Understanding Extractables & Leachables: Ensuring Product Safety with Datwyler

In the latest post in our series P.E.R.F.E.C.T.-ing the Pharmaceutical Packaging Selection Process, we explore the common challenges with extractables and leachables in pharmaceutical packaging and how to mitigate its occurrence.

An Introduction to Extractables and Leachables

Extractables and leachables (often referred to as “E&L”) are essential considerations in drug packaging. In this context, the term “extractables” refers to substances inherent to the rubber formulation which can be pulled out of components over time. “Leachables” refers to substances from rubber components which migrate into a drug product under normal storage conditions, specific to the pharmaceutical with which they are paired.

Using these definitions, we can see that a company which produces rubber components should have full knowledge of potential extractables, as they are inherent to the ingredients used in the creation of a rubber product. Leachables, however, are specific to the interactions between a single rubber formulation and a single drug product. Therefore, leachables must be evaluated for every individual combination thereof.

Understanding Typical Timelines for Extractables & Leachables Testing

Extractables and leachables are often some of the first testing pursued by a drug company searching for an appropriate elastomeric closure. As soon as the stopper or plunger is received, it is paired with the drug product (or an approximation thereof, with similar pH and excipients) and put into storage to demonstrate the long-term effects of contact between the two.

Sometimes, accelerated aging is performed to estimate what the effects may be after several years. Accelerated aging involves using higher-than-normal temperatures and humidity to replicate in a short period the effects that would typically be seen in a longer period at lower temperature and humidity. Accelerated aging can be performed over a timespan of months, rather than years.

From E to L: Evaluating Theoretical Extractables to Uncover Leachables

Reviewing theoretical extractables is the first step to evaluating leachables; however, it is also important to test the chosen pharmaceutical packaging system with each unique drug product. Pharmaceuticals can react with the rubber packaging components, as well as any substances pulled out of the rubber. Any resulting material can be considered a leachable.

Typically, packaging components are chosen out of a desire to limit the production of leachables. Sometimes, this can be done by choosing a low-extractables rubber; sometimes, by pairing rubber components with coatings and films to mitigate interactions between the rubber and the drug product. In some situations, leachables can actually provide a benefit to the drug packaging; chemical reactions may produce preservatives that help to stabilize the drug product. This is not usually the goal when evaluating leachables, but it is sometimes the reason why one rubber formulation may work better with a certain drug product than another.

Mitigating E&L Risks in Drug Products: A Comprehensive Approach

When considering E&L, the following should be targeted:

• The drug product does not lose any efficacy due to E&L.
• The drug product does not become dangerous to the patient due to E&L.
• Any substances formed in a reaction between the drug product and the packaging are not harmful to the patient.

A toxicologist may be employed to analyze shelf life leachables data and its potential risks to a patient. Any risks present must be multiplied by recommended dosage over a given period of time; therefore, something given once or rarely (like a vaccination) might have a different threshold for leachables than a daily (or multiple-times-daily) injection such as insulin. Indeed, different patient populations (such as infants, the elderly, or those with immunodeficiencies) may require different safety considerations as well. A third factor is route of injection; an intramuscular injection, for example, may have a different tolerance for leachables than an injection into an eye.

Taking into account the leachables observed while the product is on stability, the dose and frequency of the injection, the patient population, and the route of administration, each drug product can be individually evaluated for E&L risk.

Enhancing Drug Safety: Coatings vs. Films for E&L Prevention

One way to minimize E&L is to use a stopper or plunger with a coating or a film. This provides a physical barrier between the drug product and the rubber formulation, helping to decrease interactions between the two (and any undesirable substances that could result).

Coatings and films differ in physical presentation, though they are similar in intent and function. A “coating” is a liquid substance applied to a stopper or plunger after molding. A tumbling machine is loaded with molded rubber components and a set amount of coating is applied while they spin in the cycle. Sometimes, this happens through a lump deposit of coating at the beginning, followed by spinning; other times, a meticulous spraying process occurs inside of the machine, ensuring every inch of product is evenly coated.

“Films”, on the other hand, are applied in a way similar to lamination. A sheet of film is created separately from the elastomer. Then it is applied during the molding process and formed onto the rubber product. In this way, film can be precisely applied to only certain parts of the stopper or plunger. It is common for film to be applied to the drug-contact-side of serum vial stoppers, with the intention of mitigating E&L. However, an added benefit of films and coatings is their lubricity, which is helpful during fill/finish. Films may be added to the tops (or “non-drug-contact side”) of lyophilization stoppers, which will be in contact with lyo shelves, and which must not stick to them. Coatings, since they are applied to the entire elastomer, would also be helpful during the lyophilization process.

Relevant Compendia 

The compendia and guidances most crucial to understand in this space include:

• USP<1663> Assessment of Extractables Associated with Pharmaceutical Packaging Delivery Systems (2017)
• FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics (May 1999)
• EMA Guidelines on Plastic Immediate Packaging Materials (2005) (CPMP/QWP/4359/03-EMEA/CVMP/205/04)

Exploring Key Analytical Methods for Extractables Evaluation

The following analytical methods are commonly used to evaluate extractables:

• Headspace-Gas Chromatography / Gas Chromatography / Mass Spectrometry to determine Volatile Organic Compounds (VOC) and Semi-Volatile Organic Compounds (SVOC)
• High Resolution Accurate Mass – Ultra Performance Liquid Chromatography / Mass Spectrometry to determine Non-Volatile Organic Compounds and polar Non-Volatile Organic Compounds (NVOC, polar NVOC)
• Inductively Coupled Plasma / Optical Emission Spectroscopy / Mass Spectrometry
• Liquid Chromatography
• Ion Chromatography

Conclusions

Overall, Extractables & Leachables are vital touchstones when choosing an elastomeric closure for a pharmaceutical injectable. Reducing the risk of harmful extractables and leachables can help to promote a higher-quality product and lower the chance of harm to the end-user. 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.

Look for the next post in the P.E.R.F.E.C.T.-ing the Pharmaceutical Packaging Selection Process series, in which Regulatory will be addressed.

Sources

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