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Plastic has emerged gradually as a viable packaging material, even for sterile products. Acceptance of plastics has been encouraged by blow–fill–seal (BFS) technology, which provides scientific and commercial benefits. BFS technology has, however, brought new challenges for formulation-development scientists. This article highlights the specific concerns for the development of sterile liquid products and the formulation strategies to address these concerns.
Sterile liquid products are liquid dosage forms of therapeutic agents that are free from viable microorganisms (1). Many sterile liquid products are available commercially and can be classified according to their volume, use, and physical state (see Figure 1) (2–4). All sterile products must pass a sterility test. In addition, any solutions that are injected directly into the bloodstream (e.g., intravenous preparations), poured into body cavities and surgical areas (e.g., irrigation solutions), in direct contact with blood (e.g., hemofiltration), or introduced into body cavities (e.g., peritoneal dialysates) must be formulated as nonpyrogenic preparations that are essentially free from particulate matter (3). Hence, parenterals present numerous challenges that necessitate their comprehensive physicochemical characterization to achieve compatibility of active drug and excipients. The processing of sterile liquid products is a highly specialized area requiring careful evaluation and stringent control of critical process parameters to create a robust product that meets requirements for sterility, pyrogen level, and particulate matter (5).
To varying degrees, pharmaceutical containers protect products from environmental conditions and minimize constituent loss (6). Although glass has been the traditional choice for packing sterile products, plastic containers have emerged as a viable alternative during the past few decades. Plastic containers are inexpensive, shatter-proof, and allow the fabrication of custom-designed containers. Blow–fill–seal (BFS) technology was developed in the 1930s in Europe and initially was used to fill liquid, food, cosmetics, and nonsterile medical devices. This technology now is being used to produce sterile pharmaceutical products aseptically.
Figure 1: Classification of sterile liquid products.
BFS technology facilitates an advanced aseptic processing technique that allows containers to be made, filled immediately, and sealed aseptically in one continuous process within the sterile environment of one machine (7). The process involves the inflation of a plastic parison with compressed air to form containers (see Figure 2). Each cycle takes about 10–18 s, after which a conveying system transfers the product for further processing. It also is possible to automatically insert parts such as a dropper, rubber stopper, or a probe before sealing the container, thus enabling innovative packs (8). The introduction of rubber plugs allows the development of multidose injections. Such injections would not be possible otherwise because the plastic packs cannot be resealed after being punctured. A high sterility assurance is provided by a three-stage filtration process:
The main polymers used for extrusion blow-molding are polyolefins (i.e., polyethylene and polypropylene). They allow economical processing and satisfy regulatory requirements (9). They also form containers with sufficient clarity for visual inspection to verify the absence of mechanical impurities.
Figure 2: The blowâfillâseal process.
Formulation development in BFS
Formulation development is influenced by scientific, commercial, and regulatory factors and by intellectual property rights. The process can be divided into four distinct phases. The first phase includes preformulation studies. The second phase encompasses prototype formulation development, process development, accelerated stability studies, and pack development. The third phase consists of scale-up studies, evaluation of critical process parameters, and protocol-bound stability studies. The fourth phase involves the manufacture of commercial and validation batches.
Preformulation studies. Preformulation studies of sterile liquids essentially are similar to those of other pharmaceutical liquids (10). Solubility, stability, and excipient compatibility are the most important study subjects. Compatibility studies can be performed by isothermal stress testing, differential scanning calorimetry studies, and "miniformulation" studies, which are more realistic and efficient for products in BFS containers because the interaction of the formula with the packaging material can be evaluated simultaneously (11).
Prototype development and optimization. Preformulation is followed by the selection and optimization of excipients, prototype formulation development, and accelerated stability studies. Cosolvents, buffers, stabilizers, isotonicity-adjusting agents, preservatives, and viscosity-enhancing agents are classes of excipients usually (but not always) used in liquid preparations. The process of selection and incorporation of excipients into a solution essentially is the same whether the solution is a sterile liquid formulation packed in BFS containers or another solution formulation. No special issues are involved in incorporating isotonicity-adjusting agents and vehicles. The following properties of the plastics used as primary packaging material in BFS containers, however, necessitate special formulation-development efforts (see Table I) (12):
The following sections discuss formulation concerns specific to sterile products in BFS containers.
Table I: Problems encountered during formulation development in blowâfillâseal packs and their potential solutions.
Solubilization. The solubilization approaches such as alteration of pH to form in situ salt, the addition of a surfactant or complexing agent, and the incorporation of cosolvents are largely the same for any pharmaceutical solution. In addition, concerns about the permeation and sorption of organic cosolvent into the pack or the incompatibility of cosolvents and surfactants with the plastic packaging material (9, 13, 14) must be addressed by conducting appropriate studies using quasi-isostatic, isostatic, gravimetric (15), or Fourier transform infrared spectroscopy techniques (16).
Oxidation. A major problem formulation scientists face is the susceptibility of BFS formulations to oxidative degradation because of the containers' high gas permeability. In contrast, the only weak spot for gas permeation that glass vials have is their rubber plug, and glass ampuls have no weak spot. The high gas permeability of BFS packs precludes inert-gas purging and the reduction of headspace as strategies for controlling oxidative degradation. The incorporation of an antioxidant into the formulation is the most simple and effective means of controlling oxidative degradation in BFS packs. Three categories of antioxidants are used: true antioxidants, reducing agents, and antioxidant synergists (17). An appropriate antioxidant must be chosen according to the nature and components of the formulation. It is important to conduct real-time stability studies because accelerated studies may not assess accurately the effect of constant ingress of atmospheric oxygen on the formulation's stability.
Like all gases, oxygen permeates plastic films at a rate dependant on its solubility into the polymer and its mobility within the film. These factors, in turn, depend on the polarity, density, and crystallinity of the polymer and on the external temperature and humidity. Low-density polyethylene is a popular polymer for BFS technology and has low crystallinity, which, along with the absence of polar groups, increases oxygen permeation. Polymers with a large number of polar groups such as –OH, CN, and –Cl have the lowest oxygen permeability. Ethylene vinyl alcohol resin is a purely synthetic polymer with numerous hydroxy functionalities. Consequently, it has good barrier properties. It is manufactured commercially inserted between two layers of cheaper and more hydrophobic plastics such as polypropylene because of its moisture-sensitivity (18). Coextrusion BFS machines have been developed to produce multilayer packages that include a barrier layer to protect oxygen-sensitive products (19). Polyethylene terephthalate is an alternative to polyethylene and polypropylene polymer for packaging products other than parenterals. The advantages of polyethylene terephthalate are its glass-like clear appearance and its superior barrier properties. Secondary packaging also has gained widespread acceptance, and an increasing number of BFS products are being sold in secondary aluminum-foil pouches sealed under a nitrogen blanket (19). Secondary packaging such as aluminum pouches also provides a barrier to light, thus protecting photodegradable formulations.
Loss of volatile components. Volatile excipients such as alcohol tend to evaporate from BFS packs because of the higher permeability of plastics, compared with that of glass. This process is accelerated during terminal sterilization using superheated water. Another unique phenomenon observed in BFS packs is the loss of water from the containers, especially in high-temperature, low-humidity conditions. Water loss could decrease the content volume and subsequently increase the concentration of actives. Similarly, volatilization of low boiling-point preservatives such as chlorobutanol and benzyl alcohol in plastic containers can reduce preservative effectiveness. This loss can be prevented by using preservatives with high boiling points. The loss of volatile components also can be prevented by using packaging strategies mentioned in the previous section.
Sorption. Lipophilic actives such as diazepam and nitroglycerine, oils, and preservatives adsorb on plastics (20). The mechanism proposed for such a loss is partitioning, followed by diffusion (of lipophilic solute) into the matrix (21). The correlation of formulation components' sorption potential and octanol–water partition coefficients can form the basis of a formulation strategy to alleviate this problem (22). Partitioning also is affected by the pH of preservatives (23). A quality-control approach involves quantifying the initial level of preservative content, quantifying the reduced level after the end of the shelf life, and performing a preservative efficacy test.
An increasingly popular packaging option involves using single-dose packs to eliminate the need for preservatives. Another strategy for multidose containers of ophthalmic products uses containers with nozzles incorporating 0.22-μm filters, thus also avoiding the need for preservatives (24).
pH shift. Instances of pH shift during shelf life are more common in BFS containers because of the constant ingress of air through plastics and the absorption of gases such as carbon dioxide by the formulation. The latter is especially observed in highly alkaline solutions. Gas absorption may necessitate the inclusion of a buffer system to keep the product within pH limits dictated by the formulation's solubility and stability needs. The buffer capacity should be kept to a minimum, however, to enable quick adjustment to physiological pH, failure of which might lead to irritation at the site of administration (25). Low buffer strength also poses lesser compatibility concerns and does not contribute significantly toward isotonocity.
Sterility assurance in BFS technology. The US Food and Drug Administration prefers terminal sterilization to aseptic processing for the manufacture of sterile drug products (26). Terminal sterilization traditionally is achieved by using moist heat in two approaches: the overkill approach and the bioburden-based approach (27). The overkill approach is designed to reduce a presterilization Geobacillus stearothermophilus (a biological indicator highly resistant to heat with a D121 value of 2 min) population of 106 to a sterility assurance level (SAL) of 10–6 , which would result in an autoclave cycle yielding an approximate F0 value (the equivalent sterilization time in minutes at 121 °C) of 20. The overkill cycle does not take into account the actual presterilization bioburden in terms of quality or quantity. As a result, the product is exposed to a much larger amount of heat than necessary. The bioburden-based approach is not based on the use of G. stearothermophilus and takes into consideration the actual population and thermal resistance of the presterilization bioburden.
Thermostable product filled in polypropylene BFS packs withstands the conventional autoclaving temperature of 121 °C, but polyethylene containers cannot withstand temperatures higher than 110 °C (28). In Europe, sterilization cycles used for plastic packaging use lower temperatures and longer cycle times. The BFS process involves the aseptic filling of a sterile, filtered formulation, thus resulting in a low initial bioburden. In such cases, an average F0 value of 4–8 is acceptable for terminal sterilization, instead of the recommended value of 15 (29). Table II shows the sterilizing time required to obtain different F0 values at an autoclaving temperature of 106 °C (30). This type of bioburden-based autoclaving cycle delivers the least heat to the product and, therefore, can be applied successfully to polyethylene BFS packs that cannot withstand the conventional autoclaving cycle.
Table II: Corresponding sterilization time at 106 8C for different F0 values.
Alternative sterilization techniques. BFS containers traditionally are sterilized with a superheated water-spray autoclave (31). The advantages of this technique include short cycle time (resulting from good heat transfer from the water through the plastic wall of the bottle), homogenous heat distribution throughout the autoclave load, and retention of the plastic bottle's shape. Sterilization by microwaves has the advantage of rapid heating of bottle contents and excellent temperature control (31). Water must be used for cooling, however, and this presents a problem currently without a technical solution.
"PureBright" technology, developed by PurePulse Technologies, a subsidiary of Maxwell Technologies (San Diego, CA, www.maxwell.com), is a terminal-sterilization method that uses intense flashes of light to kill bacteria (32). The method can be used for terminal sterilization of transparent solutions in transparent containers. In this method, product is exposed to pulses of broad-spectrum, high-intensity light (90,000 times the intensity of sunlight) that kills bacteria without chemicals, ionizing radiation, or heat. The combination of aseptic filling of a sterile product (during the BFS process) and terminal sterilization using PureBright technology should achieve an acceptable SAL and satisfy the regulatory requirements for terminally sterilized products.
The integration of processing steps such as filtration, filling, and sealing offers advantages over the conventional parenteral manufacturing process (7). The following are other advantages offered by BFS technology:
Conventional parenteral manufacturing requires filling and sealing to be carried out in a Class 100 environment and necessitates considerable validation efforts. A BFS machine need not be housed in a Class 100 area because its activities are protected within the machine itself by an air shower. This protection considerably reduces validation efforts.
Sterility and particulate matter are two of the most critical requirements for sterile products, and BFS technology offers distinct advantages over conventional parenteral manufacturing in this regard. As mentioned above, three filtering processes in series and minimal human intervention result in an increased sterility-assurance level for the final product (34). Similarly, decreased levels of particulate matter have been reported in products in BFS containers, compared with products in preformed glass and polyvinyl chloride containers (35). A challenge study by Whyte et al. showed an air shower prevents airborne contamination effectively at the point of fill (36).
Particle generation has been reported when an electrically heated knife is used to cut off the parison. The patented "KleenKut" parison cutoff mechanism applies ultrasonics to eliminate more than 99% of nonviable particulates at the source, compared with a conventional electrically heated cutoff knife (8).
The BFS process is amenable to large, uninterrupted batches, even in excess of 500,000 units. The process also accommodates fill durations of as long as 120 hours. These characteristics increase productivity and reduce operational costs.
High-temperature exposure during filling. During the extrusion of polymer melt and blow-molding, the temperatures reach as high as 170 °C. These high temperatures, although helpful in destroying microbes, raise the possibility of the thermal degradation of a thermolabile product during the filling process. Unicep's (Sandpoint, ID, www.unicep.com) "Modified Blow–Fill–Seal" (MBFS) process was introduced to address this limitation of the standard BFS process (37). This modified technology minimizes the processing impact to the product by reducing the heat and dwell exposure.
Leak testing. The demand for the detection and prevention of leaks in the container has increased considerably because of their serious consequences for product sterility. The BFS process has been much criticized for producing leaky containers. Through time, however, technological developments have addressed this critical area of quality assurance.
Bonfiglioli Pharma Machinery (Ferrara, Italy, www.bonfigliolipharma.com) designed pharmaceutical microleak testing machines that insert BFS containers into an airtight testing chamber (38). A vacuum is applied to create negative pressure inside the chamber. Specially designed sensors monitor the pressure patterns inside the chamber during the test cycle.
Another system that offers high-speed inspection for BFS containers is "Ampuscan" from Automation Tooling Systems (Cambridge, Canada, www.atsautomation.com). The Ampuscan system is based on machine-vision technologies and performs inspection of faults such as molding deformities, broken tabs and twist tops, separated ampuls, wall discoloration, and foreign-particle inclusions. The system functions at a detection rate greater than 60 cards/min (39). One test subjects hermetically sealed containers to high voltage (40). The packs are made of nonconductive plastic, but the product has some conductivity. If any pinhole is present in the pack, the discharge current will flow through the pinhole into the container, thereby causing it to be rejected automatically. This method presents no risk of contamination, requires minimal human intervention, and detects very small pinholes. The product should have a minimum conductivity of 20 μS/cm, however, for successful application of this technology.
Die-bath testing is another well-known technique for detecting leaks, but it has many disadvantages. For example, it requires the cleaning of tested packs. In addition, tests in which the pinhole is so small that the die penetrating the solution is undetectable pose the risk of microbiological contamination (40).
Stability studies of sterile liquid products in BFS packs
BFS containers are made of semipermeable plastics. When stored in low-humidity conditions, they may exhibit vapor loss and consequent increased concentration of actives. Special storage conditions are therefore required for liquid products packed in semipermeable containers. The Q1A (R2) guidelines from the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (41) recommend a temperature of 25 ±2 °C and 40% relative humidity (RH) ±5% RH for long-term storage. A temperature of 30 ±2 °C and 35 ±5% RH also are acceptable. The guidelines suggest accelerated storage conditions of 40 ±2 °C and not more than 25% RH.
Parameters such as assay, related substances, pH, osmolality, viscosity, discoloration, clarity, sterility, bacterial endotoxins, preservative content, and preservative efficacy can be monitored during stability studies.
Products packed in BFS containers also should be evaluated for water loss during their shelf life. Water loss of 5% of initial value at three months under accelerated conditions is considered to be a significant change. For containers ≤1 mL or unit-dose products, however, 5% water loss or more may be allowable if justified (41).
As for other multidose sterile products, simulated in-use stability studies are suggested for products filled in BFS packs. Whenever a foil envelope is used as secondary packaging to combat oxidation or photodegradation, stability studies should be conducted with and without the foil packs, respectively. Product stability without the foil pack is relevant in the context of the product-usage time period after the foil envelope has been removed.
Another issue currently receiving greater attention is the leaching of packaging components (e.g., resin components, paper-label components, adhesives, and inks), which contaminates the product. Such contaminants may be toxic or may sensitize patients. A comprehensive quality-control approach involves characterization and profiling of all possible extractables. This is followed by establishing a correlation between the extractable and its leachable potential in the product (42) and setting meaningful acceptance criteria for a given leachable. Packaging alternatives to paper labels on BFS vials include embossing, debossing, and extended bottom flanges on unit-dose vials to carry labeling information.
Blow–fill–seal (BFS) technology offers an attractive alternative to conventional packages for sterile liquid products. Automated filling lines under controlled environmental conditions provide enhanced sterility assurance. Formulation problems such as oxidative degradation, loss and sorption of formulation components, and pH shift usually can be resolved by using the traditional formulation approach. Novel approaches such as coextrusion barrier packs, newer plastics with better barrier properties, and secondary foil packs occasionally can be successfully pursued. With the advent of multiple unit-dose packs, the need for preservatives can be avoided altogether. Advancements such as KleenKut technology and modified BFS technology will spur the application of BFS packaging. The combination of traditional formulation approaches with BFS technology creates numerous opportunities for developing robust and safe sterile products and viable alternatives to conventional packaging.
Aeshna Amin is a masters student in pharmacy and Arvind K. Bansal, PhD*, is an associate professor in the Department of Pharmaceutical Technology (Formulations) at the National Institute of Pharmaceutical Education and Research, Sector 67, Phase X, SAS Nagar, Punjab 160 062, India, tel. +91 (0) 172 2214682-87, fax +91 (0) 172 2214692, firstname.lastname@example.org
*To whom all correspondence should be addressed.
Submitted: May 5, 2006. Accepted: June 12, 2006.
Keywords: blow–fill–seal, sterility, formulation, liquid-dosage forms
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