GMP deficiencies

Version 1.0, August 2017

4 August 2017

When we inspect a manufacturer for compliance with GMP, we assess your level of compliance with the manufacturing principles and any other requirements (such as TGOs and conditions of authorisation).

Any non-compliance is termed a 'deficiency'. For each deficiency, the inspectors provide a manufacturer with a written explanation of how the manufacturer has failed to comply with a requirement.

Deficiencies are classified into levels of seriousness. If you have not rectified a deficiency by the time we conduct a follow up inspection, we can upgrade the classification of that deficiency.

Classification of deficiencies

A deficiency, for the purpose of a GMP inspection, is the non-fulfilment of a requirement. We classify deficiencies identified during inspections as:

Our definitions are based on the definitions in PI013-3 PIC/S inspection report format and represent the risk to product quality and patient safety.

Critical

A 'critical deficiency' is a serious situation that requires immediate resolution and will result in regulatory action being considered, including suspension or cancellation of your GMP licence or GMP clearance. A deficiency can be critical when one of the following is observed:

  • a practice or process has produced, or may result in, a significant risk of producing a product that is harmful to the user
  • the manufacturer has engaged in fraud, misrepresentation or falsification of products or data

Major

A 'major deficiency' is a non-critical deficiency for which one or more of the following apply:

  • has produced or may produce a product which does not comply with its marketing authorisation (in some circumstances this could be critical)
  • indicates a major deviation from the Code of GMP
  • indicates a major deviation from the terms of the manufacturing licence, or GMP approval (overseas manufacturers)
  • indicates a failure to carry out satisfactory procedures for release of batches
  • indicates a failure of the person responsible for QA/QC to fulfil his/her duties
  • consists of several other deficiencies, none of which on their own may be major, but which may together represent a major deficiency and should be explained and reported as such

Other

An 'other deficiency' is a deficiency that cannot be classified as either critical or major, but indicates a departure from GMP.

Deficiencies may be classified as 'other' when there is insufficient evidence to classify as major or critical. Note that these deficiencies are not considered minor, and it is important that the manufacturer appropriately investigates these issues to determine the true extent of the deficiency.

Examples of manufacturing deficiencies

Manufacturers need to comply with all manufacturing requirements. This list of examples of deficiencies is not exhaustive.

There are examples for:

All manufacturers

Examples of critical deficiencies include, but are not limited to:

  1. Absence, falsification or misrepresentation of manufacturing and packaging records
  2. Falsification or misrepresentation of analytical results or records
  3. No master batch documents
  4. No evidence that mandated recall processes have been complied with
  5. Grossly unsuitable premises so that there is a significant risk of contamination
  6. Evidence of gross pest infestation
  7. Lack of sterilisation validation
  8. Water system for sterile products not validated

Examples of Major deficiencies include, but are not limited to:

  1. Lack of validation of critical processes, utilities and equipment (can be considered critical for low dose or high potency products and sterile medicines)
  2. No or grossly inadequate air filtration to minimise airborne contaminants (applicable to all medicines and biologicals manufacturers - could be critical if possible contaminants are a safety concern and critical for sterile medicines)
  3. Cleaning program not followed and evidence of dirty premises/equipment or non-validated cleaning procedures (may be critical if resulting contamination is a safety concern)
  4. Damage (holes, cracks, peeling paint) to walls/ceilings in manufacturing areas where product is exposed
  5. Design of manufacturing area that does not permit effective cleaning
  6. Insufficient manufacturing space that could lead to mix-ups
  7. Sanitary fittings not used on liquid/cream manufacturing equipment
  8. Stored equipment not protected from contamination
  9. Individuals in charge of QC/production not qualified by education, training and experience
  10. Inadequate initial and ongoing training and/or no training records
  11. Cleaning procedures not documented and/or no cleaning records
  12. Production equipment cleaning procedures not validated
  13. Test methods not validated
  14. Complex production processes for non-critical products not validated
  15. Unapproved/undocumented changes to master batch or equivalent documents
  16. Unapproved deviations from instructions
  17. No or inadequate internal inspection program
  18. No proper release for supply procedure
  19. Product reworked without proper approval
  20. No system/procedures for handling complaints or returned goods
  21. Inadequate testing of packaging materials
  22. Product quality reviews not available
  23. Insufficient lighting in production or inspection areas
  24. Temporary devices used for equipment repair
  25. Containers from which samples have been taken not identified
  26. Equipment not properly maintained
  27. Temperature of critical temperature controlled storage areas not monitored and alarmed

Medicines and APIs

In addition to the examples that apply to all manufacturers, here are some examples specific to the manufacture of medicines and APIs.

Examples of Critical deficiencies include, but are not limited to:

  1. Raw materials not tested (including proper identification testing) to ensure compliance with specifications
  2. Inadequate segregation of manufacturing of high risk products (such as penicillins, cephalosporins, cytostatics, steroids, hormones) resulting in a risk of contamination
  3. Release of materials or finished product for a registered medicine not meeting specifications
  4. Release of materials or finished product for a listed medicine not meeting specifications (might also be considered a major deficiency)

Examples of Major deficiencies include, but are not limited to:

  1. No data available to establish the shelf-life of API or medicines
  2. No raw material sampling area for medicine manufacturers (could be classed as 'other' if adequate precautions are taken)
  3. Reduced QC testing of raw materials without data to certify suppliers
  4. Incomplete testing of raw materials
  5. No ongoing stability program and/or stability data for all products not available

Biologicals, blood and blood components

In addition to the examples that apply to all manufacturers, here are some examples specific to the manufacture of biologicals, blood, tissue or cellular therapy products of:

Examples of Critical deficiencies include, but are not limited to:

  1. Release of product without acceptable mandatory test results
  2. Incorrect labelling resulting in a lack of traceability to donor test results

Examples of Major deficiencies include, but are not limited to:

  1. Donor medical assessment procedures not compliant with the requirements of TGO 88
  2. No validation information for the transportation of cells and tissues from collection sites to processing sites
  3. Failure to maintain donor confidentiality

Version history

Version Description of change Author Effective date
V1.0 Original publication following consultation with industry in January 2017 Manufacturing Quality Branch August 2017