Containment systems are integral to the quality-by-design process of pharma manufacturing, and proving that they meet the specification is key. Alan George, of ILC Dover, highlights how new testing facilities enable them to carry out the necessary tests.
Quality-by-design represents a systematic process to build quality into a product from its inception through to final output.1 Today, quality is a given – an automatic expectation; whether buying a personal consumer product or supplying a component for someone else’s end product, failure is not an option. ILC Dover has seen this in its work with NASA on the space suits used on the moon, and currently in use on the International Space Station, as well as in the flexible containment systems it supplies to the pharma and biopharma industries.
While open area manufacturing is acceptable for many applications, the potential for particulates from the building, fork lifts and passing foot traffic makes this a less than ideal environment for devices that will come in contact with life-critical drug substances at any step in their process.
The only way that a manufacturer can be assured that the components being bought will not contaminate the end product is to ensure that suppliers of the components maintain the same cGMP standards.
From a containment performance standpoint, the pharmaceutical industry is insisting on test data for the containment systems being considered for installation and use. This testing must be performed in a consistent and defendable manner using standard methodology. In addition, reputable third party test companies with industrial hygiene experience need to be contracted to perform these tests. Without the third party testing, test results cannot be viewed as independent and accurate.
While end user requirements are generally stated as needing to be “visibly clean”, the top level requirements for the type of manufacturing area installed follow the ISO Standard 146442. This outlines the methodology for installing and operating controlled environments.
Production and QA area
The company’s initial clean work area was designed and installed inside an open bay building. The test and acceptance area and a speciality manufacturing area were in a controlled environment but the primary production area was not.
By enclosing in the entire production area as shown in figure 1, and implementing procedures to mimic a Class 100,000 work environment, the complete fabrication process of the various flexible containment devices can be controlled. The gowning and operational procedures for the enclosed work area are the same as that for the controlled area.
HEPA filters control the particulate levels in the Class 100,000 controlled production and testing work area. In the event that lower concentrations are required, this type of set-up is easily cordoned off with strip curtains to support lower particulate count manufacturing requirements.
A third party evaluation of the ISO 8 (or Class 100,000) clean work area reviewed the mean averages for 0.5µm and greater diameter particle counts. A “worst case” test while in operation was performed with the test results for the area being within the required ranges set by the standards.
SMEPAC test/demo area
For the project described below, third party facility validation and testing were employed using the ISPE’s SMEPAC (Standardised Measurement of Equipment Particulate Airborne Concentration) guide “Assessing the Particulate Containment Performance of Pharmaceutical Equipment” – 2005 Edition. This Good Practice Guide provides invaluable insight into the main factors that affect the test results for specific contained solids handling systems, including material handling, room environment, air quality, ventilation, and operator technique.2
An uncontrolled test/demo/training rig was initially installed as the second such design centre and replaced a single vessel that was installed in 1995 as part of the original DoverPac joint development project with Eli Lilly and Company.
This upgraded engineering tool included two vessels that had discharge ports installed with 12in butterfly valves and nine charging ports that simulated various sized manways, both round and oval, and nozzles. These vessels were supported by a platform system as shown in figure 2.
Prior to installing the cleanroom, monitoring with frames and plastic sheeting was employed. While this can be made to work, the repeatability of testing to the SMEPAC controls is much better with a permanent installation.
In order to provide a certified test area without losing the design tool of the open area, one of the two vessels was enclosed leaving the second available for routine use. The top floor plan view is shown in Figure 3.
The recommended environmental conditions for the test area as provided by SMEPAC 2005 were employed (see table 1). From a 3D perspective, figure 3 shows a plan of the overall installation and the resulting installation is pictured in the figures 4 & 5 .
Validation
The cleanroom certification was also co-ordinated with a third party independent Industrial Hygiene (IH) testing company. Filter and room testing was performed using the contractor’s test procedures, Federal Standard 209, ISO 14644, and the FDA Guidelines for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004.
Filter-related testing included: the HEPA filter differential pressure for filter loading diagnosis; filter historical data tracking to document filter information and the initial air volume and filter pressures; aerosol challenge testing to ensure proper installation of filters and to verify no bypass leakage or filter defects; HEPA filter media repair tracking to identify any repairs/size of repairs/total percentage of repairs per filter; as well as an aerosol introduction and fire/smoke alarm mapping to document the aerosol challenge type/introduction locations/smoke detector locations.
Room-related testing included: a room identification drawing to record the test area layout including the Reflective Ceiling Plan; room-to-room differential pressure testing to ensure the specified cascading pressure differentials between the rooms and ambient surroundings are maintained; airborne particle counts to verify the classification desired is met; lighting levels testing; and noise level testing.
These “tests” include a combination of reference records as well as passing data to the area and environmental requirements. The result of this effort was a room classification of 100,000 (ISO 8).
Without delving into the details of the tests performed when developing Standard Operating Procedures and Sampling Protocols, it is interesting to look at the level of detail that is needed in this type of testing as it does parallel the rigour involved in the use of a clean operating involvement.
SOPs/sample tests
To assure continued operational effectiveness levels, standard operating procedures were developed. These covered cleaning of the room, cleaning of the equipment, and cleanroom certification.
The initial testing to be performed centred on the offloading and charging of a vessel. In this initial trial, a co-axial neck DoverPac was used in conjunction with a flexible enclosure (shown in Figure 6).
The sampling protocols to measure these activities were developed by a certified industrial hygienist based on the equipment specific test protocols of the SMEPAC 2005 guideline. Since there is not a specific equipment set of this type in the guide, the single point transfer and rigid isolator protocols were used to develop a generic set of protocols that would accommodate complete testing of this system.
Both air and wipe samples at various locations around the test set were taken following these methods to verify system operation. The IH air and wipe sample protocols were developed in accordance with the SMEPAC 2005 document; best Industrial Hygiene practices; and the guidelines published in Section II, Sampling, Measurement, Methods, and Instruments of the Federal Occupational Safety and Health Administration (OSHA) Technical Manual.
The use of controlled work environments for the design verification, manufacture and final acceptance of flexible containment and transfer systems is an important step in assuring product safety and quality for the end customer. This is true whether that consumer is the operator in the pharmaceutical manufacturing suite or the patient consuming the final drug product.
Contact
Alan George
Pharmaceutical product line manager for containment products
ILC Dover
One Moonwalker Road
Frederica, DE
USA 19946-2080
T +1 302-335-3911
