Tablets production processes

CU-ASSAYLdat (Fig. 4.40) A tablet production process was being validated samples were pulled from the beginning, the middle, and the end of the production run Components A and B were analyzed. The requirement is that the means do not significantly differ and that the CV remains below 6%. 

Fig. 2.2 The tablet production process. Process stages are shown in boxes.

Note on GMPs The assays are conducted on individual dosage units (here tablets) and not on composite samples. The CU test serves to limit the variability from one dosage unit to the next (the Dissolution Rate test is the other test that is commonly used). Under this premise, outlier tests would be scientific nonsense, because precisely these outliers contain information on the width of the distribution that one is looking for. The U.S. vs. Barr Laboratories Decision makes it illegal to apply outlier tests in connection with CU and DR tests. This does not mean that the distribution and seemingly or truly atypical results should not be carefully investigated in order to improve the production process. 

Near-infrared spectroscopy is quickly becoming a preferred technique for the quantitative identification of an active component within a formulated tablet. In addition, the same spectroscopic measurement can be used to determine water content since the combination band of water displays a fairly large absorption band in the near-IR. In one such study [41] the concentration of ceftazidime pentahydrate and water content in physical mixtures has been determined. Due to the ease of sample preparation, near-IR spectra were collected on 20 samples, and subsequent calibration curves were constructed for active ingredient and water content. An interesting aspect of this study was the determination that the calibration samples must be representative of the production process. When calibration curves were constructed from laboratory samples only, significant prediction errors were noted. When, however, calibration curves were constructed from laboratory and production samples, realistic prediction values were determined ( 5%). 

Sales of Ca supplements alone were 875 million in the United States in 2002, and comprised 60% of all mineral supplement sales (Anonymous, 2004). In 2004, sales of Ca supplements increased by 9.3% (Uhland et ah, 2004), possibly to some extent in response to the Surgeon General s report on bone health that was issued that year. More recently in 2006, it was projected that dietary supplement sales in the United States would approach 5 billion (Anonymous, 2006). While Ca derived from a balanced diet is preferable, Ca supplements are a popular noncaloric alternative for increasing daily Ca intake. There are a vast number of oral Ca supplements available in the market place in the form of capsules, tablets, chewable tablets, effervescent tablets, liquids, powders, suspensions, wafers, and granules. However, not all Ca salts are equally soluble or bioavailable and the dose of Ca on the label of a supplement may not necessarily be reflective of the relative amount of available Ca once consumed. Furthermore, the same Ca salt may be more or less bioavailable depending on the production process and materials used to manufacture the supplement. 

This case study will summarize the development of a pan-coating process designed for the application of an enteric coating to a tablet product, provide insight into some of the early process optimization studies that were undertaken, and show how these ultimately facilitated the development of production-scale manufacturing processes. 

Example 2 In a Pet Tabs (pet vitamin tablets) production, the pharmaceutical manufacturer is using milling and micronizing machines to pulverize raw materials into fine particles. These finished particles are combined and processed further in mixing machines. The mixed ingredients are then pressed into tablets, dried, and sealed in packages. A normally distributed quality characteristic, moisture content, is monitored. Samples of n = 4 tablets are taken from the manufacturing process every hour. The data after 25 samples have been collected are shown in Table 5. 

A simple flow chart should be provided to show the logistical sequence of unit operations during product/process manufacture. A typical flow chart used in the manufacture of a tablet dosage form by the wet granulation method is presented in Figure 2. 

This is usually a transition stage between the laboratory and the projected final process. Figure 4 also shows typical responses that may have to be evaluated during the ranging studies on the tableted product. 

NDA process. A medical review of the data led to the conclusion that in the 12-hr time frame between API HC1 administrations the 25-min difference in reaching the specified 85% dissolved material was of little consequence. It was also observed that by the use of a higher pressure in tablet production, a tablet dissolution rate conforming to tablets of marketed product could be created. 

The manufacture of a processed Helianthus tuberosus product, characterized by the addition of natural oily vitamin E, is described. This provides a tableted product that can be easily prepared in desired amounts by diabetics. The tablets are preferably obtained by slicing, drying, and pulverizing H. tuberosus tubers and adding citric acid to the powder, and then the natural vitamin E in an amount of about 0.03 wt%. 

Vaginal tablets containing lactobacilli have been used in order to restore the normal vaginal flora. Formulation of these delivery systems requires specific proceedings in order to provide viability of lactobacilli and stability of the final product. Freeze drying of bacterial suspensions has been tested to obtain lyophilized powders for tablet production [81]. These powders were shown to be processable and tablet production was easy and reproducible. Also, the use of double-layer tablets (fast-release layer and slow-release layer) seems to be an interesting approach to lactobacilli administration. 

Lubricant The use of a lubricant is essential to increase the free flow of powders and to prevent manufacturing disorders in the tablet production. The type and amount of lubricant are cautiously selected in the formulation. The order of addition and mixing time is also considered in the tableting process. 

Tablet production systems can be defined as all machines which are able to produce tablets. They include tableting machines for production and research as well as tableting machine simulators, which are able to mimic the production processes of tableting machines of different size and velocity in order to facilitate scale-up.

The aim of this chapter is to give an overview of the different techniques used for production and research and further to show the possibilities, that instrumentation of tablet production systems gives in order to analyze the tableting process. The knowledge derived can be used for formulation development as well as to facilitate tablet production and scale-up. Applied techniques which are necessary for production in a good manufacturing practice (GMP) environment will also be discussed. 

Tablet production systems can be operated manually however most of the systems nowadays operate automatically in order to produce a sufficient number of tablets. Further requirements depend on the type of machine, the production process, the operation mode of the machine, and the production rate of the machine.

A low product yield is caused by loss of material during fast production processes. On rotary tableting machines this problem is solved by slightly lowering the lower punches before the compression event starts. 

It is said that a material showing a moderate to high BFI value (>0.5) is prone to laminate and cap during the process. A low value of BFI is desirable to minimize lamination and capping during tablet production. 

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