Prabir K. Basu

Improving Pharmaceutical Product Development and Manufacturing: Impact on Cost of Drug Development and Cost of Goods Sold of Pharmaceuticals

It is not commonly understood that one of the largest components of the overall cost of bringing a new drug to the market is the cost of product development. Cost of product development can account for as much as 30% to 35% of the total cost of bringing a new drug to the market. Quality of product development also affects time to market and the quality of manufacturing and therefore cost of manufacturing. Investment in basic research in the science of product development and manufacturing will pay for itself through savings achievable in the cost of new drug development and in the cost of goods sold (COGS) of pharmaceutical products. In order for us to arrive at good estimates of the saving potential, one first needs to have credible estimates of the cost of new drug development and the overall COGS for pharmaceutical products.

Understanding critical material properties for solid dosage form design

What is the role of standardized methods for determining the impact of material properties in pharmaceutical formulation and process development? In this Perspective article, we identify material properties that are potentially important in solid dosage form design, and we review approaches linking these properties to product specifications in dry granulation process development. We also assess the potential benefits that could be obtained by standardizing the methods for determining the impact of material properties of commonly used excipients and propose a program of research to achieve the desired goal of an efficient, science-based approach for incorporating material properties in solid dosage form design.

Analysis of Manufacturing Costs in Pharmaceutical Companies

In the pharmaceutical industry, costs attributed to manufacturing are a major part of a company’s total expenses. In this paper, trends in various expense and income categories of pharmaceutical companies have been analyzed with particular emphasis on manufacturing costs to gain an insight into their relationships and how they may differ among types of pharmaceutical companies such as brand name, generics, and biotechs. The study includes data published in the annual reports of leading pharmaceutical companies from 1994 to 2005. Twenty-two pharmaceutical companies were selected based on the annual revenues. The set was further divided into three groups: brand names, generics, and biotechs. The analysis shows that, between 1994 and 2005, manufacturing costs (as a percentage of total sales) are different for the three groups of companies listed above. Additionally, each group of companies differs in how savings are leveraged strategically. The data on brand-name pharmaceutical companies also indicate that there is a strong correlation between the reduction of the cost of goods sold (COGS) and the increase in R&D expenditure. This suggests the validity of Vernon’s theory that for brand-name companies, a reduction in COGS will likely have a positive impact on investments in R&D, presumably resulting in much needed innovations and future health benefits for the society.

Toward intelligent decision support for pharmaceutical product development

Developing pharmaceutical product formulation in a timely manner and ensuring quality is a complex process that requires a systematic, science-based approach. Information from various categories, including properties of the drug substance and excipients, interactions between materials, unit operations, and equipment is gathered. Knowledge in different forms, including heuristics, decision trees, correlations, and first-principle models is applied. Decisions regarding processing routes, choice of excipients, and equipment sizing are made based on this information and knowledge. In this work, we report on the development of a software infrastructure to assist formulation scientists in managing the information, capturing the knowledge, and providing intelligent decision support for pharmaceutical product formulation.

Analysis of the Implementation of Total Productive Maintenance, Total Quality Management, and Just-In-Time in Pharmaceutical Manufacturing

In the pharmaceutical industry, systems for improving operational effectiveness and efficiency are becoming more and more popular. In this paper, developments in the industry’s improvements in operational effectiveness and efficiency have been analyzed. A holistic model is presented which builds the basis for the presented study results. The study includes data gathered from pharmaceutical production sites in surveys in 2004 and 2009. The analysis is divided according to the four sub-systems: Total Productive Maintenance, Total Quality Management, Just-in-Time, and the Management System. For each sub-system, key performance indicators and associated elements (practices and instruments) from 2004 to 2009 are investigated. The data indicates that the industry did make continuous steps towards “Excellence in Operations” between 2004 and 2009. Pharmaceutical companies took control over their former low asset utilization and managed to improve the efficiency of their quality systems; however, they are still far away from having any kind of “continuous flow”, smooth production scheduling or make-to-order manufacturing. It can be said that most of the companies are still working on the effectiveness side rather than focusing on the efficiency side.

Passive Transdermal Systems Whitepaper Incorporating Current Chemistry, Manufacturing and Controls (CMC) Development Principles

In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration’s Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro–in vivo correlation considerations for transdermal systems.

Quality by design in formulation and process development for a freeze-dried, small molecule parenteral product: a case study

A case study has been developed to illustrate one way of incorporating a Quality by Design approach into formulation and process development for a small molecule, freeze-dried parenteral product. Sodium ethacrynate was chosen as the model compound. Principal degradation products of sodium ethacrynate result from hydrolysis of the unsaturated ketone in aqueous solution, and dimer formation from a Diels–Alder condensation in the freeze-dried solid state. When the drug crystallizes in a frozen solution, the eutectic melting temperature is above −5°C. Crystallization in the frozen system is affected by pH in the range of pH 6–8 and buffer concentration in the range of 5–50 mM, where higher pH and lower buffer concentration favor crystallization. Physical state of the drug is critical to solid state stability, given the relative instability of amorphous drug. Stability was shown to vary considerably over the ranges of pH and buffer concentration examined, and vial-to-vial variability in degree of crystallinity is a potential concern. The formulation design space was constructed in terms of pH and drug concentration, and assuming a constant 5 mM concentration of buffer. The process design space is constructed to take into account limitations on the process imposed by the product and by equipment capability.

Best Practices for the Development, Scale-up, and Post-approval Change Control of IR and MR Dosage Forms in the Current Quality-by-Design Paradigm

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro–in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

A QbD Case Study: Bayesian Prediction of Lyophilization Cycle Parameters

As stipulated by ICH Q8 R2 (1), prediction of critical process parameters based on process modeling is a part of enhanced, quality by design approach to product development. In this work, we discuss a Bayesian model for the prediction of primary drying phase duration. The model is based on the premise that resistance to dry layer mass transfer is product specific, and is a function of nucleation temperature. The predicted duration of primary drying was experimentally verified on the lab scale lyophilizer. It is suggested that the model be used during scale-up activities in order to minimize trial and error and reduce costs associated with expensive large scale experiments. The proposed approach extends the work of Searles et al. (2) by adding a Bayesian treatment to primary drying modeling.

Excipient interaction prediction: application of the Purdue Ontology for Pharmaceutical Engineering (POPE)

Abstract A drug product consists of a drug substance and one or more excipients that play specific roles in rendering desired properties to that product, from improvement of flow to control of the release of the drug substance. Inter-excipient and drug substance-excipient chemical reactions are to be avoided and formulators often use heuristics and past experience to avoid potential interactions during drug product development. Multiple tools are present to mechanistically predict chemical reactions: however their utility is limited due to the complexity of the domain and the need for explicit information. In this work, the Purdue Ontology for Pharmaceutical Engineering (POPE) was used to develop an excipient reaction prediction application that made use of structural, material and environmental information to predict reactions