Healthcare Shake-Up: How the Latest Innovations Are Making Meds Safer and Eco-Friendly!

Globally, injectable drug products accounted for over $530 billion dollars in sales in 2022. This will nearly double by 2032. More importantly, injectables save millions of lives every year – from insulin to heparin to vaccinations, modern medicine would simply not exist without them.

In the packaging of these life-saving products, elastomeric components (stoppers and plungers) are typically used as closures for glass or polymer vial, syringe, and cartridge systems. Choosing the correct elastomeric components can be tough – there are many factors to consider, and competing products on the market can make the decision confusing.

In this blog series, we will examine seven criteria to weigh when picking rubber closure components, including Particulate, Extractables & Leachables, Regulatory, Functionality, Engineering Capabilities, Container Closure Integrity, and Total Quality.

This final post will explain Total Quality, a broad view of quality-related factors that impact parenteral packaging.

Introduction to Quality

The term “quality” can refer to a certain aspect, caliber, or agreed-upon standard that something should meet. In this context, quality refers to measures of a product’s physical, chemical, or biological state that are previously agreed upon by manufacturer and recipient. A deviation from this agreed-upon state can result in action by the recipient, manufacturer, or both.

Physical Quality 

The physical quality of a product is ruled by its mold. This creates the size, shape, and geometry of a product, all of which are detailed in the product’s drawing. A drawing is a promise from the manufacturer of the physical quality of a component; drawings will contain nominal (or ‘goal’) dimensions, as well as tolerances within which the component must exist. Tolerances may be determined by the manufacturer (sometimes in collaboration with the recipient), but are guided by DIN-ISO 3302, “Tolerances for Rubber Molded Parts”. Though it is possible and acceptable to deviate from the tolerances set by ISO, the default assumption for any tolerance-less dimension on a drawing is to refer to this standard.

To reduce the likelihood of shipping products with physical defects or inconsistencies, some manufacturers provide the option of camera inspection. In a 100% camera inspection environment, all components will be checked by cameras at different angles. Any incorrectly molded pieces will then be ejected from the line, leaving higher-quality product to be bagged and sent to the customer.

Chemical Quality

Most elastomer manufacturers have documents defining the attributes of their formulations, films, and coatings. Any that apply to a specific product should be provided to purchasers. At Datwyler, Compound Data Sheets detail compliance information, identification information (such as ATR-FTIR spectra), and physical properties (such as hardness) for individual formulations.

Chemical quality deviations are incredibly rare because formulation recipes are highly controlled. Amounts, ingredient origins, and processing steps are strictly followed (and sometimes automated to increase consistency) to maintain consistent products. The same is true of films and coatings, whether produced by the elastomer manufacturer or outsourced.

After manufacturing and coating, product will often undergo final treatments such as wash, steam sterilization, and/or gamma sterilization. These contribute to both the chemical and biological quality of a product. Final treatments should be detailed in the product description of an item and may even be contained within an item’s name. The following terms are used at Datwyler and are common throughout the industry:

• Bulk
  • Definition: Conventionally, “bulk” is used to describe items purchased in large quantities. In the pharmaceutical packaging industry, “bulk” can also be used to refer to product that has not been washed or sterilized.
• RTS / RFS / RS
  • Acronym Meaning: Ready to Sterilize / Ready for Sterilization
  • Definition: “Ready to Sterilize” product has been washed but not sterilized.
• RTU / RU
  • Acronym Meaning: Ready to Use
  • Definition: “Ready to Use” product has been washed and sterilized, and is ready to be used in pharmaceutical fill/finish.

All elastomeric packaging components that make direct contact with drug product must be sterilized; relevant compendia include ISO 17665, ISO 11137, and USP <797>.

The cleanliness of parenteral products is commonly addressed in quality agreements and technical specifications. Three important criteria include Particulate (addressed in the first post in this series), Endotoxin, and Bioburden, all of which should be minimized as much as possible:

• Particulate
  • Definition: “Mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions” (USP)
  • Compendia: USP <788>, USP <789>, USP <790>, EP 2.9.19, EP 2.9.20, JP 6.06, ISO 8871-3
  • Context: Particulate can be found on product provided bulk, washed, or sterilized. However, wash and sterilization processes can help to decrease the amount of particulate present.
• Bioburden
  • Definition: The number of bacteria living on a surface.
  • Compendia: USP <61>, EP 2.6.12
  • Context: Bioburden should not be present on sterile product. Its destruction creates endotoxin. Nonsterile product is commonly tested for bioburden. Sterile product may be tested for bioburden, but parametric release is more commonly used.
• Endotoxin
  • Definition: Toxic heat-stable lipopolysaccharides released from a cell when the cell is destroyed; endotoxins are considered pyrogens.
  • Compendia: USP <85>, EP 2.6.14
  • Context: Endotoxin may be created from the destruction of bioburden. However, it is still not desirable, and should be limited as much as possible. Endotoxin levels may be tested on either sterile or nonsterile product.

Sampling

Sampling is commonly performed to ensure product abides by promised quality standards. A small representative number of pieces will be taken from a larger batch of components and tested against relevant standards. This may include dimensional, physical, visual, chemical, and/or biological analysis. “Retains” are samples kept by either the manufacturer post-production or the fill/finish plant post-fill, in case of future quality issues.

The method of sampling and number of samples that ought to be tested are both defined in ISO 2859-1. ANSI/ASQC Z-1.4 further defines sampling procedures based on attributes of conformity.

Applicable Standards

Important compendia related to quality include:

• ANSI/ASQC Z-1.4 “Sampling Procedures and Tables for Inspection by Attributes”
• ISO 2859-1 “Sampling Procedures for Inspection by Attributes”
• ISO 8871-3 “Elastomeric parts for parenterals and for devices for pharmaceutical use – Determination of released-particle count”
• ISO 17665 “Sterilization of health care products – Moist Heat – Requirements for development, validation and routine control of a sterilization process for medical devices”
• ISO 11137-1 “Sterilization of health care products – Radiation – Requirements for development, validation and routine control of a sterilization process for medical devices”
• DIN-ISO 3302 “Tolerances for Rubber Molded Parts”
• USP <61> “Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests”
• USP <85> “Bacterial Endotoxin”
• USP <788> “Particulate Matter in Injections”
• USP <789> “Particle Matter in Ophthalmic Solutions"
• USP <790> “Visible Particulates in Injections”
• USP <797> “Pharmaceutical Compounding – Sterile Preparations”
• EP 2.6.12 “Microbiological Examinations of Non-Sterile Products (Total Viable Aerobic Count)”
• EP 2.6.14 “Bacterial Endotoxins”
• EP 2.9.19 “Particulate contamination: sub-visible particles”
• EP 2.9.20 “Particulate contamination: visible particles”
• JP 6.06 “Foreign Insoluble Matter Test for Injections”

Conclusions

Overall, Total Quality is an important aspect of parenteral packaging components. Ensuring high levels of quality can help prevent issues down the line – including at the site of administration. In the creation 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.

Throughout this PERFECTing series, we have analyzed Particulate, Extractables & Leachables, Regulatory, Functionality, Engineering Capabilities, Container Closure Integrity, and Total Quality. Please feel free to reach out to your local Datwyler representative with questions on these, or any other topics.

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