1: 2 Vials
MANUFACTURING DIRECTIONS 1. Place 153.10 L of Item 11 and 117.95 L of Item
14 into appropriate vessels, bubble Item 13 through the solution for 15 min, and then blan-ket with Item 13.
2. Dissolve Item 7 in 13.3 L of hot Item 14 (50∞C to 60°C). Allow to cool. Add to the vessel above.
3. Add, with constant stirring, Items 15, 1, 10, 6, 5, and 4. Allow each ingredient to dissolve before proceeding.
4. Place Item 9 in a suitable container on a hot plate with stirrer and heat to 40∞C to 50°C (do not exceed 60°C), and cover with a blanket of Item 13. Do not pass gas through solution.
5. With constant stirring, add Items 2, 8, and 3 to Item 9 and allow for 5 to 6 min to mix. Carefully watch temperature — the solution should become crystal clear; turn off the heat.
6. Using 10 mL at a time, add 15.2 L of Item 11 to the polysorbate fat-soluble vitamin mix-ture. Allow the liquids to mix completely after dilution.
7. With constant stirring, pour the polysorbate mixture as a thin stream into the aqueous vita-mins. Work slowly; transfer final drops with a rubber policeman.
8. Dissolve Item 12 in 145.81 L of Item 14 and cool it to room temperature.
9. Add 10% Item 12 to a pH of 4.9 ± 0.1; allow mixture to cool.
10. Add 10% Item 12 to a final pH of 5.1 to 5.15.
11. QS to final volume with Item 14. Cover with aluminum foil; flush with Item 13.
12. Sample after 3 days. After approval, fill by fil-tering through a 0.22-mm filter into a reservoir covered with CO2 for filling; pre- and postflush vials (amber) with CO2 during filling.
Bill of Materials Vial 1 (Batch Size 561 L)
Scale/mL Item Material Quantity UOM
20.00 mg 1 Ascorbic Acid, USP, 50% excess 16.83 kg
660 IU 2 Vitamin A, use Retinol in Polysorbate 80, 50% excess, labeled 555.39 million units, factored for potency (e.g., 1.5 million units/g)
— —
40 IU 3 Vitamin D, 25% excess, labeled for 40 million units, factored for potency such as 28 million units/g
— —
0.67 mg 4 Thiamine Hydrochloride, USP, 25% excess 469.84 g
0.97 mg 5 Pyridoxine Hydrochloride, USP, 25% excess 680.21 g
7.94 mg 6 Niacinamide, USP, 10% excess 4899.77 g
2.81 mg 7 Dexpanthenola 1970.51 g
2.00 mg 8 dl-Alpha Tocopheryl Acetate, NF, 25% excess 1402.50 g
48.00 mg 9 Polysorbate-20b 26.928 kg
20.00 mg 10 Gentisic Acid Ethanolamide 11.22 kg
0.30 mL 11 Propylene Glycol 169.30 L
QS mL 12 Sodium Hydroxide, 10% solution, for pH adjustment 12,807.63 g
QS — 13 Carbon Dioxide QS —
QS mL 14 Water for Injection, USP, QS to 561.00 L
0.984 mg 15 Riboflavin, 25% excess 690.03 g
a Includes 2% excess.
bAdjust for contribution from Vitamin A and Vitamin D.
MANUFACTURING DIRECTIONS 1. Prepare a solution of Item 6 by dissolving 20.58
kg in 350 L of Item 8.
2. Weigh five times the amount of Item 2 required for the batch and dissolve in 1 L of Item 8.
3. Weigh Item 1 and completely dissolve in about 280.50 L of Item 6 solution prepared in Step 1.
4. Add Item 3 and dissolve completely.
5. Take 200 mL of Item 2 solution prepared in Step 2 and add to the compounding tank; mix thoroughly. Note: Item 2 is hygroscopic, and weighing small amounts may result in excessive variation; this step precludes this variation.
6. Add Item 4 and mix until dissolved.
7. Adjust volume to ca. 540 L with Item 8.
8. Check pH and adjust to 7.9 to 8.0, if necessary, with Item 5 solution.
9. Check pH check and filter through a 0.22-mm filter and fill under N2 in amber vials.
STOPPER STERILIZATION
Dissolve 6.375 kg of disodium edetate in 255 kg of puri-fied water. Rinse stoppers with water that has undergone reverse osmosis (RO). Cover the stoppers with disodium edetate solution and autoclave at 121°C for 1 h. Rinse stoppers at least three times with RO water.
2: Lyophilized in Covial
Bill of Materials Vial 2 (Batch Size 561 L)
Scale/mL Item Material Quantity UOM
80.00 mg 1 Folic Acid, USP, 25% excess 56.10a g
1.00 mg 2 Cyanocobalamin, USP, 25% excess 701.25b mg
12.00 mg 3 Biotin FCC, 25% excess 8.42 g
30% mL 4 Propylene Glycol 168.30 L
QS mL 5 0.2 M Citric Acid for buffer QS mL
QS mL 6 0.2 M Sodium Citrate for buffer QS mL
QS mL 7 0.2 M Sodium Hydroxide QS mL
QS mL 8 Water for Injection, USP, QS to 561.00 L
a Calculate on anhydrous basis.
b Calculate the raw material on the assay value.
Bill of Materials Lower Chamber (Batch Size 1 L)
Scale/mL Item Material Quantity UOM
200.00 mg 1 Folic Acid, 25% excess 250.00 mg
2.50 mg 2 Cyanocobalamin, 25% excess 3.125 mg
30.00 mg 3 Biotin, 25% excess 37.50 mg
7.02 mg 4 Dexpanthenol, 20% excess 8.43 g
19.84 mg 5 Niacinamide, 20% excess 23.81 g
5.00 mg 6 Mannitol 5.00 g
2.43 mg 7 Pyridoxine Hydrochloride, 20% excess 2.92 g
QS mL 8 0.2 M Sodium Hydroxide to buffer QS mL
QS mL 9 0.2 M Potassium Phosphate Monobasic to buffer QS mL
QS mL 10 Water for Injection, QS to 1.00 L
QS — 11 Nitrogen Gas QS —
Note: The lower chamber is lyophilized and filled first, followed by the upper chamber (see Manufacturing Directions).
MANUFACTURING DIRECTIONS 1. Heat 50 mL of Item 10 to 60°C and completely
dissolve Item 4. Keep aside.
2. Prepare a 0.2-M Item 8 solution by dissolving 4 g of Item 8 in 500 mL of Item 10.
3. Prepare a 0.2-M Item 9 solution by dissolving 13.61 g of Item 9 in 500 mL of Item 10.
4. Weigh accurately 312.5 mg of Item 2 and dis-solve in 1 L of Item 10. Keep aside.
5. Weight Item 1 and dissolve in 234 mL of Item 8 solution prepared in Step 2. Check pH.
6. Immediately add 246 mL of Item 9 solution prepared in Step 3.
7. Mix and note pH.
8. Add Item 3 and dissolve completely.
9. Add 10 mL of Item 2 solution prepared in Step 4.
10. Add all other ingredients one by one (including Item 4 solution prepared in Step 1) with the exception of Item 7. Check pH.
11. Add Item 7 to solution, stir to dissolve, and check pH again.
12. Adjust the pH between 8.0 and 10.0 with Item 8 or 9 solution. QS to volume with Item 10.
13. Flush Item 11 for 10 min.
14. Filter through a sterile 0.22-mm filter into the sterile area and fill the vials.
15. Lyophilize as follows:
a. Prepare shelves to –40°C or below.
b. Transfer the filled vials in covered trays onto the shelves of the lyophilizer (or if the system is autoloading, following directions accordingly).
c. Place thermocouples in appropriate vials.
d. The product thermocouples should register –35°C for at least 3 h.
e. Start condenser; let the condenser cool to –55°C or below.
f. Start vacuum and let the chamber achieve a level of 100 microns or below.
g. Set the temperature controller at –30°C and let the lyophilizer run for 24 h.
h. Raise the shelf temperature to 0°C and let run for additional 6 h.
i. Raise the shelf temperature to +20°C and run for additional 12 h.
j. Raise shelf temperature to +35°C and run additional 6 h.
k. Bleed chamber to atmospheric pressure with Item 11.
l. Open the lyophilizer chamber door, with-draw nine sample vials (three from each of the top, middle, and lower shelves repre-senting the left, center, and right positions, respectively) for determination of moisture.
m. Submit samples to QC for moisture test while keeping the chamber door shut and vacuum pulled.
n. If samples pass the test, remove them; if the samples fail the test, prolong lyophilization cycle.
o. For finished samples, place center seal, fill the upper chamber, and seal with top seal.
p. Place aluminum ferrule around the top seal.
q. Deice and clean lyophilizer.
MANUFACTURING DIRECTIONS 1. Prepare 150 mL of 10% Item 6 solution in Item
5 and let it cool to room temperature.
2. Place about 500 mL of Item 5 into a clean compounding tank and bubble Item 7 for
10 min. Keep a CO2 blanket over the solution during the remainder of the compounding steps.
3. Add Items 2, 1, 3, and 4, in order, to the tank and stir to a complete solution.
4. Bring to about 800 mL with Item 5 and check pH.
Bill of Materials Upper Chamber (Batch Size 1 L)
Scale/mL Item Material Quantity UOM
50.00 mg 1 Ascorbic Acid, USP, 50% excess 75.00 g
2.46 mg 2 Riboflavin-5¢-Phosphate USP, 20% excess 2.95 g
1.68 mg 3 Thiamine Hydrochloride, USP, 50% excess 2.52 g
0.20 mg 4 Gentisic Acid Ethanolamide 200.00 mg
QS mL 5 Water for Injection, USP, QS to 1.00 L
QS mL 6 10% Sodium Hydroxide (w/v) for pH adjustment QS mL
QS — 7 Carbon Dioxide QS —
5. Adjust the pH between 4.0 and 4.5 with 10%
Item 6 solution prepared in Step 1.
6. QS to final volume with water for injection.
7. Filter through a sterile 0.22-mm filter into the sterile room. Keep the receiving jug under CO2 blanket and protected from light.
8. Fill the upper chamber.
3: Lyophilized with Diluent
MANUFACTURING DIRECTIONS 1. Measure 3.0 L of Item 8 into a 4-L beaker, heat
to 95°C, and hold it at that temperature and agitate vigorously.
2. Add Items 6 and 7. Then add Item 5.
3. Add Item 2. Once the ingredients are in solu-tion, cool the solution to 50°C with agitation in a water bath; let it stand to room temperature.
4. Add Items 4, 1, and 3 in order. Measure pH and adjust with Item 9 to 4.3 to 4.5.
5. QS to 3.9 L with Item 8.
6. Filter aseptically into a previously sterilized vessel by passing through filter.
7. Aseptically fill into 10-mL vials. Place stoppers.
8. Lyophilize as follows:
a. Freeze to –40°C for not less than 3 h.
b. Turn vacuum on to less than 300 microns for a 20-h cycle time.
c. Raise the temperature to +15∞C for at least 8 h. Break vacuum with N2 and open under aseptic conditions.
d. Stopper and seal with aluminum three-piece caps.
MANUFACTURING DIRECTIONS 1. Add 20 L Item 5 to a glass-lined steam jacketed
kettle and heat to 95°C with stirring.
2. Add Item 2, begin continuous N2 gas flush, and cool to 50°C with cold water in jacket.
3. Add Items 1 and 3 slowly to avoid foaming and agitate well until pH is between 5.8 and 6.0.
Fumes of CO2 need to be vented out.
4. Add Item 4. Filter aseptically into a previously sterilized bottle.
5. Store in cold room until filling. Fill aseptically into 10-mL vials with N2 flush.
6. Autoclave sealed vials at 105°C and 5 psi for 10 min.
7. Remove from autoclave and cool rapidly by squelching into 21°C water.
Bill of Materials B-Complex Lyophilized (Batch Size 3.9 L)
Scale/mL Item Material Quantity UOM 50.00 mg 1 Thiamine Hydrochloride, USP, ampoule grade, 10% excess 195.00 g
5.00 mg 2 Riboflavin, USP, 14% excess 14.40 g
— 3 Riboflavin-5¢-Phosphate (combined with above for scale) 8.00 g
10.00 mg 4 Pyridoxine HCl, USP, 10% excess 39.00 g
100.00 mg 5 Niacinamide, USP, 10% excess 390.00 g
0.22 mg 6 Propyl Paraben USP 0.78 g
0.89 mg 7 Methyl Paraben, USP 3.16 g
QS mL 8 Water for Injection, QS to 3.90 L
QS mL 9 Sodium Bicarbonate, USP, for pH adjustment (4.3–4.5) QS mL Note: All ingredient quantities are based on 100% assay amounts; adjust accordingly; entire preparation protection under N2
and light.
Bill of Materials (Batch Size 45 L)
Scale/10 mL Item Material Quantity UOM 2000.00 mg 1 Ascorbic Acid, USP, ampoule grade, 10% excess 9.90 kg
1.00 mg 2 Sequestrene Disodium Purified 4.50 g
QS mL 3 Sodium Bicarbonate, USP, for pH adjustment (5.8–6.0) 4.695 (ca.) kg
10.00 mg 4 Sodium Bisulfite, USP 45.00 g
QS mL 5 Water for Injection, QS to 45.00 L