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Establishing Impurity Specifications, 19 January 2011 1

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Establishing Impurity
Specifications
Antony Fake PhD

WHO Medicines Prequalification Programme
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Abbreviations
 API – Active Pharmaceutical Ingredient
 FPP – Finished Pharmaceutical Product
 LOD – Loss on Drying
 PDE – Permitted daily exposure
 TDI – Total daily intake
 TTC – Threshold of Toxological Concern

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Impurities
 Impurities are unwanted chemicals present in the API or
FPP arising from normal manufacture.
 They are not chemicals accidently or maliciously
introduced.
 Impurities have no therapeutic value and are potentially
harmful. Therefore they need to be controlled.
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Impurities (2)
Question:
If a manufacturer controls impurity content in accordance
with a pharmacopoeial monograph can we accept the
specifications?
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Impurity (3)
Question:
If a manufacturer controls impurity content in accordance
with a pharmacopoeial monograph can we accept the
specifications?
Unfortunately no, monographs are developed based upon
how the API was prepared historically.
A particular manufacturer's manufacturing method may lead
to unexpected impurities, due to a different route of
synthesis, different reagents, etc.

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Overview
Setting an impurity limit
1. What are the potential impurities?
2. What impurities actually occur?
3. When to specify impurities.
4. Setting limits for impurities.
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What are the potential impurities?
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What are the potential impurities?
 The first step in setting impurity specifications is to
consider what potential impurities might be present,
based upon all available information.
 This step is often poorly performed by applicants.
 There is a tendency to skip this step in discussions and
just adopt pharmacopoeial specifications if a monograph
exists.
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API SM
Reaction
intermediate
Final API
FPP
Potential Impurities

What are the potential impurities? (2)
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API SM
Reaction
intermediate
Final API
FPP
Potential Impurities

Residue of the API SM
Residue of the intermediate
What are the potential impurities? (2)
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API SM
Reaction
intermediate
Final API
FPP
SM
impurities
Potential Impurities

Residue of the SM
Residue of the intermediate
Impurities in the SM

What are the potential impurities? (2)
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API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents
SM
impurities
Potential Impurities

Residue of the SM
Residue of the intermediate
Impurities in the SM
Reagents
Solvents
Catalysts
Reagents
Solvents
Catalysts
What are the potential impurities? (2)
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API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents
By-products
By-products
SM
impurities
Potential Impurities

Residue of the SM
Residue of the intermediate
Impurities in the SM
Reagents
Solvents
Catalysts
Reaction by-products
Reagents
Solvents
Catalysts
What are the potential impurities? (2)
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API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents
Degradation
By-products
By-products
SM
impurities
Reagents
Solvents
Catalysts
What are the potential impurities? (2)
Potential Impurities

Residue of the SM
Residue of the intermediate
Impurities in the SM
Reagents
Solvents
Catalysts
Reaction by-products
Degradation products
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API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents
Degradation
By-products
By-products
SM
impurities
Excipient-API
interactions
Reagents
Solvents
Catalysts
What are the potential impurities? (2)
Potential Impurities

Residue of the SM
Residue of the intermediate
Impurities in the SM Reagents
Solvents
Catalysts
Reaction by-products
Degradation products
Excipient-API interactions
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API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents?
Degradation
By-products
By-products
SM
impurities
Container-API
interactions
Excipient-API
interactions
Reagents
Solvents
Catalysts
What are the potential impurities? (2)
Potential Impurities

Residue of the SM
Residue of the intermediate
Impurities in the SM
Reagents
Solvents
Catalysts
Reaction by-products
Degradation products
Excipient-API interactions
Container closure interactions
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What are the potential impurities? (3)
 It is essential to have a detailed knowledge of the
preparation of the API and the controls place upon the
API starting materials, reaction intermediates, reagents
and solvents.
 It is essential to know how the API degrades.
 Similarly, the manner of preparation of the FPP is
important. Are there solvents involved, heat, water etc?
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What are the potential impurities? (4)
 Most of the potential impurities arise during the
preparation of the API and its subsequent degradation.
 The focus of FPP impurities is usually limited to
degradation products, or occasionally API-Excipient and
API-API interactions (isoniazid/rifampicin).
 Typically FPP impurity specifications only control for API
degradation products.
 Consequently, there is a large focus on the control of
impurities in the API.

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What are the potential impurities? (5)
 Impurities introduced during manufacture
 API degradation products
 API reaction by-products

Determining most of the potential impurities does not
require a great deal of chemistry knowledge. Impurities
can be divided into:
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What are the potential impurities? (6)
What impurities are introduced during manufacture?
 These can be determined from the detailed
manufacturing process description.
 They are the solvents, reagents, catalysts, residue
starting material, reaction intermediates used in
manufacture.

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What are the potential impurities? (7)
What are the possible degradation impurities?
 These can be determined from the results of stress
studies.
 Significant degradation products should be identified and
treated as potential impurities.
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What are the potential impurities? (8)
What are the possible reaction by-products?
 Here some chemistry knowledge would be helpful.
Advice:
 Look for areas of functionality, particularly C-O, C-N, and
double bonds.
 Consider all the impurities specified in relevant
pharmacopoeial monographs.
 Remember, it is the applicant's job to do this not yours.

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What are the potential impurities? (9)
O
O
O
OR
OH
Dimerisation
O
HO
O
O
O
OO
O
OR
OH
Dimerisation
O
HO
OO
OR OR
OH
Dimerisation
O
HO
OO
HO
At C-O bonds oxidation, reduction, cleavage, addition
and elimination can readily occur.
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What are the potential impurities? (10)
Additions to double bonds within the molecule may
occur unintentionally, and even if intentional are not
100% specific.
X
X
X
X
X
X
+
+
+
[X]
[X]
98% 1.5% 0.5%
80% 20%
X
X
X
X
X
X
+
+
+
[X]
[X]
98% 1.5% 0.5%
80% 20%
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What are the potential impurities? (11)
Stereochemical impurities can arise.
O
OH
O
OCH3
O
OCH3
+
CH
3
OH
O
OH
O
OCH3
O
OCH3
+
O
OH
OO
OH
O
OCH3
OO
OCH3
O
OCH3
OO
OCH3
+
CH
3
OH
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What are the potential impurities? (12)
Certain chemical structures "alert structures" are considered to be genotoxic.
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What are the potential impurities? (13)
 Genotoxins must be considered carefully due to their
toxicity at even very low levels.
 The most common situation that arises is the use of the
reagents methylsulphonic acid or toluene sulphonic acid.
 In the presence of alcohols like methanol or ethanol they
can form sulphonate esters. These esters are genotoxic.
 Remember, if the impurity and the API share the same
alert structure then the impurity does not need to be
controlled as a genotoxin.
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What impurities actually occur?
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What impurities actually occur?
API SM
Step 1
Step 3
Final API
Step 2
Chance
Chance of an impurity occurring
Step impurity is introduced
Enantiomers
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What impurities actually occur? (2)
 Investigation of batch analysis and long-term stability data is
required.
 Impurities present at levels greater than the ICH reporting threshold
should be reported by the manufacturer.
 Potential impurities can be excluded by either testing the final API or
FPP, or a relevant proceeding molecule.
 Some pharmacopoeial impurities may not be present if a different
manner of preparation,( reagents, synthesis) is used.
 For degradants, look to long-term stability data. The presence of an
impurity under accelerated conditions does not mean it will appear
under long-term conditions
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What impurities actually occur? (3)
Analytical methods
 If you are looking for an impurity using a test method that
can not detect the impurity then you are wasting your
time. Demonstrated specificity and appropriate
LOD/LOQs are important, especially for genotoxins.
 It is important for the manufacturer to detail the methods
used. This is often not clear in submitted dossiers if
different test methods have been used at different times.
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When to specify impurities.

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When to specify impurities
The ICH divides impurities into
 Organic impurities (process- and drug-related)
 Residual solvents
 Inorganic impurities

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When to specify impurities (2)
Organic impurities
 Any impurity routinely observed in batch data or long-term
stability trials should be controlled by the impurity
specifications.
 Impurities observed below the ICH identification threshold
need not be individually specified in the specifications.
They can be controlled under the limit for any unspecified
impurity.
 Impurities above the ICH identification threshold need to be
identified and individually specified in the specifications.
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When to specify impurities (3)
 Regardless of the related substance requirements of an applicable
pharmacopoeial monograph, a test for any unspecified impurity and
total impurities should be included.
Maximum daily dose Identification Threshold - The lower of:
% of API TDI
API < 2 g 0.10% 1.0 mg
> 2 g 0.05% -
FPP < 1 mg 1.0% 5 ug
1 mg – 10 mg 0.5% 20 ug
> 10 mg – 2 g 0.2% 2 mg
> 2 g 0.10% -
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When to specify impurities (4)
Genotoxins
 If a genotoxin is formed or is likely to be formed during manufacture or
storage then a limit for this impurity should be included in specifications.
 If batch data (6 pilot or 3 production) demonstrate that levels of the
impurity are at or below 30% of the allowable limit then non-routine
testing may be adopted. It should still be specified.
– For instance, if methylsulphonic acid and methanol were used in
the last step, but methane methylsulphonate was not detected then
it may be appropriate to test once annually.
– if methylsulphonic acid and methanol were used in the first of three
steps, but methane methylsulphonate was not detected then it may
be appropriate to specify the test is to be applied when there is a
change in manufacture.
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When to specify impurities (5)
Residual solvents




 The absence of specific test should be demonstrated on at
least 3 production batches or 6 pilot scale batches.

Used in last step Prior to the last step
Class I Specify Specify if detected
Class II Specify Specify if >10% of the ICH
Q3C limit (option I)
Class III Not specified if controlled to less than 0.5%. Control
by Loss on Drying test permissible.
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When to specify impurities (6)
Metals either used in the last step or not consistently
removed from previous steps.
> 30% of applicable limit < 30% of applicable limit
Class I Specify Non-routine test permitted
Class II Specify Non-routine test permitted
Class III Specify Not required to be specified
Metal residues: EMEA/CHMP/SWP/4446/2000
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Setting limits for impurities
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Setting limits for impurities
 The limits must be qualified as safe.
 The limits should realistically reflect batch and
stability data.
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Setting limits for impurities (2)
Organic Impurities

An organic impurity above the applicable ICH qualification threshold
needs to be qualified.
Maximum daily dose Qualification Threshold - The lower of:
% of API TDI
API < 2g 0.15% 1.0 mg
> 2g 0.05% -
FPP < 10 mg 1.0% 50 ug
10 mg - 100 mg 0.5% 200 ug
> 100 mg - 2 g 0.2% 3 mg
> 2 g 0.15% -
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Setting limits for impurities (3)
 Through toxicological trials.
 By comparison to a limit specified in the Ph.Int., Ph.Eur., or USP for
a specific impurity. It could even be in a monograph for another
substance. A statement in a monograph of "any other impurity NMT
0.5%" can not be used as justification for an impurity limit, as it is not
specific.
 By comparison to levels found in an innovator or prequalified FPP.
 By comparison to a limit previously approved in a prequalified FPP.
This is a last resort.



If the impurity limit is greater than the ICH qualification threshold then it
should be qualified:
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Setting limits for impurities (4)
 The limit for any unspecified impurity should be at the ICH
identification threshold.
 The limit for total impurity content should reflect batch data.
 These concepts are applicable to synthetic APIs, but could be used
on a case by case basis for semi-synthetic APIs.
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Setting limits for impurities (5)
Genotoxins: EMEA/CHMP/QWP/251344/2006

 Are considered unsafe at any level.
 A limit for a genotoxin with an understood toxicity can be calculated
based upon the known PDE.
 A limit for a genotoxin without sufficient toxicity information must
determine based upon a TTC of 1.5ug/day.
Max limit = TTC/maximum dose.
 Levels above this limit need to justified toxicologically.
 Limits for genotoxins like aflatoxins, N-nitroso-, and azoxy-
compounds are considered so toxic they must be justified using
toxicological study data.
TTC = Threshold of Toxological Concern
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Setting limits for impurities (6)
Residual solvents
ICH limits apply – Q3C(R4)
 Class I solvents – See table 1, Q3C(R4)
 Class III solvents – 5000 ppm is acceptable without further
justification; might be controlled by LOD (0.5%)
 Class III solvent limits above 5000 ppm are permissible, but it would
tend to indicate poor manufacturing control.

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Setting limits for impurities (7)
Class II solvents – 2 methods for calculating limits
 Option 1 – Table of Q3C(R4) - predefined limits.
Good for APIs and FPPs
 Option 2 – A limit based upon the calculated total
exposure to the solvent in the FPP.



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Setting limits for impurities (8)
For instance: Acetonitrile
 The option 1 limit is 410 ppm based on a PDE of 4.1 mg/day.
 The option 2 limit allows potentially a limit higher than 410 ppm.
 Option 2 permits up to 4.1 mg of acetonitrile in the FPP.
 The limit of 410 ppm may be exceeded in the API provided the total
amount of residual acetonitirile in the FPP does not exceed 4.1 mg.

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Setting limits for impurities (9)
This can lead to API manufacturers justifying limits like this:
Acetonitrile (PDE 4.1 mg/day) in zidovudine (300 mg per day)
Using the ICH formula:
Max limit = 1000 x 4.1/0.3
= 13,660 ppm (seems a little excessive).

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Setting limits for impurities (10)
BUT
"provided that it has been demonstrated that the residual solvent has
been reduced to the practical minimum. The limits should be realistic
in relation to analytical precision, manufacturing capability, reasonable
variation in the manufacturing process, and the limits should reflect
contemporary manufacturing standards." – ICHQ3C(R4)
Basically, we might accept 1000 ppm (i.e. >410 ppm) if supported by
batch data, but not 20 times this value.
Also, option 2 applies to the total amount of solvent in the FPP. If the
amount of solvent in the API is excessive it may cause problems for the
setting FPP limits.

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Setting limits for impurities (9)
Metal residues: EMEA-CHMP-SWP-4446-2000


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Setting limits for impurities (10)
 Either adopt the stated concentration (ppm) limits (dose <10 g), or
 Set a limit for each metal such that the content of all metals of a
particular subclass, based on maximum dose, do not exceed the
recommended PDE. Metal contamination from all sources in the
FPP must be considered.

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 Questions