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The generally accepted best practices in both the life science and advanced material market have benefited from years of trial and error, and the best efforts of leading technical/quality colleagues. Marc Stranz, a pharmacist since 1978 and a member of the USP sterile compounding panel, states, “Sterile Compounding Pharmacies are not all at PAR, they have not all figured it out, and it is still too much go-go. The Sterile Compounding Pharmacy market could benefit from collaborating with the standards already developed by IEST and FDA.”

Small pharma

Until the New England Compounding Pharmacy shipped 17,000 vials of contaminated steroid syringes in 2012, triggering a fungal meningitis outbreak which killed 64 people, small pharma was under the radar. Although all licensed pharmacists are trained in basic aseptic technique in pharmacy school from a theoretical perspective, there is a lack of practical knowledge. For example, while the pharmacist was taught about the laminar flow patterns in hoods, (s)he was not instructed in the importance of aseptic operator protocol (i.e. sterile gloves and apparel). The pharmacist was taught the HOW without the much needed WHY base knowledge.

The pharmacist is challenged to perform at the highest level of their license. That is, to fully participate in the clinical care and medical management of the patient. The highest and best value of the pharmacist is not developing and ensuring compliance with the SOP (standard operating procedures) for compounding. Although the pharmacist is technically competent in drug formulation, these competing interests are problematic.

The first standard of any type in small pharma occurred in 1991 with the “Joint Commission,” which focused exclusively on the home infusion subset of the sterile compounding pharmacy market. Although adherence to this new standard was not mandatory, the commercial insurers required accreditation for all home infusion for reimbursement. The financial incentive model was an effective enforcement tool.

It was not until 2004 that the first reference standard was introduced for the whole compounding pharmacy market, USP 797. This unenforceable standard is a diluted version of the FDA cGMP guidance 503. The standard has significant shortcomings, including the omission of requiring sterile apparel and wipers when doing aseptic compounding. There has been a gradual migration to USP 797.

Because the original USP 797 failed to address handling hazardous substances, the final submission for USP 800 is currently under review. This document gives guidance to the parameters of the hazardous substance incoming receipt, segregation, dispensing, and post system transfer. The proper handling of a hazardous substance requires negative air pressure. Like USP 797, the document contains accurate theoretical information. However, it fails to handle the “in practice” challenge of operating a positive and negative air pressure environment in often adjacent and/or contiguous space.

The regulatory organization with enforceable actions is not uniformly interpreted nationwide. The Drug Compounding Act that created 503A and 503B did make compliance to USP Chapter 797 mandatory for the 503A pharmacy, which encompasses sterile drug compounding in pharmacies. Unfortunately, states have not all subsequently adopted USP Chapter 797 verbatim. Each individual state board of pharmacy has developed its own interpretation of the standards. Approximately 50 percent of the state boards of pharmacies have an enforceable compliance standard. The state of Texas has among the most stringent standards, including continuous education requirements. A lack of resources prevents compounding pharmacies from being inspected on a routine basis. The state pharmacy board has competing interests including monitoring narcotics, preventing “pill mills,” and inspecting the compounding pharmacy.

Big pharma

Unlike small pharma, which relies on enforcement at the state level, big pharma is highly regulated by the FDA throughout the U.S. The technical/quality colleagues in big pharma receive theoretical training in university (i.e. microbiology, quality control, compliance) and significant practical training through company specific training programs and professional organizations for continuing education (PDA, ISPE, IEST). Unlike their small pharma cousins, if big pharma deviates from the FDA regulatory standard they face serious consequences that promote an organizational culture of risk avoidance and strict adherence to all recommended practices. The consequences of non-compliance can vary from the risk of a published FDA written warning to the possibility of a non-compliant facility shutdown.

The FDA mission is to ensure that every sterile manufacturing facility has a good outcome 100 percent of the time. If the good outcome (i.e. safe product) cannot be documented, tested, and verified, the product is not released to the market. The entire manufacturing process from raw material sourcing to process equipment to facility design must all be aligned in the same ecosystem.

As big pharma grew, collaborative, peer review organizations developed to provide continuous education and recommended practice guidance. Specifically, the IEST has developed a number of recommended practices around Cleanroom Housekeeping (IEST-RP-CC018) and Cleanroom Facility Design (IEST-RP-CC012). An IEST Working Group is currently working on IEST RP CC48.1, “Guidance for the design, testing, and maintenance of Sterile Compounding Facilities.”

Conclusion

The growth rate of the sterile pharmacy market has exceeded the industry’s internal technical/quality experts’ time and resources to develop a practical roadmap. Enforceable standards are geographically based on the state in which you operate. A sterile compounding pharmacy operating in some states can ship product nationwide. This puts patients at risk.

A lack of leadership and resolve at the national level of compounding pharmacies is the key culprit. The National Association of Boards of Pharmacy would disagree, and the Compounding Act does provide guidance, but not all states have adopted USP 797. That does begin to address whether USP Chapter 797 fulfills the requirements for sterile compounding. The playbooks are developed through peer review at IEST. The organization should be the source of documents for recommended
practices in small pharma.

The lack of enforceable standards in place in all states since the preventable deaths of 64 enabled by the lack of enforceable standards is disappointing. I concur with Marc Stanz, a Pharmacist of 41 years: “The sterile compounding pharmacy industry can do better.” The incorporation of IEST Recommended Practices is an overdue step in the right direction.


Greg Heiland is the Executive Director for the Global Society for Contamination Control, a non-profit peer-to-peer global learning community for contamination control professionals. He is also the CEO and Founder of Valutek, headquartered in Phoenix, Ariz. www.gsfcc.org; www.valutek.com

This article appeared in the September/October 2015 issue of
Controlled Environments.

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