FDA inspectors.

Additional Resources

If you want to learn how to prepare for FDA inspections, I recorded a webinar you can download (FREE). I recorded the webinar in May of 2014, but it’s been a couple of years, and I’ve learned a few new tricks. Therefore, I’m going to re-record the webinar and update it for lessons learned. I’ll even share a few tools and approaches to avoid findings and reduce the risk of warning letters. I’m also evaluating a new application that is designed for teams to have private chats and file sharing during an inspection. Stay tuned to my webinars page, and I’ll post that webinar soon. Maybe I’ll record something from Germany next month.

Until then, I am working on a webinar specific to medical device reporting. Many companies have still not updated their MDR procedures to reflect the eMDR process using electronic submissions gateways. Therefore, I’m releasing an updated procedure for MDRs, and I am offering a webinar bundle to train people on how to comply with 21 CFR 803 and the procedure. You might also be interested in my previous webinar specific to control of the nonconforming product.

Article explains how to determine which FDA Form 483 response you should write a corrective action plan for first and why.

In a perfect world, you would not receive any inspection observations from your next FDA inspection. However, most companies get at least one observation resulting from an FDA inspection and often there are multiple observations on an FDA Form 483. If you

Most Common FDA 483 inspection observation

Companies that have not experienced an FDA inspection before worry too much and prepare too little. Inspections are predictable and certain inspection observations are much more common than others. A couple of years ago I wrote an article analyzing the most common FDA inspection observations. The most common observations are specific to design controls (i.e., 21 CFR 820.30). However, this fact is distorted because many companies receive multiple observations during the same inspection related to design controls. For example, a client of mine recently received three from one inspector: 1) lack of design reviews, 2) lack of design validation, and 3) lack of risk analysis. All three were found during the review of the same design history file and the one corrective action addresses all three observations.

how to determine which FDA Form 483 response you should write a corrective action plan for first

2nd Most Common FDA 483 inspection observation

The second most common observation is specific to corrective and preventive actions (i.e., 21 CFR 820.100). Typically the company has inadequate procedures for verifying and validating effectiveness of corrective actions taken. If this is one of your FDA 483 observations, then you may have a problem with CAPA training or with the design of your CAPA form. If there is no place on the CAPA form to document your effectiveness check, then you might easily forget to perform the verification and validation of effectiveness. Another possibility is that personnel are confused between verification of implementation and the verification of effectiveness.

What if you have multiple FDA 483 observations?

Other common FDA 483 observations include medical device reporting, complaint handling and rework of nonconforming product. If you receive more than one FDA 483 inspection observation, you need to assume there is a chance that the inspection outcome will be “Official Action Indicated” (OAI). In this case, you need to provide a 483 response to your FDA district office within 15 business days. With such a short time to prepare your 483 response, you need to be efficient. Which 483 response should you initiate first and why?

If one of the inspection observations is related to the CAPA process, that 483 response should be your top priority. The reason for this is that the FDA will want to see objective evidence of implementing corrective actions whenever possible. If you use your CAPA procedure and form to document the 483 response, then you can show the FDA how the revised procedure or form will be used in your 483 response. If you write your 483 response for other inspection observations first, then the other 483 responses are using the existing procedure or form that the identified as inadequate.

Your first step should always be to implement corrective actions to address an inadequate CAPA process by revising the procedure or the form. Once the procedure or form is updated, then you can use the new process to document the rest of your 483 responses.

Training Webinar for an FDA 483 response

If you need help preparing an FDA 483 response, click here for our webinar explaining the 7 steps for responding to an FDA Form 483 inspection observation. You can also download a CAPA procedure and CAPA form from our SOP page.

In 2016, the FDA released a final FDA Human Factors Guidance that explains the requirements for human factors testing of medical devices.

FDA Human Factors Guidance

The FDA released a final guidance document on the subject of “Applying Human Factors and Usability Engineering to Medical Devices.” This is a final guidance document that replaces the previous version that was released in 2000 and the draft that was released in 2011. The diagram below is Figure 3 from this new FDA guidance, and it includes references to sections 5 through 9 of the guidance document.