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Pharmaceutical Manufacturing and Packing Sourcer

Sum of the Parts

Quality by design in primary packaging development is gaining in importance, but several initiatives are available to ensure a new project is up to scratch.

With new, sensitive pharmaceuticals and biopharmaceuticals being prepared for market, regulatory agencies have asked manufacturers to build quality into products from the start and to ensure consistent reliability throughout a drug product’s life cycle. To make sure that drug products maintain safety and efficacy from concept to commercialisation, and to reduce the total cost of ownership, packaging materials must evolve.

Pharmaceutical manufacturers have challenged packaging manufacturers to increase the quality of components used in parenteral packaging. High on the list of desired attributes are components with chemical cleanliness for sensitive drug products and improved material consistency. Consistent, reliable, highquality components that aid with flawless machinability and stoppering, and that are free from foreign contamination (particulate, fibres) and surface inhomogeneities (for example, black spots), are in high demand. In addition, most pharmaceutical companies are significantly increasing their requirements for component production. Among the top concerns are transparency of quality systems and products, fast response on quality issues, and continuous process and product improvement. Pharmaceutical manufacturers are also seeking partners who have built quality directly into the manufacturing process, and can provide a certificate of analysis for those products that meet compendia requirements of global regulatory agencies.

As the concept of risk assessment and mitigation becomes more and more important, the development of next generation components follows two approaches:
  • Enhanced component quality
  • Increased process understanding

For improved component quality, new rubber formulations are made using cleaner and fewer ingredients. Holistic quality by design (QbD) processes are implemented at manufacturing sites, thus achieving the highest possible process understanding and stability to increase quality for packaging components. Both clean elastomeric material and QbD processes will be needed to provide packaging options that can increase the quality, functionality and compatibility of the component with the drug product.

Component Quality

When selecting packaging for drug products, pharmaceutical manufacturers must ensure that components do not interact with the drug product itself and are applicable for the intended use. Today’s rubber formulations for pharmaceutical use should meet the following properties:

  • Lowest possible extractable and leachable profile
  • High moisture and gas protection/ barrier properties
  • Low fragmentation tendency
  • Excellent physical properties
  • Excellent self-sealing properties after needle removal
  • Comply with PhEur, USP and JP requirements

For example, high quality modern and clean halobutyl rubber formulations meet the above mentioned requirements while providing pharmaceutical-grade components that withstand industrystandard sterilisation processes using steam, ethylene oxide (ETO) or gamma irradiation (to a certain intensity). Modern halobutyl formulations are not cytotoxic and are produced according to cGMP industry standards.

When considering drug life cycle planning, modern formulations can help to improve transitioning plans for pharmaceutical manufacturers that want to move from, for example, a stopper-vial based system to a syringe-plunger based application. Some rubber formulations can be used for the production of various designs including stoppers, plungers and other primary packaging components with the exact same formulation. From a chemical analysis standpoint, this eases the transition from one container to another since rubber components that are in contact with the drug product remain the same.

Process Understanding – Applying a QbD Approach

While pharmaceutical companies work to meet new quality and compliance paradigms, a balance must be achieved between the realities of managing costs to provide a product meeting payers’ requirements and facilitating profitability to continue adequate business reinvestment.

To balance these priorities effectively, the adoption of quality by design (QbD) concepts is gathering momentum. Traditional manufacturing processes are based primarily on experience and practicality. Quality is ensured by inspection, and the focus is on equipment, capabilities and process reproducibility, rather than patient needs. Improvements are made on a one-off basis, and tend to be reactive instead of proactive.

In a QbD model, a systematic, sciencebased approach is used to view the process methodically. Quality is assured by understanding the product and process parameters, and by moving controls upstream. Unlike traditional manufacturing methods, the QbD focus is on process robustness, understanding and controlling variability. Improvements are made proactively and on a continual basis instead of waiting for an issue to provoke change. Risk assessments of all process steps involved, including incoming inspection, compounding, moulding, trimming, washing, sterilisation, packing and transportation, are carried out continuously to assure an in-depth understanding of the process to help minimise product variability.

The QbD framework can be adopted by pharmaceutical industry suppliers in order to provide benefi ts to the pharmaceutical drug manufacturer. High-quality components and sterile packaging must be well-understood to provide significant benefit to the overall container closure or delivery system. This need is a key driver for adoption of QbD for primary packaging materials such as elastomeric stoppers used for vial closures and plungers used for prefillable syringe systems.

Using the current pharmaceutical framework for QbD, as described in ICH Q8R2, pharmaceutical development, industry-leading suppliers build QbD-based components with the following elements:

  • Quality target product profile (QTPP)
  • Critical quality attributes (CQAs)
  • Risk assessments to link material attributes and process parameters to CQAs
  • Design space
  • Control strategy
  • Product life cycle management and continual improvement

These elements build the basis for an ongoing, living process that maximises product and process understanding, while also providing improved product consistency. Ultimately, the use of components based on this process allows the pharmaceutical customer to save money from a total cost of ownership standpoint. It also offers increased transparency because the supplier provides a managed knowledge base of technical information and product and process documentation.

Creating the QbD Line

A process designed with QbD principles requires a significant upfront investment. However, it delivers an improved, datadriven output providing manufacturers with superior product and process understanding that minimises process risk, emphasises patient-critical quality requirements and enhances drug effectiveness. Manufacturing with QbD principles provides a more efficient and consistent process, resulting in a higher-quality final deliverable with well understood and controlled sources of variation.

In a holistic QbD process, the QTPP forms the basis for drug product formulation and process development. A series of considerations should be made for the QTPP of a sterile product. Some of these considerations include the desired product performance based on the intended clinical setting, dosage strength and delivery mode, pharmacokinetic characteristics, drug product quality criteria, sterility, the container closure system itself, and so on.

Variables can, and do, occur in manufacturing. However, with a production process designed with QbD principles in mind, manufacturers can minimise those variations and achieve a greater understanding of how and why the variation occurs when they do happen.

To create a QbD manufacturing line, environmental upgrades, including implementing cleanroom best practices, are needed. Proper gowning is essential and should begin in the personnel locker rooms, where street clothes and cleanroom gowning must be separated. Deionisation at critical manufacturing steps also helps to avoid contamination caused by static electricity. Milling and extrusion should be completed in an ISO 8 environment with state-of-the-art equipment and high fi ltration particulate air (HEPA) fi ltration in all process rooms. Moulding should be completed by high tonnage presses for improved dimensional control. Autospray for consistent release of the agent and air-assisted mould unloading can reduce sheet distortions. O-type trim presses and enhanced trim dies can help to lower particle contamination. Precision trim control and automated control of web positioning and spraying for lubrication minimise variability.

As demands increase for elastomeric components that have specifications for extractables, these investments in the manufacturing environment will enable lot-to-lot testing that assures control of the product and process. Automatic verification and vision inspection can provide a consistent finished product that has limited variability.

As the market moves towards cleaner products and complete understanding of product and processes, ultra clean elastomeric formulations and products manufactured with QbD principles will meet these stringent quality needs. By partnering with a packaging manufacturer early in the development process, pharmaceutical manufacturers can meet and exceed quality expectations for drug product packaging, and deliver a safe, effective drug product to their customers.

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Sascha Karhöfer holds a degree in Biotechnology Engineering from the University of Applied Science, Aachen. He joined West in 2005, and spent more than five years with the Technical Customer Support Team, where he was responsible for West´s biopharmaceutical customers. Sascha served as the Key European Liaison, representing elastomers of West´s Japanese partner firm as product and technical support manager. He assumed his current position as Manager, Injectable Container Solutions Platform Europe in 2011.
Sascha Karhöfer
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