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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
•
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• Workshop Exercise
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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
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• 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
Regulatory Requirements for Cleaning
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 –
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,
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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Regulatory Requirements for Cleaning
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
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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
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• 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
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– 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
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– 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
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• 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
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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
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.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
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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
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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
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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
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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)
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• 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
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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
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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
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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
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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”
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– Reference: FDA; Guide to InspectionsValidation of Cleaning Processes, 1993
Why Clean?
• Product integrity
– -
– Microbial integrity
– Adulteration
– Lot integrity (identity, quality, purity,
efficacy and potency)
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• 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
•
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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
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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
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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
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• 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
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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
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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”)
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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
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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
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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)
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• Others – Significant indirect product contact surfaces
– Dedicated equipment
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Quality Risk Management
Guidelines
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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
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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
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– -
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 &
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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
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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
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– 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
»
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,
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
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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’..
–
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,
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
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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
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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
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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
–
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, , , .
– 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
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• 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
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– Management responsibility – Continual improvement over product lifecycle
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RISK MANAGEMENT TOOLS
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Risk Management Strategies
Avoid
Substitute
Reduce
Transfer
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Least Preferred
ccep
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Making Decisions With Uncertainty
Risk Decisions
• Process
• Knowledge
• Experience
Factors
• Controllable
• Uncontrollable(Chance)
Decision ImplementationOutcome
Good/Bad
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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
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• 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.
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• 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
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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
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– 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
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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
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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
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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
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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
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• 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
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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
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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
–
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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
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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
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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
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– 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
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– 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
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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
-
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- 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
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• 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
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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
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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
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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)
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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
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–
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
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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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