Impurities and its Qualification

Impurities are any organic material besides the drug substances and excipients that may be present as an unwanted guest in the drugs. 
The presence of these impurities even in small amounts may influence the efficacy and safety of the drug products. 

Hence ICH, International Council on Harmonization, framed guidelines for identification, reporting and qualification levels of these impurities in different forms of the drugs as mentioned below. 

1. Impurities in New Drug Substances in Q3A (R2)
2. Impurities in New Drug Products in  Q3B (R2)
3. Guideline for Residual Solvents in Q3C (R5)
4. Guideline for Elemental Impurities in Q3D

These guidelines are adopted by US, Europe and Japanese Regulatory authorities. 

ICH provides detailed information of acceptable level of impurities in the drugs based on maximum daily dosage calculated per day. Beyond certain level, the drug cannot be approved as such by the Regulatory agencies. 

Regulatory agencies basically look for 3 types of impurities  in the drugs, specified, unspecified and total impurities present in the drug. 
The acceptable limiit of these specified and unspecified impurities can be arrived based on the strength of the drug (1 mg tablet, 500 mg capsule etc.) and howmuch quantity can be taken in 24 hours (500 mg tablets every 8 hours).

Qualification thresholds for drug product

Max Daily Dose -  Threshold
<10 mg               -  1.0% or 50 μg TDI
10 mg-100 mg   -  0.5% or 200 μg TDI
>100 mg - 2 g     -  0.2% or 3 mg TDI
>2 g                      -  0.15%

Qualification thresholds for drug substance 

Max Daily Dose - Threshold
≤ 2 g                   - 0.15% or 1.0 mg TDI
> 2 g                    - 0.05%

Qualification Methods

There are different ways to qualify the impurities when exceeds the ICH recommended  limits.

1.Metabolites (M3(R2))
2.RLD (Reference Listed Drugs)
3.Pharmacopeia Reference (USP/EP)
4.Literature Reference
5.Toxicology Assessment(M7(R1)),(M3(R2))

Metabolites
If the metabolite impurity is present more than ICH limits, M3(R2) guideline can be followed.

“Nonclinical characterization of a human metabolite(s) is only warranted when that metabolite(s) is observed at exposures greater than 10% of total drug-related exposure and at significantly greater levels in humans than the maximum exposure seen in the toxicity studies.”

RLD (Reference Listed Drugs)
Impurities at above ICH levels can be qualified against RLD samples listed in Orange book when both RLD and Generic drugs are analysed and compared by using same analytical procedures.

Pharmacopeia Reference (USP/EP)
Impurities above ICH limits can be qualified if such impurities are listed in Pharmacopeia monography at higher levels.

Literature Reference
Full text published papers or database information on  impurities and it's levels can be considered for qualification.

Toxicology Assessment(M7(R1)),(M3(R2))
In silico tools employing  two complementary (Q)SAR systems (expert rule-based and statistical based) data can be used for genotoxic assessment of impurities.

In-vitro / In-vivo tests like Ames test, Chromosomal Aberration test and General Toxicity studies (14 - 90 days) can be used for qualification of impurities in drugs.

Identification, Characterisation of Impurities



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