10/15/2010

Cleaning Validation – A Risk Based

Approach

IVT – Validation Week Conference

October 25-27, 1010
Philadelphia

Agenda

• Regulatory Requirements for Cleaning

Validation
• Quality Risk Management Guideline
References
• Cleaning Defined
• Elements of Validation Strategy
• Risk Management Guidelines and Tools
• Risk Approach to Cleaning Validation
• Workshop

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Regulatory Requirements for Cleaning

Validation
USA

• 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 Specification, 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.

• Active Pharmaceutical Products Committee (APIC) policy

and guidance: “Cleaning Validation in API Manufacturing
Plants” – Policy September 1999; “Guidance on Aspects
of Cleaning Validation in Active Pharmaceutical Ingredient
Plants” – Guidance December 2000
• PIC/S: Pharmaceutical Inspection Co-operation Scheme;
July 2004
– Recommendations on Validation Master Plan, Installation and
Operational Qualification, Cleaning Validation
• Canadian, Cleaning Validation Guidelines – Guide-0028
http://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 II

http://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 and
investigational 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 2008
http://www.emea.europa.eu/pdfs/human/ich/21473207en.pdf
• ISO 14971:2007 Medical Devices – Application of Risk
Management to Medical Devices, 01Mar2007
• ISPE Risk-MaPP Baseline® Guide
• 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
– Subpart F: Production and Process Controls
– Subpart H: Holding and Distribution
– Subpart J: Records and Reports

FDA Guide To Inspection and Validation

of Cleaning Processes (July 1993)
• “FDA expects firms to have written procedures (SOP's)
detailing the cleaning processes” – direct quotation
• 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
– Analytical 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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FDA Observations on Cleaning Validation

• 483 Citations
– “Written procedures are not established for the cleaning
and maintenance of equipment, including utensils, used
in the manufacture, processing packing or holding of a
drug product. Specifically, your firm has not validated
the cleaning procedures for the product contact, multi-
use mixing rods used during formulation of product bulk
solutions. There was no evidence to support that the
mixing rods are dedicated to specific products. There
were no procedures, employee training records, or
identification showing control and dedication of an
unspecified number of multi-use formulation mixing
rods” GMP Trends (August 2008)

More 483 FDA Observations

– “The cleaning validation design did not consider possible

cross-contamination for non-dedicated equipment”
– “No time frames/limitations have been established for
production equipment from end of use to start of
cleaning.” – Dirty Hold
– “No time limit for the length of time allowed between
cleaning and the use of the manufacturing” – Clean Hold
– “Procedures for verifying design output meets design
input were incomplete. No design verification protocol
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 that
do not conform to expected criteria.”

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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
batch of material and the cleaning performed before the
initiation of the next blending process” (2009)

Warning Letters
• Inadequate written procedures for the cleaning and
maintenance of equipment, including utensils, used in the
manufacture, processing, packing, or holding of drug
products have not been established or followed [21CFR §
211.67(b)]. (November 2009)
• Records of maintenance, cleaning, and sanitization are
not 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 process
to remove a substance affixed to the porous-coating area
of implant products such as hip, shoulder, ankle, and knee
products. In addition, you currently do not monitor the
temperature or time of the sonication cleaning processes
(October 2009)

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CLEANING

Definition of Cleaning

• “The process of removing contaminants

from process equipment and maintaining
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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Containment
• Definition:
– Containment is a strategy for controlling equipment
utilization to prevent potential cross-contamination by
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”

Cleaning Validation

• “Documented evidence that an approved cleaning

procedure will consistently reduce active
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 Inspections

Validation of Cleaning Processes, 1993

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Why Clean?

• Product integrity
– Cross-contamination
– Microbial integrity
– Adulteration
– Lot integrity (identity, quality, purity,
efficacy and potency)
• Equipment reuse
• Regulatory issues

Cleaning Effects?

• Cleaning has NO effect on previously

manufactured product or intermediate
• Cleaning only affects subsequently
manufactured products or intermediates
• A different type of process validation
focused on equipment maintenance and
reuse

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Cleaning Step?
• Manufacturing
– Last step
– To protect / reuse equipment
• Quality
– First step
– To protect product to be manufactured
• Could be various intermediate steps

What Must Be Validated?

• Critical cleaning (Class I) must be validated
– Cleaning between different products
– Focus on product contact surfaces
– Applies to drug products and APIs
• Indirect (Class II)
– Significant indirect product contact surfaces
– Define the difference between between parts that come
into contact with product and parts that are in the
process flow path
– Dedicated equipment
• Not required for non-critical cleaning (Class III)
– Floors, walls, outside of vessels
– Some intermediate steps (ICH Q7A)

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Importance of Comprehensive Cleaning Validation

• More FDA emphasis on understanding

of manufacturing/cleaning processes
• Examples
– Degradation of active
– Nature of residue
• Chemical
• Physical
– Emphasis should be on laboratory scale study to
more fully understand soil characteristics and
necessary
• Where Should We Start?

Project Validation Master Plan

• Start with a blueprint of your manufacturing operations

• Define how cleaning validation program will be set-up and
implemented including phased SOP development
• Master plan will define terminology for documentation,
provide descriptions of the facility, manufacturing
processes, scope and validation sequence implementation
• Obtain process flow diagrams for the different
products/processes – operational SOPs to be included
• Define soils to be cleaned
• ID and Inventory all equipment to be cleaned and
equipment to be used in the cleaning process
• Define analytical method(s) capabilities

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Trace Matrix Contents

• Develop a trace matrix for each process that requires cleaning
validation –Derive information from manufacturing record and
Operational SOPs - Matrix should include following columns
– Step description
– Step reference
– Room number, if applicable
– Equipment and ID # if applicable
– Materials of Construction
– Soils
– Product Contact Classification (Class I, II or II)
– Cleaning SOP numbers
– Notes or deviations during cleaning
– Cleaning Validation Reports
– Soils Included in CV

Trace Matrix Continued

• How does a trace matrix help you?
– Indentifies equipment in all processes and will help with
grouping strategies (soils & equipment)
– Indentifies soils and characterization of soils be a
category such as: solubility, cleanability, viscosity,
solvent, oils, etc.
– Provides opportunity to assign a ranking for identification
of “Worst Case”.
• Worst-case soil selection is based on the difficulty
to clean, potential carryover and risk the carryover
presents to a subsequently manufactured product

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Build Soil Categories

Examples:
• Group 1 Soils: contains target carryover such as; proteins, nucleic
acids, peptides or other active ingredients
• Group 2 Soils: non-specific soils that contain components derived
from in-process activities (e.g., inorganic salts, excipients, binders, etc.).
• Group 3 Soils: non-specific soils containing small molecule organic
compounds and/or inorganic salts used in reagent solutions, inactivation
solutions and buffers
• The “Worst Case” soil should be selected from each product
grouping based on the difficulty to clean and the risk that
carryover would present to a subsequently manufactured product
as appropriate.

Risk Ranking of Non-Specific Soils

• The “Worst Case” non-specific soils out of groups 2 and 3 are

selected on sole criterion of “most difficult to clean”

Table for Risk Scoring

Parameter Risk Level Risk Level Risk Level Risk Level Risk Level Risk Level
0 1 2 3 4 5

Product Very easy to Easy to clean Moderately Moderately Difficult to Very Difficult
Difficulty to clean – water and high easy to clean hard to clean clean oily to clean such
clean - lab effective mobile in – some – viscous or substance, as denatured
study or liquid state viscosity gelatinous builder or protein,
subjective issues residue excipient carbopol,
eudragit,
titanium
dioxide

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Risk Ranking of Specific Soils

• The “Worst Case” soil out of Group 1 – the target active is
ranked based upon difficulty to clean, solubility and
toxicity of the target compound.
• The cleaning agent can be included in this group based
upon rinsability and toxicity or it can be done separately
• The soil with the highest cumulative score based upon
difficulty to clean and toxicity is selected as the “Worst
Case” for cleaning validation
• If there is an equal cumulative score toxicity can be used
as the tie-breaker to identify the “Worst Case”.

Risk Ranking Specific Soils

Parameter Risk Level Risk Level Risk Level Risk Level Risk Level Risk Level
0 1 2 3 4 5
Product Very easy to Easy to clean Moderately Moderately hard Difficult to clean Very Difficult to
Difficulty to clean – water and high mobile easy to clean – to clean – oily substance, clean such as
clean - lab effective in liquid state some viscosity viscous or builder or denatured
study or issues gelatinous excipient protein,
subjective residue carbopol,
titanium dioxide
Toxicity – ≥ 2500 mg/kg > 2500 mg/kg >1250 mg/kg >500 mg/kg and >250 mg/kg and ≥ 25 mg/kg
LD50 (oral rat) and ≤ 1250 and ≤ 500 ≤ 250 mg/kg ≤ 25 mg/kg
mg/kg mg/kg

Solubility - Very soluble Freely Soluble Soluble Slightly Soluble Very Slightly Practically
g/100mL of 100% in water 99.9 % in water 99% in water >10% but <90% Soluble < 10% Insoluble
water in water in water < 0.01% in
water

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Residue Limit Selection Method

• Lowest limit among group

Product Active Limit
1 A 25 ppm
2 B 15 ppm
3 C 8 ppm
If product 1 is worst case (most difficult to clean), then
validate Product 1 at limit of 8 ppm of A

Alternative Residue Selection Method

• 3 PQ runs each on “most difficult-to-clean” and
“most toxic”

Product Active Limit

1 A 25 ppm
2 B 15 ppm
3 C 8 ppm

Then perform 3 PQ runs of Product 1 at limit of 25

units of A
AND 3 PQ runs of Product 3 at limit of 8 ppm of C

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Identify and Define Sampling Methods

• Swabs – area to be used

• Rinse – define and qualify method
• Microbial – recovery?
• Blanks and controls – handling & methodology
• Sample locations
– ID
– Justification
– Risk rationale

Define Analytical Procedures

– List methods
– Qualification
– Validation
– Recovery for sampling methods/surfaces

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Identify Sampling Locations

• Different materials
– Glass, steel, gaskets
• Functional locations
– Blades, tank walls, fittings
• Most difficult-to-clean locations
– Prior experience
– Sub-optimal cleaning process (time,
concentration, temperature, rinse)
• Sites for non-uniform contamination
• May use forced ranking to ID “Worst Case” swab
locations

Example of Forced Ranking - Bioreactor

Sampling Critical Site: Hot Spot Affinity to Role in Cleanability
Location potential (historically MOC or process of Location/
large hard to Surface likely to lead coverage and
contaminant clean) Finish to difficult access
Ranking
area residue
Sidewall 1 1 1 1 1 5

Bottom 5 3 3 1 1 13
Outlet Valve

Dome Lid 1 1 1 1 5 9

Instrument 1 5 3 1 5 15
Port
Sampling 5 5 3 1 1 15
Port
Agitator 1 1 1 1 3 7

OTHER OPTIONS: - Combine Categories (e.g. critical area / hot spot 1 = Low Risk / -
Weight categories (cleanability) 3 = Moderate Risk
- Add Notes Category: like instrument ports are hand cleaned, 5 = High Risk / Not
bottom valves are disassemble 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

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Equipment Grouping Criteria

• Must be same type

– Cannot group cone blender and V-blender
• Normally involves either:
– Identical equipment – same configuration
– Same equipment of different sizes
• Example: 300L, 500L and 1000L tanks
• Alternatives --
– Validate separately largest /smallest sizes
– Validate together testing extremes

Grouping in a Parts Washer

• Different types of parts in same washer

• Worst cases
– Most difficult to clean part?
– Worst case loading configuration?
– Worst case location?
• Ensure that only direct and indirect product
contact (Classes I & II) are in loading
configurations for parts washer

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Overall Validation Process

Includes:
• Prequalification studies
– Cleaning trial(s)
– Setting limits
– Cleaning per Protocol
– Analytical testing & Sampling
• IQ/OQ/PQ
• Validation maintenance
– Monitoring
– Preventive maintenance/calibration
– Change control
– Re-validation

Other Cleaning Validation Objectives

• Shorter cleaning time – LEAN

• Rugged cleaning process
• Increased capacity utilization
• Extension of equipment life
• Minimized worker exposure
• Simplification
• Cost effectiveness

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Carryover in Cleaning Process

• DEFINITION:
– Maximum Allowable Carryover
(MACO): 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
over into a different product that CAN represent
potential harm to the patient.

Overall Equation

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

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

• Smallest batch size of subsequent product
• 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

volume of solvent
• 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
• Main difference is no dose
• 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

Things to Avoid in Setting Limits

• Limits based on assay limits

– LOQ (maybe?)
– LOD (never)
• Limits based on compendial water specs
– Can risk rank based on equipment product
contact class
• Limit unrelated to target residue
• Limits selected arbitrarily
• No documentation of rationale or risk
ranking for how selected

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Key Aspect

• Involves “intersection” of two products

– Product just manufactured - good
cleaning to remove residues to acceptable
level
– Product subsequently manufactured -
residue levels based on possible
contamination of next product
• Must always evaluate effects on
subsequently produced product

Quality Risk Management

Elements

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Cleaning Validation Risk Analysis

• What is RISK?
• Risk History/Development
• How Does RISK Apply?
• Quality by Design
• Design Space
• ICH Guidelines

RISK ILLUSTRATION

RISK = Probability of Occurrence X Severity of Harm

HAZARD HARM

Cause: Driver Distraction: Failure Mode Effect / Consequence

Listening to music (temporarily loses control) Severity Scale
or cell phone

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Risk Management Development History

• August 21, 2002
– FDA Press Release:
• “Pharmaceutical cGMPs for the 21st Century; A Risk-
Based Approach
• September, 2003
– FDA issues final report its “21st Century” initiative on the
regulation of pharmaceutical manufacturing and ICH Q8
is issued
• September 2004
– FDA started a pilot risk-ranking model for prioritizing
cGMP inspections of pharmaceutical manufacturing
sites

Risk Management Development History (Cont’d)

• November 2004
– ICH Q9 “Quality Risk Management”
• 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 Commissioning &
Qualification
– ISPE Baseline Guide “Risk-MaPP” – same emphasis as ICH
Q9

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FDA Risk Assessment Criteria

September 2004 – Risk based method for prioritizing cGMP Inspections
of Pharmaceutical Manufacturing Sites – a pilot risk ranking model

FDA Risk Factors

Products Process Facility
Intrinsic Process Control History
sterility product type GMP Violations
prescription or OTC operation type inspection results
Dosage Form

Recall History Contamination Vulnerability Product Volume

frequency product type type of operation
severity operation type

ISPE RISKMaPP
• Risk MaPP = Risk Based Manufacture of Pharmaceutical
Products
• ISPE Guideline in Draft – aligns 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 clear
separation of what is reasonable versus unachievable -
zero risk is not scientifically sound

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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

»PQS (Change Control, Vendor Audits and
APR)
ICH Guidance Documents for Minimization of Risk and
Quality Management

Quality By Design (QbD)

ICH Q8 Rev 1
The aim of pharmaceutical development is to design a
quality product and its manufacturing process to
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.

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Quality Risk Management – Q9

• QRM is a systematic process for the assessment,
control, communication and review of risk to the
quality of the product across the product lifecycle.
• Principles include:
– ‘Evaluation of the risk to quality based upon
systematic knowledge and ultimately link to
protection of the patient’..
– The level of effort, formality and documentation of
the QRM process should be proportional to the
level of risk

Risk Management Process

Initiate
ICH Q9 Quality Risk Management Process

Risk Assessment

Risk Identification

Risk Analysis
• Continuous Process
spanning the entire
Risk Evaluation
unacceptable product lifecycle
Risk Management tools
Risk Communication

Risk Control

Risk Reduction • Goal

= Minimize Risk
Risk Acceptance
while
Maximizing Benefit
Output / Result of the
Quality Risk Management Process

Risk Review

Review Events

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Transition from Current Process to QRM

Risk Assessments and Enhanced Design Reviews

Quality by Design
CPPs,
Design Construction C&Q Process Dev CQAs
Validation

Quality, Cost and Schedule Benefits

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 provide an assurance
of quality”

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Elements Involved in Design Space

QdB

Product design

Process
ICH Q8 Design
Understanding
Continuous Improvement Space

Product Knowledge Benefits

• QbD highlights problematic sequences
• QdB approach identifies attributes that affect manufacturability and
stability and product safety
• Target product profile identifies Critical Quality Attributes (CQA) that
are linked to process parameters, material attributes, unit operations
and material inputs
• CQAs provide insight concerning variables that impact product quality
helping to define appropriate monitoring and control strategies
• The risk management methodology is causing gradual movement of
manufacturers and regulators to QbD and Process Analytical
Technology (PAT)
• The two are complimentary:
– QbD strives for “Right First Time”
– PAT strives to provide “Continuous Process Improvement”

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What is Design Space of Cleaning

• Key inputs and data are analyzed and evaluated
– Product knowledge
– Process knowledge
– Regulations
– Quality Attributes
– Critical Processing Parameters
• Consideration must be given to:
– Soil type
– Process method, time, solubility, etc.
– Equipment design & configuration
– Utility Impact, environmental, heat, pressure, etc.

Key is “Process Knowledge”

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

• Process • Visual Inspection

Temperature • Analytical Residue
• Process Pressure Limits
• Process Flow • Microbial Limits
• Process Time • Drainability/Drying/
• Cleaning Agent Air Blows
Concentration • Clean Equipment
• Dirty Equipment Hold Time (CEHT)
Hold Time (DEHT) • Conductivity/pH

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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 process control
– Management responsibility
– Continual improvement over product lifecycle

RISK MANAGEMENT TOOLS

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Risk Management Strategies

Most Preferred
Avoid
Substitute
Reduce
Transfer
Accept
Least Preferred

Risk Decisions

Making Decisions With Uncertainty

• Process Factors
• Knowledge • Controllable
• Experience • Uncontrollable
(Chance)

Outcome
Decision Implementation
Good/Bad

Constraints
Information, Economics,
Political Environment, Time

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Risk Management Tools

PARTIAL LIST
• Failure Mode and Effect Analysis (MIL-STD-1629A)
• Hazard Analysis and Critical Control Points – (HACCP)
• Hazard and Operability (HAZOP)
• Cause & Effect Analysis (Fishbone Diagram)
• Fault Tree Analysis
• Quality Risk Classification and Filtering
• Forced Ranking

What is FMECA and How Does It Work

• “FMECA is a systematic method of identifying the effects
of a potential product or process failure and methods to
eliminate 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
of the likelihood that the failure can be detected)
• Risk Priority Number: (RPN) the total of occurrence, severity and
detection; used to prioritize the overall risk

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FMEA Procedure
• Develop a Team Charter – objectives, scope, identify team
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
– Required attendance and required consensus is an absolute
“MUST” – Remember this is a collaborative effort!
• Compile and Review Data Relevant to Project
– Use PFD’s, P&ID’s, Tech Transfer Reports, Manufacturing
Records, Historical Information, etc.
• Establish Calibration Methodology
– Develop and obtain consensus on a risk-ranking scale and risk
filtering criteria
– Independent reviewer should play “inspection / regulatory advocacy
role” in an attempt to find weaknesses in the logic and/or science.

Calibration Tool
Risk Ranking Calibration Table
Severity 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
potential regulatory issues
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

Undetectable 5 No inspection or analytical method to detect quality defect

Low Detect-ability 4 Very unlikely that defect will be detected by available PCS, in-process assays or qualitative
inspections
Medium Detect-ability 3 Controls may detect the quality defect
Highly Detectable 2 Existing controls are likely to detect the quality defect

Direct Detection Method 1 Existing control systems, in-process assays or inspections in place that will serve as a direct
detection method for the defect.

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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 knowledge
and SME opinion
– Then identify all the effects on the process/systems that
could adversely impact product quality in each failure
mode
– Next step, determine the severity of each effect, the
probability of occurrence and the potential root causes
– Identify the control and detection mechanism in place
for each cause

Failure Mode and Effect Analysis (FMECA)

Process Risk Assessment
Failure Mode and Effect and Criticality Analysis (FMECA)
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

Identify, Characterize, Analyze & Evaluate Risk

What might go What are the What is the Current State &
Product/Process wrong? consequences likelihood it Evaluate Risk
User Requirements will go wrong?
Mitigation Actions (hardware, software, analytical, procedural)
Control & Risk
Effect Causes Detection
Failure Mode

URS Description Functions Identify Analyze Determin Indentify Recommended Responsibility Action
item# Potential effect of e the Mechanism Actions & Completion Taken
New Probability
Occurrence

New Detection

Failure failures causes For date

New severity
Detection

New RPN

Modes of failure Controlling

Severity

Cause &
Detecting RPN
Failure

7 Cleaning Contain Chemical Chemical 5 No 3 Leak 15 Install leak Engineering Yes 2 1 1 2

Chemical Chemical overflows exposure overflow detection detector 05Nov09
Storage control system

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FMECA Procedure (Cont’d)

• Risk Ranking and Filtering:
– Calculate the Risk Priority Number (RPN)
– Rank the RPN on some type of risk ranking block diagram
• Develop Risk Mitigation Actions
– 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
Severity X Probability of Detection

Medium Risk Unavoidable Highly likely Occasional Unlikely Very Remote

Low Risk 5 4 3 2 1

Severity X Probability &

Probability X Severity
5X5&5X5 125 100 75 50 25

5X4&4X5 100 80 60 40 20
5X3&3X5 75 60 45 30 15

5X2&2X5 50 40 30 20 10
5X1&1X5 25 20 15 10 5

Hazard Analysis and Critical Control Points

(HACCP) – Most Often Used in Food Industry
1. Conduct a Hazard Analysis
2. Determine the critical control points
3. Establish:
• Critical limits
• Monitoring procedures
• Corrective actions
• Verification procedure
• Record-keeping and
documentation procedure
Step Hazard Analysis & Evaluation Control & Corrective Actions
No. Description Potential Justification Consequenc Severity of Likelihoo Hazard to Control Critical Monitoring Corrective
Hazards e of exposure Exposure d of be Measures Limits Procedure Actions
to hazard exposure addressed?
to hazard

5 Autoclaving Enteric Enteric Severe 10 50 Yes Autoclave Minimum Check Re-process

pathogens pathogens illness or to a specific Temp. of temp. at or dispose
e.g. have been death temperature 124ºC for completion of
Salmonella, or found in 30 of autoclaved
P. botulinum poorly minutes autoclaving item if
processed inadequate
canned foods time &
temp.

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Hazard and Operability (HAZOP)

• Analysis of operating system, design intent and process variables to ID

consequences, existing controls, risk level and remedial actions –
• Commonly uses Brainstorming techniques to identify operations that
could results in:
– Injury to personnel
– Violations of EH&S regulations
– Profitability
Ref. Operating Design Process Variable Potential Consequences Existing Risk Remediation
P&ID Intent Deviations Controls Level Actions
(use actions that
could cause
deviations)

PID215 Capping Secure seal Cam pressure, Inadequate pressure Inadequately Visual / Medium Establish procedure
Operation to finished roller pressure or too much sealed vial Physical with instruments to
vial pressure Inspection monitor pressure
range for both process
variables

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".
3. Label each ""bone" of the "fish". The major categories typically utilized
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”
– Effective tool for Environment Monitoring Excursion Investigations

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Cause & Effect Analysis (Fishbone Diagram)

Cause

Cleaning
Cleaning
Validation
Validation

Fault Tree Analysis

• Evaluates system or subsystem
failures one at time
• Failure analysis flow chart

Failure Mode Assessment Matrix

Event Description Assessment or if probability is known Assignment of Action

Negative Event

Immediate Cause
Immediate Cause

OR AND

contingent
Base human Base
event
cause error Event
event

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Getting Started with the

Risk-Based Approach to
Cleaning

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
– Examples (dirty hold time, loading
configurations, cleaning time, swabbing, etc.)

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Scale Up Components
• Keys in pilot scale/plant evaluation
– Confirm lab performance of cleaning agent
– Confirm critical control parameters during cleaning
– 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 products
– Define Analytical Method Capability and Swab
Recovery (Qualify Both)

Documentation For Cleaning Validation Rationale

• Lab studies with conclusion

• Pilot/scale up studies
• 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 as
well as for future review of program

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Risk-Based Scientific Rationales Are

Needed For The Following…..
- Product grouping or bracketing
- Equipment grouping or bracketing
- Residue selection criteria
- Limit selection and calculation
- Analytical approach (direct vs. indirect)
- Sampling method selection
- Sampling site selection criteria
- Campaign and/or minor cleaning strategies
- Disassembly / vessel entry policy
- Monitoring – what and when
- Other?

How to Start the Risk Assessment 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
• Record results and provide pertinent written explanation
of conclusions – link to Protocol/CVMP

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General Quality Risk Management Process

Systematic processes designed to

coordinate, facilitate and improve
science-based decision making
with respect to risk to quality

An effective quality risk

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

Bridge to Science & Risk Based Methodology
Quality Management
Protocol Acceptance
Engineering Runs
Risk Assessment

&Report Release
Product/Process

Design Reviews

Residue Levels
Responsibilities

Management
Development
Master Plan
Knowledge

Systems
Change
Systems
Roles &

Product Lifecycle

Science & Risk Based Approach

ICH Q8, Q9, Q10 and
FDA – GMP’s for 21st Century
Regulatory Compliance

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WORKSHOP
Group Exercise
NME Risk Scenario
For Existing Cleaning Validation
“Out of Clutter, find Simplicity”
- Albert Einstein (1879-1955)

Risk Analysis & Cleaning Validation Problem

• Situation:
– Biopharmaceutical site with two existing validated products
– Product Actives and cleaning agent residual limits established
• Products at 4 µg/cm 2 (4 ppm)
• Detergent at 10 µg/cm 2 (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

– NME calculated to have same active residual limit based upon
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 to

bioreactor at a 1:10 dilution (~ 50 mL) each day once the bioreactor
achieves production cell density to eliminate foam in 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 concentrated
into 40 liters every 2 days
– Effect of Dow Corning Antifoam C Emulsion in terms of carryover
on equipment and into the concentrated Protein A chromatography
product 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 residual
product and cleaning agent

Resolution Needed

• Using a Risk-Based Scientific Approach determine the cleaning

validation path forward for introduction of the new product without
jeopardizing existing product manufacture
• 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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