Risk-based Approach to evaluate Nitrosamines and Elemental Impurities from Single-use Components

Classification: Public
The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Risk-based approach for
evaluating nitrosamines &
elemental impurities
Janmeet Anant, Ph.D., PMP, RAC
Senior Regulatory Consultant
Plastic single-use components
Jessica Shea
Program Manager
Emprove® Program

The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

Agenda
1 Nitrosamines background and
risk factors to consider
2 Elemental Impurities and risk
factors to consider
3 Case data, information and
EMPROVE® dossiers
4 Conclusion - What are the
next steps?
Plastic single-use
components

Nitrosamines

Driving factors
Nitrosamine Contaminations found in APIs
Nitrosamines, e-Seminar | 30 June 2021
5
June 2018:
NDMA discovered, later NDEA and NDiPA.
Recalls worldwide, CEP suspensions
Since July 2018:
NDMA, NDEA, NMBA: other manufacturers,
several recalls, CEP suspension
Aug 2020:
API of biological origin with nitrosamines.
Nitroso-piperazines (MNP, CPNP) detected
at low levels: no market action
Sept. 2019:
NDMA detected. Several recalls (EU, US).
Suspension of MA (EU, US, April 2020)
Dec 2019:
NDMA found in metformine drug products.
Market actions in CAN, CHE, SGP.
May 2020: recalls in USA (ext-release)
Valsartan
Irbesartan, Losartan
Rifampin/Rifapentine
Ranitidine
Metformine
Change in API synthesis:
Nitrite / DMF solvent
Change in API synthesis.
Nitrite / DMF solvent /
N-containing bases
(?) bio/semisynthetic, vulnerable
amines in chemically synthetic
fragments.
NDMA formation likely due to
API degradation / in-vivo
formation
Nitrosamine formation during
DP production
(Putative) Root Cause
Corrective
Actions
Preventive
Actions
HA actions
EMA
Sept 2019

EMA expectations on MAHs:
• review all chemical and biological human medicines to
• identify and mitigate the risk of presence of nitrosamines
• Written response for risk evaluation (step1) by
o March 31st 2021 chemical medicines,
o July 1st 2021 biological medicines
o even if no risk is identified
 If nitrosamines are positively tested, the MAH must inform the
authority (irrespectively of the amount)
Other authorities (e.g., Health Canada, TGA Australia, MFDS Korea,
China, Japan, …) started an equivalent approach.
6
EMA Approach
Authorities call for Preventive Actions
Guidance for marketing authorization holders” on EMA page, EMA Assessment report Nitrosamine impurities in human
medicinal products EMA/369136/2020 and Questions and Answers document EMA/409815/2020 Rev. 3
Focus
 All Drug products
(chemical and biological
APIs)
 API manufacturers
shall support

3)
Changes
to the MA
1) Risk
Evaluation
 Conduct risk assessment for
the possible presence of
nitrosamines
 Conclude if risk of presence of
nitrosamines is identified
(Yes/No),
 If yes: -> Step 2
 Develop and validate test
method, perform tests,
 Inform the authority
immediately if the presence of
a nitrosamine is confirmed
− irrespectively of the amount
detected
− Develop a control strategy with
respect to acceptable intake limits
Changes to the Marketing
Authorization (MA):
 Liaise with competent authorities in
order to evaluate the type of
variation needed
 Demonstrate efficiency of
amendments to the manufacturing
process / specifications / testing
procedures
2) Confir-
matory
testing
Approach of EMA
Three-Step Process
FDA guidance
also applies a
3-step process
7

How to conduct the Risk Assessment on Nitrosamine formation?
Assess the Components, their Interaction, and Cross-Contamination
1
2
3
4
5
Key
Questions
for each reaction component
and their interaction –
risk for Nitrosamine formation
or contamination?
Is there any amide or
ammonium salt used
or present in the
manufacturing process?
Is there any a secondary
or tertiary amine present
in the manufacturing
process. Consider amines
as potential impurity or
by-product?
cross-contamination risk:
- Multipurpose equipment?
- Is this used for manu-
facturing of materials
involving nitrites?
- Use of recycled/ recovered
solvents (DMF), amine,
reagents, catalyst?
Are nitrites (or organic
nitro components) used
in the manufacturing of
the material or are
potential impurities?
Are the reaction conditions
suitable for Nitrosyl cation
formation? Weak acidic
conditions? Are nitrosyl
cations possible by-products?

9
FDA Guidance on Nitrosamines
Issued 1 Sept 2020
For immediate implementation
- Root causes for nitrosamine contamination
- Addresses nitrites in excipients as potential precursors
- Acceptable intake Limits
- Recommendations to API and Drug Product manufacturers
- deadline for risk evaluation: 31 March 2021
(within six months of publication, adjusted later to end of March)
- No FDA requirement to submit the result of the risk
evaluation, in contrast to EMA!

What comes with the 2020 guideline updates?
Nitrosamine Risk Evaluation
risk assessment for
biologic products
- Focus on biologics w/
“synthetic fragments”
- FDA: biologics not
mentioned, but not
scoped out
Potential precursor for
nitrosamine formation in
drug products
Relevant for customer’s
risk assessment
 Pharma Ind. consortium
builds up excipient
database for NO2
- level
 No general
“concentration of
concern” for nitrites or
nitrates
1 2
Additional
Focus areas
addressing the risk for
nitrosamine formation
in the drug product
10
Nitrite Content
Biologic Origin

Nitrosamine Contamination
Intrinsic and Extrinsic Risk Factors
11
Intrinsic:
Nitrosamine contamination as a
chemical property of a given
manufacturing or degradation process.
Manufacturing process
Raw materials
Reagents, process aids, catalysts
Water quality
Degradation during storage
Extrinsic:
Nitrosamine contamination is
not inherent to a given manufacturing
or degradation process.
Cross contamination, lack of cleaning of
multipurpose equipment
Recycled solvents (degradation,
contamination)
Cleaning agents
Packaging materials
Operator-related errors

Factors and Mitigation Actions to Consider
Risk Assessment – Nitrosamines
Three ways to change manufacturing materials without regulatory approval | 26th Aug, 2021
LOW
RISK
HIGH
RISK
Filters
No intrinsic or
extrinsic
nitrosating agents
No intrinsic
nitrosating agents
Excipients
Biologic
Manufacturing
with Synthetic
Fragments
Biologic
Manufacturing
Chemical
Manufacturing
Process
Single-
Use
APIs, Starting
Materials
CAUTION: Nitrocellulose materials, in combination
with printing inks, heat or energy. Rubber materials
and latex should also be evaluated.

Elemental
Impurities

Elemental Impurities
Fe, Co, V, Ni?
from equipment?
Platinoids, etc.
from metal
catalysts?
As, Cd, Pb, Hg?
from natural/
environmental sources?
March 2015 © Copyright Merck KGaA, Darmstadt Germany

Elemental Impurities
Scope
• ICH, USP, EMA, PhEur: all involved in development of
guidelines/chapters
Involvement
• Through IPEC we have been following the developments closely
from beginning
• Part of “Coalition for Rational Implementation”
Preparing Information | Testing
• Tests, equipment
• We will support providing information for the risk-based control
strategy on Elemental Impurities (Emprove products)
CONFIDENTIAL

Valid
Finalized
Finalized
Europe
EMEA/CHMP/SWP/4446/2000
In force since Sept 2008
(for new drug products)
USA
USP chapters <232>, <233>,
Applicable as of 1 Jan 2018
International
Current Regulations on Elemental Impurities
ICH Q3D: Finalized Dec 2014
EU: June 2016 new DP
Dec 2017 existing DP
March 2015 © Copyright Merck KGaA, Darmstadt Germany

18
New Obligations of the Drug Product
Manufacturer
Prepare a risk assessment
Develop controls for elemental impurities
− The limits are specified only for drug products!

19
Scope of ICH Q3D guideline
ICH Q3D Elemental Impurities include additional
contaminants that occur naturally or are introduced by
interaction
Scope of
ICH Q3D
Elements added
intentionally
(reagents, catalysts)
Elements introduced
by interaction (e.g.
with manufacturing
equipment or container
closure system)
Elemental impurities may
occur naturally
(e.g. starting materials
from natural sources
→ already in the scope of
the EMA guideline
New aspect: New aspect:

20
Risk assessment for the drug product – perspective of
drug product manufacturer
Metal impurities
in drug product
Drug substance
Water Manufacturing
equipment
Excipient 1
Primary packaging
material
Excipient 2
source
environ-
ment
materials
manufactur.
process
source
environ-
ment
materials
manufactur.
process

Elemental Impurities – Link to Manufacturing
• Class 1: The elements, As, Cd, Hg, and Pb, are human toxicants that have limited or no use in the
manufacture of pharmaceuticals. Their presence in drug products typically comes from commonly used
materials (e.g., mined excipients).
• Class 2A – Need risk assessment based on high probability
• Class 2B – No need for risk assessment, if not intentionally added.
Potential elemental impurities derived from manufacturing equipment: The contribution of
elemental impurities from this source may be limited and the subset of elemental impurities that should
be considered in the risk assessment will depend on the manufacturing equipment used in the production
of the drug product.
Source: ICH Q3D, step 4
Presentation title in footer | 00 Month 0000 Arial 8pt
21

5.7 Special Considerations for Biotechnologically-Derived Products
For biotechnology-derived products, the risks of elemental impurities being present at levels
that raise safety concerns at the drug substance stage are considered low. This is largely
because:
a) elements are not typically used as catalysts or reagents in the manufacturing of biotech
products;
b) elements are added at trace levels in media feeds during cell culture processes, without
accumulation and with significant dilution/removal during further processing;
c) typical purification schemes used in biotech manufacturing such as extraction,
chromatography steps and dialysis or Ultrafiltration-Diafiltration (UF/DF) have the
capacity to clear elements introduced in cell culture/fermentation steps or from contact
with manufacturing equipment to negligible levels.
22
As such, specific controls on elemental impurities up to
the biotech drug substance are generally not needed.
Source: ICH Q3D, step 4

Elements of Concern biologics manufacturing systems –
Information taken from ICH Q3D
23
Element Class
If intentionally
added (all routes)
If not intentionally added (Limit in PDE ug/day)
Oral Parenteral Inhalation
Cd 1 yes yes 5 yes 2 yes 2
Pb 1 yes yes 5 yes 5 yes 5
As 1 yes yes 15 yes 15 yes 2
Hg 1 yes yes 30 yes 3 yes 1
Co 2A yes yes 50 yes 5 yes 3
V 2A yes yes 100 yes 10 yes 1
Ni 2A yes yes 200 yes 20 yes 5
Li 3 yes no 550 yes 250 yes 25
Sb 3 yes no 1200 yes 90 yes 20
Cu 3 yes no 3000 yes 300 yes 30
Sn 3 yes no 6000 no 600 yes 60
Cr 3 yes no 11000 no 1100 yes 3
Ba 3 yes no 1400 no 700 yes 300
Mo 3 yes no 3000 no 1500 yes 10

Leaching of elemental entities that are present in
pharmaceutical manufacturing systems
Extractables and Leachables Safety Information Exchange (ELSIE) Consortium & International Pharmaceutical
Aerosol Consortium on Regulation and Science (IPAC-RS) has conducted a review of the available literature on
elemental entities in pharmaceutically relevant polymers and the presence of these elemental entities in
material extracts and/or drug products.
(Jenke, D.R., et al., PDA J Pharm Sci and Tech 2015, 69 1-48)
QUESTIONS:
(1) What elemental entities are present in the relevant polymers and materials and at what levels
are they present?
(2) To what extent are these elemental entities leached from these materials under conditions
relevant to the manufacturing and storage/distribution of drug products?
24

Leaching of elemental entities that are present in
pharmaceutical manufacturing systems
CONCLUSIONS:
(1)Elemental entities are present in the materials used to construct packaging and manufacturing
systems as these materials either contain these elemental entities as additives or are exposed to
elemental entities during their production.
(2)Unless the elemental entities are parts of the materials themselves (for example, SiO2 in glass) or
intentionally added to the materials (for example, metal stearates in polymers), their incidental
amounts in the materials are generally low.
(3) When elemental entities are present in materials and systems, generally only a very small fraction of
the total available amount of the entity can be leached under conditions that are relevant to packaged
drug products.
Source: Jenke, D.R., et al., PDA J Pharm Sci and Tech 2015, 69 1-48
25

2020 Update article on Elemental Impurities from Plastic
Packaging and Manufacturing Systems
Presentation title in footer | 00 Month 0000
26
Question Conclusion
Elemental entities
present and at what
levels?
• Intentionally used in materials or additives.
(potentially significant but targeted studies to
minimize risk)
• Known or inferred from materials, additives or
manufacturing of systems. (low)
To what extent are
elements leached from
these materials under
conditions relevant to the
manufacturing, storage
and distribution?
• Risk that elemental entities accumulate (leach)
at levels sufficiently high to produce an adverse
effect is low, even when significant amounts are
present.
• The information in this 2020 update paper could
be used for a risk assessment – no testing
required!
Source: Jenke, D.R. Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities
in Packaged Drug Products: An Updated Literature Review. PDA J Pharm Sci and Tech 2020, 74: 324-347.

Leaching of elemental entities that are present in pharmaceutical
manufacturing systems (update 2020)
Jenke, D.R. Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in
Packaged Drug Products: An Updated Literature Review. PDA J Pharm Sci and Tech 2020, 74: 324-347.
...it is unlikely that manufacturing and packaging systems are major
sources of elemental impurities in drug products. Although this
statement was generally true for pharmaceutical packaging, it
was unilaterally true for single use components used in
biopharmaceutical manufacturing. The validity of these statements,
supported by the information obtained in this and the previous review,
suggested that screening of packaging and especially
manufacturing systems for all possible extractable elements
generally serves no useful purpose, as packaging and
manufacturing systems were generally not an important source of
elemental impurities in drug products.
27

Further Confirmation - Internal Leachables
Study of a Fully Single-Use Process
• 200 L Single-Use Bioreactor batched with Cell Culture Media
• Full-scale operations with all devices/resins
• All unit operations utilized single-use systems & flow paths
• All process buffers prepped & stored in SU bags
• Sampling from each buffer bag/process intermediate pool
• Analysis of Samples included ICP for metals (elemental impurities)
RESULTS:
Bioreactor samples (up to 13 days of incubation) – No elements
were detected by ICP analysis except those which are part of the
media formulation.
Bulk Drug Substance samples (up to 7 days storage) – No
elements were detected by ICP analysis.
28

Factors and Mitigation Actions to Consider
Risk Assessment – Elemental Impurities
Three ways to change manufacturing materials without regulatory approval | 26th Aug, 2021
LOW
RISK
HIGH
RISK
Filters
Excipients
Steel Systems
Single-
Use
APIs, Starting
Materials
NOTE: Use industry knowledge and
supplier information for risk assessment.

Poll Question
The Emprove® Program 2021
31

32
1. Question?
a)
b)
c)
d)
f)

Case Data,
Information
Emprove®

Emprove® Portfolio for Filtration and Single-Use
Qualification of Materials and Vendors
Operational Excellence
Dossier
 Full Extractables profile
 Elemental Impurity (ICH Q3D)
 Analytical procedure
Supports process optimization
Material Qualification
Dossier
 General information
 Manufacturing flow chart
 Product characterization and qualification
 Specification, release criteria
 Biological Reactivity and Endotoxin
Testing
 Materials of construction
 Extractables summary
 Regulatory statements (AO, BPA,
Nitrosamine)
Information to start a material
qualification
Quality Management
Dossier
 Quality Self Assessment
 Supplier and CMO management
 Shelf life testing and results
 Sterilization Information
 Packaging and Sterility Validation
Answers questions during risk
assessment
34
 Filtration Products grouped by product families
 Single-Use grouped by component type

Nitrosamine Risk Evaluation
Title of Presentation | DD.MM.YYYY
35
➢ Nitrosamines and other chemicals of concern are not
purchased for manufacturing of single-use assembly and
filtration device products.
➢ No rubber are utilized for fluid contact materials of
construction.
➢ No latex materials in our single-use and filtration
products.

Emprove® Extractables Test Strategy
Elemental Impurities Testing
BioPhorum
Requirements*
USP <665> draft (Sep, 2020)
Emprove® Program
Approach
Scope Single-use components in
contact with fluid path (for
biopharmaceutical
manufacturing)
Single-use and multi-use components
and devices with fluid path contact (for
pharmaceutical and biopharmaceutical
manufacturing)
Single-use and multi-use
components and devices with
fluid path contact, all relevant
existing and new products
Solvents
1)50% Ethanol
2)0.5N NaOH
3)0.1M Phosphoric Acid
4)WFI
1) 0.2M KCl, pH 3 (C1)
2) 0.1M Phosphate buffer, pH 10 (C2)
3) 50% Ethanol (C3)
1)50% Ethanol
2)0.1M Phosphate buffer, pH 10
3)0.1M Phosphoric Acid
4)WFI
5)0.5N NaOH (when compatible)
Analytical
methods
HPLC-PDA/MS (APCI, ESI, +/-)
ICP/MS, GCMS-DI, GCMS-HS
(TOC, pH, NVR)
Described in USP <1663>. Broader
scope in methods selection.
= BioPhorum
Additionally: IC
Time points 1-3, dependent on component 1, dependent on component = BioPhorum + USP <665>
Pre-
treatment
…‘should be pre-treated the
same way before … extractables
testing…‘
“…tested when they have been
conditioned or processed in a manner
consistent with their intended use and
as specified in the manufacturer's
instructions for use.”
 Separate tests and reports for
gamma irradiation or autoclave
pre-treatment
 No pre-flush unless required
(worst case)
* BPOG protocol revised in April 2020, now BioPhorum Best Practices Guide

Operational Excellence Dossier
Detailed information as per BioPhorum
37
Elemental Impurities including:
▪ ICH Q3D
▪ Additional elements for
product quality (when
available)

No Class 1
Elements
Trace Levels
for Other ICH
Q3D elements
All Elements
significantly
below PDE
General Summary of Elemental Impurity Results
38

39
Review of Emprove® Data for Elemental Impurities
Pureflex® and
Pureflex ® Plus Film
• Barium –Class 3
Element Identified
Millipak ® Final Fill
0.22µm and
0.45µm
• No ICH-Q3D
Elements
Identified
Lynx ® ST and S2S
Connectors
• No ICH-Q3D
Elements
Identified for Lynx
® S2S
• Tin –Class 3
Element Identified
in Lynx ® ST
Millipore Express®
SHC, SHF, SHR
Opticap® XL Filters
• No ICH-Q3D
Elements

Elemental Impurity assessment
Risk based approach – Risk Mitigation
Potential patient exposure can be calculated based on process conditions, total surface in
contact with the product, product batch size and final DP max daily dose.
Analytical data
•Analytical concentration or amount of
extractables per surface unit
•Surface-to-volume ratio used for extraction
•Extraction volume used/dilution factor
applied
Potential
concentration in
the process
• Minimum batch size
Potential level of
extractables in the
DP
Potential
daily
exposure
•Correlate with dose and
posology
•Correlate with PDE
• Total surface in contact with
the product
• Normal operating volume
40
1. Correlate data to the estimated
potential max conc. level in the
product.
2. Consider the max daily dosage
for the DP and the route of
administration.
3. Establish the max potential
intake to evaluate potential
toxicity.
Daily Exposure (µ𝑔 𝑝𝑒𝑟 𝑝𝑒𝑟𝑠𝑜𝑛/𝑑𝑎𝑦) =
𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝐸𝑥𝑡 (𝑚𝑔)
𝑣𝑜𝑙𝑢𝑚𝑒/𝑏𝑎𝑡𝑐ℎ 𝐿
× max 𝑑𝑜𝑠𝑒 (𝑚𝐿)

41
Case Study

42
Barium evaluation in Pureflex ® Plus Film
Exposure Scenario
Parameters Volume
Bag Size 100 L
Fill Volume 50 L
Surface Area 2300 cm2
Barium Concentration 0.033 (µg/cm2)
Potential Barium 76 µg or 0.076 mg
0.076 mg
50 L
0.0015 mg/L or (µg/mL)

Elements of Concern biologics manufacturing systems –
Information taken from ICH Q3D
43
Element Class
If intentionally
added (all routes)
If not intentionally added (Limit in PDE ug/day)
Oral Parenteral Inhalation
Cd 1 yes yes 5 yes 2 yes 2
Pb 1 yes yes 5 yes 5 yes 5
As 1 yes yes 15 yes 15 yes 2
Hg 1 yes yes 30 yes 3 yes 1
Co 2A yes yes 50 yes 5 yes 3
V 2A yes yes 100 yes 10 yes 1
Ni 2A yes yes 200 yes 20 yes 5
Li 3 yes no 550 yes 250 yes 25
Sb 3 yes no 1200 yes 90 yes 20
Cu 3 yes no 3000 yes 300 yes 30
Sn 3 yes no 6000 no 600 yes 60
Cr 3 yes no 11000 no 1100 yes 3
Ba 3 yes no 1400 no 700 yes 300
Mo 3 yes no 3000 no 1500 yes 10

Patient Safety Evaluation – Element and Process
Specific
44
Barium
Concentration
(µg/mL)
Dosage
(mL)
Patient
Exposure
(Total µg/dose)
PDE Limit
(µg/day)
0.0015 10 0.015 700
0.0015 100 0.15 700
4,000-4,0000x lower than the PDE

Conclusion

 Single-Use Manufacturing has negligible risk
for Nitrosamines based on intrinsic and
extrinsic risks
 Single-Use Manufacturing has negligible risk
for Elemental impurities being at any level of
concern
 Demonstration from the case study shows
levels are 4,000 – 40,000x lower than the
safety threshold
46
Conclusion

© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. The vibrant M, Millipore and BioReliance are trademarks of Merck
KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is
available via publicly accessible resources.

Risk-based Approach to evaluate Nitrosamines and Elemental Impurities from Single-use Components

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