More than two billion prefilled syringes are developed and used each year. The rise of the prefilled syringe as the preferred container for injectable drugs began with Sanofi and Rhône-Poulenc Rorer's successful introduction of syringes for heparins to the European market in the early 1980s. The prefilled syringe market has expanded considerably because of factors such as the growth of biopharmaceuticals, the need to eliminate overfills, the need for precise delivery volumes, the desire for convenient delivery, the quest for cost effectiveness, and the goal of reducing dosage errors (1–4). 

Currently, most prefilled syringes are made of glass, but plastic syringes are gaining popularity, particularly in applications for which glass is an unsuitable delivery system. In the last decade, pharmaceutical protein and peptide drug products have been approved for use with prefilled plastic syringes. One example is a peptide drug product in a Daikyo Crystal Zenith (CZ) syringe (Daikyo Seiko, Tokyo) (see Figure 1). More products using plastic prefilled syringes are in various phases of drug development.  

Figure 1: Daikyo Crystal Zenith prefillable syringes (Daikyo Seiko, Tokyo). (IMAGES ARE COURTESY OF WEST) 

The need for combination-drug delivery systems

Many chronic diseases such as multiple sclerosis and rheumatoid arthritis require the self-administration of injectable treatments. This need has increased interest in combination-drug delivery systems that are safe, convenient, and help improve the administration process. 

Pen injectors and multidose cartridges were created for patients who need frequent injections. These devices were limited to specific therapies such as diabetes and growth hormones, which often require weighed dosages or dose titration. Although pen injectors were designed for frequent injections and for patients who require variable dose capabilities, they are not ideal for chronic users of fixed-dose medications, including patients suffering from impaired dexterity. The need for a safe, reliable, easy-to-use, single-dose injection system for these patients soon became apparent. 

Autoinjectors have been recognized as a convenient method for delivering drug products through an intuitive activation mechanism designed especially for patients whose poor dexterity affects their ability to inject a drug treatment effectively with a traditional syringe (see Figure 2). As patients and caregivers become increasingly involved in determining the best treatment option, biopharmaceutical, pharmaceutical, and device companies are adapting to meet consumers' needs.  

Figure 2: ConfiDose autoinjector (West, Lionville, PA). (IMAGES ARE COURTESY OF WEST) 

Traditional systems' performance problems

Autoinjector systems traditionally use 1-mL glass prefilled syringes. These systems have been successful, but they have notable limitations, including performance problems. Recent studies have shown that silicone oil, which is used to increase lubricity in syringe systems, is often distributed unevenly, thus leaving certain areas of the prefilled syringe surface with insufficient lubrication (5). The inconsistent silicone-oil coating can significantly affect the piston-travel and glide forces in autoinjectors. In 2006, commercial lots of a drug product delivered by an autoinjector that contained a glass prefilled syringe were recalled in several European countries because of problems with slow or incomplete delivery of the drug (6). Uneven silicone coating may increase travel forces and cause failures such as incomplete injections. 

Growth in the market for plastic prefilled systems is expected to result from a rise in new biotechnology products and vaccines. This growth will be associated with significant challenges in the formulation development of proteins and monoclonal antibodies, which are typically administered in high doses. High-concentration proteins tend to interact with each other and with the packaging components, thus causing protein instability, especially when the volume of delivery is approximately 1 mL. Glass prefilled syringes typically face the additional challenges of breakage, the presence of particulates, the glass's reactivity to the drug product, and potential leachables such as silicone, tungsten, and adhesive. 

Plastic prefilled syringes provide a way to solve such problems (7, 8). Cyclic olefin polymer resins such as CZ possess many advantageous properties, including glasslike transparency, which permits the visual inspection of the manufactured components and of the parenteral products that are delivered to the end user. The polymers exhibit high impact resistance and break resistance and form an excellent moisture barrier (9, 10). 

A plastic prefilled syringe can eliminate the need for silicone, tungsten, and adhesive, depending on the quality attributes of the entire prefilled system. For instance, the CZ 1-mL insert needle (IN) system uses no silicone to improve syringe functionality, no tungsten (which is often required to form glass syringes), and requires no adhesive to hold the needle in place. 

Tungsten has been identified as a leachable in glass prefilled syringes. Reports describe tungsten-based particulate matter that leached into and interacted with the protein drug product (11). Tungsten pins typically are used to keep the fluid path open at the nozzle end of the syringe during the glass-syringe formation process. Upon cooling, a needle is staked in with adhesive to make a glass prefilled syringe with a staked needle (SN). Residual tungsten can migrate into the drug product and cause the protein to form protein–tungsten aggregates. Although this phenomenon appears to occur only with specific proteins, it is important to test for protein–tungsten interaction at an early stage of drug development. Concerns about aggregation may be mitigated by plastic SN syringes. 

Silicone-oil-free syringes have been shown to have consistent travel forces over time and at various temperatures. The tighter dimensional tolerance of plastic syringes and the consistency of syringe functionality make autoinjectors' operation predictable. The break resistance of the finger flange for plastic syringes is likely to be significantly higher than that of glass syringes. Because of their higher dimensional tolerances, plastic 1-mL IN syringes are likely to have much less residual volume than glass 1-mL SN syringes. This difference means that less drug product is wasted or left behind in the barrel, and it could yield significant savings for drug manufacturers. 

Limitations on glass autoinjectors' performance may begin with their material of construction. Glass is a formed product that must be heated. Mandrels form glass syringes' overall length, nose or tip, and flanges. This process can create dimensional variability. During manual operation, a glass syringe's variability usually is mitigated by the human user. However, dimensional tolerances may vary so much that an autoinjector system may be subject to failures such as incomplete injections. 

The majority of today's autoinjector delivery systems include glass prefilled syringes that are inserted by the pharmaceutical manufacturer. The products are sold as single-dose, disposable injection systems.  

Glass creates the possibility of breakage, which is a safety concern. Upon activation, the system's spring places all of its pressure on the syringe's glass flange. The flange is the weakest point of a syringe; it snaps off if subjected to enough pressure. In autoinjectors, a strong spring is required to overcome variability in the sustaining force or inconsistent siliconization in a glass prefilled syringe. Viscous drugs require more pressure for a complete injection. This pressure can lead to breakage or an incomplete injection. A change in the place where pressure is applied, or registered, can greatly affect the safety of the delivery system.  

The simple technique of registering the force of the injection on the syringe's shoulder or nose instead of the flange creates two benefits for glass and plastic syringes. First, it places the pressure of the spring on the strongest part of the syringe, which reduces the risk of glass breakage. 

Second, registering force on the nose or shoulder compensates for the dimensional variability associated with glass syringes. For example, if the overall length of the syringe is too great, registering the pressure at the flange could affect the performance of the injection. In contrast, registering force at the shoulder makes it easier to know precisely where the end of the syringe is during needle insertion and dose delivery. The depth of needle insertion is much more consistent with this technique than it is when the syringe is supported at the flange.  

The ConfiDose autoinjector system from West (Lionville, PA) is an example of this change in design, which is meant to facilitate injections. The ConfiDose system is registered on the shoulder. The system also eliminates some steps of the injection process, which can be beneficial to patients. The three-step operation of ConfiDose automatically inserts the needle, delivers the complete dose, and retracts the needle from the injection site, thus leaving the delivery system safe for disposal. The autoretraction technology may help alleviate pain for those with poor dexterity, as opposed to manually removing the needle. 

Syringes made of cyclic olefin polymers have advantages for autoinjector systems such as tighter dimensional tolerances, increased resistance to breakage, and consistency of the travel forces over time. The combination of an autoinjector delivery system with a plastic syringe can help ensure a level of drug stability for manufacturers and provide end users with reliable product performance. 

Despite the fact that glass is still the predominant material, plastic prefilled syringes are gaining ground because of the many benefits associated with cyclic olefin polymer resins. Drug manufacturers that seek autoinjector technology for their products, particularly for biologicals and vaccines, should consult a vendor that understands primary container performance. Syringes' dimensions should be as consistent as possible, and the syringes should preferably be molded instead of formed, to help overcome the problem of break-force variability. Plastic syringes also can improve the safety of the delivery by eliminating tungsten or glue contamination. If a glass syringe is necessary, the autoinjector itself can be modified to aid the delivery process by registering the force on the strongest part of the syringe. This technique helps to overcome the dimensional variability of the glass prefilled syringe, reduce breakage, provide a consistent depth of injection, and create a reliable system that delivers the dose easily and effectively to the patient.  

 is director of strategic market development, and 

 is director of strategic market and technical development for the Daikyo Crystal Zenith prefillable and vial platform, both at West, 101 Gordon Dr., Lionville, PA 19341, tel. 732.946.2929, fax 732.945.2189.  

*To whom all correspondence should be addressed. 

 5. B. Eu et al., poster presented at AAPS National Biotechnology Conference, Toronto, June 2008. 

 6. MHRA, Class 2 Drug Alert, Medicines Recall, Reference MDR 03-10/06, Neulasta SureClick Injection Device (London, Oct. 4, 2006).  

 7. R. Esfandairy et al., poster presented at AAPS National Biotechnology Conference, Toronto, June 2008. 

www.ondrugdelivery.com/publications/prefilled_syringes_2008.pdf

Articles

The authors describe the ways in which plastic prefilled syringes can be an alternative that provides consistent performance, protects drugs prone to degradation, and enhances patient safety.

Plastic Prefilled Syringes: A Better Fit for Autoinjector Systems

Most biologicals and some small-molecule drugs are best administered through injections. Although this delivery route has its advantages, economic considerations, side effects, and practical concerns could dissuade some patients from maintaining full compliance with a parenteral-drug regime. Technological advances now make it possible to reformulate some injectable drugs for administration through other delivery routes. 

One company pursuing this goal is formulation specialist Merrion Pharmaceuticals (Dublin), which develops improved tablet and capsule dosage forms of drugs with poor bioavailability, including injectable and intravenous forms. Merrion uses an oral drug-delivery technique called Gastrointestinal Permeation Enhancement Technology (GIPET) to produce oral formulations (i.e., tablets or capsules) of drugs that are now only given parenterally. The company acquired GIPET from drug developer and manufacturer Élan (Dublin) in 2003, when the latter company refocused its activities. The technology can be applied to a wide range of compounds with various physiochemical properties and molecular weights, including traditional small molecules and biopharmaceutical peptides and proteins. 

The GIPET method uses a mixture of the therapeutic drug and various small- and large-molecule enhancers to improve absorption and bioavailability. The enhancers activate the formation of micelles, which become a passive transport system for the drug, helping to carry it efficiently within the body. With GIPET, Merrion has achieved increases in bioavailability from five- to 200-fold, and this increase is achieved consistently from patient to patient. 

Unlike other reformulation techniques, the GIPET technology does not chemically modify the drug. The therapy's previously established safety profile therefore remains unchanged. GIPET consequently eliminates the need for further toxicity studies and greatly reduces development time for the new formulation.  

Figure 1: Demonstration of how the GIPET technology works. (FIGURE IS COURTESY OF MERRION) 

To choose which enhancers to use to reformulate a parenteral drug, Merrion's scientists perform simple preclinical studies. Rapid experiments are carried out with liquid formulations that mimic what happens in the body after a tablet releases its drug load. The experiments' model allows scientists to screen various formulations that increase bioavailability and seek formulations that will release the drug quickly. After results are obtained, scientists can decide which formulation shows the most promise and begin the proper formulation-development process for a tablet. 

Formulators ensure that the drug and enhancers are mixed into a uniform blend and compressed evenly. Enteric coatings that protect the formulation from stomach acid are added as appropriate. For example, these coatings are important for formulations that incorporate fragile peptides.  

The GIPET technology uses ingredients that are generally recognized as safe by the US Food and Drug Administration. Because the reformulated drugs have already received the necessary regulatory approvals, their time to market is swift compared with that for drugs developed from scratch. Drug manufacturers can use abbreviated regulatory pathways that rely on the known efficacy and safety properties of the established drug. 

GIPET has helped Merrion to develop its own products, including Orazol (MER 101), an oral bisphosphonate traditionally administered intravenously as an oncology treatment. Biophosphonates are a class of drugs that are poorly bioavailable, and their presence in the intestinal tract is associated with side effects. In addition, infusions of zoledronic acid or Novartis's (Basel) Zometa are associated with reduced kidney function and flulike symptoms. 

GIPET technology has helped Merrion overcome these hurdles, which had hindered the development of a tablet form of the drug. The technology increases the drug's bioavailability by at least fivefold, and this increase results in a consistent, improved absorption. It also reduces the amount of drug that could remain in the intestinal tract and potentially cause side effects. Orazol is also well tolerated and has not been associated with flulike symptoms. 

The product, which has completed Phase II development, can be given weekly, instead of monthly infusions. The tablets therefore have a different absorption profile and do not require the kidney to process as much drug at a time. Orazol is intended to produce therapeutic results equivalent to those of infusions and offer a better experience for the patient than infusions, in terms of quality of life, side effects, and safety. 

During the first half of 2009, the final results of a multicenter Phase IIb cancer-patient study showed that weekly therapy with 20-mg Orazol tablets was as therapeutically effective as monthly treatment with Zometa. 

Merrion also used GIPET to develop MER 102 (fondaparinux), which the company intends to introduce as the first oral product in the class of low molecular-weight heparin drugs. These drugs are primarily used to prevent deep-vein thrombosis and are given prophylactically through daily subcutaneous injections after surgery to prevent the formation of blood clots. MER 102 is an anticoagulant designed to replace daily injections and is now in preclinical testing. 

Merrion has used GIPET in its collaborations with pharmaceutical companies such as Novo Nordisk (Bagsværd, Denmark). The companies signed a development and license agreement for the oral formulation of insulin analogues with GIPET in November 2008. In January 2009, the firms signed a second agreement for the development and commercialization of Novo Nordisk's GLP-1 receptor agonist using GIPET technology.  

Merrion is also collaborating on drug-delivery research with Ferring Pharmaceuticals (Saint-Prex, Switzerland). The companies are studying the ability of GIPET technology to provide a significant increase in an undisclosed compound's bioavailability. 

Erik Greb contributed to the reporting of this article.

 is a freelance business, science, and technology journalist based in Cratloe, County Clare, Ireland, 

The author describes how Merrion Pharmaceuticals reformulates parenteral drugs into tablets and capsules that are easier for patients to take and provide better bioavailability.

From Needle to Pill: Reformulating Injectable Drugs for Oral Delivery

The formulation process for parenteral, or injectable, solutions often follows the overly simplified method of combining water for injection (WFI), active pharmaceutical ingredient (API) and excipients in a formulation vessel (FV) located within a formulation room and mixing until dissolved. The formulated solution is filtered through one or two sterilizing-grade (0.22 μm) membrane filters into a sterilized receiving vessel located in a traditional cleanroom with an International Organization for Standardization (ISO) Class 5 unidirectional airflow, isolator, or restricted access barrier system (RABS) (1). Occasionally, however, the formulated product includes a component that cannot be sterilized through filtration because the act of filtration would render the final product ineffective. These nonfilterable components may be insoluble particles suspended in a solution or they could be molecules too large to pass through a filter membrane. With the exception of terminal sterilization of the formulated or filled product, devising a means to formulate the product aseptically may be the only solution to ensure product sterility. Performing aseptic formulation requires consideration of several aspects for the entire process.  

In making these evaluations, the analysis in this article assumes that the facility and equipment have been qualified and approved for parenteral production under good manufacturing practices (GMPs). The analysis takes the perspective of using a traditional cleanroom for manufacturing with the understanding that these approaches can be applied to advanced systems such as isolators or RABS and tailored as necessary. 

The first step in determining the approach for an aseptic-formulation project is to learn the characteristics and limitations of the product. This determination will help guide the formulation process. The key elements are: the total volume to be formulated because this will influence the formulation vessel size and design; and the various components of the product capable and incapable of being sterile filtered. 

The type, brand, and model of sterilizing filter selected may influence the sterilization process for the filters (autoclave or sterilization-in-place [SIP]) and may also influence the formulation process. Of those components that can be sterile filtered, it must be determined whether they should be filtered in series through the same set of filters or whether separate filters are needed for some or all components. This selection may influence the sterilization process for the filters and may also influence the formulation process. 

For those components that cannot be sterile filtered, it is important to understand how those will be sterilized and where such sterilization will occur (presterilized or sterilized in-house). Sterilizing the material in house could add another layer of complexity and cost to the project, depending on the characteristics of the material. Also important to know are any specific temperature conditions required for the formulation process because these conditions will influence the FV design and potential heating and cooling equipment. 

The existing facilities and available utilities may be adequate, may need to be modified, or may need to be designed and built to support aseptic formulation project needs. A source of clean, ISO 5-compliant, unidirectional airflow is critical for making aseptic connections and performing general aseptic operations. Additionally, some aseptic connection points may require the use of horizontal laminar airflow. Making the decision requires a good understanding of the aseptic formulation process as well as the intended sterilization process. 

From a utilities perspective, if the FV will be sterilized through SIP, qualified pure-steam ports and inert-gas ports will be needed in the area intended for SIP. The pure steam-system pressure should be high enough (e.g., ≥ 40 psig) to ensure that sterilization within the FV can occur at the same time as supplying other steam-consuming equipment (e.g., autoclaves, sterilizers, and lyophilizers). The inert-gas distribution system pressure will likely exceed 100 psig. Therefore, regulators will be needed to reduce the pressure for use in drying the FV following SIP. 

The FV needs to be designed for its collective intended uses, which include sterilization (autoclave or SIP), preservation of sterility following the sterilization, the aseptic-formulation process, and a robust means of aseptically transferring the sterile contents of the FV to the filling machine. The product contact surfaces of the FV should be composed of electropolished 316-L stainless steel, or they should be glass-coated if the product is not compatible with stainless steel. The FV must be sized to thoroughly mix and contain the final volume of formulated product but also able to fit through door openings within the facility. The design of the FV should include load cells for weighing materials required by the formulation. Consideration should be given to aseptic connections, in-process samples, and transferring formulated product from the FV to the filling machine (

 a dip tube or bottom-outlet port). The FV may need to be jacketed and rated for pressure and vacuum depending on the product and process needs (e.g., cooling during formulation and SIP). To facilitate the performance of the process steps, various fittings need to be connected to the FV (see Table I).  

In the event that SIP is the chosen sterilization method for the FV, the items identified in Table II should facilitate the process.  

Table II: Components for sterilization in place. 

The existing facility, utilities, equipment, and regulations establish boundaries for the chosen aseptic formulation process. In-house expertise in manufacturing, process development, and validation all factor into the success of the project. The primary goal of the aseptic formulation process is to produce a sterile product. The following guidelines improve the chances of success:  

Minimizing the number of aseptic connections.

Designing the FV in such a way so when sterilized, that all fittings needed in the aseptic formulation process are also sterilized (e.g., filters, sampling devices and valves).

Exposing the aseptic connection points to a constant supply of ISO 5 unidirectional airflow. Avoid having connection points near the floor or in other areas where there is turbulent airflow (i.e., bottom-outlet valves may present aseptic connection difficulties).

Whenever the aseptic formulation process has been developed and validated, training is critical. Train multiple operators on the "how's" as well as the "why's" of the process. If the operators fail to understand the "whys," recognizing deviations and their impact during manufacturing will be difficult. It may be helpful to include these operators in the validation activities.

Leveraging, whenever possible, existing processes and validations.

Although not directly related to sterility assurance, one also must put into place a filter integrity-testing strategy. Filter and immediately remove the filters to be postuse integrity-tested before proceeding; filter and proceed with the remainder of the formulation before integrity-test results are known or redundantly filtered using a series of two filters. Table III outlines advantages and disadvantages of the options.

Table III: Options in filter integrity testing. 

The sterilization method for the FV must be decided upon and the process developed. Preservation of sterility following the cycle is equally critical as the act of sterilization.  Common sterilization methods that could be employed are autoclave sterilization and SIP. If the FV can fit inside the autoclave, this is the simplest option. If the FV is too large for autoclave sterilization, SIP using steam from the plant's pure-steam system will fulfill the need. SIP is more difficult than autoclave sterilization, and it presents some hazards for operators. SIP will generate substantial humidity in the area where it is being performed. This moisture presents slip–and–fall hazards, and the heat of the external surfaces of the FV can scald. 

Regardless of the method chosen, the sterilization cycle needs to be developed for the FV. If autoclave sterilization will be used, the same cycle used to sterilize durable goods may be the most reasonable starting point for FV sterilization. It is suggested to place hydrophobic vent filters on the ports to be used for aseptic connections to facilitate air removal and steam penetration as well as preserving sterility following the autoclave cycle. If vent filters are not used, these connection points will be dead legs, which make air removal and steam penetration more difficult and sterilization less efficient. 

If SIP will be used, cycle development will be more involved. The FV needs to be on-hand with all fittings and any other necessary equipment. Having a good idea of the general aseptic formulation process and the connections to be made will help to set the fittings on the FV as well as determine inlet and outlet points. The use of temperature measurement tools (i.e., thermocouples or data loggers) is necessary for the development of the SIP cycle. It is assumed that the SIP will be performed in a lower classified area and the sterile FV ultimately moved into an ISO 5-compliant cleanroom for the aseptic formulation. 

The flow of steam through the system needs to be set up to ensure steam penetration and contact with all interior surfaces and product pathways throughout the FV and fittings. Dead legs should be avoided because air can become trapped, thereby reducing sterilization efficiency. When the SIP cycle starts, the steam will condense on the cold interior surfaces of the FV and exit through the outlet ports as water. Once the FV surfaces heat up, the condensate will gradually turn to steam. The inlet and outlet valves need to be adjusted to build the desired internal pressure to achieve sterilization. The valves to the jacket should be opened to prevent the buildup of pressure caused by the temperature increase within the vessel. After the steaming portion is complete, the FV will need to be cooled and dried with a sterile-filtered inert gas. The transition from steam to inert gas should be made gradually while maintaining positive pressure within the FV. 

Following the cooling and drying cycle, preservation of sterility is critical. The manner in which sterility is preserved depends on the method of sterilization. If the FV is autoclave sterilized, it will be dried but still quite warm following the cycle. Removing the FV from the autoclave should happen under the protection of unidirectional airflow. Check all clamps for tightness while the FV is still warm. Once the FV cools to room temperature, it can be removed from the unidirectional airflow and stored in lower classification environment until use. The exterior should be sanitized before aseptic formulation begins.   

If the FV is SIP sterilized, the following two options exist for preserving sterility:   

Pressurize the FV with sterile-filtered inert gas following the cool-and-dry cycle. All outlet valves will be closed, first the outermost outlet valves and last the inlet valve. All clamps should be tightened. The exterior of the pressurized FV will be sanitized (sanitization method should be qualified). The sanitized FV will be moved into an ISO 5 environment until use. The FV could remain in lower classified environments provided that the internal pressure is maintained until use. If the internal pressure is lost before being placed in an ISO 5 environment, contamination concerns will need to be addressed.

Pressurize the FV with sterile-filtered inert gas following the cool–and–dry cycle and perform an integrity test of the FV with all fittings. This integrity test will involve closing the valves and measuring the pressure decay as a result of cooling. If the FV has leaks, the pressure loss will be greater than the pressure loss due to cooling alone. Once passing results are obtained, the FV could be stored in a lower classified environment until needed for use. The exterior would still need to be sanitized.

Performance qualification of FV sterilization

Regardless of the method selected for sterilizing the FV, performance qualification (PQ) must be performed. If autoclave sterilization was the chosen method, the PQ of the cycle will follow the same process that has been used for other durable loads. If SIP was the chosen method, there are two basic parts of the SIP cycle to consider: sterilization and drying. To qualify the sterilization portion, the FV will need to be assembled as in manufacturing and probed with thermocouples, data loggers, and biological indicators (BI). The placement of the thermocouples and BIs should be in locations thought to represent the worst-case areas regarding steam penetration. The SIP cycle should be run at worst-case parameters when compared to those used for routine manufacturing. For example, if the parameters used for manufacturing are anticipated to be 30 min at a steam pressure of ≥ 18 psig, the parameters used for the PQ should use a shorter timeframe and lower pressure to provide additional sterility assurance. One method for controlling the pressure during the cycle at a specific pressure is to replace the outer diaphragm valve with a needle valve, allowing for more precise control of steam flow.   

Following the steam portion of the SIP cycle, the FV should be dried using sterile filtered inert gas. Following the drying portion, the FV will need to be closed in a manner to retain positive pressure and preserve sterility. If the strategy for manufacturing is to simply pressurize the FV and transport into the ISO 5 cleanroom, this aspect is low risk and does not need to be qualified. If the strategy is to perform a pressure hold test on the FV and relieve the internal pressure after passing results have been achieved, those success criteria need to be derived from qualification. Perform the SIP as in manufacturing (higher pressure and longer timeframe). The additional temperature and time will raise the temperature of the FV beyond that found using the sterilization-qualification parameters, which will impact the pressure loss behavior as it cools. Once the FV has been dried and cooled, close all valves to retain a positive internal pressure. Allow the FV to remain undisturbed for a short timeframe and then record the internal chamber pressure.  Allow the FV to continue cooling for several hours until it reaches room temperature. Record the internal pressure and ensure that the FV indeed has retained pressure. The pressure decay as a result of cooling will be the parameters used for integrity testing during routine batch manufacture. 

Validation of the aseptic formulation process

The process developed for aseptically formulating the product requires validation. The method for this process validation is the process simulation (i.e., media challenge). Running a process simulation for the recently developed aseptic formulation process uses the same basic concept as used for  the aseptic-filling process simulations. 

The process simulation should be performed per written batch record using the same manufacturing personnel, equipment, and facilities that will be involved in the manufacture of the actual product. Where the manufacturing process uses inert gases, these will be substituted with oil-free compressed air to promote microbial growth in the event contamination occurs. A total of three batches will be performed in which each step of the proposed manufacturing process will be included with media substituting for the product. Upon completion of the process simulation, the entire FV can be closed and incubated or a portion can be transferred as it will be performed in routine batch manufacture and that portion incubated. The media vessels should be sealed to prevent contamination from occurring during incubation. 

Assessing worst cases in process simulations is a balancing act of weighing the benefits of success against the risks and consequences of failure. Building flexibility into the process, covering worst-case and some nonroutine interventions to allow the manufacturing to operate within a larger design space is desirable. This objective can only be achieved by including these worst-case scenarios and interventions in successful media challenges. In the event the media challenge fails, time and effort will be lost on the media challenge in addition to the time and effort required of an investigation. If multiple interventions were included in a failed process simulation batch, identifying the root cause of the contamination will be challenging. 

Drug products that require aseptic formulation can present challenges. These challenges can be overcome with experienced personnel and a good understanding of the project objectives, regulatory requirements, facilities and equipment. Once the processes have been developed and validated and personnel training completed, manufacturing the aseptically formulated product will be able to proceed with relative ease. 

is manager of validation and technical services at BioConvergence LLC, 4320 West Zenith Drive, Bloomington, IN 47404, tel. 812.961.1700, fax 812.961.1733, 

Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness,

 First Edition, Sec. 2.4, p. 3, May 1, 1999. 

The author details the factors in formulation design, requirements in facilites and equipment, and validation criteria for aseptic formualtions.

Current Perspectives on Aseptic Formulations

The rise in novel biopharmaceuticals has injected new life into the injectable delivery market. The demand for injectable technologies is growing, says George Perros, managing director for Greystone Associates, a technology consultancy based in New Hampshire, which in September 2009 published an analysis on 

Drug Delivery for Self-Adminstration: Devices, Drugs, Product Strategies and Forecasts. 

The following interview with Perros describes this evolving market and recent innovations. 

What is your overall assessment of the future for injectables? 

The advent of protein and peptide drugs has spurred the development of new delivery devices. Newer more fragile drug substances present a delivery challenge. Nevertheless, we see not so much a revolution in injectable devices, as an evolution, as these devices become increasingly more sophisticated, cost-effective, and safe.  

Table I: Global historical volume and forecast for prefilled syringes (Greystone Associates). 

What are the main drivers of this evolution? 

Typically, when these biological drugs are first released onto the market, they are administered by infusion by professional healthcare providers in a healthcare facility or an outpatient setting. This is an expensive way to administer drugs, but it allows these drugs to be used in a controlled setting until enough data are available to establish a safety profile for the drug that can be used to determine whether it should be approved in a form for self-administration.  

Table II: Current and forecast global market share for pen injector segments (Greystone Associates). 

The challenge that keeps driving device evolution focuses on how to get these drugs into the hands of the patients for self-administration in a way that is safe, reliable, and economical. For drug products designed for self-injection, this means injection devices that are prefilled (also referred to as combination products). 

Another issue for biological drug developers is the fragile nature of the drugs themselves, which necessitates they be transported and stored at low temperature—the so-called 'cold chain'—which adds to the cost of distribution. To avoid the problem of temperature-dependent stability, proteins and peptides are often processed and packaged in dry or powder form. These lyophilized drugs must be reconstituted prior to injection. Special injection devices have been developed that contain two chambers, one with the lyophilized active ingredient, and the second for the formulation liquid or diluent. Upon activation, the powder and liquid are allowed to mix in the correct proportions, before being injected. 

The ability of patients to self-medicate reduces the economic and resource pressure of having a healthcare professional administer the drug to the patient. So the technology challenge is to design a delivery device that ensures that the drug is preserved properly, reconstituted properly if necessary, and administered at the right dose by a person who may have little or no experience with injectable devices. 

What kind of innovations are you seeing? 

The growth of reusable injectors with replaceable cartridges has been significant, particularly for drugs indicated for chronic conditions. Some of these devices allow the patient to adjust the dose. These are most often used for insulin administration, where the patient is adjusting the dose after measuring their blood glucose levels. 

The arrival of disposable autoinjectors is an exciting development. Autoinjectors are pen-like devices that allow the user to insert a prefilled syringe and simplify the injection event. For years, this segment was dominated by reusable autoinjectors, which are made of durable materials but are a bit pricey. Recently, disposable autoinjectors have begun to appear. These less-expensive devices are providing drug marketers with new opportunities because they can be bundled or paired with a prefilled syringe. It's extending the utility and user-friendliness of autoinjectors to a growing number of patients who would otherwise need to master the art of injection with a naked prefilled syringe. 

There have also been improvements in safety features for syringes used by healthcare providers. Retractable safety syringes, which are designed with needles that retract after injection to minimize the risk of needlestick injuries to care-givers, are starting to find traction in North America, and to a lesser degree, in Europe. 

I see that the market for antivirals seems to have plateaued since 2007. Can you explain that trend? Which antivirals in particular are you focusing on? 

Interferons for infectious diseases, particularly Hepatitis C, are designed to boost the immune response to an infection. Because of difficulty with patient compliance due to side effects, this segment has experienced uneven growth. We expect that trend to continue. 

The global market for pens containing insulin is trending up gradually. Do you see that growth coming from domestic or international growth primarily? 

Pens are already the most popular way to self-administer insulin in Europe. These devices are becoming more popular among diabetics in the US and this popularity will help overall growth in the near-term. 

Are there any technologies that seem to be losing traction? 

Needle-free injectors continue to struggle. We think that this is because the current generation of pen injectors—with their quick and relatively painless operation and user friendly features—to a large extent obviate the need for needle-free devices. 

A Conversation with Greystone Associates' George Perros. This article contains bonus online-exclusive material.

Technology Forecast for Injectables

Manufacture of sterile parenteral drug products involves a series of unit operations (1) and aseptic processing conducted under strict requirements with respect to product quality. The manufacturing process is designed and validated to address such requirements and to ensure supply of safe and efficacious products. Visually inspecting each filled and sealed container for foreign contaminants or particulates ensures that these high standards are met and the final drug product is safe for patient use (2). 

The United States Pharmacopeia (USP) provides guidance with respect to the inspection process for injectable drug products (2, 3). According to USP General Chapter <1>, the injection process shall be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates and every container whose contents shows evidence of visible particulates shall be rejected. Two methods are primarily employed by the pharmaceutical industry to address the need for visual inspection of filled and sealed containers: manual visual inspection (MVI) relying on human capability and machine based automated visual inspection (AVI).  

As the name suggests, a manual inspection relies on the ability of human operators to detect foreign contaminants in the filled containers. The inspection requires trained and certified inspectors to perform the task. Use of inspection aids such as contrasting colors and magnifying glass can improve the accuracy of human inspection. In spite of this, the subjectivity involved with manual inspection impacts effectiveness and the speed with which the inspection can be done. In addition, the process cannot be validated. Achieving required inspection throughput for a large commercial lot would require larger number of inspectors, which can add to labor costs.  

Automated inspection systems, on the other hand, rely on a machine to detect visible particulates. Compared with manual inspection, an AVI process is more consistent and can be more cost effective over a longer time period of use. The AVI system requires qualification and validation, which ensure that the performance is consistent and similar to or better than human inspection. Several comprehensive studies of Knapp and coworkers [4, 5] highlight the probabilistic nature of the inspection process and provide a mathematical framework for comparing the performance of an automated inspection system with human capability.  

Automated inspection process:  technologies and principles

The automated inspection machine (AIM) used in this study contains a light-transmission double-check system for detecting particles in filled and sealed drug-product containers. The AIM uses a static division (SD) system that divides the photo detector into independent bits that span a detection window from the base of the container to just below the meniscus. The first step in the inspection process is the spinning of the container at a specified speed. As the vial spins, the liquid inside the vial forms a vortex and, because of the centrifugal force, imparts momentum to insoluble particles. These suspended particles are forced toward the container wall. The vial is then stopped with precise timing through the application of brakes on the machine. Because of frictional drag, the vortex collapses, thereby lifting and rotating the suspended particles. The image of moving particles is projected onto the SD sensor and can be sensed through variation in the intensity of the transmitted light which is converted to an electric signal from the affected bits. The amount of change in the electric signal is proportional to the size of the particle and is compared with a preset sensitivity level. If the signal exceeds the threshold established by the preset sensitivity level, the vial is deemed faulty by the machine and is sent to the defect bin. Cosmetic defects such as scratches or stains on the vial surface do not result in any movement during inspection and are not detected by the SD sensor. 

Industry also uses a camera-based system to detect defects in filled drug-product containers. Unlike the SD sensor, which relies on light transmittance, a camera system uses light reflection to detect particles. Because the judgment of the camera system depends on the intensity of the reflected light, its performance is dependent on particle reflectivity and color. In addition to moving particles, a camera-based system can also pick up the light reflected from surface scratches and other container defects. Depending on the sensitivity of the system, this can result in increased false rejects. Alternatively, the system can be calibrated to detect specified cosmetic defects.  

In addition to cosmetic defects, the potential benefit of a camera-based system includes the improved performance at lower fill levels. For very low fill volumes, the inspection window for a SD sensor-based system is greatly reduced, thereby resulting in deteriorated performance. Such challenges can be addressed by strategic placement of cameras to target a low fill-volume window. Hybrid systems that seek to combine the benefit of camera-based and SD sensor-based technology are being developed to provide improved performance for both particle and cosmetic defects. 

Irrespective of the technology selected for automated inspection, several operational parameters (e.g., machine settings) and product properties play a key role in determining the performance of the system. Detailed characterization and optimization of these parameters is critical to developing an AVI process. Each technology needs to be qualified for its ability to detect faulty containers and to ensure that non-defect containers will not be rejected. This qualification requires a series of experiments using standard defect sets to challenge the AIM. Careful selection of experimental conditions (i.e., defect sets and machine settings) is important to minimize the number of evaluations and still generate conclusive data for entire process space. This study uses a SD sensor-based AIM to evaluate the effect of key process parameters on machine performance for inspection of liquid products in vials. Tested parameters include machine settings, formulation properties, and fill configuration.  

Eisai Automated Inspection Machine (Model 587-2, Eisai Machinery of USA, Allendale, NJ) was used to conduct an automated inspection. Mimic solutions were prepared by adding an estimated amount of PEG 1000 into desired buffer solution to reach a target viscosity value. Upon proper mixing, a sample was tested for viscosity confirmation. The mimic solution was then filtered through a 0.22μm filter and aspectically filled into vials followed by manual inspection to ensure absence of foreign particles. These clean vials were spiked with standard glass beads of three different sizes: 70μm, 100μm and 400μm (Duke Scientific Soda Lime Glass, Palo Alto, CA). Each vial was seeded with a single glass bead. The seeded vials were manually inspected a second time to ensure that each vial only had one particle and no other foreign contaminants. Two different buffer formulations (with and without polysorbate) were used to prepare PEG solutions of different viscosities. Formulations comprised of a commonly used stabilizing excipient (sucrose or sorbitol) and a buffering agent (acetate). The formulations are listed as follows and are referred to accordingly in the remaining sections of this article: 

Formulation A = PEG 1000 in acetate buffer + sucrose +  Polysorbate 20 

Formulation B = PEG 1000 in acetate buffer + sorbitol 

Vials seeded with particles were inspected on the Eisai machine through a double-check system comprising two inspection stations. A set of 24 vials (six clean and six each seeded with 70μm, 100μm and 400μm particles) were inspected at each inspection station. Each vial was inspected 32 times in a single run. A total of three runs were conducted to estimate statistical error in the performance. For selected experiments, a design of experiment (DOE) was performed using a space-filling design and spanning a range of spin and brake settings for a fill configuration of 1.7 mL in 3 cc. All DOE experiments were conducted for solutions with different viscosities using PEG solution in Formulation B. 

 Inspection data obtained from the Eisai AIM were analyzed by calculating the detection rate (%DR) as follows:  

The detection rate can then be calcuated for each vial type (clean, 70μm, 100μm and 400μm) by averaging the %DR values for all six vials in each group. For runs that were conducted in triplicates, the average and standard deviation were also computed for the detection rate for each particle size. For the data generated through DOEs, contour plots were generated to  depict detection rates for 400 μm-particle size at various spin and brake settings. 

Systematic studies were conducted to evaluate the effect of key process parameters, including machine settings, product properties, and fill configuration on the performance of the AVI system.  

 The key operating parameters for the AVI process included the machine settings used during inspection (see Table I).  

Table I: List of machine parameters potentially impacting detection rates. 

The mechanism of operation of a SD sensor-based system involved sensing the variations in the electric signal (voltage level) as a result of light interference by foreign particles. Sensitivity of the machine refers to the threshold DC voltage signal that should be exceeded to judge the vial as faulty. A higher sensitivity would improve the machine's ability to detect foreign particles, especially those of smaller sizes as shown in Figure 2. However, there is a threshold sensitivity above which the improved detection rates come at the cost of false rejection. Even clean vials with no foreign contaminants were judged by the machine as faulty (see Figure 2). Careful selection of the sensitivity levels should be made to maximize the detection rates while minimizing the business costs associated with rejection of nondefective vials.  

Figure 1: Mechanism of visible particle detection through a static-division sensor-based AVI system. (ALL FIGURES ARE COURTESY OF THE AUTHORS) 

Impact of spin speed and brake position. 

The key requirement for tuning the ability of the machine to detect particles was to adjust the balance between the vial rotation and the precise timing and position when the vial was stopped and inspected. In an optimal set-up, the liquid surface (see Figure 1) would have been completely restored right before its inspection. If the rotation of the vial is terminated too late (i.e., represented by larger brake setting here) the liquid level may not be restored at the time of inspection and the moving meniscus can send the faulty signal to the detector resulting in a false reject. On the other hand, if the rotation is terminated too early, the liquid would have slowed down and the foreign particle would have started sinking even before reaching the inspection station. This slowdown could result in the machine missing a defective vial and wrongly classifying it as an "accept." Figure 3 shows that the detection rates for all particle sizes were improved when the brake settings were increased from 7 to 9, signifying a better performance when inspection is conducted closer to the termination of rotation. Similar improvement in performance was observed when the spin speed was increased from 1600 rpm to 2200 rpm. Higher rpm rates seemed to impart larger momentum to the liquid and suspended particles and thereby keeps them moving for a longer time, making them easier to detect. The magnitude of this effect could depend on product property (e.g., viscosity) and fill configuration (e.g., container size and fill volume) as discussed in the following sections.  

Figure 2: Comparison of detection rates for particles of different sizes when using two different levels of sensitivity (Formulation A). The impact of sensitivity on detection rate for smaller particles is larger and higher sensitivity may result in false rejects (i.e., rejection of clean vials). 

In addition to the machine settings, the product properties can have a significant impact on the performance of the AVI system. Solution properties such as density, viscosity, and surface tension govern the movement of the foreign particle in the flow-field generated by spinning the the vial. The speed at which meniscus recovers, as well as the time it takes for the foreign particle to descend and stop after the application of brakes, is dependent on these solution properties. Figure 4 shows deterioration in performance of the AVI system as the product viscosity is increased. As solution becomes viscous, the particle motion relative to the solution is arrested and it becomes difficult for the machine to detect. Detection rates can improve by increasing the spin speed and brake settings as shown in the figure by the three traces of color (blue, red, and green). The Figure 4 inset shows a closeup of the data set for 2.3 cP. It was observed that the two formulations with same viscosity but different density and surface tensions (Formulation A is represented in yellow and has a density of 1.046 g/mL and surface tension of 48 mN/m2; Formulation B is represented in red and has density of 1.033 g/mL and surface tension of 61 mN/m2 at room temperature) exhibit slightly different detection rates (about 7% variation). This finding demonstrates that variation in physical properties other than viscosity can effect the way the particles are suspended and move during inspection, thereby affecting their detection rates. However, as the spin speed was increased, the overall performance improved and the differences between the detections rates for the two formulations was reduced.  

Figure 3: Effect of spin speed and brake settings on the detection rate of the machine. A setting of 1600 x 7 represents spin speed of 1600 rpm and brake setting of 7. Performance improves as spin speed is increased and inspection is performed quickly after stopping the vial. 

In addition to the physical properties discussed above, other inherent properties of the protein solution could affect the ability of the machine to differentiate between and true and false rejects. If the protein has a propensity to form or trap particulates, such protein particles can be perceived by the AVI system as rejects. In such cases, kinetics of particulate formation should be characterized to assess the feasibility of using automated inspection. The liquid formulation may also have propensity to form micro air bubbles which can be perceived by the inspection system as foreign particulates. Beccause air bubbles have a tendency to rise to the meniscus, inspection view height can be carefully selected to avoid any interference with the bubbles. Some AIMs use a pre-spin to facilitate removal of air bubbles before the inspection spin. Such AVI process issues could be very product specific and may cause costly delays during performance qualification. Selection of an appropriate mimic solution for development runs is therefore critical to identify and trouble-shoot such problems early during product development.  

Figure 4: Product properties can have a significant impact on machine performance. Detection rates (average of 100 Î¼m and 400 Î¼m particles) are reduced at higher viscosity and improve with increased speed and brake settings. Solutions with similar viscosity can also exhibit differences in detection rates based due to differences in density and surface tension. A setting of 1600 x 7 represents spin speed of 1600 rpm and brake setting of 7. Yellow fill color represents Formulation A while red represents Formulation B.  

A design of experiments can be conducted to characterize the performance of the AVI system over a wide range of operational parameters. A design space can then be created over the range that gives acceptable performance. Such design space characterization offers the assurance of a consistent and robust process. Figure 5 shows results of a DOE study conducted over a wide range of spin speed and brake settings for a fill volume of 1.7 ml in a 3cc vial using Formulation B. The contour colors represent detection rates measured by the automated inspection system for solutions of different viscosities. As discussed above the performance clearly deteriorates with increase in solution viscosity. While higher spin speed and higher brake settings results in improved detection rates, other operational issues can come into play under such conditions. For example, very high spin speed may cause the vials to shoot out of the spindles making the process operationally unfriendly. Very high brake settings (inspecting very close to the termination of vial rotation) may not provide adequate time for the meniscus to recover. The meniscus, in turn, puts a shadow on the sensor and can be wrongly classified as a defect. All these operational issues should be carefully characterized to create a design space that offers acceptable performance during commercial manufacturing.  

Figure 5: Contour plots representing the machine performance over a wide range of spin and brake settings for solutions of different viscosities. The black area represents the operational parameter range that was not studied. 

 In addition to machine settings and formulation properties, fill configuration of the final drug product presentation (i.e., size and shape of container and liquid fill volume) plays a significant role in determining the performance of an automated inspection system. The radius of the container has a direct impact on the shape of the vortex formed when the vial is spun and the recovery of the meniscus when brakes are applied. Syringe barrels usually have smaller radii than vials and pose a bigger challenge for inspection. Higher spin speeds are needed for syringes to obtain performance comparable with vials. The height of liquid level plays an equally important role as well. For a given vial size, as fill volume is reduced, the liquid level is lowered and the size of the inspection window (i.e., distance between base and meniscus level) shrinks. Figure 6 demonstrates that the automated machine's performance was consistently better for larger fill volumes for each of the three vial sizes. Inspecting very close to the meniscus level may result in false rejects due to the meniscus shadow being perceived by the sensor as foreign particle. Careful selection of inspection view height is critical to minimizing such false rejects while maximizing the size of the inspection window.  

Figure 6: Comparison of detection rates for vials of different sizes and fill volumes. Smaller fill volumes are consistently more challenging for automated inspection. 

AVI of injectable drug products offers several advantages over manual inspection, including process consistency, speed, and potential cost effectiveness. This study investigated the role of machine settings, formulation properties, and fill configuration on the performance of an AVI. Higher spin speed and brake settings were shown to improve detection rates of the AVI system. Product properties such as viscosity, density, and surface tension affect the manner and duration of particle suspension in solution and thereby affect process performance. Other inherent solution properties such propensity to form air-bubbles and/or protein particles can also cause potential interference with the inspection system resulting in false rejections. Low fill volumes are also challenging because of the smaller inspection window. It is suggested that any equipment qualification or process characterization work should evaluate the system performance over a wide range of these process parameters and solution properties to arrive at a robust and consistent visual inspection process. DOEs can be conducted to study these parameters and any potential interactions. Formulation properties and fill configurations can be bracketed to minimize the number of experiments.  

The authors wish to thank Aarti Gidh, Deborah Shnek, Erwin Freund, and Ed Walls in process development at Amgen for useful discussions and suggestions for this paper. We also thank Jeff Stephens, Ari Levy, and Damien Villanueva in clinical manufacturing at Amgen for providing valuable experimental support toward the execution of these studies.  

is principal scientist, all in drug product and device development at Amgen, Thousand Oaks, CA, 

 2. T.A. Barber, Control of Particulate Matter Contamination in Healthcare Manufacturing (CRC Press, 1999). 

 3. C. Jones, presentation before the PDA Visual Inspection Forum (Bethesda, MD, 2007). 

The authors used a light-transmission-based static division system to detect particles of foreign contaminants in prefilled vials.

Challenges and Strategies for Implementing Automated Visual Inspection for Biopharmaceuticals

Aseptic processes are some of the most difficult processes to conduct in the pharmaceutical industry. Because of the nature of aseptic processes, sterile products produced aseptically present a significantly higher risk to the patient than terminally sterilized products. Because of the high level of risk, an effective quality-risk-management program is necessary to protect the patient. An effective risk-management program aids in the careful control of the process, reducing the risk of contamination as well as wasted effort in controlling insignificant risks.  

Aseptic processing involves manipulation of sterile components in a carefully controlled environment using careful techniques to produce a sterile product. While aseptic processing usually involves filling of final drug product, there are other types of aseptic processes, including aseptic assembly of devices or combination products, aseptic crystallization or aseptic precipitation of drug product to produce a sterile bulk-drug substance, and aseptic formulation of final drug product. 

One thing all aseptic processes have in common is their high level of risk. They require careful control of the aseptic environment, of personnel practices and procedures, sterilization of equipment and components, extensive environmental monitoring, and many other controls. The number of controls required and the severe consequences of control failure make aseptic processing one of the highest-risk pharmaceutical processes. Quality risk management is an essential tool in ensuring product quality. 

Although quality risk management (QRM) is a relatively new concept to the pharmaceutical industry, it has been used in other industries for many decades, with some risk-assessment tools dating back to the World-War-II era. The pharmaceutical industry has been slow to adopt many of these tools because of the industry focus on regulatory compliance as the driving force for quality. This traditional compliance-based approach had its drawbacks that became more evident as the industry became more diverse and sophisticated. A "one-size-fits-all" approach to quality became increasingly unworkable, leading the US Food and Drug Administration to develop a quality systems approach to regulation. 

The quality systems approach to the pharmaceutical industry was launched on a large scale with the FDA publication of 

Pharmaceutical CGMPs for the 21st Century—A Risk Based Approach 

in August 2002 (1). This initiative had the ambitious goal of transforming the FDA regulatory approach to the pharmaceutical industry into a science-based and risk-based approach with an integrated quality systems orientation. 

In the time since the publication of the concept paper, this initiative has been largely successful, leading to publication of international guidance documents such as ICH Q9

 and the Parenteral Drug Association (PDA) 

Technical Report No. 44 on Quality Risk Management for Aseptic Processes 

 has further enhanced the risk-based approach to pharmaceutical manufacturing. 

There are many potential uses for quality risk management in the pharmaceutical industry, including:  

Determining the scope, complexity, and frequency of internal and external audits

Identifying, evaluating, and communicating the potential quality impact of quality defects, complaints, trends, and non-conformances

Providing a framework for evaluation of environmental monitoring data

Evaluating the impact of changes to the facility, equipment, or process on product quality

Establishing appropriate specifications and identifying critical process parameters during product and process development

Assisting facility design (e.g., determining appropriate material, equipment, and personnel flows, appropriate level of cleanliness for processing areas)

Determining the scope and extent of qualification of facilities, buildings, and production equipment and/or laboratory instruments (including proper calibration methods)

Determining acceptable cleaning validation limits

Determining the extent of computerized system validation

Identifying the scope and extent of verification, qualification, and validation activities

Determining the critical and noncritical steps in a process to assist in the design of process validation.

The uses for quality-risk-management tools are nearly limitless. A few examples of the uses of these tools in aseptic processing include:  

 QRM tools such as 3-D risk assessment can be used to identify high-risk equipment and facilities, as well as low-risk equipment and facilities; this will allow risk-control efforts to focus on eliminating the highest risks (4). Design of high-risk equipment and facilities can be enhanced using input from tools such as failure mode and effects analysis (FMEA) and fault tree analysis to identify potential failure modes. This input allows the equipment designer to add preventive measures to the equipment design to reduce the occurrence of, or even eliminate, potential failure modes.

 QRM tools can be used to identify the critical aspects of the aseptic processing equipment or facility that need to be intensively qualified, and the low-risk aspects of the equipment or facility. QRM tools can also be used to determine the extent and frequency of requalification efforts.

 QRM tools can be used to identify high-risk equipment and facilities that need to be maintained under strict change control, as well as the equipment and facilities that can be placed under a simpler engineering change management program.

 QRM tools can be used to identify the key inputs, key process parameters, and key outputs that need to be monitored and controlled. This allows for focused process validation that ensures that process parameters that are critical to product quality are appropriately validated.

Risk is the combination of the probability of harm and the severity of harm. For the purposes of QRM, it is the risk to the patient that is important, not the risk to other stakeholders such as government, industry, medical practitioners, etc. 

According to ICH Q9, quality risk management is defined as "a systematic process for the assessment, control, communication, and review of risks to the quality of the drug product across the product lifecycle" (2).

Some key concepts in this definition are that QRM is a systematic process, and that it is designed to manage the risks to product quality across the product lifecycle. The introduction of a systematic process for managing product quality is crucial to consistently providing a high-quality product to the customer. 

ICH Q9 defines the two primary principles of quality risk management as follows:  

The evaluation of risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient

The level of effort, formality, and documentation of the quality-risk-management process should be commensurate with the level of risk (2).

These principles lead to a need for a formal risk-management program for manufacturers of parenteral products. Because these products, which include most biotechnology-derived drugs, bypass many of the body's defense systems, the level of risk to the patient is significantly higher than in oral or topical products. 

ICH Q9 describes the quality risk-management process. Figure 1 illustrates the components of the quality risk-management process across the product lifecycle.  

Figure 1: Risk-management process (2). (FIGURE 1 IS COURTESY OF ICH) 

Risk assessment is the first portion of the quality-risk-management process. It consists of identifying potential hazards, analyzing hazards, and risks associated with exposure to those hazards. A few key points about the risk assessment process include:  

Risk assessments should be performed by a team of qualified experts from disciplines such as engineering, quality assurance, validation, and manufacturing, preferably facilitated by someone familiar with the risk assessment process. This team should clearly define the risk question. A poorly defined risk question can lead to lack of focus in the risk assessment.

Three fundamental questions should be answered in the risk assessment: What can go wrong, how likely is it to go wrong, and how severe are the consequences?

A few of the more popular methods for risk assessment are given in the "Risk assessment tools" section. These tools share some of the key characteristics of a risk assessment process:

Systematic identification of hazards referring to the risk question (risk identification)

Estimation of the risk associated with the identified hazard (risk analysis)

Comparison of the identified and analyzed risk against pre-determined criteria (risk evaluation).

The output of the risk-assessment portion of the risk-management process is used in the risk-control portion of the risk-management process. 

Risk control consists of developing a plan to reduce and/or accept risks. The purpose of risk control is to reduce risk to an acceptable level. The formality and effort of risk control should be appropriate for the level of risk. The following questions should be asked during this phase:  

What can we do to reduce or eliminate risks?

The author discusses the risks involved with aseptic processing, methods and tools used to identify and control risk, and regulatory guidelines relevant to the risk-management process.

Pharmaceutical Technology-11-01-2009

Plastic Prefilled Syringes: A Better Fit for Autoinjector Systems

From Needle to Pill: Reformulating Injectable Drugs for Oral Delivery

Current Perspectives on Aseptic Formulations

Technology Forecast for Injectables

Challenges and Strategies for Implementing Automated Visual Inspection for Biopharmaceuticals

Risk Management for Aseptic Processing

Targeting Therapeutics for the Middle and Inner Ear

USP's Ferrules and Caps Labeling Changes Put on Hold