Guidance  for  Federal 

Agencies and  State  and  Local 

Governments 
 
 
Potassium  Iodide  Tablets 
 
Shelf Life Extension 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department  of Health and Human  Services
  
Food and Drug Administration 
 
Center  for Drug Evaluation  and Research  (CDER)
  
 
March  2004 

Procedural
   Guidance  for  Federal 

Agencies and  State  and  Local 

Governments 
 
 
Potassium  Iodide  Tablets 
 
Shelf Life Extension 
 
 
 
 
 
Additional copies are available from: 

Office of Training and  Communication 
 
Division of  Drug Information, HFD-240 
 
Center for  Drug  Evaluation and Research 
 
Food and Drug  Administration 

5600 Fishers  Lane
  
Rockville, MD 20857 (Tel) 301-827-4573 
 
http://www.fda.gov/cder/guidance/index.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department  of Health and Human  Services
  
Food and Drug Administration 
 
Center  for Drug Evaluation  and Research  (CDER)
  
 
March  2004 

Procedural
   TABLE OF CONTENTS
  
 
 
 
 
I.  INTRODUCTION................................................................................................................. 1 

 
II.   BACKGROUND ................................................................................................................... 1 
 
 
A.  Regulatory Framework .................................................................................................................  1
  
 
B.  HHS Role in Radiological Planning  and Preparedness Activities .............................................  2
  
 
C.  FDA Guidance  on Safe and Effective Use of KI as a Radioprotective Agent ...........................  2
  
 
D.  Shelf Life Extension of KI  Tablets ...............................................................................................  3
  
 
III.  DISCUSSION ........................................................................................................................ 4 

 
A.  Observations About KI Tablet Stability Based on Historical Data........................................... 4
  
 
B.  Recommended  Protocol  for Shelf Life Extension of KI Tablets ................................................  4
  
 
C.  Identifying  a Suitable Laboratory ................................................................................................  6
  
 
D.  Identification of Batches Qualified for Extension and Notification of Expired  Batches .........  6
     Contains Nonbinding Recommendations 
 
 
Guidance  for  Federal   Agencies and 
 
1
 
State and Local Governments
 
 
 
Potassium  Iodide Tablets
  
Shelf Life  Extension
  
 
 
 
  
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking  on this  topic. It 
does not create or confer any rights for or  on  any person and does not operate to bind FDA or the public. 
You can use an alternative  approach if that approach satisfies  the requirements of the applicable statutes  
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot  identify  the appropriate FDA staff, call the appropriate 
number listed  on the title page of this guidance. 
 
 
 
 
I.  INTRODUCTION  
 
This document is intended to provide guidance to Federal agencies and to state and local governments 
on testing to extend the shelf life of stockpiled potassium iodide (KI) tablets. The Agency has 
developed this document in response to several state inquiries on this topic. This guidance discusses 
FDA recommendations on testing for such shelf life extensions, the qualifications of  laboratories 
suitable to conduct the tests, and issues regarding notification of holders of stockpiled KI tablets as 
well as end users2 about changes to batch shelf life once testing has been successfully conducted. 
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's  current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
 
II.  BACKGROUND  
 
A.  Regulatory Framework  
 
 
 
 
1 This guidance  has been prepared by the Office of Pharmaceutical Science (OPS) in the  Center for Drug Evaluation 
and Research (CDER)  at the  Food and Drug Administration.  
 
2 For purposes  of  this guidance, end users are consumers who have purchased KI, or  intermediate  holders of KI, 
such  as fire departments, health departments, hospitals, or other entities who store KI for use in emergencies.    Contains Nonbinding Recommendations 
 
 
FDA has approved two new drug applications (NDAs) for Potassium  Iodide Tablets, USP.3  
Both applications4 were approved prior to 1985 and currently provide for marketing of 130-mg  
KI tablets over the counter (OTC) (i.e., without a prescription).  Potassium iodide tablets 
manufactured by one or both holders of these NDAs have been stockpiled under controlled 
conditions for use in a radiation emergency. 
 
An abbreviated new drug application (ANDA)5 for Potassium Iodide Tablets, USP (65 mg), was  
approved on September 10, 2002.6 
 
 
B.  HHS Role in Radiological Planning  and Preparedness Activities  
 
Under 44 CFR 351, the Federal Emergency Management Agency (FEMA) has established roles 
and responsibilities for Federal agencies in assisting state and local governments in their 
radiological emergency planning and preparedness activities.  The Federal agencies, including 
the Department of Health and Human Services (HHS), are to carry out these roles and 
responsibilities as members of the Federal Radiological Preparedness Coordinating Committee 
(FRPCC).  Under  351.23(f), HHS is directed to provide guidance to state and local 
governments on the use of radioprotective substances and the prophylactic use of drugs (e.g., KI 
tablets) to reduce the radiation dose to specific organs, including dosage and projected radiation 
exposures at which such drugs should be used.  As a part of HHS, FDA has been providing 
relevant guidance to other agencies and the public on KI. 
 
C.   FDA Guidance  on Safe and Effective Use of KI as a Radioprotective Agent  
 
In November 2001, FDA provided guidance on the safe  and effective use of KI tablets as an 
adjunct to other public health protective measures in the event that radioactive iodine is released 
into the environment. The guidance Potassium  Iodide as a Thyroid Blocking Agent in Radiation 
Emergencies updated FDA's 1982 recommendations for the use of KI tablets to reduce the risk of 
thyroid cancer in radiation emergencies involving the release of radioactive iodine. The 
recommendations in that guidance addressed KI dosage and the projected radiation exposure at 
which the drug should be used.  In April 2002, FDA issued another document, Frequently Asked 
Questions on Potassium  Iodide (KI). Additional information was provided for emergency 
pediatric dosing in Home  Preparation  Procedure for Emergency Administration of Potassium  
Iodide Tablets to Infants and Small Children (Home Procedures document), updated on July 3, 
2002.7 
 
 
 
3 United States Pharmacopeia. 
 
4 NDAs 18-307  and  18-664.  
 
5 
Application ANDA  76-350.  
 
6 For an up-to-date listing of all approved KI products, consult the online version of FDA's Approved  Drug  Products  
With  Therapeutic Equivalence Evaluations  (Electronic Orange Book) at 
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. 
 
7 
The guidance and home preparation information can be found at   
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm080542.pdf, 
http://www.fda.gov/Drugs/EmergencyPreparedness/BioterrorismandDrugPreparedness/ucm072265.htm, 
and  http://www.fda.gov/kiprepare, respectively.  
  2
    Contains Nonbinding Recommendations 
 
 
 
D.  Shelf Life Extension of KI Tablets  
 
A number of state and local governments maintain stockpiles of KI tablets for use in the event of 
a  radiation emergency involving the release of radioactive iodine. Several states have asked 
FDA what would be necessary to provide  confidence that stockpiled  KI tablets have retained 
their original quality (i.e., purity and potency) after passing the expiration date. 
 
Previously, two approaches have been used to extend the shelf life of expired drug products: (1) 
the ordinary approach taken by drug manufacturers, and (2) the Department  of Defense (DOD) 
Sponsored Shelf Life Extension Program. 
 
1.  Ordinary Shelf Life Extension 
 
In the preferred method of shelf life extension for drug manufacturers, the manufacturer 
of an approved drug product may propose an extension of the expiration dating period for 
that product based on acceptable data from  full, long-term  stability studies on at least 
three production batches in accordance with a protocol approved in the application. The 
data can be reported and FDA can be notified of the extension of the expiration dating 
period in an annual report submitted to the NDA or ANDA if, after obtaining and 
analyzing the data in accordance with the protocol, the criteria set forth in the approved 
stability protocol are met.  8 
 
 
2.  DOD-Sponsored Shelf Life  Extension Program  
 
Certain drug products have been qualified for shelf life extension through the Shelf Life 
Extension Program  (SLEP), which is sponsored by the DOD and performed by FDA. 
The SLEP is sponsored by the DOD because of  the substantial savings to the government 
from  extending the shelf life of certain antibiotics and other drug products of strategic 
importance that are stored in Federal stockpiles in large quantities under controlled 
conditions. 
 
It is unlikely  that any manufacturer of  KI tablets would be willing to conduct testing of  all of  the 
lots of KI tablets that have already been distributed, and it would be infeasible for FDA to include  
KI tablets in  a DOD-sponsored program. Because  several states have inquired about possibly 
testing stockpiled KI for shelf life extension, the Agency is providing this guidance on testing for 
such shelf life extensions  of KI that is being stockpiled under controlled conditions. The Agency 
is also providing guidance on how to identify laboratories suitable to conduct the tests, how to 
notify holders of stockpiled KI tablets and end users about changes in shelf life,9 and how to 
distinguish stockpiled batches with different shelf lives. 
 
 
 
8 In  June 1998,  the Agency issued a draft guidance on  stability  testing, Stability Testing  of Drug Substances and  
Drug  Products.   Once finalized, this guidance will represent the Agency's current thinking on this topic. 
 
9 The shelf life extension testing  described in this guidance can  provide confidence only that KI that has been  stored  
in accordance with the conditions described in the labeling will retain its potency and quality for an  extended period 
of time. 
  3
    Contains Nonbinding Recommendations 
 
 
III.  DISCUSSION
  
 
Studies conducted during the SLEP program  on a variety of drug products have shown that shelf 
lives of most  drug products can be extended well beyond their expiration dates, but the 
additional stability period for a given drug can be highly variable. It was concluded that, due to 
lot-to-lot variability, the stability and quality of drug products  with extended expiration  dates 
could only be assured by continual testing and systematic evaluation of each lot.10 
 
 
A.  Observations About KI Tablet Stability Based on Historical  Data  
 
Potassium  Iodide Tablets, USP, is a compendial drug product that is manufactured to meet the  
recommended tests and specifications listed in the USP monograph. Assay and dissolution are 
the two specifications with potential relevance to stability, assuming identification and content 
uniformity testing were performed at release.11   Stability studies over many years have confirmed 
that none of the components of KI tablets, including the active ingredient, has any significant 
potential for chemical degradation or interaction with other components or with components of the  
container closure system when stored according  to labeled directions. 
 
To date, the only observed changes during stability testing have been the failure of  some batches 
of KI tablets  to meet the USP S dissolution specification, Q=75 percent in 15 minutes. Some  
1 
tablets tested required slightly longer than the specified time to achieve dissolution, but even in 
the case of a failure of this sort, the product would remain usable. In such cases, instructions can 
be provided to crush the tablets and mix them  with a juice or other liquid prior to administration 
as suggested for emergency pediatric dosing (see Home  Preparation Procedures document cited 
above). In any long-term  stability evaluation, appearance should be monitored as a matter of 
course. In the specific case of KI tablets, a yellowish discoloration would be indicative of 
stability problems. Since pure KI is known to be very stable (as long as it is protected from  
moist air),12 ongoing evaluation and testing of each batch is probably unnecessary as long as the 
market package remains intact and continues to be stored under controlled conditions as 
described in the labeling. 
 
B.  Recommended  Protocol for Shelf Life Extension of KI Tablets  
 
An example of a protocol for shelf life extension of KI tablets from  a given manufacturer 
(manufacturer A) of stockpiled KI tablets is illustrated  in the table later in this section.  
 
 
 
 
10 "Stability Profiles of  Drug Products Extended Beyond Labeled Expiration Dates," AAPS Poster Session, 
November 2001, Center for Drug Evaluation and Research, Office of Pharmaceutical Sciences, Division of Product 
Quality Research. 
 
11 The quality control division  of the manufacturer performs identification  and content uniformity testing before the 
product can be released for sale. 
 
12 "Slightly deliquescent in moist air; on long exposure to  air becomes yellow  due to  liberation  of iodine, and  small 
quantities of iodate may be formed; light and moisture accelerate the decomposition,"  The Merck Index, 12th  
edition, 7809,  Potassium  Iodide. 
  4
    Contains Nonbinding Recommendations 
 
 
We recommend that samples of three batches of KI tablets from  each manufacturer be selected 
and stored under controlled conditions of temperature and humidity and that the samples be 
tested periodically for compliance with the USP assay and dissolution specifications. Each 
sample should consist of at least 25 tablets per test, but it would be prudent to select larger 
samples so that sequential testing and extensions can be performed indefinitely. Accelerated 
stability testing storage conditions are 40C/75% relative humidity (R.H.).  These conditions 
stress the product and are thought to be conservatively predictive of future stability for a period 
of time  under room  temperature conditions.  Accelerated data are commonly  used to establish 
initial expiration dates for pharmaceuticals. The expiration dates are confirmed with real time  
stability data. For KI tablets, results of these tests could support shelf life extensions as follows: 
 
	   If the testing results are acceptable after 3 months of storage under accelerated storage 
conditions, all batches of KI tablets from  that manufacturer can be considered to be 
tentatively qualified for an additional 2 years. 
 
	   We recommend that additional samples of  the three batches, stored at room  temperature 
in a warehouse or other facility, be tested at  the end of 2 years from  the date of  initial 
sampling to confirm the shelf  life extension tentatively qualified by the accelerated 
studies. 
 
	  After this confirmation, additional shelf life extensions in increments of 2 years can be 
qualified in the same fashion (i.e., 3 months storage at accelerated conditions followed by 
confirmatory data from  samples stored  at room  temperature for 2 years). 
 
We recommend that adequate records of the testing be kept even when a batch fails stability 
testing. 
 
As already mentioned, in any long-term stability evaluation, we recommend that appearance be 
monitored. Discoloration of the tablets would provide an early indication of stability problems. 
 
Table:  Example of a Protocol for Shelf Life Extension  
 
Batch     Start  Finish 	  Tests/Specifications*     Stations Monitored  Shelf life   Expiry  
Identification   Conditions   date   date	  per USP: 
Assay: 60.1-69.9  mg  
Diss.: 75% in 60 min.  
Appearance  
Manufacturer A  90 days  10/1/02 12/31/02        0, 1, 2, 3 months  5 years (tentative)  10/04
accelerated.  (tentative) 
 	  24 months  10/02   ongoing        0, 3, 6, 9,  12,  18,  24   5  years   10/04  
long term   months  (confirmed)   (confirmed)  
confirmatory 
   90 days   10/1/04  12/31/04         0, 1, 2, 3 months  7 years  10/06
accelerated  (tentative)  (tentative) 
 	  24 months  10/02     ongoing         0, 3, 6,  9, 12,  18,  24   7  years   10/06  
long term   months  (confirmed)   (confirmed)  
confirmatory 
 
*Test    USP Specification  
Potassium  Iodide (USP method  titration)  60.1 69.9 mg  (92.5% - 107.5%) (65 mg  tablet) 
Dissolution   NLT 75% (Q) of labeled amount in 15 minutes 
Appearance (visual)  (Not  USP)   No  appreciable discoloration 
  5
    Contains Nonbinding Recommendations 
 
 
C. 	 Identifying  a Suitable Laboratory  
 
If the decision is made to contract to have shelf life testing performed, we recommend that a 
suitable laboratory  be identified. The  testing suggested in this guidance is uncomplicated, and 
most laboratories should be capable of performing the tests. General laboratory GMPs are 
discussed in detail in Guide to Inspections of Dosage Form  Drug Manufacturer's  CGMPRs.13 
 
The recommended assay test is a titration. Dissolution testing and the requisite apparatus are 
adequately described in the USP.  Because these are compendial tests, the validation  of 
methodology is straightforward (i.e., typical parameters are listed in USP <1225>). Potassium  
iodide is a very soluble drug substance and will be dissolved in the specified medium  upon tablet 
disintegration, confirmed by measurement of the UV (ultraviolet) absorbance at the specified 
wavelength using a UV spectrophotometer. 
 
D. 	 Identification of Batches Qualified  for Extension and Notification of Expired  
Batches  
 
Once KI tablets from  a given manufacturer have been qualified for shelf life extension by the 
program described above, we recommend that some provision be made to notify holders of 
stockpiled KI  and end users as to which drug product has been qualified and what the new 
expiration date should be. The identification and notification procedures should be amenable to 
additional extensions. Potassium  iodide tablets that are centrally  stored can be shrink wrapped 
and marked with the qualified shelf life extension dates to distinguish them from other KI tablets 
that have different expiry dates. Each individual container need not be relabeled. End users can 
be notified of the extension of  the expiration date using the batch identification number on each 
bottle. 
 
Due to the inherent  stability of KI tablets, stockpiled or  distributed batches will probably not 
need to be  replaced frequently. As noted previously, even if  a batch fails the dissolution test, 
instructions for crushing the tablets can be provided with distributed batches. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13 This document is available at http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074927.htm  
  6