Congress Goes After Compounding Trade Group

By Ed Silverman // December 10th, 2012 // 10:00 am

This was bound to happen. Amid the ongoing scandal over compounding pharmacies and regulatory oversight, the House Energy & Commerce Committee is now investigating the trade group of compounding pharmacies over concerns the organization may have deliberately instructed its members a year ago to impede an FDA review of ingredients used for a compounded medication.

“Allegations that your association may have encouraged compounding pharmacists to attempt to impede FDA from evaluating the efficacy and safety of their products, if true, raise serious concerns about your actions,” the committee wrote in a letter late last week to the International Academy of Compounding Pharmacists.

The missive was sent in light of an alarming outbreak of fungal meningitis that was traced to a Massachusetts compounding pharmacy, which was allegedly shipping large quantities of medicines to hospitals and physicians in numerous states, raising concerns about the ability of the FDA and state regulators to properly oversee compounders and confusion over their authority to do so. As of last week, there were 541 cases, including 36 deaths (see this).

The committee is referring to an issue that took place last year, when KV Pharmaceuticals asked the FDA to review samples of active pharmaceutical ingredients that the drugmaker alleged raised concerns about potency and purity of compounded versions of its Makena treatment for premature birth. Makena caused a separate controversy over the pricing of its drug (back stories here and here).

Early last year, you may recall, the FDA approved Makena, which is a form of progesterone that, for many years, was offered by compounding pharmacies. But KV was granted marketing exclusivity because approval was made under the Orphan Drug Act and the drugmaker, which was accused of price gouging, threatened to take compounding pharmacies to court.

The FDA agreed to review the samples provided by KV Pharma, as well as others from various API supplires and compounding pharmacies, although the agency later determined that the samples did not reveal any safety problems (read here). KV Pharma responded by suing the FDA, although it lost the lawsuit (back story).

Meanwhile, the IACP reportedly instructed members to be less than forthcoming and suggested they respond to FDA requests by saying, “We do not compound or distribute ‘samples’ of any of our prescription medications to anyone,” according toThe New York Times. If a compounded drug was found on site, IACP suggested pharmacists should say a patient was coming to get the medicine (here is the committee letter).

A spokesman for the IACP sends us this statement: “We strongly disagree with the conclusions contained in The New York Times story that was referenced in the Committee’s request. Moreover, it has diverted attention away from the cooperative efforts of the Academy in working to prevent a future tragedy as that caused by NECC and the failure of swift and decisive action by the Massachusetts Board of Registration in Pharmacy and the federal Food and Drug Administration. IACP’s submitted documents will not only refute the conclusions conveyed in the Times story but will also include correspondence with their reporters that clearly state the facts of the situation in question.”

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The Importance of Quality Control in the Production of Parenteral Drugs

Monday, December 10, 2012
Cara N. Wilder 

Elizabeth Kerrigan

Introduction

Microbial contamination of parenteral products is one of the most serious issues currently facing the pharmaceutical industry. Injectable drugs, which are administered directly into the circulatory system, bypass a number of innate human immune defenses associated with the gastrointestinal system. Therefore, to ensure the sterility of each of these products prior to patient administration, pharmaceutical companies must adhere to strict government regulations regarding quality control. Maintaining and following a robust quality control program is integral to quality standards and meeting regulatory requirements.

Adding to these pressing concerns are compounding pharmacies that function inappropriately as drug manufacturing companies, but are not legally required to adhere to federal drug manufacturing regulations. Rather, they function under more lenient state policies that govern their operation, but do not enforce quality control analysis. This lack of regulation and oversight has led to several significant microbial outbreaks, which have resulted in multiple deaths from use of contaminated parenteral steroids, cardioplegia solutions, and intravenous drugs. These events highlight the importance of effective pharmaceutical sterility procedures as well as the need for updated regulatory control policies governing the operation of compounding pharmacies. In this article, we will discuss current practices and issues associated with pharmaceutical quality control analysis, how these can affect patient health and safety, and what could be done to remedy the issue.

Pharmaceutical Manufacturing Companies

Pharmaceutical manufacturing companies are licensed facilities that develop, produce, and market drugs. To ensure the sterility of parenteral drugs, several quality control methods are employed, including operation under current Good Manufacturing Practices (cGMPs), sterility testing, and product supplementation with antimicrobial preservatives. When appropriately followed, these processes prevent product adulteration and microbial contamination.

cGMPs are Food and Drug Association (FDA) enforced regulations that govern all pharmaceutical manufacturing companies. They are intended to assure the proper design, monitoring, and control of all manufacturing procedures to confirm the sterility and quality of products. This includes establishing a reputable management system, obtaining high quality raw materials, upholding controlled operating procedures, identifying product deviations, and maintaining reliable laboratories ^[1].

To monitor compliance of pharmaceutical companies with cGMP regulations, the FDA routinely performs facility inspections and reviews publically generated product reports. Companies not in compliance with cGMPs are issued a warning and may become subject to regulatory actions. Although the FDA cannot force a company to recall a drug when compliance is not met, violations can be legally addressed and a court order can be granted allowing the seizure and disposal of drugs ^[1]. However, patient health is still at risk when these pharmaceutical products are not immediately removed from the market. To reduce these risks, it is the responsibility of the pharmaceutical and health care industries to voluntarily cease the production, distribution, sale, or use of all known non-compliant products.

In addition to cGMP compliance, pharmaceutical companies are mandated by the FDA to ensure product sterility through the use of protocols described in the United States Pharmacopeia (USP). Sterility tests commonly used include the methods described in USP Chapteras well as contemporary rapid microbiological methods (RMM). The sterility testing methods described in USPhave long been considered the gold standard for detecting microbial contaminants in parenteral drugs. These methods are based on the observation of media turbidity due to the growth of contaminating microorganisms through either direct transfer-immersion sterility testing or membrane filtration ^{[2, 3]}. However, these analyses only measure the probable, not actual, sterility of a product lot. Thus, the product administered to the patient is not directly tested for sterility ^[3]. This presents a major limitation in current sterility testing as it assumes that a small sample is representative of an entire lot. Therefore, these tests can only offer sterility control and assurance; and cannot guarantee product sterility. To fully ensure product sterility, pharmaceutical manufacturing procedures should incorporate sterility protocols, such as filtration procedures, in addition to endproduct microbial contaminant testing.

To supplement USP sterility testing methods, members of the pharmaceutical community often implement RMMs for the routine examination of microbial limit testing, bioburden assessment, environmental testing, raw materials testing, process water testing, sterility testing, and in-process testing. RMMs employed include growthand viability-based technologies, molecular methods, endotoxin testing, and rapid air monitoring. As compared to classical culture methods, such as those described in USP, RMMs can be considerably more sensitive and efficient due to a high degree of automation ^[4]. However, although these processes offer an enhancement over conventional microbial detection practices, much of the pharmaceutical industry has been reluctant to adopt RMMs. Their unwillingness is primarily centered around a reluctance to adopt new methods due to perceived increased cost, lack of expertise, or fear of the unknown ^[5]. However, to improve sterility testing methods, RMM detection techniques should be employed in addition to conventional USPsterility testing methods. By combining these sterility practices, pharmaceutical companies can ensure that quality control procedures and products are kept at the highest standards.

Another quality control method employed by pharmaceutical manufacturing companies is the addition of antimicrobial preservatives. These substances are added to products to protect them from the growth of microorganisms that are introduced during the manufacturing process or through multiple withdrawals of the product from its container. For these preservatives to be effective, the stability of the preservative, interactions with the parenteral drug product, the minimal inhibitory concentration, and optimum pH for antimicrobial activity must all be considered ^{[6, 7]}. Antimicrobial efficacy is routinely analyzed using the antimicrobial effectiveness test (AET) described in USP Chapter[8]. When properly performed, the AET provides a general gauge of antimicrobial effectiveness at levels that are non-toxic to the consumer.However, this analysis does not guarantee that a preservative system will never allow the growth of a contaminant in a product ^[8].

Overall, the quality control methods used by pharmaceutical manufacturing companies, in addition to strict FDA regulatory oversight, ensure that manufactured parenteral drug products are sterile prior to administration. However, associated regulatory procedures should be updated or modified to truly guarantee the sterility of all products. For example, when cGMP compliance is not met, products should be removed from the market immediately upon discovery and a recall issued to ensure they are not used. Additionally, sterility testing methods and protocols used to test preservative efficacy should be updated to include more sensitive assays. Maintaining high standards in manufacturing and quality practices provide customer assurance that a product is indeed safe to use.

Pharmaceutical Compounding Companies

Compounding pharmacies are companies that combine or process FDAapproved drug products to produce individualized medications to fit the unique needs of a single patient. They are often called upon when patients require limited dose strength, a unique or specialty formulation, or allergenfree medication. Presently, compounding facilities are predominantly regulated by individual state Pharmacy Boards with oversight by the FDA. Under this guidance, compounding pharmacies are required to adhere to preparatory and sterility practices as described in the Federal Food, Drugs, and Cosmetics Act (FDCA) and the USP, respectively.

Section 353a of the FDCA defines the purpose of drug compounding and what practices compounding pharmacists must follow. Further, this section indicates that compounding can only be performed with a valid prescription order that indicates the customer’s need for an individualized medication. Furthermore, this law clarifies that compounded products must be prepared in limited amounts and should not be produced when commercially available drug products exist. However, due to the limited volume of compounded products produced in each lot, this law exempts legitimately prescribed and prepared compounded drugs from review, approval, adverse event reporting, and placement of storage and labeling requirements on product vials ^[9]. Problems arise when compounding pharmacies function outside the FDCA regulations by operating as drug manufacturers. By functioning in this inappropriate capacity, compounding companies risk producing large quantities of adulterated drugs that are not manufactured under cGMPs, not properly controlled for quality, and are not FDA-approved. Thus, the sterility of compounded products received by patients cannot be guaranteed.

To help maintain the sterility of compounded parenteral drugs, compounding pharmacists are required to adhere to USP. This standard details sterility testing procedures including sampling the air, preparation surfaces, and gloved fingers for viable microbial particulates. In these particular tests, any colony forming unit counts that exceed the respective action level require identification of the source of contamination and subsequent re-evaluation of personnel work practices, cleaning procedures, operational procedures, and air filtration efficiency. However, due to lenient state regulations, many compounding facilities do not routinely perform USPtesting procedures.

Because of the continued regulatory leniency over quality control and sterility testing procedures, there have been multiple microbial outbreaks associated with compounded parenteral products. A recent example includes numerous hospitalizations and deaths attributed to contaminated parenteral steroids produced by the New England Compounding Center (NECC) [10]. Patients who received the tainted steroid product were documented to have primarily suffered from fungal meningitis as well as strokes, spinal osteomyelitis, epidural abscesses, or fungal infections associated with peripheral joints ^{[10, 11]}. In addition to this recent outbreak, there have been other past incidences of contaminated compounded parenteral drugs resulting in patient sickness and death. These include tainted cardioplegia solutions produced in 2005 by Central Admixture Pharmacy Services Inc. and bacterial-contaminated intravenous medications produced in 2011 by the Advanced Specialty Pharmacy ^{[12, 13]}.

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Clipboard: State has known of troubles at New England Compounding for years, but did not act

Clipboard: State has known of troubles at New England Compounding for years, but did not act

Advocates: Public Health Slashed Too Far, Risk ‘Not Acceptable’

December 10, 2012 | 12:52 PM | Carey Goldberg

Normally, just the words “public health infrastructure” are enough to make people’s eyes glaze over and roll upwards. But not this year in Massachusetts. Not when the state has seen a huge scandal in the state crime lab that called into questions thousands of convictions. And then a horrifying national outbreak of meningitis that killed three dozen people and raised serious questions about oversight of the local compounding pharmacy where the tainted steroids were made.

Dr. Alan Meyers connected the dots of the two scandals in a guest post here, pointing out the dangers of cutting public health funding too far. Now the latest state emergency budget cuts have been proposed. Rachel reported last week here that health care in its various forms takes the hardest hit of all. And today, the Massachusetts Public Health Association is sending over a letter to the Patrick administration imploring it to stop cutting the basic public health measures that keep us all safer.

We are writing with an urgent message that funding for basic elements of our public health infrastructure – protections that we all rely on every day – is not sufficient to meet basic needs, and we implore you to reverse the trend of disinvestment from these essential services.

That infrastructure includes food inspections, licensing of medical machines like X-rays, emergency preparedness, monitoring of the system to report on infectious diseases, and more. “This type of infrastructure is not sexy and it is not free,” the letter says. “It does not have a constituency that will hold rallies on the State House steps. But we all benefit from it each and every day – and mostly, we take it for granted.”

Read on for the association’s warning that the level of public health risk is not acceptable, and a sweeping summing-up of the drastic cuts to the state’s public health structure over the last few years.

We understand that all areas of government have needed to tighten their belts during these difficult economic times. We do not fault your Administration or the Legislature for looking for budget savings from all state agencies in order to meet your responsibility to pass a balanced budget.

However, if we accept that the pre-recession resources are no longer available to fund our public health infrastructure, we must be prepared to accept a lower level of services, oversight, and monitoring. We at the Massachusetts Public Health Association do not find this increased level of risk to be acceptable.

As we speak, Department of Public Health staff, and others inside and outside of government are working day and night in response to the mishandling of evidence at the state drug lab and the national meningitis outbreak. Individuals – inside or outside of government – who committed criminal acts must be held accountable for their actions and the harm they have caused. At the same time, Department of Public Health must put in place new systems of accountability to ensure proper oversight is in place to safeguard the public health and safety.

Both of these activities are essential, and all signs indicate that they are being addressed aggressively. However, addressing criminal activity and gaps in oversight alone will not solve our problems.

Adequate financial resources to carry out public health programs, provide oversight of those programs, and monitor compliance with public health regulations are not currently available due to several years of dramatic cuts in state funding.

Consider the recent history of state funding for DPH:
• Since the pre-recession budget of fiscal year 2009, more than $70 million has been slashed from the DPH budget for community-based programs.

• That amounts to more than 17% of state funding in just four years, and it has resulted in the loss of 117 FTEs from the Department’s community-based programs. An additional 106 DPH hospital staff have been lost due to state funding cuts; and 110 federally-funded staff have been lost during this same time due to federal budget cuts.

• The reality of these cuts for public health infrastructure is worse than it appears on the surface. Removing the six major DPH direct service programs from the equation provides a better snapshot of funding for inspections, regulatory activities, monitoring, and oversight activities that comprise the public health infrastructure. Under this scenario, cuts since FY09 amount to a full 25% of state funding. This represents a nearly $50 million budget gap.

• Further, keep in mind that numerous unfunded mandates from the legislature and Congress have added to the responsibilities of Department staff without additional resources, and that the cost of providing services increases every year, so even “level funding” results in cuts in service levels.

Numerous Programs are Funded at Dangerously Low Levels

Programs across the Department are funded inadequately. Here are just a few examples:
• State funding for Environmental Health has been cut by 18% (or $747,000) since FY09. This has led to:

o The elimination of more than 50% of the food inspectors who conduct inspections of food manufactures and wholesale establishments, a staffing level that is below federal performance standards. There has also been a significant reduction in monitoring and support for local board of health inspections of restaurants. The number of local boards of health who currently meet statutory food safety responsibilities has decreased and now stands at less than half of all municipalities. A report by the State Auditor in 2007 found severe deficiencies in food protection activities within the Commonwealth, primarily due to resource constraints. Current funding levels are below those at the time of the report’s release.

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The Quality Standard: More Legislation Introduced to Strengthen State Co...

The Quality Standard: More Legislation Introduced to Strengthen State Co...:   Source: FDA Law Blog Posted: 10 Dec 2012 09:02 AM PST By Karla L. Palmer  – On December 5, 2012, Representatives Rosa DeL...

No debate on regulating compounding pharmacies - Op-Ed - Progress-Index

No debate on regulating compounding pharmacies - Op-Ed - Progress-Index

14th patient sues NECC in outbreak

14th patient sues NECC in outbreak

http://www.bostonherald.com/news/regional/view/2022121014th_patient_sues_necc_in_outbreak/srvc=news&position=also

http://www.bostonherald.com/news/regional/view/2022121014th_patient_sues_necc_in_outbreak/srvc=news&position=also

Drug shortages worsen following pharmacy-related meningitis scare Six products supplied by a company that closed due to the outbreak are on the FDA’s critical shortage list.

By CHRISTINE S. MOYER, amednews staff. Posted Dec. 10, 2012
In October, NECC and Ameridose halted production. Ameridose’s closure is temporary.
Drug shortages are intensifying in some parts of the nation due to the recent closings of two specialty pharmacies in Massachusetts following a fungal meningitis outbreak.
During the outbreak that started in September, the New England Compounding Center and its sister company, Ameridose LLC, which was a major hospital drug supplier, recalled all of their unexpired products. NECC produced the injectable steroids that were linked to the ongoing meningitis outbreak in at least 19 states. More than 500 cases of the disease have been reported, and at least 30 deaths have occurred, said the Centers for Disease Control and Prevention.
Hospitals and other medical centers that relied on the companies for thousands of medications each month are scrambling to identify new sources for drugs, including antibiotics, lifesaving medicine and pain medications.
The FDA has listed more than 100 drugs in short supply in the U.S. in 2012.
Some hospitals are trying to boost their pharmacy capabilities so they can reconstitute and package drugs themselves rather than rely on specialty pharmacies that could have safety issues similar to those of NECC.
NECC and Ameridose “provided a service that many hospitals around the country were using,” said Anuj Goel, MPH, vice president of legal and regulatory affairs for the Massachusetts Hospital Assn. “But the impact in Massachusetts has been very severe, given the fact that [those companies are located in the state]. It was definitely a big hit.”
Boston-based Massachusetts General Hospital, which is New England’s largest hospital, is among the health centers that have been particularly hard-hit. About 17% of the nearly 400,000 doses of medication it uses each month were provided by Ameridose, said Padma Gulur, MD, the hospital’s director of inpatient pain services. A smaller amount of medication was produced by NECC.
“We have had to take [everything] in-house,” Dr. Gulur said. “Because obviously, in this environment, we’re not going to look for another manufacturer whose credentials we haven’t checked thoroughly.”
As a result, the hospital’s pharmacy, which once operated from 7:30 a.m. to 4:30 p.m., now functions around the clock. The pharmacy expanded its space to other sterile areas and is considering temporarily using one of the operating rooms, Dr. Gulur said.
Some new employees have been hired to help manage the increased workload. But most of the tasks are falling to existing staff, she said. For instance, nurses learned how to prepare certain injectable antibiotics, and anesthesiologists are reconstituting some of the medications they use.
Still, the hospital can’t produce all the medication it needs. So staff members are working to identify new sources for needed medications, Dr. Gulur said.
One challenge is that the closings of Ameridose and NECC come at the end of the year, when the nation’s supply of pain medication historically is low, Dr. Gulur said. The government limits the number of narcotics that can be manufactured for prescription medication each year.
Further complicating matters, six products supplied by Ameridose were on the Food and Drug Administration’s critical shortage list. That means the products were in short supply before Ameridose recalled its unexpired products and halted operation.
“The recall has the potential to exacerbate one or more of those shortages,” the FDA said.
The six products on the critical shortage list are:
Sodium bicarbonate injection
Succinylcholine injection
Atropine sulfate injection
Bupivacaine hydrochloride injection
Lidocaine hydrochloride injection
Furosemide injection
“Drug shortages are two words that no one wants to hear — not patients, not health care professionals and not me,” said FDA Commissioner Margaret A. Hamburg, MD. “However, drug shortages are still a serious problem, one that may be temporarily impacted by [Ameridose’s] voluntary recall of all its unexpired products.”
Steps to ease shortages
There have been shortages of more than 100 drugs in the U.S. this year, the FDA said. The problem peaked in 2011, when 251 medications were in short supply.
Contributing to the shortages are production delays and quality issues. The FDA said too few manufacturers are producing the older and widely used generic sterile injectables to meet the nation’s needs. Many companies choose not to produce these products because they are not as profitable as other drugs and manufacturing them is complex, health experts say.
Shortages of lifesaving medication, including benzodiazepine drugs to stop seizures, have led emergency medical workers in the Memphis, Tenn., area to rely on compounding centers to create those products, said emergency physician Joseph E. Holley Jr., MD.
“If there are less compounding facilities around, there will be less opportunities to have those drugs made for us,” said Dr. Holley, EMS medical director for Memphis and surrounding municipalities.
To help limit the impact of the closures on existing drug shortages, health professionals should consider keeping medication on their shelves for the maximum amount of time that is safe, the MHA’s Goel said. In some cases, drugs in hospitals are discarded after 10 days, but they could be used safely for up to 15 days, he said.
In Massachusetts, the Public Health Council adopted emergency regulations in November to allow hospitals to share safe, compounded drugs with other hospitals in times of need, said Lauren Smith, MD, MPH, interim commissioner for the Massachusetts Dept. of Public Health. The rules took effect Dec. 1. The council is an appointed board of clinicians, professors and public health advocates.
“Part of the Dept. of Public Health’s mission is to work with hospitals to ensure that they have a plan in place to respond to any unforeseen emergencies,” Dr. Smith said. “These regulations provide another tool at our disposal to respond to any urgent situations that may arise, so we may protect the public health and ensure patient safety.”

Source found here

Fungal Meningitis Epidemic in the U.S.: 541 Cases & Growing, 36 Deaths

Sunday, December 09, 2012

The U.S. Fungal MeningitisOutbreak has reached epidemic proportions, and can easily become a Pandemic given the right set of circumstances.

The Centers for Disease Control and Prevention, (CDC) traced the fungalmeningitis outbreak to 3 lots of corticosteroids used for epidural injections, a pain relief treatment for spinal stenosis and herniated discs.

Distribution of the offending medicine has been linked to more than 75medical clinics in 23 states, and has been allocated to over 14,000 patients between May 21st of this year, to September 24th, 2012 inclusive.

The CDC has indicating that 541 cases have been reported in 19 of the 23 states involved, with 36 deaths.