When responsibility shifts to the contracted facility, qualifying the pharmacy for USP <797> is of the utmost importance

By Fran McAteer, MRA

In today’s modern hospital pharmacy, a strategy for effective USP <797> compliance is to outsource high-risk medications. High-risk compounded sterile preparations (CSPs) are prepared using non-sterile components. The non-sterile aspect of these admixtures requires the use of a sterile filtration process. Media fill proficiency testing of personnel is at a more complex and more frequent level. Environmental monitoring is weekly as opposed to monthly. With these additional precautions, some modern hospital pharmacies are implementing an outsourcing strategy to established contract compounding pharmacies. In this way, the high-risk application becomes the responsibility of the outsourcing agent.

Why do many hospital pharmacies outsource CSPs?

• Quality–the hospital may not have the facility, space, or equipment to effectively produce the medication.
• Capacity–a hospital pharmacy may need additional capacity depending on various factors such as staffing shortfall, patient needs, facility construction, etc.
• Cost–it may be a simple matter of cost allocation where the outsourcer offers a lower cost of compounding.

In this strategic decision-making process, it is important to qualify the outsourcing pharmacy for USP <797> compliance. It is imperative that the hospital pharmacy research the third-party compounding operation for quality of CSPs. The hospital pharmacy is ultimately responsible for all medications that it supplies to its patients. Senior pharmacy management should perform a non-biased assessment of USP <797> programs at a potential outsourcing candidate. Outsourcing agents should furnish a list of services, including existing quality checks for ensuring the integrity of IVs, syringes, and other products that they consistently supply to their customers. This should incorporate information on compounding procedures, cleanroom applications, trained personnel, expiration dating, and stability programs. A hospital pharmacy can request a list of <797> procedures or may even provide the outsourcer with a quality-oriented questionnaire to better formalize responses. This at least provides baseline information in regard to overall quality. The best way to ascertain this information is to visit the compounding operation. Following is a description of an approved vendor program at a large urban hospital. It involves an on-site audit of the compounder’s facility to assess its commitment to <797>. This audit involves inspecting the physical cleanroom areas, observing personnel aseptic technique, reviewing compounding batch records, and checking labeling and final product storage.

When discussing a potential contract with an outsourcer, request a visit to the site where the medications will be prepared. It is a good idea to send an audit agenda to the appropriate quality representatives of the contracting organization a few weeks before the actual visit date, giving the contractor some time to prepare the information that is requested. The agenda should request a facility tour, a review of specific CSP admixture documentation (preferably a CSP that is already being produced for the hospital), a check of personnel training records, and an audit of sterility, pyrogenicity, and stability test data.

Once on site, check out appropriate licenses such as FDA, BOP, and DEA. A facility tour will help establish a sense of the organization, segregation, material, and personnel flow. Observe the cleanroom facility, look for certification to ISO standards, and observe a CSP being prepared while watching for appropriate cleanroom personnel garbing and aseptic technique. Look for dirt, clutter, and cardboard in the cleanroom; these increase potential contamination. Ask about the frequency of cleaning and sanitization programs. In touring the facility, inspect how material enters and exits the cleanroom. Pay close attention to segregated quarantine, raw materials, and final storage areas as a source of product mix-ups (especially if multiple products are being supplied to multiple hospitals).

After the physical assessment, initiate documentation review. Review environmental monitoring programs, with concentration on data that is above action levels. Is there a corrective action program? Follow a batch record for tracer information; this traceability from the batch record should include appropriate test data such as final pH, sterility, and endotoxins. Personnel training records for the indicated compounding personnel should be inspected for appropriate media proficiency and gowning certification. Equipment maintenance and calibration records should be reviewed and labeling inspected for appropriate information including medication, lot numbers, expiration dating, and NDC numbers.

At the completion of the visit, provide the contractor with a summary of the findings regarding <797> compliance. This meeting is not for discussion, but a list of findings should be presented. The close-out meeting signals the formal end to the facility tour.

Upon returning to the hospital after the visit, provide senior management with a formal report candidly discussing the overall finding. Findings should be categorized as major observations, minor observations, and recommendations. Major observations include critical issues regarding <797> compliance such as failure to do sterility tests, no environmental monitoring program, or insufficient cleanroom facilities. These are issues that impact the overall CSP quality and may eliminate the outsourcer as a supplier for that CSP. Minor observations lack the immediate impact on CSPs and can easily be corrected–lack of appropriate procedures for ancillary tasks, failure to change out tacky mats on a regular basis, etc. Recommendations are minor points that the hospital pharmacy may desire to occur during the preparation of their CSPs–points of discussion that enhance quality systems or a particular method of operation that encompasses unique measures that may be employed by the hospital pharmacy. Once the report is produced and reviewed by senior management, it should be conveyed to the outsourcer. The report may request a follow-up response to the findings within 30 days. Upon receipt of the contractor’s responses, a review with final status should be prepared as Approved, Approved upon Impending Action, or Non-Approved.

This type of approved vendor program provides hospital pharmacy with the due diligence needed to assess the quality levels of a potentially new outsourcing partner, effectively managing multiple outsourcing partners for overall quality and <797> compliance. It also gives the outsourcer the ability to showcase its quality program, which should demonstrate its ability to attract future business.

Fran McAteer is vice president at MRA, an FDA registered laboratory. The author has experience in implementing USP <797> for many hospital pharmacies.

By George Miller

Puerto Rican industry officials report little impact from an early February press report that implied sub-par quality control practices among the island’s drug makers.

“Fortunately, the pharmaceutical industry knows Puerto Rico well, knows its track record in quality compliance,” says Enrique Mirandes, director for the life sciences business unit of the government-owned Puerto Rico Industry Development Co. (PRIDCO) in Hato Rey.

He described “indignation” as the reaction from local pharmaceutical executives–those truly responsible, of course, for the quality control practices within their respective facilities.

“For every one of those isolated cases,” says Mirandes, “there are dozens of examples of facilities that have consistently achieved the highest levels of compliance.” The contamination incidents cited occurred in three out of more than 60 plants on the island. “Statistically, these are almost insignificant,” says Mirandes.

The story, authored by an Associated Press reporter, cited an AP review of “100 pages of Food and Drug Administration reports, [which show that] even modern drug plants here [in Puerto Rico] under the watch of U.S. regulators have failed to keep laboratories sterile and have exported tainted pills.” The reports stemmed from FDA inspections of 13 pharmaceutical plants between 2003 and 2007.

The AP story quotes the FDA as saying “the problems in Puerto Rico are proportionate with the large number of pharmaceutical plants here and generally no worse than those on the U.S. mainland.” However, it attempts to discredit the FDA statement by sandwiching it between an alarmist quotation from a Washington watchdog group and a charge from unnamed “consumer advocates” that the FDA “does not sufficiently monitor the industry across Puerto Rico and the mainland.”

The AP did not respond to requests for comment.

The FDA, for its part, disagrees with the theme of the AP story and reiterates the comment it made to the reporter. “The inspection results from firms in Puerto Rico [between 2003 and 2007] were similar to the types found in other areas of the U.S.,” an FDA spokesman says.

He adds that “the FDA maintains a rigorous inspection process to ensure that firms manufacturing pharmaceuticals are doing so in accordance with the appropriate regulations to make safe and effective drugs.”

The premise of the story, “Tainted Pills Hit U.S. Mainland,” which appeared on February 5 in newspapers produced by several AP subscribers, is akin to ascribing a U.S. state or region (e.g., California, Research Triangle Park, or Eastern Massachusetts) a regulatory authority which trumps that of the FDA, the European Medicines Agency (EMEA), and Japan’s Ministry of Health, Labor, and Welfare Pharmaceutical and Food Safety Bureau.

The story described three contamination incidents over the five-year period: paint flecks on Diltiazem drug capsules, a blood pressure medication made by Biovail Corp.; metal particle contamination in Teva’s diabetes treatment Metformin; and machinery pins inside bottles of Effexor, manufactured at a Wyeth plant in Guayama.

Wyeth issued a statement immediately after the AP story appeared, citing an announcement it had made nine months earlier, in May 2007, that it “had resolved FDA concerns” outlined in a warning letter.

“Also in May 2007,” the current Wyeth statement continues, “the FDA informed Wyeth that its re-inspection of the Guayama manufacturing facility had resulted in a positive re-classification of the site.” Issues found by the FDA had either been corrected or did not merit further action. The statement also mentioned that the Guayama manufacturing facility had passed “three other major regulatory inspections conducted by agencies representing Europe, Brazil, and the Gulf countries.”

The Food and Drug Administration’s (FDA’s) Office of Criminal Investigations announced that two Chinese nationals and the businesses they operate, along with a U.S. company and its president and CEO, were indicted by a federal grand jury on February 6 for their roles in a scheme to import into the United States products they claimed were wheat gluten. The products were contaminated with melamine and used to make pet food.

On March 15, 2007, a pet food manufacturer alerted FDA to the deaths of 14 cats and dogs. The animals were reported to have developed kidney failure after eating pet food that had been manufactured with the purported wheat gluten.

A federal grand jury in Kansas City, MO, returned a 26-count indictment against Xuzhou Anying Biologic Technology Development Co., LTD. (XAC), a Chinese processor and exporter of plant proteins to the United States; Mao Linzhun, a Chinese national who is the owner and manager of XAC Suzhou Textiles, Silk, Light Industrial Products, Arts and Crafts I/E Co. LTD. (SSC), a Chinese export broker that exports products from China to the United States; and Chen Zhen Hao, president of SSC and a Chinese national.

Also charged in a separate, but related, 27-count indictment were ChemNutra, Inc., a Las Vegas corporation that buys food and food components from China to sell to U.S. companies in the food industry; and ChemNutra owners Sally Qing Miller and Stephen S. Miller.

ChemNutra contracted with SSC to purchase food-grade wheat gluten, according to the indictment. SSC then entered into a separate contract with XAC to supply the wheat gluten it needed to fulfill its contract with ChemNutra.

Among the charges against all seven defendants are delivering adulterated food that contained melamine into interstate commerce and introduction of a misbranded food into interstate commerce. The indictments allege that more than 800 tons of purported wheat gluten, valued at nearly $850,000, were imported into the U.S. between Nov. 6, 2006, and Feb. 21, 2007.

By George Miller

Despite mixed signals biotech marches on, and takes contamination control technology along with it

The last quarter of 2007 displayed more discouraging signs than positive ones for the European bioprocessing industry. Yet 2008 nonetheless holds promise. Suppliers of contamination control products and services, especially those involving disposable bioprocess technology, are preparing for mid- to high-single- and even double-digit growth.

The year 2007 will be remembered as a year of contrasts for European biotech companies. Its first quarter was marked by bubbling enthusiasm for the biopharmaceutical year ahead: “The industry in the U.S. has never been stronger and we’re seeing its success story spreading to other parts of the world–particularly Europe,” trumpeted Ernst & Young’s Global Biotechnology leader Glen Giovannetti last April. “Time will determine whether these trends will be sustained, but there’s reason for optimism. Innovation is being rewarded with record revenues and unprecedented premiums in M&A transactions.”

Unfortunately, the trends were not sustained. By less than a year later, European biotech headlines were far more likely to read like the following: “Biotech sees market value slip away,” and ‘UK biotechnology in need of healthy injection,” both from the Financial Times in January.

The dire reporting that followed such bleak headlines was delivered as only the British can: “Investors should stay clear of the UK biotechnology sector and instead put their capital in alternative, low-risk industries as biotech is unlikely to generate positive returns this year, KBC Peel Hunt, the broker, has warned in a report.” Here’s another: “Paul Cuddon, an analyst at KBC, said,

By Hank Hogan

Spring may be around the corner, but the prediction is for a chill to continue for at least the first half of the year. After that, things might warm up. That’s the consensus forecast with regard to semiconductor equipment sales. There are those, however, who think the outlook is much bleaker. On a brighter note, cleanroom consumables used for semiconductor manufacturing–silicon wafers, wipes, gowns, and so on–should grow.

The difference arises because consumables are needed for daily production, while equipment is a capital expenditure. Thus, the former tracks semiconductor run rates and those look good.

“The expectation of a number of analysts following the semiconductor industry is for growth in both semiconductor units and revenues in 2008. Demand remains strong for electronics in general, thus semiconductor devices and the materials needed to fabricate such will grow in sync with that demand,” says Dan Tracy, senior director of industry research and statistics for the semiconductor trade organization SEMI (San Jose, CA).

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The latest SEMI predictions are for a 12.4 percent growth rate in 2008 for world-wide wafer fab materials, a category that includes wafers, chemicals, gases, and other items. That’s healthy, even if it is down slightly from the 15.3 percent estimate for growth in 2007.

In contrast, capital equipment spending is forecast to decline, at least for the first half of 2008. Based on data from 60 North American equipment companies, SEMI has been showing a book-to-bill ratio of less than one for months. The ratio has bounced between 0.8 and 0.9 since mid-2007, meaning that fewer new orders were booked than those that were shipped, or billed. Equipment orders for Japanese manufacturers have also declined over that same time frame.

Gartner (Stamford, CT), a technology-oriented market research company, predicts a 9.9 percent spending decrease, with sales falling from $44.8 billion in 2007 to $40.3 billion in 2008. Three-quarters of that spending will be in wafer fab equipment. The 10 percent decline is in line with SEMI’s recent book-to-bill ratio. Gartner expects sales to pick up in the second half of the year as DRAM memory chip supply and demand come into balance.

A number of reasons are cited for this lessened spending, not the least of which is that last year was a good one for equipment sales. “Even with the declining orders since early 2007, 2007 will be the second highest spending year for semiconductor equipment, second only to 2000,” says Tracy.

He adds that the ramp in 300-mm wafer technology has driven equipment spending and wafer sales over the last half decade. This year will be the tipping point, with 300-mm fab capacity finally surpassing that of 200 mm.

Not all firms are as upbeat as Gartner. Advanced Forecasting (Saratoga, CA), a semiconductor market analysis company, issued a warning about the upcoming year. President Moshe Handelsman notes that his firm uses only quantitative tools to generate its predictions, which it sells to clients. For that reason, he won’t go into detailed numbers, but the situation could be significantly worse than current expectations, says Handelsman. “The numbers are really negative.”

By Bruce Flickinger

The concept of disease prevention is simple–but not easy

Hospital-acquired infections (HAIs; also called nosocomial infections) are a distressing issue on two levels: one, it is a sad fact that many people leave the hospital with infections and associated problems that they were not admitted with; and two, these infections are, for the most part, largely preventable.

Common wisdom says the concept of disease prevention is simple but not easy. The complicating factor in the European Union (EU) is tremendous variability on several levels: patient populations; hygiene awareness; standards and practices; and most critically perhaps, the microorganisms themselves–those invisible, elusive culprits that have developed a singular proficiency for surviving and proliferating in even the most hostile environments.

These variable conditions conspire to hamper preventative efforts and provide a fertile foothold for infectious organisms, and if an experience reported this past summer in U.K. newspaper The Guardian is any indication, the battle to eradicate disease-causing organisms from our hospitals and health care facilities is far from won. In their first enforcement of the new U.K. Hygiene Code, National Health Service (NHS) officials noted that the violative hospital employed only one microbiologist working four hours a week on infection control. Even someone at the periphery of the problem knows that this is an entirely insufficient response to the problem of bacterial infection and resistance as it exists today.

Anecdotal evidence about infection control successes and failures abounds. Some European countries, such as the Netherlands, have some of the lowest rates of HAIs, while awareness and vigilance of the problem tend to lessen in Southern Europe and in the emerging infrastructures in Eastern Europe, where multi-drug-resistant tuberculosis is a problem. Fortunately, the overall trend is toward heightened government oversight and regulatory accountability–the U.K. Hygiene Code, which went into effect October 2006, is but one example. Larger pieces of hospital budgets are also going to hygiene infection control.

Figure 1. STERIS’s VaproSure™ sterilizer is effective for sterilizing targeted hospital room surfaces. Photo courtesy of STERIS.Click here to enlarge image

The bottom line, says Gerald McDonnell, PhD, vice president of Research and European Affairs with STERIS Ltd. (Basingstoke, UK), is that “life is a constant battle between humans and certain types of disease-causing microorganisms, which we attempt to control through vaccinations, our own immune systems, and good hygiene practices. When we are healthy we generally tend to win these battles, but the sad part is that oftentimes we lose.”

Standard practice, new perspectives

The tenets of winning the war against HAIs are well established. They include good personal hygiene practices; patient involvement and empowerment; instrument and equipment sterilization; isolation and infrastructure controls; and proper surgical and catheterization procedures. How effectively each and all of these are implemented in a facility and ingrained in the staff through education and training will impact infection rates.

“Infection control, or more correctly infection prevention, is always a combination of a number of interventions to reduce risk,” McDonnell says. “It starts in the ambulance or emergency ward and goes all the way through to discharge. The sicker the patients, the more at risk they are, but vigilance by patients and staff mitigates this risk, along with good practice and products.”

In addition to hygiene practices, the misuse and overuse of antibiotics has become an acute concern. A 2005 report from the European Antimicrobial Resistance Surveillance System (EARSS), a database of test results reported from 30 European countries, notes that resistance is “most convincing” where orally administered antimicrobial compounds, which are preferred in ambulatory care, are used. That is, they are convenient and often overused. EARSS says, “The growing availability of third-line antimicrobial drugs as oral formulations is a matter of concern and underscores the need of locally or nationally advised prescribing practices for both ambulatory and hospital-based care.” A number of companies serving the health care market offer antibiotic management services, in which mismatched antibiotics can be identified and formularies adjusted accordingly.

Another topic gaining more attention of late is environmental surveillance, particularly of patient-contact surfaces. This is particularly salient in light of the emphasis that is usually placed on handwashing and personal hygiene. “A number of recently published studies have shown that contact surfaces can be contaminated with important pathogens such as MRSA (methicillin-resistant Staphylococcus aureus, VRE (vancomycin-resistant Enterococcus), and Clostridium spores,” McDonnell says. “In some cases, these organisms have been shown to survive for weeks on surfaces. With patient or staff contact, this becomes a significant source of infection.”

So while infection control professionals spend a lot of time teaching hospital staff and patients about the importance of handwashing in reducing hand contamination, “we should remember what happens to those hands after they have been washed, or even gloved,” McDonnell says. “Contact with contaminated surfaces such as bedrails or bedside tables can quickly recontaminate the hands/gloves and be a further source of infection.”

McDonnell says the merits of surveillance are “often a debated point,” but that it does “make sense for hospital administrators to at least understand the levels and types of contaminants or microorganisms that can be present in high-risk areas, wards, or patients, and in particular during outbreak situations.”

Quantifying the problem

Broadly speaking, the importance of epidemiological surveillance both for better understanding HAIs and for crafting appropriate responses to them cannot be overstated. Numerous local, national, and pan-European efforts, such as EARSS, are in place to carry out this work. Another is Improving Patient Safety in Europe (IPSE), funded by the EU Directorate General for Health and Consumer Protection, which oversees HELICS (Hospitals In Europe Link for Infection Control through Surveillance). HELICS, in turn, is an international network that collects, analyzes, and disseminates data about the risks of nosocomial infections in European hospitals.

Based on the 2006 HELICS survey, which encompasses results of hospital-wide surveillance programs throughout the EU, IPSE estimates that roughly 3 million patients acquire a nosocomial infection in the EU each year, and that 50,000 of these infections result in death. The most frequent infections are urinary and respiratory tract infections (28 and 25 percent prevalence, respectively), and surgical site infections (17 percent).

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Significantly, 20 to 30 percent of nosocomial infections are considered to be preventable by intensive infection prevention and control programs, according to ISPE.

The most prevalent offender continues to be MRSA, which is isolated in approximately 5 percent of all nosocomial infections in the HELICS database. EARSS confirms this. In 2005, the database included results from more than 27,000 isolates of invasive S. aureus. Prevalence of MRSA among these isolates was under 3 percent in only seven countries, around 20 to 25 percent for most of the “EU25,” and above 40 percent for eight, primarily southern European, countries.

While not as prevalent, E. coli resistance is “a disturbing development with seemingly inexorable vigor,” EARSS says. The pathogen’s resistance to both aminopenicillins and fluoroquinolones is increasing, and combined resistance is a frequent occurrence.

It is generally thought that MRSA strains are more frequently isolated from ICU patients than non-ICU patients. This again is supported by EARSS, which says that in some countries, such as Poland, Bulgaria, Croatia, Greece, the U.K., Cyprus, and Romania, the proportion of MRSA found among ICU patients reaches over 60 percent. These figures remain troubling, and ICU infection control procedures are often a main component of a hospital’s overall program.

McDonnell and others caution against making broad generalizations about the ICU being a key problem in the spread of HAIs. “Although HAIs are often identified within ICUs and some have been acquired in ICUs, in many cases patients are already carrying various pathogenic microorganisms when they come into these departments,” McDonnell says. “An example is the recent understanding that many strains of MRSA are actually community acquired. A patient may not know they are carrying these strains, but when they become sick, are put on antibiotics, or are immunocompromised they are more at risk from these organisms causing an infection that normally they could fight off. Patients in ICUs are very vulnerable to infection. They are very sick and predisposed to illness.”

On-site epidemiology

National surveillance figures provide important information, but hospital administrators also need a better understanding of how infectious organisms and antibacterial resistance pervade their own facilities. One new tool is MedMined™, a service offered through Cardinal Health (Birmingham, AL) that enables the automated collection and standardization of infection data throughout a facility. Management can use the information to track its own infection rates and preventive efforts and, because the data is fed anonymously into a national database encompassing all MedMined sites, an individual facility’s performance can be compared to others.

A surveillance component continuously scans the hospital for problems using data uploaded from a laboratory information management system. It then uses pattern mapping and a kind of artificial intelligence to track microbial populations, potential hot spots, and the effects of any interventions. Says Patrick Hymel, MD, vice president with Cardinal Health, “You don’t have to direct the system or ask specific questions like you do with manual epidemiology. It provides regular, standardized feedback about the effectiveness of infection control procedures, so people can see change almost immediately. They’re often surprised at the opportunities they have for improvement.”

MedMined is currently in use in 250 hospitals across the U.S., and users have been able to document an average 13.5 percent reduction in infection rates in the first year of using the service, the company says.

“There are major changes coming in how payers will reimburse for complications from HAIs,” says Hymel. ‘It’s important for hospitals to know their true exposure, and it is hard to know this if they are using a strictly manual approach to case finding and tracking.”

Hymel adds, “Infection control departments have traditionally been viewed as a cost center at hospitals, but with improving practice over time, you can really transform the department into a significant source of cost savings that can be directly applied to the bottom line and improve the overall financial performance of the hospital.”

Good practice pays off

While HAI control and prevention is a complex, multi-factorial public health issue, with proper infection control implementation, such as hand hygiene, proper vaccination of staff, and sterile techniques, hospitals can save lives and minimize economic losses. This realization is turning health care into a strong market for contamination/infection control technologies and services, much like microelectronics was several years ago, observers say. Awareness and education are increasing concurrently.

“In the post-antibiotic era many countries employed medicine to treat disease, but not necessarily to prevent it. Now the focus is on prevention or controlling early, and the same should be held for infection prevention,” McDonnell says. “Medical staff should be spending significant time during training on infection prevention earlier in their careers. Some countries are doing this effectively today while others have a long way to go.”

Resources

1. Surveillance reports and other information are available from the Improving Patient Care in Europe web site at http://helics.univ-lyon1.fr/
2. The European Antimicrobial Resistance Surveillance System (EARSS) web site is http://www.rivm.nl/earss/
3. Information about the VaproSure system and other STERIS technologies is available at http://www.steris.com/aic/aic.cfm
4. Information about MedMined is available at http://www.cardinal.com/medmined/

International Organization for Standardization (ISO) standard 14644-6, Cleanrooms and controlled environments