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Today’s SpeakersDr. Mike Long, MBBDirector, 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.
Source: CH Q9 Quality Risk Management
Gaining Proficiency
Area of improvement
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…
Not Plausible ≠ “I do not think”
Risk MaPP and Plausibility
Not Plausible ≠ Can’t Happen
Not Plausible = Not Probable
Risk is defined as……the combination of the probability of occurrence of harm and the severity of that harm
Risk = S x O
High likelihood (10)
Med /moderate likelihood(5)
Low Likelihood (1)
Occurrence
Not Plausible
16
Risk Management Opportunities in
the Validation Lifecycle
Pharmaceutical Technology Webinar
11 AM – 12 PM EST
27 January 2011
Jeffrey L. Hartman, MERCK
17
AGENDA
Applications of Risk Management in Validation
Equipment / Facilities Qualification & Computerized Systems Validation
Process Validation
Cleaning Validation
18
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
19
Equipment / Facilities QualificationSTM 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
20
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.
21
Process Validation – Life Cycle
Stage 1- Process Design Product Profile Early Risk
Assessment Prelim CPPs / CQAs Development (DEV)
Plan Execute Studies (e.g.
DOE) DEV Report Update Risk
Assessment Finalize CPPs / CQAs,
process boundaries Develop Control
Strategy
Stage 2 - Process Performance Qualification Systems Commissioning /Qualification Process Performance Execution Risk Assessment Review / Update
Control Strategy
•Stage 3 – Continued Process Verification
Q8, Q9, & Q10 in Synergy
Develop Monitoring Reports
Assessing the data
on a frequent basis
Make any
changes to
assure process
remains in a state
of control. Update
Control Strategy/Risk Assessment
Develop Monitoring
Plan from ControlStrategy (CS)/
Risk Assessment (RA);monitor critical areas of the
process
22
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
23
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
24
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
25
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.
2626
Cleaning Validation – Clean Hold
Time Validation (Fault – tree)
Risk based sampling considering risks to product quality
Harm – Bioburden
Proliferation
Wet Processing
EquipmentStorage Conditions
Transport of
Equipment
Evidence of pooled
water, product
Uncovered,
Environmental
Conditions
Site to Site
Transfers, Outside
Controlled
Environment
27
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!
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
Global Regulatory Bodies Reactions
QRMP Evolution
Quantitative Studies
Qualitative Assessment (FMEA)
Development of Site Wide QRMP Document
Intro to OSO BioPharmaceuticals Manufacturing, LLC
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)
.OsoBio hired the consulting services of
Julian Wilkins, co-author of ISPE's New
Baseline Guide®, Risk-MaPP to do an
assessment of the facility with regard to
the handling of potent compounds.
Further assessments were
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
Initial Failure Modes Effects
Analysis (FMEA) of entire
process began.
FMEA finalized.
Mannitol studies conducted to
provide data to support assumptions
set forth in the FMEA.
Governing QRMP for handling of
potent compounds is approved.
2006
2007
2008
2009
Page 32
Category OEL (mcg/m3/8hrs)
1 >1,000
2 1,000 – 100
3 100 – 10
4 10 – 1
5 <1
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.
OsoBio Categorization
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:
#Severity Occurrence Detection
Max.
RPN
1Be unnoticed and not
affect performance
Once every 6-100
yearsObvious 1
3Minor nuisance
resulting in no loss
Once every 1-3
years100% inspection 27
5Likely to result in a
complaint
Once per 6
months
Statistical
sampling125
7Extreme customer
dissatisfactionOnce per batch
All manually
inspected343
10Injury to patient or end
user
More than once
per batch.
Not detectable by
current methods1000
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
Potential Routes of
Cross-Contamination
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.
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.
Page 39
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
Page 41
FMEA
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 above Limit of Detection (0.5 ng)
12 out of 176 = 6.8% 3 out of 176 = 1.7%
Maximum amount of mannitol detected in a vial
42 nanograms 2.7 nanograms
Mannitol level at which there is 99% confidence that 95% of the vials are below **
7.7 nanograms 1.3 nanograms
Page 45
Two additional Phase I and III studies have been performed with all
below limit of detection of 1.0 ng.
Conclusion of the Quantitative StudyOsoBio 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“**
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 OhlssonGlobal Manager
MU Pharma & Personal Care
Alfa Laval
www.alfalaval.comA healthy injection for your business
Equipment Safety
1. A Risk Based Approach on drug contamination
2. Quality by Design on equipment
www.alfalaval.comA healthy injection for your business
Sterilisation/sanitisation
Cleaning, rinsing, flushing
Equipment design
Drug ContaminationA Risk Based Approach
• Micro-organisms
• Pharmaceutical products
• Cleaning agents
• Material extraction/reaction from
process equipment
• Air-borne particles and dust
• Substances for operation
www.alfalaval.comA healthy injection for your business
EquipmentQuality 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
www.alfalaval.comA healthy injection for your business
1. Cleanable (flushable) Basic rules
• You can’t clean what you can’t contact
• High shear forces enhance cleaning
www.alfalaval.comA healthy injection for your business
1. Cleanable (flushable) Cleaning Impact
Increased Action, Chemistry & Temperature can speed up the process
Time
Action
Chemistry
Temperature
TACT
www.alfalaval.comA healthy injection for your business
1. Cleanable (flushable) Equipment design
• Dead legs
• Air pockets
• Pockets & Crevices
• Velocity
• Surfaces
• Drainability
www.alfalaval.comA healthy injection for your business
• 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 m100 m
2. Equipment material
www.alfalaval.comA healthy injection for your business
Equipment should seal of the environment from the
medicinal product
• The surrounding air contains contaminants
3. Aseptic design
www.alfalaval.comA healthy injection for your business
Cleaning liquids and substances for operations must not come
into contact with the medicine.
• Cleaning liquids
• Substances for operation
4. Mix-proof design
www.alfalaval.comA healthy injection for your business
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
www.alfalaval.comA healthy injection for your business
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
Polling Question #2 Results
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