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.

Applying Quality by Design Concepts to Pharmacy Compounding.

Compounding of medications is an important part of the practice of the pharmacy profession. Because compounded medications do not have U.S. Food and Drug Administration approval, a pharmacist has the responsibility to ensure that compounded medications are of suitable quality, safety, and efficacy. The Federal Government and numerous states have updated their laws and regulations regarding pharmacy compounding as a result of recent quality issues. Compounding pharmacists are expected to follow good preparation prodecures in their compounding practices in much the same way pharmaceutical manufacturers are required to follow Current Good Manufacturing Procedures as detailed in the United States Code of Federal Regulations. Application of Quality by Design concepts to the preparation process for a compounded medication can help in understanding the potential pitfalls and the means to mitigate their impact. The goal is to build quality into the compounding process to ensure that the resultant compounded prescription meets the human or animal patients' requirements.

Pharmaceutical compounding or pharmaceutical manufacturing? A regulatory perspective.

At one time, nearly all prescriptions were compounded preparations. There is an ongoing demand for compounded prescription medications because manufacturers cannot fulfill the needs of all individual patients. Compounding pharmacies are a long standing yet less frequently discussed element in the complex matrix of prescription drug manufacturing, distribution, and patient use. The drug shortage situation for many necessary and life-saving drug products is a complicating factor that has led to the numerous quality issues that currently plague large-scale compounding pharmacies. The states are the primary regulator of pharmacies, including community drug stores, large chains, and specialty pharmacies. Pharmacies making and distributing drugs in a way that is outside the bounds of traditional pharmacy compounding are of great concern to the U.S. Food and Drug Administration. The U.S. Congress has recently passed the Drug Quality and Security Act. This legislation establishes a clear boundary between traditional compounders and compounding manufacturers. It clarifies a national, uniform set of rules for compounding manufacturers while preserving the states' primary role in traditional pharmacy regulation. It clarifies the U.S. Food and Drug Administration's authority over the compounding of human drugs while requiring the Agency to engage and coordinate with states to ensure the safety of compounded drugs.

Sampling results of the improved SKC diesel particulate matter cassette.

Diesel particulate matter (DPM) samples from underground metal/nonmetal mines are collected on quartz fiber filters and measured for carbon content using National Institute for Occupational Safety and Health Method 5040. If size-selective samplers are not used to collect DPM in the presence of carbonaceous ore dust, both the ore dust and DPM will collect on the quartz filters, causing the carbon attributed to DPM to be artificially high. Because the DPM particle size is much smaller than that of mechanically generated mine dust aerosols, it can be separated from the larger mine dust aerosol by a single-stage impactor. The SKC DPM cassette is a single-stage impactor designed to collect only DPM aerosols in the presence of carbonaceous mine ore aerosols, which are commonly found in underground nonmetal mines. However, there is limited data on how efficiently the SKC DPM cassette can collect DPM in the presence of ore dust. In this study we investigated the ability of the SKC DPM cassette to collect DPM while segregating ore dust from the sample. We found that the SKC DPM cassette accurately collected DPM. In the presence of carbon-based ore aerosols having an average concentration of 8 mg/m3, no ore dust was detected on SKC DPM cassette filters. We did discover a problem: the surface areas of the DPM deposits on SKC DPM cassettes, manufactured prior to August 2002 were inconsistent. To correct this problem, SKC modified the cassette. The new cassette produced, with 99% confidence, a range of DPM deposit areas between 8.05 and 8.28 cm2, a difference of less than 3%.

Differential pressure response of 25-mm-diameter glass fiber filters challenged with coal and limestone dust mixtures.

This article summarizes results of research conducted by the National Institute for Occupational Safety and Health (NIOSH) at its Pittsburgh Research Laboratory. The objective of this work was to determine the correlation between the mass (M) of respirable coal and limestone dusts collected on 25-mm-diameter glass fiber filters mounted in cassettes and the increase in differential pressure (deltaP) that develops across the filters when drawing at constant air flow. Test aerosols were generated inside a laboratory dust chamber using various coal dusts, limestone dust, and mixes of the two. Dusts with different particle size distributions were deposited on the filters by sampling from the chamber through cyclone preclassifiers at different flow rates. Results show that the relationship between differential pressure increase (cm water) and dust mass (mg) is linear and can be approximated by the equation deltaP = KM. The K values (slopes) range from 1.14 to 1.64, depending on the parent coal of the samples. The influence of particle size distribution was also found. The overall K value for all the data summarized in this article is 1.35, with R2 = 0.84 for the summary equation. When calibrated for individual work sites, or other circumstances where great variability in dust characteristics is avoided, the relationship between collected dust mass and increase in differential pressure may provide an exploitable principle for measurement of respirable dust concentrations.