Feature article - Why one purity number cannot carry a quality claim

Cristian Bucsa, founder of ReviveLab, examines why chromatographic purity, identity and assay should remain separate analytical conclusions in speciality chemical quality decisions

A purity percentage is attractive because it looks definitive. A material is reported as 98.7%, 99.2% or 99.8% pure, and the number quickly becomes shorthand for the overall quality of the sample. 

In supplier documents, incoming-material reviews and technical discussions, it can start to carry much more meaning than the analytical procedure actually measured. That is where interpretation becomes important. 

A chromatographic purity result can be highly useful. It may show the relative contribution of a principal peak and other detected peaks under a defined method. It can support impurity profiling, batch comparison and quality control.

However, a single purity percentage should not automatically become a general statement about molecular identity, assay, composition or fitness for use. Those are separate analytical questions.

What did the method measure?

The first question when reading any analytical result should be simple: what characteristic was the method designed to measure?

High-performance liquid chromatography (HPLC) separates components according to their behaviour under a particular chromatographic system. The result depends on factors such as column chemistry, mobile phase, gradient, temperature, sample preparation, flow rate and detector conditions.

A reported value of 99% by HPLC may therefore mean that the main integrated peak accounts for approximately 99% of the total included peak area under that method. That can be strong chromatographic evidence, but it does not necessarily mean that 99% of everything in the sample is the molecule named on the label.

Detector response matters. Some compounds respond more strongly than others. An impurity with weak response at the selected wavelength may contribute relatively little peak area. Another component may co-elute with the principal peak. Material outside the method's effective analytical window may not be represented well in the calculation. The useful conclusion is therefore method-specific.

ICH Q2(R2) the current international guideline for analytical procedure validation, treats analytical uses such as identity, assay, purity and impurity testing as different intended purposes. The validation strategy is expected to show that the procedure is suitable for the purpose for which it is being used.

Purity & identity are different questions

Identity is where overinterpretation becomes especially easy. A chromatographic peak appearing at approximately the same retention time as a reference material can support an identity assessment. It shows that the unknown behaves similarly under that particular chromatographic system.

The limitation is specificity. Similar retention behaviour does not always establish that two materials are structurally identical.

ICH Q6A addresses this directly for pharmaceutical substances. It states that identification testing should be able to discriminate between closely related compounds and that identification based only on a single chromatographic retention time is not regarded as sufficiently specific. It points instead to approaches such as infrared spectroscopy, different chromatographic principles, HPLC with diode-array detection, or chromatography coupled with mass spectrometry where appropriate.

The principle is broader than pharmaceuticals. If the claim is molecular identity, the analytical evidence should be capable of supporting molecular identity. A purity method should not inherit that role simply because it produces a precise number.

Assay adds another distinction

Purity and assay are also frequently blurred. A chromatographic purity calculation may describe the distribution of detected peaks. An assay is intended to determine how much of a particular analyte is present. Those can be very different measurements. 

A sample could produce a chromatogram dominated by one peak while still containing water, residual solvent, inorganic material or other components not represented proportionally in that chromatographic result. Conversely, a well-designed quantitative assay may establish analyte content without providing a complete profile of every impurity.

ICH Q6A treats identification, assay and impurities as separate specification elements, even though the same analytical technology may sometimes contribute to more than one of them. The distinction is not about instruments. It is about the question being answered.

Read the report line by line

One practical improvement is to stop treating a certificate or analytical report as one overall quality score. Read each result independently.

If the document reports purity, ask how purity was measured. If it reports identity, ask which identity technique was used. If it reports assay, determine whether that result is quantitative and how it was calibrated. If a reference standard was involved, the report should make that relationship clear.

The language used in reporting can help enormously. ‘99.3% by HPLC area’ tells the reader what kind of number is being presented. ‘Purity: 99.3%’ leaves more room for interpretation.

Likewise, ‘Identity supported by LC-MS under method X’ communicates a narrower and more useful conclusion than a generic statement that the material ‘passed HPLC’. Keeping those boundaries visible makes technical documents easier to interpret and reduces the chance that a narrow analytical result becomes a broader downstream claim.

Orthogonal evidence reduces blind spots

No analytical technique is equally strong at answering every question. This is why orthogonal evidence can be valuable.

Chromatography may provide excellent separation and impurity information. Mass spectrometry can add molecular-mass evidence. Infrared or Raman spectroscopy can contribute structural or fingerprint information. Nuclear magnetic resonance can provide more extensive structural evidence where that degree of confirmation is justified. Chiral methods may be required when stereochemistry is relevant.

The appropriate combination depends on the material and the decision being made. There is no benefit in performing every possible test on every sample. The better approach is to identify the claim first, consider the realistic failure modes, and then ask whether the available analytical methods are capable of detecting them.

ICH Q2(R2) and Q14 both place intended purpose at the centre of analytical procedure development and validation. That is a useful principle for quality interpretation as well as method development.

Keep conclusions close to evidence

Technical quality decisions become more defensible when the wording of the conclusion stays close to the evidence that produced it. A strong chromatographic purity result should be reported as strong chromatographic evidence. A specific identity result should support an identity conclusion. A quantitative assay should support a content conclusion.

Where stronger claims require several complementary methods, the evidence should be considered together rather than allowing one convenient number to stand in for the whole analytical picture.

The goal is not to diminish the value of HPLC. It remains one of the most important tools in speciality chemical and pharmaceutical analysis. The goal is to use it precisely. A quality claim becomes stronger, not weaker, when each analytical method is allowed to answer the question it was designed to answer.

Contact:

Cristian Bucsa

Founder

ReviveLab

[email protected]