Fill-Finish Advances

There are 10 technological advances in fill-finish operations that serve as a primer for contract manufacturing organizations (CMOs) and for those who are interested in building and operating new facilities to accommodate biopharmaceutical products. Contents of this article were previously presented at International Society for Pharmaceutical Engineering (ISPE)-Interphex Meeting in Singapore this year.

1. Freeze-Thaw Technology
Bulk drug substance needs to be held frozen prior to filling and lyophilization when handling biopharmaceutical products. Large-scale freeze thaw technology can be used to perform campaign production of bulk manufacturing facilities and maximize the capacity of expensive cell culture facilities. This is achieved by producing one product for several months and switching to another product while maintaining a flow of products to the fillline by supplying stockpiled, frozen bulk drug substances.

2. Using Disposables for Formulation and Filling
Using disposables provides savings in cost and labor. It also provides shorter lead times (16-20 weeks) for custom stainless steel equipment and eliminates the labor required for Cleaning-In-Place (CIP) and Sterilization-In-Place (SIP) processes. By using disposables, a CMO could easily list expense items and potentially have a faster clinical filling project process. Costs for leachables studies could be significant, considering the time and cost needed to perform these studies on specific products. The bag supplier must therefore have a thorough validation package for extractables with water for injection (WFI) and other model solvents. Figure 1 illustrates a setup for formulating a highly potent drug in a polyethylene disposable mixing bag. A Hynetics Powdertainer bag is used for adding pre-weighed powder to a LevTech Sartorius mixing bag by attaching it to a 3" sanitary Tri-Clover type port provided at the top of the bag.

Figure 1: Disposable mixing bag used for fill-finish formulation. (Source: VLW Associates)

The mixer impeller is levitated by electromagnets without mechanical seals or friction to generate particulates or potential leaks. Such a system is used for a clinical product at 30L scale, with a capacity to scale up to 200L and 1000L for commercial production scales.

Figure 2 illustrates the use of a disposable bag in a filtration and fill configuration. The bag is also used to mix the formulation, for a sterile filter and to fill in line. It could also be used with the sterile filter to process the product into another disposable bag for sterile hold, and be filled later. A disposable product-contacting fill system with capsule fi lters that uses platinum-cured silicone tubing could enable the product-contacting stream disposable.

Figure 2: Disposable mixing bag used for filtration and filling. (Source: VLW Associates)

3. Ready Components
Ready-to-sterilize (RTS) stoppers have been an attractive alternative to in-house washing and siliconizing stoppers in recent years. Manufacturers could use the stoppers to obtain analyzed data on silicone levels, bacterial endotoxin, particulates, residual detergents and bioburden and store these data for up to two years prior to use. Arnaud Serfass, director of life sciences at Getinge (provider of stopper processors and ready components), says that about 60% of the company's stoppers are ready to sterilize, 10% are ready to use, and 30% are prepared by manufacturers/users.

4. Ready-to-Fill Pre-Filled Syringes
Pre-filled syringes are rapidly replacing vial applications due to their convenient administration and cost savings. Compared with glass vials, syringes potentially have less product holdup and waste. Companies such as West Pharmaceuticals (Daikyo Crystal Ze-nith) and Gerresheimer provide pre-sterilized plastic resin syringes that are silicone-free, possibly less immunogenic, and less reactive for biopharmaceutical products.

5. Containment Trends
Vice president of IMA Edwards Ernesto Renzi says the number of filling and lyophilization installations with restricted access barrier systems (RABS) and isolator systems have more than doubled in the last 10 years, replacing classical laminar air flow systems. This trend will likely continue as users become more comfortable at operating these systems, when they are easier to integrate and be standardized, and when more cytotoxic drug products require operator protection.

6. Filling Pump Technology
There have been some interesting developments in the filling pump technology. Bosch for example has introduced a disposable filling pump for its TL fill systems called Prevas that offers pre-assembled, pre-sterilized, and pre-validated flling systems this year. The Bosch-TL rolling diaphragm piston pump system is widely used in the US and the disposable pumps are compatible with the former Bosch-TL filling system.

Figure 3 compares the accuracy of various fill pump technologies such as piston, peristaltic, time-pressure and rolling diaphragm for filling less than 1 mL in a study performed by Al Peterson and Eric Isberg from Bosch. Interestingly, at 1 mL fill, the piston, rolling diaphragm and time-pressure pumps show similar levels at 0.5% deviation. At 0.03 mL fill, the piston pump is shown to be superior, followed closely by time-pressure, rolling diaphragm and with the peristaltic pump technology approaching 10% deviation.

Figure 3: Percent deviation vs. volume filled for various filling pump technologies (single pump). (Source: Bosch Packaging Technologies, Eric Isberg and Al Peterson)

The studies showed peristaltic pump technology is the least complex to use among the pump technologies and it may be the most attractive to use if it can manage the fill weight specifi cations. Fill weights drift during a run as tubing deforms and loses its round shape. While time pressure filling offers the fastest filling pumping technology, fewest moving parts and more accuracy over peristaltic technology, it requires a pressure sensing feedback system. The positive displacement piston pumps are therefore deemed to provide the most accurate fill.

7. Automated Loading/Unloading for Freeze Dryers
During freeze-drying of products, there is a potential exposure of open vials to personnel exists during the manual loading of partially filled vials into the freeze driers. This has been overcome in recent years by implementing automated loading/unloading systems with barriers or isolators for restricted access.

Figure 4 shows a vial loading system using conveyors and an automated push bar for moving vials from a fixed conveyor to a slot door on the freeze-dryer. Manual loading of open vials in trays by operators has been closely scrutinized by regulators in the past. Using a vial conveying system eliminates the possibility of microbial and non-viable particulate contamination by operators working over non-sealed vials. Such fixed conveying systems could be further contained by enclosing them in a RABs or an isolator.

Figure 4: Fixed conveyor vial loading/unloading system for freeze dryer. (Source: IMA Edwards)

Figure 5 shows a robot on rails that could be used for loading and unloading of vials into and out of freeze-driers. This is used when there are multiple freeze-driers supported by a filling line. For multiple pass-through freeze driers, a mixed loading and unloading system might be used - where vials are loaded using conveyors (fixed loading system) and unloaded using a robot (flexible unloading system). A fill line is able to fill a freeze-dryer, while the freeze-dried product could be unloaded from another freeze-dryer using flexible or fixed systems.

Figure 5: Flexible vial loading/unloading system for freeze dryer. (Source: IMA Edwards)

8. Advances in Freeze Dryers
A two-floor freeze-dryer installation is preferred in greenfield installations involving multiple freeze dryers as it allows multiple freeze dryers to be located more closely. This reduces the required amount of Grade A clean room space. The two-floor installation also takes advantage of gravity flow and allows CIP cleaning of the chamber and condenser in one cycle.

Liquid nitrogen (LN2) can be useful to cool freeze dryers when the LN2 source is located close to the plant. Using LN2 could save costs on maintaining mechanical refrigeration systems and it does not require compressor power during power outages.

Many biological products are unstable in solution after filling and they might be sensitive to temperature, oxygen or carbon dioxide. These sensitive products could benefit from cold shelf freezing where the product is quickly frozen (i.e. as it is loaded on the freeze dryer shelf). Freeze dryer manufacturers have also shortened the time for loading vials into the freeze dryer. Using a sub-door or slot door also minimizes the opening of the freeze dryer chamber when loading vials, mitigating the amount of condensation occurring in a cooled chamber.

Improvements are made for a product to exit a freeze dryer. Using a vial headspace characterization instrument provides a 100% online leak check and moisture and oxygen analysis for freeze-dried vials. The machine rejects the product that has elevated levels of oxygen, pressure or moisture. Jeff Milligan, vice president of technical operations at Hollister-Stier, a fill-finish CMO in Spokane Washington, has found the Vista total headspace characterization (THC) instrument by Lighthouse Instruments able to detect vial-stopper combinations and lotto- lot variations that could affect container closure integrity.

9. Modularization and Standardization of Filling Equipment
Equipment modularization and standardization facilitates installation, qualifi cation and decreases cost of production. IMA for example says its MAC equipment requires 20% of the footprint of traditional installations, offering potential cost savings for building and operating smaller clean room space. The modules are available for:
• Classical laminar air flow (LAF) installation, RABS - where facility heating, ventilating, and air conditioning (HVAC) air is exhausted out of the enclosure and into the clean room,
• Closed RABS - where facility HVAC air is re-circulated inside an enclosure, and Isolator configurations - where air is recirculated from a dedicated skid and the enclosure cleaning and sanitization is done in-situ. Figure 6 shows the IMA MAC vial washer-tunnel module and filling and stopper module (maximum 150 vials per minute) with an isolator skid system located above.

Figure 6: IMA MAC washer-tunnel module and filling and stoppering module with isolator skid system. (Source: IMA)

10. Labeling and packaging
Labeling and packaging drugs are now often used with instrumentation and software to manage tracking, inspection and line management. There are generally four levels of line management a packaging line could expand into:
• At the machine level - where vision inspection of labels and product defects occur,
• At line management and control level - where lot numbers and expiration dating information, and defects information are controlled,
• At the plant management level - where facilities information and performance of machinery history can be monitored, and
• At the corporate level - where information related to numbers of units and costs can be fed to an enterprise resource planning (ERP) system.