RISK-BASED CLEANING VALIDATION - cbinet.com 5_Paul Pluta_RB... · RISK-BASED CLEANING VALIDATION...

1

RISK-BASED CLEANING VALIDATION

Paul L. Pluta, PhD

Journal of Validation Technology and Journal of GXP Compliance

University of Illinois at Chicago (UIC) College of Pharmacy

Chicago, IL, USA

OUTLINE

• Strategy and Approach

• Lifecycle Approach to Process Validation

• Cleaning Validation Stage 1 Process Design /

Process Understanding

• Cleaning Validation Stage 2 Process Qualification

• Stage 3 Continued Process Verification / Process

Maintenance

• Implementation Strategy

• Cleaning Validation Documents Overview, Hierarchy,

and Content

• Global Cleaning Problems

2

OBJECTIVES

1. Lifecycle approach principles and description

2. Application of lifecycle approach to cleaning

validation

3. Cleaning lifecycle stage details• Process development and understanding

• Process qualification

• Maintaining the validated state

4. Cleaning validation problems

3

CLEANING VALIDATION GLOBAL PROBLEMS

HIGHEST RISK CONSIDERATIONS

PRODUCT PROBLEMS• Residue chemistry as basis for cleaning

• Solubility in worst-case residue determination

• Cleanability in worst-case residue determination

EQUIPMENT-RELATED PROBLEMS• Non-uniform contamination transfer

• Most difficult-to-clean locations

CLEANING PROCESS PROBLEMS• Manual cleaning qualification

• Cleaning procedure documentation

• Dirty hold time (time to initiate cleaning)

LABORATORY PROBLEMS• Residue stability in cleaning residue analysis

• Residue recovery studies

• Swab sampling technique, reliability, and training

4

AUDIT QUESTIONS

• Is residue chemistry considered in developing cleaning procedure?

• Is pH-solubility profile considered in worst-case matrix analysis?

• Is residue “cleanability” considered in worst-case residue

determination?

• Is non-uniform contamination considered in residue calculations?

• Are most difficult-to-clean equipment locations proceduralized?

• Are manual cleaning personnel qualified and requalified?

• Are cleaning procedures quantitative and documented?

• Are dirty hold times controlled?

• Is residue stability considered in cleaning residue analytical?

• Have analytical recovery studies been conducted? On

representative materials?

• Are swab sampling personnel trained / qualified?

5

STRATEGY AND APPROACH

• Science and technical basis

• Cultural change may be needed

• Process Validation Lifecycle approach

– Stages 1,2,3

– Application to cleaning validation

– Understand / demonstrate / monitor and

maintain

• Documentation

– Hierarchy alignment

6

STRATEGY AND APPROACH

• Science and technical basis for cleaning validation

– R&D support

– Technical reports

– QbD model

– Chemical and physical basis

– Lifecycle approach to cleaning process

– Technical expertise throughout lifecycle

• Culture change

– Cleaning is a process

– Not “we do whatever it takes”

– Organizational training

7

LIFECYCLE APPROACH TO CLEANING VALIDATION

Key point: Application of lifecycle approach to

process validation to cleaning validation.

– Value in this approach?

– Does it make sense?

Three stages in lifecycle approach

1. Design and development (understanding)

2. Validation performance (conformance lots)

3. Monitoring and maintenance (ongoing verification)

Actual experiences should lead to process improvements

8

Lifecycle Approach to Cleaning Validation –Value and Logic?

• Cleaning is a process

• Validation lifecycle concepts being applied to equipment,

facilities, utilities, computers, etc., by validation and

technical experts

• Who can argue with understanding, performing, and

maintaining the validated state?

• Consistent with QbD and ICH approaches

• Auditor interaction: Lifecycle approach (i.e.,

understanding, performing, maintaining) vs.

traditional approach – Which would you rather

present to an auditor?9

TERMINOLOGY: PROCESS VALIDATION

Process Validation – Process Qualification –

Process Performance Qualification (PPQ)

Qualification Qualification

Equipment #1 HVAC

Utilities

Equipment #2 Facilities

Computers

Equipment #3

Analytical methods validation

Cleaning process validation

Packaging process validation

Acceptable lots = Process is validated

10

UO #1Process steps

UO #2Process steps

UO #3Process steps

FDA PROCESS VALIDATION GUIDANCE (2011)

Definition: Collection and evaluation of data, from the process design

stage throughout commercial production, which establishes

scientific evidence that a process is capable of consistently

delivering quality products. Process validation involves a series of

activities over the lifecycle of the product and process.

Three stages of activities:

• Stage 1 – Process Design – Development and scale-up activities

• Stage 2 – Process Qualification – Reproducible manufacturing

• Stage 3 – Continued Process Verification – Maintaining the

validated state during ongoing manufacturing

Other topics in Guidance

• Concurrent release

• Documentation

• Analytical methodology

11

VALIDATION GUIDANCE TRANSITION

1987

Development Performance Maintenance

2004-2011

Development Performance MaintenanceAbove based on RISK

12

FDA PROCESS VALIDATION GUIDANCE (1-2011)

Stage 1. Process design

• R&D / technical development work

Stage 2. Process qualification

• Equipment considerations

• PPQ protocol, testing, results

Stage 3. Continued process verification

• Monitoring and maintaining validation

• Change control

Analytical considerations

Documentation

EXPANDED SCOPE OF PROCESS VALIDATION

CLEANING IS A PROCESS --

APPLICATION OF THE ABOVE TO CLEANING

13

WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification

Automated CIP System

Process steps Qualification

1. Residue on equipment Equipment

2. Water procedure Purified Water

3. Cleaning agent procedure Computer / software

4. Water procedure Compressed air

5. Purified Water procedure Conductivity analysis

6. Dry TOC analysis

Equipment is clean -- Process is validated

Process parameters Quality attributes

14

WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification

Manual Cleaning

Process steps Qualification

1. Residue on equipment Personnel

2. Water rinse Purified Water

3. Scrub with cleaning agent Compressed air

4. Water rinse

5. Scrub

6. Water rinse

7. Purified Water rinse

8. Dry

Equipment is clean -- Process is validated

Process parameters Quality attributes15

CLEANING VALIDATION OVERVIEW

1990s present

1. Defined cleaning procedure (SOP) – basis?

2. Product A batch does not contaminate subsequent

Product B batch

3. Acceptance limit calculated

4. Assume uniform contamination of all equipment

5. Three conformance lots = Validated cleaning procedure

6. Validated analytical method (original API)

7. Worst-case matrix approach

One-time event

16

FDA PROCESS VALIDATION GUIDANCE

LIFECYCLE APPROACH TRANSITION

APPPLICATION TO CLEANING VALIDATION

Pre Lifecycle

Cleaning development (?) PQ change control

________________________

Lifecycle Approach

Development PPQ Maintenance

EXPANDED SCOPE OF VALIDATION

INCREASED SPECIFIC STAGE REQUIREMENTS

17

LIFECYCLE APPROACH TO CLEANING VALIDATION

Scientific and technical approach

Design and development

– Residue + cleaning agent + cleaning procedure Clean equipment

– Risk considerations

Performance demonstration

Monitoring and maintenance

Rationale, responsibility, and accountability

Future process improvements

Not the following:

– Standard site method (no basis or rationale)

– Personnel driven (no control)

– “Do whatever it takes” (high variation)

– SOP (no accountability)

– Validation (?) – One-time event.

18

STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING)

APPLICATION TO CLEANING

FDA Guidance Topics

1. Building and capturing process knowledge and understanding.

2. Establishing a strategy for process control.

Application to Cleaning

Understand residue chemistry (solubility, stability)

Determine cleaning agent based on residue chemistry

Determine cleaning process

• Identify sources of variability

• Establish methods to control variability

– Process Analytical Technology

Rational analytical method and supporting work

Characterization of equipment to be cleaned and supporting work

Trained sampling personnel

DOCUMENT ALL OF THE ABOVE

19

DEVELOPMENT (STAGE 1)

CLEANING PROCESS DEVELOPMENT

• Physical and chemical properties of the residue is basis for cleaning

process

• Considerations for determination of most difficult-to-clean residue

• Residue solubility and stability in determining worst-case soils

• Residue chemistry critical for analytical method

• Cleaning agent chemistry consistent with residue chemistry

• Cleaning process chemistry and engineering and consistent with

residue and cleaning agent.

RESIDUE CHEMISTRY

– BASIS FOR CLEANING PROGRAM

– BASIS FOR ANALYICAL METHOD

20

RESIDUE PROPERTIES -- BASIS FOR CLEANING PROCESS

Case study: Antibiotic suspension containing insoluble API (base)

Original cleaning method: Water, PurW, dry

• No documented cleaning validation for many years

• Unknown peaks on original cleaning validation attempts

• API insoluble

Second method: Alkaline soap wash, water, PurW, dry

• Unknown peaks again

• API insoluble

Final method: Acid wash, alkaline soap wash, water, PurW, dry

• No residues

• Unknown peaks determined to be degradants and flavors.

• API dissolves (acid-base neutralization)

Consider active drug and other residue chemistry in development

of cleaning process

21

DETERMINATION OF

MOST DIFFICULT TO CLEAN RESIDUE

BASIS FOR CLEANING PROGRAM

Water solubility – USP Tables

• Is this adequate? NO!

pH effect – API with ionizable groups?

Solubility in cleaning agent?

• Determine solubility at range pH 1-12

• Understand solubility at pH of cleaning liquid

• Understand solubility in cleaning agent liquid

22

pH SOLUBILITY PROFILE, pH 1-12

Solubility

mg/ml

Drug A

Drug B

pH 1 7 12

23

CASE STUDY #2: SMALL MOLECULE API ORAL

LIQUID API INSOLUBLE

Original cleaning method

• Alkaline cleaning agent with manual intervention

• Acid cleaning agent (full strength) when white residue noted.

• Small parts soaked in acid cleaning agent (full strength)

• Cleaning method difficult, ineffective, and unsafe

Liquid product – alcohol / glycol solvent system

• Change cleaning method to alcohol initial rinse. API soluble

Final method: Alcohol rinse/soak, alkaline wash, water, PurW, dry –

Significant improvement

• No residues

• Easy and safe method

Consider active drug and other residue chemistry in development

of cleaning process

24

RESIDUE SOLUBILITY AND STABILITY FOR

DETERMINING WORST-CASE SOILS

Solubility considerations

• Hydrophilic and hydrophobic molecules

• Ionization – Effect of pH

• Effect of temperature

• Surface active molecules

• Liquid and semisolid product vehicle polarity

Stability considerations

• Hydrolysis, oxidation, photolysis, physical changes

What residue is really present?

Consider chemistry of residues

25

CLEANING MATRIX

Determine Worst-Case Soil

SOLUBILITY (mg / ml)

pH 1 Water pH 12 Alkaline

Cleaning Agent

Drug A 25 25 25 25

Drug B 15 15 15 15

Drug C 5 5 150 250

Drug D 150 10 10 50

Drug E 125 10 100 250

Consider acid cleaning agent for drugs D and E

26

WORST CASE CLEANING

Determination of worst-case cleaning based

on API toxicity, worst-case dose, etc.

– Standard calculation

Cleaning procedure may be based on

excipients having greatest effect on

cleaning

– Hydrophilic polymers

– Dyes

– Hydrophobic vehicles

27

BIOTECH CLEANING CHEMISTRY -- API

Protein molecules degrade in alkaline conditions

Degradation rate is slower in acidic conditions

Degradation rate increases with temperature

API residues typically consist of protein fragments and

aggregates

Analytical method: Non-specific analysis

Reference: Kendrick, Canhuto, and Kreuze. Analysis of

Degradation Products of Biopharmaceutical API Caused

by Cleaning Agents and Temperature. Journal of

Validation Technology, V15, #3, Summer 2009.

28

BIOTECH CLEANING CHEMISTRY – GROWTH MEDIUM

Medium Composition

• Acids or bases

• Monovalent salts

• Polyvalent salts

• Amino acids

• Proteins (polypeptides)

• Carbohydrates

• Aqueous soluble organics

• Non-aqueous soluble organics

Consider medium composition at end of cycle.

Reference: Azadan and Canhoto. A Scientific Approach to the Selection of

Cleaning Validation Worst-Case Soils for Biopharmaceutical manufacturing.

Cleaning and Cleaning Validation, Volume 1. 2011.

29

CLEANING CHEMISTRY MECHANISMS

• Wetting

• Emulsification

• Dispersion

• Solubility

• Chelation

• Oxidation

• Hydrolysis

30

CLEANING AGENT OPTIONS

• Water

• Commodity alkalis and acids

• Organic solvents

• Surfactants

– Anionic

– Cationic

– Amphoteric

– Nonionic

• Formulated detergents

31

COMPONENTS OF FORMULATED DETERGENTS

• Surfactants

• Alkalis

• Acids

• Sequestrants / chelants

• Dispersants / anti-redeposition agents

• Corrosion inhibitors

• Oxidizing agents

• Enzymes

• Buffers / builders

• Preservatives

MUST HAVE CONTROL OF CLEANING AGENT

HAVE CONFIDENTIALITY AGREEMENT WITH SUPPLIER

32

CLEANING ENGINEERING

Factors affecting cleaning

• Soil residue

– Soil levels, soil condition, hold times, soil mixing,

water quality and residue,

• Cleaner and parameters (TACT)

– Time, Action, Concentration, Temperature

– Others

• Surface and equipment design

33

CLEANING PROCESS

SOURCES OF VARIATION

• Cleaning agent preparation – must be exact

• Automated cleaning vs. manual cleaning

• Manual cleaning process variation

• Human physical strength variation

• “Cleaning” between same-product batches in

campaign – residue level build-up

• Campaign length – residue level build-up

• Time to initiate cleaning (dirty hold time)

• Residue chemical and physical changes

34

EQUIPMENT TO BE CLEANED

Cleaning-related qualification

• Product-contact materials

• Compatibility with cleaning agents

• Surface areas – need for residue calculations

• Equipment equivalence

• Most-difficult-to-clean locations on equipment -- Highest

risk locations for sampling

• Non-uniform contamination equipment

• Non-uniform contamination sampling locations

• Sampling methods (swab / rinse)

Part of IQ/OQ/PQ for manufacturing equipment

35

NON-UNIFORM CONTAMINATION

Typical calculation considers total surface area of all

product contact equipment, and assumes all lot A

residue from total surface area transferred uniformly to

all lot B product

Usually no consideration for residue that is not uniformly

transferred

Examples: Filling neededs, encapsulation equipment,

compressing equipment, others post final mixing

Consider and justify residue concerns in non-uniform

contamination equipment

36

EQUIPMENT TO BE CLEANED

SAMPLING LOCATIONS

UNIFORM AND NON-UNIFORM CONTAMINATION

Product A = X

Product B = X

Product B flushes filling lines with A residue

xxxxxxxxxx x x x x x x x

xxxxxxxxxx x

xxxxxxxxxx x

xxxxxxxxxx

x x x x x x x

MANUFACTURING TANK PRODUCT

37

PROCEDURE TO DETERMINE SAMPLING

LOCATIONS

Specific documented procedure recommended

• Equipment technical evaluation

• Observation of equipment after processing

• Equipment disassembly review

• Cleaning procedure review

• Equipment evaluation review

• Operator interviews

SOP describing above

Documentation of above for equipment sampling

38

EQUIPMENT SAMPLING INSTRUCTIONS FOR CLEANING VALIDATION

EQUIPMENT: IMPACT MILL

X SAMPLED

EQUIPMENT ASSET# EQUIPMENT NAME LOCATION

Equipment #XXX Impact Mill Room XXX

Equipment #XXX Impact Mill Room XXX

Equipment #XXX Impact Mill Room XXX

39

EQUIPMENT SAMPLING

LOCATION

PRODUCT

CONTACT

MATERIAL

SAMPLE TYPE RATIONALE

1. Rotor Stainless Steel SwabMaximum residue accumulation.

Maximum product contact

2. Screen Stainless Steel SwabMaximum residue accumulation.

Maximum product contact

3. Discharge Chute Stainless Steel SwabMaximum residue accumulation

Maximum product contact

1

2

3

Pictures are representative of all impact mills.

SAMPLED BY: _________________________________ DATE: _______________

VERIFIED BY: _________________________________ DATE: _______________

TIME TO INITIATE CLEANING

“DIRTY HOLD TIME”

1. Make Product A

2. Clean

3. Make Product B

How long between end of #1 and start #2?

Is residue same? Does residue change?

What can happen to the residue?• Wet and dry processes

• Chemical changes (hydrolysis, oxidation, etc.)

• Physical changes

40

CAMPAIGN LENGTH

How many lots in manufacturing campaign before

cleaning must be done?

What about “cleaning” between batches?

• Equipment should be visually clean

• Terminology: “Between lot procedure”

• How much residue “build-up?”

DO NOT IDENTIFY AS “BETWEEN LOT CLEANING”

41

MANUAL CLEANING

• Manual cleaning procedures should be

monitored and maintained with increased

scrutiny compared to non-manual procedures

• More frequent training of cleaning personnel

• Increased supervision

• Periodic (annual?) revalidation batches

Manual cleaning is high risk

42

ANALYTICAL METHOD DEVELOPMENT

Early stage 1 (development) analysis –

validation not required but must be sound

Validated method when used for Stage 2

cleaning validation and post-validation

testing (change control)

All methods and data (including stage 1) subject to

regulatory audit

43

ANALYTICAL METHOD DEVELOPMENT

Analytical method must measure actual residue –

what residue is actually present on equipment

surfaces?

• Small molecules

– API

– API degraded – specific or non-specific method

• Biotech molecules

– API degraded – non-specific method

UNDERSTAND RESIDUE CHEMISTRY

44

ANALYTICAL METHOD DEVELOPMENT

Cleaning agent residue

• Analytical method to determine residual cleaning

agent.

• Information from cleaning agent vendor

45

RESIDUE RECOVERY STUDIES

Case study

Tablet formulation, stable API, all processing on stainless steel except

compressing machine (cast iron)

Stainless steel recovery = 100%

Audit identified no recovery on cast iron

Cast iron recovery = 0%

Lab analyst spiked dye tablet with active drug.

Dry 5 minutes

Swab

Recovery = 0%

Resolution: Install stainless steel dye table.

46

RESIDUE RECOVERY STUDIES

Caution with plastics, resins, porous materials.

Obtain materials from equipment fabricators• Material composition

• Material porousity

• Surface roughness

Example: % Recovery

Neoprene smooth 79.4%

Neoprene rough 11.7%

Reference: Forsyth. J. Validation Technology, Vol15, #4, 2009.

47

RECOVERY STUDIES -- CALCULATION

Recovery data = 50% recovery

= 0.5 recovery factor

Actual residue level = analytical results

Recovery factor

= 25 mcg/sq. cm

0.5

= 50 mcg/sq. cm

48

ANALYTICAL METHOD DEVELOPMENT

Recovery studies

Can sampling procedure adequately recover residue

from equipment surfaces?

• Product contact materials

• High % of total surface area

• Obtain representative coupons from equipment

fabricators

• High (e.g., >80%) acceptance criteria

• Factor may be used in calculation

– Multiple approaches

– Factor every calculation?

All sampled surfaces must have recovery data

49

SAMPLING

Sampling methods

• Sampling (swab) critical activity

• Training program

• Trained sampling personnel– Demonstrated acceptable performance

• Documented training and retraining

• Worst case compounds / procedures in training– Volatile solvents (importance of rapid technique)

• Worst case sampling equipment– Extension poles

• Retraining considerations– Who does sampling? Personnel skills

50

SWAB SAMPLING TECHNIQUE, RELIABILITY,

AND TRAINING

PROBLEM:

• Swab sampling must recover product residue.

• Sampling personnel must be trained and qualified.

• Periodic retraining should be considered.

51

ANALYTICAL METHOD DEVELOPMENT

Sampling methods

• Sampling (swab) critical activity

• Training program

• Trained sampling personnel– Demonstrated acceptable performance

• Documented training and retraining

• Worst case compounds / procedures in training– Volatile solvents

– Problem: Solvents evaporate quickly = false negative

• Worst case sampling equipment– Extension poles

52

ANALYTICAL METHODOLOGY

Case study: Swab sampling with extension pole

Interface

Biotech tank

53

SAMPLING PERSONNEL TRAINING

Representative sampling sites

• Use of auxiliary equipment

Representative of most difficult analytical methods

• Volatile solvents – time constraints

Retraining considerations

• Who does sampling?

• Personnel skills

54

SAMPLING TRAINING

Sampling is extremely critical to cleaning

validation program

Inadequate sampling = false negative

– Insufficient pressure on surface

– Swab solvent evaporation

– Insufficient area sampled

Auditors routinely ask for sampling program training

methods and training records

55

EQUIPMENT SAMPLING INSTRUCTIONS FOR CLEANING VALIDATION

EQUIPMENT: IMPACT MILL

X SAMPLED

EQUIPMENT ASSET# EQUIPMENT NAME LOCATION

Equipment #XXX Impact Mill Room XXX

Equipment #XXX Impact Mill Room XXX

Equipment #XXX Impact Mill Room XXX

56

EQUIPMENT SAMPLING

LOCATION

PRODUCT

CONTACT

MATERIAL

SAMPLE TYPE RATIONALE

1. Rotor Stainless Steel SwabMaximum residue accumulation.

Maximum product contact

2. Screen Stainless Steel SwabMaximum residue accumulation.

Maximum product contact

3. Discharge Chute Stainless Steel SwabMaximum residue accumulation

Maximum product contact

1

2

3

Pictures are representative of all impact mills.

SAMPLED BY: _________________________________ DATE: _______________

VERIFIED BY: _________________________________ DATE: _______________

STAGE 2, PROCESS QUALIFICATION –

(VALIDATION PERFORMANCE)

APPLICATION TO CLEANING1. Design of a facility and qualification of utilities and equipment

2. Process performance qualification

3. PPQ protocol

4. PPQ protocol execution and report

Qualification of equipment, utilities, facilities

• Cleaning equipment (CIP)

Process Performance Qualification (PPQ) – commercial scale

Conclusion that process consistently produces clean equipment

Conformance batches

• All support systems, documents, training, personnel, etc. in place

• Target / nominal operating parameters within design space

• Additional testing (swab / rinse)

• Decision to “release cleaning process” for routine commercial use

• Post validation monitoring plan – Based on risk

– Drug residue properties

– Manual or CIP

57

CLEANING EQUIPMENT

CIP system must be qualified (IQ/OQ/PQ or ASTM

E2500)

Riboflavin (or other) coverage testing

Temperature controls

Flow rates, etc.

PAT inline systems– Drug disappearance – spectrophotometry, other methods

– Cleaning agent rinse -- conductivity

58

CLEANING PROCEDURE DOCUMENTATION

(Cleaning Batch Record)

SOP

• Fill tank half full

• Add half scoop of soap

• Scrub as needed

• Rinse until clean

• Re-scrub and re-rinse if needed

CLEANING PROCEDURE RECORD

• Fill tank with 500 L water. Sign/date __________

• Add 20.0 kg cleaning agent. Sign/date __________

• Disassemble Part A. Steps 1,2,3,4,5

• Scrub for 20 minutes. Sign/date __________

• Disassemble Part B. Steps 1,2,3,4,5

• Soak Part B in cleaning liquid for 10 minutes. Sign/date __________

• Rinse Part A and Part B with 50 L water. Sign/date __________

• Rinse with 50 L Purified Water. Sign/date __________

• Dry with compressed air

59

CLEANING PROCEDURE RECORD

• Fill tank with 500 L water. Sign/date __________

• Add 20.0 kg cleaning agent. Sign/date __________

• Disassemble Part A. Steps 1,2,3,4,5

• Scrub for 20 minutes. Sign/date __________

• Disassemble Part B. Steps 1,2,3,4,5

• Soak Part B in cleaning liquid for 10 minutes. Sign/date __________

• Rinse Part A and Part B with 50 L water. Sign/date __________

• Rinse with 50 L Purified Water. Sign/date __________

• Dry with compressed air

KEY POINTS

Exact concentration of cleaning agent liquid

Signature on quantitative steps

Grouping non-quantitative steps (e.g., disassembly)

60

MANUAL CLEANING -- Do you really know what is happening?

Q to operator: “Why is there so much foam in the tub?”

A: “I put in extra soap because the equipment was really dirty.”

Q to operator: “Why is there powder on the (clean) equipment?”

A: “No problem -- We’ll get the residue when we set up.”

Q to operator: “Why don’t you follow the cleaning procedure?”

A: “The cleaning procedure really doesn’t work.”

ABOVE NOT ACCEPTABLE – TRAINING NEEDED

61

MANUAL CLEANING -- Do you really know what is happening?

Q to operator: “Why is there powder on the clean equipment?”

A: “It’s clean enough.”

Q to QA (equipment inspection person): “Did you approve that the equipment

is clean?”

A: “It’s clean enough.”

Q to management: “Do you know that your equipment is not clean?”

A: “It’s clean enough.”

Q to operator: “You cleaned the gasket with pure soap – this is not the

procedure? Also it is dangerous – these are corrosive chemicals.”

A: “That is the only way to get it clean.”

Q: “So why don’t you tell someone to change the procedure?”

A: “We don’t have time.”

ABOVE NOT ACCEPTABLE – TRAINING NEEDED

62

MANUAL CLEANING -- Do you really know what is happening?

Q to management: “Did you finish cleaning the equipment? We are

here to swab for cleaning validation.”

A (very proudly): “We cleaned the equipment three times so that we

won’t have any problems.”

Q to validation person: “Did you know that the manufacturing people

always clean the equipment multiple times before it is swabbed?”

A: “Sure, we knew.

Q: “Why didn’t you stop this?”

A: “These people are our friends. We have to work with these people.”

ABOVE NOT ACCEPTABLE – TRAINING NEEDED

63

VALIDATION REQUEST / PLAN

Initiates cleaning validation

• New cleaning validation or change control process

improvements

• Strategy and approach

• Scientific and technical basis

• Specify required protocols and other work to accomplish

validation

• Risk-based

• References: Stage 1 Design / development reports

64

VALIDATION PROTOCOL

Cleaning validation protocols and other work

as specified in Validation Plan

– Risk based

Include sampling pages indicating worst

case sampling locations.

Specify acceptance criteria

65

VALIDATION RESULTS / REPORT

Test results as required in validation protocol.

• Discussion. Consistency with Stage 1

development work.

• Clear statement the cleaning process is (or is

not) validated.

• Recommendation for Stage 3 monitoring and

maintenance.

– Additional limited testing based on data and risk

– Routine monitoring based on risk

66

67

STAGE 3, CONTINUED PROCESS VERIFICATION

(VALIDATION MONITORING AND MAINTENANCE)

APPLICATION TO CLEANING

Activities to assure process remains in validated state

Change control -- evaluate impact of change and validate (test) as necessary

Trend and assess data– PAT rinse times

– Conductivity data

Study OOS and OOT (Out of Trend) data

Improve process

Improve control to detect and reduce variability

Cleaning non-conformances and deviations

Re-validation – definition: Actual batch or “paper”

• Is re-testing necessary?

• When should re-testing be considered?

Periodic Management Review

• Documentation reviewed by management

• Documented review

POST-VALIDATION MONITORING AND MAINTENANCE

1. Stage 2 specific requirements

– Additional testing based on actual data

– Ex: One location has high (acceptable result)

2. Routine monitoring and maintenance

– Risk based

3. Change control program

CHANGE CONTROL MOST IMPORTANT AND

DIFFICULT TO ADMINISTER

PERSONNEL MUST RECOGNIZE “CHANGE”

68

POST-VALIDATION MONITORING AND MAINTENANCE

Residue toxicity risk

• Residue that can be visually seen

– Room lighting must be adequate

– Provide additional lighting if necessary

• Residue that cannot be visually seen

– Swab after each batch?

CONSIDER PATIENT RISK AND COMPANY RISK

69

CHANGE MANAGEMENT

• All associated personnel must be aware of

change control

• Change control system developed

• Process improvements expected based on

ongoing experience

• Process improvements should be evaluated by

technical people (i.e., Stage 1)

• Stage 2 PPQ conducted when appropriate

based on Stage 1 technical evaluation.

70

POST-VALIDATION MONITORING

Periodic review of cleaning performance

• Deviations

• Non-conformances (dirty equipment)

• Re-cleaning

• Change control

• Other monitoring (CIP data)

• Product APR data

• Statistical Process Control data treatment

• Management review -- documented

71

CLEANING DOCUMENTATION

• High level documents

• Specific cleaning validation documents

– Design/Development, performance, monitoring/maintenance

• Specific cleaning validation support documents (equipment

qualifications)

• Cleaning validation approach documents (Worst case matrix,

calculations, sampling locations, etc.)

• Production documents (Cleaning Procedure Records)

– Production cleaning policies

• Management review documents

• Associated documents

– Personnel training in direct and associated areas

– HR records

72

CLEANING DOCUMENTATIONHigh level documents

• Corporate policy

• VMP (Cleaning VMP)

Stage 1 documents

• Cleaning process development report

• Analytical method development report

• Supporting equipment documents (materials, surface areas, equivalent equipment,

sampling, etc.)

Stage 2 documents

• Validation PPQ request, protocol, results

• Cleaning equipment qualification

• Cleaning procedure record

Stage 3 documents

• Change control documents

• Process monitoring

• Management review

CONSISTENT LIFECYCLE STRATEGY AND APPROACH

73

IMPLEMENTATION – LIFECYCLE APPROACH

1. Plan implementation strategy

Deliberate program – guarantee success

Prioritize problems

2. Get upper management agreement

Management sets direction

3. Get Validation Approval Committee agreement

Standards and responsibilities

4. Get QA agreement

QA has GMP responsibility

5. Train development group (Stage 1)

6. Train Annual Product Review group (Stage 3)

7. Train site on validation lifecycle approach

8. Train protocol writers

9. Start slowly Pilot approach Build on continuing success

74

IMPLEMENTATION – LIFECYCLE APPROACH

Change to the lifecycle approach is a culture

change for the organization.

Management change experts recommend

“crisis” approach.

Risk of failure greater with “crisis” approach.

Opportunity for validation leadership.

75

76

SUMMARY: WHERE WE ARE -- CURRENT PRACTICE

R&D Validation Commercialization

VALIDATION ONE-TIME EVENT

77

SUMMARY -- WHERE WE ARE GOING –

LIFECYCLE APPROACH TO PROCESS VALIDATION

Objectives:

• Scientific and technical process

• Demonstrate process works as intended

• Process must remain in control throughout lifecycle

• Cleaning equipment

• Equipment to be cleaned

• Effective documents consistent with the above

• Analytical methods validated (includes sampling)

Lifecycle approach:

• Validation is never completed

• Validation is always ongoing

78

SUMMARY: VALIDATION -- FUTURE

Development Performance Maintenance

VALIDATION CONTINUUM

Stage 1 Stage 2 Stage 3

SUMMARY

VALIDATION TRANSITION

1987

Development Performance Maintenance

2011

Development Performance MaintenanceAbove based on RISK

79

SUMMARY

STAGE 1 -- DESIGN AND DEVELOPMENT

INCLUDING COMMON PROBLEMS

Understanding cleaning process

• Residue properties

– Residue degradation

• Rational cleaning process based on residue

• Scientific and technical cleaning matrix

Understand and control sources of variation

• Dirty hold time

• Campaigns

Rational analytical method based on residue properties

Equipment to be cleaned characterized

• Worst case sampling

80

SUMMARY – EQUIPMENT TO BE CLEANED

INCLUDING COMMON PROBLEMS

• Equipment characterization

• Residue calculations

• Materials of product contact

• Surface areas

• Worst-case areas for sampling based on risk

– Non-uniform contamination

• Equivalent equipment

81

SUMMARY – ANALYTICAL

INCLUDING COMMON PROBLEMS

Understand residue

• Solubility and stability

• Validated analytical method for actual residue

– Specific or non-specific analytical methods

• API and cleaning agent residue

Recovery studies from product contact materials

• API and cleaning agent

Swab / rinse testing on equipment

• Most difficult to clean sampling sites

• Use of auxiliary sampling equipment (extension pole)

Swab / rinse training of sampling personnel

82

SUMMARY

STAGE 2 – PERFORMANCE

INCLUDING COMMON PROBLEMS

Cleaning Process Conformance Lots

Cleaning equipment qualified

Cleaning procedure specified (Not SOP)

Cleaning documentation– Request

– Protocol

– Results / Report

Manual cleaning – high risk

83

SUMMARY

STAGE 3 -- MAINTAINING VALIDATION

Change control -- evaluate impact of change and validate (test) as necessary

Improve process

Improve control to detect and reduce variability

Cleaning non-conformances and deviations

Periodic Management Review

84

SUMMARY

DOCUMENTATION

Consistent approach – High level documents through

protocols and post validation monitoring

Scientific and technical basis

Document everything – Stages 1, 2, 3.

Documentation must be readily available

Documentation must be

• Scientific and technical

• Thorough and clear

• Simple sentences, good grammar

85

SUMMARY -- IMPLEMENTATION

1. Plan implementation strategy

– Deliberate program – guarantee success

2. Approvals and agreements

– Upper management

– Validation Approval Committee

– Functional Management

– QA

3. Training

4. Start slowly Pilot approach Build on continuing success

Opportunity for validation leadership!

86

SUMMARY – CLEANING PROBLEMS

1. Residue and process understanding

– Technical approach

– Worst-case matrix

– Important ingredients

– Variation – Dirty hold time, campaigns

2. Equipment

– Worst-case sampling

– Non-uniform contamination

– Compatibility with cleaning agent

3. Analytical

– Residue degradation

– Recovery

– Sampling training

4. Cleaning Procedure Record

– Cleaning process culture

5. Post-validation Monitoring

87

1. PRODUCT RESIDUE PROBLEMS

Physical and chemical properties of residue as a basis for

cleaning

• Residue chemistry, cleaning agent chemistry, and process must be

consistent. Would you clean an acid with a base or with another

acid?

Residue solubility in most-difficult-to-clean matrix

• Determination of the true worst-case residue is critical for the

cleaning matrix. The consequences of incorrect identification of

worst-case products are disastrous.

“Cleanability” in determining the most-difficult-to-clean residue

• Solubility and toxicity not only considerations for determination of

worst-case compounds

88

2. EQUIPMENT PROBLEMS

Non-uniform contamination transfer

• Non-uniform contamination is a worst-case situation and should be

addressed. Calculations are demonstrated.

Most difficult-to-clean locations in equipment

• Sites should have an SOP with a defined procedure for identification

of most-difficult to clean locations in equipment. These locations are

then used in sampling for cleaning validation.

89

3. CLEANING PROCESS PROBLEMS

• Manual cleaning qualification

Manual cleaning is an inherently high risk activity.

• Cleaning procedure documentation

Cleaning procedure documentation should be equivalent to

manufacturing process documentation -- Exact requirements with

personnel accountability.

• Dirty hold time (time to initiate cleaning)

At lease one run at worst-case DHT

Worst-case DHT is not always longest DHT

• Campaign length

Max number of lots must be controlled

“Between lot procedure.”

90

4. LABORATORY PROBLEMS

Residue stability in cleaning residue analysis

• Analytical methods must measure actual residues that are present.

Residue recovery studies

• Analytical methods must include recovery studies, i.e., proof that

process residue may be quantitatively recovered by sampling.

Without recovery studies, analysis of cleaning validation samples is

questionable

Swab sampling technique, reliability, and training

• Personnel who perform swab sampling must be qualified through

training with quantitative performance requirements. Training

should utilize worst-case sampling methods and worst-case

sampling equipment.

91

WHICH ARE HIGHEST RISK?

• Type (potency) of drug in facility?

• Multi-product facility – multi use equipment?

• Matrix?

• Manual cleaning?

• SOP cleaning processes – how detailed? Signatures?

• Analytical recovery?

• Swab sampling by trained personnel?

Depending on situation, many of these could

be extremely serious issues

92

AUDIT QUESTIONS

• Is residue chemistry considered in developing cleaning procedure?

• Is pH-solubility profile considered in worst-case matrix analysis?

• Is residue “cleanability” considered in worst-case residue

determination?

• Is non-uniform contamination considered in residue calculations?

• Are most difficult-to-clean equipment locations proceduralized?

• Are manual cleaning personnel qualified and requalified?

• Are cleaning procedures quantitative and documented?

• Are dirty hold times controlled?

• Is residue stability considered in cleaning residue analytical?

• Have analytical recovery studies been conducted? On

representative materials?

• Are swab sampling personnel trained / qualified?

93

PAUL L. PLUTA, PhD

Editor-in-Chief

Journal of Validation Technology

Journal of GXP Compliance

Advanstar Communications, Iselin, NJ, USA

Adjunct Associate Professor

University of Illinois at Chicago (UIC) College of Pharmacy

Chicago, IL, USA

Editor and Chapter Author

Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and

Principles, 2009

Cleaning and Cleaning Validation, Volume 2. Application of Basics and

Principles, 2013

PDA and Davis Healthcare International (DHI) Publishing

Contact: paul.pluta@comcast.net

94