Rajiv Gandhi University of Health Sciences s83

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. NAME OF THE PATEL MEHULKUMAR DILIPBHAI

CANDIDATE AND S/O DILIP B PATEL

ADDRESS AT&P- RAMPUR

TA- DHOLKA , DIS- AHMEDABAD

GUJARAT- 387810 2. NAME OF THE KRUPANIDHI COLLEGE OF PHARMACY,

INSTITUTE CHIKKABELLANDUR, CARMELARAM POST,

VARTHUR HOBLI,

BANGALORE: 560035, KARNATAKA . 3. COURSE OF STUDY AND MASTER OF PHARMACY IN

SUBJECT QUALITY ASSURANCE 4. DATE OF ADMISSION 2010 June 3

TO COURSE 5. TITLE OF THE TOPIC:

CLEANING VALIDATION OF THE EQUIPMENTS USED IN

MANUFACTURING UNIT OF ORAL SOLID DOSAGE FORMS

6…. .. 1 BRIEF RESUME OF THE INTENDED WORK:

6.1 NEED FOR THE STUDY:

The process of providing documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels.1

Following two examples show importance of cleaning validation.

(1) An improper preparation of “Elixir of Sulphanilamide” caused mass poisoning in United states in 1937 and became responsible for death of around 100 people. This lead to broadening the existing legislation on cleaning validation.2

(2) Recently several people died from poor quality heparin supplied by scientific protein laboratories. This incidence is an eye opener for pharmaceutical industries and regulatory agencies. FDA found that it mainly occurred due to improper cleaning of tanks used in manufacturing of heparin.3

The main purpose of cleaning procedures is to prevent the contamination of products made subsequently in the same equipment, so it is necessary to have good, effective and consistent cleaning procedures to prevent cross contamination. The goal of cleaning validation is to validate those cleaning procedures and to provide pharmaceutical products of highest quality to patients. This is the basic regulatory requirement as well as goal of all those suppliers of the products and services.

It is necessary to validate cleaning procedures for the following reasons:

a. It is a customer requirement – It ensures the safety and purity of the product. b. It is a regulatory requirement in Active Pharmaceutical Ingredient product manufacturing as well as in dosage form manufacturing. c. It also assures an internal control and compliance to the quality of the process.

Cleaning validation mainly focuses on:

 Regulatory requirements in product manufacturing  Assurance of quality and minimization of contamination  Customer satisfaction- provides safety and efficacy  Prevention of hazardous effects of drugs.

Therefore cleaning validation is necessary and vital for good manufacturing practice and regulatory requirements. Thus importance of carrying out a project work in cleaning validation of equipments used in manufacturing unit of oral solid dosage form can be understood.

2 6.2 REVIEW OF LITERATURE :

International Conference on Harmonization has established guidelines (ICHQ2A) on validation of analytical procedures. It is applicable to analytical procedures like quantitative test for impurity content as well as active moiety in sample of drug product, identification test and limit test for control of impurities.4 Health Products and Food Branch Inspectorate of Canada published guidelines on cleaning validations. The guidelines include validation of cleaning processes, microbiological considerations, analytical methods, sampling, documentation and establishment of limits.5 Liquid chromatography–ultraviolet spectrometry (LC–UV) can be applied to cleaning validations because of its familiarity, robustness, ease of use, and regulatory acceptability. For low-dose compounds, equipment requiring low residue limits, and compounds lacking strong chromophores, the enhanced sensitivity and selectivity of liquid chromatography–mass spectrometry–mass spectrometry (LC–MS–MS) facilitates rapid method development for the detection of low levels of residues of active pharmaceutical ingredients (APIs). LC–MS–MS is a standard and acceptable analytical technique for the measurement of API residues for cleaning validation. LC–MS–MS offers more advantages as compared to traditional analytical techniques. LC–MS–MS gives faster determination in lesser time and that makes it technique of choice.6 One study was conducted with the aims to determine residues of anti-malarial drug on manufacturing equipment surfaces by validated reversed phase high- performance liquid chromatographic method. The work describes validation of the swabbing procedure used on stainless steel coupons and estimation of the stability of Pyrimethamine and Sulfadoxine in the swab samples. It was concluded that desired level of cleanliness was achieved with the current cleaning procedures. 7 A formula was given to determine the pharmacologically safe cleaning level for Meclizine Hydrochloride in a method to determine the acceptable residue level for Meclizine Hydrochloride (MH) on pharmaceutical manufacturing equipment surfaces after cleaning. This level was termed as specific residual cleaning Level (SRCL). The visual limit of detection (VLOD) was determined by spiking different levels of MH on stainless steel plates and having the plates examined by a group of observers. A sensitive reversed-phase HPLC method was developed and validated for the assay of MH in swabs used to test equipment surfaces. The method was successfully applied to the assay of actual swab samples collected from the equipment surfaces. The stability of MH on stainless steel plates, on cleaning swabs and in the extraction solution was investigated.8 A capillary gas chromatographic method was described for the determination of methenamine hippurate residue in swabs collected from manufacturing equipment surfaces. The method demonstrated was sufficiently linear, accurate, precise, sensitive and rugged for

3 the determination of low levels of methenamine hippurate on equipment surfaces. Stability studies demonstrate that methenamine hippurate is not very stable on the equipment surfaces or in the swabs. It was recommended that the surfaces should be swabbed immediately after cleaning and the swabs analyzed within 24 hrs after sample collection.9 In pharmaceutical industry, the same reaction apparatus is suitable to produce different active pharmaceutical ingredients. Several chromatographic methods were introduced to measure the amount of the residual substances remaining on the surface of the apparatus after the cleaning procedure. A sensitive and fairly rapid over-pressured layer chromatographic (OPLC) procedure was developed. The method was suitable to separate and control five steroid hormone compounds namely allylestrenol, estradiol, ethynodioldiacetate, levonorgestel and norethisterone produced in the same equipment at different times. The method was validated.10 An ultra-performance liquid chromatographic (UPLC) method was developed for simultaneous determination of seven steroidal active pharmaceutical ingredient (API) residues. The UPLC method was validated using an UPLC BEH C18 column with a particle size of 1.7 μm (50 mm × 2.1 mm) and acetonitrile–water (48:52, v/v) as mobile phase at a flow rate of 0.55 ml/min. Method development and method validation for cleaning control analysis were described. The rapid UPLC method was suitable for cleaning control assays within good manufacturing practices (GMP) of the pharmaceutical industry.11 Literature review shows that atomic absorption spectrometric (AAS) methods for the determination of residual active pharmaceutical ingredients (API) in rinse samples for cleaning validation were developed. In order to determine accuracy, precision, linearity, limit of detection, and quantification, the methods were validated. These methods were successfully applied for the determination of esomeprazole magnesium and lithium carbonate in rinse samples from cleaning procedures.12 Literature reveals that three different equipment cleaning verification methods using Ion Mobility Spectroscopy (IMS) were developed and validated. These methods were developed for a specific intermediate in the synthetic route for a drug substance as well as for final drug substances. The limits-of-quantitation were determined to be at the nano gram or sub-nano gram level. Swab and rinse samples were collected from the equipment surfaces and they were analyzed successfully. Manufacturing equipment down-time was significantly minimized due to the reduction in cleaning verification analysis time.13 An useful method using total organic carbon analyzers representing both combustion and wet oxidation for validating equipment cleaning procedures and verifying cleaning in a pharmaceutical pilot plant was described. The obtained results were compared with those which were obtained using high-performance liquid chromatography. Calculation of control limits was described and good results were obtained.14

6.3OBJECTIVE OF THE STUDY:.

4 Main objective of my project work lies in confirming the cleaning of equipment used in manufacturing unit of oral solid dosage form by estimating the level of residue and determining that the cleaning is capable of limiting the residues to a predetermined acceptance level for a continuous process The work will aim to:  Select a drug by worst case approach.  Validate the method of estimation for selected drug.  Recovery study of the sampling method.  Validate cleaning procedure of equipments used in manufacturing.  Collect samples from hot spots in the equipments.  Analyze the collected samples.  Check the acceptance limit for carryover of the drug to the next batch.  Prepare a validation report. 7. MATERIALS AND METHOD:

7.1 SOURCE OF DATA:

Data will be collected from literature surveys, abstracts, journals, various related websites, Industries, research publication and from libraries of Krupanidhi College of Pharmacy, Indian Institute of Sciences, Government College of Pharmacy etc.

7.2 METHOD OF COLLECTION OF DATA:

Data will be collected from the following stepwise procedures proposed in the study.

 Selection of an appropriate drug from different manufacturing batches by worst case approach.

Drug will be selected according to:

. Potency of API which will be determined by Maximum Acceptable Carryover Limits (MACO) analysis. . Solubility in cleaning solvent . Difficulty of cleaning the residue . Validation of method of estimation of the selected drug by any one of the analytical methods like HPLC,UV spectrometry ,Ion exchange chromatography, TLC etc., by determining the parameters like-precision, linearity, robustness etc., . Recovery study of the sampling method like swabbing and rinsing

. Cleaning of the equipments used in oral solid dosage form manufacturing as per suitable cleaning procedure. . Collection of sample from hot spots of equipments by sampling method like swabbing or rinsing.

5 . Check the acceptance limit for carryover of drug to the next batch, as applicable. . Preparation of validation report.

7.3. DOES THE STUDY REQUIRE ANY INVESTIGATIONS OR

INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER

HUMANS OR ANIMALS? IF SO, PLEASE DESCRIBE BRIEFLY.

7.4. HAS ETHICAL AND CLEARANCE BEEN OBTAINED FROM

INSTITUTION IN CASE OF 7.3?

6 REFERENCES:

1. Active pharmaceutical ingredient committee. Guidelines to cleaning validation in active Pharmaceutical ingredient manufacturing plants. [Online]. 1999 [cited 1999 Sep]; Available from: URL: http:/apic.cefic.org/pub/4CleaningVal9909.pdf. Retrieved on 2010 Nov 21, 8.30pm.

2. Fredrik R. The basic facts of cleaning validation. [Online]. 2004 [cited 2004 Nov 13] ; Available from: URL: http://www.pharmainfo.net/reviews/basic-facts-cleaning-validation Retrieved on 2010 Nov 21, 9.20pm.

3. http:/www.toledolaw.com/blog/2009/05/bad-chinese-heparin-supplier-cited-by.html. Retrieved on 2010 Nov 22, 1.00pm.

4. International Conference On Harmonization (ICH). Technical requirements for the Registration of Pharmaceuticals for human use: validation of analytical procedures,ICH- Q2A, Geneva; 1995.

5. Health Canada, Health Products and Food Branch Inspectorate: cleaning validation Guidelines. [Online]. 2000 [cited 2000 May 01] URL: http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/validation Retrieved on 2010 Nov 23, 9.00pm.

6. Kevin JK, Holly P, Jennifer F, Matthew M, Carol AK. Enhancing Drug Development by applying LC-MS-MS for Cleaning Validation in Manufacturing Equipment. Pharm Technol 2006 Feb 2

7. Brindusa MB, Apostolides Z, Pretorius E. A validated HPLC method for determining residues of a dual active ingredient anti-malarial drug on manufacturing equipment surfaces. J Pharma Biomed Anal 2005;37(3):461-8.

8. Mirzaa T, Lunnb MJ, Leeleyb FJ, Geogerb RC, Bodenmiller JR. Cleaning level acceptance criteria and a high performance liquid chromatography procedure for the assay of Meclizine Hydrochoride residues in swabs collected from pharmaceutical manufacturing equipment surfaces. J Biomed Anal 1999;14(5):747-56.

9. Mirzaa T, George RC, Bedenmiller JR, Belanich SA. Capillary gas chromatography assay of residual methanamine hippurate in equipment cleaning validation swabs. J Pharm Biomed Anal 1998;16(6):939-50

10. Katona Z, Vincze L, Vegh Z, Trompler A, Ferenczi K. Cleaning validation procedure eased by using overpressured layer chromatography. J Pharm Biomed Anal 2000;22(2): 349-53.

11. Fekete S, Fekete J, Ganzler K. Validated UPLC method for the fast and sensitive determination of steroid residues in support of cleaning validation in formulation area. J Biomed Anal 2009; 49(3):833-38.

7 12. Bubnic Z, Urleb U, Kreft K, Veber M. The application of atomic absorption spectrometry for the determination of residual active pharmaceutical ingredient in cleaning validation samples. Quality control, Lak pharmaceuticals. [Online] Available from: URL:http:/www.ncbi.nlm.nib.gov/pubmed. Retrieved on 2010 Nov 23, 11.00pm.

13. Qin C, Granger A, Papov V, McCaffrey J, Norwood DL. Quantitative determination of residual active pharmaceutical ingredients on equipment surfaces by ion mobility spectrometry. J Biomed Anal 2010; 51(1):107-13.

14. Queralt M, García-Montoya E, Pérez-Lozano P, Suñé-Negre JM, Miñarro M, Ticó JR. Total organic carbon (VCSN and VWP) and HPLC analysis for cleaning validation in a Pharmaceutical pilot plant. Pharm Sci Technol 2001; 63(1):42-57.

9. Signature Of Candidate

10. Remark Of The Guide: - This topic is relevant to the end product quality and is

relevant to multi product manufacturing facilities. Recommended and forwarded.

11. Name And Designation (IN BLOCK LETTERS)

11.1 Guide Mr. CHANDRAMOULI R Assistant Professor (Department of Quality Assurance) Krupanidhi College Of Pharmacy, Bangalore – 560035.

11.2 Signature Of Guide

11.3 Co-Guide

11.4 Signature Of Co-Guide

8 11.5 Head Of The Department Mr. CHANDRAMOULI R Head, Department of Quality Assurance Krupanidhi College of Pharmacy Bangalore – 560035.

11.6 Signature of HOD

12. 12.1 Remark Of The Principal: -

12.2 Signature Of The Principal (Prof. ) Principal, Krupanidhi college of pharmacy, Chikka Bellandur, Carmelaram Post, VarthurHobli,Bangalore – 560035. Karnataka