“STUDY OF CRITICAL PROCESS PARAMETERS OF

A SOLID DOSAGE FORM”.

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

PAREKH PRIYAM PRASITBHAI

B.PHARM,

UNDER THE GUIDANCE OF,

SHYAMKUMAR B.

ASSISTANT PROFESSOR,

DEPARTMENT OF QUALITY ASSURANCE

SHREE DEVI COLLEGE OF PHARMACY

MANGALORE-574 142

(2010-2012).

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE
AND ADDRESS (IN BLOCK LETTERS) / PAREKH PRIYAM PRASITBHAI.
408/6,PRABHUTRUSHA,
SARDAR PATEL SOCIETY,
OPP-SPORTS COMPLEX,
G.I.D.C-ANKLESHWAR-393002.
GUJARAT.
2. /

NAME OF THE INSTITUTION

/ SHREE DEVI COLLEGE OF PHARMACY,
AIRPORT ROAD, KENJAR VILLAGE, MALAVOOR PANCHAYAT,
MANGALORE-574 142,
KARNATAKA.
3. /

COURSE OF STUDY AND SUBJECT

/ MASTER OF PHARMACY IN
QUALITY ASSURANCE
4. / DATE OF ADMISSION OF COURSE / NOVEMBER-2010.
5. /

TITLE OF TOPIC:-

“STUDY OF CRITICAL PROCESS PARAMETERS OF
A SOLID DOSAGE FORM”.
6.
6.1
6.2
6.3
7.
7.1
7.2
7.3
7.4
8.
/ BRIEF RESUME OF THE INTENDED WORK:
NEED FOR THE STUDY:
Drugs are critical elements in health care. They must be manufactured to the highest quality levels. In the pharmaceutical industry, process validation performs this task, ensuring that the process does what it purports to do. It is also a regulatory requirement.
During manufacturing of the batch critical / process parameters identified at development stage need to be confirmed, so that the final product at Pilot scale / Test batch will meet the proposed drug product release specifications.
The identification, scientific understanding, risk assessment and subsequent control management of critical product quality attributes are the key to ensuring the long-term quality of the drug products (1).
Concept of process validation was first applied to the pharmaceutical industry and became an important part of current Good Manufacturing Practices (cGMPs). The proof of validation is obtained through the collection and evaluation of data, beginning from the process development phase and continuing through the production phase.
Validation necessarily includes process qualification (the qualification of materials, equipment, systems, buildings, personnel), but it also includes the control on the entire process for repeated batches or runs.
To comply with the general guidelines required by the regulatory bodies like WHO, USFDA, MHRA, TGA etc. Process validation is generally carried out on 3 batches of the product. The in process tests and finished product tests are carried out Validation study should be carried out by preparing Validation Protocol. It is a written plan of actions stating how validation will be conducted, who will conduct, testing parameters, sampling plans, testing methods and specifications about product characteristics equipments to be used , number of batches to be used and acceptance criteria. (2)
Tools of Quality assurance are normally designed to control pharmaceutical manufacturing processes. Determining critical process parameters and quality attributes, and validation of the same can help the pharmaceutical manufacturing industry to implement cGMP successfully.
So, the proposed study attempts to evaluate the process of prepared tablets by granulation method in order to identify its critical process parameters(CPP’s) and validate the CPP’s which effect Quality Attributes and indirectly shows their characterization on product performance.
REVIEW OF LITERATURE:
USFDA defined Validation as “Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”.
Concurrent validation includes all elements of validation except that the replicate production runs can occur in conjugation with release of product distribution. This type of validation is carried out in routine production activity and in exceptional cases (low volume products).
This involves In-process monitoring of critical processing steps and end product testing of current production and provides documented evidence to show that the manufacturing process is in a state of control. (3)
Berry, Luftuset al., (1984) (4)Studies on regulatory background of validation. Validation as best viewed as an important and integral part of Good ManufacturingPractice. Validation became regulatory requirement in 1978 in order to force theindustry to control their process. So that process outcome would be preordainedand product testing would become only a confirmation, not a determining factor ofproduct quality.
S.Sarafet al., (5) reported that Validation is a relatively new concept is pharmaceutical manufacturing to ensure total quality management and to assure products of best quality. Validation is an overall expression for a sequence of activities in order to demonstrate and document that a specific product can be reliably manufactured by the designed process.
Ted Buyers of Food & Drug Administration, “Food & Drug Administration expects the industry tobuild quality into the product” Food & Drug Administration requires the validation to be completed even atthe time of applying for approval any piece of equipment, facility or process operatedunder Current Good Manufacturing Practices should be validated.(6)
Jatto&Okhamafe(7)has described an overview of pharmaceutical validation and process controls in drug development examines the need for pharmaceutical validation, the various approaches and steps involved. They have discussed about essentials of pharmaceutical validation, major phases of validation and behaviors to validation processes.
Controlling individual steps in the production of Paracetamol tablet by NIR spectroscopy was carried out in a study in pharmaceutical industry. Physical, and chemical parameters were determined by NIR spectroscopy along with assessing the potentially of this technique as an effective and alternative method for this purpose. The study also identified critical attributes of the process which influenced the quality of the end product.(8)
Multiple linear regression analysis and ANOVA were employed to identify and estimate the effect of important parameters, establish their relationship with CQAs, create design space and model the process of microfluidization for predictive purposes. In order of importance, milling time, microfluidization pressure, stabilizer type, temperature and stabilizer concentration were identified as critical parameters affecting the formation and stability of nanosuspensions. Interaction between homogenization pressure, temperature and milling time also significantly affected the nanosuspension particle size.(9)
A task force formed under the auspices of the Pharmaceutical Research and Manufacturers of America (PhRMA) Active Pharmaceutical Ingredient (API) Technical Group recently published an article about four aspects of the US Food and Drug Administration’s February 1987 Guideline for Submitting SupportingDocumentation in Drug Applications for the Manufacture of Drug Substances. One of these aspects was the “control of critical steps and intermediates,” with particular reference to Section 3.2.S.2.4 of the Common Technical Document (CTD). The authors recognized the potential value of greater clarity and commonality of understanding among PhRMA industry members and health authorities on the subject of critical process parameters .(10)
InghelbrechtRemon found that the roller compaction behavior of different types of lactose evaluated by granule friability could be described by a linear quadratic model, the equation showed that the roll pressure was the most imp parameter, followed by the horizontal feel speed & roll speed.(11)
Quality by design is an essential part of the modern approach to pharmaceutical quality. The elements of quality by design are examined and a consistent nomenclature for quality by design, critical quality attribute, critical process parameter, critical material attribute, and control strategy is proposed. (12)
To enhance processibility and scalability, an early phase wet granulation formulation/process was optimized by implementing quality by design principles. Critical process parameters of the high shear wet granulation step were adjusted during the manufacturing and the impact on critical quality attributes, including both granule properties and tablet in-vitro/in-vivo performance, were evaluated.(13)
Study was done to identify critical granulation parameters by utilizing in-process moisture analyzer and to develop a design space for the critical process parameters identified.(14)

OBJECTIVES OF THE STUDY:

Main objectives of process validation of Critical Process Parameters (CPP’s) are involving the following.
Three consecutive batches will be taken for process validation studies. All the critical parameters will be evaluated for fixing the optimum process parameter.
Preparation of process flow charts.
Identification of critical process variables.
Challenging the identified variables.
Preparing validation protocol.
Execution of validation protocol & collection of data.
Documentation & evaluation of the same.
Preparing the accelerated stability protocol.
Execution of the accelerated stability protocol.
Documentation of the same.
MATERIALS AND METHODS:
Materials:
Drugs and excipients as needed for the specific pharmaceutical formulation under study.
Source of data:
Data will be obtained from Science Direct, Pubmed.gov and other internet facilities, literature search and related articles from library of Shree Devi College of Pharmacy, Mangalore, Digital Library of RGUHS, Bangalore, etc.
Journals
Asian Journal of Research in Chemistry.
International Journal of chem. Tech Research.
Journal of young Pharmacists.
Indian Journal of Pharmaceutical Science.
International Journal of Pharmacy and Pharmaceutical Science.
Journal of Pharmacy Research.
The Indian Pharmacist.
Pharma Times.
IDR Drug Compendium.
Text Books and Pharmacopoeia
  • Sidney,Willig, Good Manufacturing Practices For Pharmaceuticals:aA Plan For Total Quality Control From Manufacturer(Drugs And The pharmaceutical Sciences)
  • DilipM.Parikh,Handbook Of Pharmaceutical Granulation Technology(Drugs And The Pharmaceutical Sciences)
  • Robert A.Nash,AlfredH.Wachter,Pharmaceutical Process Validation:An International(Drugs And The Pharmaceutical Sciences)
  • Stephen W.hoag,LarryL.Augsburger,Pharmaceutical Dosage Forms:tablets.3rdEdition(Three volume set)
  • WHO,Good Manufacturing Practices & Inspection(Quality Assurance Of Pharmaceuticals)
  • The Indian Pharmacopoeia, Government of India, Ministry of Health and Family Welfare, Published by The Indian Pharmacopoeia commission Ghaziabad, Volume 3, 2007.
  • Nash RA, Wachter AH. Pharmaceutical process validation. 3rd ed. Basel (NY): Marcel Dekker Inc; 1993.
Internet Browsing
MethodofCollectionofData:
Data will be collected from process validations carried out on the different stages of tablet manufacture like Sifting or Pulverization, Granulation, Drying, Compression, Coating, Packaging and Finished product testing.
The following parameters will be consider as a critical process parameter.
Processing stage / Critical Process parameters
Sifting / Sieve integrity
Dry Mixing / Speed of Mixer
Mixing Time
Granulation
[Wet mixing] / Speed of Mixer & chopper
Mixing Time
Total quantity of solvent used
Drying of wet granules / Inlet air temperature
Drying time
Blending & Lubrication / Mixing time
Speed of the blender
Compression / Speed of compression
Pre-compression force (if applicable)
Compression force
Seal Coating & Enteric Coating / Pan RPM
Inlet air temperature
Bed Temperature
Peristaltic pump RPM
Spray Rate
Distance between tablet bed & spray nozzle
Air pressure
Primary Packing
[Blister Packing] / Machine speed,
Sealing & forming temperatures
Primary Packing
[Strip Packing] / Machine speed,
Sealing temperature
Primary Packing
[Container Packing] / Type of filling (manual / auto)
Power value (in %) of the induction sealing machine
The Intermediate dosage form will be evaluated for moisture content or LOD of dried granulation, granulation particle size distribution, blend uniformity, Bulk Density, Angle of repose etc.
The finished product will be analyzed for appearance, Dimensions, individual tablet weight, assay, content uniformity, friability, tablet hardness, tablet thickness and disintegration time, dissolution.
This will be followed by statistical analysis of data obtained using tools like Standard deviation, Relative standard deviation, comparision in Chart form, Tolerance limit, ANOVA etc.
Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.
- NOT APPLICABLE -
Has ethical clearance been obtained from your institution in case of 7.3?
- NOT APPLICABLE-
LIST OF REFERENCES:
(1)Health products and food branch inspectorate, GMP GUIDELINES-2009 Nov8;2:1-102
(2)Validation Guidelines For Pharmaceutical Dosage Forms;2004Aug15;1-16 [
(3)FDA, Guideline on general principles of validation, Center for Drug
Evaluation and Research (CDER); 1987.
(4)Haider SI. Validation Standard Operating Procedure. 2nd Edition,
Taylor & Francis Group.Publishers; 2006;3-9.
(5)Dashora.K, Singh.D, Saraf.S. Validation The Essential Quality
Assuarance Tool For Pharma Industries, 2005 July12.
[ p
Pharma-industries]
(6)U.S. FDA. Guidelines on general principles of Process Validation;
1987 May.
(7)Jatto E, Okhamafe AO. An Overview of Pharmaceutical Validation
and Process Controls in Drug Development. Trop J Pharm Res 2002 June; 1(2): 115-8
[
(8)Blanco M., Cueva-Mestanza R., Peguero A., Controlling individual
steps in the production process of Paracetamol tablets by use of NIR spectroscopy J Pharm biomed anal 2010 March 11;51(4):799-804 [
(9) Verma S, Lan Y, Gokhale R, Burgess DJ. Qualities by design approach
understand the process of nanosuspension preparation, IntJ Pharm 2009 July13;
377(1):185-98.
[
(10) William P. Ganzer,Joan A. Materna,Michael B. Mitchell,L.
Kevin Wall. Current Thoughts on Critical Process Parameters an
API Synthesis Pharmaceutical Technology2005July2
[
jsp?id=2607]
(11) Inghelbrecht,S and Ramon,J.P. The roller compaction of different
types of lactose.Int.J.Pharm1998May18;166(2):135-44.
[
(12) Robert a.lionberger.Sau Lawrence Lee,LaimingLee,Andre
Raw,Lawrence X,Yu.The APPS J2008June;10(2):268-76
[
(13) C-Y. Yang, Olsofsky.A, Pirjanian. A, Alvarez.P, Ku.V,
Fang.J, Emery.M. From Critical Process Parameters (CPP’s) To
Critical Quality Attributes (CQA’s): Impact of Wet Granulation Process
Optimization on in-vivo and in-vitro Tablet Performance.
[
attendee/index.aspx?content=sessionInfo&sessionId=1630]
(14) Sathigari.S, Wilson.S, Vera.H, Scoggins.M, Melendez.A,
Clark.B, Shah.U Fluid Bed Granulation: Identifying Critical
Process Parameters and Developing Design Space.
[
attendee/index.aspx?content=sessionInfo&sessionId=2529]
9. / Signature of the candidate / (PAREKH PRIYAM PRASITBHAI.)
10. / Remarks of the Guide:
“STUDY OF CRITICAL PROCESS PARAMETERS OF A SOLID DOSAGE FORM”
to be carried out by Ms. Parekh Priyam P. of M.Pharm has been discussed and worked out under my direction and supervision as an official guide. The project work envisaged is of great importance in the field of process validation and research. The work can be carried out in Quality Assurance laboratory of Shree Devi College Of Pharmacy for which facilities are available. Hence the project is viable and is recommended for clearance and approval.
11. / Name & Designation of
(in block letters)
11.1Guide / SHYAMKUMAR B.
Department of Quality Assurance.
Shree Devi College Of Pharmacy,
Airport Road, Kenjar Village,
MalavoorPanchayath,
Managalore, 574 142
Karnataka.
11.2 Signature
11.3 Head of the department / DR. SURESH D.
Department of Quality Assurance.
Shree Devi College Of Pharmacy,
Airport Road, Kenjar Village,
MalavoorPanchayath,
Managalore, 574 142
Karnataka.
11.4 Signature
12. / 12.1 Remarks of Principal:
The Programme and the Research that is undertaken by Ms. Parekh Priyam P. has the potential implication in the field of Quality Assurance. The work can be carried in the Research Laboratories of Quality Assurance Department at Shree Devi College Of Pharmacy. Hence the project is recommended and requested for clearance and approval.
12.2 Signature

1