Ensuring Safety: Regulatory Choices for Pharmaceutical Closures

In the latest post in our series P.E.R.F.E.C.T.-ing the Pharmaceutical Packaging Selection Process, we evaluate Regulatory requirements, which are crucial to consider when introducing commercial pharmaceutical drugs to the market.

An Introduction to Regulatory 

Every country has laws. In the pharmaceutical packaging sector, relevant laws are put forth by regulatory authorities to protect the health and safety of their citizens. There are also international guidelines and technical reports that play a part in standardizing these laws, addressing how certain terms are defined, which components and systems need to be tested in which manners, and how companies might test to show compliance.

It is important to recognize the difference between institutions who develop standards and institutions who enforce standards. Typically, the enforcing institutions are the health authorities who receive drug applications, review them, and issue authorizations to allow pharmaceutical products to be made commercially available in authorized markets. For example, in the United States, the United States Pharmacopoeia (USP) is the entity that develops standards. These are then enforced by the Food and Drug Administration (FDA).

Globally Recognized Regulatory Bodies

Below, a table depicts globally recognized regulatory bodies, including standardization and enforcement agencies:

Regulatory Standards

Though every country chooses which standards to adhere to, we will concentrate on the most globally recognized: the United States’ USP, Europe’s Ph. Eur., and Japan’s JP. Complying with these standards is a good indication that a product is on track to meeting standards in much of the world.

In pharmaceutical primary packaging, the standards most often considered include:

• Biocompatibility
  • USP <87> – Biological Reactivity Tests, In Vitro
    • This standard aims to determine the biological reactivity of a substance with live cells. If the substance is determined to be cytotoxic, it may not comply with USP 87.
    • Tests include Direct Contact, Agar Diffusion, and Elution Testing.
    • Elastomeric components used in pharmaceutical packaging should always pass USP <87> if used in the US market.
  • USP <88> – Biological Reactivity Tests, In Vivo
    • This standard applies only if a substance fails USP 87. At this point, in-vivo cytotoxicity must be evaluated.
    • Tests include Implantation, Intracutaneous Injection, or Systemic Injection.
  • JP 7.03
    • Cytotoxicity Test
      • This standard aims to determine the biological reactivity of a substance with live cells. If the substance is determined to be cytotoxic, it may not comply with JP 7.03.
      • Tests include Cell Lines and Culture Medium.
    • Acute System Toxicity
      • This standard applies only if a substance fails cytotoxicity testing.
      • Test includes directly exposing the substance to mice and observing effects. Weight loss, abnormality, and death result in a failure of the test.
• Chemical Properties
  • • • USP <381>
        • Appearance (Turbidity/Opalescence and Color), Acidity or Alkalinity, Absorbance, Reducing Substances, Extractable Zinc, Ammonium, Volatile Sulfides.
      • Eur. 3.2.9
        • Appearance, Acidity or Alkalinity, Absorbance, Reducing Substances, Ammonium, Extractable Zinc, Residue on Evaporation, Volatile Sulfides.
      • JP 7.03
        • Cadmium, Lead, Extractable Substances, Color, Transmittance, pH, Zinc, Reducing Substances, Residue on Evaporation, UV Spectrum.
• Functionality
  • • • • USP <381>
          • Penetrability, Fragmentation, Self-Sealing Capacity.
        • EP 3.2.9
          • Penetrability, Fragmentation, Self-Sealing Test.
• Silicone Oil Compliance
  • • • • USP – Dimethicone monograph
        • Eur. 3.1.8 General Chapter

International Agencies 

International agencies publish standards and guidance's as well. Below, a few of these agencies are listed alongside their abbreviations and purposes:

International Standards

Some international standards help to inform global expectations in lieu of patients safety. These include:

• ISO 10993-5 (Biocompatibility)
  • Assessment of in vitro cytotoxicity, specifying the incubation of cultured mammalian cells in contact with the component using appropriate biological parameters.
• ISO 8871-1 (Chemical Properties)
  • Guides evaluation of an elastomer’s chemical properties and extractables.
• ISO 48-4 (Hardness)
  • Method for determining shore hardness of vulcanized rubber.

General Ingredient and Impurities Information 

Latex

• In the beginning, there was the rubber tree (Hevea brasiliensis). Indigenous cultures of Mesoamerica used the rubber from these trees to make waterproofing materials for containers and textiles (when they weren’t using it to make balls for their games and sports). This naturally occurring rubber is now referred to as “natural rubber” or “natural rubber latex”, and also exists in the form of “dry natural rubber” or “DNR”.
• Due to latex allergies (which are actually allergies to the proteins and chemicals found in Hevea brasiliensis, and which are typically not triggered by synthetic rubber) health authorities recommend against using natural rubber latex in pharmaceutical packaging.
• At Datwyler, natural rubber latex is not used in any modern recommended formulations. However, some older formulations may contain dry natural rubber. In this case, allergens are removed from dry natural rubber during processing. Compound Data Sheets are available to confirm the status of individual formulations.
  
  

Nitrosamines

• Nitrosamines are organic compounds that contain a nitroso group bonded to a secondary amine; they tend to be carcinogenic in nonhuman animals and could cause harm to humans as well. They can be found in cigarettes and food preservatives. Nitrosamine statements can be found in Datwyler’s Compound Data Sheets.
• Related Compendia include:
  • ICH Q9
  • USP <1469>, ‘Nitrosamine Impurities’, December 2021
  • FDA Guidance to Industry ‘Control of Nitrosamine Impurities in Human Drugs’, September 2020
  • Health Canada ‘Guidance on Nitrosamine impurities in medications’, April 2022
  • EMEA/H/A-5(3)-1490, ‘Nitrosamine impurities in human medicinal products’
    • EMEA/409815/2020 Rev. 15, March 2023
  • EP 2.5.42, ‘N-nitrosamines in active substances’, January 2022
  • TRGS 552, ‘Krebserzeugende N-Nitrosamine der Kat 1A und 1B’, September 2018
    
    

Bovine Spongiform Encephalopathy / Transmissible Spongiform Encephalopathies (BSE/TSE)

• BSE and TSE are precursors of ‘mad cow disease’ and ‘chronic wasting disease’ found in cattle, sheep, and goats. They should thus not be present in any component related to parenteral packaging. The best way to ensure their avoidance is to refrain from using materials derived from animal products. Thus, elastomers should be derived from vegetable or synthetic products, or should undergo process controls to deactivate prions. BSE/TSE statements are included in Datwyler Compound Data Sheets. Related compendia include:
  • EMA/410/01
  • Eur. 5.2.8

Elemental Impurities

• Relevant elemental impurities typically looked for in elastomers include:
  
  

  Antimony	Copper	Nickel
  Arsenic	Lead	Vanadium
  Cadmium	Lithium	Zinc
  Cobalt	Mercury

Substances of Interest

• Some or all of the following substances may be notable to various regulatory agencies. Typically, the absence of such materials must be verified by an elastomer manufacturer or pharmaceutical producer:
  
  

  2-mercaptobenzothiazole(MCBT/MBT)and derivatives Aflatoxins Allergens (including gluten, lactose, sugar, peanuts, wheat, eggs, milk protein, sulfites, fish/shellfish, corn) Asbestos Azo- and Azoxy- compounds Benzoates Benzophenones Bisphenol A Diethanolamine Dimethylfumarate Free nanomaterials Galactomannan Gelatine Genetically Modified Organisms (GMOs) Hydrazines, triazines, azides Iodine Melamine

  Nitrating agents Nitroso-compounds Organomercurials Parabens Perfluoroalkyl substances (PFOA, PFOS) Persistent Organic Pollutants (POP) per EU pollutant regulation 2019/1021 Phthalates Polyvinyl Chloride (PVC) Propylene glycol Recycled materials Substances listed in RoHS 2, China RoHS, Restrictions of Hazardous Substances Directive 2011/65/EU Substances of Concern per California Prop 65 Substances of Very High Concern (SVHC) per REACH EC 1907/2006 Triphenyl phosphine oxide

Kosher, Halal, and Vegan Designations

• In some situations, it may be important to declare a product Kosher, Halal, or vegan. The simplest way to achieve all three simultaneously is to ensure that no products of human or animal origin are used in the production of a closure. Rubber pharmaceutical components are typically made from synthetically derived materials such as polymers, plasticizers, and additives, and from mined materials like clay, talc, and pigments.

Conclusions

Overall, Regulatory standards are important – and often mandatory – considerations when choosing an elastomeric closure for a pharmaceutical injectable. Requirements to prove the safety and efficacy of a drug system can help to prevent adverse events towards patients. In the manufacturing of life-saving drugs, life-threatening risks must be mitigated. Though choosing appropriate elastomeric components can be difficult, Datwyler is available to help guide our clients through the selection process.

Look for the next post in the PERFECTing series, in which Functionality will be addressed.

Sources:

https://www.futuremarketinsights.com/reports/injectable-drugs-market