Micro-Clean USP 797 Pharmaceutical Compounding Sterile Preparations

USP 797 Pharmaceutical Compounding – Sterile Preparations

United States Pharmacopeia (USP) has established enforceable and detailed procedures and requirements for Compounding Sterile Preparations (CSP). The intent is to reduce or prevent harm to patients resulting from microbial contamination, bacterial endotoxins, and contamination of Compounded Sterile Preparations. It also covers gross ingredient percentages errors and the use of wrong components.

"This is all about patient safety," said Joseph H. Deffenbaugh, director of public health and quality for the ASHP Practice Standards and Quality Division. "Let's not forget what the purpose of all this is: to protect patients from microbially contaminated preparations, but also to make sure that those preparations are compounded accurately and appropriately for the conditions for which they're being prescribed."

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Primary Barriers

Sterile Products – must be manipulated inside an ISO Class 5 or better Laminar Airflow Cleanbench certified every 6 months and when relocated.

These devices must be located within an ISO Class 7 buffer area (cleanroom) and certified for particulate levels every 6 months.
Blowers must be run continuously during compounding activity, including during compounding interruptions of less than 8 hours.
When the blower is off, only one person may enter buffer room to turn blowers on (a minimum of 30-minutes purge time is needed) and to conduct aseptic cleaning of work surfaces.

Barrier Isolators – ISO Class 5 may by used as an alternative to BSC or LFCB.

Units are certified every 6 months and when relocated.
USP approves of the use of POSITIVE PRESSURE BARRIER ISOLATORS.
If you choose to try the Barrier Isolator alternative MICRO-CLEAN STRONGLY RECOMMENDS unidirectional flow isolators to prevent cross-contamination from multi-product use.
The Isolator is preferred (but not necessary) to be located within an ISO Class 7 cleanroom.

Note: Barrier isolators require extra operating procedures for its maintenance, monitoring and control. Barrier isolators may severely limit or restrict operator movement in compounding processes, take longer to purge out transfer stations, and require greater skill levels and dexterity when manipulating materials with front-access glove ports.

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Secondary Barriers

Cleanrooms - A minimum of ISO Class 7 particulate levels using airflow dilution, temperature and humidity control within the buffer room. Walls, floor and ceiling should be smooth, impervious, free from cracks or crevices, non-shedding and resistant to disinfectants.

Cleanroom (buffer area) should attain ISO Class 7 Cleanliness Levels. Cleanroom (buffer area) should be so designed as to provide positive pressure thereby preventing particle ingress into the clean areas. Cleanroom (buffer area) should not contain sinks or floor drains.

Ante Room (clean area for donning personnel barriers and help minimize ingress of particulates into buffer room) should have a “hands-free” operating sink, air hand dryer, coat hooks and uniform storage. Supplies such as needles, syringes, ampoules, bags, vials of parenteral fluids and packages of transfer tubing sets for large volume fluids must be un-cartoned and disinfected.

Gowning will include hair/beard covers, gloves, knee-length gowns/coats or full cleanroom attire, shoe covers, and appropriate PPE. A facemask is optional when using a barrier isolator or vertical LFCB with a permanent shield between operator and sterile material, but head and facial hair must be covered. All hand and arm jewelry must be removed prior to gowning.

Cleanroom construction

Ceiling tiles should be impregnated with a polymer to render them impervious and hydrophobic. Ceiling tiles sealed with RTV to the support frame.

Lighting fixture exterior lens surface should be smooth, mounted flush and sealed.

Filtration should be of sufficient air changes to maintain Cleanliness Classification during all modes of operation. A rule of thumb would be to discount the use of LFCB and BSC discharge air.

Walls may be panel-locked and sealed or of epoxy-coated gypsum board. Junctures to ceilings and walls should be coved or caulked to avoid cracks and crevices where dirt can accumulate.

Floors are overlaid with wide sheet vinyl flooring with heat-welded seams and coving to the sidewall.

http://www.usp.org/standards/proposed797Revisions.html Proposed Revisions to USP Chapter <797>
Pharmaceutical Compounding – Sterile Preparations

This proposed document was compiled by Dr. David W. Newton. Dr. Newton is chairman of the 2000-2005 Sterile Compounding Committee, SCC, of the Council of Experts of the United States Pharmacopeial Convention, Inc., USP. The complete text of the proposed revisions to USP 797 are also summarized in future publication of IJPC and the full proposed text of USP 797 will be published in a future 2005 issue of USP's bimonthly official journal, Pharmacopeial Forum, PF. Comments on this summarized proposal should be directed to Dr. Claudia Okeke at cco@usp.org. Please continue to check our website for the date of publication of the full text in PF.

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Cleanroom Physical Design

Low and Medium Risk Compounding Sterile Preparations Environments may have a Demarcation line or physical barrier separating the Cleanroom (Buffer room) from the Ante Room (gown room). A precautionary note: A demarcation line cannot provide positive pressure needed to prevent the ingress of particulates. Physical cleanroom walls can provide the necessary pressurization to control particulate ingress.

High Risk CSP Environments must have a physical barrier separating the Cleanroom (Buffer room) from the Ante Room (gown room). Ante Room may have a Demarcation line separating clean and supply cart entry areas.

Why can’t I just use my LFCB air to maintain ISO Class 7 in my Buffer Area Cleanroom? The easy answer for this is the LFCB does not provide control to the room. High particulate levels are allowed to enter and then become diluted with the LFCB air. Control should be maintained at the source of the air into the cleanroom. USP 797 requires HEPA filtered supply air into the cleanroom.

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Environmental Monitoring

Particulate Counts

Every 6 months for each ISO Class 5 device or area, ISO Class 7 Cleanroom (buffer room) and ISO Class 8 Ante Room.
All counts are for sizes 0.5um and larger.
All testing should be updated to the ISO 14644-1:1999 format.
Viable monitoring
- Written plan and schedule to conduct active (RCS or Slit-to-Agar (STA)) or passive sampling (settling plates) of viable organisms.
- Baseline colony forming unit (cfu) levels will be determined over a time period.
- A significantly increasing trend in cfu counts over time should trigger a re-evaluation of the cleaning procedures, operating procedures, and filtration efficiency within the sterile compounding location.
- Compounding area critical points of concern are air backwash turbulence locations on LFCB or BSC.
- Addition information may be found in USP 797 “Microbiological Evaluation of Clean Rooms and Other Controlled Environments".

Temperature and humidity control

Temperature and humidity control is required within the buffer room. To have control would also imply the capability to monitor.
Recommend a calibrated temperature and humidity chart recorder installed into the buffer room.

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What is the U.S. FDA’s Guidance Position on USP 797?

Guidance for FDA Staff and Industry

Compliance Policy Guides Manual

Sec. 460.200

Pharmacy Compounding

Submit written comments regarding this guidance document to the Dockets Management Branch (HFA-305), 5630 Fishers Lane, Rm.1061, Rockville, MD 20852.

Additional copies of this document may be obtained by sending a request to the Division of Compliance Policy (HFC-230), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, or from the Internet at: http://www.fda.gov/ora/compliance_ref/cpg/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Office of Regulatory Affairs

Center for Drug Evaluation and Research

May 2002

Excerpts from above document:

DISCUSSION

FDA recognizes that pharmacists traditionally have extemporaneously compounded and manipulated reasonable quantities of human drugs upon receipt of a valid prescription for an individually identified patient from a licensed practitioner. This traditional activity is not the subject of this guidance.

FDA believes that an increasing number of establishments with retail pharmacy licenses are engaged in manufacturing and distributing unapproved new drugs for human use in a manner that is clearly outside the bounds of traditional pharmacy practice and that violates the Act. Such establishments and their activities are the focus of this guidance. Some "pharmacies" that have sought to find shelter under and expand the scope of the exemptions applicable to traditional retail pharmacies have claimed that their manufacturing and distribution practices are only the regular course of the practice of pharmacy. Yet, the practices of many of these entities seem far more consistent with those of drug manufacturers and wholesalers than with those of retail pharmacies. For example, some firms receive and use large quantities of bulk drug substances to manufacture large quantities of unapproved drug products in advance of receiving a valid prescription for them. Moreover, some firms sell to physicians and patients with whom they have only a remote professional relationship. Pharmacies engaged in activities analogous to manufacturing and distributing drugs for human use may be held to the same provisions of the Act as manufacturers.

POLICY:

Generally, FDA will continue to defer to state authorities regarding less significant violations of the Act related to pharmacy compounding of human drugs. FDA anticipates that, in such cases, cooperative efforts between the states and the Agency will result in coordinated investigations, referrals, and follow-up actions by the states.

However, when the scope and nature of a pharmacy's activities raise the kinds of concerns normally associated with a drug manufacturer and result in significant violations of the new drug, adulteration, or misbranding provisions of the Act, FDA has determined that it should seriously consider enforcement action. In determining whether to initiate such an action, the Agency will consider whether the pharmacy engages in any of the following acts:

Compounding of drugs in anticipation of receiving prescriptions, except in very limited quantities in relation to the amounts of drugs compounded after receiving valid prescriptions.
Compounding drugs that were withdrawn or removed from the market for safety reasons. Appendix A provides a list of such drugs that will be updated in the future, as appropriate.
Compounding finished drugs from bulk active ingredients that are not components of FDA approved drugs without an FDA sanctioned investigational new drug application (IND) in accordance with 21 U.S.C. § 355(i) and 21 CFR 312.
Receiving, storing, or using drug substances without first obtaining written assurance from the supplier that each lot of the drug substance has been made in an FDA-registered facility.
Receiving, storing, or using drug components not guaranteed or otherwise determined to meet official compendia requirements.
Using commercial scale manufacturing or testing equipment for compounding drug products.
Compounding drugs for third parties who resell to individual patients or offering compounded drug products at wholesale to other state licensed persons or commercial entities for resale.
Compounding drug products that are commercially available in the marketplace or that are essentially copies of commercially available FDA-approved drug products. In certain circumstances, it may be appropriate for a pharmacist to compound a small quantity of a drug that is only slightly different than an FDA-approved drug that is commercially available. In these circumstances, FDA will consider whether there is documentation of the medical need for the particular variation of the compound for the particular patient.
Failing to operate in conformance with applicable state law regulating the practice of pharmacy.

The foregoing list of factors is not intended to be exhaustive. Other factors may be appropriate for consideration in a particular case.

Other FDA guidance interprets or clarifies Agency positions concerning nuclear pharmacy, hospital pharmacy, shared service operations, mail order pharmacy, and the manipulation of approved drug products.

For a complete copy of this manual go to:
http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg460-200.html

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STATEMENT FROM THE ACTING DIRECTOR, FDA

Excerpt of Statement by Steven K. Galson, M.D., M.P.H., Acting Director
Center for Drug Evaluation and Research (CDER)
U.S. Food and Drug Administration
Department of Health and Human Services

Before the Senate Committee on Health, Education, Labor and Pensions hearing on “FEDERAL AND STATE ROLE IN PHARMACY COMPOUNDING AND RECONSTITUTION: EXPLORING THE RIGHT MIX TO PROTECT PATIENTS”

OCTOBER 23, 2003

LIMITED FDA SURVEY OF COMPOUNDED DRUG PRODUCTS

Since 1990, FDA has become aware of more than 55 product quality problems associated with compounded products, many of which resulted in product recalls. In 2001, FDA’s Division of Prescription Drug Compliance and Surveillance conducted a limited survey of drugs compounded by 12 compounding pharmacies that allowed compounded products to be ordered over the Internet. The goal of the survey was to gather information on the quality, purity, and potency of compounded drug products in the marketplace. The compounded products surveyed were selected from a cross-section of commonly compounded dosage forms based on FDA’s assessment of the potential health risks resulting from improper compounding. FDA collected the samples via air mail order in the same manner a consumer would order the products over the Internet.

The 29 products sampled included hormonal products, antibiotics, steroids, anesthetics and drugs to treat glaucoma, asthma, iron deficiency anemia, and erectile dysfunction. Five different dosage forms (i.e., sterile injectables, ophthalmic products, pellet implants, inhalation products, and oral dosage forms) were sampled.

Ten (34 percent) of the 29 sampled products failed one or more standard quality tests performed. Nine with failing analytical results failed assay (potency) testing, with a range of 59 percent to 89 percent of expected potency.

Each year, FDA routinely samples drug products made by commercial manufacturers and analyzes these samples in FDA laboratories. More than 3,000 products from commercial manufacturers have been sampled and analyzed by FDA since fiscal year 1996. The analytical testing failure rate for commercially produced samples has been less than two percent for all tests, but for assay (potency) tests there were four failures out of 3,000. Compared to the two percent failure rate, the percentage of sampled compounded products failing analytical testing in our 2001 survey (34 percent) was higher than expected. Although the 2001 survey had several limitations including a small sample size, it provided valuable preliminary information on the quality of selected compounded drug products currently marketed. We believe that these laboratory results need to be interpreted cautiously and should not be generalized beyond the particular drugs and pharmacies involved. Further, we believe that the results call for additional study and consideration by FDA, the state regulatory authorities, professional organizations, and pharmacies.

POSITIVE ACTIONS AND CHALLENGES

Some of the stakeholder groups with whom we have interacted are engaged in activities intended to provide greater confidence in the quality of compounded medications. For example, the NABP has a model code governing pharmacy compounding that substantially has been adopted by ten states. The model code provides State Boards of Pharmacy with a framework for developing requirements for compounding pharmacies. The USP has developed a new chapter in the U.S. Pharmacopeia addressing sterile drug compounding practices. The chapter sets standards for the preparation of sterile compounded drugs. The American Society of Health-System Pharmacists also has such guidelines. The APhA, NABP, and USP have been discussing the possibility of developing an accreditation program that would set standards for and monitor compounding pharmacies. All of these activities are positive steps in ensuring that pharmacy compounding is done with appropriate protections for patients, and we support them.

FDA recognizes that states have the direct ability to regulate pharmacy compounding and direct access to prescription records. However, limited state resources and varying standards and regulatory requirements are factors that affect the adequacy of state regulation. Pharmacy self-inspection is allowed in four states, which consists of pharmacist self-evaluation by questionnaire of the pharmacy’s compliance with laws and regulations. In addition, there is variability in commitment to regulate pharmacy compounding among the states. Sometimes there is conflict between State Boards of Pharmacy and Health Departments based on disparate regulatory philosophies.

Clearly, when pharmacy compounding more closely approximates commercial manufacturing, FDA has an interest in regulating that practice as it does all other drug manufacturing. One difficult issue is where to draw that line. If the line is to be drawn based on volume, how much volume makes a compounder a manufacturer? There are many large compounding pharmacies, some of which are exclusively drug compounders. Similarly, there are many small drug manufacturers that make drugs under approved new drug or abbreviated new drug applications. Through our review of these applications, we ensure that the drugs are safe and effective and that the processes by which the drugs are made produce consistently high quality products that maintain their safety and efficacy throughout their shelf life. This system of evidence-based medicine provides public health benefits to American consumers and health professionals because patients are able to rely with confidence on the medications they take and avoid ineffective therapies or those for which the risks do not exceed the benefits.

It is important to ensure that the production of drugs in pharmacy compounding does not undermine the incentives to develop and submit new drug applications to FDA with evidence of the safety and efficacy. At the same time, we recognize that pharmacy compounding is necessary where there is a medical need of a particular patient for a product that is not commercially available in an approved form. We must exercise our regulatory authority in such a way as to support pharmacy compounding that is necessary, while curbing abuses.

With this in mind, we can describe a few key areas where the Agency has taken action and where we believe a Federal role is appropriate:

First, as a result of FDAMA (Food and Drug Administration Modernization Act), we developed a list of drugs that were inappropriate for compounding because they have been withdrawn from the market for safety reasons. In many cases, FDA reviewed the data concerning adverse events from our spontaneous reporting system and other databases and determined that the risks for these drugs exceeded the benefits for the uses to which they were approved. FDA has access to nationwide and global data concerning adverse events and we have the expertise to evaluate the risks of a therapy in relation to its benefits. Once FDA has determined that the risks of a therapy exceed its benefits to the extent that the drug should be removed from the market, it would be inappropriate to expose patients to the risks of the product by allowing compounding of that drug. FDA intends to continue to maintain this list and take action against pharmacies that compound unsafe products. Similarly, if FDA has specific information about significant potential risks associated with compounding a particular drug (e.g., one that was considered for but denied FDA approval), FDA may take action against such compounding, preferably in support of, or in conjunction with, the state authorities. Furthermore, FDA has continuing concerns about compounding, without an investigational new drug application in effect using ingredients that are “experimental” or not components of FDA approved drugs.
Second, FDA believes it is in the best position to address the quality of bulk drug substances used in compounding. Many of these drugs are imported from abroad and individual states are unlikely to have the ability to conduct inspections of foreign producers and ensure the quality of these active ingredients in compounded products. As addressed in the CPG, drugs should not be compounded using active ingredients that were manufactured at facilities that are not even registered with FDA or that fail to meet accepted USP compendial standards for quality.
Third, FDA believes it is appropriate for the Agency to continue to investigate allegations of poor quality compounded drugs, in conjunction with the states, whenever possible. However, we also must act without states when state involvement is not forthcoming because of resource constraints or for other reasons. For example, an Internet or mail order pharmacy might be operating in a state with few resources for pharmacy inspections, but shipping poor quality compounded products nationwide. In such cases, FDA believes it plays an important role in addressing these dangerous practices. FDA believes that when issues regarding the quality of compounded drugs are significant enough to raise public health issues, FDA should continue to play a role in working with the states to address these public health matters, and in the event that a state is unwilling or unable to join FDA, then the Agency in some cases must be allowed to unilaterally protect the public health from compounded drugs that pose unreasonable risks.

Finally, the Agency should be able to determine when a pharmacy crosses the line between appropriate pharmacy compounding and manufacturing.

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CONCLUSION

In summary, FDA welcomes this Committee’s interest in pharmacy compounding and would like to assure the Committee that the Agency’s efforts to address pharmacy compounding issues are designed to balance the need to allow legitimate forms of pharmacy compounding with the need for Federal oversight when pharmacy compounding threatens to compromise public health.

Under the compounding-related provisions of the Food and Drug Administration Modernization Act, pharmacy compounding was not defined to include mixing or reconstituting commercial products in accordance with the manufacturer’s instructions or the product’s approved labeling. Reconstituting means the return, usually by adding liquid, of a drug previously altered for preservation and storage to its original state for administration to a patient. This type of manipulation, when done in accordance with approved labeling, should not adversely affect the safety or efficacy of the drug. (The provisions were struck down by the Supreme Court on April 29, 2002.)

For a complete transcript of this testimony go to:
http://www.fda.gov/ola/2003/pharmacycompound1023.html

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TITLE 21--FOOD AND DRUGS, SUBCHAPTER C - DRUGS: GENERAL

Subpart A General Provisions [Reserved]

Subpart B -- Compounded Drug Products § 216.23 - [Reserved] - Drug products withdrawn or removed from the market for reasons of safety or effectiveness.

http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr216_01.html

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USP 797 Pharmaceutical Compounding – Sterile Preparations

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