Seminar Pengurusan Eksekutif Pengsterilisasi Barangan

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Seminar Pengurusan Eksekutif Pengsterilisasi Barangan Perubatan Menggunakan Sinaran [ Executive Management Seminar On Radiation Sterilization Of Medical Products ]

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SEMINAR PENGURUSAN EKSEKUTIF PENGSTERILISASI

BARANGAN PERIEATAN NtEDJGGUNAKAN SIN ARAN

(Executive Management Seminar on Radiation S t e r i l i z a t i o n of Medical Products)

15-17th. September 1986 Holiday Inn on the Park

Kuala Lurapur Malaysia

Kelolaan Bersama / J o i n t l y Organised

Unit Tenaga Nuklear, Jabatan Perdana Menteri Agensi Tenaga Atom Antarabangsa (IAEA)

INTRODUCTION

Pioduct stei nidation (01 microbiological control is essential in thu health care and cosmetics industiies. The three primary methods used today are gamma madiaiion (Cobalt-60), sieam and ethylene oxide (ETO) treatment. In comparison with other methods, gamma irradiation has the following advantages:

i) it is a simpler process, involving only one paiameter, viz exposure time, other parameters such as piessure, temperature and humidity necessary in other methods (ETO, steam) are redundant.

ii) there is no residual and post sterilization treatment is not required.

iii) product of various shapes and sues can be sterilised because of the penetrating power of gamma radiation.

iv) it is more economical for large quantity.

v) there is no physical effect on the products treated, unlike those by heat treatment, and hence there is no limitation on the types of medical products to be sterilised.

There are now 135 plants in 42 countries that use gamma irradiation for the sterilization of medical products. There is one in Melaka which is operated by Ansell Company. Currently a wide range of products are being sterilised by gamma radiation. They include plastic, rubber and metal based products (e.g. sutures, catheters, surgical blades and dressing), pharnia ceuticals, tissue grafts among others.

The Nuclear Energv Unit of the Prime Minister's Department with the cooperation of the International Atomic Energy Agency (IAEA) takes the initiative to organise this seminar with the hope to create public, government and private sectors awareness on the potential and advantages of this technology.

OBJECTIVE

1. To introduce and to create awareness among the public, the government and the private sectors on the methods of medical products sterilisation by gamma irradiation and the many advantages of this technology.

2. To provide a forum for discussion the potential applications of this technology from the economic, technical, legal, safety, organisational and other aspects.

3. To seek cooperation among executives and technical staff in the government and the private sectors with the view to solve problems that may arise when implementing this technology.

i i

SECRETARIAT

Advisor: Y. Bhg. Prof. Datuk Mohd. Ghd2ah bin Hj. Abd. Rahman

Chairman: Dr. Ahmad Sobri bin Hj. Hashim

Administration: En. Adnan bin Hj. Khalid

En. Mahathir bin Din

Finance: Cik Hjh. Normah Mohd Yusof

Technical: Ir. Razali bin Hamzah

Dr. Norimah bte Yusof

Secretary: Puan Rafeah bte Amin Nuddin

Publication: En. Samsurdin bin Aha mad

IAEA representative: Dr. V. Markovic

LECTURERS

1. Dr. V. Markovic — Industrial Application and Chemistry Section. International Atomic Energy Agency ( IAEA), Austria.

2. Dr. J. Masefield — Chairman, ISOMEDIX Inc., U.S.A.

3. Dr. V. K. lya - Director, Isotope Group, Bhabha Atomic Research Centre (BARC), India.

4 Prof. G. O. Philips - Principal, The North E Wales Institutes of Higher Education, United Kingdom.

5. Prof. A. Tallentire — Department of Pharmaceutical, University of Manchester, United Kingdom.

6. Dr. Norimah Yusof — Medical-Sterilization Group. Nuclear Energy Unit (UTN), Malaysia.

7. Ir. Muhd, Noor bin Muhd. Yunus — Head of Engineering Department,

Nuclear Energy Unit (UTN), Malaysia.

PARTICIPANTS

1. Ashok Kumar

2. Ashrum Bala

3. August i n , Marcel Aloys ins

4. Azlina Mohamad

5. David Ho Sue San

(5. Foo Kooi Sim

7. Holmes, P.D.

S. Loo, Foong Choi

9. M. Ashaari Abas

10. M.G. Desai, J r .

t l . Menzies, Robert

12. Mohamad Harun

13. Mohamad Ishak Hamidon

14. Mohd. Mydin

15. Mohd. Zin Cne Awang

16. Morgans, S.W.

17. itoriah Mod Ali 1 8 . Ncorizan Abd. Aziz, Dr.

19. Shamsinar Haji Shaari

20. "Shukor Yusof

21 . Teoh All Bah

22. Thanabalan s/o A. Thannimalai

23. Yap Ming Ta

24. Wan Fatimah

25. Wan Manshol Wan Zin, Dr.

26. Dr. Abd. Qiani Hj. Mohd. Din

Mediquip Sdn. Bhd.

Lovytex Sdn. Bhd.

Euromedical Industries Sdn. Bhd.

Uhiversiti Sains Malaysia.

Ho Yan Hor Pharmaceuticals Sdn. Bhd.

Ministry of Health

Ansell Malaysia Sdn. Bhd.

Federal Industries Sdn. Bhd.

Velosi

Lovytex Sdn. Bhd.

Medical-Latex Sdn. Bhd.

UTN

Permodalan Nasional Berhad.

Tangkas Scientific Sdn. Bhd.

Ministry of Healty

DRG Medical Packaging TTN

t fa ivers i t i Sains Malaysia.

S t e r l i n g Drug (M) Sdn. Bhd.


Euromedical Indus t r ies Sdn. Bhd.


Optisol I n d u s t r i a l Sdn. Bhd.

Ministry of Health.

UTN.

ISM (Kota Baharu).

OBSERVERS

1.

2.

3.

4.

5.

Dahlan Hj. Mohamad

Daud Mohamad

Husin Md. Nor

Mat Rasol Awang, Dr.

Nik Giazali Nik Salleh

UTN

UTN

UTN

UTN

UTN

PROGRAMME

Monday,

8.30 -

9.00 •

9.10 •

9.20 -

9.30 -

10.00 -

10.30 -

, 15th, Sep

9.00 hrs

9.I0 hrs.

9.20 his.

9.30 hrs.

10.00 hrs.

10.30 hrs.

11.00 his.

11.00 • 11.30 hrs.

- Registration.

Welcoming speech by Diiuclor Gcneial <>l UTN

- Si moment by IAEA ii'piesontativf

- Opening speech by Y.B. Encik Kasn.ili bin Gndd.im. Minister in the Piime Ministers Dupai l inrnt.

- Tea. '

- Introduction of tht: Ledums and Pai licipants.

Geneial Introduction and Objectives ol Seminai — Dr. V. Markovic.

Country Status of Applications Mdiuifactuiing anil Sterilization of Single - Use Modtcal Products - Dr. Norinidh bt. Yusuf.

11.30

12.00

12.45

14.00

14.30

- 12.00 hrs. -

- 12.45 hrs -

• 14.00 hrs. -

- 14.30 hrs. -

• 15.00 hrs. -

Basic Radiation Microbiology - Prof. A. Tallentire.

- Documentry film-

Lunch .

Basic Dosimetiy - Di. V. Mai kovic.

- Dosimetry in Process Control - Dr. J. Masefield.

15.00

15.30

16.00

15.30 hrs. - Good Manufacturing Practice in Relation to Steiility Assurance Level — Microbiological Aspects - Prof. A.Tallentire.

16.00 hrs. — Good Manufacturing Practice — Quality Assurance Programmes - Mr. J. Masefield.

Tuesday. 16th September, 1986.

9.00 9.30 Ins Chemical Effects of Hidiation Piol. G. O Phillip-.

9 30 10.00 Ins Haclialion Effects. Stability .ind Instability ul Mutenals Di. V. K lya.

10.00 10.30 his Radtalion Efleets on Pltaini-iceum.als and

Related Materials l ) i . V K. lya.

10.30 11.00 his. Tea break.

11 00 1 1 30 hiv Radiation Sti'iili/ndon ol Bioluciual 'tissues - I'mI G. O. Phillips

1130 1?.00 Ins. IJTN's UamiTia lnadidlMMi I acility Drsiqn and Concept li Muhd IMnoi bin Mubd Yunus.

12.00 12.301ns Dncuimmtaiy film

12.30 14.00brs. - Lunch.

1.4.00 15.00bis. Gioup discussion.

15.00 16.00 his. - General discussion.

16.00 16.15 hrs. Closing.

16.15 • 16.45 hrs. - Tea.

Wednesday, 17th. September, 1986

9.00 -11.00 hrs. - Small group consultation All lecturers (Place : Kompluks PUSPATI, Baugi)

11.00 11.30 hrs. Tea.

16.30 hrs. Tea. 11.30 hrs. Depart for Ansell Malacca.

LECTURE 1

RADIATION TECHNOLOGY -General Introduction-

INTRODUCTION

i. Speaking about RADIATION TECHNOLOGY we usually re-fer to radiation stisrtcss and their industrial applications.

2. Radiation technology is A MEW TECHNOLOGY based on the use of ionizing radiation as a r-JEW ENERGY SOURCE -far industrial processes.

?. Hi st<3f i CS.I y , rad iatior. technology started to develops m early -ifties when high power radioactive sources became available arid when electron accelerators were developed to the stace w'-i&re '-< i 5 *-. e-ergy sr-.d high currents could be produced at ar. = f f or deb !<=• pt ice. First industrial applications were rorifKted with sterilisation a-f disposable medical products, t"?E = i or. p'spert/ of radiation to destroy harmful rsicrcorganisms.

4. From there or: radiation technology experienced development in several directions! A slow initial growth has been =5i gn i f icant ly accelerated in mid-seventies,part ialy due to development o-f new applications (for example cross 1 ink i ng o-f wire end cable,heet shr i r.t-able materials etc) and partialy due to increased interest 'or new energy sources and for energy savings i n general,

"3. It has been estimated that during the last 15 years radiation processing was growing steadily at about 10-15% per year. One of the reliable indicators of this growth is the number of industrial radiation sources, which grew not only in quantity,but alsa in average power per installation.

6. The basic advantages of using radiation for industrial processing d per.d an actual app 1 i cat. i on . There are , however, soroe general facts:

- it offers significant ENERGY SAVINGS, - it is SAFE AND RELIABLE, - it gives PRODUCTS OF SUPERIOR QUALITY, - it can be used to obtain MEW PRODUCTS.

1

"'. The basic requirements for succes-f ul radiation spplication depend on actual industrial process.Some general csr.i : I : 3ns, hawever , are common for all applications:

- r:di£.t:cn treatment shsali prscuce NO INDUCED RADIOACTIVITY,

- radiation processing should be SAFE FOR OPE.KATIMS PERSONNEL,

- ra.dits.ticn processing should be CHEAPER THAN ALTERNATIVE TECHNIQUE,

- radiation processing should be MORE RELIABLE THAN ALTERNATIVE TECHNIQUE.

8. In addition to requirements above, radiation sources and material handling equipment are expected to match capacity and reliability of standard industrial production.

9. Two types o-f radiation sources satisfy most or all of requirements mentioned above: Co-60 gamma radiation source and electron beam (EB) accelerators. The energy of Co-60 gamma rays are below the treshold level of any nuclear photon induced reactions. There is no theoretical possibility -for inducing radioactivity in irradiated materials. Similarly there is no practical possibility for induced radioactivity in materials irradiated with electrons below 10 Mev". This is accepted maximal energy of electrons for all industrial applications.

10. Eoth types of radiation sources satisfy most or ail of other requirements.The choice between the two types depends on actual application and on several technoeconomic factors.

11. Two other radiation sources have been also consioered for industrial app1ications,but til now did not encounter wide acceptance: Cs-137 garnrna radiation source and X-rays generated by interaction of fast electrons with heavy metal targets.

12. Cs-137, byproduct of irradiated nuclear fuel reprocessing has been used only occassionaly and mainly for- small sc?le dewior.strat l on or pilot scale facilities. It is not readily available in large quantities and predicted supplies in the future are not lihely to change this situation.

13. Brehrnss trah lung X-rays did not play significant role until the present time mainly due to low efficiency of energy conversion at medium electron energies. With new developments and availability of high energy (S-IO Mev") linear electron accelerators (LINACs), with high power outputs (of the order of hundreds of kW) , these energy sources might possibly play more important role in the future.

11. Several simple formulas relate the radiation power and

2

threyghput ;apscity of industrial raiittian -facility. Severs.! UW of riiiation power are -far mare e-ff ;cient than equivalent thermal prwsr.In t> e r£ii;5 of lew absorbed i;E3 applications (for e>ta:.ple rprc-jt ir.hiii'.irr. :r. cr.isns end p^tatsss) 3r.° l:W of radial ion p-wer =sr. process cbout ten tans of product per hour. Ever. is. the rrr:c<? CT hijh absorbed doses applications Iradiaiion r te - i 1 i ~s.t j en) one kW r-f radiation power can be used for s te-r i 1 i :: t i an of abcut 2000 syringes per hour or about 15 to 20 nil lion per year.

15. Easicaly the technology relies on the use o-f radiation energy to initiate chemical reactions, induce biological changes or rodi-fy chemical and physical properties o-f materials. Extrex.ely high fr-f -f i c iency o-f energy conversion results -from the transfer o-f snergy in high quanta, comparable to electron bonding energies in stems and molecules.Elementary processes of interaction Df radiation with matter include molecular and atomic e:;citstions and ionizations which result in production of a Multitude of reactive speciesifree radicals,radical iDns,excited species at different levels of excitations etc. This species initiate favourable or unfavourable chemical react ions, depending on the system and irradiation conditions.

PRESENT STATUS OF RADIATION APPLICATIONS

16. There is no common denominator for description of commercial successes of different radiation applications. In many applications the technology has been developed in laboratory or ,at a pilot scale, but has never attracted wider industrial interest. There are also several applications which are successfuly implemented, but not on a very wide scale.There are some other which can be expected to expand in the near future and many more which are in the stage of development and potentialy cculd bring a number of nevi opportunities for radiation based i ndustry.

l~?. To clarify the picture abcut the status of radiation loehrelogy worldwide, it is important to distinguish between:

- ESTABLISHED TECHNOLOGIES,those that have been in industrial operation for many years around the world,

- EMERGING TECHNOLOGIES,those that have more or less passed through the research and development stage and reached pilot or semi-industrial level,but have not yet become fully commercialized,

- DEVELOPING TECHNOLOGIES,those that are in the research and development stage with indications for future commercialization.

18. ESTABLISHED RADIATION TECHNOLOGIES include the following

3

radiation applicat ions: - radiation sterilization of disposable medical products, - :r3ss 1 i nt:i r. g applications Iv.ire and cable insulation, heat

shrinLsble nate-iels and pr cduc ts, p last ic foam.PE pipes -far hot wete- :r;tsU5ticns,etc) ,

- radiation curing (coating,adhesives, Iaminates,etc) , - raiiĕtion degradation of polymers (teflon), - radiation grafting (rnercbr anes) .

1". EMERGING RADIATION TECHNOLOGIES include the following rsdictinn applications:

- feed i r radi s t i or., - i r r sd i e t ion o-f animal -feed, - irradiation of sewage sludge for safe disposal and

'«utiIi ration, - irradiation of stack gases for removal of toxic gasaous

components»

RADIATION SOURCES

20. The selection of particular radiation source for industrial application {gamma or fast electrons) depends on several engineering and economic factors.To mention most important considerations:

- actual application which determines the type of the product to be irradiated,required penetration,dose distribution

'•"•tc; - the required capacity or throughput of production; - availability and servicing; - economic considerations.

21. The actual industrial experience indicates that for jviost radiation sterilization applications Co-60 was preferaole radiation source (currently about 135 gamma installations are in operat ion .compared to less than 10 EB i nstal 'iat ion ) . EB accelerators were exclusive choice for applications like polymer crosslinking processes,polymer degradation,surface coatings,grafting etc. Fojd irradiation is not yet developed to a large scale application,but indications are that Co-60 will also be preferable source wherever treatment of large voluminous products is required.

22. Several applications like sewage sludge treatment,disinfestation of grain,decontamination of animal feed and similar are in a initial stage of development at industrial level,Both,gamma and EB radiation sources are considered.In these

4

bo-derline exatnples,the actual technoeconomic consi deration and. some ether factors, as indicated ear 1 i er, would be decisive en the se-lection of appropriate radiation source.

rs.Factors that have to be considered for selectjsn. of appropriate radiation source include:

- penetration a-f radiation in products tc be irradiated J - throughput; - cost.

2S. Recent developments in gamma radiation facilities for industrial applications are:

- high power installations (currently up to about 6 MCi>; - pallet type irradiators» - computerized process control; - split source operation! - incremental dose systems. The last -four -features contribute signi-f icant jy to

versatility o-f irradiation -facilities in the cases when th&y are intended to be used -for a number o-f different applications,requiring handling o-f different density materials and processing at different dose levels on a simultaneous and continuous basis.

25. Current developments in design of industrial EB machines

- high power DC machines up to about 200 UW (4 MevVSO tr.A) » - filament free electron* gun systems for low energy EB

accelerators; - high speed electron beam processing systems <1 Mrad at

1500 m/min or equivalent) with increased irradiation zone length and a cooled drum technique for low energy surface applications;

- design of compact and low costimedium power LlNACs suitable for on-line applications (5-10 MeV/10-20 UWJ.

26. X-ray generators were often considered as potential radiation sources fcr industrial uses.They could offer higher penetration than e lee trans. The possibility .remains to -be t hecret i cal . There are,however,new deve lcprnents which indicate that situation may be reversed in the near future and X-nay generators could become competitive with gamma radiation sources.These developments can be expected mainly due to reported availability of high power LlMACs (several hundreds kW) a.nd engineering advancements in improving the efficiency o-f energy conversion.

27. As mentioned before,Cs-137 also often considered to be an alternative to Co-60,with main advantage of having much longer half life,has n^\/&r been brought to wider industrial use.Recently

5

implemented several projects sponsored by DOE in USA resulted (or will result in near -future) in construction of several industrial -facilities far radiation sterilization and -food irrad i at ion. However, the general availability o-f Cs-i37 in the •f• 11'.i"e «-eTiains uncertain and most likely not in the quantities required *or industrial application.

CONCLUSIONS

1. Radiation technology does not provide solution for all problems. It has beer,, however , devel oped in many useful industrial ?.pp 1 icat ions, successful y applied in many countr ies, f or Many years. Increasingly more developing countries are finding interest and benefits of this modern technology.

2. Rs.iiatinn is neither too cheap r.or too expensive. The ?.rsLC±ic& has shown, beyond any doubts, that in many instances radis.tian prcvides cheaper and r.-.ore reliable alternative to some existing process. It has also been shown that radiation processing can sometimes lead to new and superior quality products.

3. There are many new applications under development,rthich still have to prove their economic and technical viability.

4. Radiation technology is not too sophisticated for many industrial processes and actualy in some instances offers more simple and reliable process control than any alternative technology.

5. The safety record of several hundreds Df industrial installations around the world in operation for about 20-25 years indicates extraordinary high standards applied.

RADIATION TECHNOLOGY IS SAFE FOR OPERATING PERSONNEL AND FOR ENVIRONMENT.

"COUNTRY STATUS OF APPLICATION, MANUFACTURING AND

STERILIZATION OF SINGLE-USE MEDICAL PRODUCTS"

NORIMAH YUSOF

NUCLEAR ENERGY UNIT

(UTN)

ABSTRACT

The paper reviews the current s ta tus of application of single-use

medical products in Malaysia. The s ta tus of their manufacturing

and s t e r i l i z a t i o n is also discussed. The increasing production of

such items ca l l s for a more re l i ab le and ef f ic ient s t e r i l i z a t i o n

technique, in par t icular , radiation s t e r i l i z a t i o n . In l ine

with the demand and the effort to increase local production of

medical products, UTN would be providing i r radia t ion service

together with research and development in th i s par t icu lar f ie ld by

1988.

INTRODUCTION

Radiation s t e r i l i z a t i o n of medical supplies i s one of the very early

applications of ionizing radiat ion in indus t r ia l process. I t was

f i r s t successfully u t i l i z e d in 1956 when the electron beam from

accelerators was introduced. This followed by the conmissicning of

the i r rad ia t ion p lan t using Cobalt-60 as the source 3 years l a t e r in

Austra l ia . Despite i t s high cap i t a l c o s t , the i r r ad ia t ion process

has managed t o gain importance in medical industry and thus creat ing

a market for t h i s highly priced s t e r i l i z e d product owing t o i t s

advantages over other s t e r i l i z a t i o n methods* .

Rapid growth in the number of s t e r i l i s a t i o n plants using ionizing

r a d i a t i m process was only observed in 1970's ensuing a ra ther slow

i n i t i a l stage in the growth. Malaysia i a not fa r behind in t h i s

technology since the f i r s t ganma i r rad ia t ion plant was s e t up in

1976 by Ansell Malaysia Sdn. Bhd. in Melaka. The successful

2/...

2 -

application of ionizing radiation in s ter i l izing medical devices has offered an alternative method of steri l ization to our local manufacturers and also incited an Interest in the technology. However/ ignorance of the subject which s t i l l exists anong some of the producers of the medical devices explains the continuing use of the conventional procedures of s ter i l izat ion. In conjunction with th i s , the Nuclear Energy Unit (UTN) has recently engaged in a programme involving radiation sterilization of medical products. The installation of a 200 kilocuries Cobalt-60 pilot plant will in i t ia te further the development work en the industrial applications of radiation steril ization process.

APPLICATION

Hospitals are the main users of medical products in the country* ' . There is at least one government hospital in each d is t r ic t throughout the nation while private hospitals can be found scattered in certain developed areas. Numerous s ter i le medical supplies are therefore required for daily use. The two types of medical products being widely used in hospitals are pre-sterilised and non-sterilized products. The pre-sterilized products commonly known as disposable or single use medical items are normally steril ized upon purchasing. The non-sterilized products are mainly comprised of reusable art icles such as surgical instruments/ linens, soft dressings, reusable gloves/ glass syringes and stainless steel needles. These products can be recycled or resterilized usually using aitoclave before being used again.

However/ the pre-sterilized or disposable medical supplies are becoming more popular aid besides being convenient to the users, they also help reduce cross-infection. Medical items categorised as disposable medical products can be divided further into 3 groups J medical devices, medicinal and pharmaceutical products and healthcare items. Examples of each group are l is ted in Table 1. Medical devices are undoubtedly the main component of these-- disposable products while another 2 groups offer a limited items for s ter i l izat ion.

3 / . . .

3 -

Table 1: List of Disposable Medical Products

Group Examples

1, Medical Devices

1.1 Plastic Disposables

1.2 Cellulosic products

1.3 Surgical products

1.4 Pharmaceu t ical containers and others

2. Medicinal and Pharmaceutical Products

3. Health-care items

Syringes, Infusion set, blood transfusion sets , catheters, medical tubings, vein puncture sets , intra urine devices, feeding/suction set , endotracheal tubes.

Cotton wool, absorbent gaize, bandages, dressings, maternity pads, waddings.

Sutures, surgical gloves, blades, scalpels, needles, forceps.

Ointment tubes, caps, droppers, bags, petri-dishes, culture dishes, specimen containers, v ia ls .

Opthalmic preparation, skin ointment, antibiotics, some raw materials, intravenous fluids.

Sanitary pads, nappies, cosmetic materials, raw ta l c .

- 4

The export and import figures expressed in million r ingg i t in Table

2 indicated that Malaysia s t i l l imports bulks of medical products,

of' which almost 90% are medicinal and pharmaceutical products and

appliances and only 10 - 15% are disposable medical products. The

table also shows tha t 60-70% of cur export are comprised of disposable

medical predicts and the increase in these figures indicated that

medical industry in t h i s country i s continually expanding i t s ac t iv i ty .

A market survey being carried out by UTN th is year reveals that more

than 50% of locally manufactured medical products are for export.

Table 2: Malaysian Export/Import of Medical Products (3)

comodity

Medical Devices*

- Cotton wool, absorbent gauze and bandages

- Other wadding, dressing and similar a r t i c les

. for surgical purpose

- Other pharmaceutical goods

- Medical and dental instruments and apparatus

- Other medical, surgical and veterinary ins t ruments and appliances

Total

Percentage of grand t o t a l (%)

Grand t o t a l including medicinal and pharmaceuticals products, medical instruments and appliances

Export

5.3

2.5

10.1

28.6

8.3

54.8

67.2

81.5

$ million

1984

Import

5.0 .

6.5

6.7

5.9

18.5

42.6

14.8

288.6

Export

4.6

2.5

12.4

37.5

13.3

70.3

73.0

96.3

1985

Import

3.9

6.3

7.7

11.3

2.8

32.0

9.6

332.5

* As coded by Dept. of Statistics.

5/...

- 5 -

MANUFACTURING OF MEDICAL PRODUCTS

The t o t a l production of medical products in general i s estimated to

be around $500 million for 1985 and i s expected t o reach $900 million

in 1990* . Therefore, the production of single-use medical

products alcne wi l l be 'in the region of $300 million (Table 3) with

medical devices comprise two th i rds of the value. The UTN market

survey found tha t the 3 items namely surgical dressings, catheters

and surgical gloves are the main components of the medical devices.

"Table 3: Production of Disposable Medical Products

Production ($ million) Group . .

1983* 1984* 1985E

166.1 192..0 210.0

74.3 77.1 80.0

11.4 11.0 12.0

251.8 280.1 302.0

* Dept. of S t a t i s t i c s (1986)

Estimated

At present a t o t a l of about 60 companies are act ively manufacturing

a wide range of medical products, of which 16 are exclusively dealing

with disposable items. The number i s believed wi l l grow to 20 by

1987. Since 1982, about 3 companies have been approved to manufac

ture rubber gloves e i ther indus t r ia l or surgical gloves while 5 (5) companies approved for catheters . More companies wi l l be

encouraged to manufacture these items and other rubber-based products

in future.

Medical Devices Medicinal and Pharmaceut ica l products

Health-care items

Total

6 / . . .

- 6 -

As mentioned e a r l i e r , 3 methods of s t e r i l i z a t i o n are being prac t i sed

in Malt^sia. They are steam s t e r i l i s a t i o n , chemical or ETC treatment

aid radiat ion s t e r i l i z a t i o n . Steam s t e r i l i z a t i o n or a i tcclaving has

mainly been applied for s t e r i l i s i n g medical supplies in hosp i t a l s .

For those manufacturing p l a i t s with steam f a c i l i t i e s in t h e i r premises,

the above method i s u t i l i z e d for s t e r i l i z i n g items such as cotton

wool aid other ce l lu los ic products/ intravenous f luid aid raw t a l c .

However, most of the manufacturers have now turned to etylene oxide

(ETO) s t e r i l i z a t i o n e i t he r by doing i t in t h e i r ovxi p lan t s or

sending them out for treatment local ly or at parental p lants abroad.

Cnly 10 out of 16 companies manufacturing disposable medical products

have been considering ionizing radiat ion for s t e r i l i z a t i o n . The

i r rad ia t ion technique for s t e r i l i z a t i on i s pursued for various reasons:

a. as requested by customers.

b. other methods of s t e r i l i z a t i o n have been proven incompetent.

c . gamma s t e r i l i z a t i o n i s more economical.

To da t e , none of the manufactures except Ansell i s i r r ad ia t ing 100%

of t h e i r products. Ansell Malaysia Sdn. Bhd. set up in 1976 i s the

only commercially operated cobalt-60 gamma i r radia t ion f a c i l i t y in

Malaysia. The plant i s used almost exclusively for the s t e r i l i z a t i o n

of surgica l rubber gloves manufactured by the company * ' .

In addit ion, i t provides s t e r i l i z a t i o n services t o a number of

companies on a contract bas i s . The service i s minimal and governed

by the ava i l ab i l i t y of i r radia t ion time.

At present , the UTN market survey has obtained some information

on the current annual production (in m3/year) °f s t e r i l e d product

t rea ted with 3 different methods as mentioned above. Table 4 shows

tha t a t o t a l of 37,037 m3 of disposable medical products are

cur rent ly produced. Products t reated by ganma i r r ad ia t ion , ETO and

steati are about 85%, 6.3% and 8.6% of the t o t a l volume of s t e r i l i z e d

items respect ively . Of 85% garma t reated items, about 80% i s

An s e l l ' s own products and only 5% i s made up of other products such

7 / . . .

- 7 -

as surgical dressings, ca the te r s , sutures and blades. Based en the

survey, i t i s estimated tha t 730 m3 or 2% of medical products manu

factured in Malaysia are s t e r i l i z e d abroad. The remaining 36,307

m3 or 98% of the products are t reated local ly pr ior to the export

or being marketed in the coon t ry .

Table 4: Current Production of Disposable Medical Products

Items

Surgical dressings

Catheters (folley, surg ica l , e tc . )

Sutures

Surgical gloves

Scalpel blades

Endotracheal tubes

Cotton wx>l, absorbent gauze and bandages

Raw t a l c

Pe t r id i shes , blood bag, specimen container, p l a s t i c bag, centrifuge tube

Medical tubings, infusion se t , syringes t r ans fusion set

Total

Production (m3/year) Gamma

600

650

207

30,000

40

31497 (85%)

(a) - only those covered by the

(b) - s t e r i l i z ed by Ansell (M) !

ETO Steam

1130

10

2800

400

200

1000<c)

2340 3200 (6.3%) (8.6%)

survey

main ' manufacturers

1

3

1

2

1

1

3

1

> 1

> 1

37037

Sdn. Bhd. or in other countries l ike

(c) -U.K., U.S., W. Germany, Singapore,

estimated f igure .

8 / . . .

- 8 -

M s e l l ' s i r rad ia t ion p lant which has a Cobalt-60 capacity of 1.5

megacuries with the source efficiency of 25% and a t 100% u t i l i z a t i o n ^

(an average absorbed dose of 2.5 Mrad) i s capable of i r r ad ia t ing

32100 m3 of medical products annually or 100% of the products which

requi re gannia s t e r i l i z a t i o n as s ta ted in Table 4. Hence, the

volume which can be further s t e r i l i z e d using t h i s technigie i s

l imi ted. However/ according t o cur survey almost 80% of the manu

fac ture rs are wi l l ing t o use i r radia t ion services i f increase in

cost due to service and transportat ion i s minimal. This means t h a t

a fur ther of 3949 m3 can be s t e r i l i z e d using gamma rays a t an

addit ional cobalt-60 source of 1.8 k i l c cu r i e s .

Since the Maclear Energy Unit wi l l be se t t ing up a gamma p i l o t plant

of 2 k i locur ies Cobalt 60 with the source efficiency of 10% and a t 60% 3

u t i l i z a t i o n , about 2000 m of medical products can eas i ly be

s t e r i l i z e d a t cur p lant during t h i s i n i t i a l stage* ' . However, UTN

wi l l de f in i t e ly upgrade the source and increase the capacity of

u t i l i z a t i o n in order to accomodate further demand of gamma s t e r i l i

zation in the country.

THE UTN GAMMA. PILOT PLANT

As already discussed, the market survey indicates a need for the

ins t a l l a t ion of another r ad i a t ion - s t e r i l i za t ion f a c i l i t y in the

country. The UTN has decided on the se t t ing up of a p i l o t plant for

the above purpose. The establishement of such r ad i a t i on - s t e r i l i z a t i on

f a c i l i t y at UTN by 1988 wi l l f a c i l i t a t e the development of our

medical industry through various object ives:

- To promote radiat ion technique for proper s t e r i l i z a t i o n

of loca l ly manufactured medical products

- To provide the s t e r i l i z a t i o n services which wi l l help

improve the heal th standards through the ava i l ab i l i t y of

s t e r i l i z e d single-use medical suppl ies .

- To conduct a research and development programme on new

applications of radia t ion s t e r i l i z a t i o n and in finding

new products. Q /

9 -

- To provide a demonstration p lant aid t r a in ing f a c i l i t i e s

in the f i e ld of radiat ion s t e r i l i z a t i o n .

- To develop exper t ise in areas re la ted t o radiat ion

s t e r i l i z a t i o n such as packaging, material se lec t ion , maiu-

facturing hygiene, product development, e t c .

ACKNOWLEDGMENT

Thanks are due to the UTN Market Survey Group for useful discussions

and cooperation in providing the data .

REFERENCES

1. Yusof, N. Radiation Steri l ization, of Medical Products - A Project

t o Promote. Nuc. Sc. J . 2(2):80-82

2. Proceedings of the 1st Technical Review Meeting on the Sub-project

Radiation Processing of UNDP/RCA Indust r ia l Project , Kuala Lumpur

(1982).

3. Department of S t a t i s t i c s (1986)

4. M. Ishak, H. PNB Industry Review: Radiation S te r i l i za t ion Industry

No. 6 (1985)

5. MIDA Directory of Approved Compaiies in Production as at 31st Dec.,

1982.

6. Holmes, P.D. Commercial I r rad ia to r . Proceedings for Workshop on

the Applications of Ionizing Technology in Food Preservation,

Kuala Lumpur (1985).

7. PNB Quarterly Economic aid Investment Review April-June, 1986.

PP53/4/86.

8. M. Noor, Y. Personal Comnunication (1986).

NATIONAL EXECUTIVE MANAGEMENT SEMINAR ON INDUSTRIAL RADIATION STERILIZATION

OF MEDICAL PRODUCTS

September, 1986

John Masefield and

Michael C. Saylor

Isomedix Inc.

Lecture No. 5

DOSIMETRY IN PROCESS CONTROL

Summary of Presentation

Measurement of absorbed dose and dose distribution in irradiated medical products relies on the use of quality dosimetry systems, trained personnel and a thorough understanding of the energy deposition process. The interrelationship of these factors will be discussed with emphasis on the current and future practices of process control dosimetry.

I. INTRODUCTION

Controlling the reproducibility of dose delivery in a commercial radioisotope-based irradiator is achieved using dosimetry and timed process events. The quality of dosing of a product is directly related to the quality of the dosimetry system and the skill of the system's operator.

The goal of this lecture is to introduce you to the sequence of dosimetry experiments that are performed prior to routine processing, as well as discuss the significance of the results of process control dosimetry. We begin with the experiment responsible for assigning dose, namely the calibration of the dosimetry system.

II. CALIBRATION OF DOSIMETRY SYSTEMS

In order to establish traceability to National standards of absorbed dose, exposure of dosimeters to a calibrated field of ionizing radiation needs to be performed on a routine basis. Primary or Secondary Standards laboratories are utilized for this purpose. (Fig. 1A)

Thes^ laboratories employ trained technicians skilled in the accurate exposure and interpretation of absorbed dose. Detailed procedures for handling, dose delivery and subsequent data interpretation (Fig. IB) are neccessary to insure that the appropriate environmental and temporal conditions have been used in the experiment.

While accurate dose delivery can be achieved, calibration of the dosimetry system is typically the responsibility of the end-user. The dosimetry system can be defined as:

o Dosimeters o Instrumentation o Check Standards o Written Procedures o Technician(s)

Statistical analysis of all error associated with the calibration experiment yields a definitive dosimeter response function. The precision and bias of measurements are now thoroughly understood.

III. INTERCOMPARISON OF DOSIMETRY SYSTEMS

Measurement of absorbed dose requires a thorough understanding of the system and associated application procedures. A sequence of application and analysis events must occur prior to declaring delivered dose via response function. (Fig* 2A)

1

The effects of the environment under which the dosimeters are_ stored, exposed and read may lead to a serious misinterpretation of delivered dose. Such environmental factors may include:

o Temperature o Humidity o Dose Rate o Atmosphere o uv-Vis photon fields o Pressure

Proper conditioning and packaging of the dosimeter will minimize the effects of most of these environmental conditions. However, the temperature and rate at which a given dosimeter is irradiated cannot be easily controlled. Two or more dosimetry systems can be employed in a complementary fashion in order to account for environment-related modifications of a given system's response function. (Fig. 2B)

Intercomparison of two or more dosimetry systems is an essential part of functional routine process control procedure. Employing reference systems with routine systems provides a higher degree of certainty with respect to the assignment of absorbed dose. Candidates of low dose applications are the Fricke/radiochromic optical waveguide (Optichromic) systems (0.1-1 kGy). High dose systems that have proven to be highly reproducible and reliable are ceric-cerous/dyed polymethyl methacrylate (Red 4 034) operating in the range of 5-50 kGy.

IV. THE IRRADIATION EVENT

Understanding the production irradiation event starts with a solid backgound in applied physics and mathematics. Representation of an industrial irradiator in two dimensions (2-Dim) will be sufficient for this presentation. (Fig. 3A)

A 2-Dim product carrier is moved into the radiation field and dwells at Position 1 for a prescribed period of time, accumulating varying amounts of dose at all points within the carrier. (Fig. 3B) Of particular interest are the doses delivered to the lines parallel to the source, namely A, C and E. Since the design of industrial irradiators>focuses on providing as much symmetry in exposure as engineering will allow, reflection of ths planar dose distribution will occur when the product carrier is transferred to Position 2 and dwells in the radiation field for a period of time equivalent to Position 1.

The cumulative doses associated with this process are:

DA = DE > Dc (Fig. 3B)

2

The critical results of dosimetry associated with this process: (Fig. 3C)

MAXIMUM DOSE = DA or D£ (product degredation)

MINIMUM DOSE = Dc (technical effect)

UNIFORMITY DA / Dc (overdose ratio)

The uniformity of the process is a function of the product density and source-to-product distance. The minimum dose is a function of the dwell time, density and the amount of radiosotope in the source.

Doubling the dwell time will double the minimum and maximum doses, however uniformity remains unchanged. Thus, uniformity becomes an important parameter in monitoring the performance of the irradiator since it is a time-independent, power-independent quantity.

V. IRRADIATOR/PRODUCT QUALIFICATION

Soma of the key considerations involved in irradiator qualification via comprehensive dosimetry have been highlighted, other factors that need to be examined:

o Product density-dependence of dwell time at fixed dose o Uniformity as a function of density o Energy deposition as a function of source configuration o Transient dosing during product and source movement

Evaluation of the performance of an industrial radioisotope-based irradiator requires dosimeter placement in three dimensions (3-Dim) . This procedure is called dose mapping. (Fig. 4A) As you will see, the concepts behind mapping are merely an extension of the concepts we have covered in the 2-Dim irradiator model.

We begin by declaring the 2-Dim coordinates for dosimeter placement (Fig. 4B) based on observations derived from the simple 2-Dim model. Extension to the third dimension (Fig. 4C) is achieved using a fixed vertical increment corresponding to various source rack configuration parameters.

3

Notice the extensive number of potential 3-Dim coordinates that could be used in the mapping process. Since three or more carriers must be mapped in order to employ statistical analysis, the initial mapping experiment can be rather rigorous. Dose maps of 500-1000 dosimeters are not uncommon in large commercial irradiators.

Selection of a high average bulk density product or phantom can minimize map probes at lower densities. A thorough study of the planes A, C and E at all densities covering the dynamic range that the irradiator is likely to encounter is essential. Determination of the minimum and maximum dose zones, as well as the measurement of dose uniformity are the end results of this effort.

Computer models can be used to modify or verify the expected power utilization and energy deposition functions that govern the operation of the irradiator. These functions can be represented by the use of a dwell time chart. (Fig. 4D) The irradiator's dwell time chart will be adjusted for isotope decay at time intervals expected to result in a decrease of available power on the order of 1%. In the case of Cobalt-60, a new chart would be implemented in the facility at monthly intervals.

Models are only as good as the available operation data. The emphasis placed on quality systems, procedures and training of personnel will pay for itself in terms of:

o Proper utilization of available radiation o Optimization of model parameters o Optimization of radioisotope source loadings o Optimization of processing parameters o Realistic assessment of expected irradiator performance for future processing ventures

VI. ROUTINE PRODUCTION DOSIMETRY

Once the dynamic range of processing densities has been examined via comprehensive dosimetric techniques, maximum and minimum zones of absorbed dose have been identified and the dwell time chart has been generated, the irradiator is ready for routine processing. Formal procedures governing the placement of dosimeters for any given product type must be reviewed and modified according to the results of the dose mapping studies. (Fig. 5A)

Every routine processing event requires the recording of the production run's determined maximum and minimum dose prior to release of the product. Such data is useful long-term as well; simple process control charts demonstrate the effects of historical events: (Fig. 5B)

4

o Changes in dosimeter batch or typa o Changes in product bulk density or loading configuration

o Irradiator-related malfunctions o Dosimetry system malfunctions

Process control charting also improves the review procedure associated with facility audits and enhances inter-facility communications. Proper operation of the irradiation facility results in dose delivery consistent with the decay of the isotope as described by the dwell time chart. This is reflected in the control chart.

VII. DIAGNOSTICS VIA COMPREHENSIVE DOSIMETRY

An irradiator is a mechanical device, subjected to rather intense fields of ionizing radiation for prolonged periods of time. This fact, coupled with normal mechanistic wear-and-tear leads to non-optimum performance.

Machine diagnostics can be performed using the simple 2-Dim model and a routine dosimetry system. Figure 6A is an example of such an experiment. The floor (Level 0) of each carrier is dose mapped, and the product is run through the irradiator at a fixed • dwell time. Selected coordinates are analysed for absorbed dose, and a plot of the results is produced. The pattern of maximum and minimum doses per irradiation event indicates that the irradiator is not performing as expected. A review of the machine's maintenance log indicates that several malfunctions have occured. These have caused the fluctuation of the local minimum and maximum doses.

Note the pattern of dosing that appears in Figure 6A. Analysis of the relative uniformity (Fig. 6B):

UNIFORMITY (relative) - (DA + DE ) / (2DC)

indicates that the dosimetry system and technicians are performing well within the limits of precision and bias established by the calibration and intercomparison experiments. This simple pattern recognition technique has eliminated all variables associated with dose measurement, and forced examination of the irradiation event down to the machine and source level. Significant increases in. processing time and decreases in process uniformity will be achieved by repairing the faulty portions of the irradiator mechanism.

5

Calibration Of Dosimetry Systems

FIGURE 1A

VIII. THE FUTURE

With the integration of microprocessor, laser and robotic technologies into the industrial sector, automated process and inventory management systems are beginning to appear in the area of routine irradiation services. Remote measurement of carrier bulk density, identification of product type, automatic recall of processing specifications and on-the-fly measurement of absorbed dose will be available by the next decade.

These advances in measurement and process technology will enhance our effort to improve the quality of radiation processing. However, the education of facility technicians is the key to parameter optimization. Operation of an irradiator can be automated, but the goal of refining the man-machine interface indeed remains the present and future challenge.

6

Calibration Of Dosimetry Systems

Receive Samples

*

[ Review 1 Procedures

i-[ Prepare ] 1 Samples

7" \ / Irradiate \

i | Evaluate 1 1 Results 1

*

Report

—-

i

_ 1*

M

ETER

RE

AD

ING

, A

Dosimeter Response

Non-Linear Response Curve ^ r

yf \y^ Linear Response Curve

> ABSORBED DOSE, D

FIGURE IB

Routine Dosimetry

Read Dosimeters

T Evaluate

Effects Of Environment

T Review Results

System #1 Record Results

FIGURE 2A

Inter-comparison Of Dosimetry Systems

Read Dosimeters

T Evaluate


T Review Results

Review Systems

Read Dosimeters

T Evaluate


T Review Results

System #1 Record Results

System #2

FIGURE 2B

Sample Irradiator (2-Dimensional)

n

A C E A ...._C_ E

Dwell Position

2

L J

Dwell Position

1

s o u R C E

FIGURE 3A

Simple Irradiator (2-Dimensional)

I

Dwell Position

1

A C E

S 0 u R C E

A C E

Dwell Position

2

(Arbitrary Units)

Position 1

Position 2

Total

0.27

1.00

1.27 (DA)

0.49

0.49

0.98 (Dc)

1.00

0.27

1.27 (DE)

FIGURE 3B

Simple Irradiator (2-Dimensional)

I

i

1 Dwell osition

1

A

>

C E

S 0 u R C E

A C E

J

Dwell Position

2

Maximum Dose

Minimum Dose

Uniformity

Uniformity

= DMAX = D* orOc

= DMM = Dc

= DMAX/DMIN = UV>1

FIGURE 3C

IrradiaforlProduct Qualification

Review Systems

And Procedures

T Prepare

Dose Map

T irradiate

T Read

Dosimeters

T Record

DMAJCDMM UF. Dwell Time

T Ready

For Production

FIGURE 4A

Coordinates - Level " X "

C 1

C | 3

C j>

C_7

C 9

Carrier Doors

FIGURE 4B

Carrier Doors

Levels @ 4"

Increments

FIGURE 4C

Sample Dwell Time Chart *- Fixed Date *- Facility Dependent ^ Fixed DMIN

Density g/cc

.05

.06

.07

.08

.09

.10

.11

.12

.13

.14

.15

.16

.17

.18

.19 20

.21

.22

.23

.24

.25

.26

.27

.28

.29

.30

.31

.32

.33

.34

.35

.36

.37

.38

.39

.40

Dwell Time Minutes

3.16 3.22 3.27 3.34 3.40 3.46 3.53 3.60 3.67 3.74 3.81 3.89 3.97 4.05 4.14 4.22 4.31 4.41 4.50 4.60 4.70 4.81 4.92 5.03 5.14 5.26 5.38 5.51 5.64 5.77 5.91 6.05 6.20 6.35 6.50 6.66

___————____———

Density g/cc

.00

.05

.10

.15

.20

.25

.30

.35

.40

Uniformity UF

1.28 1.31 1.34 1.39 1.45 1.52 1.61 1.72 1.85

FIGURE 4D

Routine Production Dosimetry

1) Receive 2) Schedule

T Review

Processing Specifications

T Verify Loading

And Bulk Density

T Irradiate

T Review

Dosimetry Results

T 1) Log Results 2) Release

FIGURE 5A

Process Control Chart

t

2.5 2.4 2.3 2.2 2.1 2.0 1.9

° 1 8 o a 1.7

1.6

1.5

1.4 1.3

Limit ( f

• . » 1 g» •_»—»V-<» " • • ' " r a t i » •—• • •

: . •• • •• ••*? •

1.2

T T

-cr -<£ o

n<

T Limit (Min 0507 0527 0547 0567 0587 0607 0627 0647 0667 0687 0707

Production Event

o Minimum Dose • Maximum Dose

FIGURE 5B

Diagnostics via Routine Dosimetry

w £ 1.5-

AJ2TA5 •0CZ »005

FIGURE 6A

Fluctuation Of Relative Uniformity

1 .25 I i i i i i i i i i i i i i i i i i i i i i i r i i i i i i i i i i i i i i 'i i 'i I T

11 2 1 3 1 41 Event-

2 -D im C a r r i e r Equation

A C E

DA + D E

2DC U F > 1

FIGURE 6B

GOOD MANUFACTURING PRACTICE - QUALITY ASSURANCE PROGRAMS

INTRODUCTION

Good Manufacturing Practices (GMPs) in the medical device industry are based on controlling the total manufacturing process by identifying and controlling the methods and equipment used in each of the component steps in the process. Quality Assurance (QA) programs play a crucial role in assuring that finished devices conform with product and process specifications and that manufacturing methods comply with GMP requirements. The purpose of this presentation is to describe a comprehensive Quality Assurance program for the radiation sterilisation of medical devices under GMP conditions.

BASIC REQUIREMENTS OF GMP

The essential philosophy of medical device GMP is to identify each step involved in the design and production of the device. Suitable controls are then placed upon each, creating a total control system. GMP/QA programs are required to address the following elements:

A. Organization and Personnel; B. Facilities and Equipment; C. Operation and Control Procedures; D. Training; E. Documentation and Records; F. Auditing.

THE GMP/QA PROGRAM FOR RADIATION STERILIZATION

As a step in the device manufacturing process, the radiation sterilization of a medical device must be governed by a QA program for assuring GMP compliance. The GMP/QA program requirements for a radiation sterilization facility are as follows:

A) ORGANIZATION AND PERSONNEL QUALIFICATIONS: The company's structure must provide separate responsibilities for both production and quality control functions. Job descriptions for each operating function should be prepared and utilized to assure that personnel are properly qualified.

B) FACILITIES AND EQUIPMENT: The buildings and equipment used to house and perform the sterilization process must be properly designed and maintained. Important design considerations include a secure building with separate storage areas for sterile and non-sterile products, and a conveyor-based irradiation system for reproducible product irradiation. (Example - see Figure 1)

C) OPERATION AND CONTROL PROCEDURES: Approved, written procedures must be prepared to govern the performance of all routine and non-routine functions which affect the quality of the finished device. Routine QA procedures include facility standard operating procedures (SOPs), dosimetry procedures, and calibration procedures. Non-routine or special QA procedures are those involved with the validation of individual product sterilization cycles.

Outlines of the requirements for each of these procedures are given below:

2

C.l) IRRADIATION FACILITY STANDARD OPERATING PROCEDURES.

Perform and document the following for each irradiation lot:

1. Receiving. a. Inspect and count (#1) by product code, lot number, and

quantity. Reconcile counts with shippers counts; b. Segregate from sterile products while awaiting

sterilization by physical separation and/or tagging.

2. Product Loading. a. Load irradiation container per established pattern and

perform loading count (#2) by product code, lot number, and quantity;

b. Place dosimeters at minimum and maximum dose locations? c. If required, place biological indicators at minimum

dose location.

3. Processing. a. Set master timer to deliver minimum dose plus safety

margin. b. Monitor irradiator for correct source position and exposure

time. Record exposure times to verify completion of process.

4. Product Unloading. a. Unload product from irradiation container and perform

•unload count (#3) by product code, lot number, and -quantity;

b. Retrieve dosimeters and biological indicators; c. Segregate from non-sterile products by physical

separation and/or tagging.

5. Dosimetry Analysis and Records Review. a. Read-out and record dosimeter results; b. Review irradiation batch records for conformance with

written processing specifications; c. Prepare report (certificate) which lists as a minimum:

1. Name and location of irradiation facility; 2. Irradiation lot (batch) number; 3. Date of irradiation; 4. Products sterilized by manufacturer, product code lot

number and quantity; 5. Minimum and maximum process doses; 6. Process interruptions.

6. Shipping. a. Notify manufacturer of product status; b. Obtain approval to ship; c. Perform final count (#4) by product code, lot number, and

quantity. Release.

3 \

C.2) DOSIMETRY PROCEDURES.

Document the following information for each dosimetry system to be utilized:

1. Description of Dosimetry System. a. Dosimeters (physical description, dose range, precision); b. Dosimeter analysis equipment (description and

specifications) .

2. Dosimeter Handling and Use Procedures. a. Storage, preparation, placement, and retrieval; b. Environmental effects and interferences;

3. Dose Determination. a. Convert dosimeter response to absorbed dose value. b. Record and report absorbed doses.

C.3) CALIBRATION OF CONTROL AND MONITORING EQUIPMENT.

Equipment which functions to control and measure the degree of processing to which the devices are subjected is termed critical. The GMP's require a documented calibration program to assure periodic calibration of critical equipment against recognized standards. The critical equipment items in the radiation sterilization process are the process timers (master & backup) and the dosimetry system (dosimeters and required analysis equipment).

Calibration procedures should specify the following: 1. Title and scope of the procedure; 2. Calibration frequency; 3. Precision of the method; A. Interferences; 5. Required materials and equipment; 6. Specific calibration procedure; 7. Data analysis and presentation; 8. Acceptance criteria.

C.4) VALIDATION OF THE RADIATION STERILIZATION CYCLE

1) Qualification of the product. a. Determine the Radiation Compatibility of Materials. - Expose product and packaging samples to the maximum dose likely to be encountered in sterilization;

- Test irradiated samples for acceptability.

b. Determine Minimum Sterilizing Dose. - May be set by local regulations; or - Determine based on bioburden, resistance, and end use.

4

2) Qualification of the Sterilization Cycle. a. Establish the Product Loading Pattern. - Fill volume of irradiation container most efficiently.

b. Perform the Dose Mapping Study. - Use to determine the locations of minimum and maximum dose in the irradiated product, which then become the process monitoring points. The dose mapping study must be performed using:

1. the production irradiator; 2. product or simulated product which approximates the

actual product in density and load dimensions; 3. the established product loading pattern; 4. a sufficient quantity of dosimeters distributed

throughout the irradiation container.

NOTE: A study of the irradiator design and isotope geometry can be used to guide the dosimeter placement for dose mapping. This information may be obtained from the irradiator manufacturer, or may be based on irradiator qualification studies performed by the facility operator. Dosimeters can then be concentrated in the likely minimum and maximum dose zones, with lesser quantities placed in areas likely receive intermediate absorbed doses. (Example - see Figure 2)

The dose mapping study must be repeated each time isotope is added, removed, or reconfigured in the source, or following any.other change which could cause the location of the minimum or .maximum dose to change.

3) Establish a Written Processing Specification.

The processing specification dictates the irradiation conditions to be used each time a given product is sterilized. This restricts the variability of the process by controlling the sources of process variation. The only item which must be varied over time is the exposure time, which must be periodically increased to offset the decay of the isotope source. Each processing specification must include:

a. The manufacturer's name and address; b. A description of the product - (product code, case size,

case weight); c. Minimum and maximum dose requirements; d. Description of product loading pattern; e. Minimum and maximum dose locations*; f. Timer setting*; g. Special instructions (if any).

* Based on results of the current dose mapping study.

5

D) TRAINING: Requirements for initial personnel training and periodic retraining should be established. Training requirements depend upon job descriptions, and may consist of both formal training sessions and on-the-job experience. Training sessions must be documented (date of training, subject, instructor, attendees, and results of any testing).

E) DOCUMENTATION AND RECORDS: Detailed records must be maintained in order to allow the reconstruction of events related to the processing of each irradiation batch or lot of products. Such reconstruction is often performed during a GMP compliance audit, and may be required in the event of a product recall. Procedures must specify the retention of general facility records and batch records as follows:

General Facility Records:

- Facility operator and location; - Operator's organizational structure; - Irradiator type and design; - Isotope type, activity, and configuration; - Equipment maintenance records; - Facility SOPs; - Dosimetry and calibration procedures and records; - Personnel training records; - Audit records.

Irradiation Batch Records:

- Manufacturer's name and address; - Product description; - Dated product counts by manufacturer's code, lot number, and quantity (total of four: incoming, loading, unloading, and shipping);

- Dosimeter and biological indicator placements; - Minimum and maximum dose requirements; - Irradiation date and sterilization lot number; - Master timer setting; - Record of exposure time and source position; - Dosimetry data and results; - Product release approval; - signed shipping papers.

F) AUDITING: The GMP regulations require the use of compliance audits to periodically assess the adequacy of the facility Quality Assurance program. The audit should be performed by a qualified person not responsible for the functions being audited. The audit is accomplished by reviewing procedures and records and by interviewing personnel to determine the adequacy of procedures and their implementation for each element in the QA program. A report of audit findings is presented to responsible management,

6

including the scope of the audit, a summary of observations, and a listing of any deficiencies noted. Deficiencies must be responded to in writing, along with a plan for corrective action and a timetable for completion. The audit will be formally closed out after all deficiencies have been addressed and corrected.

CONCLUSION

Radiation sterilization of medical devices has proven to be both an effective and efficient method. The use of Quality Assurance procedures based on the Good Manufacturing Practices provides a means for assuring that the radiation sterilization process will be controlled to deliver results consistent with manufacturing specifications and regulatory requirements.

IRRADIATOR

1 t

O "n Z! o m >

m >

NON-STERILE STORAGE

CONVEYOR NON-STERILE PRODUCT

WAREHOUSE AREA

LOAD STATION

I

STERILE STORAGE CONVEYOR

STERILE PRODUCT WAREHOUSE AREA

UNLOAD STATION

BARRIER

RECEIVING DOCKS SHIPPING DOCKS

FIGURE 2

DOSE DISTRIBUTION IN THE PRODUCT

CONVEYOR MOVEMENT

FIRST PASS

D max

'mm PLAQUE SOURCE

Two single-direction passes of a rectangular package, once on each side ofc stationary y-ray plaque source with the regions of Dmjn t

indicated by hatching. DTrax after the second pass

INTERNATIONAL ATOMIC ENERGY AGENCY NATIONAL EXECUTIVE MANAGEMENT SEMINARS ON RADIATION STERILIZATION OF MEDICAL PRODUCTS

LECTURE t "CHEMICAL EFFECTS OF RADIATION"

PROFESSOR GLYN 0.PHILLIPS. THE HORTH EAST WALES INSTITUTE. CLWYD. WALES. U.K.

SUMMARY OF PRESENTATION

Ionizing radiations initiate chemical changes in materials because of the high energy of their quanta. In water, highly reactive free radicals are produced which can initiate secondary changes in solutes, and in chemical or biological Molecules in contact with the water. Free radicals can also be directly produced in irradiated medical products. Their fate can be identified and the molecular basis of radiation inactivation clarified. Methods have now been developed to protect and miniaise such radiation damage.

1. High Energy of "Ionizing Radiations"

Electromagnetic radiation, whether radiowaves, microwaves, infra—red, visible, ultraviolet, x—rays or the ionizing radiations used for industrial sterilization (60Co gamma-ray and electron beam sources) are propagated by the alternation of magnetic and electric fields in mutually perpendicular planes, in a direction at right angles to these fields. All can be characterised by their wavelength, and the energy of the quantum (E) is given by the Max Planck relationship

E 0< l/x, where \ is the wavelength

Due to the extremely low wavelength of soCo y -radiation, the mean quantum energy is extremely large (ca.l.25 MeV), compared with the energy of a chemical bond (ca. k eV). It is this property which accounts for its high penetration and ability to initiate physical, chemical and biological changes.

Whereas the absorption of visible and ultraviolet radiation will promote excitation of the electronic framework of molecules, electromagnetic radiation of wavelengths less than ca. I0*'8m will additionally excite to the stage where electrons are ejected from the molecule (ionization). Moreover, the absorption is non-specific, and dependent only on electron density.

The sequence of events following the absorption of ionizing radiations can be illustrated on a time-scale.

- 1 -

y-radiation energy transfer

10 sec

• [A + e] -ionization

secondary

processes 10 sec

A* d isc re te exc i ted s i n g l e t or t r i p l e t s ta tes l0" 9sec - l0" 3 sec

2 . WATER RAOIOLYSIS AND INDIRECT ACTION

A* f ree r a d i c a l s 10-6 - l ong - l i ved

For water the products have been

e • H + -H 1

•OH + «OH

e" + e" aq aq

identiffedi-

2 2

H + 20H 2

which may be summarised:-

H,0, H(hydrogen atom), .0H(hydroxyl radical), e" (hydrated electron), 2 "*v aq

H (hydrogen gas), H O (hydrogen peroxide)

Fast reaction methods, particularly pulse radiolysis, can be used to measure the yields of these free radical species and to study their reactions.

When irradiation is carried out in systems containing significant proportions of water, chemical change is initiated by the secondary reactions of the products of water radiolysis, hence the term "indirect action".

EXAMPLES

a) Hydroxy1 Radicals (powerful oxidising agent)

•*• RCHOH + RCH20H + -OH alcohols k2 = 10 M

s _ 1 Ha0 .Abstraction

2 RCHOH RCHO + RCH OH....Disproportionatlon 2

2 RCHOH RCHOH. I

RCHOH

•Dimerisation

- 2 -

When oxygen Is prawn t, paroxy radical» can ba formad,

RCHOH + a, •> RCHOH ....,.,......,.....,.,.#..Oxygen addition

I

RCHOH *• RCHO + HOi Radical Elimination

I

2H0j »' H202 + 02 Formation of Stable Products

b) Hydrated Electrons (powerful reducing agent)

H

Thymine

+e aq Electron addition

Thymine radical anion

Ag +

••sJ 1 ver ion

aq 1 0

k =4x10 M^sec-1

W .Electron transfer

siIver atoms

Micro-organisms in aqueous environment, therefore, can be inactivated by the reactions of water radiolytic products, events leading to damage of the vital DNA molecule are illustrated In Appendix I.

3- DIRECT ACT I OH

Free radicals can also be formed by ionization and excitation processes when the energy is directly absorbed in the materia! In the absence of water. These processes can trigger a sequence of reactions, which in some instances produces a chain reaction leading to extensive damage as shown for solid deoxyribose (Appendix II) Again, DNA, present in all cells can be damaged in this manner.

Biological damage, therefore, as. for example, bacterial or enzyme inactivation is the end result of a series of rapid processes following absorption of radiation, which may involve excited states, direct radical reactions and processes initiated by the reactive species produced by radiolysis of water.

- 3 -

k. PROTECTION AAA INST «API AT I OH DAHAfiE

U»\ When Damage Is Dug to Watar RadiolyaI»

The objective Is to Induce the free radicals from water to react with an additive (scavenger) to yield products which do not Initiate the degradation of the material undergoing radiation sterilization and requiring protection, say a pharmaceutical or bloproduct. The following are examples of radical scavengers!-

aq

•OH (or

<0H

•H)

<r

+

+

N20 —

RCH20H —

1- —

—»-«0H + OH + N

—a» RCHOH + Ha0 (or H2)

- • • 1- + OH"

according to whether the system Is best suited to Inorganic or organic additives. The proportion which must be added can be determined from the known rate constants for the reactions Involved.

4.2 When Damage Is Due to Direct Radiation Action

Here the technique Is to remove the energy from the chemical molecule (A) under consideration by a transfer process to an acceptor molecule (fl) which is more rapid than the Internal transformations leading to degradation.

t

A'' + B *>B •' + A followed by B" *• B excited ground excited ground state state state state

Alternatively, If mobile H atoms are the agents which promote degradation as in many polymers containing a high proportion of CH bonds, aromatic systems can Immobilise such radicals and reduce their damaging effects.

o: > p _ _ _ / V radical addition

Using these procedures many of the synthetic and biological polymers utilised in industrial radiation sterilization can be protected from radiation damage. In this way a wide range of new packaging and fabricating materials have been developed. Two biological polymers which can be protected in this way are the eye loamyloses (Appendix III) and cellulose (G.O.Phillips, U.S. Patent No.3519382).

- A -

5. SELECTED REFERENCES

1. Aqueous Systems. Radiation Chemistry. An Introduction. A.J.Swallow. Longman, London (1973).

2. Radiation Chemistry and Biology. Energetics and Mechanisms, In: Radiation Biology, Edited by G.O.Phillips. Academic Press, 1968.

3. Natural Polymers and Protection

a. The Effects of Radiation on Carbohydrates. G.O.Phillips. Chapter 26 pages 1217—1297 'n "The Carbohydrates", Second Edition. (Editors Ward Pigman/Derek Horton), Academic Press Inc. New York, I98O.

b. Photochemistry and Radiation Chemistry of Cellulose. G.O.Phillips and J.C.Arthur Jr. |nz Cellulose Chemistry and Its Applications (Eds.) T.P.Nevell and S.H.Zeronian. Ellis Horwood Ltd, I985, p.290—311.

c. Free Radical Formation and Degradation of Cellulose by Ionizing Radiations. Y.Nakamura, Y.Ogiwara and G.O.Phillips. Polymer Photochemistry, I985, 6, 135-159.

APPENDIX I

RADIATION INDUCED DNA DAMAGE

DNA STRUCTURE

DOUBLE HELIX

RADIATION DAMAGE

-A T-l

•C G -

•G C-

-T A-BASE-PAIRING

i

H — C — « *

O — C M — C

A~?!

\ o

X

/ V O L /

0 ^ \ c ^ c . \ / M >^

\

A •«*(!••

r—

.

'

p**t« t t ru* • * •**

IfvH* i m M M t l

• 1

H °

9

Zitmm o I

o

' /

' L/ C J -\

CHEMICAL STRUCTURE

"v

TYPES OF MECHANISMS INVOLVED

\_ a) Sugar damage "W (?) — \P)

Strand Break

b ) B a s e d a m a g e

AX* -°H

d-riboss phosphate

0 ^ k N > M H.O

d-ribose phosphate

H N Tôi H, OH

I OH

d-nbose phosphate

Degradat ion o f 2 -deoxy -D- r ibose in the s o l i d s t a t e by i o n i s i n g r a d i a t i o n (a cha in reac t i o n )

OH

2-deoxy-D-ribose

H

OH

2-''eoxy-D-ribose

C-OH chain Initiation

\\

OH .Chain Propagation

U C-OH • R« -+- non

2.5 di-deoxy -D-erythropentonic acid

(Chain product)

radical products Chain termination

H Where R» represents any radical

APPENDIX III

PROTECTION OF CYCLO-AHYLQSES AGAINST RADIATION DAMAGE

STRUCTURE

Chemical S t r u c t u r e o f

3 _ cyc l o -amy lose

3-D Model o f 0 - cyc lo -amy lose showing

the ' inne'r cav i t y '

Schematic d iagram r e p r e s e n t i n g the e n c a p s u l a t i o n o f an a romat i c molecu l in c y c l o - a m y l o s e

RADIATION PROTECTION

A b s o r p t i o n o f r a d i a t i o n energy by the eye l o amy lose

T r a n s f e r o f the excess energy to the encapsu la ted a romat i c mo lecu le

Cyc lo-amylose r e s t o r e ' to no rma l , r a d i a t i o n energy c o n t a i n e d w i t h i n the a r o m a t i c mo lecu le

RADIATION EFFECTS - STABILITY AND INSTABILITY OF MATERIALS

V.Markovic

i.The concept of single use implies that all products should be mads of relatively cheap materials minimizing the coat of sir.?!? '.ter.is. Plastic materials ge.neraly satisfy this requirement s'id dl'4?'ert natural s.r.d syrithetic polymer materials are most nx'5ri us<?d -to- p-oduction o-f disposable medical items.Other •iiaterisls (glass, stai nl ess steel,etc) are used only when "substitution is impassible. All these materials have to satis-fy OIR basic requirements:absence of any components which can be hamfu! for patient during appl icat ion . Therefore, sometimes special medical grade polymer materials had to be developed <low Monomer content,absence of volatile materials,selective add* *• i v?s, etc » . °equi rement s from this viewpoint will not be •further discussed here.

2. Besides standard specifications depending on the quality requirements of the products to be made,the materials used must also be able to withstand the sterilization process without significant deterioration of main physical and chemical properties.Mechanical properties are most often the subject of main consideration.

Radiation steri1ization,as one of the methods of industrial sterilization, imposes the additional requirement: RADIATION

..STABILITY.

3. Radiation in general affects the mechanical and physical properties of polymers by induced chemical changes.The two main effects are crosslinking (chemical bonds between polymer macramolecules) and scission (the break of chemical bond in the main polymer molecule chain).The crosslinking results in increase of molecular weight and finaly results in formation of three-dimensional network.Mechanical properties at room temperature at absorbed doses used for radiation sterilization are slightly or not affected at all.The scission results in decrease of average molecular weight and increase of low molecular component in polymer.As a consequence,mechanical properties can be significantly deteriorated.The tensile strength is reduced and brittlenes increases.

In addition to this effects,gaseous products are formed (hydrogen,HC1 in chlorinated polymers,methane etc.).The formation of uneaturations (trans-vinyl) is often observed,sometimes resulting in discoloration of polymers after irradiation.

4. The prediction of polymer behaviour under irradiation depends on many factors (type of polymer,molecular weight and distribution,presence of oxygen,presence of additives ,etc.) and cannot be easily predicted. In most polymers both processes,crosslinking and scission take place concurently and the pv=ral1 effect depends on the ratio of yields for these two processes. Large amount Df informations are available about radiation effects on different types of polymers and qualitative

1

prediction is often possible.

5. Pol yethylen» ( P E ) , 1 D W and high density are often used for production o-f disposable medical items. In the absorbed dose r-aioe used -for radiation sterilization, radiation does not affect nechsnical properties.Polymer predominantly crosslinks by i T "• ad i at i en . Di scclcrst ior. may sometimes be a probl etn, which can be svece-ss-fuly solved by the us© of appropriate additives.

6. Polypropylene is most comrncnly used -for production of d-spr^sab'. e syringes and ether components where excellent îechsiica! properties have to be combined with transparence. The •scission is dominant -factor affecting properties o-f irradiated l3p.Tn addition tr direct a>-,d immediate effect o-f radiat ion, Long ter-n post i >• r adist: on effects is observed in PP.Very slow chain oxidative degradation takes place in PP after irradiation with e-'-fert that several months after irradiation material becomes too brittle -for rornis! ^se,althcug i named i at el a-fter irradiation it «»?y be =Jmost una-f ected. FP has to be specialy stabilized in 0"^=r to !or? term stability of products which are sterilized by rartistion.The radiation stability of each batch of resin used for P'otiurt ion should be checked for its radiation stability.

• . PVC is often used far- production of soft clear tubings for di^fe~er.t medical devices {typical examp 1 e, blood transfusion •sets).Two main effects are of special consideration if material has to be sterilized by radiat ion;discoloration and production of HC1 which remains dissolved in polymer and could be extracted during app1ication.The use of appropriate stabilizers efficiently S D I V S S bGth problems.

3. Natural snd synthetic rubber are not affected significantly by irradiation and can be used without difficulty.

Polyesthers and polyamids generaly are acceptable for radiation sterilization.

Polystyrene is one of the most stable polymers when exposed to radistion,but its use for medical applications is very limited due to the risk of the presence of the traces of monomer in pal yrner .

Polyrnethy Imetacry 1 ate is generaly not acceptable due to the discoloration and increase of brittleness.

Teflon is unacceptable for radiation steri1ization,as a typical example of polymer when scission process is main effect of i rrad i at ion.

9. While a general recommendation regarding the choice Df raw material arid characterisation cannot be given , the basic approach to this problem should be as -follows:

- pre 1 irr: i nai- selection of main type of the palyrner with rega-d to properties o-f product and qualitative in-f ormat ions = bcut rs*ii=ticn stability;

- e-.:per irnenta! verification of radiation stability b> characteriretion immediately after irradiation;

- ertificial ageing test to verify long term behaviour arm post-i r radiat ior. effects.

Characterization most often includes measurement o-f mechanical praperties:tensile strength,elongation at br eaU, Tnodu lus,br i tt lenes, etc . In addition optical methods cam be used to determine the extent of discolaratian,if ary .crystal 1 i-,i ty measurements, etc. It is also useful to determine ths- preserct? and concentration of longlivcd free rad icals, which are usual y responsible -for post i r rad iat ion effects.

CONCLUSIONS

1. Introduction of disposable medical items into standard medical practice has significant impacts on standards of health care. The indirect economic benefits far outweigh the direct cost of applicatior of these products.

2. MP'-uf =ctire cf sterile disposable medical products is corpple-: process which requires special considerations in all st^cies of ''.ant'f actu.r e, f r om selection of raw materials to steri1i rat s or .

3. Selection of raw materials must take into account, not only functional quality of products but also its medical application and sterilisation method.

3

RADIATION EFFECTS ON PHARMACEUTICALS & RELATED HATERIALS

Dr.V.K.IYA

R a d i a t i o n s t e r i l i z a t i o n i s t h e method oF c h o i c e For

many m e d i c a l s u p p l i e s and d e v i c e s . However» b e c a u s e of t h e

i o n i s i n g n a t u r e of gamma r a d i a t i o n » one must c o n s i d e r t h e

a f f e c t of such r a d i a t i o n on t h e p h y s i c a l and c h e m i c a l

p r o p e r t i e s and on t h e b i o l o g i c a l b e h a v i o u r of p h a r m a c e u t i c a l s

and r e l a t e d m a t e r i a l s b e f o r e t h e f e a s i b i l i t y of r a d i a t i o n

s t e r i l i z a t i o n for such p r o d u c t s i s e s t a b l i s h e d . Ths

r e s u l t s of such f e a s i b i l i t y s t u d i e s c a n l e a d t o an

a p p r o p r i a t e d e c i s i o n on t h e s u i t a b i l i t y of r a d i a t i o n

s t e r i l i z a t i o n for a p a r t i c u l a r p h a r m a c e u t i c a l .

In t h e USA, r a d i a t i o n t r e a t e d / s t e r i l i z e d d r u g s a r e

c a l l e d Nag D r u g s . In t h e UK, t h o u g h i t i s no t 30, i t i s

n e c e s s a r y t o p roduce p r o o f t h a t ( i ) t h e p o t e n c y of t h e

d rug i s u n a f f e c t e d by t h e p r o c e s s ( i i ) any d e g r a d a t i o n

p r o d u c t s a r e not h a r m f u l .

P h a r m a c e u t i c a l s a r e c o n s t i t u t e d of l o u a t o m i c number

e l e m e n t s such as C, H, N, 0, F, Na, P , S, C l , K; t h e main

i n t e r a c t i o n of gamma r a d i a t i o n from c o b a l t - 6 0 w i t h t h e s e

e l e m e n t s i 3 by compton s c a t t e r i n g . D u r i n g i r r a d i a t i o n ,

m o l e c u l e s unde rgo i o n i z a t i o n AB > AB + e " and

e x c i t a t i o n t o p roduce frBe r a d i c a l s ! AB • (AB) fk +

E x t e n d e d s y n o p s i s of t a l k t o ba d e l i v e r e d by Dr . t / . K . I y a , Bhabha Atomic R e s e a r c h C e n t r e , Bombay, I n d i a , a t t h e Second N a t i o n a l E x e c u t i v e Management S e m i n a r / R e g i o n a l I n d u s t r i a l P r o j e c t .

/2/

Applications of radiation may be considered under

tha follouing broad categories and a feu specific examples

in each case uill ba given.

Inorganics - solids - aqueous solutions

Organics - solids - solutions - suspensions

- ointments

Polymers - biological-synthetic

Pharmaceutical containers

Crude drugs

Cosmetics & Toileteries

It should be recognised that the uork done or the

information made available on the uork done in these areas

is relatively limited. It is necessary to note that the

maximum dose that is tolerated by a product must be estimated*

The doss rate considerations are also sometimes important'

There is a general misapprehension that radiation

is more harmful to pharmaceuticals than other methods of

sterilisation* This is often not correct. Some degree of

change, such as discoloration and/or decomposition occurs

for certain pharmaceuticals even in the traditionalimethods

of sterilisation. As both gamma photons and high energy

/3/

electrons cause ionization and excitation, which lead fg

dissociations, some degree of degradation appaaxs to ba

inevitable. The radiation yield in terms of" a nau species

produced, the loss of target material, and tha radiolytic

yields can be determined for different doses delivered.

The extent to uhich physico chemical changes

occur at sterilisation dosBs of 10 to 25 KGY ia not

significant in «any systems. In genaral» it may be said

that certain substances are stable to radiation in the dry

state, or in suspension in oil base, or in an ointment

oatrix; they may however decompose partly or totally when

irradiated in the form of aqueous solution or suspension.

For validation of gamma irradiation procedure for a

pharmaceutical product, the following criteria are to be

borne in mind:-

- Knouladgs of the minimum and maximum doss in the

total sterilisation load configuration.

- Radiation stability of the product material.

- Knowledge of total number and radiation resistance

of microbial population of tha product.

Demonstration of the minimum sterilisation dose for

the product.

/4/

In many pharmaceuticals (eg, antibiotics, opthalmic

ointments and other synthetics) and medical products»

especially those that are extruded or moulded at high

temperatures and manufactured or assembled in premises

following the regulations of Good Manufacturing Practice(GMP),

the prasterilization microbiological population load (PSHPL.)

may be very lou, and dose levels of 10 to 15 KGY may be

sufficient, and this arguement is gaining ground in

pharmaceutical circles»

Plastic materials of the same generic name, but

uith their oun unique make up of additives» plasticisers,

^.stabilisers etc. may vary in their radiation stability

and this should be noted in daciding the feasibility of

radiation sterilization for packaging materials, containers

and disposable devices or kits*

B I B L I Q G R A P H Y

1) The Pharmaceutical Codex, 11th Ed. London, "Ehe

Pharmaceutical Press, 1979, pp. 851-854.

2) Uillix, Garrison U.H. Radiation Res. 1967, 3^, 452

3) '•Radiosterilisation of Medical Products 1984", Proc.Syrop.

Bombay, Dec. 1974, IAEA Vienna (1975).

4) Pharmacopoaial Forum, May - June 1982, the U3P

Convention Inc. (1982) 2082-2083.

5) "Radiation Sterilisation of Biomedical Products &

Pharmaceuticals", Proceedings of National Uorkshop,

8ARC, Bombay 1982

RADIATION EFFECTS ON PHARMACEUTICALS AND RELATED MATERIALS

Radiation steril isation is the method of choice for many medical

supplies and devices. However, because of the ionising nature of

gamma radiation, one must consider the effect of such radiation on

the physical and chemical properties and on the biological behaviour

of pharmaceutical and related mater ia ls before the feasibility of

radiation steril isation for such products is established . The results

of such feasibility studies can lead to an appropriate decision on the

suitability of radiation steril isation for a part icular pharmaceutical.

/ 2 /

Interaction of ionising radiation with pharmaceuticals

A knowledge of the mode of interaction of ionising radiation

is necessary for taking up a programme of feasibility studies,

Gamma radiation interact with matter in 3 ways depending on the

energy, and the atomic number of the elements in the material :

photoelectric absorption, compton scattering, and pair production.

The majority of pharmaceutical and medical products

contain mostly light elements: C, H, N , 0 , CI, P, S, Na, K, The main

interaction of gamma photons from conalt-60 with these elements

is oy compton scattering. The compton electrons may have a

maximum energy of 1. 1 MeV, the loss of whicli energy in the

product leads to ionisation and excitation of the molecules which

then lead on to bond rupture and the production of chevnically reactive

species. Thus, during irradiatiop, molecules underAionisation :

AB } AB + e and excitation to produce free radicals

A3 > (AB)* ) A' - ,V

These active species can lead to chemical changes which in some

pharmaceutical product may ae significant.

/ 3 /

Feasibility Studies : *

While some pharmaceuticals need not be sterile but must

be free from pathogens, others need to be sterile. Crude drugs

are often required to be free from pathogens as well as from

excessive microoial population. Some of these products are

sensitive to heat as well as ETO. Gamma radiation may have

a useful role upgrading or for sterilisation of such products.

/ 4 /

For validation of the gamma irradiation procedure for a

pharmaceutical product, the following criteria are to be borne

in mind: •

- Knowledge of the minimum and maximum dose in the

total sterilisation load configuration.

Radiation stability of the product material even at the

maximum dose.

- Knowledge of the total numoer of microbial population

in the product and their radiation resistance.

Demonstration of the minimum sterilisation dose for

the product.

/ 5 /

It is necessary to ascertain that the irradiation process has

not affected:

1) the potenc.' of the irradiated drug

2) the physical characterist ics of the drug

3) the safety of the drug

In the USA, radiation treated/steri l ised drugs a r e called

New Drugs. In the UK, though this is not so, it is necessary to

produce proof that (i the potency of the drug is unaffected uy the

process (ii) any degradation products are not harmful,

/ f i /

In India , the pharmaceutical manufacturer and Isomed

research group carry out feasibility studies in collaboration with

the Food & Drugs Administration. These studies are carried out

in 3 phases:

Phase I : Physicochemical studies as per pharmacopoeial

specification on the drug irradiated at graded

doses in the range of 10 to 3U KGy and beyond

if necessary. Determination of the maximum

tolerated dose, micrcruiological studies at various

doses. '

Phase II : Stabiliv studies at the selected dose. Chemical,

microbiological assay, as appropriate.

Pharrr..-.cological evaluation on animals.

Phase HI Clinic?.! trials cind bio-availability tests on humans

IV

Radiation Stability - Techniques used:

It is thus essential to establish the radiation stability of

a pha; maceutical or related material proposed to be irradiated

at a specific dose adequate to achieve the degree of microoial

inactivation/sterility required. The establishment of the chemical

purity of the product or of the impurities generated by radiation

degradation can be done by the use of several well-known and

sophisticated techniques including IR,UV & visible spectrophotometry,

polarography and chromatography. TLC, GLC & HPLC a r e particularly

useful for isolation of the impurities* when the physico-chemical

.characteristics of the impurities are similar to those of the main

compound irradiated.

It is well recognised that these impurities can be isolated

from the principal compound by TLC/GLC/HPLC enabling on-line

or subsequent examination by massspectrometry, which can give the

mass numbers of the molecular ions and thus simplify the task of

identification of the impurities, even if they are present at picogram

levels . Examination of these chemical species for toxicity,' mutagenic,

teratogenic or carcinogenic effects is more meaningful and definitive

than the gross tests on the sterilised drugs.

/ 8 /

Spectrophotometry:

This method is often used in the UV or visible mode

depending on the absorption properties of the molecule and/or the

necessity to react it with a colour producing reagent.

Ampicillin-Na, tetracycline etc. can be assayed by

UV-aosorption spectrophotometry.

Neomycin is made to react with ninhydrin for visible

aosorption spectrophotometry.

In spectrophotometry, the absorbance ratio may serve as

a useful guide for comparing the reference and test compounds.

Sometimes derivatives (first, second & other) may be useful to

establish the purity.

/ B /

b) Polarography: As this method depends on elect ro -active

(reductive or oxidative groups), it is a specific method, especially

when used in the differential pulso mode. For a successful use of

this method, the half-wave potentials must differ atleast by 100 mV.

This can oe used for purity determination of chloramphenicol,

for example.

c) Chromatographic methods: Either TLC or HPLC technique

could oe used. TLC has the disadvantage that detection is to oe

carried out after the development of the plate. In HPLC, the

detection is on-line - more than one detector (eg. UV & refractive

index) can oe used in ser ies . Some-examples of the use of HPLC

in feasibility studies may oe mentioned:

i) Oxytetracyclin HC1 is separable from most of its impurities

.jy HPLC. Control samples of the pure antioiotic and samples irradiated

at 15 KGy were studied for purity. No impurities are noted at this dose.

ii) Ampicillin sodium can .;e separated ay HPLC from a numoer

of impurities produced during irradiation in the solid state. Both this

product and penicillin-G-podium cannot stand a radiation dose oeyond

10 Gy. Detailed studies on this compound are in progress at Isomed.

iii) Using HPLC, impurities were separated from irradiated

chloramphenicol, and were tested by Ames test for rnutagenecity.

The impurities were shown to be non-mutagenic.

/ 10 /

Pharmaceuticals and Conventional Methods

There is a general apprehension that radiation is more

harmful to mater ials than other methods of s ter i l isat ion. Some

degree of decomposition occurs even with the traditional methods

of s ter i l isat ion, dry and wet heat, and ethylene oxide, as can be

seen from the examples cited below:-

i ) Sulphacetarnide, sulphadiazine, sulphadimidine, sulphathiazole

- when steril ised by heat suffer a discoloration

ii) Sulphacetamide sodium solution when autoclaved undero hydrolysis

.^ with the formation of sulphanilamide

iii) Chloramphenicol eyedrops s ter i l ised by heating at 98 C to 100°C

are likely to contain the hydrolysis product 2-amino-l-p-ni t rophenyl

propane-1 -3-diol.

iv) Sodium carboxy methyl cellulose suffers loss in viscosity whether

it i s s ter i l ised by dry heat or its aqueous solution is steril ised by

autoclaving.

v) Ethylene oxide has no clean bill of health. Owing to its high

chemical reactivity, it reacts with labile hydrogen atoms of

reactive groups as -OH, -COOH, - SH, -NH2 , etc. and with

vitamins, amino acids etc. and thus produce their hydroxy ethyl

derivatives whose nature and level of toxicity is unknown.

/ 1 1 /

Water and chlorine in drugs react with ethylene oxide and prodce

toxic ethylene chlorhydrin and ethylene glycol. It is reported that

streptomycin loses 30% activity on EO steril isation.

For certain substances, radiation has some advantages

over dry heat. F o r instance, gelatin steril ised by dry heat

(as recommended in BPC) is difficultly and only partially, soluble

in water, which-the radiation steri l ised material dissolves as easily

as the unirradiated mater ia l and the viscosity does not show any

significant change.

/ 12 /

RESIDUAL ETCH AND ETG IN SOFC PRODUCTS

( S t B r i l i s e d by pure ETO)

Produc t

G e l a t i n

— g ranu les

— capsu las

- 3ponge (2

Papain

Absorbant c o t t o n

S ta rch

Sodium a l g i n a t e

Haauy K a o l i n

P a y l l i u m haf?k

Carboxy methy l ce

i b s o r b a b l e )

u c o l

i l l u l o s B - N a

Res idua l

ETCH

12

6

ND

ND

NO

400

33

4000

ND

ND

ETG

ND

ND

4270

2790

520-760

2650

690

ND

550

3800

(ND: not d e t e c t a b l e )

/ 1 3 /

LIMITS OF ETO, ETCH AND ETC IN DRUG PRODUCTS AND

NED ICAL DEVICES

ETO ETCH ETG

ppm

D r u g P r o d u c t :

O p h t h a l m i c s ( f o r t o p i c a l 119a) 10 20 60

I n J B c t a b l a s ( i n c l u d i n g v e t e r i n a r y 10 10 20 i n t ramammary i n f u s i o n s )

I n t r a u t a r i n e dsv / i ca ( c o n t a i n i n g , a d r u g ) 5 10 10

S u r g i c a l s c r u b sponges ( c o n t a i n i n g a d r u g ) 25 250 500

Hard g e l a t i n c a p s u l e s n a i l s 35 10 35

/ 1 4 /

APPLICATIONS OF RADIATION

We may consider the applications under the following broad

categories :

Inorganic Pharmaceuticals : Solids - aq. solutions

Organic Pharmaceuticals : Solids - aq. solutions/suspensions;

oil solutions/suspensions.

Crude drugs and pharmaceutical aids

Containers and closures

Surgical ma te r i a l s and family welfare kits.

/ 1 5 /

Inorganic Pharmaceuticals :

Some examples are :

i) Diatornaceus earth, kaolin, bentonite, and talc; stable

to 20 kGy.

ii) Solid electrolytes such as NaCl, KCl, CaCl 0 , Sodium

phosphate, sodium lactate and sodium ci t ra te a r e stable,

except that some may develop colorat ion with no attendant

changes in physiological reaction.

iii) Water and aqueous solution of NaCl in polythgne, o r

^ poly ester/polythene laminate sachets ; i r radiated product

is physiologically safej for use as vehicle for injection

or as eye wash solution.

iv) Ringer 's solution for kidney perfusion and wound

cleansing.

v) Contact lens solution

vi) Weak iodine solution (for use in kits) .

/ 1 6 /

Organic pharmaceuticals:

Aqueous | solutions of organic substances a re generally unstable

under irradiation owing to the interaction of the solutes with the

radiolysis products of water : hydrogen and hydroxy 1 radicals , hydrated

electron and H90_

The organic pharmaceuticals and formulations of interest a re :

Solids : antibiotics, sieroids etc.

Oils : solutions/suspensions

Ointments : in paraffin base, or polyethylene glycol base

(free from added water).

/ 1 7 /

Antibiotics and antibacterials:

Many of the radiation steri l ised antibiotics retain their

physiochemical and microbiological charac ter i s t ics . According to

the Division of Antibiotics, National Institute for Biological Standards

&ud Control (London), gamma radiation has been used in UK for the

steri l isat ion of some parenteral antibiotic preparations for a number

of y e a r s . In cau£=eou-ntry the pharmaceutical industry has been very

hesitant to adopt the technology in this a rea .

/ 1 8 /

Some of the antibiotics a re stable only at lower radiation doses

(10-15 kGy):

eg. Pencillin G - Na (1SOMED)

ampicillin -Na (a manufacturer)

bacitracin (Bombay College of Pharmacy)

neomycin - SO. (Bombay College of Pharmacy)

Some are stable to a dose of 25 kGy:

eg. Chloramphenicol (ISOMED)

Tetracyclin HC1 (ISOMED)

Oxy " (ISOMED & a manufacturer)

Silver sulphadiazine has oeen examined by a manufacturer and

found to be radiation stable.

Quinapyramine prosa l t s , used as a trypanosomal d rug , have been

found to be stable to radiation doses of 2 5 kGy and have been steri l ised

in large quantities at ISOMED for use in veterinary medicine in the

country.

/ 1 9 /

Steroids:

Radiation is recommended for steri l isat ion of Steroids

as ETO is unsuitable. The extent of decomposition is l e ss than

1% at a dose of 25 kGy.

eg. betamethasone - 17 valera te

" - 21 phosphate

dexam ethas one

hydrocortisone

».„. hydrocortisone acetate

prednisone

Vegetable Oils:

For this class of products radiation steri l isat ion is safer than

heat steril isation. Some preparations using vegetable oil as vehicle,

and reported as radiation stable a re :

Testosterone propionate in oil

Tetracyclin ophthalmic oil suspension

Physostigmine salicylate in oil base

/ 2 0 /

Ophthalmic Ointments:

At ISOMED we have established feasibility of radiation

sterilisation of a number of ophthalmic ointments based on paraffins,

which are quite- radiation stable. Some examples of such ointments a re :

Chloramphenicol (ISOMED)

TC-HC1 (ISOMED)

OTC-HC1 (A manufacturer)

*"v Gentamycin SO. (A manufacturer)

Neomycin-HCA {ISOMED)

We are routinely radiation steril ising millions of ointment

tubes. The process is equally applicable to these ointments in sofj?

gelatin capsules.

/ 2 1 /

/ Crude drugs and pharmaceutical aids:

This class of products is invariably associated with a high

degree of microbial contamination, in excess of 10, 000/g. Upgrading

to a microbial level of less than 1000/g. is possible by using 10-20 kGy

radiation dose. Some examples of crude drugs established as radiation

steri l isable without loss of medicinal property are :

Folium belladonnae; Follium digitalis; Fructus sennae; Ergot powder;

Serpentina root powder; Psyllium husk; Starch etc.

Some of these i tems are routinely radiation steri l ised at ISOMED

for export purposes. In the case of psyllium husk, radiation steri l isat ion

is superior to ETO steri l isat ion, as the la t ter produces ETG, an i r r i tant

chemical contaminant. In the case of s tarch, microbiological upgradation

by irradiation is again superior to ETO, as the lat ter produces relatively

large quantities of ETG &. ETCH, the l a t t e r of which is mutagenic.

/ 2 2 /

PHARMACEUTICAL PRODUCTS ROUTINELY RADIATION 3TERILI3ED AT ISOrtED 4~

A b s o r b a b l e g e l a t i n s p o n g e * U^Hcj

Bentonits pouder

Belladonna dry extract?

Charcoal pouder

Ergot pouder?

Rauolfia sBrpentina (pouder)+

Fluorescein sodium (as str ips)*

Gelatin capsules (empty)

Papain (IP/BPC) +

Prickly heat poudar* (anti fungal, containing boric and '-~- salicylic acids)

Quinapyramine chLorida and.sulphate* (for vet use)

Tatracyclino+ (for intramuscular and intravenous injection)

Ophthalmic ointments in paraffin base:

- in collapsible aluminium tubes

Atropine sulphate*

Chloramphenicol*

Chlorotetracycline+

Gentamycin gulphate*

Hydrocortisone and neomycin?

/23/

Mercuric oxidai

Neomycin, Polymyxin and bacitracin (in dusting poudsr)+

Sodium sulphacatamida+

Tetracycline*

in soft gslatin capsule

Chloramphenicol*

Ophthalmic preparation in an oil basa:

• Physostigmine salicylate*

Tstracycline ophthalmic oil-suspension

Skin ointment in polyathyiane glycol bass:

Neomycin sulphate, hydrocortisone acetata, alphachymotrypsin'

Tetracycline topical ointment

Approved by FDA (flan.) for routing radiation sterilisation at ISONEID

Approved by FDA(Mah.) For export purpose only.

+ S t e r i l i s e d by r a d i a t i o n i n o the r c o u n t r i e s l i k e UK, Noruay» A u s t r a l i a .

/ 2 5 /

Polvmers & Radiation Effect

A lurge number of polymeric mater ia l s a re used in the

manufacturing of several medical devices of packaging mater ia l

and containers. In understanding the effect of ionising radiation

on polymers , v/e must remember that industrial polymers with

the same generic name may contain different types and varying

quantities of antioxidants, p las t ic i sers , dyes, f i l lers , oxidised

impuri t ies etc. as a result of which it is difficult to predict the

behaviour of the polymer under radiation. However, oroadly

speaking, the 2 main effects of radiation, apart from the formation

'••*oi free radicals , a re crosslinking and scission. Both these are

simultaneous competitive phenomena and it i s the ratio of the

2 yields that determines the net effect. A broad classification of

polymers according to the effect caused is given in Table

/2 6/

jjS.NO

'

9 t

| 1 : 9 1

i 3 J b

i -1 « •

i i a

e

I ! • i

I 7

j M

| 0

10

11

11 1

T i a t . t - 4 -

POLYMERS AND RADIATION EFFECT

CROSS-L INKING

POLVHETrfYLENC I fOt-TErMIXSVE ) ' .

- C H , - C H - , — C t ^ - C ^ -

LC'*- OE. \S i rY: c x 3

M H H H ( l^H^,H H f l p — i - c — c — c — c — r c — c — c — c —

•A.

Hi3M C £ \ \ s : 7 v :

rl M M M M H *-» H

J '-' ** ~< - * M j ) ^ H H

•%-5 " V<£,

_ ; - . _ ; , - . . ;_-M_

CL Cl

P O L - - M I D - : : • . " _ C " i ; :

— - . - i - ! ' : ^ , ; - f . r i - c — I ' C H J , 1 - : -" 6 6

PDLr - r -T f» ; ; .--;i_T£TnrLENE " R E ; " - I T M A ' _ A ~ £ OR T E R Y L E H E K

• - - C M j — C H 2 — 0 — C — C ^ 4 — C 3 — 6

P OLYD'METt.Y.. O R O I P H E N Y L ; S 'LO*A ' l£ .

— C S I — 3 i i — 0 — Si — O -

iH3 J j _ C6H, J

t- J 9 3 E R S !

— <:••••> — c-i = c - C H J -

DEGRADING

P 0 L I I S ; 2 - ' V : S , < £ :

C"3 ~ C H ,

P C ! ' . • c - M 2 T r , " U S r v « £ h £ ) :

PCLVMiTMACSll.ATES :

— c.-v— = - : i 2 — d -COO* C O M

P O L Y V S T H A C R V L A M I D C : C H , CHj

C M , C —CM. , C —

" I ' . T ' VINYLCS.SE C H ' _ O T ! S £ ) : !

C( Cl ! _ C " - - - c — C K J — c - ;

C( CJ !

— c — c —

P3LTWOflOCHl.C t!OTP-PL'^S«'3ErMyLL.Si ! K i ( F ) .

— c — c -

C r L L U L r S C : M o n • • • > : n

-o-C~^.;' ^ rVo-H v—o < ' "

C .« ,pw H OH

" i • •'• ' ^ > v r ? r

/27/

Radiation effects on some commonly used plastics

Polyethylene films invariably contain a few additives. Low

and high density polyethylenes can withstand very high doses of

gamma radiation. A sterilization dose of 25 kGy-does not produce

any significant change. Infra.red spectrum of gamma irradiated

polyethylene, however, .shows evidence of t races of OH and C=0

groupings appearing in the polyethylene molecule due to interaction

of free radicals with 0 9 . Polyethylene bottles containing normal

saline do not affect the quality or nontoxicity of the product even

after irradiation. Work carried out at ISOMED on radiation

steri l ized polyethylene films and containers show that they conform

to ISI specifications. ' *

Polyvinyl chloride (PVC) has occupied a key position in the

manufacture of plastic medical products due to its easy plasticization

and high degree of clarity in the finished products. As virgin PVC

products a re hard, plasticizers a re invariably incorporated alongwith

other additives to impart a desirable quality. On irradiation PVC

undergoes dehydrochlorination and acquires double bonds. If it is

not properly stablized, al ternate double bond formation can occur

rendering the product brownish in colour. Hence radiation stable

PVC formulations must' contain suitable plasticizer and stabil izer .

Contd. .

/ 2 8 /

European pharmacopoeia recommends a composition of plasticized

PVC for containers for human blood and blood components (table 4) .

As ionizing radiation is extensively employed in Europe for

steril ization of medical devices it is likely that the PVC formulation

recommended by European pharmacopeia may be radiation stable;

however, it has to be verified in actu.n pract ice . While i rradiated

infusion/transfusion sets of some indigenous manufactures a re

reported to conform to USP plastic class II, the sets of a few manu

facturers a re reported to conform to class III. The sets manufactured

abroad invariably a re of class VI.

Polypropylene: is a popular polymer used in medical applications

and packaging. Gamma irradiation causes chain scission and cross -

linking in polypropylene in equal amounts. In view o f th i s . i t is reported

to be suitable only for single steril ization dose of 25 kGy. Poly

propylene undergoes oxidative- degradation if irradiated in a i r . The

post-irradiation degradation is also oxidative indicating that the

residual radicals continue to react with oxygen of the a tmosphere .

Certain polypropyiones, that might be acceptable immediately

foilowir.g irradiation, would be Totally unacceptable after 6 months

due to post-irradiation degradation. Degradation is reported to be

minimised by introducing suitable additives in the formulation. Such

Contd. .

/ 2 9 /

formulations (eg. Moplen T10 G) a re reported to be available

in some countries. Irradiated caps and syringes of polypropylene

do not become noticeably brittle, but they acquire a yellow tinge.

As polypropylene films show sign of embrittlernent even at a

dose of 2 5 kGy, their use as packaging mater ia l must be viewed

with caution. Biaxially oriented polypropylene (BOPP) is reported

to be relatively more stable.

Polyformaldehyde, commonly known as "Delrin" is used

for making moulded items such as spikes and connectors for

infusion/blood transfusion se t s . They become orittle and lose

strength at doses greater than 10.kGy; they break on application

.;$*- of a gentle p ressure at the two ends of the spike. Polycarbonate

and ABS appear to be a better choice for fabrication of such i t ems .

Polyamides, such as nylon 66 (adipic acid hexamethyiene

diamine) or nylon 6 (polycaprolactam) are used as meshes in.

transfusion sets or as sutures . On irradiat ion they'may acquire a

yellowish tinge. Polyethylene meshes a re alternatively used

commercially.

Polystyrene is widely-used for making containers, syr inges ,

t issue culture plates, drip chambers of infusion administration se ts

etc. It is not heat stable. It is attacked by ETO-frebn mixture.

Contd. . "

/ 30 /

However, it is well known to be stable to radiation owing to the

piesence of benzene rings in the s t ruc ture ; the plastic is largely

unaffected even by high radiation doses. Though high impact

polystyrene is reported to be somewhat l ess stable towards

radiation effect, it is still among the more res is tant plast ics.

Robalewski et al . reported polystyrene of different kinds irradiated

to 40-50 kGy to be quite- stable on the basis of chemical and

physicochemical examination. Suitable additives may be added

to polystyrene to confer desired proper t ies .

/ 3 1 /

Physicochemical and Biological Tes t s

Plast ic medical devices come into contact with inorganic

infusion fluids, physiological fluids, blood, mucous membrane,

muscular t i s sue , etc. Texts such as USP (XX) - NF (XV) BP

198 0. European Pharmacopoeia, WHO Technical Report, Land-

field and other pharmacopoeia,prescribe cer ta in minimum physico-

chemical and biological test procedures to ascer ta in the satisfactory

quality and safety of these mater ials for medical and pharmaceutical

use.

The procedures involve tests on (i) t he content of heavy metals,

oxidisable/reducible substances, buffering capacity, impurit ies

leachable by a few specific extractants, and (ii) the reaction of living

t issue, and of normal animals to the presence of portions of the

plastics of extracts of it/* USP and NF classify plastics into six

categories (I to VI) depending on the types of extractants used and

the biological tes ts to be performed (13EEEr5). As a tentative

guideline, it may be said that packaging film may conform to c lass 1;

the devices, which may be implanted for a long t ime, mayhave to

conform to c lass VI; and the devices of intermediate type may conform

to class II to V. Besides, devices s ter i l ized by ETO must be

released for use only after ascertaining that the residual levels of

ETO, ETG and ETCH are less than the permiss ib le l imits .

/ 3 2 /

Tentative guidelines for the tests to be car r ied out on

various types of products a r e indicated in ffrMift-'=S. It is essential

for comparisons, that these tests a re car r ied out on the product

before and after sterilization, be i tETO or Radiation. Medical

grade plastics must be of standard and approved composition,

which should not be changed in the absence of an extensive tests

and evaluation programme. If the composition, ingredient, quality

or processing treatment of the plastic is al tered, the tests should

be carr ied out on such new lo t s .

„. Control samples of both unirradiated and irradiated finished

products should be kept aside as future reference samples. A

corresponding batch record of quantity manufactured, raw material

analysis repor t s , grades, codes etc. should be maintained for future

reference alongwith process/product r ecords .

To maintain high s tandsrds , stability tes ts should be performed

as a continuous product evaluation procedure, and for improvements

keeping in view the intended end-use of the products and safety.

/ 3 3 /

SOME RADIATION STABLE POLYrlERIC MATERIALS AND THEIR REPORTED U5E

tfinyls : u n p l a s t i c i z e d PVC ( r i g i d )

A n a e s t h e t i c a i r u a y s , e n d o t r a c h e a l t u b a s , t r a c h e o s t o m y t u b a s D- to-F i d p u b l e a i r u a y s , moun ts and a d a p t o r s c o n t a i n e r s .

p l a s t i c i z a d PVC ( f L a x i b l B )

T u b i n g s , c a t h e t e r s » c a n n u l a s , i n f a n t f e e d i n g t u b i n g s , b l o o d g i u i n g and t a k i n g s Q t s , b l o o d and plasma b a g s , a p r o n s and o t h e r s h a e t i n g 0

O l e f i n s : o o i y e t h y i o n e I m p l a n t s , o s s i c l e s , a r t i f i c i a l l o u - d s n s i t y , h i g h d e n s i t y t e a r d u c t s , t u b i n g , f i l m e s o e c i a i l y

bags f o r c o n t a i n i n g s t e r i l s a r t i c l e s , f i l m l a m i n a t s s 0

oîy ( m a t h y l p a n t e n e ) S y r i n g e s , c o n n e c t o r s e t h y l e n e / v i n y 1 a c e t a t e T u b i n g s , s y r i n g e s , p l u n g e r s

i t y r e n a : OD Ly s t y r e n ;

P r l y a m i d s s : N y l o n 3

<~fO

P t i l y t r i f l u r o c h L o - c - s t r s y i e n e F l u o r i o a t a d e t h y l e n e / orooy lan- : ) r -3s in3

Hyoodarmic s y r i n g e s , s o o n g e s , p n i a ]

«Su tu res , gauze f i l t e r s , i n t r a v a n o u -t u b i n g s , c a n n u U e , u r e t e r i c and a n g i o g r a o h y c a t h a t e r s , c o n n - a c t o r s , a d a p t o r s , f i l m f o r p a c k a g i n g , ,

T r a n s f u s i o n s a t c h a m b e r s , f i l - e r s , i n c L a n t s , s p e c i a l i s e d c a n n u l a - ; uouen y a r n f a b r i c f o r a o r t i c v a l v a and a r t e r i a l g r a f t s 0

P")ly = s t e r ! P ^ l y e t h ••/ l e n s t e r e D h t h a l a t e

F i l m and f i l m l a m i n a t e s , s u t u r e s

E p o x i d e r a s i n O » ' • ^> E l e c t r i c a l i n s u l a t i o n such as f o r c a r d i a c oacemaka rs

S i l i c o n e r u b b e r s T u b i n g , i m p l a n t s , h y d r o c e p h a l o u 3 v a l v e s , a r t s r i o - v a n o u 3 s h u n t s .

A c e t a l s ? P o l y c a r b o n a t e s

T h e r m o s e t t i n g m a t e r i a l s *

P h e n o l f o r m a l d e h y d e

U r s a f o r m a l d e h y d e

O x y g e n a t o r s , s y r i n g B componen t s

B o t t l e caps and c l o s u r e s

/H4/

PLASTIC F O R M U L A T I O N B A S E D O N P L A S T I C I Z E D POLY (V INYL CHLORIDE) FOR C O N T A I N E R S FOR H U M A N B L O O D

A N D B L O O D C O M P O N E N T S

They contain not less than 55% of poly (v inyl chloride) and may contain the fo l lowing addit ives:

— not more than 40 per cent of di (2Tethylhexyl) phthalate; — not more than 1 per cent of Zinc Octanoate or Z inc-2-ethy l hexanoate;' — not more than 1 per cent of calcium stearate or Zinc stearate or 1 per

cent of a mixture of the t w o ; -— not more than 1 per cent of N» N—diacylethylene diamines (in this

contetfCacyl means in particular palmitoyl and stearoyl); — not more than 10 percent of one of the fo l lowing epoxidised oil

or 10 per cent of a mixture o f the t w o : epoxidised soya oil of wh ich the oxiran oxygen content is 6 per cent to 8 per cent and the iodine value is not greater than 6; epoxidised linseed oil of wh ich the oxiran oxygen, content is not

[greater than 10 per cent and the iodine value is not greater than 7. [No colouring matter is added.

/35/

REFERENCES [ ^cUo.h«~ I Pdh+^^)

Cooper. J.. Plastic containers for pharmaceuticals—Testing and Cannot WHO. Geneva. 1974. pp. 69. 78.

Carl W. Bruch, "Sterilization of Plastic»": Toxicity o' Ethylene Oxide . Residue*", in "Industrial Sterilization". Briggs Phillips, G., and Miller. W.S. (eds.), Duke University Press, Durham, M . C 1973, (a) p. 60, (b) p. 51.

Sykos. G„ in "Methods In Microbiology". Norris. J.R., and Ribbons, D.\V. (eds). Acadamic Press. London, NY, 1969, Chap. I I I . p. 105.

Obs, T.lt, Chem. Abstr. SO. 100184h (1974).

Ethylene Oxide Sterilization: A guide for hospital personnel, US Dect. of HE 6 VV, public Health Service FDA. Bureau ol Medical Services and Diagnostic Products, Rockvile. Md.. 20852, USA, Aug. 1975.

Remington's Pharmaceutical Sciences (15th Ed.}, Anderson, J.T. (ed.). Mack Pub. Co.. Easton, PA, 1975, D. 1090.

Upton. B. et ol. Anaesthesia, Analgesia, 1971. 50, 598.

Perkins John J., Principles & Methods of Sterilization in Health Scienc». 2nd Ed., Charles C Thomas, II. 1969, p. 516. i

Harvey. S.C.. in "Remington's Pharmaceutical Sciences, 16th Ed.", Osal, A. (ed.), Mick. Pub. Co., USA, 1330, p. 1102.

Federal Register, 43*tu'2). 27482 (1978).

National Formulary XIV, American Pharm. Assoc. Washington. 1375. pp. 834-866. 886-887.

Meeann, J., Choi. E.. Yamasaki, E., and Ames, B. N„ Proc. Nat, Acad.Sci„ USA. 72(12) 2135-5139 (1975).

Morganstern, K., Formed Fabrics Industry, Feb. 1977. pp. 20 -21 .

Lacornme. M„ Lamoan, G, and Chaignean, M., Ann. Farm. Fr., 53.337(1975).

Bhirud, S.O., Commissioner, Food & Drug Administration, Maharashtra 1983 (Personal Communication).

Skisns. W.R., Hadiat. Phys. Chom., / 5 , 4 7 (1980).

Budd, R.A., "Symposium on Biological Effects, Imaging Techniques, ' and Dosimetry of Ionizing Radiations", Rockville, Maryland, June 6-3 , 1S79, US Dept. of Health & Human Services. PHS. FDA. BRH, Rockville. Md 20857, USA.

, Sztanyik. LB., "Application of Ionizing Radiation Sterilization". in "Technical Developments and Prospects of Sterilization by

| Ionizing Radiation". Int. Conf. Vienna Austria. April, 1-4. 1974. sponsored by Johnson & Johnson. E.R.L Gaughran and A.J.

I Goudie (eds). Multiscianea Pub. Ltd.. Montreal, pp. 16-17.

. Bogdansky, S.. Siegcmund. E., Lehn. P J . Abodeely, R., SaUhouse,

I T.N., and 0'Leery. R.L.. Int. J . Radiat. Sterilization, 1(41,283 (1974).

, Bruch. C.W.. Bull. Parent, Drug Assoc., 31. 18, (137.7».

2.1. Chapiro. A, "Radiation Chemistry of Polymeric Systems'" Inter-scienco. NY.. 1962. p. 423.

22, Gopal N.G.S.. Rajagopalan, S„ and Shatma. G.. in "Radiostenliza-tion of Medical Products 1974, "Proc. Symp. Bombay 9-13. Dec. 1974, IAEA Vienna. 1975. pp. 393-394.

23, Hilmy, N. and Sjdj'nm, S.. inVef.,22, p. 145. 24. Duplessis. .T.A.. Radiat. Phys. Chem. 14. 289 (1979).

25. IS: 7277-1974. Code of Practice for safe use of .Polyethylene-in contact with food stuffs. Pharmaceuticals and drinking water. ISI. Manak Bhawan. New Delhi.

•26. IS: 7288-1974. Code of Practice for safe use of Polyvinyl chloride in contact with Food stuffs. Pharmaceuticals, and drinking water. ISI. Manak Bhawan. New Delhi.

European Pharmacopoeia. 2nd Ed. Part ; l l -2 , 1981, Section VI I. 2_ Plastic materials and VI. 2.2 Plastic containers.

Geymer, D.O.. Makromol. Chem., S3,152 (1966).

Satoy,ey, R. Oammont. F.R. J , Polym. Sci., A/, 2155 (1963).

Williams, J.L, Dunn. T.S. Sugg. 4, and Stannet, VE, Radiat. Phys, Chom» 9. 445 (1977).

Radioisotope Review Sheet G1: Radiation Stability of Materials. Isotope Research Division. AERE, Harwell.

Piaster, D.W. in "Industrial Sterilization" Briggs Phillips. G„ and Milter W.S., (eds.), Ouko University Press. Durham. 1973. pp. 141-152.

Perkins, J.J. "Principles and Methods of Sterilization in health sciences", 2nd- Ed., Charles C. Thomas Pub., Springfield. I!.. USA, 1969, p. 516.

Rob3lewski, A.M., Sk3jster, J.J.,- Bryl-Sandelewski. T. and Lungowska, U.E.. Chem. Abstr., 37, 6261 (1974).

IS: 7951—1975. Coda of Practice for safe use of .polystyrene in contact with Food stuffs. Pharmaceuticals .and drinking water ISI, Manak Bhawan, Now Delhi.

Unitoj Staia* Phirmicopoeia National Formulary XV Mack Pub. Co., Easton (USA), 1980 pp. 903, 918-919, 950-953.

27.

28.

29 .

30,

3 1 .

32.

33.

34.

35.

35.

37.

38.

British Pharmacopoeia, 1980, HMSO, ' London, A200-A202. ' "- , •

pp. 565-566.

Requirements for plastic containers for pharmaceutical preparations. Annex 3, in WHO Expert Committeo on specifications for Pharmaceutical preparations, 26th report,.Tech. Rep. Ser. 614.. WHO. Genova 1977, pp. 25-53.

39. Landfiold, H„ Radial. Phys. Chem.. 15, 34-45 (1980).

40. Rof. 36, p. 1038.

41 . Martindale—The Extra Pharmacopoeia. Reynold:. J.C.F.. The-Pharmaceutical Pross, London, 28th Ed.. 1982, pp. 547-580.

Rpferencea [ ffa.eUa^ f / ^ * T M A \ * « ^ ^ « "

1. Harvey, S.C., In "Remington*e Pharmaceutical Selene»»

(16th ed . ) , (Oaol, A., Ed.) , flick Pub. Co., USA(19B0),

1102.

2 . Upton, B. f at a l , Anaeethesia, Analgesia., 1971 , 50,

578.

3 . Perkins, 3.3., "Principles_and Methods of S ter l l l za -

. tion in Health Sciences" f (2nd e d . ) , Charles C. Thomaa,

II . (1969).

4. Federal Register,' 1978, 43, (122), 27482.

5 . Bruch, C.U. , Int. 3 . Radiat. Steri l izat ion, 1973,

J., 135.

6. Roger A. Budd, "Radiation Steri l izat ion of Products

from the Bureau of Radiological Health, Food & Drug

Administration Point of Vioi * in "Symposium on B.lo-

..-»•*«. logical Effects , Imaging Techniques, and Dosimetry

of Ionizing Radiations'1, Rockville, Md., 3uno 6-8,

1979, US Dopartmcnt of Health & Human Services, PHS ,

FDA, BRII, Rockville, fid 20857, 3uly 1980.

7. Diding, N., Flink, 0 . , Dohensson, S . , Ohlaon B. ,

Redmalir., G. , and Ohrnur, B. , in "Steri l izat ion of

Medical Products by Ionizing Radiation", Int. Conf.

Vienna, Austria, April 25-28, 1977 (Gaughran, F.R.L.,

and Goudie, A.3 . , Ed.), nuit l Sciences, Pub. Ltd.,

Montreal, Canada (1978) 216-231.

6, Schnell, 3 . , Plenio, H.G., Paull, U., Braun, B.,

and Korb, G., in "Radioaterilization of Medical

Producta", Proc. Symp, Budapest, 5-9 , 3une 1967,

IAEA, Vienna (1967) 153.

9 , 3" -oba, G . P . , Pharm. Acta H e l v . , 1977 , S2_ (12) 3 0 2 - 3 0 4 .

10. Anbar, M. , in "Fundamental Processes in Radiation

Cheniatry* (Auslooa. P. Ed. , ) , Intersiconce Pub.

. . (1968)661-662. ' •,* .[.C.^^'

/*»7-

1 1 , Drmro , A . R . , •£*-:/ 3syson, G . G . , "Fundamentals of

R-diat ion Che.-.i-i ry" , London But te ruor ths (1972)

104-105. " ,

1 2 , Roberta, R., 3™ "Plassiv» Radiat ion Techniques",

(Je f ferson, S , , E d . , ) George Neunes L t d . , London,

(1964) 14-19 . " " :

13 , Brynjol fsson, *., in " S t e r i l i z a t i o n by Ion iz ing

R a d i a t i o n " . , I n * . Conf. , Vienna, A u s t r i a , 1-4 A p r i l ,

1974 (Gaughrcr, 'C.R.L., and Goudie, A . D . Ed.)

f lul t iscience P'.'h. L t d . , flontreal, Canada (1974) 140.

14 , Nablo, S . V . , i n refefence .JjS, 6A~6 9» 196-198 .

15 , Pandula, E . L . , Farkas, E. , and R a c z . , I . . , In referencs

a, 87 .

1 6. U i l l i x . , R . S . L . , and Garr ison, U.P1„, R a d i a t . R e s . ,

1967, 3 2 , 452.

4^7, " R a d i o s t e r i l i z a t i o n fledical Products 1974" , Proc. Sytnp0

Bonibay 9 - 1 3 , Deceirber 1974 , IAEA, Vienna ( 1 9 7 5 ) , ( a )

F l e u r e t t e , 3 . , 236-237; (b) F l e u r e t t e , 3 . , f lad ier , S . ,

and Tron3y f f l .3 , , - 247-248.

1 8 . Hayashi, M., K'ato, S . ( and Plorimoto, H . , I n t . 3 . Appi„

Radiat . Isotopes, 1977, 2JB, 723.

1 9, Isoir.ed (unpublished r e s u l t s ) .

2 0 . Charlesby, A . t in ra fe r e nca 7 , 288 .

2 1 . Pharmacopoeial Forum, flay-3une 1982, The USP Conventie?

Inc. (1982) 2082-2083.

2 2 . Dacobs, G . P . , Donbrou, PI,'» Eisenberg, E . , and Lapidot,,

PI., Acta Pharm. Suecica, 1977 , 1_4, 2 8 7 .

2 3 . Hllmy, N . , and S a d j i r u n , S . , in re fe rence 1 2 , 145.

24 . DuPlessis, T . A . , Rad ia t . Phys. Chem, 1979 . 14 . 2 8 9 .

-. 25# Gopal, N . G . S . , Rajagopr lan, S . , and Sharma, G . , in

reference 1j£t 393 , 3g4.

26i \ K u l k a r n i , R.O. , and Gopal,N.G.S. , i n reference JJ ,403- *0 f f

/s*/

27. Berry, R.3., in reference ,8, 54.

2B. Ogg, A.3«, in reference 8., 48-54.

29. rUller, 3.H.PI. , Chem. Abstr.» 1973, JEJ, 1516239.

30. Uenkatroman, R., Ph.D., Thesis, University of Bombay»

Boirtay, (1979), 48, 74.

31„ Hills, P.R., and Johnson, R.A., AERE Harwell, Rep. R-

3750, AERE, UK.

32. Pouer, D.H., in reference J7, 239.

33. Blackburn, R., Iddon, 8., Hoore, 3.S., Phillips, G.O.,

Pi-u«r, ,D„I»1. , and Uooduard, T.U.t in reference 1J, 2A7.

34. Basovs, L.U0, Gromov, U.A.f-Klimoua, T.R., Konevskaya,

N.O., Panin, U.I., and Usatyi, A,P., in reference J,

232-236.

35. Bor. , C., Harangi, 0«, Int. Conf, on Industrial Appli

cation of Radioisotopes and .Radiation Technology,

Grenoble, Trance, 28 Sept, - 2 Oct. 1981, IAIA, Vienna,

-•*.- IAEA-CN-4G/38P.

36. Tsuji, K., Kane, CI.P., Ralm, P.D., and Steindler, K.A.,

Radiat. Phya.Chem., 1981,18, (3-4) 583,

37. Dziegieleuski, J., Int. 3, Radiat. Phys. Chem.,1975,

J., 507.

38. Uills, P.A., in reference Vf.i 1 0 1 »

39. Gopal, N.G.S., Rajaoopaian, 5., Int. 3«. Pharmaceutics,

1981, £, 35 9.

40. Pouell, D.B., flfg. Chemist, 1959, 3,0, 435.

41. flenon, !"..n., Bhalla, H.L., and Gopal, N.G.S., 33rd ' '

Indian Pharm. Cong», Daipur, December 20-22(1981).

42. Kror.enthal, R.K., in reference ^, 1823.

43. Gopal, N.G.S., in Proc. National Workshop on Radiation

.5turiliz.-»tion of Biomedical Products & Pharmaceuticals,' K.

Feb. "17 -18 , 1982, BARC, Bombay (undBr publication).:.; ' '<

44« Duncan, r.., i n re fe rence T.i S$t+. *•• KSSsv^Hf

/ i t /

45. British Pharmaceutical Codax 1973, The Pharmaceutical

Press, London (1973) : (a) 476-478; (b) 689; (c) 447;

(d) 207.

46. Suitek, U., and Plondrezajauski, F., Pharmazia, 1976,

3_i, 81.

47. Kaye, 3., 3. Lab. Clin. Red., 1950, 35_, 823; 1952,

12, 67«,

48. Tsuji, K., and Robertson, 3.H., 3. Chromatog», 1975,

112. 6630

490 Patel, Kom0, Tantri, PI., Sharma, G.t and Gopal, N.G.S.,

Indicn 3„ Pharm. Sei., 1979, 41_, (5), 209.

50. Bcntlcy1s Textbook of Pharmaceutics, 8th £d., (Raulina,

E.A., Ed.), Baillisre Tindall, London (1977) 633.

51. Coats, D., and Richardson,*GQ, Can0 30 Pharm. Sci. 1974,

52. Rajagopalsn, 5., and Gopal, N.G.S., Indian 3. Pharm.

Scionce, 1979, £L» (3)t 113«

53. Hangay, GS( in reference _7» 247.

54. British Pharmacopoeia 1973, HPISO, London, 434.

55. 30U<, Lightboun, National Institute for Biological

Standards and Control, U.K. (Private Communication),

Harch 1933.

INTERNATIONAL ATOMIC ENERGY AGENCY

NATIONAL EXECUTIVE MANAGEMENT SEMINARS ON RADIATION STERILIZATION OF MEDICAL PRODUCTS

S e p t e m b e r , 1986

J o h n M a s e f i e l d S t e v e n Thompson

I s o m e d i x I n c .

Good M a n u f a c t u r i n g P r a c t i c e - Q u a l i t y A s s u r a n c e P r o g r a m s

L e c t u r e Number 7

* • • » » .

SUMMARY OF PRESENTATION < — : " ' " " ; ' ' , . • ' - • • . -

The concept of Good Manufacturing Practice (GMP) in the, medical device industry requires the use of controlled methods,'ahd equipment in performing each step in the device manufacturing process. Quality Assurance programs are used to maintain compliance with GMP requirements by prescribing the operating and control procedures to be used. The specific elements of a Quality Assurance program for the radiation sterilization of medical devices are described.

~" -'•''•' ••-• INTERNATIONAL ATOMIC^ ENERGYÂGENCYg^!A^^ NATIONAL EXECUTIVE MANAGEMENT SEMINARS ON

RADIATION STERILIZATION OF MEDICAL PRODUCTS

LECTURE : RADIATION STERILIZATION OF BIOLOGICAL TISSUES

PROFESSOR GLYN 0 . PHILLIPS THE NORTH EAST WALES INSTITUTE. CLWYD. WALES. U.K.

SUMMARY OF PRESENTATION

After years of neg lec t , the value of s t e r i l e non-viable ( a l l o g r a f t ) t issue gra f ts in t ransplant surgery is now being recognised. S t e r i l i z a t i o n using y - r a d i a t i o n Is now becoming the method of choice for a wide range of t issues In a spectrua of Hunan Tissue banks throughout the wor ld . The rad ia t ion treatment can i n i t i a t e physical and chemical damage in the t i s s u e s . Where necessary methods of protect ion have been developed. Examples are given of the successful u t i l i s a t i o n of r a d i a t i o n for t issue s t e r i l i z a t i o n and use.

1 . Emergence of Non-Viable Tissue ( A l l o g r a f t ) Transplantat ion .

The modern era of transplantation started with the work of Gaspare Tagliacozzi (1545-1599) who describes In his classical work "The Surgery of Muti 1 Isatlon by Grafting" the way In which a skin f lap from the forearm (autograf t ) , could be attached to a mutilated nose (autograf t ) , severing i ts original connections some weeks la ter . Tagliacozzi seemed to reject the.yse of al lografts because of the "force and power" of the individual. I t was 350 years later that this "force and power" was to be recognised as a major biological phenomenon and the rejection of tissue al lografts accepted as the rule rather than the exception.

The work of H'jnter in the 19th Century heralded a revival in surgery and Interest In skin grafting and transplantation. He f i r s t used the term "transplant", by analogy with grafting In the plant kingdom. ,

Tagliacozzi's work was revived In the Igth Century. Carpue reintroduced the forehead flaps method for replacing a destroyed nose. In 1869 the crucial factor in the success of human skin grafting was discovered, namely that the skin had to be th in . The success of autografts led to extensive use of al lografts and even xenografts. ,:>;-The: claims recorded for success were later shown to be erroneous, since epi thel ia l isat ion can occur under a rejected graft by Ingrowth from the sides, and this new skin can be confused with successful graf t ing . Schone and Lexer in the early 20th Century stated, c lear ly , that rejection of an a l lograf t was inevitable and Jensen suggested ( I903) that rejection.was an immunological; event. Medawar (I9M») was the f i r s t to show experimentally that the rejection of skin al lografts In heterogeneous rabbits had the defining characteristics of actively acquired Immunity.

The modern era has been consumed with Immunogology. The f inal death blow.to allografts came In the work of peter B,Medawar and Thomas Gibson In the MRC Burns Unit at Glasgow, who showed that a "second set" of skin g r a f t s ; from a particular patient could be rejected more quickly^ than the

.'.•.first'set. •''' .' "' /,'y';-'j::%---\'> -,'-, y ,

Experience of the past 20 years has shown that this Judgement was premature, but is still influencing some surgeons in their attitude to the use of allografts. Now allografts are in routine use.

Burwell (I963) listed the requirements for the success of human allograft as followsi-

a) The bone must be Immunologically inerti b) It must be inductively active» c) It should be capable of rapid resorption» d) tt must be planted In a vascular site and capable of vascularIsatlon e) It should be Implanted In close associitiun with osteoblasts (or in

areas of cancellous bone) or with cells having a high osteogenic potential (red marrow)j

f) It must be sterile.

Recently tnmunosuppression has been used to reduce the response to massive osteochondral allografts and the present situation may be summarlsedi-

a) Allografts of fresh cortical bone are weakly antigenic) b) Allografts of red marrow are intensely antigenic) 0) The treatment of marrow containing iliac bone by physical and chemical

methods influences the antigenicity.

A similar approach is being used with skin allo-transplantation ,

Ionizing radiation is now proving a particularly suitable method of sterilization because of (i) availability of penetration] (II) It induces no rise in temperature and ( H i ) might even reduce further the antigenicity of processed grafts. The wheel has indeed gone full circle.

2. Tissue Banking

Throughout .the world, several types of Tissue Banking facilities have been established. Some process and store all forms of tissue. Others specialise in a specific tissue, e.g. skin, bone, blood or cornea. There are, in addition, facilities that are not really Banks, but reference and collection centres. In 1975, some 30 centres around the world were concerned with tissue conservation for surgical procedures. At that time, however, few Tissue Banks existed outside Europe and the United States. However, during the past decade, the Importance of Tissue Banking In other parts of the world has been realised. Practices vary considerably, but to prepare suitable allografts all must»

a) procure the tissue from a suitable donort b) process, sterilize, package and store the tissue.

Oetails of accepted practices will be available at the Seminar. The following procedures by Triantafyllou for bone allografts are I1lustrativet

1. Removal of the specimen from fresh cadaver donors or amputated limbs» 2. Cleaning and washing of the specimen» 3« Deep freezing (-35° C)» *».,.__ Freeze drying, 5i Sterilization by gamma radiation (3.3 Mrads)» 6. Storing for 15 days» 7» Grafts ready for transplantation.

3- Radiation Effects on Tissues and Protection frow Damage

Only by understanding the mechanism of Interaction of Ionizing radiations with tissue systems Is it possible to establish the types of damage which occur, and find methods to reduce such damage to acceptable levels. Here the stages of damage In a wide ranging study of various tissues will be outlined.

3«1 Free radical formation

For Y-lrradlatlon of hard-tissue components, of which bone and tendon are suitable examples, free radicals associated with the Inorganic calcium phosphate matrix and organic collagen component can be identified (Appendix I). The radical POi," , formed by electron ejection from the P0„"3

ion, is responsible for these main features. Damage occurs In collagen randomly along the main peptide chains, and relatively few radicals are formed In the side chains of the amino acid residues. Major changes can be related to the loss of a hydrogen atom bonded to the a carbon atom in a glycine residue. Generally, the collagen component is much more stable (G radical - 0.3) than the inorganic structure, which can mainly be identified as the moiety which gives rise to the loss of strength on Y-lrradiatlon. The free radicals so Identified are useful in following bone graft resorption, creeping substitution and new bone formation.

3*2 Mechanical and Operation Properties

Apart from the radiation treatment, other stages in the preservation such as freezing, lyophi1izatlon can also influence the mechanical properties of tissues. Appendices 2 and 3 show the behaviour of skin during radiation treatment. The Increased diffusion of 2ZNa following radiation is another parameter which Illustrates the gradual disintegration of tissue membranes on y-lrradiatlon. These changes are mainly due to the breakdown of the carbohydrate ground substance component rather than the protein fibres of the connective tissue. Now, using methods which were employed to protect such glycosamlnog 1 yeans. It has been possible also to protect whole tissues to radiation damage (Appendix A).

3*3 Chemical Changes

It is now possible to relate the physical changes on irradiation to chemical effects at the molecular level. Successively/ it. has been possible to build up from simple carbohydrates, to complex polysaccharides (e.g. glycosamlnog 1 yeans), and protein-polysaccharldes such as chondromucoprotein (CMP), a viscous gel extracted from bovine nasal cartilage. In the tissue CMP is linked to collagen. Now using energy and radical scavenging even whole tissue can be protected as shown in Appendix 5 using human costal cartilage.

During the processing operations (1-4 above) it is also necessary to establish reproducible quality control procedures wh'^h define the chemical state of the tissues, particularly the nature of the; protein components of bone. One specific protein must be retained if new bone growth is to be induced by the graft.

k. Examples in Clinical Use

An Increasing number of Tissue Banks throughout the world have routinely used ionizing radiation to sterilise their tissues. A full review of this subject is available, (reference 6). Examples are a) Yorkshire Tissue Bank, U.K. i b) Central Tissue Bank of Poland t c) Czechoslovakia Tissue Bank at Hradec Kralove ; d) Bethesda Naval Tissue Bank, USA t e) Democritos Tissue Bank, Greece ; f) Burma Tissue Bank, Rangoon. There are also a number of emerging Tissue Banks in South East Asia forming part of IAEA Coordinated Research Programme. Examples will be discussed during the Seminar. In this summary details of only one of the many different types of the operations performed by the distinguished surgeon, Dr.U.Pe Khin is described in order to underline the usefulness of one of the sterilised human tissues in transplantation surgery:

"The ulnar nerve of a patient wad been severed in a knife attack and as a consequence, no flexing of the wrist was possible. Dissection exposed the severed nerve and tendon (Figure l). The graft was rehydrated and a section selected to replace the useless and missing sections of ulnar nerve (Figure 2). With delicate suturing using magnifying lenses, the graft and nerve were joined. A section of the patient's fascia lata fro* the right thigh was also removed (Figures 3 & k) and used as a bandage to cover the junctions of the graft and nerve (Figures 5 6 6), this reduces the probability of fibrous tissue growing into the junction. The operation enables the transplanted graft to be a bridge through which the host nerve can regenerate without inducing adverse immune reactions. The operation and prognosis were satisfactory. Sensation returned to the extremities of the fingers".

5. CONCLUSION

Ionizing radiations can be efficiently used, either alone or in association with more conventional procedures for the sterilization of tissues and these subsequently successfully used for transplant surgery.

6 . SELECTED REFERENCES

1 . GENERAL PRACTICES

Radiation Sterilizations Irradiated Tissues and Their potential Clinical Use (1978) Edited by G.O.Phillips, A.Tallentire and N.Triantafyllou. Published by The North East Wales Institute, Clwyd, U.K.

2. PROCEDURES (CLINICAL)

Tissue Banking for Transplantation (1976), Edited by K.W.Sell and G.E.Friedlander, published by Grune and Stratton, New York.

3. PROCEDURES (PROCESSING)

Tissue Grafts for Surgical Use (I983), Edited by F.Dexter, Yorkshire Regional Tissue Bank. Published by Clwyd County Counci1.

RADIATION PROTECTION

(a) Principle High Energy Radiation Stabilization of Cellulose Obtained by Esterifying with Benzoyl Chloride.

US Patent No.3519382 (1970) J.C.Arthur Jnr., F.A.Blouin, T.Mares, D.J.Stanonis, G.O.Phillips, and H.M.Sarkar.

(b) Chemical Level Radiation Protection of Hyaluronic Acid in the Solid State (1975). Radiation Research, 6^, 573-580, G.Armand, P.J.Baugh, E.A.Balazs, and G.O.Phillips.

(c) Tissues (a) Radiation Sterilization and Protection of Human Costal.Cartilage. G.O.Phillips, H.E.Edwards and J.S.Moore, in Radiation Sterilization i Irradiated Tissues and their Potential Clinical Use (1978). Edited by G.O.Phillips, A.Tallentire and. N.Triantafyllou, North East Wales Institute, Clwyd, U.K. PP.U7-I59.

(b) Radiation Effects on Human Tissues and Their Use in Tissue Banking. H.E.Edwards and G.O.Phillips (I983), Radiat.Phyis.Chem., 22_ 889-900.

CHEMICAL CHANGE

(a) Effects of Co Y-ieradiation on chondromucoprotein. H.E.Edwards, J.S-Moore and G.O.Phillips (1977). Int.J. Radiat.Biol., 3_2, 351-359«

(b) Chemical Effects of y-irradiation of Aqueous Solutions of Heparin and Keratan Sulphate. F.Jooyandeh, J.S.Moore, R.E.Morgan and G.O.Phillips 0 9 7 8 ) . Radiat.Res., j£,-J455-J.61 .

(c) Chemical Effects of Y-irradiation of Aqueous Solutions of Chondroitin-*4-Sulphate. J.S.Moore, G.O.Phillips and D.Rhys. CI 973). Int. J, Radiat.Biol., 23, H 3 - H 9 -

RADIATION STERILIZATION OF TISSUES

G.O.Phillips in Biological Principles of Tissue Banking by R.Klen (1982) Pergamon Press, Oxford, pp.117-123-

,#fdt&*i#t)rikM£a »**•.

FIGURE 1

FIGURE 2

FIGURE 3

FIGURE k

FIGURE 5

FIGURE 6

gi o - gi APPENDIX I

ESR spectrum of calcium phosphate after y-'rradiation. Insert a: high field line from atomic hydrogen. Insert'b: sample heated to 550 K before irradiation.

0 . 2 5 M rad

0 . 5

Y ie ld -dose p l o t f o r y - i r r a d i a t e d c o l l a g e n a t 300 K. Inset:'.'...ESR spectrum o f p a r t i a l l y deu te ra tad c o l l a g e n a f t e r Y " i r r a d i a t i o n . "

(N/m

m ^

tu

re

rup

i

•*-• m

ress

_7.

6

5

4

3

2

- I

"I

m

-

CO

0 0 1000 •2000

DOSE (rads)

APPEND rx^rr '^-- ; :

Changes in stress at rupture of rat ski n at 50 days (a) and 120 days (b) after Y-irrad iat ion.

J 3 0 0 0

o

APPENDIX III Relationship between load and extension for skin given various radiation doses.

Normal Skin

1000 rads

2 0 0 0 rads

- 3 0 0 0 rads

Extension (mm)

'«•**

APPENDIX IV

"-' 4.5,

Dose (Hrads)

EFfects of o 0Co y-l rraciatIon on the diffusion coefficients of 22Na through visceral peritoneal membrane. .

0 Membrane

8 Membrane in saline

• Membrane impregnated with CPC

Membrane impregnated with DBTAC

APPENDIX1V

Dose (x 10 2 °eV/g)

Changes, in hexose c o n t e n t o f human c o s t a l c a r t i l a g e f o l l o w i n g 6 0 C o - Y " i r r a d i a t i o n 0 ; no d e t e r g e n t s . I ; c e t y l p y r i d in ium c h l o r i d e . • ; d o d e c y l - b e n z y 1 -t r i m e t h y 1 ammonium b romide . • ; ethylammonium bromide . <S; ,dodecy l -py r id in ium b rom ide . 4 ; c e t y l t r i m e t h y l e t h y l a m m o n i u m b romide . , :•

•»rv

PROBIEWS AMD STRATEGY FOR TRANSFER OF RADIATION STERILISATION TECHNOLOGY

Dr.V.K.m.

Savaral problems have to be considered and several

questions answered in examining the question of technology

transfer to a developing country. This is all the more

important uhen it is a question of a high technology like

radiation sterilisation and involves nuclear energy*

What is the need for this technology in the country ?

The ansusr to this involves considerations of current level

of medical technology and the production of medical supplies

in the country. A critical, factor is whether and hou these

products are produced or assembled in the country and what the

sterilisation practices are* Once the need for introducing

radiation sterilisation in the country is established, it

is necessary to carry out a project report indicating the

tachno-economic implications of getting up a plant. The social,V

benefits of such a project although they may be difficult to : *;

quantify, should be brought out. A detaiLad market survey, of |

products amenable to radiation sterilisation in the country

should also be made at an early stage. _;•.• ";;' |

/2/

A decision to sat up a radiation sterilisation

plant either in the public or private sector, will depend

on hoy the funds are made available for the project. Various

alternatives of funding may ba explored and the major atapa

involved in setting up such a project from the planning to

the commissioning stage, including the problems peculiar

to developing countries should ba brought out in detail.

These aspects will be described through the presentation of

case studies. A detailed analysis of the Strength - Weaknesses»

Opportunities & Threats (SUQT analysis) in introducing a neu

technology like radiation sterilisation to a developing

country should also be made. Finally one should keep in mind

the importance of keeping the public fully informed of the

benefits of radiation sterilisation plant» This will help

to prevent the spread of undue alarm regarding radiation, arid,

at the saas time, promote the market and the right image of

this technology. The role of national and international

seminars, conferences and exhibitions in this regard is

significant.

il,-:-,..'-. ',•••;•,!.•;.- ,/.,,

UTH'3 GAMMA IRRADIATION FACILITY»

DESIGN AND CONCEPT

fll : IR. MUHD NOOR BIN MUHD YUNUS

Abstract

• . UTN is building a multipurpose gamma

irradiation facility Which comprises of

.research and pilot scale irradiation cells

in The Fifth Malaysia' Plan* The paper high

lights the basic features of the facility in'

terms of it's design and selection including

..layout sketches. Plant performances and

limitations are discussed. Plants safety is

briefly highlighted in block diagrams.

Lastly, a typical specification brief is

tabled in appendix for reference purposes».

1*0 general

In the Fifth Malaysia Plan, UTN's la planning to build a gamma irradiation facility to facilitate research works like food preservation/; improving timber quality, treatment of waste etc* and at^the same time offering services in sterilisation of disposable medical products.

The planning of this facility started back'in late 1984 at management level, followed by the setting up of a design team in Hay 1985« The plant is now being tendered at international level. The civil works, inclusive of shielding system, and other prime cost items are to be called soon. It is expected that the facility would be available for services by end of 1987 or early 1988.

.The facility comprises of two cells standing side by side sharing one common wall and adjoined by one common pool. One cell is to be used fully for research, thus -the name Jte£eerch^.Celi tRC) and the.other is the SemipCommercial "Ceil (sec) which offers service and pilot scale research irradiation. The pool is interconnected between the two cell to accomodate source'loading and transfer.

Both, cells are of panoramic type, catergory IV as defined in ANSI N43.10, with 2MC1 and 1 MCi shielding design capacity for pilot and research cell respectively. The pilot cell which is equiped with source pass mechanism is a multipurpose facility suitable for food and disposable medical product irradiation.

2.0 Design Features

2.1 Seml^Commercial Cell (SCO

2.1.1. Cell construction

The cell, having internal dimension of 5m(W) x 7m(L) x 3.5m(H) is depicted in Fig. i.O of the appendix. The primary wall thickness is about 1.9 m, based on average external surface exposure rate of 0.25 mR/hr. The maze;is .shaped in such a manner to Allow for product and personnel,entrance during maintenance, product loading etc., and at the same tine reducing the scattered radiation to permissible level at the entrance door during operation. The. source;is normally stored in 7m deep pool and thus sufficient?to shield the source to permissible level. The water is treated ;to.i.,, conductivities of better than 10*.5iemen/cm to prevent source cladding corrosion. The pool lining, made of stainless'i.N;; steĕl materi&l, is used to prevent water seepagetlost.}«All %v materials used underwater are of the same type; to prevent.;.; '-'•<[•

/ catholic corrosion effect on source cladding which"might;in- ;

•oucea ahcgpaulation integrity.

Ill*' roof is provided with celling hatch to allow for •ourca ca«k loading and unloading. .A'hoist, of,; about 6 ton capacity in provided on top of the cell to facilitate these operations! Wall penetrations or sleeves are provided on one of the walls to facilitate introduction of services (e.g. gas, liquids, etc.) into the cell for experimental purposes. An Ozone ventilation extractor serves to reduce the ozone level to permissible TLVs» A provision for an air conditioning supply outlet also being planned to facilitate food irradiation experiments.

2.1.2 Source and source racks

The radioisotope used is Co-60 and a typical AECL C-188 source pencils is specified for this plant. The source is arranged in two plaque shape racksj having total capacity of 1000 cobalt Dencils. Bach rack is divided into 12 modules and each module could take 42 pencils in a panel. Two racks design is prefered for flexibility of varying the dose rate to suit a variety of research requirements. The racks is independently operated and a combination of selection could be offered for different purposes. The source is arranged to " give a source overlap design. This is selected against the product overlap design, though this would, result in reduced Co-60 efficiency, to avoid complicated source pass mechanism and thus uneconomic, initially, and at the same time a reasonable dose uniformity could be achieved. The racks are driven up and down by pneumatic winch with safety interlocks.

2.1.3 Source pass mechanism

A two pass, source overlap batch type with overhead carriers made of aluminium is expected to be installed.for-the source pass mechanism. Pneumatic cylinders are. used "to'"push""' the carriers from one position to another,, around the, source plaque, at predetermined intervals. The time intervals ; are '<-.i

..correlated with the.dose recieved by the products.and ,4 ..;•,>,;,,/. accumulated to the desired dose.when the product undergone one complete round around the source. . .. ..

The minimum dose rec«ived by the product is determined by the speed.of the pneumatic cylinder. Dose of 6000 Rads is expected with cylinders set at maximum speed. The products are loaded, by stacking the boxes into the carriers, pushed into the cell and arrange in its resting nosition manually.;..

..Once in position, the source pass mechanism operates continiously on its own until the desired dose is achieved.

* Each carrier could accomodate boxes weighing up to 700 kq., inclusive of its own weight.

. . ... A two pass-system is selected, though at; a .-lost -of , ••-. ..... Cor60 efficiency for reason that the product hold up .volume., .,..'

is small and thus suitable for small throughput typical,.to.-pilot scale plants.

•4 Plant p<»rf dn—nce

As the plant is of multipurpose, source overlap, two pass type, the efficiency of Co-60 energy utilisation naturally would not be as high as a dedicated one product-commercial irradiator. Co-60 energy utilisation efficiency of 10% for medical disposable products of 0.1 g/cc (density) -is expected, with this plant. Highest energy efficiency is achieved-with spice having density of 0.44 g/cc which corresponds to 26%.

As far as uniformity is concerned, the highest achieable from the plant is 1.3 if loaded full width of the carrier for 0.1 g/cc density medical Droducts. Uniformity of 1.1 might be achieved with sacrifice in energy utilisation efficiency. Uniformities of 2.5 is achievable for food products.

Plant utilisation efficiency could not be predicted as the plant is a multipurpose type and not yet in operation.

Schedule of typical olant performance expected from the plant is.shown in Table 1.0 attached.

There are provisions in cell design to improve the-plant efficiency and uniformity in the future as follows:-,

(a) Doubling the passes.

(b) Using product overlap design which require shufflinq mechanism.

(c) Automatic conveyor system.

Research Cell (RC)

Cell construction

The cell, having internal dimension of 4.5 m(W) x 5m(L) x 4m(H)"basically houses the pool, source rack mechanism, irradiation bench and a l*$ton manual hoist. The useable length of the cell for low dose irradiation is not limited to only 5m as mentioned in the room size but extended beyond the maze leg for another 2.5 m making the maximum wall to source distance of 5.7 m, thus reducing the dose rate at the wall to aoproximately 32 times. The cell is designed for1 a maximum activity of 1 MCi Co-60 with primary wall, thickness of about 1.8 m, which corresponds to an average,surface dose of 0.25 mR/hr. external to the wall. The maze is designed to reduce the scatter radiation to the allowable amount at the' entrance door.' The source is normally stored underneath the water, 7m deep pool >• which ad joints to the SCC.

The stainless steel irradiation bench is marked with grid lines to guide the plotting of isodose lines. The bench also designed'to take small scale source pass mechanism in the-.future.'-. •.. l"•• Space/is; alsbjailbwed':in the. cell, for' licuid irradiation, including .the placement of small size' tank.' .;'..:

As the cell is -designed for research activities, ..services';arid '

instrumentation sleeves are-provided.on t&a-wtlls..of.the cells. A' local ventilation hood made of stainless steel is provided within the cell to facilitate the venting of corrosive off- gas produced as a result of radiolysis of some products. The pool is equipped with surface skimmer to skinh the "dissolved cbrrossive gases that might be produced within the cell. Apart from that, normal ozone extractor and other services identical to SCC are provided in the research cell.

3.2 Source and source rack

The isotope used in the research cell is also Co-;60..':•,.-. AECL C-188 Co-60 pencils are typical for this cell. The rack design is almost' similar to pilot cell accept that the rack height is of only one source pencil in length, comprises of only eight module and each module contains 10 pencils. Thus, based on 6000 Ci per pencil in one loading the maximum rack capacity is only 480 kCi compared to 6 MCi for pilot cell. Single rack is adequate, since the source numbers per module is variable, thus the source strength consequently could be varied. Source rack actuation is similar to the pilot cell. Source strength of 50 kCi is expected to be installed innitially for research cell.

Non utilised source panels are normally stored in the" stoker underneath the water.

3.3 Plant performance

The main criteria for the research cell design is the dose rate.•'Dose rates-are specified according to the anticipated research works to be carried out. Table 2.0 indicates* the range of dose rates and the type of research works to be carried out.

In general, the dose rates required for the research works ranges' from 100 Rad/miri for mutation breeding to 5 x 10' Rad/hr. for irradiation of polymeric materials.

To meet such a vast range, a lot of thought and-compromise should be given, among them were:- v

(a) Varyinq the source strength

(b) Varying the distance

(c) Using filters like lead material or equivalent.

1 The source strength could be varied by using interchangeable, preloaded source panels. Source panels containing, as low as 1000 Ci could be used for mutation breeding works. On the other hand, a 50 kCi source could be exposed upon combining .... and loading all the Danels into the rack.

Distance is also used to vary the dose rate by'virtue of ' • inverse-square law. . As'mentioned earlier, dose reduction in-access' • of thirty time is. expected at the furthest Doint from the. source .;'. pencils..-: ...;-.'v. -. .-•..-. .•••'::•:'V. "• •

"Lead filters may be desired to cut down further the dose:.-...... •

rate for low dose irradiation. This technique only applicable for nonvenergy, dependent type of research. However, for.,extremely,,: low do4e retirements, it is not practical, to use this cell as it is .. designedaf or ..specif ie juse only.

Thus upon combining the three factors above it is possible to meet the design requirements.

Plant Safety

Safety concept

In building the facility the following concept should be adhered to with regard to safety:-

(a) Plant shall be designed, manufactured, constructed and tested to safety standards.

(b) Plant shall be operated and maintained to safety standards.

Plant safety design and operation is based on ANSI N43.10 - 1984, as a minimum safety features to be incorporated into the plant. Concrete shielding design shall follow ANSI NlOl-6-1972. Shielding construction and testing shall follow various ACI standards or equivalent. Welding of components shall comply to various AWS standards specified in tender documents. Proper -quality assuarance shall be observed through out the entire project management. Beside these, operational, administrative and maintenance proceedures also shall be established and adhered to. Various regulations pertaining to transport of radioactive sources, handling of source and operating licenses shall be .-obtained from respective regulatory body like AELB of Malaysia etc. In fact standards, codes of practice and other safety=standards having direct implication on the plant safety are specified and to be observed during project execution.

. A typical safety interlock for the plant is attached in appendix 1.0 for references.

Other Services And Features

Other features not mentioned above could be deduced from the brief specification of the plant attached in the appendix 2.0

Conclusion

The facility is designed to cciter the r.eeas. of .research activities, and .as. well as providing .•irradiation services tb thie industries "and hopefully it will' become" a versatile."facility. .

From the features discussed, it is expected the».Semi-Commercial. Cell would be justifiably utilised i.e., neither .too smair"ribr/tob'r big.;-/:/;

TABLE 1.0

SCHEDULE OF PERFORMANCE OF THE SCC IRRADIATOR

Products

Onions

Rice/Grain

Papaya

Frozen Shrimp

Spices

Medical product

Product weight Per carrier

(kg)

444

555

333

665

444

111

Product Density (g/cm3)

0.4

0.5

0.3

0.6

0.4

0.1

Minimum Dose (KRad)

15

20

25

300

600

2500

Co-60 efficiency (min)

12%

16%

13%

26%

25%

10%

U Uniformity

1.4

1.5

1.3

1.6

1.4

1.3

Through-put kg/hr per

200kCi, Co-60

8,600

8,500

5,500

930

440

42

. • 1 :

H$Mote: 1).. Plant shall be designed to give optimun efficiency and uniformity. ,.TV : • 2); Maximum dose uniformity allowed is 2.5 • 1 > p ":.["' 3); The throughput is based on?product centred in the carriers resulting .•;:'. :: in maximum product stack dimensions as follows:

• <••• ••',• f ~ i '- • .'• *

i . Length - 900 mm Width - 560 mm Height - 1100 mm Volume - 0.554 .Volume per carrier - 1.109 m3

4) The accuracy of the values shown is ± 10%.

for the purpose of pilot Irradiation studies of food products. No< doubt, the.plant is also capable of. giving services in medical product sterilisation with reasonably good throughput of 3360 m / yr,~ without changing the plant features.

For research cell, it is" possible to meet the demand for low as well as high ..dose rate irradiation up to midget scale for s-various products. The plant, with slight modification, could be upgraded to pilot scale in future. £; '.':

TABLE 2.0

SCHEDULE OF PERFORMANCE FOR RESEARCH IRRADIATOR

\

1.

2.

3.

4.

5.

6.

7.

8.

Project

Grafting of Vinyl Monomer(s) onto Polymers (fibres)•

Graft Coplymerisation of Vinyl Monomers on to Natural Rubber.

Irradiation Effects on Polymeric Materials.

Wood Polymer Composites

Food Irradiation

Mutation Breeding

Vulcanisation of Natural Rubber Latex

Reutilization of Palm Oil Wastes

Dose

Min.

1 x 104 rad/hr

1 x 104 r ad Air

1 x 103 rad/hr

1 x 104 rad/hr

2.4 krad/h

100 rad/min

1 x 104 rad/hr

0.1 Mrad/hr

Rate

Max.

2 x 106 rad/hr

2 x 106 rad/hr

5 x 106 rad/hr

1 x 106 rad/hr

2 Mrad/hr

1000 rad/min

1 x 106 rad/hr

10 Mrad/hr

Total Dose (Mrad)

30

30 '

50 Mrad

2-20 Mrad

30 kGy

0.1 - 100 Krad

5 Mrad

50 Mrad

Appendix : 1.0

Some Typical Safety Interlock

System Of The Plant

Plant Condition/Status Plant Intermediate Action Plant .Pinal Action

Radiation monitor : above normal/of f/mulfunction

Power failure «off*

Pool water below present l e v e l

Emergency n u l l cable

Fire alarm

Ventilation "off"

Source pass mechanism mulfunction

Overdose timer

Air Pressure "Low"

Roof hatch opened

Maze entrance chain not secured

Access door cannot 'be oDened

H Source down

Plant shut down

Source pass mechanism stoD

Source down

m I Abort plant , operation

! Ventilation |-

"off" Plant shut down

Source down Plant shut down

Source pass mechanism L mechanism stoo

Source down

_ j Abort plant i operation

r Source down Abort Dlant , ! ooeration 1__ J

^ ^ :• • ••: '^w^mmmm TYPICAL SPECIFICATION OF UTNs

GAMMA IRRADIATION FACILITY

1.0 Building

1.1 Warehouse:

Steel structure warehouse, 42 m(L) x 26 m(W) or 1092 m

floor area.

1.2 Irradiation Cell

a) .SCGrwith batch type source pass mechanism.

Internal dimension : 5 m(W) x 7 m(L) x 3.5 m (H).

Shielding capacity : 2 MCi. of Co-60

Shielding material : Normal concrete /* = 2.35

Thickness of shielding J 1.9 m

b) RC~with standing irradiation bench.

Internal dimension : 4.5 m(W) x 5 m (L) x 4 m(H)

max. source to wall distance is

5.7 m.

Shielding capacity .: 1 MCi of Co-60

Shielding material : Normal concrete /0 « 2,35

Thickness of shielding wall : 1.8 m

1.3 Source Storage Pool

Interconnected type.

Caoacity of source storage • 2 KCi

Water depth = 7m.

Water volume = 100 m

Water quality = Deionised, lO/^S/cm or better.

0 Sotircg-Moving Mechanism

2 . 1 sec

Two numbers, independently operated rack, hoisted by

pneumaticAydraulic/motor winch and guided by taut cables .

Rated capacity = 1008 penc i l s maximum.

No. of modules/" = 2 x 12 modules.

No. o f pancils/module = 42

Dimension = 2 .7 m(H) x 1 m(w)/rack.

Total weight = 184.4 kg/rack

Source rack lifting - distance - + 7 m.

Lifting speed = ~ 6 cm/sec.

2.2 RC

Single rack, hoisted by pneumatic/hydraulic/motor winch and

guided by taut cables.

Rated capacity = 80 pencils

No. of modules = 8

No. of pencils/module = 10

Dimension « 0.5 m(H) x 1.3 m(W)

Total weight = 100 kg.

Source rack lifting distance = + 7m

Lifting speed = — 6 cm/sec.

Control Equipment

One control console for each cell.

Interlocking element :

Radiation detector

Power

Water level

Emergency switch

Ventilation

(Normal . Off . Mulfunction)

(Normal . Essential . Failure)

(Low . Normal . High)

(Personell in . Pcrsonell out)

(ON . OFF)

Position of source rack : (Up . intermediate . down)

Access door

Ceiling hatch

Air pressure

(Opened . Closed)

(Opened . Closed)

(Low . Normal)

Source pass mechanism : (OKAY . MULFUNCTION)

- ' • ' - . • . ' • • • • . ' • • • • • j , ; :*3? l

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Master tlaer : (OKAY . MULFUNCTION)

Maze entrance chain : (Opened . closed)

4.0 Gamma Ray Detector

Gamma ray ionisation chamber 2 units/cell.

5.0 Source Pass Mechanifsm (i>CC only)

- Batch type, source overlap design, hanging carriers, actuated

pneumatically/electrically/hydraulically.

- Dwell and run system.

Weight/carrier : 700 kg.

Dimension of carrier : 0.915(L) x 0.585CW) x 1.143(H)

No. of compartment : 2

Total number of carriers : 9

No. of Dasses : 2

. . . (Future provision : 4 passes and oroduct shuffling)

6.0 Services

Air Conditioner - provision

Ventilation — 1 set *

Water treatment system - 1 set, dual outlet

Stand by generator - 1 set

Air compressor - 1 set

6 ton hoist (above SCO - 1 set

1H ton manual hoist (within KO '- . l set ' • • . ' •

Pool cleanino equipment - ,1 set

Irradiation bench - 1 set-

Documents

Seminar Pengurusan Eksekutif Pengsterilisasi Barangan