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ICH Quality Guidance for Regulatory Requirements for Preformulation Study

BYDr. Suman PattanayakAssociate ProfessorDepartment of Pharma Analysis & QA.

Vijaya Institute of Pharmaceutical Sciences for Women

B. Pharm IV year/ II SemDRA, IPR & Patents

ICH Topics• Stability - Q1A – Q1F• Analytical Validation – Q2• Impurities – Q3A - Q3C (Q3D – concept paper)• Pharmacopoeias – Q4A - Q4B (and annexes)• Quality of Biotechnological Products – Q5A – Q5E• Specifications – Q6A – Q6B• Good Manufacturing Practice – Q7• Pharmaceutical Development – Q8• Quality Risk Management - Q9• Pharmaceutical Quality System – Q10• Development and Manufacturing of Drug Substances – Q11

January 18-21, 2012

Focus

• Stability - Q1A, B, C, D, E & F• Validation of Analytical Methods – Q2(R1)• Impurities – Q3A, B & C• Specifications – Q6A (Chemical Substances) &

Q6B (Biotechnology/Biological Products)

January 18-21, 2012

Stability• Q1A(R2) Stability Testing of New Drug Substances and

Products• Q1B Photostability Testing of New Drug Substances and

Products • Q1C Stability Testing for New Dosage Forms• Q1D Bracketing and Matrixing Designs for Stability Testing

of New Drug Substances and Products • Q1E Evaluation of Stability Data• Q1F Stability Data Package for Registration Applications in

Climatic Zones III & IV (withdrawn – June 2006)

January 18-21, 2012

Q1A(R2) STABILITY TESTING OF

NEW DRUG SUBSTANCES AND PRODUCTS

Drug Product Drug SubstancePhotostability testing Stress testing

Selection of batches Selection of batches

Container closure system Container closure system

Specification Specification

Testing frequency Testing frequency

Storage conditions Storage conditions

Stability commitment Stability commitment

Evaluation Evaluation

Statements/Labeling Statements/Labeling

January 18-21, 2012

Stress Testing/Photostability

Drug Product Drug Substance

One primary batch

As in ICH Q1B:

One primary batch

Effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing)

Effect of humidity (e.g., > 75%RH)

January 18-21, 2012

Selection of Batches


Data on at least three primary batches of the drug product – two pilot and third one can be smaller - same formulation and packaged in the same container closure system as proposed for marketing.

The manufacturing process used for primary batches should simulate that to be applied to production batches

Where possible, use different batches of the drug substance.

Should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied.

Data on at least three primary batches of minimum pilot scale manufactured by the same synthetic route as used for production batches.

January 18-21, 2012

Container Closure System


Studies to be carried out in container closure system identical to commercial packaging; studies carried out in other packaging materials can be used as supporting information

Studies to be conducted on the API packaged in a container closure system that is identical to or simulates the proposed commercial packaging

January 18-21, 2012

Specification Drug Substance Drug Product Studies to include attributes

susceptible to change during storage and which can influence quality, safety and efficacy: - Physical- Chemical- Microbiological

Studies to include attributes susceptible to change during storage and which can influence quality, safety and efficacy:- Physical- chemical,- microbiological,- preservative content- functionality tests (e.g. with

delivery systems)

Validated analytical methods to be employed

Validated analytical methods to be employed

June 2010January 18-21, 2012

Testing Frequency Drug Substance Drug ProductFor API with proposed re-test period/shelf-life of at least 12 months: Every 3 months over first year, every 6 months over next 12 months and annually thereafter.

For FPP with proposed re-test period/shelf-life of at least 12 months: Every 3 months over first year, every 6 months over next 12 months and annually thereafter.

Accelerated condition: Minimum of 3 time points, including initial and final time points (e.g. 0, 3 & 6 months)

Accelerated condition: Minimum of 3 time points, including initial and final time points (e.g. 0, 3 & 6 months)

Intermediate condition (due to significant change under accelerated condition): study design should include 4 time points (e.g. 0, 6, 9 and 12 months

Intermediate condition (due to significant change under accelerated condition): study design should include 4 time points (e.g. 0, 6, 9 and 12 months)

Matrixing or Bracketing may be applied

June 2010January 18-21, 2012

Storage Conditions

• General Case Drug Substance

Drug Product

Study Storage Conditions

Minimum period covered by data at submission



Long term 25 C⁰ +2 C/ ⁰60%+5%RH or30 C⁰ +2 C ⁰/65% +5%RH

12 months Long term 25 C⁰ +2 C ⁰/60%+5%RH or30 C⁰ +2 C ⁰/65% +5%RH

12 months

Intermediate

30 C⁰ +2 C ⁰/65% +5%RH

6 months Intermediate

30 C⁰ +2 C ⁰/65% +5%RH

6 months

Accelerated 40 C⁰ +2 C ⁰/75% +5%RH

6 months Accelerated 40 C⁰ +2 C ⁰/75% +5%RH

6 months

June 2010January 18-21, 2012

Storage Conditions

• Storage in refrigerator Drug Substance Drug ProductStudy Storage

ConditionsMinimum period covered by data at submission



Long term 5 C ⁰ + 3 C⁰ 12months Long term 5 C ⁰ + 3 C⁰ 12months

Accelerated

25 C ⁰ + 2 C / ⁰60% + 5% RH

6 months Accelerated

25 C ⁰ + 2 C / ⁰60% + 5% RH

6 months

June 2010January 18-21, 2012

Storage Conditions

• Storage in freezer

• Storage below - 20⁰C : Case by case basis

Drug Substance Drug ProductStudy Storage

ConditionsMinimum period covered by data at submission



Long term

- 20 C ⁰ + 5 C⁰ 12months Long term

- 20 C ⁰ + 5 C⁰ 12months

June 2010January 18-21, 2012

Storage Conditions – Drug Product

• Semi-permeable containers :Study Storage Conditions Minimum period

covered by data at submission

Long term 25 C⁰ +2 C/40%⁰ +5% RH or30 C⁰ +2 C/35%⁰ +5% RH

12 months

Intermediate 30 C⁰ +2 C/65%⁰ +5% RH 6 months

Accelerated 40 C⁰ +2 C/⁰ NMT 25% RH 6 months

June 2010January 18-21, 2012

Significant ChangeDrug Product Drug Substance->5% change in assay from the initial results

-Any degradation product exceeding its acceptance criterion

-Failure to meet acceptance criteria for appearance, physical attributes and functionality tests

-Failure to meet acceptance criteria for pH

-Failure to meet acceptance criteria for dissolution of 12 dosage units

Defined as failure to meet specifications

January 18-21, 2012

Evaluation Drug Substance Drug ProductStatistical analysis not necessary if data exhibits little or no degradation and variability

Statistical analysis not necessary if data exhibits little or no degradation and variability

Limited extrapolation of real time data permitted with justification

Limited extrapolation of real time data permitted with justification

June 2010January 18-21, 2012

Q1B PHOTOSTABILITY TESTING OF

NEW DRUG SUBSTANCES AND PRODUCTS

• Provides 2 options for sources of light:– artificial daylight fluorescent lamp combining visible and ultraviolet (UV)

outputs, xenon, or metal halide lamp– sample should be exposed to both the cool white fluorescent and near

ultraviolet lamp• Test on API first – if not photosensitive then no further testing is

required• If API is photosensitive then testing to be continued on (as

appropriate): – Tests on the exposed drug product outside of the immediate pack – Tests on the drug product in the immediate pack – Tests on the drug product in the marketing pack

• Where appropriate, impact of light during manufacturing

January 18-21, 2012

Q1C Annex to Q1A (R2)

• Additional guidance on line extensions • Reduced requirements at time of filing: 6

months accelerated and 6 months long term

January 18-21, 2012

Q1D - Bracketing

January 18-21, 2012

Q1D - Matrixing

January 18-21, 2012

Q1E

EVALUATION OF STABILITY DATA

• Provides recommendations for: (at RT, Refrigerated and Freezer storages)– treating stability data – Extending re-test period or shelf-life beyond period covered

by long-term data– Statistical approaches to analysis of stability data

• Progression: – Start with data under accelerated condition – Then assess data under intermediate condition, if appropriate– Finally evaluate trends and variability of the long-term data

January 18-21, 2012

Outcomes

When there is no significant change under accelerated conditions (RT)Retest period or shelf life can be up to twice, but NMT 12 months beyond the period covered by long-term data

Long-term and accelerated data showing little or no change over time and little or no variability

Data not amenable to statistical analysis, but relevant supporting data provided: Retest period or shelf life can be up to 1.5 times, but NMT 6 months beyond the period covered by long-term data

If a statistical analysis is performed: Retest period or shelf life of up to twice, but not more than 12 months beyond the period covered by long-term data

Long-term or accelerated data showing change over time and/or variability

January 18-21, 2012

OutcomesWhen there is significant change under accelerated conditions (RT) but no significant change at intermediate condition:

Data not amenable to statistical analysis: Retest period or shelf life can be up to 3 months beyond the period covered by long-term data if backed by relevant documentation If statistical analysis is performed: Retest period or shelf life can be up to 1.5 times, but NMT 6 months beyond the period covered by long-term data when backed by statistical analysis and relevant supporting data

January 18-21, 2012

Q2(R1) VALIDATION OF ANALYTICAL PROCEDURES

• Defines validation characteristics:– Accuracy – Precision

• Repeatability • Intermediate Precision

– Specificity – Detection Limit – Quantitation Limit – Linearity – Range

• Robustness to be considered at appropriate stage of development of the analytical method

• System suitability test parameters to be established for a particular procedure depending on the type of procedure being validated - Pharmacopoeias to be consulted for additional information

January 18-21, 2012

VALIDATION CHARACTERISTICS

Assay Impurities

Quant. limit

ID Validation characteristics

+

+

+

+

-

-

+

+

+ -

+ -

+ -

+ +

- +

+ -

+ -

+ -

-

-

-

+

-

-

-

-

Accuracy

Precision

Repeatibility

Int.Precision

Specificity

LOD

LOQ

Linearity

Range

January 18-21, 2012

Q3 Impurities

• Impurities in New Drug Substances Q3A(R2): Defines thresholds for reporting, identification and qualification of impurities in DS

• Impurities in New Drug Products Q3B(R2): Defines thresholds for reporting, identification and qualification of impurities in DP

• Guideline for Residual Solvents Q3C (R5): Classifies residual solvents by risk assessment:– Class 1 solvents: solvents to be avoided– Class 2 solvents: solvents to be limited– Class 3 solvents: solvents with low toxic potential

• Guideline for Metal Impurities Q3D (Concept paper – July 2009)

January 18-21, 2012

Q3A(R2) CLASSIFICATION OF IMPURITIES

• Organic Impurities– Starting materials– By-products– Intermediates– Degradation products– Reagents, ligands, catalysts

• Inorganic Impurities– Reagents, ligands, catalysts– Heavy metals or other residual metals– Inorganic salts– Other materials (e.g., filter aids, charcoal)

• Residual Solvents

January 18-21, 2012

Q3A(R2) Definitions

• Qualification: The process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified.

• Reporting Threshold: A limit above (>) which an impurity should be reported. • Specified Impurity: An impurity that is individually listed and limited with a

specific acceptance criterion in the new drug substance specification. A specified impurity can be either identified or unidentified.

• Unidentified Impurity: An impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time)

• Unspecified impurity: An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new drug substance specification

January 18-21, 2012

Q3A(R2)

January 18-21, 2012

Q3B(R2)

January 18-21, 2012

Q3C(R5)

• Provides 2 options for describing limits of Class 2 Solvents • Option 1: As per the table provided - calculated using TDI of 10 g and

the calculation - – Concentration (ppm) = 1000 x Permitted Daily Exposure (PDE)/ Dose– PDE is given in terms of mg/day and dose is given in g/day.

• If TDI is more than 10 g use option 2

Concentration limit (ppm)

PDE (mg/day) Solvent

410

360

4.1

3.6

Acetonitrile

Chlorobenzene

January 18-21, 2012

Example for Option 2• Option 2: It is not considered necessary for each component of the drug product to comply

with the limits given in Option 1. The PDE in terms of mg/day can be used with the known maximum daily dose and equation (Concentration (ppm) = 1000 x PDE/ Dose) to determine the concentration of residual solvent allowed in drug productExample: PDE of acetonitrile is 4.1mg/dayComponent Amount in formulation Acetonitrile content Daily exposure

Drug substance 0.3 g 800 ppm 0.24 mg Excipient 1 0.9 g 400 ppm 0.36 mg Excipient 2 3.8 g 800 ppm 3.04 mg Drug Product 5.0 g 728 ppm 3.64 mg

• The sum of the amounts of solvent per day should be less than that given by the PDE.

January 18-21, 2012

Q6A• Addresses aspects such as:

– Periodic or skip testing– Release vs shelf-life criteria– In-process tests– Design and development considerations– Limited data available at filing– Parametric release– Alternative procedures– Pharmacopoeial tests and acceptance criteria– Evolving technologies– Impact of drug substance on drug product specifications– Reference standard

January 18-21, 2012

Q6A Decision Trees

• #1 – Establishing acceptance criteria for specified impurity In DS• #2 – Establishing acceptance criteria for degradation product in DP• #3 – Establishing acceptance criteria for PSD in DS• #4 – Investigating need to set acceptance criteria for polymorphism in DS

and DP• #5 – Establishing ID, Assay and enantiomeric impurity procedures for

chiral DS and chiral DS in DP• #6 – Microbiological Quality Attributes of DS and Excipients• #7 – Setting acceptance criteria for DP dissolution • #8 – Microbiological Quality Attributes of non sterile DP

January 18-21, 2012

Periodic or Skip Testing

• Should be justified.• May be applied to certain tests only (e.g.

residual solvents and microbiological test for solid oral products)

• Recommend that it should be applied post approval

• Batch to batch retesting to be restored in the event of failure

January 18-21, 2012

Design and Development Considerations

• It may be possible to propose excluding or replacing certain tests based on experience and data accumulated: – microbiological testing for drug substances and solid

dosage forms which have been shown during development not to support microbial viability or growth (Decision Trees #6 and #8)

– extractables from product containers where it has been reproducibly shown that either no extractables are found in the drug product or the levels meet accepted standards for safety

January 18-21 2012January 18-21, 2012

Design and Development Considerations

– particle size testing may be performed as an in-process test, or may be performed as a release test, depending on its relevance to product performance

– dissolution testing for immediate release solid oral drug products made from highly water soluble drug substances may be replaced by disintegration testing, if these products have been demonstrated during development to have consistently rapid drug release characteristics (Decision Tree #7) (only accepted in exceptional circumstances and all conditions must be met including substantial development data)

January 18-21, 2012

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.

Impurities (2)

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

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.

OverviewSetting 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?

• 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)

API SM


Final API

FPP


Residue of the API SMResidue of the intermediate


API SM


Final API

FPP

SMimpurities


Residue of the SMResidue of the intermediateImpurities in the SM


API SM


Final API

FPP

ReagentsSolventsCatalysts

Solvents

SMimpurities


Residue of the SMResidue of the intermediateImpurities in the SMReagentsSolventsCatalysts



API SM


Final API

FPP


Solvents

By-products

By-products

SMimpurities


Residue of the SMResidue of the intermediateImpurities in the SMReagentsSolventsCatalystsReaction by-products



API SM


Final API

FPP


Solvents

Degradation

By-products

By-products

SMimpurities


What are the potential impurities? (2)Potential Impurities

Residue of the SMResidue of the intermediateImpurities in the SMReagentsSolventsCatalystsReaction by-productsDegradation products

API SM


Final API

FPP


Solvents

Degradation

By-products

By-products

SMimpurities

Excipient-APIinteractions




Residue of the SMResidue of the intermediateImpurities in the SM ReagentsSolventsCatalystsReaction by-productsDegradation productsExcipient-API interactions

API SM


Final API

FPP


Solvents?

Degradation

By-products

By-products

SMimpurities

Container-APIinteractions

Excipient-APIinteractions




Residue of the SMResidue of the intermediateImpurities in the SMReagentsSolventsCatalystsReaction by-productsDegradation productsExcipient-API interactionsContainer 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.

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

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

What are the potential impurities? (12)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?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)• 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)

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 impuritiesThe ICH divides impurities into• Organic impurities (process- and drug-related)• Residual solvents• Inorganic impurities

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.

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% -

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.


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 impurities

• The limits must be qualified as safe. • The limits should realistically reflect batch

and stability data.

Setting limits for impurities (2)Organic ImpuritiesAn 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% -

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:


• 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 solventsICH 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.

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.

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.

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).

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.

Setting limits for impurities (9)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

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