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

Mix-up

Wrong ingredient in wrong equipment/batch Inadequate cleaning Moving residue from one place/device to another Airborne powders can contact product or product contact surfaces

Retention

Mechanical transfer

Airborne transfer

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

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 g/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

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

January 2006 presentation to FDA

FDA very supportive of ISPEs 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
Risk Review Risk Evaluation

Estimation of risk associated with identified hazards.

Comparison of analyzed risk against given risk criteria.

Risk Control

Decision making to reduce and/or accept risks.

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

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 g/day 2. Compounds likely to be potent or highly-toxic ADE = 10 g/day 3. Compounds NOT likely to be potent, highly toxic, or genotoxic ADE = 100 g/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)

Calculate cleaning limit for product contact surfaces based on surface area, batch size, and dose of the next drug

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 g/day

Compound B

Genotoxic antineoplastic agent LD50 = 3,400 mg/kg LCD = 70 mg/day

ADE = 1 g/day

TTC

Comparison to Other Limits

Limit (g/day) Compound ADE LCD/1,000 LD50/50,000

A B

100 1

10 70

14,000 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 sensitive sub-populations bioavailability by the route of administration

Consider Consider

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.

Industrial Hygiene Applications

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

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

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

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

Surrogate Monitoring Results:

Clinical Scale Operations (g/m3)
Range Mean 1240.6 283.5 165.0 347.5 203.1 54.1 n/a 2.32 0.182

OBZ - No Control Technology

Granulation, drying (2) OBZ - Very Limited LEV Granulation, drying (6) Screening (2) Blending, sieving (6) Compression (6) Encapsulation (4) Area Samples (process room +) Airlock no controls (1) Airlock Limited LEV(12) Outer corridor (12) 88.6 0.153 3.87 0.049 0.475 93.3 671.1 153.6 176.4 77.0 752.8 64.3 531.1 40.0 59.0 947.2 - 1534

API Monitoring Results (g/m3)

Testing and release process inside ventilated enclosure
Range OBZ Samples Testing (2) Area Samples Testing (12) <6.0 - <6.9 <5.3 - <6.9 <6.5 <6.1 Mean

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!