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A Cleaning Validation Master Plan for Oral Solid Dose Pharmaceutical Manufacturing Equipment

By Julie A. Thomas McNeil Consumer Healthcare

v

W ith the benchmark con­ stantly being raised, many companies find

that they are in perpetual valida­ tion mode. Often, companies have executed validations for equipment, cleaning, and processes, but the documentation no longer stands up to the latest in validation standards. Although these validations are gen­ erally complete and on file, there are many opportunities to improve both the supporting documenta­ tion and the execution. One way to ensure that your company’s policies and procedures regarding cleaning validation are state­of­the­art is to assemble a multi­disciplined team from the appropriate manufacturing sites that can review and revise all components associated with clean­

ing validation. What follows are excerpts from a Cleaning Validation Master Plan (the Plan) that was painstakingly com­ posed and has now become the standard for planning and executing cleaning validations at several manu­ facturing sites. An outline of the Plan contains the following seven elements, the concepts of which are taken directly from the FDA publication, “Guide to Inspections of

}Often, companies have executed validations for equipment, cleaning, and pro- cesses, but the doc- umentation no longer stands up to the latest validation standards.~

Validations of Cleaning Processes – July 1993.” Each of these will be discussed in greater detail in the sec­ tions below.

n

Objective

n

Scope

n

Introduction

n

Responsibilities

n

Philosophy

n

Methodology

n

Schedule

Objective

This section should state the pur­ pose of your cleaning master valida­ tion plan and define whether you will be revalidating current procedures or prospectively validating new ones. Often, the plan will have provisions for both situations.

Scope

The scope needs to list exactly which aspects of val­ idation will be covered in the document and to which types of products and/or processes the Plan applies. For example, “This document provides steps for planning, executing, and maintaining equipment cleaning valida­

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tions for oral solid dose products at Your Company’s manufacturing facility in Your City, State.”

Introduction

The introduction should let the reader know what elements will be addressed in the Master Validation Plan and why a formal plan is necessary. For instance, “This plan is intended to be a roadmap clarifying the course the Company will take as it plans and executes the cleaning validations required by current Good Manufacturing Practices (cGMP). This program describes and defines the various categories of cleaning validation, provides the nec­ essary protocol elements, and offers guidance for unexpected results. Furthermore, it includes provi­ sions for revalidation and monitoring and serves as a mechanism to organize and store critical informa­ tion that supports the cleaning validation process.”

Responsibilities

There are many departments and disciplines involved in planning for and executing a cleaning validation. It is necessary to list each contributing area and the associated tasks for which it is respon­ sible. This serves to clarify roles and to ensure that tasks are not overlooked. Typically, representatives from Validation, Manufacturing, Quality Control, Engineering, and Research and Development (R&D) will be needed. The following are some examples of departmental responsibilities:

Validation Specialist

• Review cleaning procedures

• Assist the cleaning validation team in iden­ tifying equipment test sites for swab or rinse samples

• Write cleaning validation protocols

• Coordinate execution of the cleaning pro­ cess with the appropriate departments and laboratories

• Prepare the sampling schedule

• Assemble the test data into final report form for approval Manufacturing

• Provide technical information for the devel­ opment of protocols and reports

• Review and approve protocols and reports

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for accuracy and agreement with operating practices

• Create and/or revise related SOPs and cleaning checklists

• Perform cleaning processes per SOP as referenced in the validation protocol

• Provide documented training for all person­ nel responsible for cleaning the equipment Quality Assurance

• Review and approve protocols and reports for conformance with cGMPs and internal procedures

• Provide analytical technical support

• Provide documented training for all person­ nel responsible for sample collection and testing

• Collect analytical samples as specified in the protocol

• Perform analytical testing using validated procedures

• Label, package, and send out those samples that need to be analyzed by an external laboratory

• Review and approve analytical results

• Notify departments of test results Engineering

• Inform the affected department in advance of any anticipated change to the facility or equipment

• Include all utilities and cleaning equipment in the calibration and maintenance pro­ gram

• Review and approve equipment drawings and surface area calculations Research and Development

• Provide swab and surface recovery data for active ingredients and cleaning agents

• Validate analytical test methods for chemi­ cal and cleaning agent analyses

• Transfer validated methods to the site QC laboratories and/or contract laboratories

• Provide recommended cleaning procedures for new active ingredients and/or cleaning agents

Cleaning Validation Philosophy

This section discusses the considerations you

Julie A. Thomas

have made in developing a comprehensive cleaning validation program, such as how to define equipment holding time, equipment storage time, and campaign length. In general, the philosophy section presents the Company’s position on what is being achieved by the cleaning validation and how it will be demonstrated. For instance, “Cleaning validation is required for all manufacturing and packaging equipment that comes into contact with the product or product components during production. Prior to validation, acceptance criteria will be developed for active ingredient and cleaning agent residues. Verification of acceptable equipment holding time will be included as part of the validation. Holding time is defined as the time between the end of the last product manufactured and the start of the cleaning process. This will demonstrate that the cleaning procedure effectively removes resi­ due after the equipment has remained idle for a speci­ fied period of time. Additionally, holding time will be evaluated to ensure storage conditions are adequate for a predetermined length of time. Storage time is defined as the time between cleaning completion and the next batch processed on the equipment. Campaign length will be determined jointly by Operations and R&D and validated with at least three iterations using the maximum number of batches or maximum length of time. This approach fully challenges the cleaning procedure by providing worst­case residues.”

Cleaning Validation Methodology

To ensure all of the elements are in place for a thorough and successful validation, a chronological methodology should be followed. One such design is illustrated through the following four phases: devel­ opment, planning, execution, and maintenance. (See Figure 1) In this section of the Plan, it is appropriate to include the number of sampling/testing iterations required for each piece of equipment and/or each analyte. (See Figure 2.) If you intend to reduce the number of tests required to validate cleaning after various products by using a grouping approach, it should be explained in this section. 1

Development Phase

The initial phase of the cleaning validation plan is

preparatory and includes analytical methods valida­ tion, recovery studies, surface types, degradants, and methods transfer. There is a considerable amount of scientific activity that must be completed before the validation can begin. These steps are explored in the following sections.

1. Analytical Methods Validation

Describe how the analytical methods will be developed and validated for active ingredients, deg­ radants (if applicable), and cleaning agent residue. Validation of the method should assess reproducibil­ ity, linearity, specificity, limit of detection (LOD), and swab and surface recovery. Other elements for consideration are the instrumentation, swabbing and dilution solvents, dilution volume, and sample han­ dling and storage. 2,3

2. Recovery Studies

Recovery studies evaluate quantitative recovery of chemical residue from both the surface to be sampled and the swab material to be used for sam­ pling. The results confirm the appropriateness of the sampling method and material used. You should determine the minimum recovery criteria for each surface type and state that percentage in this sec­ tion. For instance, you may want recovery values of at least 70% of actual readily soluble residues, but may choose a much lower recovery value for rela­ tively insoluble proteins. 4 Most important, you must provide data to justify the chosen value.

3. Surface Types

Since different surface types have different affini­ ties, you may want to choose a few surface materials to represent the many product contact surfaces used in manufacturing. For oral solid dose manufactur­ ing, you may determine that stainless steel, silicone, and polypropylene are the most abundant surfaces and that they also provide varying degrees of poros­ ity. A matrix of all surface types and the representa­ tive material that will be used in recovery studies is appropriate. (See Figure 3)

4. Degradants

Many degradant products are more soluble in the cleaning solvent than are the active ingredients; there­

fore, you should determine the degree of degradant

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Figure 1

cleaning validation Flow Diagram

Development Phase

Analytical Method Analytical Method Validation Development • Degradant • Recovery identification • Surface
Analytical Method
Analytical Method
Validation
Development
• Degradant
Recovery
identification
Surface types
• Transfer
Planning Phase
Equipment
Analyte Selection
Protocol
Cleaning
and Acceptance
Development
SOP
Sample site
Criteria
selection
Write
Write
Surface area
Active ingredient
Approve
Approve
calculation
Cleaning agent
Train
Train
Schematic
execution Phase
Protocol Execution
Clean
Sample
Test
No
Incident
Pass?
Investigation
Yes
Validation Report
Write
Approve
maintenance Phase

Monitoring

Monitoring
Monitoring
Monitoring
Investigation Yes Validation Report • Write • Approve maintenance Phase Monitoring Change Control Revalidation

Change Control

Change Control
Change Control
Change Control
Investigation Yes Validation Report • Write • Approve maintenance Phase Monitoring Change Control Revalidation

Revalidation

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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.

at maximum campaign length or time period.

2

Cleaning Agent Residue

3

per cleaning procedure, per piece of equipment.

3

testing required based on the toxicity and solubil­ ity of potential degradants. Likewise, active ingre­ dients should be exposed to the selected cleaning agent under normal usage conditions to determine if degradants are formed as a result of the cleaning process.

5. Analytical Methods Transfer In this section, you can state how sampling and analytical methods will be transferred from the R&D laboratories to the site QC laboratories and how the analysts conducting validation testing will be qualified. Reference appropriate SOPs and/or Development Transfer Report.

Planning Phase

The next phase of preparation is the planning phase. This is a broad category that focuses on equipment information, analyte selection, acceptance criteria, cleaning procedures, and protocol development. At this point, you are starting to think about what equipment will be included in the validation, which analytes will be chosen, and how you will determine acceptance cri­ teria. This leads to an in­depth review of the procedures and, finally, to protocol development.

1. Equipment Information This section should detail the methodology for providing specific equipment information. One option is to prepare a binder containing detailed surface area calculations, swab sampling sites (with justification), photos, and schematic diagrams for each piece of equipment. This binder can be main­ tained separately and used as an attachment to the cleaning validation protocol as needed.

a) Sample Site Selection Explain how you will select sampling sites to rep­ resent the product contact surface area of the equip­ ment. One of the best sources of information is the operator who routinely cleans the equipment. He or she can certainly point out the areas they find most difficult to clean. Make the operator part of a larger team of experts to include representatives from Validation, QA, and Operations, and let the team determine the product contact surface areas that are most difficult to clean and those that are most repre­ sentative of the equipment. Sampling these sites will represent the entire equipment surface area using the assumption that residue will be evenly distrib­ uted over the equipment and that the most difficult to clean locations will represent the worst case for residue removal. Include the basis for selecting each

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

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site. For example, sampling sites may be deemed to be the most difficult to clean, most difficult to dry, or of different material of construction. Swab sites

Figure 4 swab site
Figure 4
swab site

can be indicated with either digital photographs or suitable diagrams. (See Figure 4)

b) Surface Area Calculation

An accurate surface area must be calculated for each piece or section of equipment. This can be done with manufacturer’s drawings, but should be confirmed by field measurements. If drawings are not available, the equipment must be measured to determine surface area (see Figure 5). Although not shown here, it is advisable to include the calcula­

Figure 5

surface area

 

swab number

area swabbed

1

Screen/ring interface gasket

2

Discharge port – inside of top circular area (top seam)

Total contact S.A. of Kason Separator (in 2 )

3,171.2

Total contact S.A. of Filter Socks (in 2 )

15.6

tions with the schematic diagram in the equipment information binder mentioned above.

c) Schematic Diagram To clearly illustrate each piece of equipment, pre­

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Figure 6

Kason Separator

Institute of Validation Technology Figure 6 Kason Separator pare schematic diagrams labeled with the major sec­
Institute of Validation Technology Figure 6 Kason Separator pare schematic diagrams labeled with the major sec­
Institute of Validation Technology Figure 6 Kason Separator pare schematic diagrams labeled with the major sec­
Institute of Validation Technology Figure 6 Kason Separator pare schematic diagrams labeled with the major sec­
Institute of Validation Technology Figure 6 Kason Separator pare schematic diagrams labeled with the major sec­
Institute of Validation Technology Figure 6 Kason Separator pare schematic diagrams labeled with the major sec­

pare schematic diagrams labeled with the major sec­ tions of the equipment. (See Figure 6) The drawings do not have to be to scale, but should appropriately represent the equipment. If a schematic is not practical (i.e., a packaging line), a photograph is acceptable. The intent is to depict the product contact surfaces that are included in the calculations. This helps to ensure that the swab samples are taken from the intended location.

2. Analyte Selection Analyte selection is required for active, excipi­ ent (possibly), and cleaning agent residues. Keep in mind that you are validating a cleaning proce­ dure, not a manufacturing process. In the situation where the same cleaning procedure is used for many product formulas, there is an opportunity to select a representative analyte to cover multiple active ingre­ dients and reduce the amount of testing.

a) Actives If several active ingredients are processed in a single

piece of equipment, a marker active, or guiding sub­ stance, can be selected based on the active ingredient solubility in water, potency, previous production expe­ rience, and R&D studies. This reduces the number of studies required to validate the cleaning procedure. 5

b) Excipients

Julie A. Thomas

The removal of excipients can either be con­ firmed by visual inspection or through analytical testing. The approach should be stated here along with training requirements for individuals perform­ ing visual inspection.

c) Cleaning Agents

Testing for cleaning agent residue is essential but is often an area in which current cleaning validations are deficient. For most cleaning agents, a marker compound can be selected for analysis based on the recommendation of the cleaning agent manufactur­ er. Removal of volatile cleaning agents that do not leave a residue, such as isopropyl alcohol, may not need to be validated.

3. Acceptance Criteria The equipment must pass visual and olfac­ tory inspection, where appropriate, as defined in the cleaning validation protocol prior to initiation of swabbing. 6 This is a critical step in the validation process that, if skipped, can lead to failed results.

a) Active Ingredient

Acceptance criteria for active ingredients should be based on medical and pharmacological properties and scientific information. Calculations using the maximum allowable carryover (MAC) and/or 10ppm formulas can be used. 7 To ensure that all active contact surfaces are consid­ ered in the carryover calculation, you may want to iden­ tify equipment trains. Acceptance criteria are calculated using the surface area from the entire equipment train; however, protocols are executed per each piece of equip­ ment. Equipment trains could be designated as follows:

n Granulation – granulator system through the product container n Compression through printing – compression, film­coating, and printing phases n Packaging – product contact surfaces for each type of packaging line

b) Cleaning Agent

Acceptance criteria for the cleaning agent marker should be based on toxicity, limit of detection of validated assay method, and/or data gathered dur­ ing certification studies. Acceptance criteria can be

calculated using a formula such as the No Observed Effect Limits (NOEL). 8

4. Cleaning Procedures

This section should indicate that cleaning procedures will be developed (or existing procedures reviewed) prior to the validation. It should also list the required elements for cleaning procedures, such as temperature, pressure, water quality, cleaning agent concentration, spray nozzle location, etc., or it should reference where these requirements can be found. 9 Additionally, you should describe the process for training the operators who will be executing the validation studies. 10

5. Protocol Development

The next step is to write a cleaning validation pro­ tocol for each cleaning procedure that you intend to validate. The protocol should describe all documenta­ tion required to complete the cleaning validation. It should also present the rationale for using a marker active to cover validation for multiple products. For ease of review, include a matrix of the products and equipment that are covered by each validation, or reference where this information can be found. For example, if there are three active ingredients processed in Fluid Bed Granulator #1, indicate which active will be used to represent the other two. Likewise, indicate which pieces of equipment will be used to validate

Figure 7

equipment cleaning matrix

 

active a

active B

active c

cleaning

agent a

Fluid Bed Gran 1

X

 

– X

 

Fluid Bed Gran 2

 

– –

 

Starch Kettle 1

 

– X

 

the removal of active ingredient and cleaning agent residues. (See Figure 7)

Execution Phase

When all of the supporting documentation is com­ plete, it is time to execute the plan. During the execu­ tion phase, you will complete the protocol, investi­ gate any nonconformances that may have occurred, and write a report to summarize your findings.

1. Protocol Execution

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Typically, three iterations of cleaning, sampling,

and testing using the same procedure are required. Acceptance criteria for all cleaning iterations must be met for both the active ingredient and the clean­ ing agent. Be sure to reference the procedure where

detailed description of the chemical swab prepara­

a

2.

Incident Investigation

This section explains how the Company will

repeatability is highly dependent on the quality and consistency of training. Monitoring should include, at a minimum, a review of changes made to the cleaning procedure or equipment, visual inspection of the equipment, and direct observation of employ­

tion and sampling methods can be found.

ees executing the cleaning procedure. For some equipment, swab samples for active ingredients may be necessary in addition to the visual inspection

handle test failures and nonconformances during execution of the validation. Once the root cause of

and observation. Indicate the frequency that you intend to monitor the cleaning process. Reference the appropriate SOP for detailed requirements of the monitoring program.

the failure has been identified, options are to addend

2.

Change Control

the protocol or start over with a new protocol. For any incident that occurs during validation, docu­ ment the investigation along with corrective and preventive actions. The incident report may contain elements such as:

Indicate how changes will be managed to ensure the validated state is maintained. Any change in the facility, process equipment, cleaning procedure, cleaning agent, product formulation, or addition

 

n

Cleaning validation protocol number

of new products to the equipment train should be 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

Describe the report format and content that will be used to summarize the validation. Reference appropriate SOPs for detailed report information. An explanation of all deviations should be included in the validation report.

change, a determination will be made as to which, if any, phases of the validation must be repeated. Reference where documentation of the revalidation will be filed. 12,13

Cleaning Validation Schedule

Maintenance Phase

The final phase of the Plan should specify how you will maintain the conditions you have just

validated. This includes periodic monitoring, using

Prioritization As is usually the case, all cleaning validations cannot commence at one time; therefore, it is nec­ essary to set up a priority list. Some situations to consider are:

control of change process, and potentially, revali­ dating.

a

n

Equipment shared between products contain­ ing different active ingredients

1.

Monitoring

n

Equipment in contact with raw material with

Unshared primary equipment currently in use

This section details how you will ensure that the conditions used during validation remain in con­ trol during routine production. This is especially

n

high potential for contamination

with outdated validations

important for manual cleaning procedures, where

n

Unshared auxiliary equipment used for pro­

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Julie A. Thomas

duction with limited potential for product contamination Tactical Schedule A proposed schedule, including equipment pri­ oritization and target initiation dates, should be pre­ sented in this section. This gives an indication that you have contemplated the order of execution, and it also provides a tool that can be used to track your progress.

Summary

There are many aspects of cleaning validation that must be carefully planned to guarantee a suc­ cessful validation program. If you begin with a phi­ losophy, this will set the stage for you to develop a structured approach. By dividing the approach into sections, such as development, planning, execu­ tion, and maintenance, it breaks down the project into manageable segments. To complete the Plan, generate a tactical schedule and begin monitoring progress towards your new and improved cleaning validation status. o

About the Author

Julie Thomas is Validation Manager at McNeil Consumer Healthcare in Round Rock, Texas. She has 14 years of experience in various aspects of solid dose pharmaceutical manufacturing. Most recently, she chaired a company-wide commit- tee to enhance cleaning validation practices and procedures for all McNeil facilities. She can be reached by phone at 512-248-4470 or by e-mail at

jthomas1@mccus.jnj.com.

This article presents only one alternative for pre­ paring a Master Validation Plan. The views expressed in this article are strictly those of the author and in no way represent the view of McNeil Consumer Healthcare, Johnson & Johnson, or this publication.

References

1.

Jenkins, K.M. and Vanderwielen, A.J. “Cleaning Validation: An Overall Perspective,” Pharmaceutical Technology, April 1994,

p.

62.

2.

McCormick, P.Y. and Cullen, L.F., Pharmaceutical Process Validation, 2nd ed., edited by I.R. Berry and R.A. Nash, 1993,

p.

334.

3.

Kirsch, R.B., “Validation of Analytical Methods Used in Pharmaceutical Cleaning Assessment and Validation,” Pharmaceutical Technology, Analytical Validation, 1998.

4.

Chudzik, G.M., “General Guide to Recovery Studies Using Swab Sampling Methods for Cleaning Validation,” Journal of Validation Technology, Vol. 5, No. 1, pp. 77­81.

5.

Hall, W.E., “Your Cleaning Program: Is It Ready for the Pre­ Approval Inspection?” Journal of Validation Technology, Vol.

4, No. 4, August 1998, p. 302.

6.

Alvey, A.P. and Carrie, T.R., “Not Seeing is Believing – A Non­Traditional Approach for Cleaning Validation,” Journal of Validation Technology, Vol. 4, No. 3, pp. 189­193.

7.

Fourman, G.L. and Mullen, M.V., “Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufactur ing Operations,” Pharmaceutical Technology, 17 (4), 1993, pp.

 

54­60.

8.

Hall, W.E., “Validation of Cleaning Processes for Bulk Pharmaceutical Chemical Processes,” Cleaning Validation An Exclusive Publication, p. 4.

9.

Hall, W.E., “Proper Documentation and Written Procedures,” Journal of Validation Technology, Vol. 4, No. 3, pp. 199­201.

10.

Tunner, J., “Manual Cleaning Procedure Design and Validation,” Cleaning Validation An Exclusive Publication, p. 28.

11.

PDA Technical Report No. 29, “Points to Consider for Cleaning Validation,” March 1998, p.43.

12.

Coleman, R.C., “How Clean is Clean?” Journal of Validation Technology, Vol. 2, No. 4, August 1996, p. 278.

13.

Jenkins, K.M. and Vanderwielen, A.J., “Cleaning Validation: An Overall Perspective,” Pharmaceutical Technology, April 1994,

p. 70.

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