Blending of active pharmaceutical ingredients (APIs) with various excipients is a common step in the pharmaceutical solid dosage form manufacturing process. The homogeneity of the blend is critical in defining the uniformity of dosage units within a batch of tablets, especially in the case of direct compression products.
Typically, the API in the compressed blend is analyzed in the finished dosage form for potency and content uniformity. For many existing formulations, it is important to ensure that both the active and excipients are uniformly distributed throughout the solid dosage form. It is important to note that each pharmaceutical product has a distinctive blend of API and excipients and thus each blending operation is also unique.
|Figure 1. Antaris Target Series Blend Monitor coupled to a 20-liter Bohle bin blender.|
The generic pharmaceutical industry implemented wide spread blend testing as a response to Judge Wolins opinion in the United States vs. Barr Laboratories court case in 1993 (Civil Action No. 92-1744). It was stated by Judge Wolin that blend testing is necessary to increase the likelihood of detecting inferior batches. Blend content uniformity testing cannot be waived in favor of total reliance on finished product testing, because finished product testing is limited. It was therefore concluded that final blend testing was required for each batch of a drug product, including ordinary production batches.
Additionally, blend uniformity is addressed in the Current Good Manufacturing Practices (cGMP) regulations and drug approval programs. Section 211.110 of cGMP requires manufacturers to establish control procedures (that) include adequacy of mixing to assure uniformity and homogeneity. The regulations, however, did not specify the blend testing approach, nor the particulars as to the acceptance criteria, limits, or methods for the testing. Once again in 1996, the FDA implied the need for blend uniformity testing of all routine manufacturing batches in an effort to make certain that a high level of quality was maintained throughout a process, and not just upon completion of the final product. (1)
In order to provide a response to the FDA and in an attempt to produce a relevant guidance, the Blend Uniformity Working Group (BUWG) was formed under the auspices of the Product Quality Research Institute (PQRI). After several revisions, BUWG developed a draft recommendation on stratified sampling of powder blends that was presented to the CDER in December 2002 and published in 2003. (2) Based upon these recommendations, the FDA published their draft guidance on stratified sampling in October of 2003. (3) The report and the new draft guidance describe the use of a stratified sampling scheme for demonstrating blend uniformity based upon thieving multiple samples from the blender in multiple places and analyzing the samples for blend uniformity via the appropriate reference method.
The accepted technique used for the sampling of powder from blenders is thief sampling. The main drawback of thief sampling is that the technique is difficult to reproduce and often the act of sampling may cause sample inhomogeneity and lead to result bias. Other potential issues with thief sampling are that it is labor intensive for both the operator and laboratory personnel and there is often a long delay from the time the blender is stopped to the time the blend uniformity result is received. There is also the concern for operator exposure, especially in the cases of high-potency APIs, and the operators must be fully gowned in order to grab samples. (4)
|Figure 2. Pharmaceutical operator thief-sampling a 2-cu.-ft. twin-shell blender.|
One potential solution to satisfy the need for blend sampling while avoiding the issues with thief sampling is the on-line monitoring of powder blending by near infrared (NIR) spectroscopy. In September 2004, the FDA published the draft guidance, PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Control, which opened the door for manufacturers to explore implementing on-line techniques for real-time blend uniformity analysis. (5)
The goal of the FDA is to encourage pharmaceutical manufacturers to build quality into products through process control and understanding rather than testing quality at the finished product stage. NIR spectroscopy is one of the techniques ideally suited for PAT applications, and has gained acceptance within the pharmaceutical industry and regulatory agencies.
NIR spectroscopy can be used to collect high quality reflectance spectra of both the active ingredient and excipients and is sensitive to chemical as well as physical properties of the powder blend. Advantages to NIR spectroscopy include that it is noncontact and nondestructive, highly reproducible, rapid and requires no sample preparation. On-line blend monitoring places certain demands on NIR instrumentation including wireless communication, battery operation, rapid data collection, appropriate hazard and cleaning rating and software/hardware validation and qualification.