Pharmaceutical Cleaning:

A Comprehensive
Approach
By Troy Fugate and David B. LaTart

INTRODUCTION
Now that the Food and Drug Administration (FDA) has decided to con-
duct 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 inter-related
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 effective system.

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 36).

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Troy Fugate and David B. LaTart

However, FDA guidance on inspection of cleaning2 describes FDA expec-

tations on validating cleaning processes for equipment, establishing
acceptance limits, and using validated analytical methods. Further, inade-
quate 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 compre-
hensive cleaning system. The first step to achieving a comprehensive
cleaning system and achieving compliance lies in considering critical
cleaning issues for each of the six systems.

Cleaning Issues in the Quality System

Some common cleaning issues in the quality system include:

Documentation

You must maintain standard operating procedures for cleaning and

keep thorough and accurate equipment cleaning records.

Validation

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 re-validation.

People

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.

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Cleaning Issues in Facilities and Equipment

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 operations.
Typically, the most effort in cleaning is expended on equipment and
for good reason. Equipment varies enormously in scale, design, and oper-
ation. 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:

Material

What material makes up the equipment and how easily can it be

cleaned?

Design

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?

Construction

Are the welds good? Is the equipment passivated that is, are its sur-
faces 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
impede cleaning?

Maintenance

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 the product?

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Troy Fugate and David B. LaTart

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 dedi-
cate as many tools as possible to a particular area?

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 before use?

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 contamination.

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 dedicated) equipment
Identify the worst-case analyte, taking into account solubility, toxi-
city, and dosage to demonstrate successful cleaning for multi-use
equipment. Then, determine the acceptance criteria for cleaning in

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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 APPROACH

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 com-
prehensively 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 sys-
tems and overlooking important interrelationships among them.
A more comprehensive, holistic approach would identify the critical ele-
ments 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 compart-
mentalized 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 ele-
ments and their supporting activities, the cross-systems approach inte-
grates all cleaning activities into one comprehensive system that con-
verges, at its center, on compliance.

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Troy Fugate and David B. LaTart

Figure 1
A Cross-Systems Approach to Cleaning

People

Componen
nts Storag
age

SOP Doc
ocu
cumen
ent

C
Fac
acilities
es Equipment
nt
V alidat
ae

C = Compliance

For each of the four critical elements of a cross-systems approach,

there are key requirements you must consider when establishing, imple-
menting, and maintaining an effective and compliant cleaning program:

Facilities

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, pres-
sure 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 of properly.

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Equipment

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 docu-
ment 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 and verifies:

Cleanliness of the most difficult to clean area(s)
Disassembly of equipment
Consistency of cleaning
Manual
Clean-in-Place (CIP) and Steam-in-Place (SIP)
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

People are involved in all of the activities that go into the other three
cross-functional elements. They must follow gowning and operating proce-
dures. 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.

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Troy Fugate and David B. LaTart

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 sys-
tems function as designed, in a consistent and effective manner, and in
accordance with pre-determined criteria.
Validation is emphatically not the cure for all issues. Validation demon-
strates 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
PROGRAM
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:

Written Program
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 Assurance (QA).
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 prod-
uct contact equipment that is used to produce one or more drug
products or final Active Pharmaceutical Ingredient (API). This
requirement also applies to dedicated equipment.

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For clinical products produced by commercial production equip-

ment, 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 diffi-
cult to obtain for clinical products. It is, therefore, acceptable to per-
form 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
Equipment Must Be Evaluated for Cleanability

Consideration should be given to modifying equipment configura-

tions, 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-con-
tamination.
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 inspec-
tion to verify equipment cleanliness.
Where equipment is assigned to continuous production or cam-
paign 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

Equipment
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

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Troy Fugate and David B. LaTart

procedure is used.
A rationale must be documented and proven when selecting this
cleaning validation approach.

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.

Calculations
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 materi-
als produced in a given area by considering the worst-case vari-
ables 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 gen-
erally not required.

Swab and Rinse Sampling Methods

Use These Methods Whenever Possible

Rinse sampling is routinely used to verify cleanliness of large,

closed, inaccessible, multipurpose areas.
Swab sampling is used in combination with rinse sampling during
validation studies.

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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, microbiologi-
cal 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 before storage).
For non-sterile pharmaceuticals (e.g., ointments, creams, etc.), the
validation of cleaning methods must contemplate the evaluation of
microbiological cleanliness.

CONCLUSION:
A COMPLIANT PROGRAM

A compliant cleaning program results when you address all of its sys-
temic 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 keep-

ing up with those changes can help you maintain a compliant and effective
cleaning system. Therefore, you should stay current on publications, semi-
nars, and the postings of professional organizations, such as those pub-
lished 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 con-
sultants 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.

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Troy Fugate and David B. LaTart

Article Acronym Listing

AAPS American Association of

Pharmaceutical Scientists
API Active Pharmaceutical Ingredient
CFR Code of Federal Regulations
CIP Clean in Place
FDA Food and Drug Administration
GMP Good Manufacturing Practice
HEPA High Efficiency Particulate Air
HVAC Heating, Ventilation, and
Air Conditioning
ISPE International Society for
Pharmaceutical Engineering
LOD Limit of Detection
LOQ Limit of Quantification
OOS Out-Of-Specification
PDA Parenteral Drug Association
QA Quality Assurance
SIP Steam in Place
SOP Standard Operating Procedure
VMP Validation Master Plan

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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 construc-
tion activities. Troy has worked around the globe on a variety of projects
and specializes in quality systems, audits, investigations, FDA issue res-
olution, and training. He may be contacted via email at: troy@compli-
ance-insight.com

David B. LaTart, a Senior Consultant for Tunnell Consulting Inc., located

in King of Prussia, Pennsylvania, consults in the areas of pharmaceuti-
cal and diagnostic compliance and has specific interests in cleaning val-
idation, analytical method development and validation, investigation
reports, and process validation. David may be contacted via email at:
latart@tunnellconsulting.com

REFERENCES
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.

Originally published in the July 2005 issue of the Journal of GXP Compliance

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Sidebar: FDA Regulations for Cleaning

The FDA provides specific regulations for cleaning four of the systems
described in the GMP quality system model: quality, facilities and equip-
ment, materials, and packaging and labeling. The regulations do not
clearly specify cleaning for the laboratory controls or the production sys-
tems. Explicit regulations for each of the four systems described therein
include:

QUALITY
21 CFR Part 211.28 Personnel Responsibilities
Protective apparel
Practice of good sanitation and
health habits
Limited access to clean areas
Report necessary health conditions
21 CFR Part 211.182 Documentation
Records of major equipment cleaning

FACILITIES AND EQUIPMENT

21 CFR Part 211.42 Design and Construction Features
Designed to prevent contamination
Floors, walls and ceilings are easily
cleanable
System for cleaning and disinfecting
the room and equipment to produce
aseptic conditions
21 CFR Part 211.50 Sewage and Refuse
Sewage, trash, and refuse shall
be disposed of in a safe and
sanitary manner
21 CFR Part 211.56 Sanitation
Building shall be clean
Provide written procedures describing
in detail the cleaning schedules,
methods, equipment, and materials
used in cleaning
21 CFR Part 211.63 Equipment Design, Size, Location
Equipment will be designed and
located to facilitate cleaning

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21 CFR Part 211.67 Equipment Cleaning

Equipment and utensils shall be
cleaned at appropriate intervals
Written procedures established
Assignment of responsibility for
cleaning
A description of the methods, equip-
ment, and materials used in cleaning
Records shall be kept as in 211.180
and 211.182
Describe disassembly and reassembly
of equipment for cleaning

MATERIALS

21 CFR Part 211.80 Control of Components

Components stored and handled in a
manner to prevent contamination
Stored off the floor
Stored to promote cleaning activities
Sampled in a clean area with clean
equipment
Provide adequate written procedures

PACKAGING AND LABELING

21 CFR Part 211.130 Inspection and Control

Inspection of packaging and labeling
facilities before use
Adequate separation to prevent
mix-ups and cross contamination

Cleaning Validation 37