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Product quality is a critical determinant for the increased New Product (NP) performance. When product quality is improved, it might affect the development speed. Hence, it is of serious and prime consideration for the chemical and pharmaceutical manufacturing industries to give stress on issues related to ensure the high quality of the products within a consistent chemistry of the compound, industrial scale-up, engineering associated to it, its stability, quality assurance systems and procedures. Particle size of a compound is a key factor for the process control of the pharmaceutical processes as particle size distribution relates with the dissolution property of the compound which in turn impacts on its bio-availability. To ensure long-term stability the most efficient process is lyophilization which has been considered to have importance to enhance the stability factors associated with labile drugs such as therapeutic proteins. For ensuring process control and enhanced product quality the integrated approach towards pharmaceutical quality assurance is the Process Analytical Technology (PAT). It is obvious that product quality is undoubtedly a desired and serious issue in pharmaceutical and chemical manufacturing units which needs a thorough and critically careful analysis throughout the process. To attain the consistent high quality products the parameters which are to be assessed are the general chemistry related to the product molecule, crystallization characteristics associated with polymorphic and co-crystal properties, stability related issues, quality assurance systems, engineering aspects with scale-up and analytical procedures.
Product quality is a critical determinant for the increased New Product (NP) performance. When product quality is improved, it might affect the development speed. Hence, it is of serious and prime consideration for the chemical and pharmaceutical manufacturing Industries to give stress on issues related to ensure the high quality of the products in a consistent chemistry of the compound, industrial scale-up, engineering associated to it, its stability, quality assurance systems, procedures etc (Pinto et al., 2011).
2. CHEMISTRY: HIGH THROUGHPUT (HT) CRYSTALLIZATION
Particle size of a compound is a key factor for the process control of the pharmaceutical processes as particle size distribution relates with the dissolution property of the compound which in turn impacts on its bio-availability. Thus, measurement and control of crystal shapes and crystal size distribution are to be ensured to obtain the desired properties in case of a crystalline drug-compound. The High throughput (HT) crystallization technology has been developed based on the strategy involved in pharmaceutical development speed and diversification in solid forms. Thus it explores the three basic steps- design of experiment (DOP), experimental protocols execution and data-analysis. The system works upon integrated software associated with a hardware component to effectively run and track the experiment and store the data and then analyze.
This software has an extensive application on screening of API (Active Pharmaceutical Ingredient) developing process-chemistry for manufacturing high quality bulk drug. Selection of salt to prepare the salt form of API is to enrich the solubility profile which in turn influences the rate of dissolution in order to achieve the highest extent of bioavailability. To ensure a consistent high quality product it is always essential to analyze the physico-chemical properties of the salt which clubs together the crystallinity and its extent, habit of the crystal, stability, solubility and hygroscopic characteristics. Nonetheless, polymorphism and formation of solvates are other important criteria to be analyzed. Example: Angiotensin II antagonist MK-996, a highly polymorphic species.
The compound has seven bonds which are rotatable and these conformations eventually give rise to a number of configurations associated with the packing of crystal. HT crystallization gives way to have several re-crystallization trials, form mixture of solvents and yield solid-forms which are allowed to harvest over a week time. Among various definite forms the form D has been identified as “disappearing polymorphs” when the hydrate form is grown as found through HT screening.
Solvates are frequently obtained as by-products of either polymorphs or the salt-screens. Co-crystals, on the other hand, are generated through re-crystallization or grinding form the solvents. It is essential for the solvent system to be such that the components undergo easy dissolution in them but at the same time should not obstruct the interactions required the solvent system to avail a number of co-crystal formers. These co-crystal formers are potentially much more suitable compared to solvates/hydrates as having lower vapor-pressure reduces the chance of evaporation form the solid form thereby preventing physical degradation and separation of phase (Morissette et al., 2004).
In crystallization it is always very important to have the degree of super-saturation in a controllable manner. This is because the product crystal irrespective of its size, shape and phase depends upon the super-saturation profile of the crystallization technique (Fujinara et al., 2005).
3. ENSURING STABILITY
To ensure long-term stability the most efficient process is lyophilization which has been considered to have importance to enhance the stability factors associated with labile drugs such as therapeutic proteins. It has been estimated that around 40-50% of the biopharmaceutical products in regards with on-going market strategy undergo lyophilization as the most usual formulation technique.
Lyophilization is indeed a technique commonly known as Freeze-drying. Inhibition or deceleration of the chemical reactions concerned with physical degeneration occurs in the solid-state of the freeze-dried condition which potentially enhances the long-term stability of the products. Nonetheless, such formulations give way to convenient handling while the products are shipped and stored.
Lyophilization cycle has three steps:
Freezing: Formulation in the liquid form is allowed to cool. Cooling continues till the ice begins nucleating followed by ice being grown. Thus segregation of water takes place in crystals of ice.
Primary Drying: Removal of the ice-crystals occurs by dint of sublimation. Consequently, the pressure inside the drying-chamber is lowered down the actual vapor-pressure of ice and the heat which has been initially taken away due to sublimation has been compensated again through the supply form increased shelf-temperature.
Secondary Drying: The residual amount of water (unfrozen) within the product is allowed to undergo desorption under decreased pressure but at temperature being raised. At the end of this stage a product formulation is achieved with the least moisture-content (Kasper et al., 2011).
4. ENSURING PRODUCT QUALITY AND PROCESS CONTROL
For ensuring process control and enhanced product quality the integrated approach towards pharmaceutical quality assurance is the Process Analytical Technology (PAT). The primary feature of PAT is quality by design-“quality should be in-built or by design” PAT significantly lowers the production cycle times, minimizes manual error and potentially facilitates continuous processing to influence and modify the process-efficiency. PAT is being played as a pivotal role as an important current regulatory factor on production processes in chemical and pharmaceutical industries. Knowledge on operational attributes and variable determinants concerning the raw materials to end-products subtly functions to ensure the product quality including improvements in continuous productions (Juan et al., 2012).
Conventional methods associated with quality control are High Performance Liquid Chromatography (HPLC) and Mass Spectroscopy (MS)- both the methods take a longer period of time and they both are costly, critical as preparation of sample takes much time and give unsatisfactory result with no data related to component-distribution in the prepared sample and is often destructive in nature. Currently, vibrational spectroscopy [Near Infra Red Spectroscopy (NIRS), Raman’s Spectroscopy (RS)] have been proved to be a worthy and reliable technique for the quality analysis of pharmaceutical products.
NIRS: This technique is concerned with (very little) or without any sample preparation, high speed tool, ability of “remote measurement”. Single spectrum helps assume the physical and chemical feature of the compound. This technique is, therefore, extensively applied for testing of raw materials and other pharmaceutical analysis like quality control and monitoring of the process. NIRS is considered to have successful impact on the development of non-invasive and quicker quantitative method for the prediction of real time towards the critical quality attributes in case of pharmaceutical granulates (moisture content, pH, content of API, flowability, particle size and angle of repose).
Raman Spectroscopy: Raman spectra compared to NIRS are more prominent and devoid of any overlapping. Based on the Raman Effect (inelastic scattering of photon) PAT implies an ample application on formulation and process analysis.
Chemical Imaging is a term which defines a technique to integrate traditional imaging and spectroscopy for getting the spatial and spectral information out from a compound.
Quality Assessment: Chemical imaging system is governed for getting the chemical images of single sample-specimen at wavelengths ranging from 1050 to 1700nm. The NIR-chemical imaging critically investigates “blending and density pattern distribution of components within a drug product”.This in turn subjects to qualitative analysis. The technique not being destructive in nature can effectively scan the faulty specimens thereby saving them for more analysis (Gowen et al., 2008).
For manufacturing a tablet the most critical issues are- quality risk assessment, analysis of data of batch made previously and high shear wet granulation. The latter affects the unit operation converging towards the quality attributes of the product. Thus, the most crucial design factors are granulation moisture-contents, time elapsed in granulation and lubrication period. DOE significantly functions over these three parameters and attains “desired flowability, compressibility and dissolution-profiles”. DOE is an important and efficient tool to influence the three critical parameters to set up design space which in turn impacts on final product quality attributes.
5. SCALE UP TO ENSURE HIGH QUALITY PRODUCT
Chemical as well as pharmaceutical industries have been benefitted in terms of process intensification through micro-channel technology which is a scalable one having a capacity to produce 10-100 tons of quality products every year. In this technology, fluid-distribution within the multi-channel device takes place adequately giving way to flow of gas. This device can effectively build a scale-up of over 550 kg using mass-production technique.
The introduction of the Quality-by-Design (QbD) initiative and of the Process Analytical Technology (PAT) framework has widened the route to the use of systematic and science-based approaches to support pharmaceutical and fine chemical development and manufacturing activities. Latent variable models (LVMs) can play in the practical implementation of QbD paradigms in the pharmaceutical and chemical industry, and the potential they may have in assisting the development and manufacturing of new products. The ultimate scope is to provide practitioners with a perspective on the effectiveness of the use of LVMs in any phase of the development of a pharmaceutical and chemical product, from its design up to its commercial production.
High-pressure homogenization (HPH, including microfluidization) and high-amplitude ultrasonic processing are presently the leading two methods applied for the production of nanoemulsions of extremely superior quality. In spite of suffering from many disadvantages, HPH is presently the method of choice for the large-scale manufacturing of pharmaceutical nanoemulsions. The ultrasonic nanoemulsification technology is free from most of the disadvantages and often used in laboratory studies. The challenge for the ultrasonic method, however, has been conjugating the gap between lab-scale research and its large-scale implementation. Due to limitations of conventional ultrasonic technology, scaling up has not been possible without a significant reduction in ultrasonic amplitudes, which compromises product quality. This limitation has been overcome by Barbell Horn Ultrasonic Technology (BHUT), which allows constructing bench and industrial-scale processors enabling the operations at high ultrasonic amplitudes.
It is obvious that product quality is undoubtedly a desired and serious issue in Pharmaceutical and chemical manufacturing units which needs a thorough and critically careful analysis throughout the process. To attain the consistent high quality products the parameters which are to be assessed are the general chemistry related to the product molecule, crystallization characteristics associated with polymorphic and co-crystal properties, stability related issues, quality assurance systems, engineering aspects with scale-up and analytical procedures. With the consistent product quality QbD has been found to have one of the main regulatory paradigms scalloped with the latent variable models that can have feasibilities for supporting the manufacturing and development attributes of the fine chemical and pharmaceutical products commensurating the requirements of the regulatory agencies. Thus, three primarily important domains have been marked suitably fitting the rational use of latent variable models that can give significant provision of process understanding, product and process design and process monitoring and control. And thus the high-quality consistency attributes in the field of fine chemical and pharmaceutical synthesis will open further research to identify.
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SINHA ROY, P. (2014). ENSURING A CONSISTENT HIGH QUALITY PRODUCT IN FINE CHEMICAL AND PHARMACEUTICAL SYNTHESIS. PHILICA.COM Article number 450.