Application of rapid methods for the risk assessment of pharmaceutical processes Tim Sandle, Ph.D.

Introduction Introduction to rapid methods Advantages of rapid methods Risk assessment of pharmaceutical processes Application of rapid methods for risk assessment: Example of the aerosol based Instantaneous Microbial Detection System (IMDA).

Rapid microbiological methods

What is a ‘rapid method’? Rapid microbiological method technologies aim to provide more sensitive, accurate, precise, and reproducible test results when compared with conventional, growth-based methods. They normally involve some form of automation. They normal capture data electronically.

What is a rapid method? Microbiological testing generally falls into one of four groups: Qualitative tests for Presence/Absence (e.g. is E. coli in the water?) Quantitative tests for Enumeration (e.g. how many bacteria are in a product sample?) Quantitative tests for Potency or Toxicity (e.g. what level of endotoxin is in the sample?) Identification tests (e.g. which species of bacteria was found in the sample?)

What is wanted from a rapid method? Faster time Greater accuracy Automation Electronic capture of data Linking of apparatus e.g. LIMS

Current guidance European Pharmacopeia “Alternative Methods for Control of Microbial Quality” (Ph. Eur. 5.1.6). USP<1223>“Validation of Alternative Microbiological Methods” FDA PAT initiative FDA's cGMPs for the 21st Century: A Risk-Based Approach ICH ICH Q8; Pharmaceutical Development, and ICH Q9; Quality Risk Management encourage PAT

General validation steps Risk Assessment Validation Master Plan (VMP) User Requirements Specifications (URS) Design Qualification (DQ) Supplier Assessment/Audit Functional Design Specifications (FDS) Requirements Traceability Matrix (RTM) Training and Standard Operating Procedures (SOPs) The Test Plan Factory Acceptance and Site Acceptance Testing (FAT and SAT) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) Validation Summary Report

Risk assessment

Importance of risk assessment An expectation of regulatory authorities. Either a quantitative or qualitative determination of one or more risks. Risks relate to a situation where a recognized hazard may result in harm. A hazard is any circumstance in the production, control and distribution of a pharmaceutical product, which can cause an adverse health effect.

What is ‘risk’? Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm i.e. What might go wrong? What is the likelihood (probability) it will go wrong? What are the consequences (severity)?

Microbiological risks Microbiological contamination in the product, which might cause patient harm. From: Equipment Air e.g. Cleanrooms: Air filtration Air direction Air movement (pressures) People Water Central issue is contamination transfer.

What does a ‘risk’ mean? Is the risk acceptable and what controls are available to mitigate the risk? Is the risk above an acceptable level? What can be done to reduce or eliminate risks? What is the appropriate balance among benefits, risks and resources? Are new risks introduced as a result of the identified risks being controlled?

Use of risk assessment Risk assessment can be: Proactive Reactive Focused on process improvements There is no such thing as ‘zero risk’ A decision is required as to what is ‘acceptable risk’. Risk Assessment is not an exact science. Different people will have a different perspective on the same hazard.

Basics of risk assessment Formal risk approaches normally share four basic concepts, which are listed below: Risk assessment, Risk control, Risk review, Risk communication. Examples: HACCP FMEA

Contamination within a cleanroom Practical example Contamination within a cleanroom

Cleanroom contamination Points of contamination: adjacent areas; supply air; cleanroom air; surfaces; people; machines; ancillary equipment; materials; containers; packaging; liquids Focus on: The reinstatement of a cleanroom following a period of production downtime.

Method of assessment Azbil BioVigilant's Instantaneous Microbial Detection System (IMDA). Uses advances in light scattering, optics and special software. Provides real-time data about particles and biological activity in air. Suited for cleanrooms and controlled environments.

IMDA In real-time: Air is passed through a laser. The instrument counts the numbers of particles in a sample of air (inert and biological) through two detectors. Biological particles are detected using a fluorescence detector, looking for three biological markers: NADH, riboflavin, and DPA. These metabolites cause fluorescence and the presence of a biological microorganism.

Cleanroom use Cleanrooms: As built At rest In-operation Downtime for maintenance E.g. HEPA filter replacement, new equipment, drilling Reinstatement Cleaning and environmental monitoring

Cleanroom reinstatement Problem: Waiting for results through environmental monitoring 3 – 10 days, depending upon media and incubation parameters. Solution IMDA can provide an assessment in less than one hour

Study Need to understand normal operating conditions Setting a baseline Observing events Understand state of the area in relation to viable monitoring, but a direct comparison is not possible.

Study Assessment during normal operations Assessment during shutdown period Highest Bio reading = 180 Highest Bio reading = 2,500

Study Assessment post-shutdown Assessment of cleaning and recovery period Assessment post-shutdown Highest bio reading = 370 Highest bio reading = 220

Assessment IMDA provides the means to: Understand what is ‘normal’ in terms of biological activity & set alert and action profiles. Understand the impact of people in the area, equipment movements etc. Understand what happens when an area is declassified. Understand the impact of cleaning. Compare the cleanroom following reinstatement with the previous status.

Pharmaceutical Microbiology: www.pharmamicroresources.com Tim Sandle Pharmaceutical Microbiology: www.pharmamicroresources.com