Risk-MaPP
Quality & IH Implications
Robert Sussman, Ph.D., DABT
Managing Principal, Eastern Operations
John P. Farris, CIH
President & CEO
Pharmaceutical IH Forum – May 18, 2011
Some slides courtesy of ISPE and PharmaConsult US
SafeBridge Consultants, Inc.
Product Quality Applications
Causes of Cross-Contamination
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Mix-up
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Retention
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Inadequate cleaning
Mechanical transfer
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Wrong ingredient in wrong equipment/batch
Moving residue from one place/device to another
Airborne transfer

Airborne powders can contact product or product contact
surfaces
Current Guidance – ICH Q7A (FDA 2001)
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“The use of dedicated production areas should also be
considered when material of an infectious nature or high
pharmacological activity or toxicity is involved (e.g., certain
steroids or cytotoxic anti-cancer agents) unless validated
inactivation and/or cleaning procedures are established and
maintained.”
Similar language in Canadian, European, and Brazilian
regulations.
 certain antibiologics, certain hormones, certain highly
active drugs
Highly Hazardous Compounds


Adapted from the NIOSH Hazardous Drug Alert

Genotoxic compounds that are known or likely to be
carcinogenic to humans

Compounds that can produce reproductive and/or
developmental effects at low dosages

Compounds that can produce serious target organ toxicity or
other significant adverse effects at low dosages
“for which validated cleaning or inactivation procedures
cannot be established (e.g., the acceptable level of residue
is below the limit of detection by the best available
analytical methods).”
Approaches to Establishing Cleaning Limits

1/1000 of the low clinical dose – May be over-protective
or under-protective, depending on the data set

LD50/50,000 – May be over-protective or under-protective,
depending on the data set

10 ppm – Arbitrary GMP-based value permits carryover
based on potency of subsequent product

100 µg/swab – Upper limit to ensure visual cleanliness
(VRL – Visual Residue Limit)
• No standard, prescribed approach
• Above methods are NOT science- or risk-based
History

June 2005 ISPE Meeting
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January 2006 – presentation to FDA
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FDA thinking of requiring “potent” or “hazardous” compounds
to be segregated similar to penicillins
Big Pharma representatives discussed alternatives
Several speakers invited to present approach at FDA
How to set ADEs
Exposure assessments
Flexible approaches to containment
Cleaning validation
FDA very supportive of ISPE’s Guideline approach &
wanted to be involved in development
Risk-Based Manufacturing of
Pharmaceutical Products
HAZARD
QUALITY
CONTROL
RISK
What is Risk-MaPP?

Risk-MaPP provides a scientific, risk-based
approach based on ICH Q9 for setting health-based
cross-contamination and cleaning validation limits

These limits drive the risk controls that are
implemented on a case-by-case basis to maintain
product quality

Engineering controls may reduce airborne dust and
obviate the need for segregation

Dedication / segregation always remain an option, but
should not be seen as precedent-setting
ICH Q9 - Quality Risk Management
Risk Identification
Systematic use of information to
identify hazards.
Risk Analysis
Estimation of risk associated with
identified hazards.
Risk Review
Risk Evaluation
Risk Control
Comparison of analyzed risk
against given risk criteria.
Decision making to reduce
and/or accept risks.
Concepts of a Risk-Based Approach
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Hazard is an inherent property of a drug
Zero risk not scientifically achievable or necessary
Risk = (Hazard X Exposure)
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Hazard is fixed
Exposure can be controlled
High Hazard does not necessarily mean high Risk
Use a consistent, robust, science-based approach
Make decisions case-by-case, not by class
Control risk by methods other than segregation
Establishing Health-Based Limits:
Acceptable Daily Exposure (ADE)
Define a daily dose of a substance, below which no
adverse effects are anticipated, even if exposure occurs
over a lifetime:
1. Identify the critical endpoint (most sensitive clinically
significant health effect)
2. Define the No-observed-adverse-effect level (NOAEL) or
Lowest-OAEL (LOAEL)
3. Consider sources of uncertainty and choose appropriate
“safety factor(s)”
4. Calculate an ADE for that route of exposure
Calculating an ADE
ADE (mg/day) = NOAEL (mg/kg/day) x BW (kg)
UFC x MF
where:
NOAEL = No-observed-adverse-effect level
BW = Body weight
UFC = Composite uncertainty factor(s)
MF = Modifying factor
Threshold of Toxicological Concern (TTC)
Provides guidance for unstudied compounds that fall
into one of three categories:
1. Compounds likely to be carcinogenic
ADE = 1 µg/day
2. Compounds likely to be potent or highly-toxic
ADE = 10 µg/day
3. Compounds NOT likely to be potent, highly toxic, or genotoxic
ADE = 100 µg/day
Dolan DG, Naumann BD, Sargent EV, Maier A, Dourson M Application of the threshold of toxicological
concern concept to pharmaceutical manufacturing operations. Regul. Tox. Pharm. 43:1-9 (2005)
Application of ADE

Calculate maximum allowable carry-over (MACO) from
one product to another
(Parenteral Drug Association cleaning guidance, 1992)
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Calculate cleaning limit for product contact surfaces
based on surface area, batch size, and dose of the
next drug
Compound A
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Opioid Analgesic
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LD50 = 10,000 mg/kg
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Lowest Clinical Dose (LCD) = 10 mg/day
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UFC = 30
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MF = 3
ADE = (10 mg/day)/(30 x 3) = 100 µg/day
Compound B
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Genotoxic antineoplastic agent

LD50 = 3,400 mg/kg

LCD = 70 mg/day

ADE = 1 µg/day
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TTC
Comparison to Other Limits
Limit (µg/day)
Compound
A
ADE
100
LCD/1,000
10
LD50/50,000
14,000
B
1
70
4,800
ADE Caveats

An ADE is for patient use and may need to include
sensitive subgroups (elderly, children) that are not
considered in developing an OEL

An ADE is NOT equal to the OEL x 10 m3
 May
use same data set, but different safety factors and
bioavailability data may be applied
 Consider
sensitive sub-populations
 Consider
bioavailability by the route of administration
FDA’s Response to Risk-MaPP

“… the firm’s rationale for the residue limits established
should be logical … and be practical, achievable, and
verifiable…”
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“Check the manner in which limits are established… The
objective of the inspection is to ensure that the basis for any
limit is scientifically justifiable.”
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“Encourage implementation of risk-based approaches that
focus both industry and Agency attention on critical areas…”
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“Ensure that regulatory review, compliance, and inspection
policies are based on state-of-the-art pharmaceutical science.”
Industrial Hygiene Applications
Industrial Hygiene Applications

Traditionally IH tools have not been accepted for quality
determination purposes
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Risk-MaPP incorporates basic safety elements of risk
assessment and risk management used for decades
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Air monitoring studies now requested by regulatory
inspectors in EU and FDA
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Sterile fill/finish company
Generics company
Specialty Device CMO
API CMO
Air Sampling Factors
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Some drug agency regulators:
Interested in personal sampling and demonstration of
health protective environment; and
 Interested in quality and prevention of releases out of
primary process rooms
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Other drug agency regulators:
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Interested only in detection of materials in adjacent areas
Industrial Hygiene Air Monitoring
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IH monitoring data intended to be compared to health-based
limits
Limits of detection of sampling & analytical methods should be
based on health limits (OELs, PELs, TLVs etc.)
Methods must be validated for air monitoring
 Samples stable in air streams
 Volume limitations determined
 Device types and samples extraction procedures established
Sampling plan should be established prior to survey
 Include personal and area samples to answer particular
questions
Issues with Air Monitoring and Quality

Air samples may be indicative of a potential to
impact product quality
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Not proof
Interpretation of data without limits established in
advance
Method sensitivity may not be appropriate
 Quantitative results must be compared to something
 Detection does not equal risk
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Inherent limitations of monitoring
+/- 25% accuracy
 Number of samples required to determine confidence
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Surrogate Monitoring Results:
Clinical Scale Operations (µg/m3)
Range
Mean
947.2 - 1534
1240.6
Granulation, drying (6)
93.3 – 671.1
283.5
Screening (2)
153.6 – 176.4
165.0
Blending, sieving (6)
77.0 – 752.8
347.5
Compression (6)
64.3 – 531.1
203.1
Encapsulation (4)
40.0 – 59.0
54.1
Airlock – no controls (1)
88.6
n/a
Airlock – Limited LEV(12)
0.153 – 3.87
2.32
Outer corridor (12)
0.049 – 0.475
0.182
OBZ - No Control Technology
Granulation, drying (2)
OBZ - Very Limited LEV
Area Samples (process room +)
API Monitoring Results (µg/m3)
Testing and release process inside ventilated enclosure
Range
Mean
<6.0 - <6.9
<6.5
<5.3 - <6.9
<6.1
OBZ Samples
Testing (2)
Area Samples
Testing (12)
Summary
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Quality audits should review cleaning validation programs
Cleaning limits should be health-protective, i.e.:
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Air monitoring is a useful indicator of potential for release of
material
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Based on the ADE developed by toxicologists
Using well-established methodology
From data in regulatory filings or the open literature
Designed for occupational health determinations
May be used as one aspect of product quality and assist with case for
multiproduct facilities
Interpretation of that data is dependant on a number of factors
Be careful what you ask for!