In this article we look at the steps involved in moving from a drug substance to a successful oral solid dosage (OSD) form, and at the analytical technologies that can be helpful. In particular, we focus on gathering the required information to progress pharmaceutical development within the context of the regulatory requirements and the application of QbD.
Over the past two decades the empirical processes which once characterized pharmaceutical development have steadily given way to the more systematic, knowledge-led approach enshrined in Quality by Design (QbD). A QbD strategy builds quality into a product from the outset through the development of a detailed understanding of the factors that influence clinical efficacy, and of an effective control strategy for manufacture, based on the mitigation of risk. The starting point for pharmaceutical product formulation is an identified, active drug substance. The goal of formulation development is to incorporate this substance in a product and to develop a manufacturing process that will deliver that product securely and consistently. In QbD terms this relies on identifying the factors that will define the clinical efficacy of the product, and then learning to control the material and process attributes that will ensure consistent delivery to the resulting quality target performance profile (QTPP).
In this white paper we look at the steps involved in moving from a drug substance to a successful oral solid dosage (OSD) form, and at the analytical technologies that can be helpful. In particular, we focus on gathering the required information to progress pharmaceutical development within the context of the regulatory requirements and the application of QbD.
The regulatory framework and QbD
ICH Q8(R2) provides detailed guidance about pharmaceutical development and suggests that the following steps represent a minimal requirement for success:
- Defining the quality target product profile (QTPP). This is the definition of what the product must deliver and includes specifications relating to quality, safety and efficacy. Developing the QTPP requires consideration of how the drug substance will be delivered, the form the pharmaceutical product will take, the strength of the drug, its bioavailability, and how stability will be maintained within the manufactured product.
- Identifying the critical quality attributes (CQAs) of the product. The CQAs of a product are the variables that directly impact clinical efficacy and quality, in other words those that impact the QTPP. So, for example, a CQA for an OSD might be dose uniformity, since this impacts the amount of drug delivered with each tablet, and the efficacy of the product.
- Determining the CQAs of the drug substance and excipients. These are different from the CQAs for the finished product. For example, while the disintegration characteristics of a tablet might impact how quickly drug substance particles are released from the tablet matrix, it could be the size of those particles that influences the rate of dissolution of the drug, and consequently bioavailability. It will also be important to select both the type and amount of excipient required to ensure reproducible tablet disintegration.
- Selecting an appropriate manufacturing process. Once the formulation is defined then attention shifts to identifying how to make the product consistently, as efficiently as possible.
- Defining a control strategy. The final element of pharmaceutical development is to identify which variables must be controlled during manufacture to ensure that the defined quality targets are met. Timely and efficient monitoring and control technologies are required for successful implementation.
QbD wraps around all of these steps and influences the rigor and approach that is taken in tackling them. For example, a QbD approach to investigating the CQAs of the drug product might extend to developing functional relationships between these CQAs and critical material attributes (CMAs) and process parameters (CPPs). In manufacturing QbD is associated with development of a design space, an operating window in which success is assured, rather than simply a fixed set of processing conditions. Control within the design space may well then be implemented through the application of relevant process analytical technology (PAT), and be associated with real-time release, as opposed to detailed final product QC.
There is no regulatory requirement to implement QbD as part of an investigational new drug (IND) submission or new drug application (NDA) but there are potential rewards. The application of QbD demands a greater understanding than more empirical approaches and is therefore associated with the more secure demonstration of risk mitigation. Manufacturers that adopt this approach are therefore permitted the freedom of changing operating conditions within the defined design space: a valuable prize. More generally there is the suggestion that by comprehensively satisfying the regulators’ requirement to minimize risk such submissions are subject to a lighter regulatory focus than those where detailed process and product knowledge is less clearly demonstrated.
In summary though, the fundamental steps involved in pharmaceutical development are identical with or without QbD. Focusing on the information required to drive these steps helps to identify analytical strategies that can support the formulation work flow.
Characterizing the drug substance
In the early stages of formulation the focus lies on the drug substance itself and how to deliver its therapeutic effect to the patient. This leads to definition of the QTPP. In this white paper the focus is on oral solid dosage forms but this stage would normally include a detailed assessment of the optimal drug delivery technology.
The pharmacological profile of a drug substance can be influenced by both biological and physicochemical properties. Understanding the impact of these properties helps with the development of a detailed specification for the drug substance and other aspects of the QTPP such as the quantity of drug substance in each tablet. ICH Q6A is helpful in identifying which tests are required to securely characterize the drug substance in an IND or NDA situation and suggests that the specifications for the drug substance might relate to:
- Physical properties such as pH, refractive index, melting point
- Particle size
- Polymorphic form/amorphous content
- Chiral identity
- Water content
- Inorganic impurity levels
- Microbial content
Many of these properties can influence the performance of the product in a number of ways and will therefore go on to be identified as CQAs for the drug. For example, particle size can affect the dissolution, solubility or bioavailability of the drug in a tablet and also, perhaps less obviously, impact the processability of a tablet blend. Finer particles may flow less easily than those that are coarser, for example, and a blend consisting of dissimilarity sized drug and excipient particles may be prone to segregation, leading to poor content uniformity.
For the majority of pharmaceutical applications the need for particle size information, and particle size control, is efficiently met by laser diffraction. Other critical drug properties, such as polymorphic form, are less readily characterized. Many drugs exist in multiple crystal forms. If a certain polymorph is identified as having desirable characteristics then the presence of others may have a detrimental effect on the product. Manual microscopy is one technique for differentiating crystal forms, but it can be both time-consuming and subject to operator variability. The following case study highlights the application of an alternative, relatively new technique, Morphologically Directed Raman Spectroscopy (MDRS), for efficient polymorph characterization.
Case study: Using MDRS to differentiate drug substance polymorphs.
The technique of MDRS, as its name suggests involves using morphological data to guide the efficient application of Raman spectroscopy, which in turn provides chemical identification. The technique is implemented using an automated imaging system with spectroscopy capabilities, such as the Morphologi G3-ID, Malvern Instruments.
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Malvern Instruments provides the materials and biophysical characterization technology and expertise that enable scientists and engineers to understand and control the properties of dispersed systems. These systems range from proteins and polymers in solution, particle and nanoparticle suspensions and emulsions, through to sprays and aerosols, industrial bulk powders and high concentration slurries. Used at all stages of research, development and manufacturing, Malvern’s materials characterization instruments provide critical information that helps accelerate research and product development, enhance and maintain product quality and optimize process efficiency. Our products reflect Malvern’s drive to exploit the latest technological innovations and our commitment to maximizing the potential of established techniques. They are used by both industry and academia, in sectors ranging from pharmaceuticals and biopharmaceuticals to bulk chemicals, cement, plastics and polymers, energy and the environment. Malvern systems are used to measure particle size, particle shape, zeta potential, protein charge, molecular weight, mass, size and conformation, rheological properties and for chemical identification, advancing the understanding of dispersed systems across many different industries and applications. Headquartered in Malvern, UK, Malvern Instruments has subsidiary organizations in all major European markets, North America, Mexico, China, Japan and Korea, a joint venture in India, a global distributor network and applications laboratories around the world. www.malvern.com severine.michel@malvern.com
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