Here’s what one senior manager of clinical compliance had to say about Cerulean’s help during this stressful time:

John’s approach to Part 11 compliance was skillful in emphasizing how pharma and biotech companies can balance bottom lines to align with FDA expectations. He demystified the technical concepts of Part 11 and translated them into real-world best practices to help us manage patients’ safety, rights, and data integrity.

- Mai Nguyen, Senior Manager, R&D Quality and Compliance, Boston, Massachusetts

If you’re looking for a trustworthy, common-sense Part 11 consultant or an electronic data integrity expert, take a look at our specialized Part 11 compliance consulting services or download and read some of our 21 CFR 11 “how to” articles. And then contact us when you’re ready to streamline, simplify and strengthen FDA Part 11 compliance.

Contact Cerulean today and start making your life easier

First, Cerulean’s experience in dealing with our specific issues of quality management. Second, Cerulean’s expertise with small and mid-sized manufacturers meant a greater understanding of how to apply cGMP and QSR to companies like ours. Lastly, the proposal that Cerulean submitted was clear, detailed, and expressed a complete understanding of the work ahead.”

Understanding how to balance business realities with FDA compliance is critical. Consultants who talk about solutions such as “just get another supplier” or “you need lots and lots of SOPs,” only demonstrate they know one side of the equation. They don’t know how to solve it. We do. Cerulean specializes in cost-effective FDA compliance for small companies, mid-size firms, and single site divisions.

Do want your compliance programs to be overhead or cost-effective? Do you want a consultant who’s focused on your success? Here’s what the president of our client said:

John Avellanet at Cerulean came to our rescue. We started as a small medical device supplier to the US Defense industry and quickly grew into a company with over twenty products. Our processes were not keeping up with our growth. When we received a warning letter from the FDA, John was there for us. He guided us through the process of bringing us compliant with the QSR and cGMPs, and helped us through the follow-up and closeout letter inspection. Cerulean was there for us from start to FDA approval.”

- Paul Harder, President, Gloucester, Virginia

If you’re looking for an FDA consultant that understands how to balance business and compliance, contact us today. Cerulean is here to help you succeed.

Get out of FDA trouble today, contact Cerulean

Cerulean provided us with intelligent regulatory guidance that allow our business to showcase its compliance and remain competitive within our industry. They understood our objective and did not try to sell us other compliance consulting services.”

- Jill Balcerzak, Director of Organizational Development & Quality, East Hartford, Connecticut

Critical to providing competitive materials and services to FDA-regulated industries is knowing how to find a balance between what a prospective customer says they need versus what you can provide and stay in business. Be aware that while pharma and device firms will try to push as much compliance responsibility off on their suppliers, ultimately – whether dealing with the FDA or the EMA – the supplier is usually not accountable to the regulators.

If you’re looking for intelligent supplier management and an FDA supplier expert you can trust to help you find the balance between compliance and profitability, get Cerulean.

For balanced supplier management, contact Cerulean today

For one CRO based in Califorinia, they originally hired us to perform a mock FDA audit and conduct cGCP training. As we got in, it became clear that a mock audit was not in their best interest. Instead, they really needed help designing a modern, simple quality system to allow a high degree of flexibility given their academic setting while giving them, their patients and sponsors, and the FDA, the level of confidence needed to achieve clinical data integrity and full patient safety.

Do you comply with confidence and flexibility?  Or just overhead?

Our analysis helped the CRO management understand that although they were doing many of the right things – they weren’t documenting as they should, their lead investigator was on the verge of being too busy to actively oversee the trials, and that a clean, streamlined, simple-to-follow clinical quality management system needed to be developed.

First, we conducted two half-day workshops – one for their management team and one for their staff (including nurses and student assistants) – on today’s FDA expectations for clinical data and clinical quality controls. This wasn’t telling them how to their job, it was showing them what FDA looks for to verify that the CRO knows what it’s doing.

We outlined how FDA trains its clinical inspection teams, what an FDA inspection looks like, and how an inspection of their clinical organization will differ from the sponsor audits they had already been through. This ensured a solid grounding for everyone – true knowledge sharing – and gave everyone a real understanding for the clinical quality system framework that needed to be put into place, why, and how to keep the SOPs and policies flexible and low-cost while retaining effective compliance.

Then, we went through their controls – whether written or unwritten – reviewing documents, interviewing personnel, and uncovering the informal controls and unwritten processes that were helping the CRO succeed.

Finally, we provided our client a detailed blueprint, including prioritized implementation timelines (and the logic behind those priorities), as well as multiple example templates and SOPs. The goal was to ensure compliance while keeping their success going. We then continued to check in with them over the year to make sure their implementation was progressing and to head off any possible challenges before they could arise, a level of courtesy follow-up that is part of working with Cerulean.

Pleased, this is what they had to say (name withheld due to confidentiality):

We used Cerulean because of their background experience, level of knowledge, and the different situations in which Cerulean had helped other clients.

John is an excellent listener and would give succinct and real answers, telling us of consequences that may occur, based on his experiences. John also linked the realities of inspections with a strategy for us to prioritize our way out. He is personable, humorous (which helps to break the tension), and very hard working.

If there is one word or phrase that describes Cerulean, it is “body of knowledge.”

- Chief Administrative Officer, Sacramento, California

If this sounds like the type of consultant you’d like to work with, or the type of success-oriented help you’d like, contact Cerulean today.

The first challenge is figuring out which supplier is a virtual company; few virtual suppliers hang out a sign saying “virtual company.”

Virtual companies also present auditing challenges because they have no material production sites of their own to inspect as they contract out services to others. Virtual suppliers that are service providers, such as calibration companies, may be set up in a converted home garage. And increasingly, consultants and other professional services operate out of home offices.

One approach to qualify virtual suppliers is to beef up incoming acceptance activities accompanied by remote audits involving teleconference interviews with pertinent personnel, Avellanet said.

Regular analyses of data provided by the supplier are also recommended to ensure product quality consistency, he added.

And drug and device companies working with virtual suppliers should become familiar with ISO 19011:2011 Guidelines for Auditing Management Systems, which covers remote auditing.

“Firms have available to them the very valuable tool of design review within their quality management systems,” said Jan Welch, Deputy Director of Regulatory Affairs in CDRH’s Office of Compliance. “To the extent that design inputs are inappropriate, unachievable, poorly characterized or not documented, the design review process should identify these concerns and flag them for resolution prior to the next design steps. The same holds true for design outputs.”

Design review – a documented, systematic examination of a product design to evaluate whether it meets user requirements – is required by Quality System Regulation 21 CFR 820.30(e) as part of the design control subsection.

Design inputs – the cornerstone of product design – establish device requirements relating to function, safety, design and performance. Meanwhile, design outputs are reviewed to ensure that input requirements have been met or addressed.

“If issues with design inputs and outputs remain unaddressed throughout the design process,” Welch said, “the firm likely has underutilized its design review mechanism.”

The QSR does not prescribe how often design reviews should be performed; it is left up to companies to decide. Design review results are documented in design history files. During an FDA inspection, “investigators often see issues with design inputs and outputs when reviewing and assessing design review results found in design history files,” Welch said.

FDA:  Design Input, Output Activities Not Documented by Manufacturers

Another serious problem FDA investigators see is firms failing to properly document design input and output activities.

“Manufacturers must have the necessary documentation to demonstrate that design inputs for their device adequately address the intended use … and the needs of the user and/or patient, including risk assessment and human factors considerations,” FDA’s Welch said.

When it comes to “design outputs, manufacturers need to have enough documentation to show that design outputs match the requirements of the design inputs,” she said.

Manufacturers sometimes wonder how much design input and output documentation will satisfy the agency.

John Avellanet, Managing Director for Williamsburg, Virginia lean compliance consulting firm Cerulean Associates LLC, said agency investigators will scour a company’s desiggn history files to ensure that every design input is traceable to an output.

For an investigator, “it’s really a process of reviewing the documentation and being able to reconstruct design decisions vis-a-vis the finished device,” he told The Silver Sheet on June 5th. “If there is enough information to satisfy that, then the firm has adequate documentation from FDA’s perspective.”

When firms ask themselves how much documentation they need for design inputs and outputs, the answer that is typically given by FDA is “something along the lines of ‘Enough to ensure the quality, safety and effectiveness of the device.’ Sadly, this is not a practical answer that allows you to go forth and decide.” Avellanet said. “What is enough documentation and detail to ensure the safety and effectiveness of a device? The person who is a perfectionist will have far more documentation and detail than the person who believes that ‘good enough is good enough.’”

Avellanet advised, “Step back and look to the end. What are the goals of the design input and design output documentation? To sit in your files with someone’s approval signature on them awaiting FDA review?”

“If we really think about our needs are in terms of design input and output records, we need design inputs and outputs to be usable and defensible. We need to use them to actually design and make the device. We need to be able to use these same records to defend any accusation by FDA that our device is unsafe or ineffective. And we need to use those same records to defend patent scrutiny. And we’ll need them to defend against the inevitable medical product liability litigation.”

Avellanet explained that with his clients, “I find that we can create a core set of defensible documents for design input and design output records by using four tools:

• design input review checklist
• design output review checklist
• the GHTF’s summary technical document (STED), and
• a simple requirements table or matrix (into which you put all the inputs and outputs together, then make sure there are no blank fields).

So, think about the design input review checklist. Just to identify a few points, use the design input review checklist to verify you have documented:

• intended use or indications for use
• human factors requirements
• functional requirements
• material biocompatibility requirements
• shelf life specifications
• durability requirements

Each of these should then be traceable to a documented decision or a report or a memo or a research finding, etc. that is maintained or otherwise referenced in the design history file. The key is to use the checklists as a summary of proof that you conducted the design input and design output activities, and have enough documentation necessary to satisfy FDA and protect yourself against the investigator and the litigator.”

Then, during design review, suggested Avellanet, use the completed checklists as one element during the review. This “closes the loop” while keeping overall design controls streamlined.

“It’s important when firms write response letters that they address the specific observations that were written down on the FDA-483,” said Stephen Rabe, a compliance officer in the FDA’s Cincinnati District Office. “And yet the huge part that is often missing from response letters:  The company addresses individual observations, but it doesn’t really get to the solution of the problem.”

Drafting a meaty response letter that thoroughly addresses inspectional observations became even more challenging after FDA placed increased pressure on manufacturers to respond within 15 workdays after the close of an inspection.

“For many companies,” said John Avellanet, Managing Director & Principal of FDA consulting firm Cerulean Associates LLC, “those 15 days are a panicked rush.”

“FDA will tell you that 15 days is 15 business days, Monday through Friday. However, firms should think about those 15 days in terms of 15 calendar days. The reason to do it this way is three-fold:

1. First, you help everyone in the organization understand that this the number one, top priority right now. A poor response guarantees a stricter regulatory enforcement action which then guarantees a decline in the value of the company and yearly sales revenue. It’s a 1:1:1 relationship.
2. Second, you actually end up giving yourself a nice buffer so you have a couple of days to sit on your response, and think about it. Is there something that, on second thought, should be added, clarified, tweaked, etc.?
3. And third, you make sure that FDA receives your response within that window and can take the time to review your response. You want to avoid the 30-second glance-over.”

Put Only Practical Timelines in Response

It’s important to include only practical corrective actions and timeframes in an FDA-483 response.

“You need to be realistic about timeframes,” said FDA district officer Rabe, “so when we go back there, everything is corrected, because if there are still problems, you’re going to get written up for them again. And, if you just got a warning letter, the next step for us would maybe be to ask for an injunction or some other more serious action because you haven’t fixed the problems, especially when you said they would be fixed.”

Avellanet urged manufacturers to not only be honest about timeframes, but to provide solid evidence of progress as well. “If you look at a lot of FDA enforcement correspondence, the agency is constantly noting that a firm’s 15-day response was insufficient. One reason is because when the firm said a problem was going to take six months to fix, the firm failed to tell the agency why it was going to take six months and then what the interim milestone steps and due dates would be,” said Avellanet. “You want to be able to say in your written response, ‘Here is our plan, here are the specific items within that plan that we are going to accomplish, here are the various milestones within that plan, and here are the final completion target dates for each element in the plan.’ In other words, FDA should be able to take what you provided, show back up in 3 months, 6 months, or a year, and know exactly where you are on solving the issues and why. If you aren’t providing that level-setting in your 15-day response, get outside help now.”

“Remember,” advised Cerulean’s John Avellanet, “once you get the FDA-483, the clock starts ticking the minute the investigator walks out the door. I suggest you encapsulate a simple checklist or observation-closure matrix in your SOP on inspection handling. Match the initial observation, the symptom, to the person held accountable in your organization for closing the gap, and then match that to the proof – the records generated – as a result of the gap closure.”

Post-Inspection Response Checklist

“First,” said Avellanet, “review all the observations that require a fix. If the investigator cites “Your change control forms were inadequate or insufficient because they were missing signatures,” your problem is not really that you have some missing signatures on a few change control forms. That’s just a symptom. Those signatures are missing for a reason. It could be your change control process is too convoluted and you need to streamline your procedures, it could be your compliance training is ineffective, and so on. You have to pause, step back and look for the underlying problem. That’s what the agency wants to see.”

“Now, 15 days can be a tight timeframe in which to do that, so you need a structured, simplified process. I have my clients use an observation-closure matrix. By listing out the documentation to be used to prove a fix, it’s easy to see if you’re inadvertently only focusing on the symptomatic FDA-483 or are tackling the larger, more systemic control breakdown. The former would only have a little bit of documentation such as an updated SOP, whereas the latter, more systemic view will need more documentation such as the revised change control SOP, a streamlined process map, a set of revised training, a revised form, and so on).”

Firms should then assemble a draft response that ensures each observation has been adequately addressed. Manufacturers should then share the draft response and potential proof verification records with their legal counsel.

“You want to have a legal review of your response and supporting evidence for two reasons,” Avellanet said. “One, you don’t want to accidentally commit your organization to do something that you can’t fulfill. And two, if push comes to shove, and a worst-case scenario develops, your legal team is not going to be happy to be brought in after the fact.”

Finally, the company would finalize its response and verification records, and submit those to FDA.

Convene a Quality System Management Review

It’s also helpful for manufacturers to hold an abbreviated quality system management review (QSMR) during FDA’s 15-day timeframe.

“In an ideal world, firms would hold that meeting regularly, but the reality is that a lot of firms still wait until the FDA inspection and they have problems. Think about holding an abbreviated or rapid QSMR focused only on FDA-483 observations and associated activities,” said Avellanet. “This allows you, for every FDA-483 observation, to go two steps beyond. The first step is the one that everyone always thinks of: ‘Okay, FDA cited us for this change control issue, so we’ll look at our overall change control process.’”

Take a “second step beyond by formulating a set of metrics that can show where you are today, where you’re going to be in the future, and how things have improved. So if we stay with our change control example, one metric could be the number of change controls, or the turnaround time, or the number of post-change control minor fixes/tweaks that have to be done after the fact,” Avellanet said.

“Those metrics do two things for you. One, they’re great for management. It’s crystal clear that you’re making progress and being productive. Metrics are easily grasped. Second, FDA likes metrics as proof. There is very little argument.”

“For example, which is more powerful:  stating that ‘We revised our change control process to be more streamlined and reduce the risk of missing signatures,’ OR, ‘We revised our change control process, etc., and now manufacturing cycle time has gone from 30 days to 25 days, the number of change controls has dropped by 50%, the product rejection rate has declined by 5%, and so on.’”

If a company doesn’t have time to hold a QSMR during the first 15 days after the inspection, it should plan to conduct one as soon as possible.

“If you miss this window of opportunity, it is far too easy to slip back into the way you were doing things before. It’s just human nature,” noted Avellanet. “If you can hold an abbreviated QSMR focused on the FDA-483 observations – a QSMR that takes less than 72 hours to prepare for and conduct – then you are on your way to thinking proactively about your quality system and how to cost-effectively, and compliantly, operate in a state-of-control.”

Conduct a Mock Inspection and Gap Analysis

After the 15-day window passes, firms may want to hire a third party to conduct a mock FDA inspection to prepare for when the agency returns.

Further, “you should conduct a gap analysis,” Avellanet said. “Do not limit the independent FDA auditor to just the FDA-483s. Remember that 483s are symptoms and FDA will use those as the starting point for their follow-up inspection.”

“Thus, you will want the auditor to come in and say, ‘Okay, here are the issues you have from a regulatory standpoint still, but you may also want to revise your clean room training. The way you’re training people is not as effective as if you were to take a different approach.’”

“In other words, you’re trying to find areas related to the FDA-483 wherein you can show improvements that go above and beyond complying with the letter of the law. FDA views the laws and regulations as minimum requirements – the starting line, not the finish line.”

Next, “review the results of the mock FDA inspection and gap analysis, and then set up projects to address the gaps and enable business success for the next two to three years,” said Avellanet. So, 15 calendar days, observation-closure matrix, supporting proof, then a rapid QSMR, and a mock FDA inspection leading to longer-term gap closures and business improvements like quality system streamlining and lean compliance. That’s how to go from panic to success.”