Protocol for Manufacturing Vessel

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ABC Pharmaceutical Company


Equipment Name

Issued on:

Protocol Number




Soft Product Compounding

Equipment Name




Written by

Validation Officer Reviewed by

Manager QA

Production Manager

QC Manager Authorized by

QA Director

Manufacturing Vessel


1000 L

Company, Country

Signature & Date

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Signature & Date

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36.1.1 Objective

The objective of this protocol is to demonstrate that the cleaning procedure will successfully and consistently reduce the level of residues to a predetermined level of acceptability for the 1000-L manufacturing vessel.

36.1.2 Scope

This protocol will cover cleaning of the semisolid manufacturing vessel (Figure 36.1.1) for the following cream and ointment products (Table 36.1.1).

The above-mentioned products are divided into different categories (group) based on water solubility, toxicity, and batch size. From each group, one worst-case products analyzed for cleaning validation (Table 36.1.2).

Since a natural herb is manufactured in both ointment and cream forms, the cleaning procedure for the ointment is deemed sufficient to meet the criteria for both the dosage forms due to more difficult cleaning of the oily product (ointment).

Based on the criteria mentioned above, selection of natural herb ointment and oxytetra-cycline ointment as worst cases for less solubility and high toxicity, respectively, will also validate the cleaning procedure for cream products. However, to further enhance the

FIGURE 36.1.1

1000-L manufacturing vessel.

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TABLE 36.1.1

Product Matrix


Active Ingredient/s

Batch Size

Toxicity LD5

Solubility Scalea

Ointment/Cream Betamethasoneb Gentamicinb Nystatin,b neomycin sulfate

Hydrocortisoneb Cinchocaine HCl ointment

Nystatin topicalb Fusidic acidb Acyclovirb Tribenoside,b lidocaine HCl

Betamethasone valerate Gentamicin sulfate Nystatin, neomycin sulfate, gramicidin, triamcinolone acetonide

Hydrocortisone Cinchocaine HCl, Betamethasone valerate

Nystatin topical Fusidic acid Acyclovir

Tribenoside, lidocaine HCl

Natural herbsb Oxytetracycline Fluticasone propionateb Clobetasol propionateb

Ointmentc Tetracycline HCl Lidocaine

Cream Products Cream A

Miconazole nitrate Diclofenac sodium Zinc oxide cream Dexpanthenol cream Fusidic acid, betamethasone cream valerate

Natural herbs Oxytetracycline Fluticasone propionate

Clobetasol propionate

Tetracycline HCl Lidocaine

Diethylamine salicyclate, chlorobutol, menthol Miconazole nitrate Diclofenac sodium Zinc oxide Dexpanthenol Fusidic acid, betamethasone

1000 200 1000

1000 200

1000 1000 15 250

1000 200 1000


750 750


1000 1000 1000 1000 1000

>3 g/kg oral rat 10,000 mg/kg oral rat

8.0 g/kg oral mouse

>3 g/kg oral rat 10,000 mg/kg oral rat

292 mg/kg oral mouse Nontoxic

680 mg/kg oral rat

6443 mcg/kg oral rat 292 mg/kg oral mouse

150 mg/kg oral rat

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TABLE 36.1.1 (continued)

Product Matrix


Active Ingredient/s

Batch Size

Toxicity LD5

Solubility Scalea

Miconazole nitrate cream Ibuprofen cream Silver sulfadiazine Cream

Miconazole nitrate

Ibuprofen Silver sulfadiazine

1000 6

1000 636 mg/kg oral rat 7

1000 >10,000 mg/kg oral rat 7

a Solubility key: 1. very soluble in water, 2. freely soluble in water, 3. soluble in water, 4. sparingly soluble in water, 5. slightly soluble in water, 6. only very slightly soluble in water, 7. practically insoluble in water or insoluble.

b Products manufactured in both cream and ointment form.

c For the cleaning validation study ointment dosage form would be considered as worst case due to its oily nature.

confidence, a high toxicity worst case is selected in cream products as well. Diclofenac sodium cream is most toxic (diclofenac sodium) in all the cream products; therefore, this product will be taken as another worst case for cleaning procedure validation.

Large batch size is also covered in the natural herbs ointment validation, which is 1000 kg; therefore a separate case of largest batch size will not be taken for validation.

36.1.3 Responsibilities

The following personnel are responsible for the execution of this protocol:

Validation officer/production officer/QA inspector/machine operator; for details, please refer to Attachment II.

TABLE 36.1.2

Worst Case for Manufacturing Vessel

Products Justification for Worst Case


Natural herb Less solubility (7), least soluble three actives

Oxytetracycline HCl High toxicity level (LD50 6.443 mg/kg oral rat)


Diclofenac sodium cream High toxicity level (LD50 150 mg/kg oral rat)

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36.1.4 Description of the Cleaning Process

The manufacturing vessel is cleaned manually as per SOP No. ABC-001.

1. Label the equipment "Under Cleaning"

2. Transfer the water and soap to the vessel by vacuum through the connected pipe

3. Set the vessel's temperature indicator at 90°C and start heating

4. Start the agitator and homogenizer at speed II, with recirculation

5. Continue mixing and homogenizing for a further 20 min after reaching 90°C

6. Connect the outlet valve of the vessel with a hose and drain out the washing in a 200-L stainless steel drum

7. Lift the vessel lid and clean thoroughly the agitator angles and the lower side of the lid with a sponge

8. Rinse the inside and the lower side of the lid of the vessel with purified water for 3 min by means of a 1" hose

9. Drain out the water in the drainage by means of a hose

10. Dismantle all the joints, valves, and pipes

11. Clean all joints, valves, and pipes with sponge wetted with 1% soap

12. Flush each part with purified water by means of a 1" hose for 30 s

13. Spray the inside and outside of the vessel with 70% alcohol

14. Label the vessel "Clean"

15. Make entries in the cleaning log and label the equipment "Clean" with the date of cleaning and signature of the supervisor as per SOP No. ABC-002

36.1.5 Identification of Critical Parameters

The critical parameters should be monitored as stated in Table 36.1.3.

TABLE 36.1.3

Critical Parameters


Specification Actual Reading

Temperature Time

Purified water volume Soap quantity

20 min after 90°C 200 L 500 mL

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36.1.6 Description of the Sampling Process Sampling Technique

The following sampling techniques are used to take the sample from the vessel:

a. Surface swabs (sterile cotton swabs wetted with purified water)

b. Water rinses (in clean bottle as listed below) Surface Swabs Procedure for Sampling

Sampling should be performed as per SOP No. ABC-003; the validation officer is responsible for taking the swab sample. Samples of the internal surfaces are taken by moistening the swab (ready-made sterile cotton swab) with a suitable solvent (purified water). Sample a 25-cm2 area and place the swab in a test tube containing 10 mL of solvent (purified water). Swab sample from each part of manufacturing vessel is collected as per Table 36.1.4. Sampling Precautions Before taking the sample, wear i. Hand gloves ii. Face mask

TABLE 36.1.4

Surface Swabs Sampling Description


Sample ID


Manufacturing vessel

As per Figures 36.1.2 and 36.1.3

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FIGURE 36.1.2

Mixer agitator.

Cleaning Validation Protocol





Vessel inner surface and mixer.

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R1-R5 & R6 Rinse Sample

FIGURE 36.1.4

Rinse sampling point (bottom drain). Rinse Sample

The rinse sampling technique is used to take samples from the vessel. After the completion of cleaning, take rinse samples from the bottom of the vessel sampling points (Figure 36.1.4) R1-R5 for the chemical analysis and R6 for bio-burden (Table 36.1.5). Handling of Samples

Samples are kept in the refrigerator if not testing immediately

Analyze the samples within 2 h after collection for pH, conductivity, and TOC and detergent detection

TABLE 36.1.5

Rinse Sampling Description

Description Sample Location Sample ID

Manufacturing vessel Bottom drain point R1-pH

R2-conductivity R3-TOC

R4-detergent determination



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HPLC analysis (maximum allowable carryover) and bio-burden must be performed within 24 h

36.1.7 Test Functions Visual Inspection

Inspection of cream and ointment manufacturing vessel is performed visually. The vessel should be clean and free from any traces of residues. For detailed information about sample ID, volume, testing specification, and testing method, see the sampling and testing plan in Table 36.1.6.

36.1.8 Verification of Documents i. Verify the cleaning procedure No. ABC-001.

ii. Verify the vessel's cleaning logbook records.

iii. Verify the staff training record (refer to Attachment IV).

36.1.9 Documentation i. All analysis results are recorded in the analysis logbook.

ii. Printouts and chromatograms are attached to the validation report and a copy of that is also attached to the analytical logbook.

iii. All analysis and data should be verified by a second analyst.

TABLE 36.1.6

Sampling and Testing Plan

TABLE 36.1.6

Sampling and Testing Plan

S. No.


Identification Labeling

Sample Volume

Sampling Bottle

Testing Specifications

Testing Method/ Procedure No.




100 mL

Clean bottle

5-7 pH unit





100 mL

Clean bottle

NMT 5.0 js/cm




50 mL

Clean bottle

NMT 500 ppb





50 mL

Clean bottle



HPLC method




100 mL


NMT 10 cfu/100 mL



Your Company's Logo ) Company's Name iv. All training records are checked by the validation officer.

v. The final report for cleaning validation should be prepared by the validation officer.

36.1.10 Acceptance Criteria a. Visual inspection: The visible internal equipment surfaces and all critical and difficult-to-clean parts are optically free from residue and the color of the final rinse water is comparable to DIW.

b. pH determination: The pH value of the rinse should be in between 5 and 7 and comparable to DIW pH value.

c. Conductivity: The conductivity of the rinse should not be more than the conductivity of the blank DIW sample kept under the same conditions.

d. Total organic carbon: The TOC of the final rinse should be comparable to the blank DIW sample kept under the same conditions (DIW TOC limit is NMT 500 ppb).

e. Detergent detection: No foam is detected on top of the rinse sample after testing.

f. Maximum allowable carryover: The active ingredient in the final rinse is either not detected or is equal to or less than the MAC (calculated theoretically for product).

Based on the solubility and maximum daily dose matrix, the MAC is calculated for each product. The MAC is calculated as follows:

MAC _ TDx BS x SF MAC _ LDD , where MAC is the maximum allowable carryover, TD is a single therapeutic dose, BS is the batch size of the next product to be manufactured in the same equipment, SF is the safety factor, and LDD is the largest daily dose of the next product to be manufactured in the same equipment.

The calculated value is the maximum amount of active ingredient of a certain product that is allowed to be carried over to the next batch.

g. Bio-burden: The bio-burden should not be more than 10 cfu/100 mL for the rinses.

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36.1.11 List of Attachments

Attachment I Description of equipment and product

Attachment II Cleaning/testing responsibilities

Attachment III Training record verification

Attachment IV Rinse analysis results

Attachment V Swab analysis results

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