Auditing an Analytical Quality & Stability Testing Laboratory


When you have completed this unit, you should be able to:

  • Understand what the GMP requirements are for the analytical quality laboratory and stability testing laboratory
  • Identify which GMP regulations govern the analytical quality laboratory
  • Use a range of information tools, from the contents of this training in support of analytical testing and stability testing auditing.
  • Recognize compliance or non-compliance of analytical quality laboratory and stability testing


Acceptance Criteria: The criteria a product must meet tsuccessfully achieve delivery requirements.

Analyte: A substance being analyzed, a single component (compound) of a mixture

Chromatography: The science which studies the separation of molecules based on differences in their structure and/or composition.  Chromatography is alsa method tseparate components of an analyte involving a mobile phase moving through a stationary phase.  Types of chromatography are thin layer chromatography, gas chromatography, liquid chromatography and paper chromatography.

Chromatogram: The record of results for the process of chromatography that shows the response of each component as a function of time and concentration of the sample.  The record may be the media itself, e.g. the paper or thin layer medium,  a piece of paper (e.g. computer print out) or it may be retained in a computer and displayed on videdisplay terminal.

Consistency: The ability of the instrument ttest the same sample numerous times under the same conditions and generate the same data within in a very strict range.

Detection limit: The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value. This is considered tbe 3 times the signal tnoise ratio, within PAR&D.

Gas chromatography (GC): A type of chromatography where a liquid sample is vaporized and then injected inta column on a carrier gas. Components of the analyte bind tthe column at different rates, with different parts of the analyte passing through the column at different times.

High performance liquid chromatography (HPLC): A type of chromatography using relatively high pressures and small diameter column packings tachieve sharp and highly reproducible elution profiles.

Laboratory Information Management System (LIMS): A system which can be used tschedule and record analytical data.

about some of the tests that can be performed in a laboratory tincrease the auditor’s understanding of the analytical laboratory environment.

Topics included in this section of the training unit are:

  • Importance of laboratory audits
  • Laboratory administration, organization and personnel training
  • General condition of laboratory
  • Sample receipt and tracking
  • Analytical testing concepts and methods validation
  • Reference standards/reagents/volumetric solutions
  • Documentation-procedures, SOPs, records and reports
  • Instrumentation and equipment-
  • OOS investigations
  • Quality standards
  • Change control program
  • Stability testing
  • Reserve/Retained sample testing
  • Certificate of Analysis

The Importance of the Laboratory Audit
An audit of the quality analytical laboratory is important for a number of reasons.
Testing is performed tassure that the drug product meets acceptance criteria throughout the drug manufacturing process and its shelf life.  Shown below are the types of testing the analytical laboratory performs and the benefits of the testing.

Type of Testing                   

Raw Material or components
Prevent unacceptable components from being used.
In-process testing
Identify potential problems before the product moves tthe next manufacturing stage. Product may be able tbe re-worked/reprocessed, salvaging the batch.
Active substance testing Final/release testing            
Confirm the purity and quality. Allow final product tbe distributed tthe market or for clinical trials with the knowledge that the product is safe, pure, and effective.
Stability testing                   
Confirm that development products or products in the market maintain identity, strength, potency, purity and quality.
Cleaning validation   
Detect residual chemical

Because testing is simportant, analytical laboratory techniques and instrumentation must perform within their specified limits continually. Documentation must be accurate and complete.

Tassure this, there must be laboratory controls in place, including:
  • Specifications, test methods and sampling plans in place that are approved.
  • Deviations and changes must be documented and justified
  • Tests must be conducted tdetermine conformance tspecifications

Linearity is another analytical parameter.  A sample should be able tbe diluted and
assayed with the assay results directly proportional tthe concentration of the analyte in the
sample.  If the test has good linearity, the plot of the results should yield a straight line

The specificity of a method defines the ability of the method tmeasure the analyte of interest tthe exclusion of other relevant components.  The test should be specific enough that even if there are other components in the sample, only one component is measured.

Each method will have a range. The range of the method is the area between the lower and the upper limits of quantitation.  The range should be linear.

The detection limit, alsknown as the Limit of Detection, allows the laboratory analyst tdetermine if a particular analyte is present but may not provide a quantity of the analyte. If an analytical instrument is used, it is usually the smallest concentration of analyte the instrument is able t“see”.

Quantification limit, alsknown as the Limit of Quantification, is the smallest amount (lowest concentration) that an analyte can be measured accurately and precisely. The detection limit and the quantification limit may be different for the same instrument being used.

Ruggedness refers tthe degree of reproducibility of test results obtained by the analysis of the same samples under a variety of normal test conditions.  Some examples of these include testing in different laboratories, using different analysts, conducting the tests on different instruments, using different lots of reagents, using different elapsed times, performing assays on different days.  Ruggedness is normally expressed as the lack of influence of operational and environmental variables of the analytical method on test results.

Robustness is the capacity tremain unaffected by small, but deliberate variations in the method parameters and provide an indication of its reliability.

Most analytical laboratory test methods are validated using some of these parameters.

Test method validation
All analytical procedures, which are used tgenerate data that could be included in a regulatory submission, must be validated tthe degree appropriate for the phase of development before use. Full validation should be preformed during phase III of the development. Analytical procedures that are used ttest a commercial finished product, active ingredient, raw material or packaging component, must be validated before use.

Records should be in place tshow what was done during the validation testing. Methods can be validated in a number of ways.  If a site uses a method that appears in the USP (or other official compendia) it is considered validated, but the method must be shown twork under the actual conditions that it will be used (method qualification).  A method is alsconsidered validated if it is part of an approved NDA.  A site can alsconduct a validation study on their method.  However, system suitability data alone is not sufficient tvalidate a method.

Method validation data must be consistent and conform tacceptance criteria. Validation results from a number of different tests, conducted under the same conditions, must demonstrate repeatability. When using varying concentrations of test solutions, the results must be linear. Many assay and impurity tests now use HPLC. It is expected that the


High Pressure Liquid Chromatography (HPLC)

HPLC works by pumping the mobile phase, composed of a solvent, through a column (the stationary phase) under very high pressure. The analyte is injected intthe moving phase or solvent, and carried through the column. In HPLC, all analytes travel the same distance (the length of the column), scompounds are characterized by retention time (i.e. the time that an analyte remains in the column). Once the analyte is eluted, it passes through a detector where data is integrated.  This data is then transformed inta chromatogram.

GAS chromatography is alsa separation method for mixtures of chemicals. The carrier gas acts as the moving phase.  The sample, usually a liquid, is injected intthe gas, and then carried through the column. A detector is attached tthe end of the column.

Certificate of Analysis

A Certificate of Analysis should be produced where appropriate tdetail the testing
completed on a batch. There should be processes in place tensure the accuracy of the certificate.

Since the analytical quality laboratory provides information that is used for release of our drug product, it is important that the laboratory follows GMP. The goal of the laboratory should be that the correct samples have the required testing performed. Taccomplish this,
  • Analytical methods must be validated and appropriately used ttest the samples
  • Laboratory personnel must be trained
  • Equipment and instrumentation must be qualified, calibrated and maintained
  • Documentation must be complete and accurate.
  • Appropriate systems must be in place tmanage OOS and OOT results, investigations, routine preventative maintenance, and change control

Key Parameters in Auditing Analytical Quality Laboratories
Prior tthe audit
  • Find out which products are tested and the test methods used
  • Choose at least one product with specifications and test methods as detailed in the
  • Marketing Authorization/NDA/CTA/IND/JNDA tfollow during the audit.
  • Request a list of laboratory SOPs
  • Review relevant Quality agreement.
  • Request a list of laboratory equipment
  • Request a list of laboratory deviations/OOS/OOT investigations from the previous 12 months
  • Review previous audits and regulatory audits tdetermine if there are pending actions

During the audit
Conduct a walk through of the laboratory by following the path of a sample tbe tested. Include sample storage areas and chambers.
Receiving and tracking samples
  • Ensure samples are labeled properly and uniquely identified.
  • Ensure that there is a system in place that assures samples are stored under correct conditions.
  • If samples are subdivided for multiple tests, ensure that the subdivision is recorded.
  • If samples are pooled for analysis, ensure that the pooling is recorded.
  • Ensure that the sample is signed in using a well documented and established procedure.
  • Ensure that there is a documented procedure for logging samples out of the laboratory.
  • Ensure that site requirements for sample handling and storage are included in a laboratory SOP.
  • Ensure that samples are managed and stored based on their storage and handling instructions.
  • Check how the laboratory handles ‘non routine samples’ e.g. for experimental work. How these are controlled, logged intthe laboratory and results recorded.

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