FMDS0736 Pharmacy

FM Global
Property Loss Prevention Data Sheets 7-36

July 2013
Page 1 of 42
PHARMACEUTICAL OPERATIONS
Table of Contents
Page
1.0 SCOPE ..................................................................................................................................................... 3

1.1 Changes ............................................................................................................................................ 3
2.0 LOSS PREVENTION RECOMMENDATIONS ........................................................................................ 3
2.1 Occupancy ........................................................................................................................................ 3
2.1.1 General .................................................................................................................................... 3
2.1.2 Manufacturing .......................................................................................................................... 6
2.1.3 Lyophilizers ............................................................................................................................ 10
2.1.4 Cooler and Freezer Storage Units ........................................................................................ 11
2.1.5 Chemical Libraries and Laboratories ..................................................................................... 11
2.1.6 Vivariums ............................................................................................................................... 13
2.2 Utilities ............................................................................................................................................ 13
2.3 Contingency Planning ..................................................................................................................... 14
3.0 SUPPORT FOR RECOMMENDATIONS ............................................................................................. 14
3.1 Industry Overview .......................................................................................................................... 14
3.2 Registration and Process Validation ............................................................................................... 15
3.3 Key Exposures ................................................................................................................................ 16
3.3.1 Liquid Transfer ...................................................................................................................... 16
3.3.2 Reactors ................................................................................................................................ 17
3.3.3 Isolation ................................................................................................................................ 20
3.3.4 Ion Exchange and Chromatography .................................................................................... 20
3.3.5 Granulation, Drying and Coating ......................................................................................... 20
3.3.6 Lyophilization ....................................................................................................................... 22
3.3.7 Ventilation ............................................................................................................................. 23
3.3.8 Waste Gas Handling ............................................................................................................. 25
3.4 Special Occupancies ..................................................................................................................... 26
3.4.1 Chemical Libraries ................................................................................................................ 26
3.4.2 Laboratories: R&D, Production, Quality Control .................................................................. 27
3.4.3 Storage Facilities excluding Chemical Libraries) ................................................................. 27
3.4.4 Vivariums .............................................................................................................................. 29
3.4.5 Cleanrooms .......................................................................................................................... 30
3.4.6 Toxic and Potent Compounds ............................................................................................... 31
3.5 Loss History ................................................................................................................................... 32
4.0 REFERENCES ..................................................................................................................................... 40
4.1 FM Global ........................................................................................................................................ 40
4.2 Other ............................................................................................................................................... 40
APPENDIX A GLOSSARY OF TERMS ..................................................................................................... 40
APPENDIX B DOCUMENT REVISION HISTORY ...................................................................................... 42
List of Figures
Fig 1a. Examples of modifiable process piping. ............................................................................................ 8
Fig. 1b. Examples of modifiable process piping. .......................................................................................... 9
Fig. 2. Batch tray dryer. .............................................................................................................................. 22
Fig. 3. Conical dryer. ................................................................................................................................... 23
Fig. 4. Fluid bed granulator. ........................................................................................................................ 24
Fig. 5. Rotary dryer. .................................................................................................................................... 25
Fig. 6a. High-value R&D laboratory equipment. ......................................................................................... 28
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photocopying, recording, or otherwise, without written permission of Factory Mutual Insurance Company.
7-36 Pharmaceutical Operations
Page 2 FM Global Property Loss Prevention Data Sheets
Fig. 6b. High-value R&D laboratory equipment .......................................................................................... 29

Fig. 7. Typical glove box installation. .......................................................................................................... 32
Fig. 8. Pharmaceutical losses by peril (percentage by number) ................................................................ 33
Fig. 9. Pharmaceutical losses by peril (percentage by gross loss cost) .................................................... 34
Fig. 10. Pharmaceutical equipment losses (percentage by number of losses) ......................................... 34
Fig. 11. Pharmaceutical equipment losses (percentage by gross loss cost) ............................................. 35
Fig. 12. Pharmaceutical natural hazard losses (percentage by number of losses) ................................... 35
Fig. 13. Pharmaceutical natural hazard losses (percentage by gross loss cost) ...................................... 36
Fig. 14. Pharmaceutical losses by main processes (percentage by number of losses) ............................ 36
Fig. 15. Pharmaceutical losses by main process (percentage by gross loss) ........................................... 37
Fig. 16. Pharmaceutical storage losses (percentage by number of losses) .............................................. 37
Fig. 17. Pharmaceutical storage losses (percentage by gross loss cost) .................................................. 38
Fig. 18. Pharmaceutical losses by ignition source (percentage by number of losses) .............................. 38
Fig. 19. Pharmaceutical losses by ignition source (percentage by gross loss cost) ................................. 39
Fig. 20. Pharmaceutical losses with an electrical ignition source (percentage by number of losses) ...... 39
List of Tables
Table 1. Typical Cleanliness Terminology for the United States ................................................................. 30
Table 2. Cleanliness Ratings Used in Farious Countries ............................................................................. 30
Table 3. Pharmaceutical vs. Semiconductor Cleanrooms ........................................................................... 31
©2008-2013 Factory Mutual Insurance Company. All rights reserved.

Pharmaceutical Operations 7-36
FM Global Property Loss Prevention Data Sheets Page 3
1.0 SCOPE
This data sheet contains loss prevention recommendations covering various operations and equipment
related to the making of pharmaceutical products. This includes the manufacture of prescription (ethical and
generic) and over-the-counter medications; the compounding and packaging of health and beauty aids,
cosmetics and perfumes; biotechnology manufacturing; and research laboratories.
This data sheet does not cover basic construction, occupancy, and protection features necessary for property
loss prevention; see the applicable occupancy-specific data sheets for those types of recommendations.
1.1 Changes
July 2013. The following changes have been made:
• Replaced references to “flammable” and “combustible” liquids with “ignitable” liquids throughout the
document.
• Reorganized the document where necessary to provide a format that is consistent with other data sheets.
• Added references to other FM Global data sheets where sprinkler protection options are covered in more
detail.
• Changed terminology for animal facilities to “vivariums.”
• Updated the loss history.
• Updated the illustrative losses.
2.0 LOSS PREVENTION RECOMMENDATIONS

Use FM Approved equipment, materials, and services whenever they areapplicable. For a list of products
and services that are FM Approved, see the Approval Guide, an online resource of FM Approvals.
2.1 Occupancy
2.1.1 General
2.1.1.1 Apply principles of inherent safety wherever possible when designing or improving chemical
processes. Inherent safety includes the following general principles (see Data Sheet 7-43, Loss Prevention
in Chemical Plants, for further information on the principles of inherent safety):
A. Intensification: Uusing smaller amounts of hazardous substances.
B. Substitution: Replacing a hazardous chemical with a non-hazardous or less-hazardous one.
C. Attenuation: Using less hazardous process conditions or a less hazardous form of a material.
D. Limitation of effects: Designing a facility to minimize the impact of a release of hazardous material or
energy; for example, by sufficient spacing or more-resistant construction.
E. Simplification/error tolerance: Designing a facility so operating errors are less likely, or the process is
more forgiving if errors are made.
Ignitable liquid and combustible dust hazards may still be present where the principles of inherent safety
have been applied. Always evaluate these hazards in accordance with the appropriate data sheets.
2.1.1.2 Implement programs to manage process safety at a level commensurate with the hazards present,
even if not required by national or local regulations.
This will help ensure hazards are identified, management programs are in place, equipment maintenance
is conducted on a regular basis, production and maintenance staffs are properly trained, and contractors
operate safely. (See Data Sheet 7-43 for details.)
2.1.1.3 Consider non-routine operations when conducting hazard evaluations of all processes and equipment,
including startup, shutdown (normal and emergency), sampling, cleaning, and maintenance, to ensure these
functions do not create hazards greater than normal operations.

For example, cleanup could involve ignitable solvents not present during the process. (See Data Sheet 7-46,
Chemical Reactors and Reactions, for details on hazard evaluations in reaction systems.)
2.1.1.4 Use noncombustible, fire-resistant, FM Approved Class I construction or FM Approved 4882 plastic.
2.1.1.5 Design the heating ventilation and air-conditioning (HVAC) systems in accordance with Data Sheet
1-45, Air Conditioning and Ventilating Systems. Focus particular attention to the following aspects:
A. Use noncombustible HVAC ductwork and noncombustible insulation.
B. Where the use of plastic or other combustible ductwork is unavoidable, provide automatic sprinkler
protection in accordance with Data Sheet 7-78, Industrial Exhaust Systems.
C. Use noncombustible materials for HVAC filters.
D. Design all HVAC systems to minimize the transfer of contaminants or products of combustion from
one area to another. Zone the HVAC systems to minimize cross-contamination, and install automatic
smoke detectors in the return ducts interlocked with fire dampers.
2.1.1.6 Before installing shutdown interlocks, as recommended in FM Global data sheets, consider all the
consequences of such an interruption of flow; for example, interruption of heat transfer fluids (i.e., cooling)
could result in a runaway reaction. Where the interlock creates an increased hazard, alternate methods to
reduce the basic hazard need to be developed. Shutdown interlocks are often recommended for limiting
the release of hazardous materials (heat transfer fluid, hydraulic fluid, ignitable liquid, etc.). See Data Sheet
7-98; Data Sheet 7-99, Heat Transfer By Organic and Synthetic Fluids; and Data Sheet 7-32, Ignitable Liquid
Operations for more details.
2.1.1.7 Where ignitable liquid is used, implement the following safeguards:
A. Limit the amount of ignitable liquid to the minimum amount needed for the operation.
B. Install drainage and/or containment for control of ignitable liquid spills and firefighting water in
accordance with Data Sheet 7-32.
C. Design for the vapor explosion potentials in any area where a room or equipment explosion hazard
exists (see Data Sheet 7-32).
D. Provide sprinkler protection as recommended in Data Sheet 7-14, Fire Protection for Chemical Plants,
or Data Sheet 7-32, as appropriate, wherever ignitable liquid is used.
E. Provide the area with low-level safety ventilation to control accumulations of flammable vapor from
small leaks and spills. (See additional guidance for mechanical ventilation in Section 2.1.1.11.)
F. Locate and protect ignitable liquid in plastic containers in accordance with Data Sheet 7-32 or Data
Sheet 7-29 as appropriate.
Where plastic drums are used to handle low flash point liquid (i.e., lower than 200°F [93°C]), they may
present unacceptable exposures to high-value operations, and alternate solutions will be needed. These
solutions could include pumping from drums located in a properly designed cutoff room, limiting the
number of drums to 1 or 2, and providing a drained catch basin specifically for the needed drums to control
and remove spilled liquids.
Plastic IBCs filled with ignitable liquid can present a severe fire exposure within a pharmaceutical
occupancy due to the large quantity of liquid that could become involved in the fire, and the limited options
for adequate fire protection.
G. Provide hazardous location electrical equipment in accordance with Data Sheet 5-1, Electrical
Equipment in Hazardous (Classified) Locations, and NFPA 70, National Electrical Code, in areas where
a volatile ignitable liquid is used.
A volatile ignitable liquid is one with:
1. a closed-cup flash point below 100°F (38°C), or
2. a closed-cup flash point of 100°F (38°C) or above, if heated higher than its flash point.

H. Avoid materials such as cast iron, high silicon iron, plastic (thermoplastic, thermoset), glass, and
aluminum in ignitable liquid piping systems due to their potential for failure (low impact strength, low
pressure ratings, low resistance to thermal shock, and low melting point).
I. Provide FM Approved fire safe valves or interlocks to shutoff valves in accordance with Data Sheet
7-32 on lines that normally contain ignitable liquids, to minimize an unmanageable liquid release.
J. Adequately bond and ground all equipment as well as permanent or temporary transfer piping (rigid
or flexible) to prevent electrostatic buildup.
K. Do not permit open-ended piping on operating equipment. Provide all dead-end piping with a screwed
or bolted flanged cap.
L. Provide appropriate automatic means to prevent overfilling.
M. Implement a mechanical integrity program for transfer piping where corrosion, leakage, or other loss
of containment can result in serious consequences (product contamination, fire, explosion, etc.).
N. Where appropriate, provide protection/bracing against earthquake for all piping containing ignitable
liquid (see Data Sheet 1-2, Earthquakes, and Data Sheet 1-11, Fire Following Earthquake).
2.1.1.8 Where direct measurement or observation instruments (gauges, meters, glass-type liquid level
indicators, sight glasses, rotameters, sample tubes, etc.) are needed on equipment containing ignitable liquid,
install them in accordance with Data Sheet 7-32.
2.1.1.9 Do not use glass equipment (such as holding tanks) and glass piping where failure could result in
an unacceptable consequence such as release of an ignitable liquid, or toxic or corrosive material.
2.1.1.10 Implement the following safeguards where combustible dust is used: (See Data Sheet 7-76,
Prevention and Mitigation of Combustible Dust Explosions and Fires, for additional details):
A. Where possible and practical, use a noncombustible dust to eliminate the hazard.
B. Design for the dust explosion potentials in any area where combustible dust is handled or processed
and could be released into a cloud. This includes processing equipment and rooms or buildings, but
usually not areas where dust is stored in bags, drums, IBCs, etc. Locate the process in a room of
damage-limiting construction as described in Data Sheet 1-44, or provide the equipment with explosion
protection as described in Data Sheet 7-76.
C. Design and maintain equipment and piping to prevent release of fugitive dust by maintaining the
equipment pressure negative with respect to its surroundings, minimizing joints in transfer systems,
providing localized dust pickup points at filling and dumping operations, and using entirely closed systems
for dust transfer.
D. Implement a mechanical integrity program for transfer piping where corrosion, leakage, or other loss
of containment events could result in serious consequences (product contamination, fire, explosion, etc.).
E. Provide hazardous location electrical equipment in accordance with Data Sheet 5-1 and NFPA 70,
National Electrical Code, in areas where combustible dust may be released, so the equipment will not
become an ignition source for either layers or clouds of dust.
F. Adequately bond and ground all equipment as well as permanent or temporary transfer piping (rigid
or flexible) to prevent electrostatic buildup.
2.1.1.11 Provide fixed mechanical exhaust ventilation for rooms or buildings wherever the following are stored
or handled:
• Ignitable liquid with a flash point below 100°F (38°C), or up to 300°F (149°C) if heated above its flash
point
• Flammable vapor or gas in a system that can be opened, or where leaks or releases from the system
are possible
2.1.1.11.1 Ensure the ventilation system meets the following requirements:
A. Operates at a rate of 1 cfm/ft2 (0.3 m3/min/m2) of the room floor area, with pickup taken within 12 in.
(30 cm) of the floor, recognizing that most kinds of flammable vapor are heavier than air.

B. Where only lighter-than-air materials are handled, high-level pickups are acceptable.
C. Mechanical ventilation ductwork should be of noncombustible construction and insulation. (If
combustible ducts are used, see Data Sheet 7-78.)
D. Locate exhaust openings so the building HVAC systems do not pick up discharged fumes/vapor.
E. Provide sufficient makeup air for all vapor extraction systems.
F. Be sure the safety ventilation system is operable when target liquids are being handled. Shut down
operations if ventilation fails.
2.1.2 Manufacturing
2.1.2.1 Where the consequence of an accident involving raw materials, intermediates, and finished products
is unacceptable, store the materials where they will not be subject to a common event. Where the production
cycle is long, keeping raw materials, intermediates, and finished products in individually separate areas could
further reduce the consequences.
2.1.2.2 Reactors used in the active ingredient manufacturing process can present serious loss prevention
challenges. (See Data Sheets 7-43 and 7-46 for additional information.) Important loss prevention features
that must be addressed include, but are not limited to, the following:
A. Conduct a thorough process hazard analysis at an early stage in development, periodically during the
process life, and whenever significant changes occur. Where possible, design the system using principles
of inherent safety.
B. Where the information is not otherwise available, conduct hazard studies on intermediates and final
product for dust explosibility, temperature sensitivity for ignition or decomposition, friction, shock or impact
sensitivity, etc.
C. Conduct reaction hazard studies to identify sensitivity to operating temperature excursions,
contaminants, mischarge of reactants, catalysts and reaction media, etc. The purpose is to determine
operating procedures, interlocks, materials of construction, vacuum and overpressure protection, etc.
D. Design all overpressure protection systems based on the worst credible scenario and current best
practices, especially the use of Design Institute for Emergency Relief Systems (DIERS) technology to
evaluate runaway reaction potentials. Do not use glass or plastic piping of any type for vent relief systems.
(See Data Sheet 7-49, Emergency Venting of Vessels, for additional information.)
E. Create detailed operating procedures based on the reaction studies to prevent the development of
hazardous conditions, and to provide guidance on the steps to be taken to recover from out-of-range
conditions.
F. If reactions involving highly energetic materials (nitroglycerin, hydroxylamine, sodium azide, etc.) cannot
be adequately vented, conduct them in a pressure-resistant cubicle or in a remote area that will minimize
damage to other important facilities.
G. Permit only qualified and trained operators to conduct potentially hazardous operations, and ensure
their continued qualification by a suitable management system that may include audits and retraining as
needed.
H. Take steps to prevent foreign material from entering the reactor via internal or shell heat transfer
systems, hydraulic systems, piping, glass, or other lining systems, etc. This can be achieved by using
proper construction materials, applicable quality control steps between batches (e.g., visual inspections),
proper training of operators and maintenance staff, and adopting a rigorous mechanical integrity program.
I. Bond and ground all equipment to prevent the accumulation of static charge, with special emphasis
on isolated metal parts internal to the vessel or those that would be introduced when adding materials (e.g.,
dumping of powders or liquids from plastic bags or plastic lined drums).
J. Add material to the reactors through closed systems.
K. Operate the reactors so the headspace is outside of the flammable range. This can be achieved by
the proper selection of solvents, reactants, and operating temperature, or by reduced oxygen concentration
(inerting or purging; see Data Sheet 7-59, Inerting and Purging of Tanks, Process Vessels and Equipment).

L. Where reactors are used for multiple reactions, thoroughly clean the reactor between batches. In
addition, assess cleaning materials to ensure they don’t create their own hazards (e.g., ignitable liquids)
or incompatibilities.
M. Eliminate “dead areas” in the reactor or system. Dead areas can be difficult to clean, and present both
contamination and long-term instability issues from the isolated material. Dead areas include pipe legs,
thermowells, measuring and sampling lines, etc.
2.1.2.3 Where frequent changing of the piping setup is required for batch processes, implement the following
safeguards as appropriate (see Figures 1a and 1b):
A. Locate piping requiring regular modification together in a suitably arranged cutoff room or a separately
curbed, drained and ventilated area, not in locations scattered throughout the process area.
B. Provide adequate mechanical support for all piping (permanent or temporary).
C. Ensure flexible hose meets the recommendations for use described in Data Sheet 7-32. Use FM
Approved flexible hose where available.
D. For transfer lines that are changed frequently, use high-integrity, quick-connect couplings (FM Approved,
where available) or bolted flanged fittings.
E. Where possible, use firesafe shutoff valves on hard piping where failure would result in an
unmanageable release. Use valves that indicate their open/closed position (e.g., quarter-turn valves).
F. Clearly identify all piping, and provide documented procedures for pipe routing changes using the same
identifying criteria.
G. Take precautions to prevent contamination or mixing of incompatible materials using such practices
as dedicated hose marked for a specific service, or thorough cleaning between uses.
H. Ensure pipe routing changes are made only by well-trained operators who follow documented
procedures exactly.
2.1.2.4 Loss prevention steps that need to be taken in areas where pharmaceutical actives are formulated
to finished product (blending, drying, grinding, tableting and coating, liquid filling, packaging, etc.) include, but
are not be limited to, the following:
A. Use fire-resistant, noncombustible, or FM Approved Class 1 building construction.
B. Prevent combustible accumulations or construction in concealed spaces as might occur above the
drop ceiling of packaging areas, mixing and blending operations, clean and sterile rooms, etc.
Combustibles could be filters, insulation, spare parts, or plastic HVAC duct.
C. Limit the amount of combustibles (packaging material, fiber drums of product, etc.) in these areas,
especially finishing operations, to the absolute minimum needed for operations.
D. Design all HVAC systems to minimize the transfer of contaminants or products of combustion from
one area to another.
E. Use noncombustible materials for ductwork that pneumatically transfers combustible dust from one
point to another.
F. Install suitable combustion safety devices where glass ampoules are sealed using a natural gas or
propane flame.
G. Install automatic sprinklers where the combustible loading in the occupancy is significant.
H. Limit the use of concealed sprinklers to light hazard occupancies unless the sprinklers are specifically
FM Approved for other uses.
2.1.2.5 Implement the following heat transfer fluid (heating or cooling) system safeguards as appropriate
(see Data Sheet 7-99 for additional criteria):
A. In order of preference, use nonignitable fluids, FM Approved fluids, or organic heat transfer fluids.
B. For fired heat transfer fluid systems, focus particular attention on implementing the following safeguards
in addition to those recommended in Data Sheet 7-99:

Fig 1a. Examples of modifiable process piping.
1. Design for the mist or vapor explosion potentials in any area where an organic heat transfer fluid
having a flash point below 425°F (218°C) is heated to or above its atmospheric boiling point. Locate the
vaporizer or heater and the user facility outdoors or in a room of damage-limiting construction as
described in Data Sheet 1-44.
2. Provide sprinkler protection as recommended in Data Sheet 7-99 wherever organic heat transfer
fluids are used.
3. Provide HTF process safety interlocks in accordance with Data Sheet 7-99.
C. For unfired heat transfer fluid systems used for cooling, focus particular attention on implementing
the following safeguards in addition to those recommended in Data Sheet 7-99:
1. Arrange to keep moisture out of the low-temperature circuit (below 30°F [-1°C]) to prevent ice plugs
in the piping.
2. Locate the heat transfer system in a cutoff room or in a dedicated curbed area where the storage
tank, expansion tank, transfer pumps, and heat exchangers are located.
3. Provide a low-level interlock in the HTF expansion tank, to shut down the transfer pumps of the
primary circuits.
4. Arrange to shut down the primary circuit transfer pumps from the main control room or from an
accessible location in the event of a fire in the cutoff room or curbed area.
5. Where an ammonia refrigeration system is used, provide explosion-relieving construction and
appropriate safeguards as described in Data Sheet 7-13, Mechanical Refrigeration.
2.1.2.6 For centrifuges, provide the following loss prevention features:

Fig. 1b. Examples of modifiable process piping.
A. Where the atmosphere inside a centrifuge can get into the explosive range during operation, provide
a continuous inert gas purge or explosion suppression, or design the equipment to withstand the explosion.
B. Provide grounding and bonding for all equipment to reduce the possibility of ignition from static sparks
during loading, operation, or unloading.
C. Ensure the enclosure is tight enough to prevent air from being drawn in by the action of the centrifuge.
D. Examine any flexible hoses or fittings needed for the operation before each operating cycle to detect
loose connections, cracked hose, corrosion, or deterioration that could affect the operation.
E. Monitor the vibration levels and provide interlocks to shut down the unit at excessive levels (as
determined by the unit manufacturer).
F. Maintain rotating components clear of accumulations that could be ignited by friction from the rotating
parts.
G. Conduct regular preventive maintenance on bearings and seals to detect unusual wear, lubrication
problems, corrosion, etc. (See Operating Standard 13-5R, Bearings, for additional information.)
H. Use lubricants and coolants that are compatible with the material being processed, or design the
equipment to prevent contamination.
2.1.2.7 For dryers (e.g., batch tray, continuous tray, continuous belt, cylinder, drum, rotary, vacuum, double
cone, spray and fluidized beds), implement the following loss prevention features:
A. Provide one of the following explosion protection safeguards where combustible dust, ignitable liquid,
or flammable vapor are processed:

1. Design vessels and connecting ductwork of sufficient strength to contain an explosion.

2. Provide explosion venting to a safe location to limit explosion pressure development to less than
the vessel strength.
3. Design the vessel and connecting ductwork to operate in a low-oxygen atmosphere (see Data Sheet
7-59).
NOTE: Inerting is preferred where hybrid mixtures may be present or material MIE is less than 10
mJ.
4. Install explosion suppression systems interlocked with explosion isolation valves in connecting
ductwork.
B. Where flammable vapor is processed, provide sufficient safety ventilation to maintain the atmosphere
outside the explosive range; usually to 25
of the LEL or less. (See Data Sheet 6-9, Industrial Ovens and Dryers.)
C. Supervise temperatures in dryers and provide interlocks to automatically cut off the supply of the heating
media (if this does not, in itself, increase the hazard) in the event of out-of-range conditions.
D. Maintain rotating components clear of dust accumulations that could be ignited by friction from the
rotating parts.
E. Check equipment for accumulations of dust that could be ignited by prolonged exposure to hot surfaces
or normal dryer temperatures. This is a particular issue with continuous belt, tray, or spray dryers.
F. Evaluate processed materials for hazardous characteristics such as dust explosibility, temperature
sensitivity for ignition or decomposition, friction, shock or impact sensitivity, etc.
G. Provide grounding and bonding of all metallic equipment and isolated metal components to reduce
the potential for electrostatic charge buildup.
2.1.2.8 Where computer-based process control systems are used, design and install safety interlock systems
with proper consideration for reliability. At a minimum, provide safety interlock systems independent of the
process control computer, either hardwired or using an independent computer system of satisfactory reliability.
(See Data Sheet 7-45, Instrumentation and Control in Safety Applications, for additional information.)
2.1.3 Lyophilizers
2.1.3.1 For lyophilizers, implement the following loss prevention features:
A. Provide a reliable source of power for the equipment to ensure the process can continue to completion.
B. Use nonignitable heat transfer fluids, nonignitable hydraulic fluids, or FM Approved industrial fluids
(if present) where possible.
C. Use non-adsorbent, noncombustible pipe insulation materials at points of potential leakage if ignitable
heat transfer or hydraulic fluids are used.
D. Locate the heating/cooling equipment in an area separate from the lyophilizers and design them in
accordance with Section 2.1.2.5.
E. Conduct regular preventive maintenance on all components, especially hoses and piping subject to
pressure or temperature cycling or movement.
F. Use flexible hoses that are rated for the process conditions and compatible with the process fluids.
G. Provide automatic sprinkler protection in the room containing the lyophilizer and any support equipment
(hydraulic and heat transfer systems) where ignitable fluids are present in accordance with Data Sheet
7-99 and Data Sheet 7-98.
H. If the fluid being removed from the product is an ignitable liquid, have the process needs evaluated
to be certain that vaporization/sublimation of the liquid does not create a flammable atmosphere in either
the lyophilizer or any off-gas-handling equipment. If an explosive atmosphere is present, provide
safeguards to prevent an explosion in accordance with Data Sheet 7-32.

2.1.4 Cooler and Freezer Storage Units

2.1.4.1 Protect walk-in cooler and freezer storage units for pharmaceutical raw materials, intermediates, and
finished products as follows:
A. Locate coolers/freezers in areas not exposed to external fire, flood, or fluid leakage (e.g., do not locate
them in a packaging materials warehouse or basement).
B. For the cooler/freezer, use noncombustible or FM Approved construction and insulation materials.
C. Provide sprinkler protection where combustibles are present in construction or storage in accordance
with Data Sheet 8-29, Refrigerated Storage, Data Sheet 1-57, or Data Sheet 7-29, as appropriate.
D. Protect sprinklers and piping from mechanical damage. (See Data Sheet 8-29.)
E. Provide an easily read temperature indicator that is checked on a regular basis, with a locally sounding
alarm to indicate out-of-range (high or low) conditions.
F. Have a contingency plan to relocate storage in the event of equipment failure.
G. Where a very high-value raw material, intermediate, or product is kept in any one unit, adhere to the
recommendations in Option 1 or Option 2 (all parts):
• Option 1
Relocate the storage to multiple units with reduced product value not exposed to a single loss event (fire,
flood, fluid leakage, loss of utilities, etc.).
OR
• Option 2
A. Limit access to those with proper authorization and keep adequate records of movement of the material
in the unit, AND
B. Provide a security system on an individual cooler or a building that contains one or more coolers in
accordance with Data Sheet 9-16, Burglary and Theft. In particular, see Table 1 of that data sheet, which
indicates both the type of system and what values or commodities should be protected, AND
C. Provide a backup emergency power supply, AND
D. Provide power supply and temperature supervision (high or low) and a high-sensitivity smoke detection
system, with alarm transmitted to a constantly attended remote location with written instructions/plans
for emergency response. (Some detection systems can be impaired by certain chemical fumes, so
compatibility with the protected storage must be confirmed.)
2.1.4.2 For master cell bank freezers, implement the following loss prevention features:
A. Locate the freezers in an area not exposed to external fire, flood, or fluid leakage.
B. Provide freezers with reliably arranged utility services. This may require emergency power supplies,
alternate refrigerant sources, etc.
C. Install alarms for critical operating parameters (e.g., temperature, power) and arrange them to sound
at a constantly attended remote location having written instructions/plans for emergency response.
D. Develop a contingency plan for obtaining master cultures to prevent production interruption.
2.1.5 Chemical Libraries and Laboratories

2.1.5.1 For research and development chemical libraries, implement the following loss prevention features:
A. Split critical individual samples into separate storage units in separate fire areas, where possible.
B. Keep records of chemical synthesis techniques or sources in a separate fire area. Back up these records
in a manner similar to other important business records. (See Recommendation 2.3.1.)
C. Locate automated storage systems in areas that have no other stored combustibles, are secure from
outside access, have necessary temperature and humidity control, and are not in areas exposed to flood
or liquid leakage.

D. Where combustibles are sufficient to operate automatic sprinklers, use quick response sprinklers (low
RTI) with the design criteria as determined by the surrounding occupancy.
E. Install a fixed fire protection system inside storage units where combustibles are sufficient to damage
storage. Plastic storage components, electric motor drives, etc., could create damage from fire or smoke.
Because the stored compounds can be sensitive to smoke damage, use a gaseous extinguishing agent
activated by high-sensitivity products of combustion detectors. (See Data Sheet 4-9, Clean Agent
Extinguishing Systems, or Data Sheet 4-11N, Carbon Dioxide Extinguishing Systems.)
NOTE: The FDA has approved FM200 for use in medicinal inhalers; it is also a recognized extinguishing
agent.
2.1.5.2 For bench-scale laboratories (unit operation of 5 gal [19 L] or less), implement the following loss
prevention features:
A. Use noncombustible or FM Approved construction throughout.
B. Provide a 1-hour fire-rated cutoff between labs and higher hazard occupancies (e.g., pilot plants).
C. Arrange the fume hood exhaust system to be independent from the normal room ventilation systems
unless the ventilation systems are once-through, without recirculation.
D. Locate electric receptacles, switches, and controls so as not to be exposed to liquid spills. This assumes
small quantities of liquid can be spilled (for typical solvents, approximately 0.5 gal [2.4 liters]) and there
is strong local ventilation. Where other conditions exist, consider the need for classification of the local area
exposed. Laboratory areas, including the interiors of fume hoods, can be “unclassified” as defined in Article
500 of NFPA 70, the National Electrical Code.
E. Handle, store, and protect radioactive materials in accordance with Data Sheet 7-61, Facilities
Processing Radioactive Materials.
F. Closely control the inventory of ignitable liquid and other hazardous chemicals. Pay special attention
to compounds that form unstable peroxides on aging (e.g., ethers and tetrahydrofuran [THF]).
G. Handle perchloric acid in dedicated hoods. Perchloric acid, when heated, gives off vapor that can
condense in ductwork and form explosive perchlorates. (See NFPA 45, Fire Protection for Laboratories
Using Chemicals, for additional guidance.)
H. Maintain a high level of housekeeping, including prompt attention to spills, cleanup of completed
experiments, proper disposal of partially used chemicals, minimum paper clutter, etc.
I. Keep the quantities of ignitable liquid to a minimum and store them in FM Approved safety cans or storage
cabinets.
J. Where ignitable liquid is kept in glass bottles or plastic containers, use small sizes (1 qt [1 L] or less)
and store them in FM Approved storage cabinets where they will not be subject to mechanical damage,
bumping, or falling.
K. Do not store ignitable liquid in ordinary refrigerators. Use only devices specifically designed for such
use.
L. Locate flammable gas cylinders outside, piped to the usage equipment. (See Data Sheet 7-50,
Compressed Gases in Cylinders, for additional guidance.) An alternative is to use suitably designed and
arranged gas cabinets. (See Data Sheet 7-7/17-12, Semiconductor Fabrication Facilities for additional
guidance.)
M. Provide fire extinguishers of an appropriate type and quantity. (See Data Sheet 4-5, Portable
Extinguishers.)
N. Install automatic sprinklers in laboratories, walk-in hoods, and other enclosures where combustible
construction is present, or where there is a large accumulation of combustible equipment, stock, or
packaging. Design the sprinkler protection in accordance with Data Sheet 3-26, Fire Protection Water
Demand For Nonstorage Sprinklered Properties, Data Sheet 7-32, or Data Sheet 1-57, Plastics in
Construction, depending on the fire hazards present.
2.1.5.3 Where pressurized liquid dispensing containers (PLDC) in capacities from 5 to 55 gal (19 to 208 L)
are used in laboratories, implement the following loss prevention features:

A. Ensure PLDCs over 5 gal (19 L) containing ignitable liquid are only used where there is automatic
sprinkler protection.
B. Do not use non-metallic containers larger than 1 gal (4 L).
C. Use FM Approved PLDCs.
D. Route the discharge of relief devices to a safe location, preferably outside.
E. Ensure the piping/hose between the container and the use point are rated for the pressure, compatible
with the material being transferred, and not subject to mechanical damage.
F. Prior to pressurizing the system, ensure all fittings and connections are secure and leak-free.
G. Provide a means to stop the flow of liquid from the container by means of a readily accessible valve,
self-closing valve, or remote actuated valve on the liquid line, and by removing the pressure being applied.
(See Data Sheet 7-32 for additional guidance on inert gas transfer that may be applicable.)
H. Pressurize containers only with nitrogen or other inert gas (i.e., do not use air) either from a cylinder
or site-wide supply. Ensure backflow into the gas supply system is not possible.
2.1.6 Vivariums
2.1.6.1 For vivariums, implement the following loss prevention features:
A. Locate vivariums away from flood exposure.
B. Use noncombustible or FM Approved building construction.
C. Separate animals from support areas with at least 1-hour fire-rated construction.
D. Keep combustible storage out of animal areas and other areas sensitive to smoke contamination.
E. Install automatic sprinkler protection in areas used for the storage of food, bedding, and cleaning
supplies; in the animal areas if plastic cages are used; and in the office areas if combustible loading is
significant. Design the sprinkler protection in accordance with Data Sheet 3-26.
F. If sprinklers are installed in cage wash areas, ensure they have a temperature rating at least 50°F (10°C)
above the normal room temperature when cleaning is being undertaken.
G. Conduct a careful evaluation of important features of HVAC systems, including source and humidity
of make-up air, ductwork (noncombustible is preferred), fire dampers, backup power, and smoke detection
and control systems. (See Data Sheet 1-45, Air Conditioning And Ventilating Systems.)
H. Back up important records related to the animals and testing in a manner similar to other important
business records.
2.2 Utilities
2.2.1 Provide sufficient reliability and redundancy of process utilities to prevent interruption to critical
processes. This may include providing N+1 reliability. Critical utilities could include process heating and
cooling; room/building air-handling systems; humidity control; power, instrument, process, and breathing air;
fuels; process and inert gases; USP and deionized water; water for injection (WFI); process waste handling;
and solvent recovery.
2.2.2 When important emergency systems are taken out of service for maintenance or repair, implement a
follow-up system similar to FM Global’s red tag permit system used for sprinkler system impairments. This
will ensure that the outage is minimized and the proper precautions are instituted for affected users.
2.2.3 Evaluate the hazards presented by systems designed to treat waste process gas, vapor, and dust
prior to atmospheric release. Multiple devices/processes may be routed to one treatment unit. This may create
loss prevention issues including, but not limited to, the following:
• Proper arrangement and protection of waste solvent recovery units (see Data Sheet 7-2, Waste Solvent
Recovery) and fume incinerators (see Data Sheet 6-11, Fume Incinerators)
• Use of plastic or other combustible materials for vent collection headers (see Data Sheet 7-78)
• Contamination of connected processes by unintended back flow

• Mixing of incompatible materials, creating unexpected reactions or corrosion

• Flammable vapor present in the explosive range (intentional or accidental) that could ignite and travel to
all connected equipment (see Data Sheet 7-88, Storage Tanks for Ignitable Liquids)
• Breakdown of the treatment system, resulting in shutdown of all connected processes, with related time
element effects
2.3 Contingency Planning

2.3.1 Duplicate and safeguard important business records. Important records could include lab books
containing discovery, optimization, and production information of successful products, animal studies, records
of production techniques, or supplier information of development chemicals and master cell cultures,
production records, and regulatory required materials. These materials may be paper or computer records.
Where records are not duplicated but have business value, ensure the storage site is secure and protected
against the various exposures noted above. Carefully evaluate the need for duplication as an alternative loss
prevention technique.
2.3.2 Develop emergency response plans and procedures that include, at a minimum, the following:
A. Action to be taken in the event of fire, explosion, natural hazard events, ignitable liquid spills, and
gaseous releases (flammable, corrosive, toxic).
B. Emergency pre-plans identifying responsible personnel. Update the list of personal regularly.
C. Train all expected responders in all of the required skills using classroom and field exercises, as
appropriate. Involve outside personnel in field exercises.
D. Keep training records and review them regularly to keep personnel up-to-date on their skills and
responsibilities.
2.3.3 Include any third-party suppliers, toll converters, etc., who provide a service critical to product delivery
in the contingency plan. Evaluations should include viability of records management, regulatory compliance,
protection against fire, explosion and natural hazard events, etc. Where effects of loss of a particular
third-party source are significant, development of an alternate/additional source may be justified.
3.0 SUPPORT FOR RECOMMENDATIONS
3.1 Industry Overview

Pharmaceutical plants use a variety of chemical and biological processes to produce prescription drugs
(ethical and generic), over-the-counter medications, health and beauty aids, and cosmetics. Pharmaceuticals
can be for human or animal use.
Primary pharmaceutical plants manufacture active pharmaceutical ingredients (APIs). APIs are usually
produced through a series of steps until the desired product is reached. Primary plants often manufacture
a number of APIs on a campaign basis, typified by relatively small volume (or tonnage), but often resulting
in finished products with high value. APIs can be made:
• Synthetically, using a variety of chemicals, other raw materials, catalysts and solvents (some ignitable
and some nonignitable), and reacting them together in correct sequence and under strictly controlled
conditions
• Biochemically or biologically, using processes such as fermentation, enzyme reaction, and ecombinant
DNA processes
• By a combination of synthetic and biochemical processes
The chemistry involved is usually extremely complex and many years of research and a lot of capital
investment are necessary to produce a marketable and profitable product. Chemical process units can be
multipurpose operations, or dedicated to a single process step for a defined component. Most pharmaceutical
companies use very similar production equipment to make their specific product. Typical equipment and unit
operations include the following:
• Mixing and blending of chemicals

• Chemical reactions
• Cell growth
• Crystallization, centrifuging, filtration, drying, milling, sieving, blending and bulk packaging
• Distillation, liquid-liquid extraction, chromatographic separation
• Heat transfer using water, brine, steam, or organic fluids
• Control of vapor, liquid, and solid emissions by collection (dust collectors, scrubbers, carbon bed adsorbers)
or destruction (catalytic or thermal oxidizers, fume incinerators)
Secondary pharmaceutical plants take the active ingredients manufactured by primary sites or toll converters
and put them into a form that is suitable for use by the customer. Operations are numerous and can include
the following:
• Blending APIs with other chemicals such as fillers (e.g., carboxymethycellulose), additives (e.g., sugar,
wax, stearates, lubricants) and even some ignitable liquids
• Granulation, where products (sometimes dissolved in ignitable liquid) are sprayed onto a nucleus in a
fluidized bed granulator/dryer
• Dissolving APIs in either aqueous or organic solutions (often ignitable), followed by several unit operations
that may include crystallization of the wanted substance (to improve purity of the finished product),
centrifuging, filtration, drying, milling, sieving, and blending
• Sterilizing of equipment and containers, often using steam-heated stainless steel autoclaves or ethylene
oxide
• Filling of bottles, syringes, ampoules, and vials with liquid actives
• Closure of ampoules with natural gas or propane flame
• Tableting
• Filling of inhalers (e.g., for asthma ventilators)
• Compounding of creams, pastes, and patches
• High-purity water production (water for injection [WFI])
• Freeze-drying of finished products (lyophilization)
• Sterile and non-sterile packaging
• Warehousing
Note that in the pharmaceutical industry, the word “aerosol” does not mean aerosol container; it means a
drug delivery technique. There are three categories of devices that generate aerosols:
• dry-powder inhalers that disperse aerosol particles to the lungs from a capsule, blister, or reservoir using
pneumatic, vibrational, or rotational forces;
• metered-dose inhalers that use metering valves and propellants to disperse aerosol droplets; and
• nebulizers that use air-jet and ultrasonic dispersion technology to generate droplets and deliver them to
the lungs.
3.2 Registration and Process Validation

Registration and process validation are necessary qualification steps that are required before an ethical or
generic drug is produced for human consumption. Completing these processes can delay the startup of a
product, increase the cost of the construction project, and affect restart of a process that has experienced
a fire or other type of property loss.
Registration is the US Food and Drug Administration’s (FDA’s) way of knowing WHO is producing WHAT
and WHERE with respect to drug production. Process validation addresses HOW it is produced.
For drugs sold in the United States, the manufacturer must comply with basic FDA construction and operation
standards as defined by various regulations. A common reference is Current Good Manufacturing Practices

(CGMP) as defined by 21 CFR, Parts 210 and 211. The regulation includes General Provisions, Organization
and Personnel, Buildings and Facilities, Equipment, Control of Components and Drug Product Containers
and Closures, Production and Process Controls, Packaging and Labeling Control, Holding and Distribution,
Laboratory Controls, Records and Reports, and Returned and Salvaged Drug Products. These regulations
are directed at maintaining drug quality and present very broad guidelines that need to be met.
If the manufacturer has a new process and new site, they have to register and successfully complete process
validation (a long process). Some validation stages can be conducted in parallel with construction.
If there is a product change at an existing site, the manufacturer may need to re-register and/or amend the
registration. The time will vary with the extent of the change.
If there is an existing product with a process change, the manufacturer may need to amend the registration
and will need to successfully complete process validation.
Finally, if there is only a replacement-in-kind of a piece of equipment, there will be a need to validate, and
this could be a relatively short process. Where the whole process is rebuilt due to a physical property loss,
validation could be a very lengthy process.
3.3 Key Exposures

Pharmaceutical plants present a number of loss prevention opportunities due to the nature of the operations
themselves (exothermic reactions and distillation of ignitable liquid, for example) and the high monetary value
associated with the product. The hazards, for the most part, are not unique or unusual. This section
describes some of the key exposures and their loss prevention opportunities.
3.3.1 Liquid Transfer

Liquid transfer operations are a significant activity in pharmaceutical operations. They may involve ignitable
liquids, acids, bases, highly toxic fluids, etc. Transfers can take place from drums, intermediate bulk
containers (IBCs), other process vessels, or tank farms. Liquid transfer can be by gravity, pumping, or
pressure differential, often through piping and/or flexible hose. Issues associated with flexible hoses are the
linking of the flexible hose to the correct pipe, and the reliability of the mechanical connection. (For additional
information see Data Sheet 7-32).
General loss prevention considerations should be control of flow, prevention of overfilling, elimination of leaks,
electrostatic grounding, and positive local and remote shutoff. Automatic methods provide the most reliable
way to isolate solvents supplied to the building. This can be achieved by an automatic interlock that shuts
off the flow of solvents by actuation of sprinkler water flow, or a cross-zoned fire detection system installed
in the processing areas.
Flow meters can be installed on process lines, where an operator enters exactly how much liquid is required.
The meter delivers the predetermined amount before automatically shutting a valve. Another way is to provide
a suitable level of automatic control with high- and high-high-level indication, alarm, and cut out for the vessel
in question and the associated piping system.
Manual “solvent-off” buttons located at stairwells and exit points are another way to shut off the flow of liquid
to a building, and relies on a manual response. Pushing one of these solvent-off buttons isolates all liquid
flow to the building, either by initiating a closure of solenoid valves on incoming lines, or by stopping remote
transfer pumps. Isolation of flow to the building in a fire or other emergency should also be achievable from
a control room or other key remote location.
Heating and cooling of process systems is important in many stages of pharmaceutical operations, both in
primary and secondary plants. In some cases, these systems have no fired heater. The heat transfer fluid
(HTF) passes through heat exchangers. There are often three circuits, one at 320°F (160°C), one at ambient
temperature, and one at -22°F (-30°C). The circuit at 320°F (160°C) can have steam as source medium in the
heat exchangers. The circuit at -22°F (-30°C) can have Freon or ammonia as the source medium in the heat
exchangers.

3.3.2 Reactors
3.3.2.1 Synthetic Manufacture of Actives

A key production step in the manufacture of APIs involves chemical reactions, often in the presence of
ignitable solvents, under a wide range of process conditions. Pressures can vary from sub-atmospheric
(vacuum) to several hundred psi (several thousand kPa), and temperatures from just above freezing to several
hundred degrees. Reactors are generally pressure vessels designed to withstand a set positive pressure,
and usually full vacuum.
Reactors have flanged nozzles for various services (heating, cooling, nitrogen inerting, etc.), transfer of
materials, agitators, instrumentation, normal and emergency vents, etc. Other flanged openings allow manual
addition of materials (liquid or solid), inspection and lighting of the contents via glass ports and frequently,
bottom discharge piping and valving. All these openings are potential sources of leakage and should be limited
to those absolutely needed.
Pharmaceutical plant reactors range in size from less than 5 gal (19 L) for high-pressure reactors to thousands
of gallons (tens of m3) for fermentation reactors. Where reactors are multipurpose, thorough cleaning
between batches is necessary primarily for quality control reasons; this also can prevent hazardous reactions
if incompatible process materials are used.
Chemical reactors can either be of a customized or standard design. Reactors are commonly fabricated from
glass-lined carbon steel or stainless steel 316L, although some reactors are made using higher grades of
stainless steel or other exotic metals (e.g., Hastelloy, which is significantly more expensive.) Unlined carbon
steel reactors tend not to be used, as they are more susceptible to corrosion (a lot of chemical reactions
use aggressive and corrosive acid chlorides) and contamination (e.g., rust formation that could contaminate
the product). Occasionally, reactor vessels will have PTFE (polytetrafluoroethylene) linings. Use of FRP or
GRP (fiber- or glass-reinforced plastic) as a material of construction for reactors is unusual.
Once the reaction has been completed, the contents are usually transferred to another vessel for additional
processing. Transfer could be by gravity, pumping, or by pressurizing the reactor with air, inert gas, or process
pressure.
In some instances, further processing, such as crystallization, phase separation, or product isolation, is
conducted in the reactor itself. This is another multipurpose service with the usual related hazards.
For many pharmaceutical reactions, precise or continuous agitation is needed; usually agitators are
electrically driven. Mechanical seals where the agitator shaft passes through the vessel nozzle prevent escape
of gas evolved during a reaction and help maintain pressure/vacuum conditions in the reactor. Older reactors
tend to have constant speed agitators, but where more precise rates of agitation are needed, or where the
reactor is multipurpose, reactor electric motors are often variable speed units (using either DC motors or
variable-speed AC units). Variable-speed agitation also can be achieved hydraulically rather than by using
electric motors directly.
For hydrogenation reactions, electrical equipment needs to be rated for Class I, Division 2, Group B. Such
motors can be difficult or impossible to find. Alternatives may include purged and pressurized enclosures for
the motors or hydraulic drives.
Temperature control, important for quality and safety purposes, is achieved using various media, including
water, steam, and organic heat transfer fluids. Heat transfer can be achieved by using limpet coils fitted to the
external walls of the reactor vessel, full jacketed internal coils, a combination of limpet and internal coils,
or (less commonly) using external heat exchangers. With the latter arrangement, the reactants are pumped
from the reactor to an external heat exchanger and then back to the reactor. Heat transfer systems can be
a source of contamination if leakage occurs into the vessel. Organic heat transfer fluids can also be an
additional fire source in the event of a leak. Leakage can be prevented by the proper selection of exchanger
materials for the service conditions, and regular inspection and maintenance.
Many reactions are carried out at reflux, where the solvent is brought up to boiling point and exits the reactor
as vapor. This vapor is condensed in an overhead condenser and then returns to the reactor. Condensers
can take a variety of forms. Usually they are shell and tube heat exchangers fabricated from stainless steel,
Hastelloy, titanium, or glass-lined carbon steel. In some plants, they can be fabricated from glass or carbon
block/graphite. Where the solvent is a ignitable liquid or where there is a contamination potential from the

coolant, control of leakage is a high priority. Contamination risk can be minimized by proper selection of
exchanger materials for the service conditions, and regular inspection and maintenance.
Pharmaceutical reactions should undergo process hazard analysis during development, scale-up, and prior
to startup (refer to Data Sheet 7-43). These reactions are frequently exothermic, sensitive to temperature
excursions or to mis-charge of the reactants, catalysts, carrier solvent, etc. Such incidents can lead to potential
overpressure of the reactor. Careful study, resulting in appropriate design criteria, can prevent an uncontrolled
pressure excursion that destroys the reactor and its surroundings.
In addition to overpressure prevention, hazard evaluation studies can identify needed process controls and
safety interlocks that keep the process in a safe operating range. Because of the nature of the hazard or
quality control requirements, programmable logic devices (computers, PLCs, etc.) are frequently considered
for both process and safety services. At a minimum, separate systems are needed for the process and safety
functions. The safety functions may be achieved by hard-wired systems or by other programmable systems.
(See Data Sheet 7-45 for additional guidance.)
3.3.2.2 Biochemical and Bilogical Manufacture of APIs: Small Scale

Natural materials or fermentation process products may be used as the starting material in biochemical
processes. Downstream operations are then frequently similar to synthetically produced APIs.
Products made by this process include antibiotics, vaccines, vitamins, bioconverted steroids (anti-
inflammatory agents such as cortisone) and enzymes.
Biocatalysis, biotransformation, and bioconversion are all names for the use of biological substances in a
biochemical process. Biocatalysts are either enzymes or whole cell organisms that act as a catalyst to carry
out a chemical conversion.
Biotransformation reactions include additions, aminations, dehalogenations, epoxidations, esterifications,
hydrolysis, hydroxylations, polymerizations, and reductions. These reactions may be for the synthesis,
interconversion, or degradation of chemical species.
Animals may be used for the production of biologically based products. Basically, the process entails using
transgenic animals (such as mice or goats) to grow cells or antibodies; the cells are then extracted from
blood or animal milk. The recovered cells are used to create a finished product.
Cell cultures may be used as the starting material in biological processes. The important differences between
cell culturing and fermentation are that the process can take much longer (two or three times longer) than
fermentation, and PET roller bottles are used during the production phase. Cells in media are put into small
PET plastic bottles. The bottles are then stacked on side in roller racks (shelf units with rollers for each bottle
that keep the bottle spinning around its axis). There may be a 3,000 to 5,000 ft2 (279 to 465 m2) room with
7 ft (2.1 m) high shelf storage of plastic bottles located in the middle of the clean production facility. This is
a significant combustible load not found in other biotech operations.
Recombinant DNA and other genetically modified cells may be used as the starting material in biological
processes. Master cells are used to produce working cells. Master calls are reproduced in a scaled process
going from vials to Petri dishes or flasks to bioreactors.
Ignitable liquids, though not commonly used, could include ethanol, acetone, dimethylformamide, and
dimethylsulfoxide.
A typical biotechnology process can include the following steps:
• Media preparation
• Fermentation or other cell growth process
• Cell separation or harvesting: ultrafiltration, centrifugation, homogenizing
• Purification: ion exchange chromatography
• Virus inactivation: organic solvent/detergent mixtures
• Purification: membrane filtration
• Purification: size exclusion chromatography
• Formulation

• Sterile filtration, filling, lyophilization

The process generally consists of adding the raw materials, the media, and nutrients to water in a bioreactor,
adjusting the pH, allowing the reaction to take place over a period of time (usually days to weeks), then
inactivating and purifying the product.
Some common exposures to loss in this industry include the following:
• Spoilage due to service interruption; lack of (or lack of control of) heat, cooling, agitation, electricity, natural
gas, instrument and sparge air, and other utilities
• Contamination due to foreign material, internal or external fire, etc.
• Cleanroom construction due to the use of plastic- and foam-insulated wall and ceiling components
• Master cultures or cell banks that may be one of a kind or difficult to replicate
Damage or loss of master cultures can have a serious impact on the ability to create product, so attention
to details that maintain critical utilities and eliminate the exposure to fire, contamination, and other nonthermal
damage is important. It is critical to have sufficient built-in safeguards to avoid a significant loss of production
if a cell bank is lost (see Section 2.1.4.2).
3.3.2.3 Biochemical Manufacture of APIs: Large Scale

In the following discussion, the basis is a large-scale fermentation process such as penicillin production.
The first step is the seeding process, where the cultures are added to nutrients in seed vessels that are usually
located in the fermentation building. Seed vessels can be up to 5300 gal (20,000 L) capacity and are usually
equipped with limpet and/or internal cooling coils. Air (or sometimes pure oxygen) is injected into the vessel
to allow seeding to proceed. Nutrients can include ammonium sulfate, corn steep liquor, rapeseed oil, starch,
glucose, and sugar. Caustic and sulfuric acid can be added to control the pH, as can anhydrous ammonia
and acetic acid (often glacial). Seeding usually takes between 72 and 80 hours.
After seeding is completed, the contents of the seed vessels are transferred to the main fermenter vessels
(sometimes called “J vessels”). Fermenters can have capacities up to 53,000 gal (201,000 L). Large
fermenters may be custom-made, requiring long replacement times. They are equipped with steam lines (for
sterilizing), air lines, cooling coils, and large agitators, often with associated gearboxes. Nutrients added to
fermenters are similar to those added to the seed vessels.
Fermentation is a batch process with a cycle time of up to several weeks. Fermenters are usually rated
pressure vessels designed for pressure and full vacuum. Operating conditions are typically 30 psig (2 barg)
with temperature not exceeding 140°F (60°C). Fermentation reactions, although slightly exothermic, are all
readily controllable. Cooling water is essential in controlling product quality.
Overpressure protection is required for fermentation reactors because CO2 gas is a reaction product. The
fermentation reactor could overheat, or the outlets could be blocked.
Direct steam injection is usually used for all sterilization of fermenter and seed vessels and all associated
pipe work. Continuous agitation and aeration are also critical to ensure good product yields and quality. Each
large fermenter is generally agitated using a top-mounted, electrically or hydraulically driven agitator, shaft,
and integral gearbox. Motors are typically rated between 200 and 600 hp (150 and 450 kW). The gearboxes
can contain up to approximately 13 gal (50 liters) of lubricating oil. The combustible loading in fermenter
buildings is usually low and sprinkler protection is not normally warranted (unless the construction is
combustible or there is a large central hydraulic system).
The use of steam in the sterilization process could also result in creation of vacuum conditions (and collapse
of the vessel) as the steam condenses. This needs to be considered in any process hazard review and
vacuum breakers should be provided as needed.
The air supplied to fermenter and seed vessels must be sterile. It is supplied through a sparge pipe via a
number of low-pressure, high-volume flow centrifugal compressors that may be electrical, diesel, or steam
turbine driven. These compressors usually cannot be rented on short notice as they need to produce sterile
and oil-free air. Lube oil usage for these compressors can be significant, and localized automatic sprinkler
protection may be warranted, especially if adjacent compressors are not cut off from one another. (See Data
Sheet 7-95, Compressors.) If the compressors use combustible filters, spares should not be stored nearby.

The “broth” leaving a fermenter is usually filtered to recover the required product, and then concentrated to
a form that is easier to handle and process for subsequent downstream operations. Further processing can
include ion exchange, solvent extraction, crystallization, reverse osmosis, and drying.
3.3.3 Isolation
“Isolation” is a general term that refers to one or a series of physical separation processes using extraction,
centrifuging, and/or filtering. The isolated product could be an intermediate used in subsequent steps, or
an API sent to a secondary operation for subsequent blending and packaging.
The desired API may be formed as a solid particle in the reaction steps or may require additional steps to
achieve crystallization. The slurry containing the solid active can then be sent to a filter or centrifuge to remove
most of the liquid. Some in-line filters remove the desired solids and return the liquid to the reactor. The wet
cake can then be washed in situ and discharged to a dryer where residual moisture is removed. If the solid
is an intermediate material, it may need to be further processed so it can be discharged into drums as a wet
cake.
Filtration is another way of separating a liquid from a solid. There are basically four ways of achieving filtration:
gravity, pressure, vacuum, and in-line filters. With sensitive powders that are susceptible to breakdown by
mechanical forces, vacuum filtration is usually preferred. Some filters are also combined filter-dryers.
Liquid from the filtration, centrifuging, and drying steps and wash liquors may be recycled, further treated,
or disposed of as waste. Treatment or disposal may be conducted on or off site. Techniques can include, but
are not limited to: distillation, adsorption, neutralization, acidification, phase separation, and incineration.
The liquid streams may be aqueous or organic. Many of the organic streams are ignitable.
In some cases, the liquid may be the desired intermediate or product. It may be further processed using
treatment steps such as distillation, ion exchange, adsorption, neutralization, acidification, and phase
separation. Unwanted cake can either be incinerated or sent off site as solid waste.
3.3.4 Ion Exchange and Chromatography

Although ion exchange is most often seen as a water purification process, some pharmaceutical processes
also use the technique. Here, a liquid stream is passed through one or a series of ion exchange columns
containing a packed resin bed having specific adsorption and chemical properties. A component from the liquid
stream is preferentially adsorbed onto the resin bed. The adsorbed component may be the desired product
or an undesired material that needs to be removed from the product stream. The remainder of the stream
passes through the column. If it does not contain product, it may be recycled back into one of the upstream
processes, sent to a recovery step, or discarded as waste. If the stream is the product, it could be sent for
further processing or finishing operations.
Saturated resin beds need to be regenerated or eluted. Whether the saturate is the product or waste, the
process is the same. The resin bed is flushed using a fresh solution (an ignitable solvent, other organic
material, steam, etc.) that has a higher affinity for the saturate than the resin bed. The regeneration fluid is then
sent for further processing.
Chromatography is a cyclic fixed or fluidized bed unit operation similar to ion exchange or adsorption. Various
techniques are available for removing a particular contaminant or for bulk separation of contaminants. Size
exclusion chromatography separates substances based on their molecular size.
3.3.5 Granulation, Drying and Coating

In a secondary pharmaceutical plant, multiple-unit operations are performed to obtain the final dose form.
The type and order of the unit operations will depend on whether the final dose form is a liquid, cream or solid.
It also will depend on whether the final dose form is parenteral, oral, aerosol or topical.
Coatings may be applied to obtain desired properties (e.g., temperature release, moisture and oxygen
barriers, aesthetic, sustained release, etc.) and may involve the use of ignitable liquid.
A wide range of drying equipment can be found in the pharmaceutical industry. Equipment that performs
two unit operations, such as filtering and drying or blending and drying, is often used. Dryers can be directly
heated (where the cake comes in direct contact with the drying medium; usually hot air or nitrogen) or
indirectly heated (where there is usually a retaining barrier between the heating medium and the cake to be
dried). Due to the sensitivity of many pharmaceutical powders to heat, dryers are often indirect heated. They

can be operated under vacuum conditions to enable drying at lower temperatures. The heating medium can
be steam, hot water, organic heat transfer fluid, or indirectly heated air or nitrogen. Dryers can be batch or
continuous.
Where ignitable solvents are driven off in dryers, a suitable level of safety ventilation is needed (see Data
Sheet 6-9). In addition, the evaporated solvent may be recovered or further processed. These processes
present their own ignitable liquid and flammable vapor hazards that need to be addressed.
Some pharmaceutical powders and hybrid mixtures can have very low MIE, resulting in a potential for ready
ignition. It may be necessary to process these materials under inert atmospheres to reduce the frequency
of ignition.
Cleaning of dryers (and other process equipment) may introduce other hazards such as the use of ignitable
solvents that may not be part of the normal operation. Cleaning may require opening and entering the
equipment, or may be cleaned in place (CIP). CIP does not necessarily introduce additional fire or explosion
hazards, but can result in sources of breakdown or contamination. These need to be recognized in any hazard
studies.
Dryers can include the following:
A. Batch tray: These dryers are the simplest and most basic. The wet cake is put into trays, which are
then manually placed into ovens where they are dried by passing hot air or nitrogen across the material.
The major hazards include overheating of the product to the point where it catches fire, or vapor explosions
if the evaporated material is a ignitable solvent (Figure 2).
B. Continuous belt: These dryers use a continuous belt or conveying screen with a hot gas passing through
or across the belt and product. The major hazards include belt warping or fire caused by overheating
or friction at rotating or rubbing parts.
C. Spray: In these dryers, the feed is atomized by a centrifugal disk or nozzle and then discharged into
a cylindrical tower where the hot gas flows concurrent or counter-current to the feed. The major hazard is
overheating of the product where it has accumulated on the interior surfaces of the dryer. The result can
be a fire or explosion. Ancillary equipment can include cyclones, bag filters, dust collectors, and
scrubbers.
D. Conical: This type of dryer consists of cones that rotate end over end at low speed to tumble and dry
the product. Heating can be provided by steam, water, or other heat transfer fluid. Hazards include both
combustible dust and flammable vapor in the unit and ancillary equipment (Figure 3).
E. Fluidized bed: These dryers are direct-heated dryers that rely on a hot, fluidizing medium (usually air,
but nitrogen can also be used) to suspend the powder to be dried, thereby providing uniform drying of
the solids. Where air is the fluidizing medium and the dust is combustible, the head space could contain
dust in the explosive range. Where the liquid removed is ignitable, the head space could contain a hybrid
mixture (dust and vapor) in the explosive range. These units often have ancillary equipment similar to spray
dryers to remove fines that are entrained in the fluidizing medium exiting the dryer (Figure 4).
Fluid beds are commonly used for combined operations such as agglomeration and drying, wet granulation
and drying, or coating and drying. They are also used for powder layering and pelletizing applications.
Fluids and powders are applied as top-spray, bottom-spray (known as Wurster method), or tangential
spray. Top-spray is commonly used for granulation. Bottom-spray is commonly used for pharmaceutical
coating. Tangential-spray is commonly used for powder spheronization and layering.
F. Rotary: This type of dryer has a jacketed shell and is often horizontal cylindrical in shape. A double
flight of spiral ribbons or heavy-duty paddles is attached to a rotating shaft inside the dryer. During
operation, the ribbons or paddles move material from the center of the dryer to the end plates and back
so the batch is constantly exposed to heated shell and shaft. Heating can be provided by steam, water,
or other heat transfer fluid. Hazards include both combustible dust and flammable vapor issues in the unit
and ancillary equipment (Figure 5).

Fig. 2. Batch tray dryer.
3.3.6 Lyophilization
Lyophilization is a freeze-drying process used for many drugs. Some products are thermolabile or unstable
at elevated temperatures in aqueous solution (instability is a quality issue in this case). The lyophilization
process creates a more stable, powder product that can be later reconstituted prior to patient use. The process
is vulnerable to spoilage in the event of an interruption.
The typical treatment cycle is that the product to be processed is first prepared as an aqueous solution or
suspension that is then cooled rapidly to a low temperature, often approaching -58°F (-50°C). The freezing
chamber is sealed, and the frozen material is then subject to heat under a high vacuum. The liquid portion
sublimes and the resulting dry product is often less than 1% moisture. The product is then packaged under
sterile and low-humidity conditions.
In a few cases, the solvent for the solution might be an ignitable liquid. If it is, the process needs to be
evaluated to be certain that vaporization/ sublimation of the liquid does not create a flammable atmosphere
in either the lyophilizer or any off-gas handling equipment.
Some lyophilizers process the solution in the final vial. Vials are loaded into the process chambers with loose
fitting tops, which are set by compressing the stack of trays at the end of the process. These units will
commonly have a hydraulic system (see Data Sheet 7-98).
Depending on the lyophilizer model, the heat transfer fluid coils can be on the exterior walls or part of the
internal trays.
To provide reliable electrical power, lyophilizers frequently have emergency power supplied by batteries and
backup emergency generators (see Data Sheet 5-23, Emergency and Standby Power Systems).

Fig. 3. Conical dryer.
Loss prevention concerns include use of ignitable heat transfer fluid or hydraulic fluid, combustible or
absorbent piping insulation, loss of power during the operation, and contamination from liquid spills or smoke
from fires.
3.3.7 Ventilation
Ventilation is installed for personnel comfort and safety, product quality, and to prevent ignitable liquid,
flammable gas, and combustible dust hazards. Requirements for manufacturing process areas, packaging
areas, laboratories, and storage areas vary broadly.
Personnel comfort and safety requirements are often specified as “x” number of air changes per hour. Systems
designed to meet personnel safety or product quality requirements can have higher volumetric requirements
than are needed to deal with flammable hazards. These systems can be used to meet the flammable vapor
hazard requirements provided there are low-point pickups and there is no recirculation of the air. If there are
only limited flammable materials involved, air recirculation could be acceptable with FM Approved vapor
detection systems interlocked to put the system in full exhaust mode.

Fig. 4. Fluid bed granulator.

Fig. 5. Rotary dryer.
In laboratories, fume hoods are used to control hazards associated with the experiments being conducted.
In most cases, codes that specify minimum air flow rates are to protect personnel. These rates would be
sufficient for the quantities of ignitable liquid or flammable gas normally handled in these devices. If the hood
has a variable speed fan, the minimum speed should meet this requirement. With fume hood systems it is
important that ventilation openings are not obstructed, ventilation systems are regularly serviced, conditions
of operation (e.g., front sash panes in proper position) are observed, and sufficient make-up air is provided.
Noncombustible ducts for fume hoods need to be routed directly outside. Exhaust openings need to be
located away from intake points for building ventilation systems.
In general, ignitable liquids with a flash point below 100°F (38°C) produce enough vapor at room temperature
to require mechanical ventilation, while unheated ignitable liquids with flash points above 100°F (38°C)
require only natural ventilation. Any ignitable liquid with a flash point up to 300°F (150°C) heated to its flash
point also will need mechanical ventilation.
3.3.8 Waste Gas Handling

Some processes generate gas as a by-products that needs to be removed. Such gases can be relatively
harmless, while others are toxic (e.g., chlorine, phosgene, carbon monoxide), corrosive (e.g., hydrogen
chloride), or flammable (e.g., carbon monoxide, hydrogen, hydrogen sulfide). Some processes can also
generate copious volumes of gas (e.g., carbon dioxide) that, although not a fire or explosion hazard, need to
be removed so as not to pressurize a reactor and associated equipment, which could result in mechanical
failure of the vessel.
Gaseous by-products may be recycled in the process or vented through piping to the outside, either directly
or through some type of gas cleaning or treatment system. The system could include a bag collector,
scrubber, thermal oxidizer or catalytic oxidizer, waste fuel boiler, etc. (see Data Sheet 6-11 and Data Sheet
7-78). Venting directly to atmosphere is limited to non-toxic, non-hazardous gases such as carbon dioxide.

Limited amounts of a flammable gas such as hydrogen may be vented directly to atmosphere; however,
these need to be routed to a safe area such as above a high roof. When vented directly outside, the vent
must be protected against rainwater entry by protective caps or inverted U-bends at the end of the pipe.
Venting gases from indoor equipment only to a nearby exhaust system should not be permitted, as the system
may not be operating when the gas is released. Where the exhaust system is interlocked with the process
requiring its operation, such an arrangement could be acceptable.
Most gases are vented to some type of treatment system prior to atmospheric release. Often, multiple pieces
of process equipment are routed to a common treatment device. This can present the possibility of
contamination or mixing of incompatible materials. If flammable vapor is handled, a fire or explosion originating
in one unit can be transferred to others. Any incident shutting down the treatment system would stop the
operation of the connected process, with related time element effects.
Scrubbers are most commonly used to remove corrosive and/or toxic components from waste gas streams.
Scrubbers are usually vertical vessels containing packed beds to allow a large surface area for good
liquid-gas contact. Scrubbers with multiple internal trays also can be used.
The scrubbing solution can be water, alkaline streams (e.g., caustic, sodium hypochlorite, etc.) for treating
acidic and some toxic vapors (e.g., hydrogen chloride, chlorine, phosgene); and acidic streams (e.g., sulfuric
or hydrochloric acid) to scrub out some alkaline streams. The equipment used is frequently of combustible
construction such as glass fiber-reinforced plastic (GRP) or fiber-reinforced plastic (FRP) shells, with plastic
(PVC or polypropylene) internal packing. External or internal components of metal, ceramic, or glass
construction are also possible. Scrubbers may be located indoors, outdoors on the roof, or outdoors at ground
level. When located indoors and of combustible construction, sprinkler protection for the area may be needed.
The major hazards associated with scrubber systems include the combustible construction, and the effect
on operation if the ability to scrub off gases is lost. Often, the process will be shut down due to local pollution
control regulations. The plant should have alternative ways of handling the waste gas in the event of the
outage of the primary equipment. This could include duplicate equipment or methods to incinerate the waste
in boilers, flare stacks, etc.
Some gaseous streams that are flammable and have a sufficiently high calorific value can be burned on
site. Vent gases containing hydrogen, acetylene or carbon monoxide can be routed to:
• Boilers (or sometimes gas turbines), where the gases are burned as supplementary fuel.
• Incinerators, where flammable gas streams are burned; sometimes these incinerators are equipped with
waste heat recovery boilers that provide steam or hot water for other processes.
• A flare stack, where the gases are ignited, and flared-off.
See Data Sheet 6-11; Data Sheet 7-2; and Data Sheet 7-78, for further guidance.
3.4 Special Occupancies
3.4.1 Chemical Libraries

Automated storage libraries are used to store small chemical samples that are part of a new product
development (R&D) cycle. The libraries are not usually used for production sample storage. The samples
may be produced in onsite development labs or purchased from outside sources. Samples may be liquid or
solid, and may be only a few micrograms each.
There are two basic types of sample storage. In the first, each sample is stored in a small glass or plastic
bottle with a cap or rubber stopper. Multiple sample containers are then stored on a metal or plastic tray in
the ALS unit. Bottles that are sealed tightly with caps result in a “low permeability” condition: compounds
not particularly susceptible to smoke and/or water damage. The second sample configuration uses
“microplates” for storage of liquid solutions. Each microplate is a plastic plate or sheet, typically with 88 small
wells containing samples. The microplates are sealed by the thin plastic sheet, resulting in a “high
permeability” condition: compounds very susceptible to smoke and/or water damage.
These units have either a manual or automated retrieval system to bring the desired sample tray to the picking
area. The trays in the unit rotate vertically and/or horizontally using gear, chain, and electric motor-driven
system. One system has 13 trays horizontally, 42 tiers, with each tray capable of holding 250 samples for
a total of 136,500 samples.

Another system is 30 × 11 × 18 ft (9.1 x 3.4 x 5.5 m) high, with a 3 ft (0.9 m) access aisle down the center.
Construction is steel frame and steel/aluminum panels. The unit is totally enclosed on all sides (including
top). Solid steel shelves (on each side of access aisle) are 9 × 3 ft (2.7 x 0.9 m). Tier height is 3-4 in.(76-102
mm) for the entire height (60 tiers). Shelves are fixed; a robot arm is programmed to remove a sample from
the shelf and bring it to the access door. The unit will hold about 1.1 million bottled samples or about 6 million
microplate samples.
Fire hazards include the use of ignitable liquid, the electric motor, and possibly large quantities of plastic.
Although the liquids stored may be ignitable, the quantities are negligible. It is possible that a very small
electric motor fire or insulation breakdown may create enough combustion products to contaminate all
samples. A significant exposure is the fact that the samples themselves may be one of a kind or expensive to
purchase from a supplier. The monetary value of the storage may be difficult to determine and includes not
only the purchase/development cost, but also the effect of a loss on on-going development programs.
3.4.2 Laboratories: R&D, Production, Quality Control

Pharmaceutical development and production requires the use of laboratories on an extensive scale. The
development facilities may or may not be on the same site as primary and/or secondary operations. Labs
associated with production and quality control are usually small, with limited amounts of analytical equipment
and associated liquids and gases. They may be part of the process building or located in the same area
as the development labs.
The basic loss prevention features for all laboratories include separation from higher hazard operations
(production) using noncombustible construction with separate ventilation systems, automatic sprinklers, and
good housekeeping, including control of hazards related to ignitable liquids and flammable gases. Manual
fire extinguishers of an appropriate type and quantity should be provided.
Laboratory areas, including the interiors of fume hoods, are “unclassified” as defined in Article 500 of NFPA
70, National Electrical Code.
R&D labs are frequently located in dedicated buildings with numerous, various-sized rooms interspersed
with offices, libraries, meeting rooms, etc. They are used to conduct development testing of various types
on a small scale, usually less than 1 gal (4 L) in vessel volume. Use of noncombustible construction
throughout, as well as complete automatic sprinkler protection, is preferred.
In addition to the normal type of chemistry labs, R&D laboratories have extensive use of high-value robotic
test and analysis equipment and associated computers. Examples of a “typical” R&D lab are shown in
Figures 6a and 6b.
In R&D facilities, there is increasing need for larger quantities of liquid, often ignitable, to serve the robotic
devices. Small plastic containers for containing the necessary liquid are an integral part of some laboratory
equipment.
Pressurized liquid dispensing containers (PLDCs) in capacities from 5 to 55 gal (19 to 208 liters), usually
of stainless steel construction for purity, are increasingly being brought into labs. These containers typically
operate at pressures of up to 15 psig (103 kPa), with the vessel rated for 60 psig (415 kPa) or higher. An
inert gas supply is used to deliver contents either to a dispensing system or directly to the instrumentation.
There are several FM Approved PLDCs listed in the Approval Guide under the classification “flammable liquid
dispensing systems.”
Devices of this type may also be available in plastic construction and with plastic liners or bladders, but they
are not FM Approved.
Records of research results, laboratory notebooks, etc. are essential items and need to be protected against
loss as important business records. This could involve control over the location and number of books
assigned to each researcher, as well as a policy on duplication and storage of these duplicates. Management
should set a formal policy in this area and see that the policy is followed.
3.4.3 Storage Facilities excluding Chemical Libraries)

Pharmaceutical facilities have a need for storage of raw materials, intermediate and final products, packaging
materials, etc. Storage is commonly located in conventional warehouses with palletized and rack
arrangements. Protection criteria should comply with the recommendations in Data Sheet 8-9, Storage of

Class 1, 2, 3, 4 and Plastic Commodities, depending on the nature of the commodity and its arrangement.
Where ignitable liquid, gas, oxidizers, organic peroxides, etc. are stored, protection is addressed in the
applicable FM Global data sheets.
Pharmaceutical storage can often present high unit values, susceptibility to contamination from products of
combustion or foreign materials, a need for temperature and humidity control, and security considerations
associated with potential burglary or theft.
Due to the high values, it may be appropriate to consider separate storage areas for raw materials,
intermediates, and final products to minimize time element losses where there are long production cycle times.
Even where cycle times are short, consider splitting high property value concentrations to reduce exposure
to a single loss event.
In many cases, final product must be stored in walk-in coolers of small to moderate size with a high unit
value, resulting in a significant financial exposure. A small combustion incident (e.g., fire, overheating of
electrical equipment, adjacent exposure fire) can result in total loss of the product before sprinklers can
operate. The best loss prevention advice is a high level of equipment maintenance, strict control of ignition
sources, and use of noncombustible construction and storage containers. However, where combustible
packaging or construction is present, fast-response fire protection systems may be required. This includes
detection and/or extinguishing components. Detection systems are classified as high sensitivity smoke
detection (HSSD) and include several operating technologies with a number of FM Approved manufacturers.
Response of a gaseous clean agent system may result in less damage than sprinkler protection could
achieve, especially in cases where water may result in loss of the product. Water discharge in freezers may
impact the operation of manual or automatic material handling systems and should be considered in
developing contingency plans.
Where humidity and temperature control is needed to maintain product, intermediate or raw material quality,
utility reliability must be evaluated.
Fig. 6a. High-value R&D laboratory equipment.

Fig. 6b. High-value R&D laboratory equipment
3.4.4 Vivariums
Pharmaceutical plants often have facilities for caring for animals that support production or research. Animals
can include almost any species, but the most common are small mammals and rodents. The animals are
genetically well defined, having been raised for specific purposes. Often, many generations of animals are
needed, and loss of one generation (or related documentation) due to disease, fire, flood, etc., can set a
development program back to its beginning.
The vivarium is best constructed of entirely noncombustible materials; for example, concrete block and
ceramic tile. The animal rooms have minimal combustibles, usually metal cages (although plastic cages may
be used on occasion), and a minimum of bedding material. Usually there are laboratories and work rooms
related to animal examination, again with minimal combustible loading. Auxiliary operations in the building can
include offices, cage wash areas, and rooms for the storage of food, cleaning materials, and bedding. These
are usually located outside the “clean” areas. The storage rooms present the largest concentration of
combustibles in the building. Automatic sprinkler protection is usually needed, and these areas are usually
separated from the vivarium by fire-rated construction.
Vivarium atmosphere is controlled to maintain temperatures and humidity within a close tolerance, arranged
so individual rooms have independent air circulation. The building conditioning system may have multiple
units to prevent contamination or cross contamination. A careful evaluation of the important features of HVAC
systems is needed to minimize the potential for a disruptive incident.
Fire alarm arrangements require extra consideration, as loud noises such as fire alarms can impact the
animals and research results.
Associated research records should be backed up similarly to other important business records.

3.4.5 Cleanrooms
Pharmaceutical plants commonly have areas referred to as cleanrooms. These cleanrooms are not
necessarily to the same as semiconductor cleanrooms. Table 1 highlights some typical (although not
universal) terminology related to cleanliness in pharmaceutical operations.
Table 1. Typical Cleanliness Terminology for the United States

Description Typical Area Terminology
Unclassified Labs, warehouse Not subject to particulate or microbiological control
Pharmaceutical Packing Not subject to particulate or microbiological control
Controlled Processing/filling rooms (non-sterile) Class 100,000
Clean Filling rooms (sterile) Class 10,000
Critical Point of fill (sterile) Class 100
The cleanliness ratings listed in Table 2 are based on the number of particles equal to or greater than 0.02
in. (0.5 mm) in 1 ft3 (0.03 m3) of air. For example, a class 10 cleanroom based on US Federal Standard
209D has a maximum of 10 particles greater than 0.02 in. (0.5 mm) in every 1 ft3 (0.03 m3) of air.
Several of the other countries’ standards on cleanrooms adopted the cleanliness ratings used in ISO 14644
when it was published in 1991, making some of the listings in table obsolete.
Table 2. Cleanliness Ratings Used in Farious Countries

Origin of
Standard Cleanliness Ratings
USA (209D)1 1 10 100 1000 10000 100000
USA (209E)2 M1.5 M2.5 M3.5 M4.5 M5.5 M6.5
Britain3 C D E or F G or H J K
France4 - - 4000 - 400000 4000000
Germany5 1 2 3 4 5 6
EU6 - - A and B - C D
ISO7 3 4 5 6 7 8
Australia8 0.035 0.35 3.5 35 350 3500
Japan9 3 4 5 6 7 8
1
US Federal Standard 209D (1988). Clean Room and Work Station Requirements, Controlled Environments. Replaced by 209E.
2
US Federal Standard 209E (1992). Clean Room and Work Station Requirements, Controlled Environments. Replaced by ISO 14644.
3
British Standard BS 5295 (1989). Environmental Cleanliness in Enclosed Spaces. Superseded by ISO 14644.
4
French Standard ANFOR X44101 (1981). Superseded by ISO 14644.1.
5
Vereinigte Deutsche Ingenieure (VDI) VDI 2083.1 (1991). Cleanroom Technology, Part 1: Fundamentals, Definitions and Determination
of classes.
6
Pharmaceutical Inspection Convention (2009). Guide to Good Manufacturing Practice for Medical Products.
7
ISO 14644-1 (1999). Cleanrooms and Associated Controlled Environments, Part 1: Classification of Air Cleanliness.
8
Standards Australia AS 1386 (1989). Cleanroom and Clean Workstations, Part 1: Principles of Clean Space Control. Superseded by AS/NZS
ISO 14644.1:2002.
9
Japanese Industrial Standards JIS-B-9920(2002). Air Cleanliness Evaluation Methods for Cleanrooms.
Typically, a Class 100 to 1,000 area is located within a clean area. This might be for sterile filling operations
and may only be 100 to 300 ft2 (9 to 27 m2) in size. These areas might be achieved using a laminar flow
hood with a HEPA filter for the air circulation. Cutoff from surrounding occupancy is achieved by clear plastic
drop curtains.
Traditional noncombustible construction methods are predominant. Modular construction methods, using
both noncombustible and combustible (metal-faced, foam-insulated) panels, are sometimes used in renovated
or temporary areas. In many cases the combustible loading of the occupancy is light to non-existent.
Table 3 highlights some of the major differences between semiconductor and pharmaceutical cleanrooms.

Table 3. Pharmaceutical vs. Semiconductor Cleanrooms

Pharmaceutical Semiconductor
Many Small Rooms 500 to 1000 ft2 Few Large Rooms 5000 ft2 and up
Size (45 to 90 m2) (450 m2 and up)
Construction Mixed materials Mixed materials
No raised floors and no under floor air plenums Raised floors and air plenums
Washable surfaces Highly susceptible to liquid damage
Equipment Small scale Large scale
‘‘Off the shelf’’ equipment Custom-designed equipment
Isolation technology (glove boxes)
HVAC Systems Differential pressure Positive pressure
Once through Recirculation
Utilities Ordinary reliability Reliability is critical (built in spares)
Breathing air may be needed
Data Sheet 1-56, Cleanrooms, provides basic guidance for evaluating this occupancy with proper
consideration for the occupancy differences. Use of noncombustible construction, smoke and contaminant
control, and sprinkler protection where combustibles are present in significant quantities continues to be good
advice. There are some areas where the combustible loading is insufficient to warrant sprinkler protection,
even though work in process and equipment values may be sizeable.
In some areas, sealed concealed sprinklers have been installed to meet US Food and Drug Administration
(FDA) cleanliness requirements as a result of local interpretations of the regulations. This type of installation
is not mandated by FDA regulations and some facilities have used standard sprinklers in the same occupancy.
Sealed concealed sprinklers use a gasket around the ceiling plate of the sprinkler to seal the small gap
formed between the ceiling plate and the tile. These sprinklers are not FM Approved and can be subject to
delayed operation. (In some cases, concealed sprinklers that are FM Approved for light hazard occupancies
have been modified by the addition of the gasket, creating an un-Approved unit.)
Data Sheet 1-57 provides guidance on plastic modular construction components that can be used in this
occupancy. The data sheet illustrates acceptable alternatives to FM Approved panels. FM Approved metal-
faced, foam-insulated panels are available for use with or without sprinklers (see the Approval Guide,
Building Materials Section, Building Insulation). Note, however, that smoke production from these panels could
be significant even though they don’t propagate fire beyond the initial ignition point. This should be considered
wherever plastic panels are installed or proposed.
There are also constructions other than rigid panels that include thin plastic facing materials (like paint
coatings or wallpaper) on a mineral board backing material. Such a facing, alone, in the absence of other
combustibles, would not likely warrant the installation of sprinklers.
3.4.6 Toxic and Potent Compounds

In the pharmaceutical industry, handling of toxic and potent compounds as raw materials, intermediates, or
final products, is quite common. As a result, every effort is made to eliminate any release of the material
outside its process equipment or handling area. Steps taken to protect operators include remote operations,
total body suits, using glove boxes, etc. (See Figure 7.) A conflict might arise between the need to control
the release of a toxic or potent compound with the need to protect the property by using damage-limiting
construction or pressure-relief devices. This can be the case where the compound itself is, or is processed
with, a combustible dust or ignitable liquid, and the process conditions can result in an explosion (deflagration)
hazard. There are methods that can be implemented where both causes are served.
For example, if vessel pressure relief is needed, without a combustible dust or ignitable liquid explosion
potential, the vented material containing toxic/potent compounds can be routed through scrubbers,
neutralizers, incinerators, etc. However, where a deflagration potential exists, standards call for damage-
limiting construction. This can involve explosion vents on dust collectors and cyclones or vent panels on
building walls. This dilemma can be resolved by reducing the hazard using inherently safer design. With
intensification, substitution, or attenuation, the hazardous material could be either the toxic compound itself

Fig. 7. Typical glove box installation.
or the diluent, solvent, or dust that creates the deflagration exposure. These frequently are valid options to
investigate. An example of attenuation would be to use an inert atmosphere in a process presenting a dust
explosion hazard.
Using limitation of effects is most practical on vessels, which can be designed to contain the explosion. This
would nominally be possible where the reaction is well defined and runaway pressures can be pinpointed,
or where a deflagration potential exists and the maximum unvented pressure has been measured (see Data
Sheet 7-76). Where this approach is extended to a building, the construction costs usually will be prohibitive
except for small buildings. Such structures would be the equivalent of blast cells used in explosive handling
processes but with no venting walls. Providing limitation by spacing is usually not an option because any
release to the outside is not permitted.
Finally, simplification or error tolerance will reduce the likelihood of an incident, but may not be acceptable
to the authority having jurisdiction where any release, no matter how infrequent, may be unacceptable.
As long as toxic/potent compounds are processed or handled, the exposure to personnel cannot be
eliminated. However, the concept of inherent safety can reduce or control property damage incidents and
indirectly reduce the exposure from release of these materials.
3.5 Loss History

Pharmaceutical occupancy losses with a total gross value of US$500,000 or more for the period 1986-2011
were reviewed. The breakdown by peril is shown in Figure 8 (percentage based on the number of incidents)
and Figure 9 (percentage based on gross loss amount). Significant losses were associated with equipment
(24%) and natural hazards (22%).

Calculated by number of events, 40% of all equipment losses were due to service interruption (Figure 10);
however, calculated by cost, service interruption only accounted for 20% of the equipment losses. The most
costly equipment losses were caused by pressure vessel breakdown (Figure 11).
The cause of the largest number of natural hazards losses was flooding, followed closely by wind and hail
events (Figure 12). Flooding is also the most costly natural hazard, making up 72% of the total gross loss
amount (Figure 13).
The pharmaceutical losses were also broken down by the main process involved in the incident. Figure 14
Other
Natural hazard
17%
22%
Fire
16%
Equipment
Explosion 24%
8%
Water damage
13%
Fig. 8. Pharmaceutical losses by peril (percentage by number)
shows process losses by the number of incidents, and Figure 15 shows processes losses by gross loss cost.
Storage losses account for the highest percentage of incidents by both number and gross loss cost (42% of
all losses in which the main process involved in the incident could be identified). Losses in cleanrooms are
infrequent (4% by number) but expensive (15% by gross loss cost).
Storage losses can be broken down into the major storage types and are shown by number of losses in
Figure 16 and gross loss cost in Figure 17.
In 60 of the losses that were over US$500,000 there was enough information to identify the ignition source.
The most common ignition source was electrical (Figure 18) at 50% of the losses. However, losses caused
by electrical ignition sources only makes up 16% of the total gross loss cost (Figure 19). Hot work losses
are the most costly (43%).
Electrical sparks/arcing and short circuits made up two thirds of all the electrical source losses (Figure 20).
The other electrical ignition sources were lightning, over-voltage, and static.

Other
10% Natural hazard
23%
Fire
22%
Equipment
16%
Explosion Water damage
17% 12%
Fig. 9. Pharmaceutical losses by peril (percentage by gross loss cost)
Electrical breakdown
18%
Service interruption Mechanical
40% breakdown
15%
Pressure equipment
breakdown
27%
Fig. 10. Pharmaceutical equipment losses (percentage by number of losses)

Electrical breakdown
9% Mechanical
breakdown
4%
Service interruption
20%
Pressure equipment
breakdown
67%
Fig. 11. Pharmaceutical equipment losses (percentage by gross loss cost)
Lighting
4%
Earthquake
15%
Wind and hail

39%
Flood
42%
Fig. 12. Pharmaceutical natural hazard losses (percentage by number of losses)

Lighting
1%
Earthquake
Wind and hail 11%
16%
Flood
72%
Fig. 13. Pharmaceutical natural hazard losses (percentage by gross loss cost)
Air
handling
Chemical reactions 2%
3%
Laboratory
Electricity supply
8% Chemical processes
interruption
9% 17%
Drug preparation
15%
Storage
42%
Clean room
4%
Fig. 14. Pharmaceutical losses by main processes (percentage by number of losses)

Air
Laboratory handling
Chemical reactions 4% 1%
8%
Electricity supply Chemical
interruption processes
2% 12%
Drug preparation
16%
Storage
Clean room 42%
15%
Fig. 15. Pharmaceutical losses by main process (percentage by gross loss)
Chemical storage
6%
Refrigerated drug
storage Drug storage
27% 25%
Pharmaceutical
storage
42%
Fig. 16. Pharmaceutical storage losses (percentage by number of losses)

Chemical storage
2%
Refrigerated Drug storage

drug storage 9%
13%
Pharmaceutical
storage
76%
Fig. 17. Pharmaceutical storage losses (percentage by gross loss cost)
Arson Chemical reaction

3% 5%
Human element
Open
9%
flame
8%
Hot work
17%
Electrical
50%
Hot surface
5%
Friction
3%
Fig. 18. Pharmaceutical losses by ignition source (percentage by number of losses)

Arson
1%
Human element
4% Open flame
Chemical reaction
11%
18%
Electrical
16%
Hot work
43%
Hot surface
7%
Friction
1%
Fig. 19. Pharmaceutical losses by ignition source (percentage by gross loss cost)
Static
7%
Spark/arcing
Short circuit 33%
33%
Over voltage Lighting

7% 20%
Fig. 20. Pharmaceutical losses with an electrical ignition source (percentage by number of losses)

4.0 REFERENCES
4.1 FM Global
Data Sheet 1-2, Earthquakes
Data Sheet 1-44, Damage-Limiting Construction
Data Sheet 1-45, Air Conditioning and Ventilating Systems
Data Sheet 1-56, Cleanrooms
Data Sheet 1-57, Plastics in Construction
Data Sheet 4-5, Portable Extinguishers
Data Sheet 4-9, Clean Agent Extinguishing Systems
Data Sheet 4-11N, Carbon Dioxide Extinguishing Systems
Data Sheet 5-1, Electrical Equipment in Hazardous (Classified) Locations
Data Sheet 5-23, Emergency and Standby Power Systems
Data Sheet 5-32, Electronic Data Processing Systems
Data Sheet 6-9, Industrial Ovens and Dryers
Data Sheet 6-11, Fume Incinerators
Data Sheet 7-2, Waste Solvent Recovery
Data Sheet 7-7/17-12, Semiconductor Fabrication Facilities
Data Sheet 7-13, Mechanical Refrigeration
Data Sheet 7-14, Fire Protection for Chemical Plants
Data Sheet 7-32, Ignitable Liquid Operations
Data Sheet 7-43, Loss Prevention in Chemical Plants
Data Sheet 7-45, Instrumentation and Control in Safety Applications
Data Sheet 7-46, Chemical Reactors and Reactions
Data Sheet 7-49, Emergency Venting Of Vessels
Data Sheet 7-50, Compressed Gases in Cylinders
Data Sheet 7-59, Inerting and Purging of Tanks, Process Vessels, and Equipment
Data Sheet 7-61, Facilities Processing Radioactive Materials
Data Sheet 7-76, Prevention and Mitigation of Combustible Dust Explosions and Fires
Data Sheet 7-78, Industrial Exhaust Systems
Data Sheet 7-88, Storage Tanks for Ignitable Liquids.
Data Sheet 7-95, Compressors
Data Sheet 7-98, Hydraulic Fluids
Data Sheet 7-99, Heat Transfer by Organic and Synthetic Fluids
Data Sheet 8-9, Storage of Class 1, 2, 3, 4 and Plastic Commodities
Data Sheet 8-29, Refrigerated Storage
Data Sheet 9-16, Burglary and Theft
Class 4910, Cleanroom Materials Flammability Test Protocol
Class 7440, Firesafe Valves
4.2 Other
American Petroleum Institute (API). Fire Test for Soft-Seated Quarter-Turn Valves. API 607.
National Fire Protection Association (NFPA). Fire Protection for Laboratories Using Chemicals. NFPA 45.
National Fire Protection Association (NFPA). National Electrical Code. NFPA 70.
U.S. Code of Federal Regulations. Current Good Manufacturing Practices for Finished Pharmaceuticals.
21 CFR, Chapter I, Part 211.
U.S. Code of Federal Regulations. Current Good Manufacturing Practices in Manufacturing, Processing,
Packing or Holding of Drugs, General. 21 CFR, Chapter I, Part 210.
APPENDIX A GLOSSARY OF TERMS

Active Product Ingredient (API): The active ingredient in a drug (as opposed to the substance the API is
contained within). Also called pharmaceutical actives or chemical actives.

BLEVE: Boiling Liquid Expanding Vapor Explosion. It occurs when, for example, a drum of liquid is exposed
to a fire, which causes the contained liquid to vaporize, overpressure and fail the drum, with the immediate
vaporization of the released liquid. If the liquid is ignitable, a large fireball will be created.
Campaign: the process of making different chemicals in a particular process system by producing chemical
A for X period of time, and then cleaning out the process system and producing chemical B for Y period
of time, etc. The period of time could be days, weeks or months.
Clean: as applied to Pharmaceutical operations, this means free from dirt, stain and other impurities. (See
Table 1.)
Combustible Dust: Combustibility of a dust is established by tests that expose the material to ignition sources
of various intensities, such as a spark, a match flame, a Bunsen burner, or a Meker burner. A combustible
dust is not always an explosible dust. Dust explosibility is established by ASTM tests E1226 or E1515, or the
national/international equivalent (e.g., ISO 6184/1). Any sample of dust with a median particle size smaller
than 500 microns is possibly explosible unless testing proves otherwise. Dust with a median particle size
greater than 500 microns can be assumed to be non-explosible as long as particles smaller than 500 microns
have not been segregated during material handling.
Cytotoxic: Compound that is toxic to cells. Chemotherapy drugs used to treat cancer are cytotoxic.
DIERS: Design Institute for Emergency Relief Systems; see Data Sheet 7-49, Emergency Venting of Vessels,
for details.
Ethical pharmaceutical: A prescription medicine on which the patent held by the developing company is still
valid (also see generic pharmaceutical).
FM Approved: References to “FM Approved” in this data sheet mean that the products and services described
have satisfied the criteria for FM Approval. Refer to the Approval Guide, an online resource of FM Approvals,
for a complete listing of products and services that are FM Approved.
Ignitable Liquid: In this document the term is used to describe any liquid that will burn.
FRP: Fiber-reinforced plastic.
Generic pharmaceutical: A prescription medicine on which the patent has expired, allowing it to be produced
by many manufacturers (also see ethical pharmaceutical).
GRP: Glass-reinforced plastic.
HAZMAT: Hazardous material. Could refer to an ignitable, corrosive, or toxic liquid; a flammable, corrosive,
or toxic gas; or a combustible, corrosive, or toxic solid.
Inherent safety: Process whereby hazards are minimized by intensification, substitution, attenuation, limitation
of effects, and simplification/error tolerance (see Data Sheet 7-43).
Master Cell Bank (MCB): MCBs are the original modified biological material. There are also Research Cell
Banks (RCBs) and Master Working Cell Banks (MWCBs). MWCBs are copied from MCBs and are used for
production. They are often kept in “straws” or milliliter-sized vials. They can be stored in liquid nitrogen flasks
of 5 gal (19 liter) capacity, or liquid nitrogen-cooled freezers of 35 to 70 ft3 (1 to 2 m2) volume.
Nutraceuticals: Nutraceuticals are biological substances specifically derived from plants.
Parenteral: Medication that is administered by a route that bypasses the gastro-intestinal tract, such as a
drug given by injection.
PLDC: Pressurized liquid dispensing container. NFPA uses the term pressurized bulk solvent storage
container (PBSSC).
Potent compound: See toxic compound.
Primary pharmaceutical plant: A facility where APIs are produced.
Secondary pharmaceutical plant: A facility where the APIs manufactured by the primary plant (or by third
parties) are converted into a form that is suitable for use by a patient.
Sterile: As applied to pharmaceutical operations, this means free from bacteria and other microorganisms.
(See Table 1.)

Thermolabile: Subject to loss of characteristic properties on being heated to or above 55°C (131°F), a
characteristic of many immune bodies, enzymes, and vitamins.
Toll converter: A third-party company that carries out one or more of the steps in the manufacturing process
of a finished pharmaceutical commodity. The toll converter could be a primary or a secondary pharmaceutical
facility. For instance, a primary plant may produce an intermediate in-house, then send it to a toll converter
who processes it further to produce the active product. The toll converter might return the processed material
to the plant, or to one of the pharmaceutical facility’s other plants, for further processing. Or, the toll converter
might formulate, package, and distribute the product on behalf of the pharmaceutical plant.
Toxic compound: A substance that is poisonous and/or may produce an injurious or deadly effect on
introduction into a living organism.
USP/NF: The United States Pharmacopeia (USP) and National Formulary (NF) are standards for potency
and purity for most common drug products. They have been published since 1833 and 1887, respectively, and
were combined for the first time in 1980. Revisions take place every 5 years.
Vivarium: An enclosed area for keeping and raising animals for observation and research.
WFI: Water for injection.
WIP: Work in process.
APPENDIX B DOCUMENT REVISION HISTORY

July 2013. The following changes have been made:
• Replaced references to “flammable” and “combustible” liquids with “ignitable” liquids throughout the
document.
• Reorganized the document where necessary to provide a format that is consistent with other data sheets.
• Added references to other FM Global data sheets where sprinkler protection options are covered in more
detail.
• Changed terminology for animal facilities (to “vivariums”).
• Updated the loss history.
• Updated the illustrative losses.
September 2010. Minor editorial changes were made.
January 2008. Minor editorial changes were made.
January 2007. Clarification was made to section 3.4.5.
January 2004. Minor editorial changes were done for this revision.
January 2002. First published.

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Property Loss Prevention Data Sheets 7-36

1.0 SCOPE ..................................................................................................................................................... 3

Fig. 6b. High-value R&D laboratory equipment .......................................................................................... 29

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2.0 LOSS PREVENTION RECOMMENDATIONS

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Fig 1a. Examples of modifiable process piping.

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Fig. 1b. Examples of modifiable process piping.

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1. Design vessels and connecting ductwork of sufficient strength to contain an explosion.

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2.1.4 Cooler and Freezer Storage Units

2.1.5 Chemical Libraries and Laboratories

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• Mixing of incompatible materials, creating unexpected reactions or corrosion

2.3 Contingency Planning

3.0 SUPPORT FOR RECOMMENDATIONS

3.1 Industry Overview

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3.2 Registration and Process Validation

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3.3 Key Exposures

3.3.1 Liquid Transfer

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3.3.2.1 Synthetic Manufacture of Actives

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3.3.2.2 Biochemical and Bilogical Manufacture of APIs: Small Scale

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• Sterile filtration, filling, lyophilization

3.3.2.3 Biochemical Manufacture of APIs: Large Scale

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3.3.4 Ion Exchange and Chromatography

3.3.5 Granulation, Drying and Coating

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Fig. 2. Batch tray dryer.

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Fig. 3. Conical dryer.

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Fig. 4. Fluid bed granulator.

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Fig. 5. Rotary dryer.

3.3.8 Waste Gas Handling

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3.4 Special Occupancies

3.4.1 Chemical Libraries

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3.4.2 Laboratories: R&D, Production, Quality Control

3.4.3 Storage Facilities excluding Chemical Libraries)

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Fig. 6a. High-value R&D laboratory equipment.

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Fig. 6b. High-value R&D laboratory equipment

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Table 1. Typical Cleanliness Terminology for the United States

Table 2. Cleanliness Ratings Used in Farious Countries