Dr Jürgen Hofmann, Hygienic Design Weihenstephan Consulting)
Dr Jean Denis Mallet, ECA & Former Head of the French Pharmaceutical Inspection Dpt. AFSSAPS
Gert Moelgaard, Past Chairman of ISPE, Senior Consultant
Markus Multhauf, Senior Consultant GMP-Engineering
Dr Ingrid Walther, Former Head of the Business Unit iv Drugs, Fresenius
This course explains how the requirements laid down in the GMP and FDA regulations can be put into technological and engineering practice. The whole lifecycle from the design, the qualification and the maintenance of equipment is covered. The new Annex 15 of the EU GMP Guide plays an important role here as well.
Technical compliance is a wide field, especially when taking into account the ICH framework which covers the whole lifecycle of pharmaceutical manufacturing.
It does not only mean to comply with regulatory guidelines but also with submissions and the technological state of the art, meaning ISO and other standards as well as accepted good practices in the pharmaceutical industry.
In this GMP course we want to focus on the main topics with regard to compliance in the technical environment:
Technical QA aspects:
There are a number of quality assurance systems which are crucial for the technical units. Most important are changes and deviations (as they also can occur in technical environment) which have or might have a direct impact on the pharmaceutical material produced. And even more important is the validation system, where the qualification of equipment, utilities and facilities has to be part of.
GMP Facility & Re-Construction
Designing an appropriate layout belongs to this part as well as understanding what the GMP requirements for the cleanrooms and for the HVAC systems are, depending on the type of manufacture. Re-Construction during on-going manufacture is supreme discipline in this field.
GMP-compliant design of equipment
A GMP-compliant design of equipment is the basis for fulfilling the technical requirements. In this respect, engineering assumes a prominent role in ensuring the safety of medicinal products. In this context, the need for material certificates is often subject to discussion.
Validation / Qualification
Not only GMP regulations but also inspectors consider qualified equipment and validated processes as the prerequisites for producing pharmaceutical quality. The identification of the equipment that has to be qualified by means of a risk analysis is a crucial point. This field has now re-gained considerable attention as the regulations are changing: After FDA’s new guide on validation (and process verification) also Annex 15 of the EU GMP Guide has been revised.
Preventive maintenance in pharmaceutical production is an essential element of the Pharmaceutical Quality System. Systems for calibration & handling of repairs are of equal importance for maintaining the qualified state. That’s why maintenance and calibration are parts of an efficient requalification system, besides the change control and deviations systems of course. Finally, auditing the own technical suppliers is a recurring activity from the beginning of a project until the outsourcing of engineering activities later on.
This course is directed at staff in pharmaceutical engineering departments, at technicians, engineers, planners as well as plant constructors and equipment suppliers who are involved in tasks related to engineering work in a cGMP environment.
QA systems with technical relevance
Part 1: Change Control, Technical Changes and Marketing Authorisations
Part 2: Deviations, CAPA & Malfunctions
- Regulatory Requirements
- Identification of „Changes“ - What has to be handled under Change Control?
- CC-Workflow and pitfalls
- Change Management in Routine Operations vs. Project work
- Marketing Authorization - Regulatory Affairs for Engineers
- Deviations in the technical environment
- Documentation in logbook and higher-level systems
- Evaluation of technical deviations
- When does a deviation require CAPAs?
- Handling of alarms
- Correlation between changes, deviations, repairs and maintenance
Qualification, Re-Qualification & Commissioning
- Managing risks in the technical environment
- Project risks
- Equipment risks
- Product risks
- Risk management tools
Materials and Surfaces
- What to write in a URS & what not
- Using risk analysis from kick-off to routine operation
- Handling impact and non-impact systems
- From URS to PQ: step by step
- How to ensure traceability?
- System Verification / Validation
- Re-Qualification: How to..? And how often?
GMP-compliant Equipment Design
- Which materials can be used and for what purpose?
- Stainless steel, plastics, polymers,…
- How smooth have surfaces to be? Roughness and structures of cleanable surfaces
- What are the requirements on welding?
- Effects of corrosion, failures, and damage
GMP Zone Concepts (sterile/non-sterile/highlypotent)
- Open and closed systems
- Overview on important construction details for sterile and non-sterile applications
- Design of gaskets and problems with gaskets
- Allowed lubricants
- Examples of GMP-compliant equipment
GMP Class Requirements (HVAC and Barrier Systems)
- Basic GMP requirements for materials & pharmaceuticals handling
- Physical requirements (areas) vs Dynamic requirements (HVAC)
- Finding the correct requirements depending on the manufacturing operation
- Defining an appropriate layout and air lock concept
- Defining personal & material flows
- Product vs Personal Protection
- Product Protection concepts, types of air flows
- Avoiding Cross Contamination: the EMA idea
- The future of barrier systems (isolator and RABS)
Upgrading, Re-construction and Renovation of Facilities
- Some HVAC system concepts (e.g. fresh air / recirculated air)
- Understanding the main parameters (volumes, pressure, cleanliness, etc.)
- GMP Classification and ISO standards, and their interaction
- The basics of air filtration and flushing air circulation
- Particle testing depending on the cleanroom zone
- Microbiological monitoring on a cleanroom
- Requirements on construction of floors, ceilings and walls
- Classification, Qualification, Requalification of Cleanrooms
Qualification and Management of Technical Suppliers
- Required as built documentation to start
- What to consider in re-construction projects?
- How to protect the ongoing manufacturing operations
- Protection of products
- Protection of equipment, rooms and HVAC
- Flow concepts and control of external personal
- Access control, pest control, cleaning
- Documentation of protective measures
- Examples from recent projects
- Contract management: Commercial- vs. Engineering- vs. GMP-issues
- Selection and auditing of suppliers with a risk based approach
- How much GMP must a supplier have?
- Review of suppliers and their performance
- How to audit a technical supplier?
- Examples of managing suppliers for equipment, technical services, ..
Pharmaceutical Water Systems
Maintenance & Calibration
- Regulation basics
- Generation: Purified Water, WFI, Pure Steam
- Components: working principles and hazards (Softener, EDI, RO,...)
- Storage and Distribution concepts
- Sanitisation principles, avoidance of biofilms
- Automation, Instrumentation, Trending
- How to handle OOS in a water system
Impact of the new GMP Thinking on Engineering
- Life-cycle model of pharmaceutical equipment
- How to set up and maintain a maintenance/calibration system
- Definition and control: frequencies, activities, tolerances, acceptance criteria, etc.
- Timing of activities
- Documentation & labeling
- Data integrity
- Impact of the new Annex 15
- State of validation / qualification in the US
- Impact of ASTM E 2500 on European projects
- Changes coming from ICH Q 8-10
- How to comply with EU and US requirements in technical projects
- Practical examples