75 
 
  Guidance for Industry 
 
 
 
 
 
S : P
TABILITY TESTING    HOTOSTABILITY TESTING 
N V D S
OF  EW  ETERINARY  RUG  UBSTANCES AND 
M P  
EDICINAL  RODUCTS
VICH GL5 
 
 
FINAL GUIDANCE 
 
 
This guidance is an annex to the VICH parent guidance entitled Stability Testing of New 
Veterinary Drug Substances and Medicinal Products (VICH GL3).  It primarily addresses the 
generation  of  photostability  information  for  submission  in  new  animal  drug  applications 
(referred to as Registration Applications in the VICH parent guidance) for new molecular 
entities and associated drug products. The guidance does not cover the photostability of drugs 
after administration (i.e. under conditions of use) and those applications not covered by the 
VICH parent guidance.  
 
This guidance represents current thinking and does not create or confer any rights for or 
on any person and does not operate to bind FDA or the public.  You may use alternative 
methods as long as they satisfy the requirements of the applicable statute and regulation. 
 
Comments and suggestions regarding the document should be submitted to Division of Dockets 
Management  (HFA-305),  Food  and  Drug  Administration,  5630  Fishers  Lane,  Rm.  1061, 
Rockville,  MD    20852.    Submit  electronic  comments  to  http://www.regulations.gov.    All 
comments should be identified with the Docket No. 1998D-0566. 
 
For questions regarding this document, contact Norman Gregory, Center for Veterinary 
Medicine, (HFV-143), Food and Drug Administration, 7500 Standish Place, Rockville, MD 
20855, 240-276-8253, e-mail:  norman.gregory@fda.hhs.gov.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
September 1999 
 
  Contains Non-Binding Recommendations 
 
 
VICH GL5 (STABILITY 3) 
May 1999 
For implementation at Step 7 
 
 
 
 
 
 
 
Stability Testing: Photostability Testing of New 
Veterinary Drug Substances and Medicinal 
Products 
 
 
 
 
 
 
 
 
Recommended for Implementation  
at Step 7 of the VICH Process 
on 20 May 1999 
by the VICH Steering Committee 
 
 
 
 
 
 
 
THIS FINAL GUIDANCE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH EXPERT WORKING 
GROUP ON THE BASIS OF THE ICH GUIDANCES ON THE SAME SUBJECT AND IS SUBJECT TO 
CONSULTATION BY THE PARTIES, IN ACCORDANCE WITH THE VICH PROCESS.  AT STEP 7 OF THE 
PROCESS THE FINAL DRAFT WILL BE RECOMMENDED FOR ADOPTION TO THE REGULATORY BODIES 
OF THE EUROPEAN UNION, JAPAN, AND USA. 
Pag e 2  Contains Non-Binding Recommendations 
 
STABILITY TESTING :  PHOTOSTABILITY TESTING OF NEW  
VETERINARY DRUG SUBSTANCES AND MEDICINAL PRODUCTS 
 
Recommended for Implementation at Step 7 of the VICH Process 
on 20 May 1999 by the VICH Steering Committee 
 
 
TABLE OF CONTENTS 
 
1. General..........................................................................................................4 
A. Preamble...............................................................................................4 
B. Light Sources.........................................................................................4 
Option 1.................................................................................................................................5 
Option 2.................................................................................................................................5 
C. Procedure..............................................................................................5 
DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG 
PRODUCTS...............................................................................................6 
2. Drug Substance............................................................................................7 
A. Presentation of Samples........................................................................7 
B. Analysis of Samples..............................................................................7 
C. Evaluation of Results.............................................................................8 
3. Drug Product ................................................................................................8 
A. Presentation of Samples........................................................................8 
B. Analysis of Samples..............................................................................9 
C. Evaluation of Results.............................................................................9 
4. Annex............................................................................................................9 
Quinine Chemical Actinometry...................................................................9 
Option 1.................................................................................................................................9 
Option 2.................................................................................................................................9 
5. Glossary......................................................................................................10 
6. References..................................................................................................10 
 
Pag e 3  Contains Non-Binding Recommendations 
 
 
STABILITY TESTING:  PHOTOSTABILITY TESTING OF 
NEW VETERINARY DRUG SUBSTANCES AND MEDICINAL PRODUCTS 
 
 
 
1. General 
The  VICH  Harmonized  Tripartite  Guidance  covering  the  Stability  Testing  of  New  Drug 
Substances and Products in the Veterinary Field (hereafter referred to as the Parent Guidance) 
notes that light testing should be an integral part of stress testing. This document is an annex to 
the Parent Guidance and addresses the recommendations for photostability testing. 
A. Preamble 
The intrinsic photostability characteristics of new drug substances and products should be 
evaluated to demonstrate that, as appropriate, light exposure does not result in unacceptable 
change. Normally, photostability testing is carried out on a single batch of material selected as 
described under Selection of Batches in the Parent Guidance. Under some circumstances 
these studies should be repeated if certain variations and changes are made to the product 
(e.g., formulation, packaging). Whether these studies should be repeated depends on the 
photostability characteristics determined at the time of initial filing and the type of variation 
and/or change made. 
 
The guidance primarily addresses the generation of photostability information for submission in 
Registration  Applications  for  new  molecular  entities  and  associated  drug  products.  The 
guidance does not cover the photostability of drugs after administration (i.e. under conditions of 
use) and those applications not covered by the Parent Guidance. Alternative approaches may 
be used if they are scientifically sound and justification is provided. 
 
A systematic approach to photostability 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. 
 
The  extent  of  drug  product  testing  should  be  established  by  assessing  whether  or  not 
acceptable change has occurred at the end of the light exposure testing as described in the 
Decision Flow Chart for Photostability Testing of Drug Products. Acceptable change is change 
within limits justified by the applicant. 
 
The  formal  labeling  requirements  for  photolabile  drug  substances  and  drug  products  are 
established by national/regional requirements. 
B. Light Sources 
The light sources described below may be used for photostability 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. 
 
Pag e 4  Contains Non-Binding Recommendations 
 
Option 1 
Any light source that is designed to produce an output similar to the D65/lD65 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. 
C. Procedure 
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. 
Pag e 5  Contains Non-Binding Recommendations 
 
DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG 
PRODUCTS 
 
 
 
START
 
 
 
yes
  FORMULATION  DIRECTLY EXPOSED
CHANGE?
 
 
 
 
  no
ACCEPTABLE  yes
  CHANGE?
 
  TEST END
no
 
 
  iMMEDIATE 
  PACK  yes IMMEDIATE PACK
CHANGE?
 
 
 
 
 
  no ACCEPTABLE  yes
CHANGE?
 
 
  TEST END
 
 
MARKETING 
 
PACK  yes MARKETING PACK
  CHANGE?
 
 
 
 
 
ACCEPTABLE  yes
  CHANGE?
 
  TEST END
no
 
 
 
REDESIGN PACKAGE 
  OR REFORMULATION
 
Pag e 6  Contains Non-Binding Recommendations 
 
2. Drug Substance 
For drug substances, photostability testing should consist of two parts: forced degradation 
testing and confirmatory testing. 
 
The purpose of forced degradation testing studies is to evaluate the overall photosensitivity of 
the material for method development purposes and/or degradation pathway elucidation. This 
testing may involve the drug substance alone and/or in simple solutions/suspensions to validate 
the analytical procedures. In these studies, the samples should be in chemically inert and 
transparent containers. In these forced degradation studies, a variety of exposure conditions 
may be used, depending on the photosensitivity  of the drug substance involved and the 
intensity of the light sources used. For development and validation purposes it is appropriate to 
limit  exposure  and  end  the  studies  if  extensive  decomposition  occurs.  For  photostable 
materials, studies may be terminated after an appropriate exposure level has been used. The 
design of these experiments is left to the applicant's discretion although the exposure levels 
used should be justified. 
 
Under forcing conditions, decomposition products may be observed that are unlikely to be 
formed under the conditions used for confirmatory studies. This information may be useful in 
developing and validating suitable analytical methods. If in practice it has been demonstrated 
they are not formed in the confirmatory studies, these degradation products need not be further 
examined. 
 
Confirmatory  studies  should then be undertaken  to provide the information necessary for 
handling, packaging, and labeling (see section 1.C., Procedure, and 2.A., Presentation of 
Samples, for information on the design of these studies). 
 
Normally, only one batch of drug substance is tested during the development phase, and then 
the photostability characteristics should be confirmed on a single batch selected as described in 
the Parent Guidance if the drug is clearly photostable or photolabile. If the results of the 
confirmatory study are equivocal, testing of up to two additional batches should be conducted. 
Samples should be selected as described in the Parent Guidance. 
A. Presentation of Samples 
Care should be taken to ensure that the physical characteristics of the samples under test are 
taken into account and efforts should be made, such as cooling and/or placing the samples in 
sealed  containers,  to  ensure  that  the  effects  of  the  changes  in  physical  states  such  as 
sublimation, evaporation or melting are minimized. All such precautions should be chosen to 
provide minimal interference with the exposure of samples under test. Possible interactions 
between the samples and any material used for containers or for general protection of the 
sample, should also be considered and eliminated wherever not relevant to the test being 
carried out. 
 
As a direct challenge for samples of solid drug substances, an appropriate amount of sample 
should be taken and placed in a suitable glass or plastic dish and protected with a suitable 
transparent cover if considered necessary. Solid drug substances should be spread across the 
container to give a thickness of typically not more than 3 millimeters. Drug substances that are 
liquids should be exposed in chemically inert and transparent containers. 
B. Analysis of Samples 
At the end of the exposure period, the samples should be examined for any changes in physical 
properties (e.g., appearance, clarity, or color of solution) and for assay and degradants by a 
method  suitably  validated  for  products  likely  to  arise  from  photochemical  degradation 
processes. 
 
Where  solid  drug  substance  samples  are  involved,  sampling  should  ensure  that  a 
representative portion is used in individual tests. Similar sampling considerations, such as 
homogenization of the entire sample, apply to other materials that may not be homogeneous 
Pag e 7  Contains Non-Binding Recommendations 
 
after exposure. The analysis of the exposed sample should be performed concomitantly with 
that of any protected samples used as dark controls if these are used in the test. 
 
C. Evaluation of Results 
The forced degradation studies should be designed to provide suitable information to develop 
and validate test methods for the confirmatory studies. These test methods should be capable 
of resolving and detecting photolytic degradants that appear during the confirmatory studies. 
When evaluating the results of these studies, it is important to recognize that they form part of 
the stress testing and are not therefore designed to establish qualitative or quantitative limits for 
change. 
 
The confirmatory studies should identify precautionary measures needed in manufacturing or in 
formulation of the drug product, and if light resistant packaging is needed. When evaluating the 
results  of  confirmatory  studies  to  determine  whether  change  due  to  exposure  to  light  is 
acceptable, it is important to consider the results from other formal stability studies in order to 
assure that the drug will be within justified limits at time of use (see the relevant VICH Stability 
and Impurity Guidances). 
3. Drug Product 
Normally, the studies on drug products should be carried out in a sequential manner starting 
with testing the fully exposed product then progressing as necessary to the product in the 
immediate pack and then in the marketing pack. Testing should progress until the results 
demonstrate that the drug product is adequately protected from exposure to light. The drug 
product should be exposed to the light conditions described under the procedure in section 1.C. 
 
Normally, only one batch of drug product is tested during the development phase, and then the 
photostability characteristics should be confirmed on a single batch selected as described in the 
Parent  Guidance  if  the  product is clearly photostable or photolabile. If the results of the 
confirmatory study are equivocal, testing of up to two additional batches should be conducted. 
 
For some products where it has been demonstrated that the immediate pack is completely 
impenetrable  to  light,  such  as  aluminum  tubes  or  cans,  testing  should  normally  only  be 
conducted on directly exposed drug product. 
 
It may be appropriate to test certain products such as infusion liquids, dermal creams, etc., to 
support their photostability in-use. The extent of this testing should depend on and relate to the 
directions for use, and is left to the applicant's discretion. 
 
The analytical procedures used should be suitably validated. 
A. Presentation of Samples 
Care should be taken to ensure that the physical characteristics of the samples under test are 
taken into account and efforts, such as cooling and/or placing the samples in sealed containers, 
should be made to ensure that the effects of the changes in physical states are minimized, such 
as sublimation, evaporation, or melting. All such precautions should be chosen to provide a 
minimal interference with the irradiation of samples under test. Possible interactions between 
the samples and any material used for containers or for general protection of the sample should 
also be considered and eliminated wherever not relevant to the test being carried out. 
 
Where practicable when testing samples of the drug product outside of the primary pack, these 
should be presented in a way similar to the conditions mentioned for the drug substance. The 
samples should be positioned to provide maximum area of exposure to the light source. For 
example, tablets, capsules, etc., should be spread in a single layer. 
 
If direct exposure is not practical (e.g., due to oxidation of a product), the sample should be 
placed in a suitable protective inert transparent container (e.g., quartz). 
 
Pag e 8  Contains Non-Binding Recommendations 
 
If testing of the drug product in the immediate container or as marketed is needed, the samples 
should  be  placed  horizontally  or  transversely  with  respect  to  the  light  source,  whichever 
provides for the most uniform exposure of the samples. Some adjustment of testing conditions 
may have to be made when testing large volume containers (e.g., dispensing packs). 
B. Analysis of Samples 
At the end of the exposure period, the samples should be examined for any changes in physical 
properties (e.g., appearance, clarity or color of solution, dissolution/disintegration for dosage 
forms such as capsules, etc.) and for assay and degradants by a method suitably validated for 
products likely to arise from photochemical degradation processes. 
 
When powder samples are involved, sampling should ensure that a representative portion is 
used in individual tests. For solid oral dosage form products, testing should be conducted on an 
appropriately  sized  composite  of,  for  example,  20  tablets  or  capsules.  Similar  sampling 
considerations, such as homogenization or solubilization of the entire sample, apply to other 
materials that may not be homogeneous after exposure (e.g., creams, ointments, suspensions, 
etc.). The analysis of the exposed sample should be performed concomitantly with that of any 
protected samples used as dark controls if these are used in the test. 
C. Evaluation of Results 
Depending on the extent of change special labeling or packaging may be needed to mitigate 
exposure to light. When evaluating the results of photostability studies to determine whether 
change due to exposure to light is acceptable, it is important to consider the results obtained 
from other formal stability studies in order to assure that the product should be within proposed 
specifications during the shelf life (see the relevant VICH Stability and Impurity Guidances). 
 
4. Annex 
Quinine Chemical Actinometry 
The following provides details of an actinometric procedure for monitoring exposure to a near 
UV fluorescent lamp (based on FDA/National Institute of Standards and Technology study). For 
other  light  sources/actinometric  systems,  the  same  approach  may  be  used,  but  each 
actinometric system should be calibrated for the light source used. 
 
Prepare  a  sufficient  quantity  of  a  2  percent  weigh/volume  aqueous  solution  of  quinine 
monohydrochloride dihydrate (if necessary, dissolve by heating). 
Option 1 
Put 10 milliliters (ml) of the solution into a 20 ml colorless ampoule seal it hermetically, and use 
this as the sample. Separately, put 10 ml of the solution into a 20 ml colourless ampoule (See 
note 1), seal it hermetically, wrap in aluminum foil to protect completely from light, and use this 
as the control. Expose the sample and control to the light source for an appropriate number of 
hours. After exposure determine the absorbances of the sample (AT) and the control (Ao) at 
400 nm using a 1 centimeter (cm) path length. Calculate the change in absorbance,  A = AT - 
Ao. The length of exposure should be sufficient to ensure a change in absorbance of at least 
0.9. 
Option 2 
Fill a 1 cm quartz cell and use this as the sample. Separately fill a 1 cm quartz cell, wrap in 
aluminum foil to protect completely from light, and use this as the control. Expose the sample 
and control to the light source for an appropriate number of hours. After exposure determine the 
absorbances of the sample (AT) and the control (Ao) at 400 nm. Calculate the change in 
absorbance,  A = AT - Ao. The length of exposure should be sufficient to ensure a change in 
absorbance of at least 0.5. 
 
Alternative  packaging  configurations  may  be  used  if  appropriately  validated.  Alternative 
validated chemical actinometers may be used. 
Pag e 9  Contains Non-Binding Recommendations 
 
 
 
Note 1: Shape and Dimensions (See Japanese Industry Standard (JIS) R3512 (1974) for 
ampoule specifications) 
 
 
 
 
  er  Stem diameter: 21.8  0.40 mm 
  m met
  Stedia
  Bore (at cutting portion) 
    Stemlength
   Bore: 7.0  0.7 mm, 
 
 
  Stem length: 80.0  1.2 mm 
5. Glossary 
Immediate (primary) pack is that constituent of the packaging that is in direct contact with the 
drug substance or drug product, and includes any appropriate label. 
 
Marketing pack is the combination of immediate pack and other secondary packaging such as a 
carton. 
 
Forced degradation testing studies are those undertaken to degrade the sample deliberately. 
These studies, which may be undertaken in the development phase normally on the drug 
substances,  are  used  to  evaluate  the  overall  photosensitivity  of  the  material  for  method 
development purposes and/or degradation pathway elucidation. 
 
Confirmatory studies are those undertaken to establish photostability characteristics under 
standardized conditions. These studies are used to identify precautionary measures needed in 
manufacturing or formulation and whether light resistant packaging and/or special labeling is 
needed to mitigate exposure to light. For the confirmatory studies, the batch(es) should be 
selected according to batch selection for long-term and accelerated testings which is described 
in the Parent Guidance. 
6. References 
Quinine Actinometry as a method for calibrating ultraviolet radiation intensity in light-stability 
testing of pharmaceuticals. 
Yoshioka S. et al., Drug Development and Industrial Pharmacy, 20 (13), 2049 - 2062 (1994) 
 
 
Pag e 10