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since any minor failure in fulfilling the standards of quality among all the phases of production process can lead to serious damages on the end user's health or even life. Moreover, quality impacts the success of a business financially as any defect in quality may result in a bad reputation and lead to serious financial damages.
All production stages need quality assurance activities at several points (Shah, 2004), consequently, quality must be considered from various points of view. It is not about products and services anymore; there are also other aspects to be taken into consideration like processes, employees, suppliers and business partners in general.
Various standards are the applicable around the World, the majority of which compliant or inspired to the wide framework of General Manufacturing Practices ("GMP").
This essay analyses some of the quality issues related to the application of these standards in secondary production of tablets, the most common drug dosage form today (http://www.pharmamanufacturing.com/articles/2008/096.html). The aim is to highlight in particular the impact on quality of product transfers both internally (across the production line) and externally (through supply chain and distribution).
Secondary manufacturing is the supply chain node where the inert materials (called "excipients") are added to active ingredients ("API") produced in the primary manufacturing step and the final product is made available for market distribution through market warehouses/distribution centres, wholesalers and retailers/hospitals (article: "Pharmaceutical supply chains: key issues and strategies for optimisation").
Firstly, the quality issue is introduced, with a particular attention to GMP framework; then some strategic and design issues in the pharmaceutical supply chain are analysed, highlighting the importance of applying quality standards on all the steps and some suggestions are given; thirdly, the production line of solid doses is analysed and some suggestions to increase the quality of the product are provided.
Quality framework in the Pharmaceutical Industry
GMP is a legal system originally inspired by Food and Drugs Administration ("FDA") concerning the minimum level of quality which is necessary to obtain in pharmaceutical and medical industries. By observing these guidelines, companies can assure drugs' specification, effectiveness, quality, purity and safety. Over 100 countries obey GMP as one of their standards, using it as the base of their quality system. This framework provides testing procedures, laboratory based examinations and measures of proportion and weight of the ingredients to be applied before, during and after manufacturing process to make sure that the predefined requirements match the finished product.(pharmainfo,2009)
While in other markets, segmentation results in various approaches to investments in product's quality, in the pharmaceutical industry, since people's health is involved, businesses must try not to compromise on quality. Releasing low quality pharmaceutical products may result in hazards and as a consequence in customer claims, which will end into financial losses. Therefore having products with good quality that provide effective healthcare for customers will improve their trust in the product and provide a financial benefit to the company.
On the other hand overspending on quality is not always a good idea. In the very high levels of quality, every small step forward will be tremendously expensive resulting in products that are not significantly better than rivals, but with higher prices. This approach is not suitable from a business point of view as, in order to maintain a competitive position in the market, companies should renounce to part of their profit margins. Hence, spending on quality should be a trade-off between higher profits and appropriate quality levels.
Expenditures should be definitely focused on the production system, but this could be inefficient if not supported by adequate supply and distribution management systems which guarantee product's reliability as illustrated in the next paragraphs.
Quality issues in the extended supply chain
Nowadays competition is not anymore a matter of independent entities interacting in the marketplace: competitive advantage lies in developing strong partnership as "supply chains compete, not companies" (Christopher cited in www.emeraldinsight.com/1750-6123.htm). Consequently, effective quality management systems should be extended to cover suppliers' and sub-suppliers' manufacturing processes and sourcing strategy should be assessed to identify possible improvements (Rathore and Low, 2010).
As raw material plays a significant role in producing quality and safe drugs; the route towards developing quality pharmaceutical products starts with selecting proper ingredients.
In secondary manufacturing processes, two main families of raw material are managed: excipients and active pharmaceutical ingredients ("API"). While the latters are already heavily regulated, controls on the formers, generally considered safe being originated from the food industry, are becoming increasingly important due to emerging of new excipients (http://www.touchbriefings.com/pdf/890/PT04_rafidison.pdf). These raw materials contribute the most to product variability and, as manufacturers are legally responsible for their quality, it is essential to put in place proper raw material management systems to minimise possible negative impacts on production's performance facilitating implementation of Quality by Design.
Nowadays most of the pharmaceutical raw material is providing from China and India. They are the main producers of raw material especially for third world countries. Besides all the rules and regulation about the quality and control limit, sometimes the quality of the product they are producing is not acceptable. By having an efficient laboratory and lab technicians it is possible to control the raw material which is coming to the factory and send back the raw material which is not in the control limit.
Perfect! Thanks, I'll add/search for references on that!
As the survey conducted in 2006 by Aberdeen Group (cited in Littlefield, 2007) indicates, pharmaceutical companies could achieve compliance and traceability success not only by automating raw material but also finished product traceability, eliminating manual activities.
Stakeholders along the whole pharmaceutical supply chain recognise the critical importance of solutions like bar coding and radio frequency identification ("RFID") to track products from manufacturing plants to retailers as the extension of traceability to the single final product maximizes quality management and safety control (ZIT, 2008). Their usage is encouraged by: regulatory agencies aiming to ensure product security eliminating inefficient paper-based systems (FALKEN Secure Networks, 2009); providers interested in quality of care and patient safety; suppliers looking for effective and cheaper methods to control inventory improving productivity and profitability (ZIT, 2008).
Track-and-trace systems are frequently used to support forward logistics activities and stem sales of counterfeited drugs, estimated to reach $75 billion in 2010 (Centre for Medicines in the Public Interest cited in ZIT, 2008); however, it could be beneficial to reverse supply chain logistics as well, considering that returns handled annually worth approximately $2 billion (Health Distribution Management Association cited in ZIT, 2008), varying between 3 and 6% of annual sales (Hunter et al. cited in Kumar and Dieveney and Dieveney, 2009).
In the majority of cases, distribution and returns are handled by third party providers (Valero cited in Kumar and Dieveney and Dieveney, 2009) not being a core competency of pharmaceutical companies and batch visibility is lost as products proceed through the supply chain (ZIT, 2008): some technology providers, as for example Falken Secure Networks (2009), are promoting the introduction of a tracking system based on RFID technology common to all players in the supply chain to improve visibility, collaboration, real-time information flow and reverse logistics efficiency. Reduction of losses along both forward and reverse logistics processes would offset costs for implementing the system (Kumar and Dieveney and Dieveney, 2009). Such systems seem to be effective: Pfizer, for example, implemented it since 2006 to limit losses for one of the most counterfeit drugs like Viagra in the United States (O'Connor, 2006).
Quality issues from the production point of view
Most of the companies in various industries are competing to improve the processes of quality management in the production process; however, quality has always been a low priority in pharmaceutical industry. This has become an issue since companies had to pay more than $700 million on observances because of low quality since 2001. On the other hand it causes a remarkable reduction in revenue. The compliances take large amount of effort to address from management level of the company, which is the most expensive human resource level, and in some cases caused up to 20% increase in unit cost.
Pharmaceutical industry managers are usually resistant to applying quality management in their companies because they believe that having regulations related to quality reduces the agility of company confronting the changes. Meanwhile, some companies in this industry have managed to use quality management and also minimizing the risk of regulations.
Having these issues, most companies decided to just throw away the defected produces in production line to make sure that customers receive high quality product. This is neither cost effective nor sustainable. Therefore, quality management among the whole processes seems to be essential rather than just monitoring the final product.
To enjoy the benefits of quality management as well as avoiding the regulations, managers tend to build a cultural inspiration among the people involved by defining, fully understanding and being committed to the quality objectives of the company. These objectives must be clear, measurable and comprehensible. Managers will exactly know what to focus in the production process to resolve the bottlenecks and produce quality products. (Dsouza, 2007)
The initial idea for making a tablet was first developed by machinery as the tablets cannot be made by pressing powders. As the result of above phenomenon, the very old traditional methods to make tablets, forced tablet producers to first make granules in a pot named the mixer blender granulating machine: this step is called "granulation". Wet granules, being made in a granulator, does not come to equal shapes and sizes and it has to be passed through a calibrating mill in which the mesh sizes of prepared granules can be made more uniformed granules. These uniformed granules led to a fluid bed drying machine where they will be dried thoroughly by the help of hot air and fluidization of the particles inside a container. Then again the particles have to be uniformed in a dry calibrating mill before going into final blender. After the preparation of the powder it will be formed by tablet press machine: this step is called "compression". Prepared tablets are then subject to coating in a machine called coater. After further quality controls, the final stage for tablets is packaging them in bottles, strips or blisters (Shah, 2004).
For each packaging system, there are different machines involved in order to protect the prepared tablets against moisture, light, temperature and most importantly against contamination.
The above procedure ever since the old times still remain the same but with much more sophistication to ensure a wider range of protection of the prepared tablets against possible above environmental effects. Such protection has hence being defined by guidance described as GMP and cGMP (can we add some details on this?).
We can put something here but it is just going to be the explanation and I don't think he is going to like it. My recommendation is not to write anymore but if you have useful information which can be add to this part and relevant to it tell me.
I just was saying, can we add:
- a reference that certifies that GMP/cGMP state that
- can we introduce cGMP in the Rules/regulations part as we don't cite it
Transferring the raw material and semi finished product
Historically, the procedure of transferring material from one machine to another during the production process was performed manually by operators. The human involvement during the pharmaceutical manufacturing process is critical for three reasons: firstly, it could affect quality of products consequently to unavoidable human errors; secondly, it could damage the product by direct contamination as a lack of employees' hygiene and sanitation can threaten quality as well; lastly, safety of employees themselves can be undermined by inhaling small particles of simple drugs at production line.
Consequently, with development of technology, more modern and automated methods were utilized to minimize the risk of contamination: the evacuation of products from one machine to the next was then helped by vacuum through special containers which involved vacuum pump and filters. Benefits achieved with this method were offset by high costs and complexity. Subsequently, a further improvement has been achieved exploiting gravity with the use of lifters enabling the product to circle around the production line in a closed loop system. This method was found to be safe, practical and also less expensive than the vacuum. For such method, special product containers were created which had a loading port on top and unloading port at the bottom, both being facilitated for manual operation or pneumatic valve for automatic operation. In some cases when a more difficult powder or wet granules was involved, a helping vibrator could also be installed to ease down the product in to these containers. These containers were made by special shape and angles so as to be able to empty all products into the next unit and it also could be attached to a lifting device.
As shown above, the presence of humans along the solid dose line can negatively affect the quality of product. To avoid the massive consequences of this, which can cause financial disasters for the business, companies could provide their employees with professional training and proper hygiene facilities as having skills and appropriate training material and constant development minimizes the errors, optimizes the efficiency and therefore improves the quality. This results in continue personnel training investments and would not completely avoid errors and contamination risks.
Differently they could opt for investments in automation which can help pharmaceutical factories to minimize operators contact with the product during the process. By reducing or even eliminating operator's involvement it is in fact possible to lower occurrence of human fault.
Suggestion for a new layout of the plants
Traditionally, pharmaceutical companies had a flat layout and there are still many factories (Reference) which are following this instruction because of its simplicity. With this layout operators have a direct contact with product as they are responsible for manually transferring the powder from one machine to the next; all machineries are in a horizontal line like the lay out below:
As shown above in this essay, technology developments leaded to the introduction of vacuum and lifters Although this method is very useful and shows a first tendency to move the production flow to a vertical layout, as shown in the picture below, this is still based on a flat factory and thereby is quite expensive and presents some technical disadvantages.
Our suggestion to improve production quality is to exploit gravity, building new pharmaceutical factories with a 4 or 5 floors layout instead of wider flat buildings.
The most important advantage of making the factory in different levels is that instead of putting the machinery in a horizontal line, it is possible to put it vertically. It is obvious that much more precaution has to be taken into account when some dangerous materials like hormones, anticancer drugs and biological and sensitive drugs are being processed. Nowadays, for this kind of material partial or total containment is designed and utilized. In such restricted areas no operators are allowed and the entire process is designed to be fully automated and monitored from an outside room using SCADA systems (Supervisory Control And Data Acquisition), compliant to rules and regulations of FDA and according to CFR21 part 11 Guidance. These systems control and monitor each and every single step of the process and record all parameters according to the validation documentations for regular and future revalidation in case of need. Such containments involve some very advanced and patented technologies and since no human is involved the risk of mistake are considerably minimized; this technology, however, is extremely expensive and cannot be used by the majority of pharmaceutical companies.
What is the problem here?
Just two things:
CFR21 part 11 Guidance ƒ what's that? Could you add further details as the reader doesn't know what is that?
Some further details also on this "validation documentations for regular and future revalidation"?
This (what?)( The reason the pharmaceutical companies are not using this technology which is expensive. Elena isn't it clear? No, sorry....it seems like we are suggesting the new layout to substitute the containment areas...) is the reason why we are suggesting this layout which is much cheaper and can be equally efficient. By using this layout we can minimize operator's presence and omit some extra machinery like vacuum and lifter.
This is our suggested layout.
By this method it is possible:
To reduce the human involvement and unwilling effects on the products;
To protect operators from possible harmful effects of raw material and semi-finished products;
To protect the environment against possible and constant distribution of product's particles and chemicals;
To control containment with regular and pre-determined conditions such as temperature and humidity;
To guarantee total protection against possible contamination coming from operators, environment or even from the equipment itself;
To reduce to a minimum creation of dust inside the powder-making room due to the closed loop created with this layout.
This essay shows the importance of product transfers as a key area on which pharmaceutical companies should work to gain quality improvement. The main focus is on production line for solid doses, the most common drugs dosage form today.
The theme of transferring material has been analysed from two points of view: external and internal to the production plant. The first refers both to supply management and the importance of properly managing raw material as it is fundamental to reduce product variability as well as to management of forward and reverse logistics. The second refers to the transfer of raw material and semi-finished product along the production line and the importance of reducing or eliminating direct human interaction as it can generate threats to product quality as well as to employees' safety.
Some suggestions for improvement are given on both aspects: the introduction of an integrated supply and distribution system would enable raw materials traceability, avoid drugs' counterfeiting and help returns management while the redesign of factory's layout can help generate higher quality levels by improving process automation and reducing to a minimum human contamination.
RAJ,G.,2009, REGULATORY ASPECTS AND QUALITY MANAGEMENT IN GENERIC PHARMACEUTICAL INDUSTRY, [Online] Available at: http://www.pharmainfo.net/gabrie/publications/regulatory-aspects-and-quality-management-generic-pharmaceutical-industry-fourrt [December 2010]
Dsouza, A., Keeling, D. and Phillips, R., 2007. Improving quality in pharma manufacturing. The McKinsey Quarterly.