Manufacture of highly potent Compounds

Manufacture of highly potent Compounds

Barcelona, Spain

Course No 9122


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Dr Andreas Flückiger, F. Hoffmann-La Roche
Frank Generotzky, Baxter Oncology
Dr Friederike Hermann, Lonza
Dr Rainer Nicolai, F. Hoffmann-La Roche
David O'Connell, Penn Pharma
Dr Harald Stahl, GEA Pharma Systems
Dr Clemens Stief, Pfizer


Main focus of this conference is on the connection of cGMPs with safety aspects, especially on avoiding cross contamination and minimizing exposure.
It will also deal with the calculation of exposure limits, limits for cleaning validation and the possibilities offered by containment technology, shown by real life examples from pharmaceutical industry ranging from the manufacture of APIs, to oral solid dosage forms and sterile medicinal preparations.


Many manufactures have to deal with the situation how to implement a new and potent product in an existing facility. Is it possible? Only by complying with regulatory demands with regards to the prevention of cross contamination and using risk management tools based on ICH Q9, a safe and cost effective solution can be found. Furthermore the Safety Working Group of the European Medicines Agency (EMA) has released a draft Guideline on setting health based exposure limits. This corresponds to updates of chapters 3.6 and 5.18/19 of the EU GMP-Guide.
This will have an impact on the handling of highly potent materials within the pharmaceutical industry and the way, risks have to be evaluated. This will have to be done in much more scientific way, based on toxicological and pharmacological data.

During this conference the following questions represent some of the issues discussed:
Which highly active substances can be handled in the same building/facility/plan?
How are OEL Limits and ADIs calculated?
How much containment do I need?
What are the different technical solutions?
What should a risk analysis contain?
How are exposure measurements carried out?
What has to be considered for the cleaning of equipment?

Well established examples for layout concepts, equipment for closed product handling and analytics are demonstrated through case studies with different pharmaceutical applications in primary and secondary facilities.

Target Group

Managers and technical experts from production, development and occupational health & safety, responsible for the manufacture and handling of highly potent materials. Also engineers who design, install and qualify containment facilities and systems.


Each participant receives an industrial guidance document on the derivation of ADE/PDE values


Principles of Assessing and Managing Occupational Health Risks in Potent Compound
Legal requirements regarding worker safety
Assessing the hazard: potency and toxicity of the compounds. Occupational exposure limits and health hazard categories
Ensuring the right level of process containment: Design exposure limits as drivers for equipment selection. The illusion of “closed processes”.
Dedicated facilities or risk-based acceptance of multi-purpose manufacturing?
Exposures to pharmaceuticals at the workplace must be controlled to below acceptable limits. For most APIs, the manufacturer himself needs to develop these limits and compliance with them must be documented. Protection of the workers from overexposure must be achieved primarily by technical means and not by means of personal protective equipment. Equipment must have adequate containment so that the required exposure control is ensured at least in all routine situations. Existing facilities must be upgraded accordingly. 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.

Review of technical requirements for contained product handling
Product transfer- review of current possibilities
Sampling 1 - Review of possibilities for contained sampling
Sampling 2 - Examples for in-line measurements allowing to drop sampling
Cleaning: Examples of automatic cleaning

A risk-based approach to define the containment strategy
Stepwise evaluation of single processing steps
Risks for employees
GMP Risks versus SHE Risks
Systematic evaluation of risks
Definition of appropriate actions: equipment, organisation, process changes,…
Usage of formal tools: GAP-Analysis, FMEA, ..

Case Study Hoffmann-La Roche
Chemical Production of Highly Active APIs - Recent Developments at F. Hoffmann-La Roche
Most of the newly developed APIs are "highly active" resulting in increased requirements on the plant installation to ensure workplace protection by technical means, rather than PPE. Some recent developments will be shown, starting from general concepts going into technical details.
hygienic design piping class for chemicals
special reactor design
isolator technologies

Case Study Carbogen Amcis
Cleaning of Equipment in the HiPo Production Plant
What is worker protection before cleaning vessels
How much do we clean before opening for visual inspection
How do we clean
What PPE for visual inspection
How much cleaning follows after visual inspection
To what limit
How do we clean the room around the vessels
Clothing rules for all people including visitors

Toxicological evaluation to set science-based [cleaning] limits
How much carry-over is allowed?
Controlling cross contamination
Old and new approach for determination of cleaning validation limits
The PDE / RiskMaPP principle in the cleaning of pharmaceutical equipment
Concrete examples

Case Study Pfizer
Design of a facility for the manufacture of oral solid dosage forms and its operation
In this case study a Pfizer high potent development plant will be presented used for the
manufacture of oral solid dosage forms for clinical trials as well as for marketed product support.

Design: Determination of the right level of containment
Environmental protection
HVAC and pressure concept
Personal Protection Equipment

Operation: Minimising exposure and cross contamination
Start up of a high containment plant considering new processes
How to introduce a new product/compound
Process evaluation
Usage of industrial hygiene data for GMP argumentations
Cleaning of equipment and premises
Waste handling (solids, liquids, air, used equipment)

Case Study Baxter
Facility and Equipment Design for High Potent Sterile Drugs produced by Aseptic Processing
Process development
Process design (Airflow concept, monitoring, decontamination).
Process equipment: Isolator vs. cRABS
Risk analysis and qualification
Routine aseptic processing steps in an highly active environment
Industrial hygiene

Case Study Lonza
Single-Use Technology/Flexible Isolators & Containment Measurements
Manufacture of highly active APIs at Lonza
Pros & cons for flexible containment technology
Proof of performance with containment measurements

Case Study Penn Pharma
Contract Development of highly active substances
How to handle substance with little knowledge on toxicity
Designing of High Potent Development and Clinical Manufacturing facility
How Develop and scale-up a high potent drug product.

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