1-6 establishing impurity specifications

Establishing Impurity Specifications, 19 January 20111 |

Establishing Impurity Specifications

Antony Fake PhD

WHO Medicines Prequalification Programme


AbbreviationsAbbreviations

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


ImpuritiesImpurities

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.


Impurities (2)Impurities (2)

Question:

If a manufacturer controls impurity content in accordance with a pharmacopoeial monograph can we accept the specifications?


Impurity (3)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.


OverviewOverview

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.


What are the potential impurities?


What are the potential impurities?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.


API SM

Reactionintermediate

Final API

FPP

Potential Impurities

What are the potential impurities? (2)What are the potential impurities? (2)


API SM


Final API

FPP


Residue of the API SM

Residue of the intermediate



API SM


Final API

FPP

SMimpurities


Residue of the SM


Impurities in the SM



API SM


Final API

FPP

ReagentsSolventsCatalysts

Solvents

SMimpurities


Residue of the SM



Reagents

Solvents

Catalysts




API SM


Final API

FPP


Solvents

By-products

By-products

SMimpurities


Residue of the SM



Reagents

Solvents

Catalysts

Reaction by-products




API SM


Final API

FPP


Solvents

Degradation

By-products

By-products

SMimpurities




Residue of the SM



Reagents

Solvents

Catalysts


Degradation products


API SM


Final API

FPP


Solvents

Degradation

By-products

By-products

SMimpurities

Excipient-APIinteractions




Residue of the SM


Impurities in the SM Reagents

Solvents

Catalysts



Excipient-API interactions


API SM


Final API

FPP


Solvents?

Degradation

By-products

By-products

SMimpurities

Container-APIinteractions

Excipient-APIinteractions




Residue of the SM



Reagents

Solvents

Catalysts



Excipient-API interactions

Container closure interactions



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?



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.



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:



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.



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.



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.



O

O

OOR

OH

DimerisationO

HO

O

O

O

OO

OOR

OH

DimerisationO

HO

OOOROR

OH

DimerisationO

HO

OO

HO

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



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

X X

XX

X

X

+

+

+[X]

[X]

98% 1.5% 0.5%

80% 20%

X X

XX

X

X

+

+

+[X]

[X]

98% 1.5% 0.5%

80% 20%



Stereochemical impurities can arise.

O

OH

O

OCH3

O

OCH3

+CH3OH

O

OH

O

OCH3

O

OCH3

+

O

OH

OO

OH

O

OCH3

OO

OCH3

O

OCH3

OO

OCH3

+CH3OH



Certain chemical structures "alert structures" are considered to be genotoxic.



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.


What impurities actually occur?


What impurities actually occur?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


What impurities actually occur? (2)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


What impurities actually occur? (3)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.


When to specify impurities.


When to specify impuritiesWhen to specify impurities

The ICH divides impurities into

Organic impurities (process- and drug-related)

Residual solvents

Inorganic impurities


When to specify impurities (2)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.



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% -



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.



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.



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


Setting limits for impurities


Setting limits for impuritiesSetting limits for impurities

The limits must be qualified as safe.

The limits should realistically reflect batch and stability data.


Setting limits for impurities (2)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% -



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:



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.



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



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.



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.



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.



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).



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.



Metal residues: EMEA-CHMP-SWP-4446-2000



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.


Questions

1-6 establishing impurity specifications

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