Who Guidance on Handling Potent/ Hazardous Substances

This presentation is compiled by “ Drug Regulations”
a non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
15-11-2015 1

This presentation is compiled from freely available
resource like the website of WHO, specifically the
WHO Guidance on GMP’s for Hazadous Substances
“Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
15-11-2015 2
Drug Regulations : Online
Resource for Latest Information

 These guidelines set out good practices for
facilities handling following hazardous substances
◦ Certain hormones
◦ Steroids or
◦ Cytotoxins
 They do not replace national legislation for
protection of the environment and personnel.
 These guidelines are in addition to other GMP
guidelines and regulations.
15-11-2015 3
Drug Regulations : Online Resource for Latest Information

 These guidelines are to be implemented in
conjunction with other WHO GMP guidelines
 The primary focus of these guidelines is on the air-
conditioning and ventilation systems of the facility;
 However, the guideline also provides some
guidance on personnel protection.
15-11-2015 4

 Facilities should be designed and operated in
accordance with the main GMP principles, as
follows:
◦ To ensure quality of product;
◦ To protect the operators from possible harmful effects of
products containing hazardous substances; and
◦ To protect the environment from contamination and
◦ Protect the public from possible harmful effects of products
containing hazardous substances.
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 The production of certain products containing hazardous substances
should generally be conducted in separate, dedicated, self-contained
facilities.
 These self-contained facilities may be in the same building as another
facility but should
◦ Be separated by a physical barrier
◦ Have, e.g. separate entrances, staff facilities
◦ Have separate air-handling systems.
 Use Risk Assessment to determine extent of the separation and sharing
of common services.
 These manufacturing facilities should be regarded as containment
facilities.
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 Effective operation of a facility may require the combination of some
or all of the following aspects:
◦ Appropriate facility design and layout
◦ Emphasis on safely containing the materials being handled
◦ Manufacturing processes using closed systems or barrier technology
◦ Manufacturing process controls including adherence to standard operating
procedures (SOPs);
◦ Appropriately designed environmental control systems (ECS) or heating, ventilation
and air-conditioning (HVAC);
◦ Extraction systems;
15-11-2015 7

 Effective operation of a facility may require the
combination of some or all of the following
aspects:
◦ Personal protective equipment (PPE);
◦ Appropriate degowning and decontamination procedures;
◦ Industrial hygiene (monitoring staff exposure levels);
◦ Medical surveillance (monitoring staff exposure levels); and
◦ Administrative controls.
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 Not all products containing hazardous substances are equally
potent
 Risk assessments should be carried out to determine the
potential hazards to operators and to the environment.
 The risk assessment should also determine applicable
requirements of these guidelines
◦ Phases of the product production cycle
◦ Control cycle
◦ From manufacture of the API to distribution of the finished product
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 Risk assessments applicable to the environment should include
airborne contamination as well as liquid effluent contamination.
 If the risk assessment determines that the products or materials
pose a risk to following then these guidelines should be followed
◦ The operators and/or
◦ The public and/or
◦ The environment
 The design and operation of the facility should be as detailed in
this document.
15-11-2015 10

 Consider occupational exposure levels (OEL) for
the product, when conducting the risk
assessment.
 The risk assessment should take into account
◦ National or international occupational health and
◦ Safety requirements for OELs in the work
environment.
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 Producing quality products, with respect to
protection from contamination and cross-
contamination,
 Follow requirements for other Pharmaceutical
products covered under other WHO GMP Guidelines
◦ Clean room class of air
◦ Temperature
◦ Humidity
15-11-2015 12

 Fundamental design principle for a facility and its production
equipment
◦ Provide product containment
◦ Provide operator protection.
 If the facility and equipment design does not provide
adequate product containment,
◦ Operator protection should be provided.
 If facility and equipment design are adequate,
◦ A spillage or non-routine incident could cause a hazardous situation, in
which case PPE should be available.
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 Unless otherwise specified in the material safety data sheet,
 Operators should be protected from exposure with an
appropriate method, such as by wearing:
◦ Flash-spun, high-density polyethylene fibre material suits or
◦ Impervious washable protective suits.
◦ Integral hoods may be required depending on the respirator type used;
◦ Flash-spun, high-density polyethylene fibre material shoes, lower leg
covers or cleanable boots;
15-11-2015 14

 Unless otherwise specified in the material safety data sheet,
 Operators should be protected from exposure with an
appropriate method, such as by wearing:
◦ Suitable single-use, disposable gloves.
◦ Double gloves should be worn where direct active contact with the product
cannot be avoided.
◦ Gloves should be taped or sealed on to the protective suit sleeves;
◦ Respirator eye and face protection with associated breathing air systems.
15-11-2015 15

 Breathing air systems
◦ These should be provided to supply safe breathing air to the
operators
◦ This will prevent them from inhaling air from within the facility.
◦ Personnel should be appropriately trained
◦ Training should be assessed in the use of these systems before
they can enter the area.
◦ The breathing air systems should comprise a protective face
mask, which should form an integral part of a protective suit.
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 The breathing air systems could be any of the systems
described below:
 A central air supply system
◦ This connects to the operator’s face mask by means of flexible
hoses and quick coupling sockets, also called an airline
respirator (AR).
◦ The air connection should incorporate a one-way air system
◦ This prevents contaminated air entering the face mask during
connection or disconnection.
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described below:
 A central air supply system
◦ The air supply should be treated to ensure a temperature and
level of humidity that are comfortable for the operator.
◦ The air source could be a high pressure fan or an air compressor.
◦ If an air compressor is used, it should be of the oil-free type or
have suitable oil removal filters fitted;
15-11-2015 18

 The breathing air systems could be any of the
systems described below:
 A self-contained breathing apparatus (SCBA) Or
Powered air purifying respirator (PAPR)
◦ This should be securely attached to the operator’s
belt
◦ It should be connected to the operator’s face mask.
15-11-2015 19

described below:
 A self-contained breathing apparatus (SCBA) Or
Powered air purifying respirator (PAPR)
◦ This system draws air from the room in which the operator is
working
◦ The air supply is delivered to the facemask by means of a
battery-driven fan.
◦ The AR provides superior protection to the PAPR apparatus;
15-11-2015 20

 The breathing air systems could be any of the systems described
below:
 Zones with lower contamination levels
◦ A half-mask high efficiency particulate air filter (HEPA) cartridge
respirator of N95-type paper filter mask may be acceptable.
◦ The selection of the respirator type is based on the relationship
between the accepted OEL and the respirator-certified protection
factor (PF).
15-11-2015 21

 The breathing air systems could be any of the systems described
below:
 Zones with lower contamination levels
◦ The air supplies should be filtered through a final filter,
◦ This should be a HEPA filter rated as an H13 filter according to EN
1822 (European Norm).
◦ The supply of breathing air into the face mask and/or protective suit
should result in the interior of the mask and suit being at a positive
pressure relative to the facility environment.
15-11-2015 22

 Central breathing air supply systems should
have a 100% back-up system in the event of
the main system failing.
 This could be in the form of a gas bottle
system with at least 5 minutes supply.
 Changeover from the normal supply to the
back-up supply should be automatic.
15-11-2015 23

 The system should have
◦ A monitoring system and
◦ Send alarm signals to a permanently manned location in the
following situations:
 Failure of main air supply;
 Temperature out of specification (OOS);
 Humidity OOS;
 Carbon dioxide (CO2) OOS;
 Carbon monoxide (CO) OOS; and
 Sulfur dioxide (SO2) OOS.
15-11-2015 24

 Breathing air should be filtered to have the
minimum air quality specifications of ISO
8573-1 3-9-1 and EN 12021:1999
 This filtration can be by means of
◦ Pre-filters,
◦ Coalescing filters and
◦ Final filters
15-11-2015 25

 Where air is delivered through a central system the piping
should not cause any contamination to be liberated into the
air stream.
 Stainless steel piping is preferred.
 The final filters should be as close as possible to the operator
connection points.
 The operator hose connection to the air supply should be a
dedicated connection specific to the breathing air system
◦ (to avoid inadvertent connection to a different gas system).
15-11-2015 26

 As hazardous products are handled in the facility
◦ Neither the product nor its residues should be allowed to escape into the atmosphere
or
◦ To be discharged directly to normal drainage systems.
 The external atmosphere and the public in the vicinity of the facility
should be protected from possible harm from hazardous substances.
 If liquid effluent poses a safety or contamination risk, the effluent should
be treated before being discharged to a municipal drain.
 Exhaust air should be filtrated to ensure environmental protection
◦ See latter section on this.
15-11-2015 27

 The premises should be designed and constructed
to prevent the ingress or egress of contaminants.
 Attention should be paid to the level of
containment provided by the equipment.
15-11-2015 28

 The link between the interior and exterior of the
premises should be through
◦ Airlocks (PAL and/or MAL)
◦ Changing rooms
◦ Pass boxes
◦ Pass- through hatches
◦ Decontamination devices
15-11-2015 29

 These entry and exit doors for materials
and personnel should have
◦ An interlock mechanism or
◦ Other appropriate system to prevent the opening
of more than one door at a time.
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 The changing rooms should have an arrangement with a
step-over- bench.
 The facilities on the exit side should incorporate showers for
the operators.
 The premises should be laid out and designed so as to
facilitate the required pressure cascades and containment.
 The premises (and equipment) should be appropriately
designed and installed to facilitate cleaning and
decontamination.
15-11-2015 31

 The manufacturing site and buildings should be described in
sufficient detail to ensure that the designation and
conditions of use of all the rooms are correctly shown.
 (by means of plans and written explanations)
 The flow of people and products should be clearly marked on
the layouts and plans.
 The activities carried out in the vicinity of the site should be
indicated.
15-11-2015 32

 Plans should describe the ventilation systems, indicating
inlets and outlets, in relation to other facility air inlet and
outlet points.
 The facility should be a well-sealed structure with no air
leakage through ceilings, cracks or service areas.
 Areas of the facility where exposed product presents a risk
should be maintained at a negative air pressure relative to the
environment.
15-11-2015 33

 The HVAC system should be
◦ Appropriately designed
◦ Installed and maintained to ensure protection of product, personnel and
the environment.
◦ Principles of
 Airflow direction,
 Air filtration standards,
 Temperature,
 Humidity and related parameters
◦ should comply with the minimum requirements as set out in Annex 2 of
the TRS fortieth report.
15-11-2015 34

 Facilities and premises dealing with hazardous
substances should have the following basic air-
handling characteristics:
◦ There should be no direct venting of air to the outside.
◦ Air-conditioning or ventilation should result in a negative
pressure relative to the outside.
◦ Air pressure differentials should be such that there is no
uncontrolled flow of air between the work area and the external
environment.
15-11-2015 35

◦ Appropriate air pressure alarm systems should be provided
to warn of any pressure cascade reversal or loss of design
pressure status.
◦ The appropriate design, alert and action limits should be in
place.
15-11-2015 36

◦ System redundancies should be in place to respond
appropriately to pressure cascade failure.
◦ The starting and stopping of the supply and exhaust air fan
should be synchronized.
◦ This should be done so that the premises remain at a
negative pressure during start-up and shut-down.
15-11-2015 37

 Facilities and premises dealing with hazardous substances
should have the following basic air-handling characteristics:
◦ The air pressure cascade within the facility, although negative relative
to the environment, should comply with normal pharmaceutical
pressure cascade requirements with regards to
 Product protection
 Dust containment
 Personnel protection
◦ Visual indication of the status of room pressures should be provided
in each room.
15-11-2015 38

◦ Air should be exhausted to the outside through HEPA filters
◦ Air should not be recirculated
◦ Can be recirculated to the same area provided that a further
HEPA filtration stage is applied to the return air.
15-11-2015 39

◦ Where possible, single-pass air-handling systems with no
recirculation should be provided.
◦ Exhaust air or return air should be filtered through a safe-
change or bag- in-bag-out filter housing.
15-11-2015 40

 The filter housing should contain pre-filters and HEPA filters.
 Both of which should be removable with the safe bagging
system.
 Changing rooms should be supplied with air filtered to the
same standard as that for the work area they serve.
 Airlocks, pass-through hatches, etc., should have supply and
extract air
 This should provide the necessary air pressure cascade and
containment.
15-11-2015 41

 The final, or containment perimeter, airlock or pass-through
hatch bordering on an external or non-GMP area should be at a
positive pressure relative to the environment.
 This prevents the ingress of contaminants to the facility.
 If the facility provides insufficient containment, and operators’
garments are contaminated with dust, the operators leaving the
containment area should pass through a decontamination
system,
◦ e.g. air showers or a mist shower system,
 This assists with removing or controlling dust particles on their
garments.
15-11-2015 42

 Operators should follow this route before de-gowning to use the
ablutions or canteen facilities.
 All garments leaving the facility for laundering should be safely
bagged.
 Appropriate means for protecting laundry staff and prevention of
contamination of other garments from non-hazardous facilities
should be in place.
 If required, appropriate measures should be taken to prevent
airflow from the primary packing area to the secondary packing
area.
◦ through the conveyor “mouse hole”
15-11-2015 43

 This could be overcome by having a pass-through chamber over
the “mouse hole”, which is maintained at a negative pressure to
both primary and secondary packing.
 This typical arrangement is illustrated in Figure 1.
 This principle can be applied to other situations where
containment from two sides is required.
 Where possible, HEPA filters in the supply air system should be
terminally mounted
 This provides protection against back-flow cross- contamination
in the event of a failure in the supply airflow.
15-11-2015 44

 In some cases consideration can be given to the use of
biosafety cabinets, isolation systems or glove boxes as a
means for containment and operator protection.
 There should be a system description including
◦ schematic drawings detailing the filters and their specifications
◦ The number of air changes per hour
◦ pressure gradients
◦ clean room classes and related specifications.
 These should be available for inspection.
15-11-2015 45

 There should be an indication of pressure gradients that are
monitored by means of digital or analogue pressure
indicators.
 Consideration should be given to providing an emergency
power supply,
 e.g. diesel generators, to ensure that safe operation of the
premises and systems can be maintained at all times.
15-11-2015 46

15-11-2015 47

 The air-handling units (AHUs) supplying air to the
facility should conform to AHU requirements as
detailed in Quality assurance of pharmaceuticals.
 The decision to use return air or recirculated air
should be made on the basis of a risk assessment.
15-11-2015 48

 Where a full fresh-air or single-pass system is
used, an energy recovery wheel could be
considered.
 In such cases, there should not be any potential for
air leakage between the supply air and exhaust air
as it passes through the wheel.
15-11-2015 49

 The relative pressures between supply and exhaust air
systems should be such that the exhaust-air system
operates at a lower pressure than the supply system.
 Alternatives to the energy recovery wheel, such as
crossover plate heat exchangers, heat pipes and water
coil heat exchangers, may be used.
 Risk management principles should be applied to
address the potential of cross-contamination where
energy wheels are used.
15-11-2015 50

 If return air is to be recirculated it should pass through a safe change
filtration system before being introduced back into the supply AHU.
 The return air fan could form part of the AHU;
 However, the safe change filter should be a dedicated unit.
 With this arrangement the return air passes through two sets of HEPA
filters in series,
◦ i.e. the return air filters in the safe change housing and the supply air HEPA filters.
 The supply air HEPA filters could either be located in the AHU or
terminally located at the supply diffusers, depending on the clean room
classification of the facility.
15-11-2015 51

 The starting and stopping of the supply and exhaust air fans, and
associated system ventilation fans, should be synchronized such
that the premises retain their design pressure and flow relationships
during start-up and shut-down.
 Processing should stop when the fans are not running.
 This fan interlock sequence should also apply if any fan should fail,
to ensure that there is no airflow reversal in the system.
15-11-2015 52

 Safe change or bag-in-bag-out filter
housings should be suitably designed
◦ To provide operator protection and
◦ To prevent dust from the filters entering the
atmosphere when filters are changed.
15-11-2015 53

 The final filters on the safe change unit should be
HEPA filters with at least an H13 classification
according to EN 1822 filter standards.
 For dusty return, air pre-filtration may also be
required to prolong the life of the HEPA filters.
 The pre-filtration filters should also be removable
through the bag-in-bag-out method.
15-11-2015 54

 For exhaust systems where the discharge contaminant
is considered particularly hazardous, two banks of HEPA
filters in series should be considered
 This provides additional protection should the first filter
fail.
 All filter banks should be provided with pressure
differential indication gauges to indicate the filter dust
loading and remaining lifespan of the filters.
15-11-2015 55

 Connection to these gauges should be copper or
stainless steel and not plastic tubing, which could
perish causing a contamination hazard.
 The tube connections on the filter casing should be
provided with stopcocks, for safe removal or
calibration of gauges.
15-11-2015 56

 Monitoring of filters should be done at regular intervals
◦ This prevents excessive filter loading that could
◦ Force dust particles through the filter media
◦ Could cause the filters to burst, resulting in ambient
contamination.
 Computer-based data monitoring systems may be
installed to monitor filter condition.
 Filter pressure gauges should be marked with the clean
filter resistance and the change-out filter resistance.
15-11-2015 57

 Installed filter leakage tests should be performed in
accordance with ISO 14644-3.
 Injection ports (upstream) and access ports
(downstream) should, therefore, be provided for
this purpose.
 The exhaust air fan on a safe change filter system
should be located after the filters so that the filter
housing is maintained at a negative pressure.
15-11-2015 58

 This poses a difficulty when carrying out filter integrity
tests,
 For this reason a bypass damper system should be
provided
 In such situation air can be circulated through the HEPA
filters, while the scanning ports are open.
◦ As illustrated in Figure 2
 Alternatively an independent booster fan system can be
used, with appropriate shut-off dampers.
15-11-2015 59

15-11-2015 60

 The bypass arrangement as shown in Figure 2 also
permits decontamination of the filters by means of
circulation of a sanitizing agent.
 Following exhaust systems should be passed through
safe change filter housings before being exhausted to
the atmosphere.
◦ Dust extraction systems
◦ Vacuum system exhaust
◦ Fluid bed drier exhaust
◦ Coating pan exhaust
15-11-2015 61

 All exhaust points outside the building should be
located as far as possible from air entry points,
 Exit points should be at a high level to minimize
the possibility of re-entrainment of exhaust air.
 Dominant and seasonal wind directions should be
taken into account when positioning exhaust and
supply points.
15-11-2015 62

 Where excessively dust-laden air is handled, a dust
collector or bag house should be considered,
 The dust collector should be located in an enclosed
room maintained at a negative pressure.
 Access control, maintenance staff, personal protection
equipment (PPE) and breathing air systems should then
be provided to protect the operators during removal of
dust from the collector bins.
15-11-2015 63

 Portable vacuum cleaners and portable dust
collectors should be fitted with H13 HEPA filters.
 These types of units should be emptied and
cleaned in a room which is under negative pressure
relative to the environment.
 Personnel should be provided with suitable PPE.
 Records of the safe disposal of all contaminated
filters and dust should be kept.
15-11-2015 64

 If required, a means of preventing contaminants
from leaving the facility on the garments of
personnel should be provided.
 This could be in the form of an air shower; mist
shower, water shower or appropriate device.
15-11-2015 65

 An air shower comprises an airlock where high velocity air is
supplied through air nozzles in order to dislodge dust
particles.
◦ e.g. from the sides of the airlock
 Air extraction grilles (e.g. at low level) should draw the air
away and return it to the filtration system.
 Some air showers may also incorporate a vertical
unidirectional airflow section at the exit end, to flush
contaminants away.
15-11-2015 66

 When air showers are used these should be correctly
designed to effectively extract dust.
 Air filtration of the supply air and return or exhaust air should
comply with the same filtration standards as used in the
manufacturing facility.
 Normally the fan should be activated by opening the door as
the operator enters the shower, with a timing device on the
exit door interlock to allow sufficient time for the
decontamination process to be effective.
15-11-2015 67

 Flushing devices similar to air or mist showers for personnel
could be used at material exits to assist with removing
contaminants.
 Wet mist or fog decontamination systems for operators can
be employed for deactivating contaminants on the operator’s
garments, or causing contaminants to adhere to the garments
so that they are not easily liberated.
 Personnel should change into clean garments after having
taken a shower.
15-11-2015 68

 Liquid and solid waste effluent should be handled in such a
manner as not to present a risk of contamination to the
product, personnel or to the environment.
 All effluent should be disposed of in a safe manner, and the
means of disposal should be documented.
 Where external contractors are used for effluent disposal they
should have certification authorizing them to handle and treat
hazardous products.
15-11-2015 69

 The efficient and safe operation of a facility handling
hazardous materials is reliant on regular maintenance being
carried out, to ensure that all parameters remain within
specified tolerances.
 See Quality assurance of pharmaceuticals. A compendium of
guidelines and related materials (1) or WHO Technical Report
Series, No. 937, Annex 2, section 8.3 (2) for further details on
maintenance.
15-11-2015 70

 System qualification and validation should be carried out as
described in other WHO guidelines.
15-11-2015 71

This presentation is compiled from freely available
resource like the website of WHO, specifically the
WHO Guidance on GMP’s for Hazadous Substances
“Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
15-11-2015 72
Drug Regulations : Online
Resource for Latest Information

Who Guidance on Handling Potent/ Hazardous Substances

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