Enhancement of an Auto-Injector Device for Self-Administration of Etanercept in Patients With Rheumatoid Arthritis Confers Emotional and Functional Benefits.

INTRODUCTION: Etanercept is effective in the management of rheumatoid arthritis (RA) and can be self-administered via an auto-injector. While these devices are generally well accepted, some patients are not comfortable with the process of self-administration; this has been cited as a reason for discontinuation of biologic treatment. Alternative routes of administration (e.g., infusion) are more resource intensive. The aim of this analysis was to explore the attributes of auto-injection devices that impact patient confidence and ability to self-administer. METHODS: Patients with RA (n = 168) and healthcare providers (n = 82) in Belgium, Germany, Japan, Spain, and the UK were interviewed (n = 250 overall). Mock injection procedures were carried out using an auto-injector device with the addition of a sleeve with a wider rubber grip. Importance of and performance of the device against a range attributes were captured using a Likert scale (1-7). Disease severity was captured using the Cochin hand function scale. RESULTS: Device attributes reported by patients to be most important were 'use without assistance' 'ease of administration', 'ease of operation', and 'ease of grip'. The device with additional sleeve performed strongly against these attributes, scoring 6.9 (out of 7), 6.8, 6.8, and 6.6, respectively with no difference observed between countries. Nurses and physicians reported similar responses. Qualitatively, patients reported that stability and grip provided a sense of control and reduced anxiety. Similar overall 'ease of operation' was reported between patients with mild (n = 89) or moderate/severe (n = 71) disease (score 6.4 vs. 6.5, respectively). CONCLUSIONS: The auto-injector plus sleeve performed strongly against key attributes even in patients with moderate/severe RA and patients with reduced grip strength. The robust grip improved patient confidence and reduced injection-related anxiety. This may be beneficial in patients who are anxious about self-administration, those new to self-administration, and potentially in patients with reduced hand dexterity as a result of either advanced disease or a painful day.

Etanercept is a medicine used to treat rheumatoid arthritis that is given by injection. It can be delivered by patients themselves, in their own homes, using an auto-injection device that looks like a pen. Some patients are not comfortable with the process of self-injecting. Other patients have severe arthritis in their hands that stops them from carrying out self-injection. One auto-injection device (MyClic) has been enhanced by the addition of a sleeve that fits over the top of the pen. This was shown to 168 patients with rheumatoid arthritis, who already use the MyClic 'pen' and 82 doctors and nurses in five countries (Belgium, Germany, Japan, Spain, and the UK). Patients, nurses, and doctors said what they believed to be the most important features of a self-injection device. Generally, patients, nurses, and doctors from the different countries had similar views. Next, the participants scored the modified auto-injection device against those features. The device plus sleeve scored highly, meaning that patients, nurses, and doctors believed it would work well for the patient population tested. Many patients said that with the added sleeve, the self-injection device was more stable and they were able to grip it better. This helped to make patients feel in control and reduced any anxiety or fear they were feeling about their self-injection. This suggests that the sleeve is a useful addition and may be particularly useful for patients who are nervous about self-injection or have difficulty gripping self-injection devices because of their arthritis.

Variability of intended copies for etanercept (Enbrel®): Data on multiple batches of seven products.

Fusion protein and monoclonal antibody-based tumor necrosis factor (TNF) inhibitors represent established treatment options for a range of inflammatory diseases. Regulatory authorities have outlined the structural characterization and clinical assessments necessary to establish biosimilarity of a new biotherapeutic product with the innovator biologic drug. Biologic products that would not meet the minimum World Health Organization's standard for evaluation of similar biotherapeutic products are available in some countries; in some cases relevant data to assess biosimilarity and appropriate regulatory approval pathways are lacking. Batches of seven intended copy (IC) products for etanercept (Enbrel®) were subjected to a subset of test methods used in the routine release and heightened characterization of Enbrel®, to determine key attributes of identity, quality, purity, strength, and activity. While a number of quality attributes of the IC lots tested met the release specifications for Enbrel®, none fell within these limits across all methods performed, and there were no IC lots that satisfied the criteria typically applied by the innovator to support comparability with Enbrel®. Although the consequences of these differences are largely unknown, the potential for unanticipated clinical outcomes should not be overlooked.

Manufacturing history of etanercept (Enbrel®): Consistency of product quality through major process revisions.

Etanercept (ETN) (Enbrel®) is a soluble protein that binds to, and specifically inhibits, tumor necrosis factor (TNF), a proinflammatory cytokine. ETN is synthesized in Chinese hamster ovary cells by recombinant DNA technology as a fusion protein, with a fully human TNFRII ectodomain linked to the Fc portion of human IgG1. Successful manufacture of biologics, such as ETN, requires sophisticated process and product understanding, as well as meticulous control of operations to maintain product consistency. The objective of this evaluation was to show that the product profile of ETN drug substance (DS) has been consistent over the course of production. Multiple orthogonal biochemical analyses, which included evaluation of attributes indicative of product purity, potency, and quality, were assessed on >2,000 batches of ETN from three sites of DS manufacture, during the period 1998-2015. Based on the key quality attributes of product purity (assessed by hydrophobic interaction chromatography HPLC), binding activity (to TNF by ELISA), potency (inhibition of TNF-induced apoptosis by cell-based bioassay) and quality (N-linked oligosaccharide map), we show that the integrity of ETN DS has remained consistent over time. This consistency was maintained through three major enhancements to the initial process of manufacturing that were supported by detailed comparability assessments, and approved by the European Medicines Agency. Examination of results for all major quality attributes for ETN DS indicates a highly consistent process for over 18 years and throughout changes to the manufacturing process, without affecting safety and efficacy, as demonstrated across a wide range of clinical trials of ETN in multiple inflammatory diseases.

Etanercept (Enbrel®) alternative storage at ambient temperature.

BACKGROUND: Biologic disease-modifying antirheumatic drugs, including tumor necrosis factor inhibitors such as etanercept (Enbrel®), have improved outcomes for patients with rheumatic and other inflammatory diseases, with sustained remission being the optimal goal for patients with rheumatoid arthritis. Flexible and convenient treatment options, compatible with modern lifestyle, are important in helping patients maintain treatment and manage their disease. Etanercept drug product (DP) is available in lyophilized powder (Lyo) for solution injection, prefilled syringe, and prefilled pen presentations and is typically stored under refrigerated conditions. We aimed to generate a comprehensive analytical data package from stability testing of key quality attributes, consistent with regulatory requirements, to determine whether the product profile of etanercept is maintained at ambient temperature. METHODS: Test methods assessing key attributes of purity, quality, potency, and safety were performed over time, following storage of etanercept DP presentations under a range of conditions. RESULTS: Results and statistical analysis from stability testing (based on size exclusion high-performance liquid chromatography, hydrophobic interaction chromatography, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis Coomassie) across all etanercept presentations (10 and 25 mg/vial Lyo DP; 25 and 50 mg prefilled syringe DP; 50 mg prefilled pen DP) showed key stability-indicating parameters were within acceptable limits through the alternative storage condition of 25°C±2°C for 1 month. CONCLUSION: Stability testing performed in line with regulatory requirements supports a single period of storage for etanercept DP at an alternative storage condition of 25°C±2°C for up to 1 month within the approved expiry of the product. This alternative storage condition represents further innovation in the etanercept product lifecycle, providing greater flexibility and enhanced overall convenience for patients.

Differentiating biosimilarity and comparability in biotherapeutics.

The manufacture of biologics is a complex process involving numerous steps. Over time, differences may arise as a result of planned changes to the manufacturing processes of a biologic from the same manufacturer. Comparability is the regulatory process that outlines the scope of an assessment required of an already licensed biologic after a manufacturing process change made by the same manufacturer. The aim of a comparability assessment is to demonstrate that any pre-manufacturing and post-manufacturing changes have no adverse impact on quality, safety, and efficacy of the biologic. A comparability assessment is distinct from a biosimilarity assessment, which involves extensive assessment of a biologic that is highly similar to the originator (reference product) in terms of quality, safety, and efficacy. The US Food and Drug Administration, European Medicines Agency, and World Health Organization have applied the fundamental comparability concepts into their respective biosimilarity guidance documents. In this review, we examine the rationale behind the distinct, highly regulated approval processes governing changes that may occur over time to an originator biologic due to planned manufacturing changes (as described by a comparability exercise) and those that outline the approval of a proposed biosimilar drug, based on its relationship with the reference product (biosimilarity evaluations).

Viral clearance studies on new and used chromatography resins: critical review of a large dataset.

Viral clearance studies for naïve and maximally cycled chromatographic resins used for cGMP recombinant protein production are reviewed for three products, comprising 10 different chromatographic steps, including affinity, ion exchange, immobilized metal ion affinity, and hydrophobic interaction modes. Thirty-two separate studies were conducted (over 90 runs in total). No consistent reductions in model virus clearance were observed with used resins. The results address the reproducibility of virus clearance studies conducted by different scientists over several years at multiple contract labs. The log reduction values (LRVs) are typically within 0.5 LRVs for new and used resin, but varied as much as 2 LRVs for resins showing no functional deterioration. This relatively large difference is not believed to reflect resin changes, but highlights the challenges encountered in modeling column clearance. Production column performance and cleaning efficacy are demonstrated for these steps by trending mock runs, impurity removal and product recovery. No deterioration in cGMP column performance is seen over the established resin lifetimes, confirming that the resin regeneration and sanitization procedures restore the resins to a suitable initial state without damage. It is proposed that for some chromatography steps, the combination of lab-scale cycling studies confirming consistent performance throughout the resin lifetime and monitoring of cGMP manufacturing preclude the need for virus clearance studies on maximally cycled resin.