Inspection of Quality Control

Laboratories

Stephanie Croft, M.Sc.

Technical Officer (Inspector), WHO

Prequalification of Medicines Programme

PQP Manufacturer's Meeting April 4-5th 2011, Geneva, Switzerland

Contents of this presentation

1. Overview of different types of laboratory inspections performed by the WHO

2. Common inspection findings

3. Major areas of concern

4. What inspectors may look out for

5. What not to do

6. Best practices

7. Relevant WHO Guidelines

8. Conclusions

1. Different types of laboratory inspections performed by the WHO

• National Quality Control Laboratories and

other laboratories whose main function is QC.

• Quality control laboratories used by API

manufacturing sites, finished product

manufacturing sites; and

• Bioanalytical CRO laboratories (Analysis of

biostudy data).

• Biowaiver CRO laboratories.

1. Different types of laboratory inspections performed by the WHO

• Different types of samples and products being

analyzed yet similar issues are often

encountered (re: preparation of samples,

following of SOPs, documentation, HPLC

analyses, etc…).

2. Common inspection findings

• Issues that were frequently encountered

during inspections:

– GC, HPLC, HPLC-MS, uv, IR : calibration parameters not

fully in line with recognized standards

– HPLC, GC: Chromatographic integration parameters

unclear

– IR: no clear acceptance criteria for passing ID tests

– OOSs: investigations not adequately carried out

– Deviations: not adequately documented

– Pharmacopoeial methods: not verified

3. Major areas of concern

• Critical deficiencies:

– Reporting data for samples not analyzed ("dry labbing")

– Falsifying existing data

– Selective use of QC data

– Overwriting files

– peak shaving, juicing (peak enhancing), deleting

– Off-record spiking of samples to artificially increase potency

– Time travel (changing times and dates)

4. Examples of what inspectors look out for: signs of data manipulation

• Data that is "too good to be true".

• Discrepancies between electronic data and paper raw data.

• Dates which do not match (e.g. dates of chromatograms do not match those being claimed for the analysis)

• Integration parameters that are not traceable or retrievable.

→ Company should be able to demonstrate that same results can be obtained when integration parameters are re-entered.

4. Examples of what inspectors look out for: signs of data manipulation

• Electronic data that is not retrievable or destroyed.

• Integration parameters being different for standards vs. the samples of the same run or between samples injections in the same run.

• Audit trails not turned on.

• Injection sequences that are not clearly documented (Repeat of analyses and picking of best results).

• Raw electronic data not containing unique identifiers and the absence of clear guidelines for the saving of analytical data.

5. What not to do! Chromatography: Peak "juicing"/ "shaving"

Figures taken from "Laboratory Ethics and Data Integrity", OTAC presentation

Denis D. Wells, Charles Lytle, October 1, 2008.

5. IR: What not to do!

6. Best practices : chromatography

• Document! Document! Document!

• Use automatic integration if possible or the most accurate manual integration.

• Sequences outlined in procedure and readily available. Naming conventions used allow quick retraceability of electronic data.

• Audit trails are turned on.

• Integration parameters are printed and are clear.

• Weighings printed, signed and dated, records of all preparations are retained.

6. Best practices: IR

• Writing clear and detailed SOPs which specify:

– Detailed method for the comparing of the spectra of sample to reference in a meaningful way to allow ID (e.g., program algorithm in combination with visual examination and a tabular peak comparison (preferable) to the reference standard spectra).

– Clear acceptance criteria for the expected wavelengths.

– Clear acceptance criteria for minimum baseline % transmittance in line with pharmacopeial requirements.

• Operator awareness and training.

• Deactivation of components allowing baseline or peak wavelength modifications.

• Use of audit trails/21CFR compliant programs.

6. Best Practices: Other important factors to consider

• Paper data vs. electronic data: the best practice is to

print sequence, all spectra and all integration

parameters, if not, full electronic data should be

readily available, identifiable and traceable –

electronic data may be consulted to confirm that

integration has been adequately performed.

• Complete data review should be performed prior to

batch release (SOPs should clearly define how

reviewer/QA will proceed to review the data from

analytical reports).

7. Relevant WHO Guidelines

• Good Practices for Pharmaceutical Quality Control

Laboratories (WHO TRS, No.957, 2010 - Annex 1)

• Quality assurance of pharmaceuticals. A compendium of

guidelines and related materials. Vol. 2, 2nd updated edition.

Good manufacturing practices and inspection (Geneva, World Health Organization, 2007)

• WHO GMP for sterile pharmaceutical products (WHO TRS, No. 957, 2010 – Annex 4)

• Model certificate of analysis (WHO TRS, No. 902, 2002 - Annex 10)

7. Relevant WHO Guidelines

• General guidelines for the establishment, maintenance and

distribution of chemical reference substances (WHO TRS, No. 943, 2007 - Annex 3)

• Guide to good storage practices for pharmaceuticals (WHO TRS, No. 908, 2003 - Annex 9)

• WHO guidelines for sampling of pharmaceutical products and

related materials (WHO TRS, No. 929, 2005 - Annex 4)

• Considerations for requesting analyses of drug samples (WHO TRS, No. 902, 2002 – Annex 4)

8. Conclusions

• Data manipulation and misrepresentation is not acceptable to the WHO and according to the law of most national regulatory authorities (could result in the publication of NOC or NOS on behalf of the WHO).

• The honest way is always the "right way".

• Good ethics are key to reliable data.

• Always prioritize data integrity – not quick batch release at any cost.

8. Conclusions

• WHO guidelines should be followed (ref: www.who.int/prequal) or the international pharmacopoeia (Ph. Int.).

• Requirements from other pharmacopoeias such as the USP, the EP and BP are also accepted in general when there are no specified requirements in the Ph. Int.

• Guidelines from stringent regulatory bodies (e.g., OMCL guidelines for analytical equipment qualification) are acceptable as well.

Thank you!Thank you!crofts@who.int