The 21st Century Initiative – PAT and Validation

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

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?

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: 

1. A strong FDA increases the safety and effectiveness of drugs and medical devices.
2. Increased safety and effectiveness of drugs and medical devices increases consumer confidence.
3. 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

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.