![RECEIPT OF RAW
MATERIAL FROM STORE
VERIFICATION OF
MATERIAL & WEIGHTS AT
SHOP FLOOR
SIFTING OF INVIDUAL
MATERIAL
DRYING
MILLING/ GRANULE
SIZING
LUBRICATION/BLENDING[
YIELD CALCULATION]
COMPRESSION
[SIMULTANEOUS
OBSERVATIONS BY
PROD.&IPQA]
VISUAL INSPECTON
[YEILD ANALYSIS]
COATING
[SIMULTANEOUS
OBSERVATIONS ON EACH
LOT BY PROD.&IPQA]
VISUAL INSPECTION
[YEILD ANALYSIS]
PM VERIFICATION AND
BATCH CODING
PACKING
[SIMULTANEOUS
OBSERVATIONS BY
PROD.&IPQA]
FINISHED GOOD
ANALYSIS
TRANSFER TO F.G.STORE
[BPR TO QA]
FLOW CHART TABLET MANUFACTURING AND
PACKING](https://image.slidesharecdn.com/pharmaceuticalsindustry-231117181213-a9e0ca92/85/Pharmaceuticals-Industry-7-320.jpg)
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Pharmaceuticals Industry
- 1. PHARMACEUTICALS INDUSTRY Presented by Tanvir SiddikeMoin Submitted to Dr. Rowshan Mamtaz Professor DEPARTMENT OF CIVIL ENGINEERING BUET
- 2. • 90% ofmedicines are taken orally with the majority being tablets. • Other routes of administration include injections, inhalation, rectal and topical. • In the pharmaceutical industry, clean water is a widely-used raw material in pharmaceutical manufacturing and plays a decisive role for the quality and safety of each product. • Therefore, in every pharmaceutical manufacturer, the water treatment system for manufacturing activities must be strictly managed, ensuring simultaneous factors: quality, stable operation. In the industry, most water, about 60-80%, is used for cleaning. However, even this water needs to be rather pure. Therefore, making water viable for use in the pharmaceutical industry is costly and energy intense. INTRODUCTION
- 3. Raw Materials • ActivePharmaceutical Ingredients (APIs). They are the central ingredients. • Excipient. The goal of the excipient is to carry and deliver the active ingredient to its destination. • While many types of drugs require many kinds of raw materials, there is a distinction in the type of raw material used. • According to the function of the raw material, it is categorized into two types. • They are as follows.
- 4. Pharmaceutical Excipients • Fillers • Binders •Disintegrants • Glidants • Coloring Agents • Antiadherent • Lubricants • Coating • Preservatives • Antioxidants • Flavoring Agents • Sweeting Agents • Sorbents • Solvent & Co-solvent
- 5. By route ofAdministration •Oral Excipients •Topical Excipients •Parenteral Excipients •Other Excipients By origin Inorganic Chemicals •Calcium Phosphates •Calcium Carbonate •Calcium Sulfate •Halites •Metallic Oxides Organic Chemicals •Carbohydrates • Sugars • Actual Sugars • Sugar Alcohols • Artificial Sweeteners •Starch • Modified Starch • Dried Starch • Converted Starch •Cellulose • Cellulose Ethers • Cellulose Esters • CMC and Croscarmellose Sodium • Microcrystalline Cellulose •Petrochemicals • Glycols • Polyethylene Glycol • Propylene Glycol •Povidones •Mineral Hydrocarbons • Petrolatum • Mineral Waxes • Mineral Oils •Acrylic Polymers •Other Petrochemical Excipients •Oleochemicals • Fatty Alcohols • Mineral Stearates • Glycerin • Lipids •Other Oleochemical Excipients •Proteins Categorization of Excipients Pharmaceutical excipients can be categorized in different ways. Such as
- 6. Antacid Tablet Composition SERIAL INGREDIENTS MG/ % PER UNIT TABLET ROLE OF INGREDIEN TS 1 Aluminum Hydroxide 200 mg API 2 Magnesium Hydroxide 200 mg API 3 Simethicone 25 mg API 4 Povidone 3.5% Binding Agent 5 Sorbitol Power 14% Sweeteners 6 Magnesium Stearate 1-2% Lubricant 7 Dicalcium Phosphate Anhydrous 0.5% Filler 8 Sodium Starch Glycolate 3% Disintegrant 9 Aspartame 0.2% Sweeteners 10 Lactose Monohydrate 16% Filler
- 7. RECEIPT OF RAW MATERIALFROM STORE VERIFICATION OF MATERIAL & WEIGHTS AT SHOP FLOOR SIFTING OF INVIDUAL MATERIAL DRYING MILLING/ GRANULE SIZING LUBRICATION/BLENDING[ YIELD CALCULATION] COMPRESSION [SIMULTANEOUS OBSERVATIONS BY PROD.&IPQA] VISUAL INSPECTON [YEILD ANALYSIS] COATING [SIMULTANEOUS OBSERVATIONS ON EACH LOT BY PROD.&IPQA] VISUAL INSPECTION [YEILD ANALYSIS] PM VERIFICATION AND BATCH CODING PACKING [SIMULTANEOUS OBSERVATIONS BY PROD.&IPQA] FINISHED GOOD ANALYSIS TRANSFER TO F.G.STORE [BPR TO QA] FLOW CHART TABLET MANUFACTURING AND PACKING
- 8. APPROVED RAW MATERIAL LINE CLEARANCE DISPENSING PRIMARYSYRUP PREPARATION FILTRATION BULK SYRUP PREPARATION FILTRATION FILING OF SYRUP IN BOTTLES SEALING OF BOTTLES PACKING TRANSFER TO FINISHED GOODS QUARANTINE TRANSFER TO FINISHED GOODS STORE FLOW CHART SYRUP MANUFACTURING
- 9. GRANULE MANUFACTURE Three principle methodsof preparing powder formulations for compression 1. Direct Compression 2. Wet Granulation 3. Dry Granulation Granulation is a unit operation in which small powder particles are gathered to form agglomerates called granules. To achieve cohesion between the powders, it is necessary to include adhesive substances called binders or granulating agents within the formulation. It is a common practice to make use of a granulation solution since it is more effective in comparison with the same quantum of the dry powder binder. Powder mixing, in conjunction with the cohesive properties of the binder, enables the formation of granules which when duly compressed using tablet press forms tablets with the desired properties.
- 10. DIRECT COMPRESSION • This isthe ideal option but is rarely achievable due to: • Active particle size/density mismatch with excipients causing poor homogeneity • Large quantity per tablet of poorly compressible active resulting in weak friable tablets
- 11. DIRECT COMPRESSION Process flowfor direct compression Dispense Security Sieve Blend • Lubricant Compress
- 12. Problems Associated WithDirect Compression If the material is a powder rather than a granule: › it will have poor flow characteristics, which can lead to uneven tablet weights. › The pressure transmission through a powder mass is poor, due to low packing density. Consequently particles do not ‘knit’ together very readily. › Powders, especially fine ones tend to blow out of the die at the top and seep out at the bottom › Dusty powders tend to mix with oil/grease and eventually cause sticking of the punches in the dies or turret bores. Powders containing two or more components may segregate. The heavier or smaller particle size components separate to the bottom of the bulk, this is made worse by the vibration of the Tablet Press. Direct compression materials are more expensive than non-DC equivalents
- 13. Advantages of DirectCompression • Few stages involved • Low handling costs • Losses near zero • No water or heat involved • Reduces the risk of degradation of the active
- 14. PROCESS AIDS Regardlessof whether a tablet is manufactured by direct compression or granulation, processing aids will be required: These materials are called excipients and are either: › Diluents › Lubricants › Disintegrants › Glidants › Binders Direct compression formulations will contain as a minimum diluents, disintegrants and lubricants. › N.B. some excipients have more than one function
- 15. DILUENTS • A diluentis simply an ingredient that is used as a bulking agent to make tablets large enough to handle and swallow. • Diluents must therefore be: • Pharmacologically inert • Cheap • No supply issues • Compatible • Stable • Processable • Diluents are commonly easily compressible especially in DC formulations. • Examples include: • Micro-crystalline cellulose • Lactose • Di-calcium phosphate
- 16. LUBRICANTS Lubricants are materialsthat lubricate powder mixes and aid tablet ejection. Without lubrication powder may stick to the punches especially if is too moist. Lubricants are typically added at a late stage and blended for the shortest possible time as they have adverse effects. Adverse effects if over-blended are poor compressibility and increased dissolution due to waxy layer covering the surface of the granule
- 17. GLIDANTS • Glidants arematerials that improve the flow of powder mixes • An example is Colloidal Silicon Dioxide • Most powders, without the aid of flow agents, simply cannot flow at speeds required for high speed tabletting. • Flow agents can decrease the capacity of powders to form bridges, create rat holes and stick to contact surfaces. • Good flow into the die will lead to uniform tablet weight as the volume of material flowing into the die will be constant
- 18. DISINTEGRANTS A material topromote disintegration of the tablet when swallowed Enhances water penetration by wicking effect Increases porosity Swells in contact with water and breaks cohesive bonds Examples include: • Starch • Croscarmellose • Sodium Starch Glycollate • Crospovidone
- 19. BINDERS • A materialthat imparts cohesiveness to the formulation • Helps bind powder particles into granules during granulation • Helps bind granules together during the compression process • Examples include: • Hydroxy propyl methyl cellulose (HPMC in water) • Starch paste in warm water • Gelatin • Polyvinyl pyrrolidone (PVP)
- 20. TRADITIONAL WET GRANULATION Dispense SecuritySieve Granulate Dry Sieve/Mill Blend • Lubricant Compress
- 21. TRADITIONAL WET GRANULATION • Mostperformed using a high shear mixer e.g., ‘Fielder’ but can be performed using low shear e.g., ‘Hobart’. • Fielder Granulator: • Two blades, main blade and chopper • Main blade speed is typically 100- 500rpm • Chopper blade up to 3000rpm • Main blade mixes and chopper breaks wet mass to form granules
- 22. TRADITIONAL WET GRANULATION Powdersare loaded into the bowl and mixed for a defined time before granulation starts Granulating solution added at defined rate or sprayed (binder is usually incorporated into the solution) Wet mass is chopped to form granule Granulation end point can be measured by current draw on main blade Process is controlled by the mixing times/speeds before and after addition of the granulating solution and the amount of solution added. Process relies on the binder and/or water-soluble elements dissolving upon granulation, then on drying forming a solid bridge between particles.
- 23. ADVANTAGES OF WETGRANULATION • Increases cohesiveness • Good for high dose/poorly compressible drugs • For example Kalms has large amount of poorly compressible Hops • Good for distributing soluble low dose drugs • For example in Kwells the hyoscine is added to the granulating solution • Prevents segregation of actives
- 24. DISADVANTAGES OF WET GRANULATION Processing parameters are derived by trial and error Mixing time varies with batch size and can be sensitive to variation in starting materials Danger of over granulation Cost (multi-stage process) Incompatibilities (chemical instability with moisture or subsequent drying)
- 25. A TYPICAL WETGRANULATION FORMULATION • Wet Binder • Polyvinyl pyrrolidone (PVP) • Increases granule size strength and compressibility • Enhances dissolution relative to DC • Granulation process aid • Micro-crystalline cellulose • Reduces water/energy requirements • Reduces process sensitivity • Less risk of over granulation • Easier wet massing and screening • Intra granular filler • Lactose • Better wet binding than insoluble fillers • Intra-granular disintegrant • Croscarmellose sodium
- 26. DRYING • The removalof water or liquid to form a dry solid • It is necessary as too much residual water can result in: • Poor flow • Poor lubrication (sticking to punches) • Chemical instability • Susceptibility to microbial growth • 2 main methods • Tray drying • Fluidised Bed Drying • Others include microwave and vacuum drying (not commonly used)
- 27. TRAY DRYING • Fanassisted convection of hot air over loaded trays • Not commonly used due to: • Large floor space • Manual handling • Labour intensive • Long drying times (up to 24 hours) • Can get non-uniform drying • Can result in hard caked product
- 28. FLUIDISED BED DRYING •Heated air is pulled through the bed of material in a removable bowl. • Filters prevent fines from escaping • Temperature can be controlled by probes monitoring input, output and bed temperatures • Airflow is adjusted according to particle size and density • Most efficient drying (minutes vs. hours)
- 29. SIEVING AND MILLING Sievingof the granule may be performed to remove large particles that may then be milled to reduce size Oversize or all of the dried granule may be milled. Various types of mill are usually used depending upon the process requirements Mills used routinely at GR Lane include Comill (Cone mill), Apex and Tornado.
- 30. MILLING • Comills (conemills) produce granule of more uniform size and shape than Apex or Tornado mills with a smaller proportion of fines • Fines are powders that are very small and ‘dusty’, which will pass through a 200 mesh screen. • Fines impede the flow, do not compress well • Mills may also be used to ‘de-lump’ granules without reducing particle size.
- 31. MILLING • Apex millshave the rotational shaft in a horizontal orientation vs Tornado that is vertical • Tornado mills have 360° mill screens and consequently produce marginally less fines than an Apex mill that has a 180° screen. • Both tornado and apex mills can be used with varying numbers of blades that throw material against the mesh that controls the maximum particle size • Hammers may also be used. These pulverize the material to a finer particle size
- 32. SPRAY GRANULATION • Thisis when granulation and drying is combined in a one-pot process • Granulation solution is sprayed into a fluidized bed • There is a greater degree of control over the size of granules formed. • Control is via spray rate, inlet temperature and air flow. • There are less losses by this method • Granule has an even moisture distribution However • Higher attrition may lead to fines • Control of rates is critical • Longer process time (may lead to de-mixing)
- 33. DRY GRANULATING • Drygranulating, also called slugging, or roller compaction, involves the pressing of mixed powders into an object to be reground into a precise powder. • This action increases particle density, improves powder flow and captures fines. • Useful for materials which are sensitive to heat and/or moisture. • Can be performed on tablet press followed by milling or by using specialized equipment • However pressure during dry granulation can result in: • granules with low porosity • Weaker tablets • May produce tablets with longer disintegration time • Dusty process
- 34. BLENDING • There aremany different types of blenders • Y cone blenders • Double cone blenders • Drum blenders • IBC blenders • Majority are low shear tumble blenders. GR Lane has opted for IBC blending to reduce handling • Blend studies are performed to determine the determine the optimum endpoint • Given enough time, components will pass from an unblended state to a relatively homogenous blend and back to an unblended state.
- 35. WEIGHT VARIATION • Weightvariation can be caused by a number of factors: • Poor flow of granule • Granule too wet • Insufficient glidant • Poor granule homogeneity • Over or under-blended • Material has settled over time • Separation of fines in hopper • Poor formulation • Tablet press set-up • Dropping punches • Sticking punches • Feed frame speed • Uneven wear or damaged tooling
- 36. POOR FRIABILITY • Poor friabilitycan be caused by a number of factors: • Low hardness • Tablet press set-up • Overblending • Poor granule • Too dry • undergranulated • insufficient binder • too many fines • Inappropriate tablet shape
- 37. CAPPING • Capping isthe term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling. • Reason: Capping is usually due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die. • Causes related to the formulation are • Large amount of fines • Granule too dry • Granule too wet • Insufficient lubricant • Causes related to the press: • Ringing in dies • Lower punch remains below the face of die during ejection. • Incorrect adjustment of take-off blade. • High turret speed • Possible remedial actions are: • Move position of compression in die • Adjust take-off blade • Slow down press
- 38. LAMINATION Lamination is theseparation of a tablet into two or more distinct horizontal layers. Reason: Air–entrapment during compression and subsequent release on ejection Causes related to the formulation: • Over lubrication of formula • Oily material in formula Causes related to the tablet press: • Rapid relaxation of the peripheral regions of a tablet, on ejection from a die. • Rapid decompression Possible remedial action: • Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°. • Use pre-compression step. Reduce turret speed and reduce the final compression pressure.
- 39. CHIPPING • There arenumber of causes of chipping that can be due to: • Machine setup • Insufficient dwell time • Compression force too low • Tooling wear • worn punches • Poor granule • too much fines • Granule too dry • Insufficient binder • Excessive lubricant • Not homogenous mix • Possible remedial actions • If clawed tooling, remove claws • Increase pressure • Slow down press
- 40. CRACKING Cracking is wheresmall, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used Causes related to the granule: • Large size of granules. • Too dry granules Causes related to the tablet press: • Tablet expands on ejection due to air entrapment • Deep concavities cause cracking while removing tablets • Too much pressure Possible remedial action: • Use tapered die • Use special take-off plate • Reduce compression force
- 41. STICKING/FILMING • Sticking refersto the tablet material adhering to the die wall. • Filming is a slow form of sticking and is largely due to excess moisture in the granulation. • Reason: Improperly dried or improperly lubricated granules. • Possible remedial action: • Increase pressure. • Reduce speed.
- 42. PICKING Picking isthe term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face. The problem is more prevalent on the upper punch faces. The problem worsens with time into the run because more and more material is added to the already stuck material on the punch face. Common causes related to the granule: › Excessive moisture in granules › Too little or improper lubrication › Too warm granules when compressing. › Too much binder. Common causes related to the tablet press: › Rough or scratched punch faces › Unpolished tooling › Insufficient pressure Possible remedial actions: › Increase compression pressure › Polish tooling by hand › Reduce press speed
- 43. BINDING • Binding inthe die, is the term used when the tablets adhere or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and they may crumble apart • Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies. • Causes due to worn dies: • Poorly finished dies • Rough dies due to abrasion • Possible remedial action: • Clean the dies properly • If worn die is due to abrasion investigate use of other steels • Reducing pressure in the tablet press may decrease binding.
- 44.
- 45. Procedure of Paracetamol 1.Add 2.1 grams of 4-aminophenol into the round-bottomed flask. 2. Using your 25 mL measuring cylinder, measure 18 mL of water and add this to the flask. 3. Add a magnetic follower to the round-bottomed flask. 4. Carefully clamp the flask at the neck and position it in the metal Dry Syn block which should be placed on the stirrer hotplate. Stir the reaction mixture using a magnetic follower. Do not apply heat at this stage 5. Assemble the apparatus for reflux as shown in the diagram below. Tip: Do not clamp the condenser
- 46. Procedure of Paracetamol 6. Usinga Pasteur pipette, measure 3 mL of ethanoic anhydride (also known as acetic anhydride) into a 10 mL measuring cylinder. Add this to your mixture by lifting the condenser and adding directly to the round- bottomed flask. 7. Replace the condenser and switch on the heat to your hotplate (set the dial to about 120°C). Make sure there is water going through your condenser. 8. The reaction is heated at reflux for 15 minutes,stirring continuously. The reaction mixture should become colorless. 9. After refluxing for 15 minutes, switch off the heat and carefully raise the round-bottomed flask away from the Dry Syn block using the boss and clamp. 10. Allow the flask to cool to room temperature. 11. On cooling, crude paracetamol should form in the round-bottomed flask.
- 47. 12. filter theprecipitate (using a Buchner funnel), washing with small amounts of cold, distilled water. 13. After drying, the crude product should be placed in a clean 100cm3 conical flask and recrystallized by heating until it just dissolves in approximately 20ml of water. Cool the flask in ice until crystals of the purified paracetamol appear. Filter the crystals under vacuum, dry in a warm oven and then record the melting point and compare with standard paracetamol tablets (~170oC). Repeat recrystalisation process to achieve a purer product Procedure of Paracetamol
- 48. •Formulation •Power Feeding •Power Blending •Granulation •HotMelt Extrusion General Unit Operations
- 49. Pharmaceutical water includesdifferent types of water used in the manufacture of drug products THE 8 TYPES OF WATER ARE: 1. Non-potable 2. Potable (drinkable) water 3. USP purified water 4. USP water for injection (WFI) 5. USP sterile water for injection 6. LUSP sterile water for inhalation 7. USP bacteriostatic water for injection 8. USP sterile water for irrigation Water for Pharmaceutical Use
- 50. Water Requirements • Wateris very much a necessity in pharmaceutical processes. • Of course, various types of water are important for various processes. • Also, the quality of water has to be certified in many cases. • Generally, most water that is used in the pharmaceutical industry is for cleaning. • Still, cleaning water needs to be potable, as non-potable water can disrupt the manufacturing process. • The other main uses of water are as an ingredient and as a carrier. • Water can be an ingredient in the pharmaceutical process for various chemical reactions. • Water is often used for hydrolysis to break down organic compounds. • In addition, water can be the medium or solvent for a particular drug, whether administered orally, as a syrup, or as an injection, where the water is a medium.
- 51. Water Quality The USPdesignation means that the water is subject to an official monograph by the US Pharmacopeia. There are four different kinds of specifications for water, and these four have different functions. Serial Parameter Potable Water Purified Water Water for Injection Sterile Water for Injection 1 Appearance Clear, colorless, and no visible particles Clear, colorless, and no visible particles Clear and colorless Clear and colorless 2 Odor Odorless Odorless Odorless Odorless 3 pH 6.5-8.5 5.0-7.0 5.0-7.0 5.0-7.0 4 Chloride NMT 250 ppm 0 ppm 0 ppm 0 ppm 5 Aluminum 0.2 mg/L 0 mg/L 0 mg/L 0 mg/L 6 Arsenic 0.01 mg/L 0 mg/L 0 mg/L 0 mg/L 7 Fluoride 1.5 mg/L 0 mg/L 0 mg/L 0 mg/L 8 Boron 0.3 mg/L 0.3 mg/L 0 mg/L 0 mg/L 9 Sulfate NMT 300 ppm 0 ppm 0 ppm 0 ppm 10 Total hardness NMT 500 ppm 0 ppm 0 ppm 0 ppm 11 Microbial count 500 cfu/ml 100 cfu/ml 10 cfu/ml 10 cfu/ml 12 Acidity or Alkalinity - NMT 0.1 ml of 0.01M NaOH NMT 0.1 ml of 0.01M NaOH NMT 0.1 ml of 0.01M NaOH 13 Ammonia 0.5 ppm 0.2 ppm 0 ppm 0 ppm 14 Heavy Metals 0.5 ppm 0.1 ppm 0 ppm 0.1 ppm
- 52. Maximum Allowable Concentration of Toxic Substances Toxic SubstancesMaximum Allowable Concentration (mg/L) Lead (Pb) 0.05 Selenium (Se) 0.01 Arsenic (As) 0.05 Chromium (Cr) 0.05 Cyanide (CN) 0.2
- 53. Sources of Water •Potable Water is generally gathered from municipal water systems or from a natural water source. • However, for other kinds of water, other processing must be done. • These can be done on site, or if the plant is a small one, higher grades of water have to be purchased. • On site, sand filters are often used for purifying and obtaining potable water. • For high grades of water, specific equipment needs to be present such as boilers, ionizers, etc. • Certain high grades of water are still purchased as it is not viable to manufacture them at a large scale as the demand may not be there.
- 55. Characteristics of wastewater generated from pharmaceutical process ParameterConcentration (mg/L) pH 6.65-7.40 Total Alkalinity 1800-2100 TDS 15500-16700 VS 6400-6600 SS 9150-9240 COD 23700-24500 BOD5 11500-12100 Chlorides 3900-4100 Sulphates 400-650 Phosphates <98
- 56. Analysis Most pharmaceutical companies outsideof Bangladesh manufacture medicine, but in Bangladesh, the ingredients and formulation is imported. In factories in Bangladesh, only the packaging and other final procedures are done. Standards in Bangladesh are not specified, and different pharmaceutical companies do different procedures. However, the standards of the ingredients and raw materials are generally met according to foreign standards.
- 57. The water usedto supply the pharmaceutical industry usually comes from • Underground-water • Water from clean water supply plants in the area • Underground-water sources are often characterized by high amounts of dissolved substances, mainly manganese, calcium, and magnesium, while clean water from water supply plants is not up to the production quality assurance. • Therefore, pharmaceutical enterprises are required to treat input water sources to remove impurities or microorganisms that affect the quality of pharmaceuticals. WHY DO WE HAVE TO TREAT WATER BEFORE USING IT TO MANUFACTURE PHARMACEUTICALS?
- 58. References • Medical WasteRules, 2008 • FDA Current Good Manufacturing Practice regulations, Federal Register, Vol. 43, No. 190, Sept. 29, 1978 • Water Programs, Environmental Protection Agency, National Interim Primary Drinking Water Regulations, Dec. 16, 1985 • United States Pharmacopeia, Water for Pharmaceutical Purposes, 1985
- 59.