High Content Solid Dispersions for Dose Window Extension: A Basis for Design Flexibility in Fused Deposition Modelling.

PURPOSE: This study uses high drug content solid dispersions for dose window extension beyond current demonstrations using fused deposition modelling (FDM) to; i) accommodate pharmaceutically relevant doses of drugs of varying potencies at acceptable dosage form sizes and ii) enable enhanced dose flexibility via modular dosage form design concepts. METHODS: FDM was used to generate ~0.5 mm thick discs of varying diameter (2-10 mm) from melt-extruded feedstocks based on 10% to 50% w/w felodipine in ethyl cellulose. Drug content was determined by UV spectroscopy and dispensing precision from printed disc mass. RESULTS: Mean felodipine content was within ±5% of target values for all print volumes and compositions including contents as high as ~50% w/w. However, poor dispensing precision was evident at all print volumes. CONCLUSIONS: In pursuit of dose flexibility, this successful demonstration of dose window extension using high content solid dispersions preserves FDM design flexibility by maintaining applicability to drugs of varying potencies. The achieved uniformity of content supports the application of varying content solid dispersions to modular dosage form concepts to enhance dose flexibility. However, poor dispensing precision impedes its utilisation until appropriate compatibility between FDM hardware and materials at varying drug contents can be attained.

Terahertz frequency-domain sensing combined with quantitative multivariate analysis for pharmaceutical tablet inspection.

Near infrared (NIR) and Raman spectroscopy combined with multivariate analysis are established techniques for the identification and quantification of chemical properties of pharmaceutical tablets like the concentration of active pharmaceutical ingredients (API). However, these techniques suffer from a high sensitivity to particle size variations and are not ideal for the characterization of physical properties of tablets such as tablet density. In this work, we have explored the feasibility of terahertz frequency-domain spectroscopy, with the advantage of low scattering effects, combined with multivariate analysis to quantify API concentration and tablet density. We studied 33 tablets, consisting of Ibuprofen, Mannitol, and a lubricant with API concentration and filler particle size as the design factors. The terahertz signal was measured in transmission mode across the frequency range 750 GHz to 1.5 THz using a vector network analyzer, frequency extenders, horn antennas, and four off-axis parabolic mirrors. The attenuation spectral data were pre-processed and orthogonal partial least square (OPLS) regression was applied to the spectral data to obtain quantitative prediction models for API concentration and tablet density. The performance of the models was assessed using test sets. While a fair model was obtained for API concentration, a high-quality model was demonstrated for tablet density. The coefficient of determination (R2) for the calibration set was 0.97 for tablet density and 0.98 for API concentration, while the relative prediction errors for the test set were 0.7% and 6% for tablet density and API concentration models, respectively. In conclusion, terahertz spectroscopy demonstrated to be a complementary technique to Raman and NIR spectroscopy, which enables the characterization of physical properties of tablets like tablet density, and the characterization of API concentration with the advantage of low scattering effects.

Terahertz frequency domain sensing for fast porosity measurement of pharmaceutical tablets.

Porosity is an important property of pharmaceutical tablets since it may affect tablet disintegration, dissolution, and bio-availability. It is, therefore, essential to establish non-destructive, fast, and compact techniques to assess porosity, in situ, during the manufacturing process. In this paper, the terahertz frequency-domain (THz-FD) technique was explored as a fast, non-destructive, and sensitive technique for porosity measurement of pharmaceutical tablets. We studied a sample set of 69 tablets with different design factors, such as particle size of the active pharmaceutical ingredient (API), Ibuprofen, particle size of the filler, Mannitol, API concentration, and compaction force. The signal transmitted through each tablet was measured across the frequency range 500-750 GHz using a vector network analyzer combined with a quasi-optical set-up consisting of four off-axis parabolic mirrors to guide and focus the beam. We first extracted the effective refractive index of each tablet from the measured complex transmission coefficients and then translated it to porosity, using an empirical linear relation between effective refractive index and tablet density. The results show that the THz-FD technique was highly sensitive to the variations of the design factors, showing that filler particle size and compaction force had a significant impact on the effective refractive index of the tablets and, consequently, porosity. Moreover, the fragmentation behaviour of particles was observed by THz porosity measurements and was verified with scanning electron microscopy of the cross-section of tablets. In conclusion, the THz-FD technique, based on electronic solutions, allows for fast, sensitive, and non-destructive porosity measurement that opens for compact instrument systems capable of in situ sensing in tablet manufacturing.

Enabling modular dosage form concepts for individualized multidrug therapy: Expanding the design window for poorly water-soluble drugs.

Multidrug dosage forms (aka combination dosage forms, polypills, etc.) create value for patients through reduced pill burdens and simplified administration to improve adherence to therapy. Enhanced flexibility of multidrug dosage forms would provide further opportunities to better match emerging needs for individualized therapy. Through modular dosage form concepts, one approach to satisfy these needs is to adapt multidrug dosage forms to a wider variety of drugs, each with a variety of doses and release profiles. This study investigates and technically explores design requirements for extending the capability of modular multidrug dosage form concepts towards individualization. This builds on our recent demonstration of independent tailoring of dose and drug release, which is here extended towards poorly water-soluble drugs. The challenging design requirement of carrying higher drug loads in smaller volumes to accommodate multiple drugs at their clinical dose is here met regarding dose and release performance. With a modular concept, we demonstrate high precision (<5% RSD) in dose and release performance of individual modules containing felodipine or naproxen in Kollidon VA64 at both a wide drug loading range (5% w/w and 50% w/w drug) and a small module size (3.6 mg). In a forward-looking design-based discussion, further requirements are addressed, emphasizing that reproducible individual module performance is predictive of dosage form performance, provided the modules are designed to act independently. Therefore, efforts to incorporate progressively higher drug loads within progressively smaller module volumes will be crucial to extend the design window further towards full flexibility of future dosage forms for individualized multidrug therapy.

Controlled Pulmonary Delivery of Carrier-Free Budesonide Dry Powder by Atomic Layer Deposition.

Ideal controlled pulmonary drug delivery systems provide sustained release by retarding lung clearance mechanisms and efficient lung deposition to maintain therapeutic concentrations over prolonged time. Here, we use atomic layer deposition (ALD) to simultaneously tailor the release and aerosolization properties of inhaled drug particles without the need for lactose carrier. In particular, we deposit uniform nanoscale oxide ceramic films, such as Al2O3, TiO2, and SiO2, on micronized budesonide particles, a common active pharmaceutical ingredient for the treatment of respiratory diseases. In vitro dissolution and ex vivo isolated perfused rat lung tests demonstrate dramatically slowed release with increasing nanofilm thickness, regardless of the nature of the material. Ex situ transmission electron microscopy at various stages during dissolution unravels mostly intact nanofilms, suggesting that the release mechanism mainly involves the transport of dissolution media through the ALD films. Furthermore, in vitro aerosolization testing by fast screening impactor shows a ∼2-fold increase in fine particle fraction (FPF) for each ALD-coated budesonide formulation after 10 ALD process cycles, also applying very low patient inspiratory pressures. The higher FPFs after the ALD process are attributed to the reduction in the interparticle force arising from the ceramic surfaces, as evidenced by atomic force microscopy measurements. Finally, cell viability, cytokine release, and tissue morphology analyses verify a safe and efficacious use of ALD-coated budesonide particles at the cellular level. Therefore, surface nanoengineering by ALD is highly promising in providing the next generation of inhaled formulations with tailored characteristics of drug release and lung deposition, thereby enhancing controlled pulmonary delivery opportunities.

Therapy for the individual: Towards patient integration into the manufacturing and provision of pharmaceuticals.

Individualized therapy with pharmaceutical products aims to elicit predictable and optimized treatment responses from specific patients. Doing so requires production platforms and technology capable of tailoring products to individual patient needs. However, despite recent manufacturing innovations and key technologies on the rise, e.g. continuous manufacturing and additive manufacturing (3D printing), the prevailing production paradigm employed in the pharmaceutical industry is mass production. Although mass production is efficient and cost-effective, it is typically based on a 'one-size-fits-all' product concept and lacks the flexibility and agility required to fully meet the needs of the individual patient. Indeed, we present data that confirm a suspected major imbalance between the recent medical evolution underpinning personalized/precision medicine and the recent advances in the associated manufacturing technologies. In this context we target the needs of the individual as a main driver for pharmaceutical products which support individualized therapy. We particularly address that a wider integration of critical patient dimensions into the manufacture and provision of pharmaceutical products is pivotal for enabling a patient-centric and efficient mass customization-based production paradigm. Here, we present a critical review of the area and its inherent challenges which aims to clarify key design requirements for establishing mass customization opportunities. Through primary sources of scientific information for individualized therapies, patient needs are captured, analysed, and conceptualized. This summarized set of key drivers provides the basis for a proposed patient-centric framework of requirements for use in design of product and production platforms for mass customization. The extent to which emerging pharmaceutical manufacturing technologies satisfy key individual patient needs is explored through a high-level assessment against the proposed patient-centric framework, with special attention paid to oral dosage forms. Altogether this holistic review and position paper, with its constituent steps, reveals major gaps in the evolution of Product-Process-Production approaches and solutions required for producing affordable individualized/personalized pharmaceuticals that respond to the needs and demands of the individual patient. Lastly, in a brief commentary and outlook, we suggest key research directions for closing gaps and addressing manufacturing technology challenges. We also articulate the importance of tackling them in a holistic, integrated way, together with challenges in product individualization and personalization.

Independent Tailoring of Dose and Drug Release via a Modularized Product Design Concept for Mass Customization.

Independent individualization of multiple product attributes, such as dose and drug release, is a crucial overarching requirement of pharmaceutical products for individualized therapy as is the unified integration of individualized product design with the processes and production that drive patient access to such therapy. Individualization intrinsically demands a marked increase in the number of product variants to suit smaller, more stratified patient populations. One established design strategy to provide enhanced product variety is product modularization. Despite existing customized and/or modular product design concepts, multifunctional individualization in an integrated manner is still strikingly absent in pharma. Consequently, this study aims to demonstrate multifunctional individualization through a modular product design capable of providing an increased variety of release profiles independent of dose and dosage form size. To further exhibit that increased product variety is attainable even with a low degree of product modularity, the modular design was based upon a fixed target dosage form size of approximately 200 mm3 comprising two modules, approximately 100 mm3 each. Each module contained a melt-extruded and molded formulation of 40% w/w metoprolol succinate in a PEG1500 and Kollidon® VA64 erodible hydrophilic matrix surrounded by polylactic acid and/or polyvinyl acetate as additional release rate-controlling polymers. Drug release testing confirmed the generation of predictable, combined drug release kinetics for dosage forms, independent of dose, based on a product's constituent modules and enhanced product variety through a minimum of six dosage form release profiles from only three module variants. Based on these initial results, the potential of the reconfigurable modular product design concept is discussed for unified integration into a pharmaceutical mass customization/mass personalization context.

Review of real-time release testing of pharmaceutical tablets: State-of-the art, challenges and future perspective.

In the last decade significant advances have been made in process analytical technologies and digital manufacturing of pharmaceutical oral solid dosage forms leading to enhanced product knowledge and process understanding. These developments provide an excellent platform for realising real-time release testing (RTRT) to eliminate all, or certain, off-line end product tests assuring that the drug product is of intended quality. This review article presents the state of the art, an RTRT development workflow as well as challenges and opportunities of RTRT in batch and continuous manufacturing of pharmaceutical tablets. Critical quality attributes, regulatory aspects and the scientific basis of enabling technologies and models for RTRT are discussed and a systematic development workflow for the robust design of an RTRT environment is presented. This includes the discussion of key considerations for the identification of the critical quality attributes and points of testing as well as the development of the sampling strategy, a hard and/or soft sensor approach and operational procedures. The final sections present two RTRT use cases in an industrial setting as well as critically discuss challenges and provide a future perspective of RTRT.

Characterization of acoustic emission analysis in applications for inhalation device performance assessment.

Acoustic Emission (AE) measurement technology has gained wide appreciation in material sciences and process monitoring. In inhalation research, AE has been used for adherence indicating applications in clinical studies. Promising results from feasibility studies using AE combined with multivariate data analysis (AE-MVDA) in the analysis of devices for inhalation have prompted a broader study reported in this paper. This work presents the novel application of AE-MVDA for assessment of the combined inhalation device and formulation performance. The purpose is to evaluate the benefits that this technology can provide to inhalation product development programs. The work was carried out using two different dry powder inhaler device model systems while investigating different performance features. The devices were filled with dry powder formulations with both placebo and with active pharmaceutical ingredient (API). The acquired AE data was analyzed using multivariate data analysis tools such as Principal component analysis (PCA) and orthogonal projections to latent structures (OPLS). The AE profiles were indicative for device and formulation performance. Normal and deviating performances were readily picked up in the AE data. Moreover, performance trends between doses withdrawn from the inhalers were also observable. Lastly, differences in the AE profile between the formulations could be detected. The overall conclusion from the AE-MVDA measurement approach evaluation is that it has the potential to add value as a cost-effective, non-invasive quality and performance monitoring technology both in development and in production of inhaled medicines.

Nanoengineering of Crystal and Amorphous Surfaces of Pharmaceutical Particles for Biomedical Applications.

The morphology, size, and surface properties of pharmaceutical particles form an essential role in the therapeutic performance of active pharmaceutical ingredients (APIs) and excipients as constituents in various drug delivery systems and clinical applications. Recent advances in methods for surface modification, however, rely heavily on liquid-phase-based modification processes and afford limited control over the thickness and conformality of the coating. Atomic layer deposition (ALD), on the other hand, enables the formation of conformal nanoscale films on complex structures with thickness control on the molecular level, while maintaining the substrate particle size and morphology. Moreover, this enables nanoengineering of surfaces of pharmaceutical particles also in the dry state. Successful nanoengineeering of crystal and amorphous surfaces of pharmaceutical particles is demonstrated in this study whereby functional properties, such as dissolution and dispersibility, were tailored for drug delivery applications. This expands on our initial work on ALD of alumina on pharmaceutical particles within the lower micro- to higher nanosize ranges to here probe both crystalline and amorphous lactose substrate surfaces (d50 = 3.5 and 21 µm). In addition, both water and ozone coreactants were evaluated, the latter having not been evaluated previously for pharmaceutical particles. The deposition process is carried out at ambient conditions in a fluidized bed reactor for a low number of cycles (i.e., from 4 to 14). Improved dissolution and extended release were achieved by the ALD nanoengineering of both crystalline and amorphous surfaces. This novel concept opens up exciting opportunities to produce more complex materials and structures using temperature- and moisture-sensitive drugs, e.g., targeting and drug delivery opportunities, as well as delivering new functionalities for novel applications in the pharmaceutical, medical, biological, and advanced materials fields. The prospects for advancing inhaled drug delivery are exemplified by the ALD surface nanoengineering concept.

Comparison between integrated continuous direct compression line and batch processing - The effect of raw material properties.

There is a current trend in pharmaceutical manufacturing to shift from traditional batch manufacture to continuous manufacturing. The purpose of this study was to test the ability of an integrated continuous direct compression (CDC) line, in relation to batch processing, to achieve consistent tablet quality over long processing periods for formulations with poor flow properties or with a tendency to segregate. The study design included four industrially relevant formulations with different segregation indices and flow properties induced through different grades of the Active Pharmaceutical Ingredient (API), paracetamol, and major filler as well as varying the amount of API. The performance metrics investigated were content, uniformity of content, tablet weight, and tablet strength. The overall process stability over time was significantly improved with the CDC line as compared to the batch process. For all the formulations with a high API content, the CDC line provided better or equal uniformity of content and tablet weight as compared to batch. The CDC line was especially efficient in providing a stable content and tablet weight for poorly flowing formulations containing the standard, cohesive, grade of API. The only formulation that performed better in the batch process was the formulation with a low API content. Thus, for this formulation, the batch process achieved lower variation in tablet content since maintaining a low feed rate for the API proved challenging in the CDC line. In addition, some of the API became stuck in the CDC line between feeding and tableting, most likely at the funnel in the mixer inlet, highlighting the need for properly designed interfaces between units. The insensitivity of the CDC line towards poor flow indicates that one could use direct compression at high drug load compositions of poorly flowing powder blends that could not be processed via batch manufacturing.

Real-Time assessment of granule and tablet properties using in-line data from a high-shear granulation process.

A method for real-time assessment of granule and tablet properties was investigated. A mixture of microcrystalline cellulose:mannitol:povidone (78.5:18.5:3) was used in the study and granulated with five different water amounts and two impeller speeds. This represents a full-factorial design with two factors, thus giving a causal structure to the variation between the experiments. Process data (power consumption, temperature and in-line near-infrared spectra) were collected during the granulations. In addition to the in-line process data, critical granule and tablet quality properties (such as particle size, porosity and tablet hardness) were measured in order to achieve in-depth process understanding. Neither power consumption nor temperature gave information that could be directly attributable to tablet properties, and these techniques were also heavily dependent on the speed of the impeller. In contrast, when using the first NIR overtone band for water (1460 nm), in-line real-time assessment of dry granule and tablet properties could be achieved.

Quantitative transmission Raman spectroscopy of pharmaceutical tablets and capsules.

Quantitative analysis of pharmaceutical formulations using the new approach of transmission Raman spectroscopy has been investigated. For comparison, measurements were also made in conventional backscatter mode. The experimental setup consisted of a Raman probe-based spectrometer with 785 nm excitation for measurements in backscatter mode. In transmission mode the same system was used to detect the Raman scattered light, while an external diode laser of the same type was used as excitation source. Quantitative partial least squares models were developed for both measurement modes. The results for tablets show that the prediction error for an independent test set was lower for the transmission measurements with a relative root mean square error of about 2.2% as compared with 2.9% for the backscatter mode. Furthermore, the models were simpler in the transmission case, for which only a single partial least squares (PLS) component was required to explain the variation. The main reason for the improvement using the transmission mode is a more representative sampling of the tablets compared with the backscatter mode. Capsules containing mixtures of pharmaceutical powders were also assessed by transmission only. The quantitative results for the capsules' contents were good, with a prediction error of 3.6% w/w for an independent test set. The advantage of transmission Raman over backscatter Raman spectroscopy has been demonstrated for quantitative analysis of pharmaceutical formulations, and the prospects for reliable, lean calibrations for pharmaceutical analysis is discussed.

Applying spectral peak area analysis in near-infrared spectroscopy moisture assays.

Spectral peak area analysis has in this study been shown to be a viable method in near-infrared spectroscopy (NIRS) moisture assays. The study also shows that the required number of calibration samples can be minimized, and the method is, therefore, especially suitable for moisture assays in early formulation development and in-situ process monitoring. Diffuse NIRS was utilized in the development of moisture assays for the model compounds polyvinylpyrrolidone and hydroxypropyl-beta-cyclodextrin and also for a lyophilized formulation. Reference data were obtained using coulometric Karl Fischer titration. The NIRS measurements were performed through the bottoms of the sample vials using either a Fourier Transform-Near-Infrared (FT-NIR) spectrometer fitted with a diffuse reflectance probe or a dispersive single beam spectrometer. The ratios of the peak areas of a water peak at 5200 cm(-1) and a reference peak were evaluated using linear regression analysis. The spectral peak area analysis method was compared with a conventional partial least squares regression method. The moisture assays were verified using independent test sets. The investigated moisture range was 0-22% for the samples of PVP, 0-8.5% for the samples of hydroxypropyl-beta-cyclodextrin and 0.5-8.5% for the samples of the lyophilized formulation. The results of the spectral peak area analysis and the conventional partial least squares regression were similar, but the peak area method was more robust and could also make accurate predictions for lyophilized PVP samples, although the calibration set consisted of non-lyophilized samples. The peak area method required fewer calibration samples than the conventional partial least squares regression method.

Provoking an end-to-end continuous direct compression line with raw materials prone to segregation.

Continuous manufacturing of solid oral dosage forms is promising for increasing the efficiency and quality of pharmaceutical production and products. In this study a whole train continuous direct compression (CDC) line has been provoked using challenging formulations typically prone to segregation in batch powder processing. Industrial compositions including components with variable size, bulk density and cohesive nature were selected. An experimental design, including variables such as API/mannitol particle size, API amount, powder feed rate and mixer speed, enabled the output quality of the provoked process to be assessed. Contrary to previous studies, a broader range of finished tablet quality attributes were probed, including content, uniformity of content, tensile strength as well as release performance. Overall, the continuous direct compression line was found to be a capable and efficient manufacturing process for the challenging compositions studied and surprisingly tolerable to handle the materials susceptible to segregation in typical batch settings. As expected, and given the 'fixed' apparatus configuration used in this study, the particulate material properties were found to have the most significant impact on the finished tablet quality attributes. The results emphasize the importance for taking a holistic approach when developing the operational windows and the strategy for control, e.g. by integrating the appropriate material properties, the actual apparatus design, and the relevant formulation design. The CDC line's ability to handle cohesive materials also seem to be one of the key advantages, thus confirming the recent promising results from other continuous direct compression studies.

Achieving a robust drug release from extended release tablets using an integrated continuous mixing and direct compression line.

In the present work the viability of integrated continuous mixing and compression processes for manufacturing of extended release (ER) matrix tablets was investigated in terms of dissolution behavior. The purpose was also to evaluate the combined effect of processing variables and compositional variables on the release robustness. The continuous process was provoked by a challenging formulation design, including variable powder characteristics and compositions of high and low amount of poorly soluble and poorly flowing drug substance (ibuprofen). Additionally a relatively low amount of two different ER matrix former grades (standard granulation grade CR and direct compression grade DC2 of hydroxypropyl methylcellulose, HPMC) was used to challenge the system. Robust ibuprofen release was obtained faster when HPMC CR was used. However, robust release was also achieved when using HPMC DC2 at high ibuprofen content, even though it took slightly longer time to reach the steady state of the process. Due to its poor flow properties, HPMC CR would be very challenging to use in traditional direct compression. The results showed that by using continuous processing it is possible to manufacture and achieve robust performance of compositions that would not be possible with traditional batch processing due to for instance poorly flowability.

Strategic framework for education and training in Quality by Design (QbD) and process analytical technology (PAT).

The regulatory and technical landscape of the pharmaceutical field is rapidly evolving from one focused predominantly on development of small molecules, using well established manufacturing technologies towards an environment in which biologicals and complex modalities are being developed using advanced science and technology coupled with the application of modern Quality by Design (QbD) principles. In order that Europe keeps pace with these changes and sustains its position as major player in the development and commercialization of medicines, it is essential that measures are put in place to maintain a highly skilled workforce. A number of challenges however exist to equipping academic, industrial and health agency staff with the requisite knowledge, skills and experience to develop the next generation of medicines. In this regard, the EUFEPS QbD and PAT Sciences Network has proposed a structured framework for education, training and continued professional development, which comprises a number of pillars covering the fundamental principles of modern pharmaceutical development including the underpinning aspects of science, engineering and technology innovation. The framework is not prescriptive and is not aimed at describing specific course content in detail. It should however be used as a point of reference for those institutions delivering pharmaceutical based educational courses, to ensure that the necessary skills, knowledge and experience for successful pharmaceutical development are maintained. A positive start has been made and a number of examples of formal higher education courses and short training programs containing elements of this framework have been described. The ultimate vision for this framework however, is to see widespread adoption and proliferation of this curriculum with it forming the backbone of QbD and PAT science based skills development.

Scatter correction of transmission near-infrared spectra by photon migration data: quantitative analysis of solids.

The scope of this work is a new methodology to correct conventional near-infrared (NIR) data for scattering effects. The technique aims at measuring the absorption coefficient of the samples rather than the total attenuation measured in conventional NIR spectroscopy. The main advantage of this is that the absorption coefficient is independent of the path length of the light inside the sample and therefore independent of the scattering effects. The method is based on time-resolved spectroscopy and modeling of light transport by diffusion theory. This provides an independent measure of the scattering properties of the samples and therefore of the path length of light. This yields a clear advantage over other preprocessing techniques, where scattering effects are estimated and corrected for by using the shape of the measured spectrum only. Partial least squares (PLS) calibration models show that, by using the proposed evaluation scheme, the predictive ability is improved by 50% as compared to a model based on conventional NIR data alone. The method also makes it possible to predict the concentration of active substance in samples with other physical properties than the samples included in the calibration model.

Characterization of different laser irradiation methods for quantitative Raman tablet assessment.

Quantitative Raman spectroscopy of conventional wet granulated pharmaceutical immediate release tablets and subsequent data evaluation was investigated. Different aspects of quantitative assessment of active pharmaceutical ingredient (API) in intact tablets with special focus on sub-sampling issues were addressed. Four different geometric laser irradiance patterns were examined to study the effect of sub-sampling within the tablets. The Raman data was evaluated using both univariate and multivariate techniques. UV absorbance spectroscopy was used as a reference method. The best result in terms of prediction error was attained by irradiating a large area of the tablets. Using multivariate calibration with multiplicative signal correction (MSC) the prediction error was 1.7%. In addition, the effect of tablet density on the Raman assessment was investigated. It was found that quantitative Raman assessment of chemical content can be made insensitive to variations in tablet density corresponding to a manufacturing compression interval of 5-20 kN provided that adequate data treatment is used. A short discussion about sample heating in the context of different irradiation patterns is included with reference to previous work. In conclusion, the present study provides a platform for developing an implementation strategy for quantitative Raman spectroscopy for both laboratory analysis and process analytical technology (PAT) applications.