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Pharmaceutical Manufacturing and Packing Sourcer

Dry State

Lyophilisation of cytotoxic drugs presents an increased challenge due to very particular safety and chemical factors. PMPS talks to Kevin Ward, Director of Research and Development at BTL, about the key considerations involved.

PMPS:What are cytotoxics?

KW: Cytotoxic drugs are therapies which are designed specifically to kill cells. The precise manner in which they work varies between products, and the term ‘cytotoxic’ can be used to refer to products which are genotoxic, oncogenic, mutagenic or hazardous in any way.

The most common cytotoxics work by preventing the rapid growth and division of cells. This makes them useful for treating cancers, in particular those which have particularly high growth factors, such as acute leukaemias and aggressive lymphomas. The connection between cancer and cytotoxics is so strong that the term ‘chemotherapy’ has come to be used almost exclusively to refer to treatment of cancer by antineoplastic drugs. However, not all cytotoxic drugs are antineoplastic. Recently, the use of cytotoxic therapies has expanded outside of the oncology field to treatment for rheumatoid arthritis, certain types of skin conditions such as psoriasis, and steroid-resistant muscle conditions.

What are the benefits of moving into this field?

Oncology therapies are big business; currently, they constitute around 18 per cent of all clinical trials and of existing oncology sales, cytotoxic drugs represent around a third. This trend is not set to decline; as the global population ages, the incidence of cancers and conditions such as arthritis are also on the increase. Furthermore, cytotoxic drugs are taking on a larger role in the development of personalised medicine, where therapeutic products are matched and formulated to individual needs. Research into targeted molecular pathways promises to enable cancer treatments to become increasingly targeted and specialised.

Many cancers, including older tumours, prostate cancer and pancreatic cancer are resistant to treatment by chemotherapy. New approaches, such as targeted delivery mechanisms, nanoparticle vectors and electrochemotherapy are working to enable existing therapies to be applied to resistant cancer types. In 2014, three of the major cytotoxic ‘blockbusters’, Eloxatin, Taxotare and Genzar, are set to lose patent protection. These three drugs currently represent 80 per cent of the cytotoxic products, and this presents a major opportunity for manufacturers of generics and for health providers seeking cheaper alternatives. The subsequent price erosion by generic manufacture is predicted to be so great that some analysts have suggested that, in dollar terms, the market will actually shrink. However, as development continues and generic versions become more affordable, unit production will continue to increase.

How are cytotoxics used and administered?

The majority of chemotherapies are delivered intravenously by injection or infusion, although a number of agents can be administered orally and isolated infusions are also sometimes used. Tablets are less common, but promise distinct benefits, particularly in that they can be taken at home and often without supervision by medical professionals.

What are the risks of dealing with cytotoxics?

The effects of cytotoxic drugs are not specific to tumours and normal cells can also be damaged, especially fast-dividing cells such as blood cells and in the gastrointestinal system. As a result, they can cause signifi cant adverse effects in anyone exposed. For non-patients the most common routes of exposure are contact with skin (involving spillage or splashing) and inhalation (for example, through overpressurised vials), with less common routes including needlestick injuries. The long-term effects of continued exposure to even small amounts of cytotoxic products remains undetermined, but several studies have indicated damage may be cumulative and therefore even minute amounts of contamination present a serious health risk.

For development laboratories and production facilities handling cytotoxic drugs, other products must also be protected from cross-contamination. For these reasons, containment and protection procedures over and above normal practice must be implemented. This commonly necessitates the use of a separate suite specifically for handling cytotoxic material, with enhanced containment and ventilation and operational procedure. In contrast with typical cleanrooms, negative pressure areas, isolators or cabinets are typically used to contain cytotoxic drugs; indeed, a facility may be held under negative pressure, with some defined positive pressure areas within the facility that an injectable cytotoxic drug is maintained in a sterile environment, while also ensuring containment and operator safety. This is a challenge that is not typically encountered for non-cytotoxic sterile drug products.

What are the benefits of freeze drying?

Freeze drying offers a number of advantages for stabilising pharmaceutical and biopharmaceutical drugs and cytotoxics are no different in this respect. Freeze dried product exhibits higher stability, greater activity and longer shelf-life than wet product. Broader temperature tolerance and greatly reduced weight also means that dried product is cheaper and easier to store and transport. Lyophilisation also offers advantages over other drying methods, including chemical and biological potency, homogeneity in the final product and avoidance of high processing temperatures that can damage sensitive biological components. Freeze dried products also permit easy reconstitution. After freeze drying, product can also be immediately sealed under a vacuum or inert gas to further improve stability.

What are the challenges of freeze drying?

While freeze drying is an established and well-understood method of stabilisation, if it is not carried out correctly there are a number of ways that problems can occur that will affect the stability, activity, shelf life, solubility and appearance of the final product. Thermal analysis of the product is vital to establish the key parameters for development of a safe and efficient cycle, but ideally product development should be carried out with freeze drying in mind from the outset. This will ensure that the final formulation will exhibit thermal characteristics that are favourable to freeze drying and allow the final process to be efficient and robust. Excipients must be selected that are compatible with the active ingredients and provide cryo- or lyo-protective benefits without producing any negative effects.

What are the challenges of freeze drying cytotoxics?

Lyophilisation is often carried out under controlled environments, but where cytotoxic products are involved, additional controls are required throughout the entire process, from the earliest stages of development to production and packaging. To ensure safe and responsible handling, staff must be protected and cross contamination with other products must be prevented. Partnering with a CRO with cytotoxic handling capabilities makes practical and economic sense for many companies, especially smaller organisations or those earlier in the development process. However, options for small-scale product and process development of cytotoxic products are limited, and of those, few have expertise in freeze drying.

What capabilities should a partner CRO have?

For a truly effective service in freeze drying product and process development, a partner should ideally have a range of experience in freeze drying, and especially in working with challenging product types. Cytotoxic handling capabilities should obviously be part of their portfolio, and a dedicated cytotoxic suite is a distinct advantage. The best facilities are built to Class 7 standards and are outstanding in terms of both containment and safety features. A full range of characterisation and analysis equipment should be available, as well as a pilotscale freeze dryer with in-process monitoring. This enables the execution of a full range of freeze drying R&D services for cytotoxic and combination therapies.

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Kevin Ward is Director of Research and Development at BTL. Kevin has worked in the freeze drying industry since 1993 when he undertook a PhD studying the freeze drying of pharmaceutical formulations and drug/vaccine delivery systems. Kevin then worked at Pfizer Central Research in Sandwich, UK, and as a Post-Doctoral Research Fellow in vaccine development at Aston University before joining BTL. Since 2007, Kevin has chaired the PHSS Freeze-Drying Special Interest Group, an international working group that produces monographs on practical aspects of freeze drying technology.

Kevin Ward
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