Common Inspection Deficiencies and Statistics

Jeffery WanMedicines InspectorManufacturing Quality BranchNational GMP Forum November 2019

Overview•

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Inspection Statistics

Common Deficiencies

Deficiency Specifics

Trending Deficiencies

Inspection ratings domestic FY 18/19Compliance level A1 = GoodA1: Few deficiencies or non-conformities were found, which are of a relatively minor nature.

Compliance level A2 = SatisfactoryA2: 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 = BasicA3: 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 = UnacceptableOne or more critical deficiencies and/or a large number of major deficiencies were found.

Inspection ratings international FY 18/19Compliance level A1 = GoodA1: Few deficiencies or non-conformities were found, which are of a relatively minor nature.

Compliance level A2 = SatisfactoryA2: 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 = BasicA3: 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 = UnacceptableOne 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 SystemChapter 2 – PersonnelChapter 3 – Premises and EquipmentChapter 4 – DocumentationChapter 5 – ProductionChapter 6 – Quality ControlChapter 7 – Outsourced ActivitiesChapter 8 – Complaints and Product RecallChapter 9 – Self Inspection

Major Deficiencies by Chapter – International 18/19

Chapter 1 – Pharmaceutical Quality SystemChapter 2 – PersonnelChapter 3 – Premises and EquipmentChapter 4 – DocumentationChapter 5 – ProductionChapter 6 – Quality ControlChapter 7 – Outsourced ActivitiesChapter 8 – Complaints and Product RecallChapter 9 – Self Inspection

Major deficiencies by annex – domestic 18/19Annex 1 – Manufacture of Sterile Medicinal ProductsAnnex 2 – Manufacture of Biological Medicinal Substances and Products for Human UseAnnex 3 – Manufacture of Radiopharmaceuticals Annex 4 – Manufacture of Veterinary Medicinal Products other than ImmunologicalsAnnex 6 – Manufacture of Medicinal GasesAnnex 8 – Sampling of Starting and Packaging MaterialsAnnex 11 – Computerised SystemsAnnex 12 – Use of Ionising Radiation in the Manufacture of Medicinal ProductsAnnex 13 – Manufacture of Investigational Medicinal ProductsAnnex 15 – Qualification and ValidationAnnex 17 – Parametric ReleaseAnnex 19 – Reference and Retention Samples

Major Deficiencies by Annex – International FY18/19

Annex 1 – Manufacture of Sterile Medicinal ProductsAnnex 2 – Manufacture of Biological Medicinal Substances and Products for Human UseAnnex 3 – Manufacture of Radiopharmaceuticals Annex 8 – Sampling of Starting and Packaging MaterialsAnnex 11 – Computerised SystemsAnnex 15 – Qualification and Validation

Critical deficienciesA '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:

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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 referencedPIC/S Part 1 Deficiencies

Clause 1.5 Management Responsibilities

• Senior management has the ultimate responsibility to ensure 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 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.

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

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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 GMPindicates 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 batchesindicates a failure of the person responsible for QA/QC to fulfil his/her dutiesconsists 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 referencedPIC/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 referencedPIC/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 referencedPIC/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.

Major deficiency annexes referencedPIC/S Annex Deficiencies

Annex1 § 81

Contamination through Grades • Components, containers, equipment and any other article required in a clean area where aseptic work takes place should be sterilised and passed into the area through double-ended sterilisers sealed into the wall, or by a procedure which achieves the same objective of not introducing contamination.

Annex1 § 8

Monitoring • Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.

Annex 11 § 9

Computerised System Audit Trails

• Consideration should be given, based on a risk assessment, to building into the system the creation of a record of all GMP-relevant changes and deletions (a system generated "audit trail"). For change or deletion of GMP-relevant data the reason should be documented. Audit trails need to be available and convertible to a generally intelligible form and regularly reviewed.

Annex11 § 12.1

Computerised System Security • Physical and/or logical controls should be in place to restrict access to computerised system to authorised persons. Suitable methods of preventing unauthorised entry to the system may include the use of keys, pass cards, personal codes with passwords, biometrics, restricted access to computer equipment and data storage areas.

Major deficiency annexes referencedPIC/S Annex Deficiencies

Annex 13 § 24

Labelling of IMPs • Packaging and labelling of investigational medicinal products are likely to be more complex and more liable to errors (which are also harder to detect) than for marketed products, particularly when “blinded” products with similar appearance are used. Precautions against mis-labelling such as label reconciliation, line clearance, in-process control checks by appropriately trained staff should accordingly be intensified.

Annex 15 § 10.1

Cleaning Validation • Cleaning validation should be performed in order to confirm the effectiveness of any cleaning procedure for all product contact equipment. Simulating agents may be used with appropriate scientific justification. Where similar types of equipment are grouped together, a justification of the specific equipment selected for cleaning validation is expected.

Annex15 § 1.7

Quality Risk Management • A quality risk management approach should be used for qualification and validation activities. In light of increased knowledge and understanding from any changes during the project phase or during commercial production, the risk assessments should be repeated, as required. The way in which risk assessments are used to support qualification and validation activities should be clearly documented.

Inspection deficiency trendsOverall improvements seen at inspection - decrease in the overall numbers of deficiencies cited

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Chapter 3 – Premises and EquipmentFacility DesignBuilding Materials UsedEquipment Calibration

Chapter 4 – DocumentationControl of DocumentationElectronic Systems

Inspection deficiency trendsAreas requiring focus - an increase in the number of deficiencies cited

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Chapter 1 - Investigations, Risk Assessments and Product Quality Reviews

Chapter 2 - Personnel specifically pertaining to training assessments

Annex 11 - Specifically relating to Computerised Systems Validation and Data integrity

Annex 15 - Specifically relating to requalification of equipment, facilities, utilities, systems at an appropriate frequency

Questions

Special Thanks to Clement Schlegel