elemental impurities testing: its role in compliance, analysis … · 2015-10-27 · elemental...
TRANSCRIPT
Elemental Impurities Testing:
Its Role in Compliance,
Analysis Components,
and Industry Collaboration around
Technical Challenges
Donna Seibert, PhD
on behalf of the
Technical and Analytical Challenges Sub-team
to the Coalition for Rational Implementation
AAPS
October 27, 2015
EI Risk Assessment Components • Model on ICH Q3D
– Illustrative examples in Appendix 4
– Scientifically sound assessment of risk
• Product Information
– Identify raw materials and weight percent in formulation
– Identify maximum daily dose and route of administration
• Documentation Review
– Sources of raw materials and related risks
– Intentionally added elements
– Potential elements from manufacturing and container closure
• Data
– Raw material or finished product
– Example: 1-6 lots of raw materials or finished products depending on
pre-assessment of risk
• Manufacturing, container closure, water
– Data
– Position papers??
2
• Literature
• Supplier Information
• Pooled Data
Fit for Purpose Methods
• Risk Assessment
– Screening methods
– Wide range of elements
• General screen (15-24 EIs)
• Target elements of interest
– Quantitative or semi-quantitative
– Typically not fully validated
3
• Formal Control
– Limit tests or quantitative tests
– Specific elements in specific products or materials
– Fully validated
– Methods & validation reports included in NDA/ANDA
filings
Elemental Impurities Testing
Challenging Terrain
• Key challenge for industry and the regulatory community
– Analytical testing required to quantitate elemental impurities in drug products, APIs and excipients down to the levels listed in USP <232> and/or ICH Q3D guideline.
• Variety and complexity of pharmaceutical samples
• Many labs expanding capabilities
– Pharmaceutical labs adapting to ICP-MS analysis
– Existing spectroscopy labs adapting to the requirements of <233>
• Technical/Analytical Challenges Project Team formed in 2013 as a sub-team of the Coalition for Rational Implementation
TECHNICAL/ANALYTICAL CHALLENGES PROJECT TEAM
Sub-Team Objectives:
• Communicate the complexity of ICP/MS methodology (including,
as appropriate, difficult and/or hazardous sample preparation
studies) and portray a realistic picture of the technique for the
benefit of industrial partners as they build expertise in elemental
impurities analysis
• Compile, elucidate, and bring visibility to technical and analytical
challenges that RM suppliers and FP manufacturers are facing
during implementation of USP/ICH Elemental Impurities controls.
• Bring industrial, regulatory, and academic partners together to
propose solutions to analytical challenges wherever possible.
5
TECHNICAL/ANALYTICAL CHALLENGES PROJECT TEAM
Team Chartered June 2013
Membership (42+ colleagues)
• Comprised of scientists from
– Coalition companies
• 5 pharmaceutical companies
• 7 raw material suppliers (API/excipient)
– 8 Contract laboratories
– 1 Government laboratory
– 1 University laboratory
Analytical Testing Considerations
• Sample Preparation
– Ensure appropriate solution preparation
– USP <233> suggests
• neat solution
• direct solution (aqueous or organic)
• indirect solution via closed vessel (microwave assisted)
• Instrumental Analysis
– System suitability/data integrity
– Options for sample introduction and interference reduction
– Data interpretation
7
Total Metal Extraction vs.
Acid Leach Methodology
8
Total Impurities = present in any form
Bioaccessible = soluble in digestive juices
Bioavailable = reach systemic circulation
Total Impurities ≥ Bioaccessible ≥ Bioavailable
“Total metal extraction is the preferred sample preparation approach
to obtain an indirect solution.” 2S (USP38)
“Alternatively, leachate extraction may be appropriate with justification
following scientifically validated metal disposition studies, which may
include animal studies, speciation, or other means of studying
disposition of the specific metal in the drug product.” 2S (USP38)
Courtesy: F. Walker, Chemical Solutions
Total Metal Extraction vs.
Acid Leach Methodology
Acid Leach methodologies
– Intended to assess bioaccessible or bioavailable levels of elemental
impurities in a material
– Typically use less aggressive conditions—heating blocks, shakers,
rotators
– Often used in environmental and food industries
– Allowed by USP <233> with supporting data
9
Courtesy: F. Walker, Chemical Solutions
Total Metal Extraction vs.
Acid Leach Methodology
Total Metal Extraction
– Not defined in USP <233>
– Intended to analyze all elemental impurities contained in the sample? Or
all that can be extracted?
– Typically use aggressive condition
– Requirement for full dissolution of the sample matrix resulting in a clear
solution
• Not explicitly stated in USP <233>
• Required by EP 2.4.20
10
Example Microwave Digestion Conditions
With HF
Load
–0.25 grams of sample
–1.5 mL 70% HNO3
–1.5 mL 49% HF
Heat
–30 minute ramp to 250 °C
–20 minutes @ 250 °C
Dilute
–to 20 mL with DI water
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Default Digestion
Load
–0.25 grams of sample
–3.0 mL 70% HNO3
–0.5 mL 37% HCl
–3.0 mL 30% H2O2
Heat
–15 minute ramp to 140 °C
–5 minutes @ 140 °C
–10 minute ramp to 240 °C
–10 minutes @ 240 °C
Dilute
–to 50 mL with DI water
ICP/MS Analysis
• Prepare Instrument for Analysis
– Daily performance checks
– Plasma alignment, MS tuning, etc.
• Sample Introduction & Instrument Parameters
– Accessories, reaction gasses & collision cells
• Interference reduction
– Internal standards
• Selected by isotopic mass or ionization potential
– Correction equations
• Calibration & LOQ
– Blank, 0.5J and 1.5J calibration standards (minimally)
– Multiple sets of standards may be needed to cover required elements
– LOQ can be a concern
• For some finished products (e.g., liquid products with large MDDs)
• When analyzing raw materials
Typical Sequence Including
System Suitability & Calibration
13
Solution Purpose/Description Requirement
Calibration Standards (5 + blank) Establish Curve r2 NLT 0.99
ICV (Initial Calibration Verification) Midpoint Std Readback w/i 80-120% of theor. conc.
ICB (Initial Calibration Blank) Carryover Check below lowest calibration std
Samples (max 10)
Preparation Blank below lowest calibration std
LCS (Lab Control Sample) Digested, spiked blank w/i 70-150% of theor. conc.
Sample (1)
Pre-digestion Spike (PDS, 1) Matrix spike w/I 70-150% after subtraction of
indigenous EIs
Remaining Samples (2-4) + PDS
CCV (Continuing Calibration Verification) Midpoint Std Readback w/i 80-120% of theor. conc.
CCB (Continuing Calibration Blank) Carryover Check below lowest calibration std
Remaining Samples & CCV/CCB
Data Interpretation
Data review
• Recognition of issues
– Instrument drift
– Carryover/memory effects
– Interferences or element-specific pitfalls
– Non-ideal recoveries
• Reportable data
– Use of multiple modes and/or reaction gasses possible
– Can require data selection
14
Analytical Considerations—Conclusions
• Clearly define goal of testing
– Screening for risk assessment or formal control
• Clearly define type of digestion
– Total metal extraction or acid leach
• Understand materials and how matrix can affect analysis
– Dissolved solids, undigested carbon, etc.
• Get to know your analyst!
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Inter-laboratory Collaborative Study Overview
OBJECTIVES:
To provide a DATA-DRIVEN way to discuss technical aspects
of ICP-MS testing for elemental impurities
• Inter-laboratory data comparison for standardized samples
• Inter-laboratory evaluation of effectiveness of microwave digestion
• Compare bio-relevant leach/extraction techniques to total metal
extraction
• Determine the correlation (good or bad) between the summation of
individual component results vs. testing the formulated tablet
PARTICIPANTS:
• 13 member laboratories participated in the collaborative study
• Blinded participation was a pre-requisite for several laboratories
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Inter-laboratory Collaborative Study Overview
SAMPLES:
• Two Treatment Groups
• Group A Tablets contained native EI levels originating from
excipients
• Group B Tablets were spiked with ICH Class 1 & 2A elements
• As, Cd, Pb, Hg, Mo, Co, Se, V
• Tablets designed with an intended MDD of 1 g, so that material
concentration (ug/g) and ICH limit (ug/day) could be plotted on the
same scale
METHODS:
• Uniform method—a defined set conditions intended to be run at
each lab
• Non-uniform methods—methods of choice for participating labs
Uniform Digestion—Arsenic
Mean (ppm): 0.57 1.47
STD: 0.98 0.91
RSD (%): 172 62
ND values: 12 0
Native Enhanced
Blue points are below LOQ,
Error bars set at 1.5 x Interquartile Range
o Open circles indicate outliers
Uniform Digestion—Lead
Mean (ppm): 1.07 3.12
STD: 0.35 0.75
RSD (%) 33 24
ND values: 3 1
Native Enhanced
Blue points are below LOQ,
Error bars set at 1.5 x Interquartile Range
o Open circles indicate outliers
Data Refinement—Lead by Uniform Digestion
Original
07-Jan-2015
Updated
05-Mar-2015
• Orange data points indicate outliers o Open circles indicate outliers
pp
m
Error bars set at 1.5 x Interquartile Range
Data Refinement—Lead by Uniform Digestion
Original
07-Jan-2015
Updated
05-Mar-2015
• Orange data points indicate outliers o Open circles indicate outliers
pp
m
Error bars set at 1.5 x Interquartile Range
Labs benefit from having comparator samples
Summary Statistics—All Methods
Element Mean
(ppm) STD RSD
(%)
As 0.16 0.05 33.94
Cd 0.02 0.04 204.28
Pb 0.88 0.14 15.37
Hg 0.06 0.07 116.52
Co 0.23 0.19 84.48
Mo 0.09 0.14 161.22
Se 0.16 0.22 137.59
V 0.85 0.50 58.57
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Element Target
(ppm) Mean
(ppm) STD RSD
(%)
As 1.77 1.25 0.27 21.65
Cd 0.38 0.36 0.06 15.78
Pb 1.58 2.87 0.38 13.27
Hg 1.30 0.31 0.09 27.95
Co 1.62 0.75 0.08 11.30
Mo 0.72 1.38 0.50 36.29
Se 1.46 0.59 0.48 80.68
V 3.10 2.14 0.40 18.80
Non-uniform, Native Levels Non-uniform, Enhanced Levels
Element Mean
(ppm) STD RSD
(%)
As 0.57 0.98 171.55
Cd 0.01 0.03 195.67
Pb 1.07 0.35 32.60
Hg 0.47 1.68 360.71
Co 0.17 0.03 18.39
Mo 0.17 0.22 134.02
Se 0.23 0.33 142.98
V 1.91 1.98 103.41
Element Target
(ppm) Mean
(ppm) STD RSD
(%)
As 1.77 1.47 0.91 61.84
Cd 0.38 0.38 0.13 33.40
Pb 1.62 3.12 0.75 24.00
Hg 1.30 0.37 0.17 46.00
Co 0.72 0.67 0.19 28.67
Mo 1.58 1.47 0.41 28.02
Se 1.46 0.57 0.38 66.39
V 3.10 2.67 1.69 63.15
Uniform, Native Levels Uniform, Enhanced Levels
Non-Uniform Methods using HF—Lead Results
• 6 HF methods vs. uniform
digestions
• Limited ability to generate clear
digestates (total digestion)
• No discernable increase in
extraction of Pb from tablets with
native levels
23
Native
pp
m
Non-Uniform Methods using HF—Lead Results
• 6 HF methods vs. uniform
digestions
• Limited ability to generate clear
digestates (total digestion)
• No discernable increase in
extraction of Pb from tablets with
native levels
24
Native
Use of HF does not guarantee clear digestate or “total” digestion
pp
m
RM Summation vs. Tablet Testing
(Native Levels, Uniform Digestion) • Outliers highly affected means for finished product analysis
(16.8% of all reported values were classified as outliers)
Raw Materials Analysis
Finished Product Analysis
Outlier Analysis
Through calculation of Odds Ratios:
• Tablet Type
– Tablets with native levels and those with enhanced levels of were not
distinguishable in frequency of outliers
• Microwave Type
– Individually pressurized vessels (IPV) vs. single reaction chamber (SRC)
systems showed that IPV systems are 6.7 times more likely to produce
outliers than SRC systems
• Correction Equations
– Use of correction equations for certain elements reduced the odds of
producing outliers by 7.7 times
26
Data Overview
• All elements across all labs
• Statistical analyses* indicate
that the variability for each
element across labs is
significantly higher with the
uniform method than the
non-uniform method
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* Measurement Systems Analysis and Assessment of Variability
Native Enhanced
Data Overview
• All elements across all labs
• Statistical analyses* indicate
that the variability for each
element across labs is
significantly higher with the
uniform method than the
non-uniform method
28
* Measurement Systems Analysis and Assessment of Variability
Labs perform best when methodology is optimized for their instrumentation
Native Enhanced
Inter-Laboratory Study Conclusions
• Data for standardized samples show high variation across
laboratories
• Labs benefit from access to standardized evaluation samples
• Comparison of summation approach and finished product testing is
confounded by low levels of native elements and high influence of
outliers
• Outlier analysis shows that microwave type may affect results and
use of correction equations is beneficial for some elements
• Tighter variation among non-uniform methods suggests need for
flexibility in methodology for testing labs
29
On-going and Future Work
• Publication of Phase I results
– Drafted
• XRF investigation on existing tablets (4 participating labs)
– Experimental planning and material distribution complete
– Sample testing is in progress
• Phase II testing
– Build on results and learnings from Phase I
30
Phase II Inter-Laboratory Study
To include:
• New tablets containing higher native EI levels
– Need to ensure that formulation remains realistic & compressible
– Spike with updated ICH Class 1 & 2A elements
• Refinement of test protocols
– Ensure adequate data around HF vs. non-HF methods
– Ensure adequate data around acid leach vs. total digestion methods
– Distribute raw materials to a larger number of labs
– Define procedures around LOQs and LODs
– More carefully consider use of reaction gases/KED, internal standards,
and correction equations
• Refinement of reporting templates
– To streamline data analysis
31
Study Participants and Acknowledgements AQura Cornel Venzago
Chemical Solutions Francine Walker
ColorCon Gary Hayes
Dow Corning Jason Sturm
ELS Brendan Murray
JM Huber Hal Garber, John Offidani
Liverpool John Moores Univ. Phil Riby
Perrigo James Bennett, Andy Kampfschulte, Josh Foote,
Rob Lievense, Matt Schmitt, Saul Gylys
Pfizer Sam Powell, Nikki Clements
P&G Denise McClenathan, Roy Dobson, Andrei Shauchuk
RTI James Harrington
Solvias Gisela Fontaine, Josephine Archinal
US Geological Survey Ruth Wolf
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…and all other TAC Team members, Thank You!!!