developing an analytical impurity control strategy using · pdf fileimpurities •...

Developing an Analytical Impurity Control Strategy Using QbD

Mark D. Argentine

Quality by Design in DevelopmentRelies upon developing knowledge around processes and products…

… for effective process and

product design and control.

Ref: M. Nasr, 2006

2IFPAC 2014M. Argentine

A + B C API

(D1, D2 …)

solvent 1 solvent 2, reagent

time, temp.,pH …(B’) (C’) (API’)

(BP1, BP2 …)

A, B = starting materialsC = intermediateAPI = active pharmaceutical ingredientB’ = starting material impurity with potential

to form C’ and API’BP = reaction by-productD = degradation product

An understanding of “What goes in” and “What goes on” in development…

3

…leads to knowledge and development of suitable, robust manufacturing and analytical controls for your process

IFPAC 2014M. Argentine

Building a Process Knowledge BaseConsider multiple synthetic variations, suppliers for starting materials, etc.

Utilize chemistry-guided and knowledge-guided approaches to potential impurities

• Knowledge-guided: What has been observed in selected samples• Chemistry-guided: What is possible/likely from and understanding of the synthetic

processes used or considered– Any potential genotoxic impurities likely/possible? Use “fit-for purpose” development methods to

explore for potential impurities.

Leverage appropriate tools to develop process and impurity formation/fate understanding - e.g., MS, NMR, IR/NIR/Raman

Control strategy development is a dynamic partnership between process and analytical and an iterative strategy

• To search for and identify impurities• To understand impurity formation and fate • To design appropriate process and analytical controls to minimize or eliminate impurities.


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Example: An HPLC-IR-NMR system to generate development knowledge

5

NMR

To NMR

From NMR to HPLC

Reactor

Pump

HPLC(configured for on-line)

From HPLC to Reactor

From NMR to HPLC

Optical Spectrometer(mid-IR, NIR, Raman, UV-vis)

Obtain valuable information on

kinetics, reactive

intermediates, relative

response factors, etc.

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90%10%

90%80% 10%20%

70%30%

10%90%

Impurity Controls Based upon Process Understanding

>98%

NMT 0.50%

NMT 0.15%

NMT 0.40%

NMT 1.0%

NMT 0.25%NMT 0.15%

Imp B’’

Imp B’Imp A’

Imp A

A

B

Imp B

Imp C’

Imp C

C

D

Imp D’

Imp D

Imp D’’

NMT 0.15%

NMT 0.10%

NMT 0.10%


Process knowledge informs analytical controls

Knowledge space studies

Understanding of measurement requirements for the quality attributes of a product that must be controlled

• What analyte(s)• What level(s)• What precision

Analytical method design space studies

7

An Analytical Target Profile (ATP)


Building an Analytical Knowledge Base -Control Strategy Development

Development MethodsHPLC broad polarity screens, multiple detectors

orthogonal techniques, on-line analysistargeted methods

Quality Control MethodsIntegral to specifications and/or process controls

Optimized for ruggedness

Process knowledge - what needs to be monitored/controlled (Analytical Target Profile definition)


QbD Tools in Impurities Method Development Strategy

• Identify key impurities from:– Typical drug substance/product samples

– Authentic impurity samples

– Process development samples with likely impurities (e.g., reaction samples, mother liquors)

– Samples from designed, forced degradation studies

– Potential drug product impurities --- review degradation and excipient interaction design study data

• Use systematic tools and designed studies to aid in appropriate method development (e.g., column screening program for design space impurities)

Design SpaceDesign Space


An example: Analytical Design Space for Impurity Method Development

Zorbax SB C8

Bonus RP

ACE Pheny l

Xterra MS C18

ACE CN

Atlantis dC18

Polaris C8-Ether

Alltima C18

Acquity UPLC BEH C18

Acquity UPLC BEH C8

Acquity UPLC BEH Pheny l

Acquity UPLC BEH Shield RP18

Acquity UPLC BEH HSS T3

SunFire C8Xbridge C8

Xbridge C18

Hypersil Gold PFP

Hypersil Gold aQ

Gemini C6-Pheny l

Luna C18(2)-HST

Halo C18Zorbax Eclipse Plus C18

Discov ery HS F5

Hypersil Gold C18

Microtech C18

Platinum C18

Platinum EPS C18

Sy nergy Max-RP

Sy nergy Hydro-RP

Gemini C18

Use column classification system*

to identify column similarities and

differences

And

Exploit column differences in HPLC method development

*e.g., Gilroy, Jonathan J.; Dolan, John W.; Snyder, Lloyd R. Column selectivity in reversed-phase liquid chromatography IV. Type-B alkyl-silica columns. Journal of Chromatography, A (2003),1000(1-2), 757-778.


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MethanolAcetonitrile

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Column 1 - C8, low pH

Column 2 – Polar Embedded, low pH

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Column 3 – Phenyl, low pH

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Column 4 – C18, high pH

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2

4

3

Perform screen with distinctly different conditions/phases

Optimize separation with modeling5

Predictions for directing additional studies

Assessing method “robustness” w/o doing experiments – power of modeling tools

12

evaluate parameters such as temperature, organic strength, and gradient sensitivity for impact on expected

minimum resolutionIFPAC 2014M. Argentine

mV

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1 2 34 5 6

7

A

B

Method selectivity of

gradient:

A= unspikedmatrix

B=matrix with 0.05%

spike for impurities

1,2,6,7,8 and impurity 5 spiked at

0.15%

13

8

Gradient Assay Identified in Development for Impurity Control

Historically, a gradient assay has been used in development to evaluate material quality and confirm the lack of late-eluting impurities


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TIME (SECONDS)

LOT G

LOT F

LOT E

LOT D

LOT C

LOT B

LOT A

BLANK

Initial Gradient Method – no significant later-eluting impurities for drug


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TIME (SECONDS)

SYS SUIT

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BLANK

Impu

rity

1 (D

I)

Impu

rity

2 (D

I)

Can be simplified to an isocratic assay for routine control

Impu

rity

3 (D

I)Im

purit

y 4

(PI)

Impu

rity

5 (P

I)

Impu

rity

6 (D

I)


Presenter

Presentation Notes

REMINDER OF ABILITY TO USE GRADIENT FOR INVESTIGATIONS/DEVIATIONS --- COMPLEMENTARY TOOLS FOR INVESTIGATIONS

System Suitability Definitionm

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AP

I

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rity

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rity

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CP 1 CP 2 Late eluting marker

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Identify meaningful system suitability controls to ensure reliable method performanceIFPAC 2014M. Argentine

17

Example Chromatography Using an API Sample

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SYSTEM SUITABILITYIm

purit

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AP

I

API

Use of system suitability samples and a “method performance sample” (if it contains measurable impurity levels and is stable) can be useful for method robustness and method transfers


18

Using Design Studies to Evaluate Method Robustness

Patten # DesignColumn Temp

(±3ºC)%ACN-Start

(±2%)%ACN-End

(±2%)%TFA

(±0.01%)Flow Rate

(±0.1mL/min)Iso. Hold (±0.5min)

pattern 0 0 40 18 80 0.1 1.5 5

pattern 1 ++++++ 43 20 82 0.11 1.6 5.5

pattern 2 ++−−−− 43 20 78 0.09 1.4 4.5

pattern 3 −+−+−+ 37 20 78 0.11 1.4 5.5

pattern 4 −−++−− 37 16 82 0.11 1.4 4.5

pattern 5 +−+−−+ 43 16 82 0.09 1.4 5.5

pattern 6 +−−++− 43 16 78 0.11 1.6 4.5

pattern 7 −−−−++ 37 16 78 0.09 1.6 5.5

pattern 8 −++−+− 37 20 82 0.09 1.6 4.5

pattern 0 0 40 18 80 0.1 1.5 5

Consider design studies during method development for more method knowledge

Leverage modeling studies (e.g., DryLab) to cover wide

operating ranges, when possible, in final method


Robustness – Statistical Design Results

Patten # Design Standard Area Total Impurities (Direct area-%)

Total Impurities (vs ext std))

Rs (resolution pair 1)

Rs (resolution pair 2)

pattern 0 000000 10002 0.68 0.71 1.96 3.71

pattern 1 ++++++ 9908 0.69 0.67 1.88 2.38

pattern 2 ++−−−− 10614 0.69 0.71 2.00 3.43

pattern 3 −+−+−+ 10759 0.68 0.70 1.89 5.20

pattern 4 −−++−− 9985 0.69 0.77 1.92 5.34

pattern 5 +−+−−+ 10384 0.67 0.73 2.03 2.18

pattern 6 +−−++− 8978 0.67 0.74 2.09 3.41

pattern 7 −−−−++ 9145 0.67 0.73 1.95 3.85

pattern 8 −++−+− 9525 0.69 0.70 1.97 3.68

pattern 0 000000 9983 0.68 0.71 1.95 3.68

Collect important performance information to justify acceptable method

performance – aids in setting meaningful system suitability

criteria


Wavelength Robustness

Evaluate response for each

impurity to assess

robustness as

structural differences may cause

spectral response

differences

Ref: J. Chrom A, 762 (1997), 227-233


Wavelength Robustness

Ref: J. Chrom A, 762 (1997), 227-233

Indeed, different spectral profiles exist for the

various compounds (with need for ~280 nm

detection)…

…and a simple wavelength system suitability sample can be

developed with commercially-available materials


Method Transfers and Maintenance Method transfers should include:

• An assessment for capability to perform the analysis AND

• The process and product knowledge and overall control strategy for intended use of the method

Important for proper method use and for reference in any future improvements

Useful tools to assess performance/variability:

• Data from robustness studies to interpret system suitability results

• Data from method performance (control) samples in development aid in confirming appropriate performance during transfer and beyond.

Transfer of knowledge regarding “investigational” methods (e.g., broader-based gradient methods, spectroscopic studies) is also useful for studying potential impact of future process design space changes relative to the analytical design space

• Example: Evaluation of new sources of starting materials or excipients22IFPAC 2014

M. Argentine

Performance data allows trends to be identified (and understood)

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data point

peak

taili

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100 120 140 160 180

data point

peak

taili

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Then…

…and more recently

(Tailing limit NMT 1.5)

Change in instrumentation affected performance

New instrumentation


Opportunities

With potential manufacturing changes…

If studies to define the knowledge space are well captured, one can leverage historical knowledge and investigational methods to study continuous improvement opportunities and either re-confirm suitability of existing controls or recognize potential concerns

• Example: use of gradient HPLC investigational method versus isocratic method to ensure appropriate evaluation for potential late-eluting impurities, if anticipated or possible

Use appropriate chromatographic and spectroscopic tools to assess post-approval process changes for method impact.


QbD/Analytical Lifecycle Summary

Advantages• Acknowledges control strategy is integrated with both process and

analytical understanding and controls• Effectively aligned with information/knowledge generation;

possibilities to leverage a wide variety of tools for effective process understanding

• Logical progression throughout development with evolution of method focus to meet varying “customer” demands

Disadvantages• Analytical methods used in development not necessarily same as for

routine control– Possibly more method development time– Possible utilization of more and varied analytical tools– More method “bridging” considerations


Additional Messages and Parting ThoughtsThe QbD/ analytical lifecycle approach supports a methodical, integrated, requirements-based approach to method development and implementation

From an industrial perspective, the knowledge, design, and control spaces are studied relative to the specific process/formulation that is being commercialized.

This approach delivers robust process and analytical understanding and controls which focus on the selected process

Analytical method development from a lifecycle perspective is performed in two parts:

• Defining and developing the overall product control strategy and method requirements• Method definition, using well-selected control parameters (system suitability) and

method performance samples can be used to ensure quality of future results. Method robustness and modeling tools help to define meaningful conditions and controls.

Analytical control methods are tailored for the selected combination of process and analytical controls for that process

Therefore, one needs to assess a compendial method for suitability with the intended manufacturing process


A few references• Olsen, B.; Gavin, P.; Wozniak, T Quality by Design Considerations for

Analytical Methods AAPS News Magazine (2007),10(12), 16-22.

• Argentine, M.; Olsen, B.; Owens, P. Strategies for the Investigation and Control of Process-Related Impurities in Drug Substances, Adv. Drug Delivery Reviews (2007), 59(1), 12-26.

• Gavin, P.; Olsen, B. A Quality by Design Approach to Impurity Method Development for Atomoxetine Hydrochloride (LY139603), Journal of Pharmaceutical and Biomedical Analysis (2008), 46, 431-441.

• Gavin, Peter F.; Olsen, Bernard A.; Wirth, David D.; Lorenz, Kurt T. A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials. Journal of Pharmaceutical and Biomedical Analysis (2006), 41(4), 1251-1259.

• Wirth, D. D.; Olsen, B. A.; Hallenbeck, D. K.; Lake, M. E.; Gregg, S. M.; Perry, F. M. Screening methods for impurities in multi-sourced fluoxetine hydrochloride drug substances and formulations.Chromatographia (1997), 46(9/10), 511-523.


Thank You!

Acknowledgements:

Bernie Olsen Steven Baertschi

Tim Wozniak Eric Jensen

Peter Gavin John Stafford

Zhenqui Shi Gordon Lambertus

Robert Forbes


Use of ICP-MS to confirm absence of “concerning” elemental impurities for simplified control

30

Pd (µg/g) As (µg/g) Cd (µg/g) Hg (µg/g) Pb (µg/g)

Range of results (n=27 batches)across development, scale-up and

validation

<0.005to

5.20All <0.005 All <0.005 All <0.005

<0.005to

0.198

Oral PDEa, µg/day 100 1.5 25 5 15

Limit in API assuming <20 mg/day MDDb, µg/g 5560 83 1390 278 833

Limit in API assuming a 10 g/day dose, µg/g 10 0.15 2.5 0.5 1.5

a Permissible Daily Exposureb Maximum Daily Dosage

• Most elements are <1/100th of safety limits (even conservative limits)• Only Pd, which was intentionally used in the manufacturing process was >30% of

the most conservative safety limit (and only in an early development batch)Control Pd routinely to NMT 10 ppm using robust, widely available ICP-OES approachJustify non routine testing/control for other elemental impurities


Another example – Use of robustness studies to define useful system suitability

31

Method developed to resolve many potential impurities (a); only a few

impurities typically seen (b)

Reference: P.F. Gavin and B.A.Olsen, J. Pharm. Biomed. Anal., 46 (2008), pp 431-441.


Robustness study through design of experiments

32

• Fractional factorial design for 5 variables with 4 center points 16+4 = 20 runs

• Tracked resolution of key resolution pairs in addition to run time and tailing data with carefully selected crude sample (contained key impurities)


Robustness Study Prediction Profile

33

Results support robustness to buffer conc. and pH; note

runtime and pressure changes with n-propanol and T changes

Rs (1-2) is correlated with Rs changes for other peak pairs and is sensitive to n-propanol

and T changes

Impurities 1 and 2 are good candidates for meaningful

system suitability assessment of method separation performance

• Impurity 2 is commercially-available • Impurity 1 can be procured or easily

formed with in-situ degradation


In-situ generation of meaningful system suitability sample


Method change and comparability – an example

35

Situation: A method change was desired after manufacturing/process change to also detect a potential new impurity (Impurity 7)

(Gradient method could detect impurity 7 but isocratic impurity method 1 could not.)

Result: Changed both Assay and Impurities methods to new methods that were more appropriate and capable for the new manufacturing process.


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7

A

B

Method selectivity of

gradient:

A= unspikedmatrix

B=matrix with 0.05%

spike for impurities

1,2,6,7,8 and impurity 5 spiked at

0.15%

36

8

Gradient Impurity Method


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rity

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I)

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rity

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I)

Analytical Profile – Method 1

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y 4

(PI)

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I)

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I)

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rity

7 (P

I)


Presenter

Presentation Notes

REMINDER OF ABILITY TO USE GRADIENT FOR INVESTIGATIONS/DEVIATIONS --- COMPLEMENTARY TOOLS FOR INVESTIGATIONS

38

Analytical Profile – Method 2m

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Lot 4

System suitability

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New method can see all of the impurities of the previous method as well as the new method


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Method Comparison - ImpuritiesR

esul

ts

0.22

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0.3

0.32

0.34

0.36

A B

Method

Oneway Analysis of Results By Method

A = Method 1

B = Method 2

Evaluation of one “impurity rich” sample by both

methods

No statistical difference between methods


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Method Comparison - Assay

Lot 2

Lot 1

97

98

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034J

D4

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lt

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B01391 B10370

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D4

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B01391 B10370

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034J

D4

resu

lt

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B01391 B10370Method 1 Meth. 2

Lot 1

resu

lt

97.598.098.599.099.5

100.0100.5101.0101.5102.0

019J

D0

Res

ult

5 10 15 20 25 30 35 40 45 50 55 60Sample

B01391 B10370

97.598.098.599.099.5

100.0100.5101.0101.5102.0

019J

D0

Res

ult

5 10 15 20 25 30 35 40 45 50 55 60Sample

B01391 B10370Method 1 Method 2

Lot 2

resu

lt


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Method Comparison01

9JD

0 R

esul

t

98

98.5

99

99.5

100

100.5

101

B01391 B10370

Method

1 2

Lot 1

Res

ult

No practical or statistical difference

between the two methods


developing an analytical impurity control strategy using · pdf fileimpurities •...

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