Pharmaceuticals active ingredients

These and other FDA policy decisions launched the pharmaceutical industry and academia into a new era of developing stereoselective processes for the manufacture of enantiopure active pharmaceutical ingredients (APIs). 

Although in many cases an enantiopure drug can be safer than the racemate, the advantages are clear. The final formulation of the drug product could be reduced inhalf, potential side effects could be minimized, and the resulting pharmokinetic and pharmacodynamic studies could clearly determine the efficacy of the active pharmaceutical ingredient (API) [21]. 

Draft Guidance for Industry on Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients Availability Notice, Fed Regist.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

Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients... 

Annex 18 Good manufacturing practice for active pharmaceutical ingredients (The ICH Guide) Annex 19 Reference and Retention Samples... 

Prashad M (2004) Palladium-Catalyzed Heck Arylations in the Synthesis of Active Pharmaceutical Ingredients. 6 181-204 Pretraszuk C, see Marciniec B (2004) 11 197-248... 

Thomas, P.W. and Ramsay, A. (2004) Continuous manufacturing of a bulk active pharmaceutical ingredient. Presented at Switching from Batch to Continuous Processing Conference,... 

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

PIC, 1987, Guidelines for the Manufacture of Active Pharmaceutical Ingredients (Bulk Drug Substances) (Document PH 2/87). 

The use of palladium as a catalyst is common in the development and synthesis of active pharmaceutical ingredients (APIs). Palladium is an expensive metal and has no known biological function. Therefore, there is a need to recover spent palladium, which is driven both by cost and by government regulations requiring residual palladium in APIs to be <5 ppm (1). Thus, much research has been conducted with the aim of heterogenizing active palladium that can then be removed via simple filtration and hopefully reused without significant loss of activity. 

The preferred and easiest intake of medicines is by oral ingestion in the form of tablets. Tablets today contain a combination of an active pharmaceutical ingredient and a (polymer) excipient-the inactive ingredient that delivers the pharmaceutical active... 

Garrett, C.E. and Prasad, K. (2004) The art of meeting palladium specifications in active pharmaceutical ingredients produced by Pd-catalyzed reactions. Advanced Synthesis and Catalysis, 346 (8), 889-900. 

Tao, J., Zhao, L. and Ran, N. (2007) Recent advances in developing chemoenzymatic processes for active pharmaceutical ingredients. Organic Process Research Development, 11, 259-267. 

Synthesis and scale-up production of active pharmaceutical ingredient (API)... 

Tab. 14.1 The role ofGMP (good manufacturing practice) in the production and processing of APIs (active pharmaceutical ingredients) from difference sources. It is not yet clear how biotechnology-derived plants fit into this scheme. Modified from the Good Manufacturing Practice Guide for Active Pharmacuetical Ingreedients, ICH (2000).

To get a better idea of the complexity of a real application scenario in these industries it makes sense to, once, exemplarily depict the planning processes in a typical production of active pharmaceutical ingredients (API production). Most pharmaceutical companies are looking at planning scenarios in which several hundred individual resources or facilities have to be accounted for, with demands and orders for some thousand final products. The planning horizon is often set to 2-5 years. Next to single equipment, there are facility pools, with one pool consisting of several individual units. 

Eventually, the final criterion, i.e. authorization and access to relevant data, led to the selection of three cases in different chemical companies using batch processes and located in The Netherlands. For reasons of confidentiality the names of these companies cannot be revealed, therefore they are named company A, B and C. Their real names are known to the author. These companies produce coating resins, active pharmaceutical ingredients and plastic granules respectively. By selecting these three... 

Figure 40 Primary process of active pharmaceutical ingredients at company B.

The pharmaceutical industry produces between 25 and 100 kg or more of waste for every kilogram of active pharmaceutical ingredient (API) manufactured.1 According to a leading practitioner of the industry, the potential waste coproduced with APIs is in the range of 500 million to 2 billion kg per year. Even at a nominal disposal cost of 1 per kg, the potential savings just in waste avoidance is significant faced to the pharmaceutical industry annual sales (almost 500 billion in 2003). 2... 

In other words, sol-gel entrapment technology provides innovative drug delivery solutions using sol gel based encapsulation systems in silica which enables new and stable combinations of APIs [active pharmaceutical ingredients] resulting in improved efficacy and usability . 

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