WHO GMP for Excipients Used in Pharmaceutical Products

WHO GMP for Excipients Used in Pharmaceutical Products - Appendix 2: List of Examples of High-Risk Excipients

Submission for Comments

• Comments on the working document can be submitted through the online platform, PleaseReview™ (https://who.pleasereview.net/Main/Default.aspx?action=loaddocument&reviewid=245).
• If not registered or included in the mailing list, request with full name, email address, and organization/affiliation to nsp@who.int.
• For technical questions, contact Dr. Steve Estevao Cordeiro, Technical Officer, Norms and Standards for Pharmaceuticals (estevaos@who.int), with a copy to Ms. Bezawit Kibret (Kibretb@who.int, nsp@who.int).
• Deadline for comments: 09 June 2024. Only comments received by this deadline will be considered for the preparation of the document.

Document Information

• This is a draft document; content is not final and may undergo revisions.
• The document may not be reviewed, quoted, reproduced, or adapted in part or whole without permission from WHO.
• Send permission requests to Ms. Bezawit Kibret, Norms and Standards for Pharmaceuticals
  • Contact: kibretb@who.int
  • Address: Department of Health Products Policy and Standards, World Health Organization, CH-1211 Geneva 27, Switzerland.
• This draft does not imply any opinion on legal status of countries or territories, nor does it endorse specific products.
• WHO is not liable for damages arising from the use of this document.

Schedule for Draft Working Document QAS/24.944

• Preparation of first draft: December 2023
• Review and finalization with an informal drafting group: February 2024
• Mailing to the Expert Advisory Panel and public posting: April 2024
• Consolidation of comments and feedback review: May – June 2024
• Virtual meeting for discussion of feedback: June – July 2024
• Preparation for discussion and possible adoption by ECSPP: August – September 2024
• Presentation at the Fifty-seventh meeting of ECSPP: October 2024
• Follow-up actions as required.

Purpose of Appendix 2

• Provides a list of examples of high-risk excipients and contaminants.
• Alerts manufacturers to take control measures for the safety, purity, and quality of excipients and finished products.
• The list will be updated periodically.
• Manufacturers must perform risk assessments to identify potential harms associated with production, control, storage, distribution, and use of excipients.
• Implement appropriate controls to mitigate risks and harm.
  • Minimum aspects to consider include:
  • Nature of the material
  • Risk of contamination during production, other chemicals, or solvents
  • Contamination from industrial products
  • Unintentional or intentional contamination by suppliers or packaging.

Manufacturer Responsibilities

• Manufacturers, suppliers, and distributors of excipients must:

  • Perform risk assessments to identify potential risks in raw materials for excipient production.
  • Purchase appropriate quality ingredients.
  • Use solvents of appropriate quality.
  • Conduct testing to determine whether excipients contain unwanted contaminants.
  • Provide assurance of excipient quality and purity with certificates of analysis based on testing results.

• For finished pharmaceutical products containing high-risk excipients, the responsibilities include:

  • Performing risk assessments specific to excipient use in finished products.
  • Sourcing pharmaceutical-grade excipients from qualified suppliers.
  • Conducting comprehensive testing upon receipt of supplies.
  • Maintaining accurate records of material purchases and testing.
  • Monitoring for signs of falsification or degradation.
  • Ensuring traceability back to the original excipient manufacturer.

Specific Examples of High-Risk Excipients

• A finite list of high-risk excipients includes:
  • Ethyl alcohol (ethanol)
  • Glycerol
  • Hydrogenated starch hydrolysate (HSH)
  • Isopropyl alcohol (IPA)
  • Maltitol
  • Propylene glycol (PG)
  • Sorbitol
• These will be updated periodically.

2.1 Ethyl Alcohol (Ethanol)

• Introduction and Use:
  • Clear, colorless, volatile organic compound; highly flammable; used in cough and cold medicine, mouthwashes, and sanitizers.
• Toxicity:
  • Overdose can cause mental confusion, vomiting, seizures, slowed heart rate and breathing, brain damage, and death.
• Risks and Controls:
  • Risk of methanol contamination due to increased demand.
  • Contamination may arise from supply chain issues.
  • Controls to include supply chain management and testing for purity, especially methanol levels (Limit: NMT 200 ppm).

2.2 Glycerol

• Introduction and Use:
  • Odorless, natural alcohol used as a solvent and sweetener in medicinal products.
• Toxicity:
  • Side effects include nausea, dizziness, and gastrointestinal discomfort.
• Risks and Controls:
  • High-risk due to potential contamination with DEG (diethylene glycol).
  • Testing for purity and contaminants should be mandated prior to distribution.
  • Analytical methods for DEG detection include gas chromatography due to the insufficiency of infrared spectroscopy methods.

2.3 Hydrogenated Starch Hydrolysates (HSH)

• Introduction and Use:
  • Commonly used in OTC medicines; mixtures of sorbitol, maltitol, and sugar alcohols.
• Toxicity:
  • High-risk due to contamination with DEG or EG.
• Risks and Controls:
  • Testing for contamination before distribution.

2.4 Maltitol

• Introduction and Use:
  • Sugar alcohol often used in cough and cold medications.
• Risks and Controls:
  • Monitor for DEG and ensure appropriate testing practices.

2.5 Propylene Glycol (PG)

• Introduction and Use:
  • Colorless, nearly odorless organic compound; used in food, cosmetics, and pharmaceuticals.
• Toxicity:
  • Can be toxic to kidneys and liver, especially children.
• Risks and Controls:
  • Implement controls to prevent contamination and ensure suitable quality.

2.6 Sorbitol

• Introduction and Use:
  • Sugar alcohol used as a sweetener in various medications.
• Toxicity:
  • Not considered toxic.
• Risks and Controls:
  • Ensure measures are in place to prevent contamination.

2.7 Other Known Contaminated Excipients

• Include:
  • Polyethylene Glycol (various molecular weights)
  • Diethylene Glycol Stearates
  • Polyoxyl Castor Oil
  • Polysorbate variants

List of Contaminants

• Include:
  • Diethylene Glycol (DEG)
  • Ethylene Glycol (EG)
  • Nitrosamines and their impurities

3.1 Diethylene Glycol (DEG)

• Introduction and Use:
  • Industrial contaminant, not approved for use in food or pharmaceutical applications.
• Toxicity:
  • Can cause severe kidney damage and possible fatality, particularly in children.
• Risks and Controls:
  • Degree of risk depends on supply chain control and rigorous testing for DEG presence.

3.2 Ethylene Glycol (EG)

• Introduction and Use:
  • Present in industrial chemicals and can be found in excipients inadvertently.
• Toxicity:
  • CNS depressant; dangerous upon ingestion leading to multiple organ failures.

3.3 Nitrosamines and Nitrosamine Impurity

• Introduction and Use:
  • Formed by reactions with nitrates and certain amines; carcinogenic potential.
• Risks and Controls:
  • Risk assessments necessary to evaluate possible nitrosamine formation during product development.

Recommendations

• All pharmaceutical excipients should comply with WHO GMP guidelines.
• Identify high-risk excipients and implement risk assessment procedures.
• Ensure excipients are purchased from reputable suppliers, with a critical focus on contamination control.
• Suggestive measures include:
  • Compliance with WHO GxP for all phases of excipient handling (production through distribution).
  • Specifications must meet pharmacopoeial standards with limits on impurities.
  • Maintain traceable certificates of analysis for every batch of excipient.
  • Training of personnel in GxP to mitigate contamination risks.
• All questionable consignment batches should be rejected if impurities exceed safety limits.