ISOPP Standards of Practice 17

Section 6 – Facilities for sterile cytotoxic

reconstitution and personal protective
equipment
Facilities for the sterile reconstitution of cytotoxic identify that the access is controlled and limited to
agents need to ensure both the protection of the authorised personnel only. The use of standard
product and the protection of the drug handlers. symbols and colours to depict cytotoxic agents is
Aseptic drug manipulation must take place in a recommended. This sign should contain wording
controlled environment to ensure the sterility of the such as:
end product. Additional protective measures are ‘‘Cytotoxic Preparation Area.
required to guarantee the safety of the operators. Access Restricted to Authorised Personnel
Only’’
6.1 Centralised preparation
Centralised preparation of parenteral cytotoxic drugs The cytotoxic facility should be designed to allow
should be implemented to protect the final product easy and adequate access for personnel, equipment,
against microbiological and particulate contamina- and cleaning. The room surfaces should be designed
tion and to protect handlers against exposure to to minimise particle shedding and to prevent the
hazardous drugs. Taking into account the pharma- build-up of particulate matter. The design must
ceutical analysis and the quality control implemen- facilitate effective cleaning. Walls must be lined
ted, centralised preparation improves the entire with a smooth, durable surface, lighting recessed
quality of the preparation and thus the safety of into the ceiling, and the room should contain as few
patients is enhanced. Centralisation of services also projecting ledges or shelves as possible. Floors
provides economic benefits. should be poured and seamless if possible. Vinyl
Centralisation is commonly located in the phar- tiles have been shown to trap and hold drugs.
macy department. Many institutions site the prepara- In the event of contamination of the eye with
tion facility within an oncology outpatient hazardous material, there should be emergency eye
department or close to the inpatient ward where wash facilities available for use by staff. Eyes that
chemotherapy is most commonly administered (that become contaminated should undergo sustained
is, a satellite pharmacy). This offers advantages in irrigation with either a commercial eye irrigation
terms of ease of transport of cytotoxics as well as solution or sodium chloride (0.9%). Due to the
enhanced communication between pharmacy, potential for water pressure damage to the eye, it is
medical, and nursing staff. not recommended to irrigate the eye directly with
running water from a tap. Consideration should also
The satellite pharmacy must be under the
be given to the installation of an emergency shower.
control of a pharmacist.
Under no circumstances should nursing staff
be permitted to prepare/reconstitute cytotoxic 6.2.1 Class of cleanroom
agents on the ward. General classification of the cleanroom (‘‘Class’’) is
given by the ISO 14644-1 international standard.1
6.2 Facilities This classification is based on the maximum level of
Due to the risk of contamination, cytotoxic recon- particulate contamination. For sterile medicinal
stitution must be performed in a room dedicated products, classification of the room must be referred
solely to that task with similarly dedicated to the classification (‘‘Grade’’) given by the EudraLex
equipment. Good Manufacturing Practices Annex 1, Volume 4,
Access to the room where cytotoxic preparation is Manufacture of Sterile Medicinal Products,2 and by
performed must be restricted to trained and validated the draft PIC/S Guidelines.3 EudraLax applies to the
pharmacy personnel. A warning sign must clearly pharmaceutical industry while the draft of the PIC/S
18 ISOPP Standards of Practice

Guidelines are meant for the pharmaceutical inspec- switched over, this data is provided for information
tion services controlling (hospital) pharmacies. only.
This classification takes into account both partic- The Grade A environment corresponds approxi-
ulate and microbiological contamination. The room mately to the ISO Class 5.
shall be designed to facilitate asepsis in the handling Both laminar airflow hoods and isolators are able to
and preparation of cytotoxic drugs, and shall also be guarantee a Grade A environment. The main differ-
designed to provide containment of cytotoxic drugs, ence between these two approaches is related to the
particularly in the event of the failure of the requirements for the immediate environment of the
biological safety cabinet/isolator or spillage outside equipment used.
the cabinet/isolator. The requirements for ‘‘Class’’ or According to the PIC/S draft Guidelines,3 when
‘‘Grade’’ environments will depend upon both the a laminar airflow hood (biological safety cabinet) is
type of preparation and the equipment used. used for aseptic manipulations, the recommended
grade of background environment is:
(a) Type of Preparation
Aseptic preparation of products with shelf life
Preparation of sterile cytotoxic drugs can be 524 hours: at least Grade D
defined as an aseptic preparation. Aseptic preparation of products with shelf life
424 hours: at least Grade B*
(b) Environmental Setting
* If aseptic procedures are extensively documen-
Sterile cytotoxic preparation using aseptic tech- ted, grade C could be accepted for existing facilities.
nique must be performed in a Grade A environment. In that case, grade B clothing should be worn.
Characteristics of a Grade A environment are shown If an isolator is used (permanently closed – see
in Table 1 (particlulate contamination) and Table 2 Section 8), the recommended grade of background
(microbial contamination). Table 3 summarises the environment is:
relationship between the ISO classification1 the Aseptic preparation of products with shelf life
EudraLex2 classification, and the US federal standard 524 hours: at least Grade D
209E with regard to particulate contamination. Aseptic preparation of products with shelf life
Note: Federal standard 209E has been replaced 424 hours: at least Grade D
with ISO Standard 14644-1. Taking into account For terminally sterilised products, the background
that some suppliers and users may not yet have environment for filling these products is at least
Grade C.
Note that an anteroom leading to a positive
Table 1. Airborne particulate classification2
pressure room may be ISO Class 8 (see Table 3) but
an anteroom leading to a negative pressure room
At rest In operation shall meet at least ISO Class 7 (see Table 3) criteria
Grade Maximum permitted number of particles/m3
equal to or above Table 3. Relationship between ISO classification,1 EudraLex
0.5 mm 5 mm 0.5 mm 5 mm Classification,2 and US federal standard No. 209 E (US FS 209E)
A 3500 1 3500 1
B 3500 1 350 000 2000 Grade/Class Maximum permitted number of particles/m3
C 350 000 2000 3 500 000 20 000 equal to or above
D 3 500 000 20 000 Not defined Not defined 0.1 mm 0.2 mm 0.3 mm 0.5 mm 5 mm

Class ISO 5 100 000 23 700 10 200 3520 29

2 (US FS 100)
Table 2. Recommended limits for microbial contamination
Grade A and / / / 3500 1
B (at rest)
Grade Air sample Settle plates Contact plates Glove print Class ISO 7 / / / 352 000 2930
cfu/m3 (diameter (diameter 5 finger (US FS 10,000)
90mm) 55 mm) cfu/glove Grade C 350 000 2000
cfu/4 hours cfu/plate Class ISO 8 / / / 3 520 000 29 300
(US FS 100,000)
A 51 51 51 51
Grade D / / / 3 500 000 20 000
B 10 5 5 5
C 100 50 25 –
*Note: US FS 209 E has been replaced with ISO Standard 14644-1.
D 200 100 50 –
 ISOPP Standards of Practice 19

so that air drawn into the negative pressure environ- container package (e.g., bag, vial) of sterile
ment is of the same ISO Class 7 (see Table 3) quality. product to make the CSP.
A pressure indicator shall be installed that can be (3) Manipulations are limited to aseptically open-
readily monitored for correct room pressurization. ing ampoules, penetrating sterile stoppers on
The BSC and Compounding Aseptic Isolator shall vials with sterile needles and syringes, and
be 100% vented to the outside air through HEPA transferring sterile liquids in sterile syringes
filtration. to sterile administration devices, package
Additional comments related to the use of containers of other sterile products, and
isolators: When isolator technology is used, the containers for storage and dispensing.
requirements for the immediate surroundings will
For a low-risk preparation, in the absence of passing a
depend upon the pressure type of the isolator, and
sterility test,5 the storage periods cannot exceed the
the type of pass through hatches. Positive air pres-
following time periods: before administration, the
sure isolators, which are totally and permanently
CSPs are properly stored and are exposed for not
enclosed, may be located in an uncontrolled room or
more than 48 hours at controlled room temperature,
a D Grade (ISO 8) environment. Negative air pressure
for not more than 14 days at a cold temperature, and
isolators must be located at least in a Grade C (ISO 7)
for 45 days in solid frozen state at 208C or colder.5
environment. Examples of low-risk compounding:
In the case of preparation of cytotoxic agents,
containment is the most important aspect to be (1) Single volume transfers of sterile dosage
considered, and special attention must be paid to the forms from ampoules, bottles, bags, and
transfer system/pass through hatches used between vials using sterile syringes with sterile nee-
the isolator and the environment. Type F4 pass dles, other administration devices, and other
transfer devices are highly recommended to remove sterile containers. The solution content of
waste and end-products. These devices use double ampoules should be passed through a sterile
interlocking doors to ensure both the containment of filter to remove any particles.
any chemical contamination and the sterility of the (2) Simple aseptic measuring and transferring
final product. Type A4 transfer devices must be with not more than three (3) manufactured
avoided because during the transfer, inside isolator air products including an infusion or diluent
can be directly exhausted into the isolator environ- solution to compound drug admixtures and
ment, especially when using a positive air pressure nutritional solutions.
isolator. See Section 8.
According to USP Chapter 57974,5 where Medium-risk conditions
three risk levels are introduced, the requirements of Medium-risk conditions include multiple individual
a Class D cleanroom for low-risk operations and a or small doses of sterile products that are com-
Class C cleanroom for medium and high-risk pounded or pooled to prepare a compound sterile
operations must be achieved. Those risk levels are product that will be administered either to multiple
assigned according to the conditions in which sterile patients or to one patient on multiple occasions.
preparations are compounded. Examples of medium risk conditions:
According to USP 5797 45 Hazardous Drugs as
CSPs (Compounded Sterile Preparations): (1) The compounding process includes complex
aseptic manipulations other then a single-
volume transfer.
Low-risk conditions (2) The compounding process requires an
(1) The CSPs are compounded with aseptic unusually long duration, such as that
manipulations entirely within ISO Class 5 required to complete dissolution or homoge-
neous mixing.
(see Table 1) or better air quality using only
(3) The compounded sterile products do not
sterile ingredients, products, components,
contain broad-spectrum bacteriostatic sub-
and devices.
stances, and they are administrated over
(2) The compounding involves only transfer,
several days.
measuring, and mixing manipulations using
no more than three commercially manufac- For medium-risk preparations, in the absence of
tured sterile products and entries into one passing a sterility test the storage periods cannot
20 ISOPP Standards of Practice

exceed the following time periods: before adminis- more than 24 hours at controlled room temperature,
tration, the CSPs are properly stored and are exposed for not more than 3 days at a cold temperature, and
for not more than 30 hours at controlled room for 45 days in solid frozen state at 208C or colder.
temperature, for not more than 7 days at a cold Examples of high-risk compounding:
temperature, and for 45 days in solid frozen state at
(1) The process of dissolving non sterile bulk
208C or colder.
drug and nutrient powders to make a solu-
Examples of medium risk compounding:
tion, which will be terminally sterilized.
(1) The compounding of Total Parenteral (2) The situation when sterile ingredients, com-
Nutrition fluids by using manual or auto- ponents, devices and mixtures are exposed
mated devices that require multiple injec- to air quality inferior to ISO Class 5.
tions and detachments and attachments of (3) The process of measuring and mixing sterile
the nutrient source products to the device or ingredients in non sterile devices before
machine to deliver all nutritional compo- sterilisation is performed.
nents to the final sterile container.
(2) The filling of reservoirs of injection and
infusion devices with multiple sterile pro- 6.2.2 Pressure differentials
ducts and evacuation of air from these According to USP 57974,5 there is no option for the
reservoirs before the filled device is pressure of the preparation room which should be
dispensed. negative.
(3) The filling of reservoirs of injection and According to the PIC/S draft guidelines3:
infusion devices with volumes of sterile
‘‘Aseptic operations (open and closed procedures)
drug solutions that will be administered
should be performed in a grade A environment in a
over several days at ambient temperatures
laminar flow cabinet (LFC) or a positive pressure
between 258 and 408C.
pharmaceutical isolator. The room should have a
(4) The transfer of multiple ampoules or vials
positive pressure (ideally 10 – 15 Pascals) and air
into a single, final sterile container or
flow relative to the surrounding areas of a lower
product.
grade in order to protect the product from
contamination.’’
High-risk conditions
High-risk conditions include: ‘‘Preparation under negative pressure, protecting
operator and environment from contamination
(1) The compounding of non sterile ingredients, should only be used for preparation of hazardous
including manufactured products for routes pharmaceuticals (e.g. cytotoxic drugs, radiophar-
of administration other than those listed maceuticals and radio labelled blood products),
under c in the introduction of the official together with appropriate precautions against con-
Pharmacopeial Forum that are incorporated tamination of the medicinal product (e.g. appro-
or a non sterile device that is employed priate background room air quality, positive
before terminal sterilization. pressure airlock systems).’’
(2) The compounding of sterile ingredients,
components, devices and mixtures exposed ‘‘LFCs are not suitable for the preparation of
to air quality inferior to ISO Class 5; this hazardous drugs. Biohazard safety cabinets
includes the storage in environments inferior (BSCs) should be used instead, with a vertical
to ISO Class 5 or opened or partially used down flow exhausting vertically from the cabinet
packages of manufactured sterile products and not towards the operator.’’
that lack microbial preservatives. Therefore, combining both recommendations, BSC’s
(3) The compounding of non sterile products of Grade A (ISO 5) are located in a negative air
exposed to air quality inferior to ISO Class 5 pressure room of Grade C (ISO 7). Positive pressure
for at least 6 hours before sterilization. isolators Grade A (ISO 5) are located in a negative air
For high-risk preparations, in the absence of passing pressure room of Grade D (ISO 8) or uncontrolled
a sterility test, the storage periods cannot exceed the Grade room. Negative air pressure isolators Grade A
following time periods: before administration, the (ISO 5) are located in a negative air pressure room of
CSPs are properly stored and are exposed for not Grade C (ISO 7).
 ISOPP Standards of Practice 21

Pressure differentials should be established within If a compounding isolator that meets the require-
the cytotoxic preparation facility with the double ments for asepsis and containment is used outside of
objective of protecting the operators and maintaining a cleanroom, the room must maintain a minimum
the sterility of parenteral product. Two possibilities negative pressure of 0.01 inch (0.0254 cm) water
exist: Positive and negative pressure differentials with column (2.4905 Pa) and have a minimum of 12 air
the surrounding environment. changes per hour.
(a) Positive Pressure Differential
6.2.3 Air changes
Positive air pressure of the preparation room and A minimum air change of 20 room volumes per hour
negative air pressure of the airlock hatches and the is required. Areas known to generate large numbers
anteroom. In this case, the negative air pressure of of particles, for example changing rooms, may have
the hatches and personnel zone acts as a trap to an air change rate of up to 60 volumes per hour.
isolate potentially contaminated air.
(b) Negative Pressure Differential 6.2.4 External exhaust of air from
the work area
Negative air pressure of the preparation room and
The air from the workplace must be exhausted to the
positive air pressure of the airlock hatches and the
atmosphere to prevent exposure of personnel.
anteroom. In this case, the positive air pressure of the
A HEPA exhaust filter should be used to decrease
hatches acts as a barrier.
contamination of the air exhausted. However, it is
(c) Pressure Differential Between Adjacent known that some anticancer drugs are vaporised and
Rooms then pass through HEPA filters. Some countries, for
example Australia, may mandate the use of activated
EudraLex2 recommends a 10–15 Pa pressure differ-
carbon filters to trap vapourised cytotoxics.
ence between adjacent rooms of different grade.
However, it should be noted that these filters may
Note: this does not apply in the case of a negative
not guarantee complete retention in all cases.
pressure room.
See Section 8.
For example, a typical graduation configuration for
The location of the exhaust point of the duct
a cleanroom used for aseptic preparation is given
is usually 2 m above the nearest building.
below:

10–15 Pa between Grade A and B 6.2.5 Temperature and humidity

8–10 Pa between Grade B and C In order to prevent microbiological contamination

2–6 Pa between Grade C and D and to ensure comfort of the personnel working in

2 Pa between Grade D and surrounding zone the area, the temperature of the preparation rooms
Note that this example of graduation has to be must be controlled. A temperature in the range of
adapted in order to reach the above proposed 18–228C is acceptable.
pressure differential (a) or (b) for aseptic preparation The humidity must be controlled in order to prevent
of toxic drugs. corrosion and condensation on any work surfaces and
In all cases, it is recommended that the room also to provide operator comfort. In addition, for
where cytotoxic agents are stored is under negative isolators which are sterilized by hydrogen peroxide
pressure to prevent the dissemination of contamina- vapour, the humidity of the surrounding environment
tion in the event of breakage. must be strictly controlled. The human comfort zone
According to USP _797`,5 Hazardous drugs as is generally in the range of 30% to 70% relative
CSP’s (Compounded Sterile Preparations): The humidity. For isolators sterilized by hydrogen
ISO Class 5 (see Table 3) BSC or Compounding peroxide a 50% relative humidity level must be
Aseptic Isolator (see definition below) shall be placed reached and controlled between 40% and 60%.
in an ISO Class 7 (see Table 3) room that is physically
separated, i.e., a different room, from other prepara- 6.2.6 Access of personnel to the cleanroom
tion areas, and optimally has no less than 0.01-inch Access to the cleanroom should be through an
(0.0254 cm) water column [2.4905 Pa] negative anteroom. An effective airlock must exist between
pressure to adjacent positive pressure ISO Class 7, the cytotoxic suite and the external environment.
or better, anterooms, thus providing inward airflow Adequate procedures must be in place to prevent the
to contain any airborne drug. simultaneous opening of doors and pass-through
22 ISOPP Standards of Practice

hatches. If interlocking doors are used, a safety shall be handled with caution using appropriate
override switch should be installed for emergency chemotherapy gloves during distribution, receiving,
situations. The doors should preferably be fitted with storage, preparing for administration, and disposal.
an audible or visual alarm to prevent both doors
being opened simultaneously.
This anteroom must be the only access to the 6.2.9 Monitoring of facilities
cytotoxic cleanroom. If possible, this anteroom An ongoing monitoring program should be estab-
should not share access to other non-cytotoxic lished. In controlled workplaces, the parameters
cleanrooms in order to prevent any cross contami- to be monitored are microbiological contamination,
nation occurring. The anteroom should provide particulate contamination, HEPA filtration, air
facilities for gowning of personnel entering the velocity, and pressure differentials. Visual inspection
cleanroom and should be ventilated through a HEPA of the surfaces and joints should be performed
filter. A full length mirror should be available in the regularly for cracks or other damage. Specifications
anteroom so that staff can check that they are to be maintained depend on the grade of the room
appropriately gowned prior to entering the clean- (see Section 6.2.1).
room. Consideration should be given to the use of A check list should be used to assess the confor-
sticky mats. Step-over barriers should be used to mity of the room and equipment before daily use.
separate the different stages of change. Attention Pressure differentials must be checked before entry
should be paid to the exit of persons and separate into the cleanroom. Consideration should be given to
circulation zones should be identified allowing the installation of manometer alarms, preferably
discarding of protective gowns and gloves before visual, which alert staff to inadequate pressure
exiting the restricted access zone. differentials.
The pressure within the anteroom may be positive Particulate contamination and air velocity should
or negative depending on the concept chosen (see be assessed on a regular basis.
Section 6.2.2) Microbiological contamination should be checked
on a daily basis by sampling surfaces (contact plates).
6.2.7 Pass-through hatches Passive air sampling should be done daily with settle
A pass-through hatch is essential to prevent direct plates (Petri dishes of diameter 90 mm) and active air
access between the cytotoxic cleanroom and the sampling done on a regular basis. Testing must be
external environment. There are two possibilities for carried out more frequently if any abnormality in any
the location of such hatches. These hatches may test is detected, or if any maintenance or repair work
either be between the cleanroom and the anteroom is carried out.
or between the cleanroom and the external environ-
Frequency of monitoring3
ment. If the latter option is selected, then interlock-
ing doors must be used and the unit must be HEPA Table 4. Minimum frequency of physical monitoring
filtered. Hatch doors should preferably be fitted with
an audible or visual alarm to prevent doors being Laminar flow cabinets Frequency
opened simultaneously. (LFCs)/Biohazard Safety
For specific hatches used for entry to a pharma- Cabinets (BSCs):
ceutical isolator see Section 8. Pressure differentials Before beginning of work,
In order to minimise cross contamination, separate between rooms usually daily
hatches for entry and exit of products are preferable. Pressure differentials across Before beginning of work,
HEPA filters (workstation) usually daily
Particle counts Yearly at rest and in the
6.2.8 Storage room operational state
According to USP 57974,5 hazardous drugs shall be Room air changes per hour Yearly
stored separately from other stock in a manner to Air velocities on workstations Yearly
HEPA filter integrity checks Yearly
prevent contamination and personnel exposure. Isolators:
Such storage is preferably within a containment Isolator glove integrity Visual checks every session
area such as a negative pressure room. The storage Pressure differentials across Before beginning of work,
area must have sufficient general exhaust ventilation, HEPA filters usually daily
Isolator pressure hold test Weekly
e.g. - at least 12 air exchanges per hour to dilute and
(with gloves attached)
remove any airborne contaminants. Hazardous drugs
 ISOPP Standards of Practice 23

Table 5. Minimum frequency for microbiological monitoring of a light hand pressure for 2–5 seconds is likely to
be satisfactory.
Settle plates Every working session in the
Maximum acceptable levels of microbiological
Grade A (ISO 5) zone
Once a week in clean room
contamination for contact plates depend on the
environment grade2:
Surface samples Weekly
Active air samples Weekly Grade A environment _1 cfu/plate
Glove finger dabs At the end of each working session Grade B environment 5 cfu/plate
Grade C environment 25 cfu/plate
Grade D environment 50 cfu/plate

6.2.11 Air particle sampling

6.2.10 Microbiological monitoring Air particle sampling is performed to verify that the
Passive air sampling is performed using environment reaches specification. Particle measure-
settle plates which must be placed according to a ment is based on the use of a discrete airborne
sampling plan previously defined. This plan may be particle counter to measure the concentration of
developed in conjunction with the institution’s particles at designated sizes equal or greater than the
department of microbiology. Settle plates should be threshold stated.
exposed under normal operating conditions for a Maximum acceptable levels of particulate con-
period of 4 hours. Maximum acceptable levels tamination depend on the environment grade2 – see
of microbiological contamination depend on the Table 1. Maximum permitted levels are given both
environment grade2: at rest and under normal operating conditions.
Grade A environment _1 cfu/plate The particulate conditions given at rest should be
Grade B environment 5 cfu/plate achieved after a short clean up period of 15–20
Grade C environment 50 cfu/plate minutes (guidance value) after completion of
Grade D environment 100 cfu/plate operations. For the grade A environment, it is
accepted that the ‘‘In Operation’’ specifications may
Active air sampling is performed using bio- not be achieved under normal operating conditions
collectors. The sampling method is based on due to the nature of the work being carried out
collecting a known volume of air during a defined (for example, over wrapping of sterile medical
period of time. Air is drawn over a nutrient agar devices). In this case, particle counts above the
surface at such velocity that any particulate specifications can be generated without compro-
contaminants are impacted onto the surface. mising the quality of the preparation. Consequently,
Active air sampling is a more sensitive method the particle control should be focussed on the ‘‘at
than passive air sampling. Maximum acceptable rest’’ conditions.
levels of microbiological contamination depend on
the environment grade2:
6.2.12 Certification and Quality Assurance
Grade A environment _1 cfu/plate Whenever possible, all equipment and processes
Grade B environment 10 cfu/plate used for cytotoxic preparation which affect
Grade C environment 100 cfu/plate product sterility or product attributes should be
Grade D environment 200 cfu/plate qualified or validated. Any certificates issued shall
Microbiological monitoring of surfaces can be be reviewed, approved, and signed off by a
performed either by contact plates (diameter designated pharmacist, and retained indefinitely.
55 mm) or using swabs. Contact plates provide a This will vary according to local practice and
higher degree of reproducibility than swabs and are regulations.
easier to use. However, swabs could be useful for Qualification is required for the room and for the
sampling inaccessible places such as corners. In equipment used. This includes the biological safety
cabinet, pharmaceutical isolator, and automated
addition, no recommendation of maximum accept-
filling pump among other equipment. This qualifica-
able levels is available for the swabs. For the
tion process consists of four steps:
contact plate method, contact with the surface to
be sampled must be applied at a defined pressure (1) Design (Design Qualification [DQ]): The
for a defined period of time. A standard procedure documented verification that the proposed
24 ISOPP Standards of Practice

design of facilities, systems and equipment is
Air distribution studies

suitable for the intended purpose.

Approval of the design and drawing: 6.2.13 Validation
This approval must be obtained, in accor- Validation is the documented evidence that the
dance with local regulations, by the body process, operating within established parameters,
responsible for pharmacy practice, for can perform effectively and reproducibly to produce
example a state board of pharmacy, cytotoxic drugs meeting all predetermined specifica-
a pharmaceutical society, or licence tions and quality attributes. In terms of sterile
inspector, and by the pharmacist facilities, validation that the processes used during
responsible for the unit. the aseptic preparation maintain the sterility of the
end product is required.
(2) Installation (Installation Qualification Validation of the process (see Section 4.10.1)
[IQ]): The documented verification that the
facilities, system and equipment, as installed
or modified, comply with the approved 6.3 Clothing & PPE
design and the manufacturer’s recommenda- The correct selection and use of personal protective
tions. At this stage, the installation is on site equipment (PPE) is required to both ensure the
but is not operational. The objective at this sterility of the end product and protect the operator.
point is to review the compliance PPE must be worn to protect personnel
with specifications. during cytotoxic reconstitution and during other
(3) Operation (Operational Qualification activities where they may come into contact with
[OQ]): The documented verification that the hazardous drugs. Activities may include opening drug
facilities, systems, and equipment, as packaging, handling vials or finished product, label-
installed or modified, perform as intended ling drug containers, or disposing of waste. PPE
throughout all anticipated ranges. The objec- includes gloves, gowns or coveralls, boots or over-
tive is to check that the installation operates shoes, masks, head coverings, and protective
effectively under normal working conditions eyewear.
but without activity. Examples of operational The specific protective equipment required will
certification for rooms are given below: depend upon the grade of room in which the
operator is working. The highest level of protection

HEPA filter integrity test is for zones A/B where the aseptic manipulations are

Functional check of pressure regulation performed (BSC in a Grade B room). Examples of PPE
and alarms required are shown in Table 6.

Air change rate per hours

Particle count (a) Gowns

Pressure differential The use of disposable coveralls or gowns made of

Noise level non-linting and non-absorbent polyethylene-coated

Light Level polypropylene material is recommended.6 The
(4) Performance (Performance Qualification gown used should have the following
[PQ]): The documented verification that the characteristics:
facilities, system and equipment taken
Long and closed at the neck
together, can perform effectively and repro-
Long sleeves with cuffs gripped at the wrist
ducibly, based on the approved process
Disposable sleeve covers to protect the wrist
method and product specification. The objec- and lower arm
tive is to check that the installation operates
Waterproof material for the front and sleeves
effectively under normal operating condi-
Sterile
tions during routine activity. Examples of
Non-linting
performance certification are given below:
Integrated coveralls which include head and foot

Checking procedures of use and monitor- coverings are very suitable in terms of both micro-
ing of the installation biological and chemical contamination.
 ISOPP Standards of Practice 25

Table 6. Clothing required for differing grades of they have been validated for the specific
environment2
purpose of cytotoxic reconstitution
Grade of Room Requirements for PPE A double pair of gloves may be used. The outer
glove must extend over the cuff of the the gown.
Grade D Hair/Beard Covering Normal
Protective Clothing Gloves should be changed at least every 30 minutes or
Grade C Hair/Beard Covering whenever damage or obvious contamination occurs.
Clothes gripped at wrist with raised Gloves should not be decontaminated with alcohol.
Collar
Clothing must not shed fibres or particles (f) Hair Covering
Grade A/B Hood or other head covering
Mask The hair must be covered with a separate head
Sterile, Non-powdered gloves covering or an integrated hood of a coverall. Men
Sterile or disinfected boots or overshoes with beards may need to wear a separate covering for
Sterile clothing which must not shed this purpose
fibres or particles
Sterile clothing must be capable of (g) Personal protective equipment for Isolator
retaining particles shed by operator and BSC III users
The gowning procedure will depend on the grade of
the room where the isolator or BSC III is located (see
above table 2). In addition, personal protective
(b) Overshoes should be worn:
equipment has to be considered for tasks performed

If shoes are worn in the production zone. outside the barrier enclosure where the risk of
Dedicated shoes should be used for this chemical contamination is present (e.g. handling
purpose. vials).

In the event of any accidental contamination
(c) Masks
REFERENCES
Surgical masks should be used during production in
cleanroom. A mask (type P2 or P3 for solids and 1 ISO (International Organization for Standardization)
liquids) is required when changing the pre-filter, in 14644-1: cleanrooms and associated controlled
the event of any accidental contamination and for environments – Part 1: classification of air cleanliness.
oral preparations. Common surgical masks offer no 1999.
protection against aerosols. 2 EudraLex. Volume 4 Medicinal Products for Human
and Veterinary Use: good Manufacturing Practice.
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