Guidance for Industry

Incorporation of Physical-
Chemical 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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 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)
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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1 Guidance for Industry1

2 Incorporation of Physical-Chemical Identifiers into Solid Oral
3 Dosage Form Drug Products for Anticounterfeiting
4
5
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.
12
13
14
15 I. INTRODUCTION

16 This document is intended to provide guidance to pharmaceutical manufacturers who want to use
17 physical-chemical identifiers (PCIDs) in solid oral dosage forms (SODFs). A PCID is a
18 substance or combination of substances possessing a unique physical or chemical property that
19 unequivocally identifies and authenticates a drug product or dosage form.

20 This draft guidance provides recommendations to pharmaceutical manufacturers on (1) design

21 considerations for incorporating PCIDS into SODFs, (2) supporting documentation to be
22 submitted in new drug applications (NDAs) and abbreviated new drug applications (ANDAs) to
23 address the proposed incorporation of PCIDs in SODFs, (3) supporting documentation to be
24 submitted in postapproval submissions to report or request approval to incorporate PCIDs into
25 SODFs, and (4) procedures for reporting or requesting approval to incorporate PCIDs into
26 SODFs as a postapproval change. This guidance also provides our recommendations regarding
27 (1) evaluation of toxicological and other concerns for PCIDs that are incorporated into packaging
28 and labeling and (2) procedures for reporting or requesting approval to add PCIDs to packaging
29 and containers as a postapproval change.

30 The incorporation of components or features used in radiofrequency identification for drug

31 products is outside the scope of this guidance. In addition, this guidance does not apply to
32 manufacturing or formulation changes, made in conjunction with the addition of a PCID, that go
33 beyond simply inserting the PCID into a blending or mixing operation (e.g., adding a PCID to a
34 non-functional tablet film coating is covered by this guidance, but adding a non-functional film
35 coating that contains a PCID to a previously uncoated tablet involves manufacturing changes that
36 are not covered by this guidance).

37 Other applicable guidance documents are located on FDA’s guidance Web site2 and should be
38 consulted to determine whether additional reporting or approval procedures may apply to other
39 proposed changes.

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.

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40 FDA's guidance documents, including this guidance, do not establish legally enforceable
41 responsibilities. Instead, guidance documents describe the Agency's current thinking on a topic
42 and should be viewed only as recommendations, unless specific regulatory or statutory
43 requirements are cited. The use of the word should in an Agency guidance document means that
44 something is suggested or recommended, but not required.

45 II. BACKGROUND

46 Pharmaceutical manufacturers aiming to thwart drug product counterfeiting have been

47 investigating readily available technologies that may make drug products more difficult to
48 duplicate. One approach that pharmaceutical manufacturers appear to be considering involves
49 adding a trace amount of an inactive ingredient(s) to an existing section3 of the dosage form. A
50 unique physical-chemical characteristic of that ingredient makes it possible to detect and
51 authenticate legitimate dosage forms and identify counterfeits.

52 Examples of substances that may be incorporated into SODFs as PCIDs include inks, pigments,
53 flavors, and molecular taggants. Such PCIDs may allow product authentication by their presence
54 alone or may be used to code the product identity into or onto the SODF.

55 There are various available means for presentation and detection of PCIDs (e.g.,
56 photolithography, holography, laser scanning devices, and excitation/fluorescence detection).
57 Many identifying characteristics, such as pigments or flavors, could be easily observed by
58 patients, healthcare practitioners, and pharmacies. Some could require the use of instrumental
59 detection (e.g., a scanner or photometric detector).

60 FDA anticipates that many of the ingredients that will ultimately be employed as PCIDs are
61 already used as food additives, colorants, or excipients with established safety profiles.

62 III. DESIGN CONSIDERATIONS FOR INCORPORATION OF PCIDS IN SOLID

63 ORAL DOSAGE FORMS

64 A. Pharmacological and Toxicological Considerations

65 If an applicant incorporates a PCID into a solid oral dosage form, we recommend that the
66 ingredients comprising the PCID be pharmacologically inactive so the ingredients can be treated
67 as excipients.

2
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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68 To minimize toxicological risk, FDA recommends using permissible direct food additives,4
69 including those affirmed as generally recognized as safe (GRAS),5 or those ingredients listed in
70 the FDA Inactive Ingredient Guide (IIG).6

71 Certain substances could present a toxicological risk when used as a PCID in a SODF if the
72 substance is:

73 • Used at a level in excess of the limitations provided in the relevant IIG listing or Code of
74 Federal Regulations (CFR) chapter for direct food additives;
75 • An ingredient that has never been used in an SODF or a direct food additive; or
76 • An ingredient that poses risk of adverse reaction (e.g., allergic reaction or irritation).

77 We recommend that applicants contact the appropriate clinical review division for more
78 information on how to assess the safety of such proposed PCIDs.

79 B. Other Design Considerations

80 A substance employed as a PCID should not adversely affect the identity, strength, quality,
81 purity, potency, or bioavailability of the SODF. To minimize the risk of adverse effects, FDA
82 recommends that applicants add a PCID to an SODF at the lowest level that ensures
83 identification of the dosage unit. Applicants also can minimize the potential for adverse
84 interactions by using a PCID that is relatively inert. Applicants also should consider the
85 potential effect of a PCID on the quality, performance, and stability of the SODF both during the
86 selection of a PCID and during the design of an SODF that will include a PCID.

87 Another factor that applicants should consider is the location of the PCID within the drug
88 product. When considering where to place a PCID, the applicant may find it helpful to
89 conceptually subdivide an SODF into sections that differ in composition that may or may not
90 contain active drug substance. For example, a core section in an SODF is likely to contain one
91 or more active drug substances, while the external sections of the SODF may not. If an applicant
92 places a PCID inside a core section of the SODF, that placement may increase the chances of
93 interactions with the drug substance that could result in degradation. If the applicant is
94 concerned the PCID will interact with core components, incorporating the PCID into an external
95 section of the SODF (e.g., in a coating or an ink-imprinted logo) may reduce the possibility of
96 such interaction.

97 The applicant should also consider whether the presence of the PCID might interfere with control
98 of the release rate of a modified-release SODF (SODF-MR), which includes extended-release
99 and delayed-release dosage forms. Thus, FDA recommends that the applicant consider
100 incorporating the PCID into a section of the SODF-MR that does not contain any release-
101 controlling excipient.7 Since the mechanisms that impart modified-release characteristics are
102 varied, the potential impact on drug product release rate and stability should be evaluated by the

4
21 CFR parts 172, 182, and 184
5
21 CFR part 184
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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103 applicant prior to incorporating a PCID into an SODF-MR, regardless of the location of the
104 PCID relative to the drug substance and release-controlling excipients.

105 IV. SUPPORTING DOCUMENTATION TO ADDRESS THE PROPOSED

106 INCORPORATION OF PCIDs IN SOLID ORAL DOSAGE FORMS

107 Section A below describes FDA’s recommendations for documentation to be submitted both by
108 applicants proposing to incorporate PCIDs into new SODFs in an NDA or ANDA for initial
109 approval of a drug product and by applicants proposing to incorporate PCIDs into SODFs as a
110 postapproval change. In addition, as described in section B below, FDA recommends that
111 applicants proposing to incorporate PCIDs into SODFs as a postapproval change submit certain
112 additional documentation.

113 A. Documentation Regarding Incorporation of PCIDs into Solid Oral Dosage

114 Forms to be Included in any Premarketing or Postapproval Regulatory
115 Submission

116 FDA recommends that applicants include the following information in appropriate sections of
117 any premarketing or postapproval regulatory submission proposing the incorporation of a PCID
118 in a SODF:

119 1. Chemical composition (names and relative amounts of each component) of the PCID.
120 2. Rationale for selection and incorporation of the PCID and description of how the PCID is
121 integrated into the design of the SODF.
122 3. An illustration showing the location of the PCID in the SODF.
123 4. Relevant physical-chemical attributes of the PCID (e.g., those relating to identity,
124 strength, quality, purity, and potency) including those attributes that make the material
125 useful as a PCID.
126 5. Information on the impurities that may be present in the PCID.
127 6. Justification for safety of the PCID including any toxicological assessment.
128 7. Information on product development pertaining to incorporation of the PCID.
129 (This information should include any study conducted during development to assess
130 compatibility of a PCID with other formulation components.)
131 8. Description of manufacturing steps and controls associated with the incorporation of the
132 PCID in the drug product.
133 9. Assurance and verification of quality, performance, and stability of the drug product
134 containing the PCID.8
135 10. A summary of a product quality and performance risk assessment associated with the
136 incorporation of the PCID.

137 B. Documentation Regarding Incorporation of PCIDs into Solid Oral Dosage

138 Forms to be Included in any Postapproval Regulatory Submission

139 When an applicant proposes to incorporate a PCID into an SODF that has already been approved
140 and marketed without the PCID, we expect that the applicant will be able to conduct certain

8
See also section IV.B regarding postapproval regulatory submissions.

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141 assessments comparing the product without the PCID and with the PCID. Assessments of
142 impurity profile, stability, and dissolution data as described below may be sufficient to address
143 item 9 in the list in section IV, A above. We recommend that such applicants provide
144 documentation regarding the assessments described below in any appropriate section of any
145 postapproval regulatory submission proposing the incorporation of a PCID in a SODF:
146
147 • The applicant should perform evaluations of the drug product containing the PCID to
148 ascertain that there is no significant increase in previously detected impurities. The
149 evaluations should be able to detect the presence of significant new impurities at levels
150 that may have toxicological consequence. Toxicological assessment, which is usually not
151 required for PCIDs that are GRAS, may be warranted if the impurity profile of the drug
152 product is altered significantly by the addition of a PCID.

153 • If the addition of the PCID to the SODF has the potential to significantly affect drug
154 release rates, FDA recommends that applicants conduct evaluations of dissolution
155 profiles. The applicant should perform dissolution testing using methods and apparatus
156 specified in the approved application. Where applicable, the submission should include a
157 statistical comparative assessment of multipoint dissolution profiles for the prechange
158 and postchange batches obtained in one or more dissolution media simulating
159 physiologically-relevant conditions.

160 • The applicant should use long-term and accelerated stability studies to evaluate impurity
161 formation and the effect of the PCID on the dissolution profile. One should conduct such
162 stability studies through the drug product expiration date, although the studies need not
163 be completed prior to submission of the change. The initial report of the change, whether
164 in an annual report or supplemental application, should include the most current stability
165 data, and the applicant should continue to provide updated data in subsequent annual
166 reports.

167 V. DETERMINING REPORTING CATEGORY FOR POSTAPPROVAL CHANGES

168 TO INCORPORATE PCIDs INTO SOLID ORAL DOSAGE FORMS

169 Applicants that propose to incorporate a PCID into a SODF as a postapproval change should
170 report the change in an annual report or submit a changes being effected (CBE-30) or prior
171 approval supplement according to the recommendations described below.9 We also describe
172 below our recommendations regarding revising the labeling of the SODF to indicate the
173 incorporation of a PCID.

174 A. Reporting Categories

175 The applicant should perform a risk assessment to determine the appropriate reporting category
176 and type of drug product testing needed to evaluate the proposed change on a case-by-case basis,
177 regardless of previous use of the same PCID in other SODF drug products. It is our hope that the
178 majority of these changes will be designed to present minimal potential to have an adverse effect
179 on the identity, strength, quality, purity, or potency of the drug product and therefore can be

9
See 21 CFR 314.70.

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180 reported in an annual report. We therefore have described the reporting categories below in
181 order of least to most risk presented by the proposed change.
182
183 1. Annual Report

184 In situations where PCID toxicological considerations and SODF design factors reduce the risk
185 such that the change would have a minimal potential to have an adverse effect on the identity,
186 strength, quality, purity, or potency of a drug product and the applicant’s evaluation of the drug
187 product containing the PCID finds no adverse effect, the applicant may report the addition of the
188 PCID to the SODF in its next annual report.10

189 2. Changes Being Effected Supplement

190 Certain SODF design factors elevate the risk of the change. Examples of such design factors are
191 adding a PCID to a core section of the SODF or adding a PCID to a section of an SODF-MR that
192 contains a release-controlling excipient. In such cases, the applicant should report the addition of
193 a PCID to the drug product by submitting a CBE-30 supplement.11

194 3. Prior Approval Supplement

195 If the incorporation of a PCID in a SODF would have a substantial potential to have an adverse
196 effect on the identity, strength, quality, purity, or potency of a drug product, the applicant may
197 not market the drug product with the PCID unless a prior approval supplement is submitted and
198 approved.12 For example, if a substance in a proposed PCID neither appears on the GRAS list
199 nor is an inactive ingredient used in a CDER-approved SODF (as indicated by IIG), the applicant
200 should submit a prior approval supplement. In this case, FDA encourages the applicant to
201 contact the appropriate clinical review division for guidance on how to provide a toxicological
202 assessment to the Agency.

203 B. Labeling

204 At their discretion, applicants may decide whether or not to revise the labeling of the SODF to
205 indicate the incorporation of a PCID. For example, applicants may wish to revise the labeling to
206 alert healthcare practitioners and patients that the SODF has a PCID with unique visual features
207 so that the practitioners and patients can verify that the drug product they receive contains the
208 PCID. If an applicant decides to revise the labeling, any labeling changes are subject to the
209 reporting and approval requirements under 21 CFR 314.70.

210 VI. POTENTIAL MIGRATION OF PCIDs ADDED TO PACKAGING OR

211 CONTAINER LABELING

212 Some pharmaceutical manufacturers may consider adding PCIDs into the packaging and labeling
213 of SODFs. We describe below our recommendations regarding (1) evaluation of toxicological
214 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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215 procedures for reporting and requesting approval to add PCIDs to packaging and containers as a
216 postapproval change.

217 A. Information Regarding Toxicological and Other Concerns

218 If an applicant proposes to affix or incorporate a PCID into a primary packaging component for a
219 SODF, the applicant should assess PCID toxicology and the potential for an adverse effect on
220 SODF quality, performance, and stability.

221 FDA’s toxicological concerns are mitigated if the added substance(s) is a permitted direct or
222 indirect food additive13 or listed in FDA IIG. Applicants proposing to use any additive as a
223 PCID in primary packaging where toxicology has not been established should provide assurance
224 that there is no migration of the PCID into the SODF.

225 We recommend that applicants identifying toxicological concerns with a proposed PCID in
226 primary packaging contact the appropriate clinical review division and/or the appropriate
227 chemistry, manufacturing, and controls review division before proceeding to discuss possible
228 adverse interactions of a proposed PCID added to packaging with the SODF.

229 Applicants proposing to use a PCID in primary packaging for a SODF in an initial NDA or
230 ANDA should include supporting information in their application addressing toxicological
231 concerns.

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

233 Postapproval

234 An applicant proposing to add a PCID to primary packaging for a SODF as a postapproval
235 change should report the change in an annual report or submit a CBE-30 or prior approval
236 supplement according to the recommendations described below.14

237 1. Annual Report

238 If the substance(s) in the PCID is a permitted direct or indirect food additive15 or listed in FDA
239 IIG, or if the added substance(s) has been previously approved for use in the primary packaging
240 of another CDER approved SODF, an applicant may report the addition of a PCID to primary
241 packaging for a SODF in its next annual report.

242 2. Changes Being Effected Supplement

243 If the toxicology of the added substance has not previously been established (as provided for in
244 the above paragraph), applicants proposing to use the substance as a PCID in primary or
245 secondary packaging may submit the change in a CBE-30 supplement if the supplement includes
246 data providing assurance that there will be no migration of the PCID into the SODF. The
247 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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248 3. Prior Approval Supplement

249 If the safe use of a PCID cannot be ensured (i.e., if the toxicology has not previously been
250 established and migration potential exists), the applicant may not market the drug product using
251 the PCID in primary or secondary packaging unless a prior approval supplement is submitted and
252 approved.

253

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