Active pharmaceutical ingredients availability

Draft Guidance for Industry on Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients Availability Notice, Fed Regist. Docket No. 98-0193, 1998. 

International Organization on Harmonisation (2000), ICH harmonized tripartite guideline Good manufacturing practice guide for active pharmaceutical ingredients, available http //www.ICH.org, accessed June 23,2005. 

Sol-gel microencapsulation in silica particles shares the versatility of the sol-gel molecular encapsulation process, with further unique advantages. Sol-gel controlled release formulations are often more stable, potent and tolerable than currently available formulations. The benefits of microencapsulation can be customized to deliver the maximum set of benefits for each active ingredient. Overall, these new and stable combinations of active pharmaceutical ingredients (APIs) result in improved efficacy and usability. 

Total sold amount in kilograms of Active Pharmaceutical Ingredient (API) on the Swedish market (including all products containing the same API) in the most recent year for which data are available. 

At the commencement of the project there were several routes available for the synthetic construction of prostanoid compounds our challenge was which to choose. For this, we were mindful of the stereochemical features of the molecule and the need for a full stereochemical characterization of the active pharmaceutical ingredient (API) produced. This was required in the regulatory submissions,... 

Based upon the advantages of the other techniques presented prior to LC-MS, large volume injection HPLC-UV, and HPLC-CAD, the decision to use electrochemical detection would be driven primarily by a unique analytical need, equipment availability and previous experience of the analytical chemist. A complex chemical matrix should not be of concern at most there could be some residual cleaning agent and residual excipients in addition to the active pharmaceutical ingredient. Since the matrix in cleaning verification is typically simple, electrochemical detection would not be the primary detection technique. However, the sensitivity afforded by ECD is excellent and can meet the most stringent of the acceptance limits outlined in Table 15.2. 

Most of the active pharmaceutical ingredients (APIs) of commercially available pharmaceuticals are manufactured either by chemical syntheses or microbial fermentations. However, some of the active ingredients are directly obtained from natural sources. This section addresses the development and manufacture... 

A more detailed discussion of the stationary phase types and mechanism of interaction and separation theory in relation to chiral compounds is given in Chapter 22. A large number of chiral stationary phases are currently available to meet the needs of the pharmaceutical industry for determination of the enantiomeric purity of active pharmaceutical ingredients, raw materials, and metabolites. As a consequence, there are a multitude of options in terms of columns, separation mode, and separation conditions to explore in achieving an enantioseparation. 

By the time an active pharmaceutical ingredient (API) is made available to an analytical chemist in the formulation development group, most or all of the physical characteristics of an API has already been studied and the information should be available in some sort of a report from the drug substance group or preformulation group. Some of the key parameters that an analytical chemist in formulation development requires from such a report are the solubility and solution stability. 

In addition, some GSK production processes address the second step noted above through the use of microorganisms as a sustainable resource to produce raw materials, enzymes, or advanced intermediates that either make up or make our medicines. Harnessing biological processes to make complex materials and active pharmaceutical ingredients is clearly an extremely desirable goal for the Pharmaceutical Industry, but the promise remains largely unrealized. The third step towards more sustainable business practices will be taken in the future as the business evolves and opportunities become more available and are better understood. 

Levothyroxine is another example of an active pharmaceutical ingredient with relatively poor stability that is available as a USP analytical reference standard in the free acid form, while the drug is formulated as the sodium salt in most commercial preparations.84 Levothyroxine is prone to extensive photochemical decomposition85 that is thought to be exacerbated by the facile ionization of the phenolic hydroxyl group.86 Supply of the USP analytical reference standard as the free acid provides a more stable form through suppression of the ionization of the phenolic hydroxyl. 

The rate and extent at which the active pharmaceutical ingredient or active moiety is absorbed from a pharmaceutical dosage form and becomes available at the site(s) of action. 

The rate and extent to which the active moiety is absorbed from a pharmaceutical dosage form and becomes available at the site(s) of action. Reliable measurements of drug concentrations at the site(s) of action are usually not possible. The substance in the general circulation, however, is considered to be in equilibrium with the substance at the site(s) of action. Bioavailability can be therefore defined as the rate and extent to which the active pharmaceutical ingredient or active moiety is absorbed from a pharmaceutical dosage form and becomes available in the general circulation. Based on pharmacokinetic and clinical considerations it is generally accepted that in the same subject an essentially similar plasma concentration time course will result in an essentially similar concentration time course at the site(s) of action. 

The setbacks experienced in these two cases from the medical point of view did not, however, eliminate the need for robust syntheses that could be scaled up and used to produce the required amounts of active pharmaceutical ingredient (API). When embarking on the ebalzotan project, the only route available for making this nontrivial molecule consisted of 13 linear steps that were utilized by the medicinal chemistry department when preparing pre-CD quantities see Scheme 7.1 for details on what reactions were used to synthesize this product. This rather long sequence was required as no suitable advanced building block was found to be commercially available. Thus, the... 

Care should be exercised when packaging materials are selected for active pharmaceutical ingredients. The materials should have no detrimental effect on the substance, and should give adequate protection against external influences and potential contamination. Suitable written specifications should be available. 

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