JVT_August2007.

qxd 8/11/07 2:41 PM Page 264

CONFERENCE REPORT

Effective Master Planning for

Cleaning Validation including
Protocol Development
P R E S E N T E D : M I G U E L M O N TA LV O L C O M P I L E D B Y J U A N I TA F U G E

INTRODUCTION Cleaning Validation Policy/Program
To establish a cleaning validation policy and pro-
The Institute of Validation Technology held a gram, first, define the purpose and objective of the pro-
conference on the topic of Cleaning Validation and Criti- gram. State the reason for the policy and set cleaning
cal Cleaning Processes in downtown Chicago, Illinois, validation (CV) requirements for the scope of the poli-
July 24 through 27. Along with the main conference, cies establishing processes for the equipment and facili-
information was presented in three tracks: engineering, ties affected. The programs policies should define
analytical, and validation. In conjunction with the princi- responsibilities, and terms, as well as include appropriate
ples presented at the conference, an offsite demonstration internal and external references.
day was sponsored mid-week by Dober
Research Works and held at their facil- Figure 1
ity where cleaning devices and methods Cleaning Validation Documentation Chart
were demonstrated and discussed to the
benefit of all who attended.

Miguel Montalvo, President of Ex-

pert Validation Consulting, Inc., served Cleaning Validation (CV)
as one of the conference speakers on Policy/Program
the validation track. Mr. Montalvo
spoke on effective master planning for
cleaning validation. The following ar-
ticle was compiled from the speakers
presentation and attendee notes.
Cleaning Validation Cleaning Validation
Procedures Master Plan

CV Protocols
and Reports

264 Journal of Validation Technology

JVT_August2007.qxd 8/11/07 2:41 PM Page 265
CONFERENCE REPORT
Once the program and policies are in place, follow
with the procedures developing in tandem a cleaning val-
idation master plan. The procedures should include cur-
rent analytical requirements and provide for updates to
the plan. These updates should include documentation
protocols, report formats and timetables, as well as other
CV maintenance guidelines such as change control pro-
cedures.
CLEANING VALIDATION MASTER
PLAN DEVELOPMENT
The essential elements for developing a cleaning val-
idation master plan include:
Master Plan Outline (see Figure 1)
Understanding FDAs Expectations and Per-
spective
Gathering Required Information on:
- Products
- Equipment
- Cleaning procedures and agents
- Hold Times
Cleaning Validation Master Plan Outline
Approvals
Objective
Scope
Responsibilities
References Cleaning Validation Policy and
additional procedures and documents
Cleaning Validation Strategy and Approach
- Matrices of products, equipment,
procedures, and cleaning agents
- Selection of test conditions products and
components to be tested
- Analytical method requirements
- Determination of acceptance criteria limits
Protocol and Final Report Requirements
Tentative Schedule
Validation Maintenance
FDAs Expectation Perspective
These comments are based on the FDAs Guide to In-
spections Validation of Cleaning Processes, published in
July 1993. This perspective is intended for chemical
residues. Products affected by microbiological contami-
nation must include these considerations during the vali-
dation and are not to be confused with sanitization chal-
lenges or validation.
The FDA expects to see a policy or general procedure
on how cleaning processes will be validated, including a
definition of responsibilities along with revalidation re-
quirements (not necessarily a cleaning validation master
plan). There should also be detailed written procedures
addressing the varied equipment and product types that
require different cleaning procedures. This includes the
cleaning differences between campaigns of the same
product, steps, and intermediate processes vs. unique
products. Residues from the cleaning processes, such as
detergents or solvents, must be removed.
Protocols per equipment are to be included with sam-
pling procedures and locations, analytical methods, accep-
tance criteria, and residue limits. A report summarizing
the results and concluding that each cleaning procedure is
considered valid because the residues have been reduced
to an acceptable level should also be included.
When considering analytical methods, the FDA ex-
pects to see criteria and validated documentation within
quantification limits. These should include sampling pro-
cedure techniques, materials and solvents used, etc. Lim-
its should be established that correlate with the analytical
method and recovery capabilities. (Suggestion: Ask
whether there are to be recovery limit minimums.)
Routine production monitoring should be established
for rinse samples, conductivity, total organic carbon
(TOC), etc. Detergents must be easily removable. There
must be adequate cleaning and drying of equipment along
with proper storage conditions. All microbiological as-
pects, including preventive measures, should be included.
You will need data to support hold times after (and before)
cleaning, and/or any sanitation procedure validation.
Cleaning Procedures and Documentation
Regarding FDAs expectations concerning cleaning
procedures and documentation reviews, you should count
on documenting each step to completion. Expect to go
into more detail for manual cleaning processes because
these have more variables and generally provide more
chances for error. Parameters should clearly define times,
temperatures, and detergent concentrations. If cleaning
between runs of same product, visibly clean may be
enough, but you must address micro and detergent or sol-
vent residue concerns.
Along with these issues, dedicated equipment and the
M a y 2 0 0 7 Vo l u m e 1 3 , N u m b e r 3 265
JVT_August2007.qxd 8/11/07 2:41 PM Page 266
CONFERENCE REPORT
use of replacement parts vs. cleaning validation should
also be discussed in the procedures and documentation.
The procedures should include a thorough equipment de-
sign review as well as your training plan or outline.
PDA Technical Report #29
An extremely useful document, PDA Technical Re-
port #29, Points to Consider for Cleaning Validation,
published August 1998, is important reading for cleaning
validation practitioners. There you will find a definition
of cleanability, a key criterion in the design of equip-
ment. You will also read details regarding PDAs stance
on non-dedicated cleaning equipment used for dedicated
processing equipment (clean-out-of-place, COPs, spray
balls). Campaign production - when cleaning between
same product must be challenged. Detailed descriptions
of grouping approaches noted earlier in this article for
product, equipment, cleaning method or agent can be use-
ful in many applications. Also described is the required
extent of disassembly of equipment, an extensive list of
sampling methods, as well as recommended safety fac-
tors and limits determinations.
Cleaning Validation vs. Cleaning Verification
Cleaning validation is generally done on known
processes with established cleaning procedures in a com-
mercial production environment. Cleaning verification is
performed on unknown, or not well established,
processes, for example, when you are developing clean-
ing procedures such as for clinical trials.
Cleaning verification is a procedure or protocol de-
signed to test each time the product is manufactured
under similar conditions as if doing cleaning validation.
The acceptability of results is evaluated for each tested
batch or process. Limits may not be well defined due to
lack of information. This lack of information may justify
the use of standard limits, such as 10ppm. Document
your reasoning for limits used in all cases.
266 Journal of Validation Technology
GATHER REQUIRED
INFORMATION
This is the heart of the master plan. Gather lists of
products, equipment, raw materials, cleaning agents, and
cleaning procedures. Construct matrices of each product
relative to its applicable production equipment, raw ma-
terials, cleaning agent(s), and cleaning procedures.
Gather information on raw materials including the MSDS
sheets, Hard to Clean materials, active ingredient
PADs, and cleaning agent components.
The master plan is based on a particular time (prod-
ucts being manufactured, procedures, equipment) but it
can be updated frequently as needed. Establish the fre-
quency of review and update within the policy.
Cleaning Validation Master Plan Key Components
Matrix Development
- Family grouping approach
- Cleaning procedure similarities
- Equipment usage by product family
Worst Case Selection
- Minimum pharmacological or therapeutic
level evaluation
- Toxicity levels evaluation
- Hardest to clean component
- Components solubility analysis
- Equipment considerations
Sampling Plan and Limits Determination Ap-
proach
Equipment Conditions and Cleaning Procedure
Review
- CIP equipment design and qualification
- COP equipment design and qualification
- Manual cleaning procedures
Analytical Methods Development and Validation
Cleaning Validation Documents
- Prerequisites
Cleaning Validation Maintenance
- Change control
- New products
- Cleaning monitoring
- Cleaning and use logs
- Training programs
- Equipment maintenance
JVT_August2007.qxd 8/11/07 2:41 PM Page 267
CONFERENCE REPORT
Matrix Development Requirements
To use a family grouping approach, develop lists of
products and group them in terms of types of product, for
example: solution vs. suspension, oil-based vs. alcohol-
based, or alcohol- vs. water-based. You might group them
by the areas in which they are manufactured. Other
grouping approaches include cleaning procedure similar-
ities or same equipment used. Develop lists of products
and look for those that use the same detergents or sol-
vents, the same cleaning parameters, or the same equip-
ment, grouping them accordingly.
Worst Case Selection
Develop a selection procedure for the worst case using
a combination of the following areas and the information
gathered on the matrices you have previously developed:
Minimum Pharmacological or Therapeutic Level
Evaluation
Toxicity Levels Evaluation
Hardest to Clean Component
Components Solubility Analysis
Equipment Considerations
These may result in several combinations selected as
worst cases.
Sampling Plan Techniques
Swab and rinse techniques are mainly used in sam-
pling, although swabbing is preferred; however, there are
drawbacks. Swabbing is technique dependent. Practition-
ers often find recovery is inhibited by swabs in that criti-
cal areas may be hard to reach. These drawbacks can be
overcome by well defined standard operating procedures
(SOPs) and thorough training programs. Recovery stud-
ies and rinse sampling can complete backup procedures
to ensure proper sampling.
Further, new technologies can be employed to ensure
adequate cleaning and mitigate risks. Some of these in-
clude:
Ion Mobility Spectrometry
Solvent - Bulk Processes
ELISA - Protein Residues
Direct Surface Analysis
Bioluminescence
Spectrophotometry
Photo Electron Emission
Diffuse Reflectance Spectroscopy (DRS)
Near Infrared Spectroscopy
Sampling Plan - Site Selection
Careful selection of sampling sites is always required.
In best case situations, you can assume an even distribu-
tion of the contaminant and that sampling of any site will
be satisfactory. But best case situations seldom exist.
The worst case, and more conservative approach, is to
consider the non-uniform distribution of the contaminant.
Site selection may be based upon:
Equipment Geometry
Difficult to Clean Locations
Potential for Non-homogeneous Contamination
Different Materials of Construction
The number of sites to be selected may be based upon
considering of all the above along with the overall dimen-
sions of the equipment.
Determining Acceptance Limits
There should be no visible residue. Remember to
focus on residue, not on cleanliness. The FDA Guidance
indicates that limits should be practical, achievable, and
verifiable. Determine the maximum acceptable residue
in the subsequent batch and consider all products that
share the equipment in question. When considering batch
sizes smaller is worst case. When considering dosage
size larger is worst case. Calculate the maximum carry-
over for each contaminant and include all applicable
safety factors.
Risk Assessment
Not all products and conditions are similar. Consider
topicals vs. parenterals vs. aseptically filled product.
Some processes eliminate the residue in later steps while
others do not. Consistency may be obtained through au-
tomated or controlled cleaning processes.
The decisions being made about the products and
their cleaning procedures imply certain levels of risk.
M a y 2 0 0 7 Vo l u m e 1 3 , N u m b e r 3 267
JVT_August2007.qxd 8/11/07 2:41 PM Page 268
CONFERENCE REPORT
These will include:
Sampling Locations
Specific Contaminants
Matrix Approaches
Selection of Parameters to be Controlled or Mon-
itored
Materials and Methods Selected for Cleaning
Selection of Test Conditions
Select worst case products or components for each
criterion. These will include: pharmaceutical therapeutic
level, toxicity, level of cleaning difficulty, and solubility.
Also consider the cleaning agents. Select one combina-
tion for each product family, cleaning procedure (if dif-
ferent), and base on equipment usage. Select components
to determine residues, and then verify that the analytical
methods are available for these components at the re-
quired quantitation levels. The residue acceptable limits
can be included in the plan or in the specific protocols.
One protocol will be developed for each test condition or
combination thereof. Review each selection to verify that
the approach is feasible and defensible.
CLEANING VALIDATION
DOCUMENTS
Protocol
Establish a test procedure and acceptance criteria. In-
clude prerequisites with cleaning procedure review;
equipment design and characteristics review; and analyt-
ical method validated to quantify below selected limits.
Training on procedures including cleaning, sampling,
testing and analysis, must also be considered. The proto-
col should include a minimum of three cleaning chal-
lenges with worst case holding time for equipment before
cleaning (dirty hold time). Include criteria visibly clean
and residue limits in a complete report format. Compare
cleaning results with established limits.
Proposed Protocol Outline
Approvals
Purpose
Scope
References
Materials
268 Journal of Validation Technology
Responsibilities
Background
General Procedures
Limits Determination
Test Plan
- Prerequisites
- Cleaning procedure documentation
- Sampling requirements
Acceptance Criteria
Change Control
Attachments
Protocol Contents
The purpose of the protocol is said to:
Establish the procedures and documen-
tation required to demonstrate the capa-
bility of the Cleaning Procedure X when
applied to equipment Y to reduce residues
from previous processes and the cleaning
process itself to an acceptable level.
Clearly define the boundaries of the system being
tested such as reactors with distillation units, process
bays, or other systems, to express the scope of the system.
Include all regulatory, references, internal company poli-
cies, and SOPs. This will aid in easy cross-reference dur-
ing use and when being audited.
Include background information. If the protocol is
being developed because of a new product, change in
cleaning procedure, changes in equipment or for other
reasons, it is important to include that information as rea-
son for the creation of the protocol. Protocols should in-
clude all materials to be used: swabs, solvents, cleaning
agents, and others. Responsibilities by functional area
should be described and defined.
General Procedures should include:
Documentation Requirements
- Documentation policies and procedure refer-
ences
Personnel Requirements
- Signatures list
Handling of Deviations
- Reference to form and procedure
- QA involvement
JVT_August2007.qxd 8/11/07 2:41 PM Page 269
CONFERENCE REPORT
Prerequisites
Having the prerequisites in proper order will help en-
sure successful cleaning validation down the road. Com-
plete a cleaning procedure review along with an
equipment design. Map out and determine the cleaning
process CIP, COP, or manual, or a combination of the
three that you will be using. Indicate in the documenta-
tion the validated analytical methods you have chosen as
well as your sampling technique and recovery testing
methods.
Training
Among the most important prerequisite criteria is per-
sonnel training. Every individual who will be working on
the equipment must be trained on the cleaning proce-
dure(s), and equipment operation as appropriate. Labora-
tory personnel must be trained and qualified on the
analytical method and the sampling technique chosen. All
must be trained on proper documentation techniques.
Documentation of the training must be maintained.
Cleaning Procedure
The cleaning procedures should be included in the de-
velopment plan for the process in question. Consideration
must be made for the advantages and disadvantages of
manual vs. automated cleaning as decisions are made.
Some of the disadvantages of choosing manual cleaning
include its repetitive and inconsistent nature from the op-
erators point of view. Other operator driven issues may
include turnover concerns, new operator training and
error problems, and possible motivation considerations. It
may also be difficult to describe procedures in specific
detail. Manual cleaning may require the use of worst case
conditions during validation. With automated cleaning,
there are the advantages of controlled parameters and the
consistency of programmed cycles. Clean-in-place (CIP)
is used frequently for biopharmaceutical processes, but
COP and manual processes may be used in combination
with CIP when appropriate. Other cleaning procedures to
be defined include those to be completed between differ-
ent products vs. during campaigns of identical product.
Outline equipment-specific vs. generic procedures.
Define procedures for different product types. Define the
use of detergents including different concentrations and
formulas. When covering cleaning agent selection be sure
to justify and document your choices, indicating re-
sources and vendors. Include other parameters covering
the unique elements of your situation such as: time for
rinse and exposure to cleaning agent, temperature, mix-
ing time, contact time, water flow or pressure during
rinse, and any other mechanical action required.
CIP Characteristics
CIP capability must be considered during the equip-
ment and facility design. These include piping, nozzles,
drains, slope, deadlegs, and other equipment surfaces.
Check for adequate flow and pressure in spray devices,
paying special attention to components such as valves,
pumps, seals, and instrumentation. Filter materials,
resins, and columns must be compatible with solutions.
Finally, check for drainability. In a typical CIP cycle there
is a pre-rinse, detergent wash (alkaline), post rinse, acid-
ified wash, final rinse. All these must be properly drained.
Include computer validation requirements as needed.
Equipment Design Characteristics
Surfaces characteristics should be chemically inert
and resistant to heat and chemical attack. Be attentive to
all connections and valves, both for their function and
their cleanability. Choose spray balls carefully consider-
ing their capability and function. Choose a closed vs.
open loop system depending upon your production
needs; adequate sanitary piping must be provided to code.
Personnel must be made familiar with all equipment in
order to effectively clean the system(s).
Cleaning Agent Selection
The products you produce and the processes you em-
ploy will produce the soils to be removed. Consider all
equipment surfaces from which these soils must be re-
moved. Often, a combination of solutions provides
greater effect than a single solution. Typical cleaners in-
clude: solvents, bulk chemicals, and aqueous detergents.
These may be acidic, neutral, or alkaline. Vendors will
supply you with product, and validation data, as well as
method of use information.
Analytical Methods
Analytical method selection is dependent on the ma-
terial being sampled and the required limit of detection or
limit of quantification. Methods must be validated in con-
junction with sampling and extraction systems. Specific
methods are preferred, but non-specific methods can
work (such as TOC). New methods are constantly being
M a y 2 0 0 7 Vo l u m e 1 3 , N u m b e r 3 269
JVT_August2007.qxd 8/11/07 2:41 PM Page 270
CONFERENCE REPORT
developed, for example: ion mobility spectrometry, and
enzymatic (for biologicals).
Specific vs. Non-Specific Methods
It is important to correlate the specific methods used
for validation to the non-specific methods used for mon-
itoring. To use specific methods, extensive development
and validation may be required, which may be expensive
and could result in delayed results. Non-specific methods
are best used when residues are at, or below, the resulting
level and no specific amount is required. Using these
methods can be cost effective; you can often detect mul-
tiple soils in one test; however, you do run the risk of a
false failure. Each method has its drawbacks and should
be considered relative to your needs and the science of
your product in order to make the best decision in your
situation.
Analytical Methods Validation
Test method accuracy and precision will be molded by
tight acceptance criteria. Once all the data is generated
and reviewed, you will summarize it for your report. Im-
portant elements include: limit of detection, limit of
quantitation, specificity, range, linearity, and ruggedness.
Recovery Requirements
Establish recovery for individual contaminant(s) with
explicit sampling methods and materials and with spe-
cific method(s) and analyst(s). Although there is no stan-
dard limit, these must be performed in conjunction with
method validation protocols.
Documentation of Cleaning Processes
Each cleaning batch must be recorded and there must
be a witness to each completed validation. See that criti-
cal parameters verification, as well as all validation steps,
is well documented and verified.
Other required records include documentation of sam-
pling locations, time, and sampler. Laboratory documen-
tation must be kept for the analysis for each sample as
well as a review of the test results. Verify results against
acceptance criteria ensuring they are visually clean and
within calculated limits. Verify that the cleaning proce-
dure execution was adequate and properly documented
and that deviations were properly handled, justified, re-
solved, and approved.
270 Journal of Validation Technology
Cleaning Validation Report
In your report, compare results with established lim-
its. Each result must be not more than the calculated
MACO, taking into consideration the stated recovery fac-
tors. Establish maximum holding time for equipment be-
fore cleaning; all three runs must be held for the
maximum hold time indicated. Deviations must be prop-
erly handled and explained in the report. Conclusions
must be well defined.
Remaining in a Validated State
A strong change control program is the key to main-
taining validated status. Monitor all changes: changes in
cleaning agents, cleaning procedures, manufacturing
equipment or procedures, and changes in product formu-
las. Maintain proper evaluation and approval pre- and
post-change implementation. Document your evalua-
tions, follow-up studies and reports. Should a new prod-
uct be introduced, determine whether there is need to
validate it based on the matrices you have established.
Be vigilant in monitoring cleaning procedures. Make
sure equipment is visually clean every time. Establish a
frequency or periodic timetable to perform analytical pro-
cedures (TOC, pH, conductivity, etc.). Keep accurate
and regular cleaning and use logs. These will help you to
evaluate your procedures, your solvents, and serve as ex-
cellent documentation of your decision making to FDA.
Equipment maintenance falls into this category. Changes
must go through the change control system and its rele-
vant procedures. Finally, and although mentioned before,
a robust training program is essential to maintaining all
elements of the system in a validated status. If your peo-
ple do not know what they are doing and why, your sys-
tem is bound to fail!
Revalidation Is it required?
Base revalidation on continuous monitoring data and
change control. Establish a frequency for data evaluation.
Do not necessarily repeat the validation blindly.
JVT_August2007.qxd 8/11/07 2:41 PM Page 271
CONFERENCE REPORT
CONCLUSION
Cleaning Validation efforts are sufficiently complex in
nature and require an effective plan for the successful ex-
ecution of the cleaning validation master plan. Applica-
tion of a matrix approach and worst case selection allows
for the program to be effective not only in terms of its ex-
ecution but also in its maintenance.
REFERENCES
1. PDA Journal of Pharmaceutical Science and Technology
- Technical Report #29: Points to Consider for Cleaning
Validation. 1998 Supplement Volume 52, Number 6.
2. FDA Guide to Inspections Validations of Cleaning
Processes, 1993.
3. Cleaning and Cleaning Validation: A Biotechnology
Perspective. PDA, 1995.
4. IVT Standards Committee Proposed Validation Standard
VS-3 Cleaning Validation, Journal of Validation
Technology, Volume 8, Number 1, November 2001.
5. Mark Altier Detergent Selection A First Critical Step in
Developing a Validated Cleaning Program, Journal of
Validation Technology, Volume 8, Number 1, November
2001.
6. William Hall Cleaning Validation: Maximum Allowable
Residue Questions and Answers, Journal of Validation
Technology, Volume 8, Number 3, May 2002.
ABOUT THE SPEAKER
Mr. Miguel Montalvo has over 23 years of valuable
experience in the areas of cGMP compliance,
quality systems, and validation functions, and re-
sponsibilities. He is the owner and President of
Expert Validation Consulting, Inc., a firm special-
izing on focused, practical consulting for the Phar-
maceutical and OTC Drug Industry.
Before forming EVC, Mr. Montalvo held positions
of increasing responsibility in the areas of Valida-
tion, Technical Services, and Quality Operations
in companies such as AAC Consulting Group, Inc,
Millipore Corporation, Raytheon Engineers and
Constructors, Mova Pharmaceutical Corp., Bris-
tol-Myers Squibb, and Baxter Healthcare Corpo-
ration. He has managed the validation efforts for
numerous facilities both existing and those under
start-ups/major renovations with processes in-
cluding bulk APIs, solid-dosage, parenterals, top-
icals, liquids, and medical devices. He has
developed comprehensive and compliant quality
and validation programs/systems for numerous
companies and provided support and assess-
ments for many existing operations.
Miguel holds a BS in Chemical Engineering from
Rensselaer Polytechnic Institute and an MBA.
His expertise includes areas such as interna-
tional regulatory compliance, process, cleaning
and controlled environment validations, equip-
ment qualifications, QA/QC procedures, manage-
ment and systems, Calibrations, Risk
Management, Utility Systems, internal/external
cGMP audits and start-up of manufacturing facili-
ties. He has been a frequent speaker and chair-
man at hundreds of validation and quality-related
conferences around the world for such groups as
IIR, IVT, Barnett International and the CTFA. His
articles and papers have been published in publi-
cations including the American Pharmaceutical
Review and the Journal of Validation Technology.
He is a member of the Journal of Validation Tech-
nology editorial advisory board. He is also a co-
author of the API Facility chapter in the book:
Good Design Practices for GMP Pharmaceutical
Facilities. Miguel can be reached by telephone at
phone (407) 587-6540 or by email at: mmon-
talvo@expertvalcon.com.
M a y 2 0 0 7 Vo l u m e 1 3 , N u m b e r 3 271