Safety certificate for components of drug products

Manufacture of medicinal products and the APIs used as starting materials in the production of these products is subject to strict GMP regulations that are designed to ensure their quality, safety and efficacy. This ensures that patients worldwide and at any time can have confidence in the quality, safety and efficacy of medicines.

The manufacturers of pharmaceutical products should aware of potential risk of contamination in components of drugs. It is important that manufacturers take steps to ensure that these components are not contaminated with the following:

• TSE /BSE
• Dioxin  
• Gluten
• Melamine
• Heparin,  and
• GMO

The objective of this article to bring awareness that will help pharmaceutical manufacturers to control their use of at-risk components that might be contaminated with drug substances and drug products and ensure the patient safety.

Medicine contamination incidents

• 1937 Elixir sulfanilamide incident: S. E. Massengill Company used diethylene glycol as the solvent, it led to the 1938 Federal Food, Drug, and Cosmetic Act.
• 1982 Chicago Tylenol murders: Tylenol pain-relief capsules were laced with potassium cyanide, leading to 7 deaths.
• 2007 Panamanian Eduardo Arias discovered that toothpaste sold in his country was labeled as containing diethylene glycol, the same ingredient that had tainted cough syrup and killed 138 Panamanians in 2006.
• 2007 Toxic cough syrup in Panama: Pharmaceutical manufacturers used diethylene glycol, which they believed to be glycerine, to make cough syrup.
• 2008 Chinese heparin adulteration.
• 2009, 84 Nigerian children were reported to have died after being given "My Pikin", a teething syrup contaminated with diethylene glycol.
• 2012: As of 2 November 2012 in the New England Compounding Center meningitis outbreak, 404 cases of fungal infection occurred with 29 deaths due to contaminated injectable medication.

What is TSE?
TSE - Transmissible Spongiform Encephalopathy. A disease capable of being transmitted by infection and gives the appearance of sponge like tiny holes in the brain. There are many types of Human TSEs. It is a rare disease occurs in Humans and Vertebrate animals (Having backbone). The first report of risk of TSE to human was reported in October 1997 through Global Alert and Response by WHO.

The Meaning of TSE:

• Transmissible – capable of being transmitted by infection.
• Spongiform – Sponge like
• Encephalopathy – Brain disease

What is BSE?
BSE - Bovine Spongiform Encephalopathy. A disease capable of transmitted by infection and gives an appearance of sponge like tiny holes in the brain of bovines. It is a rare disease occurs in Vertebrate animals (cow /cattle), generally known as ‘Mad Cow Disease’. BSE was first recognized in the UK in 1986. A large number of cattle and individual herds have since been affected.

Meaning of BSE:

• Bovine – Characteristic of or resembling cows or cattle
• Spongiform – Sponge like
• Encephalopathy – Brain disease.

What is Dioxin?
The production of dioxins in the manufacture of paper pulp products such as tampons and sanitary pads, are not only harmful to the environment, but also unnecessarily expose women to low levels of dioxins every time they use these products. Dioxin settles in the fat cells of our bodies and stay there for the rest of our lives, building up cumulatively overtime from birth, so increased exposure means increased risk.  Organochlorines are contained in many of the familiar products such as solvents, pesticides, plastics, disinfectants, plastic packaging and chlorine-bleached pulp and paper products such as toilet paper, kitchen roll and some feminine hygienic products.

Dioxins are some of the most deadly chemicals created and classified as ‘Carcinogenic’ (cause cancer). Foods of animal origin are the primary source of human exposure to dioxins.  Another source of dioxins in the environment is chlorophenol-based products, such as pentachlorophenol, which was widely used as a wood preservatives in the past until its use was restricted in 1980.

WHAT IS GLUTEN?

• Gluten is a general name for the proteins found in wheat, rye, barley and triticale. Gluten helps foods maintain their shape, acting as a glue that holds food together. On August 2, 2013, the FDA announced its long-awaited gluten-free food labeling rule.  According to the rule, when a manufacturer chooses to put “gluten-free” on food packaging, the item must comply with the new FDA definition of the term – less than 20 ppm of gluten.
• Any food product conforming to the standard may be labeled “gluten-free” even if it is naturally gluten-free (i.e., water or fresh produce). All FDA-regulated foods/dietary supplements (vitamins, minerals, herbs, amino acids)/ imported food products that are subject to FDA regulations.
• In 2007, FDA learned that certain pet foods were sickening and killing cats and dogs. FDA found that vegetable proteins imported into the USA from China and used as ingredients in pet and livestock food products were contaminated with melamine.
• In September 2008, FDA received reports from China about food article contaminated with melamine, which have resulted in thousands of hospitalization for kidney problems and at least three deaths.
• FDA issued a Health Information Advisory to make the public aware of FDA’s ongoing effort to monitor the safety of food supply by testing certain imported food ingredients derived from milk.

The cGMP regulations require that all components be tested before they are released for use in the manufacture or preparation of drug products (21 CFR 211.84). It is critical that all manufacturers determine whether they are using an at-risk component for melamine contamination to manufacture or prepare a drug product.

• Manufacturers of finished drug product test for melamine in at-risk components before they are released for use in the manufacture or preparation of the drug products. Distributors of finished products under their own label or brand should obtain certification by the manufacturer that the products are tested for the absence of melamine contamination if their product contains an at-risk component.
• Manufacturers of finished pharmaceuticals know and monitor their supply chain for any at-risk components, which means knowing the identity and role of the actual manufacturer of such components and any repackers and distributors who handle the components before receipt by the manufacturer. Manufacturers should obtain certification from the manufacturer of at-risk components that these components are tested for the absence of melamine contamination.
• Heparin is a member of the group of medicines known as anticoagulants. Anticoagulants reduce the ability of the blood to clot. By doing so, they prevent harmful blood clots from forming in blood vessels. Heparin is used to prevent conditions known as deep vein thrombosis (DVT) and pulmonary embolism. DVT is associated with the formation of blood clots in the blood vessels in the leg. Heparin is often used after a person has had a heart attack. It is also sometimes used in the treatment of strokes that are caused by blood clots.
• In March 2008, major recalls of heparin, a substance widely used as an injectable anticoagulant, were announced by the FDA due to contamination of the raw heparin stock imported from China. The raw material for the recalled heparin batches was processed in China from pig's intestines by the American pharmaceutical firm Scientific Protein Laboratories.
• The FDA was quoted as stating that at least 81 deaths were believed to be linked to a raw heparin ingredient imported from the People's Republic of China, and that they had also received 785 reports of serious injuries associated with the drug’s use. Upon investigation of these adverse events by the FDA, the contaminant was identified as an "over-sulphated" derivative of chondroitin sulfate, a closely related substance obtained from mammal or fish cartilage and often used as a treatment for arthritis.
• Since over-sulphated chondroitin is not a naturally occurring molecule, costs a fraction of true heparin starting material, and mimics the in-vitro properties of heparin, the counterfeit was almost certainly intentional as opposed to an accidental lapse in manufacturing.
• It involves the insertion of DNA from one organism into another (or) modification of an organism’s DNA in order to achieve a desired trait. Genetically Modified Organs are, very fast, precise and can introduce genes into an organisms that would not naturally occur.  GMOs are living organisms whose genetic material has been artificially manipulated in a laboratory through genetic engineering. DNA from two different species are combined to create a new species. Examples that exist: goat & spider/salmon & ocean pout/soybean & BT (bacteria)/corn & bacteria.

CONCLUSION
The pharmaceutical industry, under the oversight of the Regulatory Authorities and inspectorates consistently applies appropriate cGMP practices, there are many cases known where the standards expected from manufacturing companies have not been maintained. Manufacturers of medicinal products, APIs and registered intermediates are responsible for approving and qualifying their suppliers and to monitor on an ongoing basis the performance of their critical suppliers to ensure safe level of potential contaminants in the drug components.