Fundamental Cleaning Principles

8/2/2019 Fundamental Cleaning Principles

http://slidepdf.com/reader/full/fundamental-cleaning-principles 1/154

Cleaning Validation Principles © 2011 ISPE. All rights reserved.

Page 1

CleaningValidation

Developing,Deploying and

Cleaning Validation

Program

1Cleaning Validation

Cleaning Validation Principles

• ISPE Welcome and Opening Remarks

• Course Leader Introduction

• Housekeeping• Breaks

• Lunch

• Emergency Egress

• ISPE Membership

• Evaluations

•

?

• Overview of Notebooks• Glossary / Acronyms

• Index to Materials





Page 2


Section Description

Table of Contents

1

2

3

4

5

6

Regulatory Requirements for Cleaning Validation

Fundamentals of Cleaning Validation

Cleaning Validation Master Plans

Equipment Characterization

SOP Development for Cleaning

Selecting Residues, then Developing and MaintainingLimits

78

9

10

11

Methods Validation and Recovery StudiesEngineering Studies and Cycle Development

Cleaning Validation Protocols

Field Execution -- Collecting and Testing Samples

Cleaning Validation Reports and Beyond!



• Creation of scientificall sound rationales validation rotocols

Learning Objectives

,and reports

• Identification and characterization of potential residues includingproduct, processing aids, cleaning agents and adventitiousagents

• Selection of appropriate analytical methodology for yourselected residues

•of sampling locations that represent challenging locations foryour cleaning process

• Calculation of residue limits that meet all necessary regulatoryrequirements





Page 3


•

Job-Focused Skills

,validation strategies and maintaining the validatedstate in:• Multi-product facilities

• Campaign-based production environments

• Differentiating the requirements for cleaning

va a on or:• Manual

• Semi-automatic

• Automatic cleaning



Job-Focused Skills, cont.

approaches

• Comprehending common cleaning validation pitfalls

• Accomplishing analytical method validation andrecovery study requirements in cost-effective studies

• Evaluating your cleaning practices through internal self-audits

• Practicing what you have learned through hands-onexercises





Page 4

Class Introductions

• Name

• De artment

• Company

• Types of Products Your Company Produces

• Status of Your Cleaning Validation Efforts

• What Topics / Questions You Came to Learn About

• This course is designed to address the concerns for all,

• The principles are broadly applicable to IVD and consumerproducts, as well

• If you have a question for your industry, please ASK!!


Module 1Regulatory

equ remen s orCleaning Validation:“Limit”ing the Risk





Page 5

1997 – Quality System 2002 – 20041992/ 3 – Mid-

1997 – HACCP Adoptedfor Food Industr y

FDA Regulatory Timeline

(Relatively Speaking)

1978 – Last significantUpdate to FinishedPharmaceutical CGMPs

1986 – ProcessValidation Guidance

1996 – Qual itySystem RegulationI ssued for Devices

nspec on ec n que(QSI T) for Devices

s - aseI nspection ApproachI denti f ied &Rolled Out

Validation I nspectionGuide Finalized asNational Document

2001 – DrugI nspection Program(6 Subsystems of

-

1992 – First E-RecRule Draft – NotFinalized Unt il

1996 – 2001SUPAC Draft ed

1991 – 1993 InspectionGuides I ssued

• Aseptic Processing

• Bulk Pharmaceuti cal Chemical• Solid Dosage Form

• Semi-Solid Dosage Form• Biotechnology

• Laboratories (QC and Micro)

-

Finalized in 2 0021998 – API DraftGuidance I ssued

1996 – ProposedRevision to GMPs


Significant Sources of Regulation onCleaning and Cleaning Validation

• Worldwide GMPs,

Appendix 18) (2005)

• US FDA, Guide to Inspections of Validation of

Cleaning Processes (1993)• Pharmaceutical Inspection Convention (PIC),

Recommendations on…Cleaning Validation (2001)

• Canadian HPFB, Cleanin Validation Guidelines(2001)

• WHO Supplementary Guidelines on GMP: Validation(2005)





Page 6

Worldwide cGMPsDesign and construction features and

Equipment design, size, and location 21 CFR 211.42 EU 3.1 – 3.2521 CFR 211.63 EU 3.34 – 3.44

Any building or equipment used in the manufacture, processing,packing, or holding of a drug product shall be of:

• Suitable size

• Suitable construction

• All surfaces can be readily contacted bycleaning process; accessed for inspection

• Coved corners, free-draining, non-reactive,non-additive, non-absorptive materials ofconstruction

to facilitate cleaning, maintenance, and proper operations.

• Suitable location • Location appropriate to cleaning utilities /supplies; away from walls or otherinterfering surfaces


Worldwide cGMPs (continued)

Sanitation

Equipment cleaning and maintenance21 CFR 211.56 EU 4.2621 CFR 211.67 EU 4.28

• Written procedures for cleaning and for use of cleaning andsanitizing agents shall be followed and shall:

• Assign responsibility for sanitation• Describe in sufficient detail:

• Schedules Prevent malfunctions or

• Methods

• Equipment

• Materials to be Used

safety, identity, strength, quality, orpurity of the drug product beyondthe official or other establishedrequirements.





Page 7


Equipment cleaning and maintenance 21 CFR 211.56 EU 4.2621 CFR 211.67 EU 4.28

More specifics with regard to the procedures to be established:

• Responsibilities, Schedules, Methods, Equipment, Materials

• Methods of Disassembling and Reassembling to ensure propercleaning and maintenance

As before

•• Protection of clean equipment from contamination prior to use

• Inspection of equipment for cleanliness immediately before use

• Records shall be kept of maintenance, cleaning, sanitizing, andinspection

Recordretention

Cleani ng & Use Log



Equipment cleaning and use log 21 CFR 2 11 .1 82 EU 4.2 8 – 4.29

A written record of major equipment cleaning, maintenance anduse showing, for each batch processed:

• Date

• Time• Product

• Lot number

• Signature and date of person(s) performing

• Signature and date of person(s) double-checking

For dedicated equipment, the records of cleaning, maintenance,and use shall be part of the sequentially numbered batch record (ifno separate log is kept).





Page 8

European Requirements – EC Guide to GMP

Overall, wording and content nearly identical to variousUS requirements

Pertinent Sections:

Section 3: Premises and Equipment(3.34 – 3.44 equipment design for cleanability)

Section 5: Production(5.19 cross-contamination; 5.21 – 5.24 Validat. & Change Ctrl)

Annex 2: Manufacture of Biologicals(15, 17 – design to promote cleanability)


European Requirements – EC Guide to GMP

Overall, wording and content nearly identical to variousUS requirements

Pertinent Sections:

Annex 15: Qualification and Validation

(36 – 42 – Cleaning Validation; 45 - Revalidation) – see next

GMP Part II: GMP for APIs(5.2 – Equipment Maintenance and Cleaning;

. – 12.7 – Cleaning Validation) – aligns with ICH Q7A

Cleaning Validation




Page 9

Definition of Cleaning Validation

• Documented evidence to ensure that

residues to predetermined levels ofacceptability, taking into considerationbatch size, dosing, toxicology, equipmentsize, etc.

- World Health Organization

• Note that this definition immediatelyemploys “risk-based” language


Cleaning Validation –Sections 36 – 42 of EU Annex 15 on Qualificationand Validation

• Cleanin validation should confirm effectivenessof cleaning procedures; rationales should belogical for:

• Limits for carry-over of drug product residue, cleaningagents and microbial contamination

• Should be based on material to be cleaned





Page 10

Cleaning Validation –

Sections 36 – 42 of EU Annex 15 on Qualificationand Validation

• Sufficiently sensitive validated analyticalmethods should be employed

• Product contact surfaces only for validation;although non-product contact parts should beconsidered

• Intervals should be validated for:

• Time between use and cleaning• Time between cleaning and reuse


Cleaning Validation –Sections 36 – 42 of EU Annex 15 onQualification and Validation

• Worst-case approaches for similar materials /

• Typically three consecutive trials should be

performed

• “Test Until Clean” is not an appropriate





Page 11

Cleaning Validation –

Sections 36 – 42 of EU Annex 15 on Qualificationand Validation

• Products which simulate the physiochemical

those materials are either toxic or hazardous

Revalidation - Section 45 of EU Annex 15

• Facilities, systems, equipment and processes,includin cleanin should be eriodicall

evaluated to confirm that they remain valid; areview with evidence may suffice if no significantchanges were made


Guide to Inspections of Validation ofCleaning Processes (1993)

SOP Requirements

• For each major piece of equipment:

• Between batches of same product

• Between batches of different products• For cleaning validation process, requiring:

• Cleaning validation protocols

Dedicate where equipment is

dif f icult to clean orhazardous

• Sampling procedures

• Analytical methods

• Limits (“acceptable level”)

• Final Report

• Approval by management





Page 12

Guide to Inspections of Validation of

Cleaning Processes (1993) (continued)

Evaluation of Cleaning Process• Examine objectives of the validation process,

written procedure and documentation

• Examine training and level ofexperience of the cleaning operators

• Examine allowed length of timebetween the end of processing andeach cleaning step and its potentialeffect on the cleaning process

• Examine ste s taken to revent microbiolo ical contamination

At wh at point does a piece of

equipment o r system become clean?Does it have to be scrubbed by

hand?What is accomplished by hand

scrubbing?How variable are manual cleaning

processes from batch t o batch and

product to product?

IQ / OQ Elements to Consider• Examine equipment design especially when using CIP

• Assure proper identification of process equipment to ensure correctimplementation of cleaning procedures


Guide to Inspections of Validation ofCleaning Processes (1993) (continued)

Scientific Design of Analysis

• eterm ne t e spec c ty an sens t v ty o t eanalytical method(s) used to detect residuals orcontaminants• Testing of rinse solutions should include testing for

residues or contaminants rather than for water quality





Page 13



Scientific Design of Analysis•

with the sampling method(s) to show recovery

• Sampling techniques include direct surfacesampling and sampling of rinse solutions.

• “Test until clean” systems should not be used. The

nee or retest ng may n cate t at t e c ean ngprocess is not validated.



Scientific Limits Determination

•

• Determine how the firm established their residue limits:• Sensitivity of analytical methods is critical to establish valid limits

• Logical, practical, achievable and verifiable

• Scientifically justifiable

• Three examples given: 10ppm, biological activity levelsas 1 1000 o norma t erapeut c ose an organo ept clevels

• Cleaning Agents - “...no or very low detergent levelsremain after cleaning...” UhOh! Don’t use word s such as “absence, no or non e”

when creating your procedures or rationales!!





Page 14



Other Important Statements:•

considered; there should be some evidence that routinecleaning and storage of equipment does not allowmicrobial proliferation; equipment should be dried beforestorage

• “When variable residue levels are detected followingcleaning, one must establish the effectiveness of theprocess and operator performance.”

• “Indirect testing, such as conductivity testing, may be ofsome value for routine monitoring once a cleaningprocess has been validated. … Any indirect test methodmust have been shown to correlate with the condition ofthe equipment.”



Other Important Statements:

“ found acceptable. The most desirable is the direct method ofsampling the surface of the equipment. Another method isthe use of rinse solutions.”

• “Rinse and/or swab samples should be used in conjunctionwith the placebo method” (when it is justified for use)

• “The firm should challenge the analytical method incom nat on w t t e samp ng met o s use to s ow t atcontaminants can be recovered from the equipment surfaceand at what level, i.e. 50% recovery, 90%, etc.”

Does not mean that th ese values presented

here are “acceptance criteria” for recovery.





Page 15



Other Important Statements:• “In establishing residual limits, it may not be adequate to

focus only on the principal reactant since other chemicalvariations may be more difficult to remove…. the issue of by-products needs to be considered if equipment is notdedicated.”

• “When cleaning is between batches of the same product (ordifferent lots of the same intermediate in a bulk process) the

rm nee on y meet a cr ter a o , "v s y c ean" or t eequipment. Such between batch cleaning processes do notrequire validation.”

Not scientifically justif iable!!Does not consider by-pr oducts,cleaning agent, micro, the areain which the equipment iscleaned / stored, etc.


PIC/S, Canadian and WHOGuidance on Limits

Limits shall be logical, practical, achievable, verifiable; forexample, the most stringent of the following first three

• No more than 0.1% (1/1000th) of the normal therapeutic dose ofany product will appear in the maximum daily dose of thefollowing product

• No more than 10 ppm of any product will appear in anotherproduct

• No visible residue on the equipment after cleaning proceduresare performed *

*• Also, for certain allergenic ingredients, penicillins, cephalosporins

or potent steroids and cytotoxics, the limit should be below thelimit of detection by best available analytical methods (or mayrequire dedication)





Page 16

US - May 1996 Proposed Revision to cGMPs

Being Revised as Part of Risk-Based GMPs

¶ 211.220 Process validation

manufacturing processes including, but not limited to,computerized systems that monitor and/or control themanufacturing process.

• The manufacturing process includes all manufacturingsteps in the creation of the finished product including,

, ,weighing, measuring, mixing, blending, compressing,filling, packaging, and labeling. Cleaning is not only considered a step in

the manufacturing process, but it is theFIRST step in gett ing ready for t he nextprocess.


US - May 1996 Proposed Revision to cGMPsBeing Revised as Part of Risk-Based GMPs

¶ 211.220 Process validation (continued)

• (b) Validation protocols that identify the product and productspec cat ons an spec y t e proce ures an acceptance cr ter afor the tests to be conducted and the data to be collected duringprocess validation shall be developed and approved.

• The protocol shall specify a sufficient number of replicate processruns to demonstrate reproducibility of the process and provide anaccurate measure of variability among successive runs

Number of runs to be j ustified.Rule of three typi cally applies.

• Validation documentation shall include evidence of the suitability ofmaterials and the performance and reliability of equipment andsystems. The manufacturer shall document execution of theprotocol and test results.

Three may be the minimum !!





Page 17

US - May 1996 Proposed Revision to cGMPs

Being Revised as Part of Risk-Based GMPs


• c The manufacturer shall desi n or select e ui ment andprocesses to ensure that product specifications are consistentlyachieved.

• The manufacturer's determination of equipment suitability shallinclude testing to verify that the equipment is capable of operatingsatisfactorily within the operating limits required by the process.

• Parts of the process that may cause variability or otherwise affectproduct quality shall be tested.

Considerations for w orst-cases incleaning validation include:

• Maximum hold times• Maximum residue loads• Minimum process parameters

during validation


US - May 1996 Proposed Revision to cGMPsBeing Revised as Part of Risk-Based GMPs


• d There shall be a ualit assurance s stem in lace which re uiresrevalidation whenever there are changes in packaging, componentcharacteristics, formulation, equipment, or processes, including reprocessing,that could affect product effectiveness or product characteristics, and

whenever changes are observed in product characteristics.

Change control considerations include:• Cleaning agent s• Cleaning pr ocess paramet ers• ean ng proce ures• Training procedures• Formulation• Equipment• Environments / storage locations for clean

equipment• I ntroduction of a new product (as it might

affect the limit for an existing product – seelimits section)





Page 18

Module 2:Fundamentals of

Cleaning Validation:Emphasis on Fun!


First, Some Definitions

Cleaning Validation

• Documented evidence that provides a high degree ofassurance that a cleaning process can reproducibly producea clean piece of equipment in accordance with thedesignated specifications

• Generally cleaning validation applies the “rule of”

completed





Page 19


Verification

• documented evidence that provides a high degreeof assurance that a single cleaning event canproduce a clean piece of equipment in accordancewith the designated specifications, suitable for thenext use

• Generall verification is used for develo ment batches

where three may not be made or for infrequentlymanufactured products; when three runs have beencompleted they may be summarized as a validation ifall conditions used in the three studies were the same



• Certification – depending on the firm, certification often hasthe same meaning as verification; some companies

erent ate cert cat on as an expecte process t at woccur after each production event as a change over process,for example

• Monitoring – a routine evaluation of cleaning to determinewhether the original cleaning validation conditions are stillbeing achieved; may involve fewer samples or less invasivesam ling techni ues

• Engineering Trials – experimental cleaning trials that help toevaluate whether a cleaning process for a new / revisedproduct or process will be effective; still requires validated testmethods and sampling procedures





Page 20

Fundamentals of CleaningCleaning depends upon processcontrol…

T ime

A ction

C oncentration /

Chemistry

T emperature

Cleaning also depends upon the…

W ater

I ndividual Performing Cleaning

N ature of Soil

S urface Being Cleaned

T.A.C.T. W.I.N.S. Example





Page 21

Influences on Cleaning

Equipment Type – Major, Minor,Dedicated, Non-DedicatedProduct Type

Surfaceo e n t e r ocess – p st r eam ,

DownstreamMaterials of ConstructionSurface FinishGeometry / Complexity

anu ac ur ng rocessHold TimesCampaign Lengt h

Water QualityTimeAction / Type of Cleaning –

Manual (I ndividu al), CI P, COPConcentrationTemperature


Equipment Categories

Major Equipment - Attributes of Each Category

equ pmen cr ca o emanufacturing process(usually has a unique

identification number)

Minor Equipment -apparatus and utensils (such

significant contributor tooverall contamination

• May be dedicated

• Generally small but may beused for highly concentrated

as scoops, hoses, beakers)which perform a supportfunction

materials

• May or may not be dedicated





Page 22


Major Equipment - Consequences of Each Category

equ pmen cr ca o emanufacturing process(usually has a uniqueidentification number)

Minor Equipment -apparatus and utensils (such

• Significant contaminationcontributor; position / role inprocess will be highly critical

• Generally easy to track forcleaning status

• Generally not a significant’

as scoops, hoses, beakers)which perform a supportfunction

,them out of our program

• Difficulties arise in tracking ofsmall parts through the cleaningprocess



Dedicated E ui ment -Attributes of Each Category

equipment which is used for themanufacture of one product only

Non-Dedicated Equipment -

• Lower risk of cross-contamination

• Multi-use nature resentsequ pmen common y use orseveral products or processes

significant cross-contamination concerns





Page 23


Dedicated Equipment -Consequences of EachCategory

equipment which is used for themanufacture of one product only

Non-Dedicated Equipment -

• Potentially higher risk ofdegradant and impuritybuild-up, especially ifcampaigned

• Validation will be required

several products or processes

Remember the precautions statedearlier for the Guide to Inspection ofCleaning Validation Processes withregard to the pitfalls in not validatingthe cleaning of dedicated equipment.

or eac pro uc orrepresentative from agrouping / bracketing)

• May also be at risk fordegradants andimpurities if campaigningis observed


Types of Cleaning

Manual Cleaning - scrub brushesand high pressure hoses used by • Adaptable to varying soil loads

Attributes of Each Type

an opera or o remove pro ucresidue • Highly dependent upon training

Automated Cleaning (e.g., CIP –(Clean-In-Place) - cleaning

performed by a control system ormicroprocessor whichautomatically controls functions ofwash, rinse and dry

-

• Reproducible if equipment is

qualified for use

• Will not recognize variability in theincoming soil condition

. .,COP – Clean-Out-of-Place) -cleaning performed in a partswasher or sink; often requiresmanual intervention ordisassembly; may be automated

• Often combines strengths andweakness of the above

• May depend upon accurate loadplacement / disassembly for propercleaning





Page 24

Types of Cleaning

Manual Cleaning - scrub brushesand high pressure hoses used by • Lack of inherent reproducibility may

re uire extensive monitorin over

Consequences of Each Type

residue

time

• Detailed procedures a must!Automated Cleaning (e.g., CIP –(Clean-In-Place) - cleaningperformed by a control system ormicroprocessor whichautomatically controls functions ofwash, rinse and dry

• Need to ensure that cleaningvalidation considers the worst-case soil loads or that productioncan adequately identify outliersfor study in the future

- e.g.,COP – Clean-Out-of-Place) -cleaning performed in a partswasher or sink; often requiresmanual intervention ordisassembly; may be automated

• Detailed procedures and loadmaps are typically required

• May require monitoring aswith manual above


Position / Role in ProcessAttributes of Each Position

ps ream – equ pmen ear y n emanufacturing process, for exampleprimary reactors, initial culture,initial blending

• ay ave unreac e s ar ngmaterials present on equipment

• In-process materials may still be“crude” in that they have not yet

undergone purification

Downstream – equipment usedlater in the manufacturing orfinishing process including such

• Residues are less likely to behomogeneously distributedthrou hout the batch as often

crystallization, purification or viralreduction, filling equipment ortableting equipment

there is limited mixing after theupstream processes

• Product is often purified





Page 25

Position / Role in Process

Upstream – equipment early in the • Additional residues may need to be

Consequences of Each Position

manu ac ur ng process, or examp eprimary reactors, initial culture,initial blending

considered for cleaning validation

Downstream – equipment usedlater in the manufacturing orfinishing process including suchprocess steps as finalcrystallization, purification or viralreduction fillin e ui ment or

• Sampling sites will have to be selectedhighly critically to ensure that non-homogeneous distribution of residuesdoes not adversely affect portions ofbatch

•

tableting equipment

conservative to accommodate thecritical nature of many sampling sites

• Be careful that purification processesdon’t concentrate contaminants


Precautions withPurification Processes

• Purification processes are generally intended toremove process-related impurities only

• Don’t falsely assume that residues from priorcleaning operations will be successfully removedby purification without validation





Page 26

Precautions withPurification Processes

• Remember that cleaning validation affects the – ’

the residues from a prior process will becompatible with the next product or purificationprocess

If part of your rationale intends to use thepurification process as part of your basis for residueor limits selection, remember that FDA stated in

Human CGMP Notes that impurities are intended tocome from the starting materials or themanufacturing process itself and not from elementsleft over from the cleaning process


Module 3: CleaningValidation Master

ans: s waysGood to Have aPlan





Page 27

Transformation of Data – Knowledge Management

Source: The Certified Quality Manager Handbook, 2nd Ed., ASQ

WisdomWisdom

Wisdom is derived from t he collecti ve database ofknowledge, built from experience and values, by beingable to see the connectivity among seemingly disparate

KnowledgeKnowledge

InformationInformation

I nformation has meaning, but themeaning is based on theinterpretation of th e user of theinformation.

Knowledge is built t hrough the correlation andintegration of information w ith policies,procedures and regulations.

.

DataData

Data is meaningl ess unlesssomething is done with it .


Transformation of Data –For Cleaning Validation

You will achieve wisdom when you understand w hetheror not your policies, procedures and master plansadequately support t he complexity of your plant! Often

-

KnowledgeKnowledge


Relate the various forms of data tounderstand the equipment, cleaningprocess and product residueinteractions.

Establish poli cies, procedures and m aster plansthat int egrate the information collected about

your plant.

are necessary t o become truly enligh tened!

DataDataCollect information aboutyour equipment, productsand processes.





Page 28

So What Data Need to Be Collected?

Data Required Required For …

Formulation Attributes • Analytical method selection(i.e., dosage, toxici ty,concentration,excipients, degradants,impurities)

• Sampling method selection

• Limits determination

• Worst-case determination (if grouping / bracketing)

• Segregation requirements (if hazardous)

EquipmentCharacteristics

(i.e., materials ofconstruction, geometry,

• Materials of Construction for Recovery Studies

• Surface Area for Limits Determination

• Hard to clean sampling locations or “hot spots”

• Sampling locations where non-homogeneous contamination is

surface area, cleaningprocedure, cleaningagent, disassemblyrequirements)

likely or “critical sites”• Worst-case determination (if grouping / bracketing)

• Segregation requirements (if highly difficult to clean effectively)

So What Data Need to Be Collected?

Data Required Required For …

Process Attributes(i.e., batch size, upstream / downstream, extremetemperatures / holds, etc.)

• Residue selection

• Limits determination

• Sampling location selection

• Worst-case determination (if grouping / bracketing)

• Segregation requirements (if hazardous)

Standard OperatingProcedures

• Process parameters for validation

• Witnessing requirements

• Sampling locations

•

So w hat act ivit ies convertt hese Data into I nform ation? . . .




Page 29

Cleaning SOPDefintion

Engineering Operations Validation and Technical Operations

EquipmentCharacterization

Critical ProcessParameters

Product Grouping /Bracketing

Product Attributes

Equipment TrainDefinition

Cleaning Validation Master Plan or Policy and SOPs for Cleaning Validation

Quality ControlCleaning Agent

Usage Matrix

Equipment Grouping/ Bracketing

Hard to CleanLocations

Residue Selection

Sampling SitesAnd MOC

Methods Validation

Recovery StudiesHold Time Definition

Limits Definition

Sampling MethodSelection

Campaign Definition

Protocol Definition

orst- ase

DefinitionsEngineering Runs /Cycle Development

Protocol Execution and Summary Report Preparation

Now We Have Data and Information, WhereDoes the Knowledge Come From?…

• Knowledge is the integrationWisdomWisdom,

procedures and regulations

• We must first start bycreating our policies ormaster plan for cleaning as

KnowledgeKnowledge


govern our CleaningValidation Program

DataData





Page 30

What is a Master Plan*?Our Needs for an EffectiveProgram:

Roles of the Master Plan:

• Single source for information

• Consistent understanding byall team members

• Assessment of what needs tobe done and by whom

• Effective control of strategies

• High Level Philosophy

• Framework for consistent risk-based decision-making

• Inventory of actions andprojects, resource planning,scheduling

•

consistent

• Less time spent by regulatorsin our facility

scientific rationales

• Single source for regulatoryreview

* Frequently Master Plans are called Project Plans,Validation Plans or Policies, depending on the site’sdocument hierarchy


What are TypicalMaster Plan Sections?

1. Introduction Objective and Scope

2. Description and Background

3. References

4. Responsibilities

5. Validation Approach

• Strategy and organization

• Inventory of qualification activities to be accomplished

6. Acceptance Criteria (as appropriate)

. roce ures orma as appropr a e

8. Risk / Hazard / Failure Analysis (or may be in separate document)

9. Planning & Scheduling (as appropriate, high level, typically)

10. Appendices





Page 31

Master Plan Contents

• Introduction Objective and Scope - Goals of theMaster Plan and brief content insight as well asboundaries of the Validation Project and of theMaster Plan

Typical scope boundary elements:• Production areas included: marketed production,

clinical trial materials, R&D, laboratories, contract

• Types of Residues / Analysis included: chemical,microbiological


Master Plan Contents

• Description and Background - overview andorientation to the facility, process, technology or

,appropriate

Typical elements:• Program progress to date or significant iterations

• , ,significant attributes of products (e.g., toxic, potent),production characteristics (e.g., batch, campaign)





Page 32

Master Plan ContentsReferences - pertinent internal and external documents

Examples include:

• Scientific rationales, SOPs, risk analyses, literature supporting keyrationales or strategies

Avoid excessive generic references (e.g., GMPs)

Responsibilities – high level overview of key project participants – sufficient detail here may supercede the need to continue toreiterate responsibilities in protocols

Depart ment Responsibilit ies

Recovery StudiesAnalysis of Samples

Engineer ing Sur face Ar ea Calculat ionsMaterials of Construction I D

Validat ion Prot ocol and Report Preparat ionOper at ions Cleaning in accor dance wit h SOPs

Collecting samples


Master Plan Contents (continued)

Validation Approach – highlight the key elements of thevalidation program

• Scientific rationales (see next slide) – the basis for the selection ofthe validation testing and trade-offs

• Basis for the selection of validation priorities (e.g., New product

introductions, worst-case products, multi-purpose equipment, etc.)• Project management overview of the responsibilities for the

oversight of the cleaning validation program

• Inventory of validations to be accomplished or alreadyaccomplished in support of the plan

Cleaning Validation is as much about what you choose not to do as it is about what you choose to

do. Ensure your scientific rationales defend both!





Page 33

• Product grouping / bracketing rationale

• Equipment grouping / bracketing rationale

• Residue selection criteria

Scient if ic Rat ionales Will be Needed for …

• Limit selection and calculation rationale

• Analytical approach (specific / direct vs. non-specific/ indirect / screening)

• Sampling method selection

• Sampling site selection criteria

• Others? (e.g., disassembly philosophy, campaign or minor cleanstrategies, etc.)

Document these well as these will serve as the guideposts forfuture personnel or auditors navigating your cleaning validationprogram.



Acceptance Criteria

For cleanin validation the acce tance criteria section typically refers to the way in which the acceptance criteriawill be calculated; if more than one criterion applies, theacceptance criteria section will need to define how theterms will be applied

1/1000th of a Therapeutic Dose or

10 ppm in the next batch, whichever is lower





Page 34

Master Plan Contents (continued)Procedures & Format

Refers to Reference section for the rocedures and formats to be followed; in some cases samples of specificdocumentation samples or outlines of document headingsmay be included

Scope – Products and Procedures

Equipment Boundaries / Train Definition

Pre-Requisites (e.g., methods validation,

recovery studies, IQ, OQ of equipment, training, etc.)Validation Study Design

Sampling Plan

Acceptance Criteria



• Risk / Hazard / Failure / Criticality / Impact Analysis – maybe provided here or in a separate document to substantiate

-, , , ,CTQs or critical parameters

• Planning & Scheduling – include or reference a projectschedule for major milestones; if referenced, ensure that itexists; if included, remember the audience and keep it highlevel

• Appendices – sample flow diagrams for key processes,specimen documentation formats, supportingdocumentation for the approach, data tables of key productattributes, tables including product-specific limits, etc.





Page 35

Other Possible Master Plan Contents• Master Plans may also capture compliance and

re ulator re uirements be ond validation in orderto ensure that the project correctly integratesthese activities with the completion of validation

• This is especially valid if the program isundergoing any significant changes in strategy or

correct ve act ons ave een ent e


Other Possible Master Plan Contents

• For example:• SOP development

• Training package preparation and training of operators / technicians

• Development of test methods or in-process controls

• Vendor audits / surveillance / visits

• Factory / Site Acceptance Tests (FAT / SAT) / Commissioning and/or Qualification Activities for newCIP or COP systems





Page 36

Master Plan Maintenance• Maintain a Revision History

•Project Plan to all involved departments

• Keep the Master Plan up to date with regard tochanges in priorities and schedule

• Place the Master Plan on a periodic review cycle

scientific rationales and current approaches tovalidation


Summary Reports for Master Plans

• In some cases, where a plan is developed for aspecific project such as a new productn ro uc on, a summary repor o e p an canprovide project closure

• In other cases, an annual summary can provideupdates on critical activities / accomplishmentsrom pr or year w e prov ng g g s o goa s

for next year





Page 37

Summary Reports for Master Plans

• Summary report to a Master Plan can provide:

• Closure to validation activities for regulators orchange control purposes

• Mechanism to describe and defend deviationsfrom the original plan

• Location to tie together disparate validation

high level overview


Standard Operating Proceduresfor Cleaning Validation

• Develop an infrastructure of procedures that define the.

• Possible topics to include (in a single or in several SOPs):• Equipment Characterization (New and Existing)

• Standard Operating Procedure Development for Cleaning• Developing and Maintaining Limits Calculations

• Cleaning Validation Methods Validation and Recovery Studies

• Engineering Studies / Cycle Develo ment

• Developing Cleaning Validation Protocols and Reports

• Collecting and Testing Cleaning Validation Samples

• These topics will form the outline of the remaining sectionsof the presentation





Page 38

Module 4: EquipmentCharacterization: Do

no ose e oWhat you AreCleaning!



• We’ve already examined that the surfaceis a critical to the success of the cleaning

• So let’s examine what we can do about it:

• Equipment Design / Construction

• Equipment Characterization

• Documentation of Equipment Characterization





Page 39

Equipment Design and ConstructionProduction equipment and facilities should be designed to be cleanableand maintainable in accordance with CGMPs – other critical attributesmay apply depending on the nature of your production process

• Coved corners

• Welded seams

• Sealed joints or crevices, when necessary(with temperature / chemical resistant caulk or sealant)

• Sanitary clamp type connections

• Minimize dead leg opportunities(not only length of T but also orientation of lines)

• os ve s ope(typically minimum for long runs of 1/8 th in/ft or 10.4mm/m)

• Free-draining

• Non-additive, non-reactive, non-absorptive materials of construction

• Smooth, polished finishes (ex: 20 – 25 µin or 0.5 – 0.625 µm Ra on316L SS)


Existing Equipment Design Survey

• Survey the equipment (see example of potential tool on the nextslide)

•

• Identify risks associated with the weaknesses

• Mitigate as possible

When ranking, it may alsobe helpful to rank eachsection of thee ui ment b the

Product Contact ?

Yes No

Non-Crit ical orIncidental

Critical Site(i.e., location likely to be

-

nature of itsproduct contact:

on acdistributed in next bat ch orlocation w hich is l ikely to bein contact w ith highlyconcentrated active)

Low RiskHigh Risk





Page 40

Example of Design

Survey Risk AssessmentCharacteristic High Rating Low

RatingEquip.Section

Surveyed

Possible Mitigations / Actions for High Ratings

Positive Slope / Free Draining

Non-freedraining

Free draining Reengineering

Forced flow and forceddrying

Non-additive / Non-reactive / Non-absorptive

MOC

MOC notappropriatefor easycleaning

MOCappropriate

Reengineering

Special considerations forcleaning action / chemistry

Enhanced inspection /

cleanliness

Smooth,polishedfinishes

Finish wasnot designedto be smoothor finish hassignificantdamage

Finish issmooth,polished andin tact

Refinishing surfaces

Enhanced cleaning action / chemistry

Enhanced inspection / testing to confirmcleanliness

79

Example of DesignSurvey Risk Assessment

Characteristic High Rating LowRating

Equip.Section

Surveyed

Possible Mitigations / Actions for High Ratings

CovedCorners

Not coved andcritical productcontact

Coved ornon-criticalsurface

Tool selection forcleaning

Special instructionsduring cleaning

Joints Not sealed orsealant inapprop-riate to rigors ofcleaning

Sealed withthe correctmaterial ornot criticalto roduct /

Replace sealant

Use different chemistryor tool for that location

More frequent PM and

cleaningcontact

Dead legsurvey

Dead legs arepresent ororientations thatwould hold upproduct and fluids

No deadlegs orpoororientations

Reengineering

Disassembly for cleaningor disassembly after CIPfor inspection andadditional off-linecleaning

80




Page 41

Equipment Design

Risk Assessment ResultsProduct Risk High Low

Risk

High Reengineering tomitigate is your bestcourse of action

Reengineering is stillbest, but proceduralimprovements maysuffice

Low E ui ment is not No worries!

likely to be a problem,but take care in yourcleaning programdesign


Gather Develo

Goals of Equipment Characterization are to:

• Equipment design data:

• MOC / finish / geometry

• Difficult to clean locations• Cleaning SOP #s and

Cleaning Agent types

• MOC list for recovery studies

• Sampling site identification

• Sampling method determination• Cleaning procedure and

cleaning agent correlation toequipment for grouping /

• qu pment sur ace area ata

• Equipment train data • Equivalency rationales forgrouping / bracketing

• Limit determination





Page 42

Equipment CharacterizationField Assessments

• Set Priorities for Equipment –

(new, non-dedicated major, downstream, non-dedicated minor, upstream, etc.)

• Identify potential equivalent equipment


Equipment CharacterizationField Assessments

• Initiate the Assessment:• Identify product contact materials of construction for

processing equipment and their locations

• Use drawings, vendor certifications, field inspections

• Identify the approximate percentage of surface area thateach MOC comprises (may be approximate)

• Calculate or contact vendor for the product contact surfacearea calculations for the total piece of equipment

• List the cleaning SOPs and cleaning agents in use for theequipment

• Interview operations personnel for hard to clean locations





Page 43

Equipment Characterization Field

Assessments (cont’d)

Repeat the review for any potential equivalent members

Grouping or Bracketing

ev ew or equ va ency s ou nc u e:

• Make / Model / Geometry / Features

• Scale / Size / Capacity

• Materials of Construction / Surface Finish

• Installation and Operational Qualification Equivalence

• Same Position / Role in the Process

Equivalency will also be determined based on:

• Cleaned with same procedure• Cleaned with identical cleaning agent

• Overlap in products produced on those pieces

Grouping / bracketing equipment will then drive:

Number / organization of cleaning validation trials


Equipment Characterization Field

Assessments (cont’d)

Identify sampling locations and sampling techniques

Sampling locations should be selected based on:• Hard to clean locations or complex geometries – hot spots

• Locations that might disproportionately contribute residue tothe next process (e.g., filling needles, discharge valves,

punch and dies, chromatography skid fraction collectionvalves and piping, etc.) – critical sites

• Materials of construction or surface finishes with an affinityfor the residue

-clean residue

Number of sampling locations should be based on the:• Number of locations that fit the descriptions above

• Overall size of the equipment





Page 44

Documenting Sampling Site Selection

Rationales Through Risk Assessment

Role inProcess Likely

SamplingLocation

CriticalSite Hot Spot

Affinity to MOCor surface finish

to Lead toResidue Ranking

Risk assessment technique aids in ensuring that sampling sites areeffectively rationalized and eliminates some of the subjectivity

• Rankin s can be scaled as H M L or iven a number scale , ,

Methods for identifying sampling locations include:

• Interviewing operators for difficult to clean locations

• Witnessing cleaning procedures to identify weaknesses in cleaning

• Conducting screening studies such as Riboflavin testing

Sampling Methods - Survey

Sampling MethodSwab

Rinse(see Baby)

Placebo CouponDirect Surface

Analysis

Physical Removal Good Poor * Moderate* Good * N/A

* May get a dif ferent rat ing depending upon technique

Baby in the

Bathwater

Module 4 – Equipment Characterization

Slide 88

TechniqueDependent

Yes No No No No *

Hard to ReachLocations

Poor Good Good Poor Poor

Adaptable toIrregular Surfaces Somewhat Yes Somewhat No No *

Controlled AreaSampling

Yes No * No Yes Yes

Non-Invasive No Can Be Yes Yes * No

Adaptable to On-LineMonitoring

No Yes No * No No

Can Use Solvents Yes Yes No Yes N/A

Highly DependentOn…:

Site Selection

Training

Recovery

Solubility ofResidue

Contact Time

Homogeneity ofRinse Solution

Recovery

Ability of Placebo toRemove Residue(e.g., solubility)

Homogeneity ofResidue in Placebo

for Detection

Recovery

Ability to Defendthat Soiling and

Cleaning of Couponis Equivalent to the

ProductionEquipment

Recovery

SurfaceCharacter-ization

Qualification ofMethod

Limit of Detection




Page 45

Example of Equipment Characterization

Documentation1 . Eq ui pm en t Nam e

2. Equivalent Equipment IDs

3. Equipment Descr ipt ion & Role

5. Sampl ing Si te Se lect ionRationale and SamplingMethod

in t he Process

• Key Design Featur es

• Key PerformanceAttr ibutes (esp. those thataffect cleaning)

• Critical Sites or Hot Spots

• Rationales for Equivalency(as required)

4. Mater ia ls o f Const ruct ion

6 . Digi tal Photographs ofSampling Sites

• Highlighted samplingarea

• Text description ofsampling location

7. Calculat ion of Sampling Si teSurf ace Area

• Material• Location

• % of Total Surface Area

.

Surf ace Area

Appendix – Sampling Data Sheet*

* To be discussed in Limi ts section


Establish an Equipment Use Matrix

EquipmentName

Cleaning SOP Cleaning Agent Product A Product B

Tank 11 SOP 1234 CleanAll 345 X

Tank 12

(500 L)

SOP 1234 CleanAll 345 X X

Transfer Line101 (2”)

SOP 6789 SonicCare 657 X X

Pump 602

(diaphragm)

SOP 4567 CleanAll 345 X X

•the maximum shared equipment train between products (esp. if you useequipment surface area instead of X’s)

• Can assist in seeing logical relationships for equipment groupings / bracketing

• Records similarities and differences between pieces based on cleaning SOPs andcleaning agents




Page 46

Ensure That Your Characterization

Work Also Assesses The Following• Identify materials that should be reviewed

against cleaning agent and cleaning tools tolook for compatibility issues

• Develop rationales for those materials that willnot need to be included in sampling andrecovery studies based on elements such as:

• os t on n t e process• Overall percentage of surface area

• Similarity to other locations or materials ofconstruction


Ensure That Your CharacterizationWork Also Assesses The Following

• Materials that are candidates for dedication orfor making them disposable, such as thosethat are:

• Likely to have a high affinity to product

• Likely to be extremely difficult to clean• In contact with highly concentrated residues

• Used as ancillary components





Page 47

Discuss the Following:

Can sampling size legitimately be based on the

• Easy to discern part of the equipment (i.e., specificfixture, or identifiable part such as 1 agitator blade)

• Convenient number (e.g., 100 cm2)

• Different sizes for each sample collected


Discuss the Following:

Do you think there will be a maximum and a

collect?

(Don’t give a specific numeric value, just think about whythis might be the case)





Page 48

Module 5: SOPDevelopment for

ean ng -Reproducibility isNo Accident


FDA Perspectives on Manual Cleaning

Pre-1993 – Manual Cleaning Can’t Be Validated

• Industry Concern

• Manual Cleaning Impossible to Eliminate

1993 – Manual Cleaning Can Be Validated• Requires Detailed Procedures

• Requires Effective Training

• Requires Periodic Monitoring

So what are the elements that we need to control in

order to ensure that we meet FDA’s expectations?







Page 50

Fishbone Diagram for

Cleaning Validation

ManpowerMethods“Mother Nature”or environment

PreventingUnsuccessfulCleaning

Clean equip.storage conditions

HVACClassification

TemperatureRel. Humidity

Analyticalmethod

Samplingmethod

CleaningProcedureT.A.C.T.

Attentionto detail

Experience

Training

Cleaning Analysis CleaningResidues

Otherdistractors

a at on

MachineryMeasurementMaterials

agent

Tools forcleaning

Sampling

equipment

Manufacturingequipment

WaterQuality

Materials of construction

Geometry

Recovery

Calibration of Instruments


Question:

How do we ensure control over thesekey elements?





Page 51

A: Detailed SOPs• Materials List with part numbers and descriptions

• Responsibilities List• Pre aration

• Cleaning

• Inspection

• Procedures• Specific to categories of equipment

• Step-wise and sequenced

• Concise, clearly written in simple language, yet detailed

• nc u e . . . .• Reference distinct measures or metrics to determineachievement of T.A.C.T. parameters

• Include documentation requirements

• Include diagrams for clarity


SOP Contents• Preparation Procedures

• Documentation Procedures

• Preparation of area, tools & cleaning agent

• Status Tags, Checklists, Cleaning & Use Log

• sassem y roce ures

• Cleaning Procedures

• Completion Procedures

• Inspection Procedures

• Drying Procedures

• Wrapping / Covering / StorageProcedures

• Post-Cleaning Documentation

• xp o e agrams or g a p o os

• Step-Wise, Tools, TACT, Measures

• Cleaning of Tools, Baskets, Carts

• Methods & Tools, Locations for Inspection

• Environment / Controls

• Materials, Handling, Location

• Re-Tagging, Cleaning & Use Log

• Equipment ExpirationProcedures

• Pre-Use Inspection Procedures

• Dating Requirements, Re-Cleaning Requirements

• Verification of Expiration, Integrity of Wraps / Covers





Page 52

SOP Contents Peculiar to Cleaning

Validation• Time after use before cleaning

• Maximum interruption within a cleaning process(such as hold times after a pre-rinse or time before afinal rinse)

• Time after cleaning before use

• Cleaning Frequency(if tied to levels of cleaning such as major clean andminor clean)

Elements Affecting Cleaning That Would Be Included inBatch Records or Master Cleaning Policy

• Maximum number of batches and/or days in a campaign


Batch Record-Like Format

• Enables formal review of cleaning procedures

• Enforces consistency between operators

• Enforces se uence of activities

• Captures accomplishment of T.A.C.T. throughdocumented completion of key steps, including:

• Preparation of cleaning agent• Disassembly checklist

• Pre-rinse, Wash, Final Rinse

• Drying

•

• Covering and Storage

• Cleaning and Storage of Tools

• Captures start / stop times and critical processparameter achievement





Page 53

Special Considerations for Sanitizationor Disinfection Procedures

• Cleaning steps must be specified prior to the

• Contact time with chemical sanitant is critical

• Method of application may need to bedemonstrated to reliably leave sufficient “liquid”on the surface to effect the sanitization

• Ex iration dates for formulated sanitizers are

particularly important• Aseptic techniques should be taught and

practiced


Special Considerations for Sanitizationor Disinfection Procedures

• Other validation considerations:

•presence of known residues from processingor cleaning at the levels that are typicallypresent after an effective cleaning procedure;ensure the cleaning agent residues don’tinactivate the sanitant

• Re-use of a sanitizing solution must bevalidated as they often lose efficacy quicklywhen contaminated with residues / debris





Page 54

Challenges in Creating Effective SOPs• Too tight v. Too loose control limits

• Excessive investigations

• Limited re roducibilit

• Too much v. Too little detail• Using clockwise 50cm circular motions and the amount of pressure that

it takes to see if a pineapple is ripe, wipe the white, lint-free wipe 25times then reverse to a counter-clockwise motion in the same positionfor an additional 25 circles. When complete, move 50cm to the left,repeat, it will take 125 - 50cm circles to clean the full circumference atthe top level, when the full circumference has been wiped in thismanner, move down 50cm and repeat for the next row …

• Rinse, wash, rinse• Defining scope and applicability of SOP

• Determining extent of cross-referencing v. includingdocuments / forms


Tips for Evaluating Existing SOPs

• Witness process

• Review the actual cleaning performed against the SOP

• Are all tools / steps identified?

• Ensure critical process control steps have a measurable

or observable parameter• Consider how the parameter is assured -- is

documentation the answer?

cleaning tasks - look for variability in current practices

• Revise the SOP to reflect current practices

• Retrain all operators accordingly





Page 55

Don’t Forget

• a e y precau ons

• Personnel protective equipment

• MSDS availability to personnel

• Gowning requirements

• Procedures or handling o deviations


Effective Training

Goals of Operator Training• Reproducibility of cleaning technique• Effective cleaning• Good record keeping

• Safe operationOperators must understand• Importance of each step• Sequence of steps• Effective techniques• Good documentation practices

Skill-based training recommended





Page 56

Inspector Training• Formal training / certification of inspectors needed

• Ins ection rocedures should be formalized in so s

• Non-invasive methods where possible

• Consistent techniques

• Aided inspection where possible

• Inspection requirements should identify

• Gowning / safety / protective measures

• Extent of disassembly for inspection

• Standardized inspection tools / techniques

• Types of residue: product / cleaning process related, foreignmaterials, wear and tear


Common Mistakes with Inspection

• No written procedures for what or how

• Dissimilar levels of disassembly for inspection

• Insufficient tools for inspection

• Lack of certification or formal training

• Lack of procedures for what to do upon failedvisual inspection – • Spot cleaning sufficient?

• Retraining required

• Reporting / trending failures so that CAPA can be made





Page 57

Training Tools / Methods

• Video taping

• e y s e per ormance an nspect on

• Apprenticeship

• Challenge inspection sets for tool use (e.g., boroscope,mirror, etc.)

- next batch

General training in “aseptic” technique – priceless!


Problems to Spot During a SiteWalkthrough

• Procedure creep!!

• “Hurr u ! I need that!”

• Shortchanging parameters – mostcommonly due to lack of controls /

instrumentation for TACT elements• Differences in disassembly

• “Old” cleaning fluids sitting around and

• Failure to clean utensils

• No recleaning upon expiration

• Insufficient investigations of cleaningfailures





Page 58

Module 6: SelectingResidues, thenDeveloping and

Maintaining Limits:“How Clean is Clean?”

Is So Cliché


Residue Selection – or What MaterialsDo We Need to Set Limits For?

Potential residues for consideration include:• API (drug substance)

• Excipients / Colorants / Dyes / Fragrances / Flavors

• Preservatives

• Degradants / Impurities• Starting materials / Processing Aids

• Mother Liquors / Solvents

• Bioburden

• Mycoplasma / Prions / Viral Particles

• Endotoxin

• Particulate





Page 59

How Do We Choose?• First we identify which materials represent the

greatest risk to the next process

•

• Affect the ability to perform the next process correctly

• Create a condition that is unacceptable to consumer(e.g., muddied fragrance, off-color, off-texture)

• Hardest to clean / remove


How Do We Choose?

• Next check to see if there is justification to lookfor one residue as a “representative” or “worst-case” when com ared to the other selectedresidues

• Establish limits for the chosen materials based

on:• Pharmacologic / toxic properties

• Percent carryover

• erm ss e ase ne e.g., m cro







Page 61

What Limits are Commonly Employed

In Industry?• Exactly the three examples cited by FDA! -- they also correspond to

one of the first published articles on the definition of limits by Eli Lillyn armaceu ca ec no ogy

• How can companies use all three?

Equipment must be visually clean andmust meet 1/1000th of a T.D. (see X’s on chart below) or10 ppm in the next batch, whichever is lower…..

x

x10 ppm in next batch

> ,

to 10 ppm in the next batch as your limit

< 10 ppm, therefore defaultto this safety based limit

m g / m L


Precautions with FDAGuidance Documents

“- ...detergent levels remain after cleaning...”

• Watch out for words such as:• Absence

• No

• None







Page 63

What’s In a Limit?

Some Other Considerations

• We want to be conservative – we don’t want patients tobe in estin materials that the weren’t rescribed

• We need to recognize that some materials are morehazardous to patients than others based on theirpharmacologic effects

• We need to recognize that there are aspects of ourmanufacturing process that change from lot to lot that

…

• Batch size

• Equipment train


What’s In a Limit?Exploring the Nature Term

We need to determine how much of the

May be expressed as any of the following:

• Toxicity or LD50 (with appropriate safety factors)• Therapeutic Dosage

• Allergenic levels

• Minimum pharmacological effect level

NatureJCNatureJC

• No Observable Effect Level (NOEL)

It is always most conservativeto select the smallest amount

Overall fractiongets small





Page 64

The Nature Term

Why Select One Over The Other?

• Potency, dosage or min. pharm. effect levels will

required to elicit a pharmacologic response

• Allergenic limits are common for products whichhave a well-established allergenic history for

roducts where the aller enic res onse is below

the therapeutic response


The Nature TermWhy Select One Over The Other?

• Toxicity limits are often difficult to apply as they- ,

have a lot of value for products which have notherapeutic or dose-based index (e.g., cleaning

agents) -- industry needs good guidance on thesafety factors to apply to these limits -- usuallyused in a NOEL or ADI (Acceptable Daily Intake)approach







Page 66


Exploring the Size TermThen translate that number to a value in terms of howmuch that might represent on the surface for us to

• Size of the equipment

• May represent the full shared, maximum or next product’s equipmentsurface area of an equipment train

• Could also take into consideration a smaller area, or single piece ofequipment but only when using an individual dose or portion of the

sample / measureSizeSize

batch as the batch term in order to assess hot spots or critical sites• It is always conservative to over-estimate the surface area of the

equipment

Overall fractiongets small


The Size TermEquipment Train Example

Residue contamination will be cumulative through atrain into the next product, therefore most companies

- as the most conservative.

The train-based calculation will include thecharging equipment through the finishing / filling equipment.

Note: This approach does not prevent usfrom sampling an individual piece ofequ pmen ra er an e w o e ra n -- moreon this in a minute...

Limits are expressed as weight per unit area,therefore any unit area must live up to theestablished limit.





Page 67


Exploring the Safety Factor Term

Lastly, we want the amount that is a“ ”

may add a safety factorSFSF

• SF is any convenient number, usually a multipleof 10 (e.g., 10, 100, 1000, 10000)

• SF are optional (in most cases -- they are not optional when usingterms such as LD50)

• SF compensate for the number of non-conservative assumptionsmade in the calculation of the remainder of the limit

• The larger the SF, the greater the reduction in the limit (as theequation is multiplied by the reciprocal or 1/SF)


Safety Factor

There are a number of considerations for thedetermination of an appropriate safety factor.

In a single facility, several different safety factors maybe applied depending upon some or all of the following:

(note that list is not necessarily all inclusive)• Number and type of conservative assumptions for

distribution of residue, batch size, surface areas,osage, ose s ze, e c.

• Therapeutic category

• Relative toxicity

• Route of administration / dosage form

• Potential use and misuse of product







Page 69

Other Considerations

When reviewing the equation, other considerations ofuse may drive the selection of specific terms:

Route ofadministration

More sensitive?Increase safetyfactor

Examples:

Topical drug product contaminating a suppository

Oral liquid contaminating an inhalant

Inhalant contaminating an intraocular product


Other Considerations (continued)

When reviewing the equation, otherconsiderations of use may drive the selection ofs ecific terms:

Potential product misuse /

environment of use

Greater dosethan directions?

Increase dosetermExamples:

Prescription drug product carryover into an over-the-counter cold medicine

Prescription carryover into a topical antibacterialointment







Page 71

Other Considerations (continued)When reviewing the equation, other considerations of use may drivethe selection of specific terms:

Position / role of theindividual pieces ofequipment in theprocess *

More conservative value selectionand/or higher safety factors themore pure the product becomes orthe closer it gets to finished dosage(or the more likely contaminants willbecome concentrated) *

* (upstream v. downstream, critical sites,

homogeneous v. non-homogeneous distribution, etc.)

Critical sites such as fillers and tablet presses (see next slide)

API drying trains esp. at the discharge valves

UF / DF skids in biopharmaceutical processing


Other Considerations (continued)

• Critical sites offer the opportunity forall residual contamination to bedistributed to a single dose or singleportion of the next batch

• Limits can be calculated that take this

possibility into account, as follows:

Single or limit ed dosesOther approaches include:

NatureJC x BatchNP 1x

Size x DoseNP SFop t

Surf ace area of crit ical sites

• ncreas ng e sa e y ac or orthese locations

Or

• Justifying the routine limitsthrough the understanding ofmaterial consumed at start-up






Page 73

Result x Rinse or Diluent VolumeNatureJC x BatchNP 1x

NP o t

Limits for Cleaning

>ur ace rea x ecovery ec ma

Sampled

• In this case both sides of the equation yield a result that isexpressed as mass per unit surface area.

• In the box, you can see highlighted several terms that areconsidered the Maximum Allowable Carryover or MAC.

• ecen cr c sms o approac an e r va y …• If we were to use the MAC as our limit, we would need to

move the equipment train term over into the result as thenumerator.

Commonly Asked QuestionQ: If we calculate our limit based on a train based approach, doesn’t

that prohibit us from releasing equipment on a piece by piecebasis?

NatureJC x BatchNP 1x

A: No! We can still release on a piece by piece basis – the ratioformed by the equipment train and the surface area sampled is allwe need! By forming this ratio, we can ensure that no unit of

surface area has more than the MAC.

Size x Result x Rinse or Dil. Vol.

>ose

Also sometimes called MAC orMaximum Allowable Carryover

Sampled

As we can see, in either equationform, the equipment train surfacearea and the surface area sampledforms a ratio of the fraction ofsurface area that was sampled towhat is available





Page 74

In Other Words . . .

By dividing the allowablecarryover by the equipmentsurface area, we are determininghow much residue every squareunit of surface area of theequipment is permitted to have.

When we interpret our results,we divide by the amount ofsurface area sampled in order tocompare mass per unit surfacearea to mass per unit surfacearea.

This approach assumes uniform contamination, which we know is not always true,however we are conservative by picking those locations that we know are hard toclean and likely to have the highest concentration of residue.

In this approach every sample must pass the limit. It is inappropriate to average orfactor the results.


Limits for Cleaning Agents

• Cleaning agents constituents do not have a therapeutic index

• To determine safety for cleaning agents, companies often turn tothe only available information with regard to activity, the LD50

• LD50 are specific to an animal model (e.g., rat, guinea pig, mice,etc.) and to the route of administration (e.g., oral, topical, i.v., i.p.,s.c., etc.)

• Because we want to ensure that the carryover quantity is safe forthe person receiving the next dose, we can’t use the LD50 directlyin the nature term

• Instead, most firms first calculate either an ADI or Acceptable DailyIntake or a No Observed Effect Level

• The form for the NOEL or ADI equation is the same as thepharmacologic properties limits





Page 75

Limits of Cleaning AgentsThe typical equation for the NOEL based on an LD50 for oral routes of

administration in rats, appears as follows:

NOEL = LD50 mg/ kg x (5.6 x 10-4) x 70 kg

Conversion factor and safety factor t oconvert oral rat LD50 to or al hum an NOELNote: the safety factor makes up for: differences in

er son t o er son r es onse a var iet of ot ent ial dose

Average adult body w eightNote: it w ould be conservative touse a pediatric weight here or t oleave off t his term alt ogether,,

/ response curves that might make this material awor st case, converting t o a level at w hich No ObservedEffect i s detected.

although the safety factor included just prior is often considered tomore than make up for this term.

Ref: Doursan and Stara, J. Regulator y Toxicology and Pharmacology, 3, 224-23 8, 1983.

Other Refs: D.W. Layton, et al ., J. Regulatory Toxicology and Pharm acology, 7, 96 1987.Doursan, Toxicology, Vol. 1, No. 1, pp. 35-48, 19 86.

Doursan, Toxicology and I ndustri al Health, Vol. 4, No. 4, pp. 23-33, 1985.


Limits of Cleaning Agents

Result x Rinse or Diluent Volume

Surface Area x Recovery (decimal)

Sampled

LD50 mg/kg x (5.6 x 10-4) x 70 kg x BatchNP 1

xSize x DoseNP SFopt

>





Page 76

Let’s Examine The Last

Two Limit Approaches:

• Limits based on pharmacologicalproper es

• Percentage Contamination Limits (e.g., 10ppm)

. .,clean, process capability or analyticaldetection)


Percentage Contamination

• Defined by the amount of one product allowed inany other product w/w or v/v

• Examples such as ppm or ppb are quitecommon - where x parts of any product are

allowed in every million (billion) parts of thesubsequent product; where x may be anyconvenient value

• Note that if x is a convenient value, it is clearlynot related to product safety









Page 79

Process Capability LimitsDespite their weaknesses, there are some advantages too, andcompanies still use these limits:

• Visually Clean -- Good In Conjunction With Safety-based Limits;xce ent -over re-screen ng equ rement e ore amp ng

• Analytical Detection Levels -- May Be Used If There Is ClearEvidence That The Analytical Detection Level Is Well BelowWhat Is Required For Safety

• Cleaning Process Capability -- Starting To Be Used By Firms AsAn “Alert” Limit When Trending Monitoring Or Changeover

esu s

Mean

+3

Time

m g / m L

Safety-based limit


Data Reporting FormNow that we have our limit, how do we determine if ourlaboratory result meets the limit?

To be completed by Sampling Personnel [A, B, C, D (E&F swabs only) at the time of container ;

A B C DSample ID Equipment Location Sample Type

S–Swab; R-Rinse

E F G HDiluent Type Sample Diluent

Volume (mL)Sample

Size (cm2)

Sampling Technician

Initials / Date









Page 82

Points to Remember

on Setting Limits

• Limits may change through the life of your

• Cleaning affects the NEXT product produced,not the one that you that you are cleaning

• The introduction of new products therefore,has the greatest potential impact on the

ex s ng pro uc s n e p an


Points to Rememberon Setting Limits

• However, some of the biggest influencers on

represent the NEXT product – the batch size,daily dose and shared equipment train as the

magnitude of these terms often outweighs theNature term

• This balance between the new and the existingmust be maintained through your changecontrol program and the reassessment ofestablished limits





Page 83

Setting Limits in a Facility &

New Product Introductions

Previous Next Product

Product Prod. A Prod. B Prod. C Prod. D

Prod. A -- 0.107 0.177

Prod. B 0.052 -- 0.309 0.045

Prod. C 0.015 0.085 --

Prod. D 0.010

New products add to matrix in both directions, resulting inpossible new limits for both individual products andworst-case groups!


Work with the Team toCreate a Limits Rationale

• Document your assumptions

• ecor your ra e-o s an o -se s(i.e., less conservative assumptions in one area

my be off-set by conservative assumptions in another)

• When selecting the worst-case from a group / bracket, define the population from which thatworst-case was derived





Page 84

MicrobiologicalResidues, their

EstablishingEffective Limits


What Microbiological Residues ShouldBe Considered And When?

Bioburden and endotoxin are typically included in

contaminants are required to be limited in yourfinal product based on your product specifications

• Bioburden includes bacteria, yeast and molds that arepresent in your water system and environment and can becontributed by your raw materials, equipment and

• Endotoxin is a lipopolysaccharide present in the cellmembranes of the gram negative microorganisms; it isreleased when the organisms die and can cause a feverin patients when introduced to the blood stream





Page 85

What are the Characteristics of

Microbiological and EndotoxinContamination?

• Bioburden is living and endotoxin is derivedfrom living systems therefore pyroburden andbioburden levels will be heavily dependentupon environmental conditions• Is equipment dry, covered and closed?

• Is the environment aseptic or at least a cleanmanufacturing area that limits viable and non-

viable particulate levels, temperature and relativehumidity? (both for manufacturing and cleanequipment storage)

• How drastically do environmental conditionschange based on season of the year?


What are the Characteristics ofMicrobiological and EndotoxinContamination?

• Like environmental monitoring, bioburden andpyroburden assessments are not one-timeactivities

• It is recommended that the levels be subjectto routine monitoring with alert and action

associated with exceeding each of theselimits





Page 86

Precautions With Microbiological AndEndotoxin Contamination

• Several mechanisms can be employed for the

removal (e.g., flushing, wiping) and destruction / inactivation (e.g., chemical treatment, dry heat)

• Destruction of microbiological contaminationcan increase the possibility of endotoxin

methodology is also an effectivedepyrogenation process (e.g., dry heat)


Precautions With Microbiological AndEndotoxin Contamination

• Cleaning and sanitization / disinfection cannot

• Residues will inhibit the penetration of chemicalagents

• Rinsing, such as that typically following cleaningprocedures, may introduce additional bioburden

• Agents typically used for sanitization / disinfectionare typically poor cleaning agents as detergency isgenerally not optimal for the designated residues







Page 88

Frequency Distribution Approach to Setting

Alert and Action Limits95% Alert Limit / 99% Action Limit

# CFU # ofOccurrences

%Occurrences

TotalFrequency

Total Samples

= 300

0 59 19.67% 19.67%

1 67 22.33% 42.00%

2 47 15.67% 57.67%

3 24 8.00% 65.57%

4 32 10.67% 76.34%

5 18 6.00% 82.34%

6 27 9.00% 91.34%

7 11 3.67% 95.01%

8 5 1.67% 96.68%

9 3 1.00% 97.68%

10 2 0.67% 98.35%

11 3 1.00% 99.35%

>11 2 0.67% 100 %

<

<

Microbiological Residues Help Identifythe Source of Contamination• Speciate the representative colony forming units in

order to trend typical flora and identify potentialsources / causes

• Typical types ofcontaminants andsources ofcontamination,

Type of Contaminant Common Causes(not exhaustive, just typical)

Bacillus species • HVAC

• Environment• Sanitizer efficacy

Gram positivebacteria

• Personnel

• Gowning

• Aseptic techniques

include: Gram negativebacteria

• Water

• Environment

Mold • HVAC

• Environment

Yeast • Personnel

• Gowning

• Aseptic Technique176




Page 89

Sampling Techniques for Microbial andEndotoxin Residues

• As with chemical residues, the sampling techniquesfor microbial bioburden and endotoxin roburden mustbe qualified to ensure that there is no interference and toensure that the technique recovers the residuesappropriately.

• Common surface sampling techniques include:• Swab - applicable to both micro and endotoxin (although not as common

for endotoxin); ensure that you determine recovery

• Rinse - applicable to both micro and endotoxin, however large volumescan make this undesirable for sensitivity; can be filtered for micro purposes

• RODAC - applicable to micro only, direct surface measurement throughmedia press-plates, requires scrupulous cleaning after sampling


Other Tips on Micro Programs

• Time between sanitization and sampling should bestandardized in order to get a consistent picture of

o ur en

• Consideration should be given to measuringbioburden both after cleaning and after storage,before use

• Keep chemical cleaning and bioburden / endotoxinreduction programs under separate protocols

• Chemical cleaning programs can then be concludedwhile monitoring continues for bioburden andendotoxin





Page 90

Module 7: MethodsValidation and

It all comes downto your data!


Assay Methods

• Assay methods are preferred to be specific to the analyte

• Screenin methods e. ., non-s ecific ma be usedprovided that all analyte identified is attributed to theworst case residue limit

• Assay methods most commonly employed are thosewhich the company already have in their laboratory

• Assa methods and sam lin methods must bedemonstrated to be suitable through methods validationin conjunction with the sampling method / extractionsystem and through recovery studies





Page 91

Goals of Test Method Validation

• Demonstration that a test method is predictable (e.g.,linear, accurate, precise, specific, rugged) across therange of interest

• Demonstration that the sample preparation, instrumentand method instructions are all appropriate for use andreproducible

Goals of Test Method Transfer

• To demonstrate that a test method can be re roduced

reliably by a different laboratory on differentinstrumentation often with different personnel prior to firstuse official use


Elements and Acceptance Criteria forMethods Validation

• Industry standard practice for methods validation is taken fromUSP and ICH guidance on methods validation

• These guidances often focus on traditional analysis methodssuch as chromatography and spectroscopy, yet you may be

using more novel methods such as direct surface analysisusing an IR probe or Ion Mobility Spectrometry (IMS) thereforemodified approaches may be called for

,procedures for methods validation (which are typically writtenfor product release or stability methods), remember that yourpolicy or protocols should contain the rationale for theselection of the approach and the acceptance criteria









Page 94

What Other Elements Are There?• System Suitability is a key for complex methodswhere you want to assure that there is sufficientcontrol over the anal tical s stem beforeinterpreting your results

• Sensitivity can be interpreted from the linearitydetermination, and, when required can bedetermined more specifically throughexperimentation

• Let’s discuss each attribute in more detail


Elements of Test Method Validation

Accuracy The closeness of test results obtained by the method to the true oraccepted value. It provides an indication of any systematic erroror bias in the method and should be determined across the

’me o s range. yp c a accep ance cr er on o < s app e orchemical analysis.

e a s i n g r e s p o n s

e

o r b a n c e , p p m C , e t c . )

Theoretical

Resp. vs. Conc.ActualResp. vs. Conc.

Accuracy may be assessed with 3replicates at each of minimum of 3

concentrations representing +20% ofpoint of interest (e.g., 80%, 100% and120%). With 100% representing yourcleaning limit. Samples are prepared byspiking active in matrix, although this

increasing concentration of analyte

i n c r

( e . g . , a b s

with active only.

A Y-Intercept of 0 (or close to 0) can alsohelp to confirm that the method is notsuffering from significant bias.





Page 95

Accuracy’s Role In Cleaning Validation• It is a common approach for stability-indicating methods to

establish accuracy in the presence of degradants

•procedure as well (e.g., heat, contact with water andcleaning agent), therefore forced degradation may be aconsideration for your cleaning methods validation

• For protein-based products, for example, it is common toconsider validating the method using a degraded samplethat includes both native and denatured proteins, or

perhaps entirely denatured proteins• Consider this attribute, as critical to your analytical system

and the known degradation properties of your residue



Precision(Repeatability)

A measure of the repeatability of the method. Determination isthrough the distribution of data about a mean value over repeatedanalysis of a homogeneous sample. It provides an indication ofthe random errors in the method. (For intermediate precision, see

s i n g r e s p o n s e

b a n c e , p p m C ,

e t c . )

ActualResp. vs. Conc.

e e n on or rugge ness.


i n c r e a

( e . g . , a b s o r

Typically 6 to 7 replicates of the samesample are tested at one or more pointsacross the range. Using statistics, canalso be calculated across duplicateinjections across a full range. < 2% RSD isgenerally acceptable with <15 or 20% forbiological assays. 190Cleaning Validation




Page 96


IntermediatePrecision(Ruggedness)

The degree of reproducibility of test results obtained by theanalysis of the same samples under a variety of expectedconditions, such as different analysts, different instruments,different lots of reagents, different days, different laboratories, etc.

e a s i n g r e s p o n s e

o r b a n c e , p p m C , e t c . )

ActualResp. vs. Conc.

Oper.#1Inst.#1Lab#1

Oper.#1Inst.#1Lab#2

Oper.#2Inst.#1Lab#2

Oper.#1Inst.#2Lab#1

Oper.#2Inst.#1Lab#1

Oper.#1Inst.#1Lab#1


i n c

r

( e . g . , a b

s

Not all combinations will be required for allassays. Generally more than one operator andmore than one day are tested with at least twoconcentrations (typically twelve data points).Results are expected to be similar to thosedemonstrated during Precision, but may beslightly higher (e.g., <5%). 191

Elements of Test Method ValidationSpecificity(Selectivity)

Demonstration that there is no significant interference caused bythe sample matrix, related impurities, degradant products or thediluent.

Stock SolutionActive Only

Stock Solution

Matrix, Impurities,and/or Diluent Alone

Plus Matrix, Impuritiesand/or Diluent, etc.

Ideally, ensure that there is good separation between any peaks of interest and thoseassociated with the matrix or diluent. For cleaning we may also consider

creating impurities through forced degradation.







Page 98

Determining if the LOQ is Appropriate . . .

Try Again!Plug in LOQ inplace of sample

x diluent or rinse volumesurface area sampled x recovery

Limit? >

>=LOQ

.

OK

This presumes limit andresult of this equation willboth be expressed asmass per unit surface area


• Limits of quantitation should be less than the cleaning limit• Limits of quantitation should take into consideration the dilution, as well. See the

What Are AppropriateLimits Of Quantitation?

o ow ng examp e:

You established a total cleaning limit of 20 mg in the equipment train for a newproduct. When the testing is carried out on rinse samples, the following is reported

by the analytical lab for a 1mL test volume:Residue Total Rinse Vol.

Manufacturing Tank BLOQ 2,000 mL

Holding Tank BLOQ 2,000 mL

Transfer Hoses BLOQ 1,000 mL

Filler Equipment BLOQ 500 mL

If the limit of quantitation of the analytical method is 0.01 mg/mL, did the test resultsmeet the acceptance criteria?

What could we do differently?

BLOQ = Below Limit of Quantitation





Page 99


LinearityA method’s ability to obtain test results directlyproportional to the concentration (amount) of

Five to seven data points are typically selected to demonstrate linearity in a rangethat represents at least 50 - 150% of target concentrations. For methodsvalidation for cleaning, often this can represent the same + 20% around the 100%point of interest that was used for the Accuracy determination.

analyte in the sample over a given range.

Methods validation will require that you report the equation for the line as well asthe r2 value (the coefficient of determination – the proportion of variation in y thatis explained by the best-fit linear equation). The r2 should be > 0.995 in mostcases (>0.98 for trace analytes such as in cleaning validation may beappropriate).



Range The interval between the upper and lower levelsof analyte (inclusive) over which the linearity,

validated. Typically this will correspond to therange used in the recovery studies.

Range does not have any “acceptance criteria”, ratherrange for the assay is “reported”. It is expected, howeverthat a minimum ran e of 80% to 120% will be achieved.

You may have noticed, that if planned properly, therequirements of linearity, accuracy, precision and rangecan all be ascertained from a single experiment.







Page 101

Other Possible Variations

SpecificityandAccuracy

Consider measuring the specificity and accuracy in multipleconcentrations of placebo or diluent (e.g., 1X and 10X) to getboth a real and a “magnified” view of possible interference / bias

Stability Consider including evaluations of stability of: samples, reagentsolutions, and/or standards both on-instrument and in storageas part of the determination of method robustness andruggedness. This can be accomplished through the hold-overand testing of standards and samples during the ruggednessevaluation for different days.

Sensitivity The smallest difference in the amount of analyte which canreliably be detected over the validated range. In accordancewith USP, the slope of the line is the “sensitivity”. If methodrequires close differentiation of analyte concentrations, considerincluding sensitivity in your methods validation.


Considerations for Methods Validation:

Methods and Sampling Go Hand in Hand!

Include the following in the methods validation:

• Specify components and solvents in either sampling SOPor in analytical method

• Sample / standard stability (time of sampling to timeof test)• Refrigeration

• Light

• Extracted / unextracted (for swabs)

If thought out properly, these can be included in yourruggedness evaluation of day to day differences in yourassay and its performance







Page 103

Validation Plan for Methods Transfer• Create formal protocols for methods transfer

• Create two sets of 3 – 10 samples each representing 3 – 5 levels ofanal te or at a minimum select 3 or more sam les that re resent range of variation of actual samples

• Measure the following on one or more instruments with onetechnician in both the receiving and sending laboratory:

• Linearity

• Precision

• Accuracy

• Quantitation and Detection Limit

• Values to be assessed for both within lab and between laboratoryperformance


What are Recovery Studies?

• Recovery studies determine the amount of product that is“recoverable” from a surface each time you sample that surface

• or examp e, t ere was 100 g on a sur ace an you swa eand analyzed it, you may find that you “recovered” only 50 g ofthe material – a recovery of 50%.

100 g 100 g

50 g

50 gSpike surface oftypical MOC, allowto dry / heat, etc.

Swab / rinseaccording toprescribedprocedure

Take swab, extract andanalyze; for rinseanalysis may be direct

Identify the percentageof what was “recovered”vs. what was “spiked”





Page 104

What Else Should Be Considered In A

Recovery Study For Swabbing?• In some cases, the material releases from the surface but resists

extraction from the swab.

• o e erm ne s s po en a y w y your recovery s ow, you canstudy the analytical extraction by spiking the swab directly andassessing whether changes in swab type, diluent, pH, duration ofextraction, mechanical action (e.g., vortex, sonication) will help inincreasing the recovery.

8 g in test tube for analysis

10 g 10 g 2 g on swab unrecovered


What Else Should Be Included In AllRecovery Studies For Both Swab AndRinse?• Direct analysis of spiking solution to ensure that the theoretical spiking

quantity is accurate

• Understand whether or not you have volatile constituents in yourproduct – in these cases, your theoretical spiking quantity and theamount available on the dried surface will not match

• In these cases, consider a “loss on drying” experiment

• Blank coupon analysis as a control to show that there is nointerference / enhancement from the MOC of the surface or sample kit(or from the cleaning / preparation of them)

• Blank swab analysis as a control for the swab – note that the swab isincluded in the blank coupon analysis above, but if you want to seethe individual contributions from the sample kit components this mayhelp you to “qualify” your sampling system





Page 105

Basic Swab Sample

Recovery Study Design

Optional

Stock Solution

Blanks & Controls

Optional

(but recommended, at least initially)


Quick Pointers on Swab Sampling

• All companies swear by their personal swab sampling pattern

• Ensure that your pattern provides you with ease of training and ensurethat the necessary recovery and is demonstrated with adequatere roducibilit between ersonnel and da s

• More than one swab can be used, but be sure to extract it in the samesample tube in order to avoid increasing the error term in yourmeasurement through the inclusion of “background” from multiple

sample containers

Common Two-Direction Technique

Common Three-Direction Technique

Optional Finishing Step

Alternate Patterns Too!





Page 106

Quick Pointers on Swab SamplingTemplates are picture frames that outline thedesignated sampling area

100 cm2

10 cm

Advantages

• Permit reproducible sampling

Disadvantages

• Need to be cleanedthemselves or disposable

• May carry contaminationsample to sample if reused

• Not adaptable to curved or

Solutions for the eliminationof the use of templates:• Train personnel in the

1 0 c

complex geometries• Difficult to handle when

working with swab and testtube and paperwork

• Design sample maps thatshow samplingdimensions based onequipment “landmarks”


Recovery Studies and Rinsing

• Rinse recoveries also need to be determined

• Rinse recoveries are harder to demonstrate dueto the inherent challenges in simulating the rinseprocedure in the laboratory

• A rationale must be created that deems that thelaboratory rinse method is equivalent or a worst-

the field





Page 107

Recovery Studies and Rinsing• When performing rinse recoveries include:

• Assay of the spike solution

• Rinse recovery of blank coupon

• Rinse recovery of spiked coupon

• Optional controls include a sample of the rinsesolution directly in the sample container, ifsuitabilit has not alread been assured –

especially important for solvent sampling


Points to Consider for RecoveryStudies

• Coupons should be representative of actualmaterials of construction and surface finishes

• Sampling techniques should match those used

in the field or a justification of the laboratorymethod being a “worst-case” should beprepared

• Spiking quantity should be close to that which isanticipated to be routine residue quantity(typically people select their limit)





Page 108

Points to Consider for Recovery

Studies• Consider spiking more than one concentration

to check for “linearit ” of the recover e. . 50%, 100% and 150% of the limit)

• Samples should be tested in duplicate ortriplicate to ensure a valid test, only validatedtest methods with appropriate run controlsshould be em lo ed

• Replicate coupons should be tested to confirmthe accuracy of the recovery; consider usingmore than one person or more than one day inthe study


Qualifying Sampling Personnel

• Swab sampling is highly technique dependent

• Rinse sampling is less technique dependent, but somemethods of collection are clearl more com lex

• Sampling personnel should be qualified to collectsamples

• Typically this qualification includes:• Review of methods and techniques

• Witnessing methods and techniques

• rac ce n me o s an ec n ques

• Analysis of results through a mock-recovery with a well-characterized and/or worst-case compound

• Optionally, periodic recertification is employed





Page 109

Acceptance Criteria for Recovery

Studies• Recovery should be performed for swab and

rinse sam les -- the values ma be different!

• There are no “acceptable” or “unacceptable”recoveries

• Companies develop their own standards forrecovery

• Most scientists find it desirable to have >80%recovery


Acceptance Criteria for RecoveryStudies

• Recoveries of less than 50% should beinvesti ated, and swab methods, swab materialand diluents should be optimized, as necessary

• Be careful when interpreting results -- avoidaveraging across a population of samplers -lowest recovery is most conservative

•results such as 10 or 15% -- ensure that thevalue selected makes sense based on the assayprecision





Page 110

Discuss the Following:• What is the consequence of using a coupon in your recovery

studies that is smaller than your routine sample size?

• What is the consequence of using a coupon in your recoverystudies that is larger than your routine sample size?

• What are the possible considerations when recovery is lowfor a compound?

• What do you investigate when individuals don’t get the samerecover for a com ound one o erator to the next?

• What do you investigate if a single individual doesn’t get thesame recovery sample to sample? Would your answerchange if multiple personnel suffered the same failure?


Methods Validation and RecoveryStudies

• Testing and acceptance criteria must bedefined in a rotocol

• The protocol for the method and therecovery study may be one documentprovided that all criteria are included





Page 111

Methods Validation and RecoveryStudies -continued

• If no SOP draft exists, protocol must define thecritical method arameters / method set-u ;method must include:• Instrumentation and instrumentation operating parameters

• Specifications for standardization or calibration of method

• Instructions for how to prepare sampling kits

• Instructions for how to sample (if not already included in a stand-alone procedure)

• Conditions of storage and test of samples• Calculation / reporting of results


Methods Validation and RecoveryStudies-continued

• Results must be collected and reported inrotocol or bound laborator notebook; ood

documentation practices apply

• Summary report should be prepared whichinterprets the results and reports key valuessuch a LOQ recover





Page 112

Types of Test Methods• Specific / Direct methods

• methods that can uniquely identify an analyte; becareful as not all s ecific methods are effective at quantifying analytes; all method validationconsiderations to this point should be considered

• Non-Specific / Indirect / Screening methods• while linearity, accuracy and precision apply, generally

specificity does not as a screening method is one thatdoes not t icall uni uel identif the anal te s e. .

TOC)


Types of Test Methods

• Biological assays• due to the lack of complete characterization of many

biolo ical residuals, their ro ensit to denature ordegrade in the presence of cleaning conditions,biological materials often have more relaxed limitsassociated with methods validation; the key is to

ensure adequate reproducibility to ensure a valid test• Microbiological tests

• because the materials being measured are livingorganisms, their behavior is less predictable thanconventional chemical assays; keys here include theverification that competitive, inhibitory or enhancingmaterials do not influence the results achieved





Page 113

Examples of Potential Cleaning

Validation Chemical Test Methods

Specific / Direct Methods Non-Specific / Indirect Methods

Chromatography (HPLC)

Gas Chromatography (GC) Conductivity

Atomic Absorption (AA) Total Organic Carbon (TOC)

Inductively Coupled Plasma(ICP)

Gravimetric Analysis

pectrop otometry , s, ,Near-IR, Mid-IR, FTIR) oto e ectron em ss on

Ion Mobility Spectroscopy (IMS) Visual

Specific or Direct Methods

Specific / direct methods are often seen as being moredesirable due to their ability to uniquely identify thecontaminant – however, this may also limit their usefulness!!

• They are often unable to screen for a wide variety ofcompounds such as those that might be present in a

complex solution (e.G., Media in a fermentation process)• Can be expensive to develop; especially if the current“product release method” isn’t effectively modified for traceanalytes

•residues which may prohibit identification of the targetanalyte

• Ability to identify an analyte uniquely does not alwayscorrespond with the ability to “quantify” an analyte!







Page 115

FD483 Observation“Equipment cleaning validation consisted of only testing PurifiedWater rinses for pH and conductivity. It was not tested for chemicalcleaning agents or product.”

This 483 points out the concernof the FDA that non-specific techniquesdo not provide assurance that products

can be detected by the non-specific methods

Some residues however, are detected effectively and sensitively by,

technique (and limits!) to your analytes.

Conc. Agent A Agent B0.125% 1.0 0.10.250% 2.0 0.20.500% 4.0 0.4

Conc. Agent A Agent B0.125% 1.0 0.10.250% 2.0 0.20.500% 4.0 0.4


Potential Biopharmaceutical Impurities andContaminants and Commonly Used Methods forDetermination; 0.5 - 10ppm Level

RepresentativeBiotech Process ELISA Lowry SDS- Ion AA /Impurities & Contam TOC / RIA Protein PAGE LAL HPLC Chrom ICP

Media/Nutrients + - + + - + + -Metabolites + - - - - + + -Endotoxin + - - - + - - -DNA/Nucleic Acids + + - - - - - -

Carbohydrates + + - - - + + -Lipids + + - - - + + -Proteins:

Native + + + + - + - -Denatured + - + - - + - -

Stabilizers + - - - - + + -Filter Extractables + - - - - + + -Leachable Column Comp. + - - - - + + -Cleaning Agents:

Organic + - - - - + + -Inorganic - - - - - - + +

TOC – Total Organic CarbonELISA / RI A – Enzyme Linked Immu nosorbant Assay / Radio Immunolabeled AssaySDS PAGE – Sodium Dodecyl Sulfat e Polyacrylami de Gel Electroph oresisLAL – Limulus Amoebocyte Lysate (endotoxin test)HPLC – High Performance Liquid ChromatographyAA / ICP – Atomic Absorption / Inductively Coupled Plasma 230Cleaning Validation




Page 116

Total Organic Carbon

• TOC is popular due to:

• Wide availability of instrumentation

• Simple sample preparation and analysis

• Ability to evaluate multi-constituent residues to low levels

• Organic carbon + OH- -----> HCO3-

• Instrument measures the conductivity of the HCO3-

• Microprocessor subtracts off the conductivity of thebicarbonate present due to the CO2 dissolved in water

• Microprocessor measures slope of conductivity curve and

once it reaches a plateau, it determines the value(maximum TOC in ppm)

• Readily oxidizable substances will provide a quick readout


How Do We Assess A TOC Result?

• Amount of carbon in a compound isdetermined

• Empirically

• Through the analysis of the puresample

• Swab or rinse water sample is

analyzed

• ppm of carbon must be translatedto the amount of residual material

= mx + b

Conservative assumption allresidue found is from the most toxicor potent substance

mg / mLproduct





Page 117

Ion Mobility Spectrometry –

New Approach• Samples are ionized and flow down a “drift tube” with a low flow gas

carrier; m.w. and geometry govern drift and time to strike detector

• Great technique for low level detection (nanogram levels are common)

• Spectra characteristics for yoursubstance (likely in the presenceof your cleaning agent) needto be established

• Sample needs to be aerosolized

• ROI may be justified based onshorter equipmentquarantine

Visually Clean

• Baseline cleanliness conditions should bedocumented, especially for legacy equipment

• Visual threshold can be quantified and should be, ifused as a primary indicator – be careful of inspection

technique equivalency if conducting quantification

• May be appropriate for dedicated equipment or non-critical limits (non-toxic or non-product contactsurfaces)

• Remember that this approach is not safety relatedunless specifically compared to a safety based limit.





Page 118

Current Issues in Methods Validation

• Investigation and outcomes from unknown peaks

• Establish an investigation strategy

• Determine what “unknowns” testing will be conducted

• Will look-back on past three lots be performed?

• What will be assumed about the quantity of the unknown material?

• Selection of analytical techniques for “alternate” times ofcleaning (e.g., receipt of new equipment, after maintenance, etc.)

• Determination of methods for the validation of equipment

- ,would be particulate, bioburden and/or endotoxin)

• Correlation of results from monitoring methods (may be non-specific / indirect) to validation methods (may be specific / direct)


Module 8: EngineeringStudies and CycleDevelo ment –Just say “No!” toExperimentationDuring Validation





Page 119

Engineering Studies or Cycle Development

Goals of Engineering Studies:• Identify successful cleaning parameters (TACT)

• Optimize cleaning parameters (not always a goal!)

• “ ”

Engineering studies can:• Prevent the inclusion of failures in “untried” processes in your

validation (i.e., permits test until clean)

• Permit the establishment of parameters for equipment that isperipheral or outside of current grouping/bracketing elements

Common uses of en ineerin studies include:• New process equipment

• New cleaning equipment

• New / revised products


Engineering Studies or Cycle Development

• Random testing, especially when starting froma known, successful process can be effectivebut often isn’t time or cost effective

• Optimized parameters are often not developed

if a random or use of a previous process isfollowed

• Alternative approaches include theconsideration of tools such as Design ofExperiment to maximize the data available froma minimal number of trials





Page 120

Sample 3 Variable Screening DOE

Experiment Run Order(randomize)

Time Temperature Concentration

1 8 Low Low Low

3 2 Low High Low

4 4 High High Low

5 3 Low Low High

6 5 High Low High

7 7 Low High High

8 6 High High HighH

3 4

7 8

A graphical view of thesame experiment

Time

T e m p e r a t u r e

L H1 2

5 6H

• Here it is assumed that the “action” is constant for yoursystem.

• If you only are varying two parameters (e.g., your water isonly available at a single temperature), your experimentaldesign will be cut in half

Gathering and Analyzing Results

• Engineering studies are a potential good use ofscreening methods – especially if you aren’t trying toachieve a limit, but rather understand therelationship of one result to another

• Use analysis of variance (ANOVA) techniques toexamine results

•influential in achieving a “clean” system and whichfactors are most influential on each other(dependent variables) based on their interactions







Page 122

Validation is Not the Time for

Experimentation

Validation is intended to demonstrateprocess control.


Module 9: CreatingCleaning Validation

ro oco s –The Heart and Soulof Your Validation





Page 123

Understand Your ObjectivesTake stock of your decisions to this point:

• What equipment is the subject of your study and whatboundaries will be observed?

• What residues will you be assessing? Can you assess themin a single trial or will multiple trials be required?

• Active / Excipient

• Micro

• Particulate

• What groupings / bracketings of equipment / products have

rationale?

• What analytical methods / sampling methods will be in use?Make sure you identify them clearly for each analyte alongwith the procedure(s) to be followed.


Understand Your Objectives

Take stock of your decisions to this point:• What locations on the equipment will be sampled? Do you have

• What key parameters will you be studying / observing (T.A.C.T.)?• Will you simply be monitoring them or do you intend to challenge

them?

• Will you need to have multiple operators / shifts performing thecleaning procedures?

• Will you be witnessing the cleaning?

• How will your equipment be soiled?• Routine production – single batch

• Routine production – campaign (# of days / # of batches)

• Intentional worst-case soiling – is a justification available for this beingworst-case





Page 124

Understand Your ObjectivesTake stock of your decisions to this point:

• What is the maximum time after use before cleaning? Will

• What are your limits? Do you have a clear list of allcalculations that need to be included for the interpretation ofyour results?

• What documentation of cleaning will be included as part ofthe validation record?

• Will your study include an equipment expiration study or will

• What is the time after cleaning before next use?

• What are the conditions of storage? (covers, environment, etc.)


Worst-Case Conditions toChallenge In Validation Studies

• Worst-case conditions are typically includedin validation

• Worst-case conditions can help us assure

that our procedures / process are robust• By demonstrating robustness, we are

including an inherent safety factor that willhelp to assure that if we see minor changesin soil load, or person to person differencesthat our process will still be successful





Page 125

What Worst-Case Conditions Should Be

Considered?Worst-Case …

• Hold times before cleaning

Rationale …

• Residues may dry on surfacesor, if hygroscopic may pick up

• Personnel / Shifts

• Process parameters

• May provide representative datawith regard to person-to-personor shift-to-shift robustness

• Reducing process parameters(e.g., 5 minutes less wash time)will ensure that full parameter is

• Starting soil conditions such asmaximum campaign lengthand/or maximum batch size

a ways success u

• Will ensure that any conditionthat is less severe in terms ofsoil load will be successful


Typical Cleaning PQ Protocol Contents

• Scope / Purpose• define the equipment, procedures, practices to be

challenged; be sure to include references to anygroupings / bracketing of equipment / products thatwill also be considered validated based on asuccessful outcome

• Responsibilities• participants in the validation and their roles in the

studies

• ac groun• optional section to describe any pre-work leading to

this point; references may be included to cycledevelopment, prior trials or linked validation studies





Page 126


• Experimental Design• this section should define the key decisions and

rationales, such as:

• Equipment design or definition / boundaries

• Soil selection criteria

• Analytical method selection / sampling method

• Sampling site selection

• Worst-case conditions to be challenged (soil load,

o t mes, c ean ng parameters, etc.• Limits to be applied



• References• Include those documents that support the

accomplishment of the validation, avoidextraneous generic references• Cleaning SOPs

• Training programs• Rationales

• IQ / OQ performance of cleaning equipment andautomation

• Analytical method / sampling method SOPs

• Analytical method validation summary report

• Recovery study summary report

• Failure Investigation / OOS procedure to befollowed





Page 127


• Validation Procedure – details of each datasheet to be executed and attached to thevalidation, including all documentation to becompleted and attached

• Acceptance Criteria – include limits (or theirsource) and all calculations required for theinterpretation of results



• Revalidation conditions / parameters

• Monitoring conditions / parameters

• Data sheets for execution

1. Instrument and Calibration Checklist

2. Equipment Boundaries (if to be field verified)

3. Standard Operating Procedures / Training

4. Methods Validation / Recovery Studies (if to be field verified)

5. Witnessing of Cleaning

6. Rinse Samples

7. Visual AssessmentOrder of theseactivities is cleaning

8. Swab Samples

9. Post-Sampling Activities

10. Deviation Summary

process dependent!





Page 128

Meaning of Consecutive Successful• Validation guidelines often refer to FDA’s requirement for

“consecutive successful trials”

• Consecutive successful in these cases means consecutivetrials without intervening failures – it does not mean withoutintervening production

• Defend the timing of your cleaning evaluations as part ofyour strategy

• When you have a failure, be sure you understand andinvestigate whether they are:• Extrinsic failures – not rocess related, therefore re eat only

the failed run (e.g., utility breakdown, failure to follow SOP,etc.)

• Intrinsic failures – process related, therefore repeat the entirevalidation


Issues with Campaign Manufacture

Batch# 1

Batch# 2

Batch# 3

When gettingready for submission

PV 1

CV 1

PV 2

CV 2

PV 3

CV 3

. . .

Batch# 1

Batch# 2

Batch# 3

In real life we . . . Batch# 4

Batch# . . . n

CleaningEvent

Validation should reflect real life. We also need to have data tosupport inspections such as the PAI. Consider collecting datalater as part of the life cycle under monitoring programs.





Page 129

When Are We Through?

Batch# 1

Batch# 2

Batch# 3

Batch# 4

Batch#10

Cleaning EventSample / Test


Batch# 1

Batch# 2

Batch# 3

Batch#8


Batch# 1

Batch# 2

Batch#6

How long acampaignhave wevalidated?

How long acampaignhave wevalidated?


Time After Cleaning Before Use –Hold Time Studies or “Equipment Expiration”

• Equipment should be stored DRY and COVERED or

• Microbial propagation will depend upon:• Conditions of storage (e.g., Temperature and relative humidity

of environment, quality / cleanliness of covers, degree ofcleanliness and dryness of equipment)

• Location of storage (e.g.., Clean equipment storage room, inthe room in which cleaning is conducted or in a production roomthat is used for other purposes before equipment reuse)

• Genus and species of contamination

• Starting population





Page 130

Time After Cleaning Before Use

Hold Time Studies or “Equipment Expiration”• Beware!! Rooms retrofitted to equipment storage uses may not

have the proper pressurization to hold the equipment in a “clean”state

• Other precautions include:

• Consider whether reuse of cover material is wise

•

C l e a n

E q u i p m e n t

S t o r a g e

++ +

M a n u f a c t u r i n g

C o r r i d o r

C l e a n

E q u i p m e n t

S t o r a g e

+ ++

M a n u f a c t u r i n g

C o r r i d o r

,

• Keep foot traffic in clean equipment storage area to a minimum

• Ensure that personnel entering to retrieve equipment have onclean gloves, gowns, booties, etc.

• Prevent relocation from clean manufacturing to uncontrolledareas and back again


Time After Cleaning Before UseHold Time Studies or “Equipment Expiration”

Residues to consider include:

• Particulate (e.g., environmental dust)

• o ur en

• Endotoxin

• Product -- generally only when equipment is stored in the

production space during other processes or when theequipment is stored in the cleaning room where dirty equipmentis brought

Analytical and sampling methods may differ from those used duringthe cleaning validation:

• Rinse sampling for particulate

• TOC analysis (difficulty here is setting limits)

• Visual assessment (difficulty here is establishing whetherresidues would be assessable at appropriate limits for visualdetection)





Page 131

Time After Cleaning Before Use

Hold Time Studies or “Equipment Expiration”

Study Elements• Understand typical hold times for equipment

– -cleans prior to use – don’t try to validate to the absolute extremes, youare unlikely to be permitted to hold equipment that long!

• Ensure that routine (or intentional) interventions with equipment / storage areas, etc. will occur during study

Options / Considerations for Studies:• Justify that pre-use rinses will be sufficient to remove residues prior to

processing and eliminate the need for these studies entirely

•

fashions after cleaning and study representative members (e.g., closedvessels v. open tools)

• Because residues, especially bioburden, will change over time, keepthe equipment expiration studies as part of the routine bioburdenassessment (i.e., ongoing) rather than discrete validation studies (i.e.,3 runs)


Module 10: Collecting

Samples -Do not Break the Chain





Page 132

Laboratory Methods Transfer and

Validation Confirmation

• Confirm that all test methods required to support thevalidation have been validated or transferred with the appropriate ruggedness

• Ensure that there are clear references to the analyticalmethods and sampling methods in the validationprotocol

• If the method is sensitive and sample stability was,

appropriate procedures / tools are in place to properlyhandle the samples after collection and to record andcontrol the time between sampling and testing


Sampling

• For each analytical method, within theprotocol or in an appropriately detailed SOP or

,• Proper sampling technique

• Appropriate sampling container and tools

• Controls and standards to be sampled and testedalong with the “unknowns”

• Personnel / department qualified to collect sample

• oun samp ng p an a oes no as e resu sof one sample based upon the collection of another





Page 133

Sampling• Ensure that trained personnel are available at

the intended times of field execution

• Ensure that data collection in the datacollection sheets for the protocol isappropriate for capturing all results andcontrol samples


Field Execution Goals

The goals of field execution are to:

• Witness operations

•

• Document the testing conducted

Key capabilities of personnel participating in validationinclude:

• Understanding of the operating principles of theequipment that is being cleaned

• Clear understanding of the validation protocolrequirements

• Attention to detail and effective documentation skills





Page 134

Field Execution –

Tools to Take to the FieldMaterials & resources needed for field execution

• Approved protocol on file

• Official copy of blank attachments / checklists

• Appropriate SOPs, sampling and analytical methods,sampling maps, etc.

• Trained operators to perform the cleaning

• Qualified sampling technicians

• Calibrated test instruments (if any)• Designated sampling containers and labels, supplies and

tools Training should be conducted in job-specific proceduresas well as general “clean” / aseptic practices


Field Execution –Good Execution Practices

• Prior to validation conclude and summarize experimentation – ensure that all systems are in good working order with currentcalibration and reventive maintenance

• Ensure that all supporting rationales are documented andapproved

• Ensure that protocol and monitoring conducted in the fielddemonstrate process control

• Take notes in the protocol in an identified comments section,not within a separate notebook

• Ensure that observations are recorded, initialled and dated incase of future investigation or review

Keep comprehensive notes – Others should be ableto follow the work and repeat it.





Page 135

Field Execution –

Points to Consider• Get into the field to the equipment - no validation from your desk

• No original data should be destroyed

• Write information directly on attachments or official datasheets for the purposes of validation - NO transcribing

• Show calculations

• Protect documentation

• Use binders & sheet protectors

• Attach and label raw data printouts where availableCOPY

DRAFT

• ro oco num er, a ac men num er, pagenumber, initials, date

• Use ink stamps orclear laser labels

Protocol #: _________ Attachment #: _______ Test Step #:Page ______ of ______


Field Execution –Good Documentation Practices

• Complete all datasheet spaces

• Unused datasheet s aces• N/A or N/R as local procedures require

• Justify the omission if the information is required as part

of the test• Errors in datasheets

• Single line through, initial and date – original remark

• Put correct information above the lined out information

• If the correction rationale is unclear state the rationaleadjacent to the error or in the comments section





Page 136

Field Execution –

Good Documentation Practices• Always use dark indelible ink

• ,ensure that there is no opportunity to confuse thesymbols in use

• Always show a sample calculation for anycalculations performed; if using a spreadsheet,consider the ualification of the s readsheet

and/or print the spreadsheet such that formulaeare revealed


Chain of Custody

• Be scrupulous on sample identification

• Ensure that sampling paperwork clearly identifies the sample

• If sampling conditions vary (e.g., diluent or rinse volume and surfacearea sampled) ensure that the sample conditions are tied closely tothe sample

• Considerations for sampling paperwork includes:• Time of collection, time of submission and time of test (when

critical to sample integrity)

• The list of samples submitted to the laboratory

• The correla ion of es s o be conduc ed on each sample (e.g.,active, cleaning agent, bioburden, etc.)

• Storage location and conditions (ideally circular charts iftemperature is critical)

• Initials of personnel performing collection, storage, preparation,testing and data analysis





Page 137

Data Reporting Form

Add the timing requirements and assays called for on thesampling form or create a separate chain of custody to beissued with the sampling form.

To be com leted by Sam ling Personnel [A, B, C, D (E&F swabs only) at the time of container preparation; (E&F rinse only) G and H at the time of sample collection]

A B C DSample ID Equipment Location Sample Type

S–Swab; R-Rinse

Diluent Type Sample DiluentVolume (mL)

SampleSize (cm

2)

Sampling Technician

Initials / Date


Deviations in Field Execution

• Deviations do not mean that the validation is a failure

• Deviations require a formal investigation anddetermination of the impact to the validation as well asthe appropriateness of reusing the equipment for thenext process

• Extrinsic failures – not process related, therefore repeat only thefailed run (e.g., utility breakdown, failure to follow SOP, etc.)

• Intrinsic failures – process related, therefore repeat the entirevalidation

• Follow FDA’s guidance relative to conduct of failureinvestigations





Page 138

FDA’s Proposed Revision to the GMPs

Failure Investigation Guidelines (1996)Procedures / Written record must be available for:

• Identifying the cause of the failure or deviation

• r er a or e erm n ng w e er ou -o -spec ca on resu s werecaused by sampling or laboratory error

• Criteria for the exclusion of any test data found to be invalid due tolaboratory or sampling error

• Criteria for additional sampling and testing, if necessary, during theinvestigation

• Criteria for extending the investigation to other batches or otherproducts

• Review and evaluation of the investigation, including all test results,by the quality control unit

• Criteria for final approval or rejection of the batch involved, and fortaking action on other batches and products


Real Situations –How Would You Handle…..

• You drop a sample on the way back to the laboratory -- does it invalidate the trial?

• Your visual inspection passes, you swab the surface

and the swab comes away with a stain, upon analysisno product is detected -- does the trial pass?

• Your rinse sample passes and your swab sample fails-- w at s your correct ve act on ow oes t s a ectyour monitoring strategy?

• What happens if you can’t achieve your limit?





Page 139

Module 11: ValidationRe orts and Be ond

“To Infinity andBeyond” – Toy Story™


Validation Reports

• Approval Page - corresponding signatures to those approving theprotocol pre-implementation

• Purpose / Scope – reiterate the goals and boundaries of thevalidation; referencing supported groupings / bracketing may againbe appropriate

• Background – reiterate any pertinent relational information withregard to other studies

• Description – provide sufficient description of the system to ensurethat this document can stand alone as a summary to the executedprotocol

• Procedures / Test Methods / Equipment – define those elementsused to execute the protocol – remember that these now representthe validated operational / process state





Page 140

Validation Reports• Results - provide a summary of results and state whether acceptance

criteria were met; use tables and graphs to present data effectively;

provide evidence of how the acceptance criteria were met

• Deviations – list the deviations and their resolutions, state the impact tothe validation and/or to follow-on production, if any

• Revalidation – state the conditions under which revalidation would berequired (e.g., change in key process parameter, change in cleaningagent, modification to equipment, formulation, etc.)

• Conclusion – state whether the initial goals of the protocol were met;

reiterate any groupings / bracketing that are supported by the validation;clearly state any procedure amendments or requirements as a result ofthe qualification

• Follow the summary with the executed protocol


Review and Approve Reports

• Ensure that all groups agree with the validity of the datacollected and the conclusions reached

• Ensure that all acce tance criteria have been met

• Ensure that all groups agree that the pertinent regulatoryand policy requirements have been met – especially if

there were any failure investigations as a result of OOSor deviations

• Ensure that all groups understand any directions forfuture production (e.g., procedures to be followed forcleaning, additional disassembly procedures,inspectional requirements, etc.)





Page 141

Maintenance of the Validated State

Programs that maintain the validated state:

• Preventive Maintenance

• Calibration

• Change Control

• Monitoring


Preventive Maintenance Definition

• Planned activities (generally specified by theequipment / system manufacturer) which ensure

• Ensures ongoing operation of equipment without

fault• Ensures continued compliance with the initial

validation parameters

• equ re n e s

• Preventive maintenance is NOT repairs ormodifications





Page 142

Preventive Maintenance and CleaningFor automated systems, ensure that:

• Cleaning agent dispensing apparatus is functional andnot clogged

• Ensure spray balls / spray devices are not clogged andare freely rotating (as appropriate)

• Ensure valves are operating properly and are in goodrepair • Wear

•• Corrosion•

For manual systems, ensure that:

• Cleaning tools are routinely inspected and replaced asnecessary for:

. .,


Calibration Definition

• Testing (and adjustment if necessary) ofinstruments to ensure that they indicateaccurate y, n accor ance w t recogn zestandards, across their full or intended

operating range• Required for safety of product, equipment and

employees

• Required in the GMPs





Page 143

Calibration Considerations

• Requires demonstration of traceability to appropriatecalibrated standards

• Before each operation, confirm calibration status of all

• Incidents which might affect the calibration should bereported to ensure that the calibration can be verifiedand / or repeated, as necessary

• Ensure that procedures are clear with regard to thenotification required when “adjustments” are necessary-- define the ermissible ran e carefull !

• IQ / OQ should verify that the instrument range andaccuracy are suitable to the process control capabilitydesired


Calibration and Cleaning

• Calibration is required for all instruments thatare assuring T.A.C.T.

• Consider whether sensors (e.g., proximitysensors on a dynamic spray ball) are part of

the calibration or PM program• Ensure that instruments that are used for bothprocess monitoring / control and cleaningmonitorin / control are suitable in accuracand range to both tasks





Page 144

Change Control Definition

• Intent is to maintain validated state (i.e.,

of changes made

• Document changes made for:• Process improvements (planned changes)

• Repair / replacement (planned or unplanned)


Change Control Scope

Change Control, must exist* for:

•

• Computer software

• Computer hardware

• Process directions / procedures / forms(i.e., controlled documentation)

• Processes and formulations

• Raw materials / components

• Test methods / sampling methods

* Programs may or may not be separate for these different programs





Page 145

Change Control and CleaningConsider the necessity to review your cleaningapproach when any of the following change:

• Solvent or cleaning agent to be used for cleaning

• Batch size or dose size

• Formulation, pre-cursors or intermediates

• Processing conditions

• Process equipment

• Procedures for cleaning, sampling or testing• Campaign length

• Hold times / hold conditions


Monitoring Definition

Demonstrates consistency of initial cleaning resultsby reconfirming the results through intermittentsampling of equipment after cleaning validation iscomplete

• Most often applied for manual cleaning to confirm thecontinued good practices of the operators and toensure that there is no “drift” with time

•long campaign

• Biologics facilities often perform “verification” or“certification” activities for facilities change-over whichis really a form of monitoring





Page 146

Monitoring Considerations

Monitoring sampling techniques may be less intrusive andsomew a ess n ens ve an e or g na samp ng sucas the following examples:

• Rinse sampling used preferentially over swabbing

• Screening methods used rather than specificmethods

• May only look for one key analyte

Difficulty is correlating monitoring techniques and results tovalidation techniques and results


Monitoring Benefits

• Can be predictive of undetected change in the system

• Can help to ensure consistency of training andpersonnel performance with time

• Can provide evidence for failure investigations / rationales

• Can demonstrate that there is no build-u issue

• Can be used to add data to demonstrate suitability oflong campaign lengths or “minor” cleaning activities





Page 147

Revalidation Definition

• Intent is to reconfirm initial validationresults

• Frequency / Motivation:

• Change based program

. .,


Revalidation Drivers

• Change control history

• reven ve ma n enance s ory

• Calibration records

• Process control results (esp. automatedsystems)

• Monitoring results / trending

Re-perform validation studies in whole or in part, asnecessary based on whether the data from the ongoingprocess and in-process controls demonstrates consistency





Page 148

Revalidation and Cleaning

• May not be required if monitoring is frequent (in

• May not be required if automated cleaning systemshave in-line analysis (e.g., pH, TOC, conductivity, etc.)

• May be performed under different conditions than theoriginal validation such as different groupings / bracketin , different worst-case conditions, or

elimination of “easy” to clean systems / sampling sitesbased on original data analysis


Module 12 – Wra -U

We’ve Now Seen The Trees,

Let’s Look at the Forest

CLEANING VALIDATIONPRINCIPLES




Page 149

Module 12: Wrap-Up –

e ave ow eenthe Trees, Let usLook at the Forest


Cleaning SOPDefintion

Engineering Operations Validation and Technical Operations

EquipmentCharacterization

Critical ProcessParameters

Product Grouping /Bracketing

Product Attributes

Equipment TrainDefinition

Cleaning Validation Master Plan or Policy and SOPs for Cleaning Validation

Quality ControlCleaning Agent

Usage Matrix

Equipment Grouping/ Bracketing

Hard to CleanLocations

Residue Selection

Sampling SitesAnd MOC

Methods Validation

Recovery StudiesHold Time Definition

Limits Definition

Sampling MethodSelection

Campaign Definition

Protocol Definition

orst- aseDefinitions

Engineering Runs /Cycle Development

Protocol Execution and Summary Report Preparation298




Page 150

Fundamentals of Cleaning Validation

Policies / SOPs / WITrainingValidationMethods Validation

Recover Studies

LaboratoryControlSystem

Facilities &

ProductionSystem

QualitySystem

Management

Discrepancy Investigation

Compliance w/ SOPsEquipment LogsSampling of Equip.

OOS FailureInvestigations

LimitsRationalesAudits

SystemPackaging &

LabelingSystem

EquipmentSystem

Design / Layout toprevent x-contam &promote cleanability

Line Clearance

Cleaning AgentsTools for Cleaning

All Sys ems areCompliant


Regulatory Expectations

• Management Responsibility and Involvement

•GMPs

• Scientifically sound rationales for cleaningvalidation

• Science and precision in testing and reporting

• - , ,plan! Use risk-based approaches for prioritizationof gaps.

• Effective maintenance of the validated state





Page 151

Questions?


Glossary of Cleaning Related Terms

Term orAcronym

Definition

API Active Pharmaceutical Ingredient (drug substance)

BPC Bulk Pharmaceutical Chemical (drug substance); term replaced byinternational term API

Bracketing See grouping

Campaign

Production

Production in which multiple batches of the same product are produced

sequentially; for the period of the campaign, the equipment is dedicatedto that product; depending on the product, cleaning between batchesmay be less extensive than at the end of the campaign

CAPA Corrective and Preventive Actions – actions to be taken upon theoccurrence of a failure in order to ensure that the immediate failure iscorrec e an o preven rom recurr ng

Change-Over (may also be termed Cleaning Certification or Cleaning Verification) Termused frequently in the biotechnology and API industries to indicate theend of a campaign when the production equipment is being cleaned andturned around for the next campaign and/or next product; while cleaningprocesses are typically validated, extensive testing is typically done atthe time of change over




Page 152


Term or Acronym Definition

CIP Clean-In-Place; refers to automated cleaning performed where the equipmentwas used with little disassembly

Cleaning Establishing documented evidence that an approved cleaning procedure willValidation consistently provide equipment (or other product or incidental-product

contact surface) which is suitable for processing pharmaceuticals,biopharmaceuticals or medical devices

CleaningVerification

Sometimes also called cleaning “certification”, a verification activity istypically a single cleaning run; the sampling and testing is often the sameintensity as a validation run, however this term is used when it is notexpected that multiple trials of the same formulation or process will beconducted, therefore a true “validation” may not be possible; if multiple runsare performed over time, a validation summary can be written after three

procedures

COP Clean-Out-Of-Place; generally refers to an automated or semi-automatedprocess such as an high flow or ultrasonic bath or parts washer

Critical Sites Locations that will disproportionately contribute residue to the next dose,next batch or portion of the next batch


Term or Acronym Definition

CTQ Critical to Quality –attr ibutes that are determined to be critical to the finalquality of the product or process

EU European Union

Family See grouping

Grouping A mechanism by which related equipment, products and/or procedures

may be collectively tested, generally through the evaluation of a worst-case representative from the grouping

HACCP Hazard Analysis and Critical Control Point – FDA risk-based methodemployed by food plants to look for carryover residues of highest riskand employ methods to control / eliminate them

o po oca ons a are cu o c ean on e equ pmen may or may noalso be a critical site)

HVAC Heating Ventilation and Air Conditioning

IMS Ion Mobility Spectroscopy




Page 153

Glossary of Cleaning Related TermsTerm or

AcronymDefinition

LD50 Lethal Dose 50 – Amount of product required to kill 50% of ananimal population; LD50 are available for most materials without atherapeutic index; LD50 should always reference animal and routeof administration

LOD (or DL) Limit of Detection (or per ICH, Detection Limit)

LOQ (or QL) Limit of Quantitation (or per ICH, Quantitation Limit)

MOC Materials of Construction

NOEL No Observed Effect Level

OOS Out of S ecification

Organoleptic Of the five senses; generally means visual detection in thecleaning validation context

PAI Pre-Approval Inspection (FDA process prior to approval of a newdrug)

Glossary of Cleaning Related TermsTerm or

AcronymDefinition

PM Preventive maintenance – documented procedures which are performedperiodically to ensure the proper working condition of the equipmentfrequently including the replacement of its wear parts and andreplenishment of its lubricants

Ppm or ppb Parts per million or parts per billion

Protocol A written, approved test plan that describes the testing and analysis

required to demonstrate that a cleaning procedure is validQSIT Quality System Inspection Technique – US FDA Inspection Approach

based on Quality Subsystems throughout the factory

Ra Roughness average – measurement of the finish of metals, esp.stainless steel

Reengineering Activities performed to redesign equipment to better meet GMP orprocess requirements

RODAC Replicate Organism Detection and Counting – RODAC plates are acommon method to sample for microbial contamination on flat surfaces;RODAC plates contain agar which can be directly pressed against asurface for recovery




Term orAcronym

Definition

RSD Relative Standard Deviation

SUPAC Scale-Up and Post Approval Changes –FDA initiative to define changes

T.A.C.T. Time –Action –Concentration / Chemistry – Temperature

These represent the parameters that must be controlled in everycleaning procedure if it is to be successful

TACTWINS A variation of tact that also includes the conditions of cleaning:

Time – Action – Concentration / Chemistry – Temperature – Water –Individual – Nature of Soil -- Surface

T.D. Therapeutic Dose

Template A tool used in swab sampling to outline the area to be sampled as aguide to the sampler; must also be used in recovery studies

TOC Total Organic Carbon

WHO World Health Organization