Common Inspection Deficiencies and Statistics Jeffery Wan Medicines Inspector Manufacturing Quality Branch National GMP Forum November 2019
Overview • Inspection Statistics • Common Deficiencies • Deficiency Specifics • Trending Deficiencies
Inspection ratings domestic FY 18/19 Compliance level A1 = Good A1: Few deficiencies or non-conformities were found, which are of a relatively minor nature. Compliance level A2 = Satisfactory A2: Few major deficiencies (not more than five) and/or a larger number of minor deficiencies or non-conformities were found. No critical deficiencies were found. Compliance level A3 = Basic A3: A large number of major (more than five, not more than 10) and/or a large number of minor deficiencies/non-conformities were found. No critical deficiencies were found. Not rated = Unacceptable One or more critical deficiencies and/or a large number of major deficiencies were found.
Inspection ratings international FY 18/19 Compliance level A1 = Good A1: Few deficiencies or non-conformities were found, which are of a relatively minor nature. Compliance level A2 = Satisfactory A2: Few major deficiencies (not more than five) and/or a larger number of minor deficiencies or non-conformities were found. No critical deficiencies were found. Compliance level A3 = Basic A3: A large number of major (more than five, not more than 10) and/or a large number of minor deficiencies/non-conformities were found. No critical deficiencies were found. Not rated = Unacceptable One or more critical deficiencies and/or a large number of major deficiencies were found.
Major deficiencies by chapter – domestic 18/19 Chapter 1 – Pharmaceutical Quality System Chapter 2 – Personnel Chapter 3 – Premises and Equipment Chapter 4 – Documentation Chapter 5 – Production Chapter 6 – Quality Control Chapter 7 – Outsourced Activities Chapter 8 – Complaints and Product Recall Chapter 9 – Self Inspection
Major Deficiencies by Chapter – International 18/19 Chapter 1 – Pharmaceutical Quality System Chapter 2 – Personnel Chapter 3 – Premises and Equipment Chapter 4 – Documentation Chapter 5 – Production Chapter 6 – Quality Control Chapter 7 – Outsourced Activities Chapter 8 – Complaints and Product Recall Chapter 9 – Self Inspection
Major deficiencies by annex – domestic 18/19 Annex 1 – Manufacture of Sterile Medicinal Products Annex 2 – Manufacture of Biological Medicinal Substances and Products for Human Use Annex 3 – Manufacture of Radiopharmaceuticals Annex 4 – Manufacture of Veterinary Medicinal Products other than Immunologicals Annex 6 – Manufacture of Medicinal Gases Annex 8 – Sampling of Starting and Packaging Materials Annex 11 – Computerised Systems Annex 12 – Use of Ionising Radiation in the Manufacture of Medicinal Products Annex 13 – Manufacture of Investigational Medicinal Products Annex 15 – Qualification and Validation Annex 17 – Parametric Release Annex 19 – Reference and Retention Samples
Major Deficiencies by Annex – International FY18/19 Annex 1 – Manufacture of Sterile Medicinal Products Annex 2 – Manufacture of Biological Medicinal Substances and Products for Human Use Annex 3 – Manufacture of Radiopharmaceuticals Annex 8 – Sampling of Starting and Packaging Materials Annex 11 – Computerised Systems Annex 15 – Qualification and Validation
Critical deficiencies 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
Critical deficiency clauses referenced PIC/S Part 1 Deficiencies Clause 1.5 Management • Senior management has the ultimate responsibility to ensure Responsibilities an effective Pharmaceutical Quality System is in place • Adequate resourcing • Leadership should ensure the support and commitment of staff at all levels Clause 2.10 Training • The manufacturer should provide training for all the personnel whose duties take them into production and storage areas or into control laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product. Clause 4.8 Records and Data • Records should be made or completed at the time each Integrity action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable.
Major deficiencies 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
Major deficiency clauses referenced PIC/S Part 1 Deficiencies Clause 1.4 Pharmaceutical Quality System • A Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that: • An appropriate level of root cause analysis… • Medicinal products are not sold or supplied before an Authorised Person has certified that each production batch… Clause 1.8 Basic GMP • Good Manufacturing Practice is that part of Quality Management which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation Clause 1.10 Product Quality Reviews • Regular periodic or rolling quality reviews should be performed to: • verify consistency of the existing process • assess current specifications of starting materials and finished product • highlight any trends • identify product and process improvements. Clause 2.11 Training • Continuing training should also be given, and its practical effectiveness should be periodically assessed. • Training programmes should be available, approved by either the head of Production or the head of Quality Control, as appropriate. • Appropriate training for the duties assigned
Major deficiency clauses referenced PIC/S Part 1 Deficiencies Clause 3.19 Equipment and Premises • Storage areas should be clean and dry and maintained within acceptable temperature limits. • Check and monitor storage areas requiring special storage conditions. Clause 4.1 Documentation Controls • Complex systems need to be understood, well documented, validated, and adequate controls should be in place. • Control measures for master documents, official copies, data handling and records need to be stated. • Appropriate controls for electronic documents such as templates, forms, and master documents should be implemented. Clause 4.8 Records and Data Integrity • Records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable. Clause 5.19 Cross Contamination • Cross-contamination should be avoided by appropriate technical or organisational measures • Use of cleaning status labels on equipment • Providing appropriate air-locks and air extraction • Production in segregated areas
Major deficiency clauses referenced PIC/S Part 1 Deficiencies Clause 5.26 Starting Materials • Starting materials should only be purchased from approved suppliers named in the relevant specification and, where possible, directly from the producer. • It is recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. Clause 6.26 Stability • After marketing, the stability of the medicinal product should be monitored according to a continuous appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of impurities or dissolution profile) associated with the formulation in the marketed package. Clause 6.15 Test Methods • Testing methods should be validated. A laboratory that is using a testing method and which did not perform the original validation, should verify the appropriateness of the testing method. All testing operations described in the Marketing Authorisation or technical dossier should be carried out according to the approved methods. Clause 8.3 Complaints and Recall • Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated. The person responsible for Quality Control should normally be involved in the study of such problems.
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