Formulation and Process Development Articles

Compliance with quality regulations that protect patients' safety is a critical requirement for the pharmaceutical industry. Regulatory compliance goes a long way toward proving that a given product's target for quality has been achieved and documented. Pharmaceutical Manufacturing Handbook: Regulations and Quality is intended to help readers understand how to comply with regulations and how to adapt a quality unit's routine activities to facilitate compliance.

In the book's preface, editor Shayne Cox Gad says the book describes "all regulatory aspects and requirements that govern how drugs are produced for evaluation (and, later, sale to and use) in humans." The book's back cover says it contains "everything you need to ensure full compliance and superior quality control."

Ongoing innovation is critical for meeting the changing demands of the pharmaceutical industry for equipment, machinery, and related services. We asked the participants in Pharmaceutical Technology's Product Innovation roundtable for their input on their respective companies' product enhancements. Participating in the roundtable were: Richard Denk, director of the pharmaceutical department for Hecht Anlagenbau (Pfaffenhofen/Ilm, Germany); Dieter Forthuber, division president of KMPT USA (Florence, KY); Craig Martin, product manager at Dwyer Instruments; (Michigan City, IN); Bruce Smith, regional manager at SPX Process Equipment (Delavan, WI); Christopher Fournier, vice-president of Mar Cor Purification (Lowell, MA); and Grant Rowe, product manager for respiratory protection, Bullard (Cynthiana, KY).

Bulk-solids handling

Q: Can you outline any key product or service introductions that your company will be making in line with Interphex and/or planned for launch in 2008?

(St. Louis, MO), part of the life sciences chemicals giant Sigma-Aldrich (St. Louis, MO), is moving ahead on a plan to deliver double-digit growth in 2008 and beyond. After achieving revenue gains of more than 10% in 2007, SAFC president Frank Wicks recently outlined the company's strategy. This strategy involves growing organically and by targeted technology acquisitions.

"We hope to achieve sales of greater than $600 million in 2008," says Wicks. "We feel this goal is possible as we grow the business internally and through acquisitions that build our technological capabilities and in turn, broaden our talent pool."

In 2002, the US Food and Drug Administration publicly recognized a need for change with its current good manufacturing practices (CGMP) for the 21st century initiative (1). This new approach to GMP compliance and enforcement recognized that FDA and the drug and biologics industries were not where they needed to be in terms of quality, manufacturing science, and risk management. This changing world of GMP applied to human and veterinary drugs and biological drug products. Key to FDA's approach has been to request a holistic cradle-to-grave management of quality issues.

Quality system: What is it?

The quality system should be an integrated framework within which the design, manufacture, packaging, labeling, and distribution take place. Commitment from management is crucial; without it there is no quality system. The underlying principles are:

The i's have been dotted, and the t's have been crossed. After years of revisions, debates, and delays, the USP General Chapter 467 Residual Solvents will finally take effect on July 1, 2008. Although most large, multinational pharmaceutical companies have been preparing for these requirements for some time, there is still a significant portion of the industry, especially smaller firms, that are either not aware of how USP ‹467› will change their analytical practices or are in denial that the standards will directly affect them.

The discovery, use, and development of protein therapeutics has increased opportunities for drug-product development. Advancing the therapeutic potential of these protein-drug entities presents a challenge to formulation and delivery scientists.

The second edition of Protein Formulation and Delivery presents an updated review of recent research in the formulation and delivery of therapeutic proteins and peptides. The book contains expanded sections about protein characterization and formulation and several new chapters that focus on protein delivery.

One of the book's new chapters offers information to aid the rational choice of excipients for use during the freeze-drying process. The chapter also provides sound practical advice about bulking agents, buffers, and simple tests to predict the stability of freeze-dried formulations.

Excipients play a crucial role in pharmaceutical formulations, affecting properties such as patient acceptability, rate of release of pharmaceutical actives, and delivery-to-target tissues. Researchers around the world are currently developing new excipients with improvements to these characteristics. In addition, new active pharmaceutical ingredients (APIs) often require new excipients that are compatible with their chemical properties.

However, global commercialization of new excipients is currently hindered by the fact that they are only reviewed by regulatory agencies in the context of new drug applications (NDAs). As a result, pharmaceutical manufacturers are reluctant to include them in their formulations because any questions about the excipients could cause delays or rejection of their applications, thus adding additional uncertainty to the process.

As contract manufacturers and pharmaceutical companies gather later this month for Informex in New Orleans, discussions of approaches for the synthesis of active pharmaceutical ingredients (APIs) and intermediates will invariably ensue. A review of several sources, including contract manufacturers, academicians, and recent literature reveals several interesting approaches in API synthesis.

Nucleoside analogs

Pharmaceutical manufacturing requires the selection of residue acceptance levels for potential residues such as active pharmaceutical ingredients (APIs), excipients, degradation products, cleaning agents, bioburden substances, and endotoxins when carrying out cleaning validation studies. These levels are determined according to the potential pharmacological, safety, toxicity, stability, and contamination effects on the next product produced with the same surface or equipment. The USFood and Drug Administration's guidance for determining residue limits states that residue limits should be logical, practical, achievable, and verifiable (1). Limits are typically set for visual, chemical, and microbiological residues by taking into consideration the batch size, dosing, toxicology, and surface area for the equipment.

Crystallization from solutions is not only an important step in the fabrication of various functional materials in biological systems, but also a key separation and purification process in the manufacture of many fine chemicals and specialty chemicals, especially pharmaceuticals (1, 2). Pharmaceutical crystallizations are often carried out in batches of organic solvents or mixtures of solvents through temperature cooling (3). Because of the excess properties (i.e., the difference between the real properties and the ideal properties) for a real solution, the solubility of an active pharmaceutical ingredient (API) in a solvent mixture is sometimes higher than its solubility in a single solvent as the activity coefficient decreases (4, 5). The solubility enhancement that the solvent mix offers can bring three main advantages to pharmaceutical batch crystallization: