Panel discussion GMP inspection process – Health Canada Chantal Cazeault Executive Director, Product Quality

Health Canada- GMP inspections Health Canada is responsible for compliance monitoring and enforcement activities related to health products in order to verify that regulatory requirements are being applied appropriately. Canadian GMP requirements apply to all drug establishments that fabricate, package, label, distribute, import, wholesale, or test a drug. Drug establishments must hold an Establishment Licence and pay a fee when applying. These fees cover a portion of the cost of Health Canada's regulatory programs related to: application review, GMP inspection, Drug/laboratory analysis. Health Canada inspects domestic facilities at a defined frequency. The frequency and duration of these inspections will be based on the inherent risk posed by the nature of the activities performed. If compliance risks are identified or other risk mitigation strategies are needed, inspections will be scheduled more frequently. For foreign facilities, Health Canada will do a paper-based review of inspection results from recognized regulatory authorities. A risk-based approach is used to determine if an on-site inspection is required, based on whether or not evidence of GMP compliance is available, type of GMP evidence, compliance history of the foreign site, possibility of a joint inspection with other qualified regulatory authority, and medical necessity of the drug product.

MRAs and Harmonization Several mutual recognition agreements (MRAs) covering GMP compliance programs for drug products have been established with international regulatory authorities. The equivalency of the MRA partners' GMP compliance programs has been determined; therefore Health Canada will consider the Certificate of Compliance (CoC) as evidence to support the GMP compliance of a foreign building. Health Canada will accept the final and most recent (i.e. within the last 3 years), inspection report signed and issued by: recognized regulatory authority (e.g. FDA, EMA), World Health Organization (WHO), European Directorate for the Quality of Medicines (EDQM) Health Canada GMP standards are harmonized with those of: The World Health Organization (WHO) The Pharmaceutical Inspection Cooperation/Scheme (PIC/S) The International Council on Harmonisation (ICH)

Inspection process and risk classification During an inspection, an inspector notes deviations from Canadian GMPs. These deviations appear as observations in the inspection Exit Notice provided to the establishment. A Risk classification is assigned to each observation, in relation to the nature of the product, nature of the deviation, and number of occurrences: Critical observation (Risk 1) – Describes a situation that is likely to result in a product that may result in an immediate or latent health risk, or that involves fraud, misrepresentation or falsification of processes, products or data. Major observation (Risk 2) – Describes a situation that may result in the production of a drug not consistently meeting its marketing authorization. Other observation (Risk 3) – Describes a situation that is neither critical nor major, but is a departure from the GMPs. When observations are noted, the establishment must take corrective actions to fully comply with regulations. The establishment may also need to create and implement a corrective action and preventive action (CAPA) plan that includes target dates for completion. The timeline to respond to Health Canada and provide the plan is 20 working days.

Inspection ratings Possible inspection ratings are: C (Compliant) – the facility is found to be in compliance with the Food and Drugs Act and Regulations.  Generally, a C rating will be assigned when few risk 2 observations are noted (i.e. isolated issues) or only risk 3 observations are noted. NC (Non-Compliant) – the facility is not compliant with the Food and Drugs Act and Regulations. Generally, a NC rating will be assigned when a Risk 1 observation is noted during an inspection, or numerous Risk 2 observations are noted or repeated from previous inspections, indicating that the company does not control its processes and operations sufficiently. Or when Risk 2 observations identifying overarching systemic issues are noted. A NC rating may result in compliance and enforcement actions which may include: the expedited implementation of corrective measures, adding terms and conditions to the establishment licence, a proposal to suspend the establishment licence, and/or the suspension of an establishment licence. The immediate suspension of an establishment licence may be initiated in cases where it is deemed necessary to do so in order to prevent injury to the health of consumers. Health Canada’s compliance and enforcement response will be proportionate to the identified risk and will provide the regulated party with an opportunity to come into compliance.

Inspection process and risk classification Observations requiring immediate or expedited corrective actions will be identified by the inspector. Whenever possible, the company is given the opportunity to correct deficiencies during the inspection. Generally, a paper- based review of the response to observations is performed. A follow-up on CAPAs is typically done at the next GMP inspection. A re-inspection may be performed to make sure corrective actions have been taken (based on risk). A risk classification guide is available on the Health Canada website and provides examples of GMP observations noted during inspections: www.canada.ca/en/health-canada/services/drugs-health-products/compliance- enforcement/good-manufacturing-practices/guidance-documents/risk-classification-drug-gmp-observations- 0023.html Examples of Critical (Risk 1) issues: testing results were misrepresented or falsified, no media fills were performed to demonstrate the validity of aseptic filling operations Examples of Major (Risk 2) issues: gowning practices for clean and aseptic areas were inadequate, line clearance between production of different products was not documented and governed by a SOP Examples of other (Risk 3): investigations of non-conformances were not completed in a timely manner, there was no written procedure for archiving or retrieving electronic data Results of on-site inspections and paper-based reviews are listed in the Drug and Health Product Inspections Database: http://healthycanadians.gc.ca/apps/gmp-bpf/index-en.html