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Grouping Strategies for Cleaning Vitamins and Minerals Elizabeth Rivera, Amanda Deal, and Paul Lopolito

ABSTRACT This article addresses the selection of the worst-case product grouping for cleaning vitamin and mineral oral dosage forms, and reviews data relating to solubility, toxicity and cleaning difficulty. The article also includes laboratory experiments on final formulations to assess cleanability of different vitamins and minerals.

INTRODUCTION In June 2007, the US Food and Drug Administration issued an industry-specific regulation, 21 CFR Part 111, entitled Current Good Manufacturing Practice (cGMP) in Manufacturing, Packaging, Labeling or Holding Operations for Dietary Supplements. Compliance with this regulation was phased in over three years based upon the size of the manufacturer. By June 2010, all dietary supplement manufacturers supplying products to the United States were required to comply with this new regulation. The cGMP regulation states that manufacturers “must maintain, clean, and sanitize, as necessary, all equipment, utensils, and other contact surfaces used to manufacture, package, label, or hold components or dietary supplements.” It also states that manufacturers “must clean surfaces that do not come into contact with components or dietary supplements as frequently as necessary to protect against contaminating components or dietary supplements.” Hundreds of dietary supplement manufacturers in the US produce thousands of products in tablet, capsule, powder, liquid, and gel forms. These products contain one or more active components such as vitamins, minerals, botanicals, and amino acids.

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Depending on the dosage form, the products also contain numerous excipients (i.e., inert ingredients) used as fillers, disintegrating agents, binding agents, lubricants, colorants, or coatings. The broad diversity of actives, excipients, and product variations makes it difficult for companies to design a cleaning strategy for dietary supplement manufacturing operations, hence making it more challenging to comply with cGMP regulations. Grouping strategies for products and equipment can be useful in designing an overall cleaning program. If the products are of similar product type, manufactured in the same equipment train, and cleaned by the same cleaning methods, then grouping strategies can be used to reduce cleaning qualifications. Products are grouped based on product type (e.g., tablet, gel capsule, soft gel) solubility and toxicity of the active ingredient(s), and overall difficulty of cleaning based upon historical or laboratory data. Process equipment is grouped based on its design and size. In either case, a worst-case product or piece of equipment is selected to perform the cleaning challenges. This article addresses the selection of the worst-case product grouping for cleaning vitamin and mineral oral dosage forms and reviews data relating to solubility, toxicity, and cleaning difficulty. The article also includes laboratory experiments on final formulations to assess cleanability of different vitamins and minerals.

SOLUBILITY OF VITAMINS AND MINERALS Solubility data for the active vitamin or mineral component in water is often easy to generate or obtain (see examples in Table I). Solubility data for a cleaning

ABOUT THE AUTHORS Elizabeth Rivera is a technical services specialist for the Life Sciences Division of STERIS Corporation (Mentor, Ohio). Amanda Deal is a technical services associate for the Life Sciences Division of STERIS Corporation (Mentor, Ohio). Paul Lopolito is a technical services manager for the Life Sciences Division of STERIS Corporation (Mentor, Ohio). He may be reached by e-mail at [email protected].

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Table I: Solubility in water for select vitamins and minerals. Vitamin/mineral

Solubility (in water)—Merck Index (1)

*Solubility (in water)—USP 33 NF 28 (2)

Retinyl palmitate

Not specified

Not specified

Palmitic acid

Insoluble in water

Practically insoluble in water

Retinol

Practically insoluble in water

Insoluble in water. In solid form, may be dispersible in water

Fish liver Oil

Not specified

Practically insoluble in water

Thiamine mononitrate (B1)

Not specified

Sparingly soluble in water

Riboflavin 5'-phosphate sodium (B2)

pH 6.9—112 mg/ml, pH 5.6—68mg/ml, pH3.8—43 mg/ml

Sparingly soluble in water

Niacinamide (B3)

~1 g/ml

Freely soluble in water

d-calcium pantothenate (B5)

~1 g/2.8 ml

Freely soluble in water

Pyridoxine HCl (B6)

~1 g/4.5 ml

Freely soluble in water

d-biotin (B7)

22 mg/ml at 25°C,

Sparingly soluble in water

Folic acid (B9)

0.0016 mg/ml at 25°C, about 1% in boiling water

Very slightly soluble in water, but readily dissolves in dilute solutions of alkali hydroxides and carbonates.

Para-aminobenzoic acid

1 g/170ml at 25°C, 1 g/90ml in boiling water

Very soluble in water

Choline bitartrate

Not specified

Freely soluble in water

Inositol

14 g/100ml at 25°C, 28 g/100ml at 60°C

Very soluble in water

Dexpanthenol

Freely soluble in water

Freely soluble in water

~1 g/3 ml, 80.0% at 100°C , 40.0% at 45°C

Freely soluble in water

Practically insoluble in water

Insoluble in water

d-alpha tocopheryl succinate

Practically insoluble in water

Insoluble in water

d-beta, d-gamma or d-delta tocopherol

Insoluble in water

Insoluble in water

Phytonadione

Insoluble in water

Insoluble in water

Menaquinone-7

Insoluble in water

Not specified

Practically insoluble in water

Practically insoluble in water

Not specified

Not specified

Soluble in water

Very soluble in boiling water; freely soluble in water

Slightly soluble in water, Dibasic sol in ~5 parts water

Soluble in water

Vitamin A

Vitamin B

Vitamin C Ascorbic acid Vitamin D3 Cholecalciferol D-3 Vitamin E

Vitamin K

Calcium Calcium carbonate Chromium GTF chromium yeast Iron Ferrous sulfate Magnesium Magnesium citrate

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Table I: Continued... Potassium Potassium citrate

1 g/0.65ml

Freely soluble in water

Insoluble in water

Practically insoluble in water (selenium sulfide)

Not specified

Soluble in water

Selenium Selenium yeast Zinc Zinc gluconate

*Very soluble, less than 1 part of solvent required for 1 part of solute; Freely soluble, from 1-10; Soluble, from 10-30; Sparingly soluble, from 30 -100; Slightly soluble, from 100-1000; Very slightly soluble, from 1000-10,000; and Practically insoluble, or Insoluble, from 10,000 and over.

solution other than water should also be collected when used. However, organic solvents are not common cleaning agents for vitamins and minerals due to the difficulty of eliminating solvent residues, environmental pressures, and personnel safety challenges. For these reasons, most dietary supplement manufacturers perform cleaning by manual methods (e.g., brush, wipes, foam or spray wands) with a formulated aqueous cleaning agent. It is often assumed that the active ingredient with the lowest solubility is most difficult to clean, and is therefore the ‘worst case,’ but several factors may complicate this assumption. First, the active is often only one of many components in a product formulation. The other components, known as excipients, fillers, or inactive ingredients, may influence the solubility of the active. Excipients may be harder to clean than the active. Second, in the case of water or aqueous cleaning agents, the pH and temperature can impact solubility of the active. In addition, if a formulated cleaning agent is used, the other components of the cleaning formulation (i.e., an acid, base, chelant, dispersant, or surfactant) can affect the solubility of the active. However, if all these factors are “equal,” then solubility of the active can be useful data for a risk assessment to determine the worst-case soil.

TOXICITY OF VITAMINS AND MINERALS In the pharmaceutical industry, acceptance limits for residual actives are often calculated using the minimum daily dose of the active in the product just manufactured, and the maximum daily dose of the next product to be manufactured. This limit calculation is based on the smallest therapeutic dose, and it has been accepted industry-wide by most drug manufacturers in establishing scientifically justifiable limits for cleaning validation. The term “minimum daily dose” refers to the minimum prescribed dose of active that could cause the desired pharmacological g x p a n d j v t . co m

effects in a patient. A safety factor of 0.001 has been recommended for oral dosage forms (3). Because dietary supplements are not drug products, the application of a pharmaceutical calculation may not be relevant because pharmacological information is not available for most actives used in these products. Another measure, such as the recommended dietary allowance, may be listed on the product label or in other references but these recommended values may vary. Dietary supplements can be taken for multiple purposes, and doses can depend on individual needs, so nutritionist recommendations may differ. Therefore, recommended dietary allowances are not an appropriate substitute for the therapeutic dose data of drug products. Other residual limit calculation options may be considered instead. Another method of calculating acceptable limits is based on the use of animal toxicity data in place of the minimum daily dose. This method is particularly useful for establishing limits for materials that are not intended for therapeutic use. The toxicity information should include the route of administration, test species, and the dosage used. For example, oral LD50 (i.e., lethal dose for 50% of the population) in rats or mice is commonly available for comparison of oral dose products. Toxicity data like LD50 can be used to determine the acceptable daily intake (ADI) of a potential contaminant. The ADI takes into consideration the body weight (i.e., 25 kg for a child or 70 kg for an adult) to arrive at a “safe dose.” Such a calculation for a dietary supplement using the oral LD50 would then be seen in Equation 1, as follows: 

[Equation 1)

In this equation, the appropriate safety margin is a combination of a safety factor (given in the reference as >1,000 for prolonged or lifetime exposure to Journal of Validation Technology [Winter 2012] 63

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Table II: Recommended dietary allowance and toxicity of select vitamins and minerals. Active

Recommended dietary allowances (male, age 19-70) for vitamins (10) and Adults for minerals (11) unless noted

Vitamin A

900 mcg

Oral (mouse) LD50 1510 mg/kg (12) Oral (rat) LD50 2000 mg/kg (13)

Vitamin B

B1: 1.2 mg B2: 1.3 mg B3: 16 mg B5: 5 mg B6: 1.3 – 1.7 mg B7: 30 mcg B9: 400 mcg B12: 2.4 mcg

Vitamin B3 Oral (mouse) LD50 2500 mg/kg (14) Oral (rat) LD50 3500 mg/kg (14)

Vitamin C

90 mg

Oral (mouse) LD50 3367 mg/kg (15) Oral (rat) LD50 11.9 g/kg (16)

Vitamin D3

5 – 10 mcg

Oral (mouse) LD50 5-50mg/kg (17) Oral (rat) LD50 41.5 mg/kg (17)

Vitamin E

15 mg

Oral (mouse) LD50 > 25 ml/kg (18) Oral (rat) LD50 >7000 mg/kg (19)

Vitamin K

120 mcg

Oral (mouse and rat) LD50 25 g/kg (20)

Toxicity

Calcium (as calcium carbonate)

800-1200 mg

Oral (rat) LD50 6450 mg/kg (21)

Chromium

50-200 mcg

Oral (rodent) LD50 100-400 mg/kg (22)

Iron (ferrous sulfate)

10-15 mg

Oral (mouse) LD50 200 mg/kg (23) Oral (rat) LD50 319 mg/kg (24)

Magnesium citrate

270-400 mg

Oral (human) TDLO 4722 or 6078 mg/ kg (25,26)

Potassium citrate

4700 mg (27)

Oral (mouse) LD50 8954 mg/kg (28) Oral (rat) LD50 7200 mg/kg (29)

Selenium

200 mcg (20)

Oral (mouse) LD50 3.0 mg/kg (30) Oral (rat) LD50 4.8-7.0 mg/kg (30)

Zinc (chelated)

10-15 mg

Oral (mouse) LD50 5000 mg/kg (31)

the drug) and a modifying factor (usually between 1 and 10, based upon the judgment of the toxicologist making the determination) (4-6). ADI could be used to calculate the maximum allowable carry-over (MACO) limit in the next product batch as Equation 2, as follows:



[Equation 2]

From here, the rest of the residual limit calculation would follow a similar strategy as discussed in multiple references (3, 7). The MACO value, together with the total shared surface area or final rinse volume, can be used to determine the residue limits for each swab or rinse sample, respectively. 64 Journal of Validation Technology [Winter 2012]

Oral toxicity data is generally available for FDAapproved actives (Table II). For actives or products with limited or no toxicity data available, an ADI can be based on the threshold toxicological concern (TTC) principle (8). For product grouping, the acceptance limit for cleaning should be based on the lowest MACO value determined for the group of products (7). The toxicity data used to determine the acceptance limit should be carefully weighed with the most difficult-to-clean product(s) (9).

CLEANING VITAMINS AND MINERALS Determining the most difficult-to-clean product is based on solubility of the active, historical information from the operators on cleaning and removing the product from surfaces, or laboratory studies. The use ivthome.com

E li z abeth R ivera , A manda D eal , and Paul L opolito

Table III: List of select vitamins and minerals with active concentrations and excipients. Active

Amount per dosage form

Excipients

Vitamin A

10,000 IU

Soybean oil, gelatin, vegetable glycerin, fish ingredients

Vitamin B

B-1 (10 mg), B-2 (15 mg), niacin (25 mg),

Dicalcium phosphate, vegetable cellulose, cros-

B-6 (10 mg), folic acid (400 mcg), B-12

carmellose, silica, calcium silicate, vegetable

(400 mcg), Biotin (100 mcg), pantothenic

magnesium stearate, vegetable cellulose coat-

acid (100 mg), PABA (50 mg), choline bi-

ing maltodextrin, mannitol

tartrate (250 mg), inositol (250 mg) B-Complex, sublin-

B-12 (1.7 mg), niacin (20 mg), B-6 (2 mg),

Purified water, sorbitol, vegetable glycerin, citric

gual liquid

B-12 (1.2 mg), pantothenic acid (30 mg)

acid, potassium sorbate, natural flavor

Vitamin C

500 mg

Ascorbic acid, vegetable cellulose, croscarmellose, vegetable magnesium stearate, silica, vegetable stearic acid

Vitamin C, liquid

300 mg

Purified water, sucrose, glycerin, sorbitol, propylene glycol, ascorbic acid, rose hips, natural lime flavor, methylparaben, propylparaben

Vitamin D3 soft gel

1000 IU

Soybean oil, gelatin, vegetable glycerin, corn oil

Vitamin D3

1000 IU

Cholecalciferol D-3, dicalcium phosphate, cellulose

Vitamin E, soft gel

400 IU

Gelatin, vegetable glycerin, soybean oil

Vitamin E

400 IU

D-alpha tocopheryl succinate (vitamin E), calcium sulfate, gelatin

Vitamin K

100 mcg

Dicalcium phosphate, vegetable cellulose, vegetable stearic acid, vegetable magnesium stearate

Vitamin K, soft gel Calcium (as calcium

90 mcg, Menaquinone-7 from anatto

Medium chain triglycerides, evening primrose oil,

extract

beeswax, lecithin, gelatin

600 mg

Vegetable cellulose, vegetable magnesium

carbonate)

stearate

Chromium (GTF)

200 mcg

Iron (ferrous sulfate)

28 mg

Dicalcium phosphate, vegetable cellulose, silica, vegetable magnesium stearate Dicalcium phosphate, calcium carbonate, vegetable cellulose, vegetable stearic acid, vegetable magnesium stearate

Magnesium citrate

100 mg

Gelatin, rice flour, vegetable magnesium stearate

Potassium citrate

99 mg

Vegetable cellulose, dicalcium phosphate, vegetable stearic acid, silica, vegetable magnesium stearate

Selenium

100 mcg

Zinc (chelated)

25 mg

Dicalcium phosphate, vegetable cellulose, brewer’s yeast, vegetable magnesium stearate, silica Vegetable cellulose, dicalcium phosphate, vegetable stearic acid, silica, vegetable magnesium stearate

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Figure 1: A clean and soiled coupon on the left; a visual failure in the right center; a water break-free failure on the right.

Figure 2: Summary of cleaning parameters obtained for supplements successfully cleaned with DI water only. The figure denotes the minimum temperature and contact time required to achieve cleanliness of the test coupons.

of laboratory studies can help define critical cleaning parameters such as selection of cleaning temperature, time, cleaning agent, and concentration. Laboratory study data can also help define standard cleaning procedures, which facilitates the grouping of products for cleaning. Laboratory cleanability studies can also help determine the hardest-to-clean residue for a given set of cleaning parameters.

CASE STUDY The following describes a vitamin and mineral cleaning case study.

Materials and Methods Table III provides a list of vitamins and minerals evaluated and the list of excipients in their final dosage forms. Tablets were crushed and caplets were opened and applied as a loose or compressed powder to 304 stainless steel coupons with a 2B surface finish. Liquid products and liquids from inside soft gel caplets were 66 Journal of Validation Technology [Winter 2012]

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applied directly onto the coupons. The different coupon applications simulate different residue conditions found in manufacturing. The coated coupons were cleaned for a maximum of 60 minutes or until they achieved the following cleaning results: visually clean (VC), water break-free (WBF), and gravimetric weight of less than or equal to 0.1 mg residue per coupon (approx. 0.5 - 1.0 mcg/cm2 ). Figure 1 provides a visual illustration of a clean coupon, soiled coupon, a visual failure, and a water break-free test failure. The laboratory cleaning studies were performed using the agitated immersion method to compare various aqueous cleaning agents. Although manual cleaning is commonly used in the dietary supplement industry, agitated immersion was selected to eliminate the operator variability of typical manual cleaning methods. In addition, the agitated immersion method can also help evaluate the actual performance of cleaning chemistries because minimum mechanical force is employed. The cleaning agents evaluated were de-ionized (DI) water, neutral pH detergent, acid detergent, and alkaline detergent. The temperatures used in the study included ambient temperature, 45∘C and 60∘C. If a coupon was successfully cleaned at a lower temperature, then the higher temperature was not evaluated (for manual cleaning, typically temperatures of 45∘C or less are recommended). The concentration of the selected formulated detergent was set to 1% v/v. Low effective detergent concentrations are desirable because they impact operator safety, reduce the volume of neutralizer needed (if applicable), minimize the volume of rinse water needed, and optimize the effective use of the formulated detergent. Finally, contact times between the soils and the cleaning solution were increased (up to 60 minutes maximum) until desired results were achieved. Figures 2 through 5 summarize the results obtained for DI water and the evaluated formulated detergents. Each chart lists the soils that were successfully cleaned by the particular detergent and includes the temperature and contact time required to achieve the acceptable cleaning results. Figure 6 summarizes the group of soils that were not successfully cleaned by DI water or any of the detergents at the desired 1% v/v concentration, even at the highest temperature and contact time parameters of the test. For these soils, a higher detergent concentration of 5% v/v was evaluated. The alkaline detergent was the only formulation that achieved the acceptable cleaning results for most of the soils tested. Vitamin E was not successfully cleaned with the DI water, 1% v/v, or 5% v/v cleaning agents evaluated in this study. g x p a n d j v t . co m

Figure 3: Summary of cleaning parameters obtained for supplements successfully cleaned with a neutral detergent. Chart denotes the minimum temperature and contact time required to achieve cleanliness of the test coupons.

Figure 4: Summary of cleaning parameters obtained for supplements successfully cleaned with an acid detergent. Chart denotes the minimum temperature and contact time required to achieve cleanliness of the test coupons.

However, vitamin E was successfully cleaned with a two-product approach consisting of a formulated alkaline detergent at 1% v/v plus a detergent additive with hydrogen peroxide at 1% v/v, for 30 minutes at 60∘C. If vitamin E is considered the worst case of this cleaning evaluation, then this two-product method should also be effective for all the other products evaluated. Additional evaluations could be performed to confirm a single cleaning procedure for all vitamins and minerals. Journal of Validation Technology [Winter 2012] 67

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Figure 5: Summary of cleaning parameters obtained for supplements successfully cleaned with an alkaline detergent. Chart denotes the minimum temperature and contact time required to achieve cleanliness of the test coupons.

Figure 6: Summary of cleaning parameters obtained for supplements that required a higher concentration of alkaline detergent. Chart denotes the minimum temperature and contact time required to achieve cleanliness of the test coupons.

DISCUSSION AND RECOMMENDATIONS For vitamins, the solubility information indicated that vitamin C and vitamin B had the highest water solubility and were successfully cleaned with deionized water and with the detergents (neutral, acid, or alkaline). The other vitamins were partially or mostly insoluble in water and required a formulated detergent to clean. Vitamin D3 had the lowest recommended daily intake at 5-10 mcg and is the most toxic active in rats and mice with a LD50 of 5-50 mg/ kg. The liquid or gel caplets required the same or longer cleaning time to remove the dry residue. The cleanability studies showed the hardest-to-clean vitamins were the liquid form of vitamins A, D, E and K; vitamins K and D were the hardest dry forms to clean. Vitamin E liquid required a combination of two detergents and was the hardest to clean of the samples evaluated in the study. For minerals, the solubility information indicated that ferrous sulfate, potassium gluconate, and zinc gluconate were soluble in water, but in the final dosage forms, none were successfully cleaned with deionized water. Selenium is the most toxic substance in this group, based on an oral LD50 of 3-7 mg/kg in rats and mice. Ferrous sulfate was the hardest to clean mineral as determined by our cleanability studies, in dry and compacted powder, requiring 5% v/v of the alkaline detergent. Magnesium citrate was the second hardest to clean requiring a 1% v/v alkaline detergent to successfully remove the product. Based on the results obtained in this evaluation, several options may be recommended for grouping. For simplification purposes, it is assumed that the products evaluated are manufactured on the same equipment; however, this may not be the actual case.

Using liquid vitamin E as the hardest-toclean soil. Liquid vitamin E was the only product requiring a two-detergent combination. Overall, this was the most difficult soil to clean, so one option is to clean all other products using the same cleaning procedure recommended for liquid vitamin E. Validation can be performed for liquid vitamin E, with the acceptable residual value being based on the limits for the most toxic active in the group, selenium. A preliminary evaluation may be necessary to confirm that liquid vitamin E can be successfully cleaned down to the pre-set limits. If this is not feasible, then two separate validations could be conducted using the cleaning procedure recommended for liquid vitamin E. One validation is conducted for liquid vitamin E with cleaning limits based on the toxicity of the next most toxic active. The other valida68 Journal of Validation Technology [Winter 2012]

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tion is conducted for selenium based on the toxicity limits for selenium. The combination of these two studies would constitute the validation of the worst cases within the group in terms of hardest-to-clean and most toxic soils.

Using liquid vitamin E, vitamin A, vitamin D, and compacted ferrous sulfate as representative hardest-to-clean soils. Because liquid vitamin E was the only product requiring a two-detergent combination, a validation study could be performed in which the recommended cleaning procedure and the acceptable residual value are based on liquid vitamin E only. This will constitute a “one-product” matrix and will be applicable only for cleaning liquid vitamin E. The second product matrix includes all remaining products and is based on the cleaning procedure recommended for liquid vitamin A, liquid vitamin D, and compacted ferrous sulfate, which follow the same procedure. A validation can be performed for one of these soils, with the acceptable residual value being based on the limits obtained for selenium, or two separate validations studies could be conducted following the cleaning procedure recommended for liquid vitamin A, liquid vitamin D, and compacted ferrous sulfate. One validation is conducted for any of the aforementioned soils with cleaning limits based on the toxicity of the next most toxic active. The other validation is conducted for selenium based on the toxicity limits for selenium. Developing a single cleaning procedure for a number of products that are manufactured in the same equipment train using laboratory studies can allow the use of scientifically justified grouping strategies. Grouping strategies can significantly reduce the extent of cleaning validation protocols. A reduction in cleaning validation protocols can save time, resources, and money without compromising quality.

REFERENCES 1. Merck, The Merck Index, Whitehouse Station, NJ, 12th Edition, 1996. 2. USP, USP 33 NF 28, October 1, 2010–February 1, 2011. 3. Hall, W.A., Cleaning for Bulk Pharmaceuticals Chemicals in Validation of Bulk Pharmaceutical Chemicals; edited by D. Harpaz and I.R. Barry. Buffalo Grove, IL., USA: Interpharm Press. PP 335-370, 1997. 4. STERIS Corporation, Technical Tip #3031, Residue Limits for Cleaning Agents, 2003. 5. Kramer, H.J. et al., “Conversion Factors Estimating Indicative Chronic No-Observed-Adverse-Effect Levels from Short-Term Toxicity Data,” Regulatory Toxicology and Pharmacology, vol. 23, 249-255, 1996. g x p a n d j v t . co m

6. Layton, D.B. et al., “Deriving Allowable Daily Intakes for Systemic Toxicants Lacking Chronic Toxicity Data,” Regulatory Toxicology and Pharmacology, vol. 7, 96-112, 1987. 7. LeBlanc, D.A., Validated Cleaning Technologies for Pharmaceutical Manufacturing; Englewood, CO., USA: Interpharm Press. PP 121-140, 2000. 8. Dolan, D.G., B.D. Naumann, E.V. Sargent, A. Maier and M.L. Dourson, “Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations,” Regul. Toxicol. Pharmacol. 43, 1-9, 2005. 9. Hall, W.A., “Residue Group Strategies,” Chapter 13 in Cleaning and Cleaning Validation, Volume 1 by Paul Pluta, PDA and Davis Healthcare International Publishing LLC, p 265-279, 2009. 10. Dietary Reference Intakes: Vitamins: The National Academics, 2001. 11. Subcommittee on the Tenth Edition of the Recommended Dietar y Allowances, Food and Nutrition Board, Commission on Life Sciences National Research Council, Recommended Dietary Allowances, 10th Edition, pages 284-285, 1989. 12. Kamm, J.J., “Preclinical and Clinical Toxicology of Selected Retinoids,” in Sporn, M.B. et al. ed. The Retinoids, Vol. 2, New York, Academic Press, pp. 287-326, 1984. 13. Herold, M., “Toxicology of Vitamin A Acid,” Acta Dermato-Venereologica, Vol. 74, Supplementum, pp. 29-32, 1975. 14. Fo gar t y, P. Inv ivo High T hroughput Toxico lo g y Screening Method, U.S. Patent 6,365,129; Washington, D.C.: United States Patent and Trademark Office, 2002. 15. “Safety (MSDS) data for ascorbic acid.” Oxford University. 2010-09-03. http://physchem.ox.ac.uk/MSDS/AS/ ascorbic_acid.html. Retrieved 2011-08-22 16. Sanseverino, J., “Ascorbic Acid,” in Wexler, P. et al. ed. Encyclopedia of Toxicology, 2nd ed., Oxford: Elsevier, p.182-184, 2005. 17. Material Safety Data Sheet for DSM Dry Vitamin D3 100 SD/S 5005043 Version 1.3 dated 07/07/2010. 18. “Final Report on the Safety Assessment of Tocopherol, Tocopheryl Acetate, Tocopheryl Linoleate, Tocopheryl Linoleate/Oleate, Tocopheryl Nicotinate, Tocopheryl Succinate, Dioleyl, Tocopheryl Methylsilanol, Potassium Ascorbyl Tocopheryl Phosphate, and Tocophersolan,” International Journal of Toxicology, November 2002 21 (3 Suppl): 51-116. 19. Krasavage, WJ and Terhaar, CJ., d-alpha-Tocopheryl poly(ethylene glycol) 1000 succinate. Acute Toxicity, Subchronic Feedings, Reproduction, and Teratologic Studies in the Rat, International Journal of Toxicology, Vol. 25, (2) pp. 273-278, 1977.

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20. Molitor, H. and Robinson, H.J., Oral and Parenteral Toxicity of Vitamin K1, phthicol and 2-methyl-1,4naphthoquinone. Proceedings of the Society for Experimental Biology and Medicine, 43, 125-128, 1940. 21. “Safety (MSDS) data for calcium carbonate,” Sciencelab. com 11/01/2010, http://www.sciencelab.com/msds. php?msdsld=9927119, Retrieved Aug. 22, 2011. 22. Subcommittee on the Tenth Edition of the Recommended Dietar y Allowances, Food and Nutrition Board, Commission on Life Sciences National Research Council, Recommended Dietary Allowances, 10th Edition, pages 284-285, 1989. 23. Madinaveitia, JL., “Ferrocenes as Haematinics,” British Journal of Pharmacology, Vol. 24, pp. 352-359, 1965. 24. Yeary, R.A. et al., “Acute Toxicity of Drugs in Newborn Animals,” Journal of Pediatrics Vol. 69 (4) pp. 663-667, 1966. 25. Vuignier, BI et al., “Effect of magnesium Citrate and Clidinium Bromide on the Excretion of Activated Charcoal in Normal Subjects DICP,” The Annals of Pharmacotherapy Vol. 23 pp. 26-29, 1989. 26. Zwerling, H., “Hypermanesemia-Induced Hypotension and Hypoventilation,” Journal of the American Medical Association Vol. 266 (17) pp. 2374-2375, 1991. 27. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate, 2004, by the Panel on Dietary Reference Intakes for Electrolytes and Water, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, http://www.nap.edu/catalog/10925.html, pp. 234-235. 28. Kiso to Rinsho, Clinical Report, Vol. 20 (9) pp. 217-226. 29. Mizuta, T. General Pharmacological Study of CitrateCitric Acid Combination (Uralyt-U®) Oyo Yakuri: Pharmacometrics Vol. 21, pp. 715, 1981. 30. EMEA/MRL/249/97-Final October 1997, The European Agency for the Evaluation of Medicinal Products Veterinary Medicines Evaluation Unit, EMEA/MRL/249/97Final October 1997, Committee for Veterinary Medicinal Products – Potassium and Sodium Salts of Selenium Summary Report . 31. Wang, B et al. 2006 “Acute Toxicity of Nano- and MicroScale Zinc Powder in Healthy Adult Mice,” Toxicology Letters, Vol. 161, pp. 115-123. JVT

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ARTICLE ACRONYM LISTING ADI DI GTF LD50 MACO TTC VC WBF

Acceptable Daily Intake De-Ionized Glucose Tolerance Factor Lethal Dose for 50% of Population Maximum Allowable Carry-Over Threshold Toxicological Concern Visually Clean Water Break-Free

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