ICH Q3B

Anand Ingole
1 April 2016

IMPURITIES ?
Impurities are unwanted chemicals present
in the API or Finished Products arising
from normal manufacture.
They are not chemicals accidently or
unkindly introduced.
Impurities have no therapeutic value & are
potentially harmful. Therefore they need
to be controlled.
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Impurities in Drug Products

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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Impurities in Drug Products

What are the potential impurities?
What impurities actually occur?
When to specify impurities.
Setting limits for impurities.

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Impurities Classified As

By Products
Degradation Products
Interaction Products
Intermediates
Related Products

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Source of Impurities
SM
impurities

API SM
Reagents
Solvents
Catalysts

By-products
Reaction
intermediate

Reagents
Solvents
Catalysts

By-products
Degradation

Final API

Excipient-API
interactions
Container-API
interactions

Solvents?

FP

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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Sources of Impurities

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Potential Impurities
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 FP
is important. Are there solvents involved, heat,
water etc?

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Impurities Associated with API

Organic Impurities : During process manufacture &
Storage of Drugs. Starting Material & intermediate
The starting material of Paracetamol is phenol, which is nitrated to
give a mixture of the ortho and para-nitrotoluene. The o-isomer is
removed by steam distillation, & the p-nitro group reduced to a pamino group. This is then acetylated to give Paracetamol.

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Inorganic Impurities
Manufacturing Process identified
Reagents, Ligands and Catalysts
Heavy Metals ( e.g water & reactors)
Other Materials ( Filter aids, charcoal)
Solvent Residues ( Manufacturing Process)
Class I- Benzene, Methanol, CCl4 ( 2- 5PPM)
Class II-Acetonitrile,Methylene Choride,Pyridine(2001000 ppm)
Class III- Ethanol, IPA ( 50 mg / day)

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Impurities-Related to Formulations
The focus of FP impurities is usually limited to
degradation products, or occasionally APIExcipient & API-API interactions.
(Isoniazid/Rifampicin, Pregabalin/Lactose)
Method related: Diclofenac Sodium for parenteral
dosage form-Sterilised by autoclaving. 1-(2,6dichlorophenyl)indolin-2-one
.

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Impurities Related to Environmental

Temperature e.g. Vitamins
Light e.g. Ergometrine.
Humidity e.g. Aspirin, Ranitidine
Dosage Form Related : container,Mutual
interaction, Microbial growth,Water content,
pH of solution.
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Impurities upon aging

Mutual Interaction amongst Ingredients
B-Complex injections four vitamins, Nicotinamide
causes degradation of Thiamine
Functional Group Related :
- Hydrolysis : Aspirin
- Oxidative degradation Catecholamine,(Vitamin A)
- Photolytic Cleavage:Ciprofloxacin

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ISOLATION OF IMPURITIES

Liquid-Liquid Extraction Methods

Column Chromatography
TLC
HPLC
Supercritical Fluid Chromatography
Characterization of impurities by using LCMS-MS

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Potential Impurities
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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Potential Impurities
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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Potential Impurities
Possible reaction by-products
Here some chemistry knowledge would be
helpful.
Look for areas of functionality, particularly C-O,
C-N, and double bonds.
Consider all the impurities specified in relevant
Pharmacopoeial monographs.

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What are the potential impurities?

At C-O bonds oxidation, reduction, cleavage, addition
and elimination can readily occur.
O

O
O
OR
OH

Dimerisation

HO

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Potential Impurities
Additions to double bonds within the molecule may
occur unintentionally, and even if intentional are not
100% specific.
X

[X]

+
X

X
98%

1.5%

0.5%

[X]
+

X
80%

20%

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What are the potential impurities?

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.
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What impurities actually occur?

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 FP, 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?

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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Specified Impurities
The ICH divides impurities into
Organic impurities (process and drug
related)
Residual solvents
Inorganic impurities

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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

Genotoxins
If a Genotoxins 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.
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

Residual solvents
Used in last step

Prior to the last step

Class I

Specify

Specify if detected

Class II

Specify

Specify if >10% of the limit

Class III

Not specified if controlled to less than 0.5%. Control by Loss

on Drying test permissible.

The absence of specific test should be demonstrated on

at least 3 production batches or 6 pilot scale batches.

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Class I Solvents

540f07tltrain5sep6
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When to Specify Impurities

Metal Residues:
Metals either used in the last step or not again and
again removed from previous steps.
< 30% of applicable limit

Class I

> 30% of applicable

limit
Specify

Class II

Specify

Non-routine test permitted

Class III Specify

Non-routine test permitted

Not required to be
specified

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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

Organic Impurities
An organic impurity above the applicable ICH
qualification threshold needs to be qualified.
Maximum daily dose

API

FP

Qualification Threshold - The lower of:

% of API

Total Daily Intake

< 2g

0.15%

1.0 mg

> 2g

0.05%

< 10 mg

1.0%

50 g

10 mg - 100 mg

0.5%

200 g

> 100 mg - 2 g

0.2%

3 mg

>2g

0.15%

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Setting Limits For Impurities

If the impurity limit is greater than the ICH qualification
threshold then it should be qualified:

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 FP

By comparison to a limit previously approved in a prequalified

FP. This is a last resort.

Setting Limits for Impurities

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

Genotoxins:
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 1.5g/day.
Max limit = TTC/maximum dose.
Levels above this limit need to justified toxicologically.
Limits for genotoxins like Aflatoxins, N-nitroso-, and Azoxycompounds are considered so toxic they must be justified
using toxicological study data.
TTC = Threshold of Toxological Concern
PDE = Potential Daily exposure
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Setting Limits For Impurities

Residual Solvents
Class I solvents See table 1, Q3C(R4)
Class II 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

For example: 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 FP.
The limit of 410 ppm may be exceeded in the API
provided the total amount of residual Acetonitrile in the
FP does not exceed 4.1 mg.
PDE=Potential Daily Exposure

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Setting Limits For Impurities

We can justify limits like this:
Acetonitrile (PDE 4.1 mg/day) in Zidovudine (300
mg/day)
Using the ICH formula:
Max limit = 1000 x 4.1/0.3
= 13,660 ppm (Little Excess).

PDE=Potential Daily Exposure

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Setting Limits For Impurities

Metal Residues: