Validation as a Best Practice – Part 2

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

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

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

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

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 ...