The urgent need to dramatically improve efficiency and productivity within the pharmaceutical manufacturing sector is in the state of flux. With the US FDA’s push for moving the pharmaceutical industry into 21st century, reality of the market place, and innovation of some equipment manufacturers, number of options is being evaluated by the industry. However, number of roadblocks still exists to implement true continuous manufacturing. There are, however, some technology improvements that are available, that could offer the true continuous manufacturing.
In 2004, US FDA issued guidance document “PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance”. To encourage the pharmaceutical industry to adopt novel manufacturing methods, it cited industry resistance as follows: “the pharmaceutical industry generally has been hesitant to introduce innovative systems into the manufacturing sector for a number of reasons. One reason often cited is regulatory uncertainty, which may result from the perception that our existing regulatory system is rigid and unfavourable to the introduction of innovative systems.” Since that time, tremendous amount of activity is seen in the pharmaceutical industry with constant encouragement from the FDA to move the industry from 20th century to the 21st century. Pharmaceutical manufacturing continues to evolve with increased emphasis on science and engineering principles. Effective use of the most current pharmaceutical science and engineering principles and knowledge throughout the life cycle of a product can improve the efficiencies of both the manufacturing and regulatory processes.
The general process involved in the manufacture of drug products consists of a series of unit operations, each intended to modulate certain properties of the material being processed. From the standpoint of unit operations involved as practiced today, there are some that are inherently continuous in nature while there are others that are conducted in batch mode. For example, in case of solid dosage manufacturing, good examples could be the unit operations of tablet compression or roller compaction. However, such unit operations do require additional up stream or downstream processing that will require integrating two or three separate unit operations.
Nevertheless, there is definite shift in the mindset of the industry to move from the batch processes to continuous manufacturing. With major universities and major pharmaceutical companies investing millions of dollars towards the continuous manufacturing shift. To the duplicate food or petrochemical industry’s continuous manufacturing example, the continuous manufacturing plant in pharmaceuticals should be capable of running 24/7 for 50+ weeks/year, with no significant downtime for major cleaning (except in product or process changeover). While the technologies, and therefore development and manufacturing expertise, needed for the final dosage formulation aspects of continuous processing are different than those needed for chemical synthesis, there are many areas of overlap such as powder handling, drying processing, process safety, and process monitoring and control technologies. Most pharmaceutical companies though are currently developing a hybrid approach, in which continuous manufacturing steps may be incorporated for portions of a drug substance or drug product process, or for an entire drug substance or drug product process. The most common ones were continuous drug synthesis processes and continuous direct compression process for solid oral drug products. Ideally continuous processing should provide, seamless integration of process quality, reduced capital cost, smaller footprint, reduced inventory, easy scale up and reduced time to market. The current options for the industry are limited in that few, ‘continuous’ granulation for example, are generally, an integration of existing unit operations such as milling, blending, wet granulation, drying, tableting and coating or encapsulation. Recently, there were two products approved by FDA direct compression formulation was manufactured.
In a true continuous manufacturing process, the input material(s) are continuously and simultaneously fed into and transformed within the process, and the processed output materials are continuously removed from the system—except at the beginning and at the end of the process. The amount of material being processed at any given instance may be relatively small in a continuous manufacturing process, but as the process can run over a period of time to generate necessary quantities of finished material with desired quality. For a continuous manufacturing process, understanding process dynamics of how a material flows through the process is important with respect to the material traceability (the ability to preserve and access the identity and attribute of a material throughout the system) and performance of the unit operation and the integrated system. To manufacture solid dosage product in a continuous manner, several options are employed in the industry. These include multiple fluid bed units integrated to produce fluid bed granulation, roller compaction for dry granulation, or direct compression blending and compression followed by coating of the tablet dosage form. A combination of twin-screw extruder coupled with fluid bed dryer and the ancillary equipment as a package is utilised to wet granulate, dry, blend and compress solid dosage product.
There are number of limitations in employing the continuous manufacturing approach due to nature of the Active pharmaceutical ingredient (API) characteristics, composition of the formulation, percentages of each ingredient, and Critical Quality Attributes (CQA) of the finished dosage forms among the major ones. There are challenges posed by process analytical tools that are currently available to monitor all the critical process parameters, even though considerable progress has been made to employ NIR, Raman spectroscopy, vision systems etc. However, for continuous manufacturing, the quality of produced pharmaceuticals needs to be assessed in real-time (in-line, on-line, and at-line) and not via the traditional off-line, often destructive and time-consuming analysis methods that supply the desired information only hours after sampling.
Of all the steps in continuous manufacturing of dosage forms, feeding powder remains the most critical. If the formulation is comprised of a single ingredient, then its flow properties morphology will reflect in the challenges that it might pose. The multi-ingredient composition of the formulation poses additional challenges like segregation of ingredients, integrity of the composition throughout the process stream and final quality of the product. Powder feeding for a continuous process is currently based on volumetric or gravimetric techniques utilising the screw feeder. The measurement system with loss in weight using load cells for poorly flowing material is also utilised. Exploring this area is very critical for continuous manufacturing.
Extrusion is an inherently continuous process, which lends itself to a straightforward implementation in a continuous manufacturing environment. Systems include singleand twin-screw extruders with co-rotating twin-screw extruders being the most frequently ones used for pharmaceutical processing. Hot Melt Extruders (HME) has gained wide acceptance over the last three decades and has already established its place in the broad spectrum of manufacturing operations and pharmaceutical research developments. In addition to being an efficient manufacturing process, HME enhances the quality and efficacy of manufactured products and therefore over the past few years HME has emerged as a novel technique in pharmaceutical applications. HME has received considerable attention from both industry and the academia in a range of applications for pharmaceutical dosage forms, such as tablets, capsules, films, and implants for drug delivery via oral, transdermal, and transmucosal routes. The main use of HME is to disperse Active Pharmaceutical Ingredients (APIs) in a matrix at the molecular level, thus forming solid solutions. In the pharmaceutical industry, HME has been used for various applications, such as (i) enhancing the dissolution rate and bioavailability of poorly soluble drugs by forming a solid dispersion or solid solution, (ii) controlling or modifying the release of the drug, (iii) taste masking of bitter APIs, and (iv) formulation of various thin films.
Besides HME, the application of Twin screw extruder is increasing in the pharmaceutical industry for continuous wet granulation, because of the advantages it offers including equipment design flexibility, short residence time, wide range of throughputs and intimate mixing of formulation ingredients.
In twin screw extrusion process for wet granulation, understanding the mechanism of liquid distribution inside the granulator as it relates to the screw configuration as well as the functional role of the latter in defining the size of granules produced is essential for optimisation of granule properties obtained. Usually the screws of a twin-screw extruder are built up modularly. Generally for twin-screw processing, discrete element or a combination of screw elements are assembled on the main shaft with specific functions such as feeding, conveying, mixing or kneading. Classical conveying or forwarding elements are always inserted at cylinder openings, e.g. at barrel holes to convey material away from the feed opening or to discharge processed material at the end of the extruder Kneading elements or kneading blocks, the second classical element type, are usually used when material has to be sheared and thoroughly mixed. Combing mixer elements meet the challenge of conveying and mixing simultaneously. Basically they are conveying elements with longitudinal slots. These slots provide more space for distributive mixing without or nearly no loss in forwarding properties. Most of these twin-screw kneading elements are bi-lobe and the impart high shear on the material generating heat, and may cause degradation of the product because of amount time the material is under kneading force. Irrespective of type and complexity of the function and process, the extruder must be capable of rotating the screw at a selected predetermined speed while compensating for the torque and shear generated from both the material being extruded and the screws being used.
With a modification of kneading elements which is in traditional twin-screw units is bi-lobe, a unique fractional lobe element recently developed by STEERLife company offers ‘Integraal’ technology for the twin screw extruder with the ability to process wet granulation, drying and sizing of the product in one stand-alone equipment. This True continuous, single pot manufacturing is built on the principle of a ‘flow stream in continuity’ utilising a twin-screw processor, that has a unique ability to clean itself. The energy transfer is made effective using thermal, mechanical or chemical means at wide-ranging magnitudes with minimal shear or pressure peaks providing specific advantages in handling sensitive input materials that may or may not rely on the use of water or vapour. Granulation process can typically be achieved with residence time as little as 5-15 seconds (including granulating, drying and sizing), and the optimised granules obtained are ready to be compressed into tablets or filled into capsules. True continuous, single pot processing provides significant improvement in building both temporal and spatial control in process engineering through removal of hot spots and dead zones, while maintaining higher level of process continuity.
In summary, the industry has committed to explore and adopt continuous manufacturing paradigm, regulatory authorities are supporting it, businesses would like to see the cost of manufacturing is reduced, hence ready to invest, and patients would like to see reduced cost ofmedicine.The combination of existing technologies into integrated ‘continuous’ package is now available but the newer technologies based on twin-screw extruders has a potential to provide stand-alone equipment that performs number of unit operations for which currently separate unit operations are required thus offering a true continuous manufacturing pathway.
References:
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As an industrial pharmacist, Dilip has more than 40 years of industrial experience in solid dosage technologies, Good Manufacturing Process compliant facility planning, process engineering and manufacturing, as well as operational management at various major pharma companies in Canada and the US. At STEERLife, Dilip focuses on developing innovative continuous manufacturing technologies for solid dosage products.
