Betalactam Antibiotics Manufacturing Controls - FDA & GMP requirements

Betalactam  Antibiotics – Manufacturing Controls FDA & GMP requirements

 Beta-Lactam Antibiotics 

Betalactam antibiotics are cell wall synthesis inhibitors, which inhibit the growth of bacteria by interfering a specific step in bacterial cell wall synthesis. Beta-lactam antibiotics, including penicillins and the non-penicillin classes, share a basic chemical structure that includes a three-carbon, one-nitrogen cyclic amine structure known as the beta-lactam ring. The side chain associated with the beta-lactam ring is a variable group attached to the core structure by a peptide bond; the side chain variability contributes to antibacterial activity.

Beta-lactam antibiotics include the following five classes:

·                   penicillins (e.g., ampicillin, oxacillin)

·                   cephalosporins (e.g., cephalexin, cefaclor)

·                   penems (e.g., imipenem, meropenem)

·                   carbacephems (e.g., loracarbef)

·                   monobactams (e.g., aztreonam)

 

Beta-lactams antibiotics (penicillins & non-penicillin) have the potential to sensitize individuals, and their exposure may result in severe allergic reactions in some patients.

Allergic reactions associated with penicillins and non-penicillin beta-lactams range from rashes to life-threatening anaphylaxis. Immunoglobulin E (IgE) antibodies mediate the immediate hypersensitivity reactions that are responsible for the symptoms of hay fever, asthma, hives, and anaphylactic shock. IgE-mediated hypersensitivity reactions are of primary concern because they may be associated with significant morbidity and mortality.

It is difficult to define the minimal dose below which allergic responses are unlikely to occur in humans. There is a lack of suitable animal or receptor testing models that are predictive of human sensitivity. The threshold dose at which allergenic response could occur is extremely low and difficult to detect with current analytical methods. 

Drug cross-contamination is the contamination of one drug with one or more different drugs. During drug manufacturing process, if a drug manufacturer uses same equipment chain  for betalactam and non betalactam drugs, there could be a possibility of  cross contamination which can result in hypersensitive exaggerated allergic immune response in some people.

Manufacturing operations of betalactam drugs to be controlled to avoid cross contamination with other drugs, because

1. Betalactum antibiotics may cause anaphylatic shock and anaphylaxis or life threatening allergic reactions. 

2.Mode of action of Betalacctum antibiotics are more or less cytotoxic. 

3.Untoward consumption of betalactum antibiotics as contaminant in other product even in smaller amount may result in the development of untoward drug resistance or antibiotic resistance for betalactum antibiotics and when ever desired,betalactum drugs may not be effective in individuals who got betalactum antibiotic as cotaminant. 

Regulatory Requirements for Betalactam Manufacturing

FDA insists the drug manufacturers that operations relating to the manufacture, processing, and packing of penicillin shall be performed in facilities separate from those used for other drug products for human use.” However, FDA has clarified that separate buildings may not be necessary, provided that the section of the manufacturing facility dedicated to manufacturing penicillin is isolated (i.e., completely and comprehensively separated) from the areas of the facility in which non-penicillin products are manufactured. Manufacturers must completely separate air handling systems for penicillin from those used for other drugs for human use. Additionally, manufacturers to test non-penicillin drug products for penicillin where the possibility of exposure to cross-contamination exists, and prohibits manufacturers from marketing such products if detectable levels of penicillin are found.