As the market for biopharmaceuticals grows, manufacturers must be certain that they understand the regulatory guidelines for the production of these therapies. Because most biopharmaceuticals are administered by injection, their sterility is crucial to ensuring patients’ safety. Filtration is a central quality-assurance strategy for injectable drugs. In a 2004 guidance, FDA says that the “use of redundant sterilizing filters should be considered in many cases” (1). But not all manufacturers agree on what redundant filtration is.

A technical report published by the Parenteral Drug Association (PDA) provides some illumination. The report defines redundant filtration as “a type of serial filtration in which a second sterilizing-grade filter is used as a backup in the event of an integrity failure of the primary sterilizing filter” (2). The second sterilizing-grade filter is incorporated in line, usually upstream but possibly downstream, to provide additional assurance of sterilizing filtration, says Jerry Martin, senior vice-president of global scientific affairs at Pall Life Sciences and one of the authors of the PDA technical report.

“This approach is especially prudent when the final sterilizing filter is not preuse tested and batches are aseptically filled into small containers prior to filter-integrity testing postuse,” says Martin. “Such batches often cannot be reworked in the event of a sterilizing-filter integrity failure, so inclusion of a redundant sterilizing filter can save the batch in the event of one filter failing the postuse integrity test.”

Some professionals use the term to describe two filters, one of which is terminal, that are separated by a holding tank, but otherwise in close proximity in a processing train. “We prefer the more strict definition of two filters used in series to meet the objectives of a single processing step,” says Rick Friedman, associate director of FDA’s Office of Manufacturing and Product Quality. “But, in all cases, the key aspect is the risk mitigation afforded by using two sterilizing filters rather than one.”

Theoretically, redundant filtration is not necessary to achieve a sterile drug substance, but some drugmakers find that it improves product quality. Incorporating two 0.1-µm filters in a process helps cell culture media sterilization success rate, according to a manufacturing professional at a major biopharmaceutical company. “We did not really get to understand the mechanism why two 0.1-µm filters are better than one, but the result seems to be telling us that they’re better. It significantly reduced our cell culture contamination rate,” says the professional, who preferred to remain anonymous.

Others consider redundant filtration a waste. “The cost lies within the end-user’s court, and therefore redundant filtration should be reviewed critically,” says Maik Jornitz, senior vice-president of marketing bioprocess at Sartorius-Stedim North America. Besides increasing filter costs, redundant filtration may force the end-user to address concerns about hold-up volume, unspecific adsorption, and leachables. If two filters’ functions are not defined appropriately, a manufacturer must perform integrity testing on both of them, and cannot use one of them as insurance in the event that the other fails. Companies should ask themselves whether redundant filtration is truly necessary, whether the strategy is enacted to please regulators, or whether it is “a band-aid for a more serious penetration issue,” says Jornitz.

Manufacturers may find that redundant filtration has more value for some processes than for others. “The need for redundant filtration is process-dependent and should be based on a fully documented risk assessment that includes feed bioburden, filter-retention validation, filter-integrity history, processing time, product value, and reprocessing potential,” says Randy Wilkins, North American technical consulting team manager for EMD Millipore. “A thorough cost–benefit analysis is recommended for each specific application.”

Current regulations do not require redundant filtration, although guidance suggests that manufacturers consider it. “The requirement is for bioburden understanding and control, by whatever means are shown to be robust and validated,” says Wilkins. Thus, drugmakers are free to use their own discretion about the need for this strategy, even as they are bound to prove that their processes ensure the microbial safety of their products. 

Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practices

2. PDA, Technical Report No. 26, “Sterilizing Filtration of Liquids,” Revised 2008, 

Articles

Production Lines

In a 2004 guidance, FDA says that the "use of redundant sterilizing filters should be considered in many cases." But not all manufacturers agree on what redundant filtration is.

Can Redundant Filtration Make Sterility Assurance Double Sure?

Lechler
 Air nozzle provides chemical resistance


 Lechler’s WhisperBlast air nozzle is made of polypropylene, a chemical that complies with FDA regulations for materials used in pharmaceutical applications. The polypropylene model provides more chemical resistance than Lechler’s other air nozzles and can withstand contact with harsh acids. The unit is appropriate for applications such as blowing off rejected product, cooling blister packs, drying containers before the labeling process, and other operations that require compressed air.

Like Lechler’s other air nozzles, the polypro version is built with 16 distinct air channels into which inlet air is directed from the nozzle-inlet end. The unit can create a blowing force equal to that generated by other methods, but at lower inlet air pressures, thus reducing operating costs. The nozzle blows with directed force and is designed to be quieter than most compressed-air sprayers. The nozzle’s flat configuration allows operators to use it individually or alongside other nozzles on a header to create an air curtain.

National Bulk Equipment
 Dry bulk-material handling system increases process efficiency


National Bulk Equipment offers a bulk-bag unloading system designed and built for applications in regulated process industries. The system’s angled-plane framework with rounded radii reduces material accumulation and speeds moisture removal during washing in place. Operators can access the system’s component enclosures easily, which simplifies validation and inspection. In addition, the system’s process controls and automation comply with the specifications of the International Organization for Standardization.

A bulk-bag conditioner is integrated directly into the bulk-bag unloader’s structural framework. This design eliminates the repetitive loading and unloading that freestanding bag conditioners require and reduces the process to a single load–unload cycle. During an 8-h shift, the system’s integrated bag conditioning can increase the total number of bags processed from 12 to 16, according to the company.

The bulk-material handling system is built to handle free-flowing and fine materials, which are common to the pharmaceutical industry. Its dry and liquid product contact areas are constructed of 304–2b stainless steel.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the August 2011 edition from Lechler and National Bulk Equipment.

September 2011 Editor's Picks: Products from Lechler and National Bulk Equipment

The drug industry has used glass vials for a long time, and most industry professionals assume that these containers are safe. Yet glass vials can pose contamination risks that often are invisible to the naked eye. Glass flaking or delamination, for example, is a serious concern. It can result in a failed quality-assurance test, thus bringing production to a halt and causing substantial revenue loss. More significantly, if glass delamination remains undiscovered, it can pose a serious contamination risk to the drug product and a potential health risk to the public.

 
 Glass delamination occurs when top layers of a glass surface separate and flake off, typically at a scale invisible to the naked eye. Chemicals from the product solution or manufacturing process can cause the glass surface of the vial to delaminate or discolor. This effect can occur at any point during the vial’s life: during manufacturing, heat treatment, sterilization, or stability testing. 

Most pharmaceutical quality-control departments are not equipped to investigate the problem of glass delamination. Instead, they often turn to independent laboratories for their analytical expertise and capabilities.

First method of observation: the stereomicroscope


 Laboratories often receive pharmaceutical samples with visible particulates that need to be identified. Some clients may suspect glass delamination as the cause of the particulates, but other clients may not be aware of this phenomenon. Previous experience indicates that manufacturers should submit suspect vials for analysis when they are still filled and intact. The reason is that the fill line often is where glass delamination occurs. 

Several steps help determine the presence of glass delamination. A primary technique is using a stereomicroscope with various types of illumination. If the suspect vial was submitted filled, the first observation can be made using fiber-optic oblique lighting against a black background. This illumination may cause a twinkling effect within the vial, which is an indication of glass delamination. 

The contents of the vial are then filtered in cleanroom conditions to reduce the risk of contamination from any extraneous particles. When examining the filter that retains the particulate, the best technique for detecting glass flakes is coaxial illumination. Coaxial illumination reflects the interference colors of the flakes, thus revealing their thickness. Thin flakes are a gray-brown color, for example. In some instances, pitting is visible on the filtered particulate and on the vial wall. Pitting on the glass can be an early indicator of glass delamination.


Further chemical and microanalysis can prove definitively whether delamination and pitting have occurred. Examination of the inner vial wall, in addition to the particulate found in solution, reveals qualitative morphological information about the severity of the delamination. This technique also provides clues about where the delamination may have initiated. Common techniques include the following:

Micro-Fourier transform infrared spectroscopy is used to identify the organic materials present, as well as inorganic materials, including glass. 

Scanning electron microscopy and energy-dispersive X-ray spectrometry analysis can confirm whether a contaminant is glass and can provide clues about the conditions under which delamination most likely occurred. 

X-ray photoelectron spectroscopy (also known as electron spectroscopy for chemical analysis) can help determine the chemical nature of glass delamination. 

Potential packing problems can be overlooked easily until late in product development. To ensure product safety and to ensure that the vial is compatible with the drug, pharmaceutical companies should pretest all pharmaceutical packaging, including glass vials. It is important to test a package’s stability and integrity early in the development process to avoid problems later on. 

Kristie J. Diebold is cleanroom manager and senior research microscopist at McCrone Associates, the analytical division of the McCrone Group, 850 Pasquinelli Dr., Westmont, IL 60559, tel. 630.887.7100, 

In the Mixer

Glass flaking or delamination can result in a failed quality-assurance test, thus bringing production to a halt and causing substantial revenue loss. If glass delamination remains undiscovered, it can pose a serious contamination risk to the drug product and a potential health risk to the public.

Testing for Glass Flakes in Pharmaceutical Vials

Q: In our manufacturing process, we are running into issues with our vial stoppers clumping in the feeder bowl. How can we ensure that the stoppers go through smoothly without clumping up?

A: Clumping can result from various issues. The design of lyophilization stoppers can lead to twinning, a condition where the closures’ legs interlock and remain that way during processing. Autoclaving in an inappropriate container or in a container that holds closures too tightly may also result in twinning. Inconsistent siliconization and overprocessing can lead to clumping. If stoppers are autoclaved or dried too long, excessive heat may break down the elastomer. The result is a bowl full of tacky stoppers. 

When clumping occurs, manufacturers must first examine the type of stopper they use. It may be time to move to a newer product, such as ready-to-use or ready-to-sterilize stoppers. Suppliers of these components use validated processes to prepare pharmaceutical closures that help manufacturers streamline operations by eliminating component-preparation steps, such as washing, sterilization, and siliconization. When the packaging manufacturer performs this preparation, it can help ensure that closures are consistent. Products with barrier films or coatings may also ensure smooth processing by reducing clumping. Films and coatings also help prevent stoppered vials from sticking to the shelves of lyophilization chambers. Purchasing new stoppers will not fix the current problem, but may help to prevent future issues.

Manufacturers may need to review and adjust their processes, including washing, sterilization, and siliconization, to avoid overprocessing. If stoppers are sticky after autoclaving, reassess the autoclave conditions and validate the process at milder conditions. A process lasting no more than one hour with 121 °C steam heat (or no more than 8 h with 105 °C dry heat) should ensure that the product is not harmed by excessive heat. If the problem stems from the process flow, manufacturers should contact a technical support representative.

—Gene Polini, principal technical account specialist at West Pharmaceutical Services

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to 

 and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

In our manufacturing process, we are running into issues with our vial stoppers clumping in the feeder bowl. How can we ensure that the stoppers go through smoothly without clumping up?

Equipment and Processing Report-09-21-2011

Can Redundant Filtration Make Sterility Assurance Double Sure?

September 2011 Editor's Picks: Products from Lechler and National Bulk Equipment

Testing for Glass Flakes in Pharmaceutical Vials

Vial Stoppers That Won't Stop Clumping