New drugs, new demands
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Todays drugs are highly potent and must be packaged in sterile and contained units
Dieter Bandtel, Bosch Packaging Technology, looks at how the needs of clinical trial and pilot drug production companies are changing and how their needs are being met with the latest advanced sterile filling and finishing technologies.
Despite the current economic crisis, the drug development pipeline is still quite robust. There were 9,605 drugs being developed in 2009 compared with 7,322 in 2005 and 5,995 in 2000, according to the Pharma R&D Annual Review1 published in May 2009.
Clinical trials are a critical component of the drug development process, determining which drugs will reach the market and generate revenue to compensate for the costly r&d cycle. Due to smaller production volumes, lines used to produce drugs for clinical trial operations have always had distinct needs in terms of processing equipment. Furthermore, the drug development landscape is changing, and these changes are having important effects on clinical trial and pilot drug production.
Drug r&d activities have traditionally been dominated by large multinational pharma-ceutical companies – Big Pharma. Now the rising number of mid-size biotech and biopharmaceutical companies moving projects into clinical trials is affecting equipment demands.
While established players typically have existing clinical trial lines up and running, this is not the case for new entrants who, as an alternative to building their own lines, often outsource operations to clinical research organisations (CROs). This is just one reason why the global CRO market is expected to grow 14% p.a. during the next three years, making contract research a US$35bn industry by 2013, according to a recent report from Business Insights.2 This growth has driven the need for new and improved filling and packaging machinery with increased flexibility.
Another change in drug development is the growth in production of injectable drugs, a market that is forecast to reach US$12.6bn by 2010,3 with growth in the biogenetic, oncology and vaccine segments expected to be especially strong. Biopharmaceuticals, in particular, are experiencing continuous growth, with a steady stream of products in the pipeline as well as several recent commercial successes.
With regard to cancer treatment, 28 oncology drugs were approved in the Europe, Middle East and Africa (EMEA) region from 2005 to 2008 compared with 20 drugs between 1995 and 1999.4 More focus is also being paid to vaccines to address challenges in the area of infectious disease.5 Lastly, another trend greatly affecting the face of clinical trials is the move away from blockbuster drugs towards personalised medicine, or pharmacogenomics.
These trends are combining to change equipment needs for clinical trial production lines, as processing these types of drugs requires different sterile filling and finishing equipment from traditional drugs.
One of the most prevalent demands we have been hearing in response to the above-mentioned trends is the need for highly flexible machinery. CROs need equipment that can handle production of a variety of drugs to support multiple clinical trial operations, while personalised medicine and biotech drugs call for lower volume production runs.
With smaller batch sizes of 10,000 to 20,000 vials, manufacturers can no longer dedicate an entire filling line to one batch. Filling systems need to be used for multiple batches to maximise asset utilisation. Manufacturers and CROs now need machinery that is able to fill multiple products with short start-up times to increase efficiency. Flexible processing equipment also allows manufacturers easily to accommodate the handling of various components, including different sizes of stoppers, caps and vials, as well as easily to changeover between batches.
To solve many of the above-mentioned challenges, Bosch Packaging Technology has created the MHI vial filling and closing machine for highly sensitive and limited availability drugs, such as those for clinical trials and pilot production. It is highly automated for reproducible recipe changes and quick changeovers with minimal size parts changes.
Additionally, manufacturers require modular machinery, allowing them easily to integrate new equipment into existing lines. For example, manufacturers can buy the stand-alone MHI vial filling and closing machinery, so they conduct the sterilising process on their existing equipment. It is also possible to purchase integrated compact filling lines that include a washer, sterilisation tunnel, filling and closing machine MHI, and even an additional bypass to the freeze drying process. The MHI also adds flexibility by allowing manufacturers to use a variety of filling systems, such as disposable rolling diaphragm pumps, or peristaltic pumps with single-use hoses.
The need for systems that protect operator safety is also currently heightened with the production of more highly potent or toxic biopharm/biotech and parenteral drugs. To ensure safety, manufacturers are seeking highly automated product filling and finishing machinery under various barrier systems – Restricted Access Barrier Systems (RABS), isolator systems or high-containment systems – to reduce human interaction and cross-contamination. Additionally, automation minimises the potential for inadvertent contamination of the product.
Bosch's MHI vial filling and closing machine has a high degree of automation with minimal manual intervention needed for format changes and maintenance, reducing the potential for human error, injury and contamination.
Quality control has always been of prime importance in pharmaceutical production. The integrity of filling and finishing processes must be validated to ensure products meet potency, purity and quality requirements. With the rise in biogenetic drugs, which can cost up to €1,000 per dose or more, the need to maximise quality and minimise product waste is even greater.
Companies can also select equipment with built-in process controls to prevent under-filled vials. Gentle product handling is also critical to avoid costly product waste.
The MHI vial filling and closing machine offers various filling systems for alternative use and in-process weight control to ensure quality control. The machine’s 100% checkweighing operation mode can reduce the number of reject vials during priming and end of batch runs. Additionally, its servo-controlled, robotic handling unit gently and precisely handles and transports products to eliminate breakage of glass vials and minimise rejects. Sophisticated communication between the filling and weighing stations, combined with an intelligent transport feature, ensure optimal usage of the product, minimal product loss and minimal rejects.
As validation procedures contribute approximately 10–20% of the operating costs of a pharmaceutical production line,6 the benefits of streamlining this process can be great.
Disposable components have been used for quite some time in upstream processing functions, such as mixing and fermentation. Due to its ability to reduce the risk of cross-contamination and eliminate the need for time-consuming and costly cleaning-in-place (CIP), sterilisation-in-place (SIP) and cleaning validation processes, disposable technology is now being demanded for filling and closing operations to produce drugs for clinical trials.
The use of disposable components in filling offers various parts for different products. It also eliminates the need for large stainless-steel tanks and piping to improve plant flexibility and further reduce production costs by eliminating validation processes.
Traditionally, manufacturers have used filling equipment with piston pumps and many mechanical parts that are in direct contact with products. Cleaning and re-assembling after each use is a lengthy process. Peristaltic pumps with single-use hoses have emerged to be popular in small-scale production, especially in the manufacture of drugs for clinical trials and multi-product operations. With this technology, drugs are in direct contact with only a single piece of tubing, which can be replaced after use. Streamlining the cleaning process saves manufacturers time and effort, and increases production speed.
An example is Bosch’s PreVAS (pre-validated, pre-assembled, pre-sterilised) filling system consisting of single-use tubing and filling needles and disposable hoses for peristaltic pumps or disposable rolling diaphragm pumps. These products can be fully integrated into the filling machine control systems. The peristaltic pump can be opened and closed in two simple steps without removing any parts, saving time and increasing safety, especially for isolator applications.
Scalable equipment can further simplify validation procedures for drugs taken to full-scale production, reducing costs and speeding time-to-market.
When purchasing filling and finishing lines manufacturers are increasingly looking into the continuous use of the lines through full production, or upgrading possibilities in critical functions of filling, checkweighing and monitoring.
4 Development of Oncology Products http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=605964
6 Disposable Systems in Biopharmaceutical Manufacturing http://www.futurepharmaus.com/?mc=Disposable%20Systems&page=mt-viewarticle
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As runs get shorter, easy vial and cap changeover is key for increased flexibility
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Clinical Trial Filler – the MHI 2020 processes small batches of toxic products using barrier systems for safety and containment
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