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

10/15/2010

Regulatory Requirements for Cleaning

Validation
USA

FDA 21 CFR Parts 210, 211 (Drugs), 600.11 Biologicals, 820 Medical
Devices Subpart G
FDAs 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 (Contd)
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

10/15/2010

Regulatory Requirements for Cleaning

Validation (Contd)
EU

EC Guide to GMP Part I Annex 15 and Part II

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfsen/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 RiskBased 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 MultiProduct Facilities

10/15/2010

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

10/15/2010

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, multiuse 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.

10/15/2010

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)

10/15/2010

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

10/15/2010

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

10/15/2010

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

10/15/2010

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)

10

10/15/2010

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

11

10/15/2010

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

12

10/15/2010

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
0

Risk Level
1

Risk Level
2

Risk Level
3

Risk Level
4

Risk Level
5

Product
Difficulty to
clean - lab
study or
subjective

Very easy to
clean water
effective

Easy to clean
and high
mobile in
liquid state

Moderately
easy to clean
some
viscosity
issues

Moderately
hard to clean
viscous or
gelatinous
residue

Difficult to
clean oily
substance,
builder or
excipient

Very Difficult
to clean such
as denatured
protein,
carbopol,
eudragit,
titanium
dioxide

13

10/15/2010

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
0

Risk Level
1

Risk Level
2

Risk Level
3

Risk Level
4

Risk Level
5

Product
Difficulty to
clean - lab
study or
subjective

Very easy to
clean water
effective

Easy to clean
and high mobile
in liquid state

Moderately
easy to clean
some viscosity
issues

Moderately hard
to clean
viscous or
gelatinous
residue

Difficult to clean
oily substance,
builder or
excipient

Very Difficult to
clean such as
denatured
protein,
carbopol,
titanium dioxide

Toxicity
LD50 (oral rat)

2500 mg/kg

> 2500 mg/kg

and 1250
mg/kg

>1250 mg/kg
and 500
mg/kg

>500 mg/kg and

250 mg/kg

>250 mg/kg and

25 mg/kg

25 mg/kg

Solubility g/100mL of
water

Very soluble
100% in water

Freely Soluble
99.9 % in water

Soluble
99% in water

Slightly Soluble
>10% but <90%
in water

Very Slightly
Soluble < 10%
in water

Practically
Insoluble
< 0.01% in
water

14

10/15/2010

Residue Limit Selection Method

Lowest limit among group

Product
1
2
3

Active
A
B
C

Limit
25 ppm
15 ppm
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
1
2
3

Active
A
B
C

Limit
25 ppm
15 ppm
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

15

10/15/2010

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

16

10/15/2010

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
Location

Critical Site:
potential
large
contaminant
area

Hot Spot
(historically
hard to
clean)

Affinity to
MOC or
Surface
Finish

Role in
process
likely to lead
to difficult
residue

Cleanability
of Location/
coverage and
access

Ranking

Sidewall

Bottom
Outlet Valve

13

Dome Lid

Instrument
Port

15

Sampling
Port

15

Agitator

OTHER OPTIONS: - Combine Categories (e.g. critical area / hot spot

Weight categories (cleanability)
- Add Notes Category: like instrument ports are hand cleaned,
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

1 = Low Risk /
3 = Moderate Risk
5 = High Risk / Not

17

10/15/2010

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

18

10/15/2010

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

19

10/15/2010

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! (g/g or g/mL = ppm)
0.001 = dosage safety factor

20

10/15/2010

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.)

21

10/15/2010

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

22

10/15/2010

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

23

10/15/2010

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
HARM

HAZARD
Cause:

Driver Distraction:
Listening to music
or cell phone

Failure Mode
(temporarily loses control)

Effect / Consequence
Severity Scale

24

10/15/2010

Risk Management Development History

August 21, 2002
FDA Press Release:
Pharmaceutical cGMPs for the 21st Century; A RiskBased 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 (Contd)

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

25

10/15/2010

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

Process Control
product type
operation type

History
GMP Violations
inspection results

Contamination Vulnerability
product type
operation type

Product Volume
type of operation

Intrinsic
sterility
prescription or OTC
Dosage Form

Recall History
frequency
severity

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

26

10/15/2010

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.

27

10/15/2010

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

ICH Q9
Initiate
Quality Risk Management Process

Risk Assessment
Risk Identification

Continuous

Risk Analysis

unacceptable

Risk Control
Risk Reduction
Risk Acceptance

Risk Management tools

Risk Communication

Risk Evaluation

Process
spanning the entire
product lifecycle

Goal

= Minimize Risk
while
Maximizing Benefit

Output / Result of the

Quality Risk Management Process
Risk Review
Review Events

28

10/15/2010

Transition from Current Process to QRM

Risk Assessments and Enhanced Design Reviews

Quality by Design

Design

Construction C&Q

Process Dev

CPPs,
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

29

10/15/2010

Elements Involved in Design Space

QdB

Product design

Process
Understanding

Continuous Improvement

ICH Q8 Design
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

30

10/15/2010

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 (CPPs) Critical Quality Attributes (CQAs)

Process
Temperature
Process Pressure
Process Flow
Process Time
Cleaning Agent
Concentration
Dirty Equipment
Hold Time (DEHT)

Visual Inspection
Analytical Residue
Limits
Microbial Limits
Drainability/Drying/
Air Blows
Clean Equipment
Hold Time (CEHT)
Conductivity/pH

31

10/15/2010

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

32

10/15/2010

Risk Management Strategies

Avoid
Substitute
Reduce
Transfer
Accept

Most Preferred

Least Preferred

Risk Decisions
Making Decisions With Uncertainty

Process
Knowledge
Experience

Factors
Controllable
Uncontrollable
(Chance)

Decision

Implementation

Outcome
Good/Bad

Constraints
Information, Economics,
Political Environment, Time

33

10/15/2010

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

34

10/15/2010

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 PFDs, P&IDs, 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

Potential Impact of Failure

Very High

Effect of failure could potentially cause patient death

High

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

Moderate

Effect of failure could potentially lead to increase in patient dissatisfaction, product complaints and
potential regulatory issues

Low

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

Very Low

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

Occurrence Ranking
Unavoidable

O
5

Occurrence Frequency Probability

Equal to or greater than one occurrence/day

Highly Likely

One or more occurrences/week

Occasional

More than one occurrences/year

Unlikely

Equal to or less than one occurrence/year

Very Remote Occurrence

No more than one occurrence every 2 years

Detection Ranking

Detection Mechanism Effectiveness

Undetectable

No inspection or analytical method to detect quality defect

Low Detect-ability

Very unlikely that defect will be detected by available PCS, in-process assays or qualitative
inspections

Medium Detect-ability

Controls may detect the quality defect

Highly Detectable

Existing controls are likely to detect the quality defect

Direct Detection Method

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

35

10/15/2010

FMEA Procedure (Contd)

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

Product/Process
User Requirements

What might go
wrong?

What are the

consequences

Effect

What is the
likelihood it
will go wrong?

Current State &

Evaluate Risk

Mitigation Actions (hardware, software, analytical, procedural)

Control &
Detection

Causes

Risk

Cleaning
Chemical
Storage

Contain
Chemical

Chemical
overflows

Chemical
exposure

No
overflow
control

Indentify
Mechanism
For
Controlling
Cause &
Detecting
Failure
Leak
detection
system

Recommended
Actions

Responsibility
& Completion
date

Action
Taken

Install leak
detector

Engineering
05Nov09

Yes

RPN
15

New RPN

Determin
e the
causes
of failure

New Probability

Analyze
effect of
failures

New Detection

Identify
Potential
Failure
Modes

New severity

Functions

Detection

Description

Severity

URS
item#

Occurrence

Failure Mode

36

10/15/2010

FMECA Procedure (Contd)

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
Severity X Probability of Detection

Risk Ranking & Filtering (Severity X Occurrence X Detection)

High Risk

Frequency of Occurrence

Medium Risk

Unavoidable

Highly likely

Occasional

Unlikely

Very Remote

Low Risk

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

Severity X Probability &

Probability X Severity

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
No.

Description

Autoclaving

Hazard Analysis & Evaluation

Potential
Hazards

Justification

Enteric
pathogens
e.g.
Salmonella, or
P. botulinum

Enteric
pathogens
have been
found in
poorly
processed
canned foods

Control & Corrective Actions

Consequenc
e of exposure
to hazard

Severity of
Exposure

Likelihoo
d of
exposure
to hazard

Hazard to
be
addressed?

Severe
illness or
death

10

50

Yes

Control
Measures

Critical
Limits

Monitoring
Procedure

Corrective
Actions

Autoclave
to a specific
temperature

Minimum
Temp. of
124C for
30
minutes

Check
temp. at
completion
of
autoclaving

Re-process
or dispose
of
autoclaved
item if
inadequate
time &
temp.

37

10/15/2010

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.
P&ID

Operating

Design
Intent

Process Variable

Potential
Deviations
(use actions that
could cause
deviations)

Consequences

Existing
Controls

Risk
Level

Remediation
Actions

PID215

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 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 Ms:
Methods, Machines, Materials, Manpower
The 4 Ps:
Place, Procedure, People, Policies
The 4 Ss:
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

38

10/15/2010

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

1
2

Negative Event

Immediate Cause
Immediate Cause

AND

OR

Base
cause
event

human
error

Base
Event

contingent
event

39

10/15/2010

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.)

40

10/15/2010

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

41

10/15/2010

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

42

10/15/2010

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

Change
Management
Systems

Protocol Acceptance
&Report Release
Quality Management
Systems

Residue Levels

Engineering Runs

Design Reviews

Risk Assessment

Master Plan
Development

Product/Process
Knowledge

Roles &
Responsibilities

Bridge to Science & Risk Based Methodology

Product Lifecycle

Science & Risk Based Approach

ICH Q8, Q9, Q10 and
FDA GMPs for 21st Century
Regulatory Compliance

43

10/15/2010

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 g/cm 2 (4 ppm)
Detergent at 10 g/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

44

10/15/2010

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

45

10/15/2010

46

10/15/2010

47

10/15/2010

48

10/15/2010

49