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Pharmaceutical Manufacturing and Packing Sourcer

Keep It Clean

Recent trends towards ensuring high quality in pharmaceutical manufacturing have focused mainly on the drug product and its primary container. Many pharmaceutical and packaging manufacturers have placed emphasis on those materials in direct contact with the drug product itself, such as the glass vial, plastic syringe, and elastomeric stopper or plunger. Additional packaging elements, such as caps and seals, have not been the primary focus. However, in recent years, regulatory guidelines have significantly influenced the requirements for crimping processes.

Annex 1 – Manufacture of Sterile Medicinal Products – of the EMA’s Good Manufacturing Practice guidelines specifies that the production of sterile products is subject to “special requirements in order to minimise risks of microbiological contamination”. The EMA has stressed that quality assurance is “particularly important” and that manufacturers must “strictly follow carefully established and validated methods of preparation and procedure” to help ensure that drug products are clean and packaging sterile when used by patients.

When it comes to processing, precautions must be taken to minimise contamination, and the EMA refers, in particular, to two processes in the fill-finish area of those manufacturing plants that also perform aseptic filling: aseptic crimping and clean crimping.

Aseptic Crimping

A drug product’s biological and particulate cleanliness is best assured using aseptic crimping techniques and pre-sterilised components. Aseptic crimping requires the use of sterile seals, and for this process – as well as for reflecting the trend towards controlling particulate cleanliness – knowledge about particle specification limits may be requested.

In order to meet aseptic crimping requirements, there are a range of sterile, high-quality seals available. Such seals have a bioburden level prior to sterilisation (as referred to in EMA Annex 1, Clause 80), as well as a specified particulate level. Use of such a product helps to maintain cleanroom cleanliness levels and ensures quality for the end-user.

Clean Crimping

For clean crimping procedures, capping and crimping are performed in a non-aseptic environment under Grade A (Class 100/ISO 5) air supply. EMA Annex 1, Clause 120 notes that when vial capping is undertaken outside of the aseptic core, “vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped”.

Although the use of non-sterile seals is not excluded by the EMA Annex 1 for clean crimping processes, there is a growing uncertainty regarding the introduction of non-sterile, potentially contaminated components into the clean crimping area, and the effects on operational efficiency that this might cause.

Today’s high quality standards demand that contamination should be avoided by all means. Performing a clean crimping process with non-sterile seals means that comprehensive investigations need to be performed and maintained in order to ensure that stopper-vial integrity is not an issue. This type of testing may not be the core competency of the pharma company and, as such, may become a source of variability that can impact drug quality and regulatory compliance. Biological contamination when using non-sterile components, as well as failures or interruptions in the clean crimping processes, can not only potentially maximise the risk to patients, but also increase total costs for the business.

Combating Inefficiency and Contamination

In order to ensure the various requirements and guidelines for aseptic and clean crimping processes are met, different seal qualities with the appropriate features and benefits required by the product itself and, ultimately, the end-user, are needed. Just as different drugs may require different primary containers, secondary packaging also maintains a range of levels to ensure that the right quality is provided for the product and the manufacturing process.

To guarantee clean crimping procedures, pharma and biopharma companies are increasingly turning towards ready-to-sterilise and ready-to-use sterile packaging components. The application of high-quality, sterile products and components is necessary to avoid reject rates and increased production costs.

For many, a high-quality sealing component that is vision controlled, consistent and reliable during the capping process is an excellent choice. In particular, this type of seal can be a cost-effective method for clean crimping processes.

Since filling machines are becoming faster and more efficient, appropriate crimping procedures might also impact reject rates related to failures within the crimping and capping process. Even though rejects of finished drug product at the end of the line – due to inappropriate crimping – reduce operational efficiency and increase total costs of ownership, many crimping processes are carried out with basic products in a traditional way. Using high-quality sterile packaging components ensures a stable crimping performance, which minimises the risk of external contamination, line stoppages and equipment down-time.

Increasing quality levels for seals would include sterile, ready-to-use components that have specified and controlled bioburden levels before sterilisation. This type of seal can be used for clean crimping under Grade A air supply.

Regarding aseptic crimping processes, pharmaceutical and packaging manufacturers should seek out a clean, certified and sterilised seal that is developed for immediate use in cleanrooms and isolators. It should have a specified, low level of bioburden prior to sterilisation, as well as a certified particle level. Such a seal will be specifically manufactured for use inside a Grade A environment and designed for aseptic crimping processes. It will ensure biological cleanliness to meet regulatory guidelines and is the ideal solution for aseptic crimping procedures, in addition to helping ensure that patients are receiving a safe, effective and clean drug product.

Make Your Choice

Whether a manufacturer decides to use aseptic crimping or clean crimping, the choice of seal can aid in the process by creating operational efficiency, and eliminating potential sources of bioburden and particulates. High-quality seals are intended to meet operational and regulatory challenges, and consistently achieve reproducible and safe container integrity for the drug product. Use of such a seal will increase filling line efficiency and drug product safety, helping to meet the regulations and expectations of an industry for which quality is an ever-growing concern.

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Sylvia Marzotko is Manager, Marketing Projects Europe at West Pharmaceutical Services and is responsible for project management, as well as product-related activities such as launch preparation and execution. She holds a degree in Business Administration with a focus on Marketing from the University of Duisburg-Essen, Germany.
Sylvia Marzotko
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