Photo stability Testing of New Drug Substances and Products

The intrinsic photo stability characteristics of new drug substances and products should be evaluated to demonstrate that, as appropriate, light exposure does not result in unacceptable change.  Normally, photo stability testing is carried out on a single batch of material selected.

A systematic approach to photo stability testing is recommended covering, as appropriate, studies such as:

i)     Tests on the drug substance;

ii)    Tests on the exposed drug product outside of the immediate pack;

and if necessary ;

iii)   Tests on the drug product in the immediate pack;

and if necessary ;

iv)   Tests on the drug product in the marketing pack.

Light Sources

The light sources described below may be used for photo stability testing. The applicant should either maintain an appropriate control of temperature to minimize the effect of localized temperature changes or include a dark control in the same environment unless otherwise justified.  For both options 1 and 2, a pharmaceutical manufacturer/applicant may rely on the spectral distribution specification of the light source manufacturer. For confirmatory studies, samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter to allow direct comparisons to be made between the drug substance and drug product. Samples may be exposed side-by-side with a validated chemical actinometric system to ensure the specified light exposure is obtained, or for the appropriate duration of time when conditions have been monitored using calibrated radiometers/lux meters.  An example of an actinometric procedure is provided in the Annex.

If protected samples (e.g., wrapped in aluminum foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change, these should be placed alongside the authentic sample.

Option 1

Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp.  D65 is the internationally recognized standard for outdoor daylight as defined in ISO 10977 (1993).  ID65 is the equivalent indoor indirect daylight standard. For a light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation.

Option 2

For option 2 the same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp.

1. A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) ; and

2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm.

 Photostbility

IN- USE STABILITY

The purpose of in-use stability testing is to establish a period of time during which a multidose product can be used whilst retaining quality within an accepted specification once the container is opened. Scope This guideline refers to medicinal products in multidose containers which by nature of their physical form and chemical composition - due to repeated opening and closing, may pose a risk to its content with regard to microbiological contamination, proliferation and/or physicochemical degradation once the closure system has been breached.

Introduction The continued integrity of products in multidose containers after the first opening is an important quality issue. No specific guidance is available on defining test design and conduct of studies to be undertaken to define in-use shelf life in a uniform fashion. Therefore, this document attempts to define a framework for selection of batches, test design, test storage conditions, test parameters, test procedures etc., taking into consideration the broad range of products concerned.

The registration dossier for a multi-dose product should include either the in-use stability data on which the in-use shelf life is based or a justification why no in-use shelf life is established. This justification can also be based on experimental results.

Selection of batches : A minimum of two batches, at least pilot scale batches, should be subjected to the test. At least one of the batches should be chosen towards the end of its shelf life. If such results are not available, one batch should be tested at the final point of the submitted stability studies. The batch number, date of manufacture and size of each batch should be stated. The container and closure of the product and, if present, the medicinal device should be equivalent to that proposed for marketing. If the product is to be supplied in more than one container size or in different strengths, the in-use stability test should be applied to the product which presents the greatest susceptibility to change. The choice of the tested product should always be justified. Test design As far as possible the test should be designed to simulate the use of the product in practice taking into consideration the filling volume of the container and any dilution/reconstitution before use. At intervals comparable to those which occur in practice appropriate quantities should be removed by the withdrawal methods normally used and described in the product literature. Sampling should take place under normal environmental conditions of use. The appropriate physical, chemical and microbial properties of the product susceptible to change during storage should be determined over the period of the proposed in-use shelf life. If possible, testing should be performed at intermediate time points and at the end of the proposed in-use shelf life on the final remaining amount of the product in the container. Test storage conditions The product should be stored under the conditions as recommended in the product literature throughout the in-use stability test period. Any other storage conditions should be justified.

Test parameters : The appropriate physical, chemical and microbial properties of the product susceptible to change during use should be monitored. The tests used must be appropriate to individual dosage forms, however, examples of parameter types which may need to be studied are given below: Physical: colour, clarity, closure integrity, particulate matter, particle size Chemical: active substance assay(s), antimicrobial preservative and antioxidant content(s), degradation product level(s), pH Microbial: Total viable count, sterility Analytical procedures The analytical procedures used in the study should be described and fully validated. Stability indicating assays should be employed. Presentation of the results The results should be summarized and tabulated.

In-Use Stability might be perform as intervals

1) 1/3 starting, 2/3 Middle  3/3 at the end (Depend on pack size)

Example : consider marketed pack of 30's count than study should be done at 10days- 1/3^rd , 20days - 2/3^rd and 30days - 3/3^rd interval. 6 container of marketed or as per study requirement may be charged (also use pharmacy dispensing container if required)

Or

2) At 14days, 30days, 45days, 60 days, 90days and 120days

In-Use Stability Study

Hold time study

Pharmaceutical drug products stability studies are important for establishing the shelf life of the products. Stability studies can be performed for finished drug substances and drug products with the real time, intermediate and accelerated storage conditions. All stability study guidelines are mentioned in ICH, FDA, EMEA and WHO guidelines.

HOLD TIME STUDY

Hold time stability is evaluating for each stage in the product manufacturing. Hold stability study can demonstrates how much time is suitable for hold the blend or bulk stage before processing to the next stage. When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Hold time stability results should meet the product specifications. Hold time study shall be carried out with the storage container packing’s only. If the dosage form is stored in bulk containers for over 30 days, real-time stability data under specified conditions should be generated to demonstrate comparable stability to the dosage form in the marketed package.

As an example, for oral tablets that are coated, the following stages may be considered: 

– binder preparation to granulation 

– consider the granulate 

– wet granulation to drying 

– consider the dried granulate

– dried granules to lubrication/blending 

– consider the lubricated blend

– blend to compression

– compression to coating 

– consider the tablet cores

– coating solution to preparation 

– consider the coating solution

– coating to packing 

– consider the bulk coated tablets

– coating to packing in bulk

– packing of bulk to finished packed dosage form

Hold time flow in pharmaceutical industry

Hold time study stages in all type of dosages form

Tests dependent on the requirement

HOLD TIME STUDY

CLIMATIC ZONES

–     Partition of the world into three temperature classes based on kinetic averaging of monthly temperatures, & subdivision of the hottest class into predominantly wet or predominantly dry

–     Zones (Futscher & Schumacher 1972):

•      I           Temperate (21^oC/45%RH)

•      II         Subtropical (25^oC/60%RH with possibly high RH)

•      III        Hot & dry (30^oC/35%RH)

•      IV        Hot & wet (30^oC/70%RH)

–     The temperatures above are kinetic averages

–     Each nation within zone IV must now decide whether to adopt a stability test condition of          

–     30^oC & 65%RH, or

–     30^oC & 75%RH

–     ASEAN nations & Brazil have adopted 30^oC & 75%RH

Climatic Zone

Pharmaceutical stability requirement

Stability Data requirement for

New Drug Substances and Products

Objectives of the Document

On the basis of revised version of the ICH Q1A guideline and defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC, Japan, and the United States. It does not seek necessarily to cover the testing for registration in or export to other areas of the world. And also include requirement of Canada and Brazil regulatory requirement for stability to get approval of submitted drug product submission.

Scope of the Document

The Document addresses the information to be submitted in registration applications for new molecular entities and associated drug products. This document does not currently seek to cover the information to be submitted for abbreviated or abridged applications, variations, clinical trial applications, etc.

General Principles

The purpose of stability study is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.

The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV.

Stress Testing

Stress testing of the drug substance can help identify the likely degradation products. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved.

Stress testing is likely to be carried out on a single batch of the drug 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 drug substance.  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.  

General case

Study	Storage condition	Minimum time period covered by data at submission
Long term$	25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH	12 months
Intermediate##	30°C ± 2°C/65% RH ± 5% RH	6 months
Accelerated	40°C ± 2°C/75% RH ± 5% RH	6 months

^$It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

^##If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

New drug substances intended for storage in a refrigerator

Study	Storage condition	Minimum time period covered by data at submission
Long term	5°C ± 3°C	12 months
Accelerated	25°C ± 2°C/60% RH ± 5% RH	6 months

New drug substances intended for storage in a freezer

Study	Storage condition	Minimum time period covered by data at submission
Long term	- 20°C ± 5°C	12 months

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 re-test period applicable to all future batches of the drug substance manufactured under similar circumstances. The degree of variability of individual batches affects the confidence that a future production batch will remain within specification throughout the assigned re-test period.

The data may show so little degradation and so little variability that it is apparent from looking at the data that the requested re-test period will be granted. Under these circumstances, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient

General case

Study	Storage condition	Minimum time period covered by data at submission
Long term$	25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH	12 months
Intermediate##	30°C ± 2°C/65% RH ± 5% RH	6 months
Accelerated	40°C ± 2°C/75% RH ± 5% RH	6 months

^$It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

^##If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

Other comparable approaches can be developed and reported for non-aqueous, solvent-based products.

Study	Storage condition	Minimum time period covered by data at submission
Long term*	25°C ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH	12 months
Intermediate**	30°C ± 2°C/65% RH ± 5% RH	6 months
Accelerated	40°C ± 2°C/not more than (NMT) 25% RH	6 months

Other comparable approaches can be developed and reported for non-aqueous, solvent-based products.

Study	Storage condition	Minimum time period covered by data at submission
Long term*	25°C ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH	12 months
Intermediate**	30°C ± 2°C/65% RH ± 5% RH	6 months
Accelerated	40°C ± 2°C/not more than (NMT) 25% RH	6 months

*It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH.

**If 30°C ± 2°C/35% RH ± 5% RH is the long-term condition, there is no intermediate condition.

Drug products intended for storage in a refrigerator

Study	Storage condition	Minimum time period covered by data at submission
Long term	5°C ± 3°C	12 months
Accelerated	25°C ± 2°C/60% RH ± 5% RH	6 months

Drug products intended for storage in a freezer

Study	Storage condition	Minimum time period covered by data at submission
Long term	- 20°C ± 5°C	12 months

stability data requirement for regulatory submission

Drug Development flow chart