View
228
Download
0
Category
Preview:
Citation preview
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
Resources
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 4
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!
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 5
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!
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 6
An Example Approach
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 7
Global Assessment Confirmation Life Cycle Strategy Example Testing Management
Strategy
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 8
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
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 9
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.
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 10
Risk Assessment
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 11
Assessment Template
Product Profile
Standard Risk Assessment
Risk Questions
Summarize Controls
Risk Time
ICH Q3D Alignment
Drug Product
Alignment
Risk Assessment Example
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 12
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
Excipients
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 14
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
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 15
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)
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 16
EI = Elemental Impurities COA = Certificate of Analysis
NO
YES
Primarily Lilly data, 3
lots
Excipients
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 17
Section of template:
Link to Supplier
Responses
Instructions
Drug Product (Confirmation) Testing
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 18
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
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 19
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
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 20
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
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 21
E/L = Extractable or Leachable
Challenges
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 23
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
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 24
Structure Recommendation
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 25
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
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 26
Standard Risk Assessment
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
11/16/2016 Company Confidential ©2015 Eli Lilly and Company 27
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
Recommended