White Paper

Qualification And Validation Of Isolator Systems

By Jürgen Metzger and Andrey Yermakovich


Manufacturing of high performance pharmaceutical machines and equipment must follow strict guidelines.  There is no room for failure, therefore all involved parties should be aware and must follow relevant norms. Bosch qualification and documentation processes start in the planning phase of a project, follow through manufacturing and lifecycle of the equipment.

The user requirements and equipment functions need to be defined in the early state of a project. The specification shall clearly define CQAs and CPPs (Critical Quality Attributes and Critical Process Parameters). The materials, processes (e.g. welding) and assembly must be ensured. Materials properties and influences to certain substances must also be specified. Surface properties and radiuses shall be considered as well. Electrical equipment (e.g. sensors, actuators) and automation platform need to be considered in a Hardware Design Specification. Software and its structure is applicable in Software and Module Design Specs.

Bosch Packaging Technology has a mature and robust quality management system which consists of:

  • Norm database (consists of thousands of ISO- and DIN- Norms)
  • Hundreds of internal SOPs and guidelines.

Every step from planning through design, manufacturing, commissioning, etc. is reviewed and well documented.

Of course, sophisticated processes must be checked, which guides us directly back to the topic.

How does one verify that everything is designed as specified and built as designed and functioning?

  • By careful planning, robust documentation practice and execution of qualification and/or verification.
    BIT (Bosch Internal Testing) and extensive Qualification and Validation activities.

What activities are recommended to have full GMP compliance in a project?

  • Ideally IQ/Cal/OQ+AFT, highly recommended is also DQ.

What does IQ, OQ, PQ, etc. stand for?

  • Before immersing into qualification and validation activities, let´s clarify a few abbreviations.

VMP – Validation Masterplan (see also PQP)
PQP – Project Qualification Plan
URS – User Requirement Specification
RTM – Requirement Traceability Matrix
FS – Functional Specification
HDS/SDS – Hardware Design Specification / Software Design Specification
SMDS – Software Module Design Specification
ICD – Internal Checkout Documentation
IQ – Installation Qualification
CAL – Calibration
OQ – Operational Qualification
PQ – Performance Qualification
CD/CV – Cycle Development / Cycle Validation
DQ – Design Qualification
RA – Risk Analyses
(c)FAT – (customized) Factory Acceptance Test
DR – Disaster Recovery
AFT – Alarm & Function Testing
(c)SAT – (customized) Site Acceptance Test

Bosch qualification activities are tailored to the customer needs based on authority regulations.

The right sequence of actions guarantees most efficient qualification / validation performance.

Here´s a brief description of activities to be GMP compliant:

The Installation Qualification (IQ) is the executed test protocol documenting that a system has the necessary prerequisite conditions to function as expected. In other words, everything is installed as designed and specified.

The Calibration (Cal) is the executed test protocol documenting that the process relevant devices and gauges work in their specified range. In other words, the measured values must be reliable from the sensor to the display within the defined accuracy range.

The Operational Qualification (OQ) is the executed test protocol documenting that a system meets the defined functional requirements, or that the system does what it’s supposed to do.

The Performance Qualification (PQ) is the executed test protocol documenting that a system meets the defined requirements to function in the production environment. In other words, to guarantee theperformance of production environment with all its integrated / connected systems.

The Alarm & Function Testing (AFT) is the executed test protocol documenting that the Software of a system (like HMI, PLC, IPC, SCADA) meets the defined requirements to function as it’s supposed to do.

Example of Qualification / Validation on Isolators:

  • Calibration (full loop from sensor to display)
  • HEPA/ULPA filter integrity test (e.g. DEHS)
  • Air change rate per hour
  • Air velocity test during production – air distribution (flow, velocity, smoke) studies
  • Room classification of isolator and LF – areas
  • Leak testing of the enclosure
  • Sterilizer tests (for H2O2)
  • Temperature mapping (H2O2 distribution pipe and Isolator chamber)
  • Micro-biological sterilization tests: Cycle Development (CD) and Cycle Validation (CV) with BIs, CIs
  • Aeration test (Aeration time to reach residual H2O2 concentration level of e.g. < 1ppm … < 0,05ppm)

Cycle Development and Cycle Validation for H2O2 Biodecontamination

Cycle Development includes:

  • Set of engineering studies to determine the impact of direct environmental- and external factors to decontamination process
  • OQ-studies
  • Tests with chemical indicators (CI)
  • Tests with bio indicators (BI), which are stainless steel coupons inoculated with 6 log of the most resistant viable spores of Geobacillus Stearothermophilus.

Cycle Development is designed to determine process parameters, worst-case positions for BIs and investigation of process limits needed for a successful distribution of H2O2 during biodecontamination. Critical factors are for instance temperature, humidity, amount of H2O2 to reach a certain concentration (ppm) by having the right injection rate of peroxide for a 6-log reduction in Isolators.

The distribution of hydrogen peroxide in an Isolator is assessed by using Chemical Indicators (CIs).

Before starting CD/CV, every lot of BIs supposed to use, will be verified / tested in your own laboratory to ensure they meet our high quality standards.

After a bio-decontamination cycle, the BIs will be transferred from the isolator into a nutrient broth and incubated at 55°C for seven days.

Once Cycle Development is finished, the Cycle Validation follows.

The calculations for statistical interpretation of results is performed according to ISO 14161.

Sophisticated internal processes guarantee the highest level of quality from scratch.

Transparency, reliability as well as continuous improvement are some of our principles to meet customer expectations.

We as Bosch Packaging Technology work closely with you as our highly valued customer and want to make sure, that we guide you safely through your project. Furthermore, It´s our pleasure to support your daily tasks in operating your equipment made by Bosch Packaging Technology.

About the Authors:

Jürgen Metzger is Barrier Systems & Process Specialist at Robert Bosch Packaging Technology, Inc.
Andrey Yermakovich is Validation & Project Manager at Robert Bosch Packaging Technology, Inc.