Predevelopment Tasks for Drug Making

Stability — Drug stability can be impacted by the processing conditions used to produce the drug. For example, a drug substance can exist in two or more crystalline phases that have different arrangements and/or conformations (forms) of the molecules in the crystal lattice.  Depending on the processing conditions of temperature, solvent selection, processing time and formulation controls, these forms can change from one crystal form to the other or can become amorphous. The process is called polymorphic transition. Critical polymorphic transitions may be accompanied by change in particle size or melt and transition properties such as segregation, precipitation or sedimentation. These changes can affect drug substance activity as well as result in adverse impact on drug product stability.

Polymorphs have different stabilities and may spontaneously convert from an unstable form to the stable form at a particular temperature. They also exhibit different melting points and solubilities, which affect the dissolution rate of drug and consequently bioavailability in the body.

Many compounds absorb water vapor or moisture. This absorption (or hygroscopicity) affects API/product stability. Understanding hygroscopicity during the formulation and process development phase is key in determining process and product controls including handling, storage, and critical processing conditions. APIs can be classified into slightly hygroscopic, very hygroscopic and deliquescent.

Predevelopment activities, including identification and control of critical process parameters are designed to determine the most stable form of a polymorphic drug.

Quality — Pharmaceutical quality has many definitions, but pharmaceutical quality as specifically applied to drug product quality includes assurances designed to produce a drug product that is free of contamination and reproducibly delivers the therapeutic benefit promised on the consumer label. [6.10] All properties that impact drug product SSQUIPP also impact on drug product quality.
Process-related physical properties can influence particle size, handling methods, manufacturability, API specification, labeling, packaging and storage condition requirements, as well as other key product criteria.

Early characterization and control of drug chemical properties relating to degradation, reactivity and compatibility under normal and stressed conditions favorably impact drug stability. Sound preformulation, feasibility formulation and process development involve activities that help ensure the development of a drug product that meets safety, stability, quality, identity, purity and potency (SSQUIPP) requirements through the application of quality by design [6.11].

Identity — Typically, drug identity refers to labeling considerations. But Identity issues can arise when the drug product is not what it is claimed to be. Identity issues can be avoided by following correct standard operating procedure for manufacturing, storage, distribution and administration of approved drug products as well as ensuring strict compliance with all GMP and regulatory requirements.

Purity — Impurities are foreign materials not part of the defined drug substance, excipients or other additives. There are many sources of impurities, including those from the raw materials (drug substance, excipients or other additives), residual solvents, degradation products and foreign materials.

Impurities can also arise from exposure to light, heat, humidity, container or label interactions, pH drift during storage and other means. Impurities can also arise from crystallization or recrystallization of drug substance during processing or storage, residual solvents or other by-products of the API manufacturing process. Predevelopment experiments are designed to assess the potential sources of drug impurities and to determine remediation steps to avoid impurity prone processes or interactions in the future.

Potency — There are several physical factors in the production setting that may impact drug potency including weighing mistakes, and losses during processing (transfer losses, sorption losses (adsorption or absorption). Process equipment trains can produces losses as well. Other factors, such as polymorphic transitions may reduce potency. Degradation and /or drug-excipient interactions may impact potency claims as well. Here, sound predevelopment and feasibility development procedures can help detect potential product potency variables, identifying remedial measures and support consistent production of drug product at the targeted potency.

Development Costs and Time to Market

The main objective of conducting predevelopment activities is to produce and deliver a drug product that meets SSQUIPP requirements to the end user. Failure to perform well-planned predevelopment activities early in the development stage is likely to lead to time-consuming and costly delays [6.13]. There are enormous cost implications involved with poorly executed drug product development. Mistakes or missteps resulting from improperly planned and executed physicochemical characterization or process development studies can raise development costs dramatically. Similarly, incomplete product knowledge stemming from poorly executed development studies instead of systematic and deliberate creation of product quality suitable for intended patients by design has the real potential to delay or derail a drug product launch.

Product development delays and costs most likely will increase if there is not a well-planned and systematic approach to development challenges. These challenges can be addressed by engaging in a systematic and deliberate process to ensure product quality suitable for intended patients by design. This QBD approach requires a thorough understanding of the physical properties of drug substance and excipients — knowledge obtained by exhaustive characterizations of API, excipient and feasibility product during predevelopment stage. The baseline data generated at this stage is critical for the formulation of a stable, efficacious and safe dosage form compatible with delivery system.

The advantages of well-planned and executed predevelopment activities are therefore not only realized in minimizing the potential for costly delays to drug development but also has direct impact on product overall quality (SSQUIP), reduction of product development costs, acceleration of time to market and getting planned activities right the first time.

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References

6.1  G. Steele, “Preformulation as an Aid to Product Design in Early Drug Development,” in Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, M. Gibson, Ed. (Interpharm Press, Denver, CO, 2001), pp. 196–210.
6.2  J. Sharp, “What Do We Mean by ‘Sterility?” PDA J. Pharm. Sci. Technol. 49 (2), 90–92 (1995).
6.3  C.P. Croce, A. Fischer, and R.H. Thomas, “Packaging Material Science,” in The Theory and Practice of Industrial Pharmacy, L. Lachman, H.A. Lieberman, and J.L. Kanig, Eds. (Varghese Publishing House, Bombay, India, 3rd ed., 1991), pp. 711–732
6.4  G. Brittain (Ed.), P1-34 “Polymorphism in Pharmaceutical Solids”, Marcel Dekker,  Inc., New York, 1999
6.5  W. Lund, (Ed). Principles and Practice of Pharmaceutics, The Pharmaceutical Press, London, UK, 12th ed., 1994
6.6  PDA Journal of Pharmaceutical Science and Technology, Technical Report #42, Process Validation of Protein Manufacturing, Supplement Volume 59, pages 3-7, September/October 2005.

Published in the February 2013 issue of Pharmaceutical Manufacturing magazine