Nov-Dec 2023

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 49 microcornea. Ophthalmic Paediatr Genet. 1984;4:59–66. 13. Duke-Elder S. Coloboma choroid. In: System of ophthalmology. St Louis: CV Mosby Company; 1961. p. 489. 14. Mann I. Developmental abnormalities of the eye. London: Cambridge University Press; 1937. p. 65–103. Dr. Kavita Bajiya, MBBS Vitreo Retinal Services, Department of Ophthalmology, Sawai Man Singh Medical College & Hospital, Jaipur Rajasthan India. Corresponding Author: DOS TIMES

DOS Times Volume 29, Number 6, November-December 2023 www.dosonline.org/dos-times 50 Update on Retinopathy of Prematurity Surabhi Gupta, MBBS, MS, DNB, Rushil Kumar, MBBS, DNB, FICO, FLVPEI Dr Shroff’s Charity Eye Hospital. Abstract: Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease affecting preterm and low birth weight infants and is a leading cause of visual morbidity and blindness worldwide.[1] In developing countries like India due to improved health care services a greater number of preterm babies are surviving annually and the occurrence of ROP is not only seen in preterm but also in more mature and larger babies.[2] There is constant need of creating awareness among health care providers and parents for healthy survival of preterm babies and timely screening and treatment interventions to avoid blindness. Introduction Retinopathy of prematurity (ROP) is a retinal vascular disease affecting preterm and low birth weight infants. Terry described ROP as retrolental fibroplasia in 1942 and the term ROP was coined by Heath in 1951.[3,4] Epidemiology Due to advancement in neonatal health care services and increased survival rate of preterm babies, ROP is emerging as a third epidemic in developing counties. In India, approximately over 3.5 million preterm infants born annually and are at risk of developing ROP.[5] The incidence of ROP in low birth weight babies in India ranges from 38 to 51.9%.[6] Pathogenesis The normal retinal vessels start to grow outward from disc and reach the nasal ora by 36 weeks and temporal ora by 40 weeks of gestational age.[3,7] The “classical” and “spindle cell” theory explains the pathogenesis of ROP. Classical theory by Aston and Patz states that due to prolonged exposure to high concentration of oxygen there is severe vasoconstriction and irreversible vascular occlusion leading to ischemia and resultant fibrovascular proliferation.[8,9] Spindle cell theory by Kretzer proposed free oxygen diffusion from choroid to retina in state of hyperoxia causing free radical damage to spindle cells. These damaged cells interfere with normal vascular formation and migration and secrete angiogenic factors which incite the neovascular process. The retina remains in the state of physiological hypoxia in utero. The development of ROP is a biphasic process which is explained in figure-1.[10] In phase 1 there is initially delayed physiologic retinal vascular development, resulting in a peripheral avascular area of the retina and in phase 2 there is angiogenesis at the junction of vascularized and avascularized retina causing vasoproliferation. Figure 1: Two phase hypothesis of ROP. DOS TIMES

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 51 Risk Factors and Screening Guidelines Preterm birth and low birth weight are identified as the most important risk factor for development of ROP, others being exposure to supplemental oxygen therapy, respiratory distress syndrome, sepsis, multiple blood transfusions, multiple births (twins/triplets), apneic episodes, intraventricular hemorrhage.[6] Whom to Screen: All preterm neonates who are born <34 weeks gestation and/ or <1750 grams birth weight; as well as in babies 34-36 weeks gestation or 1750-2000 grams birth weight if they have risk factors for ROP.[11,12] When to Screen: For infants born more than 28 weeks of gestation should be screened during the first 30 days of life and infants less than 28 weeks or weighing below 1200g should be screened early, 2-3 weeks after birth which helps in early detection of aggressive ROP (AROP).[6] How to Screen: The baby is kept 1 hour fasting prior to procedure. Before examination dilation is achieved using phenylephrine (2.5%) and tropicamide (0.5%) in half strength which can be prepared by diluting 1:1 with tear supplements. The drops are instilled twice 15 minutes apart with punctual occlusion to avoid systemic absorption. Plus disease should be suspected in cases Figure 2: Schematic representation of zone borders and clock hour sectors describe the location of vascularization and extent of retinopathy. of poor dilation. Sterile Alfonso speculum is used to retract the lids and wire vectis for gentle depression. Findings at each screening should be well documented including zone, stage, presence of plus disease, extent and if A-ROP is present or not.[6] Classification and Staging The international classification for retinopathy of prematurity (ICROP) suggested the ROP classification system which was first published in 1984 and expanded in 1987 and was revised in 2005. The third revision of ICROP has been done in 2021.[13] The retina is divided into 3 zones centred on optic disc (Figure-2).[13] • Zone 1 is defined by a circle with radius twice the distance between disc and centre of fovea. • Zone 2 is a ring shaped region extending nasally from outer limit of zone 1 to nasal ora and similar distance superiorly, temporally and inferiorly. Zone 2 posterior is defined as region 2 disc diameter temporal to zone 1 border. • Zone 3 is the crescent of temporal retinal area beyond zone 2. The term Notch has been included in ICROP3 which is inclusion of 1-2 clock hour of horizontal meridian by ROP stage into more posterior zone as compared to rest of the retinopathy and is recorded as “secondary to notch”.[13] Stage 1: Demarcation line- it is a flat, white line within the planes of retina at the junction of vascular and avascular retina. Stage 2: Ridge- it is when the demarcation line gains width and height. Sometimes small tuft of vascular tissue can be seen posterior to ridge which is called as “popcorn lesions”. Stage 3: Extraretinal fibrovascular proliferation extends from ridge into vitreous causing ragged appearance as the proliferation becomes extensive. DOS TIMES

DOS Times Volume 29, Number 6, November-December 2023 www.dosonline.org/dos-times 52 Stage 4: Partial retinal detachment can occur in treated or untreated eyes and can be tractional or exudative. Exudative detachments are usually associated with laser therapy and tractional with presence of progressive fibrovascular proliferation. Eyes with A-ROP can present with volcano tractional detachment involving fovea where the peripheral retina is attached.[14] Stage 4 A- Partial retinal detachment sparing fovea. Stage 4 B- Partial retinal detachment involving fovea. Stage 5: Total retinal detachment is now divided into 3 configurations.[15,16] Stage 5 A- Optic disc is visible suggesting open funnel configuration. Stage 5 B- Optic disc is not visible suggesting close funnel configuration. Stage 5 C- Stage 5B along with anterior segment abnormalities (anterior lens displacement, marked anterior chamber shallowing, iridocapsular adhesions, capsule-endothelial adhesion with central corneal opacification suggesting a closed-funnel configuration) Aggressive Retinopathy of Prematurity (A-ROP): Aggressive posterior ROP has been replaced by A-ROP in ICROP3 due to its increased prevalence in larger preterm infants and beyond the posterior retina. Plus and Pre Plus Disease: Plus disease is defined as venous dilation and arteriolar tortuosity of posterior pole vessels within zone 1.[17] Preplus disease is defined to represent retinal vascular dilation and tortuosity that is abnormal, but insufficient for plus disease.[18] Treatment of ROP Timely screening and detection of infants requiring treatment is crucial for avoiding blindness due to ROP. Treatment in the vasoproliferative stage can yield good visual outcomes however once the vitreoretinal traction and detachments occur the visual prognosis is usually poor. Laser Photocoagulation: It aims at destruction of hypoxic peripheral avascular retina which contributes to increased VEGF production and consecutive vasoproliferation. It can be done using 532nm frequency doubled Nd-YAG or 810nm diode laser. Green lasers have replaced the diode laser due to its added advantages of less tissue penetration, less pain, less cost and more portability.[19] Protocol for Laser Photocoagulation: The infant is kept fasting for an hour and after obtaining a written informed consent , ROP laser is performed under the supervision of paediatrician or anaesthesiologist under topical anaesthesia. Laser to the entire avascular retina till ora serrata and close to ridge is performed in both the eyes in same session using near confluent burns. Skip areas if identified on follow up screen should be lasered to avoid recurrent disease. In presence of fibrovascular proliferation in vitreous cavity laser posterior to ridge helps in better regression, less traction and perhaps better outcome.[20] In presence of fibrovascular proliferation in vitreous cavity, laser posterior to ridge helps in better regression, less traction and perhaps a better outcome. Laser photocoagulation is considered as the mainstay of treatment and has been reported to have 96-100% success rate.[21] Anti-Vascular Endothelial Growth Factor (VEGF) Therapy: The landmark study BEAT-ROP has brought revolution for use of anti VEGF therapy for ROP treatment.[22] 0.625mg/0.025ml for Bevacizumab and 0.25mg/0.025ml for Ranibizumab, or half of the adult doses have been used for treatment in ROP. The use of anti VEGF over laser provides ease of administration, less tissue damage, revascularization of avascular retina, low risk of myopia, preservation of visual field and treatment in special circumstances like non dilating pupil and media haze.[23] There are certain concerns with use of anti VEGF in treatment of ROP, due to leakage into systemic circulation anti VEGF interfere with physiological angiogenesis and have been found to be associated with neurodevlopmental delay.[24] ROP crunch is another concern of treatment with anti VEGF.[25] It refers to development of tractional detachments following severe contraction of fibrovascular proliferation in advanced ROP. Regression: The vascular signs of regression are more rapid in anti VEGF treated eyes (1-3 days) as compared to laser photocoagulation (7-14 days). These include decreased signs of plus disease, vascularisation into peripheral avascular retina, regression of tunica vasculosa lentis, regression of haemorrhage, pupillary dilatation and better media clarity.[26] Reactivation: Reactivation of ROP is more with anti VEGF treated eyes as compared to spontaneous regression and rarely with laser photocoagulation. Reactivation is mostly noted at 37-60 weeks of post menstrual age.[27] Vascular signs include recurrent vascular dilation, tortuosity or both, extra retinal vessels formation causing contraction and tractional detachment.[14] Surgery for Stage 4 and Stage 5 ROP: Advanced stages of ROP that is stage 4A, 4B and stage 5 are managed surgically. Scleral buckling is modality of treatment for stage 4A ROP with peripheral traction however lens sparing vitrectomy is mostly preferred for stage 4 ROP. With MIVS the intraoperative and postoperative complications are less and therefore have become popular for ROP surgeries. Anatomical success of 96% in stage 4A and 70% in stage 4B following LSV at final visit has been reported by Bhende et al.[28] Eyes with prior laser treatment are found to have less iatrogenic break during surgery as compared to treatment naive eyes.[29] Stage 5 have worst prognosis.[30] Anatomical and functional DOS TIMES

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 53 outcome post vitrectomy are often poor. Recurrence of detachment is noted in up to 22% of cases.[31] Rehabilitation: Care for the babies does not end with treating the disease itself. Post treatment amblyopia management, refractive correction and rehabilitation services must be provided to the child, especially in stage 5 disease. Telemedicine, Artificial Intelligence (AI) and Novel Imaging in ROP Campbell et al. evaluated the efficacy of AI in diagnosis of ROP through the use of fundus imaging similar in accuracy compared to indirect ophthalmoscopy.[32,33] The Imaging and Informatics in Retinopathy of Prematurity Deep Learning (i-ROP DL) system has been found to diagnose plus disease and also help to predict progression of ROP requiring treatment. AI has the potential to be integrated into ROP screening programs and used for monitoring disease in different NICUs.[33] India being the capital of premature birth where the maximum population live in remote areas and do not have access to tertiary health care services, tele screening programmes like Karnataka Internet Assisted Diagnosis of Retinopathy of Prematurity (KIDROP) are in increasing need for timely identification of at risk infants.[34] Higher cost of widefield imaging system like RETCAM is the major limitation for routine use. The ICON system, PanoCam LT, 3nethra Neo have been developed over past decade and provide wider field of examination with high sensitivity and specificity for diagnosis of ROP at a much lower cost.[35,36] Conclusion With ROP being on the rise more efficient and robust screening modalities are the need of the hour. Early diagnosis and prompt intervention followed by timely refractive and rehabilitation services is essential for good anatomical and functional outcome for the babies. References 1. Hellström A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet. 2013 Oct 26;382(9902):1445-57. doi: 10.1016/S0140- 6736(13)60178-6. Epub 2013 Jun 17. PMID: 23782686; PMCID: PMC4389630. 2. Quinn GE. Retinopathy of prematurity blindness worldwide: phenotypes in the third epidemic. Eye Brain. 2016 May 19;8:31-36. doi: 10.2147/EB.S94436. PMID: 28539799; PMCID: PMC5398741. 3. Terry TL. Extreme prematurity and fibroblastic overgrowth of persistent vascular sheath behind each crystalline lens. I. Preliminary report. Am J Ophthalmol. 1942;25:203–4. 4. Heath P. Pathology of retinopathy of prematurity, RLF. Am J Ophthalmol. 1951;34:1249–68. 5. Kankaria A, Duggal M, Chauhan A, et al. Readiness to provide antenatal corticosteroids for threatened preterm birth in public health facilities in Northern India. Glob Health Sci Pract. 2021;9(3):575– 589. 6. Jalali S, Anand R, Kumar H, Dogra MR, Azad R, Gopal L. Programme planning and screening strategy in retinopathy of prematurity. Indian J Ophthalmol. 2003;51(1):89–99. 7. Pejawar R, Vinekar A, Bilagi A. National Neonatology Foundation’s Evidence-based Clinical Practise Guidelines (2010), Retinopathy of Prematurity, NNF India, New Delhi 2010:253–62. 8. Ashton N, Ward B, Serpell G. Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasia. Br J Ophthalmol. 1954; 38:397–432. [PubMed: 13172417]. 9. Patz A, Eastham A, Higginbotham DH, Kleh T. Oxygen studies in retrolental fibroplasia. Am J Ophthalmol. 1953; 36:1511–22. [PubMed: 13104558]. 10. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012 Dec 27;367(26):2515-26. doi: 10.1056/NEJMra1208129. PMID: 23268666; PMCID: PMC3695731. 11. American Academy of Pediatrics, Section on Ophthalmology. Screening examination of premature infants for retinopathy of prematurity. Pediatrics ; 117: 572-576. 12. Erratum for Section on Ophthalmology et al., AAP Policy 117 (2) 572-576. Pediatrics;118:1324. 13. Chiang MF, Quinn GE, Fielder AR, Ostmo SR, Paul Chan RV, Berrocal A, Binenbaum G, Blair M, Peter Campbell J, Capone A Jr, Chen Y, Dai S, Ells A, Fleck BW, Good WV, Elizabeth Hartnett M, Holmstrom G, Kusaka S, Kychenthal A, Lepore D, Lorenz B, Martinez-Castellanos MA, Özdek Ş, Ademola-Popoola D, Reynolds JD, Shah PK, Shapiro M, Stahl A, Toth C, Vinekar A, Visser L, Wallace DK, Wu WC, Zhao P, Zin A. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021 Oct;128(10):e51-e68. doi: 10.1016/j.ophtha.2021.05.031. Epub 2021 Jul 8. PMID: 34247850. 14. Hartnett ME, McColm JR. Retinal features predictive of progressive stage 4 retinopathy of prematurity. Retina. 2004;24(2):237e241. 15. Gadkari SS, Deshpande M, Kulkarni S. Minimally fibrotic stage 5 ROP: a clinical prognostic factor in eyes undergoing vitrectomy for stage 5 retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. 2016;254(7):1303e1309. 16. Ozsaygili C, Ozdek S, Ozmen MC, et al. Preoperative anatomical features associated with improved surgical outcomes for stage 5 retinopathy of prematurity. Retina. 2021;41(4):718e725. 17. Quinn GE, Schaffer DB, Johnson L. A revised classification of retinopathy of prematurity. Am J Ophthalmol. 1982;94(6): 744e749. 18. Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991e999. 19. Sen P, Wu WC, Chandra P, Vinekar A, Manchegowda PT, Bhende P. Retinopathy of prematurity treatment: Asian perspectives. Eye (Lond). 2020 Apr;34(4):632-642. doi: 10.1038/s41433-019-0643-4. Epub 2019 Oct 29. PMID: 31664193; PMCID: PMC7093470. 20. Ells AL, Gole GA, Hildebrand PL, Ingram A, Wilson CM, Williams RG. Posterior to the ridge laser treatment for severe stage 3 retinopathy of prematurity. Eye. 2013;27:525–30. 21. Katoch D, Sanghi G, Dogra MR, Beke N, Gupta A. Structural sequelae and refractive outcome 1 year after laser treatment for type 1 prethreshold retinopathy of prematurity in Asian Indian eyes. Indian J Ophthalmol. 2011;59:423–6. 22. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011 Feb 17;364(7):603- 15. doi: 10.1056/NEJMoa1007374. PMID: 21323540; PMCID: PMC3119530. DOS TIMES

DOS Times Volume 29, Number 6, November-December 2023 www.dosonline.org/dos-times 54 23. Mintz-Hittner HA. Retinopathy of Prematurity: Intravitreal injections of bevacizumab: timing, technique, and outcomes. J AAPOS. 2016 Dec;20(6):478-480. doi: 10.1016/j.jaapos.2016.10.002. Epub 2016 Nov 2. PMID: 27816750. 24. Morin J, Luu TM, Superstein R, Ospina LH, Lefebvre F, Simard MN, et al. Neurodevelopmental outcomes following bevacizumab injections for retinopathy of prematurity. Pediatrics. 2016;137:e20153218. 25. Yonekawa Y, Wu WC, Nitulescu CE, Chan RP, Thanos A, Thomas BJ, et al. Progressive retinal detachment in infants with retinopathy of prematurity treated with intravitreal bevacizumab or ranibizumab. Retina. 2018;38:1079–83. 26. Kwon JY, Ghodasra DH, Karp KA, et al. Retinal vessel changes after laser treatment for retinopathy of prematurity. J AAPOS. 2012;16(4):350e353. 27. Wallace DK, Dean TW, Hartnett ME, et al. A dosing study of bevacizumab for retinopathy of prematurity: late recurrences and additional treatments. Ophthalmology. 2018;125(12): 1961e1966. 28. Bhende P, Gopal L, Sharma T, Verma A, Biswas RK. Functional and anatomical outcomes after primary lens-sparing pars plana vitrectomy for stage 4 retinopathy of prematurity. Indian J Ophthalmol. 2009;57:267–71. 29. Gadkari SS, Deshpande M. Variation in the vitreoretinal configuration of Stage 4 retinopathy of prematurity in photocoagulated and treatment naive eyes undergoing vitrectomy. Indian J Ophthalmol. 2017;65:846–52. 30. Sen P, Jain S, Bhende P. Stage 5 retinopathy of prematurity: An update. Taiwan J Ophthalmol. 2018 Oct-Dec;8(4):205-215. doi: 10.4103/tjo. tjo_61_18. PMID: 30637192; PMCID: PMC630256. 31. Kondo H, Arita N, Osata M, Hayashi H, Oshima K, Uchio E. Late recurrence of retinal detachment following successful vitreous surgery for stages 4B and 5 retinopathy of prematurity. Am J Ophthalmol. 2009;147:661–6. 32. Campbell JP, Singh P, Redd TK, et al. Applications of artificial intelligence for retinopathy of prematurity screening. Pediatrics. 2021;147(3):e2020016618. https://doi.org/10.1542/peds.2020-01 6618. PMID: 33637645; PMCID: PMC7924138. 33. Brown JM, Campbell JP, Beers A et al (2018) Automated diagnosis of plus disease in retinopathy of prematurity using deep convolutional neural networks. JAMA Ophthalmol 136:803–810. 34. Vinekar A, Gilbert C, Dogra M, Kurian M, Shainesh G, Shetty B, Bauer N. The KIDROP model of combining strategies for providing retinopathy of prematurity screening in underserved areas in India using wide-field imaging, tele-medicine, non-physician graders and smart phone reporting. Indian J Ophthalmol. 2014;62(1):41–9. 35. Valikodath, N. MD*; Cole, E. MD*; Chiang, M. F. MD†; Campbell, J. P. MD†; Chan, R. V.P. MD*. Imaging in Retinopathy of Prematurity. Asia-Pacific Journal of Ophthalmology 8(2):p 178-186, March 2019. | DOI: 10.22608/APO.201963. 36. Patel SN, Shi A, Wibbelsman TD, Klufas MA. Ultra-widefield retinal imaging: an update on recent advances. Ther Adv Ophthalmol. 2020 Jan 20;12:2515841419899495. doi: 10.1177/2515841419899495. PMID: 32010879; PMCID: PMC6971964. Dr. Surabhi Gupta, MBBS, MS, DNB Vitreoretina Fellow, Dr Shroff’s Charity Eye Hospital, Kedarnath Lane, Daryaganj, New Delhi. Corresponding Author: DOS TIMES

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 55 Overview of Intraocular Tamponading Agents Used in Vitreoretinal Surgeries Sanjeev Kumar Nainiwal, MD, DNB, MNAMS, Lucky Badesra, MBBS, Prithvi Raj, MS, Neha Kharwas, MBBS, Mansi Sonwar, MBBS, Sunil Kumar Gurjar, MBBS, Raju Beniwal, MBBS Vitreo Retinal Services, Department of Ophthalmology, Sawai Man Singh Medical College & Hospital, Jaipur Rajasthan, India. The word “Tamponade” is defined as a plug or tent inserted tightly into a wound, orifice, etc, to arrest haemorrhage. In context to retinal detachment surgery, tamponade agents is used to provide surface tension across retinal breaks, which prevents further fluid flow into the subretinal space until the retinopexy (photocoagulation or cryopexy) provides a permanent seal. Silicone oils and Gases are the most commonly used tamponade agents. In 1911, Ohm gave the first description of use of tamponade agents in the treatment of RD, who reported successful treatment of two patients using intravitreal injection of sterile air, although he did not use the term “tamponade”. And later, Gonin describes the role of retinal breaks in the pathogenesis of Retinal detachment. In 1938 Rosengren used the term tamponade and reported the successful treatment of Retinal detachment with air. Intraocular tamponade is used in various vitreoretinal surgeries like retinal detachments, gaint retinal tears, macular hole, endophthalmitis, pneumatic retinopexy, subretinal blood etc. Silicone oil (SO) was introduced as an internal tamponade agent in the early 1960s by Paul Cibis before pars plana vitrectomy was introduced. Dates back a century, the first use of intraocular gas in treating retinal detachment. At that time, relationship between retinal break and detachment was not fully appreciated. Later, the importance of localization and sealing of retinal breaks was done and then the concept of air injection was introduced. Rosengren described the internal tamponade with air after subretinal fluid (SRF) drainage, along with external diathermy to create adhesion which increases the success rate in retinal detachment treatment. Air is absorbed quickly than other longer-lasting gases. Sulfur hexafluoride and the perfluoropropane are most popular intraocular gases. In1980s, pneumatic retinopexy was introduced by Lincoff, and popularized by Hilton and Grizzard. The Silicone Study was done with a series of randomized controlled trials comparing the efficacy and safety of Silicone oil against intraocular gases, sulfur hexafluoride (SF6), and perfluoropropane (C3F8), in the management of retinal detachments with PVR, showed that there is no significant difference between Silicone oil and intraocular gases as expected. Chemical Properties of Silicone Oil The generic term silicone refers to all materials made up of siloxane. Siloxane made up of a silicone and an oxygen molecule [−Si-O−]. Silicone is able to forming two additional bonds on its sides, to form polymer different organic or inorganic side chains could be attached to the silicone molecule and they have different properties. Silicone oil is either lighter or heavier than water. Heavierthan-water Silicone oil is a made up of polymethylsiloxane and semifluorinated alkanes or alkenes. Lighter silicone oils (i.e., conventional SOs) vary in viscosities. The specific gravity of PDMS is 0.97, lighter-than-water. If a methyl and a trifluoropropyl side chain will be added to the siloxane unit to form polytrifluoropropylmethylsiloxane or fluorosilicone oils. Fluorosilicone oils is heavier than water because they have a specific gravity of 1.25–1.3. Silicone oil is highly purified oil. This means that removal of impurities that are usually present, which impact on the chemical properties of the end product.[1] The lower-molecularweight Silicone oils tends to emulsified easily. Highly purified Silicone oil means impurities and the lower molecular weight components were removed. Determinants of viscosity is molecular weights of polymer chains and are in proportional relationship. So, viscosity may be higher if more high molecularweight polymers are produced and low if more low-molecularweight polymers are produced. The product is essentially a mixture of compounds, viscosity is determined by measuring the overall average value as a whole.[2] So, commercially available Silicone Oils are sold and classified according to the average viscosities of that compound. Physical Properties of Silicone Oil Specific Gravity Specific gravity of aqueous is around 1.01. So, it is assumed to be same as water (1.00). Specific gravity of Polydimethylsiloxanes (PDMS) is 0.97. It must be noted that specific gravity of all PDMS remains the same regardless of its chain length or molecular weight. This is because of the repeating unit of dimethylsiloxane molecular density which is independent of the chain length. Hence, specific gravities of all PDMS is 0.97, and they all float in water or aqueous. Buoyancy Buoyancy is the tendency of an object to float in a liquid. The area in contact with the retina, and shape and size of the bubble determines the effectiveness of tamponade by a bubble. This is governed by buoyancy. In gas bubble the buoyancy is large, the bubble takes the shape of a spherical cap. A spherical cap is DOS TIMES

DOS Times Volume 29, Number 6, November-December 2023 www.dosonline.org/dos-times 56 a sphere which have a flat bottom. Conversely, In Silicone Oil when buoyancy is small, the bubble assumes a round shape. That’s why, a gas bubble will make a larger area of contact against the retinal surface than an equivalent volume of Silicone Oil bubble. It has been seen that Silicone Oil bubble virtually makes no contact with the retina until the eye is near 50% filled. In contrast to Silicone oil, a small gas bubble (as small as 0.28 mL) Surface Tension and Interfacial Tension Surface tension is defined by Van de Waal forces between molecules. Interfacial tension is a general term which relates to the surface tension between two immiscible liquids. Interfacial tension is the force that tends to keep a bubble as a whole. It’s found that an oil bubble remains intact as long as the interfacial tension is more than 6 mN/m (milli-Newton/meter). This is important as a single bubble enhances effectiveness of the tamponade. When Silicone oil (1000 cSt) with pure water, interfacial tension was found to be 40 mN/m. and reduced to 33 mN/m when it is physiologic fluid. Interfacial tension is altered by presence of impurities such as proteins and lipids, or simply blood. For example, it was found that the interfacial tension in presence of blood can be further reduced to 14 mN/m.[4] already tamponades the retina up to 90° of arc on the retina.[3] So in order to achieve a good tamponade effect cavity is nearly 100% fill. Slightly underfill cavity with silicone oil predisposes the formation of a fluid film between silicone oil bubble and retina this reduces the tamponade effect because buoyancy of oil is less than gas. Figure 1: (A)Silicone oil globule a round shape due to lower buoyancy, leaving a film of fluid between it and retina. This occur even with only a slight underfill. (B)When the eye is slightly underfilled with C3F8,the tamponade effect is relatively better with only a film of fluid underneath the bubble. Viscosity Viscosity means the resistance of a fluid being deformed when under shear stress. Therefore viscosity is also known as shear viscosity. To deform a highly viscous liquid higher energy is required, while lower energy is required to deform a less viscous fluid. Generally, longer chain lengths Silicone oils have higher viscosity. This property of Silicone oils has practical implications, that is an ease of injection and removal is directly proportional to viscosity and two kinds of viscosities are involved, “shear” and “extensional” viscosities. It has been shown the greater the propensity for dispersion means lower the shear viscosity; and extensional viscosity is a measure of the resistance of the Silicone oil to break up when a globule is drawn into a strand. Satellite droplets is form when the strand breaks. DOS TIMES

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 57 Figure 2: Demonstration of how a thin strand of silicone oil breaks up when pulled apart. Physical Properties of Intraocular Gas Availability • Readily available • Not expensive Biocompatibility and safety • Nontoxic • Odourless • Colorless • Inflammable • Not cause lens opacity Variability in terms of longevity and expansile property • Water soluble Stable when mixed with air. There is no single gaseous product who have all the above desired properties. Gases could be used in pure forms or mixture with air. By mixing the pure form with air in different proportions the expansile property could be adjusted. Most commonly used gases are air, sulphur hexafluoride (SF6), perfluoroethane (C2F6) and perfluoropropane (C3F8). whereas Xenon was used for its shortest intraocular longevity. When the retinal breaks are multiple and their locations are widely separated then a large postoperative bubble is desirable. 20% concentration of SF6 is non expansile. If the vitreous cavity was totally filled with a bubble of 20% SF6 would last for about 2 weeks.[5] The bubble would be relatively large to give a sufficiently large area of tamponade in first few days to widely separated retinal breaks. SF6 is seldom used neat and it is inert, nontoxic, colourless, and is five times heavier than air. Hydrolysis occurs at high temperatures (>500°C) only. Water solubility varies according to the carbon chain length. Hence longer the carbon chain, the lower the solubility in water, so longer is the intraocular longevity. Effectiveness of tamponade is determined by shape of the bubble. The bubble would take the shape of the vitreous cavity when buoyancy is large and assume a flat bottom. In this way, most of the volume would contribute to making contact with the retina and to forming the meniscus a very little volume would be wasted. In case of Silicone oil, the buoyancy is small and the shape of the bubble would be rounded. In other words, very little of the volume would contribute to making contact with the retina; much of the volume of bubble would go to form the meniscus, and this would make no contact with the retina. The extreme case would be a spherical bubble inside a spherical cavity. Unless the fill is 100%, the contact would go from nil to total, total tamponade is probably unachievable practically. Function of Gas 1. Provide internal tamponade 2. Flatten folded retina 3. Enable visualization 4. Replace globe volume 5. Reduce intraocular currents Internal Tamponade Main indication of intraocular gases is to provide internal tamponade for retinal detachments. By utilizing the surface tension of the bubble, purpose is to oppose the break. As compared with liquid tamponade agents such as Silicone Oil, surface tension of gas is high. The upward force is greatest at the apex of the bubble, whereas it is near zero at the bottom, this will gives an estimation of the volume of the gas injected and the effective arc of tamponade. In preventing proliferative vitreoretinopathy (PVR), the tamponade bubble also acts to seal off the break, such that cellular elements can no longer escape from the subretinal space into the vitreous cavity. However, cellular elements who have already gone into the vitreous cavity tend to concentrate just beneath the bubble as a thin film of fluid. That’s why postoperative PVR is more commonly found inferiorly.[6,7] Unfolding and Folding of Retina To unfold the retina the surface tension and buoyancy play a major role. Sometimes circumferential folds occur with high radial buckles. These folds would be less prominent if SRF was drained and air was injected and the retinal redundancy would be minimized, as the retina would be made to follow closely the contour of the indent. Retinal fold will occur if SRF drainage was incomplete and a large bubble was injected. The patients would be very symptomatic when these folds involve the macula, complaining of distortion and poor vision.[8] This complication could be prevented by complete drainage of SRF before injection and postoperatively judicious posturing of the patients. This posturing might involve “steamrolling,” with the patient lying first with the retina break lowest most, then turning slowly to DOS TIMES

DOS Times Volume 29, Number 6, November-December 2023 www.dosonline.org/dos-times 58 position the bubble to the posterior pole, followed by posturing on the correct side. This type of maneuver use the bubble to drain the SRF out through the retinal break and to protect the macula from retinal folds. Post Operative Visualisation After vitrectomy and gas tamponade in postoperative period, the view of the fundus may be obscured by vitreous haemorrhage. By looking through the gas bubble it is possible to see the upper fundus, the aim is to look through the lower flat bottom surface of the gas bubble. But when the bubble is small, then fundoscopy is difficult and B-mode ultrasonography should be done. Replace Globe Volume In conventional scleral buckling surgery after the drainage of SRF, air is used. The air prevents SRF being recruited again. The air also restores the IOP. Without the presence of SRF, break localization would be more accurate and cryotherapy would be limited. This way, air serves a role as an intraoperative tool. Dynamics of Gas Bubble Inside Eye Different Phases of Gas Resorption Inside the eye the gas bubble undergoes three phases before complete resorption. The three phases are expansion, equilibration and dissolution. These phases occurs when pure expansile gases (i.e., SF6, C2F6, or C3F8) are injected, and air does not expand. pure SF6, C2F6, and C3F8 will expand when injected into the eye due to their lower water solubility than nitrogen. This is because nitrogen diffusion rate in the bubble is high than the rate of gas dissolved into the surrounding tissue fluid compartment. Initially in 6-8 hours, expansion is most rapid and is similar for all gases. Therefore rate is mostly affected by the convection currents in the surrounding vitreous fluid. The bubble reaches its maximum size when the gaseous diffusion in bubble is equilibrates. For SF6, maximum expansion occurs around 1-2 days after injection and for C3F8, it takes 3-4 days to reach its maximum size.[9] Practical implication of this is IOP may rise if the outflow facility cannot cope with the rapid increase in intraocular volume. Without significant IOP changes, the eye can accommodate up to 1.2mL of pure expansile gas injection. This equals to 20-25% of the vitreous cavity volume. Pure expansile gases should be avoided in eyes with occludable angles, or use prophylactically IOP-lowering agents. The equilibration phase begins when the partial pressure of nitrogen in the bubble equals that in the surrounding fluid compartment. There is a small net diffusion of expansile gases occur into the fluid compartment during this phase. This is due to the higher solubility of nitrogen, such that nitrogen equilibration is reached at a faster rate than other expansile gases. So during this phase the bubble diminishes slightly in volume. Duration of equilibrium phase is different for different expansile gases and is dependent on solubility.[9] Dissolution phase occur when partial pressure of all gases within the bubble equals that in the fluid compartment and this phase is longest in all three phases. As gases dissolve into the fluid compartment, the size of gas compartment gradually decreases and decrease in volume follows first-order exponential decay. Internal tamponade is only effective during the initial 25% of the bubble’s lifespan but a bubble takes 6-8 weeks to reabsorbs completely, because it requires at least 50% of the initial size to provide an effective tamponade. Internal tamponade is ineffective if the bubble is smaller than 50% or it breaks into a few smaller bubbles (i.e., fish eggs). Clinically, expansile gas is mixed with air to give a “nonexpansile” concentration. The time taken for complete resorption of the bubble will also depends on other factors such as lens status, aqueous turnover, presence of vitreous, presence of periretinal membranes, ocular blood flow, and ocular elasticity. In phakic non vitrectomized eyes the lifespan of SF6 and C3F8 may be more than twice than in aphakic vitrectomized eye. Intraocular Gases with General Anaesthesia During general anesthesia, the inhaled anaesthetic gases may interfere with intraocular gas volume. Nitrous oxide (N2O) is 34 times more water-soluble than nitrogen and 117 times than SF6.[10] If SF6 is used with N2O, the bubble may increase up to three times than its original size. After 15-20 minutes of nitrous oxide use because of its solubility max rise in IOP occur; and IOP decreases when it’s discontinued, as it diffuses out of the body via ventilation. The concentration of nitrous oxide in the lung alveolars is reduced by 90% after it has been stopped for 10 minutes. Therefore, nitrous oxide should be discontinued for at least 15 minutes prior to intraocular gas injection. Special attention is for those patients who undergoing general anesthesia for nonocular purposes while they still have an intraocular gas in situ. Central retinal artery occlusion and choroidal ischemia have been reported and that lead to severe visual loss. Response to Changes in Altitude When there is a change in altitude, significant change may occur in bubble size. This is important for patients undertaking air travel shortly after surgery. At an altitude of 8000 feet the airplane cabin pressure is equal to atmospheric pressure. during airplane ascent that is 2000-3000 feet per minute and the rapid expansion of bubble size may cause the IOP rise, that results into Central retinal arterial occlusion, and air bubble size may change during scuba diving. During scuba diving inhaled oxygen from compressed air tanks, gaseous equilibrium is affected by atmospheric conditions. When the diver returns to the surface, the increase in IOP will occur when the bubble expands inside the eye. Indications of Silicone Oil Retinal Detachment with Proliferative Vitreoretinopathy The Silicone Study defines the role of Silicone oil in the management of retinal detachments.[11] It was a multicenteric prospective randomized clinical trial compared the effect of Silicone oil and long-acting intraocular gases (SF6 and C3F8) in the management of complex retinal detachments associated with PVR grade C3 or above. In reattaching the retina, Silicone DOS TIMES

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 59 oil was effective as C3F8, and better than SF6 within first year of study and during follow up the difference diminishes at the end of second year.[11] Silicone oil and C3F8 were equivalent in terms of improving visual function and lower complication rates. The postoperative complications, particularly hypotony and keratopathy, Silicone oil did better than SF6. Relative contraindications of Silicone oil use is deficient iris diaphragm (e.g., aniridia) that might predispose to keratopathy. Gaint Retinal Tears In giant retinal tears, the posterior flap of retina is independently mobile, because the posterior flap edge does not have any vitreous attachment. When the extent of the tear is >90° it has a tendency to slip posteriorly. Role of Silicone oil in management of giant retinal tears is to unroll folded retina and to act as an extended internal tamponade agent. With introduction of PFCLs, folded retinal flap are unrolled and repositioned and endophotocoagulation is performed along edge of tear. The purpose of surgery is to reattach the retinal detachment without slippage or exposing a large area of RPE. Silicone oil over gas is preferred when the tear is more than 90° and especially when it involves the inferior retina. Severe Proliferative Diabetic Retinopathy Silicone oil tamponade is frequently used in primary vitrectomy for traction retinal detachment associated with severe proliferative diabetic retinopathy (PDR). Silicone oil have advantages if used as a tamponade agent following vitrectomy, It enables rapid visual recovery; it reduces postoperative vitreous haemorrhage and during examination it allows clear visualization of the fundus; it provide better tamponade for those patients who cannot posture after operation. Because Silicone oil occupies most of the vitreous cavity and it confines all dissolved oxygen in the anterior segment. It also prevents vascular proliferative factors in the posterior segment which are coming from anteriorly. This can be beneficial in cases of severe PDR especially in postoperative period where anterior segment neovascularization is prominent.[12] Injection of Silicone oil should be done after when haemostasis has been achieved and preretinal blood has been aspirated and this will reduces the risk of proliferative changes after the surgery. Macular Hole Treatment of choice for macular hole vitrectomy with or without internal limiting membrane (ILM) peeling, followed by internal tamponade with either gas or Silicone oil, with postoperative face-down posturing because the mechanical force generated by the tamponade agent and posturing would be helpful in closing the hole. A trial by Lai, compares the efficacy of macular hole closure rate with either gas or Silicone oil as tamponade after vitrectomy revealed a lower closure rate with Silicone oil. Due to the differences in results, gas has grown in popularity as the agent of choice. A recent study by using spectral domain optical coherence tomography (OCT) to capture macular hole closure showed that 77% closure rate was achieved on postoperative day 1 following vitrectomy with ILM peeling and gas tamponade. In pathological myopia, retinal detachments associated with macular holes, the currently vitrectomy is performed with an intraocular gas tamponade. Viral Retinitis Retinal detachment with viral retinitis is diffuse, relentless, and have a high redetachment rate. This is commonly due to cytomegalovirus (CMV) retinitis, as seen in immunocompromised patients, and acute retinal necrosis (ARN) is associated with herpes simplex type 1. Necrosis of the retina will cause retinal defects that lead to the detachments. Under these circumstances, Silicone oil provide long-term internal tamponade, and reduces the risk of redetachment. After surgery when the eye is filled with Silicone oil, intravitreal injection of ganciclovir would be concentrated as a thin layer of fluid film between the Silicone oil and retina. This will cause retinal toxicity. A recent study shows that by combining vitrectomy with Silicone oil tamponade, and ganciclovir implant insertion, 100% reattachment rate was achieved and 80% showed no CMV retinitis progression. Complicated Paediatric Retinal Detachment Main indications of Silicone oil tamponade in the paediatric population are retinal detachments associated with trauma, retinopathy of prematurity, congenital anomaly such as coloboma or optic disc pit, and myopia. Wong and colleagues have published a method in which sequential use of conventional Silicone oil and Densiron a heavier-than-water Silicone oil, has helped to reduces the number of reoperations. Trauma In severely traumatized eyes, internal tamponade with Silicone oil leads to flatten the retina and prevent haemorrhage, which increases the risk of PVR formation. In a recent retrospective case series of 88 patients with ocular injury and retinal detachment, Nashed and associates performed primary vitrectomy and Silicone oil tamponade within 8 hours of injury. Nashed concludes that frequency of endophthalmitis was relatively low and the development of postoperative PVR was avoided in most of the cases. This might be due to Silicone oil in situ. Endophthalmitis Apart from acting as an internal tamponade agent, Silicone oil also posses antimicrobial activity. Azad and associates performed a prospective randomized controlled trial, in posttraumatic endophthalmitis comparing the effect of vitrectomy with or without Silicone oil tamponade in 167 cases. Cases where Silicone oil was used, vision achieved a level of 20/200 or better in 58% of cases (seven out of 12), versus only 8% (one out of 12) among those where Silicone oil was not used. In another study, Yan and associates performed vitrectomy with Silicone oil tamponade in 18 posttraumatic endophthalmitis eyes and Postoperative visual acuity was increased in 83% of eyes. In a case series, 108 eyes with bacterial endophthalmitis were randomly assigned to receive either vitrectomy and intravitreal antibiotic alone, or with silicone oil as tamponade. The success rate was higher with silicone oil than those without oil. DOS TIMES

DOS Times Volume 29, Number 6, November-December 2023 www.dosonline.org/dos-times 60 Indications of Intraocular Gases In Vitrectomy for Retinal Detachments This is the one of the most common indications for intraocular gas injection. The choice of gas is depend on the availability of gases, and the surgeon’s experience and preferences. The choice of gas is depend on the intended duration of tamponade. In simple cases where duration required is short, air could be used. In more complicated cases where longer tamponade is needed, the nonexpansile concentration of gas/air mixture (18% SF6 or 14% C3F8) should be used. When a larger bubble is needed, a gas/air mixture with an expansile concentration should be used. This is for inferior breaks where a larger bubble could provide better tamponade and also has an advantage of being able to unroll folded retina. Pneumatic Retinopexy Before gas is injected, there are several prerequisites: (1) the retinal detachment is in the superior half of the retina (there is no inferior breaks or retinal thinning); (2) the break or hole is ideally solitary or grouped within 1–2 clock-hours; and (3) preferably the presence of posterior vitreous detachment (PVD). Local anaesthesia is usually sufficient. In this opposition of the retina to choroid is provided by the bubble initially, and later by the chorioretinal adhesion induced by cryotherapy. Gas is injected only after adequate cryotherapy. Pure expansile gas should be used. If the break is located at 12 o’clock, then the injection is at the midline. Gas is injected via 27G needle, 3.5-4 mm behind the limbus. To avoid “fish-egg” formation (small bubbles instead of one large bubble), the injection site is rotated such that it is in the uppermost part. The needle is inserted just deep enough to penetrate all layers, and the injection force should be swift and constant, aiming to create a single bubble. After injection, before pulling the needle out of the eye the injection site should be rotated laterally. To prevent leakage it is ensure that the bubble moves away from the opening before the needle is retrieved. If fish-egg formed, then the sclera is gently tapped a few times to promote fusion of the small bubbles. After injecting gas, to counter the increase in intraocular volume AC paracentesis can be done. The patient’s head is then rolled 180°, face-down position. This serves to unroll the folded retina associated with the break. The patient is then instructed to assume that position as much as possible, until the complete dissolution of the bubble has occurred. In Scleral Buckling for Retinal Detachment Generally Intraocular gas injection is not required with provided adequate drainage of SRF and relieving of traction with the buckle has been achieved. However, the use of intraocular gas is still invaluable in certain cases, for example when fishmouthing of the break on a circumferential buckle is seen and is insufficiently opposed by the buckle, or as a “salvage” procedure to save the patient from a reoperation. Intraoperatively we inject the gas towards the end of operation. This is because after injection the view of the fundus will be obscured. The injection technique is same as that in pneumatic retinopexy. In this major therapeutic component is sclera buckle, whereas gas bubbles only act as an adjunct to buckle. In Macular Hole Surgery In macular hole surgery, injection of intraocular gas tamponade is done followed by face-down posture for 1 week. For closure of macular hole this bubble provides a mechanical effect by the buoyancy force. The injecting technique is same as in retinal detachment surgery via vitrectomy approach. Closure rate was found similar between air and 20% SF6, and between 20% SF6 and 12% C3F8. The choice of gas is based on the surgeon’s preference and experience. In Displacement of Sub Retinal Blood Pneumatic displacement of subretinal blood clot is in treatment of polypoidal choroidal vasculopathy, macroaneurysm, choroidal neovascularization, and trauma. It shown the early recovery of vision, and reduce the harmful effect of blood on the photoreceptors. The treatment procedure starts within 1 week from onset of haemorrhage, with tissue plasminogen activator (TPA) injection. With use of TPA there is improvement in vision and reduction in scar area. Distinction between subretinal blood and intraretinal blood should be made prior to injection. In intraretinal blood the gas will not displace the clot, rather increases the chances of blood dispersing into the vitreous. The injection technique is same as in pneumatic retinopexy. Complications of Silicone Oil Silicone Oil in Anterior Chamber This occur when the barrier at the level of the lens- iris diaphragm is inadequate to stop Silicone oil from migrating into the anterior chamber. This is due to aphakia, loose zonular support, blockage of the inferior peripheral iridectomy (frequently occurs with extensive surgery involving retinotomies, 360° photocoagulation, and extensive cryotherapy) or a break in the posterior capsule. Silicone oil in the AC occur either during surgery or in the postoperative period. Silicone oil can be undetected when the AC is completely filled with Silicone oil, because there is no fluid meniscus. Confirmatory signs of an AC completely filled with Silicone oil is a slightly posterior bulging iris, shimmering reflex on the iris crypts, and absence of aqueous flare in the AC. With raised IOP the pupil can be mid-dilated. Because the AC is completely filled with Silicone oil, the cornea is clear and hydration of the cornea is not possible. Corneal oedema occurs if Silicone oil is removed and significant damage to the corneal endothelium has occurred. With air or viscoelastic agents the Silicone oil is displaced back into vitreous cavity at the end of the surgery. An inferior peripheral iridectomy should be done, and the patient should be postured upright or slightly face-down. A small bubble of Silicone oil in the AC would empty itself into the large bubble behind in the vitreous cavity, if they were allowed to join. This is due to Laplace’s Law which states that smaller bubbles have higher surface energy compared with larger bubbles. If a small bubble in the AC does not reunite with the larger bubble of vitreous so it’s not causing any complications and it can be left in DOS TIMES

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 61 situ. If silicone oil is left in AC, it can cause visual disturbance, induce corneal endothelial cell loss, and trabecular damage. Late migration of Silicone oil into the AC is due to recurrent detachment or hypotony. Hypotony is caused by a combination of ciliary body shutdown and over drainage of aqueous by the uveal-scleral pathway (especially where large retinotomies have been done). Conservative management is appropriate. Glaucoma After surgery with Silicone oil rise in IOP can divided into: 1. Pupil block glaucoma 2. Overfilling of vitreous cavity with silicone oil 3. Secondary open and close angle glaucoma 4. Migration of Silicone oil into the AC Pupil block glaucoma occurs in an aphakic eye, usually in early postoperative period, with nonfunctioning peripheral iridectomy,[13] or blockage by inflammatory products such as fibrin or blood. When the peripheral iridectomy is nonfunctioning then aqueous accumulates behind the iris and forces Silicone oil bubble through the pupil. When this phenomenon progresses that result in pupil block. Treatment is reopening the peripheral iridectomy with YAG laser or surgically. If blockage is due to by fibrin or clot then injection of tissue plasminogen activator (tPA) into anterior chamber. If the cause of IOP rise is overfill of the eye with Silicone oil, the anterior chamber appears shallow. In aphakic eye, Anterior chamber is so shallow that it will lead to secondary angle closure. Overfill eye with silicone oil in pseudophakic or phakic eye can result in oil coming in front of the crystalline or intraocular lens, and herniating through the pupil. Overfill in aphakic eye can be treated with removal of oil via a corneal or pars plana incision. In the pseudophakic or phakic eye, removal of the oil from the posterior segment is not sufficient, evacuation is difficult once the oil is trapped between the lens or intraocular lens and the iris and the patient is taken back to theater for complete evacuation of the oil and reinjection. Pressure should be normal at the end of surgery so that overfilling can be avoided. This applies if encircling or scleral buckling is applied after Silicone oil injection. The cause of secondary open angle glaucoma is due to mechanical blockage of the trabecular meshwork due to silicone oil, or trabeculitis induced by emulsified Silicone oil. Medication comprises the initial treatment. If IOP continues to rise then over trabeculectomy (risk of failure due to fibrosis) glaucoma surgery in the form of drainage device is prefered. Silicone oil under the conjunctiva causes periocular fibrosis involving foreign body giant cell reaction. In the Silicone Study, at 36 month follow up 8% of cases that underwent Silicone oil tamponade experienced glaucoma. In refractory cases, transscleral cyclodiode photocoagulation (TSCP) could be used to lower IOP. Secondary angle closure glaucoma is a diagnosis of exclusion and ensure that the peripheral iridectomy must be patent. Chronic Hypotony This complication occurs in late postoperative period and defined as= IOP ≤5 mmHg in the Silicone Study. Low IOP is due to combination of increased aqueous uveal–scleral outflow and reduced production. Large retinectomies is the cause of increased aqueous uveal–scleral outflow. Ciliary body alterations is the cause of reduced aqueous production. Removal of SO risks the progression to phthisis, hence hypotony. IOP measurement in patients with uveal–scleral outflow should be done with care. With applanation tonometry, the IOP can appear to be high initially. increase in uveal outflow occur with act of applanation and indentation. With repeated measurements, the IOP can come to zero. Removal of Silicone oil will further increase the uveal–scleral pathway and promote phthisis. Hence, the Silicone oil is preferably left in situ. Cataract Formation Formation of cataract in phakic eyes after vitrectomy and Silicone oil tamponade is multifactorial. The exact mechanism is uncertain, although an impaired metabolic exchange across the posterior capsule and direct toxicity is speculated. In case of gas tamponade, posterior subcapsular feathery lens opacity is seen in the early postoperative period. A more specific and early feature of Silicone oil-induced cataract is lens vacuoles in the posterior part of the lens. Early posterior lens opacities may resolve and give a way to nucleus-sclerosis. Cataract formation associated with vitrectomy is nucleus sclerosis little or no brunescence. Finally, rapid progression to hypermaturity can occur with white cataracts. The lens swells up quickly over a matter of days, and leakage of protein occur into anterior chamber and brisk uveitis. However, it resolves spontaneously with time. Cataract is inevitably forms if Silicone oil is kept in situ for long-term tamponade purposes in the form of posterior subcapsular cataract or nucleus sclerosis. To minimise the risk of cataract formation early removal of Silicone is done, but there are cases of cataract formation even with Silicone oil removal as early as 6 weeks after surgery. Leaver and associates showed that in relatively young patients, despite early removal of silicone oil cataract occurs with follow-up of 2 years. So some surgeons prefer combined phacovitrectomy. In phakic Silicone oil-filled eyes, combined phacoemulsification with continuous capsulorrhexis of the posterior capsule, with implantation of the intraocular lens in the bag, With introduction of PMMA and acrylic IOLs, the use of silicone IOLs become less popular. Risk associated with silicone IOLs in eyes with Silicone oil in situ is formation of intractable adhesion of Silicone oil onto the surface of IOLs. Silicone oil adherent to intraocular lens implant cause blurred vision, polyopia, and distortion. Removal of these droplets is proved to be difficult. In a recent study by Stappler and colleagues, F4H5, a hydrophobic semifluorinated alkane, was used to dissolve adherent Silicone oil droplets on IOLs.[14] With ultrasound biometry, measurements of axial lengths in Silicone oil filled eyes is affected by differences in the speed of sound wave in vitreous and Silicone oil. The speed of sound wave in Silicone oil is 986 meters per second (m/s), and in vitreous DOS TIMES

DOS Times Volume 29, Number 6, November-December 2023 www.dosonline.org/dos-times 62 fluid is 1552 m/s. Hence, in Silicone oil filled eye, the time taken for the sound wave to return to the receiving sensor is longer than when the same eye is filled with vitreous. The resulting axial length is falsely long, which leads to a hyperopic shift if the uncorrected measurement is used for IOL power calculation. In a recent study, immersion B-scan guided ultrasound biometry is found to better as compared to contact A-scan biometry in Silicone oil filled eyes. A “conversion factor” of 0.71 gives good accuracy with a mean of only 0.74 diopters difference between the predicted and actual postoperative refraction. While ultrasound biometry with special formulae is the “gold standard” to measure axial lengths in Silicone oil filled eyes. Using infrared partial coherence interferometry, measurements in axial length could be done. A myopic shift is reported with the use of combined phacovitrectomy and intraocular lens implantation, with or without tamponade. Reccurent Retinal Detachment Missed retinal breaks cause recurrent retinal detachments even in the absence of PVR, either with Silicone oil or after Silicone oil removal. Results from the Silicone Study shows that the rates of redetachment when compare with Silicone oil or to gas were not significantly different. Redetachment is not have a direct relationship with whether Silicone oil was used or not. Jonas and associates identified risk factors associated with redetachment after Silicone oil removal among 225 patients. They include the number of previously unsuccessful retinal detachment surgeries, preoperative visual acuity, incomplete removal of the vitreous base, and absence of an encircling band. Redetachment rate were independent of Silicone oil removal methods and duration of endotamponade. A prospective randomized trial by Avitabile and associates examined benefit of prophylactic 360° laser in cases where there is a need for Silicone oil tamponade. In 151 eyes Prophylactic 360° laser was done, while no laser was done in 152 control eyes. Redetachment occurred in 8.63% study eyes, compared to 20.93% among the control eyes (p=.007). Hence, 360° laser is considered as an adjunct to enhance the chance of anatomic success after Silicone oil removal. Emulsification Emulsification of SO is an inherent problem. Dispersion of SO means breaking-up of large bubbles into smaller droplets. The surface energy of smaller droplets is higher therefore they have a tendency to coalesce to form a larger bubble. When surface energy of the droplets is reduced in the presence of surfactants then emulsification occur. Surfactants include phospholipid, protein, lipoprotein, or even solid cellular debris. Dispersion requires shear force between the oil and the retinal surface and it is dependent on rate of eye movement. Normal saccadic velocity reaches 300-400/second. When the eye moves intraocular fluid remains relatively stationary. The peak shear velocity is approximately closely to the saccadic velocity of the eye. The shear force depends on this relative velocity, and also the thickness of the film of aqueous between the Silicone oil and film of fluid can be very thin if eye is completely filled with silicone oil. It is found that higher viscosity Silicone oils tend to be more difficult to disperse. Higher the shear viscosity means higher the extensional viscosity (extensional viscosity is usually three times that of shear viscosity, depending on the shear strength). Emulsification leads to glaucoma, inflammation, and PVR formation. Emulsification occur as quickly as 1 week after surgery, but the mostly occur few months after surgery. It was due to combined result of friction between Silicone oil and other intraocular fluids, and a reduction in the interfacial tension as a result of absorption of active components from other intraocular fluid, that causes the emulsification process and emulsification of Silicone oil is inversely proportional to its viscosity. Keratopathy Prolonged use of Silicone oil may cause keratopathy, either in the form of band keratopathy, which is more commonly seen in early stages, and bullous keratopathy present in late stages. Keratopathy rate observed in the Silicone Study was 27% after 24-month follow-up. This was identical to the rate seen in eyes randomized to C3F8. Contact between Silicone oil and the corneal endothelium has a major contributor to the development of keratopathy. To minimize the risk of keratopathy is reducing the chance of Silicone oil migration into the AC. This is ensure by a patent peripheral iridectomy and removal of the Silicone oil. Unexplained Visual Loss After Silicone Oil Tamponade The exact mechanism is unclear. It is speculated that it may be due to sudden change in physiologic environment affecting ionic exchange. Scheerlinck investigated the contents in retro-oil fluid and paired serum from 16 patients who underwent oil removal. Results shows that the mean potassium levels in retro-oil fluid and vitreous humour were similar and the levels of magnesium and chloride were lower in retro-oil fluid compared with vitreous humour and Lactate dehydrogenase levels (LDL) level were higher in retro-oil fluid. However, differences in magnesium levels and LDL across the retro-oil fluid and vitreous humour give hints to further research to find out the ultimate cause. Removal of Silicone Oil In practice deciding when to remove SO is difficult. Theoretically, chorioretinal adhesion will form certainly by 1 month. However, Silicone oil is retained longer than this, the presence of the oil and the tamponade force resist any traction caused by reproliferation. The duration of the reproliferating process is less certain if the retina remains attached and it is assumed that the cellular process of PVR would naturally resolve. Removal should be done when the Silicone oil bubble served its purpose, and further retention increase the risk of complications. Removal within the first 6 months after surgery is generally recommended. Emulsified droplets adhere to the ciliary processes, zonules, and posterior aspects of the iris. These become obvious postoperatively and patient complains when patients put their head down, when these bubbles come near the line of sight. Emulsified droplets is adhere to cellular debris such that they are almost density neutral. They may drift in the visual DOS TIMES

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 63 field gives the sensation of floaters. During removal of Silicone oil, the cannula stays within the main bubble. With aspiration, see a “vortex” developing within the oil and If the cannula comes out of the bubble, the individual bubble of oil is isolated and left behind. Therefore, during surgery, the vortex is closely observed, and the cannula is manipulated such that it does not aspirate infusion fluid or come out of the oil. Complications of Intraocular Gas Cataract Formation Gas-induced cataract in the form of feathery posterior subcapsular cataracts or appear as vacuoles at the superior portion of the lens. Incidence of cataract is higher if the eye is two-thirds or more filled with gas and also more likely if the gas is highly pure and longer longevity.[15] It is Assumed that prone position and leaving a thin layer of anterior hyaloid helps in prevent the cataract formation because they isolate the bubble from the lens. In mild form, gas-cataracts resolves without treatment. For persistent opacities, sometimes surgical removal may be required, especially when view of the fundus is compromised. If cataract extraction is done with bubble is in situ then aspiration of gas before cataract extraction is needed. Otherwise, the bubble will push the posterior capsule upwards and increase the risks of complications. Raised Intraocular Pressure Expansile gases of high purity tend to cause IOP rise more frequently. Risk factors for rise in IOP includes the combined use of encircling band, the agent of tamponade, and the combination of cataract extraction and usually due to overfill or expansion of the bubble, which cannot be compensated by the outflow facility and this is usually short-lived and can be managed without difficulty using antiglaucoma medications. Refractory cases may be due to outflow compromise by peripheral anterior synechiae (PAS), preexisting angle closure glaucoma, or neovascular glaucoma. So in these cases air or a nonexpansile gas/air mixture should be used to reduce the risk of postoperative IOP rise. Other than medical treatment, excess gas could be partially aspirated and reduce the volume and hence the IOP. Secondary glaucoma with intraocular gas use is infrequently seen. It occur with angle disruption from forwardly displaced lens-iris diaphragm by a large bubble especially if they cannot adopt prone posture after surgery. Therefore in patients with cervical spine problems who cannot assume a face-down posture, nonexpansile gas or air should be used, and complete filling is avoided. Hypotony Hypotony results if a bubble can leak from sclerotomies either at the end of operation during wound maneuvers, or postoperatively, through a leaky wound. It should not be overlooked, because with prolong hypotony choroidal effusion or haemorrhage may occur. Observation is enough for mild cases but when hypotony is prolonged or if the risk for choroidal haemorrhage is high then reinjecting the gas is indicated by pars plana approach at the slit lamp. Subretinal Gas Migration of gas into the subretinal space occur in both intraoperatively, or in postoperative period. It occur either because the bubble is smaller than the tear, or when persistent traction elevates the retina and allows passage for gas into the subretinal space. The bubble can be displaced with scleral depression externally if noted intraoperatively. In postoperative period, if the bubble has gone into the subretinal space, it can affect proper attachment of the break and lead to redetachment. Gas in Anterior Chamber and Corneal Decompensation This occur in aphakic eyes or in pseudophakic eyes with nonintact posterior capsule and view of the fundus is oftenly compromised. If noted intraoperatively, AC will be filled with viscoelastics prior to proceeding and If found postoperatively, it will left alone and will be absorbed within a few days. Prolonged contact of the bubble in aphakic eyes may predispose the corneal endothelium to hypoxia and decompensation. This is due to the interruption of aqueous flow to the endothelium, which lead to reduces the oxygen supply. In such cases, Avoiding lying supine that may reduce bubble-endothelium contact and reduce the risk of corneal decompensation. Intraocular Lens Capture During phacovitrectomy and intraocular gas injection, the intraocular lens (IOL) may be pushed forward into the AC and causing optic capture. This can be prevented by limiting the anterior capsulorrhexis to a size smaller than the optic of the IOL. The patient is advised to avoid a faceup posture. The condition is left alone if there is no tilting of the IOL and disturbance to vision is minimal. Repositioning of the IOL is needed if dislocation has occurred or pigment dispersion is significant. Summary Intraocular tamponades are a useful surgical tool because they simplified the surgical management of many vitreoretinal diseases. With modern vitrectomy system, use of different tamponade substances has improved the prognosis of several diseases and silicone oil has proven itself to be an effective endotamponade agent, especially in the management of complex retinal detachments associated with proliferative vitreoretinopathy. High-molecular-weight silicone oil can reduce the risk of emulsification. In the Silicone Study, efficacy of silicone oil is equally effective when compared with C3F8. Also the Intraocular gas has grown into an indispensable part of vitreoretinal surgery. The high surface tension and buoyant force is highest in gases among the available vitreous substitutes. Surgeon can manipulate the procedure according to clinical scenarios due to versatility of types and concentration of gases available and has hugely improved the operative success rate. The anatomic success is reliant on the complete removal of tractional membranes, and the tamponade agent serves best as an adjunct to it, regardless whether it is Silicone oil or intraocular gas. DOS TIMES

DOS Times Volume 29, Number 6, November-December 2023 www.dosonline.org/dos-times 64 References 1. Pankratov MM, Sebag J, Refojo MF, et al. Biochemical effects of intraocular silicone oil in the squirrel monkey. Invest Ophthalmol Vis Sci 1987;28:S210. 2. Ference M, Lemon HB, et al. Analytical experimental physics. 2nd ed. Chicago, IL: University of Chicago Press; 1956. p. 141–68. 3. Parver LM, Lincoff H. Mechanics of intraocular gas. Invest Ophthalmol Vis Sci 1978;17:77–9. 4. Yamanaka A, Matsuda T, Nakamae K, et al. Interfacial aspects of liquid silicone as an artificial vitreous body. Presented in part at the Fifth Vail Vitreoretinal Seminar, Vail, CO, March 1986. 5. Noble J, Kanchanaranya N, Devenyi RG, et al. Evaluating the safety of air travel for patients with scleral buckles and small volumes of intraocular gas. Br J Ophthalmol 2014;98(9): 1226–9. 6. Khan MA, Brady CJ, Kaiser RS. Clinical management of proliferative vitreoretinopathy: an update. Retina 2015;35(2): 165–75. 7. Pastor JC, Rojas J, Pastor-Idoate S, et al. Proliferative vitreoretinopathy: a new concept of disease pathogenesis and practical consequences. Progr Retinal Eye Res. 2016;51:125–55. 8. van Meurs JC, Humalda D, Mertens DA, et al. Retinal folds through the macula. Doc Ophthalmol 1991;78(3–4):335–40. 9. Peters MA, Abrams GW, Hamilton LH, et al. The nonexpansile, equilibrated concentration of perfluoropropane gas in the eye. Am J Ophthalmol 1985;100:831–9. 10. McCarthy D. The effect of nitrous oxide on intra-ocular pressure. Anaesthesia 2012;67(6):680–1. 11. McCuen BW 2nd, Azen SP, Stern W, et al. Vitrectomy with silicone oil or perfluoropropane gas in eyes with severe proliferative vitreoretinopathy. Silicone Study Report 3. Retina 1993;13: 279–84. 12. Castellarin A, Grogorian R, Bhagat N, et al. Vitrecctomy with silicone oil infusion in severe diabetic retinopathy. Br J Ophthalmol 2003;87:318–21. 13. Madreperla SA, McCuen BW II. Inferior peripheral iridectomy in patients receiving silicone oil. Retina 1995;15:87–90. 14. Stappler T, Williams R, Wong D. F4H5: a novel substance for the removal of silicone oil from intraocular lenses. Br J Ophthalmol 2010;94:364–7. 15. Thompson JT. The role of patient age and intraocular gas use in cataract progression after vitrectomy for macular holes and epiretinal membranes. Am J Ophthalmol 2004;137(2): 250-7. Dr. Prithvi Raj, MS Senior Resident SMS Medical College, Jaipur Rajasthan. Corresponding Author: DOS TIMES

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 65 Drug Master File: Importance and Benefits Rahul Pathak, PhD, Rajat Singal, MD, Sandip Mitra, PhD, Sanjay Koul, PhD, Supriya Sharma, MBA Mankind Pharma. Abstract: Ensuring the safety and quality of the medicine stands as a pivotal element in the evolution of any pharmaceutical industry. This necessitates rigorous oversight in both the manufacturing and marketing phases of the drug development. A Drug Master File (DMF) is a confidential document used to provide detailed information about facilities, processes or articles used in the manufacturing process, packaging and storing of one or more human drug. Numerous countries operating within highly regulated markets rely on the DMF system. This reliance serves the dual purpose of safeguarding intellectual property rights while furnishing precise and detailed information about products to regulatory entities. The adoption of a DMF system in India may provide substantial advantages for regulatory bodies, pharmaceutical industries and ultimately, patients. This review aims to present a comprehensive perspective on the DMF, emphasizing the importance of its integration into the regulatory framework in India. Keywords: DMF, Pharmaceutical industries, India Introduction The Indian pharmaceutical industry ranks third globally in pharmaceutical production by volume and is known for its generic medicines and low-cost vaccines. The sector contributed to around 1.32% of the Gross Value Added (at 2011-12 constant prices) of the Indian Economy in 2020-21. The total annual turnover of Pharmaceuticals in the fiscal year 2021-22 was Rs. 3,44,125 crore (USD 42.34 Bn). Major segments of Indian Pharmaceutical Industry include generic drugs, OTC medicines, bulk drugs, vaccines, contract research & manufacturing, biosimilars and biologics. There are 500 API manufacturers contributing about 8% in the global API Industry. India is the largest supplier of generic medicines. It manufactures about 60,000 different generic brands across 60 therapeutic categories and accounts for 20% of the global supply of generics. Because of the low price and high quality, Indian medicines are preferred worldwide, making it “pharmacy of the world”.[1] While the Indian pharmaceutical industry is a significant contributor to the global pharmaceutical market and has made substantial progress, it has faced various challenges related to quality issues. Some of the common quality issues in the Indian pharma market include: Data Integrity Concerns: Instances of data manipulation and lack of data integrity have been reported. Proper documentation and adherence to good documentation practices are crucial to ensuring the reliability and accuracy of data.[2] Good Manufacturing Practices (GMP) Compliance: Adherence to GMP guidelines is essential for ensuring the quality and safety of pharmaceutical products. Some companies in the Indian pharma market have faced challenges in consistently maintaining GMP compliance, leading to quality issues.[3] Contamination and Cross-Contamination: Contamination of pharmaceutical products or crosscontamination during manufacturing can compromise product quality. Stringent measures are needed to prevent such issues, especially in facilities manufacturing different products.[4] Quality Control and Testing Challenges: Inadequate quality control measures and testing procedures can lead to the release of substandard or contaminated products. Ensuring robust quality control processes is critical for maintaining product quality.[5] Regulatory Compliance Issues: Some companies may face challenges in meeting regulatory requirements, both domestic and international. This can lead to regulatory actions, including warning letters and product recalls.[6] Counterfeit Drugs: The prevalence of counterfeit drugs is a concern in the Indian pharmaceutical market. These fake drugs may contain incorrect ingredients or incorrect dosage levels, posing serious risks to patient health.[7] Documentation and Record-Keeping: Inadequate documentation practices and poor record-keeping can lead to difficulties in tracing the manufacturing history of a product. This is critical for investigating quality issues and implementing corrective actions.[8] API Sourcing and Quality: The sourcing of Active Pharmaceutical Ingredients (APIs) from suppliers with substandard quality control measures can affect the overall quality of finished pharmaceutical products.[9] To address these issues, there has been an increased focus on regulatory enforcement, industry collaboration, and continuous INDUSTRY NEWS

DOS Times Volume 29, Number 6, November-December 2023 www.dosonline.org/dos-times 66 improvement initiatives. Regulatory authorities, both in India and globally, play a crucial role in ensuring that pharmaceutical companies adhere to the highest quality standards to protect public health. Additionally, industry stakeholders are working together to promote a culture of quality and compliance within the Indian pharmaceutical sector. Drug Master File A Drug Master File (DMF) is a sensitive document that contains complete, factual, and correct information about the active pharmaceutical ingredient. DMF is a document prepared by the drug products manufacturer or excipient and submitted to the targeted market’s regulatory authority. It is a submission to the FDA (Food Drug and Administration) covering information on chemistry, stability, purity, impurity profile, packaging, and cGMP status of any API. The US FDA requires a DMF submission of a drug substance, drug product, and container closure if there is an absence of relevant information in the CMC (Chemistry, Manufacturing, and Controls) section of an application, to allow FDA to review facts such as confidential details about procedures, facilities, components, or articles used in the manufacturing, processing, packaging, and storing of one or more APIs and human drugs. The information available in a DMF is used to support a New Drug Application (NDA), Investigational New Drug Application (IND), an Abbreviated New Drug Application (ANDA), another DMF, an Export Application, or related documents.[10] While applications mentioned above may contain information about the drug, a DMF provides additional unique information and facilitates communication between manufacturers and regulatory bodies while protecting intellectual property rights (IPR). There are different type of DMF submission such as (Type II) Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation; or Drug Product, (Type III) Packaging Material, (Type IV) Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation and (Type V) FDA-Accepted Reference Information.[11] Role of DMF • DMF plays a crucial role for the manufacturers of Drug products and supports the documents for drug products’ registration/approval. • Registered APIs published on websites helps in the marketing of APIs to all drug product manufacturers. • In the CMC sections of the drug submission, drugs identity, purity, strength, and quality. • To protect proprietary and confidential information.[10] Need of Having a DMF: An Indian Outlook DMF is a common application in many countries with highly regulated markets. India does not have its own DMF guidelines.[10] This absence warrants the need of establishing a DMF system in India to promote a better quality of pharmaceutical products benefitting the pharmaceutical companies as well as the patients.[10] It is important to note that the DMF provides confidential and comprehensive information about human drug development to the regulatory bodies while safeguarding the intellectual property rights of the manufacturer. By serving as a confidential repository of scientific and technical information, DMF secures the information from competitors and unauthorized access. DMF filing can be a game changer when multiple partners are involved in the development and production of a drug product. It facilitates efficient communication and collaboration with better information sharing, eventually resulting in streamlined and cost-effective processes for drug development. It also encourages drug manufacturers to comply with regulatory requirements and adhere to good manufacturing practices (GMP).[10] Given the advantages of DMF filing in better patient care, Mankind Pharma is currently involved in building awareness around it, among all stakeholders. As on date, Mankind has a number of DMFs for various products, spread across therapy areas such as ophthalmology, dermatology, endocrinology, pulmonary, cardiology, dermatology etc., with a strong resolve to continue its efforts to include many more products in this category.[12] As a part of its continuing efforts, Mankind has even introduced DMF quality material for manufacturing of packaging material. Through these DMFs, Mankind strives to ensure that high-quality medicines are available to the public at affordable prices. Future Perspectives Ensuring compliance with the regulatory authority’s guidelines and measuring up to the quality of the global market is impertinent for Indian pharmaceutical manufacturers to facilitate the growth of the Indian pharmaceutical industry with quality products. DMF can prove to be a key element in bringing about significant improvements, to the same. Disclaimer DMF is not mandated under India Law and is not a quality norm for products in India. References 1. https://pharmaceuticals.gov.in/sites/default/files/Annual%20 Report%202022-23%20Final-3_0.pdf. 2. Data-integrity woes have come back to haunt Indian pharma. How can it deal with the USFDA’s glare? 99712904. 3. https://economictimes.indiatimes.com/industry/healthcare/biotech/ pharmaceuticals/most-small-drug-companies-unnerved-by-gmpcompliance-norm/articleshow/103998338.cms. 4. https://www.cnbctv18.com/healthcare/drug-contaminationcrisis-toxic-cough-syrup-norris-medicines-fourrts-india-cdscocrackdown-17967621.htm. 5. https://www.akums.in/the-pharma-industrys-quality-andregulatory-challenges-in-india-lessons-learned-way-forward. 6. https://www.drishtiias.com/daily-updates/daily-news-editorials/ regulatory-challenges-of-indian-drugs. 7. https://timesofindia.indiatimes.com/blogs/voices/counterfeit-drugsa-major-public-health-threat/. INDUSTRY NEWS

www.dosonline.org/dos-times DOS Times Volume 29, Number 6, November-December 2023 67 8. Patel KT and Chotai NP. Documentation and Records: Harmonized GMP Requirements. J Young Pharm. 2011 Apr-Jun; 3(2): 138–150. 9. www.statnews.com/2019/07/22/indian-pharmaceutical-industrydrug-quality-charges/. 10. Sravanti, Veera Kota Lakshmi, Ruchitha Bandla, and Ravi Kumar Reddy Juturi. “Filing of DMF in the US, EU, and India, and its comparative review.” International Journal of Drug Regulatory Affairs 9.1 (2021): 22-32. 11. https://www.fda.gov/drugs/drug-master-files-dmfs/types-drugmaster-files-dmfs. 12. Data on file. Mankind Pharma. 2023. Dr. Rahul Pathak, PhD Senior Manager, Medical Affairs Mankind Pharma. Corresponding Author: INDUSTRY NEWS

DELHI OPHTHALMOLOGICAL SOCIETY A-23, 1st Floor, Green Park Main, New Delhi - 110016 Email: [email protected] / [email protected] Web: www.dosonline.org