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ProtocolDevelopment 01
ProtocolDevelopment 01
CONFERENCE REPORT
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.
CV Protocols
and Reports
CONFERENCE REPORT
Once the program and policies are in place, follow dation and are not to be confused with sanitization chal-
with the procedures developing in tandem a cleaning val- lenges or validation.
idation master plan. The procedures should include cur- The FDA expects to see a policy or general procedure
rent analytical requirements and provide for updates to on how cleaning processes will be validated, including a
the plan. These updates should include documentation definition of responsibilities along with revalidation re-
protocols, report formats and timetables, as well as other quirements (not necessarily a cleaning validation master
CV maintenance guidelines such as change control pro- plan). There should also be detailed written procedures
cedures. addressing the varied equipment and product types that
require different cleaning procedures. This includes the
CLEANING VALIDATION MASTER cleaning differences between campaigns of the same
PLAN DEVELOPMENT product, steps, and intermediate processes vs. unique
products. Residues from the cleaning processes, such as
The essential elements for developing a cleaning val- detergents or solvents, must be removed.
idation master plan include: Protocols per equipment are to be included with sam-
Master Plan Outline (see Figure 1) pling procedures and locations, analytical methods, accep-
Understanding FDAs Expectations and Per- tance criteria, and residue limits. A report summarizing
spective the results and concluding that each cleaning procedure is
Gathering Required Information on: considered valid because the residues have been reduced
- Products to an acceptable level should also be included.
- Equipment When considering analytical methods, the FDA ex-
- Cleaning procedures and agents pects to see criteria and validated documentation within
- Hold Times quantification limits. These should include sampling pro-
cedure techniques, materials and solvents used, etc. Lim-
Cleaning Validation Master Plan Outline its should be established that correlate with the analytical
Approvals method and recovery capabilities. (Suggestion: Ask
Objective whether there are to be recovery limit minimums.)
Scope Routine production monitoring should be established
Responsibilities for rinse samples, conductivity, total organic carbon
References Cleaning Validation Policy and (TOC), etc. Detergents must be easily removable. There
additional procedures and documents must be adequate cleaning and drying of equipment along
Cleaning Validation Strategy and Approach with proper storage conditions. All microbiological as-
- Matrices of products, equipment, pects, including preventive measures, should be included.
procedures, and cleaning agents You will need data to support hold times after (and before)
- Selection of test conditions products and cleaning, and/or any sanitation procedure validation.
components to be tested
- Analytical method requirements Cleaning Procedures and Documentation
- Determination of acceptance criteria limits Regarding FDAs expectations concerning cleaning
Protocol and Final Report Requirements procedures and documentation reviews, you should count
Tentative Schedule on documenting each step to completion. Expect to go
Validation Maintenance into more detail for manual cleaning processes because
these have more variables and generally provide more
FDAs Expectation Perspective chances for error. Parameters should clearly define times,
These comments are based on the FDAs Guide to In- temperatures, and detergent concentrations. If cleaning
spections Validation of Cleaning Processes, published in between runs of same product, visibly clean may be
July 1993. This perspective is intended for chemical enough, but you must address micro and detergent or sol-
residues. Products affected by microbiological contami- vent residue concerns.
nation must include these considerations during the vali- Along with these issues, dedicated equipment and the
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Prerequisites the unique elements of your situation such as: time for
Having the prerequisites in proper order will help en- rinse and exposure to cleaning agent, temperature, mix-
sure successful cleaning validation down the road. Com- ing time, contact time, water flow or pressure during
plete a cleaning procedure review along with an rinse, and any other mechanical action required.
equipment design. Map out and determine the cleaning
process CIP, COP, or manual, or a combination of the CIP Characteristics
three that you will be using. Indicate in the documenta- CIP capability must be considered during the equip-
tion the validated analytical methods you have chosen as ment and facility design. These include piping, nozzles,
well as your sampling technique and recovery testing drains, slope, deadlegs, and other equipment surfaces.
methods. Check for adequate flow and pressure in spray devices,
paying special attention to components such as valves,
Training pumps, seals, and instrumentation. Filter materials,
Among the most important prerequisite criteria is per- resins, and columns must be compatible with solutions.
sonnel training. Every individual who will be working on Finally, check for drainability. In a typical CIP cycle there
the equipment must be trained on the cleaning proce- is a pre-rinse, detergent wash (alkaline), post rinse, acid-
dure(s), and equipment operation as appropriate. Labora- ified wash, final rinse. All these must be properly drained.
tory personnel must be trained and qualified on the Include computer validation requirements as needed.
analytical method and the sampling technique chosen. All
must be trained on proper documentation techniques. Equipment Design Characteristics
Documentation of the training must be maintained. Surfaces characteristics should be chemically inert
and resistant to heat and chemical attack. Be attentive to
Cleaning Procedure all connections and valves, both for their function and
The cleaning procedures should be included in the de- their cleanability. Choose spray balls carefully consider-
velopment plan for the process in question. Consideration ing their capability and function. Choose a closed vs.
must be made for the advantages and disadvantages of open loop system depending upon your production
manual vs. automated cleaning as decisions are made. needs; adequate sanitary piping must be provided to code.
Some of the disadvantages of choosing manual cleaning Personnel must be made familiar with all equipment in
include its repetitive and inconsistent nature from the op- order to effectively clean the system(s).
erators point of view. Other operator driven issues may
include turnover concerns, new operator training and Cleaning Agent Selection
error problems, and possible motivation considerations. It The products you produce and the processes you em-
may also be difficult to describe procedures in specific ploy will produce the soils to be removed. Consider all
detail. Manual cleaning may require the use of worst case equipment surfaces from which these soils must be re-
conditions during validation. With automated cleaning, moved. Often, a combination of solutions provides
there are the advantages of controlled parameters and the greater effect than a single solution. Typical cleaners in-
consistency of programmed cycles. Clean-in-place (CIP) clude: solvents, bulk chemicals, and aqueous detergents.
is used frequently for biopharmaceutical processes, but These may be acidic, neutral, or alkaline. Vendors will
COP and manual processes may be used in combination supply you with product, and validation data, as well as
with CIP when appropriate. Other cleaning procedures to method of use information.
be defined include those to be completed between differ-
ent products vs. during campaigns of identical product. Analytical Methods
Outline equipment-specific vs. generic procedures. Analytical method selection is dependent on the ma-
Define procedures for different product types. Define the terial being sampled and the required limit of detection or
use of detergents including different concentrations and limit of quantification. Methods must be validated in con-
formulas. When covering cleaning agent selection be sure junction with sampling and extraction systems. Specific
to justify and document your choices, indicating re- methods are preferred, but non-specific methods can
sources and vendors. Include other parameters covering work (such as TOC). New methods are constantly being
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CONFERENCE REPORT
developed, for example: ion mobility spectrometry, and Cleaning Validation Report
enzymatic (for biologicals). In your report, compare results with established lim-
its. Each result must be not more than the calculated
Specific vs. Non-Specific Methods MACO, taking into consideration the stated recovery fac-
It is important to correlate the specific methods used tors. Establish maximum holding time for equipment be-
for validation to the non-specific methods used for mon- fore cleaning; all three runs must be held for the
itoring. To use specific methods, extensive development maximum hold time indicated. Deviations must be prop-
and validation may be required, which may be expensive erly handled and explained in the report. Conclusions
and could result in delayed results. Non-specific methods must be well defined.
are best used when residues are at, or below, the resulting
level and no specific amount is required. Using these Remaining in a Validated State
methods can be cost effective; you can often detect mul- A strong change control program is the key to main-
tiple soils in one test; however, you do run the risk of a taining validated status. Monitor all changes: changes in
false failure. Each method has its drawbacks and should cleaning agents, cleaning procedures, manufacturing
be considered relative to your needs and the science of equipment or procedures, and changes in product formu-
your product in order to make the best decision in your las. Maintain proper evaluation and approval pre- and
situation. post-change implementation. Document your evalua-
tions, follow-up studies and reports. Should a new prod-
Analytical Methods Validation uct be introduced, determine whether there is need to
Test method accuracy and precision will be molded by validate it based on the matrices you have established.
tight acceptance criteria. Once all the data is generated Be vigilant in monitoring cleaning procedures. Make
and reviewed, you will summarize it for your report. Im- sure equipment is visually clean every time. Establish a
portant elements include: limit of detection, limit of frequency or periodic timetable to perform analytical pro-
quantitation, specificity, range, linearity, and ruggedness. cedures (TOC, pH, conductivity, etc.). Keep accurate
and regular cleaning and use logs. These will help you to
Recovery Requirements evaluate your procedures, your solvents, and serve as ex-
Establish recovery for individual contaminant(s) with cellent documentation of your decision making to FDA.
explicit sampling methods and materials and with spe- Equipment maintenance falls into this category. Changes
cific method(s) and analyst(s). Although there is no stan- must go through the change control system and its rele-
dard limit, these must be performed in conjunction with vant procedures. Finally, and although mentioned before,
method validation protocols. a robust training program is essential to maintaining all
elements of the system in a validated status. If your peo-
Documentation of Cleaning Processes ple do not know what they are doing and why, your sys-
Each cleaning batch must be recorded and there must tem is bound to fail!
be a witness to each completed validation. See that criti-
cal parameters verification, as well as all validation steps, Revalidation Is it required?
is well documented and verified. Base revalidation on continuous monitoring data and
Other required records include documentation of sam- change control. Establish a frequency for data evaluation.
pling locations, time, and sampler. Laboratory documen- Do not necessarily repeat the validation blindly.
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.
CONFERENCE REPORT
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