forced degradation: what? why? how? - cbi | powering … b(1).pdf · · 2015-12-02forced...

Forced Degradation:What? Why? How?

Thomas R. SharpFreeThink Technologies, Inc.

Groton, Connecticut([email protected])

1www.freethinktech.com

What?

• buzzwords

– forced degradation

– stability testing

– stress testing

• interconnected, but not equivalent or interchangeable

www.freethinktech.com 2

What?

• nothing is infinitely stable – entropy!

• determining “mtbf” (mean time before failure)

– electronics industry: how soon can you expect your hard disk to crash, your monitor to go dark?

– automobiles: how soon will the exhaust system or the fenders rust away?

– pharma: when should I throw that old bottle of aspirin away?

3www.freethinktech.com

teacups

• manufacturing teacups?

• nobody wants to buy a faulty teacup!

• nobody wants it to “fail” soon after purchase

• why test?

– correct manufacturing faults

– set life expectancies

– demonstrate robustness


teacups

• failure modes

– different failure modes

– but all have failed!


teacups

• how to test?

• which tool?

• too much?


How it all fits together


degradationmechanisms

degradantidentification

formulationdevelopment

packaging

Current Practices

• ICH guidelines

– degradant = compound resulting from chemical change caused over time by light, temperature, pH, humidity, excipients, etc.

– where the guidelines fall short

• not big on specific details

• subject to individual & regulatory agency interpretation and discretion

• not uniformly interpreted across all countries/marketplaces

freethinktech.com 9

Why?

• provides materials used to develop stability-indicating assays

– method that actually differentiates good from bad

– forced degradation products demonstrate that one has a stability-indicating method

• demonstrates product robustness

• set rational shelf life expectations & expiry dates

• safety considerations (toxics or genotoxics?)

• because it’s required!10www.freethinktech.com

How?

• identify condition(s) that induce “failure”

– pH, temperature, humidity, light, time, etc.

• choose rational conditions that induce failure

– how much is enough, how much is too much?

– “little hammer or BIG hammer”

– not too much, not too little

• ~10% to 20% loss of drug substance

• don’t over-degrade and chase unnecessary degradants


How it all fits together





packaging

identifying degradants

• how much “identification” is enough?

– phase-dependent

• early phase: a little bit can be enough

• late phase: the whole enchilada!

• presumptive vs. confirmatory identification

– (relative) retention times, retention indices

– LC-UV vs. LC-MS

– NMR characterization

– synthesis (the final word!) & comparison

freethinktech.com 13

computer-assisted identification?

• Two fundamental approaches

– logic-oriented

• ab initio computation – quantum chemistry

• expert systems– CAMEO, Delphi, Zeneth®

– information-oriented

• databases, algorithms, statistics, examples– Pharma D3® drug degradation database

• 393 drugs, >1200 degradants, literature references

• http://d3.arxspan.com/

– Marvin (ChemAxon), ACD Labs, XLogP, etc.


http://d3.arxspan.com/

ab inito – what to compute?

• C-H bond dissociation energies to indicate reactive sites

• some energies change with protonation


• Thomas R. Sharp (2011). Calculated carbon-hydrogen bond dissociation enthalpies for predicting oxidative susceptibility of drugsubstance molecules. International Journal of Pharmaceutics 418,304-317.

• Thomas Andersson, Anders Broo, Emma Evertsson (2014). Prediction of drug candidates’ sensitivity toward autoxidation: Computational estimation of C-H dissociation energies of carbon-centered radicals. Journal of Pharmaceutical Sciences 103,1949-1955.

in silico predictions

• Zeneth® – logic-based

– knowledge from the literature

– perception of structures & patterns

– prediction based on chemical “rules”

– interactions of drugs with themselves & with excipients


• Alexis D.C. Parenty, William G. Button, Martin A. Ott (2013). An expert system to predict the forced degradation of organic molecules. Molecular Pharmaceutics 10,2962-2974.

• Mark H. Kleinman, Steven W. Baertschi, Karen M. Alsante, Darren L. Reid, Mark D. Mowery, Roman Shimanovich, Christopher Foti, William K. Smith, Dan W. Reynolds, Marcela Nefliu, Martin A. Ott (2014). In silico prediction of pharmaceutical degradation pathays: A benchmarking study. Molecular Pharmaceutics 11,4179-4188.


Steven W. Baertschi, Karen M. Alsante, Dinos P. Santafianos (2011). Chapter 3. Stress testing: The chemistry of drug degradation. in S.W. Baertschi, K.M. Alsante, R.A. Reed, Pharmaceutical Stress Testing: Predicting drug degradation (2nd Ed). London: InformaHealthcare. Pp. 49-141.

insights from Pharma D3 database• 0: isomerization, etc.

• -2: dehydrogenation

• +1: amide to acid

• ±16: add/subractoxygen

• ±18: add/subtract water

acid/base

• aqueous 0.1 N acid or base

• organic co-solvents acceptable if necessary

– choose to avoid solvent side reactions

• room temperature & in the dark

– to separate acid/base lability from temperature-or light-induced effects

• timecourse – 24 hours, up to 1 week

• what about intermediate pHs?


bupropion

• Welbutrin® – numerous therapeutic indications

• solution-stable below pH 5

• several degradants between pH 5 and pH 10

• mcba above pH 10

• OH− catalyzed degradation of free base


Cl

O

HN

Cl

O

OHCl

O

O

Cl

O OH

Cl

HO

Obupropion

m-chlorobenzoic acid

propanedione

(degradant E)

hydroxypropanone 1

(degradant C)

hydroxypropanone 2

(degradant F)

Paul M. O’Byrne, Robert Williams, John J. Walsh, John F. Gilmer (2010). The aqueous stability of bupropion. Journal of Pharmaceutical and Biomedical Analysis 53,376-381.

when we want it to degrade!

• dabigatran etexilate (prodrug, Pradaxa®)

– anticoagulant

• mimicking

– stomach, pH 1.5

– blood, pH 7.4


N

N

NH

HN

HN

N

O

O

O

N

O

O

thermal and humidity challenge

• humidity control using colligative properties of saturated salt solutions

• monitors to record actual temp/humidity exposure (don’t just assume)

• Arrhenius chemistry

– elevated temp/humidity speeds reactions


• Lewis Greenspan (1977). Humidity fixed points of binary saturated aqueous solutions. Journal of Research of the National Bureau of Standards – A. Physics and Chemistry 81A(1),89-96.

• Paul W. Winston (1960). Saturated solutions for the control of humidity in biological research. Ecology 41(1),232-237.• F.E.M. O’Brien (1948). The control of humidity by saturated salt solutions. Journal of Scientific Instruments 25,73-76.

Arrhenius chemistry


Gary Scrivens (2015). Personal communications

• moisture-modified Arrhenius equation

ln k = ln A – Ea/RT + B(RH)

Arrhenius chemistry

• moisture-modified Arrhenius equation

ln k = ln A – Ea/RT + B(RH)

• moisture “B” term important for solid state

– hygroscopic drug, excipients (or both)

– deliquescence

• Ea – temp sensitivity

• “A” term – contact


• a very complex problem

• multiple modes and mechanisms

– hydrogen abstraction

• autoxidation

• radical-initiated

– oxygen addition

• peroxide-mediated

– electron loss


oxidation

S.W. Baertschi (2015). Personal communications

oxidation


S.W. Baertschi (2015). Personal communications

oxidation

• oxygen exposure

– H2O2 (3%) historically used, but not predictive of molecular oxygen reactions

– pressurized oxygen – not very stability-indicating?

• diazene free radical initiators

– AIBN, AAPH, etc.

– organic co-solvents (ACN preferred over MeOH)

– elevated temperatures


photostability

• standard portions of EM spectrum• visible – 400 nm to 800 nm

• UV-A – 320 nm to 400 nm

• UV-B – 290 nm to 320 nm

• UV-C – 200 nm to 290 nm

– Option 1: D65 (outdoor daylight) and ID65 (indoor indirect daylight) ISO 10977(1993) standards

– Option 2: both cool-white (similar to above) and near-UV with a range of 320 nm to 400 nm (UV-A)


How?

• other “inadvertent” conditions?

– drug salt forms – drug-counterion interactions?

– drug-drug interactions

• multiple active ingredients

• degradants quantitated initially (area%) to the lowest active ingredient

– drug-excipient interactions?

– excipient-excipient interactions


mechanical processing

• milling adds a lot of “energy” to the drug substance

• blending with excipients

• annealing

• sonication

• etc.


sample preparation is important!

• sonication generates radicals

– can induce peroxide oxidation

– inadvertent forced degradation


• Christian Petrier, Andre Jeunet, Jean-Louis Luche, Gilbert Reverdy (1992). Unexpected frequency effects on the rate of oxidative processes induced by ultrasound. Journal of the American Chemical Society 114(8),3148-3150.

• Steven W. Baertschi, Pat Jansen et al. (2006). IIR Forced Degradation Conference, Short Hills, N.J.• Steven W. Baertschi (2015). Personal communications.

Maillard reaction

• early lore suggests only primary amines react

• fluoxetine (secondary amine) and lactose


David D. Wirth, Steven W. Baertschi, Ross A. Johnson, Steven R. Maple, Marybeth S. Miller, Diana K. Hallenbeck, Stephen M. Gregg (1998). Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine. Journal of Pharmaceutical Sciences 87(1),31-39.

OHN

F

F

F

O

OH

OH

OH

HO

OH

OH

HO

N O

F

F

FO

OH

OH

OH

HO

OH

OH

OH

HO

H2O

H2O

cetirizine (Zyrtec®)

• an aggressive carboxylic acid (pKa 3.6)

• forms esters, amides with

– other drug substances in the formulation

– amides/alcohols of excipients/other actives

• glycerol ester

• pseudoephedrine ester/amide

• poly(ethylene glycol) ester

• β-cyclodextrin esters


Cl O

OH

O

N

N

cetirizine PEG esters

• PEG 300 in the formulation

• “aggressive” ester formation


Cl O

O

O

N

N

OH

cetirizine PEG esters

C2 1H2 5N2O3Cl[C2H4O]n

r.m.m. 388 + [44]n

n formula r.m.m.

6 C21H24N2O2Cl(OC2H4)6OH 652.3

7 C21H24N2O2Cl(OC2H4)7OH 696.3

trovafloxacin & excipients

• amide formation with fatty acids in magnesium stearate excipient (tablet press lubricant)


F

F

F

O

OH

O

N

NH

N N

H

HO

n

azithromycin single-dose sachet

• high-temperature annealing step

• ester formation with fatty acids (“magnesium stearate”) in formulation


O

O

OH

O

OO

O

OH

OH

HO

OH

O

N N

HO

HO

HO

O

O

O


Steven W. Baertschi, Karen M. Alsante, Dinos P. Santafianos (2011). Chapter 3. Stress testing: The chemistry of drug degradation. in S.W. Baertschi, K.M. Alsante, R.A. Reed, Pharmaceutical Stress Testing: Predicting drug degradation (2nd Ed). London: Informa Healthcare. Pp. 49-141.

insights from Pharma D3 database

• an unusual M+58 adduct

• only 1 in Pharma D3

database


M+58 adduct

• sodium starch glycolate (Explotab®, Ac-Di-Sol®)

– tablet disintigrant – GRAS

– starch carboxymethylated with Na chloroacetate

P.M. Young (2009). Sodium starch glycolate. in R.C. Rowe, P.J. Sheskey, M.E. Quinn, Handbook of Pharmaceutical Excipients (6th Ed). London: Pharmaceutical Press. Pp. 663-666.

M+58 adduct

• varenicline (Chantix®) tablet formulation containing sodium starch glycolate

• residual chloroacetic acid in the excipient reacts with drug substance


D. Santafianos (personal communications). varenicline-excipient interaction

Cl

OH

O

HCl

excipient-excipient interactions

• tromethamine & benzaldehyde form a Schiff base in vehicle, appear in chromatogram

– tromethamine, for pH control

– benzaldehyde, from cherry flavor

– reversible – goes away on incubation


solid-state vs. in-solution stability

• pick the right indicator degradant!

• not always the same indicator degradant(s)

– in solid state

– does not accumulate in solution-degraded drug samples. Reactive – goes on to other degradants (?)


N

OH

R

N

O

R

additional stability criteria

• does not have to be a degradant appearing in a chromatogram

• define a stability test and an objective failure criterion

– color/appearance – tristimulus measurement

– dissolution – the Q point



• dissolution

– attempts to correlate in vitro dissolution performance with in vivo oral drug performance & bioavailability

– establish specifications for batch-to-batch quality assurance

– becomes the official compendial specification for all subsequent immediate release products with the same active ingredient



• dissolution

– Q point

• specified % dissolution at a specified time

• the quantitative endpoint to measure “failure”

• becomes compendial specification on FDA registration of the drug/formulation

• often a very conservative specification


0.0

20.0

40.0

60.0

80.0

100.0

0 5 10 15 30 45

% D

isso

luti

on

Time, minutes


• dissolution –10 mg tablet

– compendialQ = 85% @ 15 minutes

– conservative


0.0

20.0

40.0

60.0

80.0

100.0

0 5 10 15 30 45

% D

isso

luti

on

Time, minutes

Control

60C/66%RH D21

60C/66%RH D24

60C/75%RH D6

60C/75%RH D8

60C/75%RH D14

60C/51%RH D10

60C/66%RH D36


• dissolution –10 mg tablet

– clear changes with stress

– but many still pass compendialrequirement



• appearance/color

– expert evaluator – subjective, dependent on the training of the individual

– tristimulus testing – a quantitative color endpoint

– total reflectance visible spectroscopy

– International Commission on Illumination

• CIE x,y,z scale

• CIE L*a*b* scale

• Hunter L,a,b scale


• CIE - Commission Internationale de l'Eclairage

• quantitative measure of appearance failure

– tristimulus L,a,b measurements on caplets deemed to fail appearance testing, establishing a quantitative “failure” measurement

– stability challenge caplets under accelerated time, temperature, humidity conditions

– measure L,a,b



• appearance/color

– use one (or more) of tristimulus parameters to model stability, predict “failure”

– use in decision(s) to modify formulation, adjust packaging, etc.

• change excipients

• adapt/change packaging

• film-coat



forced degradation of biologics?

– what is the stress?

– what are the quantifiable endpoints?

– no problem with chemical stability

• covalent bond breakage (peptide or disulfide)

• oxidation of residue(s)

• loss of prosthetic group, post-translational modifications

– what about protein conformation?

• active vs. denatured forms?

• correctly folded?


how it all fits together





packaging


• Steven W. Baertschi, Karen M. Alsante, Robert A. Reed (Eds.)

– 2nd Edition

– Informa Healthcare

– ISBN 978-1-4398-0179-6

References

General references

• Satinder Ahuja, Stephen Scypinski (Eds.) (2001). Handbook of Modern Pharmaceutical Analysis (1st Ed). New York: Academic Press. (ISBN 0-12-045555-2)

• Satinder Ahuja, Stephen Scypinski (Eds.) (2011). Handbook of Modern Pharmaceutical Analysis (2nd Ed). New York: Academic Press. (ISBN 978-0123756800)

• Steven W. Baertschi (Ed.) (2005). Pharmaceutical Stress Testing: Predicting Drug Degradation (1st Ed.). Boca Raton, FL: Taylor & Francis. (ISBN 978-0-8247-4021-4).

• Steven W. Baertschi, Karen M. Alsante, Robert A. Reed (Eds.) (2011). Pharmaceutical Stress Testing: Predicting Drug Degradation (2nd Ed.). New York, N.Y.: Informa Healthcare. (ISBN 978-1439801796)

• Satinder Ahuja, Karen M. Alsante (Eds.) (2003). Handbook of Isolation and Characterization of Impurities in Pharmaceuticals. New York: Academic Press. (ISBN 0-12-044982-X)


References

Forced degradation

• Karen M. Alsante, Robert C. Friedmann, Todd D. Hatajik, Linda L. Lohr, Thomas R. Sharp, Kimberly D. Snyder, Edward J. Szczesny (2001). Degradation and impurity analysis for pharmaceutical drug candidates. in Satinder Ahuja, Stephen Scypinski (Eds.) (2001). Handbook of Modern Pharmaceutical Analysis (1st Ed). Pp. 85-172. New York: Academic Press. (ISBN 0-12-045555-2).

• Karen M. Alsante, Steven W. Baertschi, Michael Coutant, Brian L. Marquez, Thomas R. Sharp, Todd C. Zelesky (2011). Chapter 3: Degradation and Impurity Analysis for Pharmaceutical Drug Candidates. in S. Ahuja & S. Scypinski (Eds.) Handbook of Modern Pharmaceutical Analysis (2nd Ed). Pp. 59-169. (ISBN 978-0123756800).


References


Oxidation

• E.T Denisov, T.G. Denisova, T.S. Pokidova (2003). Handbook of Free Radical Initiators. Hoboken, N.J.: Wiley Intersciences. 67 pp.

• Seema Betigeri, Ajit Thakur, Krishnaswam Raghavan (2005). Use of 2,2’-azobis(2-amidinopropane) dihydrochloride as a reagent tool for evaluation of oxidative stability of drugs. Pharmaceutical Research 22(2),310-317. (doi 10.1007/s11095-004-1199-x)

• Eric D. Nelson, Paul A. Harmon, Renee C. Szymanik, Martin G. Teresk, Randal A. Seburg, Robert A. Reed (2006). Evaluation of solution oxygenation requirements for azonitrile-based oxidative forced degradation studies of pharmaceutical compounds. Journal of Pharmaceutical Sciences 95(7),1527-1539. (doi 10.1002/jps.20626)

References

Photodegradation

• Satomi Onoue, Naoko Igarashi, Shizuo Yamada, Yoshiko Tsuda (2008). High-throughput reactive oxygen species (ROS) assay: an enabling technology for screening the phototoxic potential of pharmaceutical substances. Journal of Pharmaceutical & Biomedical Analysis46,187-193. doi 10.1016/j.jpba.2007.09.003

• Satomi Onoue, Yoshiki Seto, Graham Gandy, Shizuo Yamada (2009). Drug-induced phototoxicity; An early in vitro identification of phototoxic potential of new drug entities in drug discovery and development. Current Drug Safety 4,123-136.

• Yoshiki Seto, Kazuhiro Hosoi, Hironori Takagi, Kazuichi Nakamura, Hajime Kojima, ShizuoYamada, Satomi Onoue (2012). Exploratory and regulatory assessments on photosafety of new drug entities. Current Drug Safety 7,140-148.

• Brian Henry, Christopher Foti, Karen Alsante (2009). Can light absorption and photostabilitydata be used to assess the photosafety risks in patients for a new drug molecule? Journal of Photochemistry and Photobiology B: Biology 96,57-62. doi10.1016/j.jphotobiol.2009.04.005


References

Identification of impurities &degradants

• Karen M. Alsante, Todd D. Hatajik, Linda L. Lohr, Dinos Santafianos, Thomas R. Sharp (2003). Chapter 14: Solving impurity/degradadation problems: Case studies. in S. Ahuja & K.M. Alsante (Eds.), Handbook of Isolation and Characterization of Impurities in Pharmaceuticals.New York: Academic Press. Pp. 361-400. (ISBN 0-12-044982-X).

• Linda L. Lohr, Andrew J. Jensen, Thomas R. Sharp (2003). Chapter 12: NMR Characterization of Process Related Impurities and Degradation Products from Pharmaceutical Drug Candidates. in S. Ahuja & K.M. Alsante (Eds.), Handbook of Isolation and Characterization of Impurities in Pharmaceuticals. New York: Academic Press. Pp. 301-340. (ISBN 0-12-044982-X).

• Karen M. Alsante, Todd D. Hatajik, Linda L. Lohr, Thomas R. Sharp (2001). Isolation and Identification of Process Related Impurities and Degradation Products from Pharmaceutical Drug Candidates. Part I. American Pharmaceutical Review 4(1),70-78.


References

Identification of impurities

• Linda L. Lohr, Thomas R. Sharp, Karen M. Alsante, Todd D. Hatajik (2001). Isolation and Identification of Process Related Impurities and Degradation Products from Pharmaceutical Drug Candidates. Part II: The Roles of NMR and Mass Spectrometry. American Pharmaceutical Review 4(3),104-113.

• Thomas R. Sharp (2006). Impurity Identification in Pharmaceuticals: An integrated approach and examples of how well it works! (Part 1). American Pharmaceutical Review 9(3),100-105.

• Thomas R. Sharp (2006). Impurity Identification in Pharmaceuticals: An integrated approach and examples of how well it works! (Part 2). American Pharmaceutical Review 9(7),84-91.

• Thomas R. Sharp, Brian L. Marquez (2006). Chapter 19: Combined chromatography-spectroscopy techniques: GC-MS, LC-MS and LC-NMR. In S. Ahuja and N. Jesperson (eds.), Comprehensive Analytical Chemistry, Vol. 47: Modern Instrumental Analysis. Amsterdam: Elsevier. Pp. 691-754. (ISBN 0-444-52259-X).

• Thomas R. Sharp , Todd C. Zelesky , Mark T. Zell (2013). Impurity Identification in Pharmaceuticals. In J. Swarbrick (Ed), Encyclopedia of Pharmaceutical Science and Technology (4th Ed.). New York: Taylor and Francis. Pp.1914-1940.


References

Specific studies of impurities/degradants

• Anthony M. Campeta, Franco Lombardo, Thomas R. Sharp, George J. Horan, Diane M. Rescek(1999). Identification of Photodegradants of Droloxifene by a Combined LC-MS, NMR Spectroscopy and Computational Chemistry Approach. Journal of Physical Organic Chemistry 12,881-9. doi: 10.1002/(SICI)1099-1395(199912)12

• Karen M. Alsante Peter Boutros, Michel A. Couturier, Robert C. Friedmann, James W. Harwood, George J. Horan, Andrew J. Jensen, Oscar Q. Liu, Linda L. Lohr, Ronald Morris, Jeffrey W. Raggon, George L. Reid, Dinos P. Santafianos, Thomas R. Sharp, John L. Tucker, Glenn E. Wilcox (2004). Pharmaceutical impurity identification: A case study using a multidisciplinary approach. Journal of Pharmaceutical Sciences 93,2296-2309. doi: 10.1002/jps.20120

• Andrew Blanchard, Carlos Lee, Beverly Nickerson, Linda L. Lohr, Andrew J. Jensen, Karen M. Alsante, Thomas R. Sharp, Dinos P. Santafianos, Ronald Morris, Kimberly D. Snyder (2004). Identification of low-level degradants from low dose tablets. Journal of Pharmaceutical and Biomedical Analysis 36,265-75. doi: 10.1016/j.jpba.2004.05.012


forced degradation: what? why? how? - cbi | powering … b(1).pdf · · 2015-12-02forced...

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