ALCOHOL IN PHARMACEUTICAL PRODUCTS DZULKIFLY MAT HASHIM.

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2 ALCOHOL IN PHARMACEUTICAL PRODUCTS DZULKIFLY MAT HASHIM HALAL PHARMACEUTICAL FORUM, PULLMAN BANGSAR HOTEL, 29 Sept 2018

3 CONTENT OF THE DECISION (SIGHAH) ON ALCOHOL IN FOOD & DRINK, PERFUMES AND PHARMACEUTICAL PRODUCTS (2011)

4 FATWA (LEGAL RULING) ON ALCOHOL IN FOOD & DRINK, PERFUMES AND PHARMACEUTICAL PRODUCTS (2011) The National Fatwa Council for Islamic Religious Affairs Malaysia discussed the issue of alcohol in food, drinks, perfumes and medicines on the 14th to 16th July, 2011 and reached the following decisions: 6. Food or drinks with flavouring or colouring that contains alcohol for stabilisation purposes are permissible to be consumed provided that the alcohol is not produced from the winemaking process, the quantity of such alcohol in the final product is not intoxicating and the alcohol level does not exceed 0.5% 5. Food or beverages containing natural alcohol such as fruits, nuts, grains or their juices, or alcohol that incidentally forms during the production process of certain food or beverages is not considered impure and is permissible to be consumed 1. Every wine contains alcohol. However, not all alcohol are intoxicants. Alcohol that is extracted from the winemaking process is ruled as prohibited (haram) and impure 7. Medicines and perfumes containing alcohol as a solvent is not impure (Najs) and are permissible provided such alcohol is not extracted from the winemaking process 4. A beverage made with the intention and method of producing wine, regardless of whether its alcohol content is high or low or whether their alcohol content removed by distillation or evaporation, its consumption is prohibited 2. Alcohol that is not produced through the winemaking process is not ruled as impure (Najs), but is prohibited (haram) to be consumed in its original form as it is poisonous and can kill 3. Light beverages processed/made not for the purpose of producing wine and containing alcohol below the level of 1% v/v are permissible to be consumed

5 ALCOHOL IN PERFUMES AND PHARMACEUTICALS 7. Medicines and perfumes containing alcohol as a solvent agent are not impure (Najs) and are permissible provided such alcohol is not extracted from the winemaking process.

6 What should be the alcohol content from a halal (Shariah) standpoint for pharmaceutical products? Malaysia (through any existing regulation on pharmaceutical products) does not have a standard on the shariah compliant (permissible) level of alcohol in pharma products Alcohol is permissible to be used in pharma products as long as it is not extracted from a brewery process (ethanol in alcoholic beverages may be obtained or separated through distillation or vacuum evaporation) The question is whether alcohol is a necessary excipient in pharma products?

7 ALCOHOL CONTENT OF SOME PHARMA PRODUCTS

8 MEDICATIONS CONTAINING ALCOHOL

9 QUESTION : SHOULD THE FDA PROPOSAL BE THE BASIS OF A HALAL COMPLIANT LEVEL FOR PHARMA PRODUCTS?

10 Should the FDA proposal be a basis?

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12 FROM A HALAL (SYARIAH) STANDPOINT, WHAT SHOULD BE THE APPROPRIATE ALCOHOL LEVEL FOR PHARMACEUTICAL PRODUCTS? Pharmacists and Islamic scholars can establish guidelines on the alcohol content of pharma products Need to consider whether the excipient (amount of ethanol as a solvent) is really necessary deliver the right efficacy of the pharma product Considerations are based on safety and shariah compliant factors of pharma products

13 QUESTION : WHAT IS THE BASIS OF THE GUIDELINE ON ALCOHOL IN FOOD AND DRINK?

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17 DEFINITION OF KHAMR (ARAK or INTOXICATING DRINK)

18 THE SYARIAH DEFINITION OF KHAMR (INTOXICATING DRINK)

19 MEANING OF KHAMR كل مسكر خمر وكل خمر حرام Anything that intoxicates is Khamr and all Khamr (intoxicant) is haram (prohibited)" (Hadith in Muslim)

20 USE OF KHAMR : Whether in Small or Large Quantity are Equally Prohibited The majority of Islamic scholars by consensus (ijma ) consider kham r as prohibited even though it is consumed in small quantity, whether it will cause intoxication or otherwise ما أسكر كثيره فقيله حرام Anything that intoxicates, whether it is consumed in large quantity or small quantity is (still) considered as haram" (Hadith narrated by Nasa 'i and Abu Daud)

21 THE PROHIBITION OF KHAMR IN AL-QUR'AN ي ا أ ي ه ا ال ذ ين آم ن وا إ ن م ا ال خ م ر و ال م ي س ر و ا ل نص اب و ا ل ز ل م ر ج س م ن ع م ل الش يط ا ن ف اج ت ن ب وه ل ع ل ك م ت ف ل ح ون O You who believe, verily kham r and gambling and idol worship and and chance of fate using arrows are deeds which are abhorred and deeds of the evil one. Avoid them so that you may be successful. (Surah Al-Maidah: verse 90)

22 MEANING OF KHAMR وكل مسكر خمر كل مسكر حرام Anything that intoxicates is Khamr and all Khamr (intoxicant) is haram (prohibited)" (Hadith in Muslim)

23 THE USE OF KHAMR The majority of scholars by consensus (ijma ) consider khamr as prohibited even though it is consumed in small quantity, whether it will cause intoxication or otherwise ما أسكر كثيره فقيله حرام Anything that intoxicates, whether it is consumed in large quantity or small quantity is (still) haram" (Hadith narrated by Nasa 'i and Abu Daud)

24 THE PROHIBITION OF KHAMR IN AL-QUR'AN : ي ا أ ي ه ا ال ذ ين آم ن وا إ ن م ا ال خ م ر و ال م ي س ر و ا ل نص اب و ا ل ز ل م ر ج س م ن ع م ل الش ي ط ان ف اج ت ن ب وه ل ع ل ك م ت ف ل ح و ن O You who believe, verily khamr and gambling and idol worship and and chance of fate using arrows are deeds which are abhorred and deeds of the evil one. Avoid them so that you may be successful. (Surah Al-Maidah: verse 90)

25 DEFINITION OF ETHANOL, ALCOHOLIC DRINK AND INTOXICANTS

26 DEFINITION OF KHAMR (INTOXICATING) AND INDUSTRIAL ETHANOL KHAM R Liquid Intoxicatan t Intoxicating Product of fermentation of fruits and cereals Ethanol is the component causing intoxication Najis (Najasa) Filth or impurity (Rijsun) INDUSTRIAL ALCOHOL ETHANOL Not an impurity, not a product of alcoholic beverage Solvent and cleaning agent Produced by fermentation of agriculture biomass Synthetically produced from byproduct of petroleum refinery

27 DEFINITION OF INTOXICATING DRINK IN MALAYSIA FOOD REGULATIONS (1985)

28 DEFINITION OF ALCOHOLIC BEVERAGE IN FOOD REGULATIONS (1985) : REGULATION 361(1-2)

29 SYARIAH CRIMINAL ENACTMENT (1995), STATE OF SELANGOR

30 SYARIAH CRIMINAL ENACTMENT (1995) SECTION 18(1), STATE OF SELANGOR

31 DEFINITION OF ALCOHOL AND ETHANOL

32 CHEMICAL DEFINITION From a chemistry perspective, Alcohol refers to any compound with a hydroxyl group ( OH) Examples: isopropanol methyl alcohol (methanol) butyl alcohol (butanol) propyl alcohol (propanol) sorbitol

33 CHEMICAL AND STRUCTURAL PROPERTIES OF ETHANOL Chemical name = Ethyl Alcohol Colourless Volatile Flammable Soluble in water Intoxicating Poisonous

34 INDUSTRIAL ALCOHOL Synthetic Alcohol Chemically Synthesized from Ethylene Process: 1. Indirect hydration through addition of sulfuric acid 2. Direct catalytic hydration of ethylene Agricultural Alcohol Derived from Biological Fermentation Process of Carbohydrate Source Fermentation of Sugar Fermentation of Starch

35 SYNTHETIC ALCOHOL DIRECT CATALYTIC HYDRATION OF ETHYLENE [H + ] H2C=CH2 + H2O C2H5OH ethylene ethanol» Ethylene is olefin produced from ethane-propane cracking.» Using phosphoric acid (H3PO4) as catalyst» Hydration occurs in gaseous phase

36 PRODUCTION OF INDUSTRIAL ALCOHOL

37 INDUSTRIAL ALCOHOL

38 INDUSTRIAL PRODUCTION OF ETHANOL FROM CORN

39 (Courtesy of Fermpro Sdn Bhd.)

40 DENATURED ALCOHOL Ethanol produced either from petrochemical or agricultural feedstock to which a denaturant, such as methyl alcohol, pyridine, denotorium has been added. The word denatured refers to the removal of a specific property to make it poisonous and undrinkable, as opposed to changing the ethanol chemically Other denaturants for industrial application: Isopropyl alcohol, gasoline, methyl ethyl ketone, chloroform, methyl-isobutyl ketone, denotonium benzoate.

41 APPLICATIONS OF ETHANOL Alcoholic beverage (present in) Solvent A chemical for laboratory use Fuel Industrial use Flavor carrier for the food industry A solvent for extraction of coloring compounds Solvent for extraction in pharmaceutical products Diluent for fragrance essences in perfumes

42 INTOXICATION

43 MODEL FOR METOBOLISM AND INTOXICATION OF ETHANOL Introduced by Erik Matteo Prochet Widmark ( ), a medical Professor and physiology expert from Sweden Wrote the book, Principles and Applications of Medico-legal Alcohol Determination (1932)

44 WIDMARK S FORMULA Where: N = No of drinks W = Body weight (oz.) r = Distribution volume = Widmark factor (L/kg) C t = BAC (for time) (kg/l) β = Kadar uraian (Kg/L/hr) t = time of drinking (jam) d = ethanol density = 0.82 (oz./fl.oz.) Z = amount of alcohol in a drink (fl. oz.)

45 WIDMARK S EQUATION Rearranging Widmark formula : C t = Blood Alcohol Concentration (BAC) (kg /L atau %) Reference : Gullberg, R.G. (2007). Estimating the uncertainty associated with Widmark s equation as commonly applied in forensic toxicology. Forensic Science International (2007) 172,

46 RELATIONSHIP BETWEEN BLOOD ALCOHOL CONTENT (%) AND STATE OF INTOXICATION *BAC (%) STAGE CLINICAL SYMPTOMS Sub-clinikal Normal behaviour Euphoria - Increased confidence, like to socialize, more talkative, sensory motor /happy disturbed, lack in attentiveness - Loss of self control, decreased ability to make good judgement Excitement /extremely happy - Emotionally unstable, loss of judgement - Disturbed perception, memory and speech Confusion /confused state - Loss of balance on standing, loss of self control, hallucination, headache, vision affected - State of confusion, emotionally disturbed, vision affected, weak, speech slurred, muscular movement uncoordinated Stupor /pressured - Motor function affected, cannot respond to stimulation, cannot stand and walk - Cannot control bowel function, vomiting, sleepy Coma - Unconscious, abnormal body temperature, uneven blood flow and respiration > 0.45 Death - Dead - Can cause death

47 MECHANISM OF ABSORPTION OF ETHANOL BY THE BODY Ethanol passes through the mouth and through the esophagus to the stomach and to the small intestine. Ethanol can be absorbed at any point of these body parts. It is estimated that ethanol is absorbed (estimated at 20%) and small intestine (estimated at 80%). Alcohol is then absorbed by the bloodstream Ethanol reaches the brain via the blood

48 KINETICS OF INTOXICATION

49 WIDMARK S FORMULA BAC will depend on state of fullness or hunger. BAC is doubled 2 in an empty stomach

50 INTOXICATING POTENCIES OF VARIOUS ALIPHATIC ALCOHOLS

51 APPLICATION OF WIDMARK FORMULA IN ESTIMATION OF STATE OF INTOXICATION

52 VOLUME (in ml) OF DRINK CONSUMED IN 1 HOUR BEFORE REACHING THE STATE OF INTOXICATION(BAC = 0.05 % W/V) * Assumptions Gender = Female Weight = 55kg Time = 1 hour Volume (ml) 1000 ** Faktor Widmark = * Based on the Widmark Formula Alcohol (%) ** The kidneys can optimally process around ml in 1 hour

53 AMOUNT CONSUMED BEFORE REACHING STATE OF INTOXICATION (BAC = 0.05% w/v) ALCOHOL CONTENT(%) VOLUME (ml) NO. OF GLASSES COMMENT , Not possible (X) , Not possible (X) , Not possible (X) 0.5 5, Not possible (X) Possible (/) / Not possible (X) Possible (/) Volume of one glass (mug) = 270 ml Volume of one glass (ordinary) = 165 ml

54 MALAYSIA MALE Average weight : 70 kg Average height : 165 cm Widmark factor (r) = 0.71

55 AMOUNT CONSUMED BEFORE REACHING STATE OF INTOXICATION (BAC = 0.05% w/v) ALCOHOL (%) VOLUME (ml) NO. OF GLASSES* COMMENT , Not Possible (0) , Not possible(0) , Not possible (0) , Not possible (0) , Not possible (0) ,160 8 Possible(1) Possible (1) *1 Glass = 270ml

56 VOLUME (ml) VOLUME (ml) CONSUMED BEFORE STATE OF INTOXICATION (BAC = 0.05% w/v) 1,000, ,000 81,000 40,500 8,100 4,050 2,160 1, ALCOHOL CONTENT (%)

57 MALAYSIA FEMALE Average weight : 50 kg Time = 1 jam Widmark factor (r) = 0.55

58 VOLUME CONSUMED BEFORE REACHING STATE OF INTOXICATION (BAC = 0.02% W/V) ALCOHOL CONTENT(%) VOLUME (ml) NO. OF GLASSES* COMMENT , Not Possible (0) , Not possible(0) , Not possible (0) ,430 9 Not possible (0) ,350 5 Not possible (0) Possible (1) Possible (1)

59 VOLUME (ml) AMOUNT CONSUMED BEFORE REACHING THE STATE OF INTOXICATION (BAC = 0.05% w/v) 1,000, ,100 62,100 31,050 1,000 6,210 3,240 1, ALCOHOL CONTENT (%)

60 MALAYSIA FEMALE Average weight : 60 kg Average height : 153 cm Widmark factor(r) = 0.63

61 Amount of drinks consumed (ml) before reaching the state of intoxication (BAC = 0.05% w/v) ALCOHOL CONTENT (%) VOLUME (ml) NO. OF GLASSES COMMENT , Not possible (0) , Not possible (0) , Not possible (0) , Not possible 0) , Not possible/possible (0) ,620 6 Possible (1) Possible (1) 1 Glass = 270 ml

62 VOLUME (ml) AMOUNT TAKEN IN 1 HR BEFORE REACHING STATE OF INTOXICATION (BAC = 0.05% w/v) 1,000, ,100 62,100 31,050 1,000 6,210 3,240 1, ALCOHOL CONTENT (%)

63 BAC (%) INCREASE IN BAC FOR MALE DUE TO CONSUMPTION OF DRINK CONTAINING ALCOHOL BLOOD ALCOHOL CONTENT ('REASONABLE MAN') NUMBER OF GLASS (x270 ml)

64 BAC (%) COMPARISON IN THE INCREASE OF BAC IN MALE AND FEMALE DUE TO CONSUMPTION OF DRINK CONTAINING ALCOHOL BLOOD ALCOHOL CONTENT(%) Lelaki Wanita NO. OF GLASS (x 270 ml)

65 BAC (%) COMPARISON OF INCREASE IN BAC DUE TO ACUTE AND PROPORTIONAL INTAKE FOR FEMALE COMPARISON OF INCREASE IN BAC DUE TO ACUTE INTAKE AND PROPORTIONALLY FOR FEMALE Secara Akut Secara Berkadar BILANGAN GELAS (x270 ml) Kandungan alkohol = 1% Isipadu = 1000ml Akut = Ambil mendadak (0 jam) Berkadar = Ambil dalam 1 jam

66 BAC (%) COMPARISON BETWEEN MALE AND FEMALE IN THE INCREASE OF BAC DUE TO ACUTE INTAKE OF A DRINK CONTAINING ALCOHOL 0.09 EFFECT ON THE BLOOD ALCOHOL CONTENT (BAC) Wanita Lelaki Alcohol content = 1% Volume = 1000ml Acute= immediate intake (0 hr) Proportional = taken in 1 hour ALCOHOL CONTENT(% v/v)

67 ISSUE # 1 If ethanol is produced by the same process as in winemaking (fermentation), does it make it (ethanol) non-halal? Fermentation is a preservation process which is ordinarily involved to produce various food products from various botanical sources such as cereals (sour dough), fish (budu or fermented anchovies), fruits (tempoyak or fermented durian), shrimps (belacan & cincalok) and legumes (soya sauce) The fermentation process is not necessarily just to produce product for the purpose of intoxication (alcoholic beverage) The halal status of a product will depend on the objective (niyyah) for which the product is produced (Al Umur Bi Maqasidiha) and also on how it is going to be used.

68 ISSUE # 2 Is the ethanol produced as an industrial alcohol the same that is that is produced in an alcoholic beverage (khamr)? Some misunderstanding occurred when the original term in Arabic which is khamr (Arab) to alcohol (in English) The meaning of alcohol has a wider meaning and connotation and not only limited to ethanol or the alcoholic beverage only The halal status will depend on the intention or the purpose of the product (Al Umur Bi Maqasidiha). Ethanol does not necessarily mean khamr although the intoxicating constituent of khamr is ethanol.

69 ISSUE #3 What is the amount of alcohol that can be allowed to be present in food and drink for it to be considered as halal compliant? To benchmark the permissible level of alcohol in food and drink at a level between 0.01% hingga 0.05% is not practical as it was found that the non-alcoholic products have alcohol levels more than 0.01%. It is found that there are some products where the level of alcohol was found to be higher than 0.1%) such as energy drinks, cultured drinks and vinegar but does not bring about the possibility of intoxication. There are Intermediate products such as in flavours and colours which may have higher alcohol contents but these are often diluted when they are used in the final product and the level of alcohol is around 0.01%. They are not consumed directly in its original form.

70 ISSUE # 4 Will adding khamr in the preparation of food and drink be permissible? Will the constituent be totally evaporated off? It is not permissible to add khamr in any food/drink preparation as adding it with khamr is considered as a contaminant. Khamr (residues) will remain to be present even food preparations even after they have been vigourously cooked or heated for a long time.

71 ISSUE #5 Can the medico-legal principles of intoxication be applied as the basis to determine the level of alcohol in food and drink? The basis of deciding the permissible level of alcohol in food and drink must be on a clear basis and not to be decided randomly The Principles of intoxication that is used as a basis in medico-legal cases related to drink-driving can be used to assist the decision in determining the permissible level of alcohol in food and drink It is suggested that a maximum level of 1% v/vis adopted as the permissible level of alcohol in food and drink

72 ISSUE #6 What is the amount of alcohol that is permissible to be present in fermented food and drink? The maximum amount of alcohol in nabidh from dates on the 3rd day is 0.06%. Tapai is found to have an alcohol content of higher than 1%, but no cases of intoxication has been reported thus far. The influence of density and the presence of a solid matrix may bring about in dampening the absorption of alcohol by the human digestive system this has to be investigated further. The levels of alcohol in nira (Arengata pinata) and nipah (coconut) palm saps are high and also need further investigations.

73 FROM A HALAL (SYARIAH) STANDPOINT, WHAT SHOULD BE THE APPROPRIATE ALCOHOL LEVEL FOR PHARMACEUTICAL PRODUCTS? Pharmacists and Islamic scholars can establish guidelines on the alcohol content of pharma products Need to consider whether the excipient (amount of ethanol as a solvent) is really necessary deliver the right efficacy of the pharma product Considerations are based on safety and shariah compliant factors of pharma products

74 QUESTION : WHAT IS THE BASIS OF THE GUIDELINE ON ALCOHOL IN FOOD AND DRINK?

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77 CONCLUSION A scientific and shariah-based approach is used to assist in the determination of level of alcohol in food and drink The medico-legal (medico-legal principles) has been utilised to determine the level of alcohol in food and drink To overcome uncertainties and proper cordination of the levels of alcohol in various products is pertinent in helping the expansion of the halal industry. 1% (v/v) is determined as the maximum level of alcohol in food products produced through natural fermentation.

78 Thank You