Materials management and impact on extractables and leachables

According to these guidelines (1), these changes may require subsequent approval under Section 506A of the US Food, Drug, and Cosmetic Act and Code of Federal Regulations (CFR) Title 21 a.314.70 (21 CFR 314.70) (2).

These documents describe the classification of a change (minor to major) and the regulatory requirements to manage these different levels of change.

A minor change, according to FDA guidelines, has “minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product, as these factors may be related to the ‘safety or efficacy of the drug product’ (1 ).

In CFR Title 21, FDA indicates that the applicant must describe minor changes in the next annual report (2).

In an FDA guideline, a moderate change has “moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product because these factors may be related to the safety or efficacy of the drug product” (1).

Typically, these changes require the drug manufacturer to submit a supplement called Changes Made in 30 Days (CBE-30). This supplement will contain information describing the effects of the change. The drugmaker must wait 30 days after the CBE-30 submission before implementing the change and must not implement the change if the FDA responds with a request for additional information to support the change.

Finally, the FDA states that a major change has “substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product because these factors may relate to the safety or efficacy of the medicinal product” (1 ).

These changes require the drug manufacturer to submit a Prior Approval Supplement (PAS). The drugmaker must await FDA approval of the PAS before implementing the change.

Historical hardware changes

Hardware changes can impact both product quality and the patient. There are a few well-known examples. The most cited example relates to the period from 1998 to 2002, when there was an increased incidence of aplasia of antibody-positive pure red blood cells in patients receiving subcutaneous administration of EPREX ( epoetinum alfa). At the time, two simultaneous changes occurred. First, the drug product formulation was changed to include polysorbate 80; and second, the coated plug was replaced with an uncoated one (3). Additional compounds were observed during leaching analysis of the new product. However, these leachable compounds were only observed when the product contained both polysorbate 80 and used the uncoated cap, but these new leachable species were not observed when the two were used separately.

Early in E&L testing, prior to proper change management, a change in material composition was first known during an ongoing test and a new extractable profile – or worse, a leachable profile was observed. Since leachables generally take a long time to form, this observation implied that a change had occurred, potentially, several months prior. This first E&L observation also precedes the founding document of the Product Quality Research Institute on Safe Thresholds and Best Practices for Extractables and Leachables in Oral and Nasal Inhaled Drug Products in 2006(4). This recommendation set the stage for E&L testing in the years that followed. Although only a recommendation, it was written with input from the FDA and Health Canada.

Aerosols and sprays for inhalation

Aerosols and inhalation vaporizers are considered to have the highest likelihood of packaging component-dosage form interaction and the highest degree of concern based on the route of administration. As such, it is not too surprising that most of the early work on regulatory requirements focused on oral and nasal inhaled pharmaceuticals. It was groups such as the International Pharmaceutical Aerosol Consortium on Regulation & Science that initiated and developed the supply chain interaction and understanding. The group’s initial work was published in the 2011 paper, “Recommended Baseline Requirements for Materials Used in Orally Inhaled and Nasal Drug Products (OINDP),” and a subsequent update was provided in 2017 (5).

Nor is it necessarily the direct container closure system that can cause patient safety and product quality issues. Around 2010, there were product recalls due to the wooden pallets on which the crates of product were stored. A biocide used to treat the pallets had degraded and one of its degradants, 2,4,6-tribromoanisole (TBA), had migrated into the products and contaminated them. TBA has a very low odor threshold, which means that very small amounts can cause unpleasant musty and musty aromas. A total of 55 million bottles of Tylenol were recalled over a six-month period in 2010 due to this issue (6). This incident led several pharmaceutical companies to stop using wooden pallets to transport products.

Single-use systems

Hardware changes can potentially have more impact on biologics that are manufactured with single-use systems. A particular biological product may be affected by small amounts of leachable species. The exact mechanism of this is unknown. The most cited example is “Identification of a Leachable Compound Detrimental to Cell Growth in Single-Use Bioprocess Containers”, an Amgen research article (7). The researchers found that a minute amount of a breakdown product of a common antioxidant, Irgafos 168, was detrimental to cell growth. The level of this antioxidant was well below typical screening levels that would be needed due to typical toxicological issues.

Organic Products

Additionally, it is well known that biologics/peptides pose a significant risk of reaction with E&L. The greatest risk concerns the formation of covalent bonds for which there are several well-known examples. An example includes the reaction of the common leachable from halobutyl rubbers. This leachable, the C13 halogenated aliphatic, can undergo SNOT2 reaction with the protein, forming a new chemical species.

Acrylic acid, which can be used as a glue in syringes, is known to modify peptides either through the lysine side chain or histidine through a Michael addition reaction. The level of modification has been reported at 0.2-5% of a range of proteins (8).

Other reactions may occur, such as the basic Schiff reaction of butylated hydroxytoluene degradation products and acylation reactions (9). It is often observed when materials undergo sterilization, which leads to the degradation of additives, such as antioxidants, and the formation of potential reaction products. It is important to mention that if these antioxidants were not present, the polymer would degrade very quickly and the container closure would no longer be usable. It is therefore likely that any changes to the materials used with biologics could have a greater impact on patient safety (whether due to safety or efficacy) than those with small molecules or devices. medical. Further work is underway to help identify potential issues with common leachables.

The future

Cumulatively, this leads to the importance of understanding the materials used in container closure systems and biologics and peptide manufacturing systems to avoid potential problems, rather than solving them after the fact. Having appropriate data on materials used for biologics/peptides can help reduce the risk of interaction with leachables. Appropriate data includes extractable data obtained from studies that are undertaken on sterilized/processed materials under appropriate extraction conditions (where extractables can be correlated with leachables) with sufficient sensitivity.

What does the future hold? As mentioned at the beginning of the article, change is inevitable, but new potential changes are coming. There is a push for greener materials and the reduction of single-use plastics. Will additive packages change to allow polymers to be depolymerized back to starting monomers so they can potentially be used as virgin materials rather than recycled? It is through an understanding of the likelihood and impact of change that potential patient safety can be understood and mitigated.


1.FDA, Guidance for industry, amendments to an approved NDA or ANDA (CDER, April 2004).
2. CFR Title 21, Part 314, Vol. 5, subchapter D (Government Printing Office, Washington, DC), accessed June 2022.
3. K. Boven et al., Kidney International 67(6) 2346–2353 (2005).
4. PQRI, Safety Thresholds and Best Practices for Extractables and Leachables in Oral and Nasal Inhaled Pharmaceuticals (8 September 2006).
5. IPAC-RS, “Recommended Basic Requirements for Materials Used in Oral and Nasal Inhalation Medicinal Products (OINDP),” (February 9, 2017).
6. G. Miller and E. Teichert, “The Battered Brand: A Tylenol Recall Timeline,” (January 18, 2011).
7. M. Hammond et al., PDA JPST 67(2) 123–134 (2013).
8. D. Liu et al., PDA JPST 66(1) 12–9 (2012).
9. K.Li et al., PDA JPST 69(5) 590–619 (October 2015).

About the Author

Andrew Feilden is Element’s European E&L Strategic Director.

Item details

Pharmaceutical technology
Volume 46, number 7
July 2022
Pages: 48 to 51


When referencing this article, please cite it as A. Feilden, “Material Management and the Impact on Extractables and Leachables,” Pharmaceutical technology 46(7) 48–51 (2022).

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