“PROCESS VALIDATION AND EVALUATION OF HERBAL CAPSULE DOSAGE FORM”

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

SONY CHERIAN

B.PHARM

UNDER THE GUIDANCE OF,

SHYAMKUMAR.B

ASSISTANT PROFESSOR,

DEPARTMENT OF QUALITY ASSURANCE

SHREE DEVI COLLEGE OF PHARMACY

MANGALORE-574 142

(2012-2014).

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE
AND ADDRESS: /
SONY CHERIAN
S/O CHERIAN.P.P
PADICKAKUDY(HO)
THURUTHY(PO)
PERUMBAVOOR- 683545
KERALA.
2. / NAME OF THE INSTITUTE: /

SHREE DEVI COLLEGE OF PHARMACY,

AIRPORT ROAD,KENJAR VILLAGE, MALAVOOR PANCHAYAT,
MANGALORE-574 142,
KARNATAKA.
3. / COURSE OF THE STUDY AND SUBJECT: /

MASTER OF PHARMACY IN

QUALITY ASSURANCE

4. / DATE OF ADMISSION TO THE COURSE: / DECEMBER 2012
5. / TITLE OF THE TOPIC:
“PROCESS VALIDATION AND EVALUATION OF HERBAL CAPSULE DOSAGE FORM”
6 / BRIEF RESUME OF THE INTENDED WORK:
6.1  Need of the Study:
Drugs 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.
According to Food and Drug Administration (FDA), the goal of validation is “To Establish documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specification and quality attributes.”[1]
Process validation is to create a robust manufacturing process that consistently produces a drug product with minimum variation that adheres to quality criteria of purity, identity and potency. It is generally carried out on 3 to 4 consecutive batches of product. In process test and finished product tests are conducted and it gives assurance of quality of final product.
In the last few decades there has been an exponential growth in the field of herbal medicine. It is getting popularized in developing as well as in developed countries owing to its natural origin and lesser side effects.
In olden times, Vaidyas used to treat patients on individual basis, and prepare therapies according to the requirement of the patient. But now, herbal medicines are being manufactured on the large scale in Pharmaceutical units, where manufacturers come across many problems such as availability of good quality raw material, authentication of raw material, availability of standards, proper standardization methodology of single drugs and formulation, quality control parameters. So, presently quality assurance is a thrust area for the evaluation of traditional used medicinal plants and herbal formulations.
At present no official standards are available for the herbal preparations. Manufactures those who are conducting some of their formulations, have fixed their own parameters, most of which are only preliminary in nature. It is also very difficult to identify the presence of all the ingredients as claimed in the formulation. Herbal medicines are not necessarily always safe simply because they are natural. Some have given rise to serious adverse side effects such as carcinogenicity and hepatotoxicity, Also herbal drugs are known to frequently fail to meet the standards owing to problems such as, difficulties in identification of plants, genetic variability, variations in growing conditions, diversity in harvesting procedures and processing of extracts, lack of information about active pharmacologic principles.[2]
Herbal preparations will only be able to benefit the health of human beings when they are used appropriately. Thus the validation for herbal product manufacturing is essential. Herbal industries have some parameters to assure the quality of herbal products.
Stability study is an essential factor to determine quality, safety and efficacy of a drug product. The stability studies for validated manufactured dosage form is conducted as per ICH guidelines for determining the quality of test which ever applicable for solid dosage form like stability, storage conditions, re-test periods, shelf lives, expiry date , degraded product weight variation, content uniformity, disintegration test, dissolution test and assay study to ensure efficacy of dosage form.[3]
As per pharmacopoeia quality control test of solid dosage form which ever applicable will be carried out in the stability studies for three to four batches using parameters like weight variation, content uniformity, disintegration time, dissolution study, assay, solid state stability, compatibility study , and microbial limits.
Therefore, our study will attempt to conduct process validation on herbal capsule dosage forms and provide insight and suggestions for improvement of quality control systems already in place in the industry.
6.2  Review of Literature:
The review of various published works related to the subject and objective of study has revealed the following.
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 good manufacturing practice (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.[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]
A review has explored the difficulties in the raw material supply chain like lack of Good Agricultural and Collection Practice (GACP), lack of transparency and problems in the authentication of herbal raw materials. It has also outlined the strategies to overcome them. It was concluded from the study that the herbal medicinal industry is independently evolving its own rigid quality assurance and control systems using Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) guidelines.[2]
Guidelines on quality of herbal medicinal product /traditional herbal medicinal products cover the general quality aspects of herbal medicinal products (for human and veterinary use), including traditional herbal medicinal products for human use. The guidelines mention that the specification should be established on the basis of recent scientific data. Stability testing of new active substances and products, control tests on the finished product, qualitative and quantitative determination of the composition of the active substance has also been mentioned. It is suggested that the comprehensive specification for the herbal substance must be followed by a description and validation of the manufacturing process for the herbal preparation.[9]
M.J. Groot has reviewed 3that quality control is an important tool in the production of high-quality herbal products, because lack of control can result in inferior products that may lead to health problems in the consumers. The review also suggests that the Enterprise Resource Planning (ERP) system enhances the quality and provides knowledge for quality management regarding traceability. It was also suggested that quality control could be an important tool for sustainable high-quality production systems for herbal products.[10]
A study has described a series of tests of stability assessment, safety, and efficacy of herbal drugs for assessing the quality of medicinal plant materials which was designed primarily for use in national drug quality control laboratories in developing countries. It has also complemented those described in ‘The international pharmacopoeia’ which provides quality specifications only for the few plant materials included in the WHO ‘Model List of Essential Drugs’. Review also addresses the importance of total quality management production of herbal drugs.[1]
The scientific validation being applied for the production and development of allopathic medicine can be adopted as guides for the herbs-based drug development. Very few documented monographs are available (like British Herbal Pharmacopoeia and SE-30 German Herbal Monograph) which present a limited number of plant based materials and their Validation is an essential part for the specification of quality control methods. Specification indicated for the validation of quality attributes of herbals can be powder fineness and sieve size, organoleptic analysis of sampling of material in bulk, determination of foreign matter, powdered microscopy, Thin layer chromatographic techniques, water and volatile matter contents, hemolytic activity and pesticide residue parameters. The study has concluded that the herbal dosage form validation is necessary for establishing documented evidence by which the system can produce an herbal medicine what it purports to serve.[4]
Stephen Bent has reviewed the efficacy, safety, and regulation of herbal medicines in the United States. He has emphasized that herbal products can become an important alternative to standard medical therapies, if only there are changes to the regulation, standardization, and funding for research of these products.[5]
Good manufacturing practice and process control parameters can control the safety and quality of herbal supplements. And the main and most utilized instrument used to correct the hazard is the hazard analysis critical control point (HACCP) system which can guarantee the safety of the product.
Donner AD reviewed a statistical support for using spectroscopic methods to validate the content uniformity of solid dosage forms. Process Analytical Technologies (PAT), offered the possibility of large scale monitoring of tablets as they came off the press.[7]
A Review by Vlietinck A has suggested that the manufacturing, quality, and applications of traditional herbal medicinal products have to fulfill the same requirements as applications for a marketing authorization in-order to be acceptable globally. Similarly a European monograph has implemented the criteria for quality and specifications for herbal products in the different guidelines of the European Medicines Agency (EMEA).[8]

A White paper on herbal products by American College of Clinical Pharmacy has suggested that regulations should be implemented at a federal level to require basic levels of standardization and quality control in the manufacture of herbal products. Indexing terms in medical bibliographic systems should be expanded to target herbal products. [10]

New screening method also developed for determination of stability of pharmaceuticals. For obtaining parameters describing the length of oxidation induction periods from non-isothermal differential scanning colorimetric measurement. The method has also been applied for screening stability. Method coincides with the order of reaction determined by classical stability test. [14]

A review has stated the method of Chemical fingerprints obtained by chromatographic and electrophoretic techniques and recommended the same for the purpose of quality control of herbal medicines. The said method can be used to represent "chemical integrities" of the herbal medicines and used for authentication and identification of the herbal products. Study has also showed that the combination of chromatographic fingerprints of herbal medicines and the chemo metric evaluation is a powerful tool for quality control of herbal products.[11]
An article has reviewed the need for quality assurance of herbal products. Study has suggested that the Quality standards have to apply to both starting materials and finished products. Pharmacopoeia monographs, has given the criteria for analytical testing including materials and methods, test limits, and acceptance ranges for results and analytical methods applicable to the evaluation of herbal products. Study has concluded that the limitations to testing still exist because of the complex and variable nature of the herbal ingredients.[12]
International Conference for Harmonization (ICH) has outlined purpose of stability studies, criteria for selection of batches, storage conditions, study/test designs during stability studies along with description on evaluation of stability data under guidelines for stability testing of new drug substances and products.[15]
6.3 Objective of the Study:
The present study “process validation and evaluation of herbal capsule dosage form” is designed to meet the current regulatory requirements and to ensure that the products meet the predetermined specifications, quality & stability attributes.
The objective of this study is to systematically conduct the concurrent process validation and stability studies pertaining to the manufacturing process of drug product.
Three or four consecutive batches will be taken for process validation studies. All the critical parameters will be evaluated for fixing the optimum process parameter.
The following plan of work is designed and proposed, based on the Master Manufacturing Formula (MMF) and stability guidelines as per ICH;
w  Preparation of process flow charts.
w  Identification of critical process variables
w  Challenging the identified variables
w  Preparing validation protocol
w  Execution of validation protocol
w  Documentation of the validation process
The objective of the proposed study is to conduct process validation for establishing documented evidence that a system does produce an herbal product what it purports to serve.
Process validation of herbal dosage form is proposed to be carried for the following unit operations in a systematic manner:
1) Process evaluation and selection.
Ø  Milling.
Ø  Drying.
Ø  Mixing and Blending
Ø  Capsule filling.
Ø  Polishing and removal of improper tablet.
2)  Statistical Evaluation of obtained Data
Statistical process control comprises the various mathematical tools used to monitor a manufacturing process and keep it within in-process and final product specification limits. Some of the statistical method that may be employed to analyze numerical output data from the manufacturing process of herbal products will be ANOVA, regression analysis etc.
7. / Materials and Methods:
7.1 Source of Data:
Data will be obtained from the publication of USFDA, WHO, PICS, MHRA guidelines as well as from Shree Devi college of pharmacy library, Science Direct and other internet facility.
7.2 Method of Collection of Data (including sampling procedure, if any):
Data on stability indicating process validation are collected from standard books and literature survey. The data will also be collected from methodologies which are outlined briefly as follows.
w  Preparation of a Process flow chart involves grinding, mixing, blending, filling, polishing and packaging.
w  Identifying critical process variables like mixing and blending technique, speed and time, drug uniformity, excipients uniformity, equipment capacity, milling type, screen size, milling speed, and feed rate.
w  Preparation of validation protocol, validation will be carried out for this process and documentation will be maintained for this process in written form as per guidelines.
w  Elevated temperature studies, stability under high-humidity condition, stability to oxidation and various evaluation tests will be carried out for preparation and execution of accelerated stability protocol.