Fill and Finish Operations

Biopharmaceutical products are subject to stability problems distinct from traditional sterile pharmaceutical processing and thus require more care in handling and preservation than do classical "small-molecule" drugs. Most biopharmaceutical formulations are aqueous, and protein products have limited stability in their liquid state.

Aqueous therapeutics, therefore, are often frozen and then thawed, freeze-dried to be rehydrated when needed, or encapsulated in liquid form without being touched by the atmosphere. The container that touches the product, the label, the patient instructions, the outside packaging, transportation to a variety of global climates, and the promotional materials are all part of filling and finishing a product as it gets ready for market.

All production lines must be approved by FDA (or regulatory bodies in other countries) before they can be used to manufacture drugs. The approval process involves documenting and demonstrating that the line functions as designed and within established criteria for cleanliness and sterility. The manufacturer is responsible for providing that documentation.

Freeze-Thaw

One of the most effective preservation techniques is freezing, but that and subsequent thawing stresses protein molecules. Processing time, temperature, solute distribution, pH, stratification, and the porosity of the recrystallization must all be controlled.

Some companies find freezing and thawing to be an essential manufacturing step. Freezing adds flexibility to the manufacturing process, particularly when multiple products are being made, and allows cost savings from pooling lots or batches. Vessel design is a critical feature of a successful freeze-thaw system so that the product doesn't have to be transferred between containers. Each additional thaw operation increases degradation.

Small batches have higher potential for contamination, cause more frequent operational stops, require additional quality-control testing, and need multiple batch freezing. So, the larger the freeze batch, the better. However, storage time before freezing should be kept short, and the size of the freezer and the storage facilities must be considered.

Freezing. Sometimes a specially designed, jacketed, portable, stainless steel freeze-thaw vessel that can be cleaned or steamed in place is used for freezing, sized to the product batch. Some containers use heat transfer surfaces with fins, which divide the vessel volume into compartments to reduce the freeze-thaw time. As water crystallization occurs, product and excipient concentrations between the crystals of ice greatly increase, a process known as cryoconcentration. The goal is to solidify these non-crystalline areas within the frozen product. The quicker that occurs, the less the product will be damaged. Usually, freezing is conducted from the bottom up to keep the warmest point at the top for temperature testing. The same container in which the product is frozen can then be used to ship the frozen product to fill-and-finish facilities around the world.

The freezing process takes the product from the liquid state through multiphase solidification to a low-temperature solid. The drug must not change physicochemical characteristics nor lose bioactivity during freezing. Considerations in a freezing plan include minimizing freezing time, cryoconcentration, and convection; promoting dendritic ice growth; preventing mechanical stresses in the vessel; developing a sanitary design; and monitoring and validating the system.

Thawing. Thawing is required before further processing (final purification, dilution, filling) can take place. During thawing, a vessel jacket or internal heat exchanger warms the product. A strict temperature limit (determined by product stability studies in small containers) sets the rate of warming. The goal is to make it as rapid as possible while preventing product deterioration. Control considerations include avoiding overheating, achieving maximum convection in the liquid phase, encouraging recirculation, preventing molecular and microscopic interactions related to the formulation, analyzing the heat and mass transfer, and designing a unique mechanical system to meet the requirements of the therapeutic. As crystalline ice undergoes internal melting, and since it is less dense than water, the liquid advances into the solid and necessarily creates a negative pressure cavity whose surface may theoretically degrade a protein. As much as possible, the controls avoid internal melting.

Filling Basics

Modern parenteral pharmaceuticals have well-defined and well-established manufacturing requirements to meet regulatory and market needs. First and foremost, injectable drugs must be free of all microorganisms. To achieve that aim, they are packaged aseptically in a Class 100 cleanroom with strict limits on viable and particulate contamination. (Cleanrooms are classified by the number of particles larger than 0.5 µm in each ft

³

of air.) Production personnel wear gowns, gloves, goggles, and hair and shoe covers to keep the drug from being exposed to human-borne materials because humans are the single biggest source of contamination in pharmaceutical production. Aseptic operations are not truly sterile although the products produced are labeled sterile. All products, including those that are terminally sterilized by steam, still have a probability for a non-sterile unit. In the case of aseptic processing, that probability is clearly higher.

Typical parenteral doses are filled in vials, cartridges, syringes, and ampoules. Usually, an automated parenteral production line consists of a washer to clean the glass containers, a depyrogenation tunnel to dry and sterilize all surfaces, and a filler (with companion check-weigher to ensure accurate dosages). The filled vials are stoppered and covered with an aluminum cap. The final product is inspected manually, labeled, and inserted in a carton with accompanying patient insert information. Lyophilized products are filled in liquid form but are then placed in a freeze-dryer, which removes the water and completes the sealing process.

An alternative to vials is the glass ampoule. Ampoule filling machines seal glass tops with a gas flame or CO₂ laser that melts the glass and seals products inside. The advantage is that the drug contacts only one material: glass. Disadvantages include the possibility of glass reactivity with protein products and the fact that the glass tops are snapped off for use, creating the possibility of tiny glass fragments entering the formulation.

A filling machine in operation

Recent trends in fill and finish include the development of barrier isolation systems. Such machines reduce the need for a cleanroom by enclosing the fill operation. This design reduces the risk of introduced human-borne contaminants. Cleanroom conditions are reproduced in a cost-effective, minimal area that is maintained and serviced in aseptic conditions. Barrier isolators are rapidly gaining acceptance in the industry and by FDA because they significantly reduce the chance of opportunistic microorganisms contamination. Barrier systems may be unique to the product and process being used. The major advantage of an isolator is the ability to sterilize equipment and avoid traditional aseptic filling. The major disadvantages are lack of flexibility, difficulty in cleaning, and complexity of design — especially for lyophilized products.

Blow-Fill-Seal (BFS)

Use of BFS machinery allows protein solutions to remain in aqueous form because they are not exposed to the atmosphere. BFS uses in-line machinery to form a plastic container, fill the container, and then seal it. Critical environmental exposure is protected by a HEPA-filtered air shower. The issues involved in deciding whether to use BFS include facility design, sterility assurance, validation, and operational performance.

BFS offers some advantages over traditional aseptic processing. Automation and the use of a barrier system mean that fewer personnel are needed in the fill room. Packaging in single-dose units requires no preservatives or antimicrobials. Glass containers are replaced with safer, patient-friendly alternatives. All this streamlining decreases costs. Most issues in BFS are the same as those confronting classic pharmaceuticals, but for biopharmaceuticals, additional concerns include the heat imparted to the product during plastic extrusion, extractables from the plastic resin, and product stability.

The process. BFS containers are formed, filled, and sealed in one continuous, integrated operation within a single automated machine or system. The process begins when low-density polyethylene resin pellets are melted and sterilized in an extruder at high temperatures and pressures. The resin is then formed into plastic tubes (parisons). Molds close on the parisons, using vacuum holes and hot knives to form containers. Then the containers are chilled in the molds and moved to the filling system where a HEPA-filtered air shower protects the product as it is put in the containers. The molten necks of the containers are then sealed by the chilled molds. Finally, the molds open and release the filled containers, which are conveyed for deflashing, inspection, and packaging, while the molds return to the parison area.

BFS allows different shapes, sizes, and dispensing designs. Extended tabs at the base of the container can add additional labeling area. Containers can be embossed with product name, lot number, and expiration dates. Product can be packaged in multiple attached vials or single-dose regimes. Medical insurance reimbursement sometimes dictates packaging so that five cards of six ampoules are in a carton as a 30-day supply, rather than seven ampoules for a one-week supply. Many closure designs are possible (such as the Luer-lock for single-dose parenterals), elastomeric closures for multiuse parenterals, and closures for pharmaceutical dispensing needs.

Peripheral equipment can include container conveyors to move the product through each in-line accessory, inspection cameras measuring the fill-level height, a vision system against cosmetic defects, and a deflashing unit to remove excess plastic (flashing) that can be recovered, granulated, and reused.

Containers can be heat-sealed in a laminated foil pouch package to protect the ampoule, and that packaging equipment can be installed in-line or separate from the BFS machine. The containers also can be packaged with inert gas, such as helium, for automatic leak detection using a helium leak detector.

Labeling, Packaging, and Logistics

Labeling and packaging facilities are often congested by the sheer volume of product or bulky packaging materials. Planning is needed to avoid mix-ups of containers, labels, and packaging materials for simultaneous or campaigned operations. Large amounts of particulates are usually found in labeling and packaging areas — such rooms are dirty from staff and material movements — so they must be separate from the processing stream.

Documenting Pharmaceutical Development of Biotechnology-Derived Medicinal Products

Before leaving the shipping dock, products must meet predetermined quality attributes and be properly labeled. FDA has found that 26-32% of all product recalls were due to mislabeling, mostly label mix-ups. Such mix-ups are usually caused by undedicated packaging lines, labels that look alike, and the use of cut labels. If any of these processes are used, extra scrutiny is required.

The packaging and labeling procedure should be simple, logical, and appropriate to the facility layout and the product flow through the labeling and packing area. It helps if a vision machine inspects the labeled product and if packages are color-coded for different sizes and different products and using different labels and visible bar coding. Weight checks on the package line should be used to identify missing inserts or product in the final package.

Accessories. When bulk liquids must be moved in-house, they are often contained in pillow-shaped bags. Dry ice is often used in shipping containers. Platforms are sometimes required to raise containers above the floor to prevent condensation, and interlocking tongue-and-groove lids and bases can retain heat or cold. Time-temperature indicators are needed to alert shippers to adverse conditions the product may have encountered in transit.

Services and supplies needed for shipping and packaging can include insulated shippers, refrigerants, data loggers, time-temperature indicators, package design and environmental testing services, thermal audits of existing shipping and distribution plans, thermal profiling, qualification and validation of new containers, labeling software and supplies, dust-free polyester liners, and clean-room adapted thermal transfer printers with "no-flake, no-smear" ribbons or print.

Regulations. Most of the label regulations are in Title 21, Part 201, of the US Code of Federal Regulations. It states that labels or patient instructions should include (in this order) descriptions, clinical pharmacology, indications and usage, contraindications, warnings, precautions, adverse reactions, drug abuse and dependence information, overdosage details, dosage and administration, and descriptions of how the drug is supplied.

The Healthcare Compliance Packaging Council (HCPC) recommends that labels be easy to read, include the expiration date, and illustrate the product. Labels should have consistent placement of warnings and concentrations and should be free of technical jargon and abbreviations. HCPC recommends that packages be bar coded and include detailed instruction sheets. Consumers want packages that provide easy access; that are environmentally friendly by generating minimal trash; that fit in the hand, purse, or pocket; and that protect products after opening. HCPC suggests that packages adhere to standards without looking like other products. They should be easy to open and reclose, come in unit-dose form, and discourage counterfeiting. The council also says that an ideal package would indicate when one dose was taken and the next due while cost-effectively protecting product stability.

Particulate Control

Validation

Many departments must sign off on written documents for materials release. Purchasing must audit the vendors. Inspection and receiving departments need to create incoming inspection documents. Safety and environmental departments need to handle special labels for hazardous materials. Chemistry and microbiology need to decide on the tests for lot-to-lot evaluations. Toxicology must validate the lot-to-lot toxicity tests. The specifications department must write product SOPs and specifications. Project engineers need to explain what materials can be used in the process. Emergency response and evacuation planning may be required when hazardous products are used.

The regulatory involvement in packaging and shipping may involve the Occupational Health and Safety Administration (OSHA), the Environmental Protection Agency (EPA), FDA, the Nuclear Regulatory Commission (NRC) (for radioactive materials or wastes), state agencies for employee health and safety, air and water standards, and local agencies fire districts, air and water standards authorities).

The Department of Transportation (DOT) and Federal Aviation Administration (FAA) oversee the movements of hazardous materials by rail, waterway, road, and air. All shipments of both products and wastes must be properly labeled, supplied with proper manifests from site of origin to final destination, and packaged in approved containers. Regardless of what contractors are hired, the product sponsor is responsible and liable for any hazardous material. Sponsors must fill out Uniform Waste Manifests. Recombinant DNA is primarily regulated by NIH, which determines its hazard classification and handling procedures.

Validating labels. Validating the labels means choosing the right labels and equipment, operator training, process flow and controls, and SOPs for quarantine, inspection, release, handling, shipping, and product inserts. The machine vision system and the packaging line weight checker should be validated by using limited samples with known defects: labels with wrong lot numbers or expiration dates, packaged products missing product inserts, and product containers with low-fill volumes.

Validating storage. Increasingly, FDA asks that shipped and stored material be validated. Disposable or reusable temperature or temperature-humidity data loggers can be packaged with the product to monitor conditions along the supply chain and pinpoint deviations. Temperature-sensitive packaging must meet ASTM D-3101 (The Standard Test Method for Thermal Insulation Quality of Packaging). FDA's guidance for packaging is The Container Closure System for Packaging Human Drugs and Biologics (May 1999). Title 21 of the Code of Federation Regulations contains additional regulations on packaging and shipping: Part 201 outlines label procedures, Part 600.15 details shipping temperatures for various therapeutics, Part 601.12 addresses changes to a label, and Part 601.45 discusses promotional material. Real-time shipping validation studies include temperature deviations and shaking tests.

Issues with Prefilled Syringes

Product stability needs to be tested before and after storage at various times, temperatures, and humidity. Stability-indicating parameters include pH, color, clarity, protein concentration determined by UV spectroscopy or enzyme-linked immunosorbent assays (ELISAs) for vapor transmission; protein bioactivity bioassays; the presence of protein fragments and aggregates by gel chromatography; and percent of deamidation by tryptic mapping. Other tests can be performed on container-closure integrity, preservative efficacy, changes from upright or inverted handling, package or stopper extractables, in-use tests, and test product remaining after in-use periods. Global climate zones and regulatory conditions require that therapeutics planned for other countries anticipate region-specific registration requirements.

Costs

Campaign manufacturing is a critical economic concept that allows sequential manufacturing of different products in the same facility so that common facilities and equipment can be used for multiple products. Because of economies of scale, lower unit costs result from larger volumes, and smaller-volume products will have a lower cost of goods if they are produced in a shared or multiuse facility. Expenses in production include facilities, utilities, validation, containment, raw materials, labor, royalties, depreciation, insurance, and rent.

Multiproduct facilities can be subject to operations congestion, process equipment contamination, airborne contamination, increased staff activities, and increased regulatory caution. Factors involved in economic multiproduct finishing and filling include facility siting, operational efficiency, dedicated equipment, validation contingencies, flow separation, materials storage, product transfers, personnel access, and gowning and pass-through air locks. Such working environment considerations as flooring, walls, ceiling, and fixed furniture must be considered. Cell banking, seed preparation laboratories, fermentation media and preparatory formulation, harvest product recovery, purification, buffer preparation, product formulation rooms, product filling, lyophilization, labeling and packaging, quality laboratories, instrument calibration, routine maintenance work space, and equipment washing are all factors in product validation.

Freezing and lyophilization provide a cost savings by allowing product to be pooled into larger and fewer lots. Production-scale bulk can be frozen and thawed multiple times and sampled at intervals to extend its expiration date with adequate testing. Shipping and storing at subzero temperatures may not be technically or economically feasible in many markets — Europe does not guarantee refrigerated delivery, so lyophilization may be the most cost-effective choice for global distribution to a wider market. The goal is to design the fastest and most robust cycle possible, consuming the least amount of energy without affecting product quality.

BFS is an attractive economic alternative to glass vials because the process is streamlined and usually requires no preservatives or antimicrobials. Capital costs may be less than those for equipment and facilities needed to sterilize components and the processes to fill, stopper, and cap glass vials. BFS machines can form, fill, and seal a set of containers in 12 seconds. Scale-up is accomplished by increasing the number of mold cavities used. Quality control testing for a filled vial (not including quality control of the bulk product) is estimated to be 12-20% of the total cost of goods.

Packaging and labeling. Many product recalls are due to mislabeling. They can devastate a company financially in terms of consumer confidence and in the reputation of both the company and the biopharmaceutical industry as a whole. Although biopharmaceuticals are not yet competing against generics, a recent consumer network survey suggested that seven of ten consumers would change a purchasing decision based on improved drug packaging. u