Guidance for Industry 

Incorporation of PhysicalChemical Identifiers into Solid 

Oral Dosage Form Drug 

Products for Anticounterfeiting 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 90 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact John L. Smith 301-796-1757. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

July 2009 

CMC 

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Guidance for Industry 

Incorporation of PhysicalChemical 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) 

July 2009 

CMC 

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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...............................................................4

V. DETERMINING REPORTING CATEGORY FOR POSTAPPROVAL CHANGES 

TO INCORPORATE PCIDs INTO SOLID ORAL DOSAGE FORMS..................... 5

A. Reporting Categories.....................................................................................................................5

1. Annual Report ..................................................................................................................................6

2. Changes Being Effected Supplement................................................................................................6

3. Prior Approval Supplement .............................................................................................................6 

B. Labeling ..........................................................................................................................................6

VI. POTENTIAL MIGRATION OF PCIDs ADDED TO PACKAGING OR 

CONTAINER LABELING.............................................................................................. 6

A. Information Regarding Toxicological and Other Concerns ......................................................7

B. Reporting Categories for Adding PCIDs to Packaging or Container 

Labeling Postapproval...................................................................................................................7

1. Annual Report ..................................................................................................................................7

2. Changes Being Effected Supplement................................................................................................7

3. Prior Approval Supplement .............................................................................................................8

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Guidance for Industry1 1 

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Incorporation of Physical-Chemical Identifiers into Solid Oral 

Dosage Form Drug Products for Anticounterfeiting 

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6 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 

7 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

8 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

9 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

10 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

11 the appropriate number listed on the title page of this guidance. 

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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 draft 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. This guidance also provides our recommendations regarding 

(1) evaluation of toxicological and other concerns for PCIDs that are incorporated into packaging 

and labeling and (2) procedures for reporting or requesting approval to add PCIDs to packaging 

and containers 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). 

Other applicable guidance documents are located on FDA’s guidance Web site2

 and should be 

consulted to determine whether additional reporting or approval procedures may apply to other 

proposed changes. 

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 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. 

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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. 

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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 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, laser scanning devices, and excitation/fluorescence detection). 

Many identifying characteristics, such as pigments or flavors, could be easily observed by 

patients, healthcare practitioners, and pharmacies. Some could require the use of instrumental 

detection (e.g., a scanner or photometric detector). 

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. 

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 CDER guidance documents can be found on the Internet at http://www.fda.gov/cder/guidance/index.htm. We 

update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 

guidance Web site. 

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 and functional characteristics that distinguish it from other sections in that dosage form 

and by 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). 

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To minimize toxicological risk, FDA recommends using permissible direct food additives,4

including those affirmed as generally recognized as safe (GRAS),5 or those ingredients listed in 

the FDA Inactive Ingredient Guide (IIG).6 

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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 a direct food additive; or 

• An ingredient that poses risk of adverse reaction (e.g., allergic reaction or irritation). 

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, 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. 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 active drug substances, 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 a modified-release SODF (SODF-MR), which includes 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 releasecontrolling excipient.

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varied, the potential impact on drug product release rate and stability should be evaluated by the 

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 21 CFR parts 172, 182, and 184 

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6 http://www.fda.gov/search/databases.html

7 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.

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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. 

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IV. SUPPORTING DOCUMENTATION TO ADDRESS THE PROPOSED 

INCORPORATION OF PCIDs IN SOLID ORAL DOSAGE FORMS 

Section A below describes FDA’s 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. 

4. Relevant physical-chemical attributes of the PCID (e.g., those relating to identity, 

strength, quality, purity, and potency) including those attributes that make the material 

useful as a PCID. 

5. Information on the impurities that may be present in the PCID. 

6. Justification for safety of the PCID including any toxicological assessment. 

7. 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.) 

8. Description of manufacturing steps and controls associated with the incorporation of the 

PCID in the drug product. 

9. Assurance and verification of quality, performance, and stability of the drug product 

containing the PCID.8

 

10. A summary of a product quality and performance risk assessment associated with the 

incorporation of the 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 

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 See also section IV.B regarding postapproval regulatory submissions. 

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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 9 in the list in section IV, A above. We recommend that such applicants provide 

documentation regarding the assessments described below in any appropriate section of any 

postapproval regulatory submission proposing the incorporation of a PCID in a SODF: 

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• The applicant should perform evaluations of the drug product containing the PCID to 

ascertain that there is no significant increase in previously detected impurities. The 

evaluations should be able to detect the presence of significant new impurities at levels 

that may have toxicological consequence. Toxicological assessment, which is usually not 

required for PCIDs that are GRAS, may be warranted if the impurity profile of the drug 

product is altered significantly by the addition of a PCID. 

• 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. 

167 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 an annual report or submit a changes being effected (CBE-30) or prior 

approval supplement according to the recommendations described below.9

 We also describe 

below our recommendations regarding revising the labeling of the SODF to indicate the 

incorporation of a PCID. 

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. It is our hope that the 

majority of these changes will be designed to present minimal potential to have an adverse effect 

on the identity, strength, quality, purity, or potency of the drug product and therefore can be 

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 See 21 CFR 314.70. 

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reported in an annual report. We therefore have described the reporting categories below in 

order of least to most risk presented by the proposed change. 

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1. Annual Report 

In situations where PCID toxicological considerations and SODF design factors reduce the risk 

such that the change would have a minimal potential to have an adverse effect on the identity, 

strength, quality, purity, or potency of a drug product and the applicant’s evaluation of the drug 

product containing the PCID finds no adverse effect, the applicant may report the addition of the 

PCID to the SODF in its next annual report.10 

2. Changes Being Effected Supplement 

Certain SODF design factors elevate the risk of the change. Examples of such design factors are 

adding a PCID to a core section of the SODF or adding a PCID to a section of an SODF-MR that 

contains a release-controlling excipient. In such cases, the applicant should report the addition of 

a PCID to the drug product by submitting a CBE-30 supplement.11 

3. 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.12 For example, if a substance in a proposed PCID neither appears on the GRAS list 

nor is an inactive ingredient used in a CDER-approved SODF (as indicated by IIG), the applicant 

should submit a prior approval supplement. In this case, FDA encourages the applicant to 

contact the appropriate clinical review division for guidance on how to provide a toxicological 

assessment to the Agency. 

B. Labeling 

At their discretion, applicants may decide whether or not to revise the labeling of the SODF to 

indicate the incorporation of a PCID. For example, applicants may wish to revise the labeling to 

alert healthcare practitioners and patients that the SODF has a PCID with unique visual features 

so that the practitioners and patients can verify that the drug product they receive contains the 

PCID. If an applicant decides to revise the labeling, any labeling changes are subject to the 

reporting and approval requirements under 21 CFR 314.70. 

210 VI. POTENTIAL MIGRATION OF PCIDs ADDED TO PACKAGING OR 

CONTAINER LABELING 

Some pharmaceutical manufacturers may consider adding PCIDs into the packaging and labeling 

of SODFs. We describe below our recommendations regarding (1) evaluation of toxicological 

and other concerns for PCIDs that are incorporated into packaging and labeling and (2) 

10 21 CFR 314.70(d)(1) 

11 21 CFR 314.70(c)(1) 

12 21 CFR 314.70(b)(1) 

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procedures for reporting and requesting approval to add PCIDs to packaging and containers as a 

postapproval change. 

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A. Information Regarding Toxicological and Other Concerns 

If an applicant proposes to affix or incorporate a PCID into a primary packaging component for a 

SODF, the applicant should assess PCID toxicology and the potential for an adverse effect on 

SODF quality, performance, and stability. 

FDA’s toxicological concerns are mitigated if the added substance(s) is a permitted direct or 

indirect food additive13 or listed in FDA IIG. Applicants proposing to use any additive as a 

PCID in primary packaging where toxicology has not been established should provide assurance 

that there is no migration of the PCID into the SODF. 

We recommend that applicants identifying toxicological concerns with a proposed PCID in 

primary packaging contact the appropriate clinical review division and/or the appropriate 

chemistry, manufacturing, and controls review division before proceeding to discuss possible 

adverse interactions of a proposed PCID added to packaging with the SODF. 

Applicants proposing to use a PCID in primary packaging for a SODF in an initial NDA or 

ANDA should include supporting information in their application addressing toxicological 

concerns. 

B. Reporting Categories for Adding PCIDs to Packaging or Container Labeling 

Postapproval

An applicant proposing to add a PCID to primary packaging for a SODF as a postapproval 

change should report the change in an annual report or submit a CBE-30 or prior approval 

supplement according to the recommendations described below.14 

1. Annual Report 

If the substance(s) in the PCID is a permitted direct or indirect food additive15 or listed in FDA 

IIG, or if the added substance(s) has been previously approved for use in the primary packaging 

of another CDER approved SODF, an applicant may report the addition of a PCID to primary 

packaging for a SODF in its next annual report. 

2. Changes Being Effected Supplement 

If the toxicology of the added substance has not previously been established (as provided for in 

the above paragraph), applicants proposing to use the substance as a PCID in primary or 

secondary packaging may submit the change in a CBE-30 supplement if the supplement includes 

data providing assurance that there will be no migration of the PCID into the SODF. The 

supplement should also include information addressing toxicological concerns. 

13 21 CFR parts 172, 174-178, 182, 184, and 186 

14 21 CFR 314.70. 

15 21 CFR parts 172, 174-178, 182, 184, and 186 

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3. Prior Approval Supplement 

If the safe use of a PCID cannot be ensured (i.e., if the toxicology has not previously been 

established and migration potential exists), the applicant may not market the drug product using 

the PCID in primary or secondary packaging unless a prior approval supplement is submitted and 

approved.