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Monday, March 8, 2010

Controling Endotoxins (Pyrogens).Aspectes of sterile dosage form (Injectable dosage form) manufacturing, Regulatory aspects

What are bacterial toxins , endotoxin , exotoxins :
In simple words bacterial toxins are classified in to two categories.
1.Exotoxins.
2.Endotoxins.

1.Exotoxins:- Exotoxins is a proteinaceous substance secreted by any bacterial cell and secreted out of cell , this toxins may harm any other living cell which come in contact with it , it may cause cell wall rupture or lysis of other cell, or may dissolve a cell (enzymatic actions) , exoroxins are bacterial supportive system of its own which helps in bacterial growth , which makes it easy for them to grow on a substrate.

2.Exotoxins:-
These are toxins secreted by bacterial cell within its cell , are also part of the basic metabolic function of bacterial cells. Endotoxins constitute lipopolysaccharide and are mostly found in gram negative bacteria .
They act as antigen and in case if they enter in to systemic circulation, even in very trace amount , they can trigger a strong anaphylactic reactions , which may result in to a anaphylactic shock.
This is particularly very dangerous in case of infants, and children’s.

What are pyrogens :-
Pyrogens are proteinecious materials usualy lipopolysaccharides, can be constituents , remainants of living or dead bacterias , and their cellular componats , pyrogens are responcible for conditions like increase in body temparature once pyrogen enters in to systemic circulation directly , or they are responsible for other anaphylatic reactions , raise in body temparature is due to immunological reactions , pyrogens are mostly bacterial endotoxins , the ability induce fever is becaue of antigen and antibody reaction , resulting in release of prostaglandins PGE2  (immunological events taking place once pyrogen enters in to systemic circulation directly).

The severity of reactions depends up on type of antigenic activity of pyrogen which can  be a life threatening too.

Controlling Endotoxins in paranteral dosage forms :-
Endotoxin contamination of an injectable dosage form occurs due to poor CGMP controls. Some patient particularly newborn (neonates), and patients who receive injections concomitantly, and patients who are administered injectable dosage form in atypically large volumes / doses are at the danger for pyrogenic , anaphylactic reaction which may result in to anaphylactic shock , than anticipated by the established limits based on body weight of a normal healthy adult .

These clinical concerns reinforce the importance of exercising appropriate current good manufacturing (CGMP) controls to prevent generation of endotoxins.
Pharmaceutical / Drug product components, containers, closures, storage time limitations, and manufacturing equipment are among the areas to address in establishing endotoxin control.

Properly designed and adapted cleaning, drying, and storage of equipment procedures and controls are of great importance in controlling bioburden and help to prevent contribution of endotoxin load.
see here Quality by Designe concept
Equipment should be designed to be easily assembled and disassembled, cleaned, sanitized, and/or sterilized. If adequate procedures are not employed, endotoxins are contributed by both upstream and downstream processing equipments.
Sterilizing-grade filters and moist heat sterilization are not effective in removing endotoxin. Endotoxin on equipment surfaces can be inactivated by high-temperature dry heat, or removed from equipment surfaces by cleaning procedures. Some clean-in-place procedures employ initial rinses with appropriate high purity water and/or a cleaning agent (e.g., acid, base, surfactant), followed by final rinses with heated water for injection ( WFI ). Equipment should be dried following cleaning, unless the equipment proceeds immediately to the sterilization step.
 
What are the regulatory FDA guidelines for endotoxin controll in sterile pharmaceuticals or injectable dosage form purporting to be sterile.

21 CFR 211.63 states that “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.”

 
21 CFR 211.65(a) states that “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”

21 CFR 211.67(a) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identify, strength, quality, or purity of the drug product beyond the official or other established requirements.”

21 CFR 211.94(c) states that “Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.”

21 CFR 211.167(a) states that “For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed.”
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