Development Pharmaceutics and Process Validation of Solid
Oral Dosage form: Tablets
SYNOPSIS FOR REGISTRATION
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
Department Of Pharmaceutics
DAYANANDA SAGAR COLLEGE OF PHARMACY
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. Name of the Candidate RAGHAVENDRA S.V
and Address DAYANANDA SAGAR COLLEGE OF PHARMACY
DAYANANDA SAGAR COLLEGE OF
2. Name of the Institution PHARMACY
3. Course of Study and Subject M. Pharm – Pharmaceutics
4. Date of Admission 02/07/2008
5. TITLE OF TOPIC:
Development Pharmaceutics and Process Validation of Solid Oral Dosage
6.0 Brief resume of the intended work:
6.1 – Need for the study:
Process Validation is establishing documented evidence which provides a high degree of
assurance that a specific process will consistently produce a product meeting its pre-
determined specifications and Quality Standards.
Process Validation has now become a part of Current Good Manufacturing Practices
Regulations (cGMP), it is mandatory for manufacturers to go through Process Validation
much more rigorously than earlier. Various statuary regulations and certifying authorities do
insist upon suitable validation programmes. Moreover, the concept of cGMP is meaningless
without Process Validation.
It is obvious that Process Validation ensures improved levels of quality which inturn is bound
to lead to reduced production costs by way of prevention of product failures. Thus Process
validation also can be seen as a sound business proposition. Pharmaceutical industries deploy
elaborate facilities, highly qualified personnel, expensive materials and sophisticated
equipments. Efficient use of all these resources is vital for the continued success and
necessary even for survival of the Pharmaceutical industries. In right of this, the number of
Product failures- rejects, reworks, recalls and complaints gets reduced.
By careful design and validation of both the process and process controls that a manufacturer
can establish a high degree of confidence that all manufactured units from successive lots will
be acceptable. Successfully validating a process may reduce the dependence upon intensive
in-process and finished product testing.
6.2 - Review of Literature:
Berman J, Planchard J. A et al reported on Extensive data from three validation
batches manufactured at each of two production sites demonstrate consistently and
significantly lower drug content in the lubricated granulation than in the finished
product. The variability of the granulation data as characterized by the standard
deviation is, for the most part, acceptable and comparable to that of the tablets.1
Johan A, Westerhuis, Pierre M.J.Coenegracht and Coenraad F.Lerk et al reported on
the process of tablet manufacturing with granulation is described as a two step process.
The first step comprises wet granulation of the powder mixture, and in the second step
the granules are compressed into tablets. For the modeling of the Pharmaceutical
process of wet granulation and tableting, two models are constructed and compared.
The first model relates the crushing strength (CS), disintegration time (DT) and
ejection force (EF) of the tablets with process variables of the powder mixture. In
addition to these predictor variables, the second model also uses physical properties of
the first model. Model 1 has to be used at the stard of the process to find settings for
the process variables and the composition of the tablet mixture that produce tablets
with specific properties. Model 2 is used, in everyday production, for each new
Goutte F, Guemguem F, Dragan C, Vergnault G and Wehrl P reported Experimental
design studies (EDS) used in the Pharmaceutical Industry for drug formulation or
process optimization. The situations in which this methodology is applied for
validation purposes. The power of this statistical tool, key element of a global
validation strategy, is demonstrated for a multilayer tablet manufacturing process.
Applied to the Geomatrix system generally composed of one compression an three
granulation processes, time and strictness gains are non-negligible. Experimental
design studies are not used in this work for modeling. Introduced at each important
step of the process development, they allow for the evaluation of process ruggedness
at pilot scale and specifications for full production. A demonstration of the complete
control of key process parameters is given, identified throughout preliminary studies.3
Michael Levin et al reported the understanding of the general principles of tablet press
instrumentation and the benefits thereof by the formulators, process engineers,
validation specialists, and quality assurance personnel, as well as production floor
supervisors who would like to understand the basic standards and techniques of getting
information about their tableting process.4
Wstheinrich K, Schmidt P.C et al reported on the instrumentation and validation of a
laboratory-scale fluidized bed apparatus for continuous control of the process, the
apparatus is instrumented with sensors for temperature, relative humidity (RH), and air
velocity. Conditions of inlet air, fluidizing air, Product, and exhaust air were
determined. The temperature sensors were calibrated at temperatures of 0.0ºC and
99.9ºC. The calibration of humidity sensors covered the range from 12%RH to
98%RH using saturated electrolyte solutions. The calibration of the anemometer took
place in a wind tunnel at defined air velocities. The calibration led to satisfying results
concerning sensitivity and precision. To evaluate the reproducibility of the process, 15
trail batches of granules were prepared under identical conditions. The influence of the
type of pump used for delivering the granulating liquid was investigated. Particle size
distribution, bulk density, and tapped density were determined. Granules were tableted
on a rotary press at four different compression force levels, followed by determination
of tablet properties such as weight, crushing strength, and disintegration time. The
apparatus was found to produce granules with good reproducibility concerning the
granule and tablet properties.5
Hisatoshi Emori, Yoko Sakuraba, Koji Takahashi, Toshiaki Nishihata, Tadanori
Mayumi reported the general utility of a method for determination of high-shear wet
granulation end point by monitoring the wet granule particle size distribution was
evaluated. Wet granulation was conducted in a 25-liter high-shear mixer using four
model drugs with different solubilities and particle sizes (ethenzamide, unmillled and
milled acetaminophen, and antipyrine). For each drug formulation, its wet granule
particle size fraction and target range for granulation end point determination were
selected based on the tablet characteristics that are known to be influenced by the wet
granulation process. Granules manufactured under different conditions (i.e, different
main and chopper blade speeds and binder supplying rate) but manufactured to the
same granulation end point determined by the selected fraction and range showed very
similar granule characteristics and subsequently very similar tablet characteristics.
From the fact that there was a good correlation between the wet and dry-sized granule
particle size distributions even if the drying method was changed from fluid-bed
drying to vacuum drying, the general application of the end point determining method
was verified. Further the method was shown to be sensitive to the critical granulation
parameters for granulation progression and to be very capable of determining the
granulation extent. Thus, it was suggested that the method is applicable to various
drugs and formulations for determination of wet granulation end point.6
Newnes L.B. A et al reported on Computer controlled solution for the powder
processing of tablet production within the pharmaceutical industry is presented. It is
anticipated that this solution will assist in the automation of pharmaceutical powder
production by providing a link between process inputs and outputs using a single
vessel. A review of the traditional manufacturing approach and the present day
advancements towards minimizing product transfer is given, with the work being
placed in context with current advances in automation. The proposed solution
eliminates the need for the traditional seven distinct unit operations by combining
these within a single vessel. The effectiveness of the vessel is ascertained by
examining each of the sub-processes within the processing cycle. The vessel is
described in its entirety and offers a detailed description of its performance for the
sub-processes of size reduction and mixing. Validation of the vessel is achieved by
investigating the performance of the vessel under three modes of operation using two
types of powders. The findings from the size reduction process indicated performance
measures comparable with current technology, while the mixing sub-process results
indicate a performance level comparable with homogeneities achievable using optimal
turbulent blending. It is anticipated that the new vessel will aid in the overall
automation of pharmaceutical and food production, providing a facility which enables
flexible powder processing, a reduction in plant size and greater throughput with
equivalent or improved quality of output.7
Robert A. Nash reported the Various stages, Phases, and steps in the product and
process development sequence of solid-dosage form design (tablet and capsule) using
process validation principles and practices as a guide. The challenge for the
Pharmaceutical industry as its approaches the next millennium is to streamline and/or
simplify validation requirements without sacrificing product quality and process
flexibility. Cost-contaminent pressures in the future will necessitate the use of more
process automation and innovative ways of manufacturing products. In the final
analysis, these objectives can best be accomplished with the cooperation of a
worldwide regulatory commitment to achieving harmonization goals for both good
manufacturing practices and process validation. 8
6.3 Objectives of the study:
The aim of Process validation is to reduce Product recalls and Trouble shooting assignments
which results in more economical manufacturing process and Quality products.
The objectives of the present investigation are:
1. To ensure drug product quality.
2. To ensure the consistency of the manufacturing operation and reproducibility of the
3. To demonstrate the robustness of the process.
4. To ensure the existence of all necessary quality assurance systems within the
5. To ensure that personnel producing the drug product are properly trained and qualified
to produce the product.
6. To understand the current Process Validation guidelines like ICH, WHO, FDA
7.0 Materials and Methods:
7.1 SOURCE OF DATA
I. Review of Literature from
a. Journals & articles :
International Journal of Pharmaceutical Sciences.
Journal of Validation Technology.
Express Pharma Pulse.
Journal of Pharmaceutical Sciences.
b. Internet Browsing.
c. Text Books
- Modern Pharmaceutics , 4th edition, revised and expanded by Gilbert
S. Banker, Christopher T.Rhodes.
- Good Manufacturing Practices for Pharmaceuticals , 4th edition,
revised and expanded by Sidney H.Willig.
- Pharmaceutical Dosage Forms: Tablets , 2nd edition, revised and
expanded by Herbert A.Lieberman, Leon Lachman and Joseph
- Pharmaceutical Process Validation , 3rd edition, revised and expanded
by Robert A.Nash, Alfred H.Wachter.
- Pharmaceutical Product Development by N.K. Jain.
II. Laboratory based studies.
7.2 Methods of data collection:
1. Determining critical control point of a tablet granulation process.
a. Particle size distribution of the active.
b. Blending time for the powder.
c. Granulating time and speed.
d. Amount of granulating fluid-binder concentration.
e. Drying time- final moisture content, granule particle size distribution.
f. Granule active content and homogeneity, blending time of external phase.
2. Solid dose mixing.
a. Homogeneity in blending.
b. Sampling strategy.
c. Sample site, label, container.
3. Methods of analysis.
4. Statistical analysis.
a. Inter batch.
b. Intra batch.
c. Within sample-site.
5. Tablet Compression Variables.
a. Fill Volume.
b. Pre-Compression force, Compression force.
c. Turntable speed.
d. Dwell time.
e. Granule size and feed.
f. Ejection force, Lubrication.
6. Tablet Coating Variables.
a. Spray rate.
b. Inlet and Outlet air temperature.
c. Coating weigh.
7.3 Does the study require any investigation or intervention to be conducted on patients
or other human or animals?
7.4 Has ethical clearance been obtained from your institute?
8. List of References
1. Goutte F, Guemguem F, Dragan C, Vergnault G and Wehrl P. Power of Experimental
Design Studies for the Validation of Pharmaceutical Process: Case Study of a Multilayer
Tablet Manufacturing Process. Drug Development and Industrial Pharmacy.2002 Aug;
2. Johan A, Westerhuis, Pierre M.J.Coenegracht and Coenraad F.Lerk. Multivariate Modelling
of the tablet manufacturing process with wet granulation for tablet optimization and in-
process control. Drug Development and Industrial Pharmcay.1997 june; volume4, Issue
3. Berman J, Planchard J.A. Blend Uniformity and Unit Dose Sampling. Drug Development
and Industrial Pharmcay. 1995 june; 21(11):1257-1283.
4. Robert A.Nash, Process Validation: A 17 year Retrospective of Solid-Dosage forms. Drug
Development and Industrial Pharmcay. 1996 jan; 22(1):25-34.
5. Michael Ferrante. A Simple way to Establish Acceptance Criteria for Validation Studies,
Catalytica Pharmaceutical. Journal of Validation Technology.1999 feb; 5(2):1-3.
6. Raghunandhan R. Validation of Pharmaceutical Processes. Pharma Times. 1999 Nov;
7. Savant D.A. Current Pharmaceutical Validations and Documentation for Aseptic and Non
Aseptic Facility. Express Pharma Pulse, Technology Trends.1998; 13.
8. Berry I.R, Loftus B.T and Nash R.A. Pharmaceutical Process Validation. Marcel Decker,
Inc, New York,2nd Edition, 203-249.
9. Traisnel M and Gayout A.T. Process of Validation. Drug Development and Industrial
10. Patrick Jeater J and Robert A. Jacobs, Wyeth Laboratories. Validation of New
Formulations. Paoli, Pennsylvaniam, Marcel Decker, Inc, New York, 1st Edition,1986:507-
11. Michael Levin. Tablet Press Instrumentation. Encyclopedia of Pharmaceutical
12. Wstheinrich K, Schmidt P.C. Evaluation and Validation of a Fully Instrumented Httlin
HKC 05-TJ Laboratory-Scale Fluidized Bed Granulator. Drug Development and Industrial
Pharmcay. 2000 may; 26(6):621-633.
13. Hisatoshi Emori, Yoko Sakuraba, Koji Takahashi, Toshiaki Nishihata, Tadanori Mayumi.
Prospective Validation of High Shear Wet Granulation Process by Wet Granule Sieving
Method. II. Utility of Wet Granule Sieving Method. Drug Development and Industrial
Pharmcay. 1997; 23(2):203-215.
14. Newnes L.B. Flexible Pharmaceutical Powder Prodution. International Journal of
Computer Integrated Manufacturing. 1996 may; 9(3):227-233.
9 Signature of the candidate:
10 Remarks of the Guide: Recommended
11 Name and Designation of:
11.1 Institutional Guide: Mr. Anna Balaji. M.Pharm (Ph.D)
Department of Pharmaceutics.
11.3 Co-Guide: Mr. N.Ravi Kumar
Head of Product development,
Apotex research Pvt. Ltd.
11.5 Head of the Department: Dr. Arshia Shariff
Professor & Head,
Department of Pharmaceutics
12 12.1 Remarks of the Chairman and Principal Forwarded to the University for scrutiny
Dr. V. Murugan
Dayananda Sagar College of Pharmacy
Bangalore – 560 078.