SOLUTIONS FOR UROLOGY Sterile irrigation solutions

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STERILE AGUETTANT SOLUTIONS FOR IRRIGATION IN UROLOGY TECHNICAL FILE

Sodium Chloride 0.9% Sterile Water Glycine 1.5%

Aguettant Ltd The Barn, 41a Main Road Cleeve Somerset BS49 4NZ Tel : 01934 835 694 Fax: 01934 876 790 email: [email protected] Aguettant Limited

INT042/00 April 2013

SOLUTIONS FOR UROLOGY Sterile irrigation solutions

TECHNICAL FILE

CONTENTS

1. GENERAL DESCRIPTION OF PRODUCTS 1.1 Composition 1.2 Container 1.3 Indications & presentations 1.4 Directions

2. UROLOGY BAGS: MANUFACTURE AND QUALITY CONTROL 2.1 Preparation of solutions 2.2 Filling of bags 2.3 Sterilization of bags 2.4 Physicochemical quality control of the finished product

3. BIOCOMPATIBILITY OF MATERIALS 3.1 Container/contents compatibility tests 3.2 Results of compatibility tests

4. PHYSICAL AND CHEMICAL STABILITY 4.1 Stability test conditions 4.2 Physicochemical tests 4.3 Results of stability tests

5. NORMS APPLIED

6. BIBLIOGRAPHIC REFERENCES

7. CE MARKING CERTIFICATE CE ATTESTATION OF COMPLIANCE

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SOLUTIONS FOR UROLOGY Sterile irrigation solutions

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1. GENERAL DESCRIPTION OF PRODUCTS

There are three different solutions for urology: - Sterile Distilled Water - NaCl 0.9% - Glycine 1.5% for urology and arthroscopy Solutions for urology are medical devices which are covered by EEC Directive 93/42 of 14/6/93 pertaining to medical devices. They are sterile, apyrogenic solutions supplied in PVC bags.

1.1. COMPOSITION

Sodium Chloride 0.9% - Sodium chloride - Sterile distilled water

q.s.

0.9 g 100 ml

q.s.

1.5 g 100 ml

q.s.

1000 ml

Glycine 1.5% - Glycine - Sterile distilled water

Sterile Distilled Water Distilled water

1.2. CONTAINER

Our urology bags are made of polyvinyl chloride (PVC). The 3-liter bags have a single chlorobutyl puncture (“minitulip”) outlet; other sizes have both a puncture (“minitulip”) outlet and an injection site. The bags carry graduation marks to show the volume of solution remaining during use. Bags are sterilized in their secondary packaging. A precut site is provided to make the bag easy to open.

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1.3. INDICATIONS AND PRESENTATIONS

a. Sodium Chloride 0.9% INDICATION: postoperative irrigation of the bladder. PRESENTATIONS: box containing 5 x 2-liter bags box containing 4 x 3-liter bags b. Glycine 1.5% INDICATION: Bladder irrigation and arthroscopy With reference to Circular Letters 987990 and 989222 (08/98) on “the adverse effects of Glycine-containing irrigation solutions”, it has been reported that the most common adverse effect encountered is due to the absorption of irrigation fluid into the blood: the so-called “TURP syndrome”. Warnings on this subject can be found in the “Instructions For Use” of Glycine.

REVIEW Glycine is a water-soluble amino acid which readily crosses the blood-brain barrier. It is an inhibitory neurotransmitter which, like GABA, acts on chloride channels. Its inhibitory activity is manifest in the retina, the brain stem, the anterior horn of the spinal cord and the gray matter of the central nervous system (as well as other sites). It tends to reduce peripheral resistance and heart rate, and can therefore induce cardiovascular depression (2). The main catabolic pathway for glycine involves hydroxymethylation which leads to the formation of serine and ammonia. Other catabolic pathways generate oxalic acid and creatinine (4). It has a biological half-life of 85 minutes (3). Healthy volunteers experience malaise and nausea following IV administration of 372.9 mg/kg of glycine—this is equivalent to the absorption of 1.74 liters of a 1.5% solution in a subject who weighs 70 kg. The Glycine 1.5% solution is miscible with water, non-conducting, not strongly hemolytic because it is only slightly hypotonic (200 mOsm/L), and transparent [and has good optical qualities] (9).

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DEFINITION AND PATHOGENESIS OF “TURP Syndrome”

Trans Urethral Resection of the Prostate (TURP) syndrome describes a set of clinical manifestations resulting from the absorption of excess irrigation fluid into the general circulatory system (4). It involves: - symptoms due to intracellular hyperhydration: nausea, headache, drowsiness, agitation and confusion; this can lead to convulsions and coma. - impaired vision (non-reactive bilateral mydriasis, transient blindness or unfocused vision) which are due to glycine toxicity (and which can be masked by general anesthesia). - hyponatremia, hypo-osmolarity, and reductions in hematocrit (also due to bleeding and dilution) and blood protein concentration. Glycine absorption can be assessed by measuring blood glycine levels which can rise as high as 10,000 µmol/L (2). However, clinical symptoms do not always correlate with absolute blood glycine concentration because other factors are important, including the severity of the hyponatremia, whether or not there is hypovolemia, and the subject’s ability to metabolize glycine (6).

PUBLISHED DATA

1.1

"TURP SYNDROME" ASSOCIATED WITH TRANSURETHRAL RESECTION OF THE PROSTATE (TURP)

According to some reports, 70% of patients undergoing transurethral resection of the prostate (TURP) absorb irrigation fluid. Reports differ with respect to the mean volume absorbed: according to Leisner (7), the mean is 203  483 ml (maximum 2.6 l) whereas according to CHARLTON (1), it is about 20 ml/min. The risk factors for TURP syndrome are: the duration of the procedure (> 90 minutes); the volume of fluid absorbed (> 1.5 to 2 liters); the number of open sinuses (which is related to the amount of tissue resected); poor surgical technique; high pressure in the bladder and the prostatic compartment; and general anesthesia (because it masks the earliest signs which should prompt discontinuation of the procedure) (9). The importance of all these risk factors has been confirmed in a prospective study (7) conducted on 214 patients undergoing a TURP procedure. In the 5% who developed TURP syndrome, the procedure had been longer, a greater volume of prostate tissue had been resected, more peroperative incidents had been reported and a greater volume of fluid had been absorbed. The incidence of TURP-related TURP syndrome is between 0.6 and 10% (8, 9). In a retrospective study of 3,885 patients who had undergone a TURP procedure, 2% had developed TURP syndrome and 0.07% had died as a result (9).

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"TURP SYNDROME" ASSOCIATED WITH ARTHROSCOPY

For some years now, glycine-containing irrigation fluids have also been used in arthroscopy procedures, although this type of application is not covered in the MA. There are fewer reports of arthroscopy-related TURP syndrome. According to Ichai (6), some glycine is always absorbed during this type of procedure because, in his study of 22 patients who had undergone shoulder arthroscopy, all had higher blood glycine levels and lower blood sodium levels than at the beginning of the operation; one patient had signs of TURP syndrome. This would make the incidence of glycine absorption in this type of procedure higher than that reported by Hahn (70%) for transurethral resection of the prostate (5).

TURP syndrome is a serious complication of using glycine-containing solutions. Although the possibility of this complication is well recognized by teams that are experienced in the use of glycine solutions—notably in transurethral resection of the prostate—it is not taken into account to the same extent in arthroscopy, in which field such solutions have only been brought into use relatively recently. Possible complications arising from systemic absorption of glycine are mentioned on the labeling of the bags containing our Glycine Solution in the following form:

Throughout the procedure, the patient should be monitored for excess absorption of irrigation fluid into the blood (TURP syndrome: a syndrome of hemodilution with hyponatremia) by monitoring for the following signs: - non-reactive bilateral mydriasis in a patient under general anesthesia; a sign that systemic absorption of glycine has occurred, - the following clinical symptoms in a patient under regional anesthesia: nausea, headache, drowsiness, agitation and confusion (which can lead to convulsions and coma or death), out-of-focus vision or amaurosia, - hypervolemia producing dyspnea, changes in blood pressure or even acute pulmonary edema. These signs are due to intracellular hyperhydration which can be fatal. The procedure should be discontinued immediately and bleeding carefully controlled. Blood sodium levels and hematocrit should be measured straight away and appropriate treatment undertaken as soon as possible. These symptoms may appear at the end of the procedure.

PRESENTATION:

box containing 4 x 3-liter bags

c. Sterile Distilled Water INDICATION: irrigation of the bladder (to wash the bladder through and irrigation during certain intravesical procedures) PRESENTATIONS:

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box containing 10 x 1-liter bags box containing 4 x 3-liter bags

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1.4. DIRECTIONS

1. Check that the solution is clear and that the bag and secondary packaging are undamaged before opening. 2. Reveal the puncture outlet by removing the breakable part. 3. Connect a tube (a simple or a Y-tube) 4. Make sure there are no air bubbles in the tube

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2. UROLOGY BAGS: MANUFACTURE AND QUALITY CONTROL

2.1. PREPARATION OF SOLUTIONS

Water for Injection, Sodium Chloride and Glycine are in compliance with the relevant Monographs in the currently applicable European Pharmacopeia. They are all prepared in a Class C Clean Room.

2.2. FILLING OF THE BAGS

The bags are filled in a Class A (or Class 100) Clean Area. The solution coming from the tank is prefiltered through a membrane with a pore size of 0.5 µm. Finally, the solution is dispensed into the bag through a 0.22 µm membrane under laminar flow. The filled bag is sealed with a puncture outlet. The first filled bags undergo quality control procedures to check the dispensed volume and the pH of the solution. 2.3. STERILIZATION OF THE BAGS The bag is inkjet-marked with its Batch Number and Expiration Date before secondary packaging. Bags are autoclave-sterilized in their secondary packaging. Bags are packaged in a Class C Clean Area.

2.4. PHYSICOCHEMICAL QUALITY CONTROL OF THE FINISHED PRODUCT The resistivity and osmolality of the solutions are measured, in addition to routine quality control parameters, namely: - Appearance of the solution - Extractable volume - pH - Particulate contamination - Sterility - Endotoxin assay - Identification of glycine (or NaCl 0.9%) - Quantitative determination of Glycine (or NaCl 0.9%).

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3. BIOCOMPATIBILITY OF MATERIALS

All materials used are well characterized and have been in regular use for at least 20 years. 3.1. CONTAINER/CONTENTS COMPATIBILITY TESTS

The following tests have been performed: - checking of particulate contamination levels according to currently applicable EP (European Pharmacopeia).

- quantitative determination of calcium and zinc by atomic emission spectrophotometry with a plasma torch (the validated analytical technique). These two elements can leach out of stabilizers used in the production of the PVC bag.

- quantitative determination of DEHP by HPLC (the validated analytical technique): a plasticizing agent which enters into the composition of the PVC bag.

3.2. RESULTS OF COMPATIBILITY TESTS

The results are within our specifications ( specifications of the European Pharmacopeia for DEHP and particulate contamination). It can be concluded that container and contents are compatible for 2 years for all the volumes.

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4. PHYSICAL AND CHEMICAL STABILITY

4.1. STABILITY TEST CONDITIONS Stability tests were carried out under both normal storage conditions (25°C) and accelerated conditions with units in their normal secondary packaging.

4.2. PHYSICOCHEMICAL TESTS The tests were exactly the same as those for routine finished product quality control. As well as the osmolality of the solutions, the following routine quality control parameters were checked: - Appearance of the solution - Extractable volume - pH - Particulate contamination- Sterility - Endotoxin assay - Identification of sodium, chloride (or glycine) - Quantitative determination of sodium chloride (or glycine)

4.3. RESULTS OF STABILITY TESTS

The results obtained under normal conditions and accelerated storage conditions allow a shelf life of 2 years for all the volumes , provided they are stored at a temperature of 25°C or below.

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5. NORMS APPLIED AND REFERENCE TEXTS

REFERENCE TEXT: European Directive 93/42/EEC of 14/06/93 pertaining to medical devices as amended by Directive 2007/47/EEC of 05/09/2007.

NORMS APPLIED: 

ISO 13485 (2003/AC/2009) : Medical devices - Quality management systems - Requirements for regulatory purposes.



ISO 9001 (2008) : Quality management systems – Requirements.



ISO 14971 (2012) : Medical devices – Application of risk management to medical devices.

 ISO 17665-1 (2006) : Sterilization of health care products –Moist heat.  NF EN 556-1 (2001/AC/2006) : Sterilization of medical devices - Requirements for medical devices to be designated STERILE - Part 1 : requirements for terminally sterilized medical devices.  EN 980 (2008) : Symbols to be used with medical device labeling..  ISO 11607-1 (2009): Packaging for terminally sterilized medical devices -- Part 1: Requirements for materials, sterile barrier systems and packaging systems.  ISO 11607-2 (2006): Packaging for terminally sterilized medical devices -- Part 2: Validation for Forming, Sealing, and Assembly Processes.  ISO 11737-1 (2006/AC/2009): Sterilization of medical devices – microbiological methods.  NF EN 62366 (2008): Medical devices – Application of usability engineering to medical devices.  Set of ISO 10993 norms: Biological evaluation of medical devices

OTHERS: - Currently applicable Good Manufacturing Practices, - Currently applicable European Pharmacopeia.

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6. BIBLIOGRAPHIC REFERENCES

1

CHARLTON A.J. Cardiac arrest during transurethral prostatectomy after absorption of 1.5% glycine. Anaesthesia (1980), 35: 804-806.

2

CLEMENT P., PAULET C. Résorption du liquide de lavage au cours des résections transurétrales de la prostate. (Absorption of irrigation fluid during transurethral resection of the prostate) Ann. Urol. (1990), 24: 565-568.

3

DIMBERG M., NORLEN H., ALLGEN L.G. A comparison between two hypotonic irrigating solutions used in transurethral resections of prostate: sorbitol (2%)-mannitol (1%) and 1.5% glycine solutions. Scand. J. Urol. Nephrol. (1992), 26: 241-247.

4

FELLAHI J.L., RICHARD J.P., BELLEZZA M. Passage intravasculaire du glycocolle lors de la chirurgie rénale percutanée. (Intravascular absorption of glycine during percutaneous renal surgery) Cah. Anesthésiol. (1992), 40: 343-347.

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HAHN R.G. Blood ammonia concentrations resulting from absorption of irrigating fluid containing glycine and ethanol during transurethral resection of the prostate. Scand. J. Urol. Nephrol. (1991), 25: 115-119.

6

ICHAI C., CIAIS J.F., ROUSSEL L.J., LEVRAUT J., CANDITO M., BOILEAU P., GRIMAUD D. Intravascular absorption of glycine irrigating solution during shoulder arthroscopy: a case report and follow-up study. Anesthesiology (1996), 85: 1481-1485.

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LEISNER C. Le syndrome de résection transurétrale de prostate. Etude prospective. (Transurethral resection of the prostate syndrome: a prospective study)

Thèse de médecine - TOURS 1994. 8

SHEPARD R.L., KRAUS S.E., BABAYAN R.K., SIROKY M.B. The role of ammonia toxicity in the post transurethral prostatectomy syndrome. Br. J. Urol. (1987), 60: 349-351.

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TAUZIN-FIN P., SANZ L. Le syndrome de résection transuréthrale de la prostate. (Transurethral resection of the prostate syndrome) Ann. Fr. Anesth. Réamin. (1992), 11: 168-177.

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SOLUTIONS FOR UROLOGY Sterile irrigation solutions

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7. CE MARKING CERTIFICATE CE ATTESTATION OF COMPLIANCE

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