Impurities

Dr Antony Fake

WHO Prequalification Team - Medicines

3.2.S.3.2 Impurities,
1 Malaysia, 29 September 2011
1
1| Impurities, PQT Training May 2014
 Introduction

⚫ This presentation is made with reference to the

preparation of the API.

⚫ This is because the API is the source of the majority of

impurities.

⚫ When considering FPPs, the focus is largely on

degradants, although excipient-API and leaching from
containers must not be overlooked.

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 What kinds of impurities are there?

⚫ Things we add during preparation:

3| Impurities, PQT Training May 2014

 What kinds of impurities are there?

⚫ Things we add during preparation:

Solvents, metal catalysts, starting materials, reagents

4| Impurities, PQT Training May 2014

 What kinds of impurities are there?

⚫ Things we add during preparation:

Solvents, metal catalysts, starting materials, reagents

⚫ Things we unintentionally add during preparation:

5| Impurities, PQT Training May 2014

 What kinds of impurities are there?

⚫ Things we add during preparation:

Solvents, metal catalysts, starting materials, reagents

⚫ Things we unintentionally add during preparation:

Starting materials impurities; impurities within solvents, pesticides...

6| Impurities, PQT Training May 2014

 What kinds of impurities are there?

⚫ Things we add during preparation:

Solvents, metal catalysts, starting materials, reagents

⚫ Things we unintentionally add during preparation:

Starting materials impurities; impurities within solvents, pesticides...

⚫ Unwanted things that are made during preparation:

7| Impurities, PQT Training May 2014

 What kinds of impurities are there?

⚫ Things we add during preparation:

Solvents, metal catalysts, starting materials, reagents

⚫ Things we unintentionally add during preparation:

Starting materials impurities; impurities within solvents, pesticides...

⚫ Unwanted things that are made during preparation:

Reaction intermediates, related-substances

8| Impurities, PQT Training May 2014

 What kinds of impurities are there?

⚫ Things we add during preparation:

Solvents, metal catalysts, starting materials, reagents

⚫ Things we unintentionally add during preparation:

Starting materials impurities; impurities within solvents, pesticides...

⚫ Unwanted things that are made during preparation:

Reaction intermediates, related-substances

⚫ Things that are formed after preparation:

9| Impurities, PQT Training May 2014

 What kinds of impurities are there?

⚫ Things we add during preparation:

Solvents, metal catalysts, starting materials, reagents

⚫ Things we unintentionally add during preparation:

Starting materials impurities; impurities within solvents, pesticides...

⚫ Unwanted things that are made during preparation:

Reaction intermediates, related-substances

⚫ Things that are formed after preparation:

Degradation products

10 | Impurities, PQT Training May 2014

 What are the potential impurities?

Potential Impurities
SM
impurities API SM
Reagents Residue of the SM
Solvents
By-products Catalysts Residue of the intermediate
Impurities in the SM
Reaction
Reagents
intermediate
Reagents Solvents
By-products Solvents Catalysts
Catalysts
Reaction by-products
Degradation Final API
Degradation products

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 Where do we find information on impurities?

⚫ Things we add during preparation:

Solvents, metal catalysts – 3.2.S.2.2

⚫ Things we unintentionally add during preparation:

SM impurities; impurities within solvents, pesticides - 3.2.S.2.3

⚫ Unwanted things that are made during preparation:

Reaction intermediates (3.2.S.2.3), related-substances (3.2.S.3.2)
⚫ Things that are formed after preparation:
Degradation products (3.2.S.7)

And of course 3.2.S.3.2 – Discussion of impurities

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 Types of Impurities

⚫ Organic impurities
Related substances and Degradation products

⚫ Solvents

⚫ Metals

⚫ Genotoxins

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 API Monographs

⚫ You can not rely upon an API monograph entirely for

potential organic impurities.

⚫ Many impurities are specific to the manner of API

preparation and may not have been considered when
the monograph was published.

⚫ Of course monographs are a great start.

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 Potential Organic Impurities

⚫ The applicant should consider all potential impurities and

then by logic, or by testing, reduce the set of potential
impurities to a set of probable impurities.

⚫ There are probably four categories:

– Degradants
– Synthetic by-products of the API
– Remnants of earlier intermediates
– Synthetic by products of earlier intermediates

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 Degradants

Degradants:

⚫ Forced degradation studies will provide information on

major degradants.

⚫ Forced degradation studies will provide information on

the acceptability of the analytical technique

⚫ Monographs tend to be better at listing degradants.

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 Related Substances

⚫ Impurities are more difficult to predict.

⚫ Test method sensitivity is extremely important. What

can it detect?

⚫ Mass balance should be kept in mind.

⚫ If there are multiple pharmacopoeial monographs, then

at the very least consider all of these impurities. At
least for investigation purposes.

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 Setting specifications

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 Thresholds and limits

Thresholds

⚫ The ICH reporting, identification, and qualification

thresholds indicate levels at which the applicant is
expected to undertake increasing control of an impurity.

Limits

⚫ In contrast an impurity limit is the non-negotiable

allowable level for an impurity in a batch.

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 Thresholds

QF Threshold

ID Threshold

Reporting
Threshold

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 This is a limit

In contrast an impurity limit is the non-negotiable allowable

level for an impurity in a batch.

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 Reporting threshold

⚫ For APIs taken less then 2g per day

0.05%

⚫ For APIs taken greater then 2g per day

0.03%

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 Exceeding the Reporting threshold

QF Threshold

ID Threshold

Reporting
Threshold

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 Reporting threshold

⚫ Every time a peak is observed above the reporting

threshold it needs to be recorded in the laboratory results.

⚫ It prevents the applicant from having to report every little

peak that is observed in the chromatogram.

⚫ A peak above the reporting threshold does not

(necessarily) need to be specified in the API
specifications.

⚫ However, any peak above the reporting threshold must

be counted towards the Total impurity content reported in
the Certificate of Analysis.

24 | Impurities, PQT Training May 2014

 Identification threshold

⚫ For APIs taken less then 2g per day

The lesser of 0.10% or 1.0 mg TDI

⚫ For APIs taken greater then 2g per day

0.05%

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 Exceeding the ID threshold

QF Threshold

ID Threshold

Reporting
Threshold

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 Exceeding the ID threshold

If a peak is observed routinely above the ID threshold

then the impurity must be:

⚫ Specified individually in the API specifications (by

name or RRT).

⚫ Identified (or efforts made to do so)

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 “Routinely Observed”

⚫ Normally, the decision to include an impurity in the

specifications is based upon the likelihood it will occur
routinely.
– For instance, observed above the ID threshold in long-term
stability data, or commonly occurs in batches when tested at
release.

⚫ An impurity only occurring in accelerated stability trials,

forced degradation trials, or during development may
not need to be included.

28 | Impurities, PQT Training May 2014

 Qualification threshold

⚫ For APIs taken less then 2g per day

The lesser of 0.15% or 1.0 mg TDI

⚫ For APIs taken greater then 2g per day

0.05%

⚫ An impurity limit above the Qualification threshold must

be known to be safe.

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 Exceeding the QF thresholds

QF Threshold

ID Threshold

Reporting
Threshold

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 Justifying a limit exceeding the
Qualification Threshold

⚫ Refer to a limit in a recognised monograph-

WARNING – it must be a specified Impurity.
…Impurity A , no more than 0.25% - OK
…Any impurity no more than 0.5% - Not OK

⚫ Present literature evidence in support of the limit.

⚫ Present the results of toxicological studies supporting

the safety of the limit.

⚫ Set the limit to 0.15% (or 1 mg TDI) and modify the

process to meet this limit.

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 The lesser of 0.15% or 1.0 mg TDI

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 Example 1

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 800 mg total daily dose

Reported peak Threshold Above QF threshold?

0.15%

Reported peak Equivalent in mg Above QF threshold?

33 | Impurities, PQT Training May 2014

 Example 1

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 800 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15%

Reported peak Equivalent in mg Above QF threshold?

0.09%

34 | Impurities, PQT Training May 2014

 Example 1

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 800 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15% No

Reported peak Equivalent in mg Above QF threshold?

0.09%

35 | Impurities, PQT Training May 2014

 Example 1

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 800 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15% No

Reported peak Equivalent in mg Above QF threshold?

0.09% 0.72 mg

36 | Impurities, PQT Training May 2014

 Example 1

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 800 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15% No

Reported peak Equivalent in mg Above QF threshold?

0.09% 0.72 mg No

37 | Impurities, PQT Training May 2014

 Example 2

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 1150 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15%

Reported peak Equivalent in mg Above QF threshold?

0.09%

38 | Impurities, PQT Training May 2014

 Example 2

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 1150 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15% No

Reported peak Equivalent in mg Above QF threshold?

0.09%

39 | Impurities, PQT Training May 2014

 Example 2

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 1150 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15% No

Reported peak Equivalent in mg Above QF threshold?

0.09% 1.035 mg

40 | Impurities, PQT Training May 2014

 Example 2

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 1150 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15% No

Reported peak Equivalent in mg Above QF threshold?

0.09% ~1.0 mg

41 | Impurities, PQT Training May 2014

 Example 2

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 1150 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15% No

Reported peak Equivalent in mg Above QF threshold?

0.09% ~1.0 mg No

42 | Impurities, PQT Training May 2014

 Example 3

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 1800 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15% No

Reported peak Equivalent in mg Above QF threshold?

0.09%

43 | Impurities, PQT Training May 2014

 Example 3

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 1800 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.15% No

Reported peak Equivalent in mg Above QF threshold?

0.09% 1.62 mg

44 | Impurities, PQT Training May 2014

 Example 3

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 1800 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.10% No

Reported peak Equivalent in mg Above QF threshold?

0.09% 1.6 mg Yes

45 | Impurities, PQT Training May 2014

 Example 4

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 2500 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09%

Reported peak Equivalent in mg Above QF threshold?

0.09%

46 | Impurities, PQT Training May 2014

 Example 4

⚫ A peak is observed at 0.086%.

⚫ Is this above the Qualification threshold?

⚫ At 2500 mg total daily dose

Reported peak Threshold Above QF threshold?

0.09% 0.05% Yes

Reported peak Equivalent in mg Above QF threshold?

0.09%

47 | Impurities, PQT Training May 2014

 Relative response factors

API

UV Abs

Imp A
Imp B

Which impurity peak is bigger?

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 Relative response factors

API

UV Abs

Imp A
Imp B

Which impurity is present in the greater amount?

49 | Impurities, PQT Training May 2014

 Relative response factors

API

UV Abs

Imp A
Imp B

Which impurity is present in the greater amount?

It is impossible to tell without further information.

50 | Impurities, PQT Training May 2014

 Relative response factors

⚫ The size of a peak in a chromatogram is determined by

the amount of impurity present, but also how well it
responds to the detector.

⚫ In HPLC-UV techniques the response is due to the

inherent UV absorbance of the impurity at the detected
wavelength.

⚫ Some impurities will not be detected at all!

⚫ RRF = Response of Imp/Response of API, but always check

the formula just in case the ratio is described differently.

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 Response factors

⚫ At the time of initial development and investigation it is

assumed the response factor = 1.

⚫ For reporting thresholds it is assumed the response

factor = 1.

⚫ When impurities are identified their response factor

must be considered.

⚫ The RRF for all identified impurities should be

established.

52 | Impurities, PQT Training May 2014

 Relative response factors

⚫ When an RRF of between 0.8 to 1.2 is it not mandatory

to apply the correction.

⚫ The use of a RRF could shift an observed impurity from

one threshold to another.

⚫ This is often of benefit to the applicant. If the response

of an impurity is greater than the equivalent amount of
API (RRF>1) it could mean a peak no longer exceeds
the Qualification threshold.

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 Conclusion

⚫ The applicant should discuss the possible generation of related

substances in 3.2.S.3.2

⚫ They must undertake a rigorous testing investigation, including use of

appropriate test methods.

⚫ Monographs are an excellent source of information on possible

related substances and degradation impurities but are not complete.

⚫ When applying thresholds consider TDI and RRF of the impurity

54 | Impurities, PQT Training May 2014

 Further information

Please feel free to ask me any questions now or later.

http://www.who.int/prequal/info_applicants/API_info_applicants.htm

Or email me at:

Fakea@who.int

Thank you

55 | Impurities, PQT Training May 2014