cleaning validation - a risk based approach

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3/10/2010

1

Cleaning Validation – A Risk Based

Approach

IVT – Ireland Conference

March 22-24, 2010

Dublin, Ireland

Agenda

• Regulatory Requirements for Cleaning Validation

• ua y s anagemen u e ne e erences

• Definition of Cleaning

• FDAA REMS Impact

• Risk Management Guidelines and Tools

•

Ireland IVT Workshop

• Workshop Exercise



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2

Regulatory Requirements for Cleaning

ValidationUSA

• FDA 21 CFR Parts 210, 211 (Drugs), 600.11 Biologicals, 820 Medical

Devices Subpart G

• FDA’s New Guidance -"Process Validation: General Principles and

Practices“, November 2008

• FDA Inspection Guide, “Validation of Cleaning Processes, July 1993

• FDA Inspection Guide, Guide to Foreign Medical Device

Manufacturers, September 1995


• ASTM E2500 - 07 Standard Guide for Spec if ication, Design, and

Verification of Pharmaceutical and Biopharmaceutical

Manufacturing Systems and Equipment (a precursor to cleaning

validation) http://www.astm.org/Standards/E2500.htm


Validation (Cont’d)

•

World

Regs.

and guidance: “Cleaning Validation in API ManufacturingPlants” – Policy September 1999; “Guidance on Aspectsof Cleaning Validation in Active Pharmaceutical IngredientPlants” – Guidance December 2000

• PIC/S: Pharmaceutical Inspection Co-operation Scheme;July 2004 –


,

Operational Qualification, Cleaning Validation• Canadian, Cleaning Validation Guidelines – Guide-0028http://www.hc-sc.gc.ca

• WHO Supplementary Guidelines on GMP: Validation,2005



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Validation (Cont’d)EU

• EC Guide to GMP Part I Annex 15 and Part IIhttp://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfs-en/v4an15.pdf

• EC Guide on Risk Assessment Annex 20• European Medicines Agency (EMA)

– Directive 2003/94/EC for medicinal products andinvestigational medicinal products for human use (Article


8)

– EudraLex – Volume 4 GMP Guidelines (Annex 15) – EMA website: http://www.emea.europa.eu

References Regarding Risk Management• FDA “Pharmaceutical cGMPs for the 21st Century, A Risk-

Based Approach”, September 2004• ICH Q7A – GMP for API –November 10, 2000• ICH Q9, “Quality Risk Management”, November 2005

http://www.ich.org/LOB/media/MEDIA3562.pdf

• ICH Q10: Pharmaceutical Quality System, June 2008http://www.emea.europa.eu/pdfs/human/ich/21473207en.pdf

• ISO 14971:2007 Medical Devices – Application of RiskManagement to Medical Devices, 01Mar2007

• ISPE Risk-MaPP Baseline® Guide


• Guidance for Industry Risk Evaluation and MitigationStrategies (REMS), September 2009

• CBER Guidance on Processing Live Vaccines in Multi-Product Facilities



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FDA Regulations

• 1963 GMP 133.4, “ Equipment shall be maintained in a

clean and orderly manner”.

• 1978 cGMPs (21 CFR 210 & 211) have many subparts

that are relevant to cleaning validation:

– Subpart C: Buildings and Facilities

– Subpart D: Equipment

– Subpart E: Control of Components and Drug Product

Container and Closures


– u par : ro uc on an rocess on ro s

– Subpart H: Holding and Distribution – Subpart J: Records and Reports

FDA Guide To Inspection and Validationof Cleaning Processes (July 1993)

• “FDA expects firms to have written procedures (SOP's)

” –

• Emphasis on having different cleaning SOP between

batches of different product – Defines expectation that FDA expects written cleaning validation

process policy

– Documented cleaning processes - protocols

– Appropriate equipment design

– Anal tical methods suitable to detect residues or contaminants


– Sampling – Direct and Rinse – Monitoring

– Residue limits (rationale that is practical, achievable & verifiable)

– Other issues e.g.; placebo product, detergent and test until clean



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European Regulations and ICH Q7A

• 4. Buildings and Facilities – 4.1 Design and Construction to facilitate cleaning, maintenance and

operations

– 4.2 All utilities shall be qualified

– 4.3 Water suitable for use of manufactured product

– 4.7 Buildings properly maintained and kept in clean condition

• 5. Process Equipment – 5.1 Equipment Design – cleanable – not additive or absorptive

– 5.2 Equipment Maintenance and Cleaning• 5.20 Schedules and procedures

• 5.21 Written cleaning procedures

• 5.22 Equipment and utensils


• 5.23 Campaign production

• 5.24 Non-dedicated equipment

• 5.25 Acceptance criteria for residues• 5.26 Equipment identification

• 12.7 Cleaning Validation

FDA Observations on Cleaning Validation• 483 Citations

– “Written procedures are not established for the cleaningand maintenance of e ui ment, includin utensils, usedin the manufacture, processing packing or holding of adrug product. Specifically, your firm has not validatedthe cleaning procedures for the product contact, multi-use mixing rods used during formulation of product bulksolutions. There was no evidence to support that themixing rods are dedicated to specific products. Therewere no rocedures, em lo ee trainin records, or


identification showing control and dedication of anunspecified number of multi-use formulation mixingrods” GMP Trends (August 2008)



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More 483 FDA Observations

– “Cleaning procedures are non specific on the detergentquantity to be used and cleaning time for manufacturingequipment”

– “The cleanin validation desi n did not consider ossible cross-contamination for non-dedicated equipment”

– “No time frames/limitations have been established forproduction equipment from end of use to start ofcleaning.” – Dirty Hold

– “No time limit for the length of time allowed betweencleaning and the use of the manufacturing” – Clean Hold

– “Procedures for verifying design output meets design


.that would set out specific parameters to be tested during

verification, the acceptance criteria for those parameters,or steps to be taken in the event results are obtained thatdo not conform to expected criteria.”

Another 483 Observation

• “Equipment used in product of oral solid dosage forms is

not always maintained and/or kept in proper condition for

manufacturing operations and to prevent the

contamination of the products processed in the

equipment. The rubber gasket/ring of the drum inverter

valve were observed to be deteriorated and broken (cut).

This rubber gasket in the drum inverter is a product

contact surface. Neither the firm’s current preventive


ma n enance proce ure nor e opera on an c ean ng

procedure for the drum inverter equipment includes an

inspection of the equipment gasket for signs of

deterioration.” GMP Trends, October 15, 2009



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FDA Observations (Microbial Contamination)

• There is currently no cleaning validation data to support

the one-month expiration for cleaned items and the one

month expiration on sterile items that are routinely

assigned to equipment and goods (2006)

• GMP Cleaning Validation does not include the worst case

scenario of allowing the blending tanks to stand “not

cleaned” for the observed time between a manufactured


a c o ma er a an e c ean ng per orme e ore e

initiation of the next blending process” (2009)

Warning Letters

• Inadequate written procedures for the cleaning andmaintenance of equipment, including utensils, used in themanufacture, rocessin , ackin , or holdin of druproducts have not been established or followed [21CFR §211.67(b)]. (November 2009)

• Records of maintenance, cleaning, and sanitization arenot kept as specified in 21 CFR §§ 211.180 and 211.182[21 CFR § 211.67(c)]. (November 2009)

• Your firm failed to validate the sonication cleaning processto remove a substance affixed to the orous-coatin area


of implant products such as hip, shoulder, ankle, and kneeproducts. In addition, you currently do not monitor thetemperature or time of the sonication cleaning processes(October 2009)



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More Warning Letters

• Your firm failed to perform and document equipment

cleaning validation for the production of Healon D

ophthalmic viscoelastic devices. (September 2009)

• The company took NO ACTION to reduce the risk or

create additional control measures after the risk priority

numbers for the changed design fell within an

unacceptable zone for set screws, multiaxial body

assemblies and offset body assemblies. The QA team did


no prepare a r s managemen repor an pos -mar e ng

reviews were not conducted or documented annually.(July 2009)

What is FDAA REMS?

• FDAAA = Food and Drug Administration Amendments Act• REMS = Risk Evaluation and Mitigation Strategy

• FDAA REMS Title IX, Subtitle A, section 901 created newsection 505-1 of FD&CA which authorizes the FDA to requirepersons submitting certain application to submit a proposed RiskEvaluation and Mitigation Strategy to ensure that the benefits of thenew drug outweigh the risks. – Applicable drug application submission must include a REMS – REMS within 120 days which includes an assessment timetable – Elements to Ensure Safe Use (ETASU)


• Package Inserts• Labeling• Communication Plan• Administration Videos, etc.



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List of FDA Approved REMS

Licensed drug and

biological products

that were submitted

with risk mitigation


now deemed to

have REMS

Risk Evaluation & Mitigation Strategy

• REMS Warning Letters – “The flash card omits material information, thereby presenting an

unsubstantiated superiority claim for Tracleer, and omits some ofthe most serious and im ortant risk information associated with theuse of Tracleer. Thus, the flash card misbrands the drug in violationof the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C.352(a) and 321(n). Cf. 21 CFR202.1(e)(3)(i); (e)(6)(i) & (e)(6)(ii). “Warning Letter – November 2008

– Video news releases are false or misleading because they omit andminimize the risks associated with EMBEDA, fail to present thelimitations to its approved indication, and present misleadingclaims. The video news releases therefore misbrand the drug in


violation of the Federal Food, Drug, and Cosmetic Act (Act), 21

U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(5) & (e)(6)(i).Warning Letter – October 2009

• Reference:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf



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CLEANING


Definition of Cleaning

• “The process of removing contaminants

the condition of equipment such that the

equipment can be safely used for

subsequent product manufacture”

• A contaminant is the presence of a minor


ingredient in another chemical or mixture,often at the trace level.

• Emphasis is on “ CONTROL”



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Cleaning Validation

• “Documented evidence that an approved cleaning

pharmaceutical ingredients (API), process

residues, cleaning agents and microbial residues

from product contact equipment surfaces to

acceptable levels for the processing of drug

products”


– Reference: FDA; Guide to InspectionsValidation of Cleaning Processes, 1993

Why Clean?

• Product integrity

– -

– Microbial integrity

– Adulteration

– Lot integrity (identity, quality, purity,

efficacy and potency)


• Equipment reuse• Regulatory issues



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Cleaning Step?

• Manufacturing

– Last step

– To protect / reuse equipment

• Quality

– First step

– To protect product to be manufactured

•


Cleaning Effects?

• Cleaning has NO effect on previously

• Cleaning only affects subsequently

manufactured products or intermediates

• A different type of process validation

focused on equipment maintenance and


reuse



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Carryover in Cleaning Process

• DEFINITION:

– Maximum Allowable Carryover

: is the mathematically calculated

quantity of residue from a previous product

(based upon toxicity/pharmacology, mode of

administration, batch size, shared equipment

surface area plus a safety factor) when carried


potential harm to the patient.

Overall Equation

(0.001)(min.dose act. A) (B.S.) (S.A.)

. . . . . . . .

For swab sample, where:

• B.S. = minimum batch size Prod. B

• S.A. = sampled area

• S.S.A. = shared surface area


• S.D.A. = solvent desorption amount• Use care in units! (µg/g or µg/mL = ppm)

• 0.001 = dosage safety factor



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Conservative Assumptions for Swab Analysis

• Largest shared surface area

• Largest daily dose of subsequent product

• Smallest pharmacological dose of active

residue

• Conservative assumption results in lowest


value for limit

Simplest Rinse Calculation

• Sampling small parts by immersing in fixed

• Sampling small parts by flushing with fixed

volume of solvent

• S.A. = surface area of part

• S.D.A. = volume for extraction


Otherwise Calculation is the same:(0.001)(min.dose act.A) (B.S.) (S.A.)

(max.dose Prod.B)(S.S.A.)(S.D.A.)



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Cleaning Agent Limits

• Use same principles as for finished drugs for limit

in subsequent product

•

• In place of dose/safety factor, use ADI

• ADI estimated based on LD50

– Same route of administration: ADI = LD50 X body weight

(conversion factor “105”)


Limit (ppm)= ADI of cleaning agent X 106

maximum dose of next product

Containment• Definition:

– Containment is a strategy for controlling equipment

utilization to revent otential cross-contamination b

dedicating equipment to a specific product.

EXAMPLE of Dedicated Facilities & Equipment

– 21 CFR Section 211.42 (d) states, “ Operations relating

to the manufacture, processing and packing of penicillin


shall be performed in facilities separate from those used

for other drug products for human use”



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Key Aspect

• Involves “intersection” of two products

– -

cleaning to remove residues to acceptable

level

– Product subsequently manufactured -

residue levels based on possible


contamination of next product

• Must always evaluate effects onsubsequently produced product

What Must Be Validated?

• Critical cleaning must be validated

–

– Focus on product contact surfaces

– Applies to drug products and APIs

• Not required for non-critical cleaning

– Floors, walls, outside of vessels

– Some intermediate steps (ICH Q7A)


• Others – Significant indirect product contact surfaces

– Dedicated equipment



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Quality Risk Management

Guidelines


Cleaning Validation Risk Analysis• What is RISK?

• Risk Histor /Develo ment

• How Does RISK Apply?

• Quality by Design

• Design Space

• ICH Guidelines




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RISK ILLUSTRATION

RISK = Probabi lity of Occurrence X Severity of Harm

HAZARD

Cause: Driver Distraction:

Listening to music

or cell phone

Failure Mode

(temporarily loses control)

Effect / Consequence

Severity Scale


Risk Management Development History

• August 21, 2002 – FDA Press Release:

• “ st -

Based Approach

• September, 2003 – FDA issues final report its “21st Century” initiative on the

regulation of pharmaceutical manufacturing

• September 2004


– -

cGMP inspections of pharmaceutical manufacturingsites



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Risk Management Development History (Cont’d)

• November 2004 – ICH Q9 “Qualit Risk Mana ement

• August 2007 – ASTM E-2500 is published, approved and accepted

internationally as a standard guide for commissioning &

qualification

• In Development – Revision to ISPE Baseline Guide on Commissionin &


Qualification

– ISPE Baseline Guide “Risk-MaPP” – same emphasis as ICH

Q9

FDA Risk Assessment Criteria

September 2004 – Risk based method for priorit izing cGMP Inspections

of Pharmaceutical Manufacturing Sites – a pilot risk ranking model

s ac ors

Products Process Facility

Intrinsic

sterility

prescription or OTC

Dosage Form

Process Control

product type

operation type

History

GMP Violations

inspection results


Recall Historyfrequency

severity

Contamination Vulnerabilityproduct type

operation type

Product Volumetype of operation



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ISPE RISKMaPP

• Risk MaPP = Risk Based Manufacture of Pharmaceutical

Products

• ISPE Guideline in Draft – ali ns intent of ICH Q9 for

setting health-based cross contamination limits and

cleaning validation limits using a science-based approach

– ISPE Risk MaPP Rationale is that health based limits

should be developed by pharmacologists, toxicologists

and as part of clinical trial data for NDA or ANDA

submissions


– Emphasis is on distinguishing between what constitutes

a HAZARD and what is termed a RISK. It is a clearseparation of what is reasonable versus unachievable -

zero risk is not scientifically sound

Risk Analysis, Management

• ICH Q8 = Pharmaceutical Development

»QbD (Quality by Design)

• ICH Q9 = Quality Risk Management

»QRM (Use of Risk Management Tools)

• ICH Q10 = Pharmaceutical Quality System

»


,

APR)ICH Guidance Documents for Minimization of Risk and

Quality Management



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Quality By Design (QbD)

ICH Q8

The aim of pharmaceutical development is to design a

consistently deliver the intended performance of the

product.

The information and knowledge gained from

pharmaceutical development studies and manufacturing

experience provide scientific understanding to support the


establishment of the design space, specifications and

manufacturing controls.

Quality Risk Management – Q9

• QRM is a systematic process for the assessment,

control, communication and review of risk to the

qua y o e pro uc across e pro uc ecyc e.

• Principles include:

– ‘Evaluation of the risk to quality based upon

systematic knowledge and ultimately link to

protection of the patient’..

–


,

the QRM process should be proportional to thelevel of risk



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Risk Management Process

ICH Q9Risk Assessment

Risk Identification

Initiate

Quality Risk Management Process

•

R i s k C o m m u n i c a t i o n

Risk Evaluationunacceptable

Risk Control

Risk Analysis

Risk Reduction

Risk Acceptance

Ri s k M an a g em en t t o ol s

spanning the entire

product lifecycle


Risk Review

Review Events

Output / Result of theQuality Risk Management Process

Transition from Current Process to QRM

Risk Assessments and Enhanced Design Reviews

Design Construction C&Q Process DevCPPs,

CQAsValidation

Quality by Design


Quality, Cost and Schedule Benefits



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Definition of “ DESIGN SPACE”

• Defined in ICH Q10 as:

- “The multidimensional combination and

interaction of input variables (e.g.,

material attributes) and process

parameters that have been

demonstrated to rovide an assurance


of quality”

What is Design Space of Cleaning• Key inputs and data are analyzed and evaluated

– Product knowledge

–

– Regulations

– Quality Attributes

– Critical Processing Parameters

• Consideration should be given to: – Soil type

–


, , , .

– Equipment design & configuration – Utility Impact, environmental, heat, pressure, etc.



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Key is “Process Knowledge”

• • Visual Inspection

Critical Process Parameters (CPP’s) Critical Quality Attributes (CQA’s)

Temperature

• Process Pressure• Process Flow• Process Time• Cleaning Agent

• Analytical ResidueLimits

• Microbial Limits• Drainability/Drying/

Air Blows• Clean E ui ment


• Dirty EquipmentHold Time (DEHT)

Hold Time (CEHT)

• Conductivity/pH

ICH Q10

Product Quality Systems (PQS)

• Contents – Introduction – Pharmaceutical “Quality Systems”

• Design considerations• Product realization from a quality perspective• Continual improvement (Change Control,

CAPA, Documentation change management)• QRM to introduce rocess control


– Management responsibility – Continual improvement over product lifecycle



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RISK MANAGEMENT TOOLS


Risk Management Strategies

Avoid

Substitute

Reduce

Transfer


Least Preferred

ccep



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Making Decisions With Uncertainty

Risk Decisions

• Process

• Knowledge

• Experience

Factors

• Controllable

• Uncontrollable(Chance)

Decision ImplementationOutcome

Good/Bad


Constraints

Information, Economics,

Political Environment, Time

Risk Management Tools

• Failure Mode and Effect Analysis (MIL-STD-1629A)

• Hazard Anal sis and Critical Control Points – HACCP

PARTIAL LIST

• Hazard and Operability (HAZOP)

• Cause & Effect Analysis (Fishbone Diagram)

• Quality Risk Classification and Filtering

• Forced Ranking




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What is FMEA and How Does It Work

• “FMEA is a systematic method of identifying the effects ofa potential product or process failure and methods toeliminate or reduce the chance of that failure occurring”

• Failure Mode: the way by which a failure is observed• Failure Effect: the consequence of the failure mode• Failure Cause: the precipitating event - reason for the failure• Occurrence: a measure of the probability or likelihood that the

cause will occur.• Severity: a measure of the effect of the potential failure• Detection : method by which a failure can be discovered (a measure


• Risk Priority Number : (RPN) the total of occurrence, severity and

detection; used to prioritize the overall risk

FMEA Procedure

• Develop a Team Charter – objectives, scope, identifyteam facilitator/sponsor – Key – someone with Experience – Select the SME team from QA, Regulatory,

Manufacturing, QC, Validation, Engineering,Maintenance (as applicable to project)

– Establish ground rules – eliminate subjectivity

• Compi le and Review Data Relevant to Project – Use PFD’s, P&ID’s, Tech Transfer Reports,

Manufacturin Records, Historical Information, etc.


• Establish Calibration Methodology – Develop and obtain consensus on a risk-ranking scaleand risk filtering criteria



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Calibration Tool

Risk Ranking Calibration TableSeverity Ranking S Potential Impact of Failure

Very High 5 Effect of failure could potentially cause patient death

High 4 Effect of failure could potentially cause injury and will certainly create regulatory non-compliance

Moderate 3 Effect of failure could potentially lead to increase in patient dissatisfaction, product complaints and

Low 2 Effect of failure could lead to some patient dissatisfaction but unlikely to generate product complaints

Very Low 1 Failure may not be detected and will not result in direct product quality problems

Occurrence Ranking O Occurrence Frequency Probability

Unavoidable 5 Equal to or greater than one occurrence/day

Highly Likely 4 One or more occurrences/week

Occasional 3 More than one occurrences/year

Unlikely 2 Equal to or less than one occurrence/year

Very Remote Occurrence 1 No more than one occurrence every 2 years

Detection Ranking D Detection Mechanism Effectiveness


Undetecta e 5 No nspect on or ana yt ca met od to detect qua ty de ect

Low Detect -abilit y 4 Ver y unlikely t hat def ect will be detect ed by available PCS, in-process assays or qualit at ive

inspections

Medium Detect-ability 3 Controls may detect the quality defect

Highly Detectable 2 Existing controls are likely to detect the quality defect

Dir ec t De te ct ion Metho d 1 Exis tin g co nt ro l s ystems, i n-proc es s as say s or i ns pec ti on s i n p la ce t ha t wil l s er ve as a di rec tdetection method for the defect.

FMEA Procedure (Cont’d)

• Risk Identification & Analysis – Select each user requirement and agree on description

& function – Identify all potential failure modes for each function

based on historical information, scientific knowledgeand SME opinion

– Then identify all the effects on the process/systems thatcould adversely impact product quality in each failuremode


– Next step, determine the severity of each effect, theprobability of occurrence and the potential root causes

– Identify the control and detection mechanism in placefor each cause



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Failure Mode and Effect Analysis (FMEA)Process Risk Assessment

Failure Mode and Effect Analysis (FMEA)

System: Revision:

Subsystem: Revision Date

Designer: Prepare by:

USAGE: Evaluate possible risks relating to product or GMP Impacts (System Approach)

Inputs: Process Flow Diagrams, P&ID, User Requirements Specifications

Definition:

Failure Mode: the way in which the product defect could occur –causing the URS to fail

Effect: consequence of a product defect on the patient

Cause of Failure: the likely cause of failure

RPN: Risk Priority Number = severity X probability X detection

Product/Process

User Requirements

Identify, Characterize, Analyze & Evaluate Risk

Mitigation Actions (hardware, software, analytical, procedural)

What might go

wrong?

What are the

consequences

What is the

likelihood it

will go wrong?

Current State &

Evaluate Risk

Failure Mode

Effect Causes

Control &

Detection

Risk

URS D escription Funct ions Ident if y Analyze Det ermin Indentify Recommended Responsibilit y Action


item# Potential

Failure

Modes

effect of

failures

e the

causes

of failure

Mechanism

For

Controlling

Cause &

DetectingFailure

Actions & Completion

date

Taken

7 Cleaning

Chemical

Storage

Contain

Chemical

Chemical

overflows

Chemical

exposure

5 No

overflow

control

3 Leak

detection

system

15 I nst all leak

detector

Engineering

05Nov09Yes 2 1 1 2

O c c u r r e n c e

D e t

e c t i o n

S e v

e r i t y

N e w

s e v e r i t y

N e w

P r o b a b i l i t y

N e w

D e t e c t i o n

N e w

R P N

RPN

FMEA Procedure (Cont’d)

• Risk Ranking and Filtering:

– Calculate the Risk Priority Number (RPN)

– Rank the RPN on some type of risk ranking block diagram

•

– Assign responsibility for each high significant risk to product quality

and track progress

Risk Ranking & Filtering (Severity X Occurrence X Detection)

High Risk Frequency of Occurrence

Medium Risk Unavoidable Highly likely Occasional Unlikely Very Remote

Low Risk 5 4 3 2 1

Severity X Probability &

Probabilit X Severit i l i t y o f D e t e c t i o n


5 X 5 & 5 X 5 125 100 75 50 25

5 X 4 & 4 X 5 100 80 60 40 20

5 X 3 & 3 X 5 75 60 45 30 15

5 X 2 & 2 X 5 50 40 30 20 10

5 X 1 & 1 X 5 25 20 15 10 5

S e v e r i t y X P r

o b a b i



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Hazard Analysis and Critical Contro l

Points (HACCP) – Food Industry1. Conduct a Hazard Analysis2. Determine the critical control points.

• Critical limits• Monitoring procedures• Corrective actions• Verification procedure• Record-keeping and

documentation procedure

Step Hazard Analysis & Evaluation Control & Corrective Actions

No. Descr ip tion Potential Justi fi ca tion Consequen Sever ity o f L ikel ihood Hazard to Control Cri ti ca l Monitoring Corrective


exposure

to hazard

exposure

to hazard

addressed?

5 Canning Enteric

pathogens

e.g.

Salmonella, or

P. botulinum

Enteric

pathogens

have been

found in

poorly

processed

canned foods

Severe

illness or

death

10 50 Yes Canning to

a specific

temperature

Minimum

Temp. of

124ºC for

30

minutes

Check

temp. at

completion

of canning

Re-process

or dispose

of canned

food if

inadequate

time &

temp.

Hazard and Operabili ty (HAZOP)• Analysis of operating system, design intent and process variables to ID

consequences, existing controls, risk level and remedial actions –

• ommon y uses ra ns orm ng ec n ques o en y opera ons a

could results in:

– Injury to personnel

– Violations of EH&S regulations

– Profitability

Ref.

P&ID

Op erat in g Des ig n

Intent

Process Variable Potential

Deviations(use actions that

could cause

deviations)

Co ns eq ue nc es Ex is ti ng

Controls

Risk

Level

Remediation

Actio ns


PI D215 Capping

Operation

Secure seal

to finished

vial

Cam pressure,

roller pressure

Inadequate pressure

or too much

pressure

Inadequately

sealed vial

Visual /

Physical

Inspection

Medium Establish procedure

with instruments to

monitor pressurerange for both process

variables



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Cause and Effect Analysis Process (Fishbone)

1. Draw the fishbone diagram....

2. List the problem/issue to be studied on the "head of the fish".

"" " " ". .

are:

• The 4 M’s:

– Methods, Machines, Materials, Manpower

• The 4 P’s:

– Place, Procedure, People, Policies

• The 4 S’s:

– Surroundings, Suppliers, Systems, Skills


• Start with a “Cause” and “Why” for each category as issue

– Drill down to root cause using group “brainstorming technique”

Cause & Effect Analysis (Fishbone Diagram)

Cleaning

Validation

Cleaning

Validation




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Fault Tree Analysis

• Evaluates system or subsystem

failures one at time

• Failure analysis flow chart

Negative Event

Immediate Cause

Immediate Cause

Failure Mode Assessment Matrix

Event Description Assessment or if probabil ity is known Assignment of Action

1

2


OR AND

Base

Event

contingent

eventBase

cause

event

human

error

Quality Risk Classification & Filtering Overview

L

O

M

E

H

I

L

O

M

E

H

I

Risk Likelihood 2 Probability of Detection 3

W D G

H

High

Medium

W D G

H

HighLevel 3

Q u a l i t y

1Level 3

i f i c a t i o n

4


Low Low

I m p a c t

o n

Level 2

Level 1

Level 2

Level 1 R i s k C

l a s



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• API represents greatest patient quality risk – 1 –

Complete the Two Risk Tables for API,

EXCIPIENT, Preservatives & Cleaning Agent

– .

– Abil ity to detect i t reliably to low levels is small

– Pharmacology can be signi ficant with potent actives

•Excipient represents smallest patient risk - 2 – Carryover potential high - it constitutes majority of

–


represent very small risk

– Visual abili ty to detect it to safe levels is good

Complete the Two Risk Tables for API,

EXCIPIENT, Preservatives & Cleaning Agent (Cont ’d)

• Preservatives are hazardous to patients - 3 – Concentrat ion is t ical l smal l

– Abil ity to detect i t reliably at low levels is smal l

• Cleaning Agent may be a high patient risk - 4 – Carryover should be moderate to low

– Abil ity to detect is high when using those systems

w/in-line H and ro rammed conductivit rinse set


points – Validated analytical and swab methods can lower

carryover concerns at reasonable limi ts



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Example of Forced Ranking - Bioreactor

Ranking

Cleanabilityof Location/

coverage and

access

Role inprocess

likely to lead

to difficult

residue

Aff ini ty t oMOC or

Surface

Finish

Hot Spot

(historically

hard to

clean)

Critical Site:potential

large

contaminant

area

Sampling

Location

Ranking

Cleanabilityof Location/

coverage and

access

Role inprocess

likely to lead

to difficult

residue

Aff ini ty t oMOC or

Surface

Finish

Hot Spot

(historically

hard to

clean)

Critical Site:potential

large

contaminant

area

Sampling

Location

1511355Sampling

Port

1551351Instrument

Port

951111Dome Lid

1311335Bottom

Outlet Valve

511111Sidewall

1511355Sampling

Port

1551351Instrument

Port

951111Dome Lid

1311335Bottom

Outlet Valve

511111Sidewall


731111 Agi tato r 731111 Agi tato r

OTHER OPTIONS: - Combine Categories (e.g. critical area / hot spot 1 = Low Risk /

- Weight categories (cleanability) 3 = ModerateRisk

- Add Notes Category: like dome ports are hand cleaned, 5 = High Risk / Not

bottom valves are di sassemble and cleaned

- Draw equivalence for like ranking (instrument & sample port)

- If ranking locations keep in mid that some of the “ simple locations” may also need to be

assessed to confirm that these locations are “in fact” clean

Risk-Based Approach to

Cleaning




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Cleaning Validation Emphasis on

“ Scientific Adequacy”

• Documentation, decisions need to demonstrate

cleaning is adequate

• Must meet expectations of “current” in cGMPs

• But, NOT a regulatory requirement that each step

be the best choice but must consider RISK and

apply scientific-based rationale


– xamp es r y o me, c ean ng me,

swabbing,etc.)

Scale Up Components

• Keys in pilot scale/plant evaluation – Confirm lab performance of cleaning agent

–

– Confirm adequate engineering design & control

– Optimize time(s), conditions

– Determine rinse conditions

– ID sampling locations

– Evaluate analytical method and swab method

– Define Residue limits for roducts


– Define Analytical Method Capability and Swab – Recovery (Qualify Both)



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Documentation For Cleaning Validation Rationale

• Lab studies with conclusion

•

• Any related studies (toxicology, TOC, clinical

dosage)

• Key decisions based on professional judgment

– Include why not addressing certain items

• Collate as “technology transfer” or “development


report” package

• Documentation value will be regulatory support aswell as for future review of program

Risk-Based Scientif ic Rationales AreNeeded For The Following…..

- Product grouping or bracketing

- qu pmen group ng or rac e ng

- Residue selection criteria

- Limit selection and calculation

- Analytical approach (direct vs. indirect)

- Sampling method selection

- Sampling site selection criteria

-


- Disassembly / vessel entry policy- Monitoring – what and when

- Other?



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How to Start the Assessment Risk Process?

• Identify the topic to be addressed

• Collect topics or potential arguments for/against the issue

• Use brainstorming/process mapping techniques to provide

exhaustive coverage of the cleaning issues

• Select proposed RiskMAPP tool to record decisions/data

• Gather supporting evidence pro/con for the expected

arguments

• Explore all arguments exhaustively pro/con


• ecor resu s an prov e per nen wr en exp ana on

of conclusions – Protocol/CVMP

Best Practice for Developing Scientific Rationale

as in FMEA example

– Establish a team of interdisciplinary SME’s who have a variety of

perspectives on the issue.

•

• R&D / Technical Operations

• Manufacturing / Engineering/Maintenance

• Validation

– Develop the rationale

– Share the rationale in a design review with an independent review

before approval.

• Independent reviewer should play “ inspection / regulatory


advocacy role” in an attempt to find weaknesses in the

logic and/or science.• Required attendance and required consensus is an

absolute “MUST” – Remember this is a collaborative effort!



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General Quality Risk Management Process

Systematic processes designed to

coor na e, ac a e an mprove

science-based decision making

with respect to risk to quality


An effect ive quali ty r isk

management system provides a proactive means to identify, control and improve

decision making when a quality problems arises

ICH Fit for Cleaning Validation Risk Analysis

t n c e

Bridge to Science & Risk Based Methodology

e n

t

s

R o

l e s

&

R e s p o n s

i b i l i t i e s

P r o

d u c

t / P r o c e s

K n o w

l e d g e

M a s

t e r

P l a n

D e v e

l o p m e n

t

R i s k A s s e s s m e

D e s

i g n

R e v

i e w s

R e s

i d u e

L e v e

l s

P r o

t o c o

l A c c e p

t

& R e p o r t

R e

l e a s

Q u a

l i t y M a n a g e

S y s

t e m s

C h a n g e

M a n a g e m e n

t

S y s

t e m s

Product Lifecycle

E n g

i n e e r i n g

R u


Science & Risk Based Approach

ICH Q8, Q9, Q10 and

FDA – GMP’s for 21st Century

Regulatory Compliance



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WORKSHOPGroup Exercise

s cenar o

For Existing Cleaning Validation

“Out of Clutter, find Simplicity”

- Albert Einstein (1879-1955)


Risk Analysis & Cleaning Validation Problem

• Situation: – Biopharmaceutical site with an two existing validated products

– Product Actives and cleaning agent residual limits established

• Products at 4 µg/cm2 (4 ppm)

• Detergent at 10 µg/cm2 (10 ppm)

– Cleaning Validation Master Plan closed with most recent product

qualification – in validation maintenance state for both products

• Problem: New Molecular Entity (NME) being introduced to site


–

pharmacological dose and shared surface area of equipment – Desire is to use the same cleaning cycles for CIP and COP Washer

Systems



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Problem – additional details

– NME requires addition of Dow Corning Antifoam C Emulsion tobioreactor at a 1:10 dilution (~ 50 mL) each day once the bioreactor

– duration of antifoam addition approximately 56 days

– No existing analytical test method for Dow Corning Antifoam C – Harvest is concentrated and purified using Protein A

chromatography as first step where ~ 1,000 liters is concentratedinto 40 liters every 2 days

– Effect of Dow Corning Antifoam C Emulsion in terms of carryoveron equipment and into the concentrated Protein A chromatographyproduct stream is unknown – no data supplied from R&D as part of


technology transfer – See attached MSDS for Dow Corning

Antifoam C Emulsion – Currently using TOC as the method for determination of residualproduct and cleaning agent

Resolution Needed

• Using a Risk-Based Scientific Approach determine the cleaning

validation path forward for introduction of the new product without

eopar z ng ex s ng pro uc manu ac ure

• Form an SME TEAM with representatives from QA, QC, Validation,

Manufacturing, and any other required department member to

complete a design review and set a strategy for introduction and

validation of the new SME using a risk-based approach




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