“PROCESS VALIDATION OF SOLID DOSAGE FORM …



“VALIDATION OF CRITICAL STEPS INVOLVED IN MANUFACTURING

OF LIQIUD ORAL DOSAGE FORM IN PHARMACEUTICAL INDUSTRY”

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

SUNIL K

M.PHARM, PART-I

DEPARTMENT OF QUALITY ASSURANCE

NARGUND COLLEGE OF PHARMACY

BANGALORE-85

(2009-2011)

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

|1. |NAME OF THE CANDIDATE |SUNIL K |

| |AND ADDRESS (IN BLOCK LETTERS) |NARGUND COLLEGE OF PHARMACY, |

| | |DATTATREYANAGAR, II MAIN, |

| | |100 FEET RING ROAD, |

| | |BSK III STAGE, |

| | |BANGALORE-85, |

| | |KARNATAKA. |

|2. |NAME OF THE INSTITUTION |NARGUND COLLEGE OF PHARMACY, |

| | |DATTATREYANAGAR, II MAIN, |

| | |100 FEET RING ROAD, |

| | |BSK III STAGE, |

| | |BANGALORE-85, |

| | |KARNATAKA. |

|3. |COURSE OF STUDY AND SUBJECT |MASTER OF PHARMACY IN |

| | |QUALITY ASSURANCE |

|4. |DATE OF ADMISSION OF COURSE | |

| | |1st JUNE 2009 |

| | | |

| | |“VALIDATION OF CRITICAL STEPS INVOLVED IN MANUFACTURING OF LIQIUD ORAL |

|5. |TITLE OF TOPIC |DOSAGE FORM IN PHARMACEUTICAL INDUSTRY” |

| | | |

| | |

|6. |Brief resume of the intended work: |

|6.1 |Need for the study: |

| |Quality cannot be inspected or tested into finished product. Thereby each step must be controlled to maximize probability that |

| |finished products meets all specification. |

| |There are several important reasons for validating a product and/or process; manufacturers are required by law to conform to cGMP|

| |regulations. Good business dictates that a manufacturer avoids the possibility of rejected or recalled batches. Validation helps |

| |to ensure product uniformity reproducibility and quality. |

| |In pharmaceutical industry validation has become a necessary step to ensure that you are maintaining quality of medicinal product,|

| |throughout manufacturing, storage, handling and distribution environment 1. |

| |Hence, there is need to validate process involved in manufacturing of pharmaceuticals. In this work, process validation of |

| |manufacturing of liquid orals is planned at the site of production. |

| | |

| |Review of literature: |

|6.2 |Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform |

| |effectively and reproducibly to produce an intermediate or active pharmaceutical ingredient (API) meeting its predetermined |

| |specifications and quality attributes. |

| |There are three approaches to validation: - |

| |Prospective validation should normally be performed for all API operations/process those are critical to the quality and purity of|

| |the API. |

| |Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of |

| |API |

| | |

| |batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has |

| |been modified. |

| |An exception can be made for retrospective validation for well-established processes that have been used without significant |

| |changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process 2. |

| |Literature survey reveals that there are efficient methods to measure the parameters that control the quality of product and this |

| |will help for process validation studies. |

| |O. Okhamafe et al. gave an overview of pharmaceutical validation and process controls in drug development. It has always been |

| |known that facilities and processes involved in pharmaceutical production impact significantly on the quality of the products. The|

| |processes include raw material and equipment inspections as well as in-process controls. Process controls are mandatory in GMP. |

| |The purpose is to monitor the on-line and off-line performance of the manufacturing process, and hence, validate it. Thus |

| |validation is an integral part of quality assurance 3. |

| | |

| |M.B. Brown et al. discussed a novel laser diffraction particle sizing system for hydrofluoroalkane (HFA) pressurized metered dose |

| |inhalers. The median volume diameter obtained using laser diffraction of both the salbutamol sulphate and fluticasone propionate |

| |suspended either in 2H, 3H-decafluoropentane or perfluoropentane was over one-order of magnitude larger than the particle sizes of|

| |the drugs suspended in HFA 134a 4. |

| | |

| |Westerhuis et al. developed simple assessment of homogeneity in pharmaceutical mixing processes. Determination of homogenous |

| |mixing of active pharmaceutical ingredient (API) is an important in-process control within the manufacturing of solid dosage |

| |forms. In this paper two new near-infrared based methods were presented; a qualitative and a quantitative method. Both methods are|

| |based on the calculation of net analyte signal (NAS) models which were very easy to develop, |

| | |

| |specific with respect to the API and required no additional reference analysis 5. |

| | |

| |G.A. Zachariadis et al. developed a rapid multi-element method of analysis of antitussive syrups by inductively coupled plasma |

| |atomic emission spectrometry and direct sample introduction. A new method was developed and optimized for routine multi-element |

| |determination of traces of metals in antitussive syrups using direct introduction of diluted syrup into the nebulization system of|

| |inductively coupled plasma atomic emission spectrometer (ICP-AES). Using a Scott-type double-pass spray chamber combined with a |

| |cross-flow nebulizer, the optimum ICP conditions, like RF incident power, argon gas flow rate and nebulizer sample uptake flow |

| |rate were found. A critical objective of the study was to evaluate the matrix effect on the intensity and consequently on the |

| |sensitivity of developed method 6. |

| | |

| |Mei-Ling Chen worked on lipid excipients and delivery systems. This review discusses some regulatory considerations in the use of |

| |lipid excipients and delivery systems for pharmaceutical development. Implications in the regulatory determination of |

| |pharmaceutical equivalence, bioequivalence and therapeutic equivalence are also illustrated7. |

| | |

| |Joseph Wong et al. worked on suspensions for intravenous (IV) injection. This article reviews various challenges associated with |

| |developing intravenous nano-suspension dosage forms, various formulation considerations specific to intravenous nano-suspensions |

| |and various clinical studies 8. |

| | |

| |Linda M Thienpont analyzed an analytical method development should aim at delivering reliable measurements within a given |

| |application. This implies that method validation is integrated in the development process because it enables to establish method |

| |performance capabilities and demonstrate its fitness for the purpose 9 |

| | |

|6.3 |Objectives of the study: |

| |Process validation is establishing documented evidences which provide high degree of assurance that a specific process will |

| |consistently produce a product meeting its predetermined specification and quality characteristics. |

| |The objective of the present work is to validate critical steps involved in manufacturing of liquid orals at Juggat |

| |Pharmaceuticals, Bangalore. |

| | |

| |Materials and Methods |

|7. |Materials and equipments will be used which are involved in liquid orals manufacturing of the particular product at JUGGAT PHARMA |

| |LIMITED, Mysore road, Bangalore. |

| |Source of data: |

| |Data will be obtained from Science direct, Pubmed, Pharmainforma, Medline, 3pdf and other internet facilities, literature search |

|7.1 |and related articles from library of Nargund College Of Pharmacy and digital library of Rajiv Gandhi University Of Health Science.|

| |A. Journals and articles: |

| |Tropical journal of pharmaceutical research |

| |European journal of pharmaceutics and biopharmaceutics |

| |International journal of pharmaceutics |

| |Journal of pharmaceutical and biomedical analysis |

| |Journal of chromatography B |

| |Analytical chemical acta |

| |Pharmaceutica acta helvetiae |

| | |

| |B. Internet browsing:- |

| |sciencedirect,com |

| | |

| | |

| |helinet.jccc.in |

| | |

| | |

| |.au |

| | |

| | |

| |C. Text books and guidelines:- |

| |Robert A. Nash and Alfred H. Wachter, “Pharmaceutical process validation”, third edition, CBS publishers. |

| |International conference on harmonization of technical requirements for registration of pharmaceuticals for human use, ICH |

| |harmonised tripartite guideline, “Good manufacturing practice guide for active pharmaceutical ingredients” Q7, current step 4 |

| |version dated 10 November 2000. |

| |P.P. Sharma, “How to practice GMPs”, fifth edition, Vandana publications. |

| |Manohar A. Potdar, “Pharmaceutical quality assurance”, second edition, Nirali prakashan publishers. |

| | |

| | |

| | |

|7.2 |Method Of Collection Of Data :- |

| |The process validation includes: |

| |Identification of the process in manufacturing of liquid orals. |

| |Decision of number process runs for validation. For prospective and concurrent validation, three consecutive successful |

| |production batches will be used. |

| |Identification of device(s) in manufacturing of liquid orals. |

| |Objective and measurable criteria in manufacturing of liquid orals. |

| |Length, duration , shifts, operators, equipment in manufacturing of liquid orals. |

| |Identification of utilities for the process equipment and quality of the utilities. |

| |Complete description of the process. |

| |Relevant specifications that relative to the product, components manufacturing materials, etc. |

| |Any special controls or conditions to be placed on proceeding processes during the validation. |

| |Process parameters to be monitored and methods for controlled and monitoring. |

| |Product characteristics to be monitored and method for monitoring (Physical and/ or chemical analysis). |

| |Any subjective criteria like sampling, sample analysis used to evaluate the product. |

| |Statistical method for data collection and analysis. |

| | |

| | |

| |Does the study require any investigation or intervention to be conducted on patients or other humans? if so please mention |

| |briefly. |

| |-NOT APPLICABLE- |

| |Has ethical clearance been obtained from your institution in case of 7.3? |

| |-NOT APPLICABLE- |

|7.3 | |

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|7.4 | |

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|8. |LIST OF References: |

| | |

| |Nash RA and Wachter AH. Pharmaceutical process validation. CBS publishers, 3rd ed: 159-90. |

| |International conference on harmonization of technical requirements for registration of pharmaceuticals for human use, ICH |

| |harmonised tripartite guideline, “Good manufacturing practice guide for active pharmaceutical ingredients” Q7, current step 4 |

| |version, dated 10 November 2000:27-30. |

| |Jatto E, Okhamafe AO. An overview of pharmaceutical validation and process controls in drug development. Trop J Pharm Res 2002; 1:|

| |115-22. |

| | |

| |Jones SA, Martin GP, Brown GM. High-pressure aerosol suspensions—A novel laser diffraction particle sizing system for |

| |hydrofluoroalkane pressurized metered dose inhalers. Int J Pharm 2005; 302: 154–65. |

| |Skibsted ETS, Boelens HFM, Westerhuis JA, Witte DT, Smilde AT . Simple assessment of homogeneity in pharmaceutical mixing |

| |processes using a near-infrared reflectance probe and control charts. J Pharm Biomed Anal 2006; 41: 26–35. |

| |Zachariadis GA, Kapsimali DC. Development of a rapid multi-element method of analysis of antitussive syrups by inductively coupled|

| |plasma atomic emission spectrometry and direct sample introduction. J Pharm Biomed Anal 2006; 41: 1212–19. |

| |Chen M. Lipid excipients and delivery systems for pharmaceutical development: A regulatory perspective. Advanced Drug Delivery |

| |Reviews 2008; 60: 768–77. |

| |Wong J, Brugger A, Khare A, Chaubal M, Papadopoulos P, Rabinow B, Kipp J et al. Suspensions for intravenous (IV) injection: A |

| |review of development, preclinical and clinical aspects. Advanced Drug Delivery Reviews 2008; 60: 939–54. |

| |Stockl D, D’Hondt H, Thienpont LM. Method validation across the disciplines-Critical investigation of major validation criteria |

| |and associated experimental protocols. J Chromatogr B 2009; 877: 2180-90. |

|9. |Signature of the candidate | |

| | | |

| | | |

| | | |

| | |(SUNIL K) |

|10. |Remarks of the Guide |RECOMMENDED FOR THE DISSERTATION WORK. |

|11. |Name & Designation of (in block letters) | |

| |Guide |MR. RAJESH ANTONY |

| | |ASSISTANT PROFESSOR, |

| | |DEPARTMENT OF QUALITY ASSURANCE, |

| | |NARGUND COLLEGE OF PHARMACY. |

| |11.2 Signature | |

| | |MR. RAJESH ANTONY |

| |Co-guide |MR. VENKATESH GS |

| | |DGM-QA, JUGGAT PHARMACEUTICALS,BANGALORE |

| | | |

| | |MR. VENKATESH GS |

| |Signature | |

| |11.3 Head of the department |DR. J.N. NARENDRA SHARATH CHANDRA |

| | |PROFESSOR ,HEAD OF THE DEPARTMENT |

| | |DEPARTMENT OF QUALITY ASSURANCE, |

| | |NARGUND COLLEGE OF PHARMACY. |

| |11.4 Signature | |

| | |DR. NARENDRA SHARATH CHANDRA |

|12. | 12.1 Remarks of Principal |FORWARDED AND RECOMMENDED FOR |

| | |FAVOURABLE CONSIDERATION. |

| |12.2 Signature. | |

| | |PROF. M.S.HARISH |

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