Henriëtte de Braal

Reducing energy consumption and carbon footprint are major focus areas for the pharmaceutical industry. Many articles are being published describing the need for and advantages of sustainable processing. However, achieving this is not as simple as reducing the amount of business travel, using energy-saving light bulbs or even bringing renewable energy sources into the business. More drastic measures must be taken to make a business sustainable. 

Some companies have already made a large step in reducing their carbon footprints and environmental impact by drastically altering production processes. The product portfolio of our business group in DSM consists mainly of semisynthetic penicillins (SSPs) and semisynthetic cephalosporins (SSCs). The production processes of these wellestablished APIs of the betalactam type traditionally starts with an already green process step: fermentation of a microorganism yielding an aqueous slurry containing both the producing biomass, byproducts and the required precursor for the product. The precursor must then be obtained in a purified form from this broth. This is generally where the non-green processing begins. Isolating a pure product requires the use of many chemicals, such as several types of organic solvents. Furthermore, for converting the precursor antibiotic into the various APIs, a range of other chemicals is required.  

The use of many different chemicals has a negative effect on the environment; for example, the use of volatile organic substances often leads to emissions, and energy consuming solvent production and recovery processes. Moreover, the use of a lot of chemicals in the production process also has implications for the impurity profiles of the antibiotic products themselves. 

Since SSPs and SSCs have been well established in the market for many years, the current safe impurity profiles of these products are increasingly covered by the monographs in the different pharmacopeias. It is well known in the business that chlorinated solvents are not healthy. In general, it is now recognized that omitting the use of such substances would be better for human health.  

The move towards greener processes for the production of the beta-lactam precursor products, as well as for the conversion of these into the final SSPs and SSCs, is based on using enzymes as biocatalysts. Being compounds of biological origin, enzymes require an aqueous environment to perform their catalytic action. Therefore, solvents are no longer used in this part of the process, which considerably reduces the ecological footprint of the production process. 

In 2000, enzymatically produced SSCs were introduced onto the market, followed in 2002 by SSPs produced 

 similar enzymatic routes. The change to industrial scale enzymatic manufacturing processes was accomplished after several years of intensive R&D. This resulted in significantly higher purity and stability, the absence of residual solvents and improved physical characteristics of the products.

  The absence of solvents and many chemicals from the chemical production processes also results in products with a noticeably better smell and taste. 

Since the enzymatic product is more pure, the crystal size increases somewhat (while crystal form and habit remained the same) and a significant improvement in flow ability is observed; for example, the compressibility index as a measure for flow ability improved from approximately 45% to 33%.

  Improved flow characteristics were also found in the compacted grades produced for capsulating and tabletting. Additionally, less dust formation reduced the risks of sensitization for workers handling the products. The benefits are, thus, not only for the environment, but for API and final dosage form (FD) manufacturers and, ultimately, for patients. Testing of these green APIs by FD manufacturers led mostly to enthusiastic reactions. At first, it seemed that all hurdles towards a better production method, as well as a better product, had been overcome, but the biggest obstacle still remained. 

Introduction of these green antibiotics into the less-regulated API markets (i.e., those outside Europe and the US) is running smoothly and successfully. Here the advantages of the new processes, resulting in improved product quality and lower environmental impact, are rapidly and fully harvested. However, introduction into the more strictly regulated API markets, where greater enthusiasm for products manufactured in a more environmentally friendly way would be expected, was hampered by significant set-backs and difficulties. 

In highly regulated markets, the hurdles for the authorization of changes in manufacturing processes of APIs are extremely high. When APIs are supplied to multiple customers, the complexity of regulatory authorization procedures for switching to APIs produced with the adjusted processes forms an almost insurmountable barrier. These highregulatory barriers undermine incentives to develop environmentally friendly processes to replace traditional chemical ones. Instead, the pharma industry still uses old technologies, and lacks focus on continuous improvement and innovation in manufacture. 

Previously, FD manufacturers have fine-tuned their processes to the less advantageous physical characteristics of SSPs and SSCs (e.g., a worse flow ability or more dust). When changing from chemically produced APIs to enzymatically produced APIs, small adjustments in the formulations are sometimes required to maintain bioequivalence of the final dosage forms; for example, the amount of magnesium stearate used in the tabletting of compacted APIs must be decreased in the case of enzymatically produced API because the larger crystals require less lubricant. The use of too much lubricant would have a detrimental effect on the dissolution behaviour of the tablets, impairing bioequivalence.  

FD manufacturers supplying to highly regulated markets are often hesitant to accept these types of changes because of the large implications for registration. Obtaining authorization for such changes requires extensive efforts and high costs for every customer of the API manufacturer. Therefore, changes proposed by API suppliers are normally met with reluctance or blunt refusal from customers, even though the changes offer important benefits for the environment and product quality.  

For example, in the case of Purimox (DSM Anti Infectives, The Netherlands), the enzymatic version of amoxicillin, and Purilex (DSM), the green equivalent of cephalexin, the purity improved significantly compared with their chemical counterparts. Nevertheless, this alteration is generally considered a major change that requires a Prior Approval Supplement in the US and a Variation Type II in Europe. As most of the older antibiotics are registered in Europe 

 National Procedures, overall approval timelines of several years are not unusual. One customer linked more than 300 applications to one API, which illustrates how complex, time consuming and expensive a switch to a green API can be. FD manufacturers are, therefore, often not inclined to accept the proposed changes and will not seek the required authority approvals. Moreover, the costs and efforts required to obtain the authorizations for such changes may often be too high to be compensated for by the perceived added value of the green product. 

So it appears the road to the introduction of green APIs into highly regulated markets is long, bumpy and, often, results in a dead end. Only by applying a more holistic approach from the side of the authorities based on the total benefits to society of developing green APIs, circumstances can be created for encouraging such highly beneficial innovations instead of blocking them. 

Current regulatory initiatives in the US and Europe that are aiming to accommodate continuous improvement and innovation in pharmaceutical manufacture should focus on adjusting the regulatory barriers to facilitate the implementation of green processes for API manufacture, without compromising patients' safety. One could, for example, consider fast track approval trajectories for such innovations, if developed by companies that have a proven track record in quality and compliance. The fact that APIs resulting from these new technologies have consistently appeared to be of higher quality and to have better safety characteristics should be taken into account as well. 

Many companies, including ourselves, continue to look for additional ways to improve production processes as we recognize that sustainable production is the way forward. Specific tools are currently being implemented that will take this approach one step further: by calculating the impact that individual process changes have on the company's ecological footprint, it can be determined which process optimizations should be favoured over others. In future, targets for ecological footprint reduction might even be set both at production and at management level. Without this continual focus, irrespective of the regulatory environment, such improvements will not be achieved. 

However, with both the EU and FDA in the process of significantly lowering the regulatory hurdles for process improvements through revision of the EU Variations Regulations and FDA's 21st Century Quality Initiative, DSM is confident that the current regulatory hurdles in highly regulated API markets will ultimately be lowered to levels that will render the development of green APIs an extremely attractive objective also for these markets. 	

 is a scientist working on product and process development in the innovation department for DSM AntiInfectives (The Netherlands). 

www.dsm.com/en_US/html/dai/DSMPureActivesIntroduction.htm

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Reducing ecological footprint and achieving more sustainable production of pharmaceuticals could help create a better future.