Manufcaturing Process/Product Risk Assessment

1.0 PURPOSE

The purpose of this document is to provide a procedure for performing Risk Assessment and Mitigation Plan of the Accidently Contamination of Ethylene Glycol or Di ethylene Glycol in Liquid oral dosages form.

2.0 SCOPE

This QRM document is applicable to Risk Assessment of Accidently Contamination of Ethylene Glycol or Di ethylene Glycol in Liquid oral dosages form.

3.0 REFERENCE DOCUMENT

1. Philippines FDA STATEMENT || On Diethylene glycol and Ethylene glycol.
2. WHO Medical Product Alert N°7/2022: Substandard (contaminated) pediatrics liquid dosage medicines
3. SOP for Risk Assessment
4. SOP for Vendor Management
5. SOP for Receipt and Handling of raw material
6. SOP for Sampling of raw material
7. SOP for Dispensing of Raw Material
8. SOP for Line Clearance
9. SOP for Product Release 

4.0 INTRODUCTION AND PROPOSE METHODOLOGY

Ethylene glycol and diethylene glycol are toxic to humans when consumed and can prove fatal.

The substandard products are unsafe and their use, especially in children, may result in serious injury or death. Toxic effects can include abdominal pain, vomiting, diarrhoea, inability to pass urine, headache, altered mental state, and acute kidney injury which may lead to death.

All pharmaceutical products, especially cough and cold syrups, that use glycerine as solvent, diluent, and thickening agent, are mandatorily required to be tested for purity as raw materials when used.   Diethylene glycol and ethylene glycol are cheap alternatives used by non-GMP compliant manufacturers.  Both impurities have industrial applications including as anti-freeze and brake fluid agents.  Only those glycerines that have passed laboratory analysis under GMP requirements are allowed to be present in pharmaceutical preparations.

Manufacturers of liquid dosage forms, especially syrups that contain excipients including propylene glycol, polyethylene glycol, sorbitol, and/or glycerin/glycerol, are urged to test for the presence of contaminants such as ethylene glycol and diethylene glycol before use in medicines.

The proposed methodology encompassed the use of the risk assessment tool Failure Mode Effects Analysis (FMEA) to determine the risk of finding Accidently Contamination of Ethylene Glycol or Di ethylene Glycol in Liquid oral dosages form.

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1.0 PURPOSE

The purpose of this document is to provide a procedure for performing Risk Assessment and Mitigation of the Presence of Nitrosamine Impurities in oral dosages form.

2.0 SCOPE

This QRM document is applicable to Assessment of Nitrosamine Impurities.

3.0 REFERENCE DOCUMENT

1. WHO Information Note: Update on Nitrosamine Impurities. (2019). Available at: https://www.who.int/medicines/publications/drugalerts/InformationNote_Nitrosamine- impurities/en/. (Accessed: 18th February 2020)
2. International Conference on Harmonization (ICH), Guideline M7(R1) on Assessment and Control of DNA Reactive (mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, 2017.
3. FDA. Information about Nitrosamine Impurities in Medications. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine- impurities-medications. (Accessed: 15th March 2020)
4. European Medicines Agency: EMA/189634/2019 - Information on nitrosamines for marketing authorization holders. Available at: https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490- information-nitrosamines-marketing-authorisation-holders_en.pdf. (Accessed: 18th February 2020)

4.0 INTRODUCTION AND PROPOSE METHODOLOGY

N-nitrosamines (or nitrosamines) are probable or possible human carcinogens to which man can be exposed from several known sources, such as food, drinking water, tobacco smoke and cosmetic products.

These impurities were first detected in the Valsartan active pharmaceutical ingredient (API) and subsequently other sartan medicines were also implicated. Meanwhile, these impurities have also been detected in a few non-sartan APIs and/or medicinal products.

The proposed methodology encompassed a) the construction of a fishbone diagram, to identify and organize the possible sources of nitrosamines in medicines, taking into consideration the information gathered from a literature review, and b) the use of the risk assessment tool Failure Mode Effects Analysis (FMEA) to determine the risk of finding nitrosamine impurities in oral dosages form.

Critical compound combinations responsible for nitrosamine formation in sartans given below table

DEA – diethylamine, TEA - triethylamine, DIPEA - diisopropylethylamine [Hünig's base], NMP - N- methylpyrrolidone, MBA – methybutylamine, NMPA - N-nitrosomethylphenylamine, TBAB- tetrabutylammonium bromide, DBA – dibutylamine and TBA – tributylamine.

The Limits established for some specific nitrosamines.

So far nitrosamine impurities have also been identified in batches of pioglitazone hydrochloride, ranitidine (and nizatidine outside EU), metformin and rifampicin (and rifapentine in the USA).

Fishbone diagram of the possible root causes for the presence of nitrosamine impurities in medicines (where DP stands for drug product).

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