Last Updated on December 28, 2021 by The Health Master
Benzene should be avoided in the manufacturing process of drugs
The USFDA is evaluating the root cause of benzene contamination in certain drugs and is alerting drug manufacturers to the risk of benzene contamination from drug components and other potential risk factors.
Benzene is a known human carcinogen that causes leukemia and other blood disorders. Certain hand sanitizers and aerosol drug products have been recalled due to benzene contamination.
This contamination may be related to inactive ingredients such as carbomers (thickening agents), isobutane (a spray propellant), or other drug components made from hydrocarbons.
USFDA reminds drug manufacturers they are required to establish scientifically sound and appropriate specifications and test procedures to assure drug components (active and inactive ingredients) and finished drug products.
This includes testing of raw materials and finished product batches prior to release to ensure they meet appropriate specifications for identity, strength, quality, and purity.
One way manufacturers can meet the requirements is by using tools such as risk assessments to determine whether they have the appropriate specifications, test methods, and controls to ensure drugs are free from contamination.
The USFDA has discussed with manufacturers conducting risk assessments to evaluate the possible presence of benzene in their drug products and components, including active ingredients and inactive ingredients.
In particular, the USFDA has also discussed with manufacturers the need for a special focus on ingredients that are hydrocarbons or are manufactured with benzene or other hydrocarbons.
Drug manufacturers should avoid using benzene in the manufacturing process
Manufacturers should not use benzene in the manufacture of drugs. The International Conference on Harmonization (ICH) Q3C Impurities: Residual Solvents guidance and companion document Q3C Tables and List provide guidance on limited cases where the presence of benzene may be tolerated.
Specifically, the ICH Q3C guidance explains that class 1 solvents such as benzene should not be employed in the manufacture of drug substances, excipients, or drug products because of their unacceptable toxicity.
The guidance notes that if benzene use is unavoidable to produce a drug product with a significant therapeutic advance, then its levels should be restricted to 2 parts per million (ppm), unless otherwise justified.
What drug manufacturers should do
Drug manufacturers are required to ensure the safety and quality of their drugs. As USFDA works to better understand the potential sources of benzene in drugs, USFDA reminds manufacturers of drugs marketed under approved applications and manufacturers of other drugs, including over-the-counter monograph drug products, of their obligation to ensure their products conform to appropriate quality specifications.
Consistent with the recommendations of the ICH Q3 guidance, manufacturers should not use benzene in the manufacture of drugs.
Ingredients that are hydrocarbons or are manufactured with benzene or other hydrocarbons may indicate a higher likelihood of benzene contamination.
USFDA is also aware of ingredients, such as the antifungal preservative sodium benzoate, that may form benzene under certain conditions.
The formation of benzoate from benzene can impact the appropriate measurement of benzene if this is not considered and controlled for in the analysis.
USFDA reminds manufacturers that changes in raw materials throughout the lifecycle of the drug, including changes in raw material suppliers, warrant additional scrutiny for the potential risk of benzene contamination.
Drug manufacturers with a risk of benzene contamination should test their drugs accordingly and should not release any drug product batch that contains benzene at or above 2 ppm, consistent with the recommendations described in ICH Q3C.
If any drug product batches with benzene above 2 ppm are already in distribution, the manufacturer should contact USFDA to discuss the voluntary initiation of a recall by contacting the appropriate Division of Pharmaceutical Quality Operations in the Office of Regulatory Affairs.
When testing reveals benzene in a product, manufacturers of nonapplication products, including over-the-counter monograph drug products, should contact USFDA using the information in the table below.
Manufacturers should also be prepared to provide USFDA with test results and any information available on the potential source of the benzene to assist in USFDA’s analysis.
Benzene limits in drug products
As USFDA evaluates the root cause of benzene contamination in certain drugs, the agency is taking a stepwise approach to address the potential for benzene contamination in marketed drug products by first identifying products that should be immediately recalled or not released for distribution based on a benzene level in the products above 2 ppm consistent with the considerations described in ICH guidance.
Concurrently, the agency will review any Field Alert Reports from drug manufacturers that identify the presence of benzene, in addition to other available information.
This information will help inform further updates to USFDA’s approach to limiting benzene levels in drug products, as appropriate.
We note that certain United States Pharmacopeia – National Formulary (USP-NF) carbomer monographs allow for levels of benzene of 100 ppm or greater. To eliminate confusion and because of the safety concerns associated with these unacceptable levels of benzene, USFDA has asked USP to remove (or “omit”) these monographs from their compendium.
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