Now that the Food and Drug Administration
(FDA) has decided to conduct inspections according
to quality systems, it seems only prudent for pharmaceutical
operations to re-evaluate their cleaning
system and its policies and procedures. Cleaning
seems simple enough; however, upon closer examination,
the system of cleaning is complex and interrelated
with several other functions in various areas.
This paper is intended to explore those relationships,
to enable readers to evaluate their cleaning
systems for compliance with FDA Code of Federal
Regulations (CFR) 21, Parts 210 and 211, and to
offer a comprehensive approach to establishing an
THE GMP QUALITY MODEL:
SIX KEY SYSTEMS
The FDA Good Manufacturing Practice (GMP)
quality system model is comprised of six key systems:
quality, facilities and equipment, materials,
production, laboratory controls, and packaging and
labeling.1 Of the six systems, only laboratory controls
and production are not governed by explicit
FDA rules for cleaning (see sidebar page 47).
However, FDA guidance on inspection of cleaning2
describes FDA expectations on validating cleaning
processes for equipment, establishing acceptance
limits, and using validated analytical methods. Further,
inadequate or improper cleaning of laboratory
glassware is often one of the major reasons for Out-
Of-Specification (OOS) analytical results. Pharmaceutical
organizations should, therefore, apply the
principles that arise from explicit FDA guidance to
all of the systems to ensure a comprehensive cleaning
system. The first step to achieving a comprehensive
cleaning system and achieving compliance lies
in considering critical cleaning issues for each of the
Cleaning Issues in the Quality System
Some common cleaning issues in the quality
You must maintain standard operating procedures
for cleaning and keep thorough and accurate
equipment cleaning records.
You must validate your cleaning process and the
analytical methods that support it.
➤ Change Control
Any changes must be accomplished through a
change control process to evaluate their impact on
cleaning practices. At the least, the quality function
must review and approve changes and may require
People are the most important element in pharmaceutical
cleanliness.You must ensure that they
are well trained, follow proper procedures, and document
their activities. They should carefully observe
the condition of equipment, facilities, and components,
and properly operate and handle equipment,
utensils, and components. They should be aware of
their movement in and out of “clean” areas. They
should also be healthy and immediately report any
open wounds or lesions to superiors.
Cleaning Issues in Facilities and Equipment
Some of the common cleaning issues in facilities
are really matters of common sense. Trash must be
kept in suitable containers and disposed of as soon
as possible. There should be no flaking paint, rust,
or water leaks. Air cleanliness must be maintained,
including evaluating viable and non-viable counts of
particles and microorganisms. In addition, you
should have a schedule and procedures that effectively
and efficiently maintain cleanliness in the facilities’
Typically, the most effort in cleaning is expended
on equipment – and for good reason. Equipment
varies enormously in scale, design, and operation.
Even equipment designed to perform the same
operation can differ significantly from manufacturer
to manufacturer. Some common questions to consider
in the cleaning of equipment include:
What material makes up the equipment and how
easily can it be cleaned?
How well designed is the equipment to facilitate
its cleaning? Are there difficult to access nooks and
crannies? Can it easily be cleaned manually, if necessary?
Are the welds good? Is the equipment passivated
– that is, are its surfaces treated to ensure adequate
cleanability and to prevent decay? Piping should
have a minimum of threading to reduce inevitable
build-up of material around threads – material that
could contaminate the next material that might flow
through the pipe. Does the construction limit or
Can you ensure that maintenance activities do
not contaminate the equipment or product or that
lubricants or other items do not impact the quality of
➤ Movement from Area to Area
Given that maintenance personnel are usually
the people permitted to move from area to area, it is
imperative that their tools, equipment, and uniforms
be clean before they are introduced into any area.
Do you dedicate as many tools as possible to a particular
➤ Hold Times
Have you established an acceptable clean hold
time/storage to protect clean equipment from contamination?
Have you established an acceptable dirty
hold time – the maximum time you can hold dirty
equipment before the validated cleaning process
would no longer be successful? Do you adequately
inspect equipment for cleanliness immediately
Cleaning Issues in Materials
Materials and components include raw materials;
active ingredients; inactive ingredients; reagents;
excipients for color, flavor, or fragrance; film coating;
cleaning agents; and water. These may be stored in
a variety of ways (containers, vessels) and areas
(pre-production, post-production) where cleaning
may have an impact. The issues in container cleaning
and storing are similar to those in equipment
cleaning. Storage area cleaning procedures are also
similar to those for facilities cleaning. As in facilities
cleaning, you must pay attention to environmental
conditions, airflow, and the potential for microbial
Cleaning Issues in Packaging and Labeling
Just as with the issues in materials, the issues
for the packaging and labeling system resemble
those for facilities and equipment.
Cleaning Issues in the Laboratory
and Production Systems
The lab control system, through validation of the
cleaning process, and the production control system(
s), through the monitoring of production, support
the cleaning processes used on equipment.
Several issues are common across both systems. To
help ensure compliance in both areas you should:
• Have a validated cleaning process for production
processes that employ multi-use (versus
• Identify the “worst-case” analyte, taking into
account solubility, toxicity, and dosage to
demonstrate successful cleaning for multi-use
equipment. Then, determine the acceptance
criteria for cleaning in the worst case, thus
ensuring that all of the lesser cases are
accommodated as well.
• Develop and validate analytical methods to
detect and measure the analyte (residual
active ingredient, residual soap, etc.).
TAKING A CROSS-SYSTEMS
Although an FDA inspection of GMP quality may
concentrate on only two or three of the systems
(and always includes the quality system), all six systems
are subject to inspection. If an inspector gets
the impression that things are not clean or are in
disarray, then you will be trying to change that belief
as the inspection progresses. Moreover, inadequacies
in one of the systems under inspection could
point the inspector toward any one of the other systems.
And, because cleaning is complex and
involves interrelations among systems, such a chain
of events could easily occur. Therefore, an effective
and compliant cleaning program must comprehensively
encompass all six systems.
A common approach to establishing and maintaining
an effective and compliant cleaning program
is to adopt a “cleaning policy and cleaning master
plan,” and to identify a group or department to be
responsible for it. However, such an approach runs
the risk of compartmentalizing the systems and overlooking
important interrelationships among them.
A more comprehensive, holistic approach would
identify the critical elements across the systems that
a successful cleaning program must address. By
focusing on these critical elements, you ensure that
you are addressing all six systems as well as the
interrelationships that a compartmentalized
approach might miss.
Figure 1 depicts one such cross-systems
approach. In this model, the four critical, cross-system
elements are people, facilities, equipment, and
components storage, all of which have relationships
to each of the six quality systems and which depend
upon each other for GMP compliance. Moreover,
three critical activities must be undertaken for each
element: validation, documentation, and the establishment
of Standard Operating Procedures (SOPs).
As the figure suggests, by focusing on the four elements
and their supporting activities, the cross-systems
approach integrates all cleaning activities into
one comprehensive system that converges, at its
center, on compliance.
For each of the four critical elements of a crosssystems
approach, there are key requirements you
must consider when establishing, implementing, and
maintaining an effective and compliant cleaning program:
Within your facilities, you must be able to remove
components (raw materials and excipients), remove
or eliminate viable organisms, and remove pyrogens.
You must document your methods – how, when,
where – for performing these operations, the people
who perform them, and the cleaning agents used.
Facilities parameters must exist to evaluate High
Efficiency Particulate Air (HEPA) filters and Heating,
Ventilation, and Air Conditioning (HVAC) systems,
including: viable counts, non-viable counts, air balancing,
pressure differential, airflow, and velocity.
Rooms, walls, and floors must be washed or
mopped and be visibly clean. Cleaning equipment
and supplies must be stored and trash must be disposed
When cleaning equipment, you must be able to
remove components (raw materials/final), cleaning
agents, and pyrogens, and be able to remove or
eliminate viable organisms. As with facilities, you
must document your methods – how, when, where –
for performing these operations, the people who
perform them, and the cleaning agents used.
A compliant equipment cleaning process identifies
• Cleanliness of the most difficult to clean
• Disassembly of equipment
• Consistency of cleaning
✓ Clean-in-Place (CIP) and Steam-in-Place
✓ Time storage limitations of clean equipment
In addition to using laboratory testing, you should
use your senses to verify equipment cleanliness. Do
you see discolored surfaces, worn or torn parts,
residue, or water remaining in equipment? Do you
smell odors that should be investigated? Do you
hear sounds that differ from the norm?
➤ Components and Storage
Component cleaning and storage activities
include sampling area or facilities, cleanliness of
sampling tools, and proper storage of cleaning tools,
equipment, and supplies.You must also validate
water – certainly a component – in terms of production,
storage, and distribution. In addition to employing
analytical and microbiological testing, use your
senses to verify component cleanliness for signs of
water damage, pests, rodents, torn containers, color
variations, and suspicious odors.
People are involved in all of the activities that go
into the other three cross-functional elements. They
must follow gowning and operating procedures.
They are responsible for activities such as cleaning
as well as for documenting those cleaning activities.
In addition, training records for all personnel must
be complete and current.
Validation, Documentation, and SOPs
As Figure 1 suggests, addressing the four key
elements also requires validation, documentation,
and the establishment of SOPs.When it comes to
cleaning, you should live by the axiom: If it is not
documented, then it did not happen.
To verify that cleaning is performed properly, you
must validate the proper functioning of all four elements:
facilities, equipment, components, and people.
In validating the operation, you document evidence
that systems function as designed, in a
consistentand effective manner, and in accordance
with pre-determined criteria.
Validation is emphatically not the cure for all
issues. Validation demonstrates that, when systems
are functioning in the same conditions as they were
when the validation took place, there is a high probability
of an acceptable outcome. To demonstrate
consistency and continuing proper operation, you
must apply continuingly effective cleaning practices
and routine monitoring.
BENCHMARKING A CLEANING
To develop and implement a compliant cleaning
program, a cleaning team composed of representatives
familiar with each of the six systems should be
brought together. As they develop the cleaning program,
they should benchmark it against regulations
and a cleaning standard. Once the program is in
place, the team should review it periodically to
ensure its effectiveness and its level of compliance.
The following is an example of a cleaning standard:
➤ A Written Program Must Be in Place
• Cleaning policy, procedures, and Validation
Master Plans (VMPs) must be documented.
These documents must be approved by Quality
• Written procedures shall be established for
cleaning and for the identification of the cleaning
status of equipment.
• At a minimum, cleaning procedures shall be
validated for all product contact equipment
that is used to produce one or more drug
products or final Active Pharmaceutical Ingredient
(API). This requirement also applies to
• For clinical products produced by commercial
production equipment, the equipment must be
verified as clean before and after the clinical
production process. Cleaning validation typically
requires three consecutive, successful
operations. However, this may be difficult to
obtain for clinical products. It is, therefore,
acceptable to perform an amended cleaning
protocol for fewer than three lots or batches.
Cleaning validation may not be required until
the clinical product enters the final manufacturing
process (Phase III or later).
➤ Equipment Must Be Evaluated for Cleanability
• Consideration should be given to modifying
equipment configurations, as appropriate, and
to removing and reducing difficult to clean
areas such as product contact piping
deadlegs. Localized areas where residue
could build up and could go undetected by
sampling or analysis should be identified.
• Multi-product use equipment (non-dedicated)
shall be cleaned between the production of
different materials to prevent cross-contamination.
• For same product equipment (dedicated),
cleaning shall also be performed when going
from a higher dosage to a lower dosage product.
Dedicated equipment requires a minimum
of visual inspection to verify equipment cleanliness.
• Where equipment is assigned to continuous
production or campaign production of successive
batches, equipment shall be cleaned at
appropriate intervals to prevent build-up and
carry-over of contaminants (e.g.: degradents).
The maximum number of cycles or time
between cleanings shall be established.
• The maximum time that may elapse must be
established between both the:
✓ Completion of processing and cleaning
✓ Cleaning and re-use
➤ Worst-case Approach
• In a multi-purpose facility or work center, the
approach of the most difficult to clean material
or product (worst-case approach) should be
used to validate the cleaning procedure when
the same cleaning procedure is used.
• A rationale must be documented and proven
when selecting this cleaning validation
Analytical Test Methods
➤ Validate and Establish Limits
• Analytical test methods used to verify equipment
cleanliness must be validated.
• Limits of Detection (LOD) and the Limits of
Quantification (LOQ) for the analytical test
method must be established.
Perform Dose, Toxicity, and Weight Percent Calculations
• When it is possible to calculate, the three limits
must be compared and the most conservative
limit chosen for the area.
• Drug residue cleaning limits must be calculated
for each cleanup, considering the material
being cleaned out and the next material to
be produced. Alternatively, one limit may be
calculated for all materials produced in a given
area by considering the worst-case variables
for the calculation.
• Cleaning agent (including solvents) limits must
be stated, or a rationale provided as to why
they are not required. For example, if the
cleaning agent is a solvent that is dried from
the equipment after cleaning or used in the
next processing step, solvent limits are generally
Swab and Rinse Sampling Methods
➤ Use These Methods Whenever Possible
• Rinse sampling is routinely used to verify
cleanliness of large, closed, inaccessible, multipurpose
• Swab sampling is used in combination with
rinse sampling during validation studies.
Microbiological and Endotoxin Cleaning Limits
➤ As Part of the Cleaning Validation
• For aseptically produced or crystallized APIs
destined for sterile drug products and for sterile
pharmaceutical products, microbiological
and endotoxin cleaning limits shall be considered
as part of the cleaning validation.
• For aseptically produced or crystallized APIs,
direct product contact surfaces used during
aseptic processing must be sterilized utilizing
validated sterilization methods.
• For non-aseptically crystallized or produced
APIs, there is generally no requirement for validation
of cleaning methods as they relate to
microbiological “cleanliness.” Specific cases
may warrant evaluation of the cleaning methods
for microbiological cleaning effectiveness.
However, after cleaning, equipment should be
handled and stored in a manner that does not
allow for microbial proliferation (e.g.: equipment
should be dried after cleaning and
• For non-sterile pharmaceuticals (e.g., ointments,
creams, etc.), the validation of cleaning
methods must contemplate the evaluation of
A COMPLIANT PROGRAM
A compliant cleaning program results when you
address all of its systemic elements, understand
their interdependence, and complete activities
across the multiple quality systems. Once you have
defined the relevant regulations, identified critical
issues and activities, and created an approach to
establish and maintain a cleaning program of quality,
you must continue to maintain and improve it.
Regulations, guidances, and technology change
frequently, and keeping up with those changes can
help you maintain a compliant and effective cleaning
system. Therefore, you should stay current on publications,
seminars, and the postings of professional
organizations, such as those published by the Parenteral
Drug Association (PDA), the International
Society for Pharmaceutical Engineering (ISPE), or
the American Association of Pharmaceutical Scientists
(AAPS). Utilize the knowledge of outside consultants
and experts to keep current with evolving
cleaning trends and new regulations. Cleaning is a
recurring activity – and so is the job of maintaining a
compliant cleaning system. ❏
The Article “Sidebar” appears on page 47.
ABOUT THE AUTHORS
Troy Fugate, Vice President for Compliance
Insight, Inc, located near Cincinnati, Ohio, is a
worldwide compliance consultant in the areas of
pharmaceutical quality, operations, packaging, laboratory,
and construction activities. Troy has
worked around the globe on a variety of projects
and specializes in quality systems, audits, investigations,
FDA issue resolution, and training. He
may be contacted via email at: troy@complianceinsight.
David B. LaTart, a Senior Consultant for Tunnell
Consulting Inc., located in King of Prussia, Pennsylvania,
consults in the areas of pharmaceutical
and diagnostic compliance and has specific interests
in cleaning validation, analytical method
development and validation, investigation reports,
and process validation. David may be contacted
via email at: firstname.lastname@example.org
1. Draft Guidance: “Guidance for Industry Quality Systems
Approach to Pharmaceutical Current Good Manufacturing
Practice Regulations”, FDA, September 2004.
2. “Guide to Inspections Validation of Cleaning Processes,” FDA
Website, ORA, July 2004.
Article Acronym Listing
AAPS American Association of
API Active Pharmaceutical Ingredient
CFR Code of Federal Regulations
CIP Clean in Place
FDAFood and Drug Administration
GMP Good Manufacturing Practice
HEPA High Efficiency Particulate Air
HVAC Heating, Ventilation, and
ISPE International Society for
LOD Limit of Detection
LOQ Limit of Quantification
PDA Parenteral Drug Association
QA Quality Assurance
SIP Steam in Place
SOP Standard Operating Procedure
VMP Validation Master Plan