Regulatory Aspects of Impurities in Biological Products - IIR

Regulatory Aspects of Impurities in
Biological Products
Timothy K. Hayes, Ph.D.
Vice President, Analytical Chemistry / QRA
ProMetic BioTherapeutics, Inc.
&
Nadine Ritter, Ph.D.
Senior Consultant
Biologics Consulting Group, Inc.

Where is it written?
Presentation Outline
Classification of impurities in biological products
Focus on ICH Q6B
Example Approach to supporting Specifications
for Process Related Impurities

Where It Is Written
FDA has no specific guidance
ICH Web Site:
http://www.ich.org/cache/compo/276-254-1.html
ICH Q3 Series on Impurities in Pharmaceutical Products
excludes Biotechnology / Biological Products from scope
ICH Q6B – Specifications; Test Procedures; and Acceptance
Criteria for Biotechnology / Biological Products
ICH Q5C – Quality of Biotechnology Products: Stability Testing
of Biotechnology / Biological Products
ICH Q5D – Derivation and Characterization of Cell Substrates
Used for Production of Biotechnology / Biological Products
ICH Q5E – Comparability of Biotechnology / Biological Products
Subject to Changes in Their Manufacturing Processes

CMC Strategy Forum July 2004
Gold Sheet Vol. 38 No. 9 September 2004
F-D-C Reports
http://www.thegoldsheet.com/FDC/monthly/gold/PrevMenu.htm
CMC Strategy Forum White Papers (BioProcess
International) Defining Your Product Profile and Keeping
Control Over It
http://www.bioprocessintl.com/default.asp?page=cmc
Part 1: Simmerman and Donnelly (June 2005) Process Related
Impurities
Part 2: Champion, Madden, Dougherty, and Shacter (Sept 2005)
Challenges of Monitoring Host Cell Protein Impurities
Part 3: Boerner and Clouse (Oct 2005) Product Related
Impurities
Part 4: Broerson and Phillips (Nov 2005) Product Related
Impurities: Tackling Aggregates

ICH Q6B Overview
Specifications; Test Procedures; and Acceptance Criteria for
Biotechnology / Biological Products
August 1999
Outilines the nature and extent of elements needed to set
meaningful specifications for:
Test Methods
Process
Product
Specifications are the sponsor’s contract with regulatory authorities
Q6B defines the key CMC information that is required to support the
design of specifications throughout the entire product development
cycle
Acceptance Criteria and Specifications are based on:
The capabilities of the test methods
The capabilities of the process that produces the product
The nature of the lots of product produced for phase I-II-III clinical trials
The stability of the bulk substance and final biological product

Q6B Recognizes the Heterogeniety of
Biological Products

Q6B Defines Product-Related Substances

Q6B Defines Process-Related Impurities
Impurities derived from the process
Host cell proteins or source derived proteins
Host cell nucleic acids
Cell culture components
Antibiotics, chemical induction reagents (methyltrexate)
Medium components like transferrin or insulin
Down-stream process related impurities
Organic solvents and detergents (TNBP, tween, triton)
Column leachables (protein A, antibodies, small ligands,
metals)
Enzymes (proteases)
Denaturants (guanidine HCl)

Q6B Defines Product-Related Impurities
Variants of the product that arise during
manufacturing and/or storage that do not have
propertie comparable to those of the desired
product.
Product precursors
Product degradants
Fragments
Dimers, trimers, oligomers
Oxidation, deamidation, deglycosylation, etc.

Q6B Defines Contaminants
Adventitious Agents
Mycoplasma
Bacteria
Viruses
Prions*
Entotoxins and pyrogens
Inactivation and/or clearance for safety

Q6B Suggests a Specifications Design Record
for Impurities
Identify the impurity
Measure the impurity with suitable test methods
Assess safety risks of the impurity
Design the process to be capable of clearing or at least
reducing impurities of concern
Characterize / validate the process to understand and
demonstrate critical process parameters that yield
impurity control for the product
Submit impurity specifications that reflect an
understanding of impurity risk and process capability to
produce a product with safe impurity levels

Specifications vs Process Validation
CMC Strategy Forum July 2004
Consensus of attendees: validation of a
process to consistently remove or control
impurities could reduce the number of
specifications for a biotech product.
Process validation generally is not substantial
enough to reduce impurity specifications until
after phase III trials.

Process-Related Impurity Decision Tree and
Specifications Inspired by Q6B
Heather Simmerman of Amgen first suggested a
decision tree format at the CMC Strategy Forum,
July 2004
Basis in Q6B
Identify Impurity
Develop a suitable assay to measure the impurity
Assess the safety risk of the impurity
Understand the capability of the process to control the
impurity
Set meaningful specifications from the understanding
of critical process parameters that produce a product
with appropriate impurity characteristics

Question 1
Is the nature and source of the impurity known?
Have sensitive and broad detection methods been
used to discover impurities?
Yes- go to question 2
No
Demonstrate your impurity screening methods are not
insensitive and/or have narrow vision
Categorize the nature and source of the impurity
Process-Related, Product-Related, Contaminant
Inorganic, organic, biochemical, microbiological, physical
Cell substrate, cell culture, down-stream, adventitious

Question 2
Can you measure the amount of the impurity
with appropriate sensitivity, accuracy and
precision?
Yes – go to Question 3
No
Develop an appropriate method and monitor the
impurity at appropriate process points

Question 3
Is the impurity generally considered safe by the
industry and/or a qualified toxicologist familiar
with the area? Is the impurity within published
limits considering the dose and route of
administration?
Yes – No acceptance criteria is necessary,
provided that product quality or stability is not
compromised (Move to question 7)
No – move to Question 4

Is the impurity qualified by toxicology,
pharmacology, and safety data?
Yes – Question 5
Question 4
No – Perform studies to correlate, if possible, the
level of impurity with
Toxicological
Pharmacological effects
Consider
Route of administration
Dose and regimen
Duration
Target population

Question 5
Is the level of the impurity throughout the
process known?
Yes – Question 6
No
Measure the impurity at appropriate process points
Determine the reproducibility at the appropriate
process points
Is the stability of the impurity impacted by different
process variables? Adjust approach based on data.

Question 6
Is the level of the impurity below the qualified
safety level?
Yes – Question 7
No – Improve the process to reduce the impurity
to acceptable levels

Question 7
Would the impurity pose a significant safety risk if
present or does it affect the stability of the drug
substance?
Yes
Set acceptance criteria for impurity in drug substance
Base on pre-clinical and clinical safety studies and the process
capability to remove
Consider regulatory compendial requirements and guidance
documents
Establish mass balance for toxic additives
No
Consider setting in-process acceptance criteria or limits to
ensure control of process removal
If the impurity co-purifies, binds-to, or modifies the drug
substance, these controls are more important

Process Consistency
Major components of the impurity profile are
important considerations
Process-related impurities
Product-related impurities
Product-related substances
Comparability studies also rely heavily on
comparable impurity profiles

Q6B Suggests a Specifications Design Record
for Impurities
Identify the impurity
Measure the impurity with suitable test methods
Assess safety risks of the impurity
Design the process to be capable of clearing or at least
reducing impurities of concern
Characterize / validate the process to understand and
demonstrate critical process parameters that yield
impurity control for the product
Submit impurity specifications that reflect an
understanding of impurity risk and process capability to
produce a product with safe impurity levels