By Bhupatsinh Vihol
The topic of pharmaceutical solids is broad and complex. The criticality of a thorough understanding of the solid-state physiochemistry of a new drug is unquestioned from a scientific, quality, and regulatory point of view. Even though chemical properties may remain the same in solid state, the compound may not always act in the same way. These differences could affect how a drug works in the human body. Appropriate instrumentation, analytical methods, and scientific expertise are necessary, not only to generate information during form screening, but also for troubleshooting problems that may arise with solid drug substance, finished dose production, and throughout the product’s life cycle.
Generally, a combination of advanced techniques is required to perform a rigorous solid-state characterization. This will utilize the higher-level principles of chemistry, physics, and mathematics. Beyond the obvious science, the secret to performing a thorough solid-state characterization involves, integrating all data that may be generated across various instruments at different laboratories and properly interpreting the collective data set to adjust the drug’s formulation. This requires a deft team of analytical scientists who bring with them the experience from working on a variety of formulations and new formulation technologies, as well as a wide array of instrumentation. It is also critical that these scientists have a strong command of manufacturing processes to proactively anticipate and mitigate the typical problems that arise not just at lab or pilot scale, but also in a commercial production environment.
With solid oral drug products, the active pharmaceutical ingredient (API) is blended with excipients that may include colors, flavors and substances that function to bind particles together, and ingredients that help a drug disintegrate into particles, small enough to reach the bloodstream quickly. The ingredients are blended until they are uniform, to ensure consistent composition of each individual tablet. It is essential to conduct compatibility experiments to accumulate knowledge about the physicochemical properties of the API and excipients. If any incompatibility exists between them, the physical and chemical stability of the API may be compromised.
Other characteristics of the solid drug (such as moisture content) may influence formulation behavior, particularly in tableting processes such as compression or granulation. Issues that occur here can lead to physical defects and dissolution problems, ending in product failure. Finally, sensitivity of the API to high temperature, high humidity, light, and other conditions must be controlled to maintain product reliability. To evaluate susceptibility to oxidation, reduction, hydrolysis, decomposition, photochemical reactions, and thermal rearrangements, solids are subjected to stresses (heat, humidity, light) and investigated in solution as well as in solid state. Any sensitivities will influence how the drug needs to be packaged and stored (e.g., addition of a drying agent to prevent moisture uptake or amber glass containers to minimize light exposure) as well as handled during transport.
Using Multiple Research Methods
Pharmaceutical solids can exist in several crystal forms, i.e., chemically identical but physically discrete, known as polymorphism. Polymorphs can have significant differences in their physical properties even though they are chemically identical, including solubility, melting point, particle size, dissolution rate, hygroscopicity, and others. Laboratory studies determine the potential of a compound to form multiple polymorphs, conditions under which the polymorphs are formed, physical properties of each polymorph, and stability of each polymorph. It is highly desired to use the most stable polymorph to avoid the risk of transformation into another form. Early polymorph screening identifies and selects the most stable forms and involves recrystallization of the drug from a variety of solvents under different conditions. There are many techniques used to confirm polymorphic form, including optical microscopy, X-ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR), Near Infrared (NIR), Raman, and solid-state Nuclear Magnetic Resonance (NMR). Even with the use of these sophisticated methods, the key is linking data with other physiochemical information that has been accumulated and being able to interpret it to make the right formulation adjustments.
In addition to polymorphs, solvents or water molecules can become an integral part of the crystal structure. DSC, thermogravimetric analysis and XRD are especially useful for confirmation of hydrated or solvated forms, while Raman and NIR are well-suited to monitor hydrate formation, during processing. There is also increasing attention on the non-crystalline (amorphous) drug forms for solubility enhancement. These can be innately unstable and create challenges for formulation due to chemical reactivity and hygroscopicity. Understanding crystalline content in an amorphous substance requires appropriate methods; XRD is a common technique, along with spectroscopic methods (FTIR, NIR, Raman, solid-state NMR), isothermal microcalorimetry, and dynamic vapor sorption. Again, this data must not stand alone, but be integrated with other experiments so that every aspect of the drug’s solid state is considered.
Process Transformations and Monitoring
One of the most overlooked, yet important aspects of solid-state characterization is understanding transformations that can occur to drug formulations during manufacturing processes. Many commercial-scale manufacturing problems go back to the physical properties of the API and/or excipients. During commercial production, certain unit operations such as heating, milling, and exposure to solvents may induce a change in the crystal form. This could have a significant impact on product quality. The approaches used to ensure process understanding and control at lab scale and in an earlier stage of development, may vary considerably from those used for larger-scale processes and in a later stage of development.
Because pharmaceutical manufacturing is based on the use of strict cGMP controls, once a manufacturing process has been validated and approved, it is fixed. Any process changes must be submitted and accepted by a regulatory authority. It is therefore difficult to make modifications later in development. Early on in product development, it is critical that the analytical scientists have the requisite knowledge and experience in the at-scale production environment to collaborate effectively with chemists and engineers on process development to avoid late-stage changes that may cause a regulatory delay.
In the traditional drug manufacturing approach, a process is sampled, and the sample is transported to a lab for analysis. This results in a delay between process sampling and when the results are available and process adjustments can be made. Real-time process analytical technology (PAT) interfaces routine production processes with analytical instruments and may include a feedback loop to modify the process based upon real-time analysis. This real-time data may aid both process control and product quality. An example of a PAT approach involves attaching a spectrometer to the blender to monitor the mixing. In the PAT approach, one is recording activities inside the blender over time. Once the spectra does not change any further, the blend is considered homogeneous. In the traditional offline approach, one is essentially taking several samples, at the same time, from different locations in the blender and bringing these samples to a lab for analysis. There is a delay between lab results and any process adjustments that might need to be made.
The obvious advantage of PAT is being able to make real-time process adjustments. One of the perceived downsides is the increased regulatory scrutiny (for example, in areas of model development, maintenance, number of samples tested) that might occur during market application review. This may add a regulatory burden, including country-specific requirements, more complex product life cycle management tasks, and increased time to product approval.
Linking and Interpreting Data
Many pharma companies must use outsourced labs for certain aspects of solid-state characterization to access technology, resources, and expertise that may not be readily available in-house. This means data can be generated from various labs and instruments. It is important that there is a central data integration point that employs best-in-class analytical science capabilities, extensive commercial manufacturing experience, and understanding of the local regulatory environment to streamline the capture and analysis of data from disparate sources.
Communicating between independent systems whether using electronic notebooks, instruments, or sophisticated laboratory information management systems and automating the process of data collection are important to develop the complete picture of the drug’s solid state. Beyond the efficiency that an electronic data collection affords, the scientists’ experience and expertise from working on a variety of formulations and new formulation technologies is perhaps more important. Sound scientific reasoning will contribute to keeping the overall drug developmental timeline, troubleshooting problems (that hopefully have been seen before), and avoiding costly experimental do-overs.
Comprehensive Data Analysis is Key
Solid-state characterization is constantly evolving with diverse technologies and changing quality and regulatory requirements. New instruments and methods deliver more tech-driven, rapid, and compliant results. PAT offers the potential to deliver real-time data right on the production floor to aid in process development and monitoring. The problem is that data by itself consists of only facts and figures. Collecting and organizing the data from potentially numerous sources so it can be explored in meaningful ways, then structured into useful information is the best way to enable decision making and aid in troubleshooting production issues that may arise. Rigor in understanding the compound’s physiochemistry will help in formulation, manufacturing, shipping, handling, and ultimately dispensing the drug to patients with greater assurance and long-term success.
About the author: Bhupatsinh Vihol, Sr. Principal Scientist at Piramal Pharma Solutions, Ahmedabad - India, leads a team of 28 (#) analytical scientists who deliver an average of 20 drug development projects (Phase 1 to 3 new chemical entities and generics) annually for European and U.S.- based pharmaceutical clients.
About Piramal Pharma Solutions
Piramal Pharma Solutions is a contract development and manufacturing organization (CDMO), offering end-to-end development and manufacturing solutions across the drug life cycle. We serve our clients through a globally integrated network of facilities in North America, Europe and Asia. This enables us to offer a comprehensive range of services including Drug Discovery Solutions, Process & Pharmaceutical Development services, Clinical Trial Supplies and Commercial supply of APIs and Finished dosage forms. We also offer specialized services like development and manufacture of Highly Potent APIs and Antibody Drug Conjugation. Our capability as an integrated service provider & experience with various technologies enables us to serve innovator and generic companies worldwide. Our Development centers & Manufacturing sites have accreditations from regulatory bodies in U.S., Europe & Japan. With a pool of over 450 scientists, including nearly 150 Ph.D’s across the globe, we are committed to Research & Development programs. To know more visit: www.piramalpharmasolutions.com.