Validation and Regulatory Compliance for Life Science Professionals

Don't Worry…After All, What Can FDA Do to Us?

2011-05-16T15:34:00.001-04:00

Written By: Jeff Boatman - CQA, Senior Subject Matter Expert, Quality Systems, QPharma

Quite a lot, actually!

Something that I often hear as I travel around the country preaching quality systems, Agency guidances, and Best Practices is some variety of: "I read the regulations and it doesn't say we have to do that so we won't." Often, the person making that pronouncement is a lawyer or an MBA with little experience in the real world of regulated industry and who has no personal knowledge of the range of tools that FDA—or any regulatory body—has at its disposal to make life difficult for recalcitrant firms. I’ll recap some of these, both from the news and my own experiences, in the hope that the reader may learn that instead of asking “how do we fight them,” perhaps the correct question should be “why are we fighting them at all?”

Don't get me wrong; FDA is made up of people who misinterpret requirements, let emotions and personal agendas color their decisions, and are just as bullheaded and plain wrong as anybody else. I’ve had my disputes with them, in fact I’m in the middle of arguing a client’s point right now. But when a consultant who’s been in industry for 20+ years makes a recommendation, or FDA writes a Guidance or a Compliance Guide, there’s usually a pretty good reason for it and perhaps your time might be better spent trying to understand that reason, and why it does or does not apply to you, than arbitrarily deciding “I don't have to do that so I won't.”

1. Greasing the Skids

This leads me to my first example. In my Quality System Regulation training, I used to recommend to all my medical device clients that they register with FDA while they were still in the design control phase. After all, it didn't cost anything (at the time) and was one less thing to worry about later on.

Well, of course a client—more specifically, a client's lawyer –looked up the regulation and noticed “oh, it doesn’t require registration until 30 days from commercial distribution. We’re nowhere near that so we don't have to do it.” And of course, they never came back to the consultant (me) for whose practical, real-world experience they were paying, to find out why they might want to register even if the regulation didn’t require it.

A few months later, I got a panic call from the client – the U.S. Customs Service had put a hold on their desperately needed materials for an ongoing clinical study. You can probably guess why: Customs had checked their database and found that the company had no FDA registration number! Fortunately, I knew the FDA liaison at the Customs’ office in Port Elizabeth and was able to get the product moving with minimal delay. So here's something that the consultant knew, but which you won't find in any regulation: having a registration can help get your materials through Customs. (Note that since FDA now charges to register and to re-register, I no longer give this blanket advice; but it is still something worth considering.)

2. The “Guidance” Document that's Anything But

If there’s one source of pushback I get from clients that tops the list, it’s that they don't have to follow an FDA guidance. Mind you, if I heard that they don't have to follow a guidance because they've analyzed the document and found that it does not apply to them—or that they already employ systems that are even better—I’d be very happy. Unfortunately, that’s rarely what happens; it’s usually “if it’s not in a regulation then we don’t have to follow it.” Au contraire – if it’s not in a regulation then perhaps you cannot get a 483 for not following it (maybe – try telling that to the authors of FDA’s new guidance on Process Validation), but there are all sorts of examples why that attitude is less than helpful.

For example, FDA has a guidance document on hemodialyzers; if you follow that guidance, then your product will be classified as Class II and you can market it on a 510(k) clearance, which is a far cheaper and faster way to get to market. If you don’t follow it, then to be sure, FDA cannot cite you and the Justice Department will not show up to handcuff you…but your product will automatically become a Class III device, requiring Premarket Approval and millions of dollars and years of extra work to market.

A similar and more general guidance is the one for Part 11. On many of my audits, I’ve made observations that firms don’t have inventories of their computerized systems and written risk assessments. “That’s not in a regulation, so we aren’t going to do that!” That’s absolutely correct – and absolutely self-defeating, because having those inventories and risk assessments allow you to reduce your controls and validation coverage below that strictly required by 21 CFR 11.10, 11.50, and (arguably) 820.70(i). By refusing to follow the guidance, you are condemning your firm to have to follow the strict and (even by FDA’s own admission) sometimes absurdly onerous requirements that are in the regulation.

Speaking of Part 11, I remember a statement in one of the drafts floating around in the early 2000s. Now this was not only a guidance, it was a draft. Surely it carried no weight! Until you read the clause “This draft guidance is used by FDA staff in conducting inspections.” There’s nothing “optional” about that at all – that document told you what the FDA inspector will be looking for, so shame on you if you ignored that invaluable information!

Finally, on January 15th of this year, FDA issued a Final Guidance on the subject of registration of tobacco products. This document, clearly marked “CONTAINS NONBINDING RECOMMENDATIONS” (hah!), set forth the rules for tobacco manufacturers to get in their “905(j)” submission reports within three months (i.e. by this past March). Companies that failed to do so in accordance with the guidance are guilty of selling misbranded product, liable to confiscation and legal action.

“Nonbinding” my eye!

3. The Mystery of the Mandatory Optional SOP

Here’s an example of why you sometimes need to find a true Subject Matter Expert, and not just tell an employee to “go read the regulation.” Under 21 CFR 820.30, manufacturers and designers of Class II and Class III medical devices must have written procedures for design inputs, outputs, verification, validation, review, and transfer. 21 CFR 820.30(j) requires you to maintain a Design History File on your product. But nowhere does it say that you must have a procedure explaining how you maintain that file. So if you don’t have such a procedure, FDA cannot possibly write you up. No 483, no Warning Letter, no Consent Decree.

Of course, just because you are not gigged for a regulatory violation doesn’t mean your submission will actually get approved, and in this case it won’t. That’s because buried inside FDA’s guidance (yep, yet another guidance document) on quality information submitted in Premarket Approval applications is a list of procedures that must be provided before FDA will review your application…and your procedure for maintaining your Design History File just happens to be one of them!

4. Obey the Law

“Finished dosage form” pharmaceutical companies must produce drugs in compliance with the Good Manufacturing Practices of 21 CFR 210/211. It says so right in 210.1(a) and 210.3(a)(3). It doesn’t say anything about the vendors of the drug firm, though. Sure, there is an expectation that a drug firm ensures that their vendors provide quality products meeting their expectations (that whole “safety, purity, identity, and quality” thing, plus there’s an implied expectation under 21 CFR 820.50(a), applicable to a drug firm under 21 CFR 820.1(b) – you did know that, right?), but surely FDA cannot directly cite a vendor if the regulation doesn’t give them that authority.

À nouveau, au contraire! FDA regularly inspects Active Pharmaceutical Ingredient manufacturers and cites them against Part 210/211, as guided by ICH Q7A (yes, another of those pesky guidance documents)…because the predicate Safe Food, Drug, and Cosmetic Act’s definitions of adulterated (21 U.S.C. §501(a)(2)(B)) and drug (21 U.S.C. §201(g)(1)) authorizes them to do so.

5. Recalls, Recalls, Recalls

In case you missed this, FDA just got sweeping new authority to preemptively order recalls of food products. Prior to 2011, FDA only had such statutory authority over a narrow subset of foods (baby formula, acidified canned products); they’ve also had this authority over medical devices for years. This underlines a common confusion about which regulations actually cover recalls: generally, they’re described in 21 CFR 7, but because Congress has granted FDA preemptive authority over various industries over the years, Part 7 is often supplemented by an industry-specific regulation (in the case of devices, you’ll find those additional regulations in 21 CFR 810).

There was a move to include preemptive drug recalls in the Food Safety Modernization Act but it got dropped…for now. I expect the McNeil situation to re-ignite this debate in Congress, which had quieted down a bit since the last person was killed by adulterated heparin.

6. Miscellany

FDA’s ability to order recalls—along with their power to refuse or rescind Certificates of Foreign Governments, detain product at Ports of Entry (as opposed to outright confiscation requiring court order), suspend Clinical Trials, and their greatly underappreciated ability to pick up the phone and call Labor, EPA, OSHA, Customs, etc.—has rarely been diminished during their entire history and in fact continues to increase with time.

Often forgotten is the fact that FDA has non-judicial administrative options beyond just the approving or clearing of products, especially the rarely-invoked but powerful federal debarment of individuals. Think debarment is just a personal matter? Consider FDA’s recent move to debar the CEO of Forest Labs in connection with marketing shenanigans – if he is debarred, then he must either leave company management or Forest will lose its ability to submit for federal reimbursement from sCHIPS, Medicaid, Medicare, and Veteran’s Administration programs – money that few large pharmaceutical companies can survive without. FDA’s stated stance is they can debar him irrespective of proving his actual knowledge of wrongdoing because debarment is not a legal proceeding. As FDA chief Margaret Hamburg continues to look for outside-the-box ways of bending wayward firms to her will, I expect to only see more actions like this because FDA is simply not seeing companies change their ways in response to mere fines.

7. When You Can’t Beat ‘Em, Join Their Competitors

Speaking of outside-the-box thinking, I’ve saved for last the item that triggered this blog entry. Consider KV Pharmaceuticals: GMP issues, recalls, FDA inspections, 483s, Warning Letters, Consent Decree, third-party oversight. FDA essentially shuts down their operations, two of their three divisions promptly go out of business, several rounds of layoffs. Income stream is, well, challenged.

In a move no doubt intended to inject some much-needed cash, KV buys the exclusive rights to distribute a prenatal care medication, Makena, an Orphan drug that provides critical health benefits and for which there is no real alternative. Note that KV is a generics company, so this is something of a foray into the tradename business for them; patent owner Hologic developed the drug in conjunction with NIH.

The medicine in Makena was a true bargain at $20 per injection. KV decided to raise the price a little: $1,200 a dose!

FDA doesn’t regulate pricing, so what exactly can FDA do about this? Here’s what: FDA just announced that they intend to exercise “enforcement discretion” against pharmacies that compound their own version of Makena and sell it to prescribers. It’s unclear what recourse KV or Hologic may have in suing these pharmacies for intellectual property violations, but with this announcement FDA has basically declared open season on KV by promising that if you make your own version of Makena (and presumably don’t sell it for $1,200) then FDA will not go after you for misbranding.
I bet KV management didn’t see that one coming!

Conclusion

All too often, I find that Top Management of Life Science firms believes that the best and most cost-effective strategy is to always do as little as possible. That top-level philosophy inevitably trickles down to middle management and brews a culture of noncompliance – spend your time on figuring out ways to avoid complying with FDA’s recommendations rather than efficient ways to implement Agency expectations.

In my nearly quarter-century in this industry, I have yet to see a single instance where this approach actually worked, but I have seen countless cases where it backfired in ways that management never dreamed of. In the March 2005 Gold Sheet (volume 39, number 3), no less a personality than David Elder, Director of Enforcement for FDA's Office of Regulatory Affairs, said it best:

“If we ask a question and the answers are so guarded that they are one-syllable answers, you are creating an impression. When you could clarify something, but choose not to under corporate policy or advice of counsel, you are creating an impression. I do not know if it is doing you any good, because you are extending the period of time we will be there...if we do not get the full answer that we are looking for, we are going to ask the question six different ways, and on different occasions. The people that are proud of their operations...have nothing to hide.”

When FDA finds that a firm goes out of its way to avoid adopting best practices and Agency recommendations, that creates an impression. Impressions are formed by strategies, strategies are formed by culture, and culture is established by management’s attitude. If Top Management doesn’t understand that FDA has ways of punishing them that go far beyond anything taught in an MBA class, they may be dooming the very business objectives they are trying so hard to achieve.

The Twelve Towers - A Project Management Novel: Excerpt 3 – The Project Management Plan

2011-05-02T15:20:00.001-04:00

Written by Bruce Fieggen - V.P. of Project Management, QPharma

Below is the third excerpt from the Project Management novel Bruce Fieggen, QPharma’s V.P. of Project Management, is writing in his ‘spare time’. The novel tells the story of a Gwilym, a Project Manager, charged with building twelve towers scattered throughout King Arthur’s Britain. Gwilym’s assistant, Fred, also appears in this excerpt. This excerpt takes place in chapter two of the book, a year after the previous excerpts and after the first tower is completed.

Readers, think about the various projects you are tasked with and see how you can use the tools shown in these blog posts to assist you in ‘building your towers’.

This third excerpt shows the beginning of the development of the third tool: The Project Management Plan.

The next morning, as they loaded their cart with their few possessions, the largest of which were the two scroll boxes, they were happy to see Fred ambling up the road, leading a laden pony. “Tha were serious last night, weren’t tha? Me ma said tha were just bein’ kind, and that I were a fool to believe tha.”

Gwilym clapped the man on his shoulder and told him to pack his goods in the wagon and tie the pony behind. “We’ll all be comfortable in the cart together.”

The three of them picked up the pallet, together with the sleeping babies inside and stowed it safely in the space left between the boxes. With a last look on the quiet village, they headed off on the eastern track to meet the Roman road.

The cart was not heavily laden so they made steady progress but the bumping threatened to wake the babies. Fred was getting more anxious and finally burst out, “Tha knows I’m t’better driver. Give me t’reins.” Taking these from Gwilym, he steered the cart around all the bumps in the road. They traveled away from the coast and through a country unspoiled by Saxon raids. While Bleddyn stared silently at all the new sights around him, Gwilym and Bleddyn discussed the new project.

“I’ll know more when I get on the site, but Sir Kay has given me a new charter that explains a lot. He likes these charters and gives them out to all the new builders.” Gwilym smiled at Fred who touched his nose significantly.

“That were a great idea of tha, gettin’ it all written down so none could argue. So what do this one say?”

“Well, it’s curious. They want a watch-tower; I suppose it is one of a series of watchtowers leading from the north coast inland to warn of marauding Norsemen. But if it is just for passing on signals, why is it built to hold a garrison of men and to be defensible? There is a ferry there across the Ouse, so perhaps it needs to defend the ford? We’ll have to see when we arrive.”

“And how will we be makin’ this tower better than t’last one?”

Gwilym thought long and hard. “There were a lot of problems last time and they seem to all stem from not knowing exactly, what everyone wanted. The charter showed what the king wanted, and I did well following that exactly, but I think instead we need more of an overall understanding from the king, and allow the people who will be using the tower and the people who have to build it to have some say in what the real requirements are. And from there we can figure out exactly what we are doing and how to get it done.”

Fred was humming softly to himself and thinking hard about something. “What were you just doing?” asked Gwilym when Fred seemed to be finished.

Fred blushed deeply and mumbled, “Oh, just trying to remember what tha told me.”

“Please explain.”

“Well, tha knows I cannae write. I’m too stupid for that. Even your son can write and here I am, a grown man but too stupid. So I remember things by songs. I know, it be stupid but it’s me only way.”

“Fred. You’re not a stupid man. I’ve seen you grasp the concepts of building faster than any other man I’ve worked with. Ignorance of the skill of writing is not stupidity. Men were remembering things by song long before someone thought to write them down. These scrolls I carry are just the written words of long-ago songs. But sing me your song about tower building. I’d be privileged to be your first audience.”

Fred alternated blushing and smiling and stammered out that it wasn’t a song about building towers. “I figure that t’song would work for any kind of buildin’, any kind of project for that matter. It be a song about gettin’ a group together and doin’ sommat…when they be not thy men…when tha not be in charge of them tha see?”

Gwilym smiled in genuine respect and asked the man, “Sing me your song. I think I could learn a lot from it.”

“Tha be the one teachin’ me. I’m just rememberin’ it. T’song’s not ready yet but I can give tha a taste for it.”

“Please do.”

If you want your project to be no harder
Go to the king to sign your charter
Make sure it says how small or large
And says quite clearly that you’re in charge
It should show how it meets the kingdom’s need
And keeps all the others from their greed

It went on like this for a while, describing the charter, the list of stakeholders and some awkward verses about scope and requirements. Fred stopped then and said he had to work out those last verses better when he knew more about them and had seen how they work.

“Fred! You’ve done a great thing here. Please keep building on your song. When it’s done you’ll have the guide for Project Management. I can write it down for you in a scroll and you’ll be famous as a teacher of future Project Managers.”

“Ach! Tha’s just havin’ fun wi’ me now. Leave off.”

“No Fred. I’m quite serious. You’ve created something important. Please do keep it going.”

If you are enjoying the excerpts and would like to read more of the story in order, go to http://twelvetowers.blogspot.com/ to read the first five excerpts. A new excerpt appears here every two weeks

What’s The Deal with McNeil’s Consent Decree?

2011-04-25T13:14:00.000-04:00

Written by Clinton Ballard - Validation Specialist, QPharma

After nearly 2 years of recalls totaling more than 47 million units of very popular over the counter (OTC) drugs (Sudafed, Tylenol, Rolaids, Sinutab Sinus, Benadryl, Motrin, and Zyrtec) on March 10, 2011 McNeil-PPC, Inc. subsidiary of Johnson & Johnson Services, Inc. (J&J) signed a consent decree with the FDA covering manufacturing facilities in Las Piedras, PR, Fort Washington, PA, and Lancaster, PA.

The details of the Consent Decree requires McNeil to destroy all drugs under their control that have been manufactured or recalled from the Fort Washington, Las Piedras, and Lancaster facilities since December 2009 to the date of entry of the Consent Decree. McNeil is allowed to continue manufacturing operations in the Las Piedras, PR and Lancaster, PA facilities but manufacturing and distributing drugs from its Fort Washington, Pa., facility is prohibited until the FDA determines that its operations are compliant with federal regulations. McNeil must comply with a stringent corrective action plan across all three sites set forth by the FDA. The full details of the corrective action timetable are outlined in the Consent Decree. The key arrangements of the Consent Decree requires that McNeil establish and implement a quality assurance / quality control (QA/QC) program that is applicable to cGMP regulations and in coordination with J&J’s corporate level QA/QC program. McNeil is also required to hire an independent cGMP expert to: inspect all three facilities to determine whether the violations the FDA found during their audits have been corrected, ensure that proper manufacturing processes are in place, and verify that the agreements made in the Consent Decree are met. After certification from an independent expert, the FDA will determine if the facilities are in compliance. If McNeil maintains all three facilities in a state of continuous compliance with applicable regulations and the Consent Decree for at least sixty (60) months they may petition the courts for relief from the Consent Decree.

McNeil is required to pay the cost of all of the FDA investigative expenses while under consent decree. As of the date of entry of the Consent Decree the cost of FDA inspection is $87.57 / hour, the cost for any laboratory work is $104.96 / hour, and $0.51 / mile for travel. If McNeil violates the agreements of the Consent Decree, the FDA can order McNeil to cease all manufacturing, recall products, and take other corrective action, including levying fines of $15,000 for each day and an additional $15,000 for each violation of the law, up to $10 million annually.

J&J will end up paying a nice chunk of change for their McNeil sites’ failure to comply with federal regulations. But, considering the repeated recalls and how long the FDA has been telling McNeil, to clean their act up McNeil got off rather easy based on the agreements of the Consent Decree. McNeil is not required to cease production of any of their recalled products which is usually agreed upon in most FDA consent decrees. McNeil was also able to circumvent paying a hefty disgorgement fee like Schering-Plough who signed a consent decree with the FDA and was required to pay $500 million dollars to the United States Treasury back in 2002. J&J CEO, Bill Weldon was also not listed as a defendant on the Consent Decree but in past consent decrees involving Schering-Plough, Abbott Laboratories and Genzyme the CEO was listed as a defendant. In McNeil’s case the Vice President (VP) of quality and the VP of operations for OTC products are listed as the defendants. Essentially this Consent Decree is a slap on the wrist for McNeil and merely shines light on the implicated McNeil sites’ lack of commitment to “high quality” as stated in the J&J’s corporate company credo.

J&J is a leader in the healthcare product industry, reporting $61.6 billion in sales for 2010. OTC pharmaceutical sales made J&J $4.6 billion in 2010 accounting for 7.7% of their total sales. Recalls were estimated to have cost J&J $900 million in sales in 2010. Considering the amount of money on the line and the brand J&J has created with their McNeil Consumer Healthcare product division it would not be in the company’s or stockholders best interest to not come out of this Consent Decree as a transformed company with a newfound commitment to the J&J Credo.

The transformation has already begun. Recently J&J has announced that they will be splitting the McNeil Consumer Healthcare unit up into divisions by geography and product type, allowing for more focus on consumer drug operations. Under this new infrastructure, the product lines will be organized into four categories: OTC drugs, skin care, oral care and women's health. The regional divisions: Asia-Pacific, North America, Europe/Middle East/Africa and Latin America will market all of the product lines.

Fortunately J&J can afford the cost of coming out of a FDA consent decree, but do they have the necessary internal McNeil leadership and support required to guide them out of this Consent Decree is a question that only time can answer. Stay tuned as we continue to monitor J&J’s attempt to come out of this Consent Decree.

Frankenfish Part 2

2011-04-19T10:27:00.000-04:00

Written by Paul Melamud - Validation Manager, QPharma

Continued ...

ANSWERING THE QUESTION – HOW FDA REGULATES THIS PRODUCT

The question posed at the start of this article asked you to try to figure out as what kind of product FDA regulates this salmon. Most people say “food”, because of course this fits the definition in 21 USC 321(f):

The term "food" means (1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article.

While this salmon is most certainly a food, it is not regulated as such, because this product is much more than that (as we will see in a minute). It is also worth noting that food producers (such as farms) and processed food manufacturers do not need to do anything other than register with FDA – there is no formal pre-marketing review/approval process.

And I can hear now “but surely I am partially correct, this must be some sort of combination product!” – and to be honest, I agree with that in spirit. Frustratingly, the definition in 21 CFR 3.2 for combination products (which stems from 21 USC 353(g)(1)) excludes food as a component of a combination product! The likely explanation for this is that this concept was intended to reflect only therapeutic products with differing approval pathways. Perhaps this definition will be updated if AquaBounty’s salmon is approved. Anyway, no, you can’t win this argument with me on a technicality, either =).

So how is this product regulated? Let’s look at the other types you were given to choose from:

This product cannot be a dietary supplement, which (summarized from 21 USC 321(ff)) is considered a type of food that contains a vitamin, mineral, herb or other botanical, amino acid, or some other type of ingredient to supplement the diet by increasing total dietary intake.

This product is also not a cosmetic, which is defined in 21 USC 321(i) as an article intended to be applied to the human body “for cleansing, beautifying, promoting attractiveness, or altering the appearance”, although this technically does not include soap (and our fishy friend is obviously not a soap, either!).

So – is this a drug, biologic, or medical device, and then, “human” or “animal”? Have you figured it out yet?

Let’s look at a boiled down version of the definitions:

1. Drugs (human and animal) are ALL of the following (per 21 USC 321):

Recognized in an official compendium (like the USP/NF)
Intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, and/or a product that affects the structure or any function of the body of man or other animals

2. Medical Devices (human or animal) are ALL of the following (per 21 USC 321):

Recognized in an official compendium (like the USP/NF)
Intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals
A product that does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.

3. Biologic products are ALL of the following (per PHSA 21 USC 262, referenced to by FDA in 21 CFR 3.2):

A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide)… (or any other trivalent organic arsenic compound)
Applicable to the prevention, treatment, or cure of a disease or condition of human beings

The trick to answering this question lies in understanding that regardless of the final use of the product, the genetic change to the animal is also subject to FDA regulation because it fits one of the definitions. Specifically, if you take a salmon egg, change its structure (by adding DNA) and function (salmon grows faster), and then later use that salmon for food, then of the three types above, only “drug” is defined by a chemical change that alters the structure and function of a body. From there, as this is a change to an animal and not a human, “animal drug” is your correct answer – this product is regulated as a new animal drug.

The Center for Veterinary Medicine (CVM) is indeed responsible for the regulation of GE animals, whether they are intended for human consumption or not. As of today, there are no CFRs for GE products, and only one guidance document (approved 01/2009):

CVM GFI #187 Regulation of Genetically Engineered Animals Containing Heritable Recombinant DNA Constructs (PDF - 128KB).

FINAL THOUGHTS

The three days of meetings provided plenty of criticism of the science used by the FDA to determine that the GE salmon is safe, as well as of the legal arguments that would not require special labeling of the salmon as “Genetically Engineered”. Critics call this modified salmon a “Frankenfish” that could cause allergies in humans and the eventual decimation of the wild salmon population.

Will the public have an appetite for this product? GE is already widely used for crops, but the government until now has not considered allowing the consumption of modified animals. Although the potential benefits – and profits – are huge, many people have qualms about manipulating the genetic code of other living creatures.

But what do the leaders at FDA, the Department of Health and Human Services, and even the White House, want? The approval of the GE salmon, as of now, could go either way.

What do you think? Would you eat a piece of salmon if you knew it was one of these genetically engineered variety? If you would knowingly avoid it, would you care at all if you found out after the fact? Do you think the benefits outweigh the risks?

Frankenfish Part 1

2011-04-05T13:19:00.005-04:00

Written by Paul Melamud - Validation Manager, QPharma

INTRODUCTION
Sometimes, I don’t think FDA is given enough credit. Yeah, I know it’s always fun to armchair-quarterback their decisions and policies, or to scoff “how could they let that happen”s at some company’s shenanigans… But every once in awhile, they get something really cool to play with, and they give the science (and the company) a legitimate chance to justify themselves. And if you’re working for one of these groundbreaking, innovative sorts of companies, then you’ll agree it’s important to be able to figure out what kind of product your new “something” is, so you can start the laborious process of getting it approved the right way.

In that regard, I’m going to tell you a little story about salmon eggs, and the part I find most interesting is how FDA regulates this product. Do you think you can figure it out before I spill the answer? Let’s limit your choices – is this product regulated as a food, dietary supplement, human drug, animal drug, therapeutic biologic product, cosmetic, or medical device?

Let’s take a step away for a moment, though. As the world’s populations grow, fishing and hunting increase to meet rising demand (among other things, of course), and, as history shows, this can lead to depopulation, extinction of species, habitat destruction, and environmental activists sabotaging boats.

As you likely know, farming in general has been a dying art, subject to higher regulations and costs of doing business, and many are on the verge of collapse, unable to make a profit while trying to meet such high market needs. Consider the delicious world of aquaculture (AKA “fish farming”, AKA “the Blue Revolution”) for example, which is able to fulfill around 50% of the world’s piscine appetites and thereby circulates around $80B dollars.

In an effort to thwart these depressing factors, scientists have been teaming up with farmers to create new products that should help provide equal or more of the product at lower cost and impact. It is with one of these products that I start my story of roe.

ENTER THE FRANKENFISHAs recently as this past October, the government held three days of meetings about whether to approve AquaBounty’s AquAdvantage® salmon – a transgenic species whose eggs are genetically engineered (GE) to grow twice as fast – for human consumption. Some people have been referring to this product as the “Frankenfish”.

AquaBounty intends to market this product, making the following claim in its FDA application:

“AquAdvantage® Salmon (AAS) reach market size twice as fast as traditional salmon. This advancement provides a compelling economic benefit to farmers (reduced growing cycle) as well as enhancing the economic viability of inland operations, thereby diminishing the need for ocean pens. AAS are also reproductively sterile [except for the small breeding stock maintained in land, which eliminates the threat of interbreeding amongst themselves or with native populations, a major recent concern in dealing with fish escaping from salmon farms. AAS grow faster and reach mature size earlier than standard salmon, but they do not grow to be larger. Mature AAS are indistinguishable from their conventional counterparts.”

The website www.eatocracy.com has provided an excellent summary of what alterations make this salmon different from typical “wild type” Atlantic salmon:

“The fish’s rapid growth will be boosted by the injection of a combination of a growth gene (GH-coding sequences) from the Pacific Chinook salmon and genetic material (the AFP gene) from the ocean pout – a large, eel-like fish – into the fertilized eggs of Atlantic salmon, making the recombined DNA present in cells throughout the body of the fish. The Chinook gene promotes the growth to market size, and the pout gene allows the fish to grow in the winter as well as the summer.”

Growth rate comparison of an AquAdvantage® Salmon

vs. a non-transgenic (wild-type) Atlantic salmon.

Size comparison of an AquAdvantage® Salmon (background) vs. a non-transgenic

Atlantic salmon sibling (foreground) of the same age.

So far, FDA has agreed with AquaBounty’s assessment that the salmon is as safe to eat as the wild variety, but they have not yet decided whether to approve the product. If approved, this will be the first GE food animal available in US supermarkets!

PROS AND CONS

As you can imagine, this controversy stems from a number of pros and cons that are very important considerations as GE technology continues to increase. Here is a quick summary, with a nod toward www.frankenfish.com for having compiled this information succinctly:

....... So, any guesses yet as to how this product gets approved and which part of FDA regulates it? Stay tuned for this author’s next blog entry on Monday June 6th, 2011, in which he will walk through the different product types and why or why not the FDA regulates the Frankenfish in that manner. In the meantime, share your guesses and your other thoughts about this product with us!

The 21st Century Initiative – PAT and Validation

2011-03-28T13:52:00.000-04:00

Written by Frank Jakubiec - Validation Engineer

Late last year, while exhibiting for ISPE at the New Jersey Science & Engineering Festival (October, 2010 in Clifton, NJ), I had a short discussion with an attendee regarding the adoption of Process Analytical Technology (PAT) and its impact on Validation. While the person was of the opinion that PAT will reduce or eliminate the need for validation, I contend that the adoption of PAT is an opportunity to incorporate validation into processes at an early stage in their life cycle.

The FDA considers PAT to be ‘a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.’1 Practically speaking, PAT is a form of continuous process monitoring that can include feedback loops connected to process controls. Thus, PAT appears to be a potentially powerful and comprehensive tool for pharmaceutical research, development, and production.

The FDA’s position on ensuring drug quality includes the following two relevant points:

Quality cannot be adequately assured merely by in-process and finished-product inspection or testing.
Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications.2

Viewing the FDA’s definition of PAT through the lens of the above two points, it is clear that adopting PAT is not, in and of itself, the ‘magic bullet’ for ensuring final product quality. PAT is merely one part of the toolkit that the FDA intends to be used across the industry.

Qualification and validation are generally necessary to demonstrate and document control over the design and performance of one’s products and processes. Despite its capabilities, when PAT is implemented, it must be validated for it to provide any value and contribute adequately to process and product quality, performance, and understanding. In addition to being used during production, PAT can be introduced into the early stages of the Product Development Life Cycle and, when the implementation is properly qualified and validated, the data obtained can be leveraged in many aspects of your operations including: Product and Process Design, Risk Assessment and Dynamic Control Plans, Root Cause Analysis and CAPA, Process Optimization, Qualifications/Validations, Internal/External Audits, and Regulatory Submissions.

The FDA’s 21st Century Initiative, most notably PAT, is part of the paradigm shift from Quality by Testing to Quality by Design, which will be discussed in an upcoming blog post.

¹United States. FDA. Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. Washington: GPO, 2004.
²United States. FDA. Guidance for Industry: Process Validation: General Principles and Practices. Washington: GPO, 2011.

FDA Considers Regulation of Genetic Testing

2011-03-21T10:29:00.002-04:00

Written by Gregg Mauriello - Validation Manager, QPharma

Over the past several years, an emerging market in direct-to-consumer (DTC) genetic test kits has developed. DTC genetic kits give consumers the ability to freely gain access to their own genetic information without a doctor’s permission. The FDA feels that marketing genetic tests directly to consumers introduces potential risks; with this information a patient can then make decisions that would have the potential to adversely affect their health. There are many who believe that excessive regulations will raise the cost of DTC kits and will hinder the development of smaller genetic companies by raising the cost to start a new business.

Last year, Dr. Jeff Shuren, Director of the Center for Diseases and Radiological Heath (CDRH) presented the FDA’s recent activities related to DTC genetic tests to the House of Representatives. He stated that:

[the] “failure to validate the accuracy, reliability, and clinical implications of a test can result in patient harm from misdiagnosis, failure to treat, delay in treatment, inappropriate treatment, or avoidable adverse events”

Since the test kit is considered an in-vitro diagnostic (IVD) test and is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, the test kit is classified as a Medical Device. Congress gave FDA the authority to regulate medical devices, including in vitro diagnostic tests in the 1976 Medical Device Amendments to the Federal Food, Drug and Cosmetic Act (FD&C). An IVD test such as a genetic test kit may be classified as a Class III device and would be subject to pre-market approval requirements. Only test kits that would be used for the diagnosis of disease or condition would be considered a medical device, a test kit to determine ancestry would not. The FDA would also regulate the laboratory-developed tests (LDT) utilized to analyze the test kits to ensure the accuracy of the results. In recent years, the FDA has found problems with LDT’s which include faulty data analysis, exaggerated clinical claims, fraudulent data, lack of traceability, poor clinical study design and unacceptable clinical performance. The FDA feels that pre-market reviews of LDTs would ensure that tests are evaluated for analytical validity. Validation of the tests would be important to reduce the risk of misdiagnosis and inappropriate treatment decisions.

Excessive regulations would raise the cost of testing for the consumer. Along with the higher cost, the FDA would also require a prescription for the test and a qualified practitioner would have to perform the test. Currently, consumers order the test kit and can collect the samples to be tested in the convenience of their own home before sending the test kit off to the vendor for analysis. Interpretation of the data would have to be performed by a qualified practitioner as well. This lack of convenience may hinder the sales of genetic testing as well.

Is the FDA taking away the right for people to obtain their genetic code or are they looking to make sure that the public are obtaining the correct interpretation of this information? Will regulation take the genetic testing out of the hands of the consumer and will it hinder the development of new innovations in the industry? When the FDA approves the regulation of genetic testing kits, they will have to make sure that they find a balance to allow for the safety of the consumer, but allow the costs to stay affordable as well.

Who Wants a Strong FDA?

2011-03-14T10:19:00.001-04:00

Written by Jonathan Wozniak - Validation Specialist, QPharma

Last Valentine’s Day (14 Feb 2011) saw the release of the United States Federal Budget for Fiscal Year (FY) 2012. Included in this was a $4.4 billion budget request for the FDA. This request represents an increase of approximately $1billion or 33% since 2010. Budget proposals include increased investment in food safety initiatives, medical product safety, and regulatory science. This announcement came mere days after House Republicans unveiled a spending bill that included a $241 million cut to FDA funding for the remainder of FY2011 as part of a $100 billion overall spending cut package. The case for or against a strong FDA, however, does not divide clearly down party lines. As professionals in an industry directly regulated, guided, and affected by the strength of the FDA, we are right to wonder: who wants a strong FDA?

In March 2011, the Alliance for a Stronger FDA (an “alliance of patient groups, consumer advocates, biomedical research advocates, health professionals, and trade associations”) released a white paper entitled “The U.S. Food and Drug Administration: A Cornerstone of America’s Economic Future.” (http://fdaalliance.files.wordpress.com/2009/11/fda_cornerstone_of_american_economy_final.pdf)

In this report, the Alliance outlines a number of ways in which the FDA is critical to the future of economic growth. The first main argument put forth in the paper is, roughly, this:

A strong FDA increases the safety and effectiveness of drugs and medical devices.
Increased safety and effectiveness of drugs and medical devices increases consumer confidence.
Increased consumer confidence fuels the industry; people buy more products from an industry they trust.

The second argument suggests that a better-funded FDA will have more, better-trained employees (the FY2012 Budget Request claims 1,251 new employees could be hired). This will expedite approval times and increase the frequency and effectiveness of inspections. For example, the FDA has a two year backlog of generic drug applications due to funding restraints. Better FDA funding means more employees tackling this paperwork. This could result in an increased availability of generic drugs, which saves the consumer money and decreases overall health care spending in America. The Healthcare Reform Act passed last year (H.R. 3590) also included a provision to remove the cap on members of the National Health Service Officer Corp and increase the National Health Service Corp budget by over $8 billion between 2010 and 2016. This would increase the size and reach of the American public health response, but the program- like most current spending initiatives- is now in question. The Alliance also points to the potential consequences of a weakened FDA, namely the increased potential for food borne illness outbreaks and increased frequency of drug and device recalls.

The FDA makes a number of strong claims to its effectiveness and importance: it creates jobs, increases safety and effectiveness of drugs and devices, increases consumer confidence fueling industry growth, and reduces health care costs.

However, the FDA is not without its critics. There are many who believe the FDA is actually too strong, as it is. The first major criticism is that raised by Republican spending cuts: people everywhere have to tighten their belts in difficult economic times; the government should have to do the same. Increases in FDA funding are not necessary, critics claim, because the system works fine as it is. Increased spending on food safety is unnecessary as food borne illnesses are rare. This is, generally speaking, the argument that a strong FDA costs too much. Rep. Jack Kingston, Chairman of the House Subcommittee on Agriculture, Rural Development, Food and Drug Administration, and Related Agencies, commented after the passage of the Food Safety Bill in January, “There is a high possibility of trimming this whole package back… the system we have is doing a darn good job.” He also noted our food safety rate is “very high, 99.99% safe”. (http://www.foodsafetynews.com/2011/01/fda-food-safety-funding-still-on-chopping-block/)

The second major criticism of a strong FDA is that industry growth is actually stifled. There were only 21 new drugs approved in 2010 (by 21 separate companies). Extra clinical trials, extended review processes, and comparative effectiveness studies are just a few of the measures implemented by the FDA that actually deter companies from new product development. The measures designed to increase safety and improve patient outcomes inherently delay approvals, and these delays cost time, money, and lives. The potential stagnation of innovation in the industry creates opportunities for foreign markets to catch up to the American pharmaceutical and medical device industries moving jobs and revenue overseas.

Meanwhile, FDA faces major statutory initiatives to introduce generic biologics and to require premarket clearance of tobacco products; lack of sufficient personnel to execute these programs could result in their getting shelved, or alternatively, firms facing endless delays; these two alternatives will definitely make some people happier than others, but will increase uncertainty no matter who winds up the winner.

So where should we stand? As professionals in the industry it remains hard to say and might actually vary depending where we work. Drug and device makers might appreciate a weakened FDA in the short term. Inspections, warning letters, and sanctions would be fewer and farther between. Pre-market approval processes could be restructured to facilitate new product release. Drugs not subject to strict comparative effectiveness studies will remain on the market longer. These parties, however, should not forget that approvals may take longer in an understaffed agency, and the potential for recalls increases with an expedited approval process. (http://www.latimes.com/health/la-na-medical-devices-20110215,0,4206876.story)

As a consulting firm dealing largely in compliance and regulation, it would seem on the surface that a more active and involved FDA would create more work for us. The more inspections, rulings, warning letters, and white papers- the more work there is for us helping our clients comply. We would not be shortsighted, however, and ignore the possibility that a strengthened FDA could stifle industry. After all, a company not making money is not hiring consultants.

As experts in industry, we have a responsibility to keep an eye on the strength of the FDA – especially in a time of complicated economic turmoil and incremental health care overhaul. We can help our companies position themselves better for change when we are able to anticipate shifts in the strength of the FDA as a regulating body and what they will mean for industry. A large part of our doing business—from staffing, to setting rates, to training—depends on where and how we anticipate the FDA to act; while the strength of the FDA, predicated by its funding and staffing, largely determines its reach and impact.

Purchasing Medications Online

2011-03-07T10:15:00.000-05:00

Written by Teresa Jaworski - Subject Matter Expert, QPharma

Using the Internet to purchase items has become a very popular and convenient way of acquiring things we need without leaving the comfort of our homes. In addition, the Internet allows us to browse many different websites quickly so that we can compare costs and buy products at the most affordable prices.

However, when purchasing medications online, we should be very cautious. You could purchase a drug that is not safe and put your health at risk. Many websites that sell medications online are not US state-licensed pharmacies or are not pharmacies at all. Therefore you run the risk of purchasing counterfeit medicines that contain dangerous ingredients; are not manufactured according to standards; contain the incorrect dosage of ingredients; are contaminated; are not labeled, stored or shipped properly; or have expired. Counterfeit drugs are illegal!

The FDA issued a draft guidance document dated July 2009, Draft Guidance for Industry: Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting, which will provide guidance for pharmaceutical manufacturers in using inks, pigments, flavors, and other physical-chemical identifiers (PCIDs) when making a drug product in solid oral dosage forms. The use of PCIDs will make it more difficult to counterfeit a drug thus making it easier to identify a genuine version of the drug. According to an FDA News Release dated July 13, 2009, “Drug counterfeiting is a serious public health concern,” said Commissioner of Food and Drugs Margaret A. Hamburg, M.D. “We look forward to working with industry to help ensure that consumers are not exposed to products containing unknown, ineffective, or harmful ingredients.”

A PCID is a substance or combination of substances with a unique physical or chemical property used to identify and validate a drug product. According to FDA, a substance used as a PCID should not adversely affect the identity, strength, quality, purity, potency, or bioavailability of the drug product. The PCID can often be detected by wholesalers or pharmacists however, in some cases an analytical instrument may be necessary to detect the PCID in order to determine if the drug products are genuine.

The FDA expects that most of the impending PCID ingredients are already being used as food additives, colorants, or other types of inactive ingredients and have already been established as safe. FDA recommends using the lowest amount of PCID that allows for identification of the product and recommends that the PCID be a substance with no medicinal effect. Refer to the draft guidance document located at www.fda.gov for additional information.

In a recent FDA News Release, the FDA warned consumers about a potentially harmful product, “Generic Tamiflu. The product did not contain Tamiflu’s active ingredient, Oseltamivir, but Cloxacillin, an ingredient in the same class of antibiotics as Penicillin.” FDA warned that using this product could result in an allergic reaction for patients that are allergic to penicillin including “a sudden, potentially life-threatening reaction called anaphylaxis, with symptoms that include difficulty breathing, chest tightness, swelling of the throat or tongue, hives, dizziness, loss of consciousness, or a rapid or weak pulse.”

Upon learning of the so called “Generic Tamiflu”, FDA purchased a package of the product without a prescription from a website that claimed to be an online drugstore. The “Generic Tamiflu” was received in a postmarked package from India. The product was stored in two blister packages with foil-backing labeled “Oseltamivir Phosphate 75mg. Capsules TM-FLU Capsules” and “Manufactured by: TRYDRUGS Pharmaceuticals PVT. LTD.” An FDA-approved generic drug for the prescription drug “Tamiflu” does not exist.

In another FDA News Release, dated January 25, 2010, the FDA warned consumers about a counterfeit version of the weight-loss drug Alli being sold at online auction sites over the Internet. FDA indicated that this counterfeit product was unsafe and illegal. “Alli is an FDA-approved, over-the-counter weight-loss drug that contains Orlistat as its active ingredient. The counterfeit version of Alli does not contain Orlistat; instead it is made with varying amounts of Sibutramine, a stimulant drug.” Laboratory testing completed by FDA determined that the dosing directions specified a dosage of three times the usual daily dose of Sibutramine, which could result in elevated blood pressure, stroke, and heart attack for people with a history of cardiovascular disease. Additionally, healthy people taking this product could suffer anxiety, nausea, heart palpitations, racing heart, insomnia, and small increases in blood pressure.

FDA continuously monitors the Internet and even makes purchases so they can test the drug products to verify product authenticity. However, consumers need to protect themselves as well by knowing how to recognize a genuine internet pharmacy. A genuine internet pharmacy will be licensed by the U.S. Board of Pharmacy and will follow the relevant laws and regulations. In addition, the National Association of Boards of Pharmacy Verified Internet Pharmacy Sites Seal (VIPPS Seal) provides a seal of approval to pharmacy sites that meet state license requirements. A pharmacy that carries this seal can be found at www.vipps.info.

New FDA Regulation for Medical Device Data Systems (MDDS)

2011-02-28T09:14:00.000-05:00

Written By Elise Miner - Validation Manager, QPharma

Earlier this month, the FDA proposed a regulation that will reclassify certain hardware and software products used with medical devices. The new regulation defines these products, known as Medical Device Data Systems (MDDS), as systems that are intended to provide one or more of the following uses:

The electronic transfer or exchange of medical device data from a medical device, without altering the function or parameters of any connected devices
The electronic storage and retrieval of medical device data, without altering the function or parameters of connected devices
The electronic display of medical device data, without altering the function or parameters of connected devices
The electronic conversion of medical device data from one format to another format in accordance with a preset specification

Previously, MDDS were categorized as Class III, high-risk and requiring pre-market approval. This was the case because all medical devices unknown prior to 1976 were automatically placed in Class III by default. However, according to the new rule, MDDS will now be Class I, low-risk and subject to general controls and quality standards. The rationale behind this reclassification stems from the amazing growth and development of the use of medical devices and MDDS over the past decade. Such expansion has led to new risk factors that did not previously exist.

But the changes the FDA are making to the MDDS rule affect both sides of the spectrum. It simultaneously enlarged the MDDS category to include more software that might have been thought to be unregulated, but also now captures products that might otherwise have been placed in higher risk categories.

Manufacturers finding themselves with products that fit the MDDS description must now adhere to all Class I requirements including registering with the FDA, listing their MDDS products, reporting adverse events and complying with FDA’s Quality Systems regulation. By the same token, manufacturers that had previously categorized their MDDS as high –risk now stand a less taxing path to market.

The rule is set to become effective on April 14, 2011. By May 14, 2011, companies that make MDDS must have registered with FDA and listed the MDDS product. By April 2012, companies making MDDS must have fully functioning quality systems and be in compliance with the medical device reporting rules.

Is this measure a preview of more to come? It proves to clarify the boundaries around this one particular class of products, but begs the question - When the FDA will take steps to further define and reclassify more software and hardware. At the very least, it’s a step in the right direction.

FDA Proposed Rule: http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-2325.pdf

Patient Assistance Programs are Consolidating

2011-02-23T08:45:00.002-05:00

Written by Michael Milunec - Manager of Operations PDMA and Fulfillment Services, QPharma

Pharma’s Mergers & Acquisitions impact on Manufacturer provided Patient Assistances Programs

Looking back over the past decade, Pharma mergers and acquisitions (M&A) have been an ebb and flow relationship with 2009 being a tidal wave. I am sure Pfizer /Wyeth, Merck/Schering-Plough and Roche/Genentech mergers were the number one contributing factors. In a ten year M&A data review from DealSearchOnline.com, Pharma’s M&A hit a whopping 147.2 billion – translating into a 66% increase from the second highest M&A in that ten year span (2000-97.4 billion).[refer to chart below]

What does this mean for PAP?
Regardless of the reasons for companies consolidating with other companies (growing generic competition, shrinking drug pipeline, our Economy) the fact remains it is happening and that means a changing landscape for patient assistance programs. As these mergers continue on patients, patient advocates, healthcare community will feel, to some extent, the pain before they feel the gain. In this case the gain being greater program continuity.

When manufacturers merge together, many decisions relative to PAP programs need to be made. Some of these considerations are if the program(s) will stay independent or if they will be consolidated? Given the mega mergers mentioned above in all cases they consolidated all their support programs into and under one company with the exception of Roche keeping their ACCU-CHECK program in place. Consolidating Patient Assistance programs is not an easy task. here are many other considerations that need to be addressed such as standardizing enrollment rules, keeping the same medication(s) or even the same access points i.e. phone, IVR, web? Furthermore, if these manufacturers outsource their programs (as most do) it now begs the question of which vendor to consolidate with and how comprehensive their program transition plan is so they do not leave patients behind or without medication.

As QPharma has been consolidating PAP programs for some time now, we have seen an increased need to ensure the client’s transition plan to address outdated access points, primarily on the web. Furthermore not only should they address these avenues but there should be a monitoring program in place to ensure these points of access do not change or lead to a dead end, broken web-link or busy signal.

To test my opinion, I applied our content site consolidation methodology as a hypothetical for the Pfizer/Wyeth PAP, a merger that happened over a year ago… and found that there were still some sites that think Wyeth exists as Wyeth as well as their assistance programs. Furthermore, you can still get an outdated application form off them. What is even more shocking to me is that one site in particular refers to themselves as a leading provider of online patient assistance.

To conclude Companies are looking to acquire, consolidate and streamline their business and this will eventually lead to easier access points into those companies Patient Assistance Programs. If I could be so bold as to make a future prediction regarding the Sanofi-Aventis/Genzyme consolidation I would say it could go one of two ways – Currently they are using 2 vendors between the both of them to run their programs, 18 all together. One vendor provides services to both companies and the other vendor only provides services to Sanofi-Aventis. I would implement an RFP proposal, engage other service providers not currently engaged, assess their price points, use these price points to negotiate new terms/pricing with the vendor who currently holds the most knowledge of both programs and establish service level agreements to ensure patients who utilize these programs are handled compassionately and receive their medication in a timely manner.

Managing the Validation of Custom Databases

2011-02-14T09:31:00.000-05:00

Written by Frederick Sperry - Validation Manager, QPharma

The management of custom databases does not need to be an onerous task. When taken seriously, one can justify the management of the details associated with the database as Good Business Practices. Even the elephant can be eaten – one bite at a time.

Initially, as in any other activity in the regulated industry, know your process. Identify the key parameters that user requirements have defined for the database. What are the macros supposed to be doing, or any critical connections or formulas expected to produce? Document the findings as an initial deployment of the system, and get a system user review and approval of the requirements for the database.

Validate your process. Document the settings and verify the any formulas, macros of interfaces do what they are supposed to accomplish. Adjust any settings that do not meet the needs of the end users. Then update your documentation, and get review and approval signatures of the documentation. Typically this is in the form of a System Design Specification, System Configuration or Functional Specification document. The title of the document is not important; the current information is the critical item.

After the ‘deployment’ of the database keep the documentation current. The database configuration and settings are liable to change over the course of normal system usage. Keep track of the changes and periodically update the system documentation, and obtain the crucial user or management review, approval and sign off of the updated system settings.

Keep current with the data and database and embrace the new era paradigm shift from documentation to information. The documentation must empower the system users to be able to use the information as knowledge. In this new millennia day and age of information, knowledge is truly power.

The Twelve Towers - A Project Management Novel: Excerpt 2 – Identify Stakeholders

2011-02-08T12:01:00.000-05:00

Written by Bruce Fieggen - VP of Project Management & Training

Below is the second excerpt from the Project Management novel Bruce Fieggen, QPharma’s V.P. of Project Management, is writing in his ‘spare time’. The book follows the Project Management Body of Knowledge Guide (PMBOK) but uses the format of a novel, and promises to be much more readable. The novel tells the story of a Gwilym, a Project Manager, charged with building twelve towers scattered throughout King Arthur’s Britain. Gwilym’s oldest son, Bleddyn, also appears in this excerpt. There is some overlap between this excerpt and the one posted November 1 2010, so you can see where it fits in the novel.

Readers, think about the various projects you are tasked with and see how you can use the tools shown in these blog posts to assist you in ‘building your towers’.

This second excerpt shows the development of the second tool: The Stakeholder List.

King Arthur stood, gravely shook Bleddyn’s hand, then Gwilym’s and told them he would be keeping a close eye on this tower and on them. “And there is no need to worry about Tarrant. I didn’t trust those beady eyes when he came here. You, I trust.”

Gwilym and Bleddyn were asked to join in the feast in exchange for a tale to add to the merriment. He told a story of his travels as a young man. “I was in a bazaar in an Arab town near the Holy Land”. This caught all the knights’ attention. “The men there sold their wares to all comers and it was to their advantage to guess the language of their customers as they walked by and to speak to them in that language with what little they could pick up. I passed a seller of brass-works in a street full of brass. He looked at me, smiled and shouted, in highly accented English, ‘Just looking! Just looking!’ He must have heard these words so many times from other Englishmen he became sure this was a greeting of some kind.”

The knights roared in laughter and toasted Gwilym, begging for more stories. He obliged them once, then turned the conversation back to them and listened to their stories until he saw his son stifling his third yawn. “I must return early on the morrow, gentlemen. Thank you so much for your hospitality. My king; thank you for the royal charter. I shall not disappoint you.”

Bleddyn walked by his father’s side on their way to the tavern, looking up at him with a new respect. “Did you really have those adventures, Da? I never knew you had traveled so far. Was I with you?”

“No lad. That was during my misspent youth. I did many dangerous and fool-hardy things at that age that I don’t want you to try. Please forget the stories.”

“But Da, what did your father say about the things you did while you were traveling?”

“My Mother and Father were dead when I was quite young. I did no-one else’s bidding at that age.”

___________________________

At the second cock crow, they left Caerleon, arriving at the ferry dock in time to see the boat approaching from Brycgstow. While they waited, Bleddyn asked his father about the charter.

“It’s a document that describes the project to everyone who cares about it. That way there can be no arguments about what to do. It’s also a contract between all the people who work on the project and King Arthur. And that includes me. I have to make sure I build it for the amount of silver I promised and as quickly as I promised.”

“Who are all these people who care about the project?”

“The quarryman is one. He’s the one who started this whole thing and caused me to make up the charter. I’ll be looking forward to showing him King Arthur’s signature. But there will be others who argue in the future and I can show them the charter at that time.”

“Why not show them the charter first, Da, before they make any trouble?” Bleddyn questioned. “That might save some time.”

“That’s a grand idea, son! Let’s make a list of everyone we should show it to while we wait. There are all the builders on the site, Father Drew, the quarryman, the bishop, the forester, the masons, the carter, the village chief, the inn-keeper who brings food to the site. Who else?”

“What about Tarrant?”

“Now that’s an interesting point. I should also be thinking of people who want the project to fail. I’ll have to keep them in mind for this list of people who care. Though I may not go out of my way to find him, I’ll keep the charter safe so I can show him if he argues again. It clearly says who’s in charge.”

“What do you call this list of people, Da?”

“They are all people who have a stake in this project, one way or another. I’ll call it a list of ‘stakeholders’ then.”

The ferry arrived and they made their way back to Brycgstow and spent the rest of the day and night there. Gwilym hobbled from square to square, sitting down in each and allowing Bleddyn to explore each place. He was exhausted when they returned to the tavern and fell immediately to sleep. Bleddyn, his mind racing from all he’d seen, lay awake for another hour, and then fell into a contented sleep.

They arose early again and rode as fast as Gwilym was able to the quarry near Huish, and found the quarryman hard at work in the pit.

A Practical Guide to Handling Product Complaints

2011-02-01T11:39:00.000-05:00

Written by Zina Bulbuc - Validation Engineer, QPharma

Complaints System

Complaints, complaints, complaints….
Everybody gets them: from friends and family members, from customers and business partners, from bosses and co-workers. How do we handle them to keep everybody happy?
I will start with customer product quality complaints and later, we may extrapolate the model for other types of product complaints (Adverse Events, Medical Device Reports) or even for complaints in other areas of our lives (but that will be part of another blog…)

All marketed products (drugs, medical devices or combination products), will sooner or later generate a number of complaints. Handled correctly, complaints can be used by the manufacturer and others, in a constructive way.
While the number and content of complaints may vary for each product, they all have something in common: they have to be acknowledged, investigated, resolved, reviewed, and where applicable, reported. We must have a system in place that will handle them in a timely and organized manner.

What do we expect from a complaints system?

First, we want to make sure it is compliant with the CFR requirements.
Second, it has to be a good feedback tool for the manufacturer: on the product’s design, on the product’s efficiency or efficacy and on users’ satisfaction.
And third, the complaints system should be user friendly and economical to run.

When creating a complaints system we are faced with two - often opposing - decisions: business and compliance. The first one will guide us to spend the least possible amount of money and resources and the second, to invest as much as necessary to ensure a thorough and safe handling of complaints.

The main steps to follow in creating a complaints system are:

Define complaints (CFR provides different definitions for different types of complaints);
Decide how you can assure a complete and consistent collection of complaints;
Decide how you will keep track and monitor complaints: will you use an electronic log, or a paper based system? Do you have an electronic system in place to handle them (TrackWise, Oracle)?
Designate a quality group / quality unit to handle complaints;
Define the content of a complete complaint file;
Define the time frame to close a complaint and retention time for complaint files.

Now, that we have a overview of what is expected from a complaint handling system, let’s get to answering some of the most frequent questions on this subject.

Complaints Defined
Q: How do we define drug complaints? 21 CFR 210.3 does not have a definition for complaints.
A: This is true, 21CFR 210.3 does not explicitly define ‘complaints’. We have a guidance of what the Agency considers a drug complaint through 21CFR 211.198(a) which states: … Such procedures shall include provisions for review by the quality control unit, of any complaint involving the possible failure of a drug product to meet any of its specifications…
In the mean time, we have a clear definition for complaints for medical device in 21CFR 820.3(b); … any written, electronic or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or performance of a device after it is released for distribution.
Since the medical device complaints definition is more comprehensive and includes “identity, quality, … safety, effectiveness or performance” one can equally apply it to drugs.

Q: Are dissatisfaction about price or availability considered complaints? They do not meet the definition of a complaint as per the 21CFR.
A: FDA does not include these in their ‘complaints’ definition because they do not pose any direct risk for the patient / user (although, the indirect effects of such complaints can be disputed). The difference here is the investigating entity and the corrective action’s target. Do we want to treat them as ‘regular’ complaints? The answer is ‘yes, absolutely’! But, they should be labeled as ‘non product-quality’ complaints (or a similar term), to draw a regulatory distinction between them and those other ‘complaints’ that we are specifically required by regulation to maintain files for. This way, we satisfy the strict legal obligations for complaint handling (keeping the lawyers happy), while continuing to capture and act on customer satisfaction issues (keeping the product managers happy).

Q: Are Service Calls (for medical devices) complaints?
A: This is a hot topic in medical device companies; due to the number of incoming service calls, risking overload to the complaints system. First, service calls are “allegations of … performance” and fit the definition of a (quality) complaint. You may argue that in some cases, the allegations are about an ‘error message’ that is in line with the instrument’s specifications. The regulations cover the ‘failure to meet specifications’ in the definition of an MDR, but not so in the definition of a (quality) complaint. Second, these are calls that require an investigation and a corrective action, so they do not fall in the ‘inquiries’ category. And third, sometimes it is hard to delimitate where a ‘service call’ ends and a ‘complaint’ begins. The safest way is to have them handled as complaints. And make sure to have them clearly identified for trending purposes (also required by 21 CFR 820.200 Servicing and 21 CFR 820.250 Statistical Techniques).

Validation as a Best Practice – Part 2

2011-01-25T16:15:00.000-05:00

Written by Scott Collins - Sr. Validation Manager

Several months ago I wrote about why validation is a best practice with a link to Part 1 of a presentation on how to complete a validation. This time I will summarize the activities associated with completing a validation and provide a link to Part 2 of the same presentation.

In Part 1 of the presentation, Validation as a Best Business Practice – Part 1, I stated the first steps for a validation project: Validation Project Plan and the User Requirements Specification (URS). While the Validation Plan may or may not be required depending upon the project, the URS is critical for all validation efforts. This document provides the team as well as the equipment or system developer with enough information to provide an end product that meets its intended use. Each requirement must be clear, concise, specific, non-conflicting with other requirements, and most of all testable.

For best results the next two steps should be completed with help or input from the developer or vendor. The next document to be developed is the Functional Requirement Specification (FRS). The FRS addresses at a high level how each requirement will be met by the equipment or system. This is best answered by the developer or vendor. The FRS is also a great tool for deciding which developer or vendor to use, so very often a customer will supply the URS to many developers or vendors and make their supplier decision based on the FRS. Once a developer or vendor has been identified, each functional specification is detailed in the Design Specification (DS). The FRS can be expanded into the DS to reduce the number of documents and to make sure that each functional specification has been addressed.

After the DS has been created, the developer or vendor can build or supply the equipment or system. If the equipment or system is being built, then the customer should insist on a Factory Acceptance Test if possible. Keep in mind that it may not be practical to perform and FAT on a major utility system or an off-the-shelf system. Major utility systems are too big and need t be installed in their final location before performing testing and an off-the-shelf system has been tested at many client sites so there is little chance that it will not work once installed at the final location. The FAT allows for the developer or vendor to work out the bugs in the system before installing at the client site. It also allows the client to test the system for their intended use at the developers or vendors site so any bugs or changes can be addressed quickly and easily, and usually without additional cost to the client.

Once the FAT is completed and all issues addressed, the equipment or system is delivered and installed at the client site. After everything is set up, but before the developer or vendor leaves, the Site Acceptance Testing (SAT) should be completed. The SAT usually reruns the FAT tests. This proves that nothing was changed or affected by breaking the equipment or system down and shipping to the client site.

Another activity that should be completed before the developer or vendor leaves or is given the final payment is Commissioning. Commissioning usually involves the developer or vendor performing their checks and tests on the equipment or system. Be sure to get the executed documents for your records. If you intend to use the Commissioning document to support less testing later on, then you need to have the documentation meet your internal standards.

Now that the equipment or system has been installed, the validation testing can begin. The validation testing involves Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). These documents can be combined into one if preferred. Some companies insist on these being separate documents to force the team to complete one phase before moving to the next phase. The critical point to make here is that the tests that are developed are clear, concise, and test, at a minimum, all of the critical user requirements.

The best way to make sure all requirements have been tested is by developing Traceability Matrix. The Traceability Matrix can be a table that lists each requirement with its unique number down the left column, the next column includes the Functional Specification number(s) that address each requirement, the next column lists the Design Specification number(s) that address each Functional Specification, and the last column lists the protocol and test number(s) that verify each Design Specification. For more detailed information please review the Validation as a Best Business Practice – Part 2 presentation.

Following this process, even at a high level will help insure that you have a piece of equipment or system that meets your intended use. This is one critical part to ensuring that your product meets the critical quality attributes determined during the development phase of the product lifecycle. This is why Validation is a best business practice.

OBAMACARE and INDUSTRY Part II

2011-01-17T09:07:00.000-05:00

Written by Jeff Boatman - Senior Subject Matter Expert, QPharma
As promised continued from OBAMACARE and INDUSTRY Part I

Title VII, Improving Access to Innovative Medical Therapies

Section 7002 could wind up being the “sleeper” of the new law: it establishes rules for biosimilar biological entities...in essence, generic biologics. Even after a biologics patent runs out, it is in many instances theoretically impossible for a competitor to produce an absolutely identical copy (many of these products come from unique cell lines, for example), so FDA has been charged with coming up with criteria for considering a “copy” to be “close enough.” In principles, this is really nothing new: generic drugs do not have to be identical to the original drug they are based on, and in fact can be quite different in composition and manufacture.

This new provision is in response to FDA’s testimony before Congress that existing laws do not permit licensing of biosimilars, while the Europeans have been moving ahead in this area. Congress is fully aware of how competitive—and litigious—this industry is: more than half of this lengthy section deals with detailed rules for patent exclusivity! The law requires a report to Congress in January 2012 on recommendations, and Congress is required to then establish (through separate legislation) a user fee program...so don’t expect any biosimilar products to be on the U.S. market any time soon.

Title IX, Revenue Provisions

Speaking of user fees: drug manufacturers and importers have long been paying to register their facilities and market their drugs. The Medical Device world has largely avoided this (I used to recommend that my Medical Device clients ignore FDA’s “30 days before commercial distribution” regulation and just register their facility as soon as possible “because, after all, it’s free”); but in recent years, that has changed as well.

Usually, companies know in advance how much they have to pay FDA for the privilege of staying in business because Congress would pass a clearly identifiable law with the words “user fee” in the title: the FDA Modernization and User Fee Act, the Prescription Drug User Fee Act, etc. Well, if you can’t find the latest round, it doesn’t mean you no longer have to pay the government...it just means that this information is buried inside the healthcare reform bill.

Branded prescription drug fees are covered in Section 9008; sales less than five million dollars are exempt and orphan drugs are excluded. Medical device fees are discussed in Section 9009, with exemptions for Class I and certain Class II devices (under $100 retail). Companies with less than five million dollars in sales are excluded.

If you are looking for the exact dollar amount you need to write a check for, you will be disappointed; the section only explains how the fee will be calculated. You’ll still need to keep an eye on fda.gov and pay the amount the Agency subsequently publishes.

Title X, Strengthening Quality, Affordable Health Care for All Americans

Note: don’t get fooled by the fancy title – this is just where Congress dumped all the amendments that were added after the main bill was adopted

Section 10608 adds some minor tweaks to the ANDA process, clarifying that the generic drug’s submitted labeling need not be identical to the original when the text changes result from 21 CFR 355(i) (in other words, clinical research), so long as the “Warnings” section remains the same and there are no remaining patent conflicts. FDA has 60 days to review the new labeling and demand revisions; the Agency can then choose to deny the ANDA on the basis that the final submitted labeling impacts safe use.

Confused? Me too; expect guidance on this from FDA in the future.

MISCELLANEOUS UNRELATED ITEMS

So that’s my list of items in the healthcare bill that impact our industry. If you saw something else, or if I got something wrong (entirely possible considering how complicated the Act is) or just want to let us know your opinion, please post a comment!

Meanwhile, here are a couple of interesting items I came across in my reading.

Do you know any cosmetic surgeons? Section 9017 changes the Internal Revenue Code to require doctors to collect a 5% federal excise tax on cosmetic procedures.
Senior citizen with unreimbursed medical bills? Section 9013 decreases the threshold for deducting medical expenses from the current 10% of income down to 7.5% – but only if you or your spouse are over 65, and only from 2013 through 2016.
Are you a high earner? You’ll be seeing a non-deductible FICA “hospital” tax equaling 0.5% of all income above $200,000.
Enjoying your winter tan? Section 10907 is an amendment that imposes a 10% excise tax on non-medical tanning procedures. The amendment also nullifies a pertinent section of the Internal revenue Code, so I don’t know if this is a completely new tax or just an increase.

Finally, you have no doubt heard about the provisions in Section 4205, requiring chain restaurants and vending machine operators with more than twenty stores or machines to post full nutritional information, including on signs at drive-throughs and on the sides or near vending machines (I won’t comment on the practicality of that last one). But the law then goes on to inform owners of less than twenty restaurants and vending machines that even if they aren’t legally required to post nutritional information under the Act, they can voluntarily comply...by registering with FDA! So: if the owner of a diner decides to tell customers how many calories are in that hamburger but doesn’t first register with FDA, is he committing a federal crime? Or on a more serious note, what about municipalities that mandate posting of nutritional information at restaurants within their jurisdiction? Does that now mean the chain must also register with FDA, even if only 15 restaurants (to use New York City’s rules as an example) are within the city limits?

FDA'S NEW TOBACCO SUBMISSION REQUIREMENT

2011-01-10T12:36:00.000-05:00

Written by Jeff Boatman - Senior Subject Matter Expert

Companies must file reports by March 2011 "or else" ...

On January 5th, Health and Human Services Secretary Kathleen Sebelius announced that FDA was introducing a new notification initiative to review and clear tobacco products placed into commercial distribution since 2007. In a stunning and perhaps unprecedented move, FDA simultaneously issued a guidance on the required submission (called a "905(j) report" after the corresponding section of the Tobacco Control Act) that was released as a final document without public comment or even Federal Register notification. The guidance, while "optional for implementation," is as mandatory as they come: noncompliance = illegal distribution.

As explained in FDA's news release <http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm238924.htm>, every manufacturer of a "tobacco product"--which includes not only cigarettes and cigars but any accessory marketed as part of tobacco use, both to the public such as pipes and rolling papers and wholesale for further manufacturing such as filters and tips--that was not already on the market prior to 15 Feb 2007 must submit a 905(j) BEFORE MARCH 22 OF THIS YEAR, otherwise such products will be misbranded and adulterated.

Small companies that often introduce new products are obviously a target, and noncompliance will make it simple for the feds to shut them down. But large cigarette companies may be affected as well, not only for new consumer products but especially for changes in their manufacturing suppliers. FDA warns that each manufacturer is responsible for maintaining objective evidence of when their products were placed into commercial distribution (presumably with adequate change control records).

This is no doubt just the first salvo on a new front in the government's efforts to limit tobacco use and shut down small operators, one that has explicit congressional authority. Companies that sell tobacco products, including sundries such as papers, pipes, filters, and especially "specialty" cigarettes and cigars would do well to make every effort to get their 905(j) reports in before the deadline.

Many small companies probably will not have the knowledge or resources to get these reports in on time, which of course is likely exactly what the feds are hoping for. Since this guidance literally came out of the blue, there are no "905(j) tobacco consulting experts" to turn to. The best bet is probably to hire a consulting company that deals in similar submissions--medical device 510(k)s, for example--because these people are already used to the types of information and the expected format that will get the new 905(j) through the review process efficiently. (510(k)s are particularly appropriate, because much of the information required in the new reports are very similar to medical device design history files, even if FDA isn't using that exact term).

Can a company simply hang on until after March and then submit? Alas, no: FDA explains that this is an interim step to "catch up" all the products placed on the market since 2007 (a date that Congress basically post-dated the Tobacco Act back to), and then a new, more formal premarket notification process (again, similar to a 510(k)) will be introduced going forward.

If you make tobacco products, call us. Soon!

INCOMING BOMBSHELL -- FDA's Latest Tobacco Initiative

2011-01-10T11:53:00.001-05:00

Written by Paul Melamud - Validation Manager

Note: this article is about FDA's implementation of the labeling requirements of the Tobacco Control Act. For details of FDA's imminent tobacco submission program, click here.

In June of 2009, Congress enacted the Family Smoking Prevention & Tobacco Control Act (FSPTCA), finally giving FDA authority over this real “thorn in their side” set of products.

For those unfamiliar with the bill, highlights include:

Creation of a new Center within FDA specifically to regulate tobacco products
Increased labeling requirements – some examples:

Warning labels must cover 50% of both sides of the pack
Cigarettes may no longer be labeled “mild”, “light”, or “low”, since this suggests “safer” or “better for you” with no clinical trials to back it up

Banning of flavored cigarettes (always thought to be targeted to children)
Restriction of advertising; for instance, none allowed within 1000 feet of schools or playgrounds
Further restrictions on cigarette vending machines and “illicit trade”
Requirements for listing cigarette ingredients (similar to food and drug requirements)

In the year that followed, FDA put forth a few regulations (see 21 CFR 1140 et seq.) governing sales, advertising, and labeling of cigarettes and smokeless tobacco products.

As noted above, the FSPTCA charges FDA to issue final regulations requiring new warning labels for cigarettes by June 22, 2011, requiring compliance within 15 months of the final rule’s issuance. In fact, the public comment period ends this Tuesday (January 11, 2011). The proposed rule is Required Warnings for Cigarette Packages and Advertisements.

But these aren’t simply updates to C. Everett Koop’s relatively subdued warning statements (see pictures below, required by the 1984 Comprehensive Smoking Education Act) – these are disturbing and even gory portrayals of what happens from smoking (see examples below; there are a total of 9 proposed by FDA at this time) that will supplement them. These images will be extremely prominent, encompassing at least 50% of each package (front and back), and 20% of each advertisement. And manufacturers won’t get to “pick and choose” – all nine warnings must appear an equal number of times on each brand of cigarettes, and must be randomly distributed in all areas in the US in which the product is marketed. For advertisements, the warning statements are to be rotated quarterly.

FDA expects these new graphics to educate smokers – particularly adolescents – about the dangers of smoking (one article published in the NY Times claims 19.5% of US high school students, or 3.4 million adolescents, are smokers). Perhaps understandably, if weakly, some cigarette manufacturers have vowed to fight these graphics, claiming they infringe on free-speech and property rights.

As covered in an accompanying article on this week's blog, FDA is not simply sitting on its hands waiting for compliance--the January 5th announcement that tobacco firms have to get all of their new premarket notifications in by March or be forced off the market is ample proof that the Obama administration is deadly serious about putting cigarette companies in a headlock.

OBAMACARE and INDUSTRY - PART 1

2011-01-03T16:20:00.000-05:00

Written by Jeff Boatman - Sr. Subject Matter Expert

How does the recent healthcare reform law affect manufacturers?

Earlier this year, President Obama signed Public Law PL 111-148, the Patient Protection and Affordable Care Act. This law introduces sweeping and controversial changes to the American healthcare system by limiting an insurer’s ability to deny coverage and expanding the role of state and federal governments in our healthcare affairs.

Most of the press has been about Title I, “Quality, Affordable Health Care for all Americans.” But the law is 906 pages long; surely ample room for Congress to stash other goodies. I just reviewed the entire document, looking for items that affect QPharma and its clients. Sure enough, I found a number of items that directly impact upon Life Science manufacturers. Today’s blog consists of summaries of what I found, along with a couple of non-sequiter notes at the end.

Note: at last count there were some two dozen lawsuits seeking to overturn various sections of the PPACA, so this may be subject to change!

Title III, Improving the Quality and Efficiency of Health Care

Section 3507 directs FDA to consider if summarizing risks and benefits of prescription drugs in a standardized labeling table would “improve healthcare decision making by clinicians and patients and consumers.” [sic] Within one year (i.e. by March 2011), FDA is to consult with health care groups, manufacturers, representatives of minority advocacy groups, and experts in women’s and children’s health, and determine if standardized labeling should be implemented; and if so, implement Final Rules within three years.

This is, in short, a prescription drug version of the tried-and-true Principle Display Panel (“Drug Facts”) box on most non-prescription drug products as established by the Over-The-Counter regulations in 21 CFR 201 Subpart C, to become part of the labeling for some or potentially most prescription medicines.

Stay tuned!

Title IV, Prevention of Chronic Disease and Improving Public Health

Section 4203 amends the Rehabilitation Act of 1973, Title V, section 510, to require FDA and the Architectural and Transportation Barriers Compliance Board, within 24 months (i.e., mid-2012), to promulgate regulations establishing the minimum technical criteria for medical diagnostic equipment used in hospitals, clinics, physicians’ offices, emergency rooms, and “other medical settings” to ensure that the equipment allows independent entry to, use of, and exit from the equipment by disabled persons.

If you design and manufacture certain types of large diagnostic devices, this is could be huge! 21 CFR 820.30(c) and ISO 13485:2003:7.3.2 already require Medical Device firms to include specific requirements of users and patients as design criteria. The basic need for Medical Devices to accommodate, to the extent practical, the capabilities of the patient has already become a E.U. expectation (MMD 2007/47/EC, Annex II, paragraph 1, amendment to Annex I of 93/42/EEC), but this new law authorizes the little-known A&TBCB* to come up with specific technical requirements that will then be one of the standards that are used in the design of future diagnostic devices. Like compliance with other consensus standards, it is entirely possible that you may have to redesign your products to meet the new requirements even if you feel your existing design is fine (try getting NRTL approval of your electronic Medical Device on the argument that it’s “just as good” as meeting the latest revision of IEC 60601 and see how far you get). If you make diagnostic devices for which accessibility could be an issue, you will want to watch this carefully to see how it develops!

*I admit it: I never heard of them either until I read this section of the Act and looked them up at http://www.access-board.gov/about.html

Title V, Health Care Workforce

Have you ever been visited by an FDA official wearing a smart white uniform? Those are members of the Public Health Service’s Commissioned Corps (the Surgeon General is an Admiral in the Corps). Outside of FDA headquarters these folks are a rare sight because their numbers were capped by law at 2,800. Section 5209 removes that cap, and Section 5210 established a “Ready Reserve,” based on the military’s reserve forces, to backfill regular PHS/FDA duties. This is backed by a financial commitment of five million dollars for establishing this reserve force, increasing to over twelve million. You’ll no doubt be impressed by the professional attitude and appearance of these young officers...as they hand you a 483.

Title VI, Transparency and Program Integrity

The most widespread changes for manufacturers and distributors are probably those found in Title VI, which was originally the “Physician Payment Sunshine Act” before it got absorbed into the overall reform legislation (you will still hear people refer to Title VI as the “Sunshine Act”). This severely limits what gifts or other considerations Life Science firms can give to hospitals and practitioners; requires extensive reporting; and introduces some changes to the Prescription Drug Marketing Act regarding reporting free samples given to doctors. (Of drugs; on a federal level, there continues to be no equivalent for Medical Devices – but check your state’s regulations.) Unfortunately, the elements of Title VI consist mostly of amendments to the Social Security Act and until they are consolidated into the United States Code, they can be very difficult to read and understand (pending transcription, you’ll need the healthcare bill, and the amendments to the healthcare bill in Title X, and the social security law in front of you to make sense of it all).

The requirements are too extensive to cover here in detail, but I’ll try to hit the highlights. Meanwhile, please check our previous blog entry on Title VI at http://validationandregulatorycompliance.blogspot.com/2010/06/physician-payment-sunshine-provisions.html and if you want more information, e-Mail me at Jeff.Boatman@QPharmacorp.com and we’ll “take it off-line.”

Section 6001 modifies existing limits on a doctor’s ability to partly or completely own hospital facilities or refer patients to facilities they in turn own, and requires certain notifications to HHS and patients. Some of this deals with rural facilities where there may not be many alternatives for patients. This probably doesn’t apply to many manufacturers, but several industry watchdog groups have investigated and publicly criticized drug firms for not carefully screening their physician consultants. If a drug or device firm is hiring doctors as bone fide consultants, then depending on the capacity they are hired for, you might want to make sure that they are in compliance with this section. Ditto the self-referral rules in Section 6003 where doctors happen to own their own diagnostic equipment (MRIs, PET scanners, CT scanners).

Section 6002 requires reports of corporate payments to doctors, starting in March 2013. This section does not itself establish specific limits on what a doctor may or may not accept (but see other rules such as the PhRMA and AdvaMed Codes of Conduct, as well as individual state’s legislation that prohibit certain gifts and expenditures), just what needs to be reported, which is: practically everything! Furthermore, this information will then become publicly available through the Internet, and to top it off, HHS will send reports to each state so that the state government can take any actions according to their own laws and regulations (the quid pro quo being that your state government will not be able to require you to file a separate report directly to them – but a state can still demand reports when they require information that goes beyond the scope of this section).

By the way, I hear a lot of confusion about this: for example, that this only applies to cash payments to doctors, or only applies to prescription drug manufacturers. Be warned! It applies to anything of value given to, exchanged with, or assigned to any practitioner or teaching hospital; and it applies not only to drug firms but any also the manufacturer or distributor of any “biological product, device, or medical supply” that is or could conceivably be reimbursable under Medicare, Medicaid, or CHIPs. And bear in mind that FDA interprets the term “manufacturer” far more broadly than common parlance; to quote the Act: “any entity which is engaged in the production, preparation, propagation, compounding, or conversion of a covered drug, device, biological, or medical supply…or provides support to such entity with respect to the production, preparation, propagation, compounding, conversion, marketing, promotion, sale, or distribution of a covered drug, device, biological, or medical supply.”

In other words: if you make a healthcare product or market a healthcare service that Uncle Sam could wind up paying for, then you are subject to this section, period!

There are a mind-boggling number of exclusions to the reporting requirements (including income earned by the doctor because he happens to own your common stock – but if you gave the doctor that stock, then that stock transfer is reportable). Some of the more common scenarios include:

1.      The doctor in question is not an independent practitioner acting as your consultant but your full-time employee who just happens to have a medical degree (i.e. not a practicing physician).

2.      You are not required to report payments or transfers of less than $10, but: a) you still need to follow the applicable PhRMA/AdvaMed codes (which may be “voluntary,” but some states require you to follow them or their own similar versions), and b) if you allow “payments or transfers”—and yes, that includes your Sales Rep dropping off ballpoints—you will then need an “aggregate spend” policy and program to track the total amount of transfers to each doctor, and report anything that goes over a certain limit. This “certain limit” is itself complicated, because it will start out at $100 per year, but will then increase according to the “Urban Consumer Price Index.” And don’t forget that the PhRMA and AdvaMed codes further restrict what can be handed out. So manufacturers should be asking themselves: is it really worth the trouble?

3.      Patient product samples are not reportable as an expense, although for prescription drugs there continue to be the accountability requirements of the Prescription Drug Marketing Act and 21 CFR 203. Samples of Medical Devices continue to be a reporting loophole – but your state (or the state you are marketing in) may say otherwise!

4.      Warranty replacements, and temporary equipment loans or demonstrators (these are fairly common arrangements with durable electronic medical devices, e.g. under 21 CFR 820.200).

5.      Educational materials for patients (a patient brochure is an obvious example).

6.      I’ll mention this just so the reader can’t say “nobody told me that”: there is an exclusion in the event that another party makes payment to a doctor without the manufacturer’s knowledge. But before anyone starts setting up some shell company to pay doctors off-the-books, they should first look up the criminal penalties for conspiracy in 18 U.S.C. 286 et al. I expect the HHS Inspector General to take a dim view of such schemes!

Section 6004 mirrors the Prescription Drug Marketing Act’s requirements for drug sample tracking, but clarifies that aggregate summaries of all drug samples are to be reported to the federal government (starting April 2012) whenever such drugs are, or could be, federally reimbursable. There are no penalties defined, no timeline set, no publication objectives, and no directive for Agency procedures. The information that is required to be collected is identical to that already captured under 21 CFR 203. Does this mean that you are not to report drug samples that are not federally reimbursable? Or (for simplicity) can you report everything irrespective of its Medicare status? I suspect there will be a fair amount of confusion about this until FDA finalizes their rules.

Section 6005 amends the Social Security Act to require special reporting by Pharmacy Benefits Managers (these are middlemen organizations who arbitrage product distributions and payments on a large scale). Basically, they will be required to report what payments they receive versus what they disbursed, and how much of their prescriptions were filled via mail order versus through retail locations (think Walgreens). The federal government is keenly interested in this because of the growth of Prescription Drug Plans and accompanying fraud (think, um, Walgreens). Again, this section does not define the actual amounts or conditions that are violative or of concern, just the reporting – but such rules do exist elsewhere, e.g. the federal “best pricing” requirements for Medicare reimbursement.

Section 6507 contains clarifications to the uniform coding system for medical procedures and tests. You’re probably thinking “that doesn’t apply to me,” but hold on – in some special cases, a manufacturer (in the broadest sense) of Medical Devices may be subject to this provision. Consider this: you receive patient samples to conduct diagnostic testing, which is conducted using commercially available (and FDA-approved or -cleared) Medical Devices…but in a unique or proprietary way. You are both a provider of medical services in the practice of medicine, and ALSO a Medical Device manufacturer (specifically, you are a Medical Device specification developer (21 CFR 807(3)(d)(3)) – the “device” being the process itself). I’ve been called in to help several companies like this, who didn’t know they happened to be both kinds of companies until the FDA showed up at their door. If such a “manufacturer” is or could be directly or indirectly reimbursed by the federal government, they need to comply with this section (and private insurance companies will no doubt insist on it as well).

To be continued ...

Happy Holidays

2010-12-23T11:15:00.000-05:00

Happy Holidays!

LabWare LIMS Validation

2010-12-21T10:51:00.000-05:00

Written by Kimberly Stanton - Associate, Validation Manager

As with all LIMS applications implemented in regulated environments, LabWare LIMS implementations must go through Validation prior to being released for routine use. LabWare implementations present unique challenges due to the ability for companies to create complex static data and work-flows, configure many different Sample Types, manage Standard/Reagents, manage Equipment/Instruments and the ability implement Stability Studies.

A Validation Plan for any LIMS implementation must be created to detail the Purpose, Scope, Deliverables, Responsibilities and the Acceptance Criteria to release the new LIMS application in the Production environment for routine use. If the LIMS application is to be installed in multiple sites with different hardware and potentially different requirements due different regulatory constraints or business work-flows it maybe necessary to create more then one Validation Plan.

User Requirements for a LabWare LIMS application should document the following to ensure a smoother implementation and Validation effort:

All applicable Regulatory requirements
System Administration requirements
Multiple Site requirements if applicable
Laboratories that will be utilizing the new LIMS application
User Roles that will need to be implemented
All Sample Types that will need to be implemented
Work-flows to include Lots, Samples, Projects, Batches and Stability as applicable
Test Methods functionality must be documented, however, since the amount of Test Methods that will need to be documented will vary, the use of an Appendix to the URS or a reference to Data Migration plan may be considered
Product Specification functionality must also be documented and similar to Test Methods mentioned above if there are many Product Specifications to be implemented an Appendix or Data Migration plan reference may be considered
Reports to include Certificate of Analysis, Standard and Reagents, Stability Results, and any other applicable reports
Any Interface requirements such as Instruments, SAP, TrackWise, etc.
Standard Operating Procedures applicable to the LIMS implementation

A Risk Assement(s) should be created to determine the Risk Level of the Requirements documented for the LIMS application. Risk Levels will help determine the level of testing that will need to be performed, Standard Operating Procedures that should be created and the level of Training that should be conducted. For example if there is Requirement that has a high Impact if it fails, high Probability that it will fail (mainly if it is a configured or customized part of the application) and Data Integrity could be impacted if the Requirement fails, testing activities would include Unit Testing, Operational Testing and Performance Testing. A corrective action for this Requirement could be User Training and Standard Operating Procedure development. If a Requirement is considered less of Risk if it fails, for example a core part of the LIMS application that satisfies the Requirement, testing may not even be necessary if the company implementing the application is satisfied with the level of testing LabWare performs on their core product, this would be verified during a Vendor Audit or minimal testing in the Operational Testing could be conducted.

Considerations regarding how to document Design/Configuration Specifications should be planned, since the complexity of a LabWare implementation can vary it may be helpful to create multiple Design/Configuration Specifications. For example a separate Design/Configuration Specifications for System Administration, Material Management, Lot Manager, Batch Manager, Project Manager, Sample Manager, Stability Manager and any applicable Interface functionality maybe a good approach. This approach will need special attention from the Project Manager since managing multiple documents can be very difficult.

One of the most overlooked pieces of a LabWare implementation is Static Data planning, configuration, verification and process testing. Static Data, depending on the Data’s complexity can be as or sometimes more complicated then the software piece of the LabWare implementation.

A Data Migration plan is key to Static Data planning, the plan should include references to all of the Static Data that will be implemented into LabWare, the instance (environment of the application) the Data will be configured in, how the configuration of the Static Data will be documented (separate Design Spec to include LIMS Basic Code design) and how the Data will be verified prior to being imported into the Validation (and Training environment if applicable) environment.

As with other LIMS and regulated applications implementation there should be multiple instances (environments) of the application one for software development, one for Static Data development, one for Validation testing, and the Production environment. It is also recommended that a Training environment is available, the Training environment should include verified Static Data for the new Users to train with. If it is not possible to obtain a Training environment one of the Development environments can be used as the Training environment as long as verified Data is available and software developments/updates are not taking place during training sessions.

The Validation and Production environments must go through an Installation Qualification. It is not required that the Development or Training environments go through an Installation Qualification, however, there must be adequate controls in place that ensures that any software changes or Static Data updates are implemented into all of the environments that are not required to go through IQ verification.

Since LabWare implementations can be very ‘data centric’ careful consideration must be made regarding what Static Data will be used during testing, if the Static Data has not been setup correctly any testing conducted has a potential of failing due to the Data. For example say a Product Specification that has Test Method that cannot be completed unless the Sample the Test Method is associated to is added to a Batch and the Quality Control Samples are not properly configured in the Batch Protocol has been selected for testing, the Sample will never be able to be Reviewed or Approved and the Lot the Sample is associated to cannot be approved if the Sample is not Approved the testing will fail.

Also, careful considerations on Requirements that may require special Static Data setup must be made. If a script requires the tester to verify that a Result entered on a Component of Test Method can be canceled, the Test Method selected for testing must have ‘Allow for Cancel’ option selected in order for the Result(s) to be canceled. If the configuration of the Static Data is not correct the script will fail.

Prior to formal Validation testing informal Unit Testing maybe considered, informal testing can minimize deviations either caused by system inconsistencies (nice way of saying Bug) or script errors. The Unit Testing can be conducted with Operational Qualification scripts created by the Validation team. This also provides the testers the opportunity to learn the system and become familiar with Test scripts that will be executed during the Operational Qualification.

The Operational Qualification testing phase for a LabWare implementation should include functional and negative testing much like any other Validation project, however, a LIMS OQ can be a large undertaking due to the complexity of the configurations of the Software and Static data, therefore, multiple testers (preferably from different Labs) should be used to reduce the amount of time it takes to execute OQ test scripts. Since the training of the testers on the new LabWare application maybe limited it is important for the OQ scripts to be created using a ‘point and click’ methodology, this will make the execution effort easier for the testers.

User Training must be conducted prior to the Performance Qualification testing phase of the LabWare implementation. Training tailored to the individual Labs may help be a better alternative as oppose to large Training sessions that include all users. Since the Labs using the new LIMS application will have different access to functionality of the system an overall Training session may confuse Users. For example let’s say if one Lab will primarily do their work in the Batch Manager and they do not have access to Lot Manager, Training on Lot Manager will be lost on them.

Performance Qualification testing can either be conducted in a simulated Production environment of the LabWare application or in a live Production environment depending on the confidence level of the implementation. If the Performance Qualification is conducted in a simulated Production environment it recommended that Performance Monitoring testing phase is conducted once the application is considered approved for routine use. Critical business/regulatory processes and Products/Testing for all Laboratories involved with the new LabWare application should be included in any Performance Qualification testing phase to ensure the new LIMS application is meeting all business and regulatory needs.

A Traceability Matrix is recommended to ensure testing coverage, corrective actions for non testable requirements and/or reasoning for lack of testing for all User Requirements documented for the LabWare LIMS implementation. The Traceability Matrix will also trace Configuration Requirements and possibly Standard Operating Procedures where system Configuration Requirements cannot satisfy a User Requirement.

There are many points to consider when implementing a LabWare LIMS application; this blog just highlights some of major components to ensure a successful implementation. We sincerely hope that the information presented is helpful.

Auditing Your Aggregate Spend Program

2010-12-13T16:30:00.000-05:00

Written by Alexis Stroud, Director Quality and Compliance, QPharma

1. What components of the audit process need to be implemented to ensure compliance with state aggregate spend and Healthcare Reform regulations?

In order to comply with state aggregate spend and healthcare reform legislation and regulations, you need to have policies, procedures, systems, controls, and monitoring and auditing processes designed to maintain data integrity and compliance with the various state and federal reporting requirements.

Life science companies must clearly understand and interpret the regulatory challenges to comply with each States’ reporting requirements, as well as begin preparation for the Patient Protection and Affordable Care Act (PPACA) – and possibly new state legislation. Based on these interpretations, their policies, procedures, monitoring controls, and auditing steps need to be developed and implemented to ensure reporting compliance is maintained. This becomes even more challenging for a life science company, because the necessary data and systems are generally not centrally located or maintained (i.e. a cross-functional effort). In addition, the required data elements required to comply with the current Federal reporting requirements may be incomplete or non-existent within these systems.

Using a process-based audit approach enables a company to understand all of its interactions with Healthcare Providers (HCPs) and how those interactions are performed and recorded within its existing systems. This type of assessment delivers a detailed understanding of the current environment in which your company is operating; identifies policy and procedure gaps, control weaknesses, and opportunities to implement industry best practices; and positions your company to ensure accurate and complete state and federal disclosure.
Note: Some of the state laws (NV and MA, for example) require certification that a manufacturer has conducted audits as part of its compliance program.

What should your Auditing and Monitoring Program consider?

Is the process documented? What is the process for reporting findings?
Does the compliance auditing and monitoring program incorporate key approval points such as HCP credentialing, needs assessment, payment authorization, and reporting accuracy?
Have you built into the formal compliance audits a degree of independence?
Are audits performed at least annually?
How aware are your Internal Audit teams of the requirements of the state and federal regulations.
When reviewing past audit reports, how comprehensive were those reviews? Were findings investigated and closed out?

Things to consider when auditing your aggregate spend program:

Do you have a Federal- and State-specific reporting policy? Is it adequate and is it being followed? How are you keeping up to date with the changing legislation and regulations and how is that information being communicated within the organization and to any third party providers?
Do you have assessments of third party vendors?

Third party vendors are acting as agents of a Company. Their activity is ultimately the activity of the Company.
Monitoring/auditing should include activities of third party vendors. Perform contract reviews.
Third party vendors should be informed of this requirement and will have to potentially provide data and other documentation for the audit.

Do you understand the underlying data controls?

Process – How is data captured, approved, and updated?
Systems – What systems are the data maintained in and what are the relevant controls and validation procedures?

Data – What data elements are available to meet the reporting requirements?
Procedures – What processes are necessary to capture accurate and complete relevant data?

What are your data collection challenges? How can you improve current processes to address these challenges?
Are there enough resources within your organization to perform various data gathering, validation, and reporting functions?
Have you had any prior incomplete or inaccurate State reporting filings?
What tools/procedures (checklists, sign-offs, sub-certification process) and monitoring controls are in place to address the day-to-day process designed to enhance compliant state reporting?

ensure accuracy of data through consistent and efficient data review
identify and investigate outliers and compliance red flags

Have you tested any system-based tools to ensure they are working properly?
Is your system flexible enough to change and adapt over time with new/updated laws and are you collecting data at the most granular level?
Has training been provided to all levels of the organization related to the current and future reporting environment requirements, company policies and standard operating procedures, and monitoring and auditing techniques?
Is the company using the information obtained for state reporting requirements to enhance business operations, as well as overall corporate compliance?
Do you have disciplinary actions for employees that do not comply with your procedures?

The FDA Enters Education E-Style

2010-12-06T12:12:00.000-05:00

Written by Nancy Tomoney - Associate Validation Manager, QPharma

The FDA, in its process improvement program, is enhancing education for companies and consumers on the FDA website, www.FDA.gov.

CDRH is the first center to add course material at CDRH Learn, www.fda.gov/Training/CDRHLearn. Most material is available in three languages: English, Spanish and Chinese. Courses offered are in most medical device regulations, regulated software, BIMO and the 510K process. The e-learning posted represents the areas that lead in lack of compliance for medical device folks with the code of federal regulations. Most educational courses that are currently listed are focused on the health care industry, manufacturers and clinicians.

For those of use seeking to enhance our knowledge on regulations, it represents a good starting point. However, it will not stop the foolish manufacturers who continue to rack up 483s, Warning Letters and other noncompliance notifications by willful violation. It may assist the unwitting violator, who broke the regulations because they were unclear or unlearned. The courses do not replace annual site training in the good manufacturing practices.

Can we guess why FDA has done this? We shouldn't have to. Over the last two decades, many companies have reduced their budgets for employee education. This has become evident by the fall-off in professional conference attendance. Companies don't have the time to train employees in groups on site, and conference costs continue to rise. A company may send one employee to a conference and expect them to return to the site and train others. - a common practice that often falls short in follow-through and substance. Trying to bring a conference on-site also becomes expensive.

QPharma offers both Lunch & Learns and customized onsite training, as well as compliant e-Learning for the entire organization. Lunch & Learns consist of one hour programs on hot button FDA topics; never a sales pitch and as the name states, lunch is on us. Customized training solutions are offered on a fee basis. They represent truly site specific training. They are more detailed, transparent to the client’s own education platforms and tailored for the client site’s processes. They represent better value as the instructor is not lecturing to a mixed audience, but a group with specific needs; and since CDRH is the only FDA center offering e-learning, QPharma can supply your needs from specifics on the other centers, such as CDER, CVM and CBER. We take education seriously, considering the environment we come from!

$4.3 Billion - The Current Price of Compliance?

2010-12-01T09:30:00.003-05:00

Written by Nancy Tomoney - Associate Validation Manager, QPharma

In October 2010, two major news releases coincided. First, the Inspector General of Health and Human resources and the Commissioner of the FDA decided to enforce an existing rule that allows industry executives to be prosecuted and barred from industry even if they have a left a company where compliance issues were found by FDA or reported by a whistleblower. Second, the initial fine by the courts in the Case of the United States of America versus GlaxoSmithKline (GSK) was awarded, $750 million dollars. There is still potential for additional fines by the 50 US states and other US territories against GSK. Cheryl Eckerd, the GSK whistleblower who pointed FDA and United States Department of Justice to additional problems at the GSK Cidra Puerto Rico site, will receive close to $100,000,000 dollars out of the collected court fines.

In the last year, six companies have amassed fines totaling $4.3 billion dollars based on whistleblower testimony. All of the whistleblowers were insiders, quality compliance personnel, fed up with their individual companies push off of GMP issues reported in audits by internal staff.

FDA had performed an inspection of the GSK Cidra site and issued significant 483s in June of 2002 and a subsequent Consent Decree in 2005. Cheryl Eckerd was a key person leading the compliance remediation team for GSK at the GSK Cidra Puerto Rico facility where FDA found the issues. She reported additional issues of noncompliance to her superiors at Cidra. Cheryl refused to focus solely on fixing just the FDA noted violations and was eventually terminated in 2003. GSK stated that her termination was part of position cutbacks for redundant job descriptions that were no longer required. Ms. Eckerd took her amassed documentation and ran to the FDA. The United States Department of Justice, in coordination with FDA, then began further undercover investigations of GSK at Cidra and documenting evidence for their case.

The products made in Cidra were slowly transferred to other GSK facilities and Cidra closed. The compliance issues at the plant, once unique to facilities operated off shore of North America have now spread onshore. Quality obedience has become second to profits and market share; and pardon my skeptic nature but, I think it will continue to be such, until Congress, FDA, physicians, and consumers start fighting back.

There are changes pending to the Pure Food, Drug and Cosmetic Act, but most outside of the industry have not taken notice. To the companies receiving the judicial fines, $4.3 billion dollars, an average of $710,000,000 per company, is substantial, but they seem not to care. Management seems to still not hear the cries of quality first. Hence more and more Warning Letters are issued daily. When will the industry learn?

Quality is not cheap, it is not easy, and sometimes it is inconvenient. I once had $4 million dollars of product on quarantine for nine months while we investigated the testing surrounding it. We knew it was an analyst error, but proving it takes time. However, my management would rather do the right thing than potentially maim or kill someone. In the end, the investigation was well documented, and the material was sent to market. Sales hated me for the backorders, but I was not punished. But then I worked for a company run by a physician concerned with quality.

Part of the problem in our industry is who is at the top. Are they ethical? Are they scientists or medical professionals? Too often they are professional business people, great at business management, but with no real knowledge of what is required to put a pharmaceutical or medical device product on the market that is safe, pure and effective. However, they are very willing to cut costs in quality. Often, they look at quality and compliance as unnecessary and government mandated. Quality and compliance are not the enemy, they are the last line of defense. Quality and compliance are all that stands between success and a tarnished corporate image, but management does not often recognize that. Let quality and compliance do their jobs.

The profitability of whistleblower cases is hurting industry, hurting corporate market share, hurting corporate profits. The CEOs and boards need to wake up and understand this. Fund quality, let them investigate, do the right thing, and Oh My Goodness, you will actually make more money. The offset spent on quality will help, not hurt, the bottom line.

The FDA and Justice Department have mastered the art of the whistleblower investigation. They are now smarter than the cost cutters who are cutting corners on compliance and quality enforcement in our plants. Cheryl Eckerd may earn a payout from her whistle blowing, but for all the good she feels about it, it would be nice for her to be able to take an aspirin and wonder - wonder if that aspirin was made in a plant with compliance and GMP issues. We would not need whistleblowers if we just do it right the first time. Quality in, quality out. We can only hope the board room wakes up so we can all take our medications without fear.

Happy Thanksgiving! Don't Miss Our End of Year Events!

2010-11-23T12:12:00.029-05:00

Will you be attending any of these events? We hope you will be joining our Subject Matter Experts as they share their insight and expertise on some of the most pressing issues before the close of the year!

IPA'S Good Laboratory Practices

November 30 – December 1, 2010 - Montreal, Canada
Introduction, Requirements and Tools for Implementation

You've probably met Nancy Tomoney at past conferences - we hope you got a chance to view her presentation at RAPS 2010! If not, please introduce yourself, as Nancy will be attending and presenting at IPA's GLP conference in Canada this year. She joins a high profile panel of speakers with talks on Testing and Reporting Controls, among others.

Click here for more information, or to register for this event.

BIOCOM Presents: Off Label Promotion
November 30, 2010 - San Diego, California
Managing the Regulatory Compliance and Products Liability Risks
Alexis Stroud, our Director of Quality and Compliance, is another popular face on our speaking circuit. She is jointly presenting with Medmarc on this topic for BIOCOM members, as well as non-members! This is a must-see presentation that will cover, among other topics:

-Prosecution of off-label promotion as a form of Medicare fraud
-FDA guidance on the dissemination of medical and scientific journal articles;
-The impact of off-label promotion on certain, key products liability defenses; and
-Best practices for preventing off-label promotion.

Click here for more information, or to register for this event.

MASSMedic FDA Update

December 1, 2010 - Waltham, Massachusetts

Important FDA Regulatory News and Policies covered by Dr. Jeffrey Shuren, Director of the Center for Device and Radiological Health

When the FDA has something to say, a lot of people will be listening! So register early and claim your seat at this pivotal end-of-year program. In conjunction with the American Society for Quality/New England Biomedical Discussion Group & the Regulatory Affairs Professional Society/Boston Chapter, QPharma's Fred Sperry and Bruce Fieggen (crowd favorites!) will be giving you some inside info on:

- Project Management - What We All Need to Know

- 21 CFR Part 11 Compliance - What's New

Click here for more information, or to register for this event.

On behalf of QPharma's entire team, we wish you a Happy, Safe, and Fun Thanksgiving!

Recommendations for an Effective Vendor Qualification Program - Part 2 of 2

2010-11-16T09:01:00.001-05:00

Written by Teresa Jaworski – Subject Matter Expert, QPharma

In last week’s post, I shared with you some preliminary guidelines for qualifying a vendor. Here is Part 2 of that post:

Pre-Audit Questionnaire

If it is determined that a new vendor is needed, you should select a minimum of three (3) vendors, if possible, which can supply the product or services needed ( raw materials, components, manufacturing equipment, testing equipment, consulting services, etc.). The approved procedure should provide guidance for selecting these vendors. Once the potential vendors are selected, a pre-audit questionnaire should be provided to and completed by each of the potential vendors. The results from the completed questionnaire should be used to determine if the vendor will continue in the qualification process.

Onsite Vendor Audit

If it is determined that the potential vendor meets the criteria for continuing the qualification process per review of the completed questionnaire, schedule an initial, onsite audit as defined in the approved procedures.

When conducting the audit, the appropriate audit checklist should be used according to whether the vendor is defined as a critical or non-critical vendor. In addition, the onsite audit should include verification that the established requirements and specifications can be met by the vendor. Then based on the overall results, the potential vendor can be either accepted or rejected. If accepted, the vendor is considered qualified. If rejected, the company can either work with the vendor to resolve discrepancies and qualify the vendor or select another potential vendor. All auditing activities and results should be documented and maintained.

Quality Agreement

If it is determined that the vendor is qualified, a written Quality Agreement should be developed and approved between the company and the vendor. According to Hasselbalch, “a GMP guidance detailing expectations for quality agreements is in the works as well, and the regulations may be further upgraded to support the guidance in this area. The guidance will explain the expectation that the agreement be in writing and specify clearly what each party commits to do.”

Development and approval of the Quality Agreement should include members from all relevant areas within the company’s organization, including but not limited to quality, procurement, manufacturing, product development, process development, regulatory, and legal. This agreement should define required quality standards; products or services provided; quality requirements and specifications including but not limited to training, qualifications, and monitoring expectations; key contacts; quality roles and responsibilities; locations; and necessary communications regarding quality-related activities.

Recommendations for an Effective Vendor Qualification Program - Part 1 of 2

2010-11-08T10:39:00.001-05:00

Written by Teresa Jaworski - Subject Matter Expert, QPharma

According to a June 16, 2010 article posted on the International Pharmaceutical Quality (IPQ) website, FDA Fast-Tracking Supply Chain cGMP Upgrades; Other GMP Changes, Quality Agreement Guidance Taking Shape, “FDA is fast-tracking a set of changes to 21 CFR Part 211 targeting control of raw materials, excipients and components used in pharmaceutical manufacturing.”

The Center for Drug Evaluation and Research (CDER) Office of Compliance Team Leader Brian Hasselbalch announced these impending GMP proposals at a Global Outsourcing Conference at Xavier University on June 14, emphasizing that “adulteration issues represent credible threats to our marketplace and that raw material controls have to be improved.”

Hasselbalch further explained “They will require drug producers to know who the original manufacturer is for all excipients and active ingredients, and any subsequent repackers and relabelers – that you know who they are, who handles [the material] in the supply chain, similarly to the EMA proposed pedigree.”

As discussed earlier in a September 2010 blog, the U.S. Food and Drug Administration (FDA) Guidance for Industry Q10 Pharmaceutical Quality System, which is in accordance with 21 CFR Part 820.50, specifies that Pharmaceutical companies are ultimately responsible for ensuring that processes are in place to assure the control of outsourced activities and quality. We are now going to dig a little deeper to discuss how these controls can be accomplished.

A company should establish and implement processes that can determine the suitability and competence of a vendor for their specific needs. These processes should include establishing approved procedures; performing audits; ensuring the vendor is qualified prior to selecting them as a vendor; and continuing to monitor the vendor’s performance after qualification including re-qualifying the vendor at established time intervals.

Establishing Approved Procedures

When establishing approved vendor qualification procedures, keep in mind that the procedures should include, at minimum, guidelines for the following:

selecting a potential vendor for the products or services needed
defining and documenting requirements and specifications to be met by the vendor
determining whether the vendor is a critical or non-critical vendor
auditing requirements for both a critical and non-critical vendor
distributing the pre-audit questionnaire for completion by the potential vendor
determining the vendor suitability as a result of the completed pre-audit questionnaire
planning, scheduling and conducting on-site vendor audits
preparing audit reports
following up on any audit findings to ensure appropriate CAPAs have been implemented
defining time intervals for re-qualifying/re-auditing vendor
completing and maintaining vendor Quality Agreements
developing and maintaining an Approved Vendor List
storing all required vendor qualification documentation including pre-audit questionnaires, audit checklists and notes, audit reports, Quality Agreements, Approved Vendor List, etc.
handling vendor relationships when requirements are no longer being met

It is also recommended that the following templates be included, or their location referenced, in the vendor qualification procedures to ensure consistency and to ensure that requirements are being met:

Pre-audit Questionnaire, which should comprise requests for relevant information such as the following:

company name
company location
contact information (telephone, fax, email)
company history
product(s) or service(s) provided
number of employees
details of implemented quality systems
dates of last regulatory audits (FDA, ISO, etc.)

Audit Checklist for auditing critical vendors
Audit Checklist for auditing non-critical vendors
Audit Report
Quality Agreement
Approved Vendor List

Training should be conducted and documented on the approved procedures prior to being used, emphasizing the need for quality support during all phases of the vendor qualification process.

Stay tuned for Part 2, coming next Monday, November 15th!

The Twelve Towers - A Project Management Novel: Excerpt 1 - The Project Charter

2010-11-01T11:00:00.003-04:00

Below is an excerpt from the Project Management novel Bruce Fieggen, QPharma’s V.P. of Project Management, is writing in his ‘spare time’. The book follows the Project Management Body of Knowledge Guide (PMBOK) but uses the format of a novel, and promises to be much more readable. The novel tells the story of a Gwilym, a Project Manager, charged with building twelve towers scattered throughout King Arthur’s Britain. Gwilym has three sons, the oldest of whom, Bleddyn, is also introduced in this excerpt.

Readers, think about the various projects you are tasked with and see how you can use the tools shown in these blog posts to assist you in ‘building your towers’.

This first excerpt shows the development of the first tool: The Project Charter.

After laying down the foundation logs, the men started laying down the side logs, marveling how each fit neatly into place on top of the one below and to right angles with it. With each additional log, the structure pulled tighter together.

Once the men had the hang of the design, Gwilym left Fred in charge and rode his horse painfully and slowly to the quarry to see about some new stone to dress the tower’s outside. Some stones had been salvaged from the old tower, but much more needed to be added. The quarry was around the other side of the hill but it still took Gwilym two hours of careful riding to reach there given his painful leg. On arriving he asked to sit down and put his leg up.

The quarryman was a short, barrel-chested, old man with sinewy arms and a grizzled beard. “I thought it about time you came to me for stone. How much will ye be wanting?”

“I need 100 tons for now, cut square about 2 feet to a side. When can you deliver that much?”

“I can start delivering 2 tons at a time as soon as I get gold for first shipment.”

Gwilym looked confused and said, “But Father Drew said that the quarry belongs to the church and it is his to use.”

“Aye, church owns it but tower is being built for defense of city. So money must come from king.”

“But Father Drew appointed me the Project Manager. He is the one in charge of the tower. And he is of the church.”

“Father Drew is priest of village church. Quarry belongs to whole church. And for that, you either pay me gold or get permission from bishop.”

“Start cutting now, quarryman. I’ll get the permission in time to take shipment.” Gwilym limped off to his horse and rode painfully back to the village.

___________________________

“How goes the tower, Gwilym?” were Merlin’s first words.

Gwilym was intimidated by this old man of whom he had heard many stories. He looked like the wise old Druid he was reputed to be and his bright eyes sparkled under his bushy eyebrows. His long, grey hair made him seem much older than he was. His hands were strong and showing no signs of age and his well muscled arms handled the reins expertly.

“It goes well sir. The wooden structure is almost finished and we now need to face it with stone.” Gwilym remembered yesterday’s confrontation at the quarry and his mind switched to this other problem in his life. “But now the quarryman wants to charge us for stone, even though the quarry belongs to the church.”

“And what will you do to solve this?”

“I’ll get an order from the bishop to make him give up the stone.”

“And will that be your answer to the next problem that arises?”

“What’s that sir?”

“What will you do the next time you run into a problem like this with your tower?”

Gwilym felt like a fool. What was he missing? “I can’t guess all the problems that will arise; I just have to deal with them as they come up.”

“What will you do if the men decide to stop working? Or if the priest says he wants the tower to be taller, or if some knight asks that it be made round?”

“I need a letter that says what the tower should be and who is to pay for it. And I need it signed by someone whom everyone respects. Like the king! Even the bishop has to listen to the king. Is that what I need, Merlin?”

Merlin’s eyes twinkled but he said nothing. Gwilym looked at him curiously and said, “You know a lot more about building towers than you let on and I’m onto you. Can I ask you other questions later on when I hit other snags?”

“Did I answer your first one?”

“Not with an answer; that’s true, but you asked the right questions that let me come up with the right answer.”

____________________________

When Sir Kay escorted Gwilym and his son, Bleddyn, into the great hall...

...at Caerleon, the place was in an uproar. Hunting dogs ranged around, some were resting in a pile of rags near the fire, some snapping up food from the table, others fighting for dominance. King Arthur sat at the center of a group of unruly, feasting men, all of whom showed their devotion to the young king by their attentions. They shouted their hunting exploits over one another, wrestled for sport, yelled insults to each other and crowded as close to the king as they could.

One of them spotted Gwilym and yelled out, “Watch out fellows, here comes a Saxon giant!” The rest looked Gwilym’s way and they all seemed compelled to make sport of him.

“Where did you get your leg wound, Saxon, did I leave one of you alive in my wake?”

“Have you come to beg peace of us at last, Saxon king?”

The entire company burst into laughter at this last jest. Sir Kay walked Gwilym and Bleddyn close to the king’s side. The men quieted one by one with Gwilym’s approach until Arthur stopped his conversation with Launcelot and looked up expectantly.

“How came you by that wound, Saxon?” Launcelot inquired?

“I’m no Saxon warrior, Sir Launcelot.” replied Gwilym. “I am in charge of rebuilding the battle tower at Huish and come to ask help of the king.”

“Ask away” said the king. Gwilym was shocked at the king’s youth. He was just starting his first beard and his skin had the rosy hue of a boy. Yet he appeared comfortable in his role and wasn’t constantly looking for the approval of his elders in the way of other young leaders Gwilym had encountered before.

“My lord,” said Gwilym, relating his much-practiced speech. “The battle-tower at Huish is an essential part of your country’s defenses as it watches one of the major invasion routes of the Saxons. It provides early warning of their approach and serves also as a signal tower to the rest of England. The completion of this tower cannot be delayed.”

“And yet is has been delayed, some say deliberately!” interrupted one of the knights. “The old master builder has informed us that someone deliberately sabotaged the tower, causing it to collapse and getting himself appointed to the rebuilding. What say you to this charge?”

“I say that this Tarrant says many things when witnesses are not around and little when there are people to dispute him. Think you Father Drew a fool that he fire Tarrant and put me in his place? If you wish to see why his tower fell and my design will not, my 8-year old son will demonstrate with two models while I continue.” This drew the eyes of the curious knights as Bleddyn soaked the small sticks in water and began assembling the two towers, explaining the differences as he went.

“Do you agree, my lord, that this tower cannot be delayed?” asked Gwilym. He received King Arthur’s assent with a firm nod of the head.

“And do you agree that there are many things that could delay its construction: supplies of logs, stone, men and masons?” Once again he received a nod.

“And if my lord were with me at all times when I struggled to obtain these items and continue with the building, no delays would ever appear due to your presence?”

At this, Arthur looked disturbed and argued, “I’ve no plans to stay by your side during a tower construction, my good man. While it is important, there are many other things I need to do during this time.”

“Quite true my lord. But what if I carried with me a royal charter, spelling out what I was charged with building, how much wood, stone and skilled men I needed, where I was to obtain these, how much I were to pay for these, where the tower should stand and how high? What if this charter could say your words for you, while you continued with your other leadership duties in peace?”

“I would ask to see this charter”

Gwilym pulled the scroll from his bag and unrolled it in front of the king. Arthur, Launcelot, Kay and a couple of the other knights read it with interest. The others feigned indifference, probably to disguise their illiteracy, and paid closer attention to the models being built by Bleddyn.

“You would like me to affix my signature to this, ahh…Gwilym?” said King Arthur, scanning the charter again for his name.

“Plus the royal seal in the space at the bottom if you would, my lord. I want it to be an impressive document, even for those who cannot read it.”

“What say you, Launcelot?” he asked of the handsome knight to his right who was studying Gwilym with interest.

Launcelot paused and looked deep into Gwilym’s eyes. Gwilym felt uncomfortable but met his gaze. “And what does Merlin say of this charter?”

“It was Merlin’s idea”

“Merlin never tells anyone what to do. What do you mean it was his idea?”

“Merlin asked me questions that made me think of this solution.”

“Ha!” Launcelot barked out a quick laugh. “That’s Merlin alright.” He turned to King Arthur, “I think you should sign this charter and watch this Saxon to see how well it works. My kinsman has good ideas, even if he never says them out loud.”

King Arthur called for quill, ink and wax and was pleased to see that Kay had them all ready. He signed the charter with a flourish, attached a red ribbon to the bottom with some drips of red wax, then pressed his ring into the cooling wax to leave an imprint of the dragon seal. He handed this back to Gwilym and asked to see the models.

Bleddyn stepped forward and stammered out a description of the two designs. Arthur paid close attention and played with both models and set them carefully by the fire to dry. Bleddyn blushed happily from the attention. Arthur placed his hand on the boy’s shoulder. “May I keep these fine models, son?” Bleddyn was torn inside and looked aghast at his father.

Gwilym nodded to his son and told him he’d build him another set. Bleddyn said, “Yes, my king. It would be my pleasure to give them to you. Just soak them in water for 10 minutes to take them apart.”

____________________________

They arose early again and rode as fast as Gwilym was able to the quarry near Huish, and found the quarryman hard at work in the pit. Gwilym hailed him and the man worked his way back up to the road.

“I have a royal charter signed by the High King that authorizes me to use your stone to build the tower.” Gwilym carefully unrolled the charter. He knew instinctively that the man was illiterate but, like most of his kind, held words in awe akin to magic.

“Where says it how much stone you may take?” he inquired, his eyes, scanning the document and lingering long on the seal and red ribbon.

Gwilym showed the man the passage about the stone and circled the amount with his fingers, knowing that the man knew his numbers. “I see you’ve been careful to cut the stone, knowing that this misunderstanding would be resolved soon. I commend you for your foresight, brother.”

The quarryman swelled with pride, forgetting that he had been ordered to cut the stone by Gwilym days ago.

Stay tuned for the next installment from this novel coming November 15th!

It’s All About State Compliance

2010-10-25T09:05:00.006-04:00

Written by Alexis Stroud - Director, Quality and Compliance, QPharma

We are approaching the end of 2010, and by now, you should have filed your state aggregate spend reports for D.C., Massachusetts, Maine, Minnesota, Vermont, and West Virginia* . You are most likely also preparing for the Physician Payment Sunshine Provision, included in the Patient Protection and Affordable Care Act (PPACA). But are you aware of the numerous other state laws and regulations that affect the sales and marketing teams within your organization? In this post, I will review some of the state legislation that you should be aware of including:

•    Compliance Programs
•    Sample Theft/Loss Reporting
•    Sample Transparency
•    Lobbying
•    Data Privacy
•    Representative Licensing

*Medical Device companies – You are not off the hook! You too are required to track and report aggregate spend in CA (declaration of compliance), MA, and VT. You will also be required to report under the federal PPACA in 2013.

Compliance Programs
The company must have a compliance program in place with certain elements. For example:
•    Adhere to, at a minimum, PhRMA Code (CA, MA, NV, CT)
•    Program must be in accordance with OIG Guidance (CA, CT)
•    Compliance Training (CA, CT, MA, NV, VT)
•    Compliance Monitoring (CA, CT, MA, NV, VT)

Sample Theft/Loss Reporting
Certain states require the reporting of sample thefts and/or losses in addition to federal reporting. For example:
•    Vermont and Washington require reporting immediately
•    Arkansas, Florida, Hawaii, Indiana, Louisiana, Oregon, Wyoming require reporting within 3 working days
•    Colorado and Ohio require reporting within 30 days
•    New Mexico, North Dakota, South Carolina, and Virginia also have reporting requirements

Sample Transparency
Vermont’s Senate bill 88 (“SB88”) amends Vermont’s Pharmaceutical Marketing Disclosure Law by requiring manufacturers of prescribed products to disclose to the Vermont Attorney General’s Office all free samples of prescribed products provided to health care providers during the preceding calendar years.
•    “Sample” includes starter packs and coupons or other vouchers that enable an individual to receive a prescribed product free of charge or at a discounted price

•    This bill requires manufacturers to identify for each sample the product, recipient, number of units, and dosage
•    The first report is due on April 1, 2012 for the previous year's sampling activity

Lobbying
These laws require “lobbyists” to register and file a report that contains certain expenditure data. For example:
•    Colorado requires expenditures in excess of $50 to be reported
•    Florida requires a signed statement under oath of expenditures in excess of $25
•    Connecticut and Kentucky require a report for all expenditures
•    Louisiana requires reporting on expenditures that exceed $50 on any one occasion or $250 in a reporting period

Data Privacy
These laws require that certain prescriber data remain private. For example:
•    New Hampshire became the first state to pass a law that restricts the sale and use of prescriber data.
•    Vermont enacted a data privacy law which keeps prescriber data confidential unless practitioners request that their data be made available to the public.

There are also several other states that provide prescribers the option to “opt out” of being included in lists. This includes lists of practitioner licensure data used for practitioner validation. States also vary on the type of information they will provide within the list.

Representative Licensing
D.C. is currently the only state which requires all “detailers” doing business in DC to be licensed and held to a professional code of conduct. The bill also requires detailers to have an appropriate educational background.

Keep On Top of State Laws!
These were just a few of the state issues you should familiarize yourself with. Others include mid-level prescriptive authority, distributing controlled substances, distributor licensing (wholesaler, virtual, 3PL, samples only), and pedigrees. Many of the states also have fines for violating their laws (and investigate noncompliance). Pleading ignorance is not acceptable, so it’s important that you understand the legislation and know how to comply with it.

Looking for Regulatory Compliance help? Email us your questions at info@qpharmacorp.com!

Best Practices for Validation of a Software as a Service (SaaS) Customer Relationship Management (CRM) Solution - Part 2

2010-10-18T12:56:00.000-04:00

Part 2: Best Practices for the Validation of a SaaS Application

Written by Gregg Mauriello - Validation Manager, QPharma

In Part 1, I gave an overview of what Cloud Computing and SaaS are, and I promised more information in the coming months. Part 2 is here, and now I can discuss the best practices for the validation of a SaaS application. I will look at the methodology for the validation of a SaaS CRM Application and compare it to the conventional methodology for the validation of a CRM Application.

Since all customers utilize the same instance of a SaaS application, the core functionality of the application can be validated just once. Also, the vendor may perform a baseline configuration of the application to meet best practices for a CRM application. This baseline would also be validated just once. The customer validation, therefore, can be limited to the customer-specific configuration of the application that deviates from the pre-validated baseline. The validation of the core application and baseline configuration will follow the conventional methodology for validation, including installation and operational qualification. The vendor must develop business requirements and functional specifications against which to test including the definition of the baseline configuration. Note: The focus of validation testing will be on functionality of the system with regulatory impact.

Deliverables:

The Vendor Validation Plan will document the process, activities, and deliverables required for the validation of the core application and baseline configuration.
An Installation Qualification will be developed to document all core software and hardware required for the application. Note: The vendor IQ will not address the field device used for the sales force as this will vary greatly by customer.
An Operational Qualification will be developed to test the functionality of the core application and baseline configuration.
A Performance Qualification will not be developed as the system will not be utilized in a production environment until it is deployed for a particular customer.
All validation activities will be summarized in a Validation Summary Report and a Release Memo will be generated, which will document that the application has been validated and is ready for customer configuration and implementation.

All customers utilizing the application will be able to leverage the validation of the core system and baseline configuration, allowing for a lean validation to be performed by the customer. It is recommended that the customer perform a vendor audit of the core configuration validation package to determine two factors:

A) If the validation documentation is in line with their internal quality processes and

B) How much validation of their specific configuration will be required.

The vendor will also provide a service level agreement which will define the vendor’s role in maintenance and the administration of the system and data. All procedures that are performed by the vendor, such as backup and recovery, change management (for code and infrastructure), disaster recovery, physical and logical security, system administration, and training, will be documented by the vendor.

Still interested in hearing more? I will be presenting information on this subject during an interactive workshop, at IVT’s 16th Annual Validation Week on October 26th (Session 4 on Day 2!). The workshop will be presented along with my colleague, Elise Miner.

If you are not attending Val Week, stay tuned for Part III, where I will discuss customer responsibilities in the validation of a SaaS CRM system.

The Drug Safety and Accountability Act of 2010

2010-10-04T12:03:00.000-04:00

Written by Elise Miner - Associate Validation Manager, QPharma

Michael Bennet,
courtesy of politico.com

On August 3rd, 2010, Senator Michael Bennet, a Democrat from Colorado, introduced a new piece of legislation - the Drug Safety and Accountability Act of 2010. The Act aims to put in place the steps needed to ensure the safety of the U.S. drug supply. The bill would grant the Food and Drug Administration (FDA) more authority regarding drug safety, and at the same time increase the accountability that drug companies own over the drugs that they manufacture and sell to the public.

The introduction of this Act comes at the same time as the release of a survey commissioned by the Pew Prescription Project and conducted by Public Opinion Strategies and Hart Research Associates. The poll included interviews from approximately 800 likely voters in 2010, which were sampled demographically to represent the national electorate. The results showed that Americans strongly endorse individual regulatory measures. For example, 85% strongly favored that manufacturers must inform the FDA when they find contamination. Similarly, 82% strongly favored the FDA having the power to issue mandatory drug recalls. Overall, nearly 9 in 10 Americans supported new measures be put in place to ensure drug safety.

Senator Bennet’s bill would improve upon the system the FDA uses to track international manufacturers providing ingredients and drugs to the U.S., thereby giving the drug companies better oversight of their contractors. However, one of the most significant authorities the bill would grant would be to empower the FDA to mandate drug recalls when safety issues arise.

What do you think? What are your attitudes towards prescription drug safety in the U.S.? Is the system working well the way it exists now, or do we need stronger safety measures?

Don't Validate That Software! Part II

2010-09-29T11:45:00.005-04:00

NOTE: This discussion is a continuation of Monday's post by Jeff Boatman - CQA and Sr. Subject Matter Expert, QPharma. To read the 1st part of this post, please click here.

INTEGRAL SOFTWARE

Suppose I have three autoclaves. They’re used to sterilize final product for human implantation: major potential for serious health consequences (and remember, you don’t get to say “it doesn’t matter because we wind up testing our product”—it matters). All three of these autoclaves use software.

The first one has a separate PC connected to it, and the software resides on that computer’s hard drive, interfacing with the autoclave through a serial port. The PC is a general-purpose computer that can interface with a number of different autoclave models, and allows the user to set up specialized cycle profiles and alarms. Does that software need to be validated? You bet!

The second one sounds different, but in most ways, it’s not. That autoclave has a computer built right into it, running software with a user interface that permits customized cycles and alarms. Now there is indeed a difference: it is not designed to be disconnected from one autoclave and hooked up to another. Clearly there is some amount of scale-down that is appropriate in not needing to check that the computer can be reliably moved from one autoclave to another. But the core expectations remain the same: not only does the software, as it is configured right now, run the autoclave in such a way that it consistently works (OQ = correct temperature/pressure/cycle profiles, PQ = actually sterilizing loads); it also must demonstrably provide confidence that a range of different parameters and program sequencing will be reliably translated into actual machine operation and that those profiles are consistently implemented. That’s a qualification that goes beyond simply how the machine itself operates: it is software validation. We may have used a risk assessment to scale down the amount of testing needed, but there is definitely a separate software aspect to this.

Now consider the third example. This autoclave is computerized, but the software is programmed for one specific cycle profile; it is not customizable. There are a couple of ways this could be done: the autoclave could truly be a one-trick pony, with the computer no more customizable than a four-function calculator; or more and more commonly, the software is customizable, but the manufacturer has decided that the configuration will be “locked down” and never changed, at least not outside formal change control (which includes, of course, a process for evaluating changes for the need to perform re-validation).

I contend that in this last example, the whole concept of “software validation” goes out the window. If indeed the system has any potential for changing settings and parameters, then certainly you must both explain the measures used to preclude anyone from making unauthorized and unvalidated changes, and then demonstrate the effectiveness of those controls; and if the autoclave electronically captures or transmits any digital records that are used for GxP purposes, then validation for Part 11 may still apply. Those could include actual cycle monitoring records, any data input by users such as batch identification, or confirming the identity of authorized users.

But provided you have covered these Part 11 items, there is no regulatory obligation to...
...perform a specific “software” validation. You should be able to trace whatever software that is in the unit, including any customizations prior to its "lockdown," back to a backup or code listing somewhere (to prove that you would be able to get the machine back to its validated state and to satisfy the “written copy of the program…” requirement in 21 CFR 211.68(b)), but if the software cannot be changed and you show that the autoclave meets its requirements and works as expected, then what exactly is the advantage of having a separate validation plan, OQ, and report just for its “software” aspects? You are going to have to validate that autoclave for its proper function anyway [21 CFR 211.113(b), 820.75(a), and a host of FDA and industry standards]; why not simply treat the software functions as part of the hardware so if you validate one, you’ve validated both?

Admittedly, an autoclave is perhaps not the best example; autoclaves are becoming increasingly sophisticated precisely because manufacturers want flexibility in customizing cycles to circumstances, the old “15 minutes at 121” becoming antiquated. It probably also does not apply to most CNC-driven production equipment for the same reason, but I have definitely seen CNC mills that have become “one-trick ponies” where my argument could also apply.

Where I do often see this is in machines that are manufactured by a tool maker to be adapted to a variety of industries, and which the drug or device firm then buys with a particular set of ladder logic in its Programmable Logic Controller (PLC). Consider a heat-sealer used to seal foil pouches; there are two types of pouches used, and they each require a particular temperature and a specific belt speed. The manufacturer allows a multitude of settings, but you have programmed it only to do those two, and you will never change them (perhaps the temperature is set by a PID so human intervention to maintain temperature is unnecessary, in fact that’s one of the requirements being validated). Assuming that you can show that these settings really cannot be changed, either because you have objectively validated the effectiveness of the controls around them or because there simply isn’t any interface that would allow them to be changed, then what is the point of performing a software validation?

Key to this argument is the assumption that the software genuinely will perform consistently. If I type “clear 5 x 5 =” on my calculator, I should always get the same answer. The calculator may have a serious software bug, but if that one calculation works once, it should work again. But if I now type “clear 5 x 6 =,” that software bug may suddenly impact my results. So suppose my heat sealer software allows me to input batch number, user name, and product ID into fields to be stored. Could different inputs result in changing the ladder logic? Probably not, but I have seen a case where typing into a field overran the software’s table entry and overwrote the next instruction, causing bizarre, non-repeatable behavior. If your equipment allows variable inputs and you cannot document why you are confident that they could not affect program execution, then software validation is probably in the cards for you. (This could in principle apply to data outputs as well.) As the complexity of the software and in particular the amount of input the operator has increases, there will come a tipping point at which software validation is needed.

Yes, of course the temperature of a heat sealer needs to be consistently met whether you are processing one pouch or a hundred. And sure, if the software allows the user to raise or lower the temperature by five degrees to compensate for on-the-line peel test results, you need to exercise the program at its limits. But all of that is true regardless of whether the machine is computerized, analog, or “other”: I once worked on a manufacturing machine whose PLC was executed as a series of air valves acting as logic elements. It could, in fact, be “re-programmed” by changing the order of which valves were connected to which tubes. Was that “software”? Sure, by the strict definition. Was it an “electronic record”? Absolutely not, and it would have been crazy to have written a separate “software validation” protocol. We took a photograph of its internal workings, attached that to a drawing showing the correct configuration, attached that to the IQ, buttoned the unit up, and stuck a security seal over it and gave the maintenance department the extras. We then validated it based on what it was intended to do, and not on what it could theoretically do.

SUMMARY

In General Principles of Software Validation, FDA proclaims “software is not hardware.” In case that isn’t self-evident, the guidance goes on to explain why it is true: software evolves and improves over time, software can act in nonobvious ways, software’s sequence of execution can change. I say, “yes, but sometimes software can be treated like hardware during validation,” with the proviso: “if you’re careful.”

Validating computerized manufacturing equipment certainly requires consideration of the software aspects of its operation. If that equipment utilizes or generates GxP electronic records, then the 21 CFR 11 implications must be evaluated and validated. If that software has general-use capabilities or interfaces with other systems such that one can control the other, either directly or through the relay of information, then software validation is an important part of the overall validation. Certainly the default position from a regulatory standpoint is to perform software validation.

But if equipment follows software instructions that are fixed, or at least have a very limited ability to change parameters and no ability to change logical sequencing (including as an unexpected result of inputting or outputting data), then so long as it can be demonstrated that the ability to make changes to that system are tightly controlled (or impossible), then incorporating the validation of software functionality into the conventional qualification of the equipment itself may be a viable, cost-saving, and compliant option worth considering. Since risk assessments are already an FDA expectation when it comes to validation anyway, spending a few extra minutes evaluating whether the software in a piece of equipment actually needs its own validation effort and documenting that finding and its reasoning could be time well spent indeed.

Please leave your comments on the blog. Do you agree? Or disagree?

Don't Validate that Software!

2010-09-27T12:43:00.002-04:00

Written by Jeff Boatman - CQA and Sr. Subject Matter Expert, QPharma

BACKGROUND

General software validation became an official part of U.S. regulated Life Sciences in 1996 with the finalization of the Quality System Regulation. Contained within that Rule is 21 CFR 820.70(i), which states when computers or automated data processing systems are used as part of production or the quality system, the manufacturer shall validate computer software for its intended use according to an established protocol. It is important to note that while Part 820 is a Medical Device regulation, another section [21 CFR 820.1(b)] gives FDA the authority to apply this requirement to other companies as well.

Prior to this, there was no specific regulation dealing with software validation; the closest was 21 CFR 211.68, which since 1964 has stated that if a manufacturer uses an automated system to produce a drug product, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Bear in mind that computers were practically a novelty when that Rule was finalized, and modern validation practices were only beginning to emerge; the first software inspectional guidance wasn’t issued until 1983.

In 1997, FDA followed up with 21 CFR 11, which states that systems that create, store, process, or transmit electronic records used to satisfy regulations must include validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records [21 CFR 11.10(a)]. Shortly after, the Center for Devices and Radiological Health published Guidance for Industry: General Principles of Software Validation, which has since gone through several draft and Final revisions. While that guidance is from FDA’s Medical Device division and does include sections on the validation of software which is, or is used within, a Medical Device, it also has broad applicability to other Life Science firms as well.

The broad applicability of 21 CFR 820.70(i), the virtually universal applicability of Part 11, and the adoption of the standards in FDA’s software validation guidance make it clear that FDA has very high demands for software validation at Life Science firms, and indeed consulting firms like QPharma rely upon FDA’s comprehensive expectations to stay in business. It must be obvious to the reader that the problem that we see most often is too little software validation, too poor software validation, and too poorly executed software validation. Further complicating this is the latest move by CDRH to vastly increase the scope of what FDA considers to be "Medical Device Software" into areas that traditionally have been considered outside CDRH’s (and even FDA’s) jurisdiction.

THE USUAL...AND THE UNUSUAL

When we do audits, our comments are usually: you need to validate this...you forgot to validate that...you didn’t consider this. But once in a while, our comment is: why did you validate that?

Let’s hit some of the basics. First, you need a Traceability Matrix (TMX), which shows all of your requirements, all of your testing planned (and performed), and linking them together. Traceability of requirements to testing is always a good idea, but for software validation, it’s mandatory: the FDA guidance mentions it repeatedly. The most important purpose of a TMX is to ensure that every requirement actually gets validated or otherwise verified. But it also goes the other way: if you are testing something and it is not traceable back to a requirement, then why are you testing it?

Another low-hanging fruit is risk assessment. If you take the validation requirements of 21 CFR 11.10(a) and 820.70(i) literally, you’ll probably never manage to make any product for sale: all you will ever do is validate, validate, validate. (As an example, if you literally accept 820.70(i)’s obligation to validate all software changes prior to implementation, can you imagine the potential implications for daily antivirus definitions and Microsoft Windows patches?) In both its software validation guidance and the 2003 Guidance for Industry: Part 11, Electronic Records; Electronic Signatures – Scope and Application, FDA has been putting increasing emphasis on doing risk assessments of systems to determine exactly what truly needs to be validated. In particular, the Part 11 guidance offers companies the possibility of exempting broad swaths of functionality from validation provided that you can back that up with documented risk assessments. FDA may object to lesser validation based on a risk assessment they disagree with, but they will object to lesser validation without a written risk assessment at all.

In both of these examples—validation of functions that aren’t required, and validation of functions that a risk assessment could have exempted—we would caution our client that they are going overboard and that their validation dollars are better spent elsewhere. But how about software that runs a manufacturing process, and that process (and therefore that software) really does have a significant impact upon product quality, and even public health?

More on this topic and the answer this Wednesday, September 29th!

Live Informative Sessions - Join Us!

2010-09-20T14:45:00.000-04:00

The experts at QPharma will be giving some presentations towards the end of the year - and we want you to join us! We hope you have found our blog to be informative, interesting, and at times, entertaining. Come meet the subject matter experts who write our articles at the following venues:

October 24-27: 2010 RAPS Annual Meeting - San Jose, California

Come join Nancy Tomoney at our Sponsor Spotlight Session on Monday, October 25th! Nancy will be giving an informative learning session on:

Current Events Impacting FDA Registration and Sale for Products Marketing Through CDRH, CDER, CBER and CVM.

QPharma is also giving away a Flip Video Camcorder - just stop by our Booth #525 and enter for your chance to win!

October 25-27: IVT'S Validation Week - Philadelphia, PA

Session 4, Day 2 - Tuesday October 26th Gregg Mauriello and Elise Miner are headed to Philadelphia, PA to give their talk on: Best Practices for Validation of a Software as a Service (SaaS) Customer Relationship Management (CRM) Solution. One of our most popular blog posts, this duo will be answering your questions on this process and addressing your most pressing concerns when it comes to validation "in the cloud".

Check out the description of their Session Track here (scroll to "Session 4").

November 7-10: ISPE 2010 Annual Meeting - Orlando, FL

Nancy will be joined by Kim Stanton, another of QPharma's Validation Managers, at ISPE's meeting in Orlando this year. Our experts will be giving the following presentations on November 8th, 7:00 AM - 8:00 AM on Stage 2:

- Case Study in Good Laboratory Control Practices - Applying GAMP, Calibration Management, Good Laboratory Control and Good Engineering Practices for a Successful Move.

Talk will detail the tasks, checklists, and activities used to relocate an Analytical Laboratory from one operating site location to another.

- Applying Best Practices using Validation Test Management Tools for Validating Computer Systems.

Presentation will detail the efficiencies of Test Management Tools and how to apply best practices to Test Management tools to meet regulatory standards for Validation deliverables.

Visit us at our Booth #415 to talk to our Subject Matter Experts!

We hope to see you there!

Test Management Tools - What Are They & Why You Need Them

2010-09-13T13:25:00.001-04:00

Written by Kim Stanton, Associate Validation Manager at QPharma

As anyone that has been involved in a Validation effort can attest to, the old Validation Standards of requirements/system design documentation, over-testing, paper based script development and execution can be burdensome, resource/budget intensive and time consuming. This is making Pharmaceutical, Biopharmaceutical and Medical Device companies search for Test Management Tools that will streamline their validation efforts.

Computer System Validation (CSV) Test Management Tools manage the validation process by providing the ability to gather requirements, conduct risk assessments, create test plans, execute scripts manually or automatically, manage deviations and create summary reports.

Since many Test Management Tools are web-based they have the ability to centralize a company’s validation processes, allowing for resources from various locations to be involved in all aspects of validation efforts without the need for travel budgets and travel resource downtime. Execution times are greatly reduced since testers do not have to transcribe pages of test results, attachments and deviations. Also, multiple testers can execute simultaneously (unless there are script dependencies) since all activities are performed in the Test Management Tool. In addition to streamlining the execution process, the following steps are greatly improved using Test Management Tools: traceability of requirements to testing, attachments to test steps and deviation to test steps.

No matter which Test Management Tools are used to manage a company’s validation processes there could be a number of issues that will need to be addressed during the implementation of a Test Tool. Moving from a paper-based test management process to a system-based process requires changes in current procedures and resource training.

Many Test Management Tools have the ability to configure Workflows. Workflows are critical for controlling the validation process, from requirements documentation to summary report close out. Workflows ensure consistency for each validation effort managed by the Test Management tool no matter what type of application is being validated, what department of the company is conducting the validation, or what location of the company is performing the validation. A controlled workflow ensures compliance with the companies Standard Operating Procedures (SOPs) and regulatory guidelines. If workflow configuration is not available in the chosen Test Management Tool, a SOP for workflow management/operation must be documented and approved.

The Test Management Tools selected should be compliant with 21 CFR Part 11 requirements, which includes:

• The Test Tool must only be accessible by personnel with a valid user account.

• A well defined Approval process (see above) must be implemented.

• Electronic signatures should be configured.

• Audit trails to capture creation and changes to all validation deliverables including the executed scripts must be implemented.

All personnel involved in Validation processes must be educated and trained on the Test Management Tool to include Quality Assurance personnel. This will ensure that resources that perform validation activities will realize the benefits of the Tool, ensuring that it will be used in a compliant manner.

Since the Test Management Tool will be configured by both Regulatory and Business requirements, the System Development Life Cycle (SDLC) of the tool will need to be managed to include support, tool-specific SOP documentation and validation of the tool.

For more information on QPharma's validation services, please email us at info@qpharmacorp.com, or give us a call: 888-742-7620 and ask for Rob Finamore to discuss your needs!

FDA Announces Plans to Revise cGMP Regulations for Auditing Vendors

2010-09-07T12:50:00.000-04:00

Written by Teresa Jaworski – Senior Validation Specialist at QPharma

By year end 2010, FDA is planning to release new regulations that will include requirements for Pharmaceutical manufacturers to physically audit their vendors, no longer allowing paper audits to be acceptable. This change is being considered because of the large number of gaps being found in manufacturers’ quality systems due in part to the growth of production outsourcing. It is expected that once the drafting process of these proposed regulations is completed, they will be available for review and comments for approximately three to six months.

Brian Hasselbalch

According to Brian Hasselbalch, representing the Office of Compliance’s Division for Manufacturing and Drug Product Quality within FDA’s Center for Drug Evaluation and Research, at a conference held jointly by the agency and Xavier University in Cincinnati, Ohio, June 13-16, “between 2001 and 2007, the number of products manufactured outside the United States and the number of manufacturing sites abroad doubled. Some of the new products being imported into the US come from countries with less developed regulatory systems.”

As indicated in the U.S. Food and Drug Administration (FDA) Guidance for Industry Q10 Pharmaceutical Quality System, which is in accordance with 21 CFR Part 820.50, Pharmaceutical companies are ultimately responsible for ensuring that processes are in place to assure the control of outsourced activities and quality. In doing so, companies should implement processes to access the suitability and competence of a vendor prior to outsourcing operations or selecting them as a vendor. This can be accomplished by establishing approved procedures, performing audits, and ensuring qualifications. Note that defined quality requirements should be used during the auditing process to ensure the vendor is capable of meeting these requirements. The evaluation results should be documented.

If it is determined that the vendor is qualified, an approved, written agreement, often referred to as a Quality Agreement, that defines quality requirements, responsibilities, and communications necessary for quality-related activities, should be created and approved between the two parties. Records of acceptable vendors should be established and maintained via an Approved Vendor List.

If a company does not have an Approved Vendor List, it cannot be concluded that vendors being used by the company are qualified to provide the products and services being used for cGxP purposes. With the establishment of an Approved Vendor List, a company can work smarter, not harder. A company will be able to determine if a qualified vendor is currently available that can provide the necessary products or services instead of going through the entire qualification process each time a new vendor is needed. It also ensures that several vendors are not being used for identical products or services. In the end, this will result in better utilization of resources, an improved state of regulatory compliance, and a cost reduction for the company.

However, having these procedures in place does not ensure proper implementation of them. Training should be conducted and documented on these approved procedures, emphasizing the need for quality in all aspects of the vendor qualification process including ensuring that all required vendor assessment and auditing documentation is stored in a centralized, secure location.

A vendor audit does not have to be conducted by a company representative. It is acceptable to use contracted resources to perform these audits as long as the resources are qualified to perform the tasks and the qualifications are documented. According to Hasselbalch, “We will not demand that you individually audit. We acknowledge and recognize a surrogate or a third party audit arrangement. It may be more efficient and more effective, quite honestly. A third party audit would have to be performed by a credible auditing arm [with] certain characteristics that assure the integrity and the quality of the audits.”

Refer to the links below for FDA MedWatch reports relevant to outsourcing.

Embracing the Computerized System Lifecycle – GAMP 5

2010-08-30T12:46:00.001-04:00

Written by John Wasynczuk - Senior Subject Matter Expert, Ph.D at QPharma

For those of us that have participated in developing and implementing new or upgrading existing software applications, from customized distributed control systems (a.k.a. manufacturing control systems) for automated control of Bioprocessing operations, manufacture of vaccines, production of API’s, etc., Building Management Systems, PLC controlled equipment, to Laboratory Information Management or other IT Systems, we are most likely familiar and have applied the life cycle approach presented in Good Automated Manufacturing Practice (GAMP) 5 Guideline entitled “A Risk Based Approach to Compliant GxP Computerized Systems” (2008). For those of you that are new to the game and are in the process of evaluating feasibility of a new project or have progressed to development of scope, budget, and preliminary engineering design, you need to familiarize yourself with GAMP 5 and begin developing policies, practices and procedures, consistent with its content as early as possible. Doing so will certainly increase your chances for completing the project in an efficient, cost effective, and most importantly, regulatory compliant, manner. This is possible because GAMP 5 incorporates ideas defined and described in FDA’s 21st Century Initiative; ICH documents Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality Systems; ISPE’s Product Quality Lifecycle Implementation (PQLI) Initiative; and ASTM E2500 Standard Guide for Specification, Design and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment.

GAMP 5 is based on developing and integrating the following five concepts into a cohesive computerized system development, validation and maintenance program:

Product and process understanding: System requirements must be developed to ensure the system is fit for its intended use focusing on aspects that are critical to patient safety, product quality and data integrity, including Critical to Quality Attributes and Critical Process Parameters.
Life Cycle Approach with a QMS (Quality Management System): Activities and quality management systems need to be developed for each Life Cycle phase, from conception to retirement, that promote continuous process and system understanding through periodic reviews of performance and process data, root cause analysis of failures, change control, etc., assuring compliance with regulatory requirements.
Scaleable Life Cycle Activities: Life Cycle Activities should be scaled according to system impact on patient safety, product quality, and data integrity; system complexity and novelty; and outcome of supplier assessments.
Science Based Quality Risk Management: Risk Assessments should be performed to identify critical aspects that may impact on patient safety, product quality, and data integrity; develop and implement risk mitigation reduction strategies or controls to reduce risks to acceptable levels; and monitor controls to ensure ongoing effectiveness.
Leveraging Supplier Involvement: Perform Supplier Assessments and follow up audits, and if acceptable, avoid duplication of activities by leveraging their knowledge, experience and documentation by seeking their assistance in developing specifications, testing, support, and maintenance where applicable

The following diagram, from ASTM E2500 introduces us to the Automated System Life Cycle by providing an overview of the Specification, Design and Verification process highlighting application of GEP’s, Risk Management, Design Review and Change Management throughout the life cycle.

Automated System Life Cycle

GAMP 5 goes on to classify the Computerized System Life Cycle as follows:

Concept
Project

Planning
Specification, Configuration, and Coding
Verification
Reporting and Release

Operation
Retirement

Aspects relating to the Project Phase will be covered in future discussions. Stay tuned!

The Growing GE (Genetic Engineering) Sector - Part II - A BUDDING INDUSTRY

2010-08-23T13:28:00.001-04:00

(Note: This article is the 2nd in a 3 part series on Genetic Engineering. To read the 1st part, please click here. )

Written by Paul Melamud - Validation Manager, QPharma

Introduction

When we refer to organisms that are “transgenic”, this means that DNA from one species has been inserted into another species for expression. Gene transfer between organisms of the same species is often called “intragenic”, and that between species that are sexually compatible is called “cisgenic”. These latter types are widely known; for example, Gregor Mendel selectively mated pea plants to study genetics in the 1800s, and for another, dog breeders continually attempt to create dogs that perfectly match the personality and stature conformation standards set forth by the Americal Kennel Club. These also comprise the basics behind the theory of evolution.

The first transgenic products were plants, made primarily to create disease-resistant and higher-nutrition foodstuffs (refer, for example, to Hope, a traditionally-produced (non-recombinant) hybrid that saved American wheat crops in the 1930s). In the 1980s, the first true Genetically Engineered or "GE" plants (tobacco) were made with inherent insecticidal and herbicide-resistant properties. These days, there are many bright prospects for products being dubbed “plantigens” and “plantibodies” that will contribute to public health at large, if introduced into standard crops. What may be surprising to learn, then, is that there are not yet any FDA-approved, plant-biopharmed pharmaceutical products.

Processes

There are two main processes that are used to genetically engineer plants for traits such as herbicide resistance. Similar techniques would be employed to cause the plant to express phenotypes with human therapeutic use. The first process, bacteria-mediated transformation, is accomplished with a bacterial vector, most commonly Agrobacterium tumefaciens, a plant parasite that can cause tumors by injecting DNA into host cells. It is this unique mechanism that scientists have harnessed to deliver DNA of their choosing for expression in plants. The second process, biolistic transformation, involves coating pellets of metal, such as tungsten or gold, with DNA and literally firing them into plant cells so that they lodge in the nuclei. Once there, the DNA separates from the metal and becomes integrated with the host DNA for expression.

These two processes are illustrated below, one diagram from McGraw-Hill Higher Education and the other from BBC News (see links below image for references).

http://www.mhhe.com/biosci/pae/botany/botany_map/articles/article_03.html

http://news.bbc.co.uk/2/shared/spl/hi/pop_ups/03/sci_nat_how_a_plant_is_genetically_modified/html/3.stm

There are a few other, less common methods that are used, including electroporation (electrically inducing transient holes through cell walls and membranes through which DNA can be introduced) and viral transduction (analogous to the bacterial vector transformation method). Electroporation is illustrated below.

http://www.inovio.com/images/IMG_how_ep_delivers.gif

Any of these methods can be used to attempt to transform millions or billions of cells – and that’s a good thing, because successes may occur as rarely as one in a billion. Scientists can’t look at every cell, so they have developed techniques (as illustrated above) that can easily distinguish the successes and allow for their isolation. The above method illustrates the use of a “selective agent” or “selectable marker,” which means that only the successfully transformed cells will survive exposure to the negative stimulus (i.e. the herbicide against which the genetic change would protect). Another method is coupling the desired gene with a second one that will provide a “screening marker”, which can be observed by a scientist; an example would be a gene that causes a cell to fluoresce under UV light, which would indicate successful integration of the DNA that was introduced.

Regulation

We can all appreciate how relatively new such products are, and that the process of development, testing, and eventually clinical trials and/or field studies to bring these products to the market would still be underway. There are a few other reasons, though, that I think explains why we don’t see such products on the market yet.

One reason behind this is that...

a large number of agencies are involved with new and evolving regulations governing transgenic plant products, including:

USDA – its Animal and Plant Health Inspection Service (APHIS) branch has jurisdiction over the planting of GE crops, and focuses on the risks of such crops escaping a farm and becoming agricultural pests. Authority is granted to them by the Plant Protection Act (PPA, 2000).
USEPA – has responsibility for plant-incorporated protectants (PIPs), focusing on the environmental health and safety related to their pesticide qualities. Authority is granted to them by the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA, 1947 et seq.), the Toxic Substances Control Act (TSCA, 1976), and the Food Quality Act (FQPA, 1996).
FDA – has jurisdiction over most food and feed uses of plants by humans (and other animals). Authority is granted to them by the Federal Food, Drug, & Cosmetic Act (FFDCA, 1938 et seq.).
FDA again – has jurisdiction over the derived drug intended to be administered to humans or animals (for veterinary products).

Publications by regulatory bodies regarding transgenic plant products include (note: not intended to be an exhaustive list):

USDA (APHIS): Guidance for APHIS Permits for Field Testing or Movement of Organisms Intended for Pharmaceutical or Industrial Use, July, 1998.
USFDA (CBER): Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology, April, 1985 (DRAFT).
USFDA (CBER): Draft Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals, April, 2003.
EMEA: 2001/18/EC, Directive on the Deliberate Release into the Environment of Genetically Modified Organisms (2001).

Also see http://www.biotethics.org/downloads/articles/EU%20Legislation%20GMOs.pdf, which covers many other EU regulations, recommendations, and guidances on this subject.

Additionally, the reader is directed to 40 CFR Parts 700-725 for the US Environmental Protection Agency's (EPA) regulations on microbial products of biotechnology, which are enforced under the auspices of the Toxic Substances Control Act (TSCA) of 1976. EPA defines “new” microbial products as those “formed by deliberate combinations of genetic material from organisms classified in different taxonomic genera,” and therefore they have some overlap with this discussion of transgenic organisms.

Controversy

As stated in the introduction to my previous blog, there are already a few transgenic animal products (e.g. ATryn) on the market – so numerous and potentially confusing regulatory pathways cannot be the barrier here. Why then are there no transgenic plant pharmaceutical products on the market?

I haven't found the difference explicitly spelled out in the literature anywhere, but the biggest distinction is in the isolation and intended administration of the product. Generally speaking: GE plants would be ingested to impart their inherent therapeutic properties to the host, while animals tend to be engineered to produce a therapeutic agent (e.g. in blood or milk) that is treated more traditionally like a pharmaceutical chemical; namely: separated, purified, and administered as would most types of drugs (e.g. oral tablets, patches, injections). Given our history, risks are better understood in the latter “chemical production” processes.

So, what are the biggest risks considered inherent to GE plant products?

According to numerous articles, a primary concern is that the introduction of genes for antibiotic or viral resistance may be transferred to bacteria within the body of an animal or human that ingests the GE plants. The concern, then, is that the bacteria themselves could be transformed to be resistant, which would render even the conventional treatments ineffectual.

But to me, the main obstacle to extensive promotion and market acceptance of such products certainly lies in the ecological risks, as continually emphasized by public advocate and lobbying groups under the buzzword “biosafety.” Of particular concern is the fact that control of containment is difficult to manage (especially when compared to controlling animal breeding), as pollens can float through the air and off of the farm to hybridize with non-GE plant crops. Will escape of the gene cause massive changes in the wild-type flora, and ultimately affect the ecosystem? What if these changes render plants inedible to animals that rely on them for sustenance? Not only does this send ripples up the animal food chain, but it might create “superweeds” that could become invasive since they are no longer naturally kept in check. It is for increasing public awareness and concern for these risks that many governments (e.g. Japan, and even local governments in California) have been instituting bans on new GE food crops, with extensive testing against these kinds of risks to be presented before consideration shall be granted to allow a company to grow such a crop in one of those countries or states.

There are numerous other concerns that I feel are far lesser hurdles for public acceptance of such products. For example, ethically speaking, should corporations be allowed to own a food source (could this lead to a monopoly)? Would superior food be withheld from impoverished areas because there is little to no money to be made on such investment?

I recognize that public fears do erode over time, with the onset of scientific understanding and promises of wonderful things. For example, how many of us remember the introduction of the microwave oven? These devices took many years to gain wide public acceptance; in fact, we now use colloquially the expression “nuking one’s dinner” in a positive way, while it still echoes the main fears of ingesting irradiated food. These days, it is the rare modern household that does not own at least one of these handy appliances. So despite the major challenges presented here, I do predict a future for GE-plant-based biopharmaceuticals.

Further Reading
For more reading on this subject, I recommend the websites referenced within this article, and additionally the following articles, which are available for free on-line:

Questions to Our Readers:

What do you think of the author’s opinions about why we don’t have any transgenic plant-based drugs on the market yet? Is he missing something, or do you agree?
Vaccination by way of eating potatoes was referenced last week – a pretty crazy and cool idea, huh? Does this technology give you any interesting or even fantastical concept for a new plant-based product?
What do you see for the future of transgenic plant-based products?
Can you provide hyperlinks any other articles on this subject that might be of interest to the readers?

In the next blog entry, I shall focus on transgenic animal products. Stay Tuned!

FDA's De Novo/510(k) Initiative - Time to Call Your Congressman?

2010-08-16T09:51:00.000-04:00

Written by Jeff Boatman, CQA - Sr. SME, Medical Devices and Quality Systems, QPharma

On August 5th, the Center for Devices and Radiological Health (CDRH) announced its preliminary findings on the need to update the Premarket Notification ("510(k)") process. An overview of the evaluation process can be found at http://www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHReports/ucm221069.htm, while the preliminary (read: almost certain to dramatically change) findings themselves are at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDRH/CDRHReports/UCM220784.pdf. Not linked, but available on FDA's website, is a second part of the report dealing with internal recommendations on the burden of scientific evidence that should be required by FDA's Office of Device Evaluation.

First, a recap of the current situation. In late 1976, Congress passed the Medical Device Amendments, and followed up a few years later with the Safe Medical Device Act. These laws, which for the first time brought medical devices under FDA's direct pre-market authority, designated two types of FDA authorizations: the Premarket Approval (PMA) process, and the Premarket Clearance ("510(k)"), named after the corresponding section of the original Act. PMAs are the medical device equivalent to the drug world's NDA, and correspond to the European Union's Design Dossier submission (in other words: big, complicated, and expensive), while 510(k)s are a somewhat similar idea to a generic drug's ANDA, and somewhat similar to the E.U.'s Technical File (simpler, quicker, and consisting mostly of documentation that the manufacturer would have anyway). There is also a "Product Development Protocol" route that parallels the PMA process, but it is almost never used.

In theory, a PMA is always required for a Class III device, and a Class III device is always the most serious type of medical device: complex, new and novel (i.e. unproven), can easily injure or kill someone. And also in theory, a 510(k) is for a Class II device (and sometimes for certain Class I devices) and a Class II device is one that has a markedly lower risk to public health, especially with regards to familiarity: substantially equivalent to a device that is already on the market, the idea being that a lot is already known about that type of device.

Makes sense, right? The idea is that if you have a relatively simple device or a device whose design has already been proven through extensive experience with similar devices, you don't have to file eighteen binders of a thousand pages each. There is also a somewhat esoteric legal distinction: technically speaking, FDA only "approves" a Class III device; in the case of a Class II device, FDA merely agrees that the device is in fact Class II and that basic safety and design information is properly documented.

But unfortunately, Congress wrote a requirement into the original law that, while it may have made sense at the time, is a major burden to FDA and industry (and drives European and Japanese companies crazy): for a device to be considered Class II, and therefore be eligible for the simpler submission, it must be equivalent to a device that was already on the market when the law was written. In 1979 that may have made sense, but now more than a quarter of a century has gone by. Look at it this way: in 1979, you could sell your medical device by showing it was equivalent to something marketed in 1975 (four years earlier), but today, you cannot sell your medical device by showing it is equivalent to something marketed in 2000 (ten years earlier). Obviously this is a logical contradiction, but FDA cannot do anything about it directly because it is the law.

In response, companies routinely come up with crazy-quilt arguments that their device is similar to device A marketed in 2000, which is similar to device B marketed in 1990, which is kinda sorta like device C marketed in 1975. I should add that this doublespeak logic also can go in the opposite direction: I have been on projects developing devices that absolutely, clearly were Class II (injectable wrinkle remover), but due to the thread of prior "predicate" devices—marketed for much more serious indications—this Class II device became by default Class III.

It is in reference to this last situation (which happens quite often, actually) that FDA invented the "De Novo" submission process. This is an attempt by FDA to clone the Class IIa/Class IIb Notified Body review process used by the Europeans. The idea is that some (actually, make that "many") medical devices that cannot trace back to a pre-1977 predicate device simply do not pose a serious health risk (but still are not so obvious as to sidestep risk management processes such as Design Controls, which would have classified the device as Class I like a tongue depressor). But the De Novo process is convoluted and rarely utilized, and even then, it only addresses part of the overall problem just described. CDRH's analysis linked above is FDA's latest attempt to come up with a science-based approach to intelligently classify and approve or clear medical devices, rather than ODE and firms coming up with ad hoc and frankly often silly daisy-chains of pre-1977 pedigree.

As is often the case (look at the recent debacle over electronic cigarettes!), FDA tries to do the right thing, but finds itself hamstrung by the constraints Congress wrote into a law. For example, in a recent post on this blog I expressed dismay over FDA launching new initiatives regarding software as a medical device because I feel it is driving FDA outside of what the law allows…and opening the door for endless lawsuits and reversals.; and this latest initiative still cannot ultimately address the need to base the level of device scrutiny on the actual risk it poses, and not on some arbitrary date (although similarity to an existing device can certainly be used as a mitigating consideration, and indeed that is precisely the European regulatory model).

Again in this case, the predicate law (which FDA has no choice but to obey, even if that means finding technical loopholes and workarounds) is hopelessly out of date and needs to be revised to place the U.S. device industry on a firm footing with the rest of the world and base device review and approval on science (what is the potential risk of this device?) and not bureaucracy (did Jimmy Carter use this device?).

In the FDA Modernization Act, Congress directed FDA to harmonize regulations with those of other countries. The result was the Quality System Regulation, universally recognized as the best GMP regulation in the world (and one that the Center for Drug Evaluation and Research is inching towards adopting in their own fashion). Perhaps it is time that Congress do a repeat performance; this time, to allow—or order—FDA to bring the device approval process into the next millennium.

Update on CDRH and The 510K Reform Process

2010-08-09T09:57:00.000-04:00

Written by Nancy Tomoney - Associate Validation Manager, QPharma

In 2009, in response to fraud and device recalls associated with the 510K approval of medical devices at CDRH, FDA began a process of review of CDRH’s 510K approval process. The evaluation was completed in June 2010, and the report submitted for FDA review and government approval. The report was issued on August 4, 2010 in two parts.

The FDA’s evaluation of the medical devices process consists of two separate reports with their recommendations and is an outcome of internal discussions, public meetings and external discussion with industry. The evaluation consists of two reports:

Report #1: The CDRH Preliminary Internal Evaluations -- Volume I: 510(k) Working Group Preliminary Report and Recommendations, focuses on ways to strengthen and clarify CDRH’s review process for 510(k) approval exempt from a full premarket approval (PMA) review.

Report #2: The CDRH Preliminary Internal Evaluations -- Volume II: Task Force Utilization of Science in Regulatory Decision Making Preliminary Report and Recommendations, details CDRH’s use of science in decision-making, focusing on adapting new scientific information while maintaining regulatory innovation.

Based on these reports FDA has identified three major tasks for improving medical devices: fostering device innovation, enhancing regulatory predictability, and improving patient safety. Each of these major tasks has its own sub tasks.

As a means of fostering device innovation, CDRH has identified three sub areas of concentration: streamlining the premarket pathway for lower-risk novel devices; enhancing science-based professional development for CDRH staff; and establishing a network of external experts to better inform the review of cutting-edge technologies.

In an effort to enhancing regulatory predictability, CDRH has identified four sub areas of concentration: Increase the predictability of 510(k) data needs by establishing a new “Class IIb.; Create a new “Notice to Industry” tool to more rapidly communicate changes in premarket expectations; Clarify the meaning of key terms in the 510(k) “substantial equivalence” review standard to improve the consistency, transparency, and timeliness of the review process and establishing a Center Science Council as a new governance model to assure quality and consistency in CDRH’s science-based decision making.

To ensure improved patient safety, CDRH has identified three sub areas of concentration: requiring the up-front submission of more complete safety and effectiveness information to support the review of 510(k) devices; creating a searchable online public database to provide more detailed, up-to-date medical device information to industry, the health care community, and patients; and clarifying CDRH’s 510(k) rescission authority and the circumstances under which a device should not be used as a predicate.

The reports can be found on the FDA website at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm221166.htm

The tasks and identified sub tasks would certainly require a budgetary increase for CDRH to implement. The question becomes this: is the United States Congress willing to increase the already underfunded FDA budget? That question can be easily answered by the response of the United States Congress to Senate Bill S. 3690, A Bill to Provide for Additional Quality Control of Drugs, which was introduced on August 3, 2010 by Freshman Senator Michael Bennett (D-Colorado). The bill would amend and add new sections to the Food Drug and Cosmetic Act, specifically focused on quality in pharmaceuticals. The bill’s ability to come out of the Committee on Health, Education, Labor, and Pensions and be passed will speak to how seriously the current constituted government takes funding of the FDA. That bill and the list of CDRH reforms would requires serious funding and expansion of the FDA.

The Growing GE (Genetic Engineering) Sector - Part I - Of Course I've Heard of Cows!

2010-08-04T09:48:00.000-04:00

For the next few weeks, we’re going to try something a little different. One of our Validation Managers has picked a “hot topic” that hasn’t been talked about much anywhere else, and would like to present it in the manner of an open discussion forum so that all of our blog readers, as well as our other blog writers, can learn from each other. The topic for the next couple of weeks highlights drugs that are the result of genetic engineering. We hope you find this to be a really cool and unique opportunity, and will gladly do it again with another topic if our readers enjoy this.

__________________________________________________

OF COURSE I’VE HEARD OF COWS…

Written by Paul Melamud - Validation Manager, QPharma

…but have you ever heard the buzzwords “pharming” or “biopharming” before? The terms refer to a growing sector of FDA-regulated industry that uses recombinant DNA technologies to genetically engineer (GE) animals (pharming) or plants (biopharming) to generate proteins and protein metabolites that they would not otherwise be capable of creating.

Such products might be delivered to a patient in a variety of ways:

Through ingestion, perhaps as an "edible vaccine"; such was conducted as "proof of concept" by the University of Maryland's School of Medicine ('98) www.niaid.nih.gov/news/newsreleases/1998/pages/ediblevacc.aspx

Through injection, as with the first FDA-approved transgenic animal product, which is produced in the milk of goats genetically modified to produce the anti-clotting drug Atryn (FDA-approved in 2009, approved in 2006 by EMEA) www.transgenics.com/pressreleases/pr020609.html

Through body contact, perhaps through patches, lotions, or even clothing articles

Pharming has an innovative (and to this author, fascinating) approach to mass-production of drug products, with obvious advantages compared to more traditional processes, including cheaper facilities (e.g. farms), flexible scale-up and scale-down capabilities (e.g. breeding programs), and, to a degree, renewable/reusable bioreactors (e.g. plants or animals).

And the potential lucrativeness of these ventures is no joke! Case in point: a fairly recent Scientific American article (see: http://www.scientificamerican.com/article.cfm?id=atryn-pharming-goats-transgenic) estimated start-up for a standard mammalian cell bioreactor facility producing 100kg/year of a drug to cost hundreds of millions of dollars, while an equivalent-volume farm could be put into service for only tens of millions of dollars, and with far cheaper operating costs – “at literally chicken feed with our chickens,” as one manufacturer put it.

While DNA was discovered as early as 1869 and its genetic ties identified in the early 1950s, and despite the fact that human drug manufacturers using transgenic recombinant DNA techniques have been around since the 1970s, regulations remain largely unspecific toward this type of process. As you can surely imagine, the relative novelty and complexity of the products and their production processes place pharmed proteins in what often seem like “uncharted waters” for development and regulatory approval.

In fact (confirmable through the below-referenced website), the U.S. government has not issued any new legislation (Acts) specific to GE products, instead relying on predicate health and safety laws to regulate them. However, regulatory agencies have issued some interesting and helpful guidelines that help manufacturers to address the special needs for these types of products. These are managed through a tripartite arrangement between government agencies, called the Coordinated Framework for Regulation of Biotechnology, which is responsible for jointly overseeing all such products. This framework was authorized in 1986 (51 FR 23302; also refer to http://usbiotechreg.nbii.gov/). It is noted that the European Union has gone a bit further than the U.S., with an official Directive (2001/18/EC) and numerous derivative regulations and guidances specific to transgenic organisms ( see http://www.biotethics.org/downloads/articles/EU%20Legislation%20GMOs.pdf for a comprehensive list, as of 2006, with hyperlinks).

Of course, where the genetic enhancement of a living organism is concerned, there is always political and humane-interest controversy. We will take a closer look at the controversy next week as we explore the current world of transgenic plants, and the week after with transgenic animals.

More on this topic next week...stay tuned!

Questions To Our Readers:

1) Have you ever heard of or been involved with (as a manufacturer or a user) any really cool products created through genetic engineering?

2) Given that the technology has been around for nearly 40 years, do you have any thoughts as to why there are few of these products yet on the market?

3) There’s been quite a bit of controversy, public opinion, and even fear out there regarding therapeutic products like these. Are there any risks and benefits about this biotechnology or the products that either scare you or thrill you? Do you think genetic engineering products, either or both from plants and/or animals, is a good idea?

Let's get a discussion started!
Please share your answers in the comment section below!

Best Practices for Validation of a Software as a Service (SaaS) Customer Relationship Management (CRM) Solution

2010-07-19T09:26:00.000-04:00

Written by Gregg Mauriello - Validation Manager, QPharma

Part 1: An Introduction to Cloud Computing and SaaS

What is “Cloud Computing”? Cloud Computing is essentially computing over the internet without the expense and maintenance of an in house data center. With cloud computing, applications are accessed over the internet and maintained by the third-party hosting the application. Using a third-party hosted application reduces initial development costs and recurring system maintenance costs. Since the application is hosted over the internet, data storage issues and maintenance responsibilities also rest on the third party hosting the application. The customer only pays for the resources utilized, or on a subscription basis, such as the “Software as a Service (SaaS)” model. Cloud Computing enables large amounts of data to be shared across a large amount of users, since system access is through a web browser and can be accessed from virtually any location. Security of the system is also centralized, which also places the responsibility of solving security issues on the third party, rather than the customer help desk support. Keep in mind that there are also risks involved with cloud computing, which include login security, access to audit trails, data recovery and data storage location. Risk Assessments should be performed to identify all risks and Vendor Audits should be performed to determine if and how the vendor can handle these risks.

The “Software as a Service (SaaS)” model refers to multi-tenant software that is deployed over the internet through a third-party vendor, such as Salesforce.com. The vendor provides the application license to the customer through a “pay as you go” or a subscription service. The customer will rent the software platform, rather than owning the software. With this model, all users from different customer organizations utilize the same instance of the software; therefore, everyone is operating on the same version of the application. This allows for centralized updates to the system, and also leads to more efficient administration of the system. Although all users operate on the same version of the software, data is logically separated and some configuration is typically allowed. In this way, SaaS applications are scalable and configurable to allow the customer to fit the software to their business processes without affecting the common infrastructure. Due to the centralized nature of the application, the core system can be validated once for use in regulated environments, leading to a validation savings for the end user. The customer-specific configurations of the system must still be validated for that particular customer, although the validation burden will be much reduced.

In Part II, we will outline the best practices for the validation of an example SaaS CRM application.

*Gregg will be presenting more information on this subject during an interactive workshop, at IVT’s 16th annual Validation Week on October 26th. The workshop will be presented along with our colleague, Elise Miner.

QPharma's has a host of solutions that are helping clients stay compliant "in the cloud", including training and practitioner validation web-based solutions. For more information, contact us at info@qpharmacorp.com, Subject: "Web Based Solutions".

Considerations for Risk Based Validation

2010-07-12T10:06:00.000-04:00

Written by Alexis Stroud, CQA - Manager, Regulatory Compliance at QPharma

“Risk based validation” is now a commonly heard expression in the pharmaceutical industry, but the methodology to implement it is unclear. The consensus is that an effective risk based validation process will reduce the overall time and effort spent on validation, thereby increasing productivity and profitability within the company. However, if you are unaware on how to implement such an approach, chances are the real benefits will not be seen.

The Food and Drug Administration (FDA) and others are actively embracing the advantages of a “risk based” approach to validation. The guidance on General Principles of Software Validation states: “The selection of validation activities, tasks, and work items should be commensurate with the complexity of the software design and the risk associated with the use of the software for the specified intended use.” The FDA’s Part 11 Scope and Application guidance document states: “We recommend that you base your approach (to implement Part 11 controls, e.g., validation) on a justified and documented Risk Assessment and a determination of the potential of the system to affect product quality and safety, and record integrity.”

If there is one area of focus that is worthy of the time spent, it is in conducting the Risk Assessment. A Risk Assessment can be used to guide the scope of the entire validation effort, allowing you to target more intensive testing in high risk areas while minimizing testing in lower risk areas. Risk based validation also presents the opportunity for significant cost savings since comprehensive validation testing may be reduced or eliminated in low risk areas of the application. Another thing to remember about risk based validation is that “if it’s not documented, it didn’t happen.” It is not enough to simply assess the risk and make the decisions based on that risk. The process of assessing risk must be documented as well. A validation approach that is based on an undocumented analysis would be difficult to defend in an audit. The approach taken, the findings uncovered, the decisions made, and the justification for those decisions must be documented and available for inspection during an audit.

When assessing risk, the level of effort, formality and documentation should commensurate with the level of risk. There are several key factors to consider when evaluating the risk of a system:

1.     Risk
What is the impact on product efficacy and safety? What is the GxP criticality? What is the business criticality and impact on business continuity? What is the risk of inspection by a regulatory agency?

2.     Complexity
How complex is the system? What is the level of networking and influence on other systems?

3.     Novelty
How new is the technology? How mature is the system? What is the level of customization?

Once the critical risk factors are documented, the next step in assessing risk is a comprehensive evaluation of the risk and its associated impact. A Risk Assessment will examine three fundamental questions:
1.    What might go wrong?
2.    What is the likelihood (probability) it will go wrong?
3.    What are the consequences (severity)?

The classification and prioritization of risks can then be used to help determine the need for and/or extent of validation. An effective and efficient risk based validation process will result in less validation work, faster system deployment and a reduction in overall validation costs.

For more information on risk based validation, please contact us at 888-742-7620, and ask to speak to Robert Finamore - Director, Professional Services.