VALIDATION PROTOCOL OF MANUFACTURING AND FILLING PROCESS OF OPHTHALMIC SOLUTION IN THREE PIECE CONTAINERS

M. Pharm Dissertation Protocol

Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore – 560041

By

Mr. PATEL MILANKUMAR M, B.Pharm

I M. Pharm (Quality Assurance)

Under the Guidance of

Prof.A.CENDILKUMAR

Head,

Department of Quality Assurance

Acharya & B.M. Reddy College of Pharmacy,

Soladevanahalli, Chikkabanavara Post, Bangalore -90.

2010-2012

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 / Name of the Candidate and Address / PATEL MILANKUMAR MAHESHBHAI
S/O Patel Maheshbhai Raojibhai
4/A,Sarvoday society
Amul dairy road,
Anand-388 120
Gujarat.
2 / Name of the Institution / ACHARYA & B.M REDDY COLLEGE OF PHARMACY,
Soldevanahalli,
Bangalore.
Pin-560090.
3 / Course of Study and Subject / M. PHARM
(QUALITY ASSURANCE)
4 / Date of the Admission / 8/9/2010
5 / Title of the Topic
VALIDATION PROTOCOL OF MANUFACTURING AND FILLING PROCESS OF OPHTHALMIC SOLUTION IN THREE PIECE CONTAINERS
6.0 BRIEFRESUME OF THEINTENDED WORK:
6.1 NEED FOR THE STUDY
Drugs must be manufactured to the highest quality levels in the pharmaceutical industry, process validation performs this task.
The U.S. Food and Drug Administration (FDA) has proposed guidelines1 with the following definition for process validation:
“Establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics”.
The cGMP regulations for validating pharmaceutical (drug) manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess.
Type of Process Validation:
  • Prospective validation
  • Concurrent validation
  • Retrospective validation
  • Revalidation validation
Ophthalmic solution:
Ophthalmic solution isa sterile solution, free from foreign particles, viable micro-organisms and non viable micro-organisms, for administrationof medication into the eye.
Important factors to be considered in preparing anophthalmic medication include the
following:
  • Appearance (colour)
  • Particulate matter
  • Sterility
  • pH
  • Assay
  • Preservative content
  • Related substances (impurities)
  • Osmolality/Osmolarity
  • Stability in an appropriate vehicle (water for injection)
  • Viscosity
  • Packaging
  • Storage of the finished product (appropriate storage condition)
It is a systematic approach for identifying, measuring, evaluating, documenting, and re-evaluating a series of critical steps in the manufacturing process.
There are various reasons for validating a product or process, such as:
An existing product is transferred from one manufacturing location to another.(site transfer product)
Changes in the excipient.(less than 10%)
Change in existing formula or process.(Revised manufacturing process)
Change in equipment chain.
Increasing batch size of product.
Changes in API vendor.
Changes in raw material specification.
Production area and support system changes.
As per regulatory body requirement.
Process or product validation depends on various supportive activities. Absence of these activities has only minimal utility, as it is only through the integration of these other practices that gives a meaningful validation.
Many dosage forms have one or more active ingredients and excipients. So there are chances of interaction between API and other excipients. So it is necessary to validate each and every step of manufacturing process.
Validation does not improve processes but it confirms that these have been properlydeveloped and are under control.
Three-piececontainersare plastic bottles,which contains body, plug, and cap.
Phases of Validation2
The activities relating to validation studies may be classified into three phases:
  • Phase 1:
Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale
batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, Equipment Qualification, Installation Qualification, master production documents, Operational Qualification, Process Capability.
  • Phase 2:
Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under the“worstcase”conditions.
  • Phase 3:
Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including Change Control procedures.
6.2REVIEW OF LITERATURE:
Three principles are involved in the validation process for sterile product.To build sterility into a product. To demonstrate to a certain maximum level of probability that the processing and sterilization methods have established sterility to all units of a product batch. To provide greater assurance and support of the results of the end product sterility test.3
Handling of sterile starting materials and components should be done in a gradeA environment with gradeB background. Preparation of solutions which are to be sterile filtered during the process should be done in a gradeC environment. Filling of aseptically prepared products should be done in a gradeA environment with a gradeB background. Prior to the completion of stoppering, transfer of partially closed containers, as used in freeze drying should be done either in a gradeA environment with gradeB background or in
sealed transfer trays in a gradeB environment.4
The pharmaceutical quality system should include the following elements: process performance and product quality monitoring, corrective, and preventive action, change management and management review.Identification of the processes within the pharmaceutical quality system, as well as their sequences, linkages and interdependencies. Process maps and flow charts can be useful tools to facilitate depicting these in a visual manner.5
For ophthalmic preparations that must be sterilized,an appropriate and validated method of sterilizationshould be determined on the basis of the characteristicsof the particular product and container. Filtrationof thepreparation through a 0.22μm filter into a sterile
final container is a commonly used method.6
The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process. Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.7
The justification for conducting concurrent validation must be documented and Validation Team must approve the protocol. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. It is generally considered acceptable that a minimum of three consecutive batches within the finally agreed parameters, giving the product the desired quality would constitute a proper validation of the process.8
All finished drug products are tested to determine if they meet the required quality standards. These tests help to characterize the product so that the QA/QC function can determine whether or not the product has the proper strength and is safe, pure, andefficacious, yet these tests do not build quality into the product; rather, they are a measure of the product’s quality.9
Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. This principle incorporates the understanding that the quality, safety, and efficacy are designed or built into the product and quality cannot be adequately assured merely by in-process and finished-product inspection or testing.
6.3 OBJECTIVES OF THE STUDY:
The main objective of this study is to perform systematically the concurrent process validation of Manufacturing and Filling of Ophthalmic Solution in three piece Containers to assure the quality of the product.
Concurrent process validation of Manufacturing and Filling of Ophthalmic Solution in three piece Containers is going to be perform at Micro Labs Ltd (Bangalore).
To provide documented evidence that the batches processed using standard procedure meets the requirements as per the approved process validation protocol.
 Process validation is generally accepted to mean three consecutive batches run with pre-determined parameters.
7.0 MATERIALS AND METHODS:
7.1 SOURCE OF DATA:
Data will be collected from Literature Surveys, abstracts, Journals, various related Websites, Pharmaceutical Industries-Micro Labs (Bangalore), Research publication and from library of Acharya & B M Reddy College of Pharmacy, ICH Guideline, WHO Guideline,etc.
7.2 METHOD OF COLLECTION OF DATA:
Data will be collected for Manufacturing Process Validation of Ophthalmic Solution in three piece container:
Manufacturing and Filling Process Critical Steps and Evaluation :
1) Bulk solution production /
  • Duration of mixing
  • Mixing speed
  • Particle size(only for suspension)

2) Filtration ( for clear solution) /
  • Pressure to be applied during filtration
  • Filtration rate

3) Containers, Nozzles & Caps
(Pre-sterilized) /
  • Sterility

4) Filling /
  • Pressure of nitrogen during pre-purging
  • Pressure of nitrogen during post-purging
  • Filling machine speed
  • Fill volume

5) Packaging /
  • Labeling printing
  • Labeling quality
  • Over printing matter

7.3DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON THE PATIENTS OR OTHER HUMAN/ANIMALS? IF SO, PLEASE DESCRIBE BRIEFLY.
- No-
7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3?
- Not Applicable-
8.0LIST OF REFERENCES:
  1. USFDAguidance for industry process validation general principles and practices [online].2011 Jan 25[cited on 2011 May11]; Available from: URL:
Guidelines/UCM070336.pdf
  1. Canada validation guidelines for pharmaceutical dosage forms (GUI-0029) [online]. 2009 Dec 1[cited on 2011 May11]; Available from: URL:

  1. Nash AR, Wachter AH. pharmaceutical process validation; vol 129. 3rd Ed. New York: Marcel Dekker Inc; 2003. p.124.
  2. EU guidelines togood manufacturing practice medicinal products for human and veterinary use. [Online]. 2008 Nov 25 (rev.) [updated 2010 March 01; cited on 2011 May 17]; Available from: URL:

  1. ICH topic Q10 pharmaceutical quality system guidance for industry.2007 May 9; [cited on 2011 May 11]; Available from: URL:

/Quality/Q10/Step4/Q10_Guideline.pdf
  1. ASHP guidelines on pharmacy-prepared ophthalmic products. Am J Hosp Pharm.[Online]. 1993 [cited on 2011, May 15]; 50:1462–3 Available from:
URL:
  1. PIC/S guide to good manufacturing practice for medicinal products; Part II [online].2009 Sept 1; p. 31-2. [cited on2011 May11]; Available from: URL:
  2. SFDA guidelines for process validation of pharmaceutical dosage forms version2[online]. 2010 [cited on 2011 May11]; Available from: URL:
  3. Nash RA, Wachter AH. Pharmaceutical process validation. 3rded. New York: MarcelDekker, Inc;2003:794.

9.0. / SIGNATURE OF THE CANDIDATE
10.0 / REMARKS OF THE GUIDE
11.0 / NAME AND DESIGNATION OF:
11.1 GUIDE / Prof. A. Cendil Kumar,
Head,Department of Quality Assurance,
Acharya & B.M. Reddy College of Pharmacy,
Soldevanahalli,
Bangalore-560 090.
11.2 SIGNATURE
11.3 CO-GUIDE / Mrs. MAHABUBI
(QA & IPQA Section Head)
Micro Labs Ltd,
Plot No. 113 TO 116, KIADB,
Bommasandra Industrial Area,
4th Phase, Anekal Taluk,
Bangalore-560099
11.4 SIGNATURE
11.5 HEAD OF THE DEPARTMENT / Prof. A. Cendil Kumar,
Head, Department of Quality Assurance,
Acharya & B.M. Reddy College of Pharmacy,
Soldevanahalli,
Bangalore-560 090.
11.6 SIGNATURE
12.0 / 12.1 REMARKS OF THE PRINCIPAL
12.2 NAME OF THE PRINCIPAL / Dr. Divakar Goli,
Principal,
Acharya & B.M. Reddy College of Pharmacy,
Soldevanahalli,
Bangalore-90.
12.3 SIGNATURE

1