Richard M. Bonner, Chairman of ECA and the European QP Association, formerly Eli Lilly, UK
Dr Andreas Flückiger, F. Hoffmann-La Roche, Switzerland
Dr Jean-Denis Mallet, ECA & former head of the AFSSAPS, France
This GMP training course aims at unveiling possible risks of cross contamination during the production process of pharmaceutical products and APIs. This is especially important as chapters 3 and 5 of EU GMP Guideline are being updated at the moment, with a new focus on the avoidance of cross contamination
- how to detect possible risks,
- how to avoid cross contamination,
- how to determine exposure limits
Cross Contamination is one of the highest risks for patients using pharmaceutical products. Not only the presence of small amounts of antibiotics or other highly potent compounds in medicines can cause severe damage but also carryover of products into another pharmaceutical product is of high risk to the patient. According to the Medicines & Healthcare Products Regulatory Agency in the United Kingdom Product contamination is the second to third highest reason for recalls in the UK in recent years.
Cross Contamination is one of the highest risks for
patients using pharmaceutical products. Not only the presence of small amounts of antibiotics or other highly potent compounds in medicines can cause severe damage but also carryover of products into another pharmaceutical product is of high risk to the patient. According to the Medicines & Healthcare Products Regulatory Agency in the United Kingdom Product contamination is the second to third highest reason
for recalls in the UK in recent years.
It is therefore not surprising that the EU commission published an update of the chapters 3 (premises & equipment) and 5 (production) with the focus on minimizing the risk of cross contamination. Almost at the same time a new EMA Guide on setting health based exposure limits was published. This new guide has massive impact on the dedication of facilities and also on the calculation of limits for cleaning validation. The currently used 1/1000 dose or 10 ppm criteria will become completely obsolete.
Reasons for cross contamination can be manifold and caused by technical as well as organisational deficiencies. Insufficient cleaning of equipment, poor facility design or inappropriate design of the HVAC system may be reasons as well as contamination due via personnel or primary packing material. But also the design of the production process itself can be the cause for cross contamination, for example due to open product handling during transfer or sampling operations in shared plants.
It is therefore extremely important to avoid or minimise the risk of cross contamination, starting when process and equipment are designed. It is also important to learn how contamination risks can be detected, either by visits on-site or by reviewing of the documents which can be SOPs or technical drawings.
Inspectors & QA staff are target group of this course but also responsible persons from production and engineering.
Most frequent findings during GMP Inspections
The regulatory requirements: EU GMP and handling of potent compounds
- inspector’s approach to detect cross contamination risks
- poor practices observed
- examples of deficiencies
- recalls related to cross contamination
Principles of assessing toxicological risks – the basis for calculating limits
- EU GMP-Guide chapters 3.6 and 5.17-21: what are the consequences
- Risk Management
Cross Contamination through poor facility design and maintenance practices
- The toxicological and pharmacological basis of assessing APIs with the objective of worker protection is the same as the one justifying GMP cleaning validation criteria and acceptance of multi-product use of a facility.
- Assessing the hazard: potency and toxicity of the compounds. Occupational exposure limits and health hazard categories
- Definitions: ADE, PDE, NOEL, LOEL, OEB, OEL
- Classification of substances into hazard categories
- How is patient safety connected with the occupational exposure limit ?
- Use of correction factors to fill data gaps
Environmental Control – Cross Contamination Risks through failures in the HVAC System
- A model for identifying cross-contamination risks
- Cross-contamination due to poorly designed facilities (surfaces, cracks and other sources)
- Contamination and cross-contamination due to equipment and their maintenance
- Inadequate segregation of processes involving sensitising products from other products
Contamination caused by inappropriate cleaning of equipment
- Airborne contamination and airborne cross-contamination
- Capture of contaminants where dust is generated
- Air handling and prevention of dust dissemination
- Failures in HVAC design (filtration, airflow pattern, pressure differentials)
- Failures in HVAC operation (e.g. energy saving, unbalanced pressure differentials)
- Risk of Contamination in non-sterile production processes
- What is a risk-based approach to understanding contamination control? How do you decide if the risk is acceptable or not?
- Where can you apply Q9 principles to assess contamination risk during production?
- In Drug substance manufacture
- In Drug product manufacture and packaging
- During sampling, weighing/material transfers
- In the warehouse and distribution chain.
How much cross contamination is allowed?
- What is clean?
- What is “worst case”
- Inadequate cleaning procedures
- The use of non-validated cleaning practices
- The use of non-validated analytical test methods
Workshop: Calculation of cleaning validation limits according to the new EMA requirements
- Cleaning limits in accordance with the new EMA guideline
- Controlling cross contamination
- Old and new approach for the determination of cleaning validation limits
- Requirements from the new EMA Guideline on the setting of risk/health based limits
- RiskMaPP in the cleaning of pharmaceutical equipment
- Concrete examples / calculation examples
In this workshop you will learn how the new EMA guideline on setting health-based limits can be applied in practice. You will learn how to calculate substance-specific limits, also called ADEs (acceptable daily exposures) and PDEs (permitted daily exposures).
To do this, you will learn how to determine the right starting point for each calculation, the NOEL (No-observed-effect-level) and how correction factors are used.