Guidance for Industry 
Incorporation of Physical-
Chemical Identifiers into Solid 
Oral Dosage Form Drug 
Products for Anticounterfeiting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
October 2011 
CMC 
 
   
Guidance for Industry 
Incorporation of Physical-
Chemical Identifiers into Solid 
Oral Dosage Form Drug 
Products for Anticounterfeiting 
 
 
Additional copies are available from: 
Office of Communication 
Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Avenue 
Bldg. 51, rm. 2201 
Silver Spring, MD  20993-0002 
(Tel) 301-796-3400 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
October 2011 
CMC 
 
 
 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  DESIGN CONSIDERATIONS FOR INCORPORATION OF PCIDS IN SOLID 
ORAL DOSAGE FORMS................................................................................................2 
A.  Pharmacological and Toxicological Considerations...................................................................2 
B.  Other Design Considerations........................................................................................................3 
IV.  SUPPORTING DOCUMENTATION TO ADDRESS THE PROPOSED 
INCORPORATION OF PCIDs IN SOLID ORAL DOSAGE FORMS......................4 
A.  Documentation Regarding Incorporation of PCIDs into Solid Oral Dosage Forms to be 
Included in any Premarketing or Postapproval Regulatory Submission.................................4 
B.  Documentation Regarding Incorporation of PCIDs into Solid Oral Dosage Forms to be 
Included in any Postapproval Regulatory Submission...............................................................5 
V.  DETERMINING REPORTING CATEGORY FOR POSTAPPROVAL CHANGES 
TO INCORPORATE PCIDs INTO SOLID ORAL DOSAGE FORMS.....................5 
A.  Reporting Categories.....................................................................................................................6 
1. Prior Approval Supplement.............................................................................................................6 
2. Changes Being Effected Supplement................................................................................................6 
3. Annual Report..................................................................................................................................6 
 
B.  Labeling..........................................................................................................................................6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
Incorporation of Physical-Chemical Identifiers into Solid Oral 
Dosage Form Drug Products for Anticounterfeiting 
 
 
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 the 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 pharmaceutical manufacturers who want to use 
physical-chemical identifiers (PCIDs) in solid oral dosage forms (SODFs).  A PCID is a 
substance or combination of substances possessing a unique physical or chemical property that 
unequivocally identifies and authenticates a drug product or dosage form. 
This guidance provides recommendations to pharmaceutical manufacturers on (1) design 
considerations for incorporating PCIDS into SODFs, (2) supporting documentation to be 
submitted in new drug applications (NDAs) and abbreviated new drug applications (ANDAs) to 
address the proposed incorporation of PCIDs in SODFs, (3) supporting documentation to be 
submitted in postapproval submissions to report or request approval to incorporate PCIDs into 
SODFs, and (4) procedures for reporting or requesting approval to incorporate PCIDs into 
SODFs as a postapproval change.     
The incorporation of components or features used in radiofrequency identification for drug 
products is outside the scope of this guidance.  In addition, this guidance does not apply to 
manufacturing or formulation changes, made in conjunction with the addition of a PCID, that go 
beyond simply inserting the PCID into a blending or mixing operation (e.g., adding a PCID to a 
non-functional tablet film coating is covered by this guidance, but adding a non-functional film 
coating that contains a PCID to a previously uncoated tablet involves manufacturing changes that 
are not covered by this guidance).  The incorporation of a PCID into the packaging or labeling is 
not covered in this guidance. 
Other guidance documents, which may be applicable to proposed changes outside the scope of 
this guidance, are located on FDAs guidance Web site2 and should be consulted to help to 
                                                 
1 This guidance has been prepared by the Office of New Drug Quality Assessment, Office of Pharmaceutical 
Science in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.  
2 CDER guidance documents can be found on the Internet at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the CDER guidance 
Web site. 
  1 Contains Nonbinding Recommendations 
 
determine whether additional reporting or approval procedures may apply to proposed changes 
outside the scope of this guidance. 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidance documents 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 an Agency guidance document means that 
something is suggested or recommended, but not required.  
II.  BACKGROUND 
Pharmaceutical manufacturers aiming to thwart drug product counterfeiting have been 
investigating readily available technologies that may make drug products more difficult to 
duplicate.  One approach that pharmaceutical manufacturers appear to be considering involves 
adding a trace amount of an inactive ingredient(s) to an existing section3 of the dosage form.  A 
unique physical-chemical characteristic of that ingredient makes it possible to detect and 
authenticate legitimate dosage forms, and to identify counterfeits.  
Examples of substances that may be incorporated into SODFs as PCIDs include inks, pigments, 
flavors, and molecular taggants.  Such PCIDs may allow product authentication by their presence 
alone or may be used to code the product identity into or onto the SODF. 
There are various available means for presentation and detection of PCIDs (e.g., 
photolithography, holography, optical microscopy, laser scanning devices, 
excitation/fluorescence detection).  Some identifying characteristics, such as pigments or flavors, 
could be easily observed by patients, healthcare practitioners, and pharmacies.  Others could 
require the use of a detection instrument (e.g., a scanner, photometric detector, mass 
spectrometry).     
FDA anticipates that many of the ingredients that will ultimately be employed as PCIDs are 
already used as food additives, colorants, or excipients with established safety profiles.   
III.  DESIGN CONSIDERATIONS FOR INCORPORATION OF PCIDS IN SOLID 
ORAL DOSAGE FORMS  
A.  Pharmacological and Toxicological Considerations  
If an applicant incorporates a PCID into a solid oral dosage form, we recommend that the 
ingredients comprising the PCID be pharmacologically inactive so the ingredients can be treated 
as excipients.   
To minimize toxicological risk, FDA recommends using permissible direct food additives,4 food 
substances that are generally recognized as safe (GRAS) (including direct food substances 
                                                 
3 Section is the term used for a discrete, contained solid or a layer in a solid oral dosage form.  Any section can be 
described by its composition, the functional characteristics that distinguish it from other sections in that dosage 
form, and its position relative to other sections that may be present (e.g., coatings, capsule shells, encapsulated 
particles, a layer in a bi-layer tablet, and compressed powders). 
4 See 21 CFR parts 172. 
  2 Contains Nonbinding Recommendations 
 
affirmed as GRAS),5 or those ingredients listed in the FDA Inactive Ingredient Guide (IIG) that 
have been used in SODFs.6  
Certain substances could present a toxicological risk when used as a PCID in a SODF if the 
substance is:   
  Used at a level in excess of the limitations provided in the relevant IIG listing or Code of 
Federal Regulations (CFR) chapter for direct food additives 
  An ingredient that has never been used in an SODF or as a direct food additive  
  An ingredient that poses risk of adverse reaction (e.g., allergic reaction or irritation), 
including an ingredient derived from a major food allergen (i.e., milk, eggs, fish, 
Crustacean shellfish, tree nuts, peanuts, wheat and soybeans)7 
  
We recommend that applicants contact the appropriate clinical review division for more 
information on how to assess the safety of such proposed PCIDs. 
B.  Other Design Considerations 
A substance employed as a PCID should not adversely affect the identity, strength, quality, 
purity, potency, or bioavailability of the SODF.  To minimize the risk of adverse effects on these 
characteristics, FDA recommends that applicants add a PCID to an SODF at the lowest level that 
ensures identification of the dosage unit.  Applicants also can minimize the potential for adverse 
interactions by using a PCID that is relatively inert (i.e., unreactive).  Applicants also should 
consider the potential effect of a PCID on the quality, performance, and stability of the SODF 
both during the selection of a PCID and during the design of an SODF that will include a PCID. 
Another factor that applicants should consider is the location of the PCID within the drug 
product.  When considering where to place a PCID, the applicant may find it helpful to 
conceptually subdivide an SODF into sections that differ in composition that may or may not 
contain active drug substance.  For example, a core section in an SODF is likely to contain one 
or more drug substances,8 while the external sections of the SODF may not.  If an applicant 
places a PCID inside a core section of the SODF, that placement may increase the chances of 
interactions with the drug substance that could result in degradation.  If the applicant is 
concerned the PCID will interact with core components, incorporating the PCID into an external 
section of the SODF (e.g., in a coating or an ink-imprinted logo) may reduce the possibility of 
such interaction. 
The applicant should also consider whether the presence of the PCID might interfere with control 
of the release rate of modified-release SODFs (SODF-MRs), including extended-release and 
delayed-release dosage forms.  Thus, FDA recommends that the applicant consider incorporating 
the PCID into a section of the SODF-MR that does not contain any release-controlling 
excipient.9  Since the mechanisms that impart modified-release characteristics are varied, the 
                                                 
5 See 21 CFR parts 182 and 184. 
6 See http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.  
7 See section 201(qq) of the Federal Food, Drug, and Cosmetic Act.   
8 The term drug substance is defined in FDAs regulations at 21 CFR 314.3. 
9 A release-controlling excipient is any ingredient in the SODF that controls the rate at which a drug substance is 
made available for absorption in the gastrointestinal tract after it is administered. 
  3 Contains Nonbinding Recommendations 
 
potential impact on drug product release rate and stability should be evaluated by the applicant 
prior to incorporating a PCID into an SODF-MR, regardless of the location of the PCID relative 
to the drug substance and release-controlling excipients.  
IV.  SUPPORTING DOCUMENTATION TO ADDRESS THE PROPOSED 
INCORPORATION OF PCIDs IN SOLID ORAL DOSAGE FORMS 
Section A below describes FDAs recommendations for documentation to be submitted both by 
applicants proposing to incorporate PCIDs into new SODFs in an NDA or ANDA for initial 
approval of a drug product and by applicants proposing to incorporate PCIDs into SODFs as a 
postapproval change.  In addition, as described in section B below, FDA recommends that 
applicants proposing to incorporate PCIDs into SODFs as a postapproval change submit certain 
additional documentation.  
A.  Documentation Regarding Incorporation of PCIDs into Solid Oral Dosage 
Forms to be Included in any Premarketing or Postapproval Regulatory 
Submission  
FDA recommends that applicants include the following information in appropriate sections of 
any premarketing or postapproval regulatory submission proposing the incorporation of a PCID 
in a SODF: 
1.  Chemical composition (names and relative amounts of each component) of the PCID. 
2.  Rationale for selection and incorporation of the PCID and description of how the PCID is 
integrated into the design of the SODF. 
3.  An illustration showing the location of the PCID in the SODF, unless the location can be 
easily explained without the use of an illustration. 
4.  Relevant physical-chemical attributes of the PCID (e.g., those relating to identity, 
strength, quality and purity) including those attributes that make the material useful as a 
PCID. 
5.  Specification10 for the PCID.   
6.  Information on the impurities that may be present in the PCID. 
7.  Justification for safety of the PCID including any toxicological assessment. 
8.  Information on product development pertaining to incorporation of the PCID.    
(This information should include any study conducted during development to assess 
compatibility of a PCID with other formulation components.) 
9.  Description of manufacturing steps and controls associated with the incorporation of the 
PCID in the drug product. 
10. Assurance and verification of quality, performance, and stability of the drug product 
containing the PCID.11  
11. A summary of a product quality and performance risk assessment associated with the 
incorporation of the PCID. 
The amount of information provided for a PCID will depend on its pharmacological and 
toxicological characteristics as well as the design of the SODF.  For example, less 
                                                 
10 The term specification is defined in FDAs regulations at 21 CFR 314.3. 
11 See also section IV.B. regarding postapproval regulatory submissions. 
  4 Contains Nonbinding Recommendations 
 
information would be expected for a PCID, which is a permissible direct food additive, a 
food substance that is GRAS, or listed in the IIG, than for a novel PCID.    
B.  Documentation Regarding Incorporation of PCIDs into Solid Oral Dosage 
Forms to be Included in any Postapproval Regulatory Submission 
When an applicant proposes to incorporate a PCID into an SODF that has already been approved 
and marketed without the PCID, we expect that the applicant will be able to conduct certain 
assessments comparing the product without the PCID and with the PCID.  Assessments of 
impurity profile, stability, and dissolution data as described below may be sufficient to address 
item 10 in the list in section IV, A above.  We recommend that such applicants provide 
documentation regarding the assessments described below in the appropriate section of any 
postapproval regulatory submission proposing the incorporation of a PCID in a SODF: 
 
  The applicant should perform analyses to determine whether the impurity profile of the 
drug product has been altered by the addition of the PCID, either through the presence of 
new impurities or increased levels of previously detected impurities.  To prepare your 
submission in accordance with 21 CFR 314.70, FDA suggests that applicants follow the 
recommendations in the International Conference on Harmonisation guidance entitled 
Q3B(R2) Impurities in New Drug Products12 regarding the reporting, identification, 
and qualification thresholds, even if the PCID is a permissible direct food additive, a food 
substance that is GRAS, or listed in the IIG.   
  If the addition of the PCID to the SODF has the potential to significantly affect drug 
release rates, FDA recommends that applicants conduct evaluations of dissolution 
profiles.  The applicant should perform dissolution testing using methods and apparatus 
specified in the approved application.  Where applicable, the submission should include a 
statistical comparative assessment of multipoint dissolution profiles for the prechange 
and postchange batches obtained in one or more dissolution media simulating 
physiologically-relevant conditions. 
  The applicant should use long-term and accelerated stability studies to evaluate impurity 
formation and the effect of the PCID on the dissolution profile.  One should conduct such 
stability studies through the drug product expiration date, although the studies need not 
be completed prior to submission of the change.  The initial report of the change, whether 
in an annual report or supplemental application, should include the most current stability 
data, and the applicant should continue to provide updated data in subsequent annual 
reports.  
The applicant should also ascertain whether any analytical procedures should be revalidated as a 
consequence of adding the PCID.  
V.  DETERMINING REPORTING CATEGORY FOR POSTAPPROVAL CHANGES 
TO INCORPORATE PCIDs INTO SOLID ORAL DOSAGE FORMS  
Applicants that propose to incorporate a PCID into a SODF as a postapproval change should 
report the change in a prior approval supplement, a changes being effected (CBE-30) 
                                                 
12 This guidance is available on FDAs website.  See footnote 2.   
  5 Contains Nonbinding Recommendations 
 
supplement, or an annual report according to the recommendations described in section A 
below.13  Section B below describes our recommendations regarding revising the labeling of the 
SODF to indicate that a PCID has been incorporated.   
A.  Reporting Categories 
The applicant should perform a risk assessment to determine the appropriate reporting category 
and type of drug product testing needed to evaluate the proposed change on a case-by-case basis, 
regardless of previous use of the same PCID in other SODF drug products.    
 
1.  Prior Approval Supplement 
If the incorporation of a PCID in a SODF would have a substantial potential to have an adverse 
effect on the identity, strength, quality, purity, or potency of a drug product, the applicant may 
not market the drug product with the PCID unless a prior approval supplement is submitted and 
approved.14  Examples of situations in which an applicant should submit a prior approval 
supplement include, but are not limited to, when a substance in a proposed PCID is not a 
permissible food additive, a food substance that is GRAS, or an inactive ingredient used in a 
CDER-approved SODF (as indicated by IIG), or if it poses the risk of an adverse reaction in 
patients.  In such circumstances, FDA encourages the applicant to contact the appropriate clinical 
review division for guidance on how to provide a toxicological assessment to the Agency.   
2.  Changes Being Effected Supplement 
If the incorporation of a PCID in a SODF would have a moderate potential to have an adverse 
effect on the identity, strength, quality, purity, or potency of a drug product, the applicant should 
submit a CBE-30 supplement at least 30 days before distribution of the drug product made using 
the change.15 Examples of situations in which an applicant should submit a CBE-30 include, but 
are not limited to, a situation in which the applicant proposes to add a PCID (which is not a 
PCID for which a prior approval supplement should be submitted) to a core section of the SODF 
or to a section of an SODF-MR that contains a release-controlling excipient.  
3.  Annual Report  
If the incorporation of a PCID in a SODF would have a minimal potential to have an adverse 
effect on the identity, strength, quality, purity, or potency of a drug product, the applicant should 
describe the addition of a PCID to the drug product in its next annual report.16  
B.  Labeling 
Applicants should review the statute and all regulations to determine how the incorporation of a 
PCID may impact the labeling of their drug.  FDA does not intend to object if ingredients used as 
PCIDs are not included in the list of ingredients in a drug's labeling.  If the incorporation of a 
PCID changes the identifying characteristics (e.g., color) of the SODF, then the labeling must be 
                                                 
13 See 21 CFR 314.70. 
14 See 21 CFR 314.70(b)(1) 
15 See 21 CFR 314.70(c)(1) and 314.70(c)(4).   
16 See 21 CFR 314.70(d)(1) 
  6 Contains Nonbinding Recommendations 
 
revised in accordance with 21 CFR 201.57(c)(4).  All labeling changes are subject to the 
submission and approval requirements under 21 CFR 314.70. 
  7