Michael Causey, Editor & Publisher, eDataIntegrityReport.com

One of my favorite all-time bands, The Kinks, have a fantastic tongue-in-cheek song called “Have a Cuppa Tea” that satirizes the British belief that a good hot cup of tea will solve all of the world’s problems.

• 820.198 Complaint files
• 820.90 Nonconforming Product
• 820.80 Acceptance Activities
• 820.200 Servicing
• 820.22 Audits
• 803 Medical Device Reporting (MDR)
• 806 Reports of Corrections and Recalls…

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

Deciphering the FDA is a bit like trying to understand what the old USSR was up to in the days of the Cold War.  In those days, it was called Kremlinology, or the study of a complex, secretive organization.  We need a catchphrase for those of us today who try to figure out what the FDA means when it says something, or what it means when it says nothing, or what it means when it tells you what it means. You get the idea.

The FDA has been talking a lot of late about transparency. Its 2011 initiative is an agency attempt, it says, to open up about how it does business. FDA is accepting comments on it until February 28.  The jury is still out on whether this initiative will accomplish much.

Our latest piece of FDA evidence is CDRH’s 2012 Strategic Priorities.

CDRH devotes the Introduction of the document about looking ahead to patting itself on the back for its 2011 achievements, e.g. its report, “Understanding Barriers to Medical Device Quality,” that reviews the challenges that the FDA and industry face in supporting well‐integrated, best‐quality manufacturing practices and strategies that industry and the FDA can take to overcome these barriers.

CDRH also reminds us that “to complete this work [in 2011] our staff went above and beyond their already demanding workload. This is a remarkable achievement.”

Good to know.

In 2012, CDRH says it will continue to emphasize four priority areas:

1. Fully Implement a Total Product Life Cycle Approach
2. Enhance Communication and Transparency
3. Strengthen Its Workforce and Workplace
4. Proactively Facilitate Innovation to Address Unmet Public Health Needs

CDRH promises in 2012 to “improve” its premarket programs. By April 1, it pledges to begin its Triage of Pre-market Submissions Pilot to “increase submission review efficiency and better manage the pre-market review workload.”

And by the end of the year, CDRH pledges to publish a proposed rule to clarify the circumstances under which it could rely on clinical studies conducted in and for other countries. CDRH also says it will finalize all guidance documents it has issued as part of its overall plan to improve its premarket programs.

We’ll keep an eye on these and other promises throughout the year and report back as FDA hits or misses its own targets.

Patrick Stone, President, TradeStone QA

Here’s an idea: More FDA inspections outside the US, at a lower cost.

How?

If FDA trained other countries health organizations to conduct FDA business with Memorandums of Understanding (MOU), less money could be used to travel with more inspections completed. This training could be accomplished online and by going out with FDA International Investigators. The EMA should have a MOU if their model is similar to FDA’s. The advent of all electronic review should alleviate the need for more international inspections.

I admit I may be over-simplifying the issues with training monies and bringing foreign inspectors to US training facilities. But I think the basic idea holds water.

Host nations can send their inspectors for knowledge sharing and training with justifiable beneifits to the host nations public health. FDA can also video link for training, as is done currently for new hire training.

Unfortunately, innovative options are scarce at the FDA Senior Executive Service level (SES) and the old way of doing business is ingrained into the government model. For the short term FDA will try to increase international inspections in all program areas with a focus on food work.

I’ve observed many international drug and device firms receiving warning letters and multiple item 483 forms. If this current warning letter trend continues, the blame may fall on lack of FDA regulatory guidance.

The core mission of FDA is to protect the US public from harmful health products. Sending FDA field Investigators to where the products are manufactured and undergo human clinical trials is one of the only ways to accomplish the core mission. Ensuring that field investigators are proficient for the task and seasoned investigators stay engaged will be the challenge.

The international firms with compliance issues should be reviewed by their country’s FDA equivalent for cross training on regulatory compliance.

On the job training is used here at home as a component of new hire training. FDA will have to think outside the box if Congressional Mandates for International travel are to be met.

Congress must also understand that it is not only the amount of funds that insure successful international travel, it is also about proficient field investigators as well.

I have faith that FDA field staff will answer the challenge because they always do.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

The new mantra for food manufacturers better be prevention, prevention, prevention according to current and former FDAers commenting on the January 2011 passage of the mammoth Food Safety and Modernization Act.

“This law represents a sea [of] change for food safety in America, bringing a new focus on prevention…” FDA Commissioner Margaret Hamburg says.

But former FDA Commissioner of Foods Dr. David Acheson takes it further in a new white paper from Plex Online. The new law “will result in significant changes for FDA-regulated food manufacturers and processors.” FDA’s emphasis on prevention will require registered facilities to develop and maintain a written food safety plan, for starters, Acheson stresses in a new white paper “Food Safety plans: New Requirements for Registered Facilities.”

As we’ve blogged before, most registered food facilities will be required to develop a clear, detailed safety plan that documents the facility’s:

• Prerequisite programs are in place to ensure food is produced in a safe and sanitary manner;
• Hazard analysis that identifies all potential risks throughout processing;
• Preventive controls that are implemented to mitigate risks;
• Monitoring of preventive controls to ensure they are properly implemented;
• Verification that the preventive controls have the intended reduction in risk; and
• Re-analysis of the hazards and preventive controls when there are significant changes in the process or every three years.

Acheson, now with Leavitt Partners, notes that regulated entities must soon be “able to quickly access records and demonstrate compliance with the food safety plan requirements.” They’ll also be expected to have “implemented a robust food safety program” if they want to maintain a position as a food safety leader.

He advises regulated entities to develop well-documented safety plans with strong monitoring procedures and corrective actions, for nine key areas:

1. Facility Information: Facilities will need to document a description of the food, the methods of distribution and storage, the intended use and intended customer for all products produced.
2. Prerequisite Programs: These programs will require a written plan, established monitoring procedures, established corrective action procedures, and an established recordkeeping system.
3. Hazard Analysis: Facilities will be required to conduct and document these to identify potential product-related hazards, including biological, chemical, and other hazards such as terrorism.
4. Preventive Controls: Once identified, each hazard must be evaluated to determine the significance of the hazard if it isn’t controlled, the likely occurrence of the hazards, and if it constitutes a “critical control point” that must be addressed.
5. Monitoring: Each critical control point must be then monitored to ensure compliance with the critical limits.
6. Corrective Actions: Beyond on-going monitoring, facilities must establish and document procedures for taking proper and effective corrective actions when critical limits aren’t met.
7. Verification: Facilities will then need to verify that the preventive control and critical limits result in the intended control and reduction of hazard.
8. Record-keeping: The new legislation authorizes the FDA to request access to a regulated entities’ Food Safety Plan. Each entity must establish a record-keeping system that documents their hazard analysis, critical control points, monitoring, verification, and corrective action plans and follow-up.
9. Re-analysis: facilities are required to conduct one of their food safety plan and hazard assessment whenever they implement significant changes or every three years.

It will take some time for the FDA to decide exactly how it will enforce the new law, and its interpretation will clearly have some impact on food manufacturers and other regulated entities. But it’s equally clear that the new law means big changes for companies that make food for a living.

Patrick Stone, President, TradeStone QA

The balance between cost effectiveness and a safe drug supply may be measured in the amount of poor/under-employed patients not receiving their medication. These individuals may seek their pharmaceuticals online from imported sources thus breaking the law and possibly receiving harmful counterfeit drug products. Counterfeit drugs and placebos, labeled as heart medications, blood pressure medications, diabetes medications, etc., are currently hospitalizing a vulnerable proportion of American citizens.

The FDA does not publicly go after counterfeit drug operations and the Office of Criminal Investigations (OCI) at FDA would be responsible for the interdiction of such criminal activity. There are very few OCI agents in the FDA, so counterfeit drug searches are not conducted Sheriff or Texas Ranger style. If the FDA OCI get a tip about a counterfeit operation they usually go in with Sheriff and FBI/DEA/HS for back up.

FDA public affairs and media relations may not go far enough explaining and describing the extreme dangers of buying health care maintenance drugs from an unapproved imported source.

There are many reputable foreign pharmaceutical companies legally and safely distributing effective imported medications. The FDA is currently focused on tobacco and food products like rural milk production; counterfeit pharmaceuticals appear to be low priority. Many of the counterfeit drug operations take place outside the United States and are imported in through legal or illegal channels.

The FDA Import Division would be the most responsible resource for stopping the flow of harmful drug products. The DEA and DOJ are focused on scheduled narcotics and bulk illegal substances. When the product comes in a pill bottle sold in most drug stores the priority may also be very low.

Health-care customers and marketing business firms need to understand the US regulations for importing health-care products from licensed broker that goes through the FDA/US Customs regulatory oversight. It is always good to verify that the product you purchased matches the description on the package insert.

The US government is trying to balance security and freedom of choice on the razors edge. It may take some time to ensure security at the cost of your advertising freedom. It is always a good idea to ask your doctor or pharmacist about your drug products and how to physically identify your medications.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.

Patrick Stone, President, TradeStone QA

Our domestic pharmaceutical drug shortage situation is a direct result of FDA regulations, FDA reviewer turn-over/project overload and pharmaceutical companies outsourcing production outside the United States.

These three factors are a key part of the current shortage which has many ingredients such as the high cost of conducting business (shipping, labor, tax, and mfg/dist plant overhead). With all of the current pharma mergers and acquisitions, it’s a miracle only 246 products are in short supply.

Those pharma companies that left Puerto Rico and the mainland United States now have to deal with US Customs and the FDA Import Division along with your host nation’s requirements. The low foreign labor cost benefit analysis may not have accurately accounted for shipping supply delays and operating cost over-runs.

FDA, along with the center specific review divisions, have some turn-over and training issues to contend with, too. Maintaining domestic compliance with 21 CFR Drug Regulations through the systems approach with certified drug investigators is proving to be a difficult task for the FDA Districts and Center Departments. The perfect storm conditions have gathered for a serious drug shortage beyond the 246 we currently have on the books.

It is a national security issue when the US has drug shortages of vulnerable population drugs and critical care maintenance pharmaceuticals on the shortage list. The Quality by Design (QbD) system will further compound the domestic and International chemical & biotechnology drug product development cycle. The ability to react to a vulnerable population drug shortage should be the focus — not outdated chemistry manufacturing control (CMC) regulations.

The pharmaceutical industry and FDA must collaborate to mitigate further risk to national security. We all have a major stake in health care continuity and national security.

Sound scientific method without FDA manufacturing micro-management should be the focus. A drug supply contingency plan must be approved by FDA for drug production to react to a major market shortage. Let drug manufacturers put in a market shortage contingency plan for their drug products or let the market figure out the best way to conduct business.

FDA needs to focus on QA and not the business side of the pharma industry.

A final message to the pharmaceutical industry: come back home to the US. There are plenty of truly skilled individuals ready to work, and land prices plus pad sites have generally gone down. Come on down and build your plants in my state of Texas — we are a business friendly state with no state tax.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

A sobering report from the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists (ASA), the American Society of Clinical Oncology (ASCO), and the Institute for Safe Medication Practices (ISMP) highlights a serious and growing drug shortage problem in this country – and the FDA is one of the big problems, according to many in the drug industry.

“This is a national security and health risk conundrum,” says former FDA reviewer and now industry consultant (and fellow Assurx blogger) Patrick Stone.

“If the pill well runs dry on our seniors or high risk folks they may expire or degrade further in health,” Patrick worries. The FDA’s “GMP controls and tightly held batch quotas are a mess. QbD will add fuel to this fire by doubling the number of drugs that don’t make it to the shelves.”

A distressing article from Marginal Revolution raises further questions about why this is happening and FDA’s role in it. “Currently there are about 246 drugs that are in short supply, a record high. These shortages are not just a result of accident, error or unusual circumstance, the number of drugs in short supply has risen steadily since 2006. The shortages arise from a combination of systematic factors, among them the policies of the FDA.”

Stone’s take: “The FDA simply doesn’t understand how many drugs are impacted by its regulations.” He challenges the agency to track that, just as it tracks 483 violations and other issues.

Editor’s Note: Watch for a new Patrick Stone blog on this topic next week.

Patrick Stone, President, TradeStone QA

What products will be affected by QbD? It will apply to new Marketing Authorization Applications (MAAs)/New Drug Applications (NDAs), Type II Variations/Prior-approval supplements (sNDA) and Scientific Advice requests/CMC formal meeting request that include QbD/PAT elements and are submitted to FDA & EU new applications, for MAAs/NDAs where the sponsor/applicant has agreed to a parallel evaluation by both agencies.

Upon request from the sponsor/applicant, and where procedural time-lines will allow, Type II Variations/NDAs may also be considered on a case by case basis. Right now this is a voluntary pilot with some pharma companies being tapped or nudged by FDA & EMA to join in.

Our geographically diverse health product market involves more contracting and outsourcing for many product components. Finished product real time testing and design space requirements will be crucial for implementing QbD.  ICH third party QA mandates will result from this pilot program.

QbD products will be as unique as the individuals who receive them (personalized medicine). This new model may impact two-thirds of the new health care products in the pipeline (cell therapies, gene therapies, and molecular entity therapy).   There will be many approaches to high order characterization and some are not cost effective at present.  Many of the details will take years to sort out. Collaborations between the FDA, Japan Ministry of Health, and  European Medicines agency will require funding along with mutual scientific trust.

Emerging technologies and laboratory techniques will be required to accomplish the QbD paradigm shift. FDA can’t continue using the chemistry approval model for biotechnology products.  This paradigm shift may increase development times and cost structures.  The ICH model will also bring mandatory third party QA review so prepare your models for this as well.

Here are the essential points to focus on for QbD products:

1. Target the product profile,
2. Determine CQAs (Critical Quality Attributes),
3. Link raw material attributes and process parameters to CQAs,
4. Risk assessment,
5. Develop a design space,
6. Design and implement a control strategy.

The biotechnology sector QbD product development focus will be on design space and real time release testing. The pilot discussion focus for both regulatory agencies will be on ensuring consistent implementation of ICH Q8, Q9, and Q10 guidelines in the assessment process and to facilitate sharing of regulatory discretion & new regulatory concepts manufacturers of small-molecule generic drugs have concerns the initial lag-time in course correcting for the QbD initiative may exponentially delay the application file time for their products.

It appears some generic-drug manufacturers are not willing to implement any QbD concepts until closer to final harmonization and discussion time frames.

Why do you need higher order structure modeling?  Higher order structure product applicants will have to provide protein folding kinetics models with characterization integration into the application and annual report.  Your research models and early development modeling may be progressed for this function. Personalized medicine with batch to batch consistency including stability of 1-90 days is recommended. There are also talking points about including variants and aggregates of your products in the higher order structure models.  Intra and inter chain disulfide bonding, aggregation, and complete polypeptide modeling may be requested application material.

This may prove to be more cost effective while two juggernauts (FDA & EMA) iron out the red tape that will flow from this type of global initiative.  If the funds necessary to make this effort progress are not available on the FDA or EMA, side delays in the process are inevitable.

Molecular and personalized medicine can’t continue to be reviewed with the FDA chemical entity systems approach, approval model.   Effective cancer therapies and molecular medicine may not have the statistical significance necessary when only a handful of patients are treated with the cell or gene therapy.

Warning to Industry: FDA will obviously not let you have your cake and eat it too.  Innovate inevitable change by comments to FDA or accept the QbD change that is inevitable.   Your comments to the FDA will be monitored on the FDA’s Facebook page and current open comment requests. Contact your respective FDA liaison or center contact for discussion points directly related to your product.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.

Patrick Stone, President, TradeStone QA

In a book he says is neither a “toasting or a roasting,” former inspector Patrick Stone clearly loves the FDA he worked at from August 1998 until March 2011, but hates some of what he’s seen happen at the agency.

“Bubble Gum Badge” is invaluable for regulated companies because, among other things, it shows the importance of gauging the human side of FDA inspectors. As Stone notes, they have different approaches and interpretations to how they do their work, including what they look for on inspections and what they consider problems. It’s incumbent on regulated companies to have best practices in place, but also to be prepared to explain their rationale to inspectors.

“FDA investigators, the good ones, at least, can read individuals like a book; and your lack of experience is on the front page. Good leaders listen to the experts in the field and are willing to learn from a subordinate,” Stone advises higher-ups at regulated companies. His book is full of such practical, nuts and bolts advice.

Stone also calls for both industry and the FDA to do a better job with electronic data integrity and electronic record keeping. There’s lots of room for improvement on both sides. He lays out several areas where each needs to raise the bar, but for industry it boils down to taking it seriously, using common sense, and not trying to hide violations. For the FDA, it’s about practicing what it preaches, and issuing some vastly overdue new guidances for 21 CFR Part 11, among other electronic record areas. Fuzzy FDA directives aren’t helping anyone, Stone maintains.

This isn’t a rough hatchet job, but more of a carefully considered critique of an agency Stone loves, but wishes could be better. “I am not a disgruntled employee… I have nothing but respect for the field investigators, laboratory staff, support staff, and frontline workers as well as the center reviewers.”

I hope some current senior FDA staff read this book and take it to heart.

Click here to purchase his book.

Connect with Stone, and to read a book excerpt visit http://www.bubblegumbadge.com or email him at patrick@tradestoneqa.com.

Dennis Payton, Executive Director of Product Marketing, Expandable Software, Inc.

With the explosive growth in imported goods to the US and very tight budgets to maintain a level of public safety, what is the FDA doing to insure it maintains a level of service inspection to insure the best protection of the public health? Some obvious answers are to partner with supplying exporting countries but another, perhaps less obvious one is to demand of itself the same level of systems it requires of the medical device industry and other industry segments they oversee. While the FDA pushes even harder on the medical device and lifescience industry toward electronic reporting to the FDA, internally they must not only tackle the challenge to how to handle eMDR and other e-submissions, but also to be much more efficient internally with ever pressing budget cuts.

As the medical device industry grows, the FDA continues its effort to reach out to industry manufacturers to provide updates, allow the agency to be better connected, and to open an avenue of two way communication in sharing current regulatory thinking.

As medical device industry leaders, we know the attention to detail that is required in setting up a validated, comprehensive and business workable quality system in compliance with FDA regulation. While the FDA’s mandate of safe products in the US marketplace is paramount, there is also a strong mission and vision to make sure there is support for new technology and goods for the advancement of public health.

Turns out the FDA faces some of the same challenges all medical device companies face – how to do more with less while ensuring a level of world-class excellence in an ever-growing global economic supply chain.

In this quarter’s FDA update (Q2, 2011), Mo Samimi of the FDA presents some of the details behind the FDA in defining, setting up, implementing and managing its own internal FDA quality system. Similar to any national or international quality system standards, the FDA for the most part holds itself to some of the same requirements and standards that are required of the medical device industry and other life science, food, and drug industries they regulate.

Mo outlines how the FDA drives their quality system from mission statement and vision to day-to-day operations. He also shows how some of these same goals align with companies that are positioning themselves to become world suppliers of regulated goods with limited resources that must become more efficient over time.

Click here to request the full report.