SafeBridge Consultants, Inc.

1
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.

2
Product Quality Applications
3
Causes of Cross-Contamination

• Mix-up
• Wrong ingredient in wrong equipment/batch
• Retention
• Inadequate cleaning
• Mechanical transfer
• Moving residue from one place/device to another
• Airborne transfer
• Airborne powders can contact product or product
  contact surfaces

4
Current Guidance ICH Q7A (FDA 2001)

• 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

5
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).

6
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

7
History

• June 2005 ISPE Meeting
• 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
• January 2006 presentation to FDA
• How to set ADEs
• Exposure assessments
• Flexible approaches to containment
• Cleaning validation
• FDA very supportive of ISPEs Guideline approach
  wanted to be involved in development

8
Risk-Based Manufacturing of Pharmaceutical
Products
9
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

10
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
Comparison of analyzed risk against given risk
criteria.


Risk Control
Decision making to reduce and/or accept risks.
11
Concepts of a Risk-Based Approach

• Hazard is an inherent property of a drug
• Zero risk not scientifically achievable or
  necessary
• Risk ?(Hazard X Exposure)
• 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

12
Establishing Health-Based LimitsAcceptable
Daily Exposure (ADE)

• Define a daily dose of a substance, below which
  no adverse effects are anticipated, even if
  exposure occurs over a lifetime
• Identify the critical endpoint (most sensitive
  clinically significant health effect)
• Define the No-observed-adverse-effect level
  (NOAEL) or Lowest-OAEL (LOAEL)
• Consider sources of uncertainty and choose
  appropriate safety factor(s)
• Calculate an ADE for that route of exposure

13
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
14
Threshold of Toxicological Concern (TTC)
Provides guidance for unstudied compounds that
fall into one of three categories

• Compounds likely to be carcinogenic
• ADE 1 µg/day
• Compounds likely to be potent or highly-toxic
• ADE 10 µg/day
• 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.
431-9 (2005)
15
Application of ADE

• Calculate maximum allowable carry-over (MACO)
  from one product to another
• (Parenteral Drug Association cleaning guidance,
  1992)
• Calculate cleaning limit for product contact
  surfaces based on surface area, batch size, and
  dose of the next drug

16
Compound A

• Opioid Analgesic
• LD50 10,000 mg/kg
• Lowest Clinical Dose (LCD) 10 mg/day
• UFC 30
• MF 3
• ADE (10 mg/day)/(30 x 3) 100 µg/day

17
Compound B

• Genotoxic antineoplastic agent
• LD50 3,400 mg/kg
• LCD 70 mg/day
• ADE 1 µg/day
• TTC

18
Comparison to Other Limits
19
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

20
FDAs Response to Risk-MaPP

• the firms rationale for the residue limits
  established should be logical and be practical,
  achievable, and verifiable
• 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.
• Encourage implementation of risk-based
  approaches that focus both industry and Agency
  attention on critical areas
• Ensure that regulatory review, compliance, and
  inspection policies are based on state-of-the-art
  pharmaceutical science.

21
Industrial Hygiene Applications
22
Industrial Hygiene Applications

• Traditionally IH tools have not been accepted for
  quality determination purposes
• Risk-MaPP incorporates basic safety elements of
  risk assessment and risk management used for
  decades
• Air monitoring studies now requested by
  regulatory inspectors in EU and FDA
• Sterile fill/finish company
• Generics company
• Specialty Device CMO
• API CMO

23
Air Sampling Factors

• 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
• Other drug agency regulators
• Interested only in detection of materials in
  adjacent areas

24
Industrial Hygiene Air Monitoring

• 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

25
Issues with Air Monitoring and Quality

• Air samples may be indicative of a potential to
  impact product quality
• 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
• Inherent limitations of monitoring
• /- 25 accuracy
• Number of samples required to determine confidence

26
Surrogate Monitoring Results Clinical Scale
Operations (µg/m3)
27
API Monitoring Results (µg/m3)

• Testing and release process inside ventilated
  enclosure

28
Summary

• Quality audits should review cleaning validation
  programs
• Cleaning limits should be health-protective,
  i.e.
• Based on the ADE developed by toxicologists
• Using well-established methodology
• From data in regulatory filings or the open
  literature
• Air monitoring is a useful indicator of potential
  for release of material
• 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!