'Unit ...

4
STABILITY TESTING OF HERBAL
MEDICINES

14.1 INTRODUCTION
A stability study is a routine procedure that ensures the maintenance of herbal medicines,
its safety, quality and efficacy throughout the shelf life.
The stability testing is used in investigating the quality of herbal products which varies
with the time under the influence of environmental factors such as; temperature, humidity,
light, oxygen, moisture, other ingredient or excipient in the dosage form, the particle size of
the drug, microbial contamination, trace metal contamination, leaching from the container,
etc. and also provide statistics for the determination of shelf lives.
Stability studies should be performed on at le.ast three production batches of the herbal
products for the proposed shelf life, which is normally denoted as long term stability and is
peirformed under natural atmospheric conditions.
Factors affecting the stability of herbal medicines:
1. Physical instability:
Herbal medicines are usually susceptible to physical instability due to the presence of
impurities and reaction with the container. Microbial contamination and insect feeding
affect the secondary metabolites and chemical composition of the plants. Volatile active
components of herbal medicine have the problem of volatility and decreasing activity
during storage for a long time.
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2. Chemical instability:
• Herbal drugs are subjected to degradation during storage by hydrolysis, oxidation,
crystallization, emulsion breakdown. enzymatic deterioration and chemical reaction
with the additives and excipients.
• Temperature - The rate of degradation of most chemical increase with an increase in
temperature. That is why "Tropical" area must be taken in consideration during
preparation of the formula of the herbal medicines.
• Moisture absorbed on to the surface of solid drug will increase the rate of
decomposition.
• Presence of enzyme in the product also increases the rate of chemical degradation.
• Light - Many chemical reactions induced by exposure to light of high energy.
Autoxidation of volatile oil/fixed oil takes place and the substance becomes colored.
3. Environmental conditions:
Environmental conditions such as; altitude. temperature. rainfall. soil, storage
conditions as well as different harvesting procedures. time and method of collection.
manufacturing processes (selecting, drying, extracting. purifying and genetic variability)
can create variability in the product quality, �!ability and in the concentration of active
constituents.
4. Variability in the complex mixture:
Herbal formulations are the complex mixtures of different components obtained
during the extraction process. Each component has variable shelf life, activity,
concentration and consistency. It creates a problem during storage condition
determination as it is not easy to determine the stability of final herbal preparation based
on the activity and stability profile of a single component.
5. Drug interaction. deterioration. decomposition during storage:
Moisture content above the critical value and growth of micro-organisms in natural
products can cause the interaction of active components with the packaging material.
Interaction of active component with the other ingredients of formulation such as;
additives can also cause alteration in the novel drug activity.
Ro'le of markers in determining the stability of herbal drugs:
Markers are chemically known compounds, which may or may not have a therapeutic
effect they are used to calculate the quantity of herbal medicinal ingredients in herbal
medicinal products.
It is important to isolate and structurally elucidate chemically defined substances in
plants, drugs or drug preparation so that. they can be used as markers that not only help to
understand the active principle of herbal drugs but also can enhance analytical quality
control.
4.2
Analytlcal methods to determine the stability of
· herbal products:
The analysis of herbal preparation is mostly done by modern chromatographic or
spectroscopic methods like; HPLC, gas chromatography (GC), TLC, quantitative determination
by UV visible spectroscopy or a combination of these. HPLC and GC methods can be used for
identification and purity testing as well as the detection of single compound for the assay.
Shelf life or Expiration date:
• An expiration date is defined as the time up to which, the herbal product will remain
stable when stored under recommended storage conditions. Thus, an expiration date
is a date beyond which it is predicted that the herbal product may no longer retain
fitness for use.
• If the herbal product is not stored in accordance with the manufacturer's instructions,
then the product may be expected to degrade more rapidly.
• Shelf life is the time during which the product. if stored appropriately as per the
manufacturer's instructions, will retain fitness for use (>90% of label claim of
potency).
Protocol for Stability Testing:
A well-designed stability protocol should contain the following information:
(a) Batches: Stability studies at developmental stages are generally carried out on a
single batch while studies intended for registration of new product or unstable established
product are done on first three production batches, while for stable and well-established
batches, even two are allowed. The selection of batches should constitute a random sample
from the population of pilot or production batches.
(b) Containers and closures: The testing is done on the product in immediate
containers and closures proposed for marketing. The packaging materials include; aluminum
stri'p packs, blister packs, HOPE bottles, etc. This may also include; secondary packs, but not
shippers. Products in all different types of containers/closures, whether meant for distribution
or for physician and promotional samples, are to be tested separately.
(c) The orientation of storage of containers: Samples of the solutions, dispersed
systems and semi-solid drug products for stability studies must be kept upright and
positioned either inverted or on the side to allow for full interaction of the product with the
container closure. This orientation helps to determine, whether the contact between the drug
product or solvent and the closure results in the extraction of chemical substances from the
closure components or adsorption of product components into the container closure.
(d) Frequency of testing: The frequency of testing should be such that it is sufficient to
establish the stability profile of the new drug substance. For products with a proposed shelf
life, of at least 12 months, the testing frequency at the long-term storage condition should be
every 3 months over the first year, every 6 months over the second year and annually
thereafter throughout the proposed shelf life e�piration date. In the case of accelerated
storage conditions, a minimum of three-time points including; the initial and end points, for
example, 0, 3 and 6 months is recommended.
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 When testing at the intermediate storage condition is necessary as a result of significant
change at the accelerated storage condition, a minimum of four test points including; the
initial and final time points, is recommended, for example, 0, 6, 9 and 12 months.
(e) Sampling Plan: The sampling plan for stability testing involves planning for the
number of samples to be charged to the stability chambers and sampling out of the charged
batch so as to cover the entire study.
The first step should be the development of the sampling time points followed by the
number of samples needed to be drawn at each pull point for a complete evaluation of all
test parameters and finally adding up to get the total number of samples. For example, there
would be a requirement of about 100 tablets per pull out in a long term or accelerated
stability studies including; 10 each for assay, hardness and moisture determination, 6 each for
dissolution and disintegration and 50 for friability.
This multiplied by the total number of pull outs will give the total number of tablets
required for a study. This is followed by the development of a sampling plan, which includes;
the selection of the containers representing the batch as a whole but in an unbiased manner.
(f) Test parameters: The stability test protocol should define the test parameters that
would be used for evaluation of the stability samples. The tests that monitor the quality,
purity, potency and identity which could be expected to change upon storage are chosen as
stability tests. Therefore, appearance, assay, degradation products, microbiological testing,
dissolution and moisture are standard tests performed on stability test samples.
Microbiological tests include; sterility, preservative efficacy and microbial count as
applicable.
The batches used for the stability study must meet all the testing requirements including;
heavy metals, residue on ignition, residual solvents, etc. Some of these are required at the
time of product release but not required to be repeated during stability testing.
4.1.1 Application of Various Chromatographic Techniques in
Standardization of Herbal Products
Chromatography represents the most versatile separation technique and readily available.
Chromatography is defined as a technique of isolation and identification of components or
compounds or mixture into individual components by using the stationary phase and mobile
phase. Plant materials are separated and purified by using various chromatographic
techniques.
(i) Thin Layer Chromatography (TLC):
Thin layer chromatography (TLC) is one of the most popular and simple chromatographic
technique used for the separation of compounds. TLC is being employed extensively in the
standardization of herbal products.
Applications:
• It enables rapid analysis of herbal extracts with minimum sample cleanup
requirement.
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 • It enables the quantification of chemical constituents.
• TLC can be used to identify natural products like; essential oils or volatile oil, fixed oil,
glycosides, waxes, alkaloids, etc.
• For visualization of separated spots no specialized detectors are required.
• lt is widely used in separating multicomponent pharmaceutical formulations.
• TLC can be carried out with a minimal quantity of high expensive solvents thus,
making process economical.
• lt is used to purify herbal drug sample and direct comparison is done between the
test sample and the standard sample.
• lt is used in detection of pesticides or insecticides in food and water.
• lt is used in the food industry, to separate and identify colours, sweetening agent and
preservatives.
• It is used in the herbal cosmetic industry.
• TLC is used to separate non-volatile mixtur,es.
• It is used in separation of Vitamins (vitamin E, vitamin D3 and vitamin A).
(ii) High-Performance Thin Layer Chromatography (HPTLC):
HPTLC technique is widely employed in pharmaceutical industry in process development,
identification and detection of adulterants in herb.al products and helps in standardization of
herbal drugs. HPTLC is an advanced sophisticated form of TLC. It is more efficient than TLC
due to the smaller particle size of adsorbent (mean particle size 5 - 6 µm) and narrow range
of particle size distribution (4·8 µm). Further, the sample is loaded in the form of band rather
than spot which causes uniform distribution and compact diffusion of the analyte. The
automatic sample applicator of HPTLC can apply the sample in microliter quantity and with
the accurate volume of sample on to the plate. Several samples can run simultaneously by
use of a smaller quantity of mobile phase than in HPLC. It has also been reported that mobile
phases of pH 8 and above can be used for Hf>TLC. Another advantage of HPTLC is the
repeated detection (scanning) of the chromatogram with the same or different conditions.
Applications:
• HPTLC is suitable for both the qualitative and quantitative analysis of herbal extracts
and formulations.
• Due to integrated software, all the analysis parameters and results can be stored
digitally.
• It enables rapid analysis of herbal extracts with minimum mobile phase.
• In HPTLC, application of sample, scanning and data analysis can be performed
individually.
• HPTLC do not require extensive sample clean-up procedure.
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(ill) High-Performance liquid Chromatography (HPLC):
HPLC is another form of separation technique used in analytical chemistry and in herbal
drug research for the separation. identification and quantification of components of a
mixture. In HPLC, high pressure generating pumps are used to pass liquid containing the
sample mixture and the mobile phase through a column filled with solid adsorbent material
leading to the separation of sample components. A typical HPLC instrument is composed of
degasser, sample injection port, pump, column, column oven and detector. HPLC is also
equipped with microprocessor and a software through which one can control all the
parameters like; mobile flow rate, pressure, the composition of the mobile phase, column
oven temperature and data analysis.
Applications:
• As HPLC is carried out under high pressure, it provides high degree of separation and
resolution.
• Mobile phase composition can be varied at any time which can affect the complete
separation of phytoconstituents which is not possible in HPTLC.
• Column temperature can be controlled accurately which can affect the separation and
resolution of separated phytoconstituents,
• Detection of impurities in pharmaceutical industries.
• Quantity of sample required for analysis is very less (up to nanogram).
(iv) Gas chromatography (GC):
Gas chromatography (GC) is another type of analytical technique used for separating,
characterization, quantization and identification of volatile compounds. It can be used in
many different fields such as; pharmaceuticals, cosmetics and even for environmental toxins.
The powerful separation efficiency and sensitive detection make GC a useful tool for the
analysis of essential oils from herbal drugs. In GC, the mobile phase is an inert gas such as;
helium or nitrogen or hydrogen. The stationary phase is usually a layer of liquid or polymer­
supported on inert solid material inside a column made of either glass or metal column.
Applications:
• GC can be used to determine the identity of herbal products containing complex
mixtures of similar compounds.
• It is most suitable for the separation and analysis of volatile compounds such as;
essential oils and fatty oils.
• It is used in the analysis of foods like; carbohydrates, proteins, lipids, vitamins,
steroids, drug, pesticide residues and trace elements.
• Pollutants like; formaldehyde, carbon monoxide and DDT can be analyzed.
• It serves both qualitative and quantitative purposes.
• It is used in analysis of dairy product for rancidity.

4.6
(v) Column chromatography (CC):
Column chromatography is a separation technique in which, the substances to be
separated are introduced onto the top of a column packed with the solid adsorbent. The
mobile phase is then loaded at the top of the column and is allowed to flow down slowly and
continuously through the column. The components with lower adsorption and affinity to the
sta·tionary phase travel faster when compared to the greater adsorption and affinity with the
sta·tionary phase. The components that move fast are removed first whereas, the components
that move slowly are eluted out last.
Applications:
• Column chromatography is used to isolate active ingredients.
• It is very helpful in separating compound mixtures.
• It is used to determine drug estimation from drug formulations.
• Column chromatography has wider choice of mobile phase.
• Automation is possible.
• Column chromatography is most preferred and the only separation technique in
phytochemistry for the separation of active constituents from the plant.
• Used to isolate metabolites from biological fluids.
• It is used to remove impurities.
• Since the flow of mobile phase is under the influence of gravitational force so, no
special mechanical devices are needed to carry out the operation.
(vi) Gel Permeation Chromatography:
Gel permeation chromatography is also called as gel filtration or size exclusion
chromatography. It is a separation technique in which the separation is based on the analyte
molecular sizes since the gel behaves like a molecular sieve. In gel permeation
chromatography, the stationary phase is a porous matrix made up of compounds like; cross­
linked polystyrene, dextran, polyacrylamide gels, agarose gels, etc. The molecules in the
sample are pumped through specialized columns containing such microporous packing
material (gel). The flow of the mobile phase causes larger molecules to pass through the
column unhindered, without penetrating the gel matrix whereas, smaller molecules will be
retarded according to their penetration on the gel.
Applications:
• The gel permeation chromatography technique is used for the separation of proteins,
polysaccharides, enzymes and synthetic polymers.
• Purification.
• Can be used to determine the quaternary structure of purified proteins.
• Separation of sugar, proteins, peptides, rubbers and others on the basis of their size.
• There is no sample loss. Only small amount of mobile phase is required.
4.7
 PREPARATION OF DOCUMENTS FOR NEW DRUG
APPLICATION (NDA) AND EXPORT REGISTRATION
For decades, the regulation and control of new drugs in the United States has been based
on the New Drug Application (NOA). Since 1938. every new drug has been the subject of an
approved NOA before US commercialization.
The New Drug Application (NOA) is the vehicle through which drug sponsors such as;
organizations, pharmaceutical companies formally propose that the FDA approve a new
Phytopharmaceuticals for sale and marketing. Every country has its own regulatory authority,
which is responsible to enforce the rules and regulations and issue guidelines to regulate the
marketing of herbal drugs.
The documentation required in an NOA is supposed to tell the drug·s whole story
including; what happened during the clinical tests, what are the ingredients of the drug, the
results of the animal studies. how the drug behaves in the body, and how it is
extracted/isolated, manufactured, processed and packaged, so that they are safe and
patient's well-being is protected.
In India, the traditional herbal medicines such as; Ayurveda, Siddha and Unani (ASU) are
usually considered safe because of their long history of use. As such, no safety and efficacy
studies are required for marketing approval, as per the Drugs and Cosmetics Act of 1940.
4.2.1 Preparation of Documents for New Drug Application (NDA) in India
When any pharmaceutical company in India wants to manufacture or import a new
Phytopharmaceutical drug, it has to apply to seek permission from the licensing authority,
Drug Controller General of India (DCGO by submitting the data as given in Schedule Y of
Drugs and Cosmetics, Act 1940 and Rules 1945. To prove its efficacy and safety in Indian
population, it has to conduct clinical trials in accordance with the guidelines specified in
Schedule Y and submit the report of such clinical trials in specified format to FDA.
FDA Botanical Drug Development Guidance describes appropriate development plans for
botanical drugs to be submitted in New Drug Applications (NOA) and specific
recommendations on submitting lnvestigational New Drug applications (IND). The term
botanical means products that include; plant materials, algae, macroscopic fungi and
combinations thereof. FDA guidance recommends that IND must contain sufficient
information to demonstrate that the drug is safe for testing in humans and that the clinical
protocol is properly designed for its intended objectives.
In addition to general regulatory requirements for an NOA, non-clinical
pharmacology/toxicology studies, clinical evidence of efficacy and safety for botanical drugs,
there are special requirements to ensure the safety and quality of botanicals as follows:
• Description of product and documentation of prior human experience.
• Description of botanical raw materials used and known active constituents or
chemical constituents.
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 QuaUty control:
• Botanical raw materials.
• Botanical drug substance and drug product: Identity, chemical characterization,
manufacturing processes, biological assay, specifications, stability, current good
manufacturing practices and environmental assessment.
Evidence to ensure therapeutic consistency:
• Botanical raw material control test
• Quality control by chemical test(s) and manufacturing control
• Biological assay
• Clinical data: Dose-response data and multiple batch clinical data.
In India, ASU drugs have been under the purview of the Department of AYUSH and
regulatory requirements for phytopharmaceuticals are under the purview of the Central
Drugs Standards Control Organization (CDSCO). This gazette notification defines regulatory
provisions for phytopharmaceuticals and regulatory submission requirements for scientific
data on quality, safety and efficacy to evaluate and permit marketing for an herbal drug.
In Schedule Y, the newly added Appendix I B describes data to be submitted along with
th@ application to conduct a clinical trial or import or manufacture of a phytopharmac@utical
drug in the country. The regulatory requirements for NDA for the phytopharmaceutical drug
include; standard requirements for a new drug-safety and pharmacological information,
human studies and confirmatory clinical trials. For phytopharmaceutical drug, there is a lot of
stress on:
• Available information on the plant formulation and route of administration, dosages
and therapeutic class for which it is indicated and the claims to be made for the
phytopharmaceutical and supportive information from published literature on safety
and efficacy and human or clinical pharmacological information.
• Data generated on:
o Identification, authentication and source of the plant used for extraction and
fractionation.
o Process for extraction and subsequent fractionation and purification.
o Formulation details of the phytopharmaceutical drug.
o The manufacturing process of formulation.
o Stability data.
The new phytopharmaceuticals regulation permits the development of the drug-using
advanced techniques of solvent extraction, fractionation, potentiating steps, modern
fonmulation development etc.
After NDA approval from CDSCO, the marketing status of the new phytopharmaceutical
drug would be like that of a new chemical entity-based drug.

4.9
 Applicant

Application to Ethical Committee IND application filing to COSCO

headquarter

Report of Ethical Commiuee Examination by New Drug Division

If positive
Detail review by IND Committee

Reccmmendation to OCGI

IND application approved

Within 12 weeks
Clinical trial started

Applicalion for New Drug RegislraUon

to COSCO

Review by DCGI

If not complete If complete

Rejected to grant license License is granted

Fig. 4.1: Flow Chart Showing Drug Approval Process in India

4.2.2 Preparation of Documents for Export Registration
Introduction: A manufacturer holding valid license copy in Form-25 and Form-28 can
obtain No Objection Certificate from Zonal/Sub Zonal offices of Central Drugs Standard
Control Organization (COSCO) for export purpose only for approved/unapproved new
drugs/banned drug from India.
Purpose: Requirement for the common submission format for issuance of No Objection
Certificate for export of approved/unapproved new drugs/banned drugs from India. This
document is made as per guidelines issued by the Ministry of Health and Family Welfare for
Export purpose and Rule 94 of the Drugs and Cosmetic Act, 1940.
The following documents are required to be submitted in the following manner and
order for issue of the No Objection Certificate for export of drugs from India:
1. Covering Letter: The covering letter is an important part of the application and
should specify the intent of the application. The list of documents that are being
submitted as well as any other important .and relevant information may be provided
4.10
 in the covering letter. The covering letter mentioning list of products to be exported
indicating name of the drug, dosage form, composition and strength, packet size
along with quantity and country to be exported duly signed and stamped by the
authorized signatory, indicating the name and designation of the authorized
signatory along with the name and address of the firm. Each application should be
made by the manufacturer only.
2. Purchase order: Order from the foreign buyer either in the name of manufacturer or
in the name of trader mentioning list of products to be exported clearly indicating
name of the drug, dosage form, composition and strength, packet size duly signed by
the competent authority with specific destination point of the importing country. It
should be signed by the authority with a valid purchase order number and recent
date not more than 6 months prior to the application made by the firm.
3. Manufacturing License: License issued by the State Licensing Authority should be
enclosed along with each application for the required location to manufacture the
drug for export purpose.
4. Performa Invoice: A copy of the Performa invoice from the importing country should
accompany with the application for import of unapproved Active Pharmaceutical
Ingredients, used in the drug formulation, it should be duly signed by the competent
authority.
S. Registration Certificate:
• For the export of drugs which are banned in India by Central Government, which
comes under list of drugs prohibited for manufacture and sale through gazette
notifications under section 26-a of Drugs and Cosmetics act, 1940 by the Ministry of
Health and Family Welfare.
• A copy of registration certificate from the specific importing country along with
composition and strength of the drug should accompany with the application.
• Registration certificate should be provided in the name of the manufacturer.
Rules Related to Export of Drugs from India:
(A) Rule 94: Packing and labeling of drugs otheir than Homeopathic Medicines
(i) Labels on packages or containers of drugs for export should be adapted to meet the
specific requirements of the law of the country to which the drug is to be exported.
o Name of the drug,
o The name, address of the manufacturer and the number of the license under
which, the drug has been manufactured,
o Batch or lot number,
o Date of expiry, if any.
(ii) Each consignment of export should be accompanied by requisite import license from
the importing country.
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 (iii) The applicant should obtain a No Objection Certificate from the Drugs Controller,
India for the manufacture of such formulations to be exported with code number
against each export order along with certificate from the regulatory authority of the
importing country controlling Narcotic Drugs and Psychotropic Substances that they
do not have any objection for the import of the drug with code number.
(iv) The State Licensing Authority should issue the manufacturing license for these
formulations on each export order on the basis of a No Objection Certificate from
Drugs Controller, India.
(v) A No Objection Certificate should be obtained from the Drugs Controller, India for
export of each consignment.
(vi) A No Objection Certificate should be obtained from the Narcotic Commissioner of
India, Gwalior for export of each consignment of the drug.
(vii)The provisions of Rules 96 to 101 inclusive, should not apply to medicine made up
ready for treatment. whether after or without dilution, which is supplied on the
prescription of a registered practitioner provided that the medicine is labelled with
the following particulars:
o The name and address of the supplier,
o The name of the patient and the quantity of the medicine,
o The number representing serial number of the entry in the prescription register,
o The dose, if the medicine is for internal use,
o The words - FOR EXTERNAL USE ONLY should be printed on the label if the
medicine is for external application.
(B► Rule 95: Prohibition of sale or distribution unless labelled: Subject to the other
provisions of these rules, no person should sell or distribute any drug (including a patent or
proprietary medicine) unless it is labelled.
(C), Rule 96: Manner of Labeling: The following particulars should be either printed or
written in indelible ink and should appear in a conspicuous manner on the label of the
innermost container of any drug and on every other covering in which, the container is
packed, namely:
(i) The name of the drug:
(a) For drugs included in the Schedule For Schedule F (1), the name was given therein.
(b) For drugs included in the Pharmacopoeia� and official compendia of drug standards
prescribed in Rule 124, the name or synonym specified in the respective official
pharmacopoeias and official compendia of drug standards followed by the letters I.P.,
or, as the case may be, by the recognized abbreviations of the respective official
pharmacopoeias and official compendia of drug standards.

4.12
 (c) For drugs included in the National Formulary of India, the name or synonym specified
therein followed by the letters NF!.
(d) For other drugs, the international non-proprietary name, if any, published by the
World Health Organization or not published the name descriptive of the true nature
or origin of the substance.
Gui"delines for the Export of Drug issued by Ministry of Health and Family Welfare:
During the issue of NOC's for the manufacturing of new (Unapproved) drug solely for
export, the following conditions should be taken into consideration:
1. The application should provide copy of valid export order and NOC will be issued on
a case by case basis against each such order.
2. The applicant should identify the premises where, the drug will be manufactured for
export.
3. The applicant should mention whether the batch to be exported has undergone
Quality control testing or should be tested at the destined site.
4. The applicant should ensure that the drug(s) manufactured on the basis of NOC given
as per (1) above its exported and that no part of it is diverted for domestic sale in
India.
5. The applicant should make available for inspection of the appropriate authorities, on
completion of the export orders, information regarding each consignment
dispatched, remaining stock of drug and related raw materials and intermediates in
hand.
6. The applicant should ensure the physical destruction of all unexported quantity of
drugs. This should be included as a condition of the manufacturing license issued to
the applicant by the State Licensing Authority.
7. The applicant should ensure that the drug for which, NOC has been given should
cease to be manufactured or exported if the drug is prohibited in future in the
country or in the importing country.
GMP REQUIREMENTS AND DRUGS AND COSMETICS ACT
PROVISIONS
Good Manufacturing Practices (GMP} comes in Schedule M in Drugs and Cosmetics Act
1940 and Rules 1945. GMPs are the requirements that the drug and
methods/control/facilities used in their manufacturing, processing and packaging conforms
to practice that will assure the safety and efficacy of the product. GMPs include a set of
practices that ensure quality at every level of operation in industry. It takes into consideration
the following aspects:
4.13
 Raw materials quality Record keeping of substances
assurance throughout the manufacturing
process

Production & process Standards fOf c�anliness and safety

control

ln•house testing Qualiflcations of manufacturing

personnel

Warehousing & distribution

Fig. 4.2: Flow Chart Showing Different Levels of Operation in an Industry that
Ensures Quality
f
Dif erent parts of GMP are:
1. General provisions: The regulation in this part contains the minimum cGMP for
preparation of drug products for administration to human beings or animals.
2. Organization and personnel: The establishment and maintenance of a satisfactory
system of quality assurance and the correct manufacture of quality products relies upon
people. For this reason, there must be sufficient qualified personnel with the necessary
qualifications and practical experience to carry out all the tasks which are the
responsibility of the manufacturer.
• Important personnel includes; the head of Production, the head of Quality Control,
and the head of Engineering.
• The manufacturer should provide training for all the personnel.
• Personnel working in areas where, contamination is a hazard, e.g. clean areas or areas
where, highly active, toxic, infectious or sensitizing materials are handled should be
given specific training.
• Detailed hygiene programs should be established and adapted to the different needs
within the industry. It should include; procedures relating to the health, hygiene
practices and clothing of personnel.
• All personnel should receive medical examination upon recruitment.
• Every person entering the manufacturing areas should wear protective garments
appropriate to the operations to be carried out.
• Eating, drinking, chewing, smoking or storage of food, drink, smoking materials or
personal medication in the production and storage areas should be prohibited.
• Direct contact should be avoided between the operator's hands and the exposed
product.
• Personnel should be instructed to use the hand washing facilities.
4.14
3. Building and Facllltles:
Table 4.1: Building and Facilities Requirement under GMP
Building Facilities Requirement under GMP
Requirements
Premises Premises must be located, designed, constructed, adapted and maintained
to suit the operations to be carried out. Layout and design of the premises
must aim to minimize the risk of errors and permit effective cleaning and
maintenance in order to avoid cross-contamination, the buildup of dust or
dirt and in general, any adverse effect on the quality of products.
Design and The building should have adequate space for orderly placement of
construction equipments and materials to prevent mix-up. It should be designed in such
fe;itures a way to facilitate cleaning, maintenance and proper operation. Floors,
wall, ceiling surface should be easily cleanable. Temperature and humidity
control should be provided.
Lighting Adequate lighting should be provided in all the areas.
Ventilation, Air Air ventilation system should be provided. Equipment for control over
filtration pressure1 microorganism, dust, humidity and temperature should be
provided.
Plumbing Potable water should be supplied. Drains should be of adequate size and
preventive measures should be taken to prevent back siphonage.
Sewage and Sewage waste and other refused material from building and intermediate
refuse premises should be disposed off in a safe and S<lnitary manner.
Washing and Suitable washing facilities should be provided including; hot and cold
toilet facilities water, soap or detergent, air drier, towel and clean toilet facilities easily
accessible to working area.
Sanitation Any building used in manufact,uring, processing, packing or holding of a
drug product should be maintained in a clean and sanitary condition. Such
buildings should be free of infestation by rodents, birds, insects and other

..
vermin.
Maintenance The building should be maintained in a good state.
Premises should be carefully maintained, ensuring that repair and
maintenance operations do not cause any hazard to the quality of

. products.
Lighting, temperature, humidity and ventilation should be appropriate
and such that they do not adversely affect, directly or indirectly, either
4.15
 the medicinal products during their manufacture and storage or the
accurate functioning of equipment.
Premises should be designed and equipped so as to afford maximum
protection against the entry of insects or other animals.
Steps should be taken in order to prevent the entry of unauthorized
people.
Interior surfaces (walls, floors and ceilings) should be smooth, free from
cracks and open joints and should not shed particulate matter and
should permit easy and effective cleaning and if necessary, should be
disinfected.
Pipework, light fittings, ventilation points and other services should be
designed and sited to avoid the creation of recesses that are difficult to
clean.
Weighing of starting materials should be carried out in a separate
weighing room designed for that use.
Storage areas should be of sufficient capacity to allow orderly storage
of the various categories of materials and products: starting and
packaging materials, intermediate, bulk and finished products,
products in quarantine, released, rejected and returned.
Segregated areas should be provided for the storage of rejected,
recalled or returned materials or products.
Highly active (controlled) materials or products should be stored in safe
and secure areas.
Quality control laboratories should be separated from production
areas.
Rest and refreshment rooms should be separate from other areas.
Facilities for changing clothes and for washing and toilet purposes
should be easily accessible and appropriate for the number of users.
Animal houses should be well isolated from other areas, with separate
entrance (animal access) and air handling facilities.
4. equipments:
Equipments must be located, designed, constructed, adapted and maintained to suit
the operations to be carried out. Their layout and design must aim to minimize the risk of
errors and permit effective cleaning and maintenance in order to avoid cross·
contamination, the buildup of dust or dirt.
4.16
 Design, size
and location

Equipments

Automatic, Cleaning,
Mechanical and maintenance
Electronic

Fig. 4.3: Location, Design, Construction and Maintenance of Equipments

• Design, size and location: Equipment used in manufacturing, processing, packaging
or holding of a drug product should be of appropriate design, adequate size and
easy to clean.
• Construction: Equipment should be constructed so that surface that, contacts,
materials should not be reactive.
• Cleaning and maintenance: Equipments and utensils should be cleaned, maintained
and sanitized at intervals to prevent contamination that may alter safety, identity,
strength and quality of drug product.
• Automatic, mechanical and electronic equipment: Computers or related systems
may be used in manufacturing and in other processes. It should be routinely
calibrated, inspected or checked to assure proper performance.
5. Control of components, drug product containers and closures:
• There should be written procedures describing in details of receipt. identification,
storage, handling, sampling, testing and approval or rejection of components and
drug product containers and closures.
• It should not be reactive, additive or absorptive which may alter the safety, identity,
strength, quality or purity of the herbal drug.
• It should provide protection against environmental hazards.
• It should be clean and sterilized.
6. Production and process control:
• There should be written procedure for production and process control designed to
assure that the drug products have the identity, strength, quality and purity that they
are represented to possess.
• To assure the batch uniformity and integrity of drug products, written procedures
have to be established to monitor the output and to validate the performance of the
manufacturing process responsible for causing variability.

4.17
7. Packaging and labeling control:
• Labeling and packaging materials should be examined or tested upon receipt and
before use in packaging or labeling of drug products.
• Records should be maintained for each shipment.
• Packaged and labelled products have to be examined after finishing the operations to
assure that containers and packages in the lot have the correct label.
• Label should bear an expiry date determined by appropriate stability testing method.
8. Holding and Distribution:
• Warehouse procedure include: Storage of drug products under appropriate
conditions of temperature, humidity and light so that, the identity, purity of drug
products are not affected.
• Di.stribution procedure include: Oldest approved stock of drug product is
distributed first. Distribution of each lot of drug product can be readily determined to
facilitate its recall if necessary.
9. Laboratory Control:
• Laboratory control should include; appropriate specifications, standards, sampling
plans and test procedures designed to assure that components, drug product
containers, closures, in-process materials conform to appropriate standards of
identity, strength, quality and purity.
• There should be written testing program designed to assess the stability
characteristics of drug products.
• Animals used in the testing should be maintained and controlled in a manner that
assures their suitability for their intended use.
10. Records and Reports:
• Production, quality control and distribution records are recuired to be maintained
and should be retained for at least 1 year after the expiration of the batch. (For OTC
drugs: 3 years).
• All maintained records should be available for authorized inspection.
• A written record of major equipment cleaning, maintenance should be included in
individual equipment logs, that show the date, time, product and lot number of each
batch processed.
• Identity and quantity of each shipment of each lot of components, with receiving
code and date of receipt should be maintained.
• To assure uniformity from batch to batch, master production and control records for
each drug product including; each batch size, should be prepared, dated and signed
by one person and checked by second person, which includes:
o Name and strength of product, description of dosage form.
o Name and weight of active ingredient per dosage unit.

4.18
 The system of quality assurance suitable to the manufacture of the pharmaceutical
product should ensure that:
• Pharmaceutical products are designed and developed in compliance of the
requirements of GMP including; GLP and GCP.
• Production and quality control operations are properly documented.
• Managerial responsibilities are specified in job descriptions.
• Arrangements are made for the manufacturing, supply and use of correct starting and
packaging material.
• There should be proper quality control on raw materials, intermediate products, bulk
products and packaging material.
• Calibration and validation are carried out.
• Finished products are correctly processed and checked.
• Test every production batch.
• There should be satisfactory facilities to ensure the safety, quality and efficacy of
products.
• There must be procedure for self-inspection.
• Deviations are reported, investigated and documented.
• There is a system for approving changes tllat may have an impact on product quality.
Quality Assurance in production consists of the following steps:
1. General requirements: Handling of materials and products such as; receipt
sampling, storage should be done in accordance with a written procedure.
2. Prevention of cross-contamination and bacterial contamination in production:
Protective clothes should be worn, provided with appropriate air lock and pressure
differentials.
3. Processing operations: Intermediate and bulk products: In-process control and
environmental control.
4. Packaging operation: Filling, sealing, printing, embossing should be distinct and
resistant to fading or erasing.
Quality Audit:
Quality audit is the process of regular examination of a quality system carried out by an
internal or external quality auditor or an audit team. This helps to determine if the
pharmaceutical industry complies with the defined quality system processes and can involve
procedural or results-based assessment criteria.
Quality audit consists of:
Preparing a list of items (procedures, equipment set-ups, quality records,
measurements, etc.)
• Checking and going to the areas responsible for these items for an actual check or
audit of these items.
4.20
Types of Quality Audit:

·- Product Audit

� SysemAudit
�-------'

Fig. 4.4: Different Types of Quality Audit

Objectives of Auditing:
1. To determine the conformity or non-conformity of the quality system.
2. To determine the effectiveness of the implemented quality system.
3. To provide the audit team with an opportunity to improve the quality system.
4. To meet the regulatory requirements.
5. To permit listing of audited organizations in a register.
Steps to perform a Quality Audit:
1. To plan and prepare for the audit.
2. To arrange and announce for the audit.
3. To arrive at the site of the audit, meet people and explain the purpose.
4. To perform a quality audit.
5. Informal oral report finding.
6. A formal report with recommendation.
7. Finally to follow up the deficiencies.
Standard Operating Procedure (SOP) for Auditing:
Every pharmaceutical company prepares a Standard Operating Procedure (SOP) for
auditing which includes:
• Information regarding the company policy pertaining to auditing.
• Composition of auditing team.
• Scope of audit.
• Selected area subjected to auditing.
• Frequency of auditing.
• Written reports on audits including their distribution.
• Corrective actions of deficiencies.
4.24