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. 2013 Apr 3;48(4):282–294. doi: 10.1310/hpj4804-282

Guidelines for the Safe Preparation of Sterile Compounds: Results of the ISMP Sterile Preparation Compounding Safety Summit of October 2011

Darryl S Rich *, Matthew P Fricker Jr , Michael R Cohen , Stuart R Levine §
PMCID: PMC3839457  PMID: 24421477

Abstract

Significant patient safety incidents related to sterile drug compounding have occurred for many years. Previous guidelines have focused on ensuring sterility, but serious compounding errors have occurred as well. National efforts are needed to identify and reduce the potential for such errors and their causative factors. In response, the Institute for Safe Medication Practices (ISMP) convened in October 2011 a summit of 60 invited experts in the field for the purpose of establishing by consensus guidelines, safe practices, and standard operating procedures needed to ensure the safe preparation of compounded sterile preparations, especially intravenous admixtures. The resulting guidelines were categorized into 14 core processes: policies and procedures, order entry and verification, drug storage, assembling products and supplies, compounding, drug conservation during drug shortages, preparation of source/bulk containers, technology/automation used, IV workflow software, automated IV compounding devices, quality control/final verification, product labeling, record keeping, and staff management. They were also classified into 3 levels: mandatory, standard, and recommendation. The guidelines presented in this article were felt to be applicable to any health care organization that prepares sterile compounded products. The consensus of the group was that adherence to these guidelines will improve the safety of sterile product compounding and reduce harmful errors in patients receiving these products. Incorporation of these guidelines into sterile compounding practices of health care organizations is an important component of improving patient safety.

Keywords: compounding, guidelines, organizations, patient safety, pharmacy, quality assurance, sterile products


Significant patient safety incidents related to sterile drug compounding have occurred for many years. In the early 1970s, there was an outbreak of septicemia caused by contaminated intravenous (IV) products that the authors referred to as an “epidemic.”1 In 1984, 11 patients received pharmacy-prepared cardioplegia solutions contaminated with Enterobacter cloacae resulting in 5 deaths.2 There have been at least 12 incidents of contaminated pharmacy-prepared sterile compounds reported nationally between 1990 and 2005 involving over 19,000 patients and resulting in at least 15 deaths.3 The US Food and Drug Administration (FDA) stated that there have been 200 adverse events reported involving 71 compounded products since 1990, some of them with “devastating repercussions.”4

The initial release of the United States Pharmacopoeia (USP) chapter <797>5 in 2004 created standards for sterile compounded preparations that was intended to become the standard of practice, aimed at reducing the risk of infectious contamination of pharmacy-prepared sterile products, and to be enforced by federal and/or state laws and regulations. Yet, a recent survey has shown that only 18 states directly require compliance with this standard,6 only 65.2% of hospitals adhere to USP <797> requirements for clean rooms,7 and less than 17% of hospitals comply with all USP <797> requirements.8 More important, serious infections still occur. In 2011-2012, there were 4 serious incidents of contaminated pharmacy-prepared sterile products resulting in harm to more than 244 patients.3 In a state that directly mandates compliance with USP <797> (Massachusetts),6 more than 17,000 doses of contaminated pharmacy-prepared sterile products were dispensed by a compounding pharmacy, sickening at least 704 people and killing at least 46, as of February 11, 2013.4,9,10 The pharmacy was found to be acting outside of the scope of its license8 and was not complying with USP <797>.4

Infectious contamination is not the only safety issue related to sterile drug compounding. Serious compounding errors have also been reported. In 2009, 30% of surveyed hospitals experienced a patient event involving a compounding error within the prior 5 years.11 A 5-hospital observational study found a mean daily error rate of 9%, meaning that almost 1 in 10 products dispensed were prepared incorrectly.12 Error rates were highest for complex solutions such as parenteral nutrition (37% when manually prepared and 22% when partial automation was utilized). Serious sterile compounding errors involving 15 patients, 8 of which died, have been reported from 2005 to 2011, mostly due to the wrong concentration/strength of the product dispensed (overdose),13-17 wrong product or diluent used in compounding,18,19 or product mislabeling by the pharmacy.20

Even though sterile product compounding is subject to the same general error-prone processes as all other medications, these products are associated with additional risk factors that make them even more error prone. The Institute for Safe Medication Practices (ISMP) has identified those drugs that bear a heightened risk of causing significant patient harm when they are used in error and refers to these as “high-alert” medications.21 Most of these medications are sterile compounded products. Through analysis of the medication error reports it receives, as well as the on-site medication risk assessment it conducts for hospitals, ISMP has identified several additional risks for sterile compounded products.

Lack of standardized concentrations. Despite The Joint Commission requirement for the use of a limited number of standardized concentrations (MM.02.01.01, EP 6),22 a recent national American Society of Health-System Pharmacists (ASHP) survey showed many hospitals (25%) do not use standard concentrations for IV infusions of commonly used high-alert medications in adult, pediatric, or neonatal patient populations.23 Even when standardized concentrations are defined, many hospitals allow prescribers to prescribe nonstandard concentrations of medications that must be compounded. Many hospitals do not effectively use the formulary process to ensure standardization of sterile products.

Lack of use of current technology solutions. In 2010, one hospital was able to implement extensive sterile processing automation reducing the number of sterile medications that needed to be prepared by human hands in the hospital to 4.3% with significant improvements in the accuracy of medication preparation.24 However, the use of automation and technology in sterile compounding is not typical of hospital pharmacies in the United States. A 2011 survey7 showed only 2.5% of US hospitals use a stand-alone robotic device for preparing syringes, 12.5% use an automated syringe filling device (partial automation), and 20.4% use automated total parenteral nutrition (TPN) compounders (also partial automation). The survey also revealed that only 3.6% of hospitals used remote video supervision of IV technician preparation and 11.9% use barcode verification during IV medication preparation, despite evidence showing that use of both these technologies together improved accuracy of preparation of sterile medications by decreasing the likelihood of using the incorrect product or quantity of drug.25 Finally, hospital pharmacies rarely use technology to measure specific gravity or final product weight or use photometric analyzers to evaluate the final compounded product.

Poor environment. Based on ISMP on-site medication system risk assessments, many hospitals have insufficient or inadequate workspace to prepare sterile medications, including inadequate counter preparation space, inadequate space/number of hoods, and inadequate space for the checking process. Lack of adequate space often does not allow adequate segregation to prevent mix-ups. As mentioned previously, less than 66% of hospitals have cleanrooms that are compliant with USP <797>.7

Variability in practices across the country. ISMP on-site risk assessments and medication error reports submitted to the ISMP national medication error reporting program (ISMP-MERP) demonstrate that pharmacies vary tremendously with respect to the provision of information and documentation used (eg, preparation ticket, directions, worksheet) to ensure standardized compounding processes; use of the original order (instead of the label) to prepare compounded solutions; labeling procedures; restrictions on time of day for ordering/production; standardized preparation procedures between technicians and pharmacists; and the checking process before, during, and after preparation. This may be due, in part, to the absence of specific practice guidelines related to product preparation checks, but inadequate training in schools of pharmacy may be responsible as well.26

Finally, ISMP believes that there is a lack of awareness of associated risks by pharmacists, senior leadership, and risk management with relation to sterile compounding. This is evidenced, in part, by the fact that over 70% of hospitals now partially or completely outsource the production of sterile products,7 yet few evaluate the quality of the provider chosen to prepare the products on their behalf, despite the availability of national guidelines related to this.27

Clearly, national efforts are needed to identify and eliminate or reduce errors and their causative factors. Therefore, ISMP held a national invitational Sterile Preparation Compounding Safety Summit, October 25-26, 2011, at the ACE Conference Center in Lafayette Hill, Pennsylvania.

Stakeholders

More than 60 invitees agreed to attend the summit (see Appendix). Those who participated came from a variety of backgrounds, including medication safety officers, experts in IV safety technology, pharmacy technicians, pharmacists, nurses, health care consumers, and representatives of the medical product vendor community. Based on the pre-summit survey, one-third of responding participants represented hospitals with 100 to 299 beds and half were from hospitals with over 500 beds. All participants were volunteers and received no compensation other than travel and meeting expense reimbursement.

The meeting was sponsored and conducted by ISMP, an independent, nonprofit charitable organization that works closely with health care practitioners and institutions, regulatory agencies, consumers, and professional organizations to provide education about medication errors and their prevention. ISMP represents more than 35 years of experience in helping health care practitioners keep patients safe, leading efforts to improve the medication use process. ISMP is a federally certified patient safety organization (PSO).

The meeting was cosponsored by the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) and the ASHP and attended by a representative from the FDA as well as a representative of the United States Pharmacopeia Committee that is overseeing future revisions of USP <797>.

Summit

Attendees were surveyed prior to the summit to gather information about their facilities, the preparations they compounded, standard admixture practices, quality control mechanisms, use of automated processes, and software used related to compounded sterile preparations (CSPs). Participants were asked to review and comment on a compendium of ISMP-recommended best practices sent to all attendees prior to the summit. Those best practices with less than 90% agreement by attendees were included for discussion during the summit. Otherwise they were accepted for inclusion in the guidelines.

Errors identified through the ISMP National Medication Errors Reporting Program and other reporting programs (eg, FDA MedWatch program; and Quantros MEDMARX program) were reviewed. A literature review was also conducted to identify additional published admixture-related errors. Reports highlighted fatal medication errors associated with IV compounding in pharmacies, often involving infants or children.

At the summit, participants were asked a variety of questions regarding best practices when applied to preparation of (1) simple compounded sterile preparations (CSPs; those with 1 or 2 ingredients, such as patient-controlled analgesia infusions, single electrolyte infusions, bolus doses, or maintenance IV infusions with no more than 2 ingredients), (2) complex CSPs (those with more than 2 ingredients, such as parenteral nutrition [PN], cardioplegia solutions, or dialysis solutions), (3) pediatric and neonatal preparations, and (4) chemotherapy.

The summit focused on establishing by consensus guidelines, safe practices, and standard operating procedures (SOPs) needed to ensure the safe preparation of CSPs, especially IV admixtures. The summit comprehensively reviewed current methods used to prepare CSPs, identified manual and automated safeguards that help provide assurance that the proper preparation is dispensed for administration, addressed barriers that could inhibit safe practices, and sought to identify and standardize critical quality control practices needed for preparing and verifying the quality and safety of the final CSP.

The goals for the summit were to:

  1. Review currently employed quality control measures used to ensure the correct preparation of CSPs.

  2. Identify quality control practices that should be standardized for incorporation into the manual process to ensure the correct preparation of CSPs.

  3. Describe current and emerging technologies that assist the preparation of CSPs and how these technologies are utilized.

  4. Identify the minimum safeguards that must be in place to prepare and dispense CSPs.

  5. Recommend best practice guidelines to ensure the safe preparation of CSPs by pharmacies.

Since USP <797> provides a set of standards for ensuring that compounded products are sterile at the time of dispensing, the ISMP summit was focused on another critical aspect of IV solution compounding – IV admixture error prevention. Summit attendees agreed to fully support the quality standards outlined in USP <797>, and no discussion was specifically held to suggest any additions or revisions. Compliance with USP <797> is listed as one specific recommendation in the guidelines.

Guidelines

The summit resulted in a set of guidelines and safe practices that were agreed upon by consensus to ensure the safe preparation of CSPs (Table 1).

Table 1.

Institute for Safe Medication Practices (ISMP) guidelines for the safe preparation of sterile compounded preparations

Category Level 3 Mandatea Level 2 Standardb Level 1 Recommendationc
Policies and procedures for compounding sterile preparations (CSPs) Organizations have well-defined policies and procedures that guide the compounding of sterile preparations.
Organizations identify standardized workflow processes that include quality control, process change control,d and documentation practices. It is recognized that workflow may vary depending on the type and quantity of CSPs prepared and the sophistication of technology employed in each organization.
Organizational practices comply with USP <797> standards
Organizations develop detailed policies for batche production of CSPs.
 • Batch processing policies for simple, complex, pediatric, and chemotherapeutic CSPs include detailed preparation instructions and references when available.
 • Batch processing formulas are provided for all batch sizes (eg, production of a 50 mL batch vs a 250 mL batch), document theoretical yield vs actual yield, and account for all waste.
Organizations develop a drug conservation policy that addresses the handling and disposition of drugs (while maintaining their integrity and sterility) that may be in short supply due to market conditions, as these shortages can affect workflow conditions.

Order entry and verification All orders entered into a computerized prescriber order entry (CPOE) system are verified by a pharmacist. All orders entered into a pharmacy information system or transcribed onto pharmacy patient profiles by a non-pharmacist are verified by a pharmacist in accordance with state rules and regulations. For orders requiring pharmacy transcription for specific types of CSPs and/or selected individual products as identified by the organization (eg, chemotherapy, parenteral nutrition [PN], other selected high-alert medications), the information entered into the pharmacy system or transcribed onto pharmacy patient profiles is verified by a second qualified individual,f even when the order was entered by a pharmacist.
This review includes a comparison of the order to the pharmacy-generated label. Such a transcription review should be performed for chemotherapy, complex CSPs, pediatric/neonatal CSPs, and other CSPs as defined by the organization.
For PN, the sequence of ingredients on any pre-printed order sets or order entry screens is consistent with that of the automated IV compounder screens, the patient-specific label, and the medication administration record.

Drug storage Concentrated electrolytes are isolated from other inventory.
CSPs that have been compounded and are waiting to be checked are placed in a clearly identified and designated storage location until the checking process has been completed.
Drug inventory is minimized to avoid intermingling of products.
Sufficient space for drug storage is provided to segregate each drug concentration.
Labeling of bins or bin dividers includes generic drug name and concentration.
FDA and/or ISMP tall man lettering is employed for look-alike drug names and is incorporated into CPOE, pharmacy information systems, and product labels.
Environmental recommendations, as provided in the USP <1066>, for lighting, noise, workspace, and distractions are followed.

Assembling products and supplies for preparation Drugs, diluents, base solutions, and other supplies are gathered and placed in a separate container, (eg, a basket or bin) for each preparation or each batch to be prepared. When possible, the person gathering products should be different than the person preparing the CSPs.

Compounding Formulas (ingredients and the process to prepare) are established and standardized by the organization and are used to guide the compounding of complex CSPs (eg, dialysis solutions, cardioplegia solutions, dilutions, aliquots).
Pharmacy staff members compounding CSPs follow the sequence of steps and processes specified in the formulas and SOPs.
Only one staff member is permitted to work in the direct compounding areag when compounding chemotherapy and complex CSPs.
Two staff members are permitted to work in the compounding area simultaneously, if necessary, provided that the hood is 6 ft in length, a physical divide can be maintained between staff members, and the products being compounded are non-chemotherapy CSPs.
In facilities that care for adult, pediatric and neonatal patients, the computerized label runs for pediatric and neonatal CSPs are generated or printed separately from adult CSPs.
In facilities that care for adult, pediatric and neonatal patients, the preparation of CSPs for each population is separated by time or location. Separation strategies can include the use of different color bins for assembling products to be prepared.
Preparation of chemotherapy and complex CSPs is only performed based on the availability of qualified staff resources
Pharmacies create standard processes to address the volume of base solution when compounding CSPs. Such standard work practices address:
 • if and when there is a need to remove base solution in amounts equivalent to drug additive(s)
 • if and when there is a need to eliminate the manufacturer overfill from the base solution and the method used to accomplish removal (eg, direct removal of overfill volume or pumping the amount of base solution from a commercial container into an empty bag).
Standard operating procedures (SOPs) and formulas are supported by current literature and periodically revised as new information becomes available.
When available, commercially prepared, premixed IV products that meet the patient’s needs are used over manually compounded sterile products.
Prescribers comply with predetermined cutoff times that have been established by the organization to permit safe preparation of CSPs.
Additives are not incorporated into a commercially prepared, premixed preparation other than those designed for the addition of additives, eg, multichambered bags for parenteral nutrition.
Outsourcing the production of CSPs is considered as an alternative to in-house compounding when:
 • the volume of certain CSPs is very low, thus making it difficult to maintain staff competency for preparing the product
 • the volume for certain CSPs is high and staff resources are limited or unavailable to prepare this quantity
 • the organization does not possess the technological resources to prepare certain products according to USP <797>
 • the commercially prepared, premixed product is not available, including product shortages
Organizations use a tool, such as the ASHP Foundation’s document, “Outsourcing Sterile Products Preparation: Contractor Assessment Tool” (http://www.ashpfoundation.org/sterileproductstool), as one resource to analyze the capabilities and quality of external compounding providers prior to selecting a vendor.
A preparation label, master formulation record, or worksheet is available for compounding chemotherapy, complex, and pediatric/neonatal CSPs. This document should express drug name, base solution, patient-specific dose, preparation calculations, and final volume of the preparation and identify the appropriate drug dosage form to be used (eg, concentration and size of the container).
Only one CSP is prepared at a time. An exception is:
 One practitioner can prepare multiple CSPs safely in the hood at one time only if preparing the same doses of the same drug with the same route of administration for one or multiple patients. It is not safe to prepare multiple CSPs at the same time in the hood for different doses or routes of administration or multiple products for the same patient.

Drug conservation Heparin and insulin vials are never in the hood at the same time.
Single-dose containers of drugs in short supply that are covered by an organization-specific, drug conservation policy may be left in the hood for use up to 6 hours after initial needle puncture in accordance with USP <797> guidelines.
Partially used multidose vials, bulk containers, or single-dose containers are not left in the hood or direct compounding area for future use.
The organization-specific drug conservation policy includes safe practices that address:
 • Maintaining the integrity and sterility of these medications.
 • Methods used to segregate the drug from the direct compounding area.
 • A pharmacist performs a regular assessment of drug products stored in the hood for compliance with this policy.

Preparation of source/bulk containersh A detailed standard process is in place for preparing and checking pharmacy-compounded source/bulk containerh used to prepare multiple doses or batches.
A pharmacist conducts an independent double-checki (IDC) of all diluents and drugs before the preparation of all source/bulk containers.
Source/bulk containers prepared for use during compounding are labeled with the following information:
 • drug name
 • concentration
 • diluent
 • date of preparation
 • name of preparer
 • name of person performing the IDC
 • beyond-use date
See record-keeping section for documentation requirements.

Technology/automation used for compounding CSPs Routine preventive maintenance is performed and calibration and certification are current and documented for equipment used during the compounding of CSPs. Organizations develop a strategic plan for implementation of automation and technology for the sterile products service.
Technology and automation such as barcode verification or IV robotics are utilized as much as possible for preparing and verifying CSPs.
All current service releases for software in use are installed and tested.

IV workflow softwarej IV workflow softwarej is well-maintained and appropriately programmed with adequate infrastructure to support the system.
Organizations have SOPs that ensure that the final check of the preparation has been completed by a pharmacist possessing training and experience with this technology, prior to dispensing.
IV workflow software (eg, DoseEdge, Script Pro Telepharmacy, and I.V. Soft or similar technology) is used to augment manual processes whenever possible.

Automated IV compounding devicesk Staff members are trained in the use of automated IV compounding technology, and there is documentation of initial training, as well as ongoing competency assessment. Privileges to make changes in the database of automated IV compounding devices are restricted to staff members who are well-trained in both the theory and the mechanics of this process.
The use of a checklist/sign-off sheet is required when adding new products, new concentrations, new generics, and changes in vial size or when making other modifications to the database (eg, changes in privileges, changes in data requirements).
Two staff members possessing training and experience with this technology, one of whom is a pharmacist, are required to sign off or validate changes. (This process would not apply to inputting a new lot number for a product already in the database.)
Organizations implement specific soft limitsl and hard (catastrophic) limitsm for ingredients that are consistent with the needs of their patient population.
Only pharmacists are allowed to override alerts.
Barcode verification is used to verify product identity during set up and replacement of ingredients.
A double-check process for the initial daily set up is performed with 2 staff members using a printed checklist.
Tubing set(s) is traced from the source container to the port where it is attached during the initial daily set up and with each change in the source container.
If multiple containers of a single additive are used during the preparation of a single CSP, all empty containers are presented to the pharmacist as part of the final check process prior to dispensing the final CSP.
The use of a checklist/sign-off sheet is required and 2 staff members, (including at least one pharmacist) sign off or validate the template.
The label generated by the IV compounding device ideally is the only label attached to the completed CSP. Ensure this label reflects the sequence of ingredients and units of measure as presented on the prescriber’s original order.
Verbal affirmation with 2 staff members takes place to validate placement of all additives and base solutions including name, concentration, and container size.
Weight-based warning limits for doses should be developed by vendors. As an alternative, hospitals may develop and use their own weight-based warning limits.
Customized order entry templatesn created by organizations have a documented standard review process by qualified staff which includes review and testing of the clinical decision support that is expected to alert the pharmacist to significant warnings.
When an automated IV compounder is used, it delivers all ingredients.
Manual compounding is only used:
 • if the volume of an ingredient to be mixed is less than the compounder can accurately deliver.
 • if there is an interaction between an ingredient and a component of the compounder (eg, insulin and tubing).
 • if there is a chemical interaction between ingredients that cannot be mitigated by sequencing the addition of ingredients.

Quality control/final verification of manually prepared product All personnel are able to “stop the line” and question any concerns about any order or any sterile preparation to be compounded.
A visual check by a qualified individual is performed to verify the accuracy of all diluents and drugs (including volumes and concentrations).
Organizations that do not use IV workflow software identify in their compounding policies those CSPs that require preproduction visual confirmation of the amount of each ingredient (prior to addition to the final container). At a minimum, the list should include the following:
 • chemotherapy
 • PN admixtures
 • pediatric/neonatal preparations
 • pharmacy prepared source/bulk containers
 • preparations requiring the use of multidose vials of high-alert medications (eg, insulin, concentrated electrolytes, heparin)
 • CSPs administered via high-risk routes of administration (eg, intrathecal, epidural, and intraocular)
Proxy methods of verification such as the syringe pull-back methodo of verification are never used in the preparation of chemotherapeutic, complex, pediatric/neonatal, or high-alert CSPs and shall not be used without the presence of the actual, original source containers (medication and diluent).
Handwriting the amount of an additive on the final product label is not used as the sole method of verification of any CSP.
Errors that occur during the compounding of CSPs and are identified by either the pharmacist or technician prior to dispensing are documented and reported through the organization’s reporting system for analysis.
Serious incidents are reported to the ISMP Medication Error Reporting Program (ISMP forwards reports to FDA MedWatch) for learning purposes and dissemination of prevention measures.
Proactive risk assessments, such as failure modes and effects analysis (FMEA), are used prior to the implementation of process changes.
Internal as well as external information about medication errors, from sources such as ISMP, are reviewed and used to modify practices and procedures as needed.

Product labeling Labels are applied immediately after manual preparation of CSPs. (When certain technology is employed, it may be necessary to apply the final product label prior to compounding the preparation.)
For chemotherapy and other CSPs identified by the organization, the final volume (eg, bag volume + manufacturer’s overfill + additive volume) to be infused is present on the label.
ISMP label guidelines are utilized when formatting computer generated labels for CSPs. These are available at http://www.ismp.org/Tools/guidelines/labelFormats/Piggyback.asp.
Labels generated by an automated IV compounding device match the format and units of measure of the prescriber’s order, include the beyond-use date, and are ideally the only label attached to the completed CSP.
Preparation labels (or “prep tickets”) are never be used as the final product label.
Information on the final label matches the format and units of measure of the prescriber’s order and the medication administration record. The product label does not contain unnecessary information (eg, vial size used to prepare the CSP).

Record keeping When preparing CSPs intended for storage for anticipated needs, batch records includes:
 • Date of production
 • Individual components, including lot numbers and expiration dates
 • Expected and actual yield of the batch
 • Example of label
 • Calculations
 • Beyond-use date
 • Person preparing batch
 • Person checking batch
Label count

Staff management All staff members involved in preparing CSPs or supervising the preparation of CSPs participate in a comprehensive orientation and training program as well as an ongoing competency assessment program Pharmacy technicians involved in preparation of CSPs are Certified Pharmacy Technicians having passed the appropriate tests administered by the Pharmacy Technician Certification Board.
A national certification program for sterile-compounding specialists should be developed.
Pharmacists and pharmacy technicians who prepare CSPs have annual competency evaluation for all aspects of sterile compounding which might include:
 • performing calculations and preparing dilutions,
 • compounding base solutions,
 • using aliquots as a method of measuring ingredients below the sensitivity of a scale (by proportional dilution with inactive ingredients),
 • aseptic technique including media-fill testing,
 • preparation of medications for complex routes of administration (eg, intrathecal),
 • proper use of technology (if available).
The American Association of Colleges of Pharmacy should instruct their Academic Affairs Committee to add hands-on experience with sterile compounding into pharmacy training to achieve minimum competencies, which are developed by an interdisciplinary stakeholder group.

Note: FDA = US Food and Drug Administration; ISMP = Institute for Safe Medication Practices.

a

Level 3 (Mandate) = requirement established by law, regulation, accrediting bodies, or other binding authorities.

b

Level 2 (Standard) = minimum standard of practice set forth in this document.

c

Level 1 (Recommendation) = best practice that is strongly encouraged but that may not be applicable to all institutions or in all circumstances.

d

Process change control = formal process used to ensure that changes to a product or system are introduced in a controlled and coordinated manner.

e

Batch = preparing a number of non-patient-specific doses with the intention to use based on future patient need.

f

Qualified individual/staff = staff members adequately trained and approved to perform a particular function.

g

Direct compounding area = area within the hood where the critical site (vial septum and needle) are exposed to first-air.

h

Source/bulk container = sterile container (bottle, vial, or bag) manufactured by a commercial vendor or prepared by pharmacy, which is then used as a source from which to withdraw multiple doses.

i

Independent double-check = procedure in which 2 individuals, preferably 2 licensed practitioners, separately check each component of the work process. An example would be one person calculates a medication dose for a specific patient and a second individual independently performs the same calculation (not just verifying the calculation) and then matches their results.

j

IV workflow software = software that manages pharmacy workflow required for selecting, compounding, inspecting, tracking, and reporting for IV doses.

k

Automated IV compounding devices= equipment used by pharmacists for the extemporaneous preparation of parenteral nutrition admixtures and other types of intravenous admixtures.

l

Soft limits = alerts that are displayed but can be overridden by the operator who may then proceed with the selection.

m

Hard limits = alerts that indicate that something is outside a determined safe range. Hard limits will not allow the operator to proceed with the selection.

n

Customized order entry templates = templates created in automated IV compounders and are not part of the manufacturer's original library but rather are created by the individual institution.

o

Syringe pull-back method = presentation of the syringe(s) pulled back to display amount of medication or diluent that was added to the infusion container AND the actual drug or diluent source container(s) from which the drug or diluent was withdrawn prior to the addition to the infusion container.

The guidelines were categorized into the following core processes: policies and procedures for compounding sterile preparations, order entry and verification, drug storage, assembling products and supplies for preparation, compounding, drug conservation, preparation of source/bulk containers, technology/automation used for compounding CSPs, IV workflow software, automated IV compounding devices, quality control/final verification of manually prepared product, product labeling, record keeping, and staff management.

Most of the guidelines fit with a particular core process, but some span several core processes.

The guidelines were further categorized into 3 levels:

  • Level 3 (mandatory) was used to indicate a requirement established by law, regulation, accrediting bodies, or other binding authorities. It is realized that legal and regulatory requirements vary from state to state. Thus, only requirements that are required in the vast majority of states are included in this level. Also, certain guidelines can help meet accreditation requirements but are not required. For example, The Joint Commission requires that staff competence be assessed periodically but does not specifically require competence assessment in sterile medication preparation, hence this is not included in this level.

  • Level 2 (standard) was used to indicate what should be considered a minimum standard of practice. These are the key processes that the group felt that all organizations must do in order to ensure the safe preparation of compounded sterile preparations.

  • Level 1 (recommendation) was used to indicate a best practice that is strongly encouraged, but that may not be applicable to all institutions or in all circumstances.

The majority of the guidelines fall into 3 of the 14 categories: compounding (21%), automated IV compounding devices (20%), and quality control/final verification of manually prepared product (11%). These 3 categories also represent the highest percentage of level 3 (mandatory) and level 2 (standard) recommendations in the guidelines (57%), stressing the importance of these aspects of the sterile medication preparation process.

Complex CSPs, pediatric/neonatal preparations, and cancer chemotherapy are recognized as requiring added measures, as 11 guidelines specifically address these types of preparations (Table 2). These specific recommendations address the following areas:

  1. Batch processing policies with detailed instructions and references

  2. Order transcription review by a second qualified individual

  3. Preprinted order sequence for PN orders consistent with automated compounder screens

  4. Use of standardized formulas for ingredients and preparation process

  5. Availability and use of a preparation label/master formulation record/worksheet

  6. Allowing only one person in the direct compounding area

  7. Preparation based on availability of qualified staff

  8. Preparation of separate label runs

  9. Preproduction visual checks of the amount of each ingredient prior to addition to the final container

  10. Not using proxy methods of verification such as the syringe-pull back method

  11. Final volume inclusion on label

Table 2.

Guidelines specific to complex compounded sterile preparations (CSPs), pediatric/neonatal CSPs, and cancer chemotherapy CSPs

Category Guidelines
Policies and procedures for compounding sterile preparations Batch processing policies for simple, complex, pediatric, and chemotherapeutic CSPs include detailed preparation instructions and references when available (level 2).

Order entry and verification For orders requiring pharmacy transcription for specific types of CSPs and/or selected individual products as identified by the organization (eg, chemotherapy, parenteral nutrition [PN] or other selected high-alert medications), the information entered into the pharmacy system or transcribed onto pharmacy patient profiles is verified by a second qualified individual, even when the order was initially entered by a pharmacist (level 2).
This review includes a comparison of the order to the pharmacy-generated label. Such a transcription review should be performed for chemotherapy, complex CSPs, pediatric/neonatal CSPs, and other CSPs as defined by the organization (level 2).
For PN, the sequence of ingredients on any pre-printed order sets or order entry screens is consistent with that of the automated IV compounder screens, the patient-specific label, and the medication administration record (level 1).

Compounding Formulas (ingredients and the process to prepare) are established and standardized by the organization and are used to guide the compounding of complex CSPs (eg, dialysis solutions, cardioplegia solutions, dilutions, aliquots) (level 2).
Pharmacy staff members compounding CSPs follow the sequence of steps and processes specified in the formulas and SOPs (level 2).
SOPs and formulas are supported by current literature and periodically revised as new information becomes available (level 1).
A preparation label, master formulation record, or worksheet is available for compounding chemotherapy, complex, and pediatric/neonatal CSPs. This document should express drug name, base solution, patient-specific dose, preparation calculations, and final volume of the preparation and identify the appropriate drug dosage form to be used (eg, concentration and size of the container) (level 1).
Only one staff member is permitted to work in the DIRECT COMPOUNDING AREA when compounding chemotherapy and complex CSPs (level 2).
In facilities that care for adult, pediatric, and neonatal patients, the computerized label runs for pediatric and neonatal CSPs are generated or printed separately from adult CSPs (level 2).
Preparation of chemotherapy and complex CSPs is only performed based on the availability of qualified staff resources (level 2).

Quality control/final verification of manually prepared product Organizations that do not use IV workflow software identify in their compounding policies those CSPs that require preproduction visual confirmation of the amount of each ingredient (prior to addition to the final container) (level 2).
At a minimum, this list should include the following:
 • chemotherapy
 • PN admixtures
 • pediatric and neonatal preparations
 • pharmacy prepared source/bulk containers
 • preparations requiring the use of multidose vials of high-alert medications (eg, insulin, concentrated electrolytes, heparin)
 • CSPs administered via high-risk routes of administration (eg, intrathecal, epidural, and intraocular)
Proxy methods of verification such as the SYRINGE PULL-BACK METHOD of verification are never used in the preparation of chemotherapeutic, complex, pediatric/neonatal, or high-alert CSPs and shall not be used without the presence of the actual, original source containers (medication and diluent) (level 2).

Product labeling For chemotherapy and other CSPs identified by the organization, the final volume (eg, bag volume + manufacturer’s overfill + additive volume) to be infused is present on the label (level 2).

The impact of drug shortages was also addressed. Four guidelines specifically address the need for a drug conservation policy, the contents of that policy, what products should not be in the hood at the same time (heparin and insulin), and which products cannot be stored in the hood for future use (with exceptions). Finally, outsourcing is addressed in 2 guidelines: when it should be considered, and use of a tool to analyze the capabilities and qualities of vendors.

The guidelines are felt to be applicable to any health care organization or pharmacy that prepares sterile compounded products, including but not limited to hospitals, compounding pharmacies, home infusion organizations, long-term care pharmacies, and outpatient infusion centers as well as physician offices and ambulatory surgical centers that perform sterile compounding.

While the vast majority of the guidelines were directed to the compounding provider (eg, the pharmacy), 2 guidelines are directed to other settings: one toward the American Association of Colleges of Pharmacy in terms of what is needed in the training and experience of pharmacy students, and another to the development of a national certification program for sterile-compounding specialists. Both are located in the staff management category of the guidelines.

The consensus of the group was that adherence to these guidelines will improve the safety of sterile product compounding and reduce harmful errors in patients receiving these products. Pharmacists, pharmacy technicians, nurses, senior leadership, risk managers, and other health care providers need to understand the risks associated with sterile compounding and the resulting need for incorporation of these guidelines into their sterile compounding practices as an important component of improving patient safety within their organizations.

Acknowledgments

The ISMP summit was supported by unrestricted grants from Ameridose, Baxa, Baxter, B. Braun Medical, and Hospira.

The authors wish to acknowledge the help and support of the summit participants in the development and review of the guidelines.

APPENDIX.

List of Summit Participants

Nathan Ash, PharmD, CACP (St. Rita's Medical Center /Catholic Health Partners, Lima, OH); Mary Baker, PharmD, MBA (Hospira, Inc., Lake Forest, IL); Bona Benjamin, BS Pharm (American Society of Health-System Pharmacists, Bethesda, MD); Joe Boullata, PharmD, RPh, BCNSP (University of Pennsylvania, Philadelphia, PA); Deborah Bruggman, PharmD (Kaiser Foundation Hospital, Los Angeles, CA); LTC Jorge Carrillo, PharmD, MS, BCPS (US Army Medical Command, Fort Sam Houston, TX); Stacy Carson, PharmD, BCPS (Institute for Safe Medication Practices, Horsham, PA); Wayne Chun (Pharmacy Technician, Kaiser Permanente Medical Center, Walnut Creek, CA); William Churchill, MS, RPh (Brigham and Women's Hospital, Boston, MA); Michael Cohen, RPh, MS, ScD, FASHP (Institute for Safe Medication Practices, Horsham, PA); Janice Dunsavage, RPh, MAS (PinnacleHealth System, Harrisburg, PA); Scarlett Eckert, PharmD (University of California San Francisco Medical Center, San Francisco, CA); Frank Federico, RPh (Institute for Healthcare Improvement, Cambridge, MA); Charles Ferris, RPh (Baxter Clinical Center of Excellence, Deerfield, IL); Janice Figuracion (Pharmacy Technician, University of California San Francisco Medical Center, San Francisco, CA); Ryan Forrey, PharmD, MS (James Cancer Hospital and Solove Research Institute, Ohio State University Medical Center, Columbus, OH); Matthew Fricker, MS, RPh, FASHP (Institute for Safe Medication Practices, Horsham, PA); Catina Greer, CPhT (St. Jude Children's Research Hospital, Memphis, TN); Peggi Guenter, PhD, RN (American Society for Parenteral and Enteral Nutrition, Silver Spring, MD); Patricia Holbrook, BSP, MS (Baltimore VA Medical Center, Baltimore, MD); Michelle Holtorff, PharmD (Adventist Hinsdale Hospital, Hinsdale, IL); Christopher Jerry (The Emily Jerry Foundation, Mentor, OH); Eric Kastango, MBA, RPh, FASHP (Clinical IQ, Florham Park, NJ); Patti Kienle, RPh, MPA, FASHP (Cardinal Health, Scranton, PA); Chris Kutza, PharmD (Advocate Lutheran General Hospital, Park Ridge, IL); Rebecca Lamis, PharmD (Institute for Safe Medication Practices, Horsham, PA); Stuart Levine, PharmD (Institute for Safe Medication Practices, Horsham, PA); Sue Liu, PharmD (Institute for Safe Medication Practices, Horsham, PA); Chris Lomax, PharmD (B. Braun Medical, Bethlehem, PA); Nicole Mollenkopf MacLaughlin, PharmD, BCPS (Johns Hopkins Hospital, Baltimore, MD); Michelle Mandrack, RN, MSN (Institute for Safe Medication Practices, Horsham, PA); Shane Marshall, PharmD (St. Jude Children's Research Hospital, Memphis, TN); Melissa McAuley, PharmD (Institute for Safe Medication Practices, Horsham, PA); Judy McMeekin, PharmD (US Food and Drug Administration, Division of Prescription Drugs, Silver Spring, MD); Christina Michalek, BSc Pharm, RPh, FASHP (Institute for Safe Medication Practices, Horsham, PA); Cindy Mitman, PharmD (Lehigh Valley Health Network Cedar Crest, Allentown, PA); Susan Paparella, RN, MSN (Institute for Safe Medication Practices, Horsham, PA); Sophia Pasedis, PharmD, RPh (Ameridose, Westborough, MA); Bruce Pleskow, BS Pharm (Baxter Clinical Center of Excellence, Deerfield, IL); Amy Poppy, PharmD (The Children's Hospital, Aurora, CO); Dennis Schneider (Baxa, Englewood, CO); Dan Sheridan, MS, RPh (Marion General Hospital OhioHealth, Marion, OH); Lee Steindl, BS, RPh (Cleveland Clinic, Cleveland, OH); Nissa Stevens, CPhT (Johns Hopkins Hospital, Baltimore, MD); Dennis Tribble, PharmD, FASHP (Baxa, Englewood, CO); Allen Vaida, PharmD, FASHP (Institute for Safe Medication Practices, Horsham, PA); Chris Walsh, PharmD, RPh, FISMP (St. Joseph Medical Center, Catholic Health Initiatives, Reading, PA); Mary White, CPhT (Washington DC Veterans Administration Medical Center, Washington, DC); Heather Zimmer, CPhT (Cleveland Clinic, Cleveland, OH)

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