ASHP Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products

Drug Distribution and Control: Preparation and Handling–Guidelines 91

ASHP Guidelines on Quality Assurance

for Pharmacy-Prepared Sterile Products

Patient morbidity and mortality have resulted from incor-

rectly prepared or contaminated pharmacy-prepared

products.

1–7

Pharmacists seldom know that inaccurate

or contaminated products are dispensed when pharmacy

quality monitors are inadequate.

8–10

In contemporary health

care organizations, more patients are receiving compounded

sterile products that are stored for extended periods before

use (allowing the growth of a pathological bioload of micro-

organisms

), more patients are seriously ill, and more patients

are immunocompromised than ever before.

These ASHP guidelines are intended to help pharmacists

and pharmacy technicians prepare sterile products of high

quality.

The pharmacist is responsible for compounding and

dispensing sterile products of correct ingredient identity, purity

(freedom from physical contaminants, such as precipitates,

and

chemical contaminants), strength (including stability

and com-

patibility), and sterility and for dispensing them in appropriate

containers, labeled accurately and appropriately for the end user.

Other professional organizations have published useful

guidelines on compounding and dispensing sterile products.

The United States Pharmacopeia (USP) publishes the offi-

cial compendium The United States Pharmacopeia and The

National Formulary (USP) and its supplements, all of which

may have legal implications for pharmacists.

14,15

The reader

would especially benefit from studying the USP general infor-

mation chapter on sterile drug products for home use,

which

is referred to often in this ASHP guideline. The National

Association of Boards of Pharmacy (NABP) has published

less detailed model regulations for use by state boards of phar-

macy.

16,17

The American Society for Parenteral and Enteral

Nutrition (A.S.P.E.N.) recently published a special report on

safe practices for parenteral nutrition formulations.

Other governmental and accreditation sources are

more general. The Joint Commission on Accreditation of

Healthcare Organizations (JCAHO) publishes at least four

sets of standards that mention pharmacy compounding. The

hospital accreditation standards simply state that the organi-

zation adheres to laws, professional licensure, and practice

standards governing the safe operation of pharmaceutical

services.

The JCAHO home care standards require that

medications be safely prepared, including “using appropri-

ate techniques for preparing sterile and nonsterile medications

and products.” For example, the home care standards state

that “appropriate quality-control techniques are used to check

for preparation accuracy and absence of microbial contamina-

tion. Techniques for preparing sterile products follow guide-

lines established by the American Society of Health-System

Pharmacists.”

The JCAHO standards for long-term-care

pharmacies list important conditions for product preparation,

such as separate areas for sterile product preparation, use of a

laminar-airflow workbench or class 100 cleanroom, and quality

control systems to ensure the accuracy and sterility of final

products.

The JCAHO standard for ambulatory care infusion

centers states, among other things, several facility-related stan-

dards, for example the use of biological safety cabinets to pro-

tect personnel preparing cytotoxic or hazardous medications;

work surfaces free of equipment, supplies, records, and labels

unrelated to the medication being prepared; and a separate area

for preparing sterile products that is constructed to minimize

opportunities for particulate and microbial contamination.

The Food and Drug Administration (FDA) publishes

regulations on current good manufacturing practices that

apply to sterile products made by pharmaceutical manufac-

turers for shipment in interstate commerce. Pursuant to the

FDA Modernization Act of 1997 (FDAMA), Section 503A

of the Food, Drug, and Cosmetic Act states that pharmacy

compounding must comply with an applicable USP mono-

graph, if one exists, and the USP chapter on pharmacy com-

pounding

or be a component of an FDA-approved drug

product; or, if neither of these apply to the ingredient being

compounded, the substance must appear on a list of bulk

drug substances developed by FDA and must be accompa-

nied by a valid certificate of analysis and be manufactured

in an FDA-registered establishment.

Inactive ingredients

compounded by licensed pharmacies must comply with

applicable USP monographs, if they exist, and the USP

chapter on pharmacy compounding.

FDAMA prohibits

pharmacists from compounding drug products that appear

on a list of products that have been withdrawn or removed

from the market because they have been found unsafe or

ineffective. FDAMA also says that pharmacists may not

compound, regularly or in inordinate amounts, drug prod-

ucts that are essentially copies of commercially available

drug products; nor may they compound drug products iden-

tified by regulation as presenting demonstrable difficulties

for compounding that reasonably demonstrate an adverse

effect on safety or effectiveness.

The Centers for Disease Control and Prevention (CDC)

has published guidelines for hand washing, prevention of intra-

vascular infections, and hospital environmental control.

24,25

The ASHP Guidelines on Quality Assurance for Pharmacy-

Prepared Sterile Products are applicable to pharmaceutical ser-

vices in various practice settings, including, but not limited to,

hospitals, community pharmacies, nursing homes, ambulatory

care infusion centers, and home care organizations. ASHP has

also published practice standards on handling cytotoxic and

hazardous drugs

and on pharmacy-prepared ophthalmic pro-

d ucts.

These ASHP guidelines do not apply to the manufac-

ture of sterile pharmaceuticals as defined in state and federal

laws and regulations, nor do they apply to the preparation of

medications by pharmacists, nurses, or physicians in emer-

gency situations for immediate administration to patients (e.g.,

cardiopulmonary resuscitation). All guidelines may not be ap-

plicable to the preparation of radiopharmaceuticals.

These guidelines are referenced with supporting sci-

entific data when such data exist. In the absence of published

supporting data, guidelines are based on expert opinion or

generally accepted pharmacy procedures. Pharmacists are

urged to use professional judgment in interpreting these

guidelines and applying them in practice. It is recognized

that, in certain emergency situations, a pharmacist may be

requested to compound products under conditions that do

not meet these guidelines. In such situations, it is incumbent

upon the pharmacist to employ professional judgment in

92 Drug Distribution and Control: Preparation and Handling–Guidelines

weighing the potential patient risks and benefits associated

with the compounding procedure in question.

Objectives. The objectives of these guidelines are to provide

1. Information on quality assurance and quality control

activities that should be applied to the preparation of

sterile products in pharmacies and

2. A method to match quality assurance and quality con-

trol activities with the potential risks to patients posed

by various types of products.

Multidisciplinary Input. Pharmacists are urged to participate

in the quality or performance improvement, risk management,

and infection control programs of their health care organiza-

tions, including developing optimal sterile product procedures.

Definitions. Definitions of selected terms, as used in this

document, are provided in Appendix A. For brevity in this

document, the term quality assurance will be used to refer

to both quality assurance and quality control (as defined in

Appendix A), as befits the circumstances.

Risk-Level Classification

In this document, sterile products are grouped into three

levels of risk to the patient, increasing from least (level

1) to greatest (level 3) potential risk based on the danger

of exposing multiple patients to inaccurate ingredients or

pathogens and based on microbial growth factors influenced

by product storage time, temperature and product ability

to support microbial growth, surface and time exposure of

critical sites, and microbial bioload in the environment. When

circumstances make risk-level assignment unclear, guidelines

for the higher risk level should prevail. Consideration should

be given to factors that increase potential risk to the patient

such as high-risk administration sites and immunocom-

promised status of the patient. A comparison of risk-level

attributes appears in Appendix B.

Risk Level 1. Risk level 1 applies to compounded sterile

products that exhibit characteristics 1, 2, and 3, stated below.

All risk level 1 products should be prepared with sterile

equipment (e.g., syringes and vials), sterile ingredients and

solutions, and sterile contact surfaces for the final product.

Risk level 1 includes the following:

1. Products

a. Stored at room temperature (see Appendix A for

temperature definitions) and completely admin-

istered within 28 hours after preparation or

b. Stored under refrigeration for 7 days or less be-

fore complete administration to a patient over a

period not to exceed 24 hours (Table 1) or

c. Frozen for 30 days or less before complete

administration to a patient over a period not to

exceed 24 hours.

2. Unpreserved sterile products prepared for administra-

tion to one patient or batch-prepared products contain-

ing suitable preservatives prepared for administration

to more than one patient.

3. Products prepared by closed-system aseptic transfer

of sterile, nonpyrogenic, finished pharmaceuticals

(e.g., from vials or ampuls)

obtained from licensed

manufacturers into sterile final containers (e.g.,

syringes, minibags, elastomeric containers, portable

infusion-device cassettes) obtained from licensed

manufacturers.

Examples of risk level 1 processes include transferring

a sterile drug product from a vial into a commercially pro-

duced i.v. bag; compounding total parenteral nutrient (TPN)

solutions by combining dextrose injection and amino acids

injection via gravity transfer into a sterile empty container,

with or without the subsequent addition of sterile drug prod-

ucts to the final container with a sterile needle and syringe;

and transferring a sterile, preserved drug product into sterile

syringes with the aid of a mechanical pump and appropriate

sterile transfer tubing device.

Risk Level 2. Risk level 2 sterile products exhibit character-

istic 1, 2, or 3, stated below. All risk level 2 products should

be prepared with sterile equipment, sterile ingredients and

solutions, and sterile contact surfaces for the final product

and with closed-system transfer methods. Risk level 2

includes the following:

1. Products stored beyond 7 days under refrigeration,

stored beyond 30 days frozen, or administered beyond

28 hours after preparation and storage at room tem-

perature (Table 1).

2. Batch-prepared products without preservatives (e.g.,

epidural products) that are intended for use by more

than one patient. (Note: Batch-prepared products with-

out preservatives that will be administered to multiple

patients carry a greater risk to the patients than products

prepared for a single patient because of the potential ef-

fect of inaccurate ingredients or product contamination

on the health and well-being of a larger patient group.)

3. Products compounded by complex or numerous

manipulations of sterile ingredients obtained from

licensed manufacturers in a sterile container or

reservoir obtained from a licensed manufacturer by

using closed-system aseptic transfer; for example, TPN

solutions prepared with an automated compounder.

(Note: So many risks have been associated with

automated compounding of TPN solutions that its

complexity requires risk level 2 procedures.

)

Examples of risk level 2 processes include prepar-

ing portable-pump reservoirs for multiday (i.e., ambient

temperature) administration; subdividing the contents of a

bulk, sterile injectable (without preservatives) into sin-

gle-dose syringes; and compounding TPN solutions with

an automated compounding device involving repeated

attachment of fluid containers to proximal openings of the

compounder tubing set and of empty final containers to the

distal opening, the process concluding with the transfer of

additives into the filled final container from individual drug

product containers or from a pooled additive solution.

Risk Level 3. Risk level 3 products exhibit either character-

istic 1 or 2:

1. Products compounded from nonsterile ingredients or

compounded with nonsterile components, containers,

or equipment before terminal sterilization.

Drug Distribution and Control: Preparation and Handling–Guidelines 93

2. Products prepared by combining multiple ingredients—

sterile or nonsterile—by using an open-system transfer

or open reservoir before terminal sterilization.

Examples of risk level 3 products are calcium levu-

linate injection, estradiol in oil injection, and morphine sul-

fate 50-mg/mL injection.

Quality Assurance for Risk Level 1

RL 1. 1: Policies and Procedures.

Up-to-date policies and

procedures for compounding sterile products should be written

and available to all personnel involved in these activities. When

policies and procedures are changed they should be updated, as

necessary, to reflect current standards of practice and quality.

Additions, revisions, and deletions should be communicated to

all personnel involved in sterile compounding and related ac-

tivities. These policies and procedures should address person-

nel education and training requirements, competency evalu-

ation, product acquisition, storage and handling of products

and supplies, storage and delivery of final products, use and

maintenance of facilities and equipment,

appropriate garb and

conduct for personnel working in the controlled area, process

validation, preparation technique,

labeling, documentation,

and quality control.

Further, written policies and procedures

should address personnel access and movement of materials into

and near the controlled area. Policies and procedures for moni-

toring environmental conditions in the controlled area should

take into consideration the amount of exposure of the product

to the environment during compounding and the environmental

control devices used to create the critical area. Sources of infor-

mation include vendor-supplied inservice programs and multi-

media training programs, such as videotapes and Internet-site

information. Before compounding sterile products, all personnel

involved should read the policies and procedures. Written poli-

cies and procedures are required for all environmental control

devices used to create the critical area for manipulation of sterile

products. Examples of such devices are laminar-airflow work-

stations, biological safety cabinets, class 100 cleanrooms, and

barrier isolator workstations (see Appendix A).

RL 1.2: Personnel Education, Training, and Evaluation.

Training is the most important factor in ensuring the qual-

ity of sterile products. Pharmacy personnel preparing or dis-

pensing sterile products must receive suitable didactic and

experiential training and competency evaluation through

demonstration, testing (written or practical), or both. Some

aspects that should be included in training programs include

aseptic technique; critical-area contamination factors; envi-

ronmental monitoring; facilities, equipment, and supplies;

sterile product calculations and terminology; sterile product

compounding documentation; quality assurance procedures;

aseptic preparation procedures; proper gowning and gloving

technique; and general conduct in the controlled area. In

addition to knowledge of chemical, pharmaceutical, and

clinical properties of drugs, pharmacists should be knowl-

edgeable about the principles of pharmacy compounding.

Videotapes

37,38

and additional information on the essential

components of a training, orientation, and evaluation pro-

gram are described elsewhere.

39,40

All pharmacy and non-

pharmacy personnel (e.g., environmental services staff)

who work in the controlled area should receive documented

training on cleaning, sanitizing, and maintaining equipment

used in the controlled area. Training should be specific to the

environmental control device and equipment present in the

controlled area and should be based on current procedures.

The aseptic technique of each person preparing sterile

products should be observed and evaluated as satisfactory

during orientation and training and at least annually there-

after.

In addition to observation, methods of evaluating the

knowledge of personnel include written or practical tests and

process validation.

42,43

RL 1.3: Storage and Handling within the Pharmacy.

Solutions, drugs, supplies, and equipment used to prepare

or administer sterile products should be stored in accordance

with manufacturer or USP requirements. Temperatures in

refrigerators and freezers used to store ingredients and fin-

ished sterile preparations should be monitored and docu-

mented daily to ensure that compendial storage requirements

are met. Warehouse and other pharmacy storage areas where

ingredients are stored should be monitored to ensure that

temperature, light, moisture, and ventilation remain within

manufacturer and compendial requirements. To permit ad-

equate floor cleaning, drugs, supplies, and compounding

equipment should be stored on shelving, cabinets, and carts

above the floor. Products that have exceeded their expiration

dates should be removed from active storage areas. Before

use, each drug, ingredient, and container should be visually

inspected for damage, defects, and expiration date.

Unnecessary personnel traffic in the controlled area

should be minimized. Particle-generating activities, such as

removal of intravenous solutions, drugs, and supplies from

cardboard boxes, should not be performed in the controlled

area. Products and supplies used in preparing sterile prod-

ucts should be removed from shipping containers outside the

controlled area before aseptic processing is begun. Packaging

materials and items generating unacceptable amounts of par-

ticles (e.g., cardboard boxes, paper towels [unless lint-free],

reference books) should not be permitted in the controlled

area or critical area. The removal of immediate packaging

designed to retain the sterility or stability of a product (e.g.,

syringe packaging, light-resistant pouches) is an exception;

obviously, this type of packaging should not be removed

outside the controlled area. Disposal of packaging materials,

used syringes, containers, and needles should be performed

Table 1.

Assignment of Products to Risk Level 1 or 2 according to Time and Temperature before Completion

of Administration

No. Days Storage

Risk Level Room Temperature (15–30 °C) Refrigerator (2–8 °C)

Freezer (−20 to −10°C)

Completely administered within 28 hr

≤7

≤30

Storage and administration exceed 28 hr

>30

94 Drug Distribution and Control: Preparation and Handling–Guidelines

at least daily, and more often if needed, to enhance sanitation

and avoid accumulation in the controlled area. Trash cans

should be below the level of the laminar-airflow workbench

and should be removed from the controlled area before be-

ing emptied. Sharps containers should be safely placed into

the waste stream, according to policies developed by the

institution to comply with regulations of the Occupational

Safety and Health Administration (OSHA).

In the event of a product recall, there should be a

mechanism for tracking and retrieving affected products

from specific patients to whom the products were dispensed.

RL 1.4: Facilities

and Equipment.

The controlled area

should be a limited-access area sufficiently separated from

other pharmacy operations to minimize the potential for

contamination that could result from the unnecessary flow of

materials and personnel into and out of the area. The controlled

area is a buffer from outside air that is needed because strong

air currents from briefly opened doors, personnel walking

past the laminar-airflow workbench, or the air stream from

the heating, ventilating, and air conditioning system can

easily exceed the velocity of air from the laminar-airflow

workbench. Also, operators introducing supplies into the

laminar-airflow workbench or reaching in with their arms

can drag contaminants from the environment surrounding

the workbench.

Cleanliness of the controlled area can be

enhanced by (1) limiting access to those personnel assigned

to work in the controlled area, (2) having those personnel wear

the appropriate garb, (3) donning and removing garb outside

the controlled area, (4) keeping doors to the controlled area

closed, (5) limiting storage in the controlled area to items in

constant use, (6) using low-particulate shelving, counters,

and carts (e.g., stainless steel) in the controlled area, (7) not

allowing cardboard and other particle-generating materials in

the controlled area, (8) controlling the temperature and humid-

ity inside the room, and (9) implementing a regular cleaning

(e.g., nightly floor disinfection) and maintenance schedule.

Barrier isolator workstations are closed systems and

are not as sensitive to their external environment as laminar-

airflow equipment. It is good practice to (1) place barrier

isolator workstations in limited-access areas, (2) control the

temperature and humidity of the surrounding area, and (3)

clean and sanitize the surrounding area on a routine basis.

Special precautions should be taken to clean equipment

and compounding areas meticulously after preparing prod-

ucts that contain allergenic ingredients (e.g., sulfonamides

and penicillins). Equipment should be of appropriate design

and size for compounding and suitable for the intended uses.

Equipment and accessories used in compounding should be

inspected, maintained, and cleaned at appropriate intervals

to ensure the accuracy and reliability of their performance.

Computer entry, order processing, label generation, and

record keeping should be performed outside the critical area.

The controlled area should be well organized

and lighted

and of sufficient size to support sterile compounding activi-

ties. For hand washing, a sink with hot and cold running wa-

ter should be in close proximity to but outside the controlled

area. Refrigeration, freezing, ventilation, and room tempera-

ture control capabilities appropriate for storage of ingredients,

supplies, and pharmacy-prepared sterile products in accor-

dance with manufacturer, USP, and state or federal require-

ments should exist. The controlled area should be cleaned

and disinfected at regular intervals with appropriate agents,

according to written policies and procedures.

Disinfectants

should be alternated periodically to prevent development of

resistant microorganisms.

The floors of the controlled area

should be nonporous and washable to enable regular disinfec-

tion. Active work surfaces in the controlled area (e.g., carts,

compounding devices, counter surfaces) should be disin-

fected, in accordance with written procedures. Refrigerators,

freezers, shelves, and other areas where pharmacy-prepared

sterile products are stored should be kept clean.

Sterile products must be prepared in a class 100 envi-

ronment (i.e., the critical area).

Such an environment ex-

ists inside a certified horizontal- or vertical-laminar-airflow

workbench, a class 100 cleanroom, or a barrier isolator.

Cytotoxic and other hazardous products should be prepared

in a vented class II biological safety cabinet or a barrier isola-

tor of appropriate design to meet the personnel exposure lim-

its described in product material safety data sheets (MSDS).

Barrier isolators are gaining favor as clean environments, es-

pecially for cytotoxic drug compounding.

55–57

Properly main-

tained barrier isolators provide suitable environments for the

preparation of risk level 1, 2, and 3 sterile products.

Laminar-airflow workbenches are designed to be oper-

ated continuously. If a laminar-airflow workbench is turned

off between aseptic processes, it should be operated long

enough to allow complete purging of room air from the criti-

cal area (e.g., at least 30 minutes), then disinfected before use.

Barrier isolators, because of their closed nature, require less

start-up time. If the barrier isolator has been turned off for less

than 24 hours, a two-minute start-up time is sufficient. For

periods greater than 24 hours, the chamber should be sanitized

and the isolator should not be used for a minimum of 10 min-

utes after application of the sanitizing agent. The critical-area

work surface and all accessible interior surfaces of the work-

bench should be disinfected with an appropriate agent before

work begins and periodically thereafter, in accordance with

written policies and procedures.

The exterior surfaces of the

laminar-airflow workbench should be cleaned periodically

with a mild detergent or suitable disinfectant; 70% isopropyl

alcohol may damage the workbench’s clear plastic surfaces.

The laminar-airflow workbench should be certified by a quali-

fied contractor

every six months

or when it is relocated

to ensure operational efficiency and integrity. Prefilters in the

laminar-airflow workbench should be changed (or cleaned, if

they are washable) periodically (e.g., monthly), in accordance

with written policies and procedures.

A method should be established for calibrating and ver-

ifying the accuracy of automated compounding devices used

in aseptic processing (e.g., routine reconstitution of bulk or

individual vials, transferring of doses from a bulk container

to a minibag, syringe, or other single-dose container).

RL 1.5: Garb.

Procedures should require that personnel

wear clean gowns or coveralls that generate few particles

in the controlled area.

Scrub attire by itself is not accept-

able (but can, like street clothes, be covered by a gown or

coverall). Hand, finger, and wrist jewelry should be mini-

mized or eliminated. Fingernails should be kept clean and

trimmed. Head and facial hair should be covered. Masks

are recommended because most personnel talk

or may

cough or sneeze. Gloves are recommended. Personnel who

have demonstrated sensitivity to latex should use either

powder-free, low-latex protein gloves or, in the case of

severe allergy, latex-free (synthetic) gloves.

62,63

Drug Distribution and Control: Preparation and Handling–Guidelines 95

RL 1.6: Aseptic Technique

64,65

and Product Preparation.

Sterile products must be prepared with aseptic technique in

a class 100 environment. Personnel should scrub their hands

and forearms for an appropriate length of time with a suitable

antimicrobial skin cleanser at the beginning of each aseptic

compounding process and when reentering the controlled

area, in accordance with written procedures. Personnel

should wear appropriate attire (see RL 1.5: Garb). Eating,

drinking, and smoking are prohibited in the controlled area.

Talking should be minimized in the critical area during asep-

tic preparation (even when masks are worn).

Ingredients used to compound sterile products should

be determined to be stable, compatible, and appropriate for

the product to be prepared, according to manufacturer or USP

guidelines or appropriate scientific references. The ingredients

of the preparation should be predetermined to result in a final

product that meets physiological norms for solution osmolality

and pH, as appropriate for the intended route of administration.

Each ingredient and container should be inspected for defects,

expiration date, and product integrity before use. Expired, in-

appropriately stored, or defective products must not be used

in preparing sterile products. Defective products should be

promptly reported to the FDA MedWatch Program.

Only materials essential for preparing the sterile product

should be placed in the laminar-airflow workbench or barrier

isolator. The surfaces of ampuls, vials, and container closures

(e.g., vial stoppers) should be disinfected by swabbing or spray-

ing with an appropriate disinfectant solution (e.g., 70% isopro-

pyl alcohol or 70% ethanol) before placement in the work-

bench. Materials used in aseptic preparation should be arranged

in the critical area (within the laminar-airflow workbench or

barrier isolator) in a manner that prevents interruption of the

unidirectional airflow between the high-efficiency particulate

air (HEPA) filter and critical sites of needles, vials, ampuls,

containers, and transfer sets. All aseptic procedures should be

performed at least 6 inches inside the front edge of the laminar-

airflow workbench, in a clear path of unidirectional airflow

between the HEPA filter and work materials (e.g., needles, clo-

sures). The number of personnel preparing sterile products in

the workbench at one time should be minimized. Overcrowding

of the critical work area may interfere with unidirectional

airflow and increase the potential for compounding errors.

Likewise, the number of units being prepared in the workbench

at one time should allow unobstructed airflow over critical

areas. Automated compounding devices and other equipment

placed in or adjacent to the critical area should be cleaned, dis-

infected, and placed to avoid contamination or disruption of the

unidirectional airflow between the HEPA filter and sterile sur-

faces. Closed systems like barrier isolators require less stringent

placement of sterile units and equipment because the critical

area encompasses the entire work surface. Hand and arm move-

ments are not critical because the walls of the barrier isolator

provide protection from the outside environment.

Aseptic technique should be used to avoid touch con-

tamination of sterile needles, syringe parts (e.g., plunger,

syringe tip), and other critical sites. Solutions from ampuls

should be properly filtered to remove particles. Solutions of

reconstituted powders should be mixed carefully, ensuring

complete dissolution of the drug with the appropriate dilu-

ent. Needle entry into vials should be performed in such a

manner as to avoid coring of the vial closure. Some patients

may require a latex-free admixture to avoid severe allergic

reactions.

Latex-related policies and procedures should be

developed by each institution, given the paucity of evidence

that latex closures and syringe plungers are implicated in

patient reactions to latex.

69,70

Before, during, and after the

preparation of sterile products, the pharmacist should care-

fully check the identity and verify the amounts and sequence

of the additives in sterile preparations against the original pre-

scription, medication order, or other appropriate documenta-

tion (e.g., computerized patient profile, label generated from

a pharmacist-verified order) before the product is released or

dispensed.

RL 1.7: Process Validation.

Validation of aseptic pro-

cessing procedures provides a mechanism for ensuring that

processes consistently result in sterile products of accept-

able quality.

In risk level 1, process validation (or pro-

cess simulation) of compounding procedures is actually a

method of assessing the adequacy of an operator’s aseptic

technique. Each individual involved in the preparation of

sterile products should successfully complete a validation

process on technique before being allowed to prepare sterile

products. The validation process should follow written pro-

cedures.

42,43,45

Commercial kits are available for process val-

idation; however, their ability to support microbial growth

should be tested by challenging the intended kit with an in-

dicator organism (e.g., Bacillus stearothermophilus) that can

be purchased in known concentrations, is known not to be

pathogenic, and grows only at relatively high temperatures.

Process simulation allows for the evaluation of oppor-

tunities for microbial contamination during all steps of sterile

product preparation. The sterility of the final product is a cu-

mulative function of all processes involved in its preparation

and is ultimately determined by the processing step providing

the lowest probability of sterility.

Process simulation test-

ing is carried out in the same manner as normal production,

except that an appropriate microbiological growth medium is

used in place of the actual product used during sterile prepara-

tion. The same personnel, procedures, equipment, and materi-

als are involved. Completed medium samples are incubated.

If no microbial growth is detected, this provides evidence that

adequate aseptic technique was used. If growth is detected, the

entire sterile preparation process must be evaluated, corrective

action taken, and the process simulation test performed again.

No products intended for patient use should be prepared by

an individual until the process simulation test indicates that

the individual can competently perform aseptic procedures. It

is recommended that personnel competency be revalidated at

least annually, whenever the quality assurance program yields

an unacceptable result, and whenever unacceptable techniques

are observed; this revalidation should be documented.

RL 1.8: Expiration Dating.

All pharmacy-prepared ster-

ile products should bear an appropriate expiration date. The

expiration date assigned should be based on currently avail-

able drug stability information and sterility considerations.

Sources of drug stability information include references (e.g.,

AHFS Drug Information,

Extended Stability for Parenteral

Drugs,

Handbook on Injectable Drugs,

King Guide to

Parenteral Admixtures

), manufacturer recommendations,

and reliable, published research. When interpreting published

drug stability information, the pharmacist should consider all

aspects of the final sterile product being prepared (e.g., drug

reservoir, drug concentration, storage conditions). Methods

used for establishing expiration dates should be documented.

96 Drug Distribution and Control: Preparation and Handling–Guidelines

Appropriate inhouse (or contract service) stability testing may

be used to determine expiration dates when drug stability

data are not readily available. Home care pharmacies are of-

ten required to assign extended beyond-use dates to sterile

products, so ASHP has published guidelines for home care

pharmacies that address beyond-use dating.

74,77

RL 1.9: Labeling.

Sterile products should be labeled with

at least the following information:

1. For patient-specific products: the patient’ name and

any other appropriate patient identification (e.g.,

location, identification number); for batch-prepared

products: control or lot number,

2. All solution and ingredient names, amounts, strengths,

and concentrations (when applicable),

3. Expiration date and time, when applicable,

4. Prescribed administration regimen, when appropriate

(including rate and route of administration),

5. Appropriate auxiliary labeling (including precautions),

6. Storage requirements,

7. Identification (e.g., initials) of the responsible pharma-

cist (and technician),

8. Device-specific instructions (when appropriate), and

9. Any additional information, in accordance with state

or federal requirements; for example, a prescription

number for products dispensed to ambulatory care,

long-term-care, and home care patients.

The label should be legible and affixed to the final

container in a manner enabling it to be read while the ster-

ile product is being administered (when possible). Written

policies and procedures should address proper placement of

labels on containers.

RL 1.10: End-Product Evaluation.

The final product

should be inspected when preparation is completed and again

when the product is dispensed. This inspection includes an

evaluation for container leaks, container integrity, solution

cloudiness or phase separation, particulates in the solution,

appropriate solution color, and solution volume. The respon-

sible pharmacist should verify that the product was com-

pounded accurately with the correct ingredients, quantities of

each ingredient, containers, and reservoirs; different methods

may be used for end-product verification (e.g., observation,

calculation checks, documented records). Refractive index

measurement may also be used to verify the addition of

dextrose, for example in parenteral nutrient solutions.

RL 1.11: Handling of Sterile Products Outside the Phar-

macy.

Pharmacists should participate in developing proce-

dures for the safe use (e.g., stability, sterility) of sterile prod-

ucts once they are distributed outside the pharmacy. How the

product is transported from the pharmacy, how it is stored

outside the pharmacy, and methods for return, recycling, and

disposal should be addressed in written policies and proce-

dures.

15,83

Sterile products should be transported so as to be

protected from extremes of temperature outside their range

of stability and from light if they are photosensitive. Storage

containers and packaging verified as suitable for protection

during transport should be specified. Transit time and condi-

tions should also be specified and controlled. Delivery person-

nel should be instructed on special handling procedures. Once

delivered to the end user, sterile products should be appropri-

ately stored before use. Pharmacists should ascertain that the

user has appropriate locations and equipment for storage (e.g.,

a refrigerator with a suitable thermometer). Special instructions

for storage should be a part of the label or a separate information

sheet (e.g., instructions for cleanliness, proper storage, interpre-

tation of the expiration date and how to look for signs of product

deterioration). The pharmacist should be notified if storage con-

ditions do not remain suitable so that the pharmacist can give

advice as to the disposition of the sterile products and remedies

for storage problems. Pharmacists should participate in train-

ing end users on the proper care and storage of sterile products,

either directly or through written instructional materials.

RL 1.12: Documentation.

The following should be docu-

mented and maintained on file for an adequate period of

time, according to organizational policies and state regulatory

requirements: (1) the training and competency evaluation

of employees in sterile product procedures, (2) refrigerator

and freezer temperatures, (3) certification of laminar-airflow

workbenches, and (4) other facility quality control logs spe-

cific to the pharmacy’s policies and procedures (e.g., cleaning

logs for facilities and equipment). Pharmacists should also

maintain appropriate dispensing records for sterile products,

in accordance with state regulatory requirements.

Quality Assurance for Risk Level 2

Because the risks of inaccurate products are associated with

more complex procedures and because instability and con-

tamination are more likely with long-term storage and ad-

ministration, more stringent requirements are appropriate for

risk level 2 preparations. These requirements may be viewed

as more important in circumstances where the medical need

is routine. In circumstances where the medical need for a

product is immediate (and there is not a suitable alternative)

or when the preparation of such a product is rare, profes-

sional judgment should be applied to the extent to which

some guidelines (e.g., cleanroom design and final product

testing before product dispensing) must be applied.

RL 2.1: Policies and Procedures. In addition to all guide-

lines for risk level 1, a written quality assurance program

should define and identify necessary environmental monitoring

devices and techniques to be used to ensure an adequate envi-

ronment for risk level 2 sterile product preparation. Examples

include the use of airborne particle counters, air velocity and

temperature meters, viable particle samplers (e.g., slit samplers),

agar plates, and swab sampling of surfaces and potential con-

tamination sites. All aspects of risk level 2 sterile product prepa-

ration, storage, and distribution, including such details as the

choice of cleaning materials and disinfectants and the monitor-

ing of equipment accuracy, should be addressed in written poli-

cies and procedures. Limits of acceptability (threshold or action

levels) for environmental monitoring and process validation

and actions to be implemented when thresholds are exceeded

should be defined in written policies. For sterile batch com-

pounding, written policies and procedures should be established

for the use of master formulas and work sheets and for appropri-

ate documentation. Policies and procedures should also address

personnel attire in the controlled area, lot number determination

and documentation, and any other quality assurance procedures

unique to compounding risk level 2 sterile products.

Drug Distribution and Control: Preparation and Handling–Guidelines 97

RL 2.2: Personnel Education, Training, and Evaluation.

All guidelines for risk level 1 should be met. In addition to

guidelines for risk level 1, assessment of the competency

of personnel preparing risk level 2 sterile products should

include appropriate process validation (as described in RL

1.7: Process validation). However, process simulation pro-

cedures for assessing the preparation of risk level 2 sterile

products should be representative of all types of manipu-

lations, products, and batch sizes personnel preparing risk

level 2 products are likely to encounter.

Personnel should

also be taught which products are to undergo end-product

quantitative analysis (see RL 2.10).

RL 2.3: Storage and Handling. All storage and handling

guidelines for risk level 1 should be met.

RL 2.4: Facilities and Equipment. In addition to all guide-

lines for risk level 1, the following guidelines should be fol-

lowed for risk level 2 sterile product preparation:

1. The controlled area should meet the standards of a class

10,000 cleanroom,

as defined by Federal Standard

209E.

85,f

A positive air pressure relative to adjacent

pharmacy areas is required, as are an appropriate num-

ber of air exchanges per hour and appropriate humidity

and temperature levels.

For open-architecture clean-

rooms, it is appropriate to measure the volume of air

entering the cleanroom versus the volume of air enter-

ing adjacent rooms, so as to ensure a positive pressure

gradient for the cleanroom. To allow proper cleaning

and disinfection, walls, floors, and ceilings in the con-

trolled area should be nonporous. To help reduce the

number of particles in the controlled area, an adjacent

support area (e.g., ante-room) should be provided. A

properly maintained barrier isolator also provides an

acceptable environment.

A barrier isolator provides a

class 100 environment for product preparation; there-

fore, the isolator itself can be in a separate area of the

pharmacy but need not actually be in a cleanroom.

2. Cleaning materials (e.g., mops, sponges, and germicidal

disinfectants) for use in the cleanroom should be carefully

selected. They should be made of materials that generate

a low amount of particles. If reused, cleaning materials

should be cleaned and disinfected between uses.

3. The critical-area work surfaces (e.g., interior of the

laminar-airflow workbench) should be disinfected fre-

quently and before and after each batch-preparation

process with an appropriate agent, according to written

policies and procedures. Floors should be disinfected at

least daily. Carpet or porous floors, porous walls, and

porous ceiling tiles are not suitable in the controlled area

because these surfaces cannot be properly cleaned and

disinfected. Exterior workbench surfaces and other hard

surfaces in the controlled area, such as shelves, carts,

tables, and stools, should be disinfected weekly and after

any unanticipated event that could increase the risk of

contamination. Walls should be cleaned at least monthly.

4. To ensure that an appropriate environment is maintained

for risk level 2 sterile product preparation, an effective

written environmental monitoring program is recom-

mended.

Sampling of air and surfaces according to a

written plan and schedule is recommended.

The plan

and frequency should be adequate to document that the

controlled area is suitable and that the laminar-airflow

workbench or biological safety cabinet meets class 100

requirements. Limits of acceptability (thresholds or

action levels) and appropriate actions to be taken in

the event thresholds are exceeded should be specified.

USP presents examples of environmental monitoring.

Settle plates or wipe samples can provide a simple but

effective means of routinely monitoring airborne micro-

bial contamination in controlled and critical areas.

45,88,89

5. To help reduce the number of particles in the controlled

area, an adjacent support area (e.g., anteroom) of high

cleanliness, separated from the controlled area by a bar-

rier (e.g., plastic curtain, partition, wall), is recommended.

Appropriate activities for the support area include, but

are not limited to, hand washing, gowning and gloving,

removal of packaging and cardboard items, and cleaning

and disinfecting hard-surface containers and supplies be-

fore placing these items into the controlled area.

6. Methods should be established for calibrating and

verifying the accuracy and sterility of automated com-

pounding methods used in aseptic processing.

90–96

RL 2.5: Garb. All guidelines for risk level 1 should be met.

Gloves, gowns, and masks are required for the preparation of

all risk level 2 sterile products. Even when sterile gloves are

used, they do not remain sterile during aseptic compound-

ing; however, they do assist in containing bacteria, skin, and

other particles that may be shed even from scrubbed hands.

Clean gowns, coveralls, or closed jackets with sleeves hav-

ing elastic binding at the cuff are recommended; these gar-

ments should be made of low-shedding materials. Shoe

covers may be helpful in maintaining the cleanliness of the

controlled area. Barrier isolators do not require the same

level of gowning as laminar-airflow workstations as long as

they operate as closed systems with HEPA filtration of air

entering and leaving the barrier isolator and a separate area

for entrance, such as an air lock for product transfers.

During sterile product preparation, gloves should be

rinsed frequently with a suitable agent (e.g., 70% isopropyl

alcohol) and changed when their integrity is compromised

(i.e., when they are punctured or torn). Personnel should dis-

card gloves upon leaving the cleanroom and don new gloves

upon reentering the cleanroom.

RL 2.6: Aseptic Technique and Product Preparation.

97–99

All

guidelines for risk level 1 sterile product preparation should be

met. Relative to batch-prepared products, a master work sheet

should be developed for a batch of each discrete identity and

concentration of sterile product to be prepared. The master

work sheet should consist of the formula, components, com-

pounding directions or procedures, a sample label, and evalu-

ation and testing requirements. Once the original master work

sheet is approved by the designated pharmacist, a verified du-

plicate (e.g., a photocopy) of the master work sheet should be

used as the preparation work sheet from which each batch is

prepared and on which all documentation for each batch oc-

curs. (For small-formula, frequently prepared batches, it may

be more efficient to have multiple lines on the preparation work

sheet for documenting more than one batch.) The preparation

work sheet should be used to document the following:

1. Identity of all solutions and ingredients and their cor-

responding amounts, concentrations, or volumes,

98 Drug Distribution and Control: Preparation and Handling–Guidelines

2. Manufacturer lot number and expiration date for each

component,

3. Component manufacturer or suitable manufacturer

identification number,

4. Container specifications (e.g., syringe, pump cassette),

5. Lot or control number assigned to batch,

6. Expiration date of batch-prepared products,

7. Date of preparation,

8. Identity (e.g., initials, codes, signatures) of personnel

involved in preparation,

9. End-product evaluation and testing specifications and

results,

10. Storage requirements,

11. Specific equipment used during aseptic preparation

(e.g., a specific automated compounding device), and

12. Comparison of actual yield with anticipated yield,

when appropriate.

However documentation is done, a procedure should

exist for easy retrieval of all records pertaining to a particu-

lar batch. Each batch of sterile products should bear a unique

lot number. Identical lot numbers must never be assigned to

different products or different batches of the same product.

Lot numbers may be alphabetic, numeric, or alphanumeric.

The process of combining multiple sterile ingredients

into a single sterile reservoir for subdivision into multiple

units for dispensing may necessitate additional quality

control procedures. A second pharmacist should verify

calculations associated with this process, when possible;

this verification should be documented. Because this process

often involves making multiple entries into the intermediate

sterile reservoir, the likelihood of contamination may be

greater than that associated with the preparation of other risk

level 2 sterile products.

For preparation involving automated compounding de-

vices, a pharmacist should verify data entered into the com-

pounding device before compounding begins. End-product

checks should be performed to verify accuracy of ingredient

delivery. These checks may include weighing and visually

verifying the final product. For example, the expected weight

(in grams) of the final product, based on the specific gravi-

ties of the ingredients and their respective volumes, can be

documented on the compounding formula sheet, dated, and

initialed by the responsible pharmacist. Once compounding is

completed, each final product can be weighed and its weight

compared with the expected weight. The product’s actual

weight should fall within a preestablished threshold for vari-

ance. Visual verification may be aided by marking the begin-

ning level of each bulk container before starting the automated

mixing process and checking each container after completing

the mixing process to determine whether the final levels ap-

pear reasonable in comparison with expected volumes. The

operator should also periodically observe the device during

the mixing process to ensure that the device is operating prop-

erly (e.g., check to see that all stations are operating). If there

are doubts whether a product or component has been properly

prepared or stored, the product should not be used.

RL 2.7: Process Validation. Each individual involved in the

preparation of risk level 2 sterile products should success-

fully complete a validation process, as recommended for

risk level 1. Process simulation for compounding risk level

2 sterile products should be representative of all types of

manipulations, products, and batch sizes that personnel pre-

paring risk level 2 sterile products are likely to encounter.

RL 2.8: Expiration Dating. All guidelines for risk level 1

should be met.

RL 2.9: Labeling. All guidelines for risk level 1 should be met.

RL 2.10: End-Product Evaluation. All guidelines for risk

level 1 should be met. For complex or toxic products, it is

appropriate, when possible, to obtain quantitative testing of

the accuracy of sterile additives, for example, the dextrose

concentration in pediatric parenteral nutrient solutions or the

potassium concentration in cardioplegia solutions.

RL 2.11: Handling of Sterile Products Outside the Phar-

macy. All guidelines for risk level 1 should be met.

RL 2.12: Documentation. All guidelines for risk level 1

should be met. Additionally, documentation of end-product

sampling and batch-preparation records should be main-

tained for an adequate period, in accordance with organiza-

tional policies and procedures and state regulatory require-

ments.

100

Documentation for sterile batch-prepared products

should include the

1. Master work sheet,

2. Preparation work sheet, and

3. End-product evaluation and testing results.

Quality Assurance for Risk Level 3

Risk level 3 addresses the preparation of products that pose the

greatest potential risk to patients. The quality assurance activi-

ties described in this section are clearly more demanding—in

terms of processes, facilities, and final product assessment—

than for risk levels 1 and 2. Ideally, the activities described for

risk level 3 would be used for all high-risk products. However,

the activities may be viewed as most important in circum-

stances where the medical need for such high-risk products is

routine. In circumstances where the medical need for such a

product is immediate (and there is not a suitable alternative)

or when the preparation of such a product is rare, professional

judgment must be applied as to the extent to which some ac-

tivities (e.g., strict facility design, quarantine, and final product

testing before product dispensing) should be applied.

RL 3.1: Policies and Procedures. There should be written

policies and procedures related to every aspect of preparation

of risk level 3 sterile products. These policies and procedures

should be detailed enough to ensure that all products have the

identity, strength, quality, and purity purported for the prod-

uct.

14,101

All policies and procedures should be reviewed and

approved by the designated pharmacist. There should be a

mechanism designed to ensure that policies and procedures

are communicated, understood, and adhered to by personnel

cleaning or working in the controlled area or support area.

Written policies and procedures should define and identify the

environmental monitoring activities necessary to ensure an ad-

equate environment for risk level 3 sterile product preparation.

In addition to the policies and procedures required for

risk levels 1 and 2, there should be written policies and pro-

cedures for the following:

Drug Distribution and Control: Preparation and Handling–Guidelines 99

1. Component selection, handling, and storage,

2. Any additional personnel qualifications commensurate

with the preparation of risk level 3 sterile products,

3. Personnel responsibilities in the controlled area (e.g., steril-

ization, cleaning, maintenance, access to controlled area),

4. Equipment use, maintenance, calibration, and testing,

5. Sterilization and expiration dating,

6. Master formula and master work sheet development

and use,

7. End-product evaluation and testing,

8. Appropriate documentation for preparation of risk

level 3 sterile products,

9. Use, control, and monitoring of environmentally con-

trolled areas and calibration of monitoring equipment,

10. Process simulation for each risk level 3 sterile product,

11. Quarantine of products and release from quarantine,

if applicable,

12. A mechanism for recalling products from patients in

the event that end-product testing procedures yield un-

acceptable results, and

13. Any other quality control procedures unique to the

preparation of risk level 3 sterile products.

RL 3.2: Personnel Education, Training, and Evaluation.

Persons preparing sterile products at risk level 3 must have

specific education, training, and experience to perform all

functions required for the preparation of risk level 3 ster-

ile products. However, final responsibility should lie with

the pharmacist, who should be knowledgeable in pharmacy

compounding practice

and proficient in quality assurance

requirements, equipment used in the preparation of risk

level 3 sterile products, and other aspects of sterile product

preparation. The pharmacist should have sufficient educa-

tion, training, experience, and demonstrated competency to

ensure that all sterile products prepared from sterile or non-

sterile components have the identity, strength, quality, and

purity purported for the products.

101

In addition to the body

of knowledge required for risk levels 1 and 2, the pharmacist

should possess sufficient knowledge in the following areas:

1. Aseptic processing,

2. Quality control and quality assurance as related to

environmental, component, and end-product testing,

3. Sterilization techniques,

and

4. Container, equipment, and closure system selection.

All pharmacy personnel involved in the cleaning

and maintenance of the controlled area should be specially

trained and thoroughly knowledgeable in the special re-

quirements of class 100 critical-area technology and design.

There should be documented, ongoing training for all em-

ployees to enable retention of expertise.

RL 3.3: Storage and Handling. In addition to guidelines for risk

levels 1 and 2, risk level 3 policies and procedures for storage

and handling should include procurement, identification, stor-

age, handling, testing, and recall of nonsterile components.

14,101

Components and finished products ready to undergo

end-product testing should be stored in a manner that pre-

vents their use before release by a pharmacist, minimizes

the risk of contamination, and enables identification. There

should be identified storage areas that can be used to quaran-

tine products, if necessary, before they are released.

RL 3.4: Facilities and Equipment. Preparation of risk level

3 sterile products should occur in a class 100 horizontal- or

vertical-laminar-airflow workbench that is properly situated

in a class 10,000 cleanroom or in a properly maintained and

monitored class 100 cleanroom (without the workbench).

102

The cleanroom area should have a positive pressure differen-

tial relative to adjacent, less clean areas of at least 0.05 inch

of water. A properly designed and maintained barrier isolator

provides an aseptic environment for risk level 3 products.

To allow proper cleaning and disinfection, walls, floors,

and ceilings in the controlled area should be nonporous. To

help reduce the number of particles in the controlled area, an

adjacent support area (e.g., anteroom) should be provided.

During the preparation of risk level 3 sterile products,

access to the controlled area or cleanroom should be limited

to those individuals who are required to be in the area and

are properly attired. The environment of the main access ar-

eas directly adjacent to the controlled area (e.g., anteroom)

should meet at least Federal Standard 209E class 100,000

requirements. To help maintain a class 100 critical-area en-

vironment during compounding, the adjacent support area

(e.g., anteroom) should be separated from the controlled area

by a barrier (e.g., plastic curtain, partition, wall). Written

policies and procedures for monitoring the environment of

the controlled area and adjacent areas should be developed.

No sterile products should be prepared in the con-

trolled area if it fails to meet established criteria specified

in the policies and procedures. A calibrated particle counter

capable of measuring air particles 0.5 mm and larger should

be used to monitor airborne particulate matter.

103

Before

product preparation begins, the positive-pressure air status

should meet or exceed the requirements. Air samples should

be taken at several places in the controlled area with the ap-

propriate environmental monitoring devices (e.g., nutrient

agar plates). Surfaces on which work actually occurs, in-

cluding laminar-airflow workbench surfaces and tabletops,

should be monitored by using surface contact plates, the

swab-rinse technique, or other appropriate methods.

104

Test results should be reviewed and criteria should be

pre established to determine the point at which the preparation

of risk level 3 sterile products will be disallowed until correc-

tive measures are taken. When the environment does not meet

the criteria specified in the policies and procedures, sterile prod-

uct processing should immediately cease and corrective action

should be taken. In the event that this occurs, written policies and

proce dures should delineate alternative methods of sterile prod-

uct preparation to enable timely fulfillment of prescription orders.

Equipment should be adequate to prevent microbio-

logical contamination. Methods should be established for

the cleaning, preparation, sterilization, calibration, and doc-

umented use of all equipment.

Critical-area work surfaces should be disinfected with

an appropriate agent before the preparation of each product.

Floors in the controlled area should be disinfected at least daily.

Exterior workbench surfaces and other hard surfaces in the

controlled area, such as shelves, tables, and stools, should be

disinfected weekly and after any unanticipated event that could

increase the risk of contamination. Walls and ceilings in the con-

trolled area or cleanroom should be disinfected at least weekly.

Large pieces of equipment, such as tanks, carts, and

tables, used in the controlled area or cleanroom should be made

of a material that can be easily cleaned and disinfected; stainless

steel is recommended. Stools and chairs should be cleanroom

100 Drug Distribution and Control: Preparation and Handling–Guidelines

quality. Equipment that does not come in direct contact with

the finished product should be properly cleaned, rinsed, and

disinfected before being placed in the controlled area. All non-

sterile equipment that will come in contact with the sterilized

final product should be properly sterilized before introduction

into the controlled area; this precaution includes such items as

tubing, filters, containers, and other processing equipment. The

sterilization process should be monitored and documented.

101

RL 3.5: Garb. All guidelines for risk levels 1 and 2 should

be met. Additionally, cleanroom garb should be worn inside

the controlled area at all times during the preparation of

risk level 3 sterile products. Attire should consist of a low-

shedding coverall, head cover, face mask, and shoe covers.

These garments may be either disposable or reusable. Head

and facial hair should be covered. Before donning these

garments over street clothes, personnel should thoroughly

wash their hands and forearms with a suitable antimicrobial

skin cleanser.

Sterile disposable gloves should be worn

and rinsed frequently with an appropriate agent (e.g., 70%

isopropyl alcohol) during processing. The gloves should be

changed if their integrity is compromised. If persons leave

the controlled area or support area during processing, they

should regown with clean garments before reentering.

RL 3.6: Aseptic Technique and Product Preparation. All

guidelines for risk levels 1 and 2 should be met. Methods

should ensure that components and containers remain free

from contamination and are easily identified as to the prod-

uct, lot number, and expiration date. If components are not

finished sterile pharmaceuticals obtained from licensed

manufacturers, pharmacists should ensure that these compo-

nents meet USP and FDA standards. Products prepared from

nonsterile ingredients should be tested to ensure that they do

not exceed specified endotoxin limits, unless the ingredient

will denature all proteins (e.g., concentrated hydrochloric

acid).

105

As each new lot of components and containers is

received, the components should be quarantined until prop-

erly identified, tested, or verified by a pharmacist.

101

The methods for preparing sterile products and using

process controls should be designed to ensure that finished

products have the identity, strength, quality, and purity they

are intended to have. Any deviations from established meth-

ods should be documented and appropriately justified.

A master work sheet should be developed for the prep-

aration of each risk level 3 sterile product. Once the phar-

macist approves the master work sheet, a verified duplicate

of the master work sheet should be used as the controlling

document from which each sterile end product or batch of

prepared products is compounded and on which all docu-

mentation for that product or batch occurs. The preparation

work sheet should document all the requirements for risk

level 2 plus the following:

1. Comparison of actual with anticipated yield,

2. Sterilization methods,

106,107

3. Pyrogen testing,

108

and

4. Quarantine specifications.

The preparation work sheet should serve as the batch

record for each time a risk level 3 sterile product is prepared.

Each batch of pharmacy-prepared sterile products should

bear a unique lot number, as described in risk level 2.

There should be documentation on the preparation

work sheet of all additions of individual components plus

the signatures or initials of those individuals involved in the

measuring or weighing and addition of these components.

The selection of the final packaging system (including

container and closure) for the sterile product is crucial to main-

taining product integrity.

109

To the extent possible, presterilized

containers obtained from licensed manufacturers should be

used. If an aseptic filling operation is used, the container should

be sterile at the time of the filling operation. If nonsterile con-

tainers are used, methods for sterilizing these containers should

be established. Final containers selected should be capable of

maintaining product integrity (i.e., identity, strength, quality,

and purity) throughout the shelf life of the product.

110

For products requiring sterilization, selection of an

appropriate method of sterilization is of prime importance.

Methods of product sterilization include sterile filtration,

auto claving, dry heat sterilization, chemical sterilization, and

irra diation.

111,112

The pharmacist must ensure that the steriliza-

tion method used is appropriate for the product components

and does not alter the pharmaceutical properties of the final

product. A method of sterilization often used by pharmacists

is sterile filtration.

113

In sterile filtration, the filter should

be chosen to fit the chemical nature of the product, and the

product should be filtered into presterilized containers under

aseptic conditions. Sterilizing filters of 0.22-μm or smaller

porosity should be used in this process. Colloidal or viscous

products may require a 0.45-μm filter; however, extreme cau-

tion should be exercised in these circumstances, and more

stringent end-product sterility testing is essential.

114

To ensure that a bacteria-retentive filter did not rup-

ture during filtration of a product, an integrity test should be

performed on all filters immediately after filtration. This test

may be accomplished by performing a bubble point test, in

which pressurized gas (e.g., air in a syringe attached to the

used filter) is applied to the upstream side of the filter with

the downstream outlet immersed in water and the pressure at

which a steady stream of bubbles begins to appear is noted.

The observed pressure is then compared with the manufac-

turer’s specification for the filter. To compare the used fil-

ter with the manufacturer’s specifications, which would be

based on the filtration of water through the filter, it is neces-

sary to first rinse the filter with sterile water for injection. An

observed value lower than the manufacturer’s specification

indicates that the filter was defective or ruptured during the

sterilization process. Methods should be established for han-

dling, testing, and resterilizing any product processed with a

filter that fails the integrity test.

RL 3.7: Process Validation. In addition to risk level 1 and 2

guidelines, written policies and procedures should be estab-

lished to validate all processes involved in the preparation of

risk level 3 sterile products (including all procedures, equip-

ment, and techniques) from sterile or nonsterile components.

In addition to evaluating personnel technique, process vali-

dation provides a mechanism for determining whether a par-

ticular process will, when performed by qualified personnel,

consistently produce the intended results.

115

RL 3.8: Expiration Dating. In addition to risk level 2 guide-

lines, there should be reliable methods for establishing all

expiration dates, including laboratory testing of products

for sterility, nonpyrogenicity, and chemical content, when

Drug Distribution and Control: Preparation and Handling–Guidelines 101

necessary. These tests should be conducted in a manner based

on appropriate statistical criteria, and the results documented.

RL 3.9: Labeling. All guidelines for risk levels 1 and 2

should be met.

RL 3.10: End-Product Evaluation. For each preparation of

a sterile product or a batch of sterile products, there should

be appropriate laboratory determination of conformity (i.e.,

purity, accuracy, sterility, and nonpyrogenicity) to estab-

lished written specifications and policies. Any reprocessed

material should undergo complete final product testing.

Additionally, process validation should be supplemented

with a program of end-product sterility testing, according to

a formal sampling plan.

116–127

Written policies and proce-

dures should specify measurements and methods of testing.

Policies and procedures should include a statistically valid

sampling plan and acceptance criteria for the sampling and

testing. The criteria should be statistically adequate to rea-

sonably ensure that the entire batch meets all specifications.

Products not meeting all specifications should be rejected

and discarded. There should be a mechanism for recalling

all products of a specific batch if end-product-testing pro-

cedures yield unacceptable results. On completion of final

testing, products should be stored in a manner that ensures

their identity, strength, quality, and purity.

It is advisable to quarantine sterile products com-

pounded from nonsterile components, pending the results

of end-product testing. If products prepared from nonsterile

components must be dispensed before satisfactory comple-

tion of end-product testing, there must be a procedure to

allow for immediate recall of the products from patients

to whom they were dispensed.

RL 3.11: Handling of Sterile Products Outside the Phar-

macy. All guidelines for risk levels 1 and 2 should be met.

RL 3.12: Documentation. In addition to the guidelines for

risk levels 1 and 2, documentation for risk level 3 sterile

products should include

1. Preparation work sheet,

2. Sterilization records of final products (if applicable),

3. Quarantine records (if applicable), and

4. End-product evaluation and testing results.

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Unless otherwise stated in this document, the term sterile products

refers to sterile drugs or nutritional substances that are prepared

(e.g., compounded or repackaged) by pharmacy personnel.

Ampuls, swabbed and opened appropriately with contents filtered

upon removal, should be considered part of a “closed” system.

Isolator guidelines appear under risk level 1 sections because their

greatest use is likely to be in the preparation of cytotoxic sterile

products, most of which are risk level 1 processes.

The need to alternate germicides is controversial. According to Akers

and Moore (Microbiological monitoring of pharmaceutical clean-

rooms: the need for pragmatism, J Adv Appl Contam Control. 1998;

1[1]:23-4,26,28,30), the data do not support alternating germicides. A

literature search (Kopis EM. Cleanrooms. 1996; 10[10]:48-v50) found

little evidence for periodic alternation of disinfectants; the search did

find that alternating use of acidic and alkaline phenolic disinfectants

reduces resistance arising in pseudomonads adhering to hard surfaces.

If ethanol 70% or isopropyl alcohol 70% is used as the primary disin-

fectant, it should be sterile filtered through a 0.22-μm filter before use.

According to Trissel and Chandler (Am J Hosp Pharm. 1993;

50:1858–61), pharmacy air is nearly class 10,000 cleanroom quality

already. However, true cleanrooms add HEPA air filtering and des-

ignate room air changes and room air pressure differentials to ensure

cleanliness (Am J Hosp Pharm. 1994; 51:239-40. Letter).

Note that the International Organization for Sanitation (ISO) is prepar-

ing documents that should replace Federal Standard 209E. The ISO

documents (numbered 14644-1 through 14644-7 and 14698-1 through

14698-3) are being prepared by a technical committee consisting of

members from six countries, including the United States. Document

14644-1 is published in final form and classifies the air cleanliness of

cleanrooms and associated controlled environments. In 14644-1 ISO

cleanroom class 5 is equivalent to Federal Standard 209E class 100,

and ISO class 7 is equivalent to Federal Standard 209E class 10,000.

As in general information chapter 1206 in USP, which does not re-

quire sterility testing until the third risk level, this assumes that ster-

ile components remain sterile throughout preparation. Many sterile

products are prepared in batches too small or used too quickly after

preparation to make sterility testing meaningful. Also, one of the

purposes of process validation is to determine that personnel and

processes can produce a sterile product.

Supersedes the ASHP Technical Assistance Bulletin on Quality

Assurance for Pharmacy-Prepared Sterile Products, dated

September 24, 1993.

Approved by the ASHP Board of Directors, on April 27, 2000

Developed through the ASHP Council on Professional Affairs.

The bibliographic citation for this document is as follows: American

Society of Health-System Pharmacists. ASHP Guidelines on Quality

Drug Distribution and Control: Preparation and Handling–Guidelines 105

Assurance for Pharmacy-Prepared Sterile Products. Am J Health-

Syst Pharm. 2000; 57:1150–69.

Appendix A—Glossary

Action Level: Established particulate or microbial counts or

results that require corrective action when exceeded.

Aseptic Preparation or Aseptic Processing: The technique

involving procedures designed to preclude contamina-

tion (of drugs, packaging, equipment, or supplies) by

microorganisms during processing.

Batch Preparation: Compounding of multiple sterile prod-

uct units, in a single discrete process, by the same in-

dividuals, carried out during one limited time period.

Cleanroom: A room (1) in which the concentration of air-

borne particles is controlled, (2) that is constructed and

used in a manner to minimize the introduction, genera-

tion, and retention of particles inside the room, and (3)

in which other relevant variables (e.g., temperature,

humidity, and pressure) are controlled as necessary.

For example, the air particle count in a class 100 clean-

room cannot exceed a total of 100 particles 0.5 μm or

larger per cubic foot of air.

Clean Zone: Dedicated space (1) in which the concentration

of airborne particles is controlled, (2) that is constructed

and used in a manner that minimizes the introduction,

generation, and retention of particles inside the zone,

and (3) in which other relevant variables (e.g., tempera-

ture, humidity, and pressure) are controlled as necessary.

This zone may be open or enclosed and may or may not

be located within a cleanroom.

For example, an open-

architecture controlled area should be a clean zone.

Closed-System Transfer: The movement of sterile products

from one container to another in which the contain-

ers-closure system and transfer devices remain intact

throughout the entire transfer process, compromised

only by the penetration of a sterile, pyrogen-free nee-

dle or cannula through a designated closure or port to

effect transfer, withdrawal, or delivery. Withdrawal of

a sterile solution from an ampul through a particulate

filter in a class 100 environment would generally be

considered acceptable; however, the use of a flexible

closure vial, when available, would be preferable.

Compounding: For purposes of these guidelines, com-

pounding simply means the mixing of ingredients

to prepare a medication for patient use. This activity

would include dilution, admixture, repackaging, re-

constitution, and other manipulations of sterile prod-

ucts.

Controlled Area: For purposes of these guidelines, a controlled

area is the area designated for preparing sterile products.

This is referred to as the buffer zone (i.e., the cleanroom in

which the laminar-airflow workbench is located) by USP.

Corrective Action: Action to be taken when the results of

monitoring indicate a loss of control or when action

levels are exceeded.

Critical Area: Any area in the controlled area where prod-

ucts or containers are exposed to the environment.

Critical Site: An opening providing a direct pathway between

a sterile product and the environment or any surface

coming into contact with the product or environment.

Critical Surface: Any surface that comes into contact with

previously sterilized products or containers.

Designated Pharmacist: The pharmacist chosen by experi-

ence and training to be in charge of a sterile product

preparation area or unit in a licensed pharmacy.

Expiration Date: The date (and time, when applicable)

beyond which a product should not be used (i.e., the

product should be discarded beyond this date and

time). Expiration date and time should be assigned on

the basis of both stability and risk level, whichever is

the shorter period. Note: Circumstances may occur in

which the expiration date and time arrive while an infu-

sion is in progress. When this occurs, judgment should

be applied in determining whether it is appropriate

to discontinue that infusion and replace the product.

Organizational policies on this should be clear.

High-Efficiency Particulate Air (HEPA) Filter: A filter

composed of pleats of filter medium separated by rigid

sheets of corrugated paper or aluminum foil that direct

the flow of air forced through the filter in a uniform par-

allel flow. HEPA filters remove 99.97% of all air par-

ticles 0.3 μm or larger. When HEPA filters are used as a

component of a horizontal- or vertical-laminar-airflow

workbench, an environment can be created consistent

with standards for a class 100 cleanroom.

Isolator (or Barrier Isolator): A closed system made up

of four solid walls, an air-handling system, and trans-

fer and interaction devices. The walls are constructed

so as to provide surfaces that are cleanable with cov-

ing between wall junctures. The air-handling system

provides HEPA filtration of both inlet and exhaust

air. Transfer of materials is accomplished through air

locks, glove rings, or ports. Transfers are designed to

minimize the entry of contamination. Manipulations

can take place through either glove ports or half-suits.

Media Fill: See process validation or simulation.

Preservatives: For purposes of these guidelines, preserva-

tives refer to any additive intended to extend the con-

tent, stability, or sterility of active ingredients (e.g., an-

tioxidants, emulsifiers, bacteriocides).

Process Validation or Simulation: Microbiological simulation

of an aseptic process with growth medium processed in a

manner similar to the processing of the product and with

the same container or closure system.

Process simula-

tion tests are synonymous with medium fills, simulated

product fills, broth trials, and broth fills.

Quality Assurance: For purposes of these guidelines, quality

assurance is the set of activities used to ensure that the pro-

cesses used in the preparation of sterile drug products lead

to products that meet predetermined standards of quality.

Quality Control: For purposes of these guidelines, quality con-

trol is the set of testing activities used to determine that the

ingredients, components (e.g., containers), and final sterile

products prepared meet predetermined requirements with

respect to identity, purity, nonpyrogenicity, and sterility.

Repackaging: The subdivision or transfer of a compounded

product from one container or device to a different con-

tainer or device, such as a syringe or an ophthalmic con-

tainer.

Sterilization: A validated process used to render a product

free of viable organisms.

Sterilizing Filter: A filter that, when challenged with a solution

containing the microorganism Pseudomonas diminuta at

a minimum concentration of 10

organisms per square

centimeter of filter surface, will produce a sterile effluent.

106 Drug Distribution and Control: Preparation and Handling–Guidelines

Temperatures (USP): Frozen means temperatures between

–20 and –10 °C (–4 and 14 °F). Refrigerated means

temperatures between 2 and 8°C (36 and 46 °F). Room

temperature means temperatures between 15 and 30 °C

(59 and 86 °F).

Validation: Documented evidence providing a high degree

of assurance that a specific process will consistently

produce a product meeting its predetermined specifi-

cations and quality attributes.

Worst Case: A set of conditions encompassing upper and

lower processing limits and circumstances, including

those within standard operating procedures, that pose

the greatest chance of process or product failure when

compared with ideal conditions. Such conditions do

not necessarily induce product or process failure.

Appendix B—Comparison

of Risk-Level Attributes

This appendix does not show all details of the guidelines,

nor does it tell whether an aspect of the sterile compound-

ing process is “required” (must be) or “advisable” (should

be). Regardless of the examples given, each compounding

pharmacist must decide, according to the circumstances at

the time, what conditions are appropriate for compounding

a sterile product. In an emergency, it may be of more benefit

to a patient to receive a sterile drug prepared under lower

risk-level conditions. For the immunocompromised patient,

even simple, single-patient admixtures may need to be com-

pounded under higher risk-level conditions.

Definition of Products by Risk Level

Risk Level 1

Risk Level 2

Products that are (1) stored at room

temperature and completely

administered within 28 hours from

preparation, (2) unpreserved and

sterile and prepared for administration

to one patient, or batch prepared for

administration to more than one patient

and contain suitable preservatives, and

(3) prepared by closed-system aseptic

transfer of sterile, nonpyrogenic,

finished pharmaceuticals obtained

from licensed manufacturers into

sterile final containers obtained from

licensed manufacturers.

Products that are (1) administered

beyond 28 hours after preparation

and storage at room temperature,

(2) batch prepared without

preservatives and intended for use

by more than one patient, or (3)

compounded by complex or numerous

manipulations of sterile ingredients

obtained from licensed manufacturers

in a sterile container obtained from

a licensed manufacturer by using

closed-system, aseptic transfer.

Risk Level 3

Products that are (1) compounded

from nonsterile ingredients or with

nonsterile components, containers, or

equipment before terminal sterilization

or (2) prepared by combining multiple

ingredients (sterile or nonsterile) by

using an open-system transfer or open

reservoir before terminal sterilization.

Examples of Sterile Products by Risk Level

Risk Level 1

Risk Level 2 Risk Level 3

Single-patient admixture

Injections for use in portable pump

or reservoir over multiple days

Alum bladder irrigation

Policies and Procedures

Risk Level 1

Risk Level 2

Up-to-date policies and procedures for compounding

sterile products should be available to all involved

personnel. When policies are changed, they

should be updated. Procedures should address

personnel education and training, competency

evaluation, product acquisition, storage and

handling of products and supplies, storage and

delivery of final products, use and maintenance

of facilities and equipment, appropriate garb and

conduct of personnel working in the controlled area,

process validation, preparation technique, labeling,

documentation, quality control, and material

movement.

Risk Level 3

In addition to risk level 1

guidelines, procedures describe

environmental monitoring devices

and techniques, cleaning

materials and disinfectants,

equipment accuracy monitoring,

limits of acceptability

and corrective actions for

environmental monitoring and

process validation, master

formula and work sheets,

personnel garb, lot numbers, and

other quality control methods.

Procedures cover every aspect

of preparation of level 3 sterile

products, so that all products

have the identity, strength,

quality, and purity purported for

the product. Thirteen general

policies and procedures, in

addition to those in levels 1 and

2, are required.

Single-patient ophthalmic, preserved

Single-patient syringes without preservatives

used in 28 hours

Batch-prefilled syringes with preservatives

Total parenteral nutrient (TPN) solution made

by gravity transfer of carbohydrate and

amino acids into an empty container with the

addition of sterile additives with a syringe and

needle

Autoclaved i.v. solutions

Batch-reconstituted antibiotics

without preservatives

Batch-prefilled syringes without

preservatives

TPN solutions mixed with an

automatic compounding device

Morphine injection made from powder or

tablets

TPN solutions made from dry amino acids

TPN solutions sterilized by final filtration

Drug Distribution and Control: Preparation and Handling–Guidelines 107

Personnel Education, Training, and Evaluation

Risk Level 1 Risk Level 2

All pharmacy personnel preparing

sterile products should receive

suitable didactic and experiential

training and competency evaluation

through demonstration or testing

(written or practical). In addition

to the policies and procedures

listed above, education includes

chemical, pharmaceutical, and clinical

properties of drugs and current good

compounding practices.

Risk Level 3

Operators have specific education,

training, and experience to

prepare risk level 3 products.

Pharmacist knows principles of

good compounding practice for risk

level 3 products, including aseptic

processing; quality assurance of

environmental, component, and

end-product testing; sterilization;

and selection and use of containers,

equipment, and closures.

In addition to guidelines in risk level

1, training includes assessment of

competency in all types of risk level

2 procedures via process simulation.

Personnel show competency in end-

product testing as well.

Storage and Handling in the Pharmacy

Risk Level 1

Solutions, drugs, supplies, and equipment must be stored

according to manufacturer or USP requirements. Refrigerator

and freezer temperatures should be documented daily. Other

storage areas should be inspected regularly to ensure that

temperature, light, moisture, and ventilation meet requirements.

Drugs and supplies should be shelved above the floor. Expired

products must be removed from active product storage

areas. Personnel traffic in storage areas should be minimized.

Removal of products from boxes should be done outside

controlled areas. Disposal of used supplies should be done at

least daily. Product-recall procedures must permit retrieving

affected products from specific involved patients.

Risk Level 2

All guidelines for risk level

1 apply.

Risk Level 3

In addition to risk level 1

guidelines, procedures

include procurement,

identification, storage,

handling, testing, and

recall of components

and finished products.

Finished but untested

products must be

quarantined under

minimal risk for

contamination or loss of

identity in an identified

quarantine area.

Risk Level 3

Products must be prepared in a

class 100 workbench in a class

10,000 cleanroom, in a class 100

cleanroom, or in a suitable barrier

isolator. Access to the cleanroom

must be limited to those preparing

the products who are in appropriate

garb. Methods are needed for

cleaning, preparing, sterilizing,

calibrating, and documenting the use

of all equipment. Walls and ceilings

should be disinfected weekly. All

nonsterile equipment that is to come

in contact with the sterilized final

product should be sterilized before

introduction into the cleanroom. An

anteroom of high cleanliness (i.e.,

class 100,000) should be provided.

Appropriate cleaning and disinfection

of the environment and equipment

are required.

Risk Level 2

In addition to risk level 1

guidelines, the following are

recommended for risk level

2 products: controlled area

must meet class 10,000

cleanroom standards; cleaning

supplies should be selected

to meet cleanroom standards;

critical-area work surface

must be cleaned between

batches; floors should be

disinfected daily, equipment

surfaces weekly, and walls

monthly; and there should be

environmental monitoring of air

and surfaces. An anteroom of

high cleanliness is desirable.

Automated compounding

devices must be calibrated

and verified as to accuracy,

according to procedure.

Risk Level 1

The controlled area should be separated from

other operations to minimize unnecessary

flow of materials and personnel through

the area. The controlled area must be

clean, well lighted, and of sufficient size for

sterile compounding. A sink with hot and

cold water should be near, but not in, the

controlled area. The controlled area and

inside equipment must be cleaned and

disinfected regularly. Sterile products must

be prepared in a class 100 environment (the

critical area), such as within a horizontal- or

vertical-laminar-airflow workbench or barrier

isolator. Computer entry, order processing,

label generation, and record keeping should

be performed outside the critical area. The

critical area must be disinfected periodically.

A workbench should be recertified every six

months or when it is moved; prefilters should

be changed periodically. Pumps should be

recalibrated according to procedure.

Facilities and Equipment

108 Drug Distribution and Control: Preparation and Handling–Guidelines

Garb

Risk Level 1

In the controlled area, personnel wear low-

particulate, clean clothing covers such as

clean gowns or coverall with sleeves having

elastic cuffs. Hand, finger, and wrist jewelry

is minimized or eliminated. Nails are clean

and trimmed. Gloves are recommended;

those allergic to latex rubber must wear

gloves made of a suitable alternative.

Head and facial hair is covered. Masks are

recommended during aseptic preparation.

Personnel preparing sterile products scrub

their hands and arms with an appropriate

antimicrobial skin cleanser.

Risk Level 2

In addition to risk level 1

guidelines, gloves, gowns, and

masks are required. During

sterile preparation, gloves

should be rinsed frequently

with a suitable agent (e.g.,

70% isopropyl alcohol) and

changed when their integrity

is compromised. Shoe covers

are helpful in maintaining the

cleanliness of the controlled

area.

Risk Level 3

In addition to risk level 1 and 2

guidelines, cleanroom garb must

be worn inside the controlled area

at all times during the preparation

of risk level 3 sterile products. Attire

consists of a low-shedding coverall,

head cover, face mask, and shoe

covers. Before donning this garb,

personnel must thoroughly wash

their hands and arms. Upon return to

the controlled area or support area

during processing, personnel should

regown with clean garb.

Aseptic Technique and Product Preparation

Risk Level 1

Risk Level 2

Risk Level 3

In addition to risk level 1 and

2 guidelines, nonsterile

components must meet

USP standards for identity,

purity, and endotoxin levels,

as verified by a pharmacist.

Batch master work sheets

should also include

comparisons of actual

with anticipated yields,

sterilization methods, and

quarantine specifications.

Presterilized containers

should be used if feasible.

Final containers must

be sterile and capable

of maintaining product

integrity throughout shelf

life. Sterilization method

is based on properties of

the product. Final filtration

methods require attention to

many elements of product,

filter, and filter integrity.

In addition to risk level 1

guidelines, a master

work sheet containing

formula, components,

procedures, sample label,

final evaluation, and testing

is made for each product

batch. A separate work

sheet and lot number are

used for each batch. When

combining multiple sterile

ingredients, a second

pharmacist should verify

calculations. The pharmacist

should verify data

entered into an automatic

compounder before

processing and check the

end product for accuracy.

Sterile products must be prepared in a class 100

environment. Personnel scrub their hands and forearms

for an appropriate period at the beginning of each aseptic

compounding process. Eating, drinking, and smoking are

prohibited in the controlled area. Talking is minimized to

reduce airborne particles. Ingredients are determined to

be stable, compatible, and appropriate for the product to

be prepared, according to manufacturer, USP, or scientific

references.

Ingredients result in final products that meet

physiological norms as to osmolality and pH for the

intended route of administration. Ingredients and

containers are inspected for defects, expiration, and

integrity before use. Only materials essential for aseptic

compounding are placed in the workbench. Surfaces

of ampuls and vials are disinfected before placement

in the workbench. Sterile components are arranged in

the workbench to allow uninterrupted laminar airflow

over critical surfaces of needles, vials, ampuls, etc.

Usually only one person and one preparation are in the

workbench at a time. Automated devices and equipment

are cleaned, disinfected, and placed in the workbench

to enable laminar airflow. Aseptic technique is used to

avoid touch contamination of critical sites of containers

and ingredients. Sterile powders are completely

reconstituted. Particles are filtered from solutions. Needle

cores are avoided. The pharmacist checks before,

during, and after preparation to verify the identity and

amount of ingredients before release.

Process Validation

Risk Level 1 Risk Level 2

All persons who prepare sterile products should pass a

process validation of their aseptic technique before

they prepare sterile products for patient use. Personnel

competency should be reevaluated by process validation

at least annually, whenever the quality assurance

program yields an unacceptable result, and whenever

unacceptable techniques are observed. If microbial

growth is detected, the entire sterile process must be

evaluated, corrective action taken, and the process

simulation test performed again.

All risk level 1 guidelines apply,

and process-simulation

procedures should cover

all types of manipulations,

products, and batch sizes

that are encountered in risk

level 2.

Risk Level 3

In addition to risk level 1 and 2

guidelines, written policies

should be made to validate

all processes (including all

procedures, components,

equipment, and techniques)

for each risk level 3 product.

Drug Distribution and Control: Preparation and Handling–Guidelines 109

Handling Sterile Products Outside the Pharmacy

Risk Level 1

Sterile products are transported so as to be protected from excesses of

temperatures and light. Transit time and condition should be specified.

Delivery personnel should be trained as appropriate. Pharmacists ascertain

that the end user knows how to properly store products. End users notify

pharmacists when storage conditions are exceeded or when products

expire so that pharmacists can arrange safe disposal or return.

Risk Level 2

All guidelines for risk

level 1 should be

met.

Risk Level 3

All guidelines for risk

level 1 should be

met.

Documentation

Risk Level 1 Risk Level 2

The following must be documented according

to policy, laws, and regulations: (1) training

and competency evaluation of employees,

(2) refrigerator and freezer temperature logs,

(3) certification of workbenches, and (4) other

facility quality control logs as appropriate.

Pharmacists maintain appropriate records for the

compounding and dispensing of sterile products.

In addition to the guidelines in

risk level 1, documentation

of end-product testing and

batch-preparation records

must be maintained

according to policies,

laws, and regulations.

Risk Level 3

In addition to the guidelines in risk

levels 1 and 2, documentation

for risk level 3 products must

include (1) preparation work sheet,

(2) sterilization records if applicable,

(3) quarantine records if applicable,

and (4) end-product evaluation and

testing records.

Risk Level 3

In addition to risk level 1 and 2

guidelines, there must be a reliable

method for establishing all expiration

dates, including laboratory testing of

product stability, pyrogenicity, and

chemical content when necessary.

Risk Level 2

All guidelines for risk level

1 should be met.

Risk Level 1

Expiration Dating

All sterile products must bear an appropriate expiration

date. Expiration dates are assigned based on

current drug stability information and sterility

considerations. The pharmacist considers all

aspects of the final product, including drug reservoir,

drug concentration, and storage conditions.

Labeling

Risk Level 1

Sterile products should be labeled with at least the following information: (1) for

patient-specific product’s, the patient’s name and other appropriate patient

identification; for batch-prepared products, control or lot numbers, (2) all solution

and ingredient names, amounts, strengths, and concentrations, (3) expiration date

(and time when applicable), (4) prescribed administration regimen, (5) appropriate

auxiliary labeling, (6) storage requirements, (7) identification of the responsible

pharmacist, (8) any device-specific instructions, and (9) any additional information,

in accordance with state and federal regulations. A reference number for the

prescription or order may also be helpful. The label should be legible and affixed to

the product so that it can be read while being administered.

Risk Level 2

All guidelines

for risk level 1

must be met.

Risk Level 3

All guidelines for

risk levels 1

and 2 must be

met.

Risk Level 3

In addition to risk level 1 and 2 guidelines, the medium-fill

procedure should be supplemented with a program

of end-product sterility testing according to a formal

sampling plan. Samples should be statistically

adequate to reasonably ensure that batches are sterile.

A method for recalling batch products should be

established if end-product testing yields unacceptable

results. Each sterile preparation or batch must be

laboratory tested for conformity to written specifications

(e.g., concentration, pyrogenicity). It is advisable to

quarantine sterile products compounded from nonsterile

components pending the results of end-product testing.

Risk Level 2

In addition to risk level 1

guidelines, toxic products,

like concentrated glucose

and potassium chloride,

should be tested for

accuracy of concentration.

End-Product Evaluation

Risk Level 1

The final product must be

inspected for container leaks,

integrity, solution cloudiness or

phase separation, particulates

in solution, appropriate

solution color, and solution

volume. The pharmacist must

verify that the product was

compounded accurately as

to ingredients, quantities,

containers, and reservoirs.