Drug Development

The Six Sigma approach would appear to be ideally suited to pharmaceutical processes, yet the industry has been very slow to adopt it. This article looks at the possible reasons for this, and suggests an alternative methodology that takes advantage of Six Sigma tools and techniques, backed by good statistical principles.

The use of solid dispersion technology to increase the bioavailability of poorly water-soluble drugs has always been limited by processing and scale-up difficulties. A new approach may help to overcome some of the problems.

One of the greatest challenges facing biopharmaceutical manufacturers has been the primary recovery of recombinant materials from transgenic sources. As an alternative to existing methods, vibrating membrane technology, which is widely used in food and beverage processing, recently has been adapted to biopharmaceutical applications involving transgenic biosolutions.

With the advent of regulations such as 21 CFR Part 11 and the introduction of the electronic common technical document, it is becoming increasingly important to be able to enhance and fully utilize data management systems. Document change management is a vital tool in the construction and organization of valuable information, and can play a key role in the all-important process of getting a product to market.

Until specific audit trail requirements are available from the US Food and Drug Administration, manufacturers must define their own parameters for software system compliance and decide for themselves how to meet those requirements.

This case study describes how a major pharmaceutical manufacturer was equipped with four filling lines, for metered dose inhalers, supplied with a nitrogen cooling system to prevent spontaneous vaporization of the propellant gas. By doing so, a cost-effective and environmentally friendly solution was provided to a hazardous situation, which also complied with regulatory directives.

The aim of this study was to validate the automated clean-in-place (CIP) system installed on a capsule filling machine to determine its ability to adequately eliminate contaminants. The results obtained from the proposed cleaning validation trial showed that all the soluble tracer was removed after the washing procedure. At the end of the CIP procedure, the discharged water had the same pH, phosphate content and total organic content as the supplied water. Lack of cross-contamination in the product was also demonstrated and a recovery trial highlighted the complete elimination of the tracer from the machine.

Previous articles have presented a general review of the different types of spheres that can be obtained with a rotary fluidized bed process.1,2 This two-part study focusses on lipid spheres that can be prepared using hydrogenated castor oil, as well as examining the feasibility of the process and the main characteristics of the spheres obtained.

Erythritol is a bulk sweetener polyol that is suitable for a variety of reduced-calorie and sugar-free foods. It has been part of the human diet for thousands of years because of its presence in foods such as fruit, mushrooms and fermentation-derived products including wine, soy sauce and cheese. This article investigates the properties of erythritol and describes how it can be used as a pharmaceutical excipient.

Pharmaceutical science & technology news.

The study presented in this article used a controlled-porosity osmotic pump, which was prepared in the form of a bilayered tablet containing a drug compartment and an osmogen layer for the delayed release of diltiazem HCI.

More than 6 years have elapsed since the US Food and Drug Administration's (FDA's) 21 CFR Part 11 regulations regarding the use of electronic records and electronic signatures came into effect.1 In February 2003, FDA issued new draft guidance concerning the scope and application of Part 11, which describes how the agency intends to interpret and enforce the requirements during its ongoing re-examination of the regulations.2 Many people in the pharmaceutical industry have welcomed this new guidance and see it as a positive development that will lead to a simplified FDA approach to Part 11 and a significant reduction in the industry's compliance burden.

Paper batch records have been used for decades to record procedures, the type and quantity of each material used, and the status of each step in the manufacturing process for both pharmaceuticals and medical devices. Although paper batch records are less complicated to implement than their electronic counterparts, and the controls required for data recording and archival are well understood, a paper batch record system is laborious to maintain and prone to human error, which increases the compliance risk. Additionally, batch records have become bulky and more time consuming to prepare and review, particularly as manufacturing operations become increasingly complicated. Advances in technology and science have created a more competitive climate in life science industries than ever before, causing the need for manufacturers to reduce costs and time-to-market, and improve their ability to satisfy the compliance requirements of US Food and Drug Administration (FDA) regulations. The use of electronic batch recording systems (EBRS) and electronic batch records (EBR) offers one solution.

Part I of this article was published in the March 2003 issue of 21 CFR Part 11: Compliance and Beyond. In this issue, Part II discusses the potential advances and changes that must be made for computer validation to remain innovative and relevant to the industry.

In an interview earlier this year (Bio-IT World, April 2003), Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), stated that "The original intent of the rule (21 CFR Part 11) was to facilitate the introduction of electronic technology to the process of the US Food and Drug Administration (FDA) submissions, as well as manufacturing and production. Part 11 was created to provide common-sense guidelines on how to do in the electronic world what was previously done on paper. During the last 5 years, however, confusion regarding what is included in the regulation and how to enforce it was impeding the introduction of new technology. The rule had created exactly the opposite of what was intended."

European expert opinions regarding pharmaceutical process validation were collected and studied by performing an Internet Delphi survey. In total, 36 experts from 10 countries representing the pharmaceutical fields of industry, regulation and academia participated in the survey. The overall attitude to process validation appeared to be positive; however, a number of concerns were raised. More education, better use of prioritizing tools and increased evidence of cost-effectiveness is needed to further develop and facilitate process validation.

In December 2002, FDA notified DMV International that its pharmaceutical lactose manufacturing facility in The Netherlands had passed inspection. It was only 3 years earlier that DMV had started an ambitious programme to implement cGMP for API production conforming with ICH Q7A guidelines.

New research has led to significant advances in formulations and inhalation systems for pulmonary delivery.

The authors investigated the moisture gain of products containing ethambutol that were packaged in strip and blister packs as well as unpackaged formulations.

Good laboratory practice (GLP) regulations became effective in 1979 under 21 CFR Part 58 and apply to all non-clinical safety studies intended to support research permits or marketing authorizations. This article introduces some key elements regarding the application of GLP regulations as a quality system and how GLPs are perceived internationally.

This article examines the application of 21 CFR Part 11 to those areas of research and development (R&D) where compliance is not strictly required and the response of R&D equipment vendors to the rule's requirements and customer needs. The case is presented that vendors must accept that understanding and meeting Part 11 requirements is now part of their business environment.

This article describes a method for assessing the similarity of dissolution profiles using Hotelling's T2 statistic. The method applies a covariance structure that accounts for the heterogeneity of variance and correlation across time points. Comparing the method with the f2 criterion recommended in FDA's guidance on dissolution testing, the performance of the two methods was assessed on real examples, and simulation studies were also done to compare the method's performance with that of the f2 criterion.

Transdermal drug delivery, a vital technology of increasing interest, offers such benefits as controlled delivery for as long as a week and improved patient convenience and compliance.

Regular update from Washington.

On 20 February 2003, the US Food and Drug Administration (FDA) published a new draft guidance relating to 21 CFR Part 11. The new guidance mainly affects the compliance requirements of systems with a low risk and low impact on product quality; however, systems with a high risk and high impact on product quality, such as chromatography data systems or laboratory information management systems (LIMS), remain unaffected, as this article describes.

The US Food and Drug Administration is making changes in inspection processes, post-approval manufacturing changes and 21 CFR Part 11 policies to streamline oversight and improve product quality.

During autumn 2001, a Delphi survey was conducted using the Internet to discover the opinions of European experts from the pharmaceutical fields of industry, regulation and academia regarding pharmaceutical process validation. The Internet Delphi method was found to be an appropriate tool for exploring the opinions and experiences of pharmaceutical manufacturing because it allowed anonymous participation and discussion between geographically dispersed parties. However, to obtain reliable results, many factors were taken into account, as this article examines.

Oral dosage forms are the most popular way of taking medication, despite having some disadvantages compared with other methods. One such disadvantage is the risk of slow absorption of the active pharmaceutical ingredient (API), which can be overcome by administering the drug in liquid form and, therefore, possibly allowing the use of a lower dosage.

The pressure on the pharmaceutical industry to manufacture products faster and more cost-effectively has never been greater. Additionally, companies must also meet stringent regulations set by authorities such as the US Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA). This article explores the importance of complying with regulations and validation, how to maintain compliance and looks at some of the consequences of non-compliance.

As parenteral drug delivery becomes more complex and sophisticated, excipients that can facilitate drug (or gene) delivery to specific therapeutic targets will be required. An overwhelming majority of these excipients are derived from natural sources.