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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

ANNEXURE

REGISTRATION OF SUBJECT FOR DISSERTATION

Raosaheb Desai
1 NAME OF THE CANDIDATE Flat no 6, Krishna apartment,
ADDRESS #52/23, 21st main, 22nd cross,
Marenahalli, Vijaynagar.
Bangalore 560 040.

2 NAME OF THE INSTITUTION Al-Ameen College of Pharmacy,


Bangalore.

3 COURSE OF STUDY & M.Pharm.,Part-1


SUBJECT Quality Assurance

4 DATE OF ADMISSION 9th June 2009

Cleaning Validation of Multiple


5 TITLE OF THE TOPIC Equipments in Active
Pharmaceutical Ingredients
Manufacturing Plant.

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6.0 BRIEF RESUME OF THE INTENDED WORK:
6.1
NEED FOR THE STUDY:
Cleaning validation is a documented process that addresses special
considerations and issues pertaining to validation of cleaning procedures for
equipment used in the manufacture of pharmaceutical products. The document is
intended to cover validation of equipment cleaning for the removal of
contaminants associated with previous products, residues of cleaning agents as
well as the control of potential microbial contaminants. A validated cleaning
procedure is necessary for attaining cGMP in a pharmaceutical unit
manufacturing products using common equipments and also for regulatory and
compliance requirement1.

Cleaning is a challenging task and the design of the cleaning system depends
upon the equipment use (dedicated/multipurpose), manufacturing process
(continuous/batch), cleaning equipment (manual/automated), preparation
(commercial product/clinical supplies) and product formulation i.e., type of
materials being removed from the surface, drugs (low/high risk, sterile/non
sterile, solids/liquids) and solubility (soluble/ insoluble) of active ingredients.
The purpose of cleaning validation is to ensure that cleaning process adopted
after the manufacturing of candidate product is capable of limiting the residue
within acceptable limit that can be allowed to the next subsequent product batch
of different product2.

About the Industry and the work plan:


It is proposed to establish good cleaning practices for some of the equipments
like Rota cone vacuum dryer, Vacuum tray dryer, Glass lined reactor, Stainless
steel lined reactor, Centrifuge, Sparkle filter, Sifter, Micronizer through
established methods which are employed in API manufacturing facility at
Microlabs Ltd, Bangalore.

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Cleaning validation is performed to validate the cleaning procedure and is
generally followed as per Standard Operating Procedure for cleaning the
equipment used in API manufacturing facility of the company consistently and
concurrently to yield the results not exceeding predetermined limit residues. The
matrix approach for the product manufactured in the facility shall be made and
the worst case was selected based on calculated Maximum Allowable Carryover
(MACO) limit1,
The limit for Maximum Allowable Carryover (MACO) shall be established
according to the following equation.

TDDprevious x MBS
MACO = ------------------------------
SF x TDDnext

MACO Maximum Allowable Carryover: acceptable transferred amount from


the investigated product ("previous")
TDDprevious Standard therapeutic dose of the investigated product (in the same
dosage form as TDDnext)
TDDnext Standard therapeutic dose of the daily dose for the next product
MBS Minimum batch size for the next product(s) (where MACO can end up)
SF Safety factor (normally 1000 is used in calculations based on TDD)1

As the proposed drug batches of Ebastine, Cyclizine hydrochloride, Escilopram


oxalate are carried out in the range of 40-60Kgs and there effective dose ranges
from 20mg,20mg,50mg respectively more emphasis would be given for effective
cleaning of equipments used as any carryover of these drugs to subsequent
batches of other drugs is not desired

Before testing the active ingredients in the cleaning sample (to evaluate cleaning
effectiveness) validated methods need to be developed or such methods should
be applied, if available. Before analyzing the sample analytical method to be

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validated. Analytical methods should be validated for the parameters like
Specificity, Precision, Accuracy, Linearity & Range, Limit of Detection, Limit of
Quantification, Intermediate precision, Robustness, Ruggedness, and Solution
stability.3

6.2 OBJECTIVE OF STUDY:


The main aim of the cleaning validation is to verify the effectiveness of the
cleaning procedure for removal of product residues, degradation products,
preservatives, excipients and cleaning agents so that the analytical monitoring
may be reduced to a minimum during the routine phase.

In the proposed work, attempt shall be made :


To validate simple, precise and accurate cleaning method for Equipments
like Rota cone vacuum dryer, Vacuum tray dryer, Glass lined reactor,
Stainless steel lined reactor, Centrifuge, Sparkle filter, Sifter, Micronizer.
used in active pharmaceutical ingredient manufacturing facility for
batches involving the manufacture of Ebastine, Escilopram oxalate,
Cyclizine Hydrochloride a possible chain of sequences in manufacturing
facility.
The Cleaning method for the above mentioned Equipments shall be
carried out by Rinse method and Swab method and efficiency between
the two shall be compared through suitable analytical methods for the
residues of products, excipients, as well as cleaning agents. For analytical
determination UV spectroscopy, TOC and HPLC shall be used
The cleaning process shall be validated with the application of following
parameters such as accuracy, precision, specificity, robustness, Limit of
Detection, Limit of Quantitation, ruggedness, linearity and range.

6.3
The analysis method generally employed in cleaning validation
are listed below

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Instrumentation15
UV VISIBLE SPECTROPHOTOMETER
HIGH PERFORMANCE LIQUID CHROMATOGRAPH
TOC (TOTAL ORGANIC CARBON)

HPLC methods for swab and rinse samples


HPLC analysis can be used to determine Active Pharmaceutical Ingredients
(API) residues in swab and rinse samples; it is useful due to its high precision
and accuracy1.

UV Visible Spectrophotometer
UV Visible Spectrophotometer can be used to determine Active Pharmaceutical
Ingredients (API) residues in swab samples and rinse samples.15

Total organic carbon analysis(TOC)


TOC analysis has been shown to be effective and can provide fast and simple
analysis to detect the potential contaminants. There are currently two Cleaning
Validation methods using TOC analysis16

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7.0 REVIEW OF LITERATURE:
Detailed survey of the literature of the published works, books and periodicals
and internet, yielded the following information on Cleaning Validation of
Multiple Equipments in Active Pharmaceutical Ingredients Manufacturing Plant.

Active Pharmaceutical Ingredients Committee1(2000) gives a


comprehensive approach to the validation of cleaning procedures in
Active Pharmaceutical Ingredient manufacturing facilities, basic concepts
and terms associated with cleaning validation and described about Master
plans, Protocols and Reports for multi product manufacture. The need for
potential residue determination, Establishing acceptance criteria,
Identification of equipment, characterization of product, sampling
procedure, analytical method; validation, Validation protocol and
validation report.
Fourman et al11 (1993) has reported a method for finding out cleaning
validation acceptance limits for pharmaceutical manufacturing operations
and it depends upon the equipment used, manufacturing process, cleaning
equipment, preparation, product formulation, drugs, sterile/non-sterile,
solids/ liquids and solubility of active ingredients. With reference to the
work done by the Fourman and Mullen at Eli Lilly FDA mention limits,
such as 10 ppm, biological activity levels such as 1/1000 of the normal
therapeutic dose, and organoleptic levels such as no visible residue. This
Lilly method of establishing residue limits is widely used within the
pharmaceutical industry for determining acceptable levels of chemical
residue.
Richard J. Forsyth, Vincent Van Nostrand.7(2006) published an article
about correlation of Visible-Residue limits with Swab results for cleaning.
The correlation between swab assay results and visible residue limits for
cleaning validation.

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Edward K.White5 published an article about risk-based cleaning
validation in Biopharmaceutical API Manufacturing. In risk-based
approach, the clean in place will determine acceptable carryover and
ensure no product impact. Acceptance cleaning will depend to a given
extent on what other products are manufactured with same equipment.

Jose A. Morales Sanchez13. Published an article focuses on manual


cleaning procedures because these are considered the worst-case scenario.
It is intended to cover equipment validation for raw materials,
contaminants, cleaning agents, as well as the control of potential
microbial contaminants associated with those products.

Brian Wallace16. published an article about Implementing Total Organic


Carbon Analysis for Cleaning Validation

MicroLabs Ltd14. Standard operating procedures (SOP) for cleaning each


of equipment.

McLaughlin M12. published an article about Pharmaceutical cleaning


validation method references for Alconox, Inc. Detergents

7.1
MATERIALS AND METHODS:

SOURCE OF DATA:
Reference from library of MICROLABS Limited.
References from library of Al-Ameen College of Pharmacy.
Internet (www.chemexper.com, www.google.com, sciencedirect.com)

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7.2 METHOD OF COLLECTION OF DATA:

This project work shall be carried out at MICROLABS LIMITED API


DIVISION, Bommasandra. The company is adequately equipped with necessary
set-up and the allied requirements. Cleaning Method will be developed and the
developed method shall be validated by using various validation parameters like
accuracy, precision, specificity, robustness, ruggedness, linearity and range.

8.0 REFERENCES:
1. Active Pharmaceutical Ingredients Committee. Guidelines to Cleaning
Validation in Active Pharmaceutical Ingredient Manufacturing Plants, Dec-
2000; 1-55.
2. International Conference on Harmonisation (ICH).Technical
Requirements for the Registration of Pharmaceuticals for Human Use:
Good Manufacturing Practices for Active Pharmaceutical Ingredients.
ICH-Q7A, Nov10, 2000; 1-49.
3. International Conference on Harmonisation (ICH).Technical
Requirements for the Registration of Pharmaceuticals for Human Use:
Validation of Analytical Procedures, ICH-Q2A, Geneva; 1995.
4. International Conference on Harmonisation (ICH).Technical
Requirements for the Registration of Pharmaceuticals for Human Use:
Validation of Analytical Procedures: Methodology, ICH-Q2B, Geneva;
1996.
5. Edward K.White, Risk-Based Cleaning Validation in Biopharmaceutical
API Manufacturing. Bio-pharm Int Nov 1,2005.
6. Eric Lingenfelter, Wes Atkins, Henry Evans, Cleaning Validation
Procedures. Aug 2009.
7. Richard J. Forsyth, Vincent Van Nostrand, Application of Visible-Residue
Limit for Cleaning Validation. Pharm Tech Oct 2, 2005.
8. Tara Lukievics, Julia Roberts, Richard J. Forsyth, Vincent Van Nostrand,
Correlation of Visible-Residue Limits with Swab Results for Cleaning.

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9.0 SIGNATURE OF THE CANDIDATE

10.0 REMARKS OF THE GUIDE Forwarded for approval

11.0 NAME AND DESIGNATION OF Dr. Sanjay Pai P N

11.1 GUIDE Professor and Head,

Dept of Quality Assurance

11.2 SIGNATURE

11.3 CO-GUIDE A.SARAVANAN


Sr.Manager- QC&QA

11.4 SIGNATURE

11.5 HEAD OF THE DEPT. Dr. Sanjay Pai P N


Professor and Head,
Dept of Quality Assurance

11.6 SIGNATURE

12.0 REMARKS OF THE PRINCIPAL Forwarded for approval

Prof. B.G. Shivananda

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SIGNATURE Principal,
Al-Ameen College of Pharmacy,
Hosur Road, Bangalore -27.

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