Validation as a Best Practice - Part 1

Written by Scott Collins - Senior Validation Manager, QPharma 

 The Life Sciences industry understands validation as a regulatory requirement.  It is a process completed because regulatory agencies, such as the Food and Drug Administration (FDA), require it.  Most companies even have internal quality procedures that require validation before a piece of equipment, system, or process can be placed into routine operation.  I am still amazed by how many groups perform validation simply because it is a requirement.  When validation is performed with this as the only driver, the value and benefits of validation can be missed.

The definition of validation is documented evidence that a piece of equipment, system, or process consistently produces a product that meets its predetermined specifications (see slides 4 and 5 of this linked presentation for more definitions).  The definition implies that you know the end result that you are trying to obtain before you initiate the validation effort.  I often see groups using validation as a discovery or troubleshooting activity.  They do not understand the full scope and intended use of the equipment, system, or process before starting validation.

An adequate, full validation life cycle process requires the business or process owner to thoroughly understand the equipment, system, or process before they start the validation studies.  They must have a clear concise plan, testable user requirements, adequate design documentation, and detailed test protocols with expected results.  From a product quality perspective, validation demonstrates control over the manufacturing process, thereby increasing product quality, while minimizing risk to the customer.  From a business perspective this approach allows for maximum efficiency, minimum waste, and maximum profit.  These are the reasons why validation should be the best practice for any company. 

Follow the link below for Part 1 of the presentation Validation as a Best Practice for more information. Register or sign in and head to "Media", and then "Whitepapers": http://www.qpharmacorp.com/whitepapers

FDA's New Push on Software as a Medical Device

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

On October 26, 2006, FDA issued a Warning Letter to Patterson Technology of Effingham, IL, for marketing an adulterated medical device. That "device" was their EagleSoft patient recordkeeping software package (I am passingly familiar with EagleSoft: my dentist uses it). In that Letter, FDA claimed that EagleSoft constituted an "unclassified" medical device, subject to GMPs and Design Controls (21 CFR 820.30(a)(2)(i)).

Immediately after this Letter was issued, I received a number of inquiries both directly from software companies and through associates. What did this Letter mean? How can software which does not itself "treat, diagnose, or mitigate a disease or function" (21 U.S.C. 321) possibly be a medical device? And what does it mean to be an "unclassified" device, when the Safe Medical Device Act specifies that within the United States, a Medical Device is always Class I, Class II, or Class III?

My short-term advice was: you should have basic quality systems in-place anyway, you should be doing design controls anyway. In my opinion, FDA had no legal authority to issue such Warning Letters since there was no such thing as an "unclassified" device in the Act but hey, that didn't stop them from going after a company marketing identification tags for subdermal implantation and pursuing them for years in the courts, only to finally have a judge rule that no way did Congress give FDA that authority. But since you should be doing these basic quality things anyway, don't bother fighting it.

Meanwhile, the number of software applications that potentially touch upon the medical care of the public has absolutely exploded. This is especially true in two areas: handheld devices used by Sales Reps to collect and transmit patient information (directly or through physicians), and web-based "cloud" systems.

This year, John Murray, CDRH's Subject Matter Expert on software (and therefore the person who largely determines FDA's policy on software enforcement) has been particularly busy. He has drafted a number of new guidance documents, including off-the-shelf software used inside medical devices and "cybersecurity" (more a list of topics than an actually useful guidance, IMHO...sorry, Mr. Murray). But his biggest contribution, hands-down, was a video he made earlier this year, CDRH Regulated Software: An Introduction.

In this video, Mr. Murray clarifies that he (meaning, of course, FDA) has determined that... (Click to read more) 

Deadline Approaches - Submission of Massachusetts Disclosure Report

The pharmaceutical industry, in a number of states, is currently required to track, and in some cases report on, promotional activities, such as gifts, meals, consulting fees, and grants provided to healthcare professionals. These disclosures consist of the value, nature and purpose of gifts, payments, or other economic benefits provided to healthcare professionals in the advancement of a drug product or service. It is vital that all companies understand and comply with current marketing and advertising disclosure laws. With the state’s first disclosure report due in less than one month, it is critical that companies understand the Massachusetts reporting requirements for physician payments.

Below is summary of the legislation and frequently asked questions.

Effective Date	July 1, 2010
Disclosure Limit	$50
Reportable Items	Any fee, payment, subsidy or other economic benefit with a value of at least $50 to any covered recipient in connection with the company’s sales and marketing activities
Report Due	July 1, 2010 (for activities occurring during the period July 1, 2009 – December 31, 2009)
Reporting Responsibility	Company's Compliance Officer
Responsible Party	Any pharmaceutical or medical device manufacturing company which includes any pharmaceutical or medical device manufacturing company or distributor
Report To	Massachusetts Department of Public Health; Email:pharmameddata@massmail.state.ma.us; Disclosure Report Example (CSV) The subject line of emails should contain only the manufacturer’s Department-assigned user ID and company name. If you do not have any data to disclose for this period, send an e-mail to this address stating that fact. The Department will deem such emails as meeting the requirement for filing an annual disclosure report.
Fee	$2,000
Fine	Not more than 5,000 per transaction or occurrence

What does this regulation do?
The regulation:

• Establishes a code of conduct that must be adopted by pharmaceutical and medical device companies.
• Requires companies to designate a compliance officer and to establish a compliance program pursuant to the regulatory requirements.
• Requires disclosure of certain financial interactions between the industry and covered recipients. 

Who are "covered recipients" for the purposes of disclosure? (Click the link to read more)

Physician Payment Sunshine Provisions in Health Care Reform – The Federal Government Becomes the 51st State

Written by Alexis Stroud - Manager, Regulatory Compliance at QPharma

 In response to growing concerns of potential conflict of interest between physicians and the pharmaceutical and medical device industries, Section 6002 Transparency Reports and Reporting of Physician Ownership or Investment Interests (commonly known as the Physician Payment Sunshine Provision) was included in the Patient Protection and Affordable Care Act (PPACA) signed into law on March 23, 2010, by President Barack Obama.

QPharma has prepared a fact sheet and guidance highlighting the key elements to help our industry better understand this provision and its requirements.

Beginning in 2013, Section 6002 requires that all manufacturers of a drug, device, biological or medical supplies report any transfers of value or payments exceeding $10 (or an aggregate of $100 or more) to physicians and/or teaching hospitals to the Secretary of Health and Human Services on an annual basis.  This information will be available on a public, searchable website.

What Information is Required to be Reported? 

• Name of covered recipient (if a payment is made to an entity or individual at the request of or designated on behalf of a covered recipient, the payment must be disclosed under the covered recipient)
• Business address
• Physician specialty
• National provider identifier
• The value of the payment or transfer of value
• Date of payment
• The name of the related drug, device, or supply, if available; to the level of specificity available
• Form of payment
• Cash or cash equivalent
• In-kind items or services
• Stock or stock option (or any other return on investment)
• Nature of payment
• Consulting fees
• Compensation for services other than consulting
• Honoraria
• Gift
• Entertainment
• Food
• Travel or trip
• Education
• Research
• Charitable contribution
• Royalty or license
• Ownership or investment interest;
• Direct compensation for serving as faculty or speaker for medical education program

Does this Law Preempt State Law?
This law does indeed preempt state law, starting in 2012.  States are prohibited from collecting the same information required to be reported under this section.  States may continue to collect other types of data not captured or excluded from reporting (with the exception of threshold limits), as well as data for public health purposes or legal proceedings.

Federal preemption would not occur for State or local laws that are beyond the scope of this section.  Currently, 8 states have enacted unique laws regarding the financial arrangements between drug and/or device companies and healthcare professionals and as of Jan 2010, there are 14 states with pending disclosure bills and 8 states with pending bills that prohibit or restrict health care professionals from accepting certain items of value.

Other states, such as CA, MA, and NV, require companies to adopt a marketing code of conduct, which is not addressed at all in the PPACA.  There are also state laws on representative licensing (e.g. - DC) and lobbying laws (e.g. - FL (Dade County), CO, LA).  This means that companies will have to continue to report certain expenditures and ensure compliance to state authorities.

Is Industry Failing to Learn From Past Quality Mistakes?

 Written by Nancy Tomoney - Associate Validation Manager, QPharma

For several years now the FDA has not only published Warning Letters, but also significant Form 483’s in an attempt to educate industry on commonly observed issues.  It seems a portion of industry isn’t paying attention, as there are common problems being repeated over and over again throughout the industry at unrelated companies.  In looking at both Warning Letters and Form 483s available to the public, the questions are raised:

•    Is industry focusing too much on the risk-based approach and not enough on true compliance? 

•    Are we more concerned with profit than with quality?

•    Why are we not learning from the mistakes of others?

In 2002, the FDA issued Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century — A Risk-Based Approach.  The document outlined these goals:

1. Encourage the early adoption of new technological advances by the pharmaceutical industry;
2. Facilitate industry application of modern quality management techniques, including implementation of quality systems approaches, to all aspects of pharmaceutical production and quality assurance;
3. Encourage implementation of risk-based approaches that focus both industry and Agency attention on critical areas;
4. Ensure that regulatory review, compliance, and inspection policies are based on state-of-the-art pharmaceutical science;
5. Enhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by further integrating enhanced quality systems approaches into the Agency’s business processes and regulatory policies concerning review and inspection activities.

It seems every few years another company ends up in Consent Decree.  The Warner Lambert/Parke Davis and the Wyeth Consent Decrees preceded the FDA document. Schering-Plough’s came at the same time Pharmaceutical CGMPs for the 21st Century was issued, and more recent companies have entered into Consent Decrees, the latest being Genzyme. 

Genzyme’s Consent decree comes in parallel with significant cGMP issues at the Johnson & Johnson McNeil facility in Fort Washington, PA.  The issues observed at both Genzyme and McNeil are similar to those found in

Vermont Disclosure of Free Samples - What Will Be the End Result?

written by Alexis Stroud - Manager, Regulatory Compliance at QPharma

On May 27, 2010, Vermont Senate Bill 88, An act relating to health care financing and universal access to health care in Vermont (S.88) became law, without the Governor’s signature. Among other things, S.88 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 year. The bill authorizes the Vermont Attorney General to publicly report aggregated sample distribution information.

Who is Required to Report?
Each manufacturer of prescribed products shall disclose to the office of the attorney general all free samples of prescribed products provided to health care providers during the preceding calendar year.

“Sample” is defined as a unit of a prescription drug, biological product, or medical device that is not intended to be sold and is intended to promote the sale of the drug, product, or device. The term 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.

What Information is Required to be Reported?
This bill requires manufacturers to identify for each sample the product, recipient, number of units, and dosage.

When is the First Report Due?
The first report is due on April 1, 2012 for the previous year's sampling activity.This section will not apply to samples of prescription drugs required to be reported under Sec. 6004 of the Patient Protection and Affordable Care Act (refer to the white paper “Physician Payment Sunshine Provisions Health Care Reform” for additional information on Sec. 6004), if as of January 1, 2011, the office of the attorney general has determined that the U.S. Department of Health and Human Services will collect and report state- and recipient-specific information regarding manufacturer distribution of free samples of such prescription drugs.

What are the Penalties for Noncompliance?
Failure to Disclose - A civil money penalty of no more than $10,000 per violation. Each unlawful failure to disclose shall constitute a separate violation.

Will the Information Submitted be Available to the Public?
This bill authorizes the Vermont Attorney General to publicly report aggregated sample distribution information. Public reporting will not include information that allows for the identification of individual recipients of samples or connects individual recipients with the monetary value of the samples provided (i.e. including the names or license numbers of individual recipients).

Current Controversy over Sample Disclosure
With the passing of this bill, Vermont has become the first state to enact sample disclosure reporting requirements. This bill was passed without Governor Douglas’ signature. He states, “… the drug sample reporting provision adds burdensome new regulations that are unnecessary and could make it difficult for low-income Vermonters to receive needed medications. These sections do not represent meaningful reform; rather they detract from the serious work ahead.” Although S.88 includes these provisions, Governor Douglas decided to allow the bill to become law because it includes a critical expansion of the innovative Vermont Blueprint for Health.

This provision was initiated over concerns that there is a correlation between the distribution of samples and the prescribing patterns of doctors who receive them. A number of senators objected to the sample disclosure requirements. Rutland senator Kevin Mullin argued that the bill would have a chilling effect on the use of free samples in Vermont.


Do you think the disclosure of this information will deter practitioners from accepting or requesting products? Should manufacturers be required to report the distribution of free samples and is there a benefit to making this information available to the public? Please share your opinions here...

Understanding both Electronic and Handwritten Signatures within the Context of Part 11

Written by Robert Finamore - Director, Validation Services, QPharma

21 CFR Part 11; Electronic Records, Electronic Signatures defines the FDA’s requirements for using records and signatures in electronic form to meet the record-keeping requirements of Agency regulations.  In more than ten years dealing with Part 11 compliance, I have often seen confusion over exactly what constitutes an “Electronic Signature.”  The title of the regulation itself uses the term “Electronic Signature,” which is somewhat of a misnomer since the regulation deals with several different types of signatures that are used in electronic form.  The different types of signatures include standard electronic signatures, digital signatures, and handwritten signatures captured electronically.

Electronic Signatures (“e-sigs”) are the types of signatures most people think of when considering Part 11.  Electronic Signatures are defined as “a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual's handwritten signature.”  This indicates that some information must be entered electronically and associated to a record for that record to be considered signed.  There are two standard types of e-sigs: Biometric and Non-Biometric signatures.

Biometric Electronic Signatures involve “a method of verifying an individual's identity based on measurement of the individual's physical feature(s) or repeatable action(s) where those features and/or actions are both unique to that individual and measurable.”  This unique measurement must be captured every time a record is signed and such measurement would need to be securely linked to the signed record.  Examples of biometric signatures included fingerprint scans or iris scans.  This type of signature requires some type of measurement hardware attached to the computerized systems for the signature to be executed so it has not currently seen widespread use in the life science industries.  Biometric Signatures must comply with both the General Signature Requirements and Electronic Signature Requirements as defined in §11.50, §11.70, §11.100, and §11.200(b) of the regulation.

The other type of standard e-sig is the Non-Biometric Signature.  This type of signature requires entry of two or more distinct signature components into the computerized system as the e-sig execution action.  The traditional e-sig requires entry of a User ID and. . .