Guidance on Module 5

Good Manufacturing Practice (GMP)

is a set of regulations, codes, and guidelines for the manufacture of drugs, medical devices, diagnostic products, foods products and Active Pharmaceutical Ingredients (APIs).  Adherence to GMP ensures the manufacture of safe clinical products.

Good Clinical Laboratory Practice (GCLP)

is the practice of applying the principles established under GLP to analyze samples obtained from clinical trials and generate data to be used in regulatory submissions. Adherence to GCP principles ensures the reliability and integrity of data generated by analytical laboratories.

Good Laboratory Practice (GLP)

is a laboratory management concept intended to promote the quality and validity of test data. GLP covers the organizational infrastructure and the conditions under which laboratory studies are planned, performed, monitored, recorded and reported.

lab

Exploratory research studies

Studies conducted using methodologies and/or assays which have not been subjected to a qualification and or validation process, and for which performance parameters have not been established

GMP (cGMP):

WHO guidance on GMP

European Commission on GMP

 

Current GCP:

EMA Guidance document on GCP

GLP:

GLP handbook (WHO)

OECD website on GLP

Definition of Terms


  • Investigative protocol: An early-stage protocol for performing an assay for which assay performance characteristics have not been investigated
  • Established protocol: A protocol for performing an assay for which assay performance characteristics have been investigated and some characteristics are understood and may have been defined
  • SOP (Standard Operating Procedure):  A standardized procedural document that clearly and explicitly details all steps, reagents, equipment, and procedures to be followed to perform an assay in a standardized way, typically a controlled document requiring approvals, version control and periodic review
  • Standardized assay: An assay for which a single methodological approach (including equipment, reagents, and SOP) has been developed and is applied when performing the assay
  • Harmonized assay: An assay for which data output has been demonstrated to be similar across individual laboratories which have participated in the harmonization process
  • Qualified assay: An assay for which relevant and measurable performance characteristics (specificity, accuracy, precision, detection and quantification limits, linearity, range, and robustness) have been evaluated and understood through replicate testing, though not necessarily tested against pre-established acceptance criteria
  • Validated assay: An assay for which the performance characteristics (specificity, accuracy, precision, detection and quantification limits, linearity, range, and robustness) have been statistically established and prospectively evaluated with pre-established acceptance criteria and confirmed via an external monitoring quality assurance body

Definitions of assay performance characteristics

  • Specificity: The ability to unequivocally assess the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.
  • Accuracy: The closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found.  (Note: For T cell assays Accuracy is often difficult or not possible to determine because of the limited availability of a gold standard reference value.)
  • Precision: The closeness of agreement between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions.  Precision may be considered at three levels:  Intra-assay, intra laboratory (different days, operators, or instruments) and inter-laboratory
  • Detection limit:  The lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.
  • Quantitation limit: The lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy.
  • Linearity: The ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.
  • Range: The interval between the upper and lower concentration of analyte in the sample for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.
  • Robustness: A measure of the capacity for assay performance to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.

References for further guidance:

FDA: Guidance for Industry: Validation of analytical procedures

EMA: ICH Topic Q 2 (R1) Validation of Analytical Procedures

FDA: Guidance for Industry: Assay Development for Immunogenicity Testing.

Analytical Methods: A Statistical Perspective on the ICH Q2A and Q2B Guidelines for Validation of Analytical Methods. Steven Walfish, December 2006

These definitions and references were provided under the appreciated leadership and input of the following members of the MIATA community:

Michael Kalos, University of Pennsylvania – Marcella Sarzotti Kelsoe, Duke University – John Hural, HVTN, Fred Hutchinson Cancer Research Center – Steffen Walter, Immatics