Creative Isolation: Ensuring the Success of Containment Projects

Pharmaceutical isolation today focuses more on isolating equipment and processes to ensure safety, and less on protecting operators with Personal Protective Equipment (PPE). Engineering firm CH2M Hill Lockwood Greene has a wealth of experience in isolation projects at its LG Scott office in Puerto Rico, and two of its experts — process manager Monica Colberg and project manager Javier Rivera — share insights about what’s current in containment for solid-dosage processes.Pharmaceutical Manufacturing: A current trend in isolation is to contain the process to protect operators, not just to prevent contamination from entering the process. What are you seeing in this regard?MC/JR: An industry trend is toward the manufacture of potent drugs that have very stringent operator exposure limits (ranging from10 microgram per m3 to less than 1 nanogram per m3). Ideally the process should be an enclosed one, with Clean-in-Place or Wash-in-Place capabilities to prevent operator exposure during cleaning or maintenance. However, this is not always possible with current unit operations because existing equipment may not offer containment or processes were not established with containment in mind.We are seeing more use of equipment designed for containment, such as compression machines, coaters, fluid bed dryers (with stainless steel filters instead of removable filters), roller compactors, and high-containment valves such as split butterfly valves and cone valves.The most challenging applications include the retrofit of existing equipment to meet stricter process containment requirements. This includes the integration of isolation equipment such as glove boxes and containment valves into the unit operation, and also the addition of isolators to pilot-scale equipment such as V-blenders, oscillators and compactors.P.M.: What other isolation trends are you seeing? What new challenges are you facing for high-containment projects?MC/JR: Manufacturers are building equipment that contains the product. The equipment also includes CIP and WIP systems to remove active ingredient before breaking the integrity of the contained system to perform product changeover or equipment maintenance.Since Puerto Rico is developing as a hub for biotechnology and pilot plants, we are seeing more pilot equipment requiring containment. Pilot plants require flexibility in process steps, parts change-out and material/product changes, so equipment is typically designed for this — i.e., it’s usually benchtop, nonproduction equipment that’s easy to disassemble — and not for containment. Modular isolation systems may work in these cases, as long as they are retrofitted to make them flexible and easy to use.P.M.: What’s the secret to containment without sacrificing equipment functionality?MC/JR: Always remember that an isolator is a physical barrier between the equipment and the person. This barrier, if not designed with the process in mind, may become a barrier in the use of the equipment itself. It can also impact product yield. The design should make it easy for maintenance personnel and operators to access the equipment without breaking system integrity. An example would be to retrofit benchtop equipment so that controls and motors are on the outside of the isolator while the product contact areas are inside.For every project, it’s important to develop a mock isolator and go through all the production and maintenance steps with the mock unit. This step ensures that operators will be happy with the design outcome.P.M.: In the planning and design stages, what steps do you take to determine what kind of containment will suit a given unit operation or manufacturing line?MC/JR: Product containment, especially isolators, greatly impacts operator movement and accessibility. Every step of the process must be analyzed. This requires a team that includes people from operations, maintenance, safety and quality/validation, and from the equipment and isolator manufacturers.Key factors to analyze include:

1. Batch processing requirements
   
   a. Unit operations
   
   b. Temperature and humidity requirements
   
   c. Product weight range and volume
   
   d. Product yield
   
   
2. Production sequence and product movement through the unit operations (i.e., weigh, blend, add product, blend, oscillate, blend)
   
   
3. Safety requirements
   
   a. Product explosiveness
   
   b. Ergonomic factors (reach, weights, lateral movement through an isolator)
   
   
4. Quality requirements
   
   a. Validation
   
   b. NDA requirements
   
   c. Equipment interchangeability as specified by the FDA Guidance for Industry SUPAC-IR/MR Manufacturing Equipment Addendum.
   
   
5. Equipment restrictions
   
   a. Maintenance
   
   b. Human Machine Interface (HMI)
   
   c. Other manual controls
   
   d. Equipment settings and parts
   
   
6. Isolation restrictions
   
   a. How is product going to enter and exit the isolator?
   
   b. How is waste going to exit the isolator?
   
   c. How will equipment parts and tools enter and exit the isolator?
   
   d. How will the isolator react when system integrity is broken?
   
   e. How will the isolator be cleaned?

For the sake of efficiency, not all team members should be brought into the project at the same time. The team should work through items 1 - 4 with the plant team, then get vendor support for items 5 and 6.P.M.: What are some of the major providers of isolation technology that you’ve been working with? Do they tend to be Puerto Rico-based, or global companies doing business in Puerto Rico?MC/JR: The main isolator companies used in P.R. include Carlisle, Powder Systems Limited (PSL), Applied Containment Engineering (ACE), La Calhene and Isolation Solutions. Most of these vendors have local representatives or visit the island very frequently to provide support.P.M.: Equipment is often not designed with containment in mind, but is this changing? What kind of equipment have you seen of late that works well with isolators?MC/JR: Yes. Many oral solid-dosing equipment manufacturers are starting to include containment in their systems. Equipment makers for product weighing, blending, solution preparation, granulation, fluid bed drying, roller compaction and compression machines now consider product containment in their designs. Some achieve this by including CIP and WIP in their systems, while others include isolation technology.P.M.: Are you seeing any new ways of transporting materials into and out of larger isolators? What’s on the cutting edge?MC/JR: Isolators use five major means of access:

1. Airlocks
2. Rapid Transfer Ports (RTPs)
3. Containment valves
4. Inflatable seals for docking of drums
5. Bag In/Bag Out rings

What’s really innovative are the containers to which some of these attach — these are pre-formed bags of various sizes that can attach to containment valves. The valves themselves are often plastic and are lighter and easier to handle than stainless steel valves.P.M.: How about operator access? What are the latest technologies?MC/JR: A well-designed isolator has parts of equipment that require maintenance located outside the isolator, for easy operator access. Modifying or selecting the right processing equipment and means of access can facilitate equipment change-out and maintenance. For example, for product approaching 10 to 15 Kg, a drum docking station may be considered instead of a manual RTP connection. Or, lifting technologies may be considered to dock the RTP.P.M.: What are the challenges of putting electrical equipment within an isolator, particularly with hazardous product? Can you give us some examples of how you’ve overcome this danger?MC/JR: When the product is hazardous, electrical equipment within the isolator becomes a concern. Dust clouds have to be minimized. You can ensure safety by:

1. Having dust collection points in strategic locations;
   
   
2. Proper grounding of the isolator;
   
   
3. Using explosion-proof equipment;
   
   
4. Removing sources of ignition such as motors and controls to the outside of the isolator;
   
   
5. Inerting the isolator.

P.M.: Do the high temperatures and humidity of the island affect projects and isolation applications in any particular way? If so, how do you overcome these challenges?MC/JR: Typically, the high temperatures and humidity are controlled by the HVAC system, which is costly to install, operate and validate. One trend we’re seeing, particularly for pilot-scale systems, is to control temperature and humidity in the isolator instead of the HVAC systems.P.M.: Dry nitrogen is often used to inert contained spaces, but can dehumidify the air within. What can you do in such situations?MC/JR: You have to introduce humidity into isolator. In one case, we worked with the vendor, PSL, to add filtered deionized (DI) water or purified water to the nitrogen stream, thus increasing humidity. A humidity sensor within the isolator was used to monitor and control the process.P.M.: Relationship-building seems to be critical for successful projects in Puerto Rico. Can you explain this?MC/JR: This is a key aspect that anyone working in Puerto Rico should be aware of. If you consider the sensitive nature of pharmaceutical and biotech projects, where a) it’s important to minimize time to market, b) quality can’t be sacrificed, and c) projects are owned by multi-departmental teams, then establishing strong, balanced relationships is critical. It is also important to understand, from day one, the purpose of the project and the roles and needs of the key players, and to know when to include those players at the right times.In Puerto Rico, people feel more satisfied when they know their needs are being addressed. It’s a matter of informing and executing, rather than executing and informing.For additional information on any of the topics discussed in this article, please contact Eduardo Lockwood, Business Development Manager, CH2M Hill Lockwood Greene, in Puerto Rico at (787) 781-9050 x275.