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On July 3, 2013, Novartis issued a voluntary recall of its Menveo® vaccine. Menveo is a lyophilized meningococcal vaccine used against Neisseria meningitidis, a bacterium that causes meningitis, meningococcemia and septicemia, and rarely, carditis, septic arthritis or pneumonia.
Menveo was recalled due to observation of higher-than-specified levels of residual moisture within the lyophilized MenA component vial. This residual moisture content was not expected to impact product quality, but constitutes a deviation to registered specifications. All other aspects of this lot met the required quality standards. This recall is not just a financial burden for the manufacturer (Menveo is valued at more than $100 per dose), but also could contribute to the already controversial drug shortage crisis.
There are several reasons for high levels of residual moisture. However, the most common reason is improperly dried elastomeric components. Many people in the industry still believe that the lyo stoppers will dry during the lyophilization cycle. Data obtained using Karl Fischer titration for moisture indicates that there is little or no moisture loss after a typical lyo cycle.
So what’s going on? Lyo stoppers are commonly manufactured using a butyl rubber base elastomer. Butyl rubber is extremely hydrophobic and as such is very difficult to hydrate. So how is the moisture getting into the stopper? Moisture levels in butyl closures are stable during the manufacturing process of blending, molding, trimming and washing. Even prolonged washes in hot water for injection do not cause moisture levels to rise in stoppers. It is only after a steam autoclave process that spikes are seen in the total moisture content in butyl stoppers. Why is this? Steam autoclaves introduce live steam at high temperatures under high pressure. This energy input is sufficient to drive moisture into the butyl stopper. It is only when this process is followed by a thorough and validated dry heat process that moisture levels return to pre-sterilization levels. This is typically validated using the previously mentioned Karl Fischer Moisture titration.
So how does one prevent this from happening? First, get advice from your closure vendor as to what the temperature and time limitations are for the closure of interest. Second, ensure that your processes do not exceed these recommendations. Finally, based on one’s understanding of the moisture sensitivity of the drug product, design the drying cycle to dry the stoppers to the appropriate degree. Not too much and not too little! There is nothing gained by over-drying rubber and the ramifications may be serious. Changes to the leachables and functional (i.e. coring and reseal) profile may change due to overexposure to heat. And, of course, time is money. Lyophilization processes are said to be one of the biggest bottlenecks in the pharmaceutical process.
So the next time you are developing a lyophilization process pay attention to your closure drying process. It could save time and money!
<p><em>Dr. Heike Kofler, Amy Miller, Jennifer Riter<br /></em><em>West Pharmaceutical Services, Inc.</em></p><p>One of the critical success factors for packaging lyophilized drugs is protection against product degradation caused by moisture. Moisture can be introduced into a lyophilized drug product cake from the elastomeric stopper and from the atmospheric headspace; it can also permeate through the stopper, a process known as moisture transmission.</p>
Parenteral drugs that are moisture sensitive are produced in a lyophilized state to protect against product degradation caused by moisture. As a result, when considering the stability and shelf life of lyophilized drugs, the residual drug moisture content is critical. It is also a crucial component in the dossier submitted for regulatory filing, which begs the question: How shall the moisture level in the lyophilized drug product cake be maintained during the drug product’s shelf life?
Some pharmaceutical substances, such as proteins, monoclonal antibodies, enzymes, and vaccines, are unstable in solution. They can degrade, for example by enzymatic or hydrolytic reactions. Lyophilization (also called freeze-drying) is the most common approach to address this.* Lyophilization is the process of dehydrating a material at low temperature and reduced pressure. Absent water, the rates of degradative enzymatic/hydrolytic processes are reduced substantially, and thus drug product stability is improved.
Lyophilization (freeze drying) is the process of dehydrating a drug product at low temperature and reduced pressure. Absent water, degradation processes are greatly reduced; thus, it helps to enhance drug product stability. Moisture-sensitive drug products are often marketed in lyophilized form. For a primary package system, the selection of appropriate components is essential to prevent risks associated with alteration of the lyophilized drug product prior to reconstitution and use.
Lyophilization is widely used for pharmaceuticals to help preserve parenteral drugs that are unstable in liquid formulation, particularly biologics. Lyophilized drugs have many advantages like prolonged shelf life, easy dissolution and good stability. However, a suitable container closure system is necessary to ensure the successful lyophilization of pharmaceutical products while maintaining product quality.
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