Quality Control Testing of Raw Materials, APIs and Finished Products

In short: QC testing means analysing each sample of a raw material, API or finished product against its approved specification, using validated or verified methods, and recording every result on a worksheet. A suspect result is investigated before any retest. This overview is for QC analysts, reviewers and students.

Regulatory basis

• US FDA: components are held until sampled, tested and released by the quality control unit; at least one specific identity test is done on each component (21 CFR 211.84). Each finished batch is tested against final specifications, including identity and strength of each active ingredient, before release, using documented sampling and testing plans and validated test methods (21 CFR 211.165; 211.160).
• EU GMP Part I, Chapter 6: testing methods must be validated, or verified where the laboratory did not perform the validation. Results are recorded and trended, calculations are critically examined, and tests follow the methods in the marketing authorisation (paras 6.15 to 6.17).
• WHO TRS 1052, Annex 4 (2024), sections 6.4 to 6.9: the laboratory-practice guidance this article follows.

Planning the test

1. Test the sample according to the laboratory work plan, once the preliminary steps (sample receipt, registration, visual check) are complete. Until then, store it appropriately (WHO TRS 1052 Annex 4, para 6.46).
2. If a test cannot be done as planned, record the reason, for example on the analytical worksheet.
3. If a required test is outside the laboratory’s scope, it may go to a contract laboratory. The analyst prepares the request and sends the required number of units, each bearing the correct registration number. Results from the contract laboratory are identified as such in the final report (para 6.47). EU GMP Chapter 6 (para 6.6) adds that use of outside laboratories should be stated in the QC records and follow Chapter 7.

Test procedures

• Follow the pharmacopoeial monograph and general notices, or the method approved in the marketing authorisation.
• Describe test procedures in enough detail for trained analysts to perform them reliably and reproducibly.
• Meet the system suitability criteria defined in the method.
• Approve and document any deviation from the test procedure (para 6.48).

Recording results

Record all values, including blanks, on the analytical worksheet (or LIMS) at the time of testing. The analyst signs it, and designated qualified personnel review and approve it. Changes must show what changed, who changed it, when and why, and deleting data is not acceptable (WHO TRS 1052 Annex 4, paras 6.38 to 6.41).

Under EU GMP Chapter 6 (para 6.17), test records include the material or product and batch number, specification and procedure references, results and calculations, test dates, initials of tester and verifier, a clear approval or rejection statement with dated signature, and the equipment used.

Record retention: test records and raw data for a batch are kept for at least 1 year after the expiry date of the respective product batch (EU GMP Part I Chapter 4, para 4.11, or 5 years after QP certification if longer; 21 CFR 211.180(a)), and longer if local law or the marketing authorisation requires.

Evaluating test results

Review the results after all tests are complete to see whether they are consistent with each other and meet the specification. Consider all test data. Record quantitative results so that trends can be seen, and evaluate statistically where practical (WHO TRS 1052 Annex 4, para 6.51). Qualified personnel review and approve or reject the results.

Suspected out-of-specification (OOS) results

When a suspected OOS result appears, the supervisor reviews the testing process with the analyst, using a checklist, before any retest (para 6.76). Check that:

• original sample preparations are kept, if stable, until the investigation is complete;
• the correct procedures were followed, including validation or verification requirements;
• raw data show no discrepancies and all calculations are correct;
• equipment was qualified and calibrated, and system suitability was acceptable;
• the right reagents, solvents and reference substances were used;
• the correct glassware was used.

Then:

1. If an error that caused the aberrant result is identified, the result is invalidated and the sample is retested by the same analyst (para 6.77).
2. A suspect result may be rejected only if it is clearly due to an identified error.
3. If the investigation is inconclusive, another trained analyst performs a confirmatory determination. A similar result indicates a confirmed OOS result. If the results are not comparable, investigate the inconsistency. Confirmation with another validated method may also be advised (para 6.78).
4. Have an SOP for OOS investigation. Record all investigations and conclusions; where an error is found, perform root cause analysis and document the corrective actions; when no error is found, report all results (paras 6.80 to 6.82).

The maximum number of retests should be fixed in advance in the written SOP, based on scientifically sound principles, and not adjusted according to the results obtained (FDA guidance Investigating OOS Test Results for Pharmaceutical Production, Revision 1, May 2022).

For the full procedure, see OOS investigation, complete guide, Phase I and Phase II. For equipment status, see SOP for calibration.

Frequently asked questions

Can an analyst simply retest a failing sample? No. A documented review of the testing process comes first, and retesting follows the OOS procedure.

Do pharmacopoeial methods need validation? They are generally considered validated for the use in the monograph, but the laboratory must verify they work for its sample (WHO TRS 1052 Annex 4, para 6.25). Basic methods such as pH determination do not need method verification (para 6.28).

Is a supplier’s certificate of analysis enough for a raw material? Under 21 CFR 211.84(d)(2) it may replace full testing only if at least one specific identity test is done and the supplier’s reports are validated at appropriate intervals.

References

1. WHO. WHO good practices for pharmaceutical quality control laboratories. WHO TRS No. 1052, 2024, Annex 4, sections 6.4 to 6.9.
2. US FDA. 21 CFR 211.84, 211.160 and 211.165 (eCFR, current).
3. European Commission. EU GMP Part I, Chapter 6: Quality Control (revised 2014).
4. European Commission. EU GMP Part I, Chapter 4: Documentation, para 4.11; 21 CFR 211.180(a).
5. US FDA. Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, Guidance for Industry, Revision 1, May 2022.