Course No 15090
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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
inspector’s approach to detect cross
poor practices observed
examples of deficiencies
recalls related to cross contamination
Update on the regulatory requirements: EU GMP and handling of potent compounds
Dedicated vs shared facilities
EU GMP-Guide chapters 3.6 and 5.17-21:
what are the consequences
Principles of assessing toxicological risks – the basis for calculating limits
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
Cross Contamination through poor facility design and maintenance practices
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
Environmental Control – Cross Contamination Risks through failures in the HVAC System
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.
Contamination caused by inappropriate cleaning of equipment
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
How much cross contamination is allowed?
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
Calculation of cleaning validation limits according
to the new EMA requirements
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.