Original Article

Prospective process validation of polyherbal cough syrup formulation

Lay Desai1, Jignasa Oza2, Kapil ABSTRACT
Khatri*1
Context: Validation study is the core subject of study in quality assurance field. Validation is
1Department of Quality Assurance, necessary for the efficient use of the resources. The cost of product failure, rejects, reworks,
I.S.F. College of pharmacy, Moga, recalls, complaints are the sufficient part of total production cost. Validation study inevitably
Punjab 142001, India leads to process optimization, better productivity and lower manufacturing cost. Validation
2GM Operations, Vasu Healthcare
concept is somewhat less implemented in herbal industries. But in todays competitive era it is
Private Limited, 896/A GIDC,
essential to adopt this approach for survival.
Makarpura, Vadodara, Gujarat-
India Objective: Present work is carried out to validate the manufacturing procedure of Vasu cough
*ISF College of Pharmacy, Moga, syrup which is a polyherbal preparation and to provide assurance that it meets with
Punjab 142001, India predetermined specifications.
Contact No. +917837211519 Material and methods: Vasu cough syrup was developed and manufactured at Vasu
E-mail: [email protected]
Healthcare Private Limited, Vadodara, Gujarat. In this prospective process validation, critical

J. Adv. Pharm. Edu. & Res. process parameters were identified, the protocol and report were made and results of critical
parameters were checked for three consecutive batches to assure reproducibility of the results.
The activity was carried out in quality assurance department of Vasu Healthcare Private
Limited.
Results and discussion: Results of identified critical process parameters were checked for
their compliance and also for their reproducibility for three batches. The filling and sealing
quality were also determined for each batch.
Conclusion: The results for all batches were complying with specifications, hence the product
can be considered for scale up batches. Thus, the process of technology transfer was
successfully completed.
Key words: Process validation, Polyherbal formulation, Critical process parameters,
Specifications, Critical Quality Attributes, Formulation Development.

INTRODUCTION actually lead to the expected results. [2]

USFDA defines validation as: Validation is Process Validation is establishing documented
establishing documented evidence which evidence which provides a high degree of
provides a high degree of assurance that a assurance that a specific process will consistently
specific process will consistently produce a produce a product meeting its pre-determined
product meeting its pre-determined specifications and quality attributes. [3] Process
specifications and quality characteristics. [1] development is carried out by F & D/ R & D and,
According to European commission: Validation is actual transfer of the manufacturing process
defined as Action providing in accordance with from R & D to production, along with required
the principles of GMP, that any procedure, documents and qualified personnel are referred
process, equipment, material, activity or system to as technology transfer. The ultimate objective
Address for correspondence for successful technology transfer is to have
Dr. Kapil Khatri documented proof that the process is robust and
Associate Professor, ISF College of Pharmacy
effective in producing product meeting with pre-
Moga (Punjab) 142001 INDIA
Contact No. +917837211519 defined specification & cGMP requirements. [4, 5]
E-mail: [email protected]
Access this article online
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Journal of Advanced Pharmacy Education & Research Oct-Dec 2012 Vol 2 Issue 4 225
 Kapil Khatri, et al.: Prospective process validation of polyherbal cough syrup formulation

Process validation generally has four types: process, specification and other relevant changes
Prospective process validation, concurrent in the past.
process validation, retrospective process Revalidation is the repetition of a validation
validation and revalidation. process or a part of it. This is carried out when
Prospective validation is defined as the there is any change or replacement in
establishment of documented evidence that a formulation, equipment or site location, batch
system does what it purports to do based on a size and in the case of sequential batches that do
pre planned protocol. This validation is usually not meet product specifications. In case of no
carried out prior to the introduction of new drugs changes revalidation shall be carried out at
and their manufacturing process. This approach specific time intervals. [6]
to validation is normally under taken whenever Process validation of any formulation is carried
new formula, process or facility must be out in three stages: First stage is process design
validated before routine pharmaceutical stage. The commercial manufacturing process is
formulation commences. In fact validation of defined during this stage based on knowledge
process by this approach often leads to transfer gained through development and scale-up
of the manufacturing process from the activities. Second stage is process qualification
development function to product. The objective stage. During this stage, the process design is
of prospective validation is to prove or evaluated to determine if the process is capable
demonstrate that the process will work in of reproducible commercial manufacturing. Third
accordance with a predefined validation protocol stage is continued process verification stage.
prepared for pilot product trails. Ongoing assurance is gained during routine
Concurrent process validation is similar to the production that the process remains in a state of
prospective validation. This validation involves in control. Effective process validation contributes
process monitoring of critical processing steps significantly to assuring product quality.
and product testing. This helps to generate and Validation study is the core subject of study in
documented evidence to show that the quality assurance field. [7]
production process is in a state of control. This To carry out process validation, it is essential to
study can be carried out on commercial batches. determine critical quality attributes and control
Retrospective validation is defined as the variables. The process is validated based on these
establishment of documented evidence that a parameters. ICH Q8 guidelines of pharmaceutical
system does what it purports to do on review and development describes about role of critical
analysis of past experience of production on the quality attributes in process validation. A critical
condition that composition, procedures, and quality attribute is a physical, chemical,
equipment remain unchanged & historical biological, or microbiological property or
information. The sources of such data are characteristic that should be within an
production, QA and QC records. The issues to be appropriate limit, range, or distribution to ensure
addressed here are changes to equipment, the desired product quality. CQAs are generally
associated with the drug substance, excipients,

226 Journal of Advanced Pharmacy Education & Research Oct-Dec 2012 Vol 2 Issue 4
 Kapil Khatri, et al.: Prospective process validation of polyherbal cough syrup formulation

intermediates, and drug product. [8] Potential methyl paraben IP, sodium propyl paraben IP,
drug product CQAs derived from the quality bronopol BP, and flavored syrupy base.
target product profile and/or prior knowledge is Based on the pilot batches studies, following
used to guide the product and process parameters were identified as critical quality
development. The list of potential CQAs can be attributes which have impact on finished product
modified when the formulation and quality.
manufacturing process are selected and as The quality of purified water used in
product knowledge and process understanding manufacturing of cough syrup.
increase. Quality risk management can be used to Stirrer speed at which the liquid mixture is
prioritize the list of potential CQAs for stirred throughout the process.
subsequent evaluation. Relevant CQAs can be pH, viscosity and density of final product.
identified by an iterative process of quality risk Description and taste of the final product.
management and experimentation that assesses The filled volume of final product which is
the extent to which their variation can have an delivered with filling nozzle.
impact on the quality of the drug product. [9]
Sealing quality of the packed bottle.
Three batches were checked for above
MATERIALS AND METHODS mentioned parameters and finally validation
Following raw materials were used in protocol and report were generated. Viscosity of
formulation of Vasu Cough Syrup. All the raw the cough syrup was measured with Brookfield
materials were tested in quality control TT-220 Portable Viscometer. Conductivity of the
department of Vasu Healthcare Private Limited. purified water was measured with CM 183 EC-
Individual certificate of analysis was generated TDS Analyzer & Conductivity Meter.
and it was assured that all the materials are
complying with in-house specifications of the Manufacturing process
industry. Vasu Cough Syrup contains: Extracts of All the excipients & preservatives were mixed
glycerhiza glabra (K.Patel phyto extraction ltd), with purified water in S.S. jacketed
occimum sanctum (K.Patel phyto extraction ltd), manufacturing vessel. Simultaneously decoction
terminellia belerica, Amruta herbals pvt. Ltd.), of all herbal extracts was prepared in preheated
adhatoda vasica (Amsar pvt. Ltd.), Solanum purified water under stirring in another jacketed
xanthocarpum (Amsar pvt. Ltd.), zingiber tank for decoction. The hot liquid was allowed to
officinale (Prashant Pharmaceuticals, rajpipla, cool to room temperature. Then, the decoction
Gujarat), trikatu (Amruta herbals pvt. Ltd.), solution was filtered and transferred to mixture
curcuma longa (Konarc herbals and healthcare), of jacketed manufacturing vessel under
Powder of navsar (Canton laboratories), mentha continuous stirring. To the filtered solution
sylvestaris (Shree akshat pharma pvt ltd.), syrupy base was added to the mixture under
shudha tankan (Vishal traders), sorbitol IP, continuous stirring. Then, flavor was added to
glycerin propylene glycol and xanthan gum and the syrup under stirring. Subsequently syrup
Preservatives like sodium benzoate IP, sodium volume was made to the desired volume with

Journal of Advanced Pharmacy Education & Research Oct-Dec 2012 Vol 2 Issue 4 227
 Kapil Khatri, et al.: Prospective process validation of polyherbal cough syrup formulation

purified water. Final syrup was mixed using Control variables for purified water were decided
stirrer for 60 minutes. The steps of based upon its description given in the USP. The
manufacturing process are shown in figure no.1. water quality was checked for its compliance
Details of equipments used in manufacturing with USP specifications or not. Conductivity of
process of Vasu Cough Syrup: purified water was measured using conductivity
Following equipments were used for production meter at 25C. [10, 11] All the specifications of the
of Cough Syrup: remaining parameters were set based on pilot
1. Stainless Steel Jacketed decoction tank study in the R&D department of Vasu Healthcare
2. Stainless Steel Jacketed manufacturing Private Limited. The purified water was heated in
vessel jacketed decoction tank and temperature of
3. Stainless Steel storage vessel water was measured with inbuilt thermometer of
4. Filter press decoction tank. Syrup was filled in the washed
5. Stainless Steel material transfer bucket pet bottle through automated four head filling
6. Stainless Steel Jug. line. Fill volume was checked to ensure accurate
All the volumetric equipments were calibrated quantity of syrup being filled in the bottle. The
with 0.9% sodium chloride solution and marked syrup bottle is closed with round orange colored
according to desired volume. 0.9% Sodium cap. The cap was sealed on automated four head
chloride was used instead of water because sealing machine and sealing was checked
density of water varies with temperature while periodically for integrity. The results of filling
density of isotonic solution of sodium chloride and sealing evaluation are given in Table No. 4.
remains constant with temperature. The filled volume and sealing integrity was found
Details of sampling for process validation: to be satisfactory for all batches. Description and
Initially, 30 ml of purified water sample was taste of syrup was also complying according to
taken and tested for its appearance, pH and pre determined specifications and was found to
conductivity. Finally 30 ml of syrup sample was be reproducible. pH, density and Viscocity are the
taken which was kept in storage vessel after important parameters affecting the syrup quality.
filtration and then tested for critical process These parameters were within the limits for all
parameters mentioned in process validation three batches.
protocol. The samples were collected in amber
colored pet bottles. Sampling location for each CONCLUSION
batch is shown in figure no: 2. The manufacturing process was found to be
reproducible for three batches and each
RESULTS AND DISCUSSION parameter was complying with the specification.
Samples from batch no. 101, 102, and 103 were No change as well as deviation was reported
tested for critical process parameters. Following during manufacturing process. Thus no change
tables show the results for individual batches. control or deviation control was filed. The
Table No. 1, 2, and 3 describes the results manufacturing process for vasu cough syrup was
obtained from three individual batches. validated as per the guidelines mentioned in

228 Journal of Advanced Pharmacy Education & Research Oct-Dec 2012 Vol 2 Issue 4
 Kapil Khatri, et al.: Prospective process validation of polyherbal cough syrup formulation

Prospective Process Validation. The results of the

validation exercise were found within the
specification limit. Hence the technology transfer
process of Vasu Cough Syrup was completed
successfully and the objective of this process
validation to manufacture desired quality cough
syrup was achieved.
Fig 1: Steps for manufacturing of Vasu Cough
Syrup

ACKNOWLEDGEMENT
I would like to express my heartiest
acknowledgement to Ms. Jignasa N. Oza (G.M.
operation, Vasu Healthcare Private Limited) for
their constructive guidance and dedicated
supervision throughout the work. I will extend
my acknowledgement to the top management,
Quality Assurance and Quality Control
departments of Vasu Healthcare Private Limited,
for providing me support in this work.
Fig. 2: Sampling locations for process
validation of Vasu cough syrup.
Table no: 1 Details of critical process parameters for BATCH NO. 101 (400L)

TEST PARAMETERS SPECIFICATIONS RESULTS

Quality of purified water
Description It should be clear colorless liquid, odorless and tasteless. Complies
pH 5.00-7.00 6.35
Conductivity (250c): 1.0-1.5 s/cm 1.4 s/cm
Temperature of purified water Should not exceed 80 C 65 C
Stirrer speed 2000-3000 rpm 2000rpm
Final mixing Time 50-60 mins. 50 mins.
Clarity of final batch Must be clear Clear Liquid
Description of
Dark brown color viscous liquid with aromatic odour Complies
Syrup
pH 3.5-5.50 4.20
Density 1.10-1.20mg/ml 1.14mg/ml
Viscosity 100-200poise 161poise
Taste Characteristic sweet taste Complies

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 Kapil Khatri, et al.: Prospective process validation of polyherbal cough syrup formulation

Table no: 2 Details of critical process parameters for BATCH NO. 102 (400L)

TEST PARAMETERS SPECIFICATIONS RESULTS

Quality of purified water
Description It should be clear colorless liquid, odorless and tasteless. Complies
pH 5.00-7.00 6.30
Conductivity (250c): 1.0-1.5 s/cm 1.1s/cm
Temperature of purified water Should not exceed 80 C 65 C
Stirrer speed 2000-3000 rpm 2500rpm
Final mixing Time 50-60 mins. 55 mins.
Clarity of final batch Must be clear Clear Liquid
Description of Dark brown color viscous liquid with aromatic odour Complies
Syrup
pH 3.5-5.50 4.54
Density 1.10-1.20mg/ml 1.124mg/ml
Viscosity 100-200 poise 170 poise
Taste Characteristic sweet taste Complies

Table no: 3 Details of critical process parameters for BATCH NO. 103(400L)

TEST PARAMETERS SPECIFICATIONS RESULTS

Quality of purified water
Description It should be clear colorless liquid, odorless and tasteless. Complies
pH 5.00-7.00 6.40
Conductivity (250c): 1.0-1.5 s/cm 1.3 s/cm
Temperature of purified water Should not exceed 80 C 62 C
Stirrer speed 2000-3000 rpm 3000rpm
Final mixing Time 50-60 mins. 60 mins.
Clarity of final batch Must be clear Clear Liquid
Description of Dark brown color viscous liquid with aromatic odour Complies
Syrup
pH 3.5-5.50 4.45
Density 1.10-1.20 mg/ml 1.14 mg/ml
Viscosity 100-200 poise 170 poise
Taste Characteristic sweet taste Complies

Table No: 104 Details of filling volume and sealing quality

BATCH NO:101 BATCH NO:102 BATCH NO:103

FILL SEALING FILL SEALING FILL SEALING
VOLUME QUALITY VOLUME QUALITY VOLUME QUALITY
101 ml OK 101 ml OK 101 ml OK
101 ml OK 101 ml OK 101 ml OK
101 ml OK 101 ml OK 101 ml OK
101 ml OK 101 ml OK 101 ml OK
101 ml OK 101 ml OK 101 ml OK

REFERENCES 3. Nash Robert A, Wachter Alfred H. Pharmaceutical

1. United States Food and Drug Administration. Process Validation, 3rd Edition, volume 129,

Process validation, Compliance guide of Medical Marcel Dekker, New York; 2003:159-180.

Device Quality Systems Manual, 1st Edition, 4. Swarbrick J, Boyan J.C. Encyclopedia of

Maryland, USA; 2009:1-2. Pharmaceutical Technology, 2nd Edition, Vol III,

2. European medicines agency. Guideline on Marcel Dekker Inc, New York; 2002:2708-2709.

Process Validation (Draft), Geneva, Switzerland; 5. United States Food and Drug Administration. Q8

2012:10-11. guidelines for Pharmaceutical Development

(Draft), Revision 1, version 8.1, Maryland, USA;
2011:2- 3.
230 Journal of Advanced Pharmacy Education & Research Oct-Dec 2012 Vol 2 Issue 4
 Kapil Khatri, et al.: Prospective process validation of polyherbal cough syrup formulation

6. Venkata Raveendranath T, Kotta Kranthi Kumar 10. Van London pHoenix. Co. Education series
I, Sasaikanth K. Process validation of Citalopram conductivity guide. Houston; 2012:2-4. Available
hydrobromide Tablets. Int J Res in Pharm and Bio at: http://www.vl-pc.com/index.cfm/technical-
Science, 1 (2); 2010:27-31. info/conductivity-guide
7. United States Food and Drug Administration. 11. Cheme engineering Inc. USP water criteria,
Guidance for industry, Process Validation: Campbellville; 2008:1-2. Available at:
General Principles and Practice, Maryland, USA; http://cheme.ca/Doc/USP_Water_Criteria.pdf
2011:3-4.
8. ICH harmonized tripartite guideline, Q8 Lay Desai, Jignasa Oza, Kapil Khatri*; Prospective
Guidelines for Pharmaceutical Development, process validation of polyherbal cough syrup
Revision 2, Geneva, Switzerland; 2009:12-14. formulation; J. Adv. Pharm. Edu. & Res. 2012:; 4: 225-
9. Levin Michel. Pharmaceutical Process Scale-U, 231
2nd Edition, Taylor and Francis Group, CRC Source of Support: Nil, Conflict of Interest: Nil
Press New York; 2006:199-220.

Journal of Advanced Pharmacy Education & Research Oct-Dec 2012 Vol 2 Issue 4 231