Document ExppxBK9ZyZ2ZwVKjyBM3BnqV

MAR I 0J392 BFGOODRICH GEON VINYL DIVISION INTER-ORGANIZATION CORRESPONDENCE ******************************** To: Dr. Bob Hinderer OTM - 3 From: Chris Andersen Date: March 6, 1992 RELIANCE PETROCHEMICALS REBUTTAL TOXICITY OF PVC USE FOR BLOOD BAGS Reliance Petrochemicals Limited is our most recent operating licensee. The PVC portion of their 150,000 MTA VCM and PVC plant north of Bombay was successfully commissioned in December 1991. The VCM plant is currently being commissioned. The suspension PVC technology licensed by us is our current large poly technology and they are licensed for the full range of recipes including the low IV bottle resin (K-57 or 110X357). Attached is a letter from their Product Application and Research Centre regarding several publications released in India which claim toxicity issues regarding the use of PVC in medical areas. I would appreciate your comment and if there are any literature or media releases which we could provide for their use in responding to the issues. Thanks, f: 1541001 in Reliance Petrochemicals Limited Product Application & Research Centre Apto Afnatgwmtiem flwKng. >nrnBV MB Cwiyownd. VX Pim Utr^. Qnte, fcombty - M* T*: 2) SS22S47, 5523013, 5523228. S52S009 Fax; (2Q 5524006 Facsmile Transmittal Cover Sheet Date : 27.02.1993 Ref :?ARt/3t2/ h^olU Fax No.: 001-216-447-6551 Company: b.f. Goodrich Attn: Mr. CHRIS ANDERSEN Location: u. s. a . From: Dr. y.N. sharma cc: Total No. of pages including this page: 1 + 6=7 Covering Message One of the Manufacturers of Intravenous (I.V.) sets based on MDPE has been publishing reports in the Indian News Papers on harmful effects of PVC when it comes in contact with fluids for I.V. Sets, blood bags etc. These reports create a damaging effect on the use of PVC for medical applications. I am enclosing herewith the copies of the publications recently appeared in the News Papers. I am sure you have a large data base and will be kind enough to send us the relevant literature to publish rejoinder in the News Papers to remove misgivings created in the miDds of Indian public. Your help in preparing the rejoinders will be highly appreciated. With regards, Y.N. SHARKA Ends : Afts above ZOOTfrSTZ A Reliance Group Company P.V.C. FACTS 1 D.E.H.P. (Di-2-ethylhexylphthalate ester) For over 30 years the only collapsible non-venting intravenous containers commercially available were those manufactured from Polyvinyl Chloride. To provide the desirable physical characteristics, particularly clarity and flexibility. PVC contains significant quanti ties of plasticizers: some finished products may contain upto 40% of these plasticizers. Presently one commonly used group of plasticizer is phthaiic add esters, of which DEHP is the most widely used. Evidence has been accumulating to indicate that small quantities of plasticizers have been leaching from such materials into blood stored in PVC bags and into other I.V. solutions (1). There have been reports earlier, that PVC containers have the tendency to release plasticizers as well as additives into the I.V. solution. But concern for possible health consequences from leaching of these plasticizers was not carried out until 1970 when Jaeger and Rubin (2) found conclusively the presence of DEHP (Di-2-ethylhexyl-pthafate ester) in tissues and organs of 2 deceased patients who had received blood transfusion from a PVC container plasticized with DEHP. It has been found that PVC leached DEHP, a toxic substance and the toxicity increased as the percentage of additives increased (3). Due to the increased concern and extensive debate on the toxic effects of plastidzers like pthalate ester present in PVC, many studies have been dedicated to this particular subject. In 1972, Singh, Lawrence and Autian (1) published results which showed that phthalate ester plastidzers induced foetal malformations at high dose levels. The authors have commented that the possible cumulative nature of the effect of the plasticizer in the body should be considered and have supported the findings of Jaeger and Rubin (1) that the rat liver did not hydrolyse DEHP but tended to sequester and accumulate it Hillman, Goodman and Sherman in 1975 (4) demonstrated that the accumulation of DEHP in critically ill infants was high. DEHP was found, in the hearttissue ofpatients from the study group, having concentrations 9 times higher than those in the control group. It has been shown that due to the immature microsomal enzyme systems in newborns,they have difficulty in metabolising DEHP. Autian (5) 1973, concluded that even though it is unlikely that pregnant women will be exposed to sufficientlyhigh dose levels ofpthalate esterto produce embryotoxic effects and birth defects, caution should prevail and expectant mothers should be afforded the maximum protection against these esters. Furthermore, in PVC pouches, DEHP has been shown to be the causative factor for high particulate matter content. This is due to the liquid particles of DEHP which, in the resting position, adhere tothe wall ofthe container, buton agitation are dispersed into the solutions, S uoP fC E H Krw M TO 0Ol2Io4-J,'o35 . Mi-'V.' 1 The possibilities of interactions of drugs with the leached additives and induction of more extensive leaching by other drugs or solvents should be considered by ,-the clinician. It has been shown that the plasticizer DEHP was a major leached chemical (3). References: (1) Singh A.R., Lawrence W.H., Autian J. - Mutagenic and AntifertiDty Sensitivites of Mice to DEHPand DMEP(dimethoxyethyl pthalate)-Toxicology andApp. Pharm 29(1974) 35-46. (2) Jaeger R.J., Rubin R.J. - Magration of Pthalate Ester Plasticizer from PVC Blood Bags into Stored Human Tissues. New Engd. Jou. of Med. Nov. 30.1972 1111-1118. (3) Moorhatch P. & Chiou W.L - Interactions between Drugs and Plastic Intravenous Fluid Bags. American Jour, of Hosp. Pharm. 31. Feb. (1974) 149-152. (4) Hillman L.S., Goodman S.L, Sherman W.FL, - Identification and Measurement of Plasticizer in Neonatal Tissues after Umbilical Catheters and Blood Products, New Eud. Jr. of Med. 292 (1975) 382-386. (5) Autian J - Toxicity and Health Threats in Pthalate Esters: Review of the literature Enviromental Health Perspectives 3:26 (1973). 21541004 3 P.V.C. FACTS-2 PARTICULATE MATTER The presence of particulate matter in parenteral solutions has been a problem since the advent of this route of administration. However, only recently these particles have been shown clinically to be injurious to humans (1). Particulate matter has been defined as "The mobile, undissolved substances, uninten tionally present in parenteral solutions". Interest in particulates was first stimulated way back in 1963 by Garvan and Gunner. Further work was done by Gross of the F.D.A. of United States who stated that "It be comes evident, that particulate matter in I.V. solutions can be harmful (1). Particulate matter can cause harmful effects such as pulmonary microemboli, thrombi or granulomas in patients (2). Particulate matter is the causative factor in 70% of the pa tients developing infusion phebits (3). The highest amount of particulate matter is in P.V.C. pouches; about 3 to 4 times more that in glass or polyethylene. A major cause of concern regarding the use of P.V.C. I.V. pouches is the possible diffusion of toxic stabilizers and plasticizers from P.V.C. into the I.V. solution P.V.C. pouches contain a host of various plasticizers, stabilizers and catalysts. One such plasticizer used is di-2-ethylhexyl pthalate ester DEHP also known as dioctyi pthalate (4). A subsequent study by Whitlow et al (4) showed that the main causative factor for high particulate matter content in P.V.C. pouches was DEHP. The study was done by sub jecting P.V.C. pouches to gyrorotatory agitation, to simulate conditions of truck moving on bumpy road. The P.V.C. pouches had as high as 20,000 particles/ml of size varying between 3 to 5 microns. This phenomenon was also identified due to the presence of DEHP in P.V.C. pouches. The high particulate matter content in P.V.C. pouches may be related to the manufactur ing process also since the bags are manufactured separately, apart from the filling stage. Leaching of plasticizer from the polymer may be another source of contamina tion (5). A study was conducted in 1987, comparing the particulate matter content (Figs. 1,2, & 3) present in P.V.C. pouches with glass and polyethylene containers, it was found that P.V.C. pouches generate maximum amount of particulates per ml. (5). The findings of the above mentioned study is summarised below alongwith the Pharma copoeia) limits of British & U.S. Pharmacopoeia. 21541005 27-02-1992 13*40 FROM RPL PfiRC TO 0012164476551 P.05^07 h TvDe of container P.V.C. Pouches Glass container Polyethylene container Pharmacopoeia! limit No. of Darticles oer ml. > 2 Micron > 5 Micron 2800 550 50 1000 (B.P.) 390 42 6 100 (B.P.) >10 Micron 46 7 1 50 (U.S.P.) It has been shown that P.V.C. pouches containing infusion fluids contain additives. The increase in particulate matter is due to the high additive content in P.V.C. pouches (6). In conclusion it can be mentioned that P.V.C. pouches tend to generate maximum number of particulate matter, much greater than the permissible limits given in the vari ous pharmacopoeias. References: (1) Neil M.. Turco S. SiveBy, E-A Study of Particulate Matter in I.V. Infusion Fluids - (American Jour, of Hosp. Pharm. Vol. 27 Oct 1970 823. (2) Deluca P.P., Robert R.P.. Bivins B. Mckean H.E., Griffen W.O. - Filtration and Infusion Phlebitis a Double-Blind Prospective Clinical Study - (American J. of Hosp. Pharma) Vol. 32 Oct 75 1001-1007. (3) Petrik R.J., Loucas S.P.. Cohl J.K., Mehl. B - Review of Current Knowledge of Plastic I.V. Fluid Containers - (American J. Hosp. Pharm) Vol. 34 Apr. 77 357-362. (4) Whitlow RJ. Needham T.E. luzzi LA., - Generation of Particulate Matter in Large Volume Parental Containers (J. of Pharma Technology) Vol. C3 No. 10 Oct, 74 1610-1613. (5) Uotila, J. - Some Considerations on Particulate Matter Contamination and Proper Material Selection During the Development of Parenterats (Pharma. Industry 49) Sept. 1987 968-971. (6) Davis N.M.Turco S.-A Study of Particulate Matter in I.V. Infusion Fluids - Phase 2 (American J. of Hosp. Pharm) Vol 28 * Aug 1971 620-623. 21541006 i> P.V.C. FACTS-4 MOISTURE VAPOUR TRANSMISSION RATE (M.V.T.R.) PVC pouch looses 16% of its water content at 37"C over a period of 36 months, much before its expiry period. This increases the concentration of the drug present, by 16% during its shelf-life. Moisture Vapour Transmission Rate (M.V.T.R.) can be defined as the rate at which water vapour will permeate a film or membrane at 100"F and 100% Relative Humidity during a 24 hour period. During the process of water vapour permeation the following process takes place: From the high vapour side (ie. from inside the pouch) water dissolves into the barrier film. Water diffuses through the barrier film, at a rate proportional to the concentration gradient of water, through the barrier thickness. Water evaporates from the barrier surface into the low vapour (ie. outside the pouch) pressure side of the barrier (1). Due to the process permeability, water vapour which diffuses out of the barrier is lost into the atmosphere, thus reducing the total water content inside the pouch. This causes an increase in the concentration of the drug present in the solution. The permeation rate of PVC has been proved to be the highest amongst all plastics. In addition to PVCs high permeability to water vapour, it is also highly permeable to oxy gen and carbon dioxide. Stability studies conducted on PVC pouches show a high water transmission rate, Weighing solutions in PVC pouches, before and after storage, in simulated conditions, provide information about loss of content due to moisture vapour transmission (2). Another test which conclusively proves vapour loss is an increase in assay values of the ingredients present in the solution (2). A study conducted on PVC pouches, containing I.V. solutions, showed that it lost * 1.6% to 4% of its nomind value when stored at 25C at 33% to 75% relative humidity after a period of 12 months. Although this loss would not appear very significant, the Increase in concentration changes of the drug present, resulted in a hypertonic solution. This study concludes that the PVC pouch is not a truly closed system and there exists a potential for gaseous entry into the system (3). In India, where the average temperature is 37C, the total weight loss and increase is solute concentration in PVC pouches was * 16% over a period of 36 months. This would lead to the concentration of the drug in the pouch, to increase by 16% much before its expiry period. FEB 27 192 3:17 Or*irte nnc uonx'X G iz 6 Thus in a country, where air-conditioning is not available, this would reduce the shelf-life to less than 1 year. The various pharmacopoeias allow a variation of the concentration of the drug present at 5% during its shelf life. This study clearly demonstrates the unviability of PVC pouches in a country like ours, where the ambient temperature is always high. References: 1) Paper Film & Foil Converter: Feb. 1964. 2) Avis K.E.; Lachman L; Lieberman HA,: Pharmaceutical Dosage Forms: Parenteral Medication Vol. 2 1986 68-69. 3) Petrie R.J., Loucas S.P. Cohl J.K. Mehl B.; Review of Current Knowledge of intravenous Fluid Containers - American J. of Hosp. Pharm. 34:1977 357-362. 21541008