Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5593_Библиотеки_им_академика_М_И_Перельмана.pdf
Labelling of dispensed medicines CHAPTER 28
A batch number
When a product has been prepared extemporaneously it is good practice to award it a batch number and incorporate this onto the label. This is
standard practice in hospital pharmacy. When preparing an extemporaneous product, details of the
ingredients used should be recorded (see Ch. 25).
The batch number allows referral back to this information.
Expiry date
It is not normally necessary to put an expiry date on
the label of a dispensed medicine, although with the
increasing dispensing of manufacturers’ original packs
this information will be part of the pack labelling.
Manufacturers’ expiry dates relate to ideal storage
conditions but, unfortunately, when a product has
been dispensed and given to the patient there is no
longer any control over how it is stored. For this reason, under current legislation, when a product is
repackaged for dispensing, no expiry date is stated.
Patients should be encouraged to complete the course
of medication or, if for any reason a supply is not
finished and is no longer required, to bring any remainder back to the pharmacy.
There are, however, specific occasions when an
expiry date must be added to the label.
*
An expiry date should always be put onto any
extemporaneously prepared item.
*
An expiry date should always be used when a
product has been diluted, thereby affecting its
stability and shelf life.
*
An expiry date should always be indicated when
the preparation is sterile, e.g. eye drops. Once
opened the product is no longer sterile and if
used beyond a certain timescale there is a serious
risk of infection. It is therefore recommended
that eye drops and eye ointment, unless
otherwise specified by the manufacturer, should
be discarded 4 weeks after opening. This
instruction should be indicated on the label
(see Ch. 39 for further details).
Although the majority of patients will understand
what ‘expiry date’ means, it is important to express
the information in a clear and unambiguous way. ‘Any
unused to be discarded on ... (date)’ or ‘Do not use
after ... (date)’ are preferred methods of expressing
expiry dates.
Legal requirements in certain circumstances
Veterinary dispensed products
The words ‘For animal use only’ or similar must
always be added to the label of a dispensed veterinary product. Instead of the patient’sname,the
name of the animal’s owner should appear, along
with the owner’saddressoraddresswherethe
animal lives.
Emergency supply
When a preparation is dispensed using the emergency
supply procedures, the words ‘Emergency supply’
must appear on the label.
Private prescriptions
A label for a medicine dispensed from a private prescription must bear a reference number. This reference number will relate to the entry in the private
prescription register and will also be endorsed on the
private prescription.
Labels for vulnerable patients
Somepatientsmayhavedifficultyinreadingthe
normal print size of a label due to partial or complete blindness. In such cases consideration should
be given to providing additional support to these
patients, in the form of large print size on labels or
the provision of large print size copies of the labels.
In all cases the medicinal products should be l abelled. Additionally, consideration should be given
to providing Braille labels for those patients able to
read Braille.
Some patients may not be able to read the language on the label due to either illiteracy or being a
non-native language reader. It may be possible to
provide such a patient with a picture or series of
pictures to illustrate the instructions. Many pictograms (a symbol representing a concept, object,
activit y, place or event by an illustration) have been
developed for labelling medicines with instructions
on how often and how to take medicines. Similarly
many toxic chemicals are labelled with pictograms
319
SECTION FOUR Dispensing and related pharmaceutical practice activities
to avoid harm to the public. The Risk-benefit Assessment of Drugs-Analysis and Response (RADAR) Council of Japan has recently released a series
of new pictograms for use on pharmaceutical packaging. These may be viewed on www.pinktentacle.
com/images/pictograms.jpg.
Clearly any patient with difficulty reading or understanding a label on a dispensed medicine should be
given advice and counselling by the pharmacist before
leaving the pharmacy.
Errors in labelling
The potential for making errors when producing a
label is considerable and it is important that constant
checking is carried out. Practice procedures should be
such that the chances of errors occurring are minimized (see Ch. 24). Dispensing is usually carried
out in a busy environment with many distractions
and it takes considerable effort to maintain the
100% concentration required to ensure that errors
do not occur.
Apart from errors in interpreting prescribers’
instructions or missing off any of the details already
mentioned, the advent of computerized labelling
has brought its own problems, two of which will be
mentioned.
KEY POINTS
*
A label is used to identify and instruct on the use of
a medicine, so simple language should be used
*
All labels must be typewritten or computer
generated
*
All labels must state the name and quantity of the
preparation, patient’s name and instructions,
name and address of pharmacy, date of
dispensing and ‘Keep out of the reach of children’
*
Warning labels may also be required
*
Active verbs should be used on the label
*
Adjacent numbers should be separated by the
formulation name (e.g. ‘take two tablets three ... ’)
on a label
*
As full a name of the patient as possible should be
included on the label
*
The BNF contains details of side-effect warnings
which should be used unless there is a good reason
not to do so
*
Some warning labels may require verbal
explanation
*
It is good practice to give an extemporaneous
preparation a batch number
*
Expiry dates are required on the label when
dispensing diluted, sterile and extemporaneous
preparations
*
Computer labelling systems can increase the risk
of some types of error
Patient’s name errors
When using a computer system, if a patient presents a
prescription for several items, the patient’s name is
typed in once and the number of items to be dispensed bearing that patient’s name is entered. Occasionally an item may not be dispensed or the number
of items may be entered incorrectly. This means that
when the next prescription for a different patient is to
be dispensed, the name of the first patient will occur
on the label even if all the other information is correct.
Transposition of labels
It is not uncommon that two labels have been produced on the pharmacy computer and two medicines
have been prepared. At this point the labels could
be applied to the incorrect container unless care is
taken.
An awareness of how easily these errors can occur
is at least one step to ensuring that they do not
happen.
320
Self-assessment questions
1. The following NHS prescription was received:
Tabs Ibuprofen 400 mg
Mitte 60
one t.i.d.
The name of the patient was Mrs Marjory Nicol.
Comment on the accuracy of the following labels
produced for this prescription. (Assume that the
name and address of the pharmacy and ‘Keep out
of the reach and sight of children’ are included.)
a 60 Tabs Ibuprofen
Take one tablet three times daily with or after food
Mrs Marjory Nicol [12/5/08]
b 60 Tabs Ibuprofen 400 mg
Take one three times daily with or after food
Mrs Marjory Nicol [12/5/08]
c 60 Tabs Ibuprofen 400 mg
Take one tablet three times daily with or after
food
M Nicol [12/5/08]
Labelling of dispensed medicines CHAPTER 28
d 60 Tabs Ibuprofen 400 mg
One to be taken three times daily with or after
food
Mrs Marjory Nicol [12/5/08]
e 60 Tabs Ibuprofen 400 mg
Take three tablets daily with or after food
Mrs Marjory Nicol [12/5/08]
2. The following NHS prescription is received:
Betnovate
Ò
Ointment half Strength
Mitte 50 g
Sig. apply to affected area m. et n.
Mr James Hill
Comment on the following label:
50 g Betnovate
Ò
Ointment Half strength
Apply to affected area morning and night
Mr James Hill [12/5/08]
3. You will need to consult Appendix 9 in the BNF to
complete this exercise. Using the BNF, indicate
the cautionary and advisory labels which should
appear on the following products. Are there
products where you consider additional
information may need to be given?
a Tildiem Retard
b Ledermycin
c Solpadol
d Madopar
Ò
Ò
caplets
Ò
capsules
Ò
tablets
capsules
Self-assessment answers
1. a The strength of the drug has been omitted from
the label. This will cause problems of
identification.
b The instructions have been written with the
number of tablets and the dose frequency
together, i.e. ‘Take one three times ...’ This is
bad practice and may lead to errors in dosing.
c The status of the patient and first name have not
been included, i.e. M Nicol instead of Mrs
Marjory Nicol.
d The passive form of the verb has been used, i.e.
‘to be taken’. The active form ‘take’ is the
preferred form.
e The instructions ar e not clear. Alth ough the
patient has been told the correct number of
tablets to take in a 24-hour period,
information about frequency is missing. This
will lead to loss of efficacy and a possible
increase in the incidence of adverse
effects.
2. This preparation has been diluted, i.e. Betnovate
ointment, 25 g and 25 g of recommended diluent.
This has affected the stability and consequently
the shelf life so an expiry date should have been
indicated on the label. The manufacturer’s
recommendation is a shelf life of 14 days. This
preparation is for external use and the label should
have indicated this.
Ò
3. a Tildiem Retard
tablets require:
Label 25: ‘Swallowed whole, not chewed’.
This is a reasonably simple instruction but the
patient’s attention should be drawn to it and an
explanation of why it is necessary given. The
modified release of the preparation will be
destroyed if the tablets are crushed or chewed.
Ò
b Ledermycin
capsules require:
Label 7: ‘Do not take milk, iron preparations or
indigestion remedies at the same time of day
as this medicine’.
Label 9: ‘Take at regular intervals. Complete the
prescribed course unless otherwise directed’.
Label 11: ‘Avoid exposure of skin to direct
sunlight or sun lamps’.
Label 23: ‘Take an hour before food or on an
empty stomach’ .
The main problem here is the considerable
amount of information. The patient’sunderstanding of the information should be checked
and further explanation given if necessary.
Ò
c Solpadol
caplets require:
Label 2: ‘Warning. May cause drowsiness. If
affected do not drive or operate machinery’.
Label 29: ‘Do not take more than 2 at any one
time. Do not take more than 8 in 24 hours’.
Label 30: ‘Contains paracetamol’.
Again there is a considerable amount of
information given, all of which is important.
The pharmacist should alert the patient to the
paracetamol warning and explain that other
paracetamol-containing preparations should
not be taken.
Ò
d Madopar
capsules require:
Label 14: ‘This medicine may colour the urine’.
Label 21: ‘Take with or after food’.
Reinforcement of dosing in relation to food
intake should be given if the pharmacist
considers it necessary. If the patient has not
received the medication before, an indication
that the urine colour will be reddish should be
given.
Ò
321
This page intentionally left blank
Chapter Twenty-Nine
Production of sterile products
Derek G. Chapman
29
STUDY POINTS
*
The requirements for sterile production
*
Grades of clean areas
*
Design and operation of clean areas
*
Isolators
*
Environmental monitoring
*
Preparation of aseptic products
Introduction
The production of sterile medicinal products has special requirements. These products must be produced
in conditions that ensure that they are pure. They
must also be free from viable organisms and pyrogens
with limited, or ideally no, particulate contamination.
It is thus important that only carefully regulated and
tested procedures are used to manufacture sterile
products.
Owing to their special manufacturing requirements, sterile medicinal products are prepared in
special facilities known as clean rooms. These rooms
are designed to reduce the risk of microbial and particulate contamination at all stages of the manufacturing process.
The clean area used to produce sterile products is
commonly designed as a suite of clean rooms. With
this system, the operators enter the clean rooms by
way of a changing room. Within this area the operators
put on clean room clothing before entering into the
clean rooms. The changing room has a lower standard
of environmental quality. A clean room with a lower
environmental standard is also used to prepare solutions. These solutions are then sterilized by filtration
before being transferred into the filling room. The
clean room used to fill and seal the product containers
is the highest quality of clean room. This will reduce
the risk of product contamination.
Sterile products that are marketed in the European
Union must be produced in conditions which conform with the conditions given in the revised Annex
1 of Good Manufacturing Practices (Volume IV) of
‘The Rules Governing Medicinal Products in the
European Union’. This guidance on the procedures
for manufacturing sterile products describes the
cleanliness of the clean room environment and recommends how pharmaceutical clean rooms should be
built and used.
Sterile product production
Production of sterile products should be carried out in
a clean environment with a limit for the environmental quality of particulate and microbial contamination.
This limit for contamination is necessary to reduce the
risk of product contamination. In addition, however,
the temperature, humidity and air pressure of the
environment should be regulated to suit the clean
room processes and the comfort of the operators.
Clean areas for the production of sterile products
are classified into grades A, B, C and D. These
grades are categorized by the particulate quality of
the environmental air when the clean area is operating
in both a ‘manned’ and ‘unmanned’ state. In addition,
these areas are graded by the microbial monitoring
of the environmental air, surfaces and operators when
the area is functioning. The standards are shown in
Tables 29.1 and 29.2.
SECTION FOUR Dispensing and related pharmaceutical practice activities
Table 29.1 Airborne particle contamination for manned and unmanned clean rooms
Grade Maximum number of particles per cubic metre equal to or above the size indicated
Clean room at rest Clean room operating
0.5 mm5mm 0.5 mm5mm
A 3500 1 3500 1
B 3500 1 350 000 2000
C 350 000 2000 3 500 000 20 000
D 3 500 000 20 000 Varies with procedure Varies with procedure
Table 29.2 Limits for microbial contamination of an operating clean room
Grade Viable organisms
per cubic metre of air
A <1 <1 <1 <1
B10 5 5 5
C 100 50 25 N/A
D 200 100 50 N/A
There are two common procedures used to
manufacture sterile products. The first method
involves the preparation of products that will be
terminally sterilized. The second method involves
the aseptic filling of containers that are not exposed to terminal sterilization. Aseptic filling
requires a higher environmental quality for the
preparation of solutions and the filling of containers. The qualities of the clean rooms used for these
production procedures are detailed in Tables 29.3
and 29.4.
Table 29.3 Conditions for preparing terminally sterilized products
Procedure Required standard before terminal sterilization
Preparation of solutions for filtration and sterilization Grade C is used for products which support microbial growth
90 mm settle
plate per 4 hours
Premises
High standards are necessary for the manufacture of
sterile medicinal products. The sterile production
unit must be separated from the general manufacturing area within the hospital pharmacy or factory. This
sterile production unit must not be accessible to unauthorized personnel.
The unit is designed to allow each stage of produc-
tion to be segregated. It should also ensure a safe
Grade D acceptable if solutions subsequently filtered
55 mm contact
plate
Glove print
(5 fingers)
Filling small and large volume parenterals Grade C. For products with a high risk of contamination such
as wide-necked containers, a Grade A laminar airflow
workstation with Grade C background
Preparation and filling of ointments, creams,
suspensions and emulsions
324
Grade C
Production of sterile products CHAPTER 29
Table 29.4 Conditions for the production of aseptically prepared products
Procedure Required standard
Handling of sterile starting materials Grade A with Grade B background or Grade C if solution
filtered later in production process
Preparation of production solutions Grade A with Grade B background or Grade C if sterile
during filtered production
Filling of aseptically prepared products such
as small and large volume parenterals
Preparation and filling of ointments, creams,
suspensions and emulsions
and organized workflow and reduce the need for personnel to move around the clean rooms. The unit is
built and the equipment positioned to protect the
product from contamination. The layout must allow
efficient cleaning of the area and avoid the build up of
dust. Premises are also arranged to decrease the risk
of mix up or contamination of one product or material
by another.
The filling room is typically serviced from an
adjacent preparation room. This allows supporting
personnel to assemble and prepare materials. Staff
within the filling room area then use these materials.
Figure 29.1 shows the layout of rooms for the produc-
tion of terminally sterilized medicines such as small or
large volume injections.
Grade A with Grade B background
Grade A with Grade B background
Design and construction
Access to clean and aseptic filling areas is limited to
authorized personnel. Operators enter clean rooms by
way of changing rooms. Within the changing room the
operators can don and remove their clean room
garments.
A low physical barrier, commonly known as a passover (or cross-over) bench, extends across the changing room. It forms a physical barrier that separates the
different areas for changing by the operators.
Special precautions are needed to avoid contamination of clean and aseptic filling areas when materials
are passed through airlocks or hatchways. Thus, sterilizers and entry ports are fitted with double-sided
doors. The doors are interlocked to prevent both
doors being opened simultaneously.
Figure 29.1*Rooms for the production of terminally sterilized
medicines.
Surfacing materials
All clean room surfaces, including the floors, walls
and ceilings, should be smooth, impervious and
unbroken. This will decrease the release and
build-up of contaminating particles and organisms.
The surfaces are made of materials that allow the
use of cleaning agents and disinfectants. The ceilings
are sealed to prevent the entry of contaminants
from the space above them. Uncleanable recesses
within the clean room should be avoided. This will
reduce the collection of contaminating particles.
Thus, the junction between the wall and the floor is
commonly coved. The presence of shelves, ledges,
cupboards and equipment is minimized. Windows
should be non-opening and sealed. This will prevent
the ingress of contaminants.
325
SECTION FOUR Dispensing and related pharmaceutical practice activities
Services
Piped liquids and gases should be filtered before entering the clean room. This will ensure that the liquid
or gas at the work position will be as clean as the clean
room air. The pipes and ducts must be positioned for
easy cleaning. All other fittings such as fuse boxes and
switch panels should be positioned outside the clean
rooms.
Sinks and drains must be excluded from areas
where aseptic procedures are performed in clean
room areas. They should be avoided in the whole unit
wherever possible. In areas where sinks and drains are
installed they must be designed, positioned and
maintained to decrease the risk of microbial contamination. They are thus often fitted with easily cleanable traps. The traps may contain electrically heated
devices for disinfection.
There should be a limited number of entry doors
for personnel and ports for materials. Entry doors
should be self-closing and allow the easy movement
of personnel.
Airlock doors, wall ports, through-the-wall autoclaves and dry heat sterilizers should be fitted with
interlocked doors. This will prevent both doors being
opened simultaneously. An alarm system should be
fitted to all the doors to prevent the opening of more
than one door.
Lights in clean rooms are fitted flush with the
ceiling to reduce the collection of dust and avoid disturbing the airflow pattern within the room. Similarly,
equipment should be positioned in clean rooms to
avoid the distribution and the collection of particles
and microbial contaminants.
microbial contamination. This is carried out by filtering the air with high-efficiency particulate air (HEPA)
filters. The HEPA filter should be positioned at the
inlet to the clean room or close to it. A prefilter may
be fitted upstream of the HEPA filter. This will prolong the life of the final filter. A fan is required to
pump the air through the filter.
The HEPA filters use pleated fibreglass paper as
the filter medium. Parallel pleats of this filter material
increase the surface area of the filter and increase the
airflow through the filter. This structure allows the
filter to retain a compact volume. Aluminium foil is
used to form spacers in the traditional type of HEPA
filter. Spacers are not used in the more modern ‘minipleat’ type of filter design. These mini-pleat filters are
now widely used. They have a shallower depth in
construction than the traditional HEPA filter. Within
the structure of the filter, the filter material is sealed
to an aluminium frame (Fig. 29.2). At least one side of
the filter is protected with a coated mild steel mesh.
HEPA filters exhibit:
*
A high flow rate
*
High particulate holding capacity
*
Low-pressure drop across the filter.
HEPA filters remove larger particles from the air
by inertial impaction, the medium-sized particles
by direct interception and the small particles by
Brownian diffusion. The HEPA filters are least
efficient at removing particles of about 0.3 mm.
However, the efficiency of removing particles is
affected by the air velocity and the filter packing.
Larger and smaller particles will be removed more
efficiently.
With a new HEPA filter fitted in a clean room, the
air exits from the filter face at a rate of about 0.45 m/s
Environmental control
Potential sources of particles and microbial contaminants occurring within the clean room are:
*
The air supply of the room
*
Inflow of external air
*
Production of contaminants within the room.
Each of these possible sources can be minimized as
described below.
Air supply
The air supply to a Grade A, B or C clean room must
be filtered to ensure the removal of particulate and
326
Figure 29.2*Section through a mini-pleat high-efficiency filter,
showing its construction.
and has a 99.997% efficiency at removing 0.3 mm
particles. The initial pressure difference across the
depth of the filter is about 130 pascal (Pa). At the
end of the effective life of the filter the pressure drop
across the filter will increase to about 490 Pa. To retain the operating efficiency of the filter, the fan forcing air through the filter must be able to maintain this
pressure difference. Sensors are fitted upstream and
downstream of the filters to indicate the pressure
differential across the filter. An automatic alarm system should be fitted to indicate failure in the air
supply or filter blockage.
The HEPA filters for clean room use must conform
with the British Standard 5295 (1989) aerosol test.
The filters may have faulty seals and can be damaged
during delivery or installation. It is thus important
that they are tested in situ before use.
The filter material possesses a uniform resistance
and is constructed with a large number of parallel
pleats. This results in the air downstream of the filter
face flowing uniformly with a unidirectional configuration.
The number of air changes in clean rooms is affected by:
*
The room size
*
The equipment in use
*
The number of operators in the area.
In practice 25–35 air changes per hour are common.
The airflow pattern within the clean room must be
carefully regulated to avoid generating particles from
the clean room floor and from the operators. Various
options for ventilating clean rooms may be categorized by the airflow pattern within the room. These
are:
*
Unidirectional airflow systems
*
Non-unidirectional airflow systems
*
Combination airflow systems.
Unidirectional airflow systems
Air enters the room through a complete wall or ceiling
of high-efficiency filters. This air will sweep contamination in a single direction to the exhaust system on
the opposing wall or floor (Fig. 29.3). In the interests
of economy, the exhaust grill may be fitted low down
on the wall. The velocity of the air is about 0.3 m/s
in downflow air from ceiling filters and 0.45 m/s in
crossflow air. These are highly efficient airflow systems. However, one major disadvantage of these
rooms for pharmaceutical use is that they are expensive to construct. They also use much more condi-
Production of sterile products CHAPTER 29
Figure 29.3*Airflow pattern in a unidirectional airflow clean
room.
tioned air than rooms with non-unidirectional
airflow. This greatly increases their operating costs.
Owing to these factors, unidirectional airflow clean
rooms are not often used for pharmaceutical purposes.
Non-unidirectional airflow systems
Air enters the clean rooms through filters and diffusers that are usually located in the ceiling. It exits
through outlet ducts positioned low down on the wall
or in the floor at sites remote from the air inlet
(Fig. 29.4). With the use of this system, the filtered
inlet air mixes with and dilutes the contaminated air
within the room. As the clean room air has been previously heated and cleaned it can be recirculated to
save energy, a little fresh air being introduced with
each air change cycle.
Various designs of diffuser are used with this ventilation system. These affect the air movement and
the cleanliness of the rooms. The perforated plate
diffuser produces a jet flow of air directly beneath
it. This jet of air will carry contamination at its edges.
However, it does produce high-quality air directly
under the diffuser. It is thus important that production procedures are located directly below the diffuser. By contrast, the air released from the bladed
diffuser will mix with the clean room air.This diffuser
thus produces a reasonably constant quality of air
throughout the room.
327
SECTION FOUR Dispensing and related pharmaceutical practice activities
Figure 29.4*Airflow pattern in a non-unidirectional airflow
clean room.
Combination systems
In many pharmaceutical clean rooms it is common to
find that the background area is ventilated by a nonunidirectional airflow system. Meanwhile, the critical
areas are supplied with high-quality air from unidirectional airflow units.
The combination airflow system is often selected
for pharmaceutical clean room applications as it:
*
Produces controlled room pressure
*
Separates the manufacturing process from the
general clean room
*
Is cheaper to use.
Several types of unidirectional flow workstations or
benches are used in this combinatio n-type room.
Various vertical unidirectional airflow systems are
used in combination clean rooms. With one system,
the critical area is surrounded by a plastic curtain
with vertical unidirectional downflow air ‘washing’
over the manufacturing process and exiting under
the plastic curtains into the general clean room area
(Fig. 29.5). An alternative system is often used
with the small-scale combination-type clean room
in hospital pharmacies. With this system, a horizontal airflow cabinet (Fig. 29.6)isusedastheworkstation. With these cabinets, a fan forces air
through a HEPA filter located at the rear wal l of
the workstation. The air that exits from the filter
first washes over the cri tical work area before washing over the arms and upper body areas of the
Figure 29.5*Airflow patterns in a mixed-flow clean room with
non-unidirectional airflow background environment and unidirectional airflow protection for a critical area.
operator. Contamination arising from the operator
is th us kept downstream of the critical procedures.
Grade A environmental conditions are achieved at
the critical work area. A similar workstation known
as a vertical laminar airflow cabinet (Fig. 29.7) could
also be used in the combination room. This cabinet
passes air vertically downwards from the ceiling of the
cabinet over the critical working area. It produces a
Figure 29.6*Horizontal laminar airflow unit. (Courtesy of John
Bass Ltd.)
328