Beruflich Dokumente
Kultur Dokumente
W
v
ith the benchmark con Validations of Cleaning Processes
stantly being raised, }Often, July 1993. Each of these will be
many companies find discussed in greater detail in the sec
that they are in perpetual valida companies have tions below.
tion mode. Often, companies have
executed validations for equipment, executed n Objective
cleaning, and processes, but the validations for n Scope
documentation no longer stands up n Introduction
to the latest in validation standards. equipment, n Responsibilities
Although these validations are gen n Philosophy
erally complete and on file, there cleaning, and pro- n Methodology
are many opportunities to improve n Schedule
both the supporting documenta
cesses, but the doc-
tion and the execution. One way to umentation Objective
ensure that your companys policies
and procedures regarding cleaning no longer stands This section should state the pur
validation are state-of-the-art is to pose of your cleaning master valida
assemble a multi-disciplined team up to the latest tion plan and define whether you will
from the appropriate manufacturing validation be revalidating current procedures or
sites that can review and revise all prospectively validating new ones.
components associated with clean standards.~ Often, the plan will have provisions
ing validation. What follows are for both situations.
excerpts from a Cleaning Validation
Master Plan (the Plan) that was painstakingly com Scope
posed and has now become the standard for planning
and executing cleaning validations at several manu The scope needs to list exactly which aspects of val
facturing sites. idation will be covered in the document and to which
An outline of the Plan contains the following seven types of products and/or processes the Plan applies. For
elements, the concepts of which are taken directly example, This document provides steps for planning,
from the FDA publication, Guide to Inspections of executing, and maintaining equipment cleaning valida
tions for oral solid dose products at Your Companys for accuracy and agreement with operating
manufacturing facility in Your City, State. practices
Introduction Create and/or revise related SOPs and
cleaning checklists
The introduction should let the reader know Perform cleaning processes per SOP as
what elements will be addressed in the Master referenced in the validation protocol
Validation Plan and why a formal plan is necessary. Provide documented training for all person
For instance, This plan is intended to be a roadmap nel responsible for cleaning the equipment
clarifying the course the Company will take as it Quality Assurance
plans and executes the cleaning validations required Review and approve protocols and reports
by current Good Manufacturing Practices (cGMP). for conformance with cGMPs and internal
This program describes and defines the various procedures
categories of cleaning validation, provides the nec Provide analytical technical support
essary protocol elements, and offers guidance for Provide documented training for all person
unexpected results. Furthermore, it includes provi nel responsible for sample collection and
sions for revalidation and monitoring and serves as testing
a mechanism to organize and store critical informa Collect analytical samples as specified in
tion that supports the cleaning validation process. the protocol
Perform analytical testing using validated
Responsibilities procedures
Label, package, and send out those samples
There are many departments and disciplines that need to be analyzed by an external
involved in planning for and executing a cleaning laboratory
validation. It is necessary to list each contributing Review and approve analytical results
area and the associated tasks for which it is respon Notify departments of test results
sible. This serves to clarify roles and to ensure that Engineering
tasks are not overlooked. Typically, representatives Inform the affected department in advance
from Validation, Manufacturing, Quality Control, of any anticipated change to the facility or
Engineering, and Research and Development (R&D) equipment
will be needed. The following are some examples of Include all utilities and cleaning equipment
departmental responsibilities: in the calibration and maintenance pro
gram
Validation Specialist Review and approve equipment drawings
Review cleaning procedures and surface area calculations
Assist the cleaning validation team in iden Research and Development
tifying equipment test sites for swab or Provide swab and surface recovery data for
rinse samples active ingredients and cleaning agents
Write cleaning validation protocols Validate analytical test methods for chemi
Coordinate execution of the cleaning pro cal and cleaning agent analyses
cess with the appropriate departments and Transfer validated methods to the site QC
laboratories laboratories and/or contract laboratories
Prepare the sampling schedule Provide recommended cleaning procedures
Assemble the test data into final report for new active ingredients and/or cleaning
form for approval agents
Manufacturing
Provide technical information for the devel Cleaning Validation Philosophy
opment of protocols and reports
Review and approve protocols and reports This section discusses the considerations you
have made in developing a comprehensive cleaning preparatory and includes analytical methods valida
validation program, such as how to define equipment tion, recovery studies, surface types, degradants, and
holding time, equipment storage time, and campaign methods transfer. There is a considerable amount of
length. In general, the philosophy section presents the scientific activity that must be completed before the
Companys position on what is being achieved by the validation can begin. These steps are explored in the
cleaning validation and how it will be demonstrated. following sections.
For instance, Cleaning validation is required for all
manufacturing and packaging equipment that comes 1. Analytical Methods Validation
into contact with the product or product components Describe how the analytical methods will be
during production. Prior to validation, acceptance developed and validated for active ingredients, deg
criteria will be developed for active ingredient and radants (if applicable), and cleaning agent residue.
cleaning agent residues. Verification of acceptable Validation of the method should assess reproducibil
equipment holding time will be included as part of ity, linearity, specificity, limit of detection (LOD),
the validation. Holding time is defined as the time and swab and surface recovery. Other elements for
between the end of the last product manufactured and consideration are the instrumentation, swabbing and
the start of the cleaning process. This will demonstrate dilution solvents, dilution volume, and sample han
that the cleaning procedure effectively removes resi dling and storage.2,3
due after the equipment has remained idle for a speci
fied period of time. Additionally, holding time will be 2. Recovery Studies
evaluated to ensure storage conditions are adequate Recovery studies evaluate quantitative recovery
for a predetermined length of time. Storage time is of chemical residue from both the surface to be
defined as the time between cleaning completion and sampled and the swab material to be used for sam
the next batch processed on the equipment. Campaign pling. The results confirm the appropriateness of
length will be determined jointly by Operations and the sampling method and material used. You should
R&D and validated with at least three iterations using determine the minimum recovery criteria for each
the maximum number of batches or maximum length surface type and state that percentage in this sec
of time. This approach fully challenges the cleaning tion. For instance, you may want recovery values of
procedure by providing worst-case residues. at least 70% of actual readily soluble residues, but
may choose a much lower recovery value for rela
Cleaning Validation Methodology tively insoluble proteins.4 Most important, you must
provide data to justify the chosen value.
To ensure all of the elements are in place for a
thorough and successful validation, a chronological 3. Surface Types
methodology should be followed. One such design is Since different surface types have different affini
illustrated through the following four phases: devel ties, you may want to choose a few surface materials
opment, planning, execution, and maintenance. (See to represent the many product contact surfaces used
Figure 1) In this section of the Plan, it is appropriate in manufacturing. For oral solid dose manufactur
to include the number of sampling/testing iterations ing, you may determine that stainless steel, silicone,
required for each piece of equipment and/or each and polypropylene are the most abundant surfaces
analyte. (See Figure 2.) and that they also provide varying degrees of poros
If you intend to reduce the number of tests ity. A matrix of all surface types and the representa
required to validate cleaning after various products tive material that will be used in recovery studies is
by using a grouping approach, it should be explained appropriate. (See Figure 3)
in this section.1
4. Degradants
Development Phase Many degradant products are more soluble in the
cleaning solvent than are the active ingredients; there
The initial phase of the cleaning validation plan is fore, you should determine the degree of degradant
Figure 1
Cleaning Validation Flow Diagram
Development Phase
Analytical Method
Analytical Method
Validation
Development
D egradant
Recovery
identification
Surface types
Transfer
Planning Phase
Equipment
Analyte Selection Protocol Cleaning
S ample site and Acceptance Development SOP
selection Criteria
W rite W rite
Surface area
A ctive ingredient Approve Approve
calculation
Cleaning agent Train Train
Schematic
Execution Phase
Protocol Execution
C lean
Sample
Test
No
Incident
Pass?
Investigation
Yes
Validation Report
W rite
Approve
Maintenance Phase
Revalidation
Figure 2
Cleaning Iteration Summary Requirements
Sample Total Number of Iterations Conditions
Active Residue 3 1 at maximum campaign length or
maximum time period plus holding
time.
2 at maximum campaign length or
time period.
Cleaning Agent Residue 3 3 per cleaning procedure, per piece
of equipment.
Figure 3
Surface Recovery Matrix
Recovery Surface: 316L Stainless Steel Polyethylene Silicone
Material Used: 316L Coupon Plastic Bulk Container Hose
To Represent: 304 Stainless Teflon Rubber
Aluminum Lexan EPDM
Brass HDPE Neoprene
Figure 4
Swab Site
can be indicated with either digital photographs or pare schematic diagrams labeled with the major sec
suitable diagrams. (See Figure 4) tions of the equipment. (See Figure 6) The drawings
b) Surface Area Calculation do not have to be to scale, but should appropriately
An accurate surface area must be calculated for represent the equipment. If a schematic is not practical
each piece or section of equipment. This can be (i.e., a packaging line), a photograph is acceptable. The
done with manufacturers drawings, but should be intent is to depict the product contact surfaces that are
confirmed by field measurements. If drawings are included in the calculations. This helps to ensure that
not available, the equipment must be measured to the swab samples are taken from the intended location.
determine surface area (see Figure 5). Although not
shown here, it is advisable to include the calcula 2. Analyte Selection
Analyte selection is required for active, excipi
Figure 5 ent (possibly), and cleaning agent residues. Keep
in mind that you are validating a cleaning proce
Surface Area dure, not a manufacturing process. In the situation
Swab Number Area Swabbed where the same cleaning procedure is used for many
1 Screen/ring interface product formulas, there is an opportunity to select a
gasket representative analyte to cover multiple active ingre
2 Discharge port inside dients and reduce the amount of testing.
of top circular area
(top seam) a) Actives
Total contact S.A. of Kason Separator (in ) 2
3,171.2 If several active ingredients are processed in a single
piece of equipment, a marker active, or guiding sub
Total contact S.A. of Filter Socks (in2) 15.6
stance, can be selected based on the active ingredient
solubility in water, potency, previous production expe
tions with the schematic diagram in the equipment rience, and R&D studies. This reduces the number of
information binder mentioned above. studies required to validate the cleaning procedure.5
c) Schematic Diagram
To clearly illustrate each piece of equipment, pre b) Excipients
The removal of excipients can either be con calculated using a formula such as the No Observed
firmed by visual inspection or through analytical Effect Limits (NOEL).8
testing. The approach should be stated here along 4. Cleaning Procedures
with training requirements for individuals perform This section should indicate that cleaning procedures
ing visual inspection. will be developed (or existing procedures reviewed)
prior to the validation. It should also list the required
c) Cleaning Agents elements for cleaning procedures, such as temperature,
Testing for cleaning agent residue is essential but pressure, water quality, cleaning agent concentration,
is often an area in which current cleaning validations spray nozzle location, etc., or it should reference where
are deficient. For most cleaning agents, a marker these requirements can be found.9 Additionally, you
compound can be selected for analysis based on the should describe the process for training the operators
recommendation of the cleaning agent manufactur who will be executing the validation studies.10
er. Removal of volatile cleaning agents that do not
leave a residue, such as isopropyl alcohol, may not 5. Protocol Development
need to be validated. The next step is to write a cleaning validation pro
tocol for each cleaning procedure that you intend to
3. Acceptance Criteria validate. The protocol should describe all documenta
The equipment must pass visual and olfac tion required to complete the cleaning validation. It
tory inspection, where appropriate, as defined in should also present the rationale for using a marker
the cleaning validation protocol prior to initiation active to cover validation for multiple products. For
of swabbing.6 This is a critical step in the validation ease of review, include a matrix of the products and
process that, if skipped, can lead to failed results. equipment that are covered by each validation, or
reference where this information can be found. For
a) Active Ingredient example, if there are three active ingredients processed
Acceptance criteria for active ingredients should in Fluid Bed Granulator #1, indicate which active will
be based on medical and pharmacological properties be used to represent the other two. Likewise, indicate
and scientific information. Calculations using the which pieces of equipment will be used to validate
maximum allowable carryover (MAC) and/or 10ppm
formulas can be used.7 Figure 7
To ensure that all active contact surfaces are consid Equipment Cleaning Matrix
ered in the carryover calculation, you may want to iden
tify equipment trains. Acceptance criteria are calculated Active A Active B Active C Cleaning
using the surface area from the entire equipment train; Agent A
however, protocols are executed per each piece of equip Fluid Bed Gran 1 X X
ment. Equipment trains could be designated as follows: Fluid Bed Gran 2
Starch Kettle 1 X
n Granulation granulator system through the
product container the removal of active ingredient and cleaning agent
n Compression through printing compression, residues. (See Figure 7)
film-coating, and printing phases Execution Phase
n Packaging product contact surfaces for each
type of packaging line When all of the supporting documentation is com
plete, it is time to execute the plan. During the execu
b) Cleaning Agent tion phase, you will complete the protocol, investi
Acceptance criteria for the cleaning agent marker gate any nonconformances that may have occurred,
should be based on toxicity, limit of detection of and write a report to summarize your findings.
validated assay method, and/or data gathered dur
ing certification studies. Acceptance criteria can be 1. Protocol Execution
Typically, three iterations of cleaning, sampling, repeatability is highly dependent on the quality and
and testing using the same procedure are required. consistency of training. Monitoring should include,
Acceptance criteria for all cleaning iterations must at a minimum, a review of changes made to the
be met for both the active ingredient and the clean cleaning procedure or equipment, visual inspection
ing agent. Be sure to reference the procedure where of the equipment, and direct observation of employ
a detailed description of the chemical swab prepara ees executing the cleaning procedure. For some
tion and sampling methods can be found. equipment, swab samples for active ingredients may
be necessary in addition to the visual inspection
2. Incident Investigation and observation. Indicate the frequency that you
This section explains how the Company will intend to monitor the cleaning process. Reference
handle test failures and nonconformances during the appropriate SOP for detailed requirements of the
execution of the validation. Once the root cause of monitoring program.
the failure has been identified, options are to addend
the protocol or start over with a new protocol. For 2. Change Control
any incident that occurs during validation, docu Indicate how changes will be managed to ensure
ment the investigation along with corrective and the validated state is maintained. Any change in
preventive actions. The incident report may contain the facility, process equipment, cleaning procedure,
elements such as: cleaning agent, product formulation, or addition
of new products to the equipment train should be
n Cleaning validation protocol number documented and approved via the Change Control
n Incident report number System. The change should be reviewed by the Val
n Equipment model and location idation Group, Operations, and QA, who will decide
n Initiator and date if revalidation is necessary. Reference appropriate
n Incident description SOPs.11
n Root cause analysis
n Corrective actions recommended/taken 3. Revalidation
n Assessment of effect on product Indicate the criteria that will be used to determine
the need for revalidation. Based on the nature of the
3. Reports change, a determination will be made as to which,
Describe the report format and content that will if any, phases of the validation must be repeated.
be used to summarize the validation. Reference Reference where documentation of the revalidation
appropriate SOPs for detailed report information. will be filed.12,13
An explanation of all deviations should be included
in the validation report. Cleaning Validation Schedule