Derivation of process control strategy for biosimilar: Is it different from the way a control strategy is derived for a novel biologic?

Quality based development (QbD) has become the preferred choice for developing manufacturing process for any biologic drug. A proponent for this approach has been the US Food and Drug Association (FDA). Recently, the first QbD applications have been successfully filed with FDA. Biosimilars have also gained popularity in the recent past. Development of these drugs are very different from the way a novel biologic is developed. In the last five years, many companies around the world have started working on Biosimilars of which some companies have been able to successfully develop and get approvals for Biosimilars in both FDA and European Medicenes agency (EMA). Application of QbD for a Novel and a Biosimilar drug is quite different. By nature of the requirement for developing a Biosimilar, quality of the ‘reference product’ against which the biosimilar is being developed is considered while making decisions during process development. Though the same concepts applies for a novel drug, the target quality profile is not as defined as one can write for a Biosimilar. This is because product quality information regarding the reference product is well-known and can be thoroughly analyzed and characterized. While the targets can be easily derived for a Biosimilar, deriving a process control strategy is tough. Critical Process Parameter (CPP) is defined as a process parameter that has significant impact on the safety and efficacy of the drug. While this definition for CPP is applicable for a Bisomilar also, another aspect which requires consideration for a Biosimilar drug is the impact of process parameters on ‘fingerprint biosimilarity’. Hence the classification of process parameters as those that are critical and those that are not is not as straight forward like for a Novel drug. Derivation of acceptance range for these parameters also is different – The acceptance range for CPPs when compared to that for a novel biologic is generally found to be narrow. This is because the desired range for the outputs (such as aggregates, glycan, charge, size variants etc.) is narrow owing to the product quality ranges observed for the reference product and not just the levels of the outputs which has an effect on safety and efficacy. These subtle differences make deriving the process control strategy for a Bisomilar different from a novel biologic. In this presentation, a detailed overview of scale down model qualification, process characterization experiments, and the control strategy for Biosimilar manufacturing processes is provided. A case study will be presented which showcases some of these concepts of deriving control strategy as how it is applied for a Biosimilar process

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

High temperature magnetic properties of transition metal oxides with perovskite structure

Thesis (Ph. D.)--University of Washington, 2008.In recent years, transition metal oxides with perovskite structure have drawn considerable interest as mixed ionic electronic conductors (MIECs) that can conduct electrons and ions at high temperatures. Many phenomena of interest in perovskites occur at high temperature including electronic and ionic transport, catalysis and chemical expansion. Electronic structure controls host of critical properties that are of technological importance including oxygen nonstoichiometry, electronic and ionic conductivity.In this work, we have designed an experimental method to measure magnetization of transition metal oxide perovskites at high temperatures (600°C--1000°C) as a function of oxygen partial pressure. High temperature magnetic measurements were used to study electronic structure in two promising transition metal oxide perovskites for intermediate temperature solid oxide fuel cells: La 1-xSrxCoO3-delta(LSC) and La1-xSrxFeO 3-delta(LSF). LSF has semiconducting behavior and many of its properties have been attributed to change in oxidation state of iron with changes in temperature and oxygen partial pressure. LSC, on the other hand, has many properties that point towards metallic behavior at high temperatures.We find that at high temperatures, the oxygen nonstoichiometry and temperature dependence of magnetic susceptibility could be explained within the framework of localized electronic defects for LSF. In Contrast, the magnetic property of LSC at high temperatures suggest co-existence of localized and delocalized electronic states. We discuss this behavior in the context of existing electronic structure models, as well as transport properties

Sarežģīti vai pārāk sarežģīti ? WHARFE un BGOR 4-punktu skalu izvērtējums

MedicīnaVeselības aprūpeMedicineHealth CareKad sarežģīti ir pārāk sarežģīti? WHARFE izvērtēšanas skalas novērtējums un BGOR 4 punktu skalas piedāvājums ABSTRAKTS: Atslēgas vārdi: trešā molāra ķirurģiska izņemšana, komplicēta zoba ekstrakcija Mērķis: Treša molāra ķirurģiska izņemšana ir viena no visbiežākajām procedūrām Mutes-sejas-žokļu ķirurģijā. Sarežģītības izvērtēšanai izmanto dažādus paredzēšanas modeļus. Pētījuma mērķis bija izstrādāt visaptverošu modeli trešā molāra ķirurģiskas izņemšanas operācijas sarežģītības paredzēšanai. Iznākumu klasifikācijai tika izmantota WHARFE skala. BGOR-4 skala tiek piedāvāta un validēta kā būtisks instruments trešā molāra operācijas plānošanai. Metodes: Šajā šķērsgriezuma pētījumā 68 pacienti (86 gadījumi) pārcieta trešā molāra operāciju. Sarežģītības izvērtēšanai uz ortopantogrammas tika izmantots WHARFE modelis. Visus pacientus operēja un izvērtēja viena persona. Statistikai analīzei tika izmantos IBM SPSS 25. Pacienta WHARFE un BGOR-4 izvērtējums tika veikts preoperatīvi, un tika reģistrēts kopējais laiks minūtēs no lēvera pacelšanas brīža līdz zoba ekstrakcijai. Gadījumi tika sadalīti divās kategorijās. 1.kategorijā ietilpa gadījumi, kuru WHARFE vērtējums bija 6 un zemāks, BGOR-4 punktu skalas vērtējums bija 2 un zemāks un kopējais laiks bija 0-8 minūtes. 2.kategorijā ietilpa WHARFE punktu skaits 7 un vairāk, BGOR-4 punktu skalas vērtējums 3 un vairāk un kopējais laiks 8,1 minūte un vairāk. Hipotēzes pārbaudei tika izmantots Hī-kvadrāta tests, un izredžu attiecība tika aprēķināta, izmantojot binominālās loģistiskās regresijas modeli. Rezultāti: Hī-kvadrāta testi abiem modeļiem bija statistiski nozīmīgi. Fišera precīzā testa p vērtība (divpusējā) bija 0,027 WHARFE izvērtējumam un <0,001 BGOR 4-punktu skalai. Izredžu attiecība WHARFE skalai bija 3,3 un 11,9 BGOR-4 punktu skalai. Secinājumi: Lai arī abas skalas bija statistiski nozīmīgas trešā molāra ķirurģiskas izņemšanas operācijas sarežģītības izvērtēšanai, BGOR-4 punktu skalai ir spēcīgāka saistība sarežgītības paredzēšanai nekā WHARFE skalai. Šī modeļa validācijai ir nepieciešami turpmāki prospektīvi pētījumi.ABSTRACT: Keywords: third molar surgery, Difficult tooth extraction Objective: Third molar surgery is one of the most common surgical procedures performed in OMFS specialty. Outcome audit of difficulty is assessed by various predictive models. The aim of the study was to propose a comprehensive model to predict the difficulty of third molar surgery. Grading the outcomes of third molar surgery based was on WHARFE assessment. BGOR 4-point grading scale is being proposed and validated, as an essential tool for third molar surgery planning. Methods: In this cross-sectional study, 68 patients (86 cases) underwent third molar surgery. WHARFE model was used to assess difficulty outcome on an orthopantomogram tracing. All patients were treated and assessed by the same operator. Statistical analysis was performed in IBM SPSS 25. Patient’s WHARFE score and BGOR 4-point grading scheme was assessed preoperatively, and the total time elapsed after flap elevation till the exit of tooth is recorded in minutes. The cases were stratified into two categories. Category 1 comprised of cases whose WHARFE score was 6 and below, BGOR 4-point grading scale below 2 and time elapsed in minutes 0-8 minutes. Category 2 comprised WHARFE score 7 and above, BGOR 4-point grading scaled 3 and above and time elapsed in minutes 8.1 minutes and above. Chi square was used for hypothesis testing and Odd’s ratio was found using binomial logistic regression model. Results: Chi square tests for both models were statistically significant. In the Fischer’s exact test p value = 0.027 and p value = <0.001 exact sig (2-sided) for WHARFE assessment and 4-point grading scale respectively. The odd’s ratio was 3.3 for WHARFE assessment and 11.9 for BGOR 4-point grading scale. Conclusion: Though, both tests were statistically significant in predicting the surgical difficulty of third molar surgery, BGOR 4-point grading scale has stronger association to predict surgical difficulty than WHARFE assessment. Validation on this model has to still be done with prospective studies