ICH Guidlines guidlines for assesment of herbal drug stability testing.pptx.pdf

Herbal drug stability

1. ICH Guidelines for
Assessment of Herbal
Drugs
Stability Testing of Herbal Drugs
UNIT-4

2. Introduction:
•The International Council for Harmonisation (ICH) of Technical Requirements for
Pharmaceuticals for Human Use is unique in bringing together the regulatory
authorities and pharmaceutical industry to discuss scientific and technical
aspects of pharmaceuticals and develop ICH guidelines. Since its inception in
1990,

3. AIM
•The ICH of Technical Requirements for the Registration of
Pharmaceuticals for Human Use (ICH) was established in 1990 as a
joint regulatory/industry project to improve, through harmonisation,
the efficiency of the process for developing and registering new
medicinal products in European country, Japan and the United States,
in order to make these products available to patients with a
minimum of delay.

4. The six parties to ICH represent the regulatory bodies and research- based industry
in the three regions, Europe, Japan and the USA, where the vast majority of new
medicines are currently developed.
ICH PARTIES
❑ European Commission - European Union (EU).
❑ European Federation of Pharmaceutical Industries and Associations (EFPIA).
❑ Ministry of Health, Labour and Welfare, Japan (MHLW).
❑ Japan Pharmaceutical Manufacturers Association (JPMA).
❑ US Food and Drug Administration (USFDA).
❑ Pharmaceutical Research and Manufacturers of America (PhRMA)

5. OBECTIVES
•More economical use of human, animal, and material resources.
•Elimination of unnecessary delay in the global development &
availability of new medicines.
•Maintaining safeguards on Quality, safety, efficacy and regulatory
obligations to protect public health.

6. TOPIC OF ICH- Four Broad Categories - QSEM
1. Quality (Q): those relating to chemical and pharmaceutical Quality Assurance
(Stability Testing, Impurity Testing, etc.)
2. Safety (S): those relating to in vitro and in vivo pre-clinical studies
(Carcinogenicity Testing, Genotoxicity Testing, etc.)
3. Efficacy (E): those relating to clinical studies in human subject (Dose Response
Studies, Good Clinical Practices, etc.)
4. Multidisciplinary (M): cross-cutting Topics which do not fit uniquely into one of
the above categories (Medical Dictionary for Regulatory Activities (MedDRA),
Electronic Standards for the Transfer of Regulatory Information (ESTRI), Common
Technical Document (CTD)

7. STABILITY TESTING OF HERBAL DRUGS

∙Stability can be defined as the extent to which the drug product retains its
original properties & characteristics during its storage period.
∙Expiry date: It is a date after which the potency of the activities would be
lost or reduced to sub-potent levels.
∙Stability testing is necessary to ensure the product is of acceptable quality
throughout quality its entire storage period.

8. SIGNIFICANCE OF STABILITY TESTING

∙Chemical degradation may lead to under-medication due to lowering of the
concentration of drug in dosage form.
∙Patient has to receive the right & standard quality drug.
∙During decomposition of drug substance or drug product may lead to toxic product
∙In polyherbal formulations, degradation of any one constituent may lead to its
decreased its potency and concentration in blood.
∙The patient has to receive a uniform dose of drug throughout shelf life.
∙Determination of shelf life of a product.
∙Determination of degradation product and the possibility degradation pathway.

9. FACTORS AFFECTING STABILITY OF HERBAL
DRUG AND FORMULATIONS

10. Physical Degradation
1. Loss of volatile constituents:
∙Many constituents are volatile at ambient temperatures
∙Due to this, they may be lost from herbal preparations and formulations.
∙Example: Dill water, camphor water.
2. Loss of water:
∙Evaporation of water from liquid, semi-solid formulations & o/w emulsions
cracking of these systems.
•Loss of water from aqueous solution crystallization of solute take pace that cause
unstable formulation.

11. 3. Absorption of water/ Moisture:
∙Higher humidity may leadto moisture absorption generally observed with solid
pharmaceuticals.
∙This absorbed moisture may participate in drug degradation itself as a reactant
leading to hydrolysis, hydration, isomerization or other biomolecular chemical
reactions.
∙Remedies for stabilization against moisture absorption:
✔ Use of moisture proof packaging, dessicants are often used to eliminate
moisture in packaging.
✔ Moisture proof film coatings.

12. 4.Crystal growth:
∙It is common in syrups
∙Fluctuations in the ambient temperature i.e. in day & night crystal growth occurs.
∙Usually this problem occurs when the vehicle becomes supersaturated with solute
precipitation of solute occurs seeding occurs crystal growth.
Remedies:
∙Select suitable storage conditions.
∙Increase theproduct viscosity, so that diffusion of solute towards crystal seed
∙Incorporation of surface active agents.

13. 5. Color changes:
∙Indicative of chemical or photochemical changes.
∙Remedies for stabilization against photodegradation
∙Use of photoprotective films
∙Film coatings on the formulations, say capsules.
6. Polymorphic changes:
∙Many substances exist in two or more polymeric forms.
∙Upon storage in the dry state or in suspension inter-conversion of these forms
alterations in solubility.

14. CHEMICAL DEGRADATION

1.Hydrolysis:
∙Consideredto be major cause of deterioration of drugs.
∙Defined as the reaction of a compound with water.
Hydrolysis may be of 3 types:
∙Ester hydrolysis: Prevalent in fatty acids. Involves rupture of a covalent bond
between C- atom & O-atom.
∙Amide hydrolysis: Irreversible. Hydrolytic cleavage of an amide results in
formation of an acid & an amine.
∙Ring alteration : A hydrolytic reaction can proceed as a result of ring cleavage
with subsequent attack by H+ or OH- ion.

15. 2. OXIDATION:
•Instability in number of formulations is due to oxidation of active ingredient when
exposed to atmospheric oxygen.
• Auto-oxidation is free radical chain reaction which proceeds quite slowly under
the influence of molecular oxygen.
• Mainly occurs in oils & fats containing unsaturated linkages.
• Only small amount of oxygen is needed just to initiate the reaction.
• Rancidity is a term covering many typical off- flavors formed by auto oxidation
of unsaturated fatty acids present in oil or fat.

16. 3. ISOMERISATION:
•Isomerisation: Conversion of an active drug into a less active or inactive isomer
having same structural formula but differing in stereochemical configuration.
•In stereoisomerism, the atoms making up the isomers are joined up in the same
order, but still manage to have a different spatial arrangement.
•Most of the volatile oils and the fixed oil having active constituents in the form of
special isomers that is sis and trans isomer form.

17. Types of stability Testing

18. STABILITY TESTINGHerbal Drugs
Drug Substance(Active substances) Drug Product
1. Stress Testing 1. Selection of Batches
2. Selection of Batches 2. Container Closure System
3. Container Closure System 3. Specification
4. Specification 4. Testing Frequency
5. Testing Frequency 5. Storage Conditions
6. Storage Conditions 6. Stability Commitment
7. Stability Commitment 7. Evaluation
8. Evaluation 8. Statements/Labelling
9.Statements/Labelling

9.In-use stability
Variations
On-going Stability Studies

Parameters cover in whole stability study:

19. STABILITY TESTING FOR ACTIVE SUBSTANCE(Herbal drugs)

General:
•For active substances not described in an official pharmacopoeial monograph,
stability studies are required.
•For active substances described in an official pharmacopoeial monograph, which
covers the degradation products and for which suitable limits have been set but a
re-test period is not defined, two options are acceptable:
•The manufacturer confirms that the active substance complies with the
pharmacopoeial monograph immediately prior to the manufacture of the
pharmaceutical product. In this case no stability studies on the active substance
are required.
•The manufacturer establishes a re-test period based on the results of long term testing
stability studies conducted on the active substance.

20. 1) Stress Testing:
∙Stress testing of the active substance can help identify the likely degradation
products, which can in turn help establish the degradation pathways and the
intrinsic stability of the molecule.
∙For an active substance the following approaches may be used:
∙No data are required on the degradation products, if an active substance is
described in an official pharmacopoeial monograph.
∙For active substances not described in an official pharmacopoeial monograph,
then stress testing is carried out:

21. ∙Stress testing is likely to be carried out on a single batch of the active substance.
∙It should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.)
above that for accelerated testing), humidity (e.g., 75% RH or greater) where
appropriate, oxidation and photolysis on the active substance.
∙Photostability testing should be an integral part of stress testing.
∙The testing should also evaluate the susceptibility of the drug substance to hydrolysis
across a wide range of pH values when in solution or suspension.
∙Examining degradation products under stress conditions is useful in establishing
degradation pathways and developing and validating suitable analytical
procedures.

22. 2) Selection of Batches
∙Data from formal stability studies provided on at least 3 primary batches of the
active substance.
∙The primary batches should be manufactured to a minimum of pilot scale.
∙Pilot batches manufactured by the same synthetic route and method of
manufacture that stimulates the final process to be used for production batches.
3) Container Closure System :
The stability studies should be conducted on the drug substance packaged in a
container closure system that is the same as or simulates the packaging proposed for
storage and distribution.

23. (4) Specifications:
•Stability studies should include testing of those attributes of the drug substance
that are susceptible to change during storage and are likely to influence
quality, safety, and/or efficacy.
•The testing should cover, as appropriate, the physical, chemical, biological, and
microbiological attributes.
•Validated stability-indicating analytical procedures should be applied.
•Whether and to what extent replication should be performed should depend on the
results from validation

24. (5)Testing frequency :
•For long-term studies, frequency of testing should be sufficient to establish the
stability profile of the drug substance.
•For drug substances with a proposed retest period of at least 12 months,
The frequency of testing at the long-term storage condition should normally be
every 3 months over the first year,
every 6 months over the second year,
Annually thereafter through the proposed retest period.
•At the accelerated storage condition, a minimum of three time points, including the
initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is
recommended.
• At the intermediate storage condition, is called for as a result of significant change at
the accelerated storage condition, a minimum of four time points, including the initial
and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is
recommended.

25. (6) Storage Conditions:

27. (7) Stability Commitment:
When available long-term stability data on primary batches do not cover the proposed
retest period granted at the time of approval, a commitment should be made to
continue the stability studies post approval to firmly establish the retest period.
(8) Evaluation :
The purpose of the stability study is to establish, based on testing a minimum of three
batches of the drug substance and evaluating the stability information (including,
as appropriate, results of the physical, chemical, biological, and microbiological
tests), a retest period applicable to all future batches of the drug substance
manufactured under similar circumstances.

28. (9) Statements/Labeling :
•A storage statement should be established for the labeling in accordance with
relevant national/regional requirements.
•The statement should be based on the stability evaluation of the drug substance.
•Where applicable, specific instructions should be provided, particularly for drug
substances that cannot tolerate freezing.
•Terms such as ambient conditions or room temperature should be avoided.
•A retest period should be derived from the stability information, and a retest
date should be displayed on the container label if appropriate.

29. Stability of Herbal Drug Product
Introduction:
•The design of the formal stability studies for the drug product should
be based on knowledge of the behavior and properties of the drug
substance, results from stability studies on the drug substance, and
experience gained from clinical formulation studies.
•The likely changes on storage and the rationale for the selection of
attributes to be tested in the formal stability studies should be stated.

30. 1. Photostability Testing :
Photostability testing should be
conducted on at least one
primary batch of the drug
product if appropriate. The
standard conditions for
photostability testing are
described in ICH Q1B.
Photostability Chamber

31. (2) Selection of Batches:
•Data from stability studies should be provided on at least three primary batches
of the drug product.
•The primary batches should be of the same formulation and packaged in the
same container closure system as proposed for marketing.
•Two of the three batches should be at least pilot scale batches, and the third one
can be smaller if justified.
• Stability studies should be performed on each individual strength and container
size of the drug product.

32. (3) Container Closure System
•Stability testing should be conducted on the
dosage form packaged in the container closure
system proposed for marketing
(including,secondary packaging and container
label).
•Any available studies carried out on the drug
product outside its immediate container or in other
packaging materials can form a useful part of the
stress testing of the dosage form.

33. (4) Specification
•Should cover, as appropriate, the physical, chemical, biological, and microbiological attributes,
preservative content (e.g. antioxidant, antimicrobial preservative), and functionality tests (e.g. for a
dose delivery system). Analytical procedures should be fully validated.
(5) Testing Frequency: the frequency of testing at the long term storage condition should normally,
Every three months over the first year,
Every six months over the second year, and
Annually thereafter through the proposed shelf life.
•At the accelerated storage condition, a minimum of three time points, including the initial and final
time points (e.g. 0, 3, and 6 months) from a 6-month study is recommended.

34. (6) Storage:
∙Generally finished product should be evaluated under storage conditions (with
appropriate tolerances) that test includes:
1) Thermal stability
If applicable, its sensitivity to moisture and tempetature or potential for solvent loss
2) Photostability testing conducted on at least one primary batch of the finished
product.
∙Stability studies conducted on one batch of the pharmaceutical product for up to
three months at 50°C/ambient humidity may be useful to identify the formulation and
packaging material adequate for extremely hot and dry conditions.
∙The storage conditions and the lengths of studies chosen should be sufficient to cover
storage, shipment, and subsequent use with due regard to the climatic zone(s) in
which the product is intended to be marketed.

35. 7) Evaluation
∙If analysis shows that the batch-to-batch variability is small, it is advantageous to
combine the data into one overall estimate.
∙Thiscan bedone by first applyingappropriate statistical tests.
∙(Regression analysis)
∙If it is inappropriate to combine data from several batches, theoverall shelf life
should be based on the minimum time a batch can be expected to remain within
acceptance criteria.