Pharmaceutical Manufacturing and Process Analytical Technology

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1 Pharmaceutical Manufacturing and Process Analytical Technology Trevor Murphy IMAR Technology Gateway Institute of Technology Tralee Tralee, Ireland Abstract - Global population aging in the developed world, unprecedented growth in the generics market and universal health reforms in conjunction with advances in medicinal science, genomics and biotechnology requiring more complex process streams and supply chains has outlined the need for the pharmaceutical industry to re-evaluate its manufacturing innovation policy. Current techniques employed by pharmaceutical companies in manufacturing drugs in comparison to other industries are outdated, empirical, tedious and in need of innovation. Process Analytical Technology (PAT) and the Quality by Design (QBD) framework put forward by the FDA offer a holistic approach to manufacturing pharmaceuticals, emphasising the understanding of process variables on the end products characteristics and transmitting this information upstream to control critical process parameters that effect the critical to quality attributes of a product. This paper is based on the changing dynamics in the pharmaceutical manufacturing industry that is driving the need for manufacturing reform and outlines the QBD & PAT initiatives as a solution to the growing demands and complexity associated with current and future pharmaceuticals. Introduction Increasing demands in the pharmaceutical industry, in conjunction with new developments in medicinal science has resulted in the pharmaceutical industries methods of manufacturing their products coming under more and more scrutiny due to the inefficiencies and wastes associated with current manufacturing processes. As vast sums of revenue are ploughed into the R&D of new products, very little in comparison is spent on innovation of new manufacturing processes and has resulted in some processes not fit for purpose due to the growing complexity involved in manufacturing newly developed products. At present, the majority of pharmaceutical products are manufactured using the batch manufacturing method which involves the breakdown of the manufacturing process into stages to allow for stage by stage analysis of the material. Upon completion of each stage, a sample of material is generally extracted from the bulk and analysed in laboratory conditions to ensure the critical to quality attributes are in line with specifications. The results of the analysis then dictate whether the material can be further processed or whether corrective actions are required for the material to achieve the desired specifications

2 While the batch method of manufacturing is suited to some pharmaceutical products, it remains a tedious and inefficient method for other products due to the time and labour intensive nature of the sampling and laboratory testing which has led for calls within the industry for an innovative solution for the manufacturing of pharmaceutical products. Process analytical technology (PAT) and the quality by design framework (QBD) has been identified as the future of pharmaceutical manufacturing and the solution to the increasing demand on the industries process stream due to its ability to automate the process stream while providing information to the user on the optimisation of a given process through use of a suite of novel sensors and analysers that monitor and control through timely measurements, the critical process parameters, that effect the critical to quality attributes. The purpose of this paper is to highlight how the growth in the pharmaceutical industry has resulted in the need to restructure pharmaceutical manufacturing methods while also outlining the various growth mechanisms within this industry that is driving the need for manufacturing reform. Growth in Pharma Sector The pharmaceutical industry is experiencing a period of sustained growth since 2001 and continues to thrive through investments in the research and development of innovative treatments, biotechnology and biologics among others. In 2013 a report issued by the IMS institute on the global use of medicines stated that, global spending on pharmaceuticals will exceed 1.2 trillion by 2017 [1] which will see the industry having tripled in size over a 16 year span. With access to medicines and innovative treatments (particularly in developing nations) becoming more widespread, coupled with investments in R&D and manufacturing facilities it is expected that the industry will continue to see a growth of approximately 5.1% globally per annum [2] A major driving force behind this increase in spending has been attributed to aging populations and longer life expectancy coupled with an increase in chronic diseases. As the average age of developed countries increases, so does the reliance on medicines and treatments for diseases that in turn increase life expectancy, for example, in Japan it is expected that by % of the population will be over 65 and in Germany by 2030 it is expected 27.9% or 17 million people will be over the age of 65 [3] which will serve only to increase the demand for medicines and drive the market forward. Global health reforms have also been attributed to the pharmaceutical industry growth as many countries have implemented universal health care systems or are currently in the process of implementing universal health care systems such as the Affordable health care act in the United States and China s healthcare reform and their plans to establish a basic universal healthcare system that can provide effective, convenient and low cost healthcare to all of its 1.3 billion citizens [4]. These Global health forms will increase the accessibility to affordable medicine to billions of people worldwide while generating revenue for pharmaceutical companies that can re-invest into the research and development of innovative new treatments which drives growth within the industry further. One of the main focal points for research and development at present in the

3 pharmaceutical industry is the development of specialist therapies or personalised medicines tailored towards the specific needs of a patient and will become an increasingly more common method of treatment. Personalised medicines are drugs that rely on bio-markers that can optimise therapeutic interventions and it is through this targeted therapeutic intervention that patient safety, clinical success and cost savings through the prescription of ineffective drugs can be increased. The benefits of specialised therapies and personalised medicines is the ability to treat each person s symptoms or diseases individually as patients responses to disease and/or treatment can differ from patient to patient. Advances in genomics coinciding with a reduction in the cost of gene sequencing along with technological advances in data analytics and computational power allows for patients to be monitored and treated in a more precise and effective manner that is more suited to each patients individual needs [5]. It is expected that by 2020 this method of treatment will make up approx. 23% of the global market, becoming even more diverse as advances in nanotechnologies and stem cell research begin to yield fruit [1] How will this effect manufacturing? But what does this mean for manufacturing? If we consider the rise in global spending attributed to factors such as an aging global population, an increased life expectancy and an increase in chronic diseases alone, then it becomes apparent that demand for medication and treatments will steadily increase. The average age of a population in all developed countries is steadily on the rise due to higher quality healthcare systems providing effective medication and treatments combined with a lower fertility rate that has seen the average number of children per woman drop from almost 6 children per woman in 1972 to 2.8 children per woman today [6]. As patients grow older they require more medication to maintain their quality of life which increases their life expectancy and increases the demand on the pharmaceutical industry to supply the growing population of elderly patients with affordable drugs. Universal health care initiatives, such as the previously mentioned affordable health care act in the USA and China s healthcare reform add further strain on the pharmaceutical supply chain and aim to provide billions with affordable drugs and treatments which has resulted in the generic manufacturing sector increasing revenue to $358 billion and accounting for 18% of all pharmaceutical products worldwide [7]. Generic manufacturers do not have the financial burden of costly research and development divisions as the larger and more innovative manufacturers, and as a result can produce generic versions of post patent pharmaceuticals at a much lower cost. Manufacturers of off-patent medicines must then offer their product at a much lower price to retain volume sales resulting in reduced profit margins, or identify areas within their value stream to reduce the out of pocket costs associated with manufacturing their products. The most obvious area to focus on is process R&D and to transition away from the batch production of pharmaceuticals to a more continuous or semi-continuous mode of manufacturing, however the regulatory barriers and ineffective intellectual property incentives associated with manufacturing process innovation in the pharmaceutical industry has resulted in the industry lagging behind the innovative techniques found in other industries [8]. A pharmaceutical company can place a patent on an innovative new treatment that can potentially generate billions while

4 innovation of manufacturing processes is met with strict validation and testing procedures that could potentially delay the release of a new product and has generated a reluctance among pharmaceutical manufacturers to move away from batch manufacturing despite increasing quality issues, contamination events and drug shortages [9] However, with the emergence of personalised medicines, bioengineering and genomics requiring more complex supply chains, an increase in the diversity of treatments available and the decline of the blockbuster drug model [10], there is somewhat of a paradigm shift in the manufacturing approach to pharmaceuticals with several manufacturers investing in new technologies and data analytics as they seek to increase profitability in manufacturing through improvements on process quality, efficiency and costs related to pharmaceutical processing. The FDA in 2004, recognising the need for a change manufacturing techniques and processes due to the increasing complexity of new treatments and the inefficiencies of current methods, published industry guidelines for the implementation of Process Analytical Technology (PAT) [11] with the intention of encouraging innovation in manufacturing processes using the latest advances in science and technology and to enable a transition away from batch mode manufacturing where the critical to quality attributes are tested postprocessing, to a continuous or semicontinuous mode utilising the quality by design (QBD) framework. QBD is a scientific approach to manufacturing that emphasises product and process understanding to allow for increased levels of process control and end quality. This is achieved through the identification of Critical process parameters (CPPs) by determining the extent to which any process variation can affect the quality of the product [12] and utilising this information upstream for the optimisation of each parameter and the manufacturing process as a whole. When used in conjunction with PAT systems the QBD framework ensures higher quality levels and process efficiencies, a reduction in productions costs due to decreased operator dependencies and downtime as a result of laboratory analysis and early identifications of root causes to processing errors or quality issues. PAT process sensors located at critical process points can be used to monitor a range of critical to quality attributes of a material such as temperature, moisture content, chemical composition, particle size distribution and any other characteristic that effect end product quality. The resulting data is then analysed using a combination of data fusion, multivariate data analysis and statistical design of experiment tools and the resulting information is fed upstream to control the critical process parameters that effect the critical to quality attributes, resulting in a continually evolving and improving system that provides a more in depth understanding on maintaining, improving and optimising the manufacturing of a given pharmaceutical product. Implementation of PAT The implementation of PAT in pharmaceutical manufacturing to date has been insignificant in comparison to the scale of the pharmaceutical industry as a whole despite the FDA s efforts to promote PAT over the last 12 years with the publishing of the guidelines for industry in Profit margins are vast in the pharmaceutical industry at present [13]and the costs associated with manufacturing

5 errors pale in comparison. The disruptive nature of implementing PAT onto existing processes also remains a key issue as pharmaceutical companies would be reluctant to schedule the prolonged downtime required to upgrade existing batch processes to continuous processing along with the high costs associated with the implementation and training associated with PAT and perhaps fail to realise the returns that can be achieved from the investment. Perhaps a more suitable approach to the implementation of PAT in pharmaceuticals is to focus initially on new installations and facilities rather than a complete overhaul of existing processes and utilise these new facilities to gain a broader understanding and familiarity with the concept of QBD & PAT in pharmaceutical manufacturing similarly to the investments made by pharmaceutical giants Glaxosmithkline (GSK) [14] and Amgen [15] in continuous manufacturing facilities in Singapore. With the profit margins associated with blockbuster drug models diminishing, the growing influence of the generic market and the FDA s promotion of PAT in pharmaceutical manufacturing, early adoption of the QBD framework with PAT systems would provide manufacturers with both a competitive and financial advantage along with the ability to cope with the growing demand complexity required in manufacturing tomorrows treatments and medicines.. References [1] S. Friend, S. Arlington, J. Marshall, and W. Bailey, Pharma 2020: Supplying the Future, p. 36, [2] EvaluatePharma, World Preview 2014, Outlook To 2020, [3] E. Brandon, 10 Rapidly Aging Countries - US News, USnews, [Online]. Available: irement/slideshows/10-rapidlyaging-countries/11. [Accessed: 06- Jan-2016]. [4] C. Süssmuth-Dyckerhoff and J. Wang, China s health care reforms, Heal. Int., vol. 10, pp. p.54 67, [5] U.S. Food and Drug Administration, Paving the Way for Personalized Medicine Paving the Way for Personalized Medicine, Per. Med., pp. 5 11, [6] J. Veron, [Global fertility decline], Bull. {l Association} géographes français, vol. 73, no. 2, pp , [7] D. Fox, H. Lovells, and D. B. Actavis, The generic drug era is impacting all areas of the industry GENERICS :, no. February 2012, [8] W. Price, Making Do in Making Drugs: Innovation Policy and Pharmaceutical Manufacturing, Bost. Coll. Law Rev., vol. 55, no. 2, p. 491, [9] W. N. P. Ii and D. Ph, Problems of Innovation-Deficient Pharmaceutical Manufacturing, pp. 1 3, [10] Goodbye blockbuster medicines; hello new pharmaceutical business models Comment Pharmaceutical Journal. [Online]. Available: bye-blockbuster-medicines-hellonew-pharmaceutical-business-

6 models/ article. [Accessed: 15-Jan-2016]. [11] U. S. D. of H. and H. S. FDA, Guidance for Industry PAT A Framework for Innovative Pharmaceutical Development, Manufacuring, and Quality Assurance, no. September, p. 16, [12] W. Is and Q. By, WH AT IS Q U A LI TY B Y DESI GN ( QbD ) AND W HY SHO U L D Y O U C A R E?, no. 11, [13] Pharmaceutical industry gets high on fat profits - BBC News. [Online]. Available: [Accessed: 16-Jan-2016]. [14] GlaxoSmithKline to invest S$77 million in Singapore facility - Channel NewsAsia. [Online]. Available: ews/singapore/glaxosmithkline-toinvest/ html. [Accessed: 16- Jan-2016]. [15] Amgen opens $200M continuous purification plant in Singapore - FiercePharma Manufacturing. [Online]. Available: ing.com/story/amgen-opens-200mcontinuous-purification-plantsingapore/ [Accessed: 16-Jan-2016].

Healthcare. Healthcare. The Centre for Process Innovation. From innovation to commercialisation

Healthcare. Healthcare. The Centre for Process Innovation. From innovation to commercialisation Healthcare Healthcare The Centre for Process Innovation From innovation to commercialisation The Centre for Process Innovation From innovation to commercialisation The Centre for Process Innovation (CPI)