CGMP Training – Buildings & Facilities

•Biopharmaceutical Development Program

*Images used in this presentation are for educational purpose only

 2
WHAT WE KNOW SO FAR….

• The regulations that apply to drug products are a result

of tragedies that resulted from a lack of control by drug
manufacturers
• The Good Manufacturing Practices (GMPs) are one of the
regulations applied to drugs
• GMPs are found in the Code of Federal Regulations
(CFR)
 3
WHAT WE KNOW (continued)

• GMPs define the minimum requirements for control in the

manufacture, holding and distribution of drugs to assure the
quality of the drug.
• HOW manufacturers design their processes and systems to
provide this control is up to them and will be judged by FDA
based on the control achieved and current industry practice.
• Failure to produce drug products within a system compliant
with GMPs causes the products produced to be
ADULTERATED.
 What’s in the GMPs about Quality?
SISQP

Safety: Does no harm

Identity: Is what it’s supposed to be
Strength: Sufficiently potent
Quality: Meeting requirements
Purity: Free of contamination
 5
21 CFR 211 Subpart C. BUILDINGS AND FACILITIES

Objectives for this Section

• Explore the GMP requirements for Buildings and

Facilities
• Explore Clean Air Classifications
• HEPA Filtration
• Laminar Flow
• Air flow patterns
• Personnel flow

• Explore Water Quality Issues

• Review some Warning Letter citations related to
Buildings and Facilities
• Discuss some situations to see what you think.
 Inputs and Outputs

• The IPO diagram in the next slide shows the unique inputs
and outputs for the process of making a drug. Inputs to a
drug manufacturing process include control of personnel,
buildings, equipment, process controls, lab controls, raw
materials and packaging. The output for the process of
making a drug is the drug in the vial and documentation.
Feedback about the process is obtained through
inspections, audits, investigation of failures, trends, etc.
IPO Model – Making a Drug
(IPO: Input-Process-Output)

This IPO diagram shows the

unique inputs and outputs for
the process of making a drug.
Inputs to a drug manufacturing
process include control of
personnel, buildings,
equipment, process controls,
lab controls, raw materials and
packaging. The output for the
process of making a drug is
the drug in the vial and
documentation. Feedback
about the process is obtained
through inspections, audits,
investigation of failures, trends,
etc.
 Subpart C. BUILDINGS AND FACILITIES

• You may be aware that the drug manufacturing process

produces TWO products, the drug in the vial and all the
documentation related to the manufacturing of the drug. BOTH
of these products will be evaluated before a product can be
released to consumers. In these reviews, DOCUMENTATION is
critical. Documentation is needed to confirm that the product
was tested properly and is within the established specs set for
the product. Documentation is also needed to confirm that the
process was executed properly and meets the requirements of
the MPR and the GMPs.
• You can’t get to a defendable product release decision without
documentation that you can trust, or that is clear and
understandable.
What Happens To These Products Of
The Process?
 Subpart C. BUILDINGS AND FACILITIES

What needs to be controlled in

GMP Facilities?
• Depends on the type of drug being
manufactured. Injectable drugs have
different “issues” than topical creams or
nasal sprays (for example).
 11
Subpart C. Buildings and Facilities

“Adequate”, “sufficient”, “suitable”, “appropriate”, “as necessary”, “not

necessarily limited to” are wiggle words used over 100 times
throughout the GMPS. Some of the examples appearing in Subpart C
include -

• Any building used in the manufacture of a drug product shall be of

suitable size…..
• Any such building shall have adequate space ….
• Adequate ventilation shall be provided.
• …there shall be adequate exhaust systems or other systems
adequate to control contaminants.
• Adequate washing facilities shall be provided…
 What needs to be Controlled in GMP
facilities?

For an injectable drug …

• Building design
• Flows (how people, raw materials, products, and waste
move through the building)
• HVAC Management
• People Management
• Water & Steam
• Compressed Air & Gases
 Building Design

• Suitable size, construction, and location to facilitate cleaning,

maintenance and proper operations.
• Adequate space for equipment and materials to prevent mix-
ups
• Flow of material through building designed to prevent
contamination
• Defined areas or other control systems for specific
operations to prevent contamination and mix-ups, including
specific requirements for aseptic processing areas.
• Restrictions on handling of penicillin
 Building Design

• The Building Design determines what PROCEDURES will

be needed to use and protect the building:
• A good building design that incorporates engineering controls is
best to ensure proper flow
• Procedural controls may be difficult to enforce
• Gowning requirements
• Flow of materials and personnel
• Restrictions on certain material (cardboard, unpainted wood)

• The design must be appropriate for the operations that will

be performed in that area.
• Building requirements for a warehousing area are different than the
building requirements for vial filling.
Clean Rooms & HVAC

15
 Building Design

Clean Room - Definition

• “a room in which the concentration of airborne

particles is controlled, and which is constructed and
used in a manner to minimize the introduction,
generation, and retention of particles inside the room
and which other relevant parameters, e.g.,
temperature, humidity, and pressure are controlled as
necessary.” ISO 14644-1, Section 2.2.2
 Clean Room Design

ISO 8 (Class 100,000) – Requires HEPA

filters in the air handlers
ISO 7 (Class 10,000) – Requires terminal
HEPA filters & low returns
ISO 5 (Class 100) – Requires terminal
HEPA filters and laminar flow, total ceiling
coverage & low returns.
Laminar flow = unidirectional flow
 Clean Room Design-Obstruction to
airflow

Obstructions to airflow and laminarity need to be minimized. Note that the

windows have no ledges. They are flush with the walls. The tables are
perforated or of wire construction so the air can flow through them.
 Clean Room Design - Flooring

• Coved transitions
• Chemical resistant
coatings
• Smooth, hard,
easily cleaned
surfaces

Floor to wall transitions are coved so they’re easy to

clean and don’t hold dirt.
 Subpart C. Buildings and Facilities
Design and workflow

Process Process Process Process Process

1 2 3 4 5

C L E A N E R

How the building is operated is also part of the building design. How materials, people and
product move through the building is part of the design and how refuse, people and product
move OUT of the building is also part of building design.
Building organization and workflows must be designed so that the drug product is exposed to
only cleaner and cleaner environments as it is produced. GMPs don’t permit the product to
“move backward” into dirtier areas. This also means the product’s exposure to you and
where you have been in the building.
 Subpart C. Buildings and Facilities
Design For Product Flow

Process Process Process Process Process

1 2 3 4 5

C L E A N E R

Obviously, this manufacturing process doesn’t always move the product

to cleaner and cleaner environments and is not complaint with GMP.
 Subpart C. Buildings and Facilities
Gowning

WHAT’S WITH SPECIAL GOWNING?

• Walking person with normal clothing sheds
~ 13,500 particles / second
• “Carefully” walking person with good clean clothes
sheds
~ 1,000 particles / second.
The biggest source of airborne particles in a
cleanroom is personnel who generate both viable
and non-viable particles. These particles may
include skin flakes, hair, cosmetics, clothing
particles, perspiration and respiratory emissions.
(BioPharm International [Link]
March 2004)
 Subpart C. Buildings and Facilities

Manufacturing Area

Prod. Prod. Prod. Locker

Suite Suite Suite room
3 2 1
Other
Departments
Manufacturing Area
Process Utilities

This is a crude diagram of a part of a building housing 3 different production suites.

Different projects will be worked on in each production suite. Cross contamination
between the production suites by people is a concern. What kind of personnel flow
patterns could be implemented that would prevent the cross contamination of clean
people with dirty people?
 Subpart C. Buildings and Facilities

Design For Personnel Flow Patterns

Prod. Prod. Prod. Other

Suite Suite Suite
3 2
Departments
1

Locker
room

How about something like this? White arrows are the travels of “clean” people. Black
arrows show the travels of “dirty” people – people who have been exposed to product
because they’ve been in a production suite.
 Subpart C. Buildings and Facilities

Traffic pattern

Prod. Prod. Prod. Other

Suite Suite Suite
3 2
Departments
1
Locker
room

This traffic pattern establishes “clean” hallways and “dirty” hallways. If you have been in a production suite, you are
considered “dirty”. You aren’t in any hallways that other technicians would use to travel to enter production suites.
OK, So we’ve designed our facility to have cleaner areas for production activities. We designed entrance and egress
patterns for these production areas so that people don’t cross contaminate each other as they enter and exit production
areas.
But when a technician ENTERS the production area, a very clean environment, they have been traveling in hallways of a
“less clean” environment. Is this, OK?
 Subpart C. Buildings and Facilities

Design For Personnel Flow Patterns-

Gowning

Prod. Prod. Prod. Other

Suite Suite Suite
3 2
Departments
1
Locker
room

Gowning
Areas

People that move from a less clean environment to a more clean environment can contaminate the
clean environment that they are entering. Therefore, they GOWN when they move from a dirty to
clean environment. What gowning is appropriate will depend on the environment that you are coming
FROM and the environment that you are going TO.
 Subpart C. Buildings and Facilities

Design For Waste Flow Patterns

Prod. Prod. Prod. Other

Suite Suite Suite Departments
3 2 1
Locker
room

It’s important that the collection, removal, and storage of waste does not contaminate raw materials, in-process product,
finished product, or classified manufacturing areas.
How should waste be removed to minimize possible cross contamination? What should be the flow path? When should
waste be removed? These are all important considerations when designing flow patterns.
 Subpart C. Buildings and Facilities

Design For Waste Flow Patterns

(continued)

Other
Prod. Prod. Prod.
Suite Suite
Departments
Suite
3 2 1 Locker
room

It’s important that the collection, removal, and storage of waste does not contaminate raw materials, in-process
product, finished product, classified manufacturing areas, or clean gowned personnel.
Waste should be removed via the dirty corridors. The flow should follow the normal path that personnel follow when
leaving the production area. The waste is transported in covered bin type carts to the SERVICE elevator, moved
down to the first floor, and moved via the non-BDP general corridor to the waste storage & removal area.
Waste should be removed from GMP manufacturing areas after hours and on weekends, prior to sanitation of the
facility.
 Subpart C. Buildings and Facilities

Design For Raw Material

Prod. Prod. Prod. Other

Suite Suite Suite
3 2
Departments
1
Locker
room

Raw materials and components need to be transported into the manufacturing rooms
where they are needed in a fashion that prevents contamination of these clean areas.
How should raw materials be transported to minimize possible cross contamination?
What should be the flow path? When should raw materials be transported?
 Subpart C. Buildings and Facilities

Design For Raw Material (continued)

Prod. Prod. Prod.

Suite Suite Suite
Other
3 2 1 Departments
Locker
room

Cardboard boxes and other outside packaging should be removed prior to moving the items into our GMP manufacturing
areas.
Chemicals and other raw materials may be weighed out for use in the Dispensary. The Dispensary that is located on the
first floor can be used to pre-weigh and dispense the raw materials that are needed for manufacturing so the source bottles,
drums, etc. don’t have to be transported to the second-floor manufacturing suites.
The bottles, barrels, and packages (and the carts they are on) must be wiped down with sanitants as they transition from
the warehouse to the dispensary and from the materials transport elevator to the GMP manufacturing area. They must be
wiped down with a sanitant an additional time as they enter the suite, they will be used in.
Ensuring Proper Flow

The BDP uses these signs to indicate what is acceptable to move into
an area and what is not allowed in order to maintain the proper flow of
personnel, materials, waste, and equipment
 Subpart C. Buildings and Facilities
Preventing Contamination & Mix-ups

• GMPs require that the building be designed with defined areas or other controls to
prevent contamination or mixups in storage and holding of materials before release to
(read from slide) (manufacturing, after acceptance, in-process materials, rejected
materials, quarantined or unreleased product, and released product, manufacturing
operations, packaging and labeling operations, laboratory operations, and aseptic
processing).
• It must be clear how you have provided these defined areas or other control systems.
• Try to think of a critical operation where FDA has not required a defined area to prevent
contamination and mix-ups.
• QC testing …..it’s in there!
• Receipt of raw materials ……it’s in there!
• Warehousing …..it’s in there!
Subpart C. Buildings and Facilities
Preventing Contamination & Mix-ups
Signage for Defined Areas
 REQUIREMENTS FOR
ASEPTIC PROCESSING AREAS

• Floors, walls, ceilings of smooth, hard surfaces that are easily cleanable
• Temperature and humidity control
• Air supply filtered through high-efficiency particulate air (HEPA) filters under positive
pressure
• A system for monitoring environmental conditions
• A system for cleaning and disinfecting the room and equipment to produce aseptic
conditions
• A system for maintaining any equipment used to control aseptic conditions

Note: It makes sense to apply a number of these controls to our other GMP areas
as well.
 Subpart C. Buildings and Facilities

HVAC – Requirements
• HVAC (Heating – Ventilation – Air Conditioning). How an HVAC system is
designed into the building is part of the building design.
• What does FDA expect?
For HVAC systems, FDA expects…
• Equipment to control air pressure, microorganisms, dust, humidity
and temperature must be provided when appropriate
• Air filtration must be used on supply air to production areas, when
appropriate
− If production air is recirculated, need to control recirculation
of dust
− If contamination is an issue, there must be adequate
exhaust systems to control contamination
• Separate air handling for penicillin operations
 Subpart C. Buildings and Facilities
HVAC – Requirements (Environment)

FDA recognizes that while specialized equipment during product vialing (for example)
may be appropriate to control air pressure, microbes, dust and humidity, this amount of
control probably isn’t needed during product storage in the Warehouse when the
product is contained and boxed. GMPs allow companies to fit the needs of the
product to the environment that the company must provide. For example, HEPA
filtration is often appropriate in production areas where the product is exposed to the
environment, but HEPA filtered air is almost never needed in the Receiving Area /
Warehouse.

How your designed air system works – whether it recirculates air (and maybe dust) or
how it controls potentially contaminated air, is important to assure the quality of your
processes.

Penicillin operations must have separate air handling systems (or better yet – separate
buildings) to prevent cross contamination of product. FDA is extremely sensitive to the
proximity of penicillin operations to other drug production operations. FDA will even
evaluate whether one plant could intake air containing penicillin contaminated exhaust
from another physically distinct plant. (Concern is the extreme, life-threatening allergic
reactions some people have to penicillin and penicillin related products)
 Subpart C. Buildings and Facilities
HVAC – Design

DESIGN PARAMETERS
TO CONSIDER FOR CLASSIFIED AREAS

For certain production operations, special environments are needed. Different levels of cleanliness
are assigned different “classifications”. In the US, we used to use classifications of 100, 1,000,
10,000, & 100,000. (these classifications refer to the number of particles, >0.5u in a cubic foot of air).
ISO (International Standards Organization) has a different classification scheme. You can see that
ISO class 5 is the same as US Class 100 (≤ 100 total particles (viable and non-viable) per cubic
foot air). There are other schemes as well, for example, the European scheme which classifies areas
by letters of the alphabet.
Whatever the scheme, you need to design areas so that they can maintain these types of
environments. This takes ENGINEERING. Critical factors that affect a rooms cleanliness are the air
changes in a room / hour, the air velocity and the pressure differential between clean and less clean
areas.
 Subpart C. Buildings and Facilities
HVAC – Design Parameters

DESIGN PARAMETERS
TO CONSIDER FOR CLASSIFIED AREAS

This is the same with air velocity.

Pressures between clean and less clean areas have to be designed so that air
moves from clean to less clean and not the other way around. This requires
planning to design rooms with any hope of meeting requirements. More than
most other design considerations, getting this aspect right is very important.
Failure to do so can result in very difficult cleaning and flow control
requirements.
 Subpart C. Buildings and Facilities
HVAC – Design-validate-Monitor

Once the rooms are designed and then constructed, they are tested to determine if they
actually function the way they were designed. So non-viable particles / cubic foot are
measured. The number of viable particles / cubic foot of air are measured and the number of
viables on the surfaces are measured. It’s not sufficient to plan the areas to provide this
environmental control. You have to PROVE (with data) that you have actually achieved this
control. And you have to PROVE with data that you continue to achieve this control. This
means regular, environmental monitoring. DESIGN-VALIDATE-MONITOR. Limits in yellow
area can be found in “Guidance for Industry: “Sterile Drug Products Produced by Aseptic
Processing – Current Good Manufacturing Practice” and summarizes clean air
classifications and recommended action levels of microbiological quality.
 Subpart C. Buildings and Facilities
HVAC – HEPA Filtration

H High
E Efficiency
P Particle
A Air

(from [Link]
One of the GMP requirements for aseptic processing areas is that the air be filtered through high-
efficiency particulate air filters under positive pressure.
HEPA filters were developed by the Atomic Energy Commission during WWII to remove radioactive
dust from their plant exhaust. HEPA Filters (High Efficiency Particulate Air) are now the primary
filtration systems for electronic clean room assembly, isolation wards, surgical theaters,
bioengineering, pharmaceutical processing, and any application where maximum reduction or
removal of sub micron particulate is required.
HEPAs can be used in a variety of applications. In this example, the HEPA is mounted in the ceiling
to filter incoming air. Note that there are different types and grades of HEPA filters.
 Subpart C. Buildings and Facilities

HVAC – Clean Rooms

Cleanroom features:
• Floors, walls, ceilings of smooth, hard surfaces that are easily cleanable
• HEPA filters – ISO 7 & 5 with appropriate ceiling coverage
• Low air returns
• Coving to eliminate corners for dirt to accumulate
• Curtains separating ISO 5 area from ISO 7 area
• RABs unit to isolate open product filling environment – with glove ports
• Proper gowning with no exposed skin
 Subpart C. Buildings and Facilities
HVAC – Particulates

A particle < 10 microns is not

visible to the naked human
eye.
Human hair ……. 70 –
100 microns
Pollen …………… 5 – 100
microns
Mold …………… . 2 – 20
microns
Household dust … 0.05 –
100 microns
Skin flakes ………0.4 – 10 microns
(from [Link] [Link]
Bacteria ………… 0.35 –
10 microns

The filtration abilities of HEPAs are remarkable. In a HEPA filter, the passages through which air must flow are not straight,
but are very torturous, with many twists and turns. As particulates impact on the fibers and adhere to them, the passages
become smaller, and the filter increases in efficiency.
HEPAs can filter out almost all of the expected contaminants in cleanroom air. HEPA filtered air is 99.97% free of all
particulate down to 0.3 microns. To give you a perspective, 0.3 micron is 1/75,000 of an inch or 1/300 the diameter of the
human hair.

Therefore, HEPA filters can remove pollen, mold, many of the household dusts, skin flakes and bacteria from the filtered air .
HEPAs are fragile and easily damaged by physical contact and may suffer degradation if splashed with liquid. Leidos SOPs
for room cleaning where HEPAs are located repeatedly caution against exposing HEPAs to water during cleaning.
(from [Link] HEPA filters must be certified on at least an annual basis.
 Design of the Building - Air

This is a simplified graphic of a production suite within a building being supplied with filtered air. The air is
supplied by the Air Handling Unit (AHU) that conditions the air and passes the air through filters. The air
moves through ductwork to the production areas. Areas of classification greater than 10,000 don’t require
additional HEPA filtration before the air enters the room. For areas of class 10,000 or lower air must be
refiltered immediately before it enters the room. This HEPA filter is called the “Terminal” HEPA filter
because it is the last filter for the air before it enters the production suite.
 Design of the Building – Clean Air

The “clean” air enters the room and is usually exhausted through vents near the floor around the
perimeter of the room. This air is returned back to the air handling unit, where it is reconditioned and
sent back into the room. The air that has already been conditioned by the air handling unit is expensive
air and is usually of better quality even after passing through the production suite than fresh outside air.
So it is reconditioned and used again. The amount of “re-used” air can be higher than 50%. Some
processes that are extremely dirty – like the production of “powders” may not be able to reuse previously
conditioned air. In these cases, the room must be supplied with a constant supply of conditioned “fresh”
air, and the capacity of the air-handling units would obviously be larger (and more expensive both to
purchase and to operate).
 Design of the Building –Dirty Air

AHU

Terminal HEPA filter

Prod’n
Suite

Eddy currents

Of course, this is a simplistic diagram. We need to be concerned with turbulence.

Turbulence in the air patterns picks up particles from the “dirty” parts of the room and swirls
them up into the working area of the room where they can contaminate product.
 Design of the Building –Turbulent Airflow

AHU

Terminal HEPA filter

Prod’n
Suite

The dotted “box” is the working area of the room – maybe the table that product vialing is occurring
on. That area must only be exposed to “clean” air? This type of turbulent airflow can allow
contamination of the product.
But even with the use of HEPA filters, air turbulence that was unavoidable with normal air handling
systems made it impossible to control airborne contamination within a room. The inability to control the
problem of airborne particles impeded the development of high technology manufacturing and
assembly plants in the aerospace, electronics and pharmaceutical industries.
 Design of the Building -Air

The more streams of air that flow into a room create a

unidirectional flow (laminar flow) that reduces the
turbulence that is a source of product contamination.
If air velocity was maintained at a consistent level and the
air flows in a unidirectional manner, airborne
contamination generated by people and equipment is
swept from the critical work area. The non-turbulent,
unidirectional airflow also minimized cross-contamination
by inhibiting the movement of particles across the air
stream ([Link]
[Link]) When the initial particle counts were
performed on the first clean room it was found to be
“1,000 times cleaner than any room ever measured”

Laminar flow is unidirectional flow – flow in the same

direction. Laminar flow doesn’t just happen. It takes
effort to convert turbulent, multi-directional air flow to
laminar flow and it takes effort to KEEP laminar flow
laminar.
“Laminar air flow” technology was first used in 1961 to
overcome contamination problems in the assembly of
critical miniature components for the US NASA program.
It was found that the cleanest work environment was
achieved by locating the work in a gentle flow of HEPA-
filtered air issuing from a wall, ceiling or enclosure fitted
with HEPA filters. The most effective air velocity was
found to be 0.46 meters/second or 90 feet/minute.
 Smoke Studies/Wind Tunnel

Air flow is affected by the design of the room, how the airflow is introduced (its
direction, its velocity), and how air is exhausted from the room. Airflow is also
affected by what is IN the room. This includes people, equipment, supplies.
Rooms have to be designed keeping in mind that they will be filled with
equipment, people and supplies. How these materials are placed in the room
becomes important.
 Air flow around an object
creates turbulent flow

[Link]

Airflow patterns obviously are important in the proper functioning of a room. Unfortunately,
you can’t SEE airflow patterns. So you have to use something to visualize them. In the
past, smoke was used to visualize air flow. A recent, impressive technology is the use of
helium filled bubbles. The bubbles are neutral density. The “skin” of the bubble is offset by
the weight of the helium contained in the bubble. This is the technology used for the next
few pictures. Look at the disruption of the airflow pattern as it encounters this cylinder in its
path.*For educational purpose only, Inclusion of any images displayed in the presentation are not to be construed as an endorsement of any kind.
 Turbulence in the Work Zone can be a cause of contamination

If this were an
object or a
person within
our aseptic
processing area
where laminar
flow air is
provided from
the ceiling, you
can see how the
turbulence can
re-introduce
potential
contaminants
back to the
product.

*For educational purpose only, Inclusion of

any images displayed in the presentation
are not to be construed as an endorsement
of any kind. [Link]
 Subpart C. Buildings and Facilities

HVAC

Schering-Plough, 483 Citation, 6/01

“Your determination of your filter laminarity and air flow in your
filling rooms is inadequate in that the determination is not a
dynamic exercise. None of the employees normally present
during routine operations were present during the evaluations
to determine if the laminarity and airflow is affected by the
presence of the employees that are normally present during a
production.”
 Subpart C. Buildings and Facilities

This is a study of airflow patterns using the

same bubble technology in a cleanroom at
a cleanroom table.

Look at the shape of the bubbles between

the left side of the table and over the table.
The left side bubbles appear more as dots,
the right more as dashes. This is because
the bubbles are traveling faster on the right
and with a measured picture exposure they
travel faster and create the dashed image. [Link]

*For educational purpose only, Inclusion of any images displayed in the presentation are not to be construed as an endorsement of any kind.
 Subpart C. Buildings and Facilities
Air

Notice this small line at the top of the picture, That

is not a bubble, but a plastic curtain that separates
the table from the surrounding area to create a
clean zone. The airflow is different inside and
outside the curtain. (Remember in the table of
different room classifications, how air flow velocity
increased for more clean areas?) But what do you
think about the table. The table is positioned
against a wall. What do you think about the airflow
patterns.
The users of this cleanroom were upset with this
picture because it shows that the back 2/3 of the
table is not being supplied with laminar air. If the
purpose of laminar air is to wash the room to gently
bring contaminants toward the room exhausts, the
set up of this table is a problem. Contaminants that
find themselves on the back 2/3 of the table will
stay there a while and potentially be a cause of
[Link]
subsequent contamination.
*For educational purpose only, Inclusion of any images displayed in the presentation are not to be construed as an endorsement
of any kind.
 Subpart C. Buildings and Facilities

Same table, slightly different perspective.

What do you notice? Look at the circular
pattern under the table. Look at the dot in
the center of this pattern. That dot is a
bubble that is NOT MOVING. Is this OK?
Again, the users of this cleanroom were
upset.
By visualizing air patterns, they were able to
see that there was a stagnant area under
the table that air was not moving. Stagnant
areas provide potentials for contaminants in
the air to just “hang around”. This isn’t the
best design.

*For educational purpose only, Inclusion of any images displayed in the presentation are not to be construed as an
endorsement of any kind.
[Link]
 Subpart C. Buildings and Facilities

Special features

Just as a recap, what are some of the special

features that make this room special and
appropriate for aseptic processing.

• Easily cleanable surfaces

• Glove box (separates product from people)
• HEPAs in ceiling
• Returns on lower walls
• Gowned individuals
• Coving to minimize corners
 Contamination Control

So, if a potential source of contamination cannot be entirely eliminated from the cleanroom
environment, it must be isolated from the cleanroom environment. Therefore people, are isolated
from the clean room environment by gowns, boots, gloves and beard covers. The effectiveness of
this isolation must be appropriate and therefore technicians working in these environments are
specially trained and tested in their gowning technique to assure they don’t adversely affect the
aseptic environment. An important requirement to keep sterile things sterile is to prevent them from
being exposed to potential sources of contamination. Therefore, it is common industry practice to
prohibit cosmetics, powders and cardboard (all potential sources of contamination especially
particulate contamination) from the cleanroom where sterile products will be produced.

Additionally, the environmental conditions within the cleanroom, the temperature and humidity,
need to be balanced to protect the product (for example from clumping) and for personnel
comfort. Sweating due to high temperatures can increase shedding, Low humidity can
increase shedding as skin becomes dry and flakes off.
 Subpart C. Buildings and Facilities
HVAC – Which direction should air flow?

Prod. Prod. Prod.

Suite Suite Suite Locker
3 2 1 room
Class Class Class
10,000 10,000 10,000

Class
100,000

Remember this facility design? The production suites are classified as a class
10,000. The hallways are at a class 100,000. Which direction should air flow?
 Subpart C. Buildings and Facilities
HVAC – Directional Airflow

Prod. Prod.
Prod.
Suite Suite Locker
Suite
2 1 room
3
Class Class
Class
10,000 10,000
10,000
(ISO-7)
Class
100,000
(ISO-8)

Air would flow from the production suites at class 10,000 to the hallway
areas at class 100,000.
 Subpart C. Buildings and Facilities
HVAC – Air pressure

How do you detect that this pressure differential exists? You use
pressure monitors.
So, in this case, where air flow is a critical aspect of proper building
design, monitoring of the air pressure between rooms is crucial.
Warning Letter

WARNING LETTER

Failure to … provide a ventilation

system that will prevent the dissemination
of microorganisms from one manufacturing
area to another. For example:
a) Air pressure differentials are not
monitored between different rooms in the
____ production area.
b) Filter integrity testing has not been
performed on ______filters in the ______
rooms.

International Biologicals, Inc,

Piedmont, OK
Contamination or mix-ups [21 CFR 211.42(c)]

WARNING LETTER

Failure to establish separate or defined areas

or other control systems for manufacturing
and processing operations to prevent
contamination or mix-ups [21 CFR 211.42(c)]
in that data is not available to demonstrate
that adequate pressure differential is
maintained during filling operations …

(Medeva Pharma Ltd,

Liverpool, UK
 Subpart C. Buildings and Facilities
HVAC – Air Temperature

LOW TEMPS HIGH TEMPS

Sweating
Personal comfort (skin flaking)
Reduced microbial Increased microbial
growth growth

BALANCING TEMPERATURE
Typical is between 65 – 70°F
Temperature is another consideration for classified areas – especially aseptic processing
areas. High temperatures promote technician sweating, increasing particulate generation.
High temperatures also promote increased growth of microbes.

Low temperatures are usually more comfortable for technicians. Remember, in an aseptic
area, they’d be wearing gowns (that tend to be hot). Lower temps also reduce microbial
growth. Generally, temperatures are held in a range ~ 65 – 70 ℉.

From - Keeping Biopharmaceutical Cleanrooms Compliant, BioPharm International [Link], March 2004
 Subpart C. Buildings and Facilities
HVAC – Humidity

BALANCING HUMIDITY
LOW HIGH
Humidity Humidity
• Skin flaking • Growth of
(particle
generation) microbes
• Respiratory • Promotion
problems of
• Static rusting
electricity

Typical is between 45 – 60% RH

 Subpart C. Buildings and Facilities

Lighting

We’ve looked at design and also at HVAC. We’re going to jump back to lighting.
What does FDA expect? At least 540 lux (50 foot candles) at a surface where an
employee is working.
GMPs require that lighting be adequate. Lighting must be sufficient to properly perform
the various jobs required for the production and distribution of drug products.
The lighting required to inspect product for particulate matter of course will be different
that the lighting appropriate in the Warehouse.
 Subpart C. Buildings and Facilities

Plumbing
The Buildings and Facilities subpart of the GMPs makes
specific requirements for plumbing. What is required?
Plumbing requirements include:

WATER
• Potable (meet EPA Primary Drinking Water
Standards)
• Under positive pressure
SYSTEM
• Free of defects that could contribute to
contamination
DRAINS
• Adequate size
• Air break or alternative if connected to a sewer to
Many companies
prevent obtain their facility water from a municipal system that maintains their water at the EPA
back-siphonage.
drinking water standard. Companies should be able to document that water is of this quality either by
obtaining testing reports from the municipal water authority and/or independent testing.
Well water can be used if it is brought up to EPA standards by the use of a pretreatment plant. Again, you
need to prove that your water meets standards – you’ll need test results.
 WFI Water Systems

1933 World’s Fair - Chicago

A Century of Progress
1833 - 1933

Concepts of the Future

• Architecture of Tomorrow
• Homes of Tomorrow
• Cars of Tomorrow
• Amoebic Dysentery of Today

Consequences of backflow are more than just theoretical. One of the most
dramatic examples of the dangers of backflow occurred at the 1933 Chicago’s
World Fair. Backflow affected the water supply for this World’s Fair. During the
Fair, 1000 cases of infection by entamoeba histolytica (an intestinal parasite that
causes diarrhea) were documented along with 58 deaths due to defective
plumbing that permitted sewage to backflow into the water system and therefore
the drinking water.
 What Can Be IN Water?

“All water supplies contain contaminants. The kind of contaminant is hugely variable
and no two water sources are identical with regard to the kind and concentration.
What constitutes a contaminant is entirely dependent on the application; for drinking
water, it is defined by the Safe Drinking Water Act, a regulatory document. For
semiconductor rinsing, anything other than H2O is a contaminant and the
concentrations must be as close to zero as possible. As it is virtually impossible to
make water free of any and all contaminants, the goal of the treatment process is to
reduce the level as much as possible. It is possible to classify contaminants by
category to more easily address their removal (see table on next slide). There is no
shortage of water treatment technologies available. Some remove only a single
class of contaminants, while others are more versatile. Each technology has
strengths and weaknesses. No single technology will produce truly “ultrapure
water”. As a result, the challenge is to design a system utilizing a combination of
technologies to provide optimum contaminant removal to meet the particular “use-
specific” water quality requirements. “
What Can Be IN Water?
 Subpart C. Buildings and Facilities

Water Systems
Water is important to the manufacture of a drug product in a number of ways.
Water Systems Provide Water For:
• Facility cleaning
• Equipment and material washing / rinsing
• Product formulation
• Starting material for clean steam
Water is the largest quantity raw material Water
systems are heavily scrutinized by the FDA
Water is another utility that is used in product manufacture and the quality of the water can significantly affect the quality
of the final product. If you clean the facility or equipment or materials with “dirty” water it can affect the quality of the
product exposed to that area or equipment or materials. Inadequate quality water in a product formulation can affect the
quality of the formulation.

Water for final rinse (for example of vials) must be of the same quality as the water required for
pharmaceutical preparation.
At the very least, water used in pharmaceutical operations must meet the EPA Standards for Primary Drinking
water. But often water used in a drug manufacturing process must be of a higher quality than just drinking
water. Some products require distilled or sterile water or water suitable for injection. Manufacturing plants for
the most part already have access to water of EPA Drinking water quality because this is what is provided in
municipal water systems. But if your product or process requires water of more rigorous specifications, a
Manufacturer must design and maintain an adequate water treatment system to get this water to a higher
standard.
 Subpart C. Buildings and Facilities
Water

Water – where we get it, how we use it, what

quality is appropriate, how we treat it, how we
maintain our water treatment systems, how we
know our water treatment systems are working -
are all issues that FDA will be interested in
during an inspection because they can affect
the quality of the drug being manufactured.

Refer to USP Chapter 1231 Water For

Pharmaceutical Purposes
 ATTRIBUTES OF WATERS (Purity)

If you have trouble at the supermarket deciding to buy the “natural spring water”
the “deionized water” or the “drinking” water, don’t think it gets any easier in a
pharmaceutical plant.

Broadly, these are the types of water that are available. Well water (or river
water if you get your water from a river) is treated to make it suitable for
drinking. Drinking water must meet the specifications in the EPA’s Safe
Drinking Water Act. Water that is safe to DRINK, may not be safe when used to
formulate injectable drugs. For example, drinking water, or potable water, can
contain 500 CFU / ml. Using this water for washing a clean room environment
would contaminate the environment. They environment you are cleaning is
supposed to have <1 microbe / cubic foot of air, so you can’t clean it with water
that contains 500 microbes / ml. WFI water has reduced amounts of endotoxin
(endotoxins are bacterial byproducts that can induce fever). So pharmaceutical
companies have to obtain water of higher purity for their processes. Sometimes
they buy high quality water, most often they make it themselves using uniquely
designed, high technology, high cost water purification systems.
ATTRIBUTES OF WATERS

<5 Coliform CFUs/mL, No Endotoxin Limit

Various amounts of minerals, ions, sediment,
microbes, endotoxin, particulates, etc.
<500 CFU/mL, No Endotoxin Limit
Limited amounts of disinfection byproducts,
disinfectants, inorganic and organic chemicals,
radionuclides …)

<100 CFUs/mL, EU/mL Endotoxin

Low / no minerals, chemicals, ions, endotoxin,
particles, etc.

< 0.1 CFUs/mL, 0.25 EU/mL Endotoxin

Low / no minerals, ions, microbes, endotoxin,
particles, etc.
 What is in water?

Our United States EPA assures the quality of water that is provided by public water systems. But
what is IN this water?
The EPA sets limits for the contaminants that are allowed in our drinking water, they also
constantly evaluate whether limits should be imposed on additional contaminants.

Some contaminants can be location specific:

For example, antimony is an inorganic chemical that is discharged from petroleum refineries. If
you are pulling well water near petroleum refineries, you may need to find a way to control for the
amount of antimony in your water if you do not meet the EPA limit. If you are not in a petroleum
refining area, antimony probably isn’t an issue for your drinking water.

Alachlor is an organic chemical that comes from runoff from herbicide that is used on row crops.
Or Oxamyl is from runoff / leaching from insecticide used on apples, potatoes, and tomatoes.

So drinking water, even drinking water that is compliant to EPA standards, is permitted to have
some minimal amount of these contaminants. However, this probably isn’t the water that you
want to formulate drugs with.
Contaminants Allowed In Drinking Water
(According to the EPA)

• Microorganisms (various )
• Turbidity
• Disinfection Byproducts
• Bromate, Chlorite, Haloacetic acids…
• Disinfectants
• Chloramines, Chlorine, Chlorine Dioxide….
• Inorganic Chemicals
• Antimony, Arsenic, Asbestos, Barium, Beryllium, Lead,
Mercury….
• Organic Chemicals
• Acrylamide, Alachlor, Benzene, Carbon tetrachloride,
Dioxin, Lindane…
• Radionuclides
• Alpha particles, Beta particles and photon emitters,
Radium, Uranium
 Water Treatment Processes

Starting from drinking water, the manufacture of purified water uses a combination
of treatment processes. Systems are very unique. Decisions about designing a
system start with the quality of water that you are starting with. We obtain water
from the city of Frederick. Our drinking water here is very hard – it has a lot of
minerals in it. A different location in the country might not have that problem – but
maybe another one.

So we need to design our systems to handle these impurities. Pharmaceutical

water purification is a very specialized, high technology field. No two water systems
are exactly alike. During the manufacture of a pharmaceutical plant, water
consultants are used to help design compliant water systems based on how you’ll
use the water and the quality of the drinking water you’re starting from.

One of the big differences between purified water and WFI is the level of endotoxin.
Pyrogens don’t survive distillation process, so it is typical to incorporate a
distillation step to get to WFI. Pyrogens will penetrate an RO membrane
Water Treatment Processes-Drinking
Water
• Dechlorination
- Filtration through activated charcoal
- Injection of a reducing agent
- High dosage UV light
• Ion Removal
- Membrane processes (reverse osmosis)
- Ion exchange processes (water softeners)
- Distillation
• Bacterial Control
- UV lights
- Ozone generation Systems
- Heating systems (≥80°C)
- Chemical injection / recirculation systems
• Removal of specific impurities
- Iron, Manganese, Hydrogen Sulfide
- Hardness ions, Particulate matter, High
Conductivity
- High TOC
 Water Treatment Processes-construction

Once the system is designed, constructing it is another milestone.

How the system is constructed is important. Many of these features are

important because they prevent stagnant water within the system.
Microbes breed more easily in stagnant water.

Some of these features are also in place to prevent or minimize

contamination of the water by microbes or by other materials.
Building the Water Distribution System-
Milestone

• Pipes sloped so water does not pool and can

drain easily. Eliminate dead legs.
• Sanitary fittings and connections (no threaded
connections)
• Constructed of suitable materials such as 316L
stainless steel (to reduce corrosion)
• Piping joined by certified welding (weld
coupons)
• Circulate the water (to prevent stagnation)
• Keep it hot (to maintain low bioburden)
• Keep it turbulent to prevent stagnation
• Incorporate non-return valves (back flow
preventers)
Building the Water Distribution System

A water system
is supposed to
be turbulent.
This scours the
pipes and
prevents the
accumulation of
stagnant water.
Flow velocities
that exceed
minimum levels
have to be
maintained at
all times.
 Avoiding Dead Legs

Look at this piping. If this pipe is “X” in

diameter, a deadleg is present if the
section between the loop and the sanitary
fitting is more than 2 x the diameter of the
pipe. Bacteria in dead leg pipe lengths
and crevices are protected from flushing
and sanitization procedures and can re-
contaminate the piping system. Deadleg
rule is different for different industries.
See [Link] .

Just an interesting piece of trivia. The

definition of a deadleg USED to be that
the leg could be 4 times the diameter of
the pipe. This was changed to 2 times
because of the dairy industry. The dairy
industry had a definition of a deadleg as
2 times the pipe diameter. It was thought
that pharmaceuticals should be at least
as rigorous.
 Water Systems – Ball Valves(Dead-legs)

Ball-valves are “dead-legs.” They are not

permitted in pharmaceutical systems.
 Water Systems – Ball Valves

483 Citation:
“The ultra-Filtered Water System which produces water
used in the critical steps of API production was
observed to have ball-type valves at numerous
locations including in the finishing area for the final
bulk drug. These valves are potential “dead-legs” in
the water system. The bulk drug is intended for further
processing to manufacture sterile products for
injection.”
 Water Systems – Threaded Fittings

A water system requires a lot of plumbing to move water. The physical attributes
of the system have to be selected to protect the quality of the water that it will
contain. Threaded fittings are a problem in pharmaceutical water systems.
Materials can get caught in the threads of the fitting and be a potential source of
contamination and carry-over of products. Sanitary fittings are much better as
they have no treads.

THREADED FITTINGS – Materials

get caught in the nooks and crannies of
the threads. Potential source of
contamination and carry-over.

SANITARY FITTINGS – No Threads

 GMP Water Systems
Water For Injection
Well TREATMENT PROCESSES
Water
• Expensive to design
Drinking
Water • Expensive to build
Purified • Expensive to run
Water
• Expensive to maintain
Water for
Injection • Expensive to validate
(WFI)
These systems are EXPENSIVE. They are expensive to build. And before you’ve even built a
system, you’ve typically hired a consulting firm to help you design it. For the construction of our
water system, $500,000 was budgeted.
Once the system is built, it’s expensive to run. It takes materials like filters, chemicals, salt, pH
adjustment chemicals, cleaners, sanitants, electricity to keep the system running. It also takes a lot of
person intervention. Because incoming water is variable – it changes over the course of the
seasons, after rains, etc, people need to evaluate the raw material and make adjustments to the
system.
Typically for every 100 gallons of drinking water that start on the path to WFI, only 25 gallons will be
produced. A system that operates this way is considered an efficient system.
 WFI Water Systems
Backflow Prevention

EQUIP EQUIP
#1 #2

EQUIP EQUIP
#4 #3

A water system often supplies water to various pieces of equipment. Once

water leaves the water system to feed the water needs of equipment, it
must not be returned to the system. It’s like pouring milk that you didn’t
drink from your glass back into the milk container.
 WFI Water Systems

Backflow Prevention

Backflow can introduce contamination into the system and then to all the other
equipment that the system feeds. GMPs require that there be some physical
component of the system that prevents this backflow. Building codes also require
backflow preventers and/or air breaks on municipal water systems.
 WFI Water Systems

Drains Must Not Be Obstructed

Plumbing systems must also be maintained. Obstruction of drains must be

prevented.
No drains are permitted in ISO 7 or 5 areas. Drains in ISO 8 areas must be kept
covered when not in use.
 Subpart C. Buildings and Facilities
Waste

The Buildings and Facilities subpart of the GMPs makes specific requirements for
the handling of sewage and refuse. What is required?

GMPs require that sewage and refuse be disposed in a safe and sanitary manner.

Companies need to check that sanitary and storm sewers are not overloaded or
obstructed.

Trash should not pile up in or around the plant where it could attract rodents and
insects and potentially contaminate the building’s specially designed environments.
 Subpart C. Buildings and Facilities
Washing And Toilet Facilities

The GMPs also specify requirements for adequate washing

and toilet facilities.

GMPs require that there be …

Adequate washing and toilet
facilities
• Hot and cold water,
soap or detergent
• Air driers &/or single-
service towels
• Clean toilet facilities
accessible to work
areas
 Subpart C. Buildings and Facilities

Sanitation Requirements

Another issue in the Buildings and Facilities subpart of the GMPs – Sanitation.
What are the requirements?

This subpart of the GMPs requires that….

• Building maintained in a clean and sanitary condition
• Written procedures for sanitation to be followed
• Written procedures to be followed for use of
rodenticides, insecticides, fungicides, cleaning and
sanitizing agents
• Contractors or temporary employees must meet same
requirements
These requirements are pretty straight forward. Obviously, rodents, insects,
microbes, dust, dirt, and waste can be a source of contamination and must
be controlled and therefore procedures must be written detailing how this
control will be provided.
 Subpart C. Buildings and Facilities
Sanitation

Areas are in a constant state of flux. They get dirty due to

normal activities.
WHY DO AREAS GET DIRTY?
• People carry in dirt and debris
• Supplies and materials brought into the area bring in dirt and debris
• People shed particles
• Materials shed particles (cloth, paper, cardboard, wood, etc.)
• Infiltration of air from “dirtier” areas
• Wear of parts in the AHU, oxidation of galvanized sheet metal
• Rusting generates particles
• Equipment sheds particles as it is used
• Microbes multiply
 Subpart C. Buildings and Facilities
Infestation

As a basic requirement for all buildings, buildings

must be maintained in a clean and sanitary condition.
This means that the buildings are….

Clean and sanitary conditions

• Buildings and facilities must be free of infestation by
rodents, birds, insects, vermin
• Trash and waste must be held and disposed of in a timely
and sanitary manner
Subpart C. Buildings and Facilities
Sanitation 483 Citation

483 Citation:
In the warehouse for storage of replacement
parts such as valves for the process water
system and reverse osmosis membranes,
there were numerous pigeons observed
flying above the equipment parts and
evidence of bird droppings. This included in
the locked cage which contained the stored
reverse osmosis membranes.
 Subpart C. Buildings and Facilities
Sanitation (Plating bed)

Building design also plays a role in the

control of infestation by rodents. Take for
example Building 459. This building was
originally designed with a planting bed
around the perimeter of the building. This
landscaped bed was originally included in
the building design to beautify the outside
building appearance. However, this
planting bed created an attractive
ecosystem for rodents, insects and vermin.

You need to eliminate these pests from the

inside of the buildings, but also not attract
them to the outside of the building. An
open door, a hole in the wall…what was
once outside is now inside.
 Subpart C. Buildings and Facilities
Ecosystem

The response to this issue was to eliminate the ecosystem

that provided for these pests and replace it with something
inhospitable with something like pea gravel that provides a lot
of nooks and crannies that an insect could get “lost” in. It’s
like surrounding the building with an insect maze. Insects
enter the gravel maze at the edge of the gravel bed but the
chances are small that they’ll be able to make their way
through the maze to the other side. Can insects still get into
the building from open doors and holes in the foundation –
yes, but this reduces the number of insects that can even get
close enough to a door or a hole in the wall to sneak inside.
Want to make buildings even more insect and rodent proof? –
fix the holes in the foundations and maintain weatherstripping
around doors to eliminate this route of entrance.
Constant attention to buildings is required to assure that outside animals stay outside.
Eliminating potential nesting places for mice and other rodents is a continual challenge and
maintaining the integrity of outside building barriers is also critical. Be sensitive to conditions
that could allow insects and rodents to infiltrate our buildings. Make sure doors have proper
weather-stripping and don’t prop them open.
 Subpart C. Buildings and Facilities
Rodent Activity

Our pest control contractor

monitors rodent activity outside,
near buildings. These traps don’t
actually trap the animals, but
provide a poison that the animals
eat and take back to their nests.

Monthly, the contractor inspects

these traps and evaluates if the
poison is being consumed at a
higher activity level than in past
months. This gives them some
information to evaluate whether
rodent activity is changing.
 Subpart C. Buildings and Facilities
TRAPS!
And if the rodents and insects get
inside in spite of your best efforts? - -
TRAPS!.

Traps are typically placed inside the

doors to the outside. Using traps will
hopefully intercept vermin before they
can work their way further into the
building. And inspecting them at
periodic intervals will tell you how
penetrable your buildings are.

It is important they we all pay attention to the unwanted animal visitors in our
buildings. Evidence of mice, coach roaches or other animals within buildings
need to be brought to the attention of FME so that corrective action can be
taken.
 Subpart C. Buildings and Facilities
Unusual activity

Inside these traps, there

is an inspection label that
provides a history of the
activity of this trap.
Monthly, our contracted
pest control service
inspects these traps and
evaluates the insect (and
rodent) activity that they
observe. Unusual activity
is brought to our attention
so that we can investigate
why there is a change in
the observed activity.
 Subpart C. Buildings and Facilities
Sanitation – HOW CAN I HELP?

Our pest contractor inspects traps

monthly and also inspects our
buildings monthly to detect evidence of
insect and rodent activity. If the
buildings are not cleaned from month
to month, the inspector will not know
whether the evidence of insect or
rodent activity that is evident now is
the same evidence the inspector saw
last month or the month before that.

Also, a tip passed on from pest control

technicians - - look for spider webs. KEEP BUILDINGS
Spiders place webs in locations with CLEAN !
high insect activity. Therefore, the
presence of a spider web signals the
presence of insects.
 Subpart C. Buildings and Facilities
Sanitation – Written Procedures

GMPs require that the procedures for sanitation that you have designed
be written.
Written procedures for sanitation
must include:
• Responsibility (who)
• Schedules (when)
• Methods (how)
• Equipment (what equipment is
used?)
• Materials (what cleaning /
sanitizing agents are used?)
• Cleaning Logs
 Subpart C. Buildings and Facilities
Sanitation (Spilling )

A frequent observation by inspectors when

observing sanitizing operations is that the detergent
or sanitizing solutions are prepared without accurate
measurement (..”by spilling some of the
concentrated sanitizing agent into an unmeasured
bucket”). This practice makes it impossible to relate
the sanitizing operation being performed with any
studies that were done (using measured materials)
to prove that the sanitization process is effective in
controlling microbes.
Remember, you’ll earn a GMP violation if you can’t
prove that your processes are “effective”,
“adequate” or “suitable”.
Cleaning of Manufacturing

WARNING LETTER

Your firm consistently failed to comply

with your SOP “Cleaning of Manufacturing
Booths and Equipment” and SOP
“Cleaning of AVAX Manufacturing
Facility”

AVAX Technologies, Inc.

Kansas City, Missouri
 Subpart C. Buildings and Facilities
Sanitizing Agents

There are numerous agents that can be used for sanitization. Common practice within the
industry, to comply with the GMP sanitization requirements, is to rotate sanitizing agents (and to
rotate TYPES of sanitizing agents) at some established interval. A sporicidal agent should be
used at least once per month to help reduced spore forming microbes.

This is current practice here. Sanitizing agents must be switched at least monthly. Compliance
to this policy is easily traced through the documentation generated for sanitization.

Sanitizing agent use schedule:

 Subpart C. Buildings and Facilities
Pesticides

Facilities may need to use rodenticide, insecticides and fungicides to

control infestation with rodents, insects and fungicides. FDA requires that
these agents be used according to a written procedure and that the
procedure be designed to prevent contamination of equipment with these
agents. As a general rule, spraying to control pests is NOT performed
inside buildings where it can potentially contaminate product or
worksurfaces.

Additionally, insecticides used must be licensed and acceptable according

to the Federal Insecticide, Fungicide and Rodenticide Act.
 Subpart C. Buildings and Facilities
Who, How and When
And your burden to develop and follow written procedures for sanitation is
not relieved with the use of contractors or temporary employees. It’s your
building, your environment, your products, your responsibility – make
everyone perform these operations your way.
Written procedures for sanitation
must include:
• Responsibility (who)
• Schedules (when)
• Methods (how)
• Equipment (what equipment is
used?)
• Materials (what cleaning /
sanitizing agents are used?)
• Cleaning logs. If it wasn’t
documented, it wasn’t done!
 Subpart C. Buildings and Facilities
Sanitation ( Surface counts)

This shows the effect of

cleaning over time. Dots
indicate when cleaning was S Surface counts over time
performed. Notice that the line u
r
isn’t static. It rises and falls. f
Remember, the cleanliness of a
the area continues to degrade c
e
due to people, particle
accumulation, microbe C
o
growth, equipment rusting, u
etc. n
It may take several cleanings t
s
to knock down surface counts
to acceptable levels. Time
Once acceptable levels are reached, continued growth of microbes in the area is
evident. Sometimes, cleaning doesn’t appear to have an effect, this could indicate that
the organisms are resistant to the disinfectant being used and it should be rotated to
another type of disinfectant.

(from [Link]
 Subpart C. Buildings and Facilities
Sanitation (Effective Cleaning)

This shows the effect of cleaning over S

time. As the area is cleaned, counts u Surface counts over time
decrease. r
f
How do you know that your a Cleaning is effective,
sanitization procedures are working. - c
(counts dropping)
- You collect data. Look at the top line e
on this graph. It shows the surface C
counts over a period of time. Notice o
that the line isn’t static. It rises and u
n
falls. Remember, the cleanliness of t
the area continues to degrade due to s
people, particle accumulation, microbe
growth, equipment rusting, etc. Time

It may take several cleanings to knock down surface counts to acceptable levels.
Once acceptable levels are reached, continued growth of microbes in the area is
evident. Sometimes, cleaning doesn’t appear to have an effect, this could indicate
that the organisms are resistant to the disinfectant being used and it should be rotated
to another type of disinfectant.
(from [Link]
 Subpart C. Buildings and Facilities
Sanitation (Resistant to cleaning agents)

What’s
happening S
u Surface counts over time
here? Cleaning r
is being f
performed, but a
the counts aren’t c
e
decreasing?
This could be a C
sign that the o
u
microbes are
n
resistant to the t
cleaning agent s
used. Time
 Subpart C. Buildings and Facilities
Sanitizing agent

Changing the
sanitizing agent shows S Surface counts over time
continued dropping of u
organisms. Eventually r
f
you get them down to Change to a different type
a
a low level, they rise c of sanitizing agent
as the environment e
gets dirtier and regular
cleaning and C
sanitizing keeps o
knocks them down u
n
again.
t
s
Time

Eventually you achieve a steady state where cleaning frequency is sufficient to keep the
environment within established specifications until you see evidence that the sanitizing agent
is less and less effective, (resistance). Rotating disinfectants corrects the issue.

(adapted from [Link]

 Subpart C. Buildings and Facilities
Sanitation Effectiveness Studies

483 CITATION
…disinfecting agents used to sanitize surfaces in the
aseptic processing areas have not been adequately
qualified to assure microbial decontamination. For
example, the qualification study only evaluated stainless
steel and not other surfaces such as glass, plastic and
epoxy-painted surfaces. It also was inadequate because
it used a longer expose time to the sanitizing agent than
the time specified in the firms cleaning SOPs. The
qualification study immersed the test surface in
disinfectant instead of wiping the surface as specified in
the firm’s SOPs. (Meridian Medical Technologies, MO)
 Subpart C. Buildings and Facilities
Maintenance

And building maintenance – what is required?

What is required?….for buildings to be maintained in a

good state of repair. Remember, this includes the
EQUIPMENT that is part of the buildings – the plumbing
and heating systems, HEPA filtration systems, water
systems. These are part of the building and must also be
appropriately maintained.
 Subpart C. Buildings and Facilities
Maintenance (483 Citation)

483 Citation:
• The inside of the multi-mill granulator is
corroded.
• The interior of the vacuum dryer for crude bulk
drug is rusted.
• The transfer room of bulk drug to drums has
peeling / flaking paint on the walls and ceiling.
• (Company already had to confirm a complaint for
the presence of metallic particles in a bulk drug
shipped to a customer)
From FDA API Inspections, Robert C. Horan, PhD, FDA Pharmaceutical Inspectorate, new York District.
 Subpart C. Buildings and Facilities
Maintenance (Dirt)

Be careful of corners, edges, etc. that can hold dirt.

 Subpart C. Buildings and Facilities
Maintenance (Painting)

Note the flaking paint. Maintenance is required to keep

up with painting.
 Subpart C. Buildings and Facilities
Maintenance (Flaking)

Again - note the flaking paint.

 Subpart C. Buildings and Facilities
Maintenance

Air vents need to be inspected and cleaned.

 How Many Of You Eat Peanut Butter?

In 2007, Peter Pan brand of peanut butter

was recalled.
It was contamination with Salmonella.
It is estimated that at least 625 people
nationwide were sickened by this food.
 Peanut Butter Contamination

Do you know the cause of the contamination?

Peanut butter is a non-traditional source of salmonella. You typically think of
salmonella contamination in animal sourced products – chicken, eggs, etc. Stephanie
Childs, a ConAgra spokeswoman, said the company traced the Salmonella bacteria
to three problems at its Sylvester, GA, plant in August.
The roof leaked during a rainstorm, and the sprinkler system went off twice because
of a faulty sprinkler, which was repaired.
Moisture from these three events mixed with dormant Salmonella bacteria in the plant
that Childs said likely came from raw peanuts and peanut dust”
What does this have to do with buildings and facilities requirements for drug
manufacture?
Peanut butter is a food and must be manufactured or processed under GMPs for
foods. One of the GMP requirements for food processing is are adequate buildings
and facilities. Leaking roofs and faulty sprinklers are accidents. Things like this can
happen in a drug manufacturing facility. How can the company be responsible for
things like this?
Problem is not that the accidents occurred, but that the company didn’t properly
evaluate the impact of the event. Had they understood that the moisture could
enhance the growth of bacteria ALREADY in the plant from raw peanuts and peanut
dust, they could have taken preventive action to prevent this growth. For example,
they could have sanitized the areas exposed to moisture.
 And Problems Will Only Get Worse

April 2007 Update- Dead Rat, Rat Traps and Roaches Found at ConAgra
Peanut Butter Facility A team of attorneys representing consumers sickened by
Salmonella-contaminated peanut butter produced by ConAgra Foods, inspected the
Sylvester, GA facility in early April and found a dead rat, over a 100 rat traps, bird
feathers, roaches crawling on raw peanuts, peanut dust covering machinery and
other things “consistent with salmonella contamination,” according to a court
document filed on April 25, 2007.

This discovery contradicts statements made by ConAgra Foods, which contends in

an April 5, 2007 press release that the February Salmonella outbreak was traced to
problems with the physical components of its Georgia processing plant. Reportedly,
moisture from a leaky roof and faulty sprinkler mixed with dormant salmonella
bacteria from raw peanuts and peanut dust, which then contaminated jars of peanut
butter.

The company wanted to advertise the product’s return without discussing why it was
removed from the market.
 Application Of What We
Have Learned – Company A
Company A has developed SOPs detailing the responsibility,
schedules, methods, equipment and materials for the cleaning
and sanitization of the ISO-5 (Class 100) cleanroom
FDA Question: How do you know that the cleaning and
sanitizing agents used work? And how do you know your
cleaning interval is appropriate?
(What is a response that would prevent a citation?)

You need DATA (generated by validation studies) to prove that the cleaning and
sanitizing agents work and that your cleaning interval allows the area to meet
requirements. Studies need to be performed with the organisms typically found in
your environment. Environmental monitoring will help you determine that your
cleaning interval is suitable
 Application Of What We
Have Learned – Company B
Company B uses rodenticide “Mouse-be-Gone”. Since its
use, Company B has been able to document a decrease
in the rodent population at the company.
FDA Question: Is this rodenticide registered under the
Federal Insecticide, Fungicide and Rodenticide Act?
Company B: Probably not, it’s pretty new, but you can
see that it definitely works.
(Is this a problem?)

Yes, the GMPs require that rodenticides be registered

under the Federal Insecticide, Fungicide and
Rodenticide Act.
 Application Of What We
Have Learned – Company C
Because of staff shortages, Company C hired a “GMP” cleaning
company to clean their GMP facility. They told the cleaning company to
“do whatever they usually do” for GMP cleaning. The cleaning
company claims to be GMP – they even gave references listing two of
the prominent pharmaceutical companies in the area as clients.
(Is this OK?
No, work done by outside contractors and temporary employees
must be in compliance with company procedures. Unless Company
C discussed their procedures with the cleaning company, there is no
assurance that the cleaning will be performed according to company
procedures.
It is possible for the cleaning company to use its own SOPs for
cleaning, IF those SOPs have been approved by Company C.
 Application Of What We
Have Learned – Company D
Company D has An ISO-7 clean room (Class 10,000) with an ISO-7
gowning room adjacent to it (also Class 10,000). Air flows from the
gowning room INTO the cleanroom.
FDA: Why have you designed your airflow this way?
COMPANY D: That’s just the way it is and it’s been working fine.
This is no GMP violation. The GMPs don’t even discuss airflow
patterns.
(Is this a good response???)

No, While the GMPs don’t mention air flow patterns, they do require that rooms be
designed “appropriately” and currently industry practice is to use air flow patterns as
one of the mechanisms to create this “appropriate” environment.
A company should always be able to explain how their facilities are designed – and
why. This demonstrates to FDA that the Company was thoughtful in their designs.
 Application Of What We
Have Learned – Company E

Company G obtains their potable water from an

on-site well.
(Will this will cause an FDA citation?)

Not necessarily. If the company regularly tests the well

water to confirm that it meets EPA’s Drinking Water Standard
or if it has an on-site pretreatment plant to bring the well
water up to standard (and periodic testing confirms the
quality of the water).
Buildings and Facilities

Please contact BQA Management if you have any questions.