Risk-based approach in:

definition and classification of deficiencies

• Deficiencies are descriptions of non-compliance with GMP requirements.

A distinction is made between deficiencies as a result of: -

– a defective system or,

– failure to comply with the system.

• Deficiencies may be classified as: – Critical Observation – potential risk harm to the user – Major Observation – major deviation from GMP/GCP – Minor or Other Observation – departure from good practice

Classification of observations

Critical Observation

•An observation that has produced, or may result in a significant risk of producing, an API that, when used in a finished product, is harmful to the user.

Major Observation

A non-critical observation that:

•has produced or may produce a product which does not comply with its prequalification application (including variations); and/or

•indicates a major deviation from the GMP guide; and/or

•indicates a failure to carry out satisfactory procedures for release of batches; and/or

•indicates a failure of the person responsible for QA/QC to fulfill his/her duties; and/or

•consists of several other deficiencies, none of which on its own may be major, but which may together represent a major deficiency and should be explained and reported as such.

Other Observation

•An observation that cannot be classified as either critical or major, but indicates a departure from good manufacturing practice.

•A deficiency may be “other” either because it is judged as minor, or because there is insufficient information to classify it as major or critical.

Pfizer 10 Step ProcessPfizer 10 step process 13p

1. Collect & Organize the informationGathering relevant information, reviewing appropriate references & identifying assumptionsTools can be used to organize the informationDefine the boundaries of the QRM exercise

2. Formulate the Risk Question:Starting point of the QRM exercise, high level statement outlining

the issue & purpose for conducting the QRM exercise including riskfactors, the scope of the issue and any related limits or constraintsExample: What is the supplier audit schedule that will ensure that supplierspresenting a high risk to the patient are audited in a more frequent manner?

3. Choose ToolBasic risk management facilitation methods (flowcharts, check sheetsetc)Failure Mode Effects Analysis & Failure Mode Effects & CriticalityAnalysisFault Tree AnalysisHazard Analysis & Critical Control PointsHazard & Operability AnalysisPreliminary Hazard AnalysisRisk Ranking & FilteringSupporting statistical tools Risk Management Tool adapted from The development of a Quality Risk

Management solution designed to facilitate compliance with the risk‐based

qualification, validation and change control GMP requirement of the EU. Dublin :Dublin Institute of Technology, 2007 . Kevin O'Donnell PhD

4. Identify Risks Factors and Related Hazards:What are the Risk Factors (patient safety, compliance and business) arising from allpotential hazards identified?

5. Define the Risk Components & ScalesWhat does Severity, Probability & Detection mean in terms of this RiskQuestion?In terms of a QRM exercise to create a supplier audit scheduleSeverity ‐ Criticality of the productProbability ‐ Complexity of the site (multi‐product)Detection ‐ Audit historySeverity ScaleFactor Definition10 Sterile products6 Product orally administered3 Topical products and compounds not directly used bypatient1 Compounds used during manufacturing process

6. Create matrix

7. Determine Action Threshold•A level or value above which an action will take place and below which it will not

8. Apply the tool• Analyze the detailed risks and quantify those risks using the scales forseverity, probability and detection to provide a risk score•Determine what actions are required based on the threshold for action

9. Define Risk MitigationConsider measures/actions that could:Decrease the severity stop failure before significant consequences, reject, recallDecrease the probability Inspect defect out of batchIncrease the detection Move from manual to machine inspectionReapply the tool taking the mitigating measures into considerationDetermine if the mitigations/actions have introduced new risks

10. Document and Approve•Document and approve in a Quality Risk Assessment Report