Pharmacy Compounding: Is there any oversight?

PHARMACY COMPOUNDING DEFINED:

Pharmacy compounding involves the preparation of customized medications that are not commercially available for individual patients with specialized medical needs.

Traditional pharmacy compounding involves the act of combining, mixing, or altering ingredients to prepare a customized medication for an individual patient upon receipt of a valid prescription for the compounded product.

Driven by medical needs, cost issues, physician preferences, and in some cases drug shortages, the compounding industry has evolved over the past 20 years to include high capacity, industrialized practices involving batch production. Such products often enter interstate commerce and are delivered to health care settings in the absence of a specific patient prescription.

CURRENT PHARMACY COMPOUNDING PRACTICES:

In contrast to FDA-approved drugs, pharmacy compounded products are not evaluated for safety and efficacy, can be exempt from current good manufacturing practice requirements (cGMP), and lack standard product labels and instructions for safe use.

Compounding pharmacies also are not required to report adverse events to the FDA. Nevertheless, despite the fact that all compounded products are viewed by the FDA as “unapproved drugs,” their availability has become an integral part of the daily practice of medicine and pharmacy in this country.

The current “market” for pharmacy compounding comprises a diverse array of practices,some of which overlap.  These include: traditional compounding, anticipatory compounding, hospital pharmacy-based compounding and hospital outsourcing of sterile compounding services.

STANDARDS FOR PHARMACY COMPOUNDING:

The United States Pharmacopeia Convention (USP), publisher of the United States Pharmacopeia and the National Formulary (USP–NF), the official compendia for drugs marketed in the United States, developed a set of enforceable compounding standards for practice.

COMPOUNDING PHARMACY — REGULATION AND ACCREDITATION:

At the State Level
: 

Compounding pharmacies are licensed and regulated by their respective state boards of pharmacy. Some states require adherence to USP standards, while others rely on their own regulatory standards.  In an effort to improve standards, the Pharmacy Compounding Accreditation Board (PCAB) was created in 2006 through the combined efforts of several national pharmacy organizations and USP. The mission of PCAB is to promote high quality pharmacy compounding through a voluntary accreditation program that recognizes adherence to established principles, policies and standards.

PCAB accreditation gives patients, prescribers, and payers a way to select a pharmacy that meets or exceeds USP’s quality standards. PCAB accreditation means the pharmacy has independent, external validation that it meets nationally accepted quality assurance, quality control, and quality improvement standards. However, only about 200 compounding pharmacies are currently accredited out of an estimated total of 7,000. A searchable state-by-state listing of accredited compounding pharmacies is maintained on the PCAB website.

At the Federal Level:

The FDA has long been concerned about pharmacy compounding practices that deviate from the traditional model. The FDA first issued a Compliance Policy Guide (CPG) in 1992 that described certain factors that the Agency would consider in its enforcement approach to pharmacies that were producing drugs and appeared to be functioning more as manufacturers. That CPG remained in effect until Congress enacted the Food and Drug Administration Modernization Act of 1997. This legislation added a new Section 503A to the Food Drug and Cosmetic (FD&C) Act addressing FDA’s authority over compounded drugs. In doing so, Section 503A exempted compounded products from new drug approval, cGMP requirements, and adequate directions for use requirements under certain circumstances, and set forth conditions that must be followed by pharmacies or physicians in order to quality for these exemptions. It should be noted that the FDA revised the CPG in 2002

The FDA also can conduct “for-cause” inspections based on complaints.

RISK-BASED APPROACHES TO REGULATION AND OVERSIGHT OF PHARMACY COMPOUNDING:

Some risk factors are common to both patient specific and batch pharmacy compounding such as; facility characteristics, personnel training, level of standardization, verification mechanisms, and compliance with standard operating procedures.

For patient-specific compounding, beyond use dating and storage outside of the pharmacy also need to be addressed. For sterile batch compounding, standard operating procedures, segregation of materials, batch sizes, in-process checks, and sterilization methods assume increasing importance.

The larger the operation, the more closely these processes should be aligned with cGMP. Product quarantine, assurance of sterility, and recall mechanisms are necessary requirements for compounding manufacturers, not to mention assurance of batch potency. Product volume and whether the facility attempts to generate product beyond its capabilities or to fill a temporary gap created by commercial drug shortages represent other categories of risk.

Finally, distribution, storage, and repackaging practices also are relevant.

CURRENT LEGISLATION:

According to the National Conference of State Legislatures, several states have introduced bills related to the regulation of compounding pharmacies. One issue is potential limits on office-use dispensing, or the practice of physicians obtaining compounded products without a patient prescription to be used in an office setting. At the state level, interest is moving in the direction of regular inspections, composition of state boards to include the relevant expertise for addressing sterile compounding issues, and more widespread adoption of USP standards for sterile compounding.

In early May, bipartisan legislation intended to clarify oversight for pharmaceutical compounding was introduced in the Senate (S. 959−Pharmaceutical Compounding Quality and Accountability Act). This goal of this legislation is to establish a clear boundary between traditional compounders and compounding manufacturers, and establish uniform federal quality standards for compounding manufacturers.

The legislation also prohibits the compounding of certain categories of drugs. It also preserves the state’s primary role in the oversight of traditional pharmacy compounding, and permits limited quantities of products derived from anticipatory compounding, although biologics would be excluded from this practice, except in narrow circumstances.

The AMA submitted formal comments on the draft legislation, but it is not clear at this time how quickly this bill will move or what the final elements will be.

PHARMACY COMPOUNDING LEGISLATiON UPDATE FROM THE BOSTON GLOBE ON NOVEMBER 12, 2013:

The Senate cleared a key hurdle Tuesday for a bill intended to  increase oversight of compounding pharmacies — which operate like drug manufacturers but have been regulated loosely. Tuesday’s procedural vote in the Senate was the most significant test, requiring a 60-vote majority. It passed, 97 to 1. The House has already approved the measure. IT is expected to reach President Obama’s desk this week, once the Senate takes a final vote.

CONCLUSION:

The use of compounded products is deeply embedded in the U.S. healthcare system. While traditional compounding pharmacies licensed and regulated by states continue to provide important patient-specific services, the overall practice of pharmacy compounding has evolved into an industrial-scale national business.

Given the evolution of the pharmacy compounding industry, the current reliance of the healthcare system in this country on compounded drug products, and the accumulation of patient harm, the Council believes a clear need exists for more effective and appropriate oversight.

A need exists to establish a clear boundary between traditional compounders and compounding manufacturers and to clarify specific areas of jurisdiction for the FDA and state boards of pharmacy. Because of the extensive array of current pharmacy compounding practices, and dependence of the healthcare system on such products, changes to the current system must be accomplished in a stepwise manner and in a way that does not otherwise jeopardize patient care. In the absence of a suitable FDA-approved product, allowances also should be made for the conduct of compounding practices that can supply products needed to manage urgent and emergent care scenarios in a safe manner.

 

Read the full AMA Council on Science and Public Health report on “Pharmacy Compounding.”

—  Russell Kridel, M.D.

 

 

Are products containing nanoparticles a health risk?

Since humans are routinely exposed to a number of materials containing nanoparticles, concerns exist about how such exposure affects human health.

Little is currently known about the long-term effects of exposure to engineered nanoparticles, but cell culture and animal studies have begun to offer clues. Complicating the effort to characterize effects is the number of different nanoparticles and applications, each of which may affect cells.

Data on the cellular effects of nanoparticles come mostly from in vitro cell culture nanotoxicology studies. However, no known studies to date have examined the effects of real-world exposures in humans, i.e., exposure levels that an average human being would experience in day-to-day life. Cell culture and animal studies have used exposure levels that are thought to be far greater than those experienced by an average person. From current research findings, no evidence exists of adverse changes in human health as a result of the use of nanoparticles currently on the market. However, the known adverse health effects of ultrafine particulate matter (dust and pollutants), which is also nanoscale-sized, suggests that the effect of engineered nanoparticles on human health warrants rigorous scientific study.

What is nanotechnology?

Nanotechnology is the understanding and control of matter at dimensions of approximately 1-100 nanometers.  For comparison, a sheet of pater is about 100,000 naonmeters thick and a human hair is about 80,000 nanometers thick and a DNA double helix is about 2.5 naonmeters in diameter.

The science of nanotechnology manipulates matter to create new and unique materials and products. Nanoparticle components are present in materials such as polymers, electronics, paints, batteries, sensors, fuel cells, solar cells, coatings, computers and display systems. Nanoparticles are also found in other consumer products such as, cosmetics and pharmaceuticals.

Commercial Application of Nanotechnology

Over 800 commercial products and applications of nanoparticle-based materials exist. Selected examples are:

  • nanoscale polymer composites that make baseball bats, tennis rackets, motorcycle helmets, automobile bumpers, luggage, and power tool housings more lightweight, stiff, durable, and resilient;
  • surface treatments of fabrics that help to resist wrinkling, staining, and bacterial growth and provide lightweight ballistic energy deflection in personal body armor;
  • nanoscale materials in cosmetic products that provide better coverage and absorption, increase antioxidant and antimicrobial properties, and filter UV light;
  • nanomaterials in computing, communications, and other electronics applications provide faster, smaller, and more portable systems that can manage and store larger amounts of information; and,
  • nanocomposites in food containers minimize carbon dioxide leakage out of carbonated beverages, or reduce oxygen inflow, moisture outflow, or the growth of bacteria to keep food fresh and safe for longer periods of time.

Medical Applications of Nanotechnology

Nanotechnology is being widely applied in many facets of health care. For example, quantum dots (semi-conducting nanocrystals) show unique optical and electronic properties like size-tunable light emission, simultaneous excitation of multiple fluorescence colors, high signal brightness, and long-term photostability. These properties have enhanced both in vitro and in vivo biological imaging, and are being used to image sentinel lymph nodes, tumor-specific receptors, malignant tumor detectors, and tumor immune responses.

In another example, nanoparticle-based hydrogels used as wound dressings have been introduced. Nanoscale inorganic particles have been added to hydrogels as reinforcing agents, improving the strength, elasticity, absorptive capability, and barrier properties of the wound dressing.

Oversight and Regulation of Nanotechnology Products

Existing statutes and responsibility to protect the health of the public provide a foundation for the FDA’s regulation and oversight of nanomaterials. The FDA has not adopted a regulatory definition of “nanomaterial;” instead, it has taken a broadly inclusive approach to considering whether products contain nanomaterials or involve nanotechnology.

In Summary:

Nanotechnology has demonstrated great benefit in the improvement of consumer products and applications. Little is known about how nanomaterials affect human health and the environment, but preliminary research has shown that acute exposure to nanoparticles can affect cellular behavior and may be toxic to some components of the environment. More detailed research is needed to examine how real-world exposure levels affect human health and the environment. In the meantime, regulation of products or applications that include nanomaterials will occur on a case-by-case basis, using science-based methods to evaluate the balance of benefits and risks. AMA policy is strongly supportive of the FDA’s mission to protect the health of the public, and of the EPA’s efforts to ensure that the public is protected from environmental pollution.

Read the full AMA Council on Science and Public Health Report on Nanotechnology and Safety Regulation.

Russell W. H. Kridel, M.D.

Is it safe to go through the full body x-ray scanners at airports?

Several years ago, the Transportation Security Administration (TSA) began installing and using advanced imaging technology (AIT) at airport passenger screening checkpoints as a secondary measure to detect security threats. By early 2010, AIT was widely implemented as a primary measure because AIT is more effective at detecting weapons, explosives, and other hazardous and/or concealed items hidden under clothing than older metal detector-based screening units. The two main types of AIT used are “backscatter” models, which use low levels of ionizing radiation, and “millimeter wave” models, which use radio waves.

Debate centers on exposure to ionizing radiation from backscatter screening. Although, backscatter units use extremely low levels of ionizing radiation, concern exists that any increase exposure to radiation is biologically dangerous. Although few data exist about the safety of millimeter wave scanners, they are not believed to have carcinogenic potential, so the focus of this discussion is on backscatter screening.

Backscatter Scanner

Ionizing radiation refers to radiation that has sufficient energy to ionize atoms or molecules (cause separation of electrons from an atom) in biological systems. The electrons and positively-charged ions released as a result of ionization can cause cellular damage. X-rays, gamma rays, beta particles (high-speed electrons), neutrons (heavy uncharged particles), and alpha particles (heavy charged particles) are the principal types of ionizing radiation encountered. Of these types, x-ray and gamma rays have the lowest rate of energy transfer.

Backscatter scanning units direct an x-ray beam over the surface of the body; the x-rays are low intensity, and therefore do not travel deep into tissues or through the body as those of a medical x- ray would. Instead, the majority of the rays are reflected back from the skin. Detectors translate the reflection pattern into an image that is examined by security personnel. The backscatter pattern is dependent on material property, and thus distinguishes between organic and inorganic materials.

The imperatives raised in these resolutions are diminished somewhat based on the U.S Transportation Security Administration’s (TSA) decision in early 2013, to remove the backscatter models from U.S. airports by June 2013 and replace them with millimeter wave models. This followed an October 2012 announcement that the TSA had removed backscatter scanners from the majority of large airports, placing them in smaller airports.  According to news reports, the backscatter models removed from airports in 2013 will likely be placed in federal buildings and other locations in which security measures are needed instead. However, depending on the frequency of exposure for employees and visitors of locations in which the backscatter units may eventually be placed, the concerns raised in the Council resolutions continue to warrant examination.

In conclusion, no studies have demonstrated negative health effects in passengers scanned by backscatter units, and the cancer risk from exposure appears to be miniscule. The Council on Science and Public Health believes that no data currently exist to suggest

Current Millimeter Wave Scanner

that passengers should avoid being screened by backscatter scanners. However, it supports continued research on the safe use of the scanners, as well as maintenance, calibration, survey, and officer training procedures that are meant to ensure that the units operate as intended. The Council notes that passengers who do not wish to undergo backscatter screening may opt for alternative screening. The Council also notes that no adverse health consequences are known to occur from millimeter wave models that have replaced the backscatter models.

Read the full AMA Council on Science and Public Health Report on “Safety of X-Ray Security Scanners”.

Russell W.H. Kridel, M.D.

 

 

 

There are a lot of drug shortages. Is there anything being done to reduce or prevent them?

National drug shortages continue to threaten patient care and safety. The existence of a shortage may compromise and delay treatment leading to progression of disease, adverse outcome, or therapeutic failure.

Sources of Information on Drug Shortages: Data on drug shortages comes from different points across the supply chain.  There are two major resources:

  1. The Food and Drug Administration (FDA). The FDA tracks and focuses on shortages of “medically necessary “ drugs.
  2. The American Society of Health-System Pharmacists (ASHP) Drug Shortage Resource Center tracks all drug shortages.

In addition, wholesalers may voluntarily submit information on supply interruption, as well as hospitals, individual practitioners or the public.

General Causes of Drug Shortages: Shortages have worsened appreciably over the last few years. Compared with 2005, twice as many drug shortages were identified in 2008, and in 2010 almost 180 shortages of medically necessary drugs were identified by the FDA — triple the amount from 2005.

Sterile injectables comprise the most common type of shortage, with 72% of the shortages in 2012 involving such preparations.

The most prominent causes include manufacturing difficulties and regulatory compliance issues; corporate decision leading to product discontinuation; consolidation of the pharmaceutical industry; and raw, bulk, or active pharmaceutical ingredient shortage. Only 5 companies manufacture 85% of injectable generics.

Action Being Taken to Reduce Shortages: Early notification from manufacturers of any issue that could lead to a potential disruption in product supply has been, and will continue to be, critical to preventing or mitigating drug shortages.

On July 9, 2012, President Obama signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012.  In the new law, Congress provided FDA with new authorities to help combat shortages of drug products in the United States and imposed new requirements on manufacturers regarding early notification to FDA of issues that could lead to a potential shortage or disruption in supply of a product.

The enhanced authorities include the following:

  • The scope of the early notification requirement has been broadened by requiring all manufacturers of covered drugs to notify FDA of potential discontinuances.  The prior law applied only to sole manufacturers.
  • Manufacturers are required to report discontinuances to FDA regardless of whether they intend to discontinue the product permanently or are facing only a temporary interruption of supply.
  • FDASIA enabled FDA to require, by regulation, mandatory reporting of shortages of biological products.  The prior law excluded all biological products from the reporting requirements.
  • Clarification was made that the notification requirement applies to drugs that are used in emergency medical care or during surgery (if they are intended for use in the prevention of a debilitating disease or condition).
  • Requirement made for FDA to issue a non-compliance letter to manufacturers who fail to comply with the drug shortage notification requirements and to make the letter and the company’s response to the letter available to the public.

In addition to these new authorities, FDASIA included other provisions related to drug shortages which are outlined on their website.

The Food and Drug Administration Safety and Innovation Act also required a GAO report examining the causes of drug shortages and formulating recommendations to prevent or alleviate shortages. The next GAO report should be coming out in December 2013 or January 2014.

Clinical Impact of Drug Shortages: Nearly 90% of the hospitals reported a drug shortage in the second half of 2010 that either caused a patient safety issue, resulted in the delay or cancellation of a procedure, required more expensive substitutes, or resulted in a pharmacist having to compound a drug formulation.

More than 80% of the time, shortages occurred without advanced warning.  And two-thirds of physicians surveyed said patient outcomes were adversely affected.

Summary: National drug shortages continue to threaten patient care and safety. The AMA Council on Science and Public Health recognizes the importance of drug shortages and will continue to evaluate the issue and report on updates and progress being made for improvement or resolution.

Read the 2011 AMA Council on Science and Public Health Report on Drug Shortages and the 2012 Council Update on Drug Shortages.

Russell W.H. Kridel, M.D.

Do e-cigarettes help people quit smoking?

Electronic cigarettes, known as E-cigarettes, are not comparable to FDA-approved nicotine-delivery devices that have been shown to help people quit smoking. At this time, their dosage, manufacture, and ingredients are not consistent and the products are not clearly labeled, thus making their use by smokers wanting to quit an uninformed proposition.

More importantly, the manufacturers of e-cigarettes have not submitted the requisite applications for FDA approval of these products for smoking cessation. Only one small clinical trial, funded by an e-cigarette manufacturer has been published on their efficacy as a smoking substitute (but not as a cessation aid). The FDA has rejected claims by e-cigarette makers and distributors that their devices are safer than real cigarettes and mitigate the harm of smoking. While some distributors have implied that their products help people quit smoking tobacco products, the FDA views them as unapproved synthetic nicotine delivery devices with unknown safety and efficacy.

In 2008, the World Health Organization (WHO) noted that, “Contrary to what some marketers of the electronic cigarette imply in their advertisements, the WHO does not consider it to be a legitimate therapy for smokers trying to quit. WHO knows of no evidentiary basis for the marketers’ claim that the electronic cigarette helps people quit smoking. Indeed, as far as WHO is aware, no rigorous peer-reviewed studies have been conducted showing the electronic cigarette is a safe effective nicotine replacement therapy.”

Whether e-cigarettes can safely help people quit smoking also is unknown, but with their fruit and candy flavors, they have a clear potential to entice new smokers, especially teens. In addition, because of the unregulated dosing of nicotine, they clearly can be addictive. It is evident from what little information we have that the concentration levels of the nicotine and other compounds are variable, and that there are toxins and carcinogens present. Thus, controlled trials and test market studies are needed to determine if they are safe and effective as a smoking cessation device as is being reported in the media and on the manufacturers’ Web sites.

Similar to concerns regarding the manufacture and sale of tobacco products, the actual content, performance as a nicotine delivery device, safety, and purity of e-cigarettes is largely unknown. Due to the lack of rigorous chemical and animal studies, as well as clinical trials on commercially available e-cigarettes, neither their value as therapeutic aids for smoking cessation nor their “safety” as cigarette replacements is established and remains speculative.

Read the AMA Council on Science and Public Health Report on “Use of Electronic Cigarettes in Smoking Cessation.” http://www.ama-assn.org/resources/doc/csaph/a10csaph6ft.pdf

Russell W.H. Kridel, M.D.