BE’ELOPMENT IN PACKAGING 0F DISPOSABLE WET-DOSE PLASTIC CONTAlNERS 0F EYE SOLUTlONS Thesis fee the Degree of M; St MiCHEGAN STATE UNEVERSETY TAMIO TAN! 1973 ABSTRACT DEVELOPMENT IN PACKAGING OF DISPOSABLE UNIT-DOSE PLASTIC CONTAINERS OF EYE SOLUTIONS BY Tamio Tani Contamination of ophthalmic solutions often results in severe patient eye injury, sometimes blindness. In or- der that this problem be clearly understood, the author has surveyed the presently available literature in this area of package design and has also consulted with several ophthal- mologists as to their recommendations for preventing oph- thalmic solution contamination. Sterility is the supreme concern and aim of all packaging of eye solutions, and it can be approximated by any one of several methods. Thus, the author has attempted to survey the sterilizing techniques and packaging mater- ials available for use as eye solution containers. Lastly, in the light of the above considerations, the author has attempted to "foresee" future developments in the high speed packaging of disposable unit-dose plastic Tamio Tani containers of Ophthalmic solutions, and proposed two kinds of practical packaging systems for them. DEVELOPMENT IN PACKAGING OF DISPOSABLE UNIT-DOSE PLASTIC CONTAINERS OF EYE SOLUTIONS BY Tamio Tani A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE School of Packaging 1973 ACKNOWLEDGMENTS I wish to express my sincerest thanks to Dr. James W. Goff and Dr. Theodore I. Hedrick, without whose assis- tance this manuscript would never have been completed. And I wish to acknowledge the inspiration my wife has provided me, especially when I have needed it most. ii TABLE OF ACKNOWLEDGMENTS . . . . . . LIST OF TABLES . . . . . . LIST OF FIGURES . . . . . . INTRODUCTION . . . . . . . CONTENTS A STUDY OF EYE MEDICATION CONTAMINATION AND PRACTICAL METHODS OF PREVENTION Hazards of Contamination of Eye Medications Predominant Cause of Infection Mechanisms of Contamination Prevention of Contamination Preparation of Sterile Solutions Maintenance of Sterile Solutions A REVIEW OF STERILIZING METHODS Physical Sterilization . Thermal Sterilization . . Retort . . . . . . . . Saturated Steam . . . . Dry Heat . . . . . . . Chemical Sterilization . Hydrogen Peroxide Solution Ethylene Oxide Gas . . Ionizing Radiational Sterilization Miscellaneous . . . . . . PACKAGING MATERIALS OF UNIT-DOSE CONTAINERS iii Page ii vi \lU‘lebw N (13% 12 13 14 15 18 18 18 20 21 24 25 27 Page PROPOSAL FOR DEVELOPMENT IN PACKAGING OF DISPOSABLE UNITrDOSE PLASTIC CONTAINERS OF EYE SOLUTIONS . . . . . . . . . . . . . 30 Requirements of Disposable Container for Eye Solutions . . . . . . . . . . . . 30 Disposable Containers and Their Packaging Systems . . . . . . . . . . . . . . . . . 31 Thermal Forming, Filling and Sealing System . . . . . . . . . . . 3l Blow Molding, Filling, Sealing and Trimming System . . . . . . . . . . . . . . . 38 Outer Packages . . . . . . . . . . . . . . . . . . 42 CONCLUSION O O O O O O O O O O O O O I O C O O O O O 4 4 LITERATURE CITED 0 O O O O O O O O I O O O O O O I O 46 iv LIST OF TABLES Tables Page 1. Destruction times of bacterial spores by moist heat . . . . . . . . 2. Killing times of bacterial spores by dry heat . . . . . . . . . Figure LIST OF FIGURES Page Types of sterile containers . . . . . . . . . 9 Bend-off opening type container . . . . . . . 33 Cross section of the notching line . . . . . . 33 Peel-off opening type container . . . . . . . 34 Aseptic machinery system of thermal- forming, filling, and sealing system . . . . . 37 Bottle pack container . . . . . . . . . . . . 39 Process of bottle pack packaging . . . . . . . 40 vi INTRODUCTION The problem of the contamination of eye solutions has been realized and pointed out for more than twenty years now. All containers of eye solutions are practically sterile before opening. But once they are opened, the so- lutions they contain are exposed to many forms of contamin- ation. A multiple—dose container with a dropper, for ex- ample, will become contaminated by the dropper's contact with the patient's eye. Airborne contaminants enter the bottle itself. Some contamination is the result of opthal- mologist mishandling. Ophthalmolgists themselves have been seeking containers which are easy to use and prevent con- tamination. To fill this requirement, some disposable unit- dose containers have been developed, but they have not been widely accepted because of their high cost. To overcome the problem of high cost, unit-dose plastic containers must be developed that can be manufactured by an aseptic packag- ing system utilizing bioclean room techniques. Therefore some unit-dose plastic containers and their packaging sys- tem were proposed. A STUDY OF EYE MEDICATION CONTAMINATION AND PRACTICAL METHODS OF PREVENTION The contamination of eye medications has been re- ported since the early 1950's by Theodore (l951)29(1952)3O and King (1953)l4. Theodore,29 himself, has insisted upon the need for governmental control of the requirements for preparing sterile ophtalmic solutions. Within the past few months eyedrops were withdrawn on two occasions because of contamination with Pseudo- monas aeruginosa, an organism which is apt to produce one of the most virulent types of corneal ulcer en- countered. . . . The drug was immediately withdrawn from the market, but similar infections had in the mean- while occurred in other patients. There are probably many more instances of contamin- ation of commercially prepared eye medicaments that never reach the stage of publicity. While some of these may not be serious, the lack of suitable standards makes the possibility of dangerous contamination an ever- recurring hazard. It would seem important, therefore, in the interest of the public, for a law to be passed assuring users of all commercial ophthalmic preparations, whether they be eyewashes, eyedrops, ointments, or anything else for topical application in or about the eyes, that the pro- ducts are sterile and will produce no eye infections. Since 1953, the Federal Food, Drug and Cosmetic Act has been interpreted as requiring manufacturers of eye medi- caments to prepare practically sterile solutions fortified with adequate preservatives. This requirement does not yet apply to eye ointments or to ophthalmic medications com- pounded and dispensed by local pharmacies or hospital phar- macies. Eye solutions are generally sterile before their containers are opened but once they are opened, there is no method to insure that the solutions are not then contami- nated by improper dispensing. Eye solutions are often ex— posed to contaminated sources. In order to prevent contam- inations and provide easy handling for ophthalmologists, packaging should make an effort to develop a disposable unit—dose container. Hazards of Contamination of Eye Medications The hazards of contamination of eye medications have been reported often. Allen (1959)1 described several instances of contaminated solutions in his thesis. The following examples, of which I have firsthand or reliable secondhand knowledge, are cited anonymously to prove this point: 1. Postoperative infection occurred in five eyes subjected to intraocular surgery during a single morn- ing on a large eye service. All five eyes were lost from endophthalmitis. Pseudomonas organisms were re- covered in pure culture from the five eyes and from un- diluted, previously unopened stock bottles of benzal- konium chloride 1:1,000 and from the more dilute solu- tions that were used for preoperative preparation of the skin of these patients. 2. Postoperative infection occurred in six eyes subjected to intraocular surgery on two successive days in a large eye hospital. All six eyes were lost from endophthalmitis. Pseudomonas aeruginosa was recovered in pure culture from the six eyes and from a large demijohn used to fill 1,500 ml flasks with saline. Af- ter autoclaving, one flask was used to fill trays and basins for three operations. Among these were the con— tainers for anterior chamber irrigant. Although none of the flasks available for culturing at the time infec— tion was discovered was found to be contaminated, it was postulated that two or more flasks used for the six Operations had escaped processing in the autoclave. 3. Postoperative infection occurred in three eyes subjected to intraocular surgery in a large general hos- pital. All these eyes were lost from endophthalmitis. Pseudomonas organisms were recovered from these eyes and from a solution of a cationic detergent in which catar- act knives used on these cases were immersed. It was said that bronchoscopic instruments had been immersed in the same solution. 4. Following removal of embedded corneal foreign bodies in a large industrial eye dispensary, pseudomonas corneal ulcers developed in five eyes. Four eyes lost useful vision. Pseudomonas organisms in pure culture were recovered from previously unopened stock bottles of a proprietary sulfonamide solution that had been in- stilled into these eyes for an intended prophylactic ef- fect. In analyzing this series of clinical disaster, two observations are of the greatest significance. In the first place, in three of the four instances, the solu- tion that was found to be contaminated had been employed because of its supposed antibacterial effect. In one case the offending substance was used as a skin antisep- tic; in another, as an instrument disinfectant; and in the third, as a chemoprophylactic agent. In the second place, the causative agent of all these infections was that organism which is at once the most common contaminant of aqueous solutions and the most lethal in its effect upon the eye, the Pseudomonas aeruginosa. This omnipresent organism grows within a temperature range of 4-42°C. in the presence of little nutritional substrate. It thrives in the anterior cham- ber and spreads rapidly through the coneal stroma, where it often forms a series of concentric ring ab- scesses. Other ocular pathogens often found in solu- tions are S. aureus, B. subtilis, and members of the coliform group. Predominant Cause of Infection Pseudomonas aeruginosa is the major contaminator of solutions. Pseudomonas aeruginosa can survive in such disinfectant fluid as a quaternary ammonium compound of high strength and these omnipresent organisms grow within a temperature range of 4° to 42°C. and can reproduce in the presence of little nutritional substrate. King (1953)14 states about this bacillus: Pseudomonas aeruginosa is frequently found on the normal skin, in sweat, and in feces. Under ordinary conditions it is only slightly pathogenic. The bacterium is occasionally found in the flora of the normal eye. It may reach the eye from infection with Pseudomonas aeruginosa elsewhere, such as otitis externa and media, skin infections, infected burns, and so forth. It may cause no infection in an intact coneal epi- thelium. It is extremely virulent, however, in the abraded cornea such as that following foreign body re- moval. The severe ulcer and purulent keratoconjuncti- vitis usually result in loss of the eye. Therefore, eye medicants must be free from Pseudo- monas aeruginos, and the sterilization of the eye medicants must occur to destroy this bacterium. Mechanisms of Contamination of Medications One of the most predominant means of transferring infections is by the use of contaminated solutions and oint- ments during eye examinations and treatment. A variety of organisms including pathogenic bacteria, viruses, and fungi have been found to be contaminants. Means by which solu- tions are contaminated were pointed out by King (l953)14: Means of contamination I. Solutions A. Druggist Contamination of solutions may occur during commer- cial manufacture, as recently proved in the case of sulfonamides and cortisone.2 Others have been traced to solutions dispensed by hospital pharmacies and re- tail druggists. This may occur by preparing the original large stock solution in an unsterile manner or by contaminat- ing the solution, stoppers, or bottle while transferring the solution to smaller bottles for dispensing. The use of proper preservatives may have been neglected. Most eye medication solutions dispensed by pharma- cies arrive from manufacturers in lS-cc. bottles with a top incorporating a dropper, or capped and accompan- ied by a dropper in the same package. Most of these droppers are grossly dirty and an occasional pretense at cleanliness is made by enclosing the dropper in a loose ce110phane envelope. B. Patient The usual dropper-type bottle containing prescribed solutions is undoubtedly contaminated after a short per- iod of use. This may do no harm if the medication is used by the same patient. We all know, however, that it is common practice for several members of a family to use a "good medicine" which soothes red eyes or which has been left in the bathroom medicine cabinet for some time. C. Ward, clinic, or office practice Contamination of eye solutions probably never occurs in a modern eye operating room which uses freshly made and sterilized medications under aseptic conditions. The most common place for solutions to become unsterile is on the ward dressing tray, in the clinic, or in a private office. The usual cause, and probably the sole offender, is the contaminated eye dropper which has touched an infected eye. Such infection may be obvious, or the patient may be a "carrier" with the offending bacteria or virus in the conjunctival fluids, or a Pseudomonas may exist on the skin of the eyelids. Less likely causes of contamination may occur, such as placing the dropper upon soiled gauze or touching the tip with fingers. Contamination of the bottle top is also possible by leaving it open—-face down--on an unsterile surface while removing the solution. Prevention of Contamination Eye medicants consist mainly of eye solutions and eye ointments. Both have problems of contamination in com- mon, but the characteristics of eye solutions and ointments are quite different from the view of packaging. The former is liquid and latter is paste. Their packages, methods of sterilization, and packaging machinery systems are neces- sarily different. Therefore, in this paper, only eye solu- tions will be discussed. Preparation of Sterile Solutions Almost complete sterility of ophthalmic solutions can be achieved by autocalving. Filtration to remove bac- teria is another effective method of sterilizing ophthalmic solutions. Although widely advocated in the past, this method is now less popular because the technique is time- consuming and subject to chemical contamination. Gamma ir- radiation has been also considered19 for the sterilization of inexpensive disposable medicaments, but this method is only practical for simple chemical substances like a saline. In the case of more complex chemical substances, such as the antibiotics and local anesthetics, a change in color and pH-value may result from irradiation. In any method of sterilization, both containers and solutions must, of course, be sterilized. Maintenance of Sterile Solutions Practical methods are suggested by King (1953)14 for maintaining the sterile condition of eye Solutions un- til their application: As pointed out previously, the contamination of sterile solutions is in most instances due to used eye droppers being reinserted in the solution bottles. . . . Various methods are in use in different institutions in an effort to avoid this situation. Some will be men- tioned here: 1. Small sterile refillable containers. One hos- pital uses a small viaI* with a dropper (Figure 1-B and Figure lPC). These are sterilized in an autoclave and filled with sterile solutions for use in the hospital operating room and clinic. Each vial holds from 0.3 to 0.5 cc of collyria, enough for one application. These vials are saved, disassembled, resterilized, and refilled. To avoid residual atropine, the rubber dropper bulb which has contained atropine is marked with a brass wire around the neck so that it again goes on a vial containing that same solution. Although this procedure is expensive and tedious, it is a superior method of maintaining sterility: but it would be difficult to apply universally. Figure l-D shows a similar small screwcap bottle incorporating a drOpper, with a volume of 1.0 cc. It may be used for several applications to the same patient after which it may be resterilized and refilled as has been described. Its experimental use appears to preclude its general application in a large eye center because of its cost, waste, and the time consumed in preparation. One-use containers, however, could be employed to advantage in the operating room. 2. Disposable sterile container. As shown in Fig- ure l-A, this consists* f a glass tube with a rubber bulb and a rubber tip. It is filled with 0.5 to * "Dr0pu1"-Courtesy N. Baker, apothecary-in—chief, The New York Hospital, 525 East 68th Street, New York 21. ** Pennsylvania Glass Products Co., Inc., Pittsburg, Pa.--Courtesy Captain J. W. McNamara Chief, Pharmacy Service, Walter Reed Army Hospital, Washington 12, D.C. .muoowmuooo oaauoum mo momma .H ousmflm .Hmmmouw £DH3 manpon mmo|3mnom HHme .Hommouw Hmw> HHmEm .HMM> HHmEm .nocflmucoo maflumum manmmommflo on ADV Amy Adv ssexs ssets eqn: Stance ssets J eqni ssets ornseta 7 , Jeqan xeqqnu 'R Jeqqna 1* eqnq sseta JP Jeqqnu 10 1.0 cc. of various sterile buffered ophthalmic solutions and is intended as a single dose disposable unit. It may be used for several applications to the same eye. The rubber tip is immersed in alcohol and the rub- ber seal on the delivery tip snipped Off by scissors when the medication is to be used. The scissors, or other instrument used in cutting off the rubber end would, of course, also have to be sterile. The advantages of this ingenious device are obvious, and it is certainly a commendable step forward. The disadvantages are the time consumed in sterilizing the tip and in maintaining sterile scissors. These disposable sterile containers are too expen- sive for use in a large clinic but are ideal for the Operating room. 3. Sterile dried fluorescein. Fluorescein solution is an excellent medium for Pseudomonas aeruginosa and is the one most commonly contaminated by the eye dropper.‘ Efforts have been made to avoid the use of this stain in solution form and to apply it by other means. 4. Disposable plastic eye dropper. If the "dropper- bottle—top" applicator were eliminated from office clin- ic practice and replaced by separate sterile or clean eye droppers for one patient only, the problem of con- tamination of eye solutions would be negligible. In our clinic for the past six months e have em- ployed a cheap disposable plastic dropper. It consists of a one—piece plastic compressible tube, closed at one end. By pressing the closed end between the fingers, enough solution for one or two applications--four to five drops--can be drawn into the dropper. The tube is then thrown away and never touches patient or the solu- tion bottle again. These droppers cost a fraction as much as the cheap- est glass dropper and Offer good insurance against con- tamination . .7. . They are packaged, "sanitized" by ultraviolet rays, but may be sterilized for Operating room use by immer- sion in.a fresh solution of benzalkonium chloride for 30 minutes. The disposability feature of these droppers Offers other advantages in addition to eliminating dropper con- tamination of solutions. It is sometimes impossible to apply medications by a dropper without touching the con- junctiva of an inflamed blepharospastic eye. This may be purposely done using a disposable drOpper. * "Sanidrop," Marnel Company, Inc., 110 North St., Asaph Street, Alexandria, Virginia. 11 If the disposable plastic eye droppers were to be used in hospitals, the problem of contamination would be greatly reduced. But the chance of contamination still re- mains, because there are possibilities that eye solutions would still be exposed to airborne contaminants. The per- fect solution would be the development of an inexpensive disposable sterile container which easily dispenses its contents. A REVIEW OF STERILIZING METHODS In sterile, disposable unit-containers for eye so- lutions, not only the solutions themselves, but also their containers must be sterilized. As mentioned above, steril- ization of eye solutions can be quite complete through the use of filtration or autoclaving, but no method has at this time been developed for efficiently sterilizing containers. However, there are many container-sterilization techniques available for development, and these techniques fall into five major types: 1. Physical sterilization: Filtration 2. Thermal sterilization: Autoclaving (Retort, Saturated Steam); Dry heating 3. Chemical sterilization: Hydrogen peroxide; Ethylene oxide gas; Chlorine and iodine com- pounds 4. Ionizing radiational sterilization: Gamma ir- radiation 5. Miscellaneous: Ultraviolet light There are other sterilization techniques available, but they are not practical for packaging of the eye solu— tion containers. In a packaging system that can produce 12 13 disposable unit-dose containers for eye solutions, one of the above listed methods or a combination of them can be used. Physical Sterilization Physical sterilization utilizes physical action to remove contaminants. Filtration or centrifugal separation may be considered, but the Object of sterilization must be in liquid form or a gaseous state. Compared to centrifugal separation, filtration is more reliable. In aseptic pack- aging, a sterile condition will be needed during the filling and closing process. It can be realized by using a chamber filled with filtered, sterile air. The air pressure inside the chamber must always be kept higher than the outside in order to prevent airborne contaminants from getting in- side, and also laminar flows of filtered air can maintain a sterile space. For long-time performance of filtration, devices for delivering clean air should be simple, trouble free, and require minimum maintenance. Filters should be chosen suitable for their purpose because each filter is designed for a specific size of particles. In the case of biocleaning, high efficiency particulate air filters (HEPA * filters) have been used. The more efficient of these *Ultra high efficiency particulate air filters can arrest 99.99 percent of all particles above the 0.3 u di- ameter. However this is not sufficiently effective for viruses. 14 filters may arrest up to 95 percent of ordinary atmospheric dust particles at a high rate of air flow and with a pres- sure drop across the filter bank usually less than 0.5 of an inch water gauge for a new filter. Generally ordinary atmospheric dust particles are particles with more than 3 u diameters. Most airborne bacteria are attached to those particles. HEPA filters are composed of glass fibers aver- aging 0.8 to 3.0 u in diameter. Thermal Sterilization Thermal destruction of bacteria is the most popular method not only in the health sciences, but also in the area of food technology. This method offers the most reli- able sterility and antitoxical aspect, but it Often reduces the quality of the product through excessive heating. Mi- croorganisms survive in temperatures ranging from 23°F. (-5°C.) to 176°F. (80°C.). Exposure to temperatures above this range will result usually in rapid death of the organ- isms, with the exception of heat—resistant spores. The mechanism responsible for the death of micro- organisms when subject to heat has not been clearly under- stood until now. The traditional theory is that the death of bacteria at elevated temperatures is closely linked to the alteration of proteins involving some irreversible pro- toplasmic change within the bacterial cell. 15 To eliminate the potential hazards inherent in ther- mal sterilization, the temperature and the time of heating should be designed to eliminate the spore—forming species which are the most heat resistant form of microorganisms. Retort A common heat treatment for retort sterilization is approximately 240°-245°F. (115.6°-118.3°C.) for 15 minutes. Batch and continuous equipment are available for glass, metal, and recently, plastic flexible pouches. The major advantages of the retort method are its simple Operation and possibility of sterilizing of both the product inside a container and the container itself at the same time. But the disadvantage is the limitation of plastic materials which can stand the excessive heat. Polyester, polycarbo- nate, polypropylene and Nylon 11 may be used. Modified polyolefin* can provide heat sealability by using it as a laminate. During retort sterilization, blowing out of con— tainers occurs very Often without careful pressure control inside of the autoclaving chamber. Saturated Steam Correctly performed, exposure of objects to satur- ated steam under pressure in the autoclave is the most * Continental can's modified polyoletin C79. 16 rapid and dependable means of practical sterilization avail- able for use. The minimum time for steam sterilization against bacterial spores is dependent upon the pressure and temperature of the steam. According to Table 1, an increas— ing sterilizing temperature reduces the sterilizing time by an accelerated rate. The advantages and disadvantages of steam sterilization are as follows: Advantages: a. Rapid heating and rapid penetration of tex- tiles or fabrics b. Destruction of most resistant bacterial spores in brief interval of exposure c. Easy control of quality and lethality for var- ious materials and supplies d. No toxic residue on materials following ster- ilization process e. Most economical sterilizing agent for many conditions Disadvantages a. Failure of sterilization caused by incorrect operation of steam sterilizer b. Unsuitable method for sterilization of anhy- drous oils, greases, and powders Steam sterilization is an ideal sterilization method for products which are not affected by heat and moisture, but it is not practical for heat-sensitive materials like plas- tics, nor for moisture sensitives. For heat-sensitive ma- terials which are not liquid nor gaseous, some chemical sterilizations, especially ethylene oxide gas sterilization, are practical. For moisture-sensitive materials which are not affected by heat, dry heat sterilization may be used un- der some limitations. 17 mmfimmmav mmth "mousom m.enm.m mmnaa oaauow oomuooa ooe mflumuomn oflaflnmosumna muse: w m ma omH omv same mesmuomn Hfiom omnw oeuoa omumm omanoe ommuoom sscflasuon .Ho m oaum Aflsoama .Ho calm maum Hcmumu .Ho m.m ma as ona own mnoummcm m>fluummmuusm a mnsos ow mama mflaflunsm .m oalm mHIN mflomunucm .m omma coma omHH ooaa omoa coca ”um Ammuscwfiv mafia sowuosuummo Emwsmmuo .ummz umHoE an monomm HOHHOUUOQ mo moEHp Gofiuosuumma .H OHQMB 18 Dry Heat Dry heat should be used where direct contact of the material or substance with saturated steam is impractical or unattainable. Dry heat in the form of hot air is diffi- cult to control within narrow limits, except in a specially designed sterilizer. It penetrates materials slowly and unevenly and long exposure periods are required for steril- ization. Because of the poor penetrability and the destruc- tive effect of the high temperatures employed, dry heat or hot air is entirely unsuited for the sterilization of fab- rics, rubber, and plastic materials. On the other hand, it is well suited for the sterilization of cutting edge instru- ments, needles, syringes and glasswares. Dry heat does not exert a corrosive effect on sharp instruments as is commonly observed with steam, nor does it erode the ground glass sur- faces of syringes. The minimum destruction time in dry heat sterilization is shown in Table 2. Chemical Sterilization There are many chemicals which can destroy bacteria and bacterial spores, but most are also toxic to humans. An ideal chemical agent is: a. non-corrosive b. harmless to materials c. penetrative d. easily removed by heating or aeration e. rapid in action f. of low toxicity to humans and animals l9 swimmmav mmxmm "mousom omlma om monomm Hwom malm ovnom Hamumu .HO m mmlma om Hflsoams .HO oaum manoa mmlom mm omlma om oma Essflasuoo .HO m omlm omalom oma CD as mwomunpcm .m coma ocha coma oOmH coed coma coma "um Ammussflev OEHH coauosuummo Emflsmmuo .umms huc an monomm amaumuomn mo mmEflu OGHHHMM .N OHQMB 20 g. nonflammable and nonexplosive h. easy to handle i. bacteriacidal, sporicidal, virucidal and fungicidal at ordinary atmospheric conditions Hydrogen peroxide has been used as a sterilizing agent for aseptic packaging in the dairy industry, and eth— ylene oxide is the only practical gaseous sterilant avail— able for packaging. The main advantage of chemical steril- ization is its sterilizing operation at an inexcessive tem- perature. Hydrogen Peroxide Solution Hydrogen peroxide is well-known as a disinfecting agent, and it is evaporated by heating and aeration. When it is evaporated, it becomes a vapor of water and oxygen without leaving any toxical residues. Hydrogen peroxide somewhat affects materials such as fabrics and metals, but it does not affect glass or plastics. The time for steril- ization is so short that it may be used in a continuous operation. For example, it takes only 8 or 9 seconds to sterilize materials by dipping them into a hydrogen peroxide bath at 90°C. However, the liquid is not practical for penetrating into a small hole nor a place containing air. Sterilization using hydrogen perioxide can be applied to a complex shaped product, however. After the product goes through the hydrogen peroxide bath, a process of removing film and drying the surface 21 usually is necessary. In many packaging machines, rolls of sheet packaging materials are used. This method is practi- cal for these machine systems. Hydrogen peroxide is also used for sterilization in the form of a mist. More penetra- tion can be obtained by using this method. Ethylene Oxide Gas For a gaseous sterilant, formaldehyde vapor has limited usefulness because of its corrosiveness to aluminum and other metals, its tendency to polymerize on surfaces, and the resulting difficulty of removing the compound fol— lowing treatment of objects and spaces. On the contrary, ethylene oxide gas is a practical sterilant. It combines a sporicidal effect with penetra- tion into packages, some liquids, and certain plastics. Although flammable, it can be handled in small quantities in liquid form and in large volumes in combination with rel- atively inert gases, such as carbon dioxide and freon. Its effect is greatest in the range of moderate humidity, rather than at extremes of dryness and moisture. Reaction with Microorganisms It is believed, ethylene oxide reacts with certain chemical groups within the cell of a microorganism such as the sulfhydryl, amino, carboxyl, or hydroxyl groups and be- cause of this reaction the normal metabolic and/or 22 reproductive processes of the microbial cells are seriously altered, resulting in inactivation or death of the cell. Formulation of Sterilizing Gas Ethylene oxide in the pure form is not used for nor- mal sterilization in either the liquid or vapor state be- cause Of its flammability and toxic hazards. For practical usage, mixtures of ethylene oxide and inert gases such as carbon dioxide or fluorinated hydrocarbons are suggested. At the present time, there are several ethylene oxide mix- tures which can be safely employed as sterilizing agents un- der normal conditions. For example, 10 percent ethylene oxide and 90 percent carbon dioxide mixture or 20 percent ethylene oxide and 80 percent carbon dioxide mixture are available from the Union Carbide Corporation. Temperature and Humidity In a routine sterilization using ethylene oxide, temperatures of 120° to 140°F. (49° to 60°C.) are used; how- ever, there are some instances, e.g., the sterilization of heat-labile plastics, where these temperatures may be too high. Gaseous sterilization at room temperature is also conducted in some applications but longer exposure periods are required. 23 Time Minimum exposure time depends upon the material, the resistance of the microorganisms, humidity, concentration of gases, etc. Roughly speaking, the average exposure time is usually ranged from 4 to 8 hours for small items such as in- jection needles and syringes. Limitations Although ethylene oxide appears to be a practical sterilant for most heat-sensitive materials, there are some disadvantages or limitations which require caution in its ap- plication. Some acrylic plastic materials and polystyrene are attacked by a mixture of ethylene oxide and fluorinated hydrocarbons, particularly those containing trichloromono- fluoromethane (Freon 11). For solutions contained in plas- tic or glass containers, the exposure of these containers to ethylene oxide vapors will not result in sterile solutions as the gas does not permeate glass, but it is absorbed to some degree by the plastic. However, gaseous sterilization can be used to sterilize the outer surfaces of the vials when required. One serious disadvantage of ethylene oxide steril- ization is the time required for dissipation of the residual contained in exposed porous (absorptive) materials. Sorp- tion would not ordinarily be a serious disadvantage of eth- ylene oxide sterilization if the residual gas were nontoxic 24 and could be readily dissipated or removed from these mater- ials in a short time. Unfortunately ethylene oxide will persist in exposed products of this nature for several hours and in some instances, for several days. In the ethylene oxide gas sterilization, the process of aeration of the ob- ject is essential. Maintenance Of Sterility To maintain sterility in an item, some type of pack- aging and a protective wrapping material must be employed. Requirements of packaging materials comprise permeability to ethylene oxide and moisture, flexibility for wrapping and sealing irregular size articles, capacity to withstand normal handling, low cost, and capacity to withstand normal storage conditions without deterioration. In general, such materials as paper, cloth (muslin), and certain plastic films meet these requirements. Transparent plastic films are preferred in many cases because they allow easy identi- fication and inspection of the wrapped article. Ionizing Radiational Sterilization Gamma irradiation has become a popular method of sterilization, especially for medical products, however, there are still potential hazards inherent in this process. The dangers of gamma irradiation are changes of products in color and chemical structure. Ogg (1969)19 mentioned his 25 experimentation with gamma ray sterilization of saline in a polystyrene syringe. A 10 cm3 polystyrene syringe is filled with filtered saline and the nozzle closed with a Luer cap. Each syringe is packed in double heat—sealed polyethylene envelopes and irradiated to 25 Mrad. He found that the difference in pH value and sodium chloride concen- tration before and after irradiation was negligible and that no unwanted or toxic reactions had been observed fol- lowing the frequent use of this system during the past two years. He predicted that in the case of more complex chem- ical substances, such as the antibiotics and local anes- thetics, a change in color and pH value might result from irradiation. In the area of gamma ray sterilization today, many experiments must be performed before it can be uti- lized. Miscellaneous Ultraviolet light is sometimes used in sterilizing systems. Ultraviolet light cannot provide an adequately sterile condition in short time radiation. It is often used in a biochemical room to help keep the room sterile and kill bacteria through long-time radiation. When ultra- violet light is used in an aseptic packaging system, only a combination with other sterilizing techniques is practical. 26 When aseptic packaging systems for disposable unit- dose containers of eye solutions are designed, combinations of the above sterilizing methods must be considered care- fully. PACKAGING MATERIALS OF UNIT-DOSE CONTAINERS If a disposable unit-dose plastic container of eye solutions is to become popular, the container must be first and perhaps most importantly, inexpensive. And, the manu— facturing cost of the container can be most reduced by us- ing a fully automated packaging process, utilizing a resin or sheet form of packaging material. This method greatly reduces the cost of labor, warehousing, and transportation. Thermoformable plastic materials are now available that make such manufacturing techniques as mentioned above both inexpensive and practical. Also, on the present market are many types of thermoforming plastic materials. For use in containers for eye solutions, the material in the package must not react in any way with its contents. Eye solutions are generally aqueous, containing small amounts of some acids and chemical salts. Of all thermoformable plastics, low and high density polyethylene, polypropylene, polycarbonate, polyester, ny- lon, polystyrene, PVC, and PVDC, one must be chosen which has excellent chemical stabilities against water, acid and alkaline solutions. 27 28 Polyethylene is the lowest in cost of all the trans- parent films. It has a low moisture transmission rate, but a high gas transmission rate, especially for oxygen. An- other disadvantage of polyethylene is its poor transmission resistance to some oils and greases. Polypropylene has a high resistance to chemical at- tack and is an excellent moisture and gas barrier, but its impact strength is very poor at low temperatures around 0°F. Polypropylene is also an inexpensive material. Polycarbonate has a resistance to chemicals and high temperatures, but it is a poor barrier against moisture and gases. And, its high cost makes using it less practical. Polyester and nylon both have good chemical and heat resistance. Both are also good barriers against gases, al- though not against moisture. Both of these materials are quite expensive. Polystyrene is an inexpensive, sparkling transparent film. Barrier properties for moisture and gases are poor, and its chemical resistance is very limited. A film and sheet form of polystyrene is available containing nearly no plasticizer, though still possessing a good thermoforming characteristic. It is usually used for dry products, but it can be used for liquid products by laminating it with another plastic material, especially with PVDC. PVC has a high resistance to water, Oils, greases, petroleum solvents and chemicals. It is an excellent barrier 29 against gases, although not for moisture. For use with aqueous solutions, some coatings are necessary for films and thin gauge sheets. PVC sheets used for thermoforming include many additives, such as plasticizers, antioxidants, UV stabilizers, and antistats. In order to use a PVC ma- terial for eye solutions, these additives would have to meet FDA approval. PVC is also inexpensive. PVDC has excellent barrier properties for gases and moisture. It is an expensive material, and its machinabil- ity is fair, as it is very soft, stretchable, and has a narrow heating temperature range. But it is laminated with the other materials such as polyethylene, PVC, or polysty- rene, it adds excellent properties to these materials. Al- so, however, PVDC is quite expensive. In light of the above considerations, polyethylene resins, PVC sheets with a PVDC coat, or polystyrene sheets with a PVDC coat can be used as the packaging material of a disposable unit-dose plastic container of eye solutions. PROPOSAL FOR DEVELOPMENT IN PACKAGING OF DISPOSABLE UNIT-DOSE PLASTIC CONTAINERS OF EYE SOLUTIONS In order to prevent the contamination of eye solu— tions, many efforts must be made in hospitals and eye clin- ics, such as sterilizing containers and dispensers, careful handling of solutions, and adequate applications. The de- velopment of a disposable unit—dose sterile container which easily dispenses its contents would eliminate many of these hospital labors, thus saving much time and expense. Also, the development of such containers would render eye solu- tions reliably sterile. Requirements of a Disposable Container for Eye Solutions From the study of eye medication contamination, the requirements of a disposable container for eye solutions are summarized as follows: 1) Sterile Maintaining sterility of its contents. Maintaining sterility of portions of the con- tainer which contact the solution when dispensed. 30 31 2) Functional Easy opening without contaminating its content. Easy dispensing. 3) Nontoxic 4) Reasonably durable 5) Inexpensive 6) Disposable 7) Machinability However, it is very difficult to satisfy all of the above requirements. The first three items, sterility, func- tion, and nontoxicity are most important and essential. Disposable Containers and Their Packaging Systems Two packaging systems will be considered for dis- posable plastic containers. One is a thermal forming, fill- ing and sealing system and the other is a blow molding, filling, sealing and triming system. Thermal Forming, Filling and Sealing System Shape of Containers Bend-off opening type.--A typical bend-Off, opening type container is shown in Figure 2. The material of the bottom package is approximately a 10 mil PVC film with a PVDC coat, and that of the top film is approximately a 4 mil PVC with a PVDC coat. PVDC coated sides will be inside 32 the container. Instead of PVC film, polystyrene or other materials may be used. The bottom package has a notching line around its neck shown in Figure 3. When the content is dispensed, the neck will be bent-off towards the flats side and torn. The content can be squeezed by pressing the center of the round place. Peel-Off opening type.--A peel-Off type container is shown in Figure 4. The container consists of three ele- ments, a bottom, top and peel-Off film. The top film has a dispensing hole and is laminated with the peel—off film. The top film is approximately a 6 mil PVC film with a PVDC coat and the peel-off film is approximately a 0.35 mil foil/PE/Polyester/Peroxylene-based coating. The bottom film is approximately a 10 mil PVC film with PVDC coat. Machinery System The machinery system of thermal-forming, filling, and sealing is designed in order to achieve a perfect ste- rility of container and prevent recontamination of the eye solution. One of the machinery systems is shown in Figure 5. Rolls of the bottom and top films (1 and 10) are treated by the converters with ethylene oxide gas and sealed in PE bags. The bottom film roll is unwound and passes through a hydrogen peroxide bath (2) at 90°C. (194° F), which expose the material for 8 to 9 sec. The hydrogen 33 , Bend Off Notch line f-- .._______332 Dispense Top Bottom film film _, (__ —->- (— Squeeze Figure 2. Bend-Off Opening type container. Figure 3. Cross section of the notching line. 34 .Hosflmusoo emu» msacmmo mmolamom .e musmwm muonmsflammm Houmm mummsvm Edam mummswm Eoupom mcwmcommflo mswmcmmmflo 35 peroxide is removed from this continuous sheet by wiping- down and the rest of the hydrogen peroxide is vaporized by dry hot air, which has been filtered to obtain sterility. The bottom sheet is formed by vacuum and pressure forming with plug assisted (4). The air is also treated by filtration. In the type of bend—off opening containers, the notching line is formed in this process. The forming die has a sharp edge around the neck for forming the notch- ing line, and the assisting plug presses the plastic sheet into this line. After forming, the containers are placed within an enclosure (6) during the closed system filling (5) and seal- ing (8) operations. This area can be flushed with sterile filtered air under positive pressure, which prevents recon— tamination by airborne bacteria. The top film is unwound from the roll (10) and goes into a sterilizing chamber (9). In the chamber, the film is fogged with hydrogen peroxide. Sterile hot air (7) will be used to dissipate the hydrogen peroxide. Then the top film and the bottom formed film meet and go into the seal- ing station (8) and the triming station (11). In the type of peel-Off opening containers, the top film is already punched for the dispensing hole and laminated with peel-off tape except peeling tub area, and wound into a roll by the converter. The dispensing holes are adjusted to the bottom containers by a photo cell registrator. 36 For the sanitary shroud, a bioclean bench will be utilized. A horizontal laminar flow type of bioclean bench can be attached to the back of the machine in the area of the sanitary shroud (6). Ultra high efficiency particulate air filters can reliably remove 99.99 percent of all parti- cles above the 0.3 u diameter. Laminar flows from this filter will remove contaminants from filling and sealing area. The bioclean bench should, however, be designed at a larger size than that required, because there is always a chance that the outside will be contaminated by room air. The air flow rate also should be designed adequately from 120 to 150 ft/min. This bioclean bench method assures ster- ile circumstances during filling and sealing Operations. There are several aseptic thermal forming, filling and sealing systems on the U.S. market. Filper Corp. (San Ramon, Calif.) is Offering a system very similar to that shown in Figure 5. To sterilize the top material, an ulta- violet ray is used instead of hydrogen peroxide (9). Filper's system can produce 400 to 600 filled 4-oz. pack- ages per min. An aseptic system developed by Anderson Bros. Manufacturing Co. has been accepted by U.S. dairy manufac— turers. Anderson's system uses heating sterilization for the bottom material instead of the hydrogen peroxide bath (2) and dry hot air (3) shown in Figure 5. The film is heated by infrared rays and bacteria might be killed by heat. The production rate of the machine is 1,215 packages per min. 37 .Emummm mafiasmm UGO .msflaaflm .mcflEHOMHmEuwsu mo EmumMm MHOGHSUOE oaummmfi N ONm Onounm moanmm3 MOB .N mnmuacmm . . moflammm . mmouzo OV\\\\\\\. OI m_|&.\\\. ln\\ . 353:8 .SOE _\\\\\\\..u . . \\\. 5% was #0: 55 .m K L cflsuom am: .e MHHQ ME H o a . u u.q onAnuv smwammw «Own gnmmmom= Hwnfimno mcfluflafluoum .m was no: who .h mcflaaflm .m .m mnsmwm Qm3 mmmm.H 38 In Europe, Plastimecanique (S.A., Paris) has de- veloped an aseptic system which is very similar to the sys- tem shown in Figure 5. For sterilizing both the top and bottom materials, hydrogen peroxide baths are used. The hydrogen peroxide is dried by vacuuming in continuous trav- el. The system can produce 350 containers of 20 gram (about 0.65 oz.) portion packs per minute. However, Filper's ultraviolet ray and Anderson's infrared ray sterilizations cannot obtain sufficient ste- rility and they should be displaced by hydrogen peroxide sterilization. These three machines were developed for dairy pro- ducts such as milk and cream. In order to apply these sys- tems to eye solutions, some developments will be needed. The ultraviolet lamp method and radiated heating method can- not attain adequate sterility during short time exposure. Between the forming and the sealing station, the area must be biocleaned by means of a bioclean room technique. After these alterations, the three systems could produce dispos- able unit—dose containers of eye solutions. Blow Molding, Filling, Sealing and Triming System A typically shaped Bottle Pak is shown in Figure 6. The top of the container can be twisted-Off easily. High density polyethylene is used for the packaging material. 39 r'“———-\ L——__ Figure 6. Bottle pak container. The advantage of this system is that it is able to achieve sterility without any sterilizing process. The plastic resins will be melted and extruded at high temperature. After blow molding, the container will be filled and closed immediately. There is very little chance of contamination. The Bottle Pak Model 301 machine was developed in West Germany and is now manufactured and sold in the U.S. by Automatic Liquid Packaging Inc. The aseptic packaging is accomplished by the following successive steps shown in Figure 7: Step 1: The thermoplastic is extruded (a) into a parison of a certain size and continuously conveyed (f). After reaching the required length, the mold (e) is closed. The parison is positioned by two holding jaws (c) and sep- arated by a cutting apparatus (b). Then a mold carriage moves the mold into position for shaping, filling and seal- ing the bottle. 40 .msflquomm xmm mauuon wo mmooonm .5 musmflm 1e mmumv 1m mmumv 1m mmpmv 1H mmumv 41 Step 2: To fill the bottle a composite filling and blowing tube moves into the conical neck part (k), the hot plastic tube is inflated by a burst of compressed air (h) and pressed against the wall of the bottle mold. At the same time, a quantity of the product is dispensed into the bottle via the filling channel (9) by a precise metering machine. The air used for inflating the bottle is dis- charged through the air discharge duct (i). Step 3: As soon as the product hits the plastic walls, the bottle solidifies. The filling mandrel (k) is raised at which time the head jaws close (d) by way of two cylinders, forming and sealing the upper bottle head. Step 4: After the head is sealed, the complete mold opens (e and d) and the filled and hermetically sealed bottle leaves the machine via a bottle drop-out chute. During the above operations, the area surrounding the mold must be sterile or airborne contaminants might en- ter through the open mouth of the parison. The blowing and filling nozzle might pick up contaminants also. Filtered sterile air can prevent contaminants from entering when the space is charged at a slightly higher pressure than the out- side atmosphere by filtered sterile air. The air used for blowing should also be sterilized. 42 Outer Packages An outer package for a disposable unit-dose con- tainer is essential if the container is to be sanitary, easy handling, contain an adequate number of unit-dose con- tainers, and protect its contents from diverse environments. Unit-dose containers are sterile when manufactured because of the aseptic packaging systems used to produce them. But once they leave the sterile environment in which they were manufactured, though they remain sterile inside until Opened, the outside of these packages is readily con- taminated. When almost completely sterile conditions are nec- essary, as in the case of an operating room use, outside- container contamination can be disastrous. Thus unit-dose containers must be packed as soon as they are manufactured, in outer packages that can be sealed and maintain a sterile inside condition. The outer package might consist of a thermoformed plastic tray with a gas breathable lid, per- haps paper or Tyvek,* which is used for ethylene oxide gas sterilization. In this type of package, ethylene oxide gas sterilization can be used after sealing. Thus, the unit- dose container can be kept completely sterile until appli- cation. When ethylene oxide gas sterilization is used, the * Du Pont's Tyvek spunponded polyolefin sheet. 43 container material must be thick enough to prevent ethylene oxide gas penetration. This, unfortunately, will raise the cost of using unit—dose containers greatly. For use outside the operating room, such high-degree sterility is not necessary. Thus, unit-dose containers to be used in a doctor's Office or at home could be placed in simple outside packages consisting of a paper or plastic tray, and ethylene oxide gas sterilization would be unnec- essary. CONCLUSION In order to solve the problem of eye solution con- tamination, an aseptic packaging system, which has been de- veloped for use with dairy products, can be used. When used with eye solutions, some differences between food and pharmaceutical products must be realized. The most impor- tant difference is the degree of sterility which is re— quired for the products. The purpose of aseptic packaging in food products is to extend their shelf-life without re- frigeration. Thus, these products are only sterilized against those contaminants that cause disease or sensory microbial changes, but these products often contain many other types of contaminants. This process is referred to as "commercial sterility." However, for an ophthalmic me- dicament, a high degree of sterility must be attained. In the case of eye solutions, the slightest recontamination can bring a loss of sight to a patient. This situation must be avoided. Unit-dose containers of eye solutions should be easy opening and easy to apply. The design of the contain- ers is very important. An aseptic machine should be devel- Oped specifically for packaging eye solutions. The machine 44 45 will be designed to eliminate unnecessary parts and be very compact. A huge machine is not needed for packaging unit- dose containers which commonly contain less than 1 cc of solution. The cost of a unit-dose container should be low enough to be used in any hospital or eye clinic, as the cost of the container will be one of the most important factors in determining how well the container is accepted. LITERATURE CITED 10. 11. LITERATURE CITED Allen, Henry F. "Aseptic Technique in Ophthalmology." Transaction of the American Ophthalmological Society, Vol. 57, 1959, pp. 4044405. "All—in-one: blow—mold/fill/seal/trim." Modern Packag- ing, March 1970, pp. 64-65. "Aseptics Take Off." Modern Packaging, January 1971, pp. 46-50. Bockelmann, Bernhard V. 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New York: McGraw-HilI’BOok Co., 1971. 46 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 47 Hedrick, T. I. Report on the Status of UHT Sterilized and Aseptically‘Packaged FluidDairy Products. East Lansing: Department of Food Science, Michigan State University, 1969. Hertzson, Leon. "Aseptic Packaging Via Clean Room Methods." Dairy & Ice Cream Field, (vol. 154), November 1971, pp. 42-43, 57. King, J. H. "Contamination of Eye Medications: Prac- tical Methods of Prevention." American Journal of Ophthalmology, Vol. 36, 1953, pp. 1389-1397. Lisiecki, R. E. "Aseptic Carton System." Modern Pack- aging, January l97l, pp. 77-79. Locatcher-Khoraza, Deborah, and Seegal, Beatrice Carrier. Microbiology_of the Eye, Saint Louis: The C. V. Mosby Co., 1972. McCulloch, J. C. "Origin and Pathogenicity of Pseudo- monas Pyocyanea in Conjuctival Sac." The Archives of Ophthalmology, June 1943, pp. 924-935. "New Push for Aseptics." Modern Packaging, November 1971’ Pp. 43—45. 099, A. J. 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Van Nostrand Co., Inc., 1958. "Sterile Packages Boom as Hospitals Buy . . ." Modern Packaging, April 1972, pp. 24-27. Taterka, Michael. "Lid Change Gives Sterile Package." Package Engineering, December 1971, pp. 62-64. Theodore, Fredrick H. "Contamination of Eye Solutions." American Journal of Ophthalmology: Vol. 34, 1951, p. 1764. Theodore, Fredrick H. and Feinstein, Robert R. "Prac- tical Suggestions for the Preparation and Mainten- ance of Sterile Ophthalmic Solutions." American Journal of ophthalmology: Vol. 35, 1952, pp. 656- 659. Turtle, B. I. and Alderson, M. G. "Sterilizable Flex- ible Packaging." Food Manufacture, September 1971, pp. 23924, 26-27' 29’ 31, 370 HICHIGRN STQTE UNIV. LIBRQRIE llll llllHHll; lllllll lllll1ll llllllll Ill"