Elemental Impurities – Parenteral Dosage Form ... -...

Elemental Impurities Parenteral Dosage Form Case Study – Approach and Challenges Joy E. Mason Eli Lilly and Company

Company Confidential ©2015 Eli Lilly and Company 11/16/2016 1

Elemental Impurities

Goals • Introduce an approach to risk assessment • Evaluate differences between parenteral

and oral drug product assessments • Share challenges • Recommend an action plan

11/16/2016 Company Confidential ©2015 Eli Lilly and Company 2

Why are we anxious, about risk assessments?

Resources


ICH Q3D Modules 1 - 9

ICH Q3D Case Studies

Benchmarking Notes

Conference Notes

ICH Q3D Guideline

You have several resources available to you.

Its Complicated!


Competing Priorities

Complex Supply Chain

Limited Resources

Contract Manufacturers

Multiple Departments

Limited Excipient

Information

ICH Q3D Elemental Impurities Guideline

USP, PhEur, JP - IN ChP, IP - Out

An Example Approach

Make the process easy! Only spend time and resources where you need to!


An Example Approach


Global Assessment Confirmation Life Cycle Strategy Example Testing Management

Strategy


Strategy

Approach

Scope

Standard Risk Assessment

Decision Trees

Corporate Standards

Approved by Vice Presidents. Explains

Lilly’s interpretation of Q3D.

Scope describes elements scope (Q3D

Table 5.1), product scope and approach.

SRA describes the assessment of

common attributes.

Decision trees used to assess control and risk for products.

Ensures consistency.

Corporate standards describe life cycle management at corporate level.

Strategy


Decision Trees Responses

Risk Question

Response Describe Controls

Decision trees for each “source” reside in strategy document.

Responses to each question are followed by a description of controls.

Strategy

Decision Tree Example (Equipment) • Corrosion Resistance Tables Fifth

Edition, Revised and Expanded. Philip A. Schweitzer, P.E., 2004,

Marcel Dekker, Inc., New York • Chemical Resistance Guide for

Metals and Alloys II, Kenneth M. Pruett, 2012, Compass Publications, La Jolla, California

USA.


Risk Assessment


Assessment Template

Product Profile


Risk Questions

Summarize Controls

Risk Time

ICH Q3D Alignment

Drug Product

Alignment

Risk Assessment Example


Equipment Water Gases Excipients Drug Substance Cont. Closure

Materials of Construction

Materials of Construction?

Materials of Construction?

Trace? Elements Intentionally

Added?

Dosage Form?

Dosage Form?

Source Limits?

Source Limits?

Source?

Purification Steps?

CCS Type?

Erosion Control?

Purification?

Max Daily Intake?

Materials added After

Purification?

Coated?

Corrosion Control?

Certificate of Analysis?

Control Strategy? Extractable/ Leachable ?

Internal Specification?

Vendor Data?

CCS = Container Closure System

Excipient anxiety! Unresponsive suppliers?

Screen all excipients for all elements?

Excipients


Excipients

Analytical Screen

Total Elemental Impurities Mass

Risk Assignment

Manufacturer Inquiry

Implement Control Plan

Significant investment to screen internally. Lilly wanted ICP-MS

capability.

Technical Services follows ICH Q3D

Table A.4.8

Each excipient is assigned a risk

category.

Send questionnaires to manufacturers of

“risk” excipients.

Periodic testing for “risk” products.

Excipient Risk Assignment


No Risk Low Risk Risk

Synthetic No Catalyst Synthetic With Catalyst

Trace

Microbial

Animal Mined

Plant

Excipients

Excipient Risk Assignment

No Risk Revise Spec (Remove HM)

Low Risk Screen Calculate Total EI Mass

Revise Spec (Remove HM)

Risk Screen Calculate Total EI Mass

Monograph with Heavy Metals?

Document (data confirms control)

Vendor Inquiry

Vendor Report EI on COA/Share

Controls

Internal Testing Revise Spec (Add EI)


EI = Elemental Impurities COA = Certificate of Analysis

NO

YES

Primarily Lilly data, 3

lots

Excipients


Section of template:

Link to Supplier

Responses

Instructions

Drug Product (Confirmation) Testing


DP Confirmation

Testing

Drug Product Type

Greatest Risk

Information Unavailable

DP = Drug Product E/L = Extractable Leachable CM = Contract Manufacturer

Vials, cartridges, syringes, tablets, capsules, dermal,

suspensions, liquids.

pH, temperature, hold times, greatest

surface area, no E/L, high risk excipient

CMs may not provide the necessary level of

detail needed.

Excipients and Drug Substance


Follow ICH Q3D Table A.4.8. Add the Drug Product results, PDE, and control threshold. Include Container Closure System E/L data on table if there is an element contribution. Decide if data are needed for equipment or water. How will data be evaluated? Both are low risk -> no data.

We added DP results, PDE, and control threshold.

Life Cycle Management


Change Management

Drug Substance Periodic Review

Drug Product Periodic Review

Excipient Periodic Testing

Corporate Standards

Revise corporate and local procedures to include elemental impurities evaluation when there is a change and include elemental impurities in product periodic reviews.

.

Parenteral vs Oral Assessment

Source Parenteral Liquid Oral Tablets/Capsules Elements Class 1, 2A, 3 (Cu, Li, Sb) Class 1, 2A, Some 2Bs Class 1, 2A, Some 2Bs

Drug Substance Purification Steps (process removal steps)

Late Excipients (Risk Assignment)

Catalyst/Reagent (spec or a study)

Catalyst/Reagent (spec or a study)

Manufacturing Equipment Corrosion (compatibility studies)

Corrosion (compatibility studies)

Erosion (metal detection, visual

inspection, maintenance)

Excipients Same Same Same

Container Closure E/L or Test Expired Product E/L or Test Expired Product Not Applicable

Utilities Same Same Same


E/L = Extractable or Leachable

Infrastructure


Challenges


Challenges Solutions

Equipment Compatibility Provide engineers technical references and a global expert (slide 10) if compatibility studies are not available.

Contract Manufacturing (CM) Share strategy document and templates with CM. If CM completes assessment, add a “wrap around” document to address gaps and to internally approve the CM document.

Roles and Responsibilities Identify clear roles for execution, consultation, coordination, resourcing, implementation, life cycle management,

Excipients Create an excipient team to focus on strategy (global group), supplier communication (QA procurement), specification revisions (Quality), updates to regulatory documents (Regulatory) and periodic testing (Quality Control).

Challenges

Analysis: • ICP-MS Training • Recovery (e.g. mercury) • Background (e.g. nickel) • 7 Analytical Procedures

– Solubility challenges required different procedures – Prefer to avoid solvents – Multiple procedures for one material


Structure Recommendation


Build Infrastructure Build Bridges Make it Easy

Collaboration Site Communication Channels

Help Different Functions Speak the Same Language

Standardize Templates

OK! Maybe not easy, but at least less painful.

Content Recommendation



Template (Risk Questions)

Data

Elements Scope (Class 2B)

Process Water (Regional Regulations)

Compressed Gases (Regional Regulations)

Stainless Steel Composition Excipient Risk Assignments Life Cycle Management –

Corporate Standards

Drug Substances

Excipients Drug Products

Container Closures (E/L)

General Recommendation


Use Available Resources

Execute a Pilot Assessment

Make Adjustments

You have what you need! You will discover the weaknesses! You will improve your process!

ICH Q3D Modules 1 - 9

ICH Q3D Case Studies

Benchmarking Notes

Conference Notes

ICH Q3D Guideline

Plan Do

Check Act

Pilot

Questions


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