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USP <797> Compliance

How Will USP 797 Affect Your Sterile Compounding Operations?
Compliance Dates Established
A Controlled Environment is Required for Compounding of CSPs
Risk Levels Defined
Beyond-Use Dating Limits Established
Testing, Certification and Environment Requirements
Responsiblity of Compounding Personnel Defined
What Must be Done to be in Compliance
What Liberty Industries Can Do to Help

How Will USP 797 Affect Your Sterile Compounding Operations?
Officially, USP 797 went into effect on January 1, 2004 and is the first standard affecting sterile compounding which is enforceable by the FDA and state boards of pharmacy. It is also important to note that the CDC, OSHA/NIOSH, JCAHO, ASHP and ASPEN are supporting these standards, all with the objective to improve the quality of sterile pharmaceuticals.

BACKGROUND: The primary purpose for the creation of USP 797 was to reduce or prevent harm to patients that could result from microbial contamination, excessive bacterial endotoxins, large content error, and incorrect ingredients or contamination of compounded sterile products.

A national survey was conducted in conjunction with ASHP in 19911 in an effort to determine how pharmacies handled sterile product preparations. The results showed a real diversity in practices and many were clearly inadequate. This survey lead to the first published Technical Assistance Bulletin for Pharmacy-Prepared Sterile Products. Over the years more publications have been released including ASHP’s Guidelines on Quality Assurance for Pharmacy Prepared Sterile Products and the USP’s Chapter 1206, Sterile Drug Products for Home Use. Yet despite these efforts, the number of patients hospitalized or killed by inappropriately prepared and often contaminated sterile preparations compounded has increased.

Now all compounding pharmacies in all fifty (50) states will feel a direct and immediate impact as they prepare to comply with USP 797 as USP 797 refers specifically to “…health care institutions, pharmacies, physician’s practice facilities and other facilities in which compounded sterile preparations are prepared, stored and dispensed.” The scope of the regulations has been broadened from home care pharmacies to anyone in any practice setting, regardless of discipline, who compounds sterile preparations. This includes, not only injectable medications, but also biologics, diagnostics, nutrients, radiopharmaceuticals, inhalations, irrigations and ophthalmic and otic preparations. (back to top)

COMPLIANCE DATES ESTABLISHED: In broad terms, critical compliance dates for all Compounding Pharmacies are as follows:

July, 2004 – Should have begun the process of compliance evaluation and formulated an initial action plan.
January, 2005 – Should have conducted a risk assessment of the facility’s compliance to all provisions of this regulation.
July, 2005 – Should have a renovation plan developed.
January, 2006 – Should certify all laminar air flow workbenches (LAFW), isolators and buffer rooms every six (6) months.

Specific areas to consider for each phase of the process have also been suggested as indicated in Table 1²

Table 1
Date	Compliance Area	Details to Consider
January, 2005	Reports/Documents	Adverse event reporting. Complaint procedures. Periodic review of quality control documents.
	Storage conditions and beyond – use dating	Specific labeling requirements. Specific beyond-use dating policies, procedures and requirements
	Quality assurance practices	Visual confirmation of personnel processes regarding gowning, etc.
	CSP work environment	Interim safety measures required.
	Verification procedures – personnel training and education	Initially and annually thereafter: Didactic review Written testing Media-fill testing
	Verification procedures – environmental monitoring	Certification of laminar air flow workbench and barrier isolators every six (6) months. Certification of the buffer room/zone and anteroom/zone every six (6) months.
July, 2005	Quality assurance program	Formalized in writing which describes specific monitoring and evaluation activities.
	Maintaining product quality and control once the CSP leaves the pharmacy	Packaging, handling and transport. Policies and procedures including the packaging, handling and transport of chemotixic/hazardous CSPs. Use and storage. Policies and procedures Education/Training. Policies and procedures dealing with proper education of patients and staff ensuring all of the above. Administration. Policies and procedures dealing with such issues as hand washing, aseptic techniques, site care, etc.
	Finished product – release checks and tests	Policies and procedures that address the following: Physical inspections Compounding accuracy checks Sterility testing Pyrogen testing Potency testing
	Equipment	Policies and procedures that address calibration, routine maintenance, personnel training
	Components	Policies and procedures that address sterile components
	Processing: Aseptic technique	Policies and procedures that address specific training and performance evaluation
	Environmental control	Policies and procedures that address the following: Cleaning and sanitizing the workspace Personnel and gowning Standard operating procedures
January, 2006	Quality assurance program	Reporting and evaluating results Identification of follow-up activities when thresholds are exceeded Delineation of individual responsibilities for each aspect of the program
	Quality assurance practices	Quality testing of direct compounding environment
	Verification procedures – environmental monitoring	Bacterial monitoring using an appropriate manner

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A CONTROLLED ENVIRONMENT IS REQUIRED FOR COMPOUNDING OF CSPs: Achieving and maintaining sterility and overall freedom from contamination of a pharmaceutical product is dependent upon the quality status of the components incorporated, the process utilized, personnel performance and the environmental conditions under which the process is performed.

USP 797 states that a Laminar Airflow Workbench (LAFW) and/or a biological safety cabinet certified to ISO Class 5 for airborne particles is required. This equipment must be placed within an ISO Class 8 or better controlled environment which must include an attached anteroom of the same air quality level. The anteroom allows for movement of personnel and materials in and out of the controlled environment.

An approved alternative is the use of a barrier isolator, certified to ISO Class 5. A barrier isolator, in essence, takes the place of the controlled environment by providing controlled environment conditions within a contained workspace of a smaller footprint. Although this device may be used outside an ISO Class 8 environment, it is recommended that it also be located in the ISO Class 8 environment.

Whether the decision is to install a controlled environment or opt for a barrier isolator to be used external to a controlled environment, the primary goal is safety. It is left up to the individual pharmacy directors to make the best decision for the future of their business, their personnel and their patients.

A common means of achieving the required controlled environment is to provide unidirectional airflow through High Efficiency Particulate Air (HEPA) filters. The controlled environment should also have temperature and humidity controls and have a positive room air pressurization to keep ambient airborne contamination from entering the area. Ceilings, walls, floors, fixtures, and furnishings are to be constructed of materials that can be easily cleaned using anti-microbial agents. All surfaces should be smooth to avoid microbial growth.

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RISK LEVELS DEFINED: USP 797 identifies three (3) types of compounding risk levels:

Low
Medium
High

The risk levels are based on the potential for introducing microbial, chemical or physical contamination during compounding operations. These risk levels are then used to help determine the required compounding conditions, storage conditions, beyond-use dates and process validations procedures.

It is the responsibility of each compounding pharmacist to make a risk-level determination, using professional judgement and experience, according to each specific compounding situation and conditions at the time, to both prepare and dispense a compounded sterile preparation. The decision must be based on maintaining the highest possible standards of sterility and stability as indicated in the Table 2 below3.

Table 2
RISK LEVEL	DESCRIPTION	EXAMPLES
LOW	The CSPs are compounded with aseptic manipulations entirely within ISO Class 5 or better air quality using only sterile ingredients, products, components and devices.	Single transfers of sterile dosage forms from ampuls, bottles, bags and vials using sterile syringes with sterile needles, other administration devices and other sterile containers. The contents of ampuls require sterile filtration to remove any glass particles.
	The compounding involves only transfer, measuring and mixing manipulations with closed or sealed packaging systems that are performed promptly and attentively.	Manually measuring and mixing no more than three (3) manufactured products to compound drug admixtures and nutritional solutions.
	Manipulations are limited to aseptically opening ampuls penetrating sterile stoppers on vials with sterile needles and syringes and transferring sterile liquids in sterile syringes in sterile administration devices and packages of other sterile products.
Medium	Multiple individual or small doses of sterile products are combined or pooled to prepare a CSP that will be administered either to multiple patients or to one patient on multiple occasions.	Compounding of total parenteral nutrition fluids using manual or automated devices during which there are multiple injections, detachments and attachments of nutrient source products to the device or machine to deliver all nutritional components to a final sterile container.
	The compounding process includes complex aseptic manipulations other than the single-volume transfers.	Filling of reservoirs of injection and infusion devices with multiple sterile drug products and evacuation of air from those reservoirs before the filled device is dispensed.
	The compounding process requires unusually long duration, such as that required to complete dissolution or homogenous aging.	Filling of reservoirs of injection and infusion devices with volumes of sterile drug solutions that will be administered over several days at ambient temperatures.
	The sterile CSPs do not contain broad-spectrum bacteriostatic substances and they are administered over several days (e.g., an externally worn or implanted device.	Transfer of volumes from multiple ampuls or vials into a single final sterile container or product.
High	Nonsterile ingredients, including manufactured products for routes of administration.	Dissolving nonsterile bulk drug and nutrient powders to make solutions which will be terminally sterilized.
	Sterile ingredients, components, devices and mixtures are exposed to air quality inferior to ISO Class 5. This includes storage in environments inferior to ISO Class 5 of opened or partially used packages of manufactured sterile products that lack antimicrobial preservatives.	Sterile ingredients, components, devices and mixtures are exposed to air quality inferior to ISO Class 5. This includes storage in environments inferior to ISO Class 5 of opened or partially used packages or manufactured sterile products that lack antimicrobial preservatives.
	Nonsterile preparations are exposed for at least six (6) hours before being sterilized.	Measuring and mixing sterile ingredients in nonsterile devices before sterilization is performed.
	It is assumed, and not verified by examination of labeling and documentation from suppliers or by direct determination, that the chemical purity and content strength of ingredients meet their original or compendial specifications in unopened or in opened packages of bulk ingredients.	Assuming, without appropriate evidence or direct determination, that packages of bulk ingredients contain at least 95% by weight of their active chemical moiety and have not been contaminated or adulterated between uses.

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BEYOND-USE DATING LIMITS ESTABLISHED: Two (2) factors are critical in establishing beyond-use dating: (1) the chemical stability of the chemical entity in solution and (2) the sterility of the CSP which by definition is the absence of viable microorganisms in the CSP.

Depending on the risk level assigned to the process, in the absence of performing a sterility test, the following guidelines have been established for beyond-use dating as illustrated in Table 3.

Table 3
RISK LEVEL	ROOM TEMP	REFRIGERATION	FREEZER (= -20º C)
LOW	48 HOURS	14 DAYS	45 DAYS
MEDIUM	30 HOURS	7 DAYS	45 DAYS
HIGH	24 HOURS	3 DAYS	45 DAYS

If a sterility test is done following the methodology of USP 71, the CSP can be assigned a date beyond-use dating based on the maximum chemical stability of the of the drug in solution as permitted by valid references.

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TESTING, CERTIFICATION AND ENVIRONMENT REQUIREMENTS (Table 4):

Table 4
ENVIRONMENT	ISO CLASSIFICATION	FREQUENCY OF TESTING
Laminar Airflow Workbench	ISO Class 5 Certified for proper operation and located within an ISO Class	Every six (6) months or when moved
Barrier Isolator	ISO Class 5 Positive air pressure May be located outside an ISO Class 8 area	Every six (6) months or when moved
Cleanroom	ISO Class 5 if sterile preparations are performed without a barrier isolator or laminar air flow workbench. ISO Class 8 area and buffer zone where laminar airflow workbench of biological safety cabinet is located and used for sterile preparations. An ISO Class 8 ante room is required if high risk preparations are prepared.	Every six (6) months or when renovated
Biological Safety Cabinet	ISO Class 5 if fused for sterile preparations. Must be certified for proper operation.	Every six (6) months or when moved

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RESPONSIBILITY OF COMPOUNDING PERSONNEL DEFINED: USP 797 states that compounding personnel are responsible for ensuring that CSPs are accurately identified measured, diluted and mixed in addition to being correctly purified, sterilized, packaged, sealed, labeled, stored, dispensed and distributed. Compounding personnel are responsible for maintaining appropriate cleanliness and providing labeling and supplementary instruction for the proper clinical administration of CSPs4.

Qualified licensed health care supervisory personnel must ensure that there is in place5:

High standards for the quality and control of processes, components and environments and for the skill and knowledge of personnel who prepare CSPs.
A written quality assurance procedure for the compounding facility, including such items as accuracy and precision in measuring, labeling accuracy and completeness, beyond-use date assignment, methods of sterilization and purification, safe limits and ranges for strength of ingredients.
Established procedures for record keeping.
Compounding personnel adequately skilled, educated, instructed and trained to correctly perform and document the following activities:
1. Perform antiseptic hand cleansing and disinfection of nonsterile compounding surfaces.
2. Select and appropriately wear protective gloves, goggles, gowns, masks, and hair and shoe covers.
3. Use laminar flow clean-air hoods, barrier isolators and other contamination control devices that are appropriate for the risk level.
4. Identify, weigh and measure ingredients.
5. Manipulate sterile products, aseptically sterilized high-risk level CSP’s, and label and quality inspect CSPs.

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WHAT MUST BE DONE TO BE IN COMPLIANCE:

Determine risk level as summarized in Table 2.
Compare existing facilities, processes and procedures with USP 797 requirements and assess differences; prioritize the results.
Develop a written action plan based on the prioritized list. Refer to Table 1 for USP 797 specific date requirements.
Communicate action plan to pharmacy staff.
Document all measures of quality performance and communicate improvements in USP 797 compliance with staff, administration and accreditation organization.

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WHAT LIBERTY INDUSTRIES CAN DO TO HELP: Over fifty years of experience has put LIBERTY on the leading edge of today's cleanroom technology. If your requirements are a little out of the ordinary, don't settle for someone else's "pre-engineered" system that you have to adapt to. LIBERTY adapts the cleanroom to your needs by designing a custom cleanroom specifically to meet your requirements. Simply provide us with the size and specifications required for your project and we will fast track a custom engineered unit to fit your specs. All rooms, whether hard wall or soft wall, are built in accordance with the new cleanroom standard - ISO 14644-1 (superceding Federal Standard 209E).

Liberty offers a variety of solutions to enable compliance with the regulations no matter what the risk level.

(MISSING THIS PIC - USP7976.JPG) The diagram on the left features a Class 5 cleanroom with an integrated class 8 anteroom which provides a clean area for donning gloves, gowns, etc. with a total footprint of 6' x 8'.

Unit is supplied with lights, strip curtains and fan filter units.

Liberty's barrier isolator, pictured at the right, isolates areas from various contamination sources including the volume of air surrounding the equipment and the space from ceiling to floor. A barrier isolator encompasses a much smaller area around the process allowing a small volume and proper airflow and totally removes workers’ contamination from the process.

Both systems have their benefits and drawbacks, but it is up to the individual pharmacy directors to make the best decision for their business, their personnel and their patients.

Call us today for a free evaluation of your pharmacy facilities and let LIBERTY help you in your USP 797 compliance process. (back to top)