Acyclovir CV-L1-005-00

CLEANING VALIDATION PROTOCOL
Product: ACYCLOVIR SODIUM INJECTION

Protocol No: CV/L1/005-00 Effective Date:
Title: Acyclovir Sodium Injection
Report ID: CV/L1/005-00
Company: Aurobindo Pharma Ltd.
Facility: Unit –IV [Pashamylaram], Line1, Injection
Prepared By: N.Mishra 02/03/11
Approved By:
____________________ _______________
(Production) Date
____________________ _______________
(QA-Validation) Date
____________________ _______________
(Quality Control) Date
____________________ _______________
(Quality Assurance) Date
Residue limits have been calculated by Cleaning Validation Technologies RESIDUE software
application. The data is stored in the following database: C:\Program Files\RESIDUE\U4Line1.mdb
Page 1 of 21
TABLE OF CONTENTS
S. No. Name of the Content Page No.

1. Objective 1
2. Scope 3
3. Current Product Information 3
4. Product Information 3
5. Bases of calculation 7
6. Drug Product information 9
7. Manufacturing Equipment information 10
8. Sampling procedures information 11
Attachments for MACO limits 12-21
Page 2 of 21
1. Objective
The objective of the cleaning validation plan is to establish and assure with documented evidence that
the cleaning procedures of equipments, In process containers and area in manufacturing modules/Blocks
can reproducibly remove residue of the previous product to levels below the established acceptance
limits.
2. Scope
This documents is applicable for the validation of cleaning procedure for Equipments/Vessels in
injectables, Aurobindo Pharma Limited, Unit-IV, Pashamylaram, Hyderabad.
Company Information
APL, Unit -IV
Pashamylaram
Medak dist, AP 502307
Facility Information
Designation: Injection
Manufacturing Type: Finished Drug Product - Injections
Policy: Worst Case Approach
This protocol has been generated by Cleaning Validation Technologies RESIDUE

software application
3. Current product information

Inclusion of Acyclovir sodium injection
4. Product Information
This report covers limits for the following product(s):

Acyclovir Sodium injection
Azithromycin Injection
Heparin Injection 1000 U/mL
Heparin Injection 2000 U/2 mL
Levofloxacin Injection
Lidocaine HCl Injection
Lidocaine HCl Injection 1
Ondansetron HCl Injection (MDV)
Ondansetron HCl Injection (SDV)
Page 3 of 21
The limits were calculated based on each of the other products being a possible next product
in the manufacturing schedule.
Acyclovir Sodium injection: Azithromycin Injection Heparin Injection 1000 U/mL Heparin
Injection 10000 U/mL Heparin Injection 2000 U/2 mL Heparin Injection 5000 U/mL
Levofloxacin Injection Lidocaine HCl Injection Lidocaine HCl Injection 1 Ondansetron HCl
Injection (MDV) Ondansetron HCl Injection (SDV)
Azithromycin Injection: Acyclovir Sodium injection Heparin Injection 1000 U/mL Heparin
Heparin Injection 1000 U/mL: Acyclovir Sodium injection Azithromycin Injection Heparin
Heparin Injection 2000 U/2 mL: Acyclovir Sodium injection Azithromycin Injection Heparin
Injection 1000 U/mL Heparin Injection 10000 U/mL Heparin Injection 5000 U/mL
Injection 1000 U/mL Heparin Injection 10000 U/mL Heparin Injection 2000 U/2 mL
Levofloxacin Injection: Acyclovir Sodium injection Azithromycin Injection Heparin

Injection 1000 U/mL Heparin Injection 10000 U/mL Heparin Injection 2000 U/2 mL Heparin
Injection 5000 U/mL Lidocaine HCl Injection Lidocaine HCl Injection 1 Ondansetron HCl
Lidocaine HCl Injection: Acyclovir Sodium injection Azithromycin Injection Heparin

Injection 5000 U/mL Levofloxacin Injection Lidocaine HCl Injection 1 Ondansetron HCl
Lidocaine HCl Injection 1: Acyclovir Sodium injection Azithromycin Injection Heparin

Page 4 of 21
Injection 5000 U/mL Levofloxacin Injection Lidocaine HCl Injection Ondansetron HCl
Ondansetron HCl Injection (MDV): Acyclovir Sodium injection Azithromycin Injection

Heparin Injection 1000 U/mL Heparin Injection 10000 U/mL Heparin Injection 2000 U/2 mL
Heparin Injection 5000 U/mL Levofloxacin Injection Lidocaine HCl Injection Lidocaine HCl
Injection 1 Ondansetron HCl Injection (SDV)
Ondansetron HCl Injection (SDV): Acyclovir Sodium injection Azithromycin Injection

Heparin Injection 1000 U/mL Heparin Injection 10000 U/mL Heparin Injection 2000 U/2 mL
Heparin Injection 5000 U/mL Levofloxacin Injection Lidocaine HCl Injection Lidocaine HCl
Injection 1 Ondansetron HCl Injection (MDV)
Based on the inputs provided, residue limits have been calculated using the conventional dosed based
calculations. Calculated limits are expressed as:
L1: Limit in the subsequently manufactured product

L2: Maximum allowable carryover (MAC) in the equipment train
L3: Limit per surface area
L4 (Swab Amt): Limit per swab sample – total amount
L4 (Swab Conc): Limit per desorbed swab sample - concentration
L4 (Rinse): Limit per rinse sample
The formulas for calculating each value are specified in Attachment A.
The “safety factor” used for these calculations is: 0.001
The L1 default value used for these calculations is: 10
Basic information utilized for these calculations on these drug products is given in Attachment B.
Basic information utilized for these calculations on equipment used to manufacture the drug products is
given in Attachment C.
Basic information utilized for these calculations on sampling procedures is given in Attachment D.
Based on the inputs above, for the selected products, limits were calculated for the active of each product
with each of the other products as a possible subsequently manufactured product. These results are
presented in Attachment(s): E, F, G, H, I, J, K, L, M, N, O.
Attachment A
5. Bases of Calculations
Page 5 of 21
The RESIDUE software program utilizes well established principles for calculating limits for actives in
finished drug manufacture (Fourman and Mullen, "Determining Cleaning Validation Acceptance Limits for
Pharmaceutical Manufacturing Operations" Pharm. Technol. 17:4, 54-60, 1993; and LeBlanc, “Establishing
Scientifically Justified Acceptance Criteria for Cleaning Validation of Finished Drug Products” Pharm.
Technol. 19:5, 136-148, 1998).
L1 is the limit of the active of the cleaned product in the next manufactured product. L1 is calculated as
follows:
L1 = (safety factor) X (minimum dose of active of cleaned product)

(maximum dose of the next drug product)
If the dosing frequencies are different (for example, once a day versus once a week), the program normalizes
the dose so that it is compared on the same basis. If a default value for L1 is utilized, that default value is
utilized for L1 in subsequent calculations only if the calculated value for L1 is above the default value. The
units for L1 are either mcg/g or mcg/mL.
L2 is the maximum allowable carryover limit. L2 is calculated as follows:
L2 = (L1) X (minimum batch size of next product)
The next product utilized for batch size in the L2 calculation is the same next product utilized for the L1
calculation. Units for L2 are mcg.
L3 is the limit per surface area. It is calculated as follows:
L3 = (L2)
(total product contact surface area of equipment)
Units of L3 are mcg/cm 2. Note that if equipment surface area is entered in square inches, the program
automatically converts that value to square centimeters and uses the metric conversion for the calculation.
L4 is the limit in the analyzed sample. If the equipment is sampled by swabbing, there are two possible
expressions of L4.
L4 (Swab amt) is the total amount of active per swab. It is calculated as follows:
L4(Swab amt) = (L3) X (area swabbed)
Units of L4(Swab amt) are mcg. If swabbed area is entered as square inches, the program automatically
converts that value to square centimeters and uses the metric conversion for the calculation.
Page 6 of 21
L4(Swab conc) is the concentration of the active in the desorbed swab sample. It is calculated as follows:
L4(Swab conc) = (L3) X (area swabbed)

(amount of desorbing solvent)
Units of L4(Swab conc) are mcg/mL or mcg/g, depending on the units entered for the amount of desorbing
solvent. If swabbed area is entered as square inches, the program automatically converts that value to square
centimeters, and uses the metric conversion for the calculation.
L4 (Rinse) is the concentration of the active in any rinse solution. It is calculated as follows:
L4 (Rinse) = (L3) X (area rinsed)

(amount of rinsing solvent)
Units of L4(Rinse) are mcg/mL. The value used for “area rinsed” is the surface area of the equipment rinsed,
whether it is individual equipment items rinsed separately, or the total equipment surface area for an
equipment train rinsed as the equipment train. The “amount of rinsing solvent” is either directly entered if
the item or train is sampled with a separate, defined sampling rinse, or it is estimated as a “worst-case” if a
grab sample of the final process rinse is the sampling procedure. For equipment rinsed by a CIP process, the
“worst-case” estimate of the “amount of rinsing solvent” is usually 5-10% of the equipment volume. For
equipment rinsed by filling the entire equipment, the “worst-case” estimate of the “amount of rinsing
solvent” is 100% of the equipment volume.
For multiple subsequent products, the value selected for establishing limits for a given equipment item is
based on the lowest L3 value for that equipment item for a given residue.
If values are to be expressed as TOC, then the L1, L2, L3 and L4 values are multiplied by the TOC
percentage of the active.
These calculations represent accepted industry practices for residue limits of actives based on a dose
criterion. In any situation there may be other factors, such as allergenicity, reproductive hazards, and
cytotoxicity, which should be evaluated to see if values calculated on dosing criteria are acceptable and
stringent enough.
Page 7 of 21
Attachment B
6. Drug Product Information
NAME TYPE ACTIVE ACTIVE DOSE DOSE BATCH

CONC MIN MAX MIN
Levofloxacin Injection Injections Levofloxacin I 25 mg/mL 1 3 200 L
Ondansetron HCl Injections Ondansetron 2 mg/mL 1 8 60 L

Injection (SDV) HCl
Ondansetron HCl Injections Ondansetron 2 mg/mL 1 8 60 L
Injection (MDV) HCl
Heparin Injection 2000 Injections Heparin 5.56 mg/mL 1 8 40 L
U/2 mL
U/mL
U/mL
Heparin Injection Injections Heparin 55.56 mg/mL 1 8 70 L
10000 U/mL
Lidocaine HCl Injections Lidocaine HCl 10 mg/mL 1 10 45 L
Injection
Lidocaine HCl Injections Lidocaine HCl 10 mg/mL 1 10 215 L
Injection 1
Azithromycin Injection Injections Azithromycin 50 mg/mL 1 1 202 L
Acyclovir Sodium Injections Acyclovir 50 mg/mL 1 6 110 L

injection Sodium
Page 8 of 21
Attachment C
7. Manufacturing Equipment Information
Following are the equipments used along with the product contact surface area:
Surface area
Equipment Equipment ID No. SOP No.
[cm2 ]
Mixing Vessel 125 L PN/MVESL-010 13881.626
Mixing Vessel 1500 L 2 PN/MVESL-012 69236.13
PN043**
Mixing Vessel 1500 L 1 PN/MVESL-013 69236.13
Product Transfer Line PN/PTLIN-001 25469.8274
Buffer Tank NA 3242.75
Filling Manifold* NA 503.044
PN020**
Filling pumps * NA 977.664
Filling Nozzles* NA 288.88
**Current version shall be followed
Page 9 of 21
Attachment D
8. Sampling Procedures Information
For each active, the swab sampling calculation was performed using the following surface area and the
following swab desorption solvents and amounts.
Product Swabbed Area Solvent Desorption Amount

Azithromycin Injection 25.0 sq cm WFI 10.0 mL
Heparin Injection 1000 U/mL 25.0 sq cm WFI 10.0 mL
Heparin Injection 2000 U/2 mL 25.0 sq cm WFI 10.0 mL
Levofloxacin Injection 25.0 sq cm WFI 10.0 mL
Lidocaine HCl Injection 25.0 sq cm WFI 10.0 mL
Lidocaine HCl Injection 1 25.0 sq cm WFI 10.0 mL
Ondansetron HCl Injection (MDV) 25.0 sq cm WFI 10.0 mL
Ondansetron HCl Injection (SDV) 25.0 sq cm WFI 10.0 mL
For rinse sampling, the rinse sampling involved a separate sampling rinse. Rinse sampling involved
sampling each equipment item separately.
For rinse sampling, the following parameters were used:
Separate sample, sampled individually
Equipment Volume for Rinse

Mixing Vessel 500 L 25.0 L
Product Transfer Line 5.00 L
Mixing Vessel 1500 L 2 75.0 L
Buffer Tank 1.000 L
Filling Manifold* 1.000 L
Filling pumps and Nozzles* 1.000 L
Mixing Vessel 1500 L 1 75.0 L
NOTE:*Because of very low surface area of filling items (Manifold, pumps and nozzles) the limit will
be considered as 10 ppm for both swab and rinse samples
Page 10 of 21
Attachment E
Limits for Acyclovir Sodium injection
The following L1, L2, L3, and L4 limits were calculated for the active ingredient, Acyclovir Sodium, for
Acyclovir Sodium injection, with only the worst case reported (based on the lowest L3 value). The L4
values are given as the active.
Lidocaine HCl Injection Limit as Active

L1 10.0 mcg/mL
L2 450,000 mcg
L3 3.96 mcg/sq cm
L4 Swab Sampling Limits

L4 (Swab Conc) 9.90 mcg/mL
L4 Rinse Sampling Limits for Individual Equipment Items
Name L4 (Rinse)
Buffer Tank 12.8 mcg/mL
Filling Manifold 1.99 mcg/mL
Filling nozzles 1.14 mcg/mL
Filling pumps L1 3.87 mcg/mL
Mixing Vessel 125 L 8.80 mcg/mL
Mixing Vessel 1500 L 1 3.66 mcg/mL
Product Transfer Line 20.2 mcg/mL
Page 11 of 21
Attachment F
Limits for Azithromycin Injection
The following L1, L2, L3, and L4 limits were calculated for the active ingredient, Azithromycin, for
Azithromycin Injection, with only the worst case reported (based on the lowest L3 value). The L4 values
are given as the active.
Ondansetron HCl Injection (MDV) Limit as Active

L1 10.0 mcg/mL
L2 600,000 mcg
L3 4.43 mcg/sq cm
Ondansetron HCl Injection (MDV) Limit as Active

Name L4 (Rinse)
Page 12 of 21
Attachment G
Limits for Heparin Injection 1000 U/mL
The following L1, L2, L3, and L4 limits were calculated for the active ingredient, Heparin, for Heparin
Injection 1000 U/mL, with only the worst case reported (based on the lowest L3 value). The L4 values are
given as the active.

L1 0.923 mcg/mL
L2 41,550 mcg
L3 0.417 mcg/sq cm

Name L4 (Rinse)
Page 13 of 21
Attachment H

L1 0.923 mcg/mL
L2 41,550 mcg
L3 0.366 mcg/sq cm

Name L4 (Rinse)
Page 14 of 21
Attachment I
Limits for Heparin Injection 2000 U/2 mL
Injection 2000 U/2 mL, with only the worst case reported (based on the lowest L3 value). The L4 values are

L1 0.923 mcg/mL
L2 41,550 mcg
L3 0.798 mcg/sq cm

Name L4 (Rinse)
Page 15 of 21
Attachment J

L1 0.923 mcg/mL
L2 41,550 mcg
L3 0.417 mcg/sq cm

Name L4 (Rinse)
Page 16 of 21
Attachment K
Limits for Levofloxacin Injection
The following L1, L2, L3, and L4 limits were calculated for the active ingredient, Levofloxacin I, for
Levofloxacin Injection, with only the worst case reported (based on the lowest L3 value). The L4 values are

L1 8.33 mcg/mL
L2 375,000 mcg
L3 3.76 mcg/sq cm

Name L4 (Rinse)
Page 17 of 21
Attachment L
Limits for Lidocaine HCl Injection
The following L1, L2, L3, and L4 limits were calculated for the active ingredient, Lidocaine HCl, for
Lidocaine HCl Injection, with only the worst case reported (based on the lowest L3 value). The L4 values
Heparin Injection 2000 U/2 mL Limit as Active

L1 0.753 mcg/mL
L2 30,108 mcg
L3 0.578 mcg/sq cm
Heparin Injection 2000 U/2 mL Limit as Active

Name L4 (Rinse)
Page 18 of 21
Attachment M
Limits for Lidocaine HCl Injection 1
The following L1, L2, L3, and L4 limits were calculated for the active ingredient, Lidocaine HCl, for
Lidocaine HCl Injection 1, with only the worst case reported (based on the lowest L3 value). The L4 values

L1 1.000 mcg/mL
L2 45,000 mcg
L3 0.266 mcg/sq cm

Name L4 (Rinse)
Mixing Vessel 1500 L no 2 0.246 mcg/mL
Page 19 of 21
Attachment N
Limits for Ondansetron HCl Injection (MDV)
The following L1, L2, L3, and L4 limits were calculated for the active ingredient, Ondansetron HCl, for
Ondansetron HCl Injection (MDV), with only the worst case reported (based on the lowest L3 value). The
L4 values are given as the active.

L1 0.133 mcg/mL
L2 6,000 mcg
L3 0.060 mcg/sq cm

Name L4 (Rinse)
Page 20 of 21
Attachment O
Limits for Ondansetron HCl Injection (SDV)
The following L1, L2, L3, and L4 limits were calculated for the active ingredient, Ondansetron HCl, for
Ondansetron HCl Injection (SDV), with only the worst case reported (based on the lowest L3 value). The
L4 values are given as the active.

L1 0.133 mcg/mL
L2 6,000 mcg
L3 0.053 mcg/sq cm

Name L4 (Rinse)
Page 21 of 21

Acyclovir CV-L1-005-00

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Acyclovir CV-L1-005-00

Uploaded by

Copyright:

Available Formats

CLEANING VALIDATION PROTOCOL

Product: ACYCLOVIR SODIUM INJECTION

Title: Acyclovir Sodium Injection

Report ID: CV/L1/005-00

Company: Aurobindo Pharma Ltd.

Facility: Unit –IV [Pashamylaram], Line1, Injection

Prepared By: N.Mishra 02/03/11

S. No. Name of the Content Page No.

Attachments for MACO limits 12-21

This protocol has been generated by Cleaning Validation Technologies RESIDUE

3. Current product information

This report covers limits for the following product(s):

Levofloxacin Injection: Acyclovir Sodium injection Azithromycin Injection Heparin

Lidocaine HCl Injection: Acyclovir Sodium injection Azithromycin Injection Heparin

Lidocaine HCl Injection 1: Acyclovir Sodium injection Azithromycin Injection Heparin

Ondansetron HCl Injection (MDV): Acyclovir Sodium injection Azithromycin Injection

Ondansetron HCl Injection (SDV): Acyclovir Sodium injection Azithromycin Injection

L1: Limit in the subsequently manufactured product

The formulas for calculating each value are specified in Attachment A.

The “safety factor” used for these calculations is: 0.001

The L1 default value used for these calculations is: 10

L1 = (safety factor) X (minimum dose of active of cleaned product)

L2 is the maximum allowable carryover limit. L2 is calculated as follows:

L2 = (L1) X (minimum batch size of next product)

L3 is the limit per surface area. It is calculated as follows:

L4(Swab amt) = (L3) X (area swabbed)

L4(Swab conc) = (L3) X (area swabbed)

L4 (Rinse) = (L3) X (area rinsed)

NAME TYPE ACTIVE ACTIVE DOSE DOSE BATCH

Ondansetron HCl Injections Ondansetron 2 mg/mL 1 8 60 L

Acyclovir Sodium Injections Acyclovir 50 mg/mL 1 6 110 L

Product Swabbed Area Solvent Desorption Amount

For rinse sampling, the following parameters were used:

Separate sample, sampled individually

Equipment Volume for Rinse

Lidocaine HCl Injection Limit as Active

L4 Swab Sampling Limits

Lidocaine HCl Injection Limit as Active

L4 Rinse Sampling Limits for Individual Equipment Items

Ondansetron HCl Injection (MDV) Limit as Active

L4 Swab Sampling Limits

Ondansetron HCl Injection (MDV) Limit as Active

L4 Rinse Sampling Limits for Individual Equipment Items

Lidocaine HCl Injection Limit as Active

L4 Swab Sampling Limits

Lidocaine HCl Injection Limit as Active

L4 Rinse Sampling Limits for Individual Equipment Items

Lidocaine HCl Injection Limit as Active

L4 Swab Sampling Limits

Lidocaine HCl Injection Limit as Active

L4 Rinse Sampling Limits for Individual Equipment Items

Lidocaine HCl Injection Limit as Active

L4 Swab Sampling Limits

Lidocaine HCl Injection Limit as Active

L4 Rinse Sampling Limits for Individual Equipment Items

Lidocaine HCl Injection Limit as Active

L4 Swab Sampling Limits

Lidocaine HCl Injection Limit as Active

L4 Rinse Sampling Limits for Individual Equipment Items

Lidocaine HCl Injection Limit as Active

L4 Swab Sampling Limits

Lidocaine HCl Injection Limit as Active

L4 Rinse Sampling Limits for Individual Equipment Items