مدونة تصنيع الأدوية في المستشفيات

Manufacturing and
Compounding of
Medications
Version 1.1
1 September 2010 Page 1 of 3

Manufacturing and Compounding of
Medications
Version 1.1
Drug Sector
Saudi Food & Drug Authority
Kingdom of Saudi Arabia
Please visit SFDA’s website at http://www.sfda.gov.sa/En/Drug for

the latest update

Section –I-
Good Compounding Practices
Section –II-
Pharmaceutical Compounding-Nonsterile Preparations
Section –III-
Pharmaceutical Compounding-Sterile Preparations

Good Compounding
Practices
Version 1.1

TABLE OF CONTENTS :
1. PURPOSE .................................................................................................................................. 3
2. APPLICABLE DEFINITIONS ............................................................................................ 3
3. RESPONSIBILITIES OF THE COMPOUNDER ............................................................. 5
4. TRAINING ............................................................................................................................. 6
5. PROCEDURES AND DOCUMENTATION ....................................................................... 7
6. DRUG COMPOUNDING FACILITIES ............................................................................. 7
7. DRUG COMPOUNDING EQUIPMENT ............................................................................ 8
8. COMPONENT SELECTION ............................................................................................... 9
9. PACKAGING AND DRUG PRODUCT CONTAINERS................................................. 10
10. COMPOUNDING CONTROLS ......................................................................................... 11
11. LABELING .......................................................................................................................... 12
12. RECORDS AND REPORTS ............................................................................................... 14
13. COMPOUNDING VETERINARIAN PRODUCTS ......................................................... 14
14. COMPOUNDING FOR A PRESCRIBER'S OFFICE USE ............................................. 14
15. COMPOUNDING PHARMACY GENERATED PRODUCTS ...................................... 15

1 PURPOSE
The purpose of this chapter is to provide compounders with guidance on applying good
compounding practices for the preparation of compounded formulations for dispensing and/or
administration to humans or animals. It is expected that pharmacists or compounders engaged in
the compounding of drugs will compound in conformance with applicable compounding laws,
regulations, or guidelines.
2 APPLICABLE DEFINITIONS
Compounding (see Pharmaceutical Compounding—Nonsterile Preparations)
Compounding involves the preparation, mixing, assembling, packaging, and labeling of a drug or
device in accordance with a licensed practitioner's prescription under an initiative based on the
practitioner/patient/pharmacist/compounder relationship in the course of professional practice.
Compounding includes the following:
a. Preparation of drugs or devices in anticipation of prescription drug orders based on routine,

regularly observed prescribing patterns.
b. Reconstitution of commercial products that may require the addition of two or more
ingredients as a result of a licensed practitioner's prescription drug order.
c. Manipulation of commercial products that may require the addition of one or more
ingredients as a result of a licensed practitioner's prescription drug order.
d. Preparation of drugs or devices for the purposes of, or as an incident to, research, teaching,
or chemical analysis.
Levels of Compounding—
Level 1 Nonsterile (topical)
Mixing of one or two creams
Mixing of creams with alcohol, water, etc. (as per
manufacturer's labeling instruction)
Level 2 Nonsterile (topical)
Preparation of nonsterile topical ointment, cream
Preparations with no dosage limitation
Level 3 Nonsterile (reconstituting or flavoring)
Reconstitution according to manufacturer's

labeling instruction
Addition of flavoring
Level 4 Sterile (simple injections, e.g., reconstituted for
immediate administration)
Preparation of injections for immediate administration
Level 5 Nonsterile (dosage forms)
Preparation of solid oral dosage forms (tablets,
capsules)
Preparation of liquid oral dosage forms
(emulsion, solutions, suspensions, etc.)
Preparation of suppositories, lozenges
Level 6 Sterile (ophthalmics/otics)
Preparation of ophthalmic and otic suspensions,
solutions
Level 7 Sterile (complex injections)
Preparation of injections for many patients
Preparation of injection not for immediate
administration
Preparation of total parenteral nutritions (TPNs)
Preparation of multi-component injection
Level 8 Other sterile injections and patches
Preparation of chemotherapeutic injections or
implants
Preparation of transdermal medications
Level 9 Sterile (radiopharmaceuticals)
Preparation of radiopharmaceuticals
Manufacturing— Manufacturing involves the production, propagation, conversion, or processing

of a drug or device, either directly or indirectly, by extraction of the drug from substances of
natural origin or by means of chemical or biological synthesis. Manufacturing also includes (1) any
packaging or repackaging of the substance(s) or labeling or relabeling of containers for the
promotion and marketing of such drugs or devices; (2) any preparation of a drug or device that is
given or sold for resale by pharmacies, practitioners, or other persons; (3) the distribution of
inordinate amounts of compounded preparations or the copying of commercially available drug
products; and (4) the preparation of any quantity of a drug product without a licensed
prescriber/patient/licensed pharmacist/compounder relationship.

Component— A component is any ingredient used in the compounding of a drug product,
including any that are used in its preparation, but may not appear on the labeling of such a product.
(for additional definitions See Pharmaceutical Compounding—Nonsterile Preparations.)
Pharmacy Generated Product (PGP)— A pharmacy generated product (PGP) is a product that is
prepared, packaged, and labeled in a pharmacy and can be sold by the pharmacy without a
prescription.
Compounder— A compounder is a pharmacist or a physician who is engaged in the act of
compounding pursuant to a prescription order by a licensed prescriber.
3 RESPONSIBILITIES OF THE COMPOUNDER

a. Compounders who are engaged in drug compounding or nutriceutical compounding shall
be proficient in compounding and should continually expand their compounding
knowledge by participating in seminars and/or studying appropriate literature.
b. A compounder shall be familiar with all of the details of Pharmaceutical Compounding—
Nonsterile Preparations, Pharmaceutical Compounding—Sterile Preparations , and other
applicable compounding guidelines or laws. In addition, the compounder shall be
responsible for the following:
• Certifying all prescription orders;
• Approving or rejecting all components, drug product containers, closures, in-
process materials, and labeling;
• Preparing and reviewing all compounding records to assure that errors have not
occurred in the compounding process;
• Assuring the proper maintenance, cleanliness, and use of all equipment used in a
prescription compounding practice;
• Assuring that only personnel authorized by the compounding supervisor shall be in
the immediate vicinity of the drug compounding operations;
• Assuring that the drug product and components of drug products are not on the list
of drug products that have been withdrawn or removed from the market for public
health reasons.

c. The compounder shall ensure that personnel engaged in compounding wear clean clothing
appropriate to the type of compounding performed, e.g., coats, gowns, gloves, masks,
shoes, aprons, or other items as needed for protection of personnel from chemical
exposures and for prevention of drug contamination.
d. The compounder shall implement procedures to prevent cross-contamination when
compounding with drugs (e.g., penicillins) that require special precaution to prevent cross-
contamination.
4 TRAINING
All personnel involved in the compounding, evaluation, packaging, and dispensing of compounded
preparations shall be properly trained for the type of compounding conducted. All training
activities will be covered by appropriate standard operating procedures (SOPs) and documentation.
All compounders and all personnel involved in compounding must be well trained and must
participate in current, relevant training programs. It is the responsibility of the pharmacist to ensure
that a training program has been implemented and that it is ongoing. Standards of pharmacy
practice require that all employees be adequately trained in their job functions and that all of the
training is properly documented. Steps in the training procedure will include the following:
a. All employees involved in pharmaceutical compounding shall read and become familiar
with Pharmaceutical Compounding—Nonsterile Preparations, Pharmaceutical
Compounding—Sterile Preparations.
b. All employees shall read and become familiar with each of the procedures related to
compounding, including those involving the facility, equipment, and personnel, actual
compounding, evaluation, packaging, storage, and dispensing.
c. The compounder shall meet with employees to review their work and answer any questions
the employees may have concerning SOPs.
d. The compounder shall demonstrate the procedures for the employee, and will observe and
guide the employee throughout the procedure. The employee will then repeat the procedure
without any assistance from, but under the supervision of, the pharmacist.
e. When the employee has demonstrated to the compounder a verbal and functional
knowledge of the procedure, then and only then, will the employee be permitted to perform
the procedure without supervision.

f. When the compounder is satisfied with the employee’s knowledge and proficiency, the
compounder will sign off on the documentation records to show that both the employee and
the compounder agree.
g. The compounder shall continually monitor the work of the employee and answer any
questions the employee may have concerning the SOPs.
5 PROCEDURES AND DOCUMENTATION

All significant procedures performed in the compounding area will be covered by SOPs and will
be documented.
Procedures should be developed for the facility, equipment, personnel, preparation, packaging, and
storage of compounded preparations to ensure accountability, accuracy, quality, safety (including
access to Material Safety Data Sheets) and uniformity in a compounding practice. More
importantly, implementing SOPs establishes procedural consistency and also provides a reference
for orientation and training of personnel.
Documentation enables a pharmacy, whenever necessary, to systematically trace, evaluate, and
replicate the steps included throughout the preparation process of a compounded product.
6 DRUG COMPOUNDING FACILITIES

a. Compounding facilities shall have an adequate space that is specifically designated for
compounding of prescriptions. This area may include a space for the storage of equipment
and materials.
b. Sterile compounded preparations shall be compounded in accordance with the provisions in
Pharmaceutical Compounding—Sterile Preparations and aseptic processes shall be
conducted in an area separate and distinct from the area used for the compounding of
nonsterile products.
c. The areas used for compounding shall be maintained in clean, orderly, and sanitary
conditions.
d. The areas for drug compounding shall be maintained in a good state of repair. The
plumbing system shall be free of defects that could contribute to contamination of any

compounded product. Adequate washing facilities shall be easily accessible to the
compounding areas. Such facilities shall include, but not be limited to, hot and cold water,
soap or detergent, and an air-drier or single-use towels.
e. Potable water shall be supplied under continuous positive pressure.
f. The area for compounding shall have adequate lighting and ventilation.
g. The area for compounding shall be free of infestation by insects, rodents, and other vermin.
Trash shall be held and disposed of in a sanitary and timely manner.
h. Sewage and other refuse in the area of compounding shall be disposed of in a safe and
sanitary manner.
i. Bulk drugs and other chemicals or materials used in the compounding of drugs must be
stored as directed by the manufacturer, or according to USP monograph requirements, in a
clean, dry area (defined temperature condition), or in a refrigerator or freezer as specified.
The bulk chemicals shall be stored in a manner such that they are protected from
contamination. All containers shall be properly labeled.
j. If parenteral products are compounded, the compounder shall refer to Pharmaceutical
Compounding—Sterile Preparations  for compounding technique applications.
7 DRUG COMPOUNDING EQUIPMENT

(See also Pharmaceutical Compounding—Nonsterile Preparations .)
a. The equipment or utensils used for compounding of a drug product shall be of appropriate
design and capacity. The equipment shall be stored in such a manner as to protect it from
contamination, and shall be located in such a place as to facilitate operations for its use,
maintenance, and cleaning.
b. The equipment shall be cleaned and sanitized prior to use to prevent contamination that
may affect the safety or quality of compounded preparations.
c. The equipment shall be of suitable composition such that the surfaces that contact
components are neither reactive, additive, nor absorptive and therefore will not affect or
alter the purity of the compounded preparations.
d. Automated, mechanical, electronic, and other types of equipment used in compounding
shall be routinely inspected, calibrated as necessary, and checked to ensure proper
performance.

e. Immediately prior to initiation of compounding operations, the equipment shall be
inspected by the compounder to determine its suitability for use.
f. The equipment shall be cleaned appropriately using special instructions when cross-
contaminating products or products requiring special precaution, e.g., antibiotics,
cytotoxins, cancer drugs, and other hazardous materials, are used with the equipment. If
possible, special equipment may be dedicated for such use or if the same equipment is
being used for all drug products, appropriate procedures must be in place to allow
meticulous cleaning of equipment prior to use with other drugs.
8 COMPONENT SELECTION REQUIREMENTS

a. The compounder shall first attempt to use USP–NF drug substances manufactured in a
Ministry of health (MOH)-registered facility.
b. The compounder shall also first attempt to use inactive components manufactured in an
MOH-registered facility.
c. If components are not obtainable from an FDA-registered facility or if the FDA and/or the
providing company cannot document FDA registration, compounders shall use their
professional judgment in first receiving, storing, or using the components that meet official
compendial requirements or are provided by another high quality source.
d. If components of compendial quality are not obtainable, components of high quality such
as those that are chemically pure, analytical reagent grade, American Chemical Society-
certified, or Food Chemical Codex grade may be used.
e. When a component is not obtained from an official compendial source or is not obtainable
from the sources mentioned above, the component may be obtained from a source deemed
acceptable and reliable in the professional judgment of the compounder.
f. When a component is derived from ruminant animals (e.g., bovine, caprine, ovine) the
supplier shall provide written assurance that these animals were born, raised, or slaughtered
in countries where bovine spongiform encephalopathy (BSE) and scrapie are known not to
exist.
g. The compounder shall not use components that are listed by FDA to be withdrawn from the
market for public health reasons.

h. Components shall be stored off the floor, handled and stored to prevent contamination, and
rotated so that the oldest stock is used first.
9 PACKAGING AND DRUG PRODUCT CONTAINERS

a. The compounder shall ensure that the containers and container closures used in packaging
the compounded preparations meet the international requirements.
b. The compounder shall obtain written records from the supplier to show that the containers
meet USP requirements.
c. Containers and container closures intended for compounding of sterile preparations and
nonsterile preparations must be handled, sterilized (if appropriate), and stored as described
in Pharmaceutical Compounding—Sterile Preparations and Pharmaceutical
Compounding—Nonsterile Preparations. The use of commercially available presterilized
containers may be considered.
d. The containers and closures shall be stored off the floor, handled and stored to prevent
contamination, and rotated so that the oldest approved stock is used first.
e. The containers and container closures shall be stored in such a way as to permit inspection
and cleaning of the work area.
f. The containers and container closures shall be made of clean materials that are neither
reactive, additive, nor absorptive.
g. The containers and closures shall be of suitable material so as not to alter the quality,
strength, or purity of the compounded drug.
h. The compounder shall ensure that the containers and container closures selected to
dispense the finished compounded prescription, whether sterile or nonsterile or
radiopharmaceutical, meet the criteria in sections (a)–(f) above.
10 COMPOUNDING CONTROLS
a. The compounder shall ensure that there are written procedures for the compounding of
drug products to assure that the finished products have the identity, strength, quality, and
purity that they purport to have.

b. The compounder shall establish procedures for listing components, their amounts (weight
or volume), the order of component mixing, and a description of the compounding process.
c. The compounder shall list all equipment, utensils, and container closure systems relevant to
the sterility, stability, and intended use of a drug.
d. The written procedures described above shall be followed in execution of the compounding
process.
e. The compounder shall accurately weigh, measure, and subdivide as appropriate.
f. The compounder shall check and recheck each procedure at each stage of the process to
ensure that each weight or measure is correct as stated in the written compounding
procedures.
g. If a component is transferred from the original container to another container (e.g., a
powder is taken from the original container, weighed, placed in a container, and stored in
that other container), the new container shall be identified with the component name,
weight or measure, the lot or control number, the expiration or beyond-use date, and the
transfer date.
h. The compounder shall have drug compounding procedures available in either written form
or electronically stored with printable documentation.
i. The procedures shall include a description of (1) the components, their amounts, the order
of component additives, and the compounding process; (2) the required equipment and
utensils; and (3) the drug product container and closure system.
j. The compounder shall have established written procedures that will describe the tests or
examinations to be conducted on the product compounded (e.g., the degree of weight
variation among capsules) to assure uniformity and integrity of compounded drug products.
k. Appropriate control procedures shall be established to monitor the output and to validate
the performance of those compounding processes that may be responsible for causing
variability in the final compounded preparations. Factors that may cause variability include
(1) capsule weight variation; (2) adequacy of mixing to assure uniformity and
homogeneity; and (3) clarity, completeness, or pH of solutions.
l. Appropriate written procedures shall be designed to prevent microbiological contamination
of compounded drug products purporting to be sterile, and these procedures shall be

followed. Such procedures shall include validation of sterilization processes (see
Pharmaceutical Compounding—Sterile Preparations).
m. The compounder shall establish appropriate beyond-use dates determined either from
available USP–NF monographs, appropriate testing, or from peer-reviewed literature.
n. The compounder shall adopt appropriate storage requirements as provided in Preservation,
Packaging, Storage, and Labeling under General Notices and Requirements.
11 LABELING
1. Products prepared in anticipation of a prescription prior to receiving a valid prescription
should not be prepared in an inordinate amount. A regularly used amount should be
prepared on the basis of a history of prescriptions filled by the pharmacy. These products
shall be labeled or documentation referenced with the following:
a. A complete list of ingredients or preparation name and reference or established
name or distinct common name
b. Dosage form
c. Strength
d. Preparation date
e. Name and address of compounder
f. Inactive ingredients
g. Batch or lot number
h. Assigned beyond-use date, based on published data, or appropriate testing, or USP–
NF standards.
Storage conditions for these products shall be dictated by their composition

and sterility, e.g., stored in a clean, dry place (defined temperature condition),
in a refrigerator, or at controlled room temperature.
2. The compounder shall examine the product for correct labeling after completion of the
compounding process.

3. The compounder's prescription label shall contain the following:
a. Patient's name
b. Prescriber's name
c. Name and address of compounder
d. Prescription number
e. Established name or distinct common name (cannot use trademarked name of a
manufactured product)
f. Strength
g. Statement of quantity
h. Directions for use
i. Date filled
j. Beyond-use date/storage, etc.
k. An appropriate designation that this is a compounded prescription
4. The compounder shall label any excess compounded products so as to reference them to
the formula used, the assigned control number, and beyond-use date based on the
compounder's appropriate testing, published data, or USP–NF standards.
12 RECORDS AND REPORTS

a. The compounder shall maintain records, including but not limited to, the hard copy of the
prescription to indicate that the prescription is compounded.
b. The compounder shall keep adequate records of controlled drug substances (scheduled
drugs) used in compounding.
c. All records of all compounded products shall be kept for a period of time as set forth in the
MOH laws or regulations. Such records shall be readily available for authorized inspection.
13 COMPOUNDING FOR A PRESCRIBER'S OFFICE USE

a. Compounders may prepare compounded drug products for a prescriber's office use
pursuant to MOH requirements.
b. An order by the prescriber indicating the formula and quantity ordered may be filled in the
compounder's facility.

c. The compounder shall compound the product for the purpose of administration by or for
the prescriber.
d. A record of the compounding process shall be maintained.
e. A label may be generated and a number may be assigned.
14 COMPOUNDING VETERINARIAN PRODUCTS

a. Compounders shall compound prescriptions for animals on the basis of prescription orders.
b. These prescriptions shall be handled and filled as are human prescriptions.
15 COMPOUNDING PHARMACY GENERATED PRODUCTS

a. Compounders may prepare compounded drug products that can be sold without a
prescription.
b. Pharmacy generated products (PGP) shall be compounded using the same procedures as
those for prescription drug products detailed in this chapter.

Pharmaceutical
Compounding ‐ Nonsterile
Preparations
Version 1.1
Table of Contents
1 PURPOSE ........................................................................................................................................................................ 3
2 BACKGROUND ........................................................................................................................................................... 3
3 DEFINITIONS............................................................................................................................................................... 3
4 POLICY AND PROCEDURE................................................................................................................................. 4
5 PERSONNEL (QUALIFICATION & EVALUATION) .............................................................................. 4
6 SPACE & STORE ........................................................................................................................................................ 4
7 EQUIPMENTS & FACILITY ................................................................................................................................ 5
8 INGREDIENTS SELECTION ................................................................................................................................ 5
8.1 SOURCES ................................................................................................................................................................... 5
8.2 COMPOUNDING NONDRUG REQUIREMENTS .................................................................................................... 5
9 CHECKLIST FOR ACCEPTABLE STRENGTH, QUALITY, AND PURITY ................................ 6
10 COMPOUNDED PREPARATIONS .................................................................................................................... 6
10.1 CAPSULES, POWDERS, LOZENGES, AND TABLETS.......................................................................................... 6
10.2 EMULSIONS, SOLUTIONS, AND SUSPENSIONS .................................................................................................. 7
10.3 SUPPOSITORIES........................................................................................................................................................ 7
10.4 CREAMS, TOPICAL GELS, OINTMENTS, AND PASTES..................................................................................... 7
11 COMPOUNDING PROCESS ................................................................................................................................. 8
12 COMPOUNDING RECORDS AND DOCUMENTS .................................................................................... 8
12.1 FORMULATION RECORD........................................................................................................................................ 8
12.2 COMPOUNDING RECORD....................................................................................................................................... 9
12.3 MSDS FILE .............................................................................................................................................................. 9
13 QUALITY CONTROL............................................................................................................................................... 9
14 VERIFICATION .......................................................................................................................................................... 9
15 PATIENT COUNSELING........................................................................................................................................ 9
16 PACKAGING .............................................................................................................................................................. 10
17 STERILITY .................................................................................................................................................................. 10
18 STABILITY OF COMPOUNDED PREPARATIONS ............................................................................... 10
19 STABILITY CRITERIA AND BEYOND-USE DATING ......................................................................... 10

1 PURPOSE
• For the purposes of this chapter, the pharmacist or other licensed health care professional
responsible for preparing the compounded preparations is referred to as “compounder”.
• Compounding is an integral part of pharmacy practice and is essential to the provision of health
care. The purpose of this chapter and applicable monographs on formulation is to help define what
constitutes good compounding practices and to provide general information to enhance the
compounder’s ability in the compounding facility to extemporaneously compound preparations
that are of acceptable strength, quality, and purity.
• Compounding is different from manufacturing, which is guided by GMPs.
• Some of the characteristics or criteria that differentiate compounding from manufacturing include
the existence of specific practitioner–patient–compounder relationships; the quantity of
medication prepared in anticipation of receiving a prescription or a prescription order; and the
conditions of sale, which are limited to specific prescription orders.
• The pharmacist’s responsibilities in compounding drug preparations are to dispense the finished
preparation in accordance with a prescription or a transcriber’s order or intent and to dispense
those preparations in compliance with the requirements established by Saudi health regulations.
Compounders must be familiar with regulations that govern compounding. The compounder is
responsible for compounding preparations of acceptable strength, quality, and purity with
appropriate packaging and labeling in accordance with good compounding practices (see Good
Compounding Practices), official standards, and relevant scientific data and information.
Compounders engaging in compounding should have to continually expand their compounding
knowledge by participating in seminars, studying appropriate literature, and consulting colleagues.
2 BACKGROUND
This chapter provides procedures and requirements for compounding none sterile preparations
3 DEFINITIONS
For purposes of this chapter, the following terms shall have these meanings.
PREPARATION is a drug dosage form, a dietary supplement, or a finished device. It is the finished or
partially finished preparation of one or more substances formulated for use on or for the patient or
consumer (see General Notices and Requirements).
OFFICIAL SUBSTANCE includes an active drug entity, a dietary supplement, or a pharmaceutical
ingredient or a component of a finished device.
ACTIVE INGREDIENT usually refers to chemicals, substances, or other components of articles
intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases in humans or other
animals or for use as dietary supplements.
ADDED SUBSTANCES are ingredients that are necessary to prepare the preparation but are not
intended or expected to cause a human pharmacologic response if administered alone in the amount or
concentration contained in a single dose of the compounded preparation. The term added substances is

usually used synonymously with the terms inactive ingredients, excipients, and pharmaceutical
ingredients.
4 POLICY AND PROCEDURE

Adequate procedures and records must exist for investigating and correcting failures or problems in
compounding, testing, or in the preparation itself.
5 PERSONNEL (QUALIFICATION & EVALUATION)

The compounder is responsible for ensuring that the quality is built into the compounded preparations of
products, with key factors including at least the following general principles. (See also Good
Compounding Practices )
1. Personnel are capable and qualified to perform their assigned duties.
2. Ingredients used in compounding have their expected identity, quality, and purity.
3. Compounded preparations are of acceptable strength, quality, and purity, with appropriate
packaging and labeling, and prepared in accordance with good compounding practices, official
standards, and relevant scientific data and information.
4. Critical processes are validated to ensure that procedures, when used, will consistently result in the
expected qualities in the finished preparation.
5. The compounding environment is suitable for its intended purpose.
6. Appropriate stability evaluation is performed or determined from the literature for establishing
reliable beyond-use dating to ensure that the finished preparations have their expected potency,
purity, quality, and characteristics, at least until the labeled beyond-use date.
7. There is assurance that processes are always carried out as intended or specified and are under
control.
8. Compounding conditions and procedures are adequate for preventing errors.
6 SPACE & STORE

Areas designated for compounding have adequate space for the orderly placement of equipment and
materials to prevent mixups between ingredients, containers, labels, in-process materials, and finished
preparations. The compounding area is also to be designed, arranged, used, and maintained to prevent
adventitious cross-contamination. Areas used for sterile preparations are to be separated and distinct from
the nonsterile compounding area Pharmaceutical Compounding—Sterile Preparations). The entire
compounding area is to be well-lighted. Heating, ventilation, and air conditioning systems are to be
controlled to avoid decomposition of chemicals. Storage areas provide an environment suitably controlled
to ensure quality and stability of bulk chemicals and finished preparations.
Potable water is to be supplied for hand and equipment washing. Purified Water must be used for
compounding nonsterile drug preparations when formulations indicate the inclusion of water. Purified
Water must also be used for rinsing equipment and utensils. In those cases when a water is used to prepare
a sterile preparation, Water for Injection, Sterile Water for Injection, or Bacteriostatic Water for Injection
must be used (see Pharmaceutical Compounding—Sterile Preparations).

Compounding areas are to be maintained in a clean and sanitary condition. Adequate washing facilities
are to be provided, including hot and cold water, soap or detergent, and air driers or single-service towels.
Sewage, trash, and other refuse in the compounding area is to be disposed of in a safe, sanitary, and
timely manner. Equipment is to be thoroughly cleaned promptly after use to avoid cross-contamination of
ingredients and preparations. Special precautions are to be taken to clean equipment and compounding
areas meticulously after compounding preparations that contain allergenic ingredients (e.g., sulfonamides
or penicillins).
7 EQUIPMENTS & FACILITY

Equipment is to be of appropriate design and size for compounding and suitable for the intended uses.
The types and sizes of equipment will depend on the dosage forms and the quantities compounded (see
equipment manufacturers’ instruction manuals). All equipment is to be constructed so that surfaces that
contact pharmaceutical components, in-process materials, or finished preparations are not reactive,
additive, or adsorptive to avoid altering the safety, identity, strength, quality, or purity of the preparation.
The use of micropipets, electronic or analytical balances, or triturations or dilutions shall be considered
when needed quantities are too small to accurately measure. Equipment and accessories used in
compounding are to be inspected, maintained, cleaned, and validated at appropriate intervals to ensure the
accuracy and reliability of their performance.
8 INGREDIENTS SELECTION
8.1 SOURCES
Official compounded preparations are prepared from ingredients that meet requirements of the
compendial monograph for those individual ingredients for which monographs are provided.
A USP or an NF grade substance is the preferred source of ingredients for compounding all other
preparations. If that is not available, or when food, cosmetics, or other substances are or must be used,
then the use of another high-quality source, such as analytical reagent (AR), certified American Chemical
Society (ACS), or Food Chemicals Codex (FCC) grade, is an option for professional judgment. For any
substance used in compounding not purchased from a registered drug manufacturer, the compounder must
establish purity and safety by reasonable means, which may include lot analysis, manufacturer reputation,
or reliability of source.
A manufactured drug product may be a source of active ingredient. Only manufactured drugs from
containers labeled with a batch control number and a future expiration date are acceptable as a potential
source of active ingredients. When compounding with manufactured drug products, the compounder must
consider all ingredients present in the drug product relative to the intended use of the compounded
preparation.
A compounder may not compound a drug preparation that appears on the list of drug products withdrawn
or removed from the market for safety reasons.
8.2 COMPOUNDING NONDRUG REQUIREMENTS

If the preparation is intended for use as a dietary or nutritional supplement (to supplement the diet) or
cosmetic (e.g., to beautify), then the compounder must adhere to Good Compounding Practices and to
this chapter, and must comply with any Ministry of health requirements.

9 CHECKLIST FOR ACCEPTABLE STRENGTH, QUALITY, AND
PURITY
The following questions are to be considered carefully before compounding.
1. Have the physical and chemical properties and medicinal, dietary, and pharmaceutical uses of the
drug substances been reviewed?
2. Are the quantity and quality of each active ingredient identifiable?
3. Will the active ingredients be effectively absorbed, locally or systemically according to the
prescribed purpose, from the preparation and route of administration?
4. Are there added substances (see Definitions), confirmed or potentially present from manufactured
products, that may be expected to cause an allergic reaction, irritation, toxicity, or undesirable
organoleptic response from the patient? Are there added substances (see Definitions), confirmed
or potentially present, that may be unfavorable (e.g., unsuitable pH or inadequate solubility)?
5. Were all calculations and measurements confirmed to ensure that the preparation would be
compounded accurately?
10 COMPOUNDED PREPARATIONS
The term compounded preparations includes the terms compounded dosage forms, compounded drugs,
and compounded formulations, and means finished forms that are prepared by or under the direct
supervision of a licensed compounder.
When controlled substances are used, check the Ministry of Heath policies. Unless otherwise indicated or
appropriate, compounded preparations are to be prepared to ensure that each preparation shall contain not
less than 90.0% and not more than 110.0% of the theoretically calculated and labeled quantity of active
ingredient per unit weight or volume and not less than 90.0% and not more than 110.0% of the
theoretically calculated weight or volume per unit of the preparation. Compounded preparations include,
but are not restricted to, the following pharmaceutical dosage forms described under
10.1 CAPSULES, POWDERS, LOZENGES, AND

TABLETS
When compounding these dosage forms, the compounder is to prepare an amount of the total formulation
sufficient to allow the prescribed amount or quantity to be accurately dispensed. Selected practices and
precautions for compounding these dosage forms include the following:
• Reducing solid ingredients to the smallest reasonable particle size;
• Implementing appropriate checks to ensure that all ingredients are blended to achieve a
homogeneous mixture;
• Monitoring humidity if moisture might cause hydrolysis, dosage form adhesion to containers, or
softening or partial dissolution of capsule shells;
• Accurately performing weightings to ensure that each unit shall be not less than 90% and not more
than 110% of the theoretically calculated weight for each
• Packaging dosage units according to container specifications for capsules and tablets of the
specific active ingredient unless specified otherwise in individual monographs

10.2 EMULSIONS, SOLUTIONS, AND SUSPENSIONS
When compounding these dosage forms, the compounder is to prepare a 2% to 3% excess amount of the
total formulation to allow the prescribed amount to be accurately dispensed. Selected practices and
precautions for compounding these dosage forms include the following.
• For single-unit containers, the weight of each filled container, corrected for tare weight, shall be
the equivalent of not less than 100% and not more than 110% of the labeled volume.
• Aqueous suspensions are prepared by levitating the powder mixture to a smooth paste with an
appropriate wetting agent. This paste is converted to a free-flowing fluid by adding adequate
vehicle. Successive portions of the vehicle are used to wash the mortar, or other vessel, to transfer
the suspension quantitatively to a calibrated dispensing bottle or graduate. The preparation may be
homogenized to ensure a uniform final dispersion.
• Reducing solid ingredients to the smallest reasonable particle size.
• Solutions shall contain no visible undissolved matter when dispensed. [NOTE—An exception may
occur with supersaturated solutions such as Potassium Iodide Oral Solution.]
• Emulsions and suspensions are labeled, “Shake well before using.”
10.3 SUPPOSITORIES
• When compounding suppositories, the compounder is to prepare an excess amount of total
formulation to allow the prescribed quantity to be accurately dispensed. Selected practices and
• Not using ingredients that are caustic or irritating, and thoroughly comminute solids that are
abrasive to the mucous membranes;
• Selecting a base that allows active ingredients to provide the intended local or systemic therapeutic
effect;
• Reducing solid ingredients to the smallest reasonable particle size; and
• Weighing a representative number of suppositories to ensure that each is not less than 90% and
not more than 110% of the average weight of all suppositories in the batch.
10.4 CREAMS, TOPICAL GELS, OINTMENTS, AND

PASTES
When compounding semisolid dosage forms, the compounder is to prepare an excess amount of total
formulation to allow the prescribed quantity to be accurately dispensed. Selected practices and
• Not using ingredients that are caustic, irritating, or allergenic to the skin or other application sites
unless they are necessary for a treatment;
• Selecting a base or vehicle that allows active ingredients to provide the intended local or systemic
therapeutic effect;
• Reducing solid ingredients to the smallest reasonable particle size;
• Geometrically incorporating the active ingredients with the added substances to achieve a uniform
liquid or solid dispersion in the dosage form; and observing the uniformity of the dispersion by
spreading a thin film of finished formulation on a flat transparent surface.

11 COMPOUNDING PROCESS
The compounders are to consider using the following steps to minimize error and maximize the
prescriber’s intent.
1. Judge the suitability of the prescription to be compounded in terms of its safety and intended use.
Determine what legal limitations, if any, are applicable.
2. Perform necessary calculations to establish the amounts of ingredients needed
3. Identify equipment needed.
4. put-on the proper attire and wash hands.
5. Clean the compounding area and needed equipment.
6. Only one prescription should be compounded at one time in a specified compounding area.
7. Assemble all necessary materials to compound the prescription.
8. Compound the preparation following the formulation record or prescription (see Compounding
Records and Documents below), according to the art and science of pharmacy.
9. Assess weight variation, adequacy of mixing, clarity, odor, color, consistency, and pH as
appropriate.
10. Annotate the compounding log, and describe the appearance of the formulation.
11. Label the prescription containers to include the following items: a) the name of the preparation; b)
the internal identification number; c) the beyond-use date (see Beyond-Use Labeling); d) the
initials of the compounder who prepared the label; e) any storage requirements;
12. Sign and date the prescription affirming that all procedures were carried out to ensure uniformity,
identity, strength, quantity, and purity.
13. Thoroughly and promptly clean all equipment, and store properly.
12 COMPOUNDING RECORDS AND DOCUMENTS

All compounders who dispense prescriptions must comply with the the applicable record keeping
requirements. If the compounder compounds a preparation according to the manufacturer’s labeling
instructions, then further documentation is not required. All other compounded preparations require
further documentation. Such compounding documents are to list the ingredients and the quantity of each
in the order of the compounding process.
The objective of the documentation is to allow another compounder to reproduce the identical prescription
at a future date. The formulation record provides a consistent source document for preparing the
preparation (recipe), and the compounding record documents the actual ingredients in the preparation and
the person responsible for the compounding activity. These records are to be retained for the same period
of time that is required for any prescription under MOH laws. The record may be a copy of the
prescription in written or machine readable form that includes a formulation record, a compounding
record, and a Material Safety Data Sheets (MSDS) file.
12.1 FORMULATION RECORD

The formulation record is a file of individually compounded preparations. This record must list the name,
strength, and dosage form of the preparation compounded, all ingredients and their quantities, equipment
needed to prepare the preparation, when appropriate, and mixing instructions. Mixing instructions should
include the order of mixing, mixing temperatures or other environmental controls, such as the duration of
mixing, and other factors pertinent to the replication of the preparation as compounded. The formulation

record must include an assigned beyond-use date; the container used in dispensing, the storage
requirements, and any quality control procedures.
12.2 COMPOUNDING RECORD

The compounding record contains documentation of the name and strength of the compounded
preparation, the formulation record reference for the preparation, and the sources and lot numbers of
ingredients. The compounding record also includes information on the total number of dosage units
compounded, the name of the person who prepared the preparation and the name of the compounder who
approved the preparation, the date of preparation, the assigned internal identification number or the
prescription number and an assigned beyond-use date, and the prescription number. For all compounded
preparations, results of quality control procedures are to be recorded (e.g., weight range of filled
capsules).
12.3 MSDS FILE

MSDS are to be readily accessible to all employees working with drug substances or bulk chemicals
located on the compounding facility premises. Employees are to be instructed on how to retrieve and
interpret needed information.
13 QUALITY CONTROL
The safety, quality, and performance of compounded preparations depend on correct ingredients and
calculations, accurate and precise measurements, appropriate formulation conditions and procedures, and
prudent pharmaceutical judgment. As a final check, the compounder is to review each procedure in the
compounding process. To ensure accuracy and completeness, the compounder is to observe the finished
preparation to ensure that it appears as expected and is to investigate any discrepancies and take
appropriate corrective action before the prescription is dispensed to the patient (see the Checklist for
Acceptable Strength, Quality, and Purity, the appropriate pharmaceutical dosage form under Compounded
Preparations, and the steps under Compounding Process).
14 VERIFICATION
Compounding procedures that are routinely performed, including batch compounding, shall be completed
and verified according to written procedures. The act of verification of a compounding procedure involves
checking to ensure that calculation, weighing and measuring, order of mixing, and compounding
techniques were appropriate and accurately performed.
15 PATIENT COUNSELING
The patient or the patient's agent should be counseled about proper use, storage, and evidence of
instability in the compounded preparation at the time of dispensing

16 PACKAGING
Compounded preparations should be packaged in containers meeting USP. The container used depends on
the physical and chemical properties of the compounded preparation. Container–drug interaction is to be
considered with substances such as phenolic compounds and sorptive materials (e.g., polypeptides and
proteins).
17 STERILITY
Assurance of sterility in a compounded sterile preparation is mandatory. Compounding and packaging of
sterile drugs, such as ophthalmic solutions, will require strict adherence to guidelines presented in the
Pharmaceutical Compounding—Sterile Preparations and in the manufacturers’ labeling instructions.
18 STABILITY OF COMPOUNDED PREPARATIONS

“Stability” is defined as : the extent to which a preparation retains, within specified limits, and
throughout its period of storage and use, the same properties and characteristics that it possessed at the
time of compounding.
The compounder must avoid formulation ingredients and processing conditions that would result in a
potentially toxic or ineffective preparation. The compounder’s knowledge of the chemical reactions by
which drugs degrade provides a means for establishing conditions under which the rate of degradation is
minimized. The factors that influence the stability of compounded preparations are generally the same as
those for manufactured drug products.
19 STABILITY CRITERIA AND BEYOND-USE DATING
• The beyond-use date is the date after which a compounded preparation is not to be used and is
determined from the date the preparation is compounded. Because compounded preparations are
intended for administration immediately or following short-term storage, their beyond-use dates
may be assigned based on criteria different from those applied to assigning expiration dates to
manufactured drug products.
• Compounders are to consult and apply drug-specific and general stability documentation and
literature when available, and are to consider the nature of the drug and its degradation
mechanism, the container in which it is packaged, the expected storage conditions, and the
intended duration of therapy when assigning a beyond-use date. Beyond-use dates are to be
assigned conservatively. When using manufactured solid dosage forms to prepare a solution or
aqueous suspension, the compounder is also to consider factors such as hydrolysis and the freeze-
thaw property of the final preparation before assigning a beyond-use date.
In assigning a beyond-use date for a compounded drug preparation, in addition to using all available
stability information, the compounder is also to use his or her pharmaceutical education and experience.

• When a manufactured product is used as the source of active ingredient for a nonsterile
compounded preparation, the product expiration date cannot be used to extrapolate directly a
beyond-use date for the compounded preparation. However, a compounder may refer to the
literature or to the manufacturer for stability information. The compounder may also refer to
applicable publications to obtain stability, compatibility, and degradation information on
ingredients. All stability data must be carefully interpreted in relation to the actual compounded
formulation.
• At all steps in the compounding, dispensing, and storage process, the compounder is to observe
the compounded drug preparation for signs of instability.
• However, excessive chemical degradation and other drug concentration loss due to reactions may
be invisible more often than they are visible.
• In the absence of stability information that is applicable to a specific drug and preparation, the
following maximum beyond-use dates are recommended for nonsterile compounded drug
preparations that are packaged in tight, light-resistant containers and stored at controlled room
temperature unless otherwise indicated.
• For Nonaqueous Liquids and Solid Formulations—
o Where the Manufactured Drug Product is the Source of Active Ingredient— The beyond-
use date is not later than 25% of the time remaining until the product’s expiration date or 6
months, whichever is earlier.
o Where a USP or NF Substance is the Source of Active Ingredient— The beyond-use date
is not later than 6 months.
o For Water-Containing Formulations (prepared from ingredients in solid form)— The
beyond-use date is not later than 14 days for liquid preparations when stored at cold
temperatures between 2° and 8°C (36° and 46° F).
o For All Other Formulations— The beyond-use date is not later than the intended duration
of therapy or 30 days, whichever is earlier. These beyond-use date limits may be exceeded
when there is supporting valid scientific stability information that is directly applicable to
the specific preparation (i.e., the same drug concentration range, pH, excipients, vehicle,
water content, etc.).

Pharmaceutical
Sterile Compounding
Version 1.1
Table of Contents
1 INTRODUCTION .............................................................................................................................. 3
2 OBJECTIVE ....................................................................................................................................... 3
3 DEFINITION ...................................................................................................................................... 3
4 CONTAMINATION RISK LEVELS ............................................................................................... 3

4.1 SOURCES OF CONTAMINATION: ....................................................................................................... 4
4.2 LOW-RISK LEVEL CSPS ................................................................................................................. 4
4.3 MEDIUM-RISK LEVEL CSPS .......................................................................................................... 5
4.4 HIGH-RISK LEVEL CSPS ................................................................................................................ 6
5 STERILIZATION PROCESS: .......................................................................................................... 7
5.1 STERILIZATION BY FILTRATION ..................................................................................................... 7
5.2 STEAM STERILIZATION .................................................................................................................. 8
6 POLICY & PROCEDURS ................................................................................................................. 8
7 PERSONNEL ...................................................................................................................................... 9
7.1 PERSONNEL REQUIREMENTS .......................................................................................................... 9
7.2 PERSONNEL RESPONSIBILITIES ........................................................................................................ 9
8 STANDARD OPERATION PROCEDURE ................................................................................... 10

8.1 COMPOUNDING PROCESS ............................................................................................................. 10
8.2 INSPECTION OF FINISHED CSPS.................................................................................................... 11
8.3 LABELING .................................................................................................................................... 12
8.4 STABILITY AND BEYOND USE DATE ............................................................................................ 12
8.5 PACKAGE, HANDLING, AND TRANSPORTATION ............................................................................ 14
8.6 STORAGE ..................................................................................................................................... 16
8.7 DESTRUCTION .............................................................................................................................. 17
9 QUALITY ASSURANCE ................................................................................................................ 17
10 LIST OF REFERENCES ............................................................................................................. 19
11 APPENDIX .................................................................................................................................... 20

1 INTRODUCTION
This section is written to be a reference for the Compounding of Sterile Products (CSPs) to facilitate
practitioners’ understanding of the fundamental accuracy and quality practices of CSPs. The content of
this section applies to all facilities in which CSPs are prepared, stored, and dispensed including public
hospitals and private sectors in the Kingdom of Saudi Arabia. The Saudi Food and Drug Authority is
responsible to implement these regulations.
2 OBJECTIVE
To standardize the CSPs to avoid all harms resulting from microbial contamination, excessive bacterial
endotoxins, mixing errors of correct ingredients and errors of mixing incorrect ingredients.
Also, to understand the CSPs requirements for cleaner facilities, specific personnel training on principles
and practices of aseptic manipulations, air quality evaluation and maintenance, knowledge of sterilization
tests and solution stability principles and practices.
3 DEFINITION
CSPs include:
a. Preparations prepared according to the manufacturer’s labeled instructions and other
manipulations when manufacturing sterile products that expose the original contents to
potential contamination.
b. Preparations containing nonsterile ingredients or employing nonsterile components and
devices that must be sterilized before administration.
c. Biologics, diagnostics, drugs, nutrients, and radiopharmaceuticals that possess either of the
above two characteristics, and which include, but are not limited to, baths and soaks for live
organs and tissues, implants, inhalations, injections, powders for injection, irrigations, metered
sprays, and ophthalmic and otic preparations.
4 CONTAMINATION RISK LEVELS

This section provides a foundation for the development and implementation of essential procedures for
the safe preparation of CSP’s in the three risk levels (low, medium, or high), which are classified
according to the potential for microbial (microbial organisms, spores, and endotoxins); and chemical, and
physical contamination (foreign chemicals and physical matter)

4.1 SOURCES OF CONTAMINATION:
Potential sources of contamination include, but are not limited to:
a. Solid and liquid matter from compounding personnel and objects.
b. Nonsterile components employed and incorporated before terminal sterilization.
c. Inappropriate conditions within the restricted compounding environment.
d. Prolonged presterilization procedures with aqueous preparations.
e. Nonsterile dosage forms used to compound CSPs.
• The characteristics described below for low-risk, medium-risk, and high-risk CSPs are intended as
a guide to the breadth and depth of care necessary in compounding, but they are neither
exhaustive nor prescriptive.
• The licensed health care professionals who supervise compounding are responsible for
determining the procedural and environmental quality practices and attributes that are necessary
for the risk level they assign to specific CSPs.
• These risk levels apply to the quality of CSPs immediately after the final aseptic mixing or filling
or immediately after the final sterilization, unless precluded by the specific characteristics of the
preparation, such as lipid-based emulsions where administration must be completed within 12
hours of preparation.
• Upon subsequent storage and shipping of freshly finished CSPs, an increase in the risks of
chemical degradation of ingredients, contamination from physical damage to packaging, and
permeability of plastic and elastomeric packaging is expected. In such cases, compounding
personnel consider the potential additional risks to the integrity of CSPs when assigning beyond-
use dates.
• The pre-administration exposure duration and temperature limits specified in the following low-
risk, medium-risk, and high-risk level sections apply in the absence of direct testing results or
appropriate information sources that justify different limits for specific CSPs.
(For a summary of the criteria according to risk levels, please see the Appendix)
4.2 LOW-RISK LEVEL CSPS

CSPs compounded under all of the following conditions are at a low risk of contamination:
a. The CSPs are compounded with aseptic manipulations entirely within ISO Class 5 or better air
quality using only sterile ingredients, products, components, and devices.
b. The compounding involves only transfer, measuring, and mixing manipulations with closed or
sealed packaging systems that are performed promptly and attentively.
c. Manipulations are limited to aseptically opening ampuls, penetrating sterile stoppers on vials with
sterile needles and syringes, and transferring sterile liquids in sterile syringes to sterile
administration devices and packages of other sterile products.
d. For a low-risk preparation, in the absence of passing a sterility test, the storage periods cannot
exceed the following time periods: before administration, the CSPs are properly stored and are
exposed for not more than 48 hours at controlled room temperature for not more than 14 days at a
cold temperature, and for 45 days in solid frozen state at –20º or colder.

Examples of Low-Risk Compounding:
a. Single transfers of sterile dosage forms from ampuls, bottles, bags, and vials using sterile
syringes with sterile needles, other administration devices, and other sterile containers. The
contents of ampuls require sterile filtration to remove any glass particles.
b. Manually measuring and mixing no more than three manufactured products to
compound drug admixtures and nutritional solutions.
4.3 MEDIUM-RISK LEVEL CSPS
When CSPs are compounded aseptically under Low-Risk Conditions, and one or more of the following
conditions exists, such CSPs are at a medium risk of contamination:
a. Multiple individual or small doses of sterile products are combined or pooled to prepare a CSP
that will be administered either to multiple patients or to one patient on multiple occasions.
b. The compounding process includes complex aseptic manipulations other than the single-
volume transfer.
c. The compounding process requires unusually long duration, such as that required to complete
dissolution or homogeneous mixing.
d. The sterile CSPs do not contain broad-spectrum bacteriostatic substances, and they are
administered over several days (e.g., an externally worn or implanted infusion device).
e. For a medium-risk preparation, in the absence of passing a sterility test, the storage periods
cannot exceed the following time periods: before administration, the CSPs are properly stored
and are exposed for not more than 30 hours at controlled room temperature, for not more than
7 days at a cold temperature, and for 45 days in solid frozen state at –20º or colder.
Examples of Medium-Risk Compounding:

a. Compounding of total parenteral nutrition fluids using manual or automated devices during which
there are multiple injections, detachments, and attachments of nutrient source products to the
device or machine to deliver all nutritional components to a final sterile container.
b. Filling of reservoirs of injection and infusion devices with multiple sterile drug products and
evacuation of air from those reservoirs before the filled device is dispensed.
c. Filling of reservoirs of injection and infusion devices with volumes of sterile drug solutions that
will be administered over several days at ambient temperatures between 25º and 40º
d. Transfer of volumes from multiple ampoules or vials into a single, final sterile container or
product.

4.4 HIGH-RISK LEVEL CSPS
CSPs compounded under any of the following conditions are either contaminated or at a high risk to
become contaminated with infectious microorganisms:
a. Nonsterile ingredients, including manufactured products for routes of administration—other
than those listed under C in the definition —are incorporated or a nonsterile device is
employed before terminal sterilization.
b. Sterile ingredients, components, devices, and mixtures are exposed to air quality inferior to
ISO Class 5. This includes storage in environments inferior to ISO Class 5 of opened or
partially used packages of manufactured sterile products that lack antimicrobial preservatives.
c. Nonsterile preparations are exposed for at least 6 hours before being sterilized.
d. It is assumed, and not verified by examination of labeling and documentation from suppliers
or by direct determination, that the chemical purity and content strength of ingredients meet
their original or compendial specifications in unopened or in opened packages of bulk
ingredients1.
e. For a high-risk preparation, in the absence of passing a sterility test, the storage periods cannot
exceed the following time periods: before administration, the CSPs are properly stored and are
exposed for not more than 24 hours at controlled room temperature, for not more than 3 days
at a cold temperature, and for 45 days in solid frozen state at –20º or colder.
All nonsterile measuring, mixing, and purifying devices are rinsed thoroughly with sterile, pyrogen-free
water, and then thoroughly drained or dried immediately before use for high-risk compounding. All high-
risk CSP solutions subjected to terminal steam sterilization are passed through a filter with a nominal
porosity not larger than 1.2 µm preceding or during filling into their final containers. Sterilization of high-
risk level CSPs by filtration (see sterilization process) is conducted entirely with an ISO Class 5 or
superior air quality environment.
Examples of High-Risk Compounding:

a. Dissolving nonsterile bulk drug and nutrient powders to make solutions, which will be
terminally sterilized.
b. Sterile ingredients, components, devices, and mixtures are exposed to air quality inferior to
ISO Class 5. This includes storage in environments inferior to ISO Class 5 of opened or
partially used packages of manufactured sterile products that lack antimicrobial preservatives.
c. Measuring and mixing sterile ingredients in nonsterile devices before sterilization is
performed.
d. Assuming, without appropriate evidence or direct determination, that packages of bulk
ingredients contain at least 95% by weight of their active chemical moiety and have not been
contaminated or adulterated between uses.

5 STERILIZATION PROCESS:
The licensed health care professionals who supervise compounding are responsible for
determining that the selected sterilization method both sterilizes and maintains the strength, purity,
quality, and packaging integrity of CSPs. The selected sterilization process is expected from
experience and appropriate information sources—and, preferably, verified wherever possible—to
achieve sterility in the particular CSPs. General guidelines for matching CSPs and components to
appropriate sterilization methods include the following:
a. CSPs have been ascertained to remain physically and chemically stable when subjected
to the selected sterilization method.
b. Glass and metal devices may be covered tightly with aluminum foil, then exposed to
dry heat in an oven at a mean temperature of 250º for 2 hours to achieve sterility and
dehyrogenation. Such items are either used immediately or stored until use in an
environment suitable for compounding low- and medium-risk CSPs.
c. Personnel ascertain from appropriate information sources that the sterile microporous
membrane filter used to sterilize CSP solutions, either during compounding or
administration, is chemically and physically compatible with the CSP.
5.1 STERILIZATION BY FILTRATION

5.1.1 Commercially available sterile filters must be approved for human-use applications
in sterilizing pharmaceutical fluids. Both filters that must be sterilized before
processing CSPs and those filters that are commercially available, disposable,
sterile, and pyrogen-free have a nominal porosity of 0.2 µm, which includes 0.22-
µm porosity. They should be certified by the manufacturer to retain at least 107
microorganisms of a strain of Brevundimonas (Pseudomonas) diminuta on each
cm2 of upstream filter surface under conditions similar to those in which the CSPs
will be sterilized. In emergency situations when sterile 0.2-µm porosity membranes
are not available, filters of the same composition and 0.45-µm nominal porosity
may be used. Sterilizing filters with 0.2-µm and 0.45-µm nominal porosities will
not remove bacterial endotoxins and viruses by physical retention.
5.1.2 The supervising health care professional must ensure, directly or from appropriate
documentation, that the filters are chemically and physically stable at the pressure
and temperature conditions to be used, and that the filters will achieve sterility and
maintain prefiltration pharmaceutical quality of the specific CSP. The filter
dimensions and material must permit the sterilization process to be completed
rapidly without the replacement of the filter during the process. When CSPs are
known to contain excessive particulate matter, a prefilter or larger porosity
membrane is placed upstream from the sterilizing filter to remove gross particulate
contaminants in order to maximize the efficiency of the sterilizing filter.
5.1.3 When filter devices are assembled from separate nonsterile components by
compounding personnel, such devices shall be identified to be sterile and
ascertained to be effective under relevant conditions before they are used to
sterilize CSPs. For example, sterility can be identified using biological indicators.
Filter units used to sterilize CSPs can also be subjected to the manufacturer's
recommended integrity test, such as the bubble point test.

5.1.4 When commercially available sterile disposable filter devices are used, the
compounding personnel may accept the written certification from suppliers that the
filters retain at least 107 cfu, of Brevundimonas (Pseudomonas) diminuta on each
cm2 of filter surface. Compounding personnel must ascertain that selected filters
will achieve sterilization of the particular CSPs being sterilized. Large deviations
from usual or expected chemical and physical properties of CSPs may cause
undetectable damage to filter integrity and shrinkage of microorganisms to sizes
smaller than filter porosity.
5.1.5 Sterile, commercially available sterilizing filter devices for use on handheld
syringes may be checked by feeling for greater resistance on the plunger when
filtering air after an aqueous fluid has been filtered.
5.2 STEAM STERILIZATION

5.2.1 The process of thermal sterilization employing saturated steam under pressure, or
autoclaving, is the preferred method to terminally sterilize aqueous preparations
that have been verified to maintain their full chemical and physical stability under
the conditions employed. To achieve sterility, it is necessary that all materials be
exposed to steam at 121º, under a pressure of about one atmosphere or 15 psi, for
the duration verified by testing to achieve sterility of the items, which is usually 20
to 60 minutes for CSPs. An allowance must be made for the time required for the
material to reach 121º before the sterilization exposure duration is aimed.
5.2.2 Items that are not directly exposed to pressurized steam may result in survival of
microbial organisms and spores. Before their sterilization, plastic, glass, and metal
devices are tightly wrapped in low particle shedding paper or fabrics, or sealed in
envelopes that prevent poststerilization microbial penetration. Immediately before
filling ampuls and vials that will be steam sterilized, solutions are passed through a
filter having a porosity not larger than 1.2 µm for removal of particulate matter.
Sealed containers must be able to generate steam internally; thus, stoppered and
crimped empty vials must contain a small amount of moisture to generate steam.
5.2.3 The effectiveness of steam sterilization is verified using appropriate biological
indicators or other confirmation methods.
6 POLICY & PROCEDURS

Written Policy and Procedures are essential for generally ensuring product quality,
especially sterility assurance. All compounding facilities are required to keep a written
manual Establishing, maintaining, and assuring compliance with comprehensive policies
and procedures encompassing all responsibilities in CSPs. These written procedures and
instructions should be in line with this regulations and its updates in order to guarantee the
highest levels of safety and quality.

These written instructions should include- but not limited to -the following items:
a. Description of the general basis used to assign the beyond-use date and storage
conditions for all CSPs.
b. Description of the processes and techniques involved with transport, handling and
placement into storage.
c. Description of specific instructions for receiving, acknowledging, and dating receipts;
and for recording, or filing, and evaluating reports of adverse events and of the quality
of preparation claimed to be associated with CSPs.
d. Specifically describe appropriate packing containers and insulating and stuffing
materials, based on information from product specifications, vendors, and experience
of compounding personnel.
e. Description of a detailed Quality Assurance program to provide a mechanism for
monitoring, evaluation, correction, and improving the activities and processes
described in all sections. In addition to the appropriate follow-up program to make
certain that effective corrective actions were performed. (see Quality Assurance
Section).
f. Also, Additional procedures may be essential for certain products, devices, or
techniques. Examples where such special procedures are needed include in-line
filtration, the operation of automated infusion control devices, and the replenishment
of drug products into the reservoirs of implantable or portable infusion pumps.
7 PERSONNEL
7.1 PERSONNEL TRAINING REQUIREMENTS
7.1.1 Compounding personnel are adequately skilled, educated, instructed, and trained to be
responsible for ensuring that CSPs are accurately identified, measured, diluted, and mixed;
and are correctly purified, sterilized, packaged, sealed, labeled, stored, dispensed, and
distributed. These performance responsibilities include maintaining appropriate cleanliness
conditions and providing labeling and supplementary instructions for the proper clinical
administration of CSPs.
7.1.2 The compounding facility must design, implement, and maintain a formal education,
training, and competency assessment program that encompasses all the functions and tasks
addressed in the foregoing sections and all personnel to whom such functions and tasks are
assigned. This program includes the assessment and documentation of procedural
breaches, administration mishaps, side effects, allergic reactions, and complications
associated with dosage or administration, such as extravasation. This program should be
coordinated with the institution's adverse-event and incident reporting programs.
7.2 PERSONNEL RESPONSIBILITIES

Qualified licensed health care professionals who supervise compounding and dispensing of CSPs
shall ensure that the following compounding responsibilities are achieved:
7.2.1 Compounding personnel are performing and documenting the following activities in their
sterile compounding duties:
7.2.1.1 Perform antiseptic hand cleansing and disinfection of nonsterile compounding
surfaces.

7.2.1.2 Select and appropriately don protective gloves, goggles, gowns, masks, and hair
and shoe covers.
7.2.1.3 Use laminar flow clean-air hoods, barrier isolators, and other contamination control
devices that are appropriate for the risk level.
7.2.1.4 Identify, weigh, and measure ingredients.
7.2.1.5 Manipulate sterile products aseptically, sterilize high-risk level CSPs, and label and
quality inspect CSPs.
7.2.2 Ingredients have their correct identity, quality, and purity.
7.2.3 Opened or partially used packages of ingredients for subsequent use in CSPs are properly
stored under restricted access conditions in the compounding facility. Such packages
cannot be used when visual inspection detects unauthorized breaks in the container,
closure, and seal; when the contents do not possess the expected appearance, aroma, and
texture; when the contents do not pass identification tests specified by the compounding
facility; and when either the beyond-use or expiration date has been exceeded.
7.2.4 To minimize the generation of bacterial endotoxins, water-containing CSPs that are
nonsterile during any phase of the compounding procedure are sterilized within 6 hours
after completing the preparation.
7.2.5 Sterilization methods achieve sterility of CSPs while maintaining the labeled strength of
active ingredients and the physical integrity of packaging.
7.2.6 Measuring, mixing, sterilizing, and purifying devices are clean, appropriately accurate, and
effective for their intended uses.
7.2.7 Potential harm from added substances and differences in rate and extent of bioavailability
of active ingredients for other than oral route of administration are carefully evaluated
before such CSPs are dispensed and administered.
7.2.8 While being used, the compounding environment maintains the sterility or the
presterilization purity, whichever is appropriate, of the CSP.
7.2.9 Labels on CSPs list the names and amounts or concentrations of all ingredients. Before
being dispensed, and or administered, the clarity of solutions are visually confirmed; also
the identity and amounts of ingredients, procedures to prepare and sterilize CSPs, and
specific release criteria are reviewed to assure their accuracy and completeness.
7.2.10 When time and personnel availability so permit, compounding manipulations and
procedures are separated from postcompounding quality inspection and review before
CSPs are dispensed and administered.
8 STANDARD OPERATION PROCEDURE
8.1 COMPOUNDING PROCESS

8.1.1 The prescription orders, written compounding procedure, preparation records, and
expended materials used to make CSPs in all contamination risk levels are inspected for
accuracy of correct identities and amounts of ingredients, aseptic mixing and sterilization,
packaging, labeling, and expected physical appearance before they are administered or
dispensed.

8.1.2 Procedures for measuring, mixing, dilution, purification, sterilization, packaging, and
labeling must be done conform to the correct sequence and quality established for the
specified CSP.
8.1.3 Written procedures for double-checking compounding accuracy must be followed for
every CSP during preparation and immediately prior to release. The double check system
should meet institutes regulations and include label accuracy and accuracy of the addition
of all drug products or ingredients used to prepare the finished product and their volumes
or quantities. The used additive containers and, for those additives for which the entire
container was not expended, the syringes used to measure the additive, should be
quarantined with the final products until the final product check is completed.
Compounding personnel must visually confirm that ingredients measured in syringes
match the written order being compounded. Preferably, a person other than the
compounder can verify that correct volumes of correct ingredients were measured to make
each CSP. For example, compounding personnel would pull the syringe plunger back to
the volume measured.
8.1.4 When practical, confirm accuracy of measurements by weighing a volume of the measured
fluid, then calculating that volume by dividing the weight by the accurate value of the
density, or specific gravity, of the measured fluid. Correct density or specific gravity
values programmed in automated compounding devices, which measure by weight using
the quotient of the programmed volume divided by the density or specific gravity, must be
confirmed to be accurate before and after delivering volumes of the liquids assigned to
each channel or port. These volume accuracy checks and the following additional safety
and accuracy checks in this section must be included in the standard operating procedures
manual of the CSP facility.
8.1.5 Water-containing CSPs that are nonsterile during any phase of the compounding procedure
must be sterilized within 6 hours after completing the preparation, to minimize the
generation of bacterial endotoxins,
8.1.6 All CSPs that are intended to be solutions must be visually examined for the presence of
particulate matter and not administered or dispensed when such matter is observed.
8.2 INSPECTION OF FINISHED CSPS

8.2.1 Finished CSPs are individually inspected in accordance with written procedures after
compounding. If not distributed promptly, these products are individually inspected just
prior to leaving the storage area.
8.2.2 Each product unit, where possible, should be inspected against lighted white or black
background or both for evidence of visible particulates or other foreign matter. Pre-release
inspection also includes container–closure integrity and any other apparent visual defect.
8.2.3 When products are not distributed promptly after preparation, a predistribution inspection
is conducted to ensure that a CSP with defects, such as precipitation, cloudiness, and
leakage, which may develop between the time of release and the time of distribution, is not
released.

8.3 LABELING
No prepackaged CPS shall be offered without a label
Labels of CSPs shall be in English languages. When one language or more is used all information in the
other languages shall be the same as the information written in the English language.
Information included in the label or attached to the container of the CSPs shall be clear, prominent and
readily legible and indelible under normal conditions of handling and use. This information may not be
obscured by any other illustrated, written, or printed matter. It shall be presented in a color
distinguishable from the background. The name of the CSPs shall be written in letters of a size reasonable
related to other information printed on the label.
The method of preparation and use of the CSP shall be declared in necessary.
In summary, the labels of CSPs bear the following:
a. Correct names of (patient, medicals, additives, diluents, ingredients … etc.)
b. Amounts or concentrations of ingredients
c. Total volume
d. Beyond-use date
e. Appropriate route(s) of administration
f. Storage conditions
g. Other information for safe use
8.4 STABILITY AND BEYOND USE DATE

8.4.1 Beyond-use dates for compounded preparations are usually assigned based on professional
experience, which should include careful interpretation of appropriate information sources
for the same or similar formulations2. Beyond-use dates for CSPs are rarely based on
preparation-specific chemical assay results, which are used with the Arrhenius equation to
determine expiration dates for manufactured products. The majority of CSPs are aqueous
solutions in which hydrolysis of dissolved ingredients is the most common chemical
degradation reaction. The extent of hydrolysis and other heat-catalyzed degradation
reactions at any particular time point in the life of a CSP represents the thermodynamic
sum of exposure temperatures and durations. Such lifetime stability exposure is
represented in the mean kinetic temperature calculation3. Drug hydrolysis rates increase
exponentially with arithmetic temperature increase; thus, exposure of a beta-lactam
antibiotic solution for one day at controlled room temperature will have an equivalent
effect on the extent of hydrolysis of approximately 3 to 5 days in cold temperatures .
8.4.2 Personnel who prepare, dispense, and administer CSPs must store them strictly in
accordance with the conditions stated on the label of ingredient products and finished
CSPs.
8.4.3 When CSPs deviate from conditions in the approved labeling of manufactured products
contained in CSPs, compounding personnel may consult the manufacturer of particular
products for advice on assigning beyond-use dates based on chemical and physical
stability parameters.
8.4.4 Beyond-use dates for CSPs that are prepared strictly in accordance with manufacturers'
product labeling must be those specified in that labeling, or from appropriate literature

sources or direct testing. Beyond-use dates for CSPs that lack justification from either
appropriate literature sources or by direct testing evidence must be assigned as described
in the section Stability Criteria and Beyond-Use Dating in the general test chapter
Pharmaceutical Compounding—Nonsterile Preparations.
8.4.5 The pharmacist may refer to applicable publications to obtain relevant stability,
compatibility, and degradation information regarding the drug or its congeners. When
assigning a beyond-use date, pharmacists should consult and apply drug-specific and
general stability documentation and literature where available, and they should consider
the nature of drug and its degradation mechanism, the container in which it is packaged,
the expected storage conditions, and the intended duration of therapy.
8.4.6 Stability information must be carefully interpreted in relation to the actual compounded
formulation and conditions for storage and use. Predictions based on other evidence, such
as publications, charts, tables, and so forth would result in theoretical beyond-use dates.
Theoretically predicted beyond-use dating introduces varying degrees of assumptions, and
hence a likelihood of error or at least inaccuracy. The degree of error or inaccuracy would
be dependent on the extent of differences between the CSP's characteristics (such as
composition, concentration of ingredients, fill volume, or container type and material) and
the characteristics of the products from which stability data or information are to be
extrapolated. The greater the doubt of the accuracy of theoretically predicted beyond-use
dating, the greater the need to determine dating periods experimentally. Theoretically
predicted beyond-use dating periods should be carefully considered for CSPs prepared
from nonsterile bulk active ingredients having therapeutic activity, especially where these
CSPs are expected to be compounded routinely.
8.4.7 When attempting to predict a theoretical beyond-use date, a compounded or an admixed
product, it should be considered as a unique system that has physical and chemical
properties and stability characteristics that differ from its components. For example,
antioxidant, buffering, or antimicrobial properties of a sterile vial for injection (SVI) might
be lost upon its dilution, with the potential of seriously compromising the chemical
stability of the SVI’s active ingredient or the physical or microbiological stability of the
SVI formulation in general. Thus, the properties stabilized in the SVI formulation usually
cannot be expected to be carried over to the compounded or admixed product. Product-
specific, experimentally determined stability data evaluation protocols are preferable to
published stability information. Pharmacists should consult the general information
chapter under Pharmaceutical Stability for the appropriate stability parameters to be
considered when initiating or evaluating a product-specific stability study.
8.4.8 Compounding personnel who assign beyond-use dates to CSPs when lacking direct
chemical assay results must critically interpret and evaluate the most appropriate available
information sources to decide a conservative and safe beyond-use date.
8.4.9 It should be recognized that the truly valid evidence of stability for predicting beyond-use
dating can be obtained only through product-specific experimental studies. Semi-
quantitative procedures, such as thin-layer chromatography (TLC), may be acceptable for
many CSPs. However, quantitative stability-indicating assays, such as high performance
liquid chromatographic (HPLC) assays, would be more appropriate for certain CSPs.
Examples include CSPs with a narrow therapeutic index, where close monitoring or dose
titration is required to ensure therapeutic effectiveness and to avoid toxicity; where a
theoretically established beyond-use dating period is supported by only marginal evidence;

or where a significant margin of safety cannot be verified for the proposed beyond-use
dating period. In short, because beyond-use dating periods established from product-
specific data acquired from the appropriate instrumental analyses are clearly more reliable
than those predicted theoretically, the former approach is strongly urged to support dating
periods exceeding 30 days.
8.4.10 Expiration dating not specifically referenced in the package insert should not exceed 30
days once the MDV has been opened.
8.4.11 When CSPs will be distributed to and administered in residential locations other than
health care facilities, the effect of potentially uncontrolled and unmonitored temperature
conditions must be considered when assigning beyond-use dates. It must be ascertained
that CSPs will not be exposed to warm temperatures unless the compounding facility has
evidence to justify stability of CSPs during such exposure.
8.5 PACKAGE, HANDLING, AND TRANSPORTATION

8.5.1 Procedures essential for generally ensuring product quality, especially sterility assurance,
when readying a CSP for its subsequent administration include proper hand-washing,
aseptic technique, site care, and change of administration sets. Additional procedures may
also be essential for certain products, devices, or techniques. Examples where such special
procedures are needed include in-line filtration, the operation of automated infusion
control devices, and the replenishment of drug products into the reservoirs of implantable
or portable infusion pumps.
8.5.2 The compounding facility must have the sole authority for determining whether a CSP not
administered as originally intended can be used for an alternate patient or under alternate
conditions. All CSPs that are not used as originally intended must be returned to the
compounding facility for appropriate disposition, which may include redispensing, but
only if adequate continuing quality can be fully ensured. The following may provide such
assurance: the CSP was maintained under continuous refrigeration and protected from
light, if required; no evidence of tampering or any readying for use outside the
compounding facility exists; and there is sufficient time remaining until the originally
assigned beyond-use time and date will be reached. Thus, initial preparation and thaw
times should be documented and reliable measures should have been taken to prevent and
detect tampering. Compliance with all procedures associated with maintaining product
quality is essential. The CSP must not be redispensed if there is not adequate assurance
that product quality and packaging integrity (including the connections of devices, where
applicable) were continuously maintained between the time the CSP left and the time that
it was returned to the compounding facility. Additionally, CSPs must not be redispensed if
redispensing cannot be supported by the originally assigned beyond-use time.
8.5.3 When CSPs are distributed to locations outside the premises in which they are
compounded, packing is selected that simultaneously protects CSPs from damage, leakage,
contamination, and degradation; and protects personnel who transport packed CSPs from
harm. Written instructions that clearly explain how to safely open containers of packed
CSPs are provided to patients and other recipients.
8.5.4 Packaging selected for CSPs must be appropriate to preserve the sterility and strength until
the beyond-use date.

8.5.5 Compounding facilities that ship CSPs to locations outside their own premises must select
modes of transport that are expected to deliver properly packed CSPs in undamaged,
sterile, and stable condition to recipients.
8.5.6 Compounding personnel should ascertain that temperatures of CSPs during transit by the
selected mode will not exceed the warmest temperature specified on the storage
temperature range on CSPs labels. It is recommended that compounding personnel
communicate directly with the couriers to learn shipping durations and exposure
conditions that CSPs may encounter.
8.5.7 Compounding personnel must include specific handling and exposure instructions on the
exteriors of containers packed with CSPs to be transported and obtain reasonable
assurance of compliance therewith from transporters. Compounding personnel must
periodically review the delivery performance of couriers to ascertain that CSPs are being
efficiently and properly transported.
8.5.8 Compounding facilities that ship CSPs to patients and other recipients outside their own
premises must ascertain or provide, whichever is the appropriate case, the following
assurances:
8.5.8.1 Labels and accessory labeling for CSPs include clearly readable beyond-use dates,
storage instructions, and disposal instructions for out-of-date units.
8.5.8.2 Each patient or other recipient is able to store the CSPs properly, including the use of a
properly functioning refrigerator and freezer if CSPs are labeled for such storage.
8.5.9 Compounding facilities must clinically monitor patients treated with CSPs according to the
regulations and guidelines of accepted standards of practice. Compounding facilities must
provide patients and other recipients of CSPs with a way to address their questions and
report any concerns that they may have with CSPs and their administration devices.
8.5.10 Reports of adverse events with CSPs must be reviewed promptly and thoroughly by
compounding supervisors to correct and prevent future occurrences. Compounding
personnel are encouraged to participate in adverse event reporting and product defects
programs.
8.5.11 Techniques should be specified to prevent the depression of syringe plungers or dislodging
of syringe tips during handling and transport.
8.5.12 Disconnection of system components (for example, where CSPs are dispensed with
administration sets attached to them) must be prevented throughout the life cycle of the
product.
8.5.13 Foam padding or inserts are particularly useful where CSPs are transported by pneumatic
tube systems.
8.5.14 Inappropriate transport and handling can adversely affect the quality of certain CSPs
having unique stability concerns. For example, the physical shaking that might occur
during pneumatic tube transport, or undue exposure to heat or light, have to be addressed
on a product-specific basis. Alternate transport modes or special packaging measures
might be needed for the proper assurance of quality of these CSPs.
8.5.15 The use of tamper-proof closures and seals on CSP ports can add an additional measure of
security to ensure product integrity regardless of transport method used.
8.5.16 Chemotoxic and other hazardous CSPs require safeguards to maintain the integrity of the
CSP and to minimize the exposure potential of these products to the environment and to
personnel who may come in contact with them. Special requirements associated with the
packaging, transport, and handling of these agents include the prevention of accidental

exposures or spills and the training of personnel in the event of an exposure or spill.
Examples of special requirements of these agents also include exposure-reducing strategies
such as the use of Luer lock syringes and connections, syringe caps, the capping of
container ports, sealed plastic bags, impact-resistant containers, and cautionary labeling.
Appropriate cushioning for pneumatic tube transport should be selected and evaluated to
ensure that the products so conveyed can withstand the stresses induced by the system.
Pneumatic transport of nonevaluated packaging alternatives should be avoided. Additional
references should be consulted as necessary for further information on handling
chemotoxic and other hazardous drugs.
8.5.17 Delivery and patient-care-setting personnel must be properly trained to deliver the CSP to
the appropriate storage location. Outdated and unused CSPs must be returned to the
compounding facility for disposal or possible reuse.
8.6 STORAGE
8.6.1 Those products that are not immediately distributed are stored in an appropriate location as
described in the written procedures.
8.6.2 To inhibit microbial growth from undetected contamination, finished CSPs that will not be
immediately dispensed and administered must be refrigerated at 2º to 8º, unless their
chemical and physical stability are known to be adversely affected by cold temperatures.
When CSPs are filled into patient-worn infusion devices that are likely to attain
temperatures exceeding 30º for more than 24 hours, the chemical and physical stability at
such temperatures and durations must be confirmed from either appropriate literature
sources or direct testing.
8.6.3 If multiple-dose parenteral medication vials (MDVs) are used, refrigerate the MDVs after
they are opened unless otherwise specified by the manufacturer. Discard the MDVs when
empty, when suspected or visible contamination occurs, or when the manufacturer's stated
expiration date is reached, provided the manufacturer’s storage conditions have been
adhered to.
8.6.4 To ensure that product potency is retained through the manufacturer's labeled expiration
date, pharmacists must monitor the drug storage areas within the compounding facility.
Controlled temperature storage areas in the compounding facility (refrigerators, 2º to 8º;
freezers, 20º to 10º; and incubators, 30º to 35º; etc.) should be monitored at least once
daily and the results documented on a temperature log. Additionally, compounding facility
personnel should note the storage temperature when placing the product into or removing
the product from the storage unit in order to monitor any temperature aberrations. Suitable
temperature recording devices may include a calibrated continuous recording device or an
NBS calibrated thermometer that has adequate accuracy and sensitivity for the intended
purpose and should be properly calibrated at suitable intervals. If the compounding facility
uses a continuous temperature recording device, compounding facility personnel should
verify at least once daily that the recording device itself is functioning properly.
8.6.5 The temperature sensing mechanisms should be suitably placed in the controlled
temperature storage space to reflect accurately its true temperature. In addition, the
compounding facility should adhere to appropriate procedures of all controlled storage
spaces to ensure that such spaces are not subject to significantly prolonged temperature
fluctuations as may occur, for example, by leaving a refrigerator door open too long.

8.6.6 Written procedures have to exist to ensure that storage conditions in the patient-care
setting are suitable for the CSP-specific storage requirements. Procedures include daily
monitoring and documentation of drug storage refrigerators to ensure temperatures
between 2º and 8º.
8.6.7 The monthly inspection of all drug storage locations by compounding facility personnel.
Inspections must confirm compliance with appropriate storage conditions, separation of
drugs and food, proper use of multiple-dose containers, and the avoidance of using single-
dose products as multiple-dose containers. CSPs, as well as all other drug products, must
be stored in the patient-care area in such a way as to secure them from unauthorized
personnel, visitors, and patients.
8.7 DESTRUCTION
8.7.1 Products with observed defects should be immediately discarded or marked and segregated
from acceptable products in a manner that prevents their administration.
8.7.2 When CSPs are known to have been exposed to temperatures warmer than the warmest
labeled limit, but not exceeding 40º for more than 4 hours, such CSPs should be discarded,
unless appropriate documentation or direct assay data confirms their continued stability.
9 QUALITY ASSURANCE
In developing a specific QA plan, focus is on establishing objective, measurable indicators for
monitoring activities and processes that are deemed high-risk, high-volume, or problem-prone.
Appropriate evaluation of environmental monitoring might include, for example, the trending of
an indicator such as settling plate counts. In general, the selection of indicators and the
effectiveness of the overall QA plan (including the following steps) is reassessed on an annual
basis:
All high-risk level CSPs for administration by injection into the vascular and central nervous
systems that are prepared in groups of more than 25 identical individual single-dose packages
(such as ampuls, bags, syringes, vials), or in multiple dose vials for administration to multiple
patients, or exposed longer than 12 hours at 2º to 8º and longer than 6 hours at warmer than 8º
before they are sterilized must be tested to ensure the following:
3 They are sterile before they are dispensed or administered. The Membrane Filtration method is the
method of choice where feasible (e.g., components are compatible with the membrane). A method
not described in the USP may be used if verification results demonstrate that the alternative is at
least as effective and reliable as the USP Membrane Filtration method or the USP Direct
Inoculation of the Culture Medium method where the membrane filtration method is not feasible.
4 They do not contain excessive bacterial endotoxins. In the absence of a bacterial endotoxins limit
in the official monograph or other CSP formula source, the CSP must not exceed the amount of
USP Endotoxin Units (EU per hour per kg of body weight or m2 of body surface area).
5 positive sterility test results should prompt a rapid and systematic investigation of aseptic
technique, environmental control, and other sterility assurance controls to identify sources of
contamination and correct problems in the methods or processes.

9.1 Characteristics of a QA plan include the following:
• Written formalization.
• Consideration of all aspects of the preparation and dispensing of products as described in this
section, including environmental testing, validation results, etc.
• Description of specific monitoring and evaluation activities.
• Deficiencies in compounding, labeling, packaging, and quality testing and inspection can be
rapidly identified and corrected.
• Specification of how results are to be reported and evaluated.
• Identification of appropriate follow-up mechanisms when action limits or thresholds are

exceeded.
• Delineation of the individuals responsible for each aspect of the QA program.
9.2 Quality assurance procedures for low-risk level CSPs include, but are not limited to, the
following:
1. Routine disinfection and air quality testing of the direct compounding environment to
minimize microbial surface contamination and maintain ISO Class 5 air quality.
2. Visual confirmation that compounding personnel are properly donning and wearing
appropriate items and types of protective garments and goggles.
3. Review of all orders and packages of ingredients to assure the correct identity and amounts
of ingredients were compounded.
4. Visual inspection of CSPs to ensure the absence of particulate matter in solutions, the
absence of leakage from vials and bags, and the accuracy and thoroughness of labeling.
Example of a Media-Fill Test Procedure— This, or an equivalent test, is performed at least annually by
each person authorized to compound in a low-risk level under conditions that closely simulate the most
challenging or stressful conditions encountered during compounding of low-risk level CSPs. Once begun,
this test is completed without interruption. Within an ISO Class 5 air quality environment three sets of
four 5-mL aliquots of sterile Soybean–Casein Digest Medium are transferred with the same sterile 10-mL
syringe and vented needle combination into separate sealed empty sterile 30-mL clear vials (i.e., four 5-
mL aliquots into each of three 30-mL vials). Sterile adhesive seals are aseptically affixed to the rubber
closures on the three filled vials, then the vials are incubated.
9.3 Quality assurance procedures for medium-risk level CSPs:

Include all those for low-risk level CSPs, as well as a more challenging media-fill test passed annually, or
more frequently.
Example of a Media-Fill Test Procedure— This, or an equivalent test, is performed under conditions that
closely simulate the most challenging or stressful conditions encountered during compounding. This test
is completed without interruption within an ISO Class 5 air quality environment. Six 100-mL aliquots of
sterile Soybean–Casein Digest Medium are aseptically transferred by gravity through separate tubing sets

into separate evacuated sterile containers. The six containers are then arranged as three pairs, and a sterile
10-mL syringe and 18-gauge needle combination is used to exchange two 5-mL aliquots of medium from
one container to the other container in the pair. For example, after a 5-mL aliquot from the first container
is added to the second container in the pair, the second container is agitated for 10 seconds, then a 5-mL
aliquot is removed and returned to the first container in the pair. The first container is then agitated for 10
seconds, and the next 5-mL aliquot is transferred from it back to the second container in the pair.
Following the two 5-mL aliquot exchanges in each pair of containers, a 5-mL aliquot of medium from
each container is aseptically injected into a sealed empty sterile 10-mL clear vial using a sterile 10-mL
syringe and vented needle. Sterile adhesive seals are aseptically affixed to the rubber closures on the three
filled vials, then the vials are incubated.
9.4 Quality assurance procedures for high-risk level CSPs :

Include all those for low-risk level CSPs In addition, a media-fill test that represents high-risk level
compounding is performed semi-annually by each person authorized to compound high-risk level CSPs.
Example of a Media-Fill Test Procedure— This, or an equivalent test, is performed under conditions that
closely simulate the most challenging or stressful conditions encountered when compounding high-risk
level CSPs. This test is completed without interruption in the following sequence:
a. Dissolve 3 g of nonsterile commercially available Soybean–Casein Digest Medium in 100 mL of
nonbacteriostatic water to make a 3% solution.
b. Draw 25 mL of the medium into each of three 30-mL sterile syringes. Transfer 5 mL from each
syringe into separate sterile 10-mL vials. These vials are the controls, and they generate
exponential microbial growth, indicated by visible turbidity upon incubation.
c. Under aseptic conditions and using aseptic techniques, affix a sterile 0.2-µm porosity filter unit
and a 20-gauge needle to each syringe. Inject the next 10 mL from each syringe into three
separate 10-mL sterile vials. Repeat the process into three more vials. Label all vials, affix
sterile adhesive seals to the closure of the nine vials, and incubate them at 25º to 35º. Inspect for
microbial growth over 14 days.
A written quality assurance procedure includes the following in-process checks that are applied, as is
appropriate, to specific CSPs: accuracy and precision of measuring and weighing; the requirement for
sterility; methods of sterilization and purification; safe limits and ranges for strength of ingredients,
bacterial endotoxins, particulate matter, and pH; labeling accuracy and completeness; beyond-use date
assignment; and packaging and storage requirements. The dispenser shall, when appropriate and
practicable, obtain and evaluate results of testing for identity, strength, purity, and sterility before a CSP
is dispensed.
10 LIST OF REFERENCES
1
(Ingredient Selection under Pharmaceutical Compounding—Nonsterile Preparations)
2
(Stability Criteria and Beyond-Use Dating in the Pharmaceutical Compounding—Nonsterile Preparations)
3
(Pharmaceutical Calculations in Prescription Compounding)

11 APPENDIX
CRITERIA LOW-RISK LEVEL MEDIUM-RISK LEVEL HIGH-RISK LEVEL
Compounding f. Compounded entirely • All conditions listed under • Nonsterile ingredients
Conditions under ISO Class 5 (Class low-risk level are incorporated or a
100) conditions nonsterile device is
• Multiple individual or small employed before
g. Compounding involves doses of sterile products are terminal sterilization
only transfer, measuring, combined or pooled to prepare
and mixing a CSP that will be • Sterile ingredients,
manipulations with administered either to multiple components, devices and
closed or sealed patients or to one patient on mixtures are exposed to
packaging systems that multiple conditions air quality inferior to
are performed promptly ISO Class 5 (Class 100)
and attentively • Compounding process
includes complex aseptic • Nonsterile preparations
h. Manipulations are manipulations other than the are exposed for not more
limited to aseptically single-volume transfer than 6 hours before
opening ampuls, being sterilized
penetrating sterile • Compounding process requires
stoppers on vials with unusually long duration • Nonsterile preparations
sterile needles and are terminally sterilized
• The sterile CSPs do not but are not tested for
syringes and transferring
contain broad-spectrum bacterial endotoxins
sterile liquids in sterile
bacteriostatic agents, and are
syringes to sterile
administered over several days • It is assumed that the
administration devices
chemical purity and
and packages of other
content strength of
sterile products
ingredients meet their
original or compendial
specifications in
unopened or in opened
packages of bulk
ingredients
QA Program • Formalized in writing
See low-risk level. See low-risk level.
• Describes specific
monitoring and evaluation
activities
• Reporting and evaluation of
results
• Identification of follow-up
activities when thresholds are
exceeded
• Delineation of individual
responsibilities for each
aspect of the program
QA Practices • Routine disinfection and See low-risk level. See low-risk level.
quality testing of direct
compounding environment
• Visual confirmation of
personnel processes
regarding gowning, etc.
• Review of orders and
packages of ingredients to
assure correct identity and
amounts of ingredients
• Visual inspection of CSP
• Media-fill test procedure

performed at least annually
for each person
Outcome Monitoring Yes Yes Yes
Reports/Documents • Written policies and
procedures
• Adverse event reporting
• Complaint procedures
• Periodic review of quality

control documents

Patient and Caregiver • Formalized program that See low-risk level. See low-risk level.
Training includes
• Understanding of the therapy
provided
• Handling and storage of the
CSP
• Appropriate administration
techniques
• Use and maintenance of any
infusion device involved
• Use of printed material
• Appropriate follow-up
Maintaining Product • Packaging, handling, and

Quality and Control once transport
the CSP leaves the
Compounding facility • Written policies and
procedures including the
packaging, handling, and
transport of
chemotoxic/hazardous CSPs
• Use and storage
• Written policies and

procedures
• Administration
• Written polices and

procedures dealing with such
issues as handwashing,
aseptic technique, site care,

etc.
• Education/Training
• Written policies and

procedures dealing with
proper education of patients
and caregivers ensuring all of
the above
Storage and Beyond-Use • Specific labeling See low-risk level. See low-risk level.
Dating requirements
• Specific beyond-use dating
policies, procedures, and
requirements
• Policies regarding storage
Storage Conditions and In the absence of sterility testing, storage periods (before administration) shall not exceed the following:
Beyond-Use Dating for
completed CSP
Room temperature 48 hours Room temperature 30 hours Room temperature 24 hours
2º–8º 14 days 2º–8º 7 days 2º–8º 3 days
- 20º 45 days - 20º 45 days - 20º 45 days
Finished Product-Release Written policies and See low-risk level. See low-risk level.
Checks and Tests procedures that address:-
• Physical inspections
• Compounding accuracy
checks
Finished Product-Release Written policies and See low-risk level. See low-risk level.
Checks and Tests procedures that address
• Sterility testing

• Pyrogen testing
• Potency testing
CSP Work Appropriate solid surfaces See low-risk level. See low-risk level.
Environment
Limited (but necessary)
furniture, fixtures, etc.
Anteroom area
Buffer zone
Equipment Written policies and See low-risk level. See low-risk level.
procedures that address
calibration, routine
maintenance, personnel
training
Components Written policies and See low-risk level. Sterile and nonsterile drug
procedures that address Sterile components must meet the
components compendial standards if
available
Written policies and procedures
that address:-
• Sterile components
• Nonsterile components
Processing: Aseptic Written policies and See low-risk level. See low-risk level.
Technique procedures that address
specific training and
performance evaluation
Critical operations are carried
out in a Direct Compounding
Common Area (DCCA)

Environmental Policies and procedures See low-risk level. See low-risk level.
Control that address:
• Cleaning and sanitizing the
workspaces (DCCA)
• Personnel and gowning
• Standard operating
procedures
Verification Not required Not required Yes, recommended

Procedures
• Sterility Testing
Verification Certification of LAFW and See low-risk level. See low-risk level.
Procedures barrier isolates every six (6)
Environmental months
Monitoring
Certification of the buffer
room/zone and anteroom/zone
every six (6) months
Bacterial monitoring using an
appropriate manner at least
monthly
Verification Initially and annually thereafter See low-risk level. See low-risk level.
Procedures Didactic review
Personnel Training and Written testing
Education Media-fill testing

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مدونة تصنيع الأدوية في المستشفيات

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Manufacturing and

1 September 2010 Page 1 of 3

Please visit SFDA’s website at http://www.sfda.gov.sa/En/Drug for

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a. Preparation of drugs or devices in anticipation of prescription drug orders based on routine,

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Manufacturing— Manufacturing involves the production, propagation, conversion, or processing

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3 RESPONSIBILITIES OF THE COMPOUNDER

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5 PROCEDURES AND DOCUMENTATION

6 DRUG COMPOUNDING FACILITIES

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7 DRUG COMPOUNDING EQUIPMENT

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8 COMPONENT SELECTION REQUIREMENTS

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9 PACKAGING AND DRUG PRODUCT CONTAINERS

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Storage conditions for these products shall be dictated by their composition

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12 RECORDS AND REPORTS

13 COMPOUNDING FOR A PRESCRIBER'S OFFICE USE

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14 COMPOUNDING VETERINARIAN PRODUCTS

15 COMPOUNDING PHARMACY GENERATED PRODUCTS

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4 POLICY AND PROCEDURE

5 PERSONNEL (QUALIFICATION & EVALUATION)

6 SPACE & STORE

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7 EQUIPMENTS & FACILITY

8.2 COMPOUNDING NONDRUG REQUIREMENTS

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10.1 CAPSULES, POWDERS, LOZENGES, AND

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10.4 CREAMS, TOPICAL GELS, OINTMENTS, AND

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12 COMPOUNDING RECORDS AND DOCUMENTS

12.1 FORMULATION RECORD

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12.2 COMPOUNDING RECORD

12.3 MSDS FILE

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18 STABILITY OF COMPOUNDED PREPARATIONS

19 STABILITY CRITERIA AND BEYOND-USE DATING

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4 CONTAMINATION RISK LEVELS ............................................................................................... 3

8 STANDARD OPERATION PROCEDURE ................................................................................... 10

10 LIST OF REFERENCES ............................................................................................................. 19

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4 CONTAMINATION RISK LEVELS

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4.2 LOW-RISK LEVEL CSPS

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Examples of Medium-Risk Compounding: