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E&L case study


[Referance : 4720395]

page1 : Results of ongoing stability studies should be submitted throughout the dating period, as they become available, including the results of stability studies from the first three production lots.

page8 : To perform extractables/leachables studies and risk assessments to evaluate leachables from the container closure system(s) and manufacturing product conduct surfaces of ansuvimab drug substance and drug product and assess the potential impact of leachables on product quality at the end of drug product shelf-life. The analyses will be performed using drug substance and drug product lot(s) and/or representative samples (e.g.___________ if justified) analyzed at appropriate time points, including at the end of drug product shelf life. Appropriate methods will be used to detect, identify, and quantify organic non-volatile, volatile and semi-volatile species, and metals. Characterization of the potential impact on product quality will be assessed using adequate analytical methods. Complete data and the risk evaluation for the potential impact of leachables on product safety and quality will be provided in the final study report per 21 CFR 601.12.

[Referance : 4285070]

Extractables Testing Strategy: The Sponsor conducted an extractables study with two pre-filled glass syringes. The study was performed for another Sandoz Biopharmaceutical product (using the same syringe) and were applied to GP2017. Placebo solution was provided by the Sponsor for the extractables study. An extractables screening was conducted for known and unknown compounds present in the two different rubber materials of the syringe and in the needle adhesive. The core part of the study consisted of a set of forced extraction experiments followed by subsequent analyses of the extracts by GC/MS with and without derivatization (for semi- volatiles compounds), by HPLC/UV/MS (for non-volatile and polar compounds), by headspace-GC/MS (for volatile compounds), and by ICP-MS (for elemental analysis). The study utilized guidelines of Product Quality Research Institute (PQRI) best practices for extractable and leachable studies for orally inhaled and nasal products.

A general screening of leachables was conducted to determine the risk of exposure to the patient. No single compounds were identified in the extractables evaluation for further testing in the leachables studies. The SCT was converted into an AET based on the number of doses per day. All compounds over the AET were toxicologically evaluated. Only two leachables were detected in stability studies covering up to 32 months of storage at intended conditions.

[BLA #761071 - Reviewer : Brett Jones, PhD]

Leachables Studies

A leachables assessment was conducted on four lots of GP2017 (40 mg/ 0.8 mL solution for injection) drug product. All samples were stored in the original containers and in a horizontal position (i.e., the drug product solution was in contact with the stopper during the entire storage time). A summary of the GP2017 leachables test method program is shown in the table below.

(Excerpt from Sponsor's submission)

Table 6. Summary of GP2017 leachables stability program

Batch Packaging Storage Conditions Testing points*
[°C] [unit] months
Real Time Tests #7005939 Syringe 5±3 32
Real Time Tests #7006715 Syringe 5±3 24, 30
Real Time Tests #7007467 Syringe 5±3 8, 12, 24, 30
Real Time Tests #7007741 Syringe 5±3 2**, 12, 24, 30

* Testing dates will be calculated from filling dates (see Table 3-1) as T = 0 month. The study start date will not be considered.

** measured after 4 months (see section 7.5)

대한민국 식품의약품안전처

[대한민국 식품의약품 안전처 MFDS]

Extractables and Leachables 자료제출 (원액 / 완제 용기적합성)


[Referance : 4660463]

Primary leachables stability study tested 3 ***** manufactured ****** lots. Data from samples under accelerated stability at 40°C/75% RH and at the intended storage condition (25°C/60% RH) from release to 6 months were provided with this resubmission. The Applicant noted testing through 36 months is ongoing..