Principles for Management of Extractables and Leachables in Ophthalmic Drug Products.

Ophthalmic solutions and suspensions have long been classified into a high-risk category with respect to concerns over extractables and leachables (E&L), though specific guidance on the management of leachables in these products is generally absent from regulatory authorities or the scientific literature. As a result, ophthalmic drug products (ODPs) were originally included in the scope of the Product Quality Research Institute Leachables and Extractables Working Group for Parenteral and Ophthalmic Drug Products (PQRI-PODP). Relative to other high concern dosage forms such as metered-dose inhalers or injectables, ODPs possess unique challenges with respect to the nature of impactful E&L as well as the safety assessment of leachables. For example, extensive use of semipermeable low-density polyethylene primary packaging for ODPs necessitates a strong focus on E&L from secondary packaging sources. For safety assessment, a key challenge is the lack of a sufficient database developed on all relevant ophthalmic toxicity endpoints. As result, the working group is unable to recommend a safety concern threshold (SCT) for ODPs at this time. Nevertheless, the ophthalmic industry has developed a number of time-tested practices to manage E&L for ODPs. This article describes those science-based practices and key considerations in the analysis, management, and safety assessment of E&L in ODPs.

Simulated Leaching (Migration) Study for a Model Container-Closure System Applicable to Parenteral and Ophthalmic Drug Products.

A simulating leaching (migration) study was performed on a model container-closure system relevant to parenteral and ophthalmic drug products. This container-closure system consisted of a linear low-density polyethylene bottle (primary container), a polypropylene cap and an elastomeric cap liner (closure), an adhesive label (labeling), and a foil overpouch (secondary container). The bottles were filled with simulating solvents (aqueous salt/acid mixture at pH 2.5, aqueous buffer at pH 9.5, and 1/1 v/v isopropanol/water), a label was affixed to the filled and capped bottles, the filled bottles were placed into the foil overpouch, and the filled and pouched units were stored either upright or inverted for up to 6 months at 40 °C. After storage, the leaching solutions were tested for leached substances using multiple complementary analytical techniques to address volatile, semi-volatile, and non-volatile organic and inorganic extractables as potential leachables.The leaching data generated supported several conclusions, including that (1) the extractables (leachables) profile revealed by a simulating leaching study can qualitatively be correlated with compositional information for materials of construction, (2) the chemical nature of both the extracting medium and the individual extractables (leachables) can markedly affect the resulting profile, and (3) while direct contact between a drug product and a system's material of construction may exacerbate the leaching of substances from that material by the drug product, direct contact is not a prerequisite for migration and leaching to occur.LAY ABSTRACT: The migration of container-related extractables from a model pharmaceutical container-closure system and into simulated drug product solutions was studied, focusing on circumstances relevant to parenteral and ophthalmic drug products. The model system was constructed specifically to address the migration of extractables from labels applied to the outside of the primary container. The study demonstrated that (1) the extractables that do migrate can be correlated to the composition of the materials used to construct the container-closure systems, (2) the extent of migration is affected by the chemical nature of the simulating solutions and the extractables themselves, and (3) even though labels may not be in direct contact with a contained solution, label-related extractables can accumulate as leachables in those solutions.

Waiting for triage: unmeasured time in patient flow.

INTRODUCTION: The Centers for Medicare and Medicaid Services (CMS) requires reporting of multiple time-sensitive metrics. Most facilities use triage time as the time of arrival. Little is known about how long patients wait prior to triage. As reimbursement to the hospital may be tied to these metrics, it is essential to accurately record the time of arrival. Our objective was to quantify the time spent waiting to be triaged for patients arriving to the emergency department (ED). METHODS: We conducted this study in an urban, academic, tertiary care center with approximately 54,000 annual ED visits. All patients arriving to the ED from November 1, 2012, to October 1, 2013, were enrolled. If patients didn't go directly to a bed or triage, an observer greeted patients as they entered the ED and recorded the time of arrival. The triage time was recorded as normal. We calculated the difference between the arrival time and triage time. RESULTS: There were 50,576 patient visits during the study period. Of these, 7,795 (15.4%) patients did not go directly to a bed or triage. For patients who waited for triage, median time from arrival to triage was 11 minutes (IQR 5-19, range 1-105). When stratified by the number of new patients who arrived in the ED in the previous hour, the percentage of greeted patients who waited more than 10 minutes for triage was: 0-5 new patients - 12.4%; 6-10 new patients - 48.8%; 11-15 new patients - 64.4%; 16+ new patients - 68%. CONCLUSION: Patients often waited more than 10 minutes to be triaged. As the number of patients registered in the previous hour increased, the percentage of patients who waited more than 10 minutes for triage increased significantly. During times of peak volume, 8.5% of all patients arriving to the ED waited more than 10 minutes for triage. This wait is not accounted for in the normal reporting of ED throughput times and metrics.

Nicardipine is superior to esmolol for the management of postcraniotomy emergence hypertension: a randomized open-label study.

BACKGROUND: Emergence hypertension after craniotomy is a well-documented phenomenon for which natural history is poorly understood. Most clinicians attribute this phenomenon to an acute and transient increase in catecholamine release, but other mechanisms such as neurogenic hypertension or activation of the renin-angiotensin-aldosterone system have also been proposed. In this open-label study, we compared the monotherapeutic antihypertensive efficacy of the 2 most titratable drugs used to treat postcraniotomy emergence hypertension: nicardipine and esmolol. We also investigated the effect of preoperative hypertension on postcraniotomy hypertension and the natural history of postcraniotomy hypertension in the early postoperative period. METHODS: Fifty-two subjects were prospectively randomized to receive either nicardipine or esmolol as the sole drug for treatment of emergence hypertension at the conclusion of brain tumor resection (40 subjects finally analyzed). After a uniform anesthetic, standardized protocols of these antihypertensive medications were administered for the treatment of systolic blood pressure (SBP) >130, with the goal of maintaining SBP <140 throughout the first postoperative day. In the event of study medication "failure," a "rescue" antihypertensive (labetalol or hydralazine) was used. The O'Brien-Fleming Spending Function was used to calculate the appropriate α value for each interim analysis of the primary outcome; univariate analysis was performed otherwise, with a 2-sided P<0.05 considered statistically significant. RESULTS: The incidence of nicardipine failure (5%, 95% confidence interval [CI] 0.1%-24.9%) was significantly less than that of esmolol (55%, 95% CI 31.5%-76.9%) as a sole drug in controlling SBP after brain tumor resection (difference 99% CI 13.8%-75.7%, P = 0.0012). The presence of preoperative hypertension or the approach to surgery (open craniotomy versus endonasal transsphenoidal) had no significant effect on the incidence of failure of the antihypertensive regimen used. We did not observe a difference in the need for opioid therapy for postcraniotomy pain between drug groups (99% CI difference -39.2%-30.2%). Failure of the study drug predicted the need for rescue drug therapy in the initial 12 hours after discharge from the recovery room (difference success versus failure = -41.7%, 99% CI difference -72.3% to -1.8%, P = 0.0336) but not during the period 12 to 24 hours after discharge from the recovery room (difference success versus failure = -27.4%, 99% CI difference -63.8%-9.2%, P = 0.143). However, in those patients carrying a preoperative diagnosis of hypertension, the need for rescue medication was only different during the period 12 to 24 hours after discharge from the recovery room (difference normotensive versus hypertensive = -35.4%, 99% CI difference -66.9% to -0.3%, P = 0.0254). CONCLUSIONS: Nicardipine is superior to esmolol for the treatment of postcraniotomy emergence hypertension. This type of hypertension is thought to be a transient phenomenon not solely related to sympathetic activation and catecholamine surge but also possibly encompassing other physiologic factors. For treating postcraniotomy emergence hypertension, nicardipine is a relatively effective sole drug, whereas if esmolol is used, rescue antihypertensive medications should be readily available.

The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP).

The Product Quality Research Institute (PQRI) is a non-profit consortium of organizations working together to generate and share timely, relevant, and impactful information that advances drug product quality and development. The collaborative activities of PQRI participants have, in the case of orally inhaled and nasal drug products (OINDPs), resulted in comprehensive and widely-accepted recommendations for leachables assessments to help ensure patient safety with respect to this class of packaged drug products. These recommendations, which include scientifically justified safety thresholds for leachables, represent a significant milestone towards establishing standardized approaches for safety qualification of leachables in OINDP. To build on the success of the OINDP effort, PQRI's Parenteral and Ophthalmic Drug Products (PODP) Leachables and Extractables Working Group was formed to extrapolate the OINDP threshold concepts and best practice recommendations to other dosage forms with high concern for interaction with packaging/delivery systems. This article considers the general aspects of leachables and their safety assessment, introduces the PODP Work Plan and initial study Protocol, discusses the laboratory studies being conducted by the PODP Chemistry Team, outlines the strategy being developed by the PODP Toxicology Team for the safety qualification of PODP leachables, and considers the issues associated with application of the safety thresholds, particularly with respect to large-volume parenterals. Lastly, the unique leachables issues associated with biologics are described. LAY ABSTRACT: The Product Quality Research Institute (PQRI) is a non-profit consortium involving industry organizations, academia, and regulatory agencies that together provide recommendations in support of regulatory guidance to advance drug product quality. The collaborative activities of the PQRI Orally Inhaled and Nasal Drug Products Leachables and Extractables Working Group resulted in a systematic and science-based approach to identify and qualify leachables, including the concept of safety thresholds. Concepts from this widely accepted approach, formally publicized in 2006, are being extrapolated to parenteral and ophthalmic drug products. This article provides an overview of extractables and leachables in drug products and biologics and discusses the PQRI Work Plan and Protocols developed by the PQRI Parenteral and Ophthalmic Drug Products Leachables and Extractables Working Group.

Extractables characterization for five materials of construction representative of packaging systems used for parenteral and ophthalmic drug products.

Polymeric and elastomeric materials are commonly encountered in medical devices and packaging systems used to manufacture, store, deliver, and/or administer drug products. Characterizing extractables from such materials is a necessary step in establishing their suitability for use in these applications. In this study, five individual materials representative of polymers and elastomers commonly used in packaging systems and devices were extracted under conditions and with solvents that are relevant to parenteral and ophthalmic drug products (PODPs). Extraction methods included elevated temperature sealed vessel extraction, sonication, refluxing, and Soxhlet extraction. Extraction solvents included a low-pH (pH = 2.5) salt mixture, a high-pH (pH = 9.5) phosphate buffer, a 1/1 isopropanol/water mixture, isopropanol, and hexane. The resulting extracts were chemically characterized via spectroscopic and chromatographic means to establish the metal/trace element and organic extractables profiles. Additionally, the test articles themselves were tested for volatile organic substances. The results of this testing established the extractables profiles of the test articles, which are reported herein. Trends in the extractables, and their estimated concentrations, as a function of the extraction and testing methodologies are considered in the context of the use of the test article in medical applications and with respect to establishing best demonstrated practices for extractables profiling of materials used in PODP-related packaging systems and devices. LAY ABSTRACT: Plastic and rubber materials are commonly encountered in medical devices and packaging/delivery systems for drug products. Characterizing the extractables from these materials is an important part of determining that they are suitable for use. In this study, five materials representative of plastics and rubbers used in packaging and medical devices were extracted by several means, and the extracts were analytically characterized to establish each material's profile of extracted organic compounds and trace element/metals. This information was utilized to make generalizations about the appropriateness of the test methods and the appropriate use of the test materials.

Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome.

BACKGROUND: We recently reported that durable chimerism can be safely established in mismatched kidney recipients through nonmyeloablative conditioning followed by infusion of a facilitating cell (FC)-based hematopoietic stem cell transplantation termed FCRx. Here we provide intermediate-term follow-up on this phase II trial. METHODS: Fifteen human leukocyte antigen-mismatched living donor renal transplant recipients underwent low-intensity conditioning (fludarabine, cyclophosphamide, 200 cGy TBI), received a living donor kidney transplant on day 0, then infusion of cryopreserved FCRx on day +1. Maintenance immunosuppression, consisting of tacrolimus and mycophenolate, was weaned over 1 year. RESULTS: All but one patient demonstrated peripheral blood macrochimerism after transplantation. Engraftment failure occurred in a highly sensitized (panel reactive antibody [PRA] of 52%) recipient. Chimerism was lost in three patients at 2, 3, and 6 months after transplantation. Two of these subjects had received either a reduced cell dose or incomplete conditioning; the other two had PRA greater than 20%. All demonstrated donor-specific hyporesponsiveness and were weaned from full-dose immunosuppression. Complete immunosuppression withdrawal at 1 year after transplantation was successful in all patients with durable chimerism. There has been no graft-versus-host disease or engraftment syndrome. Renal transplantation loss occurred in one patient who developed sepsis following an atypical viral infection. Two subjects with only transient chimerism demonstrated subclinical rejection on protocol biopsy despite donor-specific hyporesponsiveness. CONCLUSIONS: Low-intensity conditioning plus FCRx safely achieved durable chimerism in mismatched allograft recipients. Sensitization represents an obstacle to successful induction of chimerism. Sustained T-cell chimerism is a more robust biomarker of tolerance than donor-specific hyporeactivity.

Germination of Bacillus cereus spores in response to L-alanine and to inosine: the roles of gerL and gerQ operons.

Bacillus cereus 569 (ATCC 10876) endospores germinate in response to inosine or L-alanine, the most rapid germination response being elicited by a combination of these germinants. The gerI operon has already been characterized as a homologue of the gerA spore-germination receptor family of operons found in all Bacillus spp. examined; the primary defect in gerI mutant spores is in the inosine germination response, although spores were also slower to germinate in L-alanine. Additional transposon-insertion mutants, from similar Tn917-LTV1 mutagenesis and enrichment experiments, now define two more operons, also members of the family of gerA homologues, important in L-alanine and inosine germination. Transposon insertions were identified in an alanine-specific germination locus, named gerL, which represents an operon of three genes, termed gerLA, gerLB and gerLC. By examining the residual germination response to L-alanine in gerI and gerL mutants, it was deduced that the GerL proteins contribute most strongly to the L-alanine germination response, and that the GerI proteins, required primarily in inosine germination, mediate only much slower germination responses to alanine. The L-alanine germination responses mediated by GerL and GerI proteins differ in their germination rates, temperature optima and germinant concentration dependence. The gerQ locus, again identified by transposon insertion, is a second inosine-related germinant-receptor operon. GerQ and GerI proteins are both required for the germination response to inosine as sole germinant, but GerQ has no role in L-alanine germination. Although near-identical homologues of gerI and gerL operons are evident in the Bacillus anthracis genome sequence, there is no evidence of a close homologue of gerQ.