# Presentation: 862878

## Pilot Risk-Ranking Model to Prioritize Manufacturing Sites for GMP Inspections

- Advisory Committee for Pharmaceutical Science
- Manufacturing Subcommittee
- July 21, 2004
- David J. Horowitz, Esq.
- Director, Office of Compliance
- Center for Drug Evaluation and Research

## GMP Initiative Announcement:August 21, 2002

- Evaluate the currency of our drug quality programs so that FDA resources are used most effectively and efficiently to address the most significant public health risks.
- In order to provide the most effective public health protection, FDA must match its level of effort against the magnitude of the risk.
- Resource limitations prevent uniformly intensive coverage of all pharmaceutical products and production.  Although the agency has been implementing risk-based programs, a more systematic and rigorous risk based approach will be developed.

## Slide 3

## ICH Q9:  Defining Risk

**Preliminary working definitions** (March 2004) from ICH EWG on Quality Risk Management (Q9):
**Risk:** Combination of the probability of occurrence of **harm** and the severity of that **harm**. ISO 14971
**Harm:** Damage to health, including the damage that can occur from loss of product efficacy, safety, **quality** or availability
- Focus on quality for our purposes

## ICH Q9:  Defining Risk (cont’d)

**Quality:** Degree to which a set of inherent characteristics of a product, system or process fulfils **requirements**
**Requirements: ***Needs or expectations* that are stated, generally implied or obligatory by the *patients or their surrogates* (e.g. health care professionals, regulators and legislators)
- Combining key terms:  Risk to quality is the probability/severity that drug will fail to meet the needs/expectations of the patients and their surrogates

## Needs and Expectations of Patients/Surrogates

- For *drug quality*, what are the needs/expectations of patients/ surrogates?
- Clinical performance is the key:
- “... delivery of efficacy and safety as described in the label, derived from the clinical trials.”
- Janet Woodcock, M.D.
- Availability
- Price?

## Clinical Performance

- Drug performs as described in the approved labeling
- Delivers the relevant *attributes* of the drug in the clinical database on which the FDA approval decision was based
- What are these attributes that can serve as surrogates for clinical performance?

## Clinical Performance Surrogates

- A product’s clinical performance surrogates are its established quality attributes, including:
- Identity/potency
- Purity
- Strength
- Bioavailability/delivery (e.g., dissolution)
- Labeling/packaging
- Physical performance/appearance (including aspects that influence adherence and acceptability)

## Identify Predicted/Known Hazards to Quality Attributes:  Risk Factors

- Risks to pharmaceutical quality can be identified based on the **probability** and **severity** of adverse impact on these quality attributes
- Explicitly include factors that mitigate probability/severity of adverse effects or factors that have a positive impact

## Risk to Quality

**Probability**

**Severity**

- HARM

**Failure to meet**
**Needs/Expectations**
**of Patients/Surrogates**

**Quality Attributes**

**Loss of Quality**

**Probability/Severity**
**of Adverse Impact on**
**Quality Attributes**

## Identifying Risk Factors

- What hazards can adversely impact drug quality attributes/surrogates?
- What processes and parameters are critical for quality attributes/surrogates?
- What factors may affect the identified hazards and critical parameters/processes?
- Other variables predictive of drug products with or without identified quality attributes?

## Probability/Severity

**of Adverse Impact on**
**Quality Attributes**

**Identify Risk Factors**

**Data Limitations**

**Prioritize **
**Improvement**

**Quantify**

**Aggregate**

**Rank**

**Revise Model**

**Incentives**

**Feedback**

## A RISK-BASED FRAMEWORK FOR PRIORITIZING SITES FOR cGMP INSPECTION

**PRODUCT**

**PROCESS**

**FACILITY**

- Site risk potential (SRP):
- A function of the risk potentials for the PRODUCT, PROCESS and FACILITY component risk factors.
- The SRP is a weighted combination of the PRODUCT, PROCESS and FACILITY risk potentials
- Semi-quantitative risk potentials represented as “high,” “medium,” or “low,” and are numerically discrete variables in calculations.

## Ranking Manufacturing Sites Based on Aggregated Risks

- Risks associated with each manufacturing site can be aggregated and ranked against risk scores for other manufacturing sites
- Goals
- Systematically incorporate our current knowledge about drug quality risks
- Prioritize sites for periodic systems-based inspections
- Data limitations
- Some predicted risk factors not captured
- Challenge and opportunity
- Create incentives for manufacturers

## Risk Ranking Model:  Product Factors

- What are the intrinsic properties of products such that deficiencies in quality, if any, would have more adverse public health impact than others?
- Recall data identifies products or dosage forms associated with frequent and/or serious recalls

## Risk Ranking Model:Facility Factors

- Are some manufacturing facilities (or manufacturers) more likely to produce a product with quality problems?
- Effectiveness of quality systems
- Inspectional record and compliance history
- Exposure: volume produced at facility
- Other characteristics?
- Macher and Nickerson study

## Risk Ranking Model:Process Factors

- Are some manufacturing processes, for particular product classes, more likely to go wrong than others?
- Use expert elicitation to identify risk factors and weightings
- Risk of contamination or mix-ups
- Maintaining state of control of the process
- Potential for process capability metrics?

## Continuous Improvement

- The model can only be as good as the scientific/technical assumptions and data that are used to develop the risk scores
- Multiple iterations and successive revisions will reflect growing knowledge base and extensive input from internal and external experts
- Your input on prioritizing areas for improvement will be very helpful