Characterization of non-compendial reference standards for ...

Characterization of non-compendial reference standards for impurities: How good is good enough?

Dr. Bernard Olsen, Webinar Presentation

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Characterization of non-compendial reference standards for impurities: How good is good enough?

Dr. Bernard Olsen, Webinar Presentation

Impurity reference standards

In contrast to API RS, not much guidance from authorities

• ICH Q3A(R2) and Q3B(R2):“Reference standards used in the analytical procedures for control of impurities (Q3B: degradation products) should be evaluated and characterised according to their intended uses.”

• Outdated document of German authority BfArM(1996, “Randnummerndokument”*), translated:“Impurity standards are used for purity tests and during method developmentand validation of those tests. Identity must be ensured and purity and assaymust be defined.”*Erläuterungen zum Antrag auf Zulassung eines Arzneimittels beim BfArM

Impurity reference standards, uses

The intended use determines the analytical effort

Two major types of uses

• Qualitative use

• System suitability

• Peak identification

• Validation of specificity parameters

• Quantitative use

• Limit test

• Quantification of impurity

• Validation of accuracy parameters


Impurity RS for qualitative use

• Identity must be secured

• Recommended combination of techniques:

• H-NMR

• IR

• CHN (free base/acid vs. salt form)

• MS (from coupling with LC or GC)

• UV/VIS (from coupling with LC)

plus

• Purity estimation (from LC/GC, sometimes H-NMR possible,>85% should be the target, otherwise difficulties possible in interpreting H-NMR and IR appropriately)


Impurity RS quantitative use

• Accepted approach (in practice):

• Identity and assay to be determined

• Identity as aforementioned:H-NMR, IRCHN (free base/acid vs. salt form, relevant for quantitative use)MS and UV/VIS (GC-MS or LC-DAD-MS)


Impurity RS quantitative use

• Accepted approach (in practice):

• Identity and assay to be determined

• Assay per 100%-method(aka mass balance; see also formula)

• Water by Karl-Fischer/coulometry

• Residual solvent by H-NMR estimation, or GC/Headspace if necessary

• Subtract all absolute percentages (aka mass fractions or weight percentages) from 100%

• Multiply then with analyte’s relative percent chromatographic purity (LC/GC)

• Or use another, sufficiently specific assay technique (e.g. qNMR)

COA, quantitative impurity RS, regularly acceptedby authorities

9

Points to consider during characterization

CHN analysis, an underestimated tool (1)

• Extremely helpful on issues concerning free base/acid vs. salt form

• Relevant if standard is used for quantification

• “Common” issue when user switching from one RS to another(see also next slide)

OH2N

ClNH

O

N

O

Metoclopramide Imp. G (EP):

Metoclopramide N-Oxide

11,936.5847,74Hydrochloride [%]

13,317,0253,25specified value [%]

13,076,8553,25result [%]

NHC

Salt form issues during RS production

Wanted: 1-(3-Chlorophenyl)piperazine Hydrochloride

ClN

HN x HCl

Literature data:

Order from commercial sources:

Hydrochloride

M=233.14

CAS 65369-76-8

mp=210-214°C

Dihydrochloride

M=269.60

CAS 51639-49-7

mp=189-191°C

Free base

M=196.68

CAS 6640-24-0

liquid

CAS

Supplier 2

Supplier 3

Supplier 1

Supply of…Melting pointMolecular mass

210-214°C (lit.)65369-76-8M=196.68 (free base)

210°C65369-76-8M=233.14

189-191°C51639-49-7M=233.14

Dihydrochloride

Dihydrochloride

Hydrochloride


CHN analysis, an underestimated tool (2)

• Use of corrected values helpful; water, residual solvent also possible

O

O–

F

N O

N+

N

N Risperidone cis-N-Oxide

C [%] H [%] N [%]value mean (n=3) 58,80 6,99 11,55theoretical value 62,87 6,81 12,22difference -4,08 0,18 -0,67

correction with 6,48% water;

(RES <0,05%)

C [%] H [%] N [%]corrected value 62,87 6,76 12,29

difference 0,00 -0,05 0,07


Look for consistency with other available results

• Example H-NMR and HPLC, case 1

Cl

O

OH

4-Chlorobenzoic acid,

bezafibrate impurity A (EP), purity HPLC 99.3%

1H-NMRHPLC



• Example H-NMR and HPLC, case 2Nabumetone Imp D (EP): Imp of imp at 5.9 minutes

O

O



Example H-NMR and HPLC, case 2Nabumetone Imp D (EP): No corres-ponding result in H-NMR

0,17% RES

Dichloromethane

organic impurities < 0,5%

TMSH

marker

Solvent

DMSO-d6



Example H-NMR and HPLC, case 2Nabumetone Imp D light sensitive

HPLC

0 h

1 h

24 h

trans cis

O

O

O O

hυ

Points to consider during use

Can I use a qualitative impurity standard (research material) for quantitative applications?

• Depending on your perspective:You can, but think twice!

• If purity indicated as for example “>80%”, or similar: What value should I use for calculation (quick survey)?

• 80%? 90%? 100%? No idea?

• Do not calculate with the minimum value (i.e. 80%)!

• Material probably purer than that value, risk of underestimation ofimpurity

• If at all: Calculate with 100%! Risk of overestimation “only”!



• Risk of overestimation of imps

• Normally no regulatory issue, as patients not at risk to receive medicineswith impurities really out of specs

• Economic risk however for pharmaceutical manufacturer

• False positive OOS results for imps: unnecessary investigations!

• During development and consideration of ICH Q3A/B:Risk of pushing yourself into unneccessary and expensive qualification studies (e.g., animal tox studies)



• The fewer analytical details – the higher the economic risk

• Depending on sources, qualitative standards often lackcorrect identity with regard to salt forms

• Also water and residual solvents not checked

• Especially water can be a considerable percentage of the substance in hydrates, see next slide



• The fewer analytical details – the higher the economic risk

• Salt form and water issues can lead to overestimation of40% and more, i.e. assuming 100% assay when in fact 70% “as is”

• Even when chromatographic purity is quite high

• Would mean you reporta 0.12% impurity as being 0.17%

• Above ICH qualificationlimit of 0.15% � unnecessary, expensive toxicity studies

0

50

100

150

200

250

300

25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

% E

rro

r a

ssu

min

g 1

00

% a

ssa

y

True Assay, %

Quantitative use: How good is good enough?

For quantitative impurity standards: Do we need a second assay method, as for primary API RSs?

• LGC gets these requests sometimes from clients

• Mainly due to requests from authorities

In my opinion: Not really …

• With the 100%-method (or qNMR), risk of underestimation ofassay of impurity RS is extremely low

• Therefore, with low chance of underestimation of imps present in medicinesthe safety risk for patients is low

• Overestimation is minimized with appropriate identification and assigned value

Thank you!

To LGC for the opportunity to present this webinar

To Dr. Andreas Sieg and Katrin Tänzler for the case study slides

And of course to you for your attention

QUESTIONS?

Also via email [email protected]

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