Egert Thomas - Session 1 - Parenteral Drug Association

Industry Working Group Update:
Extractables and Leachables in Parenteral
and Ophthalmic Drug Products (PODP)
Thomas Egert
PQRI-PODP Working Group and
Research Scientist, Boehringer-Ingelheim
PDA Europe Parenteral Packaging
March 11-12, 2014
Objectives
• Essentials of PQRI-OINDP Recommendations
• Parenteral and Ophthalmic Drug Product (PODP)
Working Group
– PODP hypothesis
– Concepts & Updates
• Toxicology sub-team
• Chemistry sub-team
• Biologics – Special Considerations
• Conclusions & Next Steps
2
E &L Complexity Affords Cooperation . . .
•
•
Facilitate scientific work that can’t be accomplished by a single
company or organization
Need for collaboration and consensus across industry and
regulatory bodies
3
Product Quality Research Institute (PQRI)
• Non-profit organization, established in 1996 as a vehicle to bring members
of the pharmaceutical industry, academia and the US Food and Drug
Administration (FDA) together to develop science-based approaches to
regulation
• Serves as forum for academia, industry and FDA to work cooperatively
 Member Organizations:
AAPS:
American Association of Pharmaceutical Scientists
CHPA:
Consumer Healthcare Products Association
FDA/CDER: U.S. Food and Drug Administration,
Center for Drug Evaluation and Research
HC:
Health Canada
IPEC:
International Pharmaceutical Excipients Council
USP:
United States Pharmacopoeia
4
PQRI OINDP E&L Working Group
2001 – 2006 PQRI OINDP
E&L Working Group
What are Orally Inhaled and Nasal
Drug Products (OINDP) ?
• Formed based on Points to
Consider response presented by
IPAC-RS
• Comprised of Chemists and
Toxicologists representing:
Industry (Pharma, CROs, Material
Suppliers), FDA, Academia




Metered Dose Inhalers
Dry Powder Inhalers
Inhalations Sprays & Solutions
Nasal Sprays
• Adressed significant gap:
In which way and how low do we have to
look for leachables ?
5
OINDP Outcome
Key Results:
•
Safety Concern Threshold
(SCT): 0.15 µg/day
(Setting the standard for
how low to look)
•
Best Practices for E&L studies:
 AET-Concept
 Identification Attributes
Decision Tree for Safety
Qualification
•
Note:
•
Not meant to be prescriptive
•
OINDP only
6
Application of AET to Chromatography
Application of SCT-derived AET exchanges “look as low as you can”…
500000
450000
400000
350000
300000
250000
200000
150000
100000
50000
0
13.50
14.00
14.50
15.00
15.50
16.00
16.50
17.00
Time-->
Adapted from C. Houston, Dec 2012
7
Application of AET to Chromatography
Application of SCT-derived AET exchanges “look as low as you can”…
500000
450000
400000
350000
AET
300000
Substances above the
AET must be identified
and reported to a
toxicologist for a risk
assessment
250000
200000
Substances below the
AET do not have to be
identified
150000
100000
50000
0
13.50
14.00
14.50
15.00
15.50
16.00
16.50
17.00
Time-->
…for a scientifically-justified, consistent standard for how low to look
Adapted from C. Houston, Dec 2012
8
Other dosage forms of ‘high’ or ‘highest’ concern exist
Degree of
Concern
Associated with
Route of
Administration
Highest
High
Low
Likelihood of Packaging Component-Dosage Form Interaction
High
• Inhalation Aerosals
and Solutions
• Injections and
Injectables
Suspensions
• Ophthalmic Solutions
and Suspensions
• Transdermal
Ointments and
Patches
• Nasal Aerosals and
Sprays
• Topical Solutions and
Suspensions
• Topical and Lingual
Aerosols
• Oral Solutions and
Suspensions
Medium
Low
• Sterile Powders
and Powders for
Injection
• Inhalation
Powders
• Topical Powders; • Oral Tablets
Oral Powders
• Oral Capsules
FDA Container Closure Guidance (May 1999)
9
From OINDP to PODP – What Makes The Difference?
Chemistry
Safety
• Materials
•
•
•
•
•
•
•
– Extractables &
Leachables Pool
• Drug product
formulation
characteristics
Administration Route
Dosing
Patient Population
Indication
Risk/Benefit-Ratio
…
Biologics
10
PQRI Parenteral and Ophthalmic Drug Products
(PODP) Leachables and Extractables Working Group
PROPOSED WORK PLAN , March 2008
Development of Scientifically Justifiable Thresholds
and Best Demonstrated Characterization Practices for
Leachables and Extractables in Parenterals and
Ophthalmic Drug Products (PODP)
Approved 2008
What Are PODP? (e.g., what’s in scope?):
• Prefilled syringes (PFS)
• Small and large volume parenterals (SVP, LVP)
• Ophthalmic solutions and suspensions
Adapted from: C. Houston, Dec 2012
11
Three Part PQRI-PODP Hypothesis (#1)
#1
OINDP Threshold concepts (not necessarily
thresholds) can be extrapolated to packaging systems
for PODP.”
#2
The ‘good science’ OINDP best demonstrated
practices can be extrapolated to packaging systems
for PODP.”
#3
“Threshold and best practices concepts can be
integrated into a comprehensive process for
characterizing packaging systems with respect to
leachable substances and their associated impact on
PODP safety.”
• Consistent with the principles of QbD and good science
12
PQRI-PODP Research Project Plan
Form toxicology and chemistry sub-teams to investigate hypothesis:
Hypothesis
#1
#2
#3
Who
Task
Toxicology Sub-Team
• Extrapolate OINDP SCT and
QT concepts to PODP
• Derive appropriate thresholds
Chemistry Sub-Team
• Extrapolate OINDP best
practices and AET concepts
to PODP
Tox. and Chem. Sub-Teams
in maximum harmony
• Integrate threshold and best
practice concepts into a
comprehensive process for
PODP container closure
characterization (QbD)
Adapted from: C. Houston, Dec 2012
13
Toxicology Sub-Team Update
14
General E&L Safety Assessment Workflow
Material
Composition
Controlled
Extraction
Study
Leachable
Study
Simulation
Study
Routine
Extraction
Testing
Identified Compound /
Substance class / Structural
subunit
•
•
•
•
•
Dosing
Patient Population
Indication
Risk/Benefit-Ratio
…
(1)
• Review Literature Data
• In-Silico/SAR-Assessment
(2)
• In Vitro / In Vivo Testing
• Animal Studies
Drug Product Specific Safety Assessment
15
Tox Sub-Team Strategy for PODP
• Do all PODP have the same safety concerns?
– Parenterals / Injectables:
• Systemic effects
• Cancer risk as a conservative endpoint (like OINDP)
– Ophthalmic solutions and suspensions:
• Local, topical effects
• Ocular irritation is a key endpoint
• Differences in PODP may drive separate
strategies
– Precedent: regulatory expectations between dosage
forms
Adapted from C. Houston, Dec 2012
16
Proposed Categorization of Compounds
SCT is an Identification Threshold
not a TTC (Threshold of Toxicological Concern)
Proposed - Pending Validation Class I &II
Threshold Level (µg/day)
Class I
Class II
Class III
150
5
1.5
Ongoing considerations:
• classification for systemic and topical effects
• Degree of information needed to support a compound
specific toxicological assessment
17
Chemistry Sub-Team Update
18
Chem Team: Extrapolating Best Practices
Guiding principles from PQRI-OINDP document have established as
‘field-tested’ elements for the E&L qualification process:
 Vigorous extraction with multiple solvents and extraction techniques
 Multiple analytical techniques
 Defined systematic process for identification
 Guided by an Analytical Evaluation Threshold (AET)
The majority of PODP are
represented by:
• aqueous based formulations
and exhibit
• potentially high daily doses
19
PODP Challenges when Extrapolating Best Practices
 Leachable Profiles differ substantially from
Extractables Profiles
 AET General Concept and Dilemma:
𝐴𝐴𝐴𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑉𝑉𝑉𝑉𝑉𝑉
= 𝑆𝑆𝑆 𝑥
𝑫𝑫𝑫𝑫𝑫 𝑫𝑫𝑫𝑫 𝑽𝑽𝑽𝑽𝑽𝑽
The AET gets lower as the daily administered
drug product volume increases !
20
PODP Identification Challenges
Daily Dose and the AET
Adapted from: D. Paskiet, Oct 2013
21
The Concept of “Simulated Solvents” will be Key for PODP
Simulation Study
Characterize candidates and assess their
worthiness for application; extractables as
tentative leachables
Simulation Study
Worst case simulation;
extractable as probable leachables
Filter:
Extractables ≠
Leachables
Product Assessment
Actual case,
measurement
of confirmed
Leachables
Jenke, D.; PDA J. Pharm. Sci Tech,
66/2, 168-83, 3/2012
22
Solvents Should Mimic Drug Product
• Cosolvents can be divided into two groups:
I Polarity Neutral
Primary function of excipient is
not drug solubilization
Generally compounds with high
aqueous solubility:
 Diluents (dextrose, saline)
 Buffers (acetate, lactate,
bicarbonate, phosphate)
 Amino acids
 Vitamins
Isoprapanol / Water
II Polarity Impacting
Components primary function is
to increase the solubility of the
drug:






Benzalkonium chloride (BAC)
Tween 80
Cyclodextrins
SDS
Lipids up to 20% wt/wt
Surfactants, Emollients
Aqueous
pH 2.5 / 9.5
Compound solubility is important !
23
How Simulation Studies Address the “AET Challenge”
• Simulation study
– Proper selection of a suitable medium / packaging system /
condition to simulate (or accelerate) final product interaction
– For PODP, not all extractables become leachables as is often
the case for OINDP
 Consider leachables solubility data and
focus on realistic scenarios
• Advantages for PODP
– Reduces number of extractables and provide more realistic
concentrations
– Simulated medium is less complex than drug product
formulation: facilitates analytical testing and ID
24
2009 – 2010 Experimental Phase I
• Intended scope:
– Small volume parenterals and prefilled syringes
• Controlled extraction studies on PODP materials
- 5 representative materials
- Development of standard protocol for CES
• Status:
– Laboratory work complete
– Results published
(PDA J Pharm Sci and Tech 2013, 67 448-511)
25
2011 – 2014 Experimental Phase II
• Intended scope:
– Large volume parenterals and ophthalmics
– Emphasis on simulated solvents (LVPs)
– Example of secondary packaging migration (label)
• Relevant to products in semipermeable containers like many
ophthalmics
• Protocol
– Materials: LDPE bottle, PP cap, rubber gasket, label
– Simulants: Aqueous pH 2.5, aqueous pH 9.5, 50/50 IPA/water
– Conditions: 1, 2, 6 months at 40°C / 75 % RH
• Status:
– Protocol completed
– Study results under evaluation
26
E&L and Biologics
27
Biologics Typically Differ from Traditional Small Molecules
• Large MW and Complex structure (e.g. Factor VII 300,000
DA; 3 different domains and glycosylated
• Abundance of both hydrophobic and hydrophilic sites may
render biologics more efficient extraction media
• Could be heterogeneous mixtures-analytical challenges?
• Produced by a complex manufacturing process employing
live organisms.
Adapted from:
Ingrid Markovic: Regulatory Perspective on E&L
USP/PQRI Workshop: Suitability and Compatibility for Packaging and Delivery Systems, Dec 9-10, 2013
28
Biologics: Risks Associated with E&L
• Quality considerations (e.g., interacting with the API or
exipients may negatively impact stability, etc.)
• Safety considerations (e.g., direct  due to toxicity;
indirect  due to effect on the API or excipients)
• Efficacy considerations (e. g., L interacting with a product
 loss of activity; L may induce development of
neutralizing activity via neutralizing Ab formation)
Adapted from:
Ingrid Markovic: Regulatory Perspective on E&L
USP/PQRI Workshop: Suitability and Compatibility for Packaging and Delivery Systems, Dec 9-10, 2013
29
Case Study: Indirect Metal – Protein Interaction
Fe Leachables Caused Protein-Preservative Adducts
Adapted from:
Ingrid Markovic: Regulatory Perspective on E&L
USP/PQRI Workshop: Suitability and Compatibility for Packaging and Delivery Systems, Dec 9-10, 2013
30
Understanding Materials
• Safety
– PQRI PODP Safety Thresholds (1.5ug TDI)
• Identification Process
• Qualification Process
– Best Practices
• Characterization Studies
• Simulation Studies
• Leachable Confirmation
• Drug / Biologic Quality
– Compatibility
– Stability
Patient – Product Focus
31
Timelines
OINDP
Recommendations
PODP
PODP
Plan
Adapted from:
Diane Paskiet; USP/PQRI Workshop: Suitability and Compatibility for
Packaging and Delivery Systems, Dec 9-10, 2013
32
Next Steps
• Combining Chemistry and Toxicology Findings
• Continue Global Outreach
• Recommendation Document
– Extraction Studies
– Considerations for Leachable Studies
– Safety Thresholds
– Biologic Considerations
• Quality and Stability
• Training Workshops
Sound Science Based on Risk
33
Acknowledgements
• PQRI Parenteral and Ophthalmic (PODP) Leachables and
Extractables Working Group
– Chair:
Diane Paskiet, Director of Scientific Affairs, West Pharmcetical Services
– Toxicology Sub Team Chair:
Douglas J. Ball, Research Fellow, Pfizer
– Chemistry Sub Team Chair:
Dennis Jenke, Ph.D. Baxter Distinguished Scientist, Baxter Healthcare
Corporation
– Development Technical Committee Liaison
Frank Holcombe, Jr., Ph.D. US Food and Drug Administration
• PQRI Member Organizations
All research work supported under the direction of PQRI
34
PODP Chemistry Sub-Team
•
•
•
•
•
•
•
•
•
•
•
•
•
Jim Castner, Ph.D., Pharma Interface Analysis, LLC.
Thomas Egert, Boehringer Ingelheim Pharma GmbH & Co. KG
Thomas Feinberg, Ph.D., Director, Structural Chemistry, Catalent Pharma Solutions
Alan Hendricker, Ph.D., Principal Scientist, Catalent Pharma Solutions
Christopher Houston, Ph.D., Senior Principal Scientist, Bausch & Lomb
Desmond G. Hunt, Ph.D., Scientist, Dept. of Standards Development, USP
Michael Lynch, Ph.D., Associate Research Fellow, Reg CMC, Pfizer
Ingrid Markovic, Ph.D., Division of Therapeutic Proteins, FDA
Kumudini Nicholas, Team Leader, Pharmaceutical Quality Review, Bureau of
Pharmaceutical Sciences, Health Canada
Daniel Norwood, Ph.D., Distinguished Research Fellow, Boehringer Ingelhgeim
Mike Ruberto, Ph.D., Material Needs Consulting, LLC
Art Shaw, Ph.D., Associate Research Fellow, Pfizer
Edward J. Smith, Ph.D., Packaging Science Resources, LLC
35
PODP Toxicology Sub-Team
•
Stephen A. Barat, Ph.D., Director, Toxicology and Operations, Forest Laboratories
•
Steve Beck, CEMDD Liaison, GlaxoSmithKline
•
William P. Beierschmitt, Ph.D., Associate Research Fellow, Pfizer
•
David Jones, Principal Scientific Officer, New Chemical Entities Unit, MHRA
•
Abigail Jacobs, Ph.D., Associate Director for Pharmacology/Toxicology, CDER, FDA
•
Jacqueline A. Kunzler, Ph.D., Director of Life Sciences Technology Resource
Division, Baxter Healthcare
•
Mary Richardson, Ph.D., Executive Director, Preclinical Development, Bausch &
Lomb
•
Tim Robison, Division of Pulmonary and Allergy Products, CDER, FDA
•
Alisa Vespa, Ph.D., Assessment Officer, Metabolism and Musculoskeletal Drugs
Division, Bureau of Metabolism, Oncology and Reproductive Sciences, Therapeutic
Products Directorate, Health Canada
36

Download Report