Complying with Regulatory Guidelines on PGIs

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Complying with Regulatory Guidelines on PGIs

• The Role and Challenges for Analytical Chemistry
• Andrew Baker, Analytical Chemistry,
• Global Process RD Avlon/Charnwood

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Content

• Summary of PGIs
• Analytical Role
• Strategies and Examples

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Introduction
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Introduction

• Regulatory Authorities have over the last few
  years become increasingly concerned over the
  presence of impurities present in Drug Substance
  that are potentially genotoxic
• Felt to not be adequately covered by ICH Q3

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What is Genotoxicity ?

• Toxic to DNA
• Interact directly or indirectly
• Cause mutations that may lead to cancer

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Where do they come from ?

• Most (although not all) arise from the synthetic
  process
• Typical compounds that may be genotoxic are
  alkylating agents, epoxides, nitrosoamines

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So why use such substances

• Produce APIs with desired properties
• eg Sulphonic Acid (sulphonate esters)
• Good synthetic reagents
• High yielding, clean synthetic routes
• eg Alkyl Halides, Epoxides

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FDA Structural Alerts
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Guidelines

• Little definitive guidance in early days
• EMEA Guidance effective Jan 2007
• Introduced concept of Virtually Safe Dose
• Threshold of Toxicological Concern (TTC)
• Already well established eg Drinking Water
• Probability/Risk based
• Equates to 1.5ug/day (assumes lifetime exposure)

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Industry View

• Remains some concern
• Uncertainty over application
• Overestimating risk vs other sources eg Food
• But focus on resolving uncertainty

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Resolving Uncertainty

• Key area of uncertainty relates to development
• Higher limits may be permitted if reduced
  exposure
• Recognised in EMEA guidelines
• Industry Task Force developed Staged TTC
• Relates limits to duration of exposure

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Role of Analytical Chemistry
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Analytical Chemistry

• Managing and Resolving Uncertainty
• Staged TTC approach
• Fundamentally relies on knowledge of PGI levels
  present
• But also
• Hard Facts and Figures vital for Projects
• Decision making eg Route Selection

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Trace Analysis

• Trace analysis well established arm of analytical
  chemistry
• But some differences here
• Diversity of analyte/matrix
• Significant chemical similarity between analyte
  and matrix
• Traditional trace techniques limited
  applicability

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Sound Bites

• Like looking for needle in a haystack when the
  needle is made of Straw as well.
• Consider the matrix- Which is easier ?
• 1ppm Benzene in Toluene
• 1ppb Benzene in Water

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Old Examples and Strategy
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Project A

• A chloroacetamide
• GCMS SIM Chromatograms
• 50ppm (wrt to drug) blue trace
• Extracted Sample black trace

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Project A

• Triple Quad GCMS
• 0.25 ppm equivalent
• Presented at BMSS by Mark Jackman AZ PRD

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Project B

• Standard

• Sample

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Project B

• Small PGI analyte
• Matrix well resolved chromatographically
• Variable ion ratios
• Key confirmatory criteria
• Presented at BMSS by Mark Jackman AZPRD

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Project B

• Triple Quad GCMS
• Standard

• Sample

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Problems

• Both required the use of a high(er) end
  analytical technique
• Both Required significant method development
• Neither was delivered within timelines required
  by project

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Challenge at AZ

• Projects want high quality results
• Fast
• How do we do this?
• Which analytical technique to use?
• Which detector to use?
• Which cleanup/sample extraction to use?
• Provide assurance/have confidence in numbers
• Also Get method development balance right
• Simple preferred Complex when required

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AZ Approach

• How can we meet this challenge?

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PGI Analysis Collaboration

• AstraZeneca Looked for a collaborative partner
• Expert in chromatography and trace analysis
• Have an established interest in this area
• Have a set up that could deliver results fast
• A partner was found and work started Jan 2007

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PGI Analysis Collaboration

• Aim
• Identify best fit analytical method(s) for
  analysis of any of the FDA structural alert
  classes of compounds
• Hit suitable technique/approach first time
• To develop a decision making process
• Along with framework of analytical methods

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Collaboration Scope

• Divided into compound classes
• Chemical functionality key to solution
• Range of test analytes
• Range of test matrices (Generic APIs)
• Selected to give good representation of chemical
  and physical properties

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Epoxide Test Analytes
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Targets for method development

• Develop method(s)
• 1ppm analyte in matrix
• Techniques open but available
• Extraction vital
• Mass Spec Sensitivity and Selectivity
• Fully integrated verification of quantification

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Currently Available Methods

• Highest priorities
• Sulphonate Esters (deriv SHS-GCMS)
• Alkyl Halides (SHS and SPME GCMS)
• Haloalkenes (SHS and SPME GCMS)
• Mustards (deriv SPME-GCMS)
• Aminoaryls (LCMS switching)
• Michael Acceptors, Epoxides and Aldehydes coming
  soon

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Working on

• Michael Acceptors
• Epoxides
• Aldehydes
• Aziridines
• Nitros
• Hydrazine/Azos
• Problem Compounds

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Examples of New Approach
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Project C

• Chloroether and Small Aliphatic Chloroalcohol
  type substances
• Ca 12 weeks
• Investigating and developing method
• Ca 10 weeks trying things that didnt work
• Project waiting for information
• Potential Delays

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From Collaboration

• Alkyl Halide test analytes included
• Chloroethanol
• Bromoethanol
• Iodoethanol
• 2-(2-Chloroethoxy)ethanol
• 4-chloro-butyl ether
• A lot of the things tried for Project C were
  unlikely to work

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Solutions from Collaboration

• Double Aqueous/Organic Extraction
• Some Triple Quad GCMS for development
• GCMS SIM analysis
• Took about 2-3 weeks
• A potential saving of 10 weeks

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Project D

• Fluorophenethyl Bromide
• 10 ppm levels in API

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Compound already studied

• Fluorobenzyl Bromide
• Recovery and Linearity data

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Alkyl Halides by SHS

• Data from collaboration
• ppm wrt to 50mg API
• 33 varied compounds in total on list

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Alkyl Halides by SPME

• Data from collaboration

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Project E

• Sulphonate Ester
• Halide
• 12 Batches
• 3.5 - 4 Days

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Confirmation

• Need to confirm for our API/matrix combination
• But work is more defined
• Project can therefore plan
• Delivering significant time savings

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Summary

• PGI analysis is a challenge
• Requires use of generic methodologies
• AZ have established a collaboration
• Will provide such methods for all PGI classes
• Subjectively is working very well (collating hard
  data)