Proposed Validation Standard VS-3

PROPOSED VALIDATION STANDARD VS-3

Cleaning Validation

Introduction

T his document is the third in a series of new proposed validation standards issued by the Institute of
Validation Technology Standards Committee (IVT/SC). The initial proposed standard (Process
Validation Standard VS-l: Nonaseptic Pharmaceutical Processes) was issued in February 2000, and
is intended to help practitioners worldwide who develop, implement, control, and validate processes that pro-
duce Active Pharmaceutical Ingredients (APIs) and drug products. Our second proposed validation standard
VS-2: Computer-Related System Validation was issued in May 2001. The current document (Cleaning
Proposed Validation Standard VS-3) is intended to offer more specific proposed standards for the cleaning
processes for equipment used to manufacture APIs and drug products. These proposed standards, will be used
by reviewers of manuscripts intended for publication in the lournal of Validation Technology (1VI).
Just as with the previous proposed standards, readers are encouraged to offer comments, questions, and rec-
ommendations. Such feedback will be useful to the IVT/SC and JVT editors in updating this document and in
developing future proposed standards. Technologies are continually changing, sometimes in ways that can influ-
ence the way validation is best conducted. Therefore, the IVT/SC plans to periodically update each proposed val-
idation standard, including its corresponding Preamble and reference list. In order to be dynamically responsive
to changing industrial practices and regulatory requirements, and make it easier for readers to cut and paste the
contents for their own use, all three proposed standards are available on the IVT web site at www.ivthome.com.
A fundamental need the IVT/SC intends to meet with its new proposed standards stems from the fact that most
Good Manufacturing Practice (GMP) regulations today call for numerous written procedures; for example, more
than 100 different kinds of written procedures are required to comply with current GMP regulations in the United
States. Many firms find it helpful to issue written policies in order to coordinate and reduce the number and length
of required Standard Operating Procedures (SOPs). Thus, the IVT proposed validation standards format includes
statements and definitions that can be excised and used directly or with minor editing in a firm's policies and SOPs.

Contents of the Proposed Cleaning Validation Standard

In order to be consistent with the prototype standard (Validation Standard VS-l) the Proposed Cleaning
Validation Standard VS-3 will be divided into the following five sections:

I. Policy statements - Proposed standards that indicate what is required

II. Procedural Statements - Proposed standards that describe how to meet requirements
III. Acronyms - Meaning of each acronym/abbreviation used in the document
IV. Glossary - Definition of key terms, which are highlighted and asterisked (*) when first used in the
proposed validation standard

~ Institute of Validation Technology

 Proposed Validation Standard VS-3

V. Regulatory Excerpts - Regulatory language (United States, Australia, Canada, World Health Organ-
ization [WHO], Japan, and European Union) related to each Standard

T he following proposed standard is intended to reflect desirable contemporary practices, is not binding in
any way, and can be modified to suit a firm's specific needs. This proposed standard incorporates imper-
ative verbs (e.g., shall, will, must) to provide users with unambiguous quality assurance auditing tools,
and is prefaced by a Preamble that provides rationale for several of the more complex concepts. This document
is also directed toward users located at a given plant site that mayor may not be a part of a larger corporation.
Terms that are bold and asterisked (*) the first time they are used are defined in Section IV - Glossary.

I. POLICY STATEMENTS

POL 1.1
The critical cleaning processes associated with the manufacture of Active Pharmaceutical Ingredients
(API)*, critical Intermediates*, Drug Products*, or In-Process Materials* shall be validated or verified.

POL 1.2
The critical cleaning processes associated with products in the development stage of the product lifecycle
shall be verified. The administrative responsibility for such products will reside in either the appropriate
development group or in the Site Validation Steering Committee (SVSC)*. If the company decides that
responsibility for cleaning verification shall reside in the appropriate development group, then the docu-
mentation describing the verification procedure and the Cleaning Verification Protocols* must also be ap-
proved by the site Quality Authority*.

POL 1.3
During development of the new product, the manufacturing equipment, batch size, and formulation is con-
stantly changing and the cleaning procedure must be appropriate and customized for each manufacturing event.
The lifecycle for the development and validation of a new cleaning procedure consists of the following steps:

l.3.1 Determine what materials need to be cleaned from the equipment or surfaces.
1.3.2 Determine what methods should be used to evaluate the anticipated residues (from Section
1.3.1). Determine the sensitivity and reproducibility of these methods.
1.3.3 Define the Critical Product Cleaning Specifications*.
1.3.4 Define the specific equipment to be used for each development batch.
l.3.5 Define the specific formulation to be used for manufacturing each individual development batch.
1.3.6 Identify the cleaning agents to be used, if appropriate.
1.3.7 Determine what other products are manufactured in the same equipment.
1.3.8 Calculate Cleaning Verification Limits* for the specific equipment taking into account the
critical product cleaning specifications as well as the other products made in the same equip-
ment.
l.3.9 Draft a Cleaning Procedure* for the specific combination of product and manufacturing equip-
ment. Identify Critical Cleaning Process Operating Parameters* and Cleaning Agents*.
1.3.10 Prepare a cleaning verification protocol.
1.3.11 Manufacture a single product batch, clean the equipment; then test the equipment, as speci-
fied in the cleaning verification protocol.
1.3.12 Once development is complete, perform Cleaning Validation* on the first three (3) commer-
cial batches.

Journal of Validation Technology

Proposed Validation Standard VS-3

1.3.13 Validate analytical methods to be used for cleaning validation samples.

1.3.14 Determine recovery factors of expected residues from representative materials (stainless steel,
glass, plastics).
1.3.15 Prepare and obtain approval of a Cleaning Validation Protocol*.
1.3.16 Train and qualify operational and supervisory laboratory and production personnel in prod-
uct-specific cleaning procedures, sampling procedures, and analytical procedures.
1.3.17 Ensure that interrelated systems (automated clean-in-place, utilities, Programmable Logic
Controllers [PLCs]) are all validated.
1.3.18 Conduct Cleaning Performance Qualification (CPQ)*.
1.3.19 Assemble and document evidence that the cleaning process is acceptable and consistent.
1.3.20 Provide for retention of archived cleaning validation files for required periods following the
last commercial lot expiration date.
POL 1.4
The cleaning processes associated with products in the marketed stage of the product lifecycle shall be val-
idated for all products manufactured with a normal frequency of production. For rare instances where prod-
ucts are infrequently manufactured (e.g., one batch per year or less frequently), it may be difficult to achieve
fully validated cleaning processes and the principle of cleaning verification should be utilized. The adminis-
trative responsibility for cleaning validation and cleaning verification of products will reside in the Site
Validation Steering Committee (SVSC). The SVSC shall adjudicate cleaning validation issues and appoint
project-specific validation teams as needed that include principal(s) having experience in the cleaning
processes involved. Such SVSC responsibilities extend to cleaning processes used by contract vendors and
suppliers of the firm's drug products and/or APIs, as well as to those cleaning processes employed on-site.

POL 1.5
A written Cleaning Verification Policy (CVP) shall be used to define and describe the strategies and
approaches used to verify cleaning procedures associated with drug products, biotechnology products,
medical devices, and APIs during the development stage of the lifecycle.

POL 1.6
A written Cleaning Validation Master Plan (CVMP)* shall be used to define and coordinate validation
activities related to any cleaning process associated with the manufacture of a commercially marketed
drug product, biotechnology product, medical device, and API.

POL 1.7
Cleaning Verification Protocols shall be used to define individual cleaning verification runs.

POL 1.8
Cleaning Validation Protocols shall be used to define individual cleaning validation runs.

POL 1.9
Cleaning Verification Reports* shall be used for documenting and summarizing results of cleaning ver-
ification studies. Definite statements must be used, especially in describing the scientific rationale for the
limits chosen and whether the cleaning process was effective in meeting the limits.

POL 2.0
Cleaning Validation Reports* shall be used for documenting and summarizing results of cleaning vali-
dation studies. Definitive statements must be used, especially in describing the scientific rationale for the
limits chosen and whether the cleaning process was effective in ensuring that these limits were met.

Institute of Validation Technology

 Proposed Validation Standard VS-3

POL 2.1
All Cleaning Verification Policies, Cleaning Validation Master Plans, Cleaning Verification Protocols,
Cleaning Validation Protocols, Cleaning Verification Reports and Cleaning Validation Reports must
be approved and available to the SVSc. All such cleaning documents created on-site must be approved by
the site Quality Authority and, when production is involved, also by the site Production Authority*.

POL 2.2
Relevant cleaning process verification and validation information from other divisions, departments
(including Research and Development), production sites, and outside contract services is to be gathered,
evaluated, utilized, and maintained by the SVSC.

POL 2.3
Certain cleaning processes are considered critical manufacturing steps and thus require validation (it
should be noted that not all cleaning procedures are considered critical and thus require validation). Once
the cleaning procedures are validated, they must not be altered without prior review, and any changes
should be subjected to a formal Change Control* review process prior to making the change. The site
Quality Authority must approve all changes to validated cleaning procedures.

II. PROCEDURAL STATEMENTS

PROC - 2.a [ref. POL 1.3.2]

Critical product cleaning specifications are known factors that can influence the development of the
cleaning process. These can be physical in nature such as solubility in a variety of solvents, polymorphic
crystal form, and stability. These factors could also be chemical in nature such as reactivity with water
or other solvents. They could also include medical information such as potency, toxicity, and allergenic-
ity. They could also be safety factors such as toxicity when inhaled and could require personal protec-
tion attire to protect the operator. These factors, which are normally determined during pre-formulation,
are vital information that must be known before meaningful cleaning procedures and limits can be devel-
oped.

PROC - 2.b [ref. POL 1.3.3]

During development, various types of equipment may be used in an effort to develop an optimum process
or effective product. This means that normally the specific equipment or the scale of the equipment may
vary from batch-to-batch. Because of this variability in the equipment used, the cleaning procedures may
also vary from batch-to-batch even for the same product. Therefore, the cleaning verification results apply
only to the specific cleaning event (i.e., the specific combination of equipment, processes, and materials)
used for the individual study. The cleaning verification report should contain the details of the specific
equipment (size, model number), formulation, and processes used.

PROC - 2.c [ref. POL 1.3.4]

During development, the formulation may vary from batch-to-batch in order to identify the combination
of ingredients that presents the best product performance 'in vitro' and 'in vivo'. Excipients may be var-
ied as well as the concentration of active ingredient. These combinations will present different degrees
of cleaning challenges. A given cleaning procedure may be adequate for one formulation but inadequate
for another formulation of the same active ingredient. This data will be useful for the selection of the
ultimate cleaning procedure that will be used for commercial product. It will be necessary to include the
formulation in the cleaning verification study, either by reproducing in total, or by reference to a formu-
la number.

Journal of Validation Technology

Proposed Validation Standard VS-3

PROC - 2.d [ref. POL 1.3.5]

Since it is other products made in the same equipment that will be contaminated due to inadequate clean-
ing, it is necessary to evaluate the other products made in the same equipment. Some of the factors per-
taining to other products that will be needed are:

Batch sizes
Normal daily doses
Route of administration

PROC - 2.e [ref. POL 1.3.6]

In order to develop a scientific basis for cleaning verification limits, information will be needed for both
the product being cleaned as well as other products made in the same equipment. The following informa-
tion should be assembled:

For product being cleaned

- Solubility in various solvents
- Potency
- Toxicity
- Stability (wet and dry)
- Allergenicity
- Route of administration
- Daily dosage
- Difficulty of cleaning
- Physical and chemical interaction with cleaning agent

For other products made in same equipment

- Batch sizes
- Daily doses
- Stability
- Chemical interaction with product being cleaned
- Route of administration

The pharmacological relationships between the potential contaminating product and other products, which
could be possibly cross contaminated, may also be significant and should be considered if known. The con-
taminating product has the potential to amplify the medical activity of other products resulting in a syner-
gistic effect. The contaminant could also partially negate the medical effect of the other products by hav-
ing an antagonistic effect.

PROC - 2.f [ref. POL 1.3.7]

Just as there are critical parameters for the manufacturing process, there are critical parameters for the
cleaning process. These factors will lead to either inadequate or inconsistent cleaning if not controlled.
Critical parameters for the cleaning process must be determined and may vary from one cleaning process
to another. Some potential critical cleaning parameters (list is not all inclusive) are:

Temperature of wash solutions

Temperature of rinse solutions
Amount of mixing or agitation during cleaning
Mechanical wiping or brushing

Institute of Validation Technology

 Proposed Validation Standard VS-3

Flow rates
Concentration of cleaning agent
Time of washing
Time of rinsing
Length of time and environmental conditions (temperature, humidity) between manufacturing and
cleaning
Nature and amounts of excipients
Concentration or amount of residue left on equipment
Physical properties of residues
Chemical properties of residues
Cleaning solvent chosen
Soak times
Contact time with cleaning agent
Rinse volumes
Order of application of cleaning solvents (acid, alkaline, and organic solvents)

PROC - 2.g [ref. 1.3.8]

Each cleaning verification protocol shall include, and is not limited to, the following:

o Statement of objective or purpose

@ Justification for cleaning verification limits, if applicable
~ Descriptions of sampling procedure(s), and locations, types, and numbers of samples to be taken
o Indications of most difficult-to-clean locations in equipment
o Experimental plan to be executed, including number of samples, and how data will be calculated
<D Descriptions of analytical methodology and sensitivity of analytical method as well as recovery factors
o Descriptions of all testing instruments to be used and specific calibration plans for each
o Complete description of acceptance criteria including visual examination (if possible) and quantitative
analytical data
o Training records of operators and analytical personnel
PROC - 2.h [ref. 1.3.11]
Prior to cleaning validation studies, analytical methods must be validated to demonstrate that they are suit-
ably sensitive to detect residues at levels below the allowable limits. Analytical Method Validation* for
cleaning validation shall include, and is not limited to, the following:

o Accuracy
@ Precision
~ Linearity
o Robustness
o Sensitivity-Limit of Detection (LOD)*, Limit of Quantitation (LOQ)*
<D Specificity

The specificity of the analytical method may not be as critical for cleaning validation as for process vali-
dation due to the fact that the levels of residue detected is very low, and often non-specific analytical meth-
ods are available that may be at least or more sensitive than specific methods. The assumption is often
made that all of the residue detected is composed of the most potent ingredient (usually the active) pre-
sent and, if this amount is still below the established limits, then the exact nature of the residue is irrele-
vant, i.e., the 'worst case' assumption was made and limits were met.

Journal of Validation Technology

Proposed Validation Standard VS-3

PROC - 2.i [ref. 1.3.12]

Following validation of the analytical method, the analytical method should be challenged concurrently
with the sampling procedure(s) to determine the percentage recovered from representative manufacturing
surfaces. The determination of recovery is important and will differ according to the composition of the sur-
face sampled (e.g., stainless steel, glass, plastics), the nature of the sampling technique, and the nature of
the residues themselves. The recovery factor must be used to correct observed analytical results to account
for portions of residue that remain on equipment even after swab and rinse sampling.

PROC - 2.j[ref. 1.3.13]

Each cleaning validation protocol shall include, and is not limited to, the following:

o Statement of objective or purpose

@ Justification for cleaning validation limits
@) Descriptions of sampling procedure(s) and diagrams of locations
o Indications of most difficult-to-clean locations in equipment
o Experimental plan to be executed, including number of cleanings to be evaluated, number of samples
from each cleaning, and how data will be calculated
<D Descriptions of analytical methodology and sensitivity of the analytical method as well as recovery factors
fi Descriptions of all testing instruments to be used and specific calibration plans for each
l) Complete description of acceptance criteria including visual examination (if possible) and quantitative
analytical data
CD Criteria for determining when the cleaning process may be considered validated, i.e., how many suc-
cessful consecutive cleanings (normally at least three (3) are required)
@ Training records of operators and analytical personnel

PROC - 2.k [ref.1.3.14]

Prior to implementation of the cleaning validation protocol, it is important to verify the training of the pro-
duction operators who actually conduct the cleaning, sampling personnel (production, analytical, valida-
tion) who sample the equipment, analytical personnel who analyze cleaning validation samples, as well
as personnel who implement the protocol and process the documentation. If documentation does not
already exist that demonstrates each of these types of training, then the training should be done before any
actual validation runs are carried out.

PROC - 2.1 [ref. 1.3.15]

Special equipment and critical utilities such as water and steam must be qualified prior to implementation
of the cleaning validation protocol. In addition, any automated cleaning equipment such as Clean-in-
Place (CIP)* systems and their associated automated controllers must also be validated or qualified prior
to implementation of the cleaning validation protocol. In the case of CIP, Sprayball Pattern Analysis*
should be carried out to verify that cleaning solutions reach all locations in closed systems. The qualifi-
cation of equipment and utilities is normally accomplished by means of an Installation Qualification
(IQ) * and an Operational Qualification (OQ) * (see next two sections).

PROC - 2.m [ref. 1.3.15]

An Installation Qualification (IQ) must exist for all equipment that is critical to the cleaning process
including specialized cleaning aids such as Spray Devices (Sprayballs)*, equipment that delivers clean-
ing solutions, high pressure wands, water heating devices, steam generators, and utilities. The IQ is to in-
clude at least the following:

Institute of Validation Technology

 Proposed Validation Standard VS-3

o List of all equipment, the operation of which has potential bearing on the quality of the cleaning process
@ As-built drawings of all specialized cleaning equipment such as pumps, high pressure delivery devices,
and hose cleaners
@) Verification that all such equipment and the installation thereof meets original intent, including applic-
able building, electrical, plumbing, and other such codes
o Preventative maintenance plans and schedules for all such equipment
PROC - 2.n [ref. 1.3.15]
An Operational Qualification (OQ) must exist for all equipment that is critical to the cleaning process and
should include at least the following:

o A list identifying each step of the cleaning process that relates to the specific equipment
@ Process operating parameters for each piece of equipment that is critical to the cleaning process
@)An OQ protocol that is designed to demonstrate via appropriate tests that the equipment operates as in-
tended throughout the cleaning process
o Report that describes the successful execution of each OQ protocol for each piece of equipment criti-
cal to the cleaning process

PROC - 2.0 [ref. 1.3.16]

At least three consecutive, successful cleanings shall be completed on the equipment used to produce the
commercial product. Normally, the cleanings follow the production of each of the batches used for the val-
idation of the manufacturing process. A Cleaning Performance Qualification (CPQ) shall be performed
when the following items are complete and commercial production has been authorized.

The cleaning process is fully defined in writing, including identification of critical cleaning process
operating parameters
A justification for Cleaning Validation Limits* has been prepared that takes into account the potency
and toxicity of the material, as well as the other products to be made in the same equipment
IQ and OQ steps are complete for critical utilities and any specialized equipment used in cleaning such
as pumps, sprayballs, high pressure wand cleaners, etc.
Operating, sampling, and analytical personnel are trained and qualified and the training is documented
An appropriate change control procedure is in place

PROC - 2.p [ref. 1.3.17]

Once the cleaning validation protocol has been implemented on three cleanings and the sampling and test-
ing has been completed, the data must be assembled and evaluated for each cleaning event. A cleaning
validation report should be prepared that consists of:

The cleaning validation protocol

All data assembled in a logical format
An analysis of the data that addresses any deviations in the protocol, explains any failures, compares
the data to the acceptance criteria, and ultimately states whether the cleaning process mayor may not
be considered validated

PROC - 2.q [ref. POL 1.5]

The Cleaning Verification Policy (CVP) can be considered to be the master plan for cleaning for a product
during the development phase of the lifecycle of the product. Since each cleaning is a unique event because
of the variability in the manufacturing equipment, formulation, and batch size between batches of the same

Journal of Validation Technology

Proposed Validation Standard VS-3

product, it is not possible to validate the cleaning process during the development phase. Still it is possible
to prepare a policy describing the testing of development equipment and what criteria will be used to deter-
mine if the equipment has been suitably cleaned. The strategy and approach to cleaning in the development
areas must be in writing and clearly explain how equipment will be sampled and tested, and how limits will
be determined, recognizing that only a single set of data will be available. Since only a single set of data is
available, it would be erroneous to refer to this situation as "validation". Thus the term "cleaning verifica-
tion" is a more appropriate description of this scenario.

PROC - 2.r [ref. POL 1.6]

The Cleaning Validation Master Plan (CVMP) may take different forms in companies around the world.
Some may have a separate independent document. Others may have a Standard Operating Procedure*
that describes in general terms how the cleaning program will operate. Still others will devote a section of
the Validation Master Plan* to cleaning. Regardless of the exact form taken, it is essential to have a writ-
ten plan describing how the cleaning program will be organized and controlled. The essential elements of
the CVMP are:

A description of the approach and strategy to be used for controlling, verifying, and/or validating in the
various departments such as Basic Research *, Research and Development *, Scale-Up! Pilot Plant*,
Production*, Packaging*, Contract Manufacturing Facilities *, and Contract Packaging Facilities *.
A mechanism for defining what is adequate cleaning, based on the potency, toxicity, potential aller-
genicity, potential teratogenicity, and potential carcinogenicity of the material, as well as other factors
such as route of administration and properties of the other products made in the same equipment.
Sampling methods to be used to evaluate cleaned equipment. Examples are Swab Sampling* and Rinse
Sampling*, or a combination of these two methods depending on the nature of the equipment or product.
Selection of sampling locations to include 'worst case' and/or most difficult-to-clean locations.
For equipment used for manufacturing multiple products, how the Worst Case Product* for cleaning pur-
poses might be selected from a group of very similar products. Typically, a Product Matrix Approach*
is used to compare the critical cleaning properties of the products in the group. Critical cleaning proper-
ties are potency/toxicity, solubility, and the inherent difficulty of cleaning.
Provision for how documentation will be developed, reviewed, and approved. This would include a list of
those responsible for preparing, reviewing, and approving Cleaning Verification Protocols, Cleaning
Verification Reports, Cleaning Validation Protocols, Cleaning Validation Reports, Cleaning Procedures,
Change Control Procedures, and Cleaning Monitoring Programs *.
Criteria for Revalidation* of cleaning procedures.
Provision for creation of a Site Validation Steering Committee (SVSC), that would serve as the group
immediately responsible for all cleaning issues. This group would normally select project teams relat-
ed to cleaning activities, e.g., for a new product.
Training of development, pilot plant, sampling, and analytical testing personnel.
Definition of resources required and allocated.
Schedule of cleaning activities including cleaning validation and assignment of responsibilities.

III. ACRONYMS

API Active Pharmaceutical Ingredient

BPC Bulk Pharmaceutical Chemical
CGMPs Current Good Manufacturing Practice (U.S.)
CIP Clean-in-Place
CPQ Cleaning Performance Qualification

Institute of Validation Technology

 Proposed Validation Standard VS-3

CVMP Cleaning Validation Master Plan

CVP Cleaning Verification Policy
IPEC International Pharmaceutical Excipients Council
IQ Installation Qualification
OQ Operational Qualification
PIC Pharmaceutical Inspection Convention
SOP Standard Operating Procedure
SVSC Site Validation Steering Committee

IV. GLOSSARY

Reference Standard
Number

POL 1.1 Active Pharmaceutical Ingredients (API) - (synonymous with drug substance). A substance
that is represented for use in a drug and, when used in the manufacturing, processing, or pack-
aging of a drug, becomes an active ingredient of a finished drug product. Such substances are
intended to furnish pharmacological activity or other direct effects in the diagnosis, cure, mit-
igation, treatment, or prevention of disease, or to affect the structure and function of the body
of humans or other animals.

Bulk Pharmaceutical Chemical (BPC) - includes active pharmaceutical ingredients (APIs) as

well as non-active excipients such as starch, lactose, rnicrocellulose, and other materials that
have no direct therapeutic effect but may indirectly affect the performance of drug dosage forms.

PROC2.h Analytical Method Validation - documented evidence that an analytical procedure will con-
sistently detect and/or quantitate materials.

PROC-2.r Basic Research - the segment of the pharmaceutical industry that evaluates new chemical
entities for potential application to treatment of disease. This includes, but is not limited to,
basic disciplines such as biochemistry, molecular biology, toxicology, pharmacology, and
pharmacokinetics.

POL 2.3 Change Control Procedure - A procedure for:

(a.) Identifying all modifications or alterations that are potentially significant to a state of con-
trol, qualification, or validation.
(b.) Implementing corrective action, such as repair, readjustment, requalification, and/or
revalidation.
(c.) Implementing interim measures to be taken until effective corrective actions are complete.
(d.) Documenting all of the above.

POL 1.3.9 Cleaning Agents - any chemical or solvent that facilitates the cleaning of equipment by dis-
solution, hydrolysis, or other chemical or physical action.

PROC-2.r Cleaning Monitoring Program - a formal, written program describing how cleaning proce-
dures can be monitored on a regular schedule to evaluate the effectiveness and consistency of
the cleaning process.

Journal of Validation Technology

Proposed Validation Standard VS-3

POL 1.3.18 Cleaning Performance Qualification (CPQ) - documented evidence that a cleaning proce-
dure is consistent in removing product residue and cleaning agent from equipment.

POL 1.3.9 Cleaning Procedure - a detailed written procedure (SOP) that describes how equipment will
be disassembled, cleaned, examined, and reassembled.

POL 1.3.12 Cleaning Validation - documented evidence that a cleaning procedure is consistent in remov-
ing product residue and cleaning agents from equipment (sometimes also referred to as
Cleaning Performance Qualification [CPQ]).

POL 1.6 Cleaning Validation Master Plan (CVMP) - a comprehensive, written plan that describes the
company's strategy in ensuring that all cleaning procedures are effective and in a state of con-
trol to ensure that all products are free of contamination and of high qUality. The plan includes
or references all appropriate cleaning procedures, and SOPs describes how protocols, cleaning
validation reports, and other documentation will be assembled, provides for the testing and
analysis of data, identifies resources to be allocated, provides for training of personnel, describes
qualification of equipment, indicates the process for assigning responsibility for the various
activities, provides a criteria for revalidation of cleaning procedures, and describes a mechanism
for controlling changes to validated procedures and equipment.

PROC-2.o Cleaning Validation Limits - The maximum allowable amounts of material that can remain
on equipment after cleaning without compromising the safety of the consumer or the quality
of the product. These limits are applied during the cleaning validation study and depending on
the manufacturing circumstances, limits may be for:

Residues of active ingredients

Residues of excipients
Degradation materials
Intermediates
Cleaning agent or by-product residuals
Bioburden
Endotoxin
Other foreign materials

POL 1.3.15 Cleaning Validation Protocol - a product specific plan of sampling and testing of equipment
after at least three consecutive cleanings to establish that equipment is appropriately cleaned
after a specific product is manufactured in a development area by a specific, detailed written
cleaning procedure.

POL 2.0 Cleaning Validation Reports - a written report that summarizes results and conclusions of
the cleaning validation study and includes:

Protocol
Test results
Analyses
Conclusions
Discussions of any deviations from procedures specified in the original protocol
Discussion of any failures

Institute of Validation Technology

 Proposed Validation Standard VS-3

Indication as to whether the testing met the acceptance criteria specified in the protocol

POL 1.3.8 Cleaning Verification Limits - Maximum amount of residue that may remain on equipment
during a cleaning verification study. These limits are derived in a similar fashion to those for a
cleaning validation study, but are applied to a single cleaning event, as versus multiple clean-
ing runs (at least three) for cleaning validation studies. Just as for cleaning validation, the lim-
its may be for any of the following:

Residues of active ingredients

Residues of excipients
Degradation materials
Intermediates
Cleaning agents or by-product residuals
Bioburden
Endotoxin
Other foreign materials

POL 1.5 Cleaning Verification Policy (CVP) - a written document describing how equipment will be
verified as clean after a single manufacturing event in a development area. This is a general
document that will pertain to all cleaning in development areas.

POL 1.2 Cleaning Verification Protocol- a product specific plan of experimental sampling and test-
ing to verify that equipment is appropriately cleaned after a specific product is manufactured
in a development area.

POL 1.9 Cleaning Verification Reports - a written report that summarizes results and conclusions of
the cleaning verification study and includes:

Protocol
Test results
Analyses
Conclusions
Discussions of any deviations in procedures from those specified in the original protocol
Discussion of any failures
Indication as to whether the testing met the acceptance criteria specified in the protocol

PROC-2.1 Clean-in-Place (CIP) - cleaning of equipment that is accomplished without disassembly of

the equipment but rather through the application of cleaning solutions delivered internally by
one or more internal spray devices (sprayballs) or recirculation of cleaning solution throughout
the equipment. CIP may be entirely automated or the cycle parameters may be controlled by
the operator. This type of cleaning is also known as closed system cleaning.

PROC-2.r Contract Manufacturing Facilities - facilities or companies that manufacture products for
customers on a contractual basis.

PROC-2.r Contract Packaging Facilities - facilities or companies that package products for customers
on a contractual basis.

Journal of Validation Technology

Proposed Validation Standard VS-3

POL 1.3.9 Critical Cleaning Process Operating Parameter - an operating variable that is assigned a
required control range with acceptability limits, outside of which exists potential for product
or process failure. A critical process operating parameter is determined by process develop-
ment and/or investigational work.

POL 1.3.3 Critical Product Cleaning Specifications - physico-chemical properties as well as therapeutic
or medical information that are used to determine cleaning procedures and set limits for cleaning
processes. Examples are solubility, stability, hydrophobicity, therapeutic potency, and toxicity.

POL 1.1 Drug Products - a finished dosage form (e.g., tablet, capsule) that contains an API, general-
ly in association with excipients. Synonymous with finished drug product.

POL 1.1 In-Process Materials - (as applied to drug product manufacture) - any material manufac-
tured, blended, compacted, coated, granulated, encapsulated, tableted, or otherwise processed
that is produced for and used in the preparation of a drug product. (Corresponding materials
used in the preparation of APIs are referred to as intermediates.)

PROC-2.1 Installation Qualification (IQ) - documented verification that equipment, system, or a sub-
system has been properly installed, adheres to applicable codes and approved design inten-
tions, and supplier recommendations have been suitably addressed.

POL 1.1 Intermediate - a material produced during steps in the synthesis of an API that must under-
go further molecular change or processing before it becomes an API. The degree to which a
given intermediate should be rated "critical" with respect to cleaning must be determined by
a firm's experts based on such criteria as:

Potential toxicity or other physiological activity

Degree to which equipment used is dedicated to the process, as opposed to having multiple uses
Ease or difficulty of removing process residuals when cleaning equipment

PROC-2.h Limit of Detection (LOD) - the lowest amount or concentration of a material that can be
detected by an analytical instrument or chemical test. Although detectable, the amount of
material in the sample cannot be determined at this level.

PROC-2.h Limit of Quantitation (LOQ) - the lowest amount or concentration of a material that can be
quantitatively determined by an analytical instrument or chemical test.

PROC-2.1 Operational Qualification (OQ) - documented verification that equipment, system, or

process performs as specified throughout representative or anticipated operating ranges.
(Note: Overlap between IQ and OQ often occurs and is considered allowable, but should be
addressed in the VMP.)

PROC-2.r Packaging - The area or department that receives bulk product and incorporates the product
in packaging that will either be sent to the customer or sent to another area for additional pack-
aging and/or labeling.

PROC-2.r Production - The unit of the company responsible for the manufacture of bulk product. This
mayor may not include the packaging function depending on the size and organization.

Institute of Validation Technology

 Proposed Validation Standard VS-3

POL-2.1 Production Authority - counterpart of quality authority, sometimes referred to as production

head or, in the case of FLP (Fill-Label-Pack) operations, packaging head.

PROC-2.r Product Matrix Approach - a chart that presents medical, toxicity, solubility, and other per-
tinent data so that a comparison can be made between products in the group in order that the
most risky product can be selected for cleaning validation. This 'worst case' approach obvi-
ates the need to perform cleaning validation studies on every combination of product and
equipment.

POL 1.2 Quality Authority - one or more persons who, collectively, have formal responsibilities for
specified quality-related operations, such as approval of manufacturing materials, release of
finished products, review and approval of documents, and adjudication of quality assurance
investigations. Titles of quality authority principals vary throughout the world; for example, in
the U.S., one term "the Quality Control (QC) unit," is all embracing; in the E.U. and Canada,
the head of quality control has some of the responsibilities, while a qualified person has oth-
ers; terms as responsible head (or person) and quality assurance (and/or control) department are
also used in other areas.

PROC-2.r Research and Development - The division of a company that is responsible for developing
the optimal manufacturing techniques and dosage form for a pharmaceutical product. It is also
responsible for the development of preliminary cleaning procedures for new products.

PROC-2.r Revalidation - repeating the original validation or selected portions for the purpose of
demonstrating that the process is still in a state of control and delivers acceptable product and
processes. As applied to cleaning procedures, the purpose would be to demonstrate that the
cleaning procedures are still effective in removing residues. Revalidation is a natural conse-
quence of making significant changes to equipment, manufacturing procedures, components,
cleaning procedures, and cleaning agents.

PROC-2.r Rinse Sampling - a type of sampling of cleaned equipment used in cleaning validation and
cleaning verification studies to determine if product-contact manufacturing surfaces are clean.
Controlled amounts of solvent are subjected to the equipment either under pressure or allowed
to stand in the equipment to allow dissolution of the residues. Mixing, spraying, and recircu-
lation may also be used to facilitate the detection of residues. Rinse solvents are usually
selected on the basis of residue solubility in that solvent. The rinses may be either heated or
at ambient temperature.

PROC-2.r Scale-UplPilot Plant - Functionally, this area of responsibility is between development and
full-scale production. This group is charged with scaling a formulation up from small scale to
large production scale and troubleshooting problems that arise as a result of the scale-up pro-
cess. They are also responsible for further refinements of the cleaning procedures handed over
by development.

POL 1.2 Site Validation Steering Committee (SVSC) - a standing committee with authority and
responsibilities for validation policies, practices, and adjudication of issues. Must include
quality authority and Production Authority representation, and often includes representatives
of other involved disciplines. The name of the SVSC may vary from firm-to-firm.

Journal of Validation Technology

Proposed Validation Standard VS-3

PROC-2.m Spray Devices (Sprayballs) - a device that may be either permanently installed or inserted
into closed systems such as tanks specifically to provide a thorough, even coverage of the
equipment surfaces by the cleaning solutions. If fixed and spherical in shape, the device is
usually referred to as a "sprayball." Sprayballs may have fixed heads or they may rotate in
complex patterns.

PROC-2.1 Sprayball Pattern Analysis - a study that establishes that cleaning solution delivered by
sprayballs will reach all equipment surfaces, especially difficult to access or shadowed areas.
The study usually consists of coating equipment with easily detectable residue (dyes or fluo-
rescent material), activating the sprayball mechanism for a normal cycle cleaning time, and
then examining the equipment to see if any material remains on the equipment surfaces.

PROC-2.r Standard Operating Procedure (SOP) - A written document describing, in detail, a specif-
ic process or procedure. These written procedures are required by the current Good Man-
ufacturing Practice regulations for all critical processes. These procedures must be current,
detailed, controlled, and revised when necessary. All personnel must be trained in a new or
revised SOP prior to its implementation. Some companies have function specific procedures,
e.g., cleaning procedures, that take the place of SOPs.

PROC-2.r Swab Sampling - a type of sampling of cleaned equipment used in cleaning validation and
cleaning verification studies to determine if product-contact manufacturing surfaces are clean.
This type of sampling makes use of small pieces of fabric (usually polyester or other synthet-
ic material) fused to the end of a plastic strip. The swab is typically wetted with solvent
(although they can be used dry). Defined surface areas of equipment, including the most dif-
ficult-to-clean locations, are swabbed. The swab is then immersed in a vial of solvent. The
residue on the swab is dissolved in the solvent, which is subsequently analyzed for product
residues. Limits are calculated on the basis of the area swabbed.

PROC-2.r Validation Master Plan (VMP) - a comprehensive, project-oriented action plan that includes
or references all protocols, key SOPs and policies, existing Validation Task Reports *, and
other relevant materials on which the specific system or process validation effort will be
based. The plan also identifies resources to be allocated, specific personnel training, and qual-
ification requirements of relevant, organizational structure, and responsibilities of the valida-
tion team, and planned schedules. The VMP is subject to periodic revisions as defined in
change control procedures.

Validation Task Report - a written report that summarizes results and conclusions following
execution of all or any portion of a Validation Master Plan (VMP) (often referred to as a final
report if summarizing all activities of the VMP).

PROC-2.r Worst Case Product - the product selected from a group of similar products that presents the
greatest risk of carryover contamination to other products made in the same equipment by
virtue of its poor solubility, unstable chemical properties, potency, toxicity, or a combination
of these factors.

Institute of Validation Technology

 Proposed Validation Standard VS-3

v. SELECTED REGULATORY EXCERPTS

Regulatory Reference

FDA Proposed Amendments to current Good Manufacturing

Practice Regulations Section Ill. C (May 3, 1996)

Under CGMP, a manufacturer will set contamination limits on a substance-by-substance basis, according to both
the potency of the substance and the overall level of sensitivity to that substance.

Because other substances, such as cytotoxic agents, or other antibiotics, pose at least as great a risk of toxicity
due to cross-contamination, FDA is proposing to expand the contamination control requirements to encompass
other sources of contamination.

The Agency has refrained from establishing a list of drugs or drug products that present such an unacceptable
risk, because such a list would quickly become obsolete.

FDA Guidance for Industry: Manufacturing,Processing, or Holding

Active Pharmaceutical Ingredients Section IV.D (March, 1998)

Nondedicated equipment should be thoroughly cleaned between different products and, if necessary, after each
use to prevent contamination and cross-contamination. If cleaning a specific type of equipment is difficult, the
equipment may need to be dedicated to a particular API or intermediate.

The choice of cleaning methods, cleaning agents, and levels of cleaning should be established and justified.

FDA Guidance for Industry: Manufacturing, Processing, or Holding Active

Pharmaceutical Ingredients Section IV.E (March, 1998)

Equipment cleaning methods should be validated, where appropriate. In early synthesis steps, it may be unnec-
essary to validate cleaning methods where residues are removed by subsequent purification steps.

If various API's or intermediates are manufactured in the same equipment and the equipment is cleaned by the same
process, a worst-case API or intermediate can be selected for purposes of cleaning validation. The worst-case selec-
tion should be based on a combination of potency, toxicity, solubility, stability, and difficulty of cleaning.

The cleaning validation protocol should describe the equipment to be cleaned, methods, materials, extent of
cleaning, parameters to be monitored and controlled, and analytical methods.

Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to
detect both insoluble and soluble residues. Swab sampling may be impractical when product contact surfaces are
not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer
pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as microniz-
ers and microfluidizers).

Validated analytical methods sensitive enough to detect residuals or contaminants should be in place.

Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue.

Journal of Validation Technology

Proposed Validation Standard VS-3

FDA Guidance for Industry: Manufacturing, Processing, or Holding Active

Pharmaceutical Ingredients Section IV.F (March, 1998)

When practical, equipment in CIP systems should be disassembled during cleaning validation to facilitate in-
spection and sampling of inner product surfaces for residues or contamination, even though the equipment is not
normally disassembled during routine use.

FDA Part 211-Current Good Manufacturing Practice for Finished

Pharmaceuticals Subpart D, Section 211.67 (1990)

Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent contamina-
tion that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other
established requirements.

Written procedures shall be established and following for cleaning and maintenance of equipment, including
utensils, used in the manufacturing, processing, packing, or holding of a drug product.

FDA Guide to Inspections of Validation of Cleaning Processes, (July, 1993)

FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on
each manufacturing system or piece of equipment, which should address such issues as sampling procedures,
and analytical methods to be used, including the sensitivity of those methods.

FDA expects firms to conduct the validation studies in accordance with the protocols and to document the results
of studies.

FDA expects a final validation report which is approved by management and which states whether or not the clean-
ing process is valid. The data should support a conclusion that residues have been reduced to an "acceptable level."

Examine the design of equipment, particularly in those large systems that may employ semi-automatic or fully
automatic clean-in-place (CIP) systems since they represent significant concern. For example, sanitary type pip-
ing without ball valves should be used. When such nonsanitary ball valves are used, as is common in the bulk
drug industry, the cleaning process is more difficult.

Examine the detail and specificity of the procedure for the cleaning process being validated, and the amount of
documentation required.

When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for
example certain bulk drug synthesis processes).

Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants.

The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge
of the materials involved and be practical, achievable, and verifiable.

Check the manner in which limits are established.

If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting
to test for residues.

FDA Guide to Inspections of Bulk Pharmaceutical Chemicals (May, 1994)

Cross contamination is not permitted under any circumstances.

Institute of Validation Technology

 Proposed Validation Standard VS-3

The cleaning program should take into consideration the need for different procedures depending on what prod-
uct or intermediate was produced.

Where mUltipurpose equipment is in use, it is important to be able to determine previous usage as an aid in inves-
tigating cross-contamination or the possibility thereof.

Cleaning of multiple use equipment is an area where validation must be carried out.

Validation data should verify that the cleaning process will remove residues to an acceptable level.

There should be a written equipment cleaning procedure that provides details of what should be done and mate-
rials to be utilized.

We expect the manufacturer to establish an appropriate impurity profile for each BPC based on adequate con-
sideration of the process and test results.

PIC Document PR 1/99-2 "Cleaning Validation" Section 1.0 (April, 2000)

Cleaning procedures must strictly follow carefully established and validated methods of execution. This applies
equally to the manufacture of pharmaceutical products and bulk active ingredients.

PIC Document PR 1/99-2 "Cleaning Validation" Section 2.1 (April, 2000)

Normally only cleaning procedures for product contact surfaces need to be validated.

PIC Document PR 1/99-2 "Cleaning Validation" Section 2.2 (April, 2000)

Cleaning procedures for product changeover should be fully validated.

PIC Document PR 1/99-2 "Cleaning Validation" Section 2.6 (April, 2000)

At least three consecutive applications of the cleaning procedure should be performed and shown to be success-
ful in order to prove that the method is validated.

PIC Document PR 1/99-2 "Cleaning Validation" Section 2.8 (April, 2000)

Control of change to validated cleaning procedures is required. Revalidation should be considered under the fol-
lowing circumstances:
(a) Revalidation in cases of changes to equipment, products or processes.
(b) Periodic revalidation at defined intervals.

PIC Document PR 1/99-2 "Cleaning Validation" Section 3.1 (April, 2000)

A validation protocol is required laying down the general procedures on how cleaning processes will be validat-
ed. It should include the following:
The objective of the validation process
Responsibilities for performing and approving the validation study
Description of the equipment to be used
The interval between the end of production and the beginning of the cleaning procedures
Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment.
Any routine monitoring requirement
Sampling procedures, including the rationale for why a certain sampling method is used
Data on recovery studies where appropriate

Journal of Validation Technology

Proposed Validation Standard VS-3

Analytical methods including the limit of detection and the limit of quantitation of those methods
The acceptance criteria, including the rationale for setting specific limits
When revalidation will be required

PIC Document PR 1/99-2 "Cleaning Validation" Section 3.3 (April, 2000)

A final validation report should be prepared. The conclusions of this report should state if the cleaning process has
been validated successfully. Limitations that apply to the use of the validated method should be defined (for exam-
ple, the analytical limit at which cleanliness can be determined). The report should be approved by management.

PIC Document PR 1/99-2 "Cleaning Validation" Section 3.4 (April, 2000)

The cleaning process should be documented in an SOP. Records should be kept of cleaning performed in such a
way that the following information is readily available:
The area or piece of equipment cleaned
The person who carried out the cleaning
When the cleaning was carried out
The SOP defining the cleaning process
The product which was previously processed on the equipment being cleaned

PIC Document PR 1/99-2 "Cleaning Validation" Section 3.5 (April, 2000)

The cleaning record should be signed by the operator who performed the cleaning and by the person responsi-
ble for the Production and should be reviewed by Quality Assurance.

PIC Document PR 1/99-2 "Cleaning Validation" Section 4.1 (April, 2000)

Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures.
Training records should be available for all training carried out.

PIC Document PR 1/99-2 "Cleaning Validation" Section 5.1 (April, 2000)

The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be iden-
tified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.

PIC Document PR 1/99-2 "Cleaning Validation" Section 5.2 (April, 2000)

Dedicated equipment should be used for products, which are difficult to remove (e.g., tarry or gummy residues
in the bulk manufacturing), for equipment, which is difficult to clean (e.g., bags for fluid bed dryers), or for prod-
ucts with a high safety risk (e.g., biologicals or products of high potency which may be difficult to detect below
an acceptable limit).

PIC Document PR 1/99-2 "Cleaning Validation" Section 6.1 (April, 2000)

The existence of conditions favorable to reproduction of microorganisms (e.g., moisture, sub-strength, crevices,
and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive micro-
bial contamination.

PIC Document PR 1/99-2 "Cleaning Validation" Section 7.1 (April, 2000)

Samples should be drawn according to a written sampling plan.

Institute of Validation Technology

 Proposed Validation Standard VS-3

PIC Document PR 1/99-2 "Cleaning Validation" Section 7.2 (April, 2000)

There are two methods of sampling that are considered to be acceptable: direct surface sampling (swab method)
and the use of rinse solutions. A combination of the two methods is generally the most desirable, particularly in
circumstances where accessibility of equipment parts can mitigate against direct surface sampling.

PIC Document PR 1/99-2 "Cleaning Validation" Section 8.1 (April, 2000)

The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable lim-
its should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The pos-
sibility of detergent breakdown should be considered when validating cleaning procedures.

PIC Document PR 1/99-2 "Cleaning Validation" Section 9.1 (April, 2000)

The analytical methods should be validated before the cleaning validation study is carried out.

PIC Document PR 1/99-2 "Cleaning Validation" Section 9.2 (April, 2000)

The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed
and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.

PIC Document PR 1/99-2 "Cleaning Validation" Section 10.1 (April, 2000)

The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a con-
sideration of the materials involved and their dosage regimes. The limits should be practical, achievable, and verifiable.

PIC Document PR 1/99-2 "Cleaning Validation" Section 10.2 (April, 2000)

The approach for setting limits can be:

Product specific cleaning validation for all products
Grouping into product families and choosing a "worst case" product
Grouping into groups of risk (e.g., very soluble products, similar potency, highly toxic products, difficult to detect)

PIC Document PR 1/99-2 "Cleaning Validation" Section 10.3 (April, 2000)

Carry-over of product residues should meet defined criteria, for example the most stringent of the following three criteria:
(a) No more than 0.1 % of the normal therapeutic dose of any product will appear in the maximum daily dose of
the following product.
(b) No more than 10 ppm of any product will appear in another product.
(c) No quantity of residue will be visible on the equipment after cleaning procedures are performed. Spiking
studies should determine the concentration at which most active ingredients are visible
(d) For certain allergenic ingredients, penicillins, cephalosporins, or potent steroids and cytotoxics, the limit should
be below the limit of detection by best available analytical methods. In practice, this may mean that dedicated
plants are used for these products. 0

About the Author

William E. Hall, PhD., is the President of Hall & Associates, where he provides consulting on cleaning validation,
process validation, and compliance issues for the pharmaceutical industry. Dr. Hall is internationally recognized
as an authority on the subject of cleaning validation. Dr. Hall serves on the Editorial AdviSOry Board of the Journal
of Validation Technology, and is a member of the Institute of Validation Technology Hall of Fame. Dr. Hall received
his PhD. from the University of Wisconsin, and is a former professor at the University of North Carolina. Dr. Hall
can be reached by phone at 910-458-5068, by fax at 910-458-5068, or bye-mail at CleanDoct@aol.com.

Journal of Validation Technology