Impurities | EUROLAB

What Is Impurities?

Impurity analysis determines organic compounds present in the product other than the active substance. By source, they are classified as starting materials, intermediates, by-products and degradation products. Measurement is mostly done by HPLC, and each impurity is reported individually and as a total.

Purpose of Impurities

The purpose is to show impurity levels are within acceptable limits for safety. ICH Q3A and Q3B set thresholds for the level above which an impurity must be reported, identified and qualified.

Which Products Is Impurities Applied To?

Active pharmaceutical ingredients
Finished dosage forms
Intermediates
Stability study specimens
Generic development specimens

In Which Sectors Is Impurities Used?

PharmaceuticalsBiotechnology

Standards Related to Impurities

ICH Q3A(R2) (impurities in new drug substances)
ICH Q3B(R2) (impurities in new drug products)
ICH M7(R2) (mutagenic impurities)
Ph. Eur. 2.2.29 and relevant monographs
Ph. Eur. 5.10 (control of impurities general chapter)

Impurities Conditions

Thresholds: Reporting, identification and qualification thresholds in ICH Q3A/Q3B are defined by daily dose
Method: A stability-indicating HPLC method that separates impurities from the active substance
Mutagenic impurities: Assessed separately, with much lower thresholds, under ICH M7

Equipment for Impurities

HPLC / UPLC (with DAD detector)
LC-MS/MS (for identification and trace levels)
GC-MS
NMR (for structure elucidation)
Preparative chromatography

Sample Requirements for Impurities

Sufficient specimen quantity
Known impurity reference standards
Batch number, manufacturing route and storage condition must be provided
Storage duration and condition must be stated for stability specimens

Duration of Impurities

Chromatographic analysis takes several working days. Isolating an unknown impurity and elucidating its structure is a separate study that takes markedly longer.

Impurities Procedure

1A stability-indicating chromatographic method is set up.
2A system suitability run is performed.
3The specimen is prepared per the monograph or method.
4Chromatographic separation and measurement are performed.
5Each impurity's area is calculated and matched against known ones.
6Individual and total impurity results are reported.

Impurities Acceptance Criteria

The acceptance criterion is not given on this page: for every active substance and every product, the limit comes from the relevant pharmacopoeia monograph or the approved specification in the marketing authorisation dossier. The pharmacopoeia's general chapter defines the method; the monograph sets the limit. ICH Q3A and Q3B also define reporting, identification and qualification thresholds tied to daily dose; impurities with mutagenic potential are subject to much lower thresholds under ICH M7.

Evaluation of Results

It is critical that the method be stability-indicating: a method that cannot separate impurities from the active substance peak renders the impurity invisible. This is demonstrated by forced degradation studies. If an unknown impurity exceeds the threshold, it must also be identified and, if needed, toxicologically qualified.

Impurities Report

Specimen identification, batch and manufacturing route
Method applied and evidence it is stability-indicating
System suitability results
Result for each impurity and total impurities
Specification and ICH thresholds compared against

Accreditation

EUROLAB holds internationally recognised accreditation obtained from accreditation bodies party to the IAF and ILAC multilateral recognition arrangements, under ISO/IEC 17025 for laboratory testing, ISO/IEC 17020 for inspection and surveillance, and ISO/IEC 17021-1 and ISO/IEC 17065 for system and product certification. This chain ensures the reports and certificates issued are accepted worldwide.

Whether this test can be offered within accredited scope depends on your product and the standard applied; since accreditation is method-based, the scope is confirmed in writing at the quotation stage.

Scope and authorisations

Related Regulations

2001/83/EC Directive on Medicinal Products for Human Use
GMP Guide (EudraLex Volume 4)

Pharmaceutical Analysis — What Does This Testing Field Cover?

The section below describes the field that the Impurities test belongs to; the conditions and acceptance criteria of this particular test are given in the sections above. The scope specific to your product is confirmed in writing at the quotation stage.

Pharmaceutical analysis determines the identity, purity, quantity and behaviour of an active substance and of the finished product. What sets this family apart is that the methods are largely defined in PHARMACOPOEIAS: the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia (USP) give both the method and the acceptance framework together.

The binding nature of the pharmacopoeial method shapes how the field works. In other sectors a laboratory can choose a suitable method, whereas here the method in the monograph governs; if an alternative method is to be used, its equivalence must be demonstrated. This is what makes results comparable worldwide.

Analyses are carried out in several groups. Identity and assay (HPLC, UV, titration) show what the product is and how much active substance it contains. The impurity profile and residual solvents look for unwanted compounds arising from the manufacturing process. Elemental impurities address metals originating from catalysts and equipment. Dissolution and disintegration behaviour is the most important in vitro indicator of how the drug will be released in the body.

The DISSOLUTION TEST is one of the most critical measurements in the field. It is not enough for a tablet to contain the right amount of active substance; that substance must dissolve at a suitable rate. The dissolution profile is used to assess the effect of formulation changes on bioavailability and holds a central place in generic drug licensing.

METHOD VALIDATION is a mandatory step in this family. If a pharmacopoeial method is used, it is verified that the method works properly under that laboratory's conditions. If an in-house method has been developed, it is validated against parameters such as linearity, precision, accuracy, specificity, limits of detection and quantification, and robustness. A result produced with an unvalidated method cannot be used in a licence dossier.

Stability studies determine shelf life and are the longest-running work in the field. The product is held under defined temperature and humidity conditions, analysed at set intervals, and the results become the basis of the shelf life and storage condition claims. Accelerated conditions give preliminary information but real-time data is what counts.

The microbiological side is a separate body of work: microbial enumeration, testing for specified microorganisms, sterility testing for sterile products and the bacterial endotoxin test. For sterile products, packaging integrity and sterilisation validation also come into play.

Data integrity has moved to the centre of inspections in recent years. It is not enough for the result to be correct; the raw data must be traceable, unalterable and auditable. Validation of electronic record systems has therefore become an inseparable part of analysis.

Method groups in this field

Identity and assay
HPLC, UPLC, UV-Vis spectrophotometry, titration, identity confirmation by FTIR.
Impurities and residues
Related impurities, degradation products, residual solvents (GC headspace), nitrosamine screening.
Elemental impurities
Determination of elemental impurities by ICP-MS and ICP-OES and the associated risk assessment.
Physicochemical
Dissolution and disintegration, hardness, friability, uniformity of dosage units, water content (Karl Fischer), particle size.
Microbiological
Microbial enumeration, specified microorganisms, sterility, bacterial endotoxin, preservative efficacy.
Stability
Real-time and accelerated stability studies; photostability and in-use stability.

Commonly confused in this field

The pharmacopoeial method is binding; an alternative method may be used only by demonstrating its equivalence.
A result produced without method validation cannot be used in a licence dossier.
Accelerated stability does not replace real-time data; shelf life is supported by real-time results.
The dissolution profile is sensitive to apparatus type, agitation rate and medium; the conditions must be complete in the report.
A shortcoming in data integrity produces a non-conformity in an inspection even when the result is correct.
A change of formulation or supplier requires analytical comparison and, where necessary, a new stability study.

Which decisions these results support

The licence dossier and batch release
Determining shelf life and storage conditions
Method transfer and method validation
Incoming raw material acceptance control from suppliers
Assessing the effect of a formulation change on bioequivalence

Related Tests

Frequently Asked Questions About Impurities

Are nitrosamine impurities covered here?

Nitrosamines are treated as mutagenic impurities under ICH M7 and are assessed with very low thresholds. Regulatory authorities also require a dedicated assessment and risk analysis for this group; standard impurity analysis does not cover it.

Why is a forced degradation study needed?

To prove the method can separate degradation products from the active substance. Unless peak separation is demonstrated in specimens deliberately degraded with acid, base, oxidation, heat and light, there is no assurance the method captures the impurities.