New FDA Inspection Plans & Other Notable Headlines

I was tempted to name this post “Six Really Cool Health Science Headlines You May Have Missed” but I wanted to give my “new post announcement” email a fighting chance to get through our subscribers’ spam filters.

I’ve been exploring Twitter lately, learning about the opportunities it presents and about the conventions and etiquette of the micro-blogging community. My last blog post blew the dust off of a 7-year old TED talk about big data. This post is rooted firmly in the present, because, as I have found, nothing on Twitter is very old…except for some of us tweeters. To build a context for the Twitter topics I’m following, I’ve been clicking a lot of links, reading articles, blog posts, newsletters, and white papers about the advances of this amazing industry as they happen. Many of these advancements do not directly relate to the work we do at Polaris, but rather than read about them, marvel, and move on, I thought I’d share them with our readers in case, as I say, you missed them.

FDA Plans to Use Big Data to Help Identify Highest Risk Manufacturers
I like the symmetry here. PatientsLikeMe, GNS Healthcare, and others are using big data to predict what treatments would have the most benefit for a given patient. Now, big data may soon be used by FDA to determine the best way to ensure the safety of those treatments. FDA has issued an RFI (Request For Information), and is looking for a vendor to supply an off-the-shelf, risk-analysis system to identify high-risk manufacturers. The system would analyze inspection and REMS (Risk Evaluation and Mitigation Strategies) reports, bioequivalence data, pre and post approvals, and other sources to help decide who should be “next on the inspection list.” To read more: http://bit.ly/ZggT6R.

.PHARMACY Domain To Weed Out Non-compliant Online Pharmacies
Here’s another headline related to patient safety and drug efficacy. The National Association of Boards of Pharmacy (NABP) found that 97% of the 10,000 online pharmacies they analyzed were out of compliance with US pharmacy laws and practice standards. They have applied for a new domain name, .PHARMACY, which would be available only to legally operating online pharmacies. To read more: http://bit.ly/10gRm1z.

Edible Electronic Medical Devices Could Be Swallowed Like Regular Pills
This is a fun one. You may recall that in August of 2012, FDA granted approval to Proteus Digital for its edible sensor, the Ingestion Event Marker. Developed to ensure that medication is taken correctly and on time, the sensor is encased in a pill. Before it is digested, the sensor relays information to a skin patch, which sends it to a mobile app, to create an ingestion data log. Now, less than a year later, Carnegie Mellon researchers have developed a non-toxic edible battery that could be used to power biodegradable electronics. The result could be tiny electronic medical devices that, when swallowed, would provide non-invasive treatments, like drug delivery or tissue-stimulation. To read more: http://bit.ly/10IB1iH.

Protocol Development via CrowdsourcingTransparency Life Sciences (TLS) is designing clinical protocols using input provided by a diverse set of doctors, researchers, patients, and caregivers. Protocol Builder, a technology TLS developed for crowdsourcing its study designs, encourages open dialog among communities of interest and collects participant input. Believe it or not, you can view the crowdsourced protocol they are developing to study Lisinopril, an adjunct treatment for multiple sclerosis, at http://bit.ly/10JDqfY. They’re not kidding about the “transparency”thing.

GlaxoSmithKline Opens its Patient-level Clinical Data to Other Researchers
In keeping with the theme of transparency and collaboration, the homepage of GSK’s new data sharing platform reads, “Access to the underlying (patient level) data that are collected in clinical trials provides opportunities to conduct further research that can help advance medical science or improve patient care. This helps ensure the data provided by research participants are used to maximum effect in the creation of knowledge and understanding. Researchers can use this site to request access to anonymized patient level data from our clinical studies to conduct further research.”

Currently, the site includes all GSK global studies since 2007, with plans to include all the studies conducted since the company’s formation in 2000. You’re even free to view studies included on the site before creating an account at http://bit.ly/16FVsor.

Open Government Data Exposes Hospital Billing and Healthcare Costs
I’ll bookend this blog post with another story about big data. On May 8, Alexander Howard wrote on E Pluribus Unum, “The Department of Health and Human Services (HHS) has released open data that compares the billing for the 100 most common treatments and procedures performed at more than 3000 hospital in the U.S. The Medicare provider charge data shows significant variation within communities and across the country for the same procedures. One hospital charged $8000, another $38,000 –for the same condition. This data is enabling newspapers like the Washington Post to show people the actual costs of health care and create interactive features that enable people to search for individual hospitals and see how they compare… According to Steven Brill, this end to hospital bill secrecy was prompted, at least in part, by his mammoth special report on healthcare pricing practices in the March 4 issue of TIME Magazine. If so, it’s one of the most important outcomes of a single feature of investigative journalism in this new century.” According to Brian Cook, an HHS public affairs director, the data release did, in fact, come in part as a response to Brill’s article. Now that’s noteworthy.

Thanks to my new Twitter community members for calling these stories to my attention, especially: @RebarInter , @Ivsin,@GCPWorks, @trialsonline, @eClincial_Jen, @Clin_Trials, @Medidata, @KGKSynergize, @Clinical_Tech, @AnnexClinical, @eclinical, @LaurieAHalloran, @Altus_Research, and @DrugSafetyNavig. You can follow them, too!

By Laurie Meehan

This blog discusses trends and issues in the pharmaceutical, medical device, and dietary supplement industries. Click the SIGN UP link to subscribe to notifications of new blog posts, or follow us on Twitter @ConsultPolaris.

Part II: What SOPs Does A Dietary Supplement Distributor Need?

Last summer, we received a lot of feedback on our post entitled “What SOPs Do I Need As A Dietary Supplement Distributor?”   To respond to your questions and comments about 21 CFR Part 111, we’re posting an expanded version of the original article.

If you look at the cGMP regulations for dietary supplements, you’ll notice that only 1 subpart includes the words “holding” or “distributing” in its title.  With only 10 or so individual requirements, the aptly-named Subpart M, “Holding and Distributing,” is shorter than most.  If you’re thinking this means there’s a much lighter regulatory burden placed on companies that simply hold or distribute dietary supplements than on companies that manufacture them, you’d be right.  At the same time, you’d be incorrect to assume that regulations for holding and distributing dietary supplements are restricted to this single subpart.  At least 8 of the 16 subparts that comprise 21 CFR Part 111 are applicable to holders and distributors, and all the activities outlined in these subparts require SOPs.

Subpart B, “Personnel” requires that your employees be qualified for the positions they hold and be trained in hygienic practices and warehouse operations.  Naturally, this training needs to be documented.  SOPs are needed to describe the procedures you have in place to comply with these staffing requirements.  That’s important, because as you read on, you’ll see the warehouse staff has a lot of responsibilities.

Subpart C, “Physical Plant and Grounds” dictates that your warehouse be clean and pest-free.  Dirt, insects, lubricants, or other agents could compromise the packaging or prevent labels from adhering.  Your facility also needs proper drainage, adequate space, and work lighting.  (Do cramped or dark conditions increase the likelihood of dangerous product mix-ups?  Is any of your product sitting directly on the floor rather than on pallets?)  You must also make sure that the product you hold is not exposed to more heat, cold, humidity, or light than the manufacturer recommends.  (Is the heat tunnel you use for sealing shrink wrap too hot?  Do you have backup refrigeration?  Is there sufficient ventilation?)

Any homeowner knows that conditions in a building are not uniform; buildings have hotspots, cold spots, and damp spots.  Just as the pharmaceutical industry has done, some dietary supplement holders are using a technique called “warehouse mapping” to help ensure safe product storage.  In warehouse mapping, the 3-dimensional warehouse space is logically divided into many smaller blocks, a sort of Rubik’s Cube.  Sensors that monitor temperature and humidity are placed in all 8 corners, the areas of the “cube” that are most subject to variations in environmental conditions.  Monitoring is performed at least seasonally, as temperature and moisture will fluctuate throughout the year in most locations.  Sensor data can help warehouse staff pinpoint specific areas of the facility that have inadequate ventilation or excess heat or moisture.  Additional fans, air conditioners, or dehumidifiers can then be deployed to remediate any adverse environmental conditions.

Subpart D, “Equipment and Utensils” discusses the care and feeding of all machines used to control environmental conditions, and to move, store, repack, or otherwise handle product.  SOPs describe proper cleaning procedures, permissible cleaning agents, and cleaning frequency.  (Could this cleaning solution cause labeling ink to fade?)  They describe inspection and maintenance requirements.  (According to the manufacturer, how often should this thermostat be calibrated?  How often is electronic inventory control data backed up?)  They outline installation and operational qualification procedures.  (Has your industrial scale been installed on a flat surface?  Is your packing peanut dispenser blowing so forcefully that it could damage labeling or product container-closure systems?)  Finally, SOPs describe all of the associated records that must be kept and the internal QA procedures to ensure it’s all being done. 

Because you cannot ensure the quality of the product you distribute without verifying the quality of the product you receive, holders and distributors must implement some of the measures identified in Subparts E and F which cover Process and Quality Controls.  The contents of incoming shipments must be confirmed against invoices and other paperwork, and applicable certificates of analysis must be verified.  Product should be visually inspected.  (Has any product reached or neared its expiry date?  Is any product damaged?)  SOPs which describe these activities, as well as the procedures for handling damaged/expired product must be documented and followed.

Since Subparts G through L apply only to manufacturers, packagers, and labelers, alphabetically we’re now up to Subpart M, “Holding and Distributing.”  Not surprisingly, this section requires that product be held in a manner that prevents its contamination and deterioration, and preserves its purity, strength, and composition. As we’ve seen, Subparts B through F outline many of the detailed regulations you need to follow in order to protect your products…but not all of them.  Temperature, ventilation, and moisture content are not just warehouse attributes; they apply to shipping environments, as well.  To ensure that product receives the same protection in transit as it received in the warehouse, distributors must conduct shipping tests at various times of year and over a variety of shipping routes. (Will our product survive the stretch of Interstate 10 between Phoenix and Tucson in the middle of August?)  Lastly, Subpart M requires that samples of each batch of product be retained for a specified period of time.  Holders and distributors should document and follow procedures for periodically reviewing the condition of the samples and for investigating the cause of any deviations discovered.  (Are the product labels legible?  Is the packaging holding up? What should you do if the the appearance of the product has changed during its shelf life?) 

Even after your product has been delivered, your regulatory obligations have not been fully discharged.  Subpart N, “Returned Dietary Supplements” outlines quarantine and disposal requirements you must follow and quality control responsibilities you must carry out when product is returned to you.  (Under what circumstances can we redistribute product?   What if the return is simply the result of excess retailer inventory?)

Subpart O, “Product Complaints” outlines your responsibilities surrounding any product complaints you may receive.  Remember those samples you’ve been storing according to Subpart M?  Get them out, because that’s where your investigation will begin.  Some of the activities here resemble those of a traditional CAPA program:  determine the root cause of the problem and take corrective and preventive action.  (What if the problem is not mine – what is the protocol for dealing with manufacturing, packaging, or labeling issues? What are my obligations if we receive an email from someone who claims that the product has made him sick?)    

Finally, as a distributor, you would likely play a key role in any product recall.
Subpart P, “Record and Record Keeping” enumerates the data you must keep in order to respond appropriately to a recall order (as well as demonstrate Part 111 compliance in general).  Conducting periodic mock recalls to test your recall SOPs will help ensure that inventory and distribution records provide the information necessary to successfully recall all targeted product.

Perhaps to those involved in pharmaceutical manufacturing or clinical research, the regulatory burden placed on holders and distributors of dietary supplements may seem light.  In fairness, comparatively, it is light.   But that doesn’t mean complying with all the necessary Part 111 provisions is easy or straight forward.  It takes even the veterans time, effort, and expertise to develop the procedures necessary to achieve compliance, and it takes vigilance to follow and maintain them.

If you’d like some assistance navigating your way through 21 CFR Part 111 compliance, please visit us at www.polarisconsultants.com.

by Laurie Meehan 

with Special Thanks to Rosanne Sylvia-Heeter, Director of GMP Compliance

This article appears in “Quality Lifeline”, a MasterControl publication.  http://www.mastercontrol.com/dietary_supplements/sops-dietary-supplement-distributor.html?source=n3w5quality|70130000000XEpx

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Notes To File (NTFs): Remedy or Enemy

People sat up straighter.  Some audience members leaned forward in their chairs.   The unmistakable sounds of pencil on paper could be heard as attendees hurried to scribble down a message they wanted to make sure they brought home.

These were the scenes at both the 2011 ExL Pharma and the ACRP conferences, when Leslie Ball of the FDA warned attendees that NTFs are a red flag to FDA inspectors.  Of course, NTFs can be appropriately used, whether to clarify seeming anomalies, for example, or to indicate the location of a document.  However, NTFs are increasingly becoming overused, even abused.  Too frequently, clinical research personnel view them as remedies for all manner of things gone wrong during the study, negating anyone’s responsibilities to actually fix the problems.  Ironically, rather than assuage FDA concerns about non-compliances, NTFs have begun to point to them.  Indeed, a recent Warning Letter stated that a sponsor’s method for securing compliance, by generating numerous NTFs to explain deviations, was not adequate.

Dr. Ball explained that the FDA encourages a proactive approach to reporting significant non-compliances, and that an NTF may be helpful in documenting the correction of a deficiency while a study is ongoing.  To that end, and to the extent that NTFs are used, it is important that they not only describe what happened, but why it happened, what was done to fix the situation, and what has changed to prevent future occurrences.

Example of a poorly written NTF:  “Urinalysis report for Patient #3 missing from Visit 6 records.”

This NTF does nothing more than record the deficiency.

Another example of a poorly written NFT:  “Jane Smith, our new study coordinator, began her assignment on 04/05/2010.  That same day, Patient #3 came in for his 6^th visit.  Though all other records were filed by Ms. Smith, the urinalysis report is missing.  Ms. Smith has been diligent about her documentation duties, and this missing report does not represent a trend.”

While this NTF offers some assurance that the oversight was anomalous, since this was Ms. Smith’s first day, it implies that perhaps she was thrown into the deep end of the pool without sufficient training or supervision.  The NTF does not indicate that steps were taken to rectify the situation.

Example of well written NTF:  “Urinalysis report for Patient #3 missing from Visit 6 records.  Upon discovering the oversight, a duplicate copy of the report was obtained from the lab, reviewed by the PI, and included in the record.  All other patient records filed by Jane Smith, the CRC, were filed correctly; this oversight was anomalous and does not represent a trend.  Ms. Smith has been trained in her duties, as her Training Records reflect.  To further assist Ms. Smith and other staff members in verifying that all required records are included in subject records, our CRC developed a QC check list for our SOP governing the maintenance of essential study records.”

The FDA is pushing for earlier detection and correction of non-compliances, so it’s no coincidence that this example NTF reads like a mini CAPA plan.  As NTFs are increasingly used to document that problems were caught, fixed, and prevented, they may well begin to lose their red flag status.

Before an FDA inspection, companies would be well advised to conduct an in-house or third party records audit to determine whether their NTFs are indeed remedies, or are actually enemies.

Expert consultants at Polaris would be happy to help you with any auditing needs you may have.  Contact us at info@polarisconsultants.com or visit our website at www.polarisconsultants.com.

by Laurie Meehan

This blog discusses trends and issues in the pharmaceutical and dietary supplement industries.  Click the SIGN UP link to subscribe to occasional notifications of new blog posts.