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 Today’s Speakers
Dr. Mike Long, MBB
Director, ValSource LLC / Group Leader, PDA Quality Risk Management Interest
Group
Jeffrey Hartman,
Validation Manager, MMD Validation Quality Assurance, MERCK/ Group Leader,
PDA Quality Risk Management Interest Group
Kimberly K. Ray,
LSS Black Belt, Sr. Manager Project Management/Customer Service, OSO
Biopharmaceuticals, Secretary of ISPE Containment Steering Committee
Per-Ake Ohlsson,
Global Manager, Market Unit Pharma & Personal Care,
Alfa Laval
Participating on the Q&A Panel: Tara Gooen,
Team Leader for New and Generic Drug Manufacturing Team, Division of
Manufacturing and Product Quality
Pharmaceutical Technology
Webinar January 27, 2011
Dr. Mike Long, MBB
Director, Valsource
mlong@valsource.com
 Intro
• Where are we going as an industry with Risk
Management
• Risk Management – words of wisdom
• Brief note on Risk MaPP
 Five Risk Guidance/Standards you
should be familiar with…
• ICH Q9 – Quality Risk Management (2005)

• ISO 14971 -Medical devices — Application of risk management to

medical devices (2007)

• ISO 31000 - Risk management—Principles and guidelines (2009)

• PDA PDA Technical Report 44, (TR 44) Quality Risk Management for
Aseptic Processes (2008)

• ISPE – Risk-MaPP : Risk-Based Manufacture of Pharmaceutical

Products (2010)
 Pharma Risk Management Maturity
Level




Source: The Chartered Quality Institute, A guide to Supply Chain Risk Management for the Pharmaceutical and Medical Device Industries and their Suppliers. 2010.
Gaining Proficiency

Area of improvement

Source: CH Q9 Quality Risk Management

 Expectations
• You have Risk Assessments performed on your
processes.

• MHRA has laid out an expectation that sites have

a formal risk register:
– High Level Document , Think “Risk Master Plan”
– Summarizes significant risks and their mitigation
– All formal risk assessments need to be linked to
Register
– Explanation of your risk review process

http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/FAQ/QualityRiskManagement/index.htm
 Words of Wisdom
• A “Risk Based
Approach” is not a gift
card to reduce testing.

• Risk Management
Requires a Balance of
identifying and
mitigating threats and
taking advantage of
opportunities
 RM Implementation
• Care must be taken to
ensure the RM does not
become a “Hammer” in
search of a “Nail”

– I have the solution, now find

me a problem!
 A note on Risk MaPP
• Risk-MaPP : Risk-Based Manufacture of
Pharmaceutical Products

• .. “provides a scientific risk-based approach

based on ICH Q9 to manage the risk of cross-
contamination to maintain an appropriate
balance between product quality and operator
safety”
 A note on Risk MaPP
• Addresses the controls to comply with 21 CFR
211.42(c)

…There shall be separate or defined areas or

such other control systems for the firm's
operations as are necessary to prevent
contamination or mixups…
 Risk MaPP and Plausibility

Not Plausible ≠ “I do not think”

Not Plausible ≠ Can’t Happen

Not Plausible = Not Probable

 Occurrence
Risk is defined as
High
……the combination likelihood
of the probability of (10)
occurrence of harm
and the severity of
that harm
Med
/moderate
likelihood(
Risk = S x O 5)

Low
Likelihood
(1) Not Plausible
Risk Management Opportunities in
the Validation Lifecycle

Pharmaceutical Technology Webinar

11 AM – 12 PM EST
27 January 2011
Jeffrey L. Hartman, MERCK

16
AGENDA

 Applications of Risk Management in

Validation
 Equipment / Facilities Qualification &
Computerized Systems Validation
 Process Validation
 Cleaning Validation

17
Equipment / Facilities Qualification
 ASTM 2500 – Standard Guide for Specification,
Design, and Verification of Pharmaceutical and
Biopharmaceutical Manufacturing Systems and
Equipment, August 2007
 New Principles
 Risk-based approach to commissioning &
qualification activities, designated as verification
 Risks to product quality and patient safety should
govern the scope and extent of verification
activities for manufacturing systems
 Subject Matter Experts have the responsibility for
verification activities, ownership not defined
organizationally
 Life Cycle approach to verification activities, not
once & done
 Risk Assessment for defining initial activities, updated
throughout system lifecycle to assure robust
manufacturing systems

18
 Equipment / Facilities Qualification
STM ASTM 2500 – Standard Guide for Specification, Design, and Verification of Pharmaceutical and
Biopharmaceutical Manufacturing Systems and Equipment, August 2007

 Resembles ICH Q9 Flowchart

 End game - Qualification / Verification resources focused on critical
attributes and functionality
 Eliminates redundant verification activities that have minimal impact or
risk to patient safety and product quality

19
 Process Validation

 FDA Draft Guidance – Process Validation: General

Principles and Practices
 Principles
 Life Cycle approach to Process Validation, 3 Stages
with Process Design, Process Performance
Qualification, Continued Process Verification
 More emphasis on process development & defining
boundaries
 Better use of statistical tools to monitor and assess
process performance
 Gain process knowledge & understanding
throughout manufacturing until decommissioning /
divesture
 Risk Management provides the tool to focus
resources and define what really is critical to both
patient and product.

20
 Process Validation – Life Cycle
•Stage 3 – Continued Process Verification
 Stage 1- Process Q8, Q9, & Q10 in Synergy
Design
 Product Profile
 Early Risk
Assessment
 Prelim CPPs / CQAs
 Development (DEV)
Plan Develop
 Execute Studies (e.g. Monitoring
DOE)
Develop Monitoring Reports
Plan from Control
 DEV Report Assessing the data
Strategy (CS)/
 Update Risk on a frequent basis
Assessment Risk Assessment (RA);
 Finalize CPPs / CQAs, monitor critical areas of the
process boundaries process
 Develop Control
Strategy

 Stage 2 - Process Performance

Qualification
 Systems Commissioning /Qualification Make any
 Process Performance Execution changes to
 Risk Assessment Review / Update
Control Strategy assure process
remains in a state
of control. Update
Control Strategy/Risk Assessment
21
 Cleaning Validation – Risk Based
Cleaning Specifications
 ISPE Risk-MaPP (Risk-Based Manufacture of
Pharmaceutical Products, September 2010)
 Baseline guide that provides a scientific risk-based
approach, based on ICH Q9, to manage the risk of
cross contamination
 Guidance on assessing how health based limits are
established for cleaning validation – Acceptable
Daily Exposure Limits (ADE)
 Justification
 Disease management at the molecular level, dosages
typically less
 Targeted mode of action where API may or may not have
systemic impact
 ADE greater precision and specificity with assessing risk
to patient health when compared to alternative
approaches, e.g. NMT 1/1000 min or LD50

22
 Cleaning Validation – Risk Based
Cleaning Specifications
 Acceptable Daily Exposure (ADE) or equivalent
 Daily dose of a substance below which no adverse
effects are anticipated, even if exposure occurs for
a lifetime

ADE (mg/day) = NOAEL (mg/kg/day) x BW (kg)

UFC x MF
where:
ADE = Acceptable Daily Exposure
NOAEL = No-Observed-Adverse-Effect Level
BW = Body Weight
UFC = Uncertainty Factor(s)
MF = Modifying Factor

23
 Cleaning Validation – Risk Based
Cleaning Specifications
 Impact
 Regulatory – ICH Q7/ EudraLex Volume 4 Part II (Scope API)
 Residue limits should be practical, achievable, verifiable and based on the
most deleterious residue. Limits can be established based on the minimum
known pharmacological, toxicological, or physiological activity of the API or
its most deleterious component.

 Cleaning specifications – With ADE, Maximum Allowable

Carryover (MACO) based on risks to patient

 Some cases, calculated limits too high

 Visual Inspection
 VRL - 95% of formulations tested detected @ levels ≤ 4 ug/cm2*
 Baseline / Process Capability Limit
 Historical experience - 0.4 – 4.0 ug/cm2

*Forsyth, Richard J. and Hartman, Jeffrey L., “A Risk Based Approach to Cleaning Validation using
Visible Residue Limits”, Pharmaceutical Engineering, Vol. 28, No. 3, 2008, pp. 8-22

24
 Cleaning Validation – Selecting Swab
Location and Number

 Can include Severity based on ADE of the API, e.g. the lower
the ADE, more Medium / Medium-Low locations tested.

25
 Cleaning Validation – Clean Hold
Time Validation (Fault – tree)

Harm – Bioburden
Proliferation

Wet Processing Transport of

Storage Conditions
Equipment Equipment

Site to Site
Uncovered,
Evidence of pooled Transfers, Outside
Environmental
water, product Controlled
Conditions Environment

 Risk based sampling considering risks to product quality

26
26
Conclusion
 Risk Management is a tool to efficiently and effectively
design, create and maintain robust manufacturing
processes. This is achieved by prioritization and focusing
resources where it brings the most value to both the
patient and product.
 Per Q9, The level of effort, formality, and documentation
of the quality risk management process should be
commensurate with the level of risk.

THANK YOU!
27
 Polling Question #1

Which of these is your highest contamination

concern:
• Cross-contamination
• Microbiological contamination
• Equipment cleanliness


Quality Risk Management Plan (QRMP)

for OSO BioPharmaceuticals
Manufacturing, LLC. (OsoBio)


 Outline

Intro to OSO BioPharmaceuticals Manufacturing, LLC

QRMP Evolution

Development of Site Wide QRMP Document

Qualitative Assessment (FMEA)

Quantitative Studies

Global Regulatory Bodies Reactions

Page 30
 OSO BioPharmaceuticals Manufacturing, LLC
(OsoBio)

 OsoBio is CMO located in Albuquerque,

New Mexico focusing on biologic and
pharmaceutical injectable finished drug
products – (sterile liquid, liquid
suspension and lyophilized
formulations).

 The site has demonstrated the ability to

handle virtually any category* of
biological or pharmaceutical product,
from clinical to commercial scale,
specializing in difficult and complex
products, including potent compounds,
proteins, and monoclonal antibodies.

*does not include beta-lactams

Page 31
 OsoBio Quality Risk Management Plan
Evolution (timeline)
. the consulting services of
OsoBio hired
Julian Wilkins, co-author of ISPE's New
Baseline Guide®, Risk-MaPP to do an
Initial Failure Modes Effects
assessment of the facility with regard to
Analysis (FMEA) of entire
the handling of potent compounds.
process began.

2007 2009
2006 2008

Further assessments were FMEA finalized.

performed which consisted of a
more thorough look at
procedures and practices as well
as in depth interviews with
manufacturing personnel.
Initial containment plans began
development
Mannitol studies conducted to
provide data to support assumptions
set forth in the FMEA.
Governing QRMP for handling of
potent compounds is approved.


Page 32
 OsoBio Categorization

OsoBio has developed a categorization system (based on the Merck

Performance Based Exposure Control Limit Categorization System) for
compounds to ensure efficient risk communication to employees and clients
and to ensure selection of the correct exposure control methodologies.

Category OEL (mcg/m3/8hrs)

1 >1,000
2 1,000 – 100
3 100 – 10
4 10 – 1
5 <1


Page 33
 ADE Concepts

 The concept of the Acceptable Daily Exposure (ADE) is introduced to

indicate a daily dosage that any population can receive for forty years
without any observable adverse effect.

 This number is derived from the No Observable Effect Level (NOEL)

information in the NDAs on the toxicity of the product to the patient. The
ADE for the API handled by OsoBio is needed in order to assess the
risk of cross-contamination from one product to another product.

 ADE values are required for all Category 4 and 5 compounds.

 OsoBio will use ADE values using an independent toxicologist, the

Threshold of Toxicological Concern or the MAC calculation.

 Monographs and other toxicological and clinical information on the

toxicology of the compounds will be used in setting the ADE. The ADEs
are either provided by the client to OsoBio or developed from industry
data.


Page 34
 Process Mapping

 Process Mapping was performed on each of the following

areas:
 Material Receipt

 Sampling

 Compounding/Formulation

 Filling

 Equipment Cleaning/Decontamination

 Capping/Exterior Vial Wash

 Lyophilization

 Lyophilization Unload

 Packaging/Inspection


Page 35
 FMEA
 OsoBio has adopted the FMEA format for risk assessment. This
technique is well proven since its introduction in 1947 and is based on
assessing:

Severity – the impact on the patient and caregivers

Occurrence – how often this effect takes place

Detection – how easily the failure can be detected.

 Each factor is multiplied by the others for a resulting risk priority number
(RPN)

S x O x D = RPN

Page 36
 Scoring
The severity, occurrence and detection levels used in the FMEA are as
follows:
Max.
Severity Occurrence Detection
# RPN
Be unnoticed and not Once every 6-100
1 Obvious 1
affect performance years
Minor nuisance Once every 1-3
3 100% inspection 27
resulting in no loss years
Likely to result in a Once per 6 Statistical
5 125
complaint months sampling
Extreme customer All manually
7 Once per batch 343
dissatisfaction inspected
Injury to patient or end More than once Not detectable by
10 1000
user per batch. current methods

Page 37
 FMEA---Scoring Severity, Occurrence
and Detection
The following Risk Priority Number (RPN) limits have been set:

 Scores from 1 – 100 are acceptable, the lower the score the lower the
risk.

 Scores between 101 and 200 should be investigated and remedied.

 Scores over 200 require immediate attention.

 During the evaluation, the severity was set at 10 for potent products as
a worst case.

 The basis for setting the severity at the highest level was concern over
the impact which carry-over from this drug could have on
immunosuppressed patients taking another drug manufactured by
OsoBio.


Page 38

Mix-Up
The ability for accidental human
error to cause the use of
contaminated equipment,
incorrect API, excipients, or
product contact materials.
Retention
Retention of material on product
contact parts from previously
processed materials due to failure
or inadequate cleaning.
Page 39
Potential Routes of
Cross-Contamination
Mechanical Transfer or Carry-Over
The transfer by mechanical means of
contaminants from non-product contact
parts, transfer systems, etc.
Airborne Precipitation
The risk of one product in airborne
suspension contaminating another
product.
 Containment Controls Utilized for FMEA

Containment Controls
 Manual Redundant Verification
 Electronic Redundant Verification
 End Product Testing
 SOPs
 Master Batch Records
 Validated Cleaning Procedures
 Sanitization/Decontamination Procedures
 Closed Processes
 Closed Transfer Processes
 Closed Bag (e.g. glove bag)
 Visual Inspection
 Dedicated/Disposable Equipment
 Engineering Controls (AHU, HEPA, Pressure Differentials, etc.)
 Separation by Time (Campaign)

Page 40
 FMEA

Page 41
 Assessment Results

 Formulation/Compounding
 For category 4 and 5 compounds the formulation vessel and
product contact parts are dedicated, indelibly labeled and
tagged or are single use disposable.
 If the API is a powder, the API is placed in a negative
pressure glove bag, sealed and the weight of API is
dispensed into a secondary container.
 The exterior of the secondary container is wiped out using
WFI and transported out via the equipment sleeve.
 The secondary container is attached to the formulation
vessel and the powder or slurry is discharged.
 If required per the batch record, the residual API is bagged
out using a double crimp technique, wiped down and
returned to the raw material storage room.


Page 42
 Assessment Results (con’t)
 The room in which this operation takes place is Grade C.

 The Formulation rooms are protected by air locks from the general
corridor.

 The compounding suites have a negative pressure differential to

the compounding airlocks.

 Each formulation step is subject to redundant manual verification at

set up, operation, disassembly and cleaning.

 All items are labeled and verified through the Ross Enterprise
Resource Planning (ERP) system.

 The Batch Record is also reviewed for proper cleaning and use
of the clean tags, therefore there is a low risk of cross
contamination.


Page 43
 Quantitative Study
The purpose of the study was to establish baseline quantitative limit
data, based on the ADE, for the manufacture of potent compounds
The study was conducted in three (3) phases
 Phase I included a mannitol run (surrogate used because of its ease of
detection, free-flowing properties, and solubility). During the run, the
equipment train was soiled in strategic locations to simulate worst-
case conditions with regard to adverse production events.
 Phase II included a water-run, immediately following the mannitol fill,
without cleaning or sanitization procedures being implemented to
simulate a complete system failure.
 Phase III included a water-run after cleaning and sanitization
procedures were executed to simulate routine manufacturing
procedures.
 Samples were collected from the Phase II and III manufacturing runs
and assayed for mannitol content.

Page 44
 Quantitative Study Results
Parameter Phase II Run Phase III Run

Percentage of samples 12 out of 176 = 6.8% 3 out of 176 = 1.7%

above Limit of Detection (0.5
ng)
Maximum amount of 42 nanograms 2.7 nanograms
mannitol detected in a vial
Mannitol level at which there 7.7 nanograms 1.3 nanograms
is 99% confidence that 95%
of the vials are below **

 Two additional Phase I and III studies have been performed with all
below limit of detection of 1.0 ng.

Conclusion of the Quantitative Study

OsoBio is capable of safely handling any pharmaceutical compounds
with a safety factor of at least 10 as defined by the ADE of the compound
/ Expected Carryover Level with 99% Confidence that 95% of Vials are
below 1.3 ng. "Table for Distribution-Free Tolerance Limits (One-Sided)”
from "Annals of Mathematical Statistics“** 

Page 45
 Reaction of Global Regulatory Bodies to the QRMP

 FDA (CDER/CBER)
 The Site and Product Specific Quality Risk Management Plan was
presented to FDA at district office with FDA representatives from
CDER and CBER (some via teleconference) – December 2009

 FDA reviewed the document on site as part of a General Inspection

– March 2010

 Although the FDA does not provide formal approval for this type of
plan, the agency does permit the handling of these products in a
multi-product facility as long as there is ample evidence to show
there is no risk to cross contamination from the product.

 Received FDA’s verbal indication that the agency was pleased with
the transparency of the presentation prior to manufacture and that
they had no major concern.


Page 46
 Reaction of Global Regulatory Bodies to the QRMP

 EMA was sent a copy of the Site and Product Specific Quality Risk
Management Plan and also reviewed the document on site at the
company's request– December 2009

 EMA/MHRA Type 5 Post Inspection Letter provided by Ian Thrussell,

GMP Inspector:

 “On the basis of the inspection, and subsequent correspondence, I

confirm that your proposed operations concerning the filling of H1N1
attenuated bulk vaccine are in general compliance with the principles
and guidelines of GMP.”

 No negative observations were noted from either agency regarding the

manufacture of potent products in the multi-product facility.

 Minor edits made to document and clarified inactivation for biological

products versus decontamination for chemical products 

Page 47


Thank You


Polling Question #1 Results
 Polling Question #2

Is your company currently applying Risk-MaPP

principles
· Yes
· No
Equipment Safety
Quality by Design based on contamination risks
January 27th 2011

Per-Åke Ohlsson
Global Manager
MU Pharma & Personal Care
Alfa Laval
Equipment Safety

1. A Risk Based Approach on drug contamination

2. Quality by Design on equipment

A healthy injection for your business www.alfalaval.com

Drug Contamination
A Risk Based Approach

• Micro-organisms Sterilisation/sanitisation
• Pharmaceutical products
• Cleaning agents Cleaning, rinsing, flushing
• Material extraction/reaction from
process equipment
• Air-borne particles and dust
• Substances for operation Equipment design

A healthy injection for your business www.alfalaval.com

Equipment
Quality by Design based on contamination risks

Equipment considerations:
1. Cleanable (flushable)
2. Equipment material
3. Aseptic Design
4. Mix-proof Design
5. Consistent performance
6. Documentation

A healthy injection for your business www.alfalaval.com

1. Cleanable (flushable)
Basic rules

• You can’t clean what you can’t contact

• High shear forces enhance cleaning

A healthy injection for your business www.alfalaval.com

1. Cleanable (flushable)
Cleaning Impact

TACT
Time
Action
Chemistry
Temperature

Increased Action, Chemistry & Temperature can speed up the process

A healthy injection for your business www.alfalaval.com

1. Cleanable (flushable)
Equipment design

• Dead legs

• Air pockets

• Pockets & Crevices

• Velocity

• Surfaces

• Drainability

A healthy injection for your business www.alfalaval.com

2. Equipment material
• Must be selected based on processed media
• Should not add any substances or wear particles

 Material used during manufacturing of equipment (polishing

paste, slipping agents, lubrications, etc)
 Equal spare parts (same recipe, dimensions, manufacturing
technique, etc.)

100 m

A healthy injection for your business www.alfalaval.com

3. Aseptic design

Equipment should seal of the environment from the

medicinal product
• The surrounding air contains contaminants

A healthy injection for your business www.alfalaval.com

4. Mix-proof design

Cleaning liquids and substances for operations must not come

into contact with the medicine.
• Cleaning liquids

• Substances for operation

A healthy injection for your business www.alfalaval.com

5. Consistent performance

• A safe system is only safe as long as it performs consistently

• All equipment needs maintenance and cleaning
• Change control procedure must be performed

A healthy injection for your business www.alfalaval.com

6. Documentation

Why is equipment documentation needed?

• Confirm correct equipment
• Secure correct installation, operation and maintenance
• Secure equal spare parts
• Keep track of installed equipment

A healthy injection for your business www.alfalaval.com

Polling Question #2 Results
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