IND Submissions for Individualized 
Antisense Oligonucleotide Drug 
Products for Severely Debilitating or 
Life-Threatening Diseases:  
Chemistry, Manufacturing, and 
Controls Recommendations 
Guidance for Sponsor-Investigators 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (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 Carla R. Lankford at 301-796-5203. 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2021 
CMC 
37775086dft.docx 
11/30/2021   
IND Submissions for Individualized 
Antisense Oligonucleotide Drug 
Products for Severely Debilitating or 
Life-Threatening Diseases:  
Chemistry, Manufacturing, and 
Controls Recommendations 
Guidance for Sponsor-Investigators 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD  20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2021 
CMC 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  GENERAL CONSIDERATIONS ON CMC INFORMATION FOR AN INITIAL 
IND ..................................................................................................................................... 2 
A.  Regulatory Considerations ............................................................................................................ 2 
B.  Additional Considerations ............................................................................................................. 4 
III.  CMC INFORMATION FOR DRUG SUBSTANCE ..................................................... 5 
A.  A Description of the Drug Substance, Including Its Physical and Chemical Characteristics . 5 
B.  The Name and Address of the Drug Substance Manufacturer .................................................. 5 
C.  The General Method of Preparation of the Drug Substance ..................................................... 5 
D.  Characterization ............................................................................................................................ 6 
E.  Control of Drug Substance ............................................................................................................ 6 
1. Specification ..................................................................................................................................... 6 
F.  Stability ........................................................................................................................................... 8 
IV.  CMC DATA FOR DRUG PRODUCT  ........................................................................... 8 
A.  Components .................................................................................................................................... 8 
B.  Quantitative Composition of the Drug Product .......................................................................... 8 
C.  Name and Address of the Drug Product Manufacturer ............................................................. 8 
D.  Brief General Description of the Manufacturing and Packaging Procedures for the  
  Product ............................................................................................................................................ 8 
E.  Control of Drug Product ............................................................................................................... 9 
F.  Container Closure System ............................................................................................................. 9 
G.  Stability ........................................................................................................................................... 9 
V.  IMMEDIATE PACKAGING LABELING .................................................................. 10 
VI.  ENVIRONMENTAL EXCLUSION ............................................................................. 10 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  IND Submissions for Individualized Antisense Oligonucleotide Drug 
2  Products for Severely Debilitating or Life-Threatening Diseases:   
3  Chemistry, Manufacturing, and Controls Recommendations 
4  Guidance for Sponsor-Investigators1 
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  The purpose of this guidance is to provide recommendations regarding the chemistry, 
19  manufacturing, and controls (CMC) information that should be provided in an investigational 
20  new drug application (IND) submitted by a sponsor-investigator2 (hereafter referred to as 
21  sponsor) developing an individualized antisense oligonucleotide (ASO) drug product for a 
22  severely debilitating or life-threatening (SDLT) disease3 caused by a unique genetic variant  
23  where only a small number of individuals are prospectively identified (typically one or two).  
24  These individualized ASO drug products should be from a well-characterized chemical class for 
25  which there is substantial clinical and nonclinical experience that is either publicly available or to 
26  which the sponsor has a right to reference.4  
27   
28  This guidance is limited to those individualized ASO drug products, as described above, that are 
29  unconjugated, manufactured using conventional methods, with formulations that are a simple 
30  aqueous or a lyophilized powder to be reconstituted before administration.    
31   
32  This guidance provides recommendations on information to be submitted in the CMC sections of 
33  an IND for an individualized ASO drug product, including the following: 
 
1 This guidance has been prepared by the Office of Pharmaceutical Quality and the Office of New Drugs in the 
Center for Drug Evaluation and Research at the Food and Drug Administration. 
 
2 A sponsor-investigator is an individual who both initiates and conducts an investigation, and under whose 
immediate direction the investigational drug is administered or dispensed. The term does not include any person 
other than an individual (see 21 CFR 312.3(b)).   
 
3 Severely debilitating means diseases or conditions that cause major irreversible morbidity. Life-threatening means 
diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and those 
with potentially fatal outcomes, where the endpoint of clinical trial analysis is survival (see 21 CFR 312.81). 
 
4 Examples of well-characterized antisense chemical classes, based on prior FDA experience, include single-
stranded phosphorothioate or mixed phosphorothioate/phosphodiester 2-methoxyethyl substituted oligonucleotides 
(by systemic or intrathecal route) and phosphorodiamidate morpholino oligonucleotides (by systemic route). 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
34   
35    Nomenclature, structure, and general ASO drug substance properties 
36    Manufacture 
37    Characterization 
38    Control of excipients 
39    Control of drug substance and drug product 
40    Reference standards or materials 
41    Container closure systems 
42    Stability 
43   
44  The CMC recommendations are to support first-in-human exposure for the individualized ASO 
45  drug products covered under this guidance and do not address regulatory considerations for 
46  continued, long-term administration of an individualized ASO drug product, for use of 
47  individualized ASO drug products for diseases that are not severely debilitating or life-
48  threatening, or for administration of ASO drug products to a population beyond the expected 
49  number of patients (typically one or two).  
50   
51  This guidance also does not address CMC requirements for commercial development of 
52  individualized ASO drug products. 
53   
54  The contents of this document do not have the force and effect of law and are not meant to bind 
55  the public in any way, unless specifically incorporated into a contract.  This document is 
56  intended only to provide clarity to the public regarding existing requirements under the law. 
57  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
58  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
59  FDA guidances means that something is suggested or recommended, but not required. 
60   
61   
62  II.  GENERAL CONSIDERATIONS ON CMC INFORMATION FOR AN INITIAL 
63  IND 
64   
65  A.  Regulatory Considerations 
66   
67  Under 21 CFR part 312 subpart E, FDA has determined that for drug products (e.g., 
68  individualized ASO drug products) intended to treat SDLT diseases, it is appropriate to exercise 
69  flexibility while preserving appropriate guarantees for safety and effectiveness.5   
70   
71  Generally, FDA regulations require sponsors, including sponsor-investigators, seeking to 
72  evaluate a drug or biological product in humans in a clinical investigation to submit an IND to 
73  FDA.6  The required content and format for INDs7 are further discussed in the guidance for 
74  industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 
 
5 See 21 CFR 312.80. 
 
6 21 CFR part 312. 
 
7 See 21 CFR 312.23. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
75  Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products 
76  (November 1995).8  That guidance includes clarification about the data that should be provided 
77  in the CMC section of an initial IND submission under 21 CFR 312.23(a)(7).  FDA expects 
78  sponsors to submit in the CMC section of an initial IND sufficient information to ensure the 
79  proper identification, quality, purity, and strength of the investigational drug product.  This 
80  information includes (1) data and information regarding drug substance; (2) data and information 
81  regarding drug product; (3) the investigational drug immediate packaging label that includes the 
82  statement Caution: New Drug  Limited by Federal (or United States) law to investigational 
83  use;9 and (4) a statement requesting a categorical exclusion from an environmental assessment 
84  under 21 CFR 25.30 or 25.31 or an environmental assessment under 21 CFR 25.40.10   
85   
86  This guidance provides recommendations about how to satisfy these general requirements for the 
87  CMC content of an IND for an investigational ASO drug product within the scope of this 
88  guidance and also provides specific recommendations regarding the quality (e.g., chemical 
89  structure, manufacturing process, and critical quality attributes) of an individualized ASO drug 
90  product that will be administered to an individual trial participant under the IND.  To expedite 
91  the initiation of clinical investigation of an individualized ASO drug product covered under this 
92  guidance, we recommend that the sponsor first submit a pre-IND meeting request to discuss the 
93  CMC plans with FDA. 
94   
95  For drug products, including drug products administered under an IND, section 501(a)(2)(B) of 
96  the Federal Food, Drug, and Cosmetic Act and FDAs implementing regulations require that the 
97  methods used in or the facilities or controls used for their manufacturing, processing, packing, or 
98  holding comply with current good manufacturing practice (CGMP) (21 U.S.C. 351(a)(2)(B); 21 
99  CFR parts 210 (general) and 211 (finished pharmaceuticals)).  However, in general, the 
100  production of an investigational drug product for use in a phase 1 clinical trial is exempt under 
101  21 CFR 210.2(c) from compliance with the regulations in part 211.  As described in the preamble 
102  to the final rule amending 21 CFR 210.2(c),11 the rationale for exempting phase 1 IND products 
103  from compliance with 21 CFR part 211 is based on many factors, including that such studies are 
104  conducted to establish the basic safety, rather than efficacy, of the drug product; are designed to 
105  determine the metabolism and pharmacologic actions of the drug product in humans; and are 
106  limited in the total number of trial participants.   
107   
108  In addition, the manufacturing and control conditions for the production of investigational drug 
109  products intended for use in relatively small phase 1 clinical trials are different from the 
 
8 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
9 See 21 CFR 312.6(a). 
 
10 See 21 CFR 312.23(a)(7)(iv)(e) and the draft guidance for industry Investigational New Drug Applications 
Prepared and Submitted by Sponsor-Investigators (May 2015).  When final, this guidance will represent the FDAs 
current thinking on this topic.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
11 The final rule, Current Good Manufacturing Practice and Investigational New Drugs Intended for Use in Clinical 
Trials, published July 15, 2008 (73 FR 40453-40462). 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
110  conditions for the production of drug products for use in larger phase 2 and phase 3 clinical trials 
111  or for commercial marketing.  Therefore, many of the specific requirements in 21 CFR part 211 
112  do not apply to the conditions under which many drug products for use in phase 1 clinical trials 
113  are produced.  FDA has described applicable CGMP recommendations for phase 1 IND products 
114  in the guidance for industry CGMP for Phase 1 Investigational Drugs (July 2008). 
115   
116  Individualized ASO drug products are not expected to follow the traditional investigational 
117  phases of drug development (i.e., clinical trial phases 1 through 3) as described in 21 CFR 
118  312.21.  As such, the applicability of 21 CFR part 211 for manufacturing individualized ASO 
119  drug product batches for clinical investigation under an IND (e.g., first clinical batch versus 
120  subsequent clinical batches) requires further clarification.  Because the rationale used to exempt 
121  phase 1 drug products from complying with 21 CFR part 211 is generally applicable to the 
122  initiation of clinical investigation of an individualized ASO drug product, in general it would be 
123  acceptable for the first clinical drug product batch to be manufactured consistent with the CGMP 
124  recommendations in the guidance for industry CGMP for Phase 1 Investigational Drugs.  
125  However, if additional batches of the individualized ASO drug product are needed for continued 
126  administration to a subject, then to ensure consistent quality, safety, and efficacy of the 
127  individualized ASO drug product, FDA generally expects that sponsors would manufacture 
128  subsequent batches of the individualized ASO drug products in compliance with 21 CFR part 
129  211 and follow the recommendations in the guidance for industry Preparation of Investigational 
130  New Drug Products (Human and Animal) (November 1992). 
131   
132  B.  Additional Considerations 
133   
134  To expedite the initiation of clinical investigations of these individualized ASO drug products, 
135  we recommend that, when possible, the same batch of drug product used for the nonclinical 
136  studies be used for initial clinical investigations.12  If different batches of the drug product are 
137  intended for nonclinical studies and clinical investigations, the sponsor should provide 
138  information to support a conclusion that the batch used in the nonclinical studies is representative 
139  of the batch intended for use in the clinical investigations, from a quality perspective.  This 
140  information should include a description of any differences in the manufacturing processes 
141  between the nonclinical and clinical batches, as well as analytical data establishing that the 
142  nonclinical batch is representative of the batch to be administered to the subject(s).   
143   
144  In some cases, CMC information can be incorporated by reference from another application or a 
145  drug master file (DMF).13  This should be discussed with FDA at the pre-IND meeting.  The pre-
146  IND meeting package, therefore, should include a description of the CMC information that will 
147  be provided in the sponsors IND for the individualized ASO drug product, as well as a list of 
148  cross-referenced applications (e.g., other INDs, including INDs for other individualized ASO 
149  products) and DMFs, including a list of the information that will be incorporated by reference 
150  from those applications and/or DMFs in the IND.  If a cross-referenced application or DMF is 
 
12 The acceptability of this approach will depend on FDAs assessment of the CMC information and the results of 
the toxicology studies provided in the IND. 
 
13 See 21 CFR 314.420 and the draft guidance for industry Drug Master Files (October 2019).  When final, this 
guidance will represent the FDAs current thinking on this topic. 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
151  submitted by a firm other than the sponsor, the IND for the individualized ASO drug product 
152  must contain a letter of authorization from the DMF holder or sponsor of the cross-referenced 
153  application authorizing FDA to review the relevant information referenced in the cross-
154  referenced application or DMF.   
155   
156  The CMC data that sponsors of individualized ASO drug products within the scope of this 
157  guidance should submit in their IND applications are described in the sections below. 
158   
159   
160  III.  CMC INFORMATION FOR DRUG SUBSTANCE14 
161   
162  A.  A Description of the Drug Substance, Including Its Physical and Chemical 
163  Characteristics 
164   
165  The sponsor must provide a description of the drug substance, which should include the 
166  structure, nomenclature, structural formula, molecular formula, molecular weight, and molecular 
167  weight of the salt form (if applicable).  In addition, the sponsor should provide a statement 
168  regarding the nature of base moieties and backbone, carbohydrate moieties, internucleoside 
169  linkages, and counter ions (if applicable) that constitute the structure of the individualized ASO 
170  drug substance.  The sponsor should provide information about the physical properties such as 
171  hygroscopicity, solubility in aqueous media, and the melting temperature (T ) (if relevant).  
m
172   
173  B.  The Name and Address of the Drug Substance Manufacturer 
174   
175  The sponsor should submit the full street address of the manufacturer (including any contract 
176  manufacturer or test laboratory) of the individualized ASO drug substance used to manufacture 
177  batches of drug product that will be used in the clinical trial. 
178   
179  C.  The General Method of Preparation of the Drug Substance 
180   
181  In addition to the information described in the guidance for industry Content and Format of 
182  Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-
183  Characterized, Therapeutic, Biotechnology-derived Products,15 the submission should include a 
184  flow diagram and a full narrative description of the manufacturing process, including purification 
185  steps.  The flow diagram should contain all representative coupling/chain elongation and 
186  deprotection steps, as well as any purification, impurity reduction, or removal steps (e.g., 
187  chromatography, lyophilization or solvent removal, desalting tangential flow filtration).   
188   
189  The narrative description should contain the chemical structures and configurations, including 
190  stereochemical information for the starting materials, intermediates (either in situ or isolated), 
191  and, when feasible, significant side products.  Furthermore, a manufacturing step should be 
192  described in detail if it is unique or critical to the synthesis or manufacturing process.  In general, 
193  FDA does not expect the sponsor to identify a column or equipment model number or 
 
14 See 21 CFR 312.23(a)(7)(iv)(a). 
 
15 See section III., F., 2., c. of the guidance. 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
194  manufacturer, but the IND should include a clear description of process controls that ensure 
195  quality of the drug substance (e.g., process steps ensuring impurity clearance).16   
196   
197  The sponsor should provide a list of materials used in the manufacture of the ASO drug 
198  substance (e.g., starting materials, reagents, solvents, auxiliary materials).  
199   
200  For sterile drug substances, the sponsor should submit a description of the sterilization process 
201  (e.g., moist or dry heat terminal sterilization, aseptic filtration), but submission of information 
202  related to sterilization process validation is not necessary.   
203   
204  D.  Characterization 
205   
206  The sponsor should confirm the chemical structure of the drug substance using physical and 
207  chemical techniques, including nucleotide sequencing, T , and mass spectral analysis.  The 
m
208  sponsor should provide the sequence determination of an ASO drug substance; however, if the 
209  sequence determination is not provided in the initial IND, the sponsor should include an 
210  adequate justification in the IND and submit the sequence in an amendment as soon as possible.  
211  The sponsor should provide information on impurities in the ASO drug substance.  The sponsor 
212  should summarize the actual and potential impurities most likely to arise during manufacture, 
213  purification, and storage of the drug substance.  FDA recommends that sponsors list ASO-related 
214  impurities and, when appropriate, group them based on their structural class or relative retention 
215  times.  
216   
217  The sponsor should provide a discussion related to the occurrence of non-ASO related impurities 
218  (e.g., elemental impurities, residual solvents, protecting groups) and how control of these 
219  impurities is ensured.  The submission should include specifications for observed non-ASO 
220  related impurities or a scientific justification for why such testing would not be required (e.g., 
221  description of the step(s) included in the manufacturing process to remove certain non-ASO 
222  related impurities). 
223   
224  If the clinical batch is different from the batch used for nonclinical studies, the sponsor should 
225  provide data (such as high-performance liquid chromatography (HPLC) chromatograms of the 
226  drug substance) to compare the quality of these batches (e.g., homogeneity and purity of the 
227  nonclinical and clinical ASO drug substance batches).   
228   
229  E.  Control of Drug Substance 
230   
231  1.  Specification 
232   
233  This section should include a table of all elements of the specification to which the batch of drug 
234  substance should conform, including the test, associated acceptance criteria, and references to the 
235  analytical procedures that will be used to perform each test.  In this section, the sponsor should 
236  provide a brief description of the analytical methods.  In addition to considering the 
237  recommendations provided in the guidance for industry Content and Format of Investigational 
238  New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, 
 
16 See 21 CFR 312.23(a)(7)(iv)(a). 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
239  Therapeutic, Biotechnology-Derived Products,17 sponsors should include the following in the 
240  specifications:  
241   
242    The identity of the ASO drug substance.  FDA recommends using a combination of two 
243  or more methods to establish the identity of the ASO drug substance.  Common methods 
244  include sequencing and molecular weight determination.  Other methods, such as the 
245  determination of T , chromatographic retention time using HPLC, may also be 
m
246  acceptable;   
247   
248    A test for the salt form (if applicable);  
249   
250    A strength assay, which should include reporting of the full-length drug product content, 
251  with exclusion of the P=O impurity (if present); 
252   
253    The determined quantities of each specified impurity or grouped impurities; 
254   
255    The quantities of individual unidentified impurities;18  
256   
257    The total impurities content;  
258   
259    Residual solvents;19  
260   
261    Moisture content;  
262   
263    Microbiological testing (e.g., microbial limits (United States Pharmacopeia (USP) 
264  General Chapter <61> and General Chapter <62> or equivalent) or sterility (USP General 
265  Chapter <71> or equivalent))20; and 
266   
267    Bacterial endotoxins (USP General Chapter <85> or equivalent). 
268   
269  The certificate of analysis (CoA) for the proposed clinical batch as well as the nonclinical 
270  batches, if any, should be included.  
271   
 
17 See section III., F., 2., d. of the guidance. 
 
18 See the International Council for Harmonisation (ICH) guidance for industry Q3A Impurities in New Drug 
Substances (June 2008). 
 
19 For details about residual solvents, consult the ICH guidance for industry Q3C Impurities: Residual Solvents 
(December 1997).  
 
20 Sterility testing is recommended if the drug substance is sterile and additional sterilization steps are not included 
during drug product manufacturing.  In addition, if the drug substance is sterile, a description of the sterilization 
steps (e.g., membrane filtration, terminal sterilization) implemented to manufacture the sterile drug substance should 
be provided.  Otherwise, drug substance specifications should include bioburden testing. 
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Draft  Not for Implementation 
272  F.  Stability 
273   
274  The sponsor should provide information relating to the stability of the synthetic ASO drug 
275  substance.  This should include available stability data and the protocol that will be used to 
276  monitor ongoing drug substance stability.  Preliminary data should be provided in tabular format.  
277  The sponsor should also provide a description of the container closure system.  
278   
279   
280  IV.  CMC DATA FOR DRUG PRODUCT 21 
281   
282  A.  Components 
283   
284  The sponsor must provide a list of all components used in the manufacture of the investigational 
285  drug product,22 including those components intended to appear in the drug product and those 
286  which may not appear, but which are used in the manufacturing process.  The sponsor should cite 
287  quality of the inactive ingredients by reference to a compendial monograph (e.g., USP and the 
288  National Formulary23) (if applicable), or the IND should contain the suppliers CoA. 
289   
290  B.  Quantitative Composition of the Drug Product 
291   
292  The sponsor should submit a brief summary, preferably a table, of the composition of the 
293  individualized ASO drug product.  For processing aid or aids that are removed during 
294  manufacture (e.g., Water for Injection used to formulate a lyophilized product), the submission 
295  should include the amount(s) of aid or aids used and amount of aid or aids removed. 
296   
297  C.  Name and Address of the Drug Product Manufacturer 
298   
299  The sponsor should submit the full street address of the manufacturer (including any contract 
300  manufacturer, packing facility, or test laboratories) of the individualized ASO drug product 
301  batches intended to be used in the clinical trial. 
302   
303  D.  Brief General Description of the Manufacturing and Packaging Procedures 
304  for the Product 
305   
306  The sponsor should submit a flow diagram and a brief written description of the manufacturing 
307  process, including any bioburden reduction and sterilization steps used (e.g., membrane 
308  filtration, terminal sterilization).  The description should include the air classification of the 
309  rooms used in the manufacture of the drug product (e.g., Class 100, Grade A, ISO 5).   
310   
 
21 See 21 CFR 312.23(a)(7)(iv)(b). 
 
22 Ibid. 
 
23 Reference to a foreign compendium that provides for equivalent quality (e.g., European Pharmacopeia, Japanese 
Pharmacopeia) is acceptable. 
8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
311  E.  Control of Drug Product 
312   
313  The IND should include specifications with corresponding test methods.24  The sponsor should 
314  test the drug product for identity, strength, impurities/degradation products (including identity, 
315  quality, and a justification for acceptable level of any new impurity present only in the drug 
316  product), foreign and particulate matter, sterility, bacterial endotoxins, and any specific tests 
317  applicable to the dosage form. As detailed in Table 1 below, the acceptance criterion for bacterial 
318  endotoxins should be established based on the maximum proposed dose and route of 
319  administration (i.e., intrathecal, intravitreal, or subcutaneous).   
320   
321  Table 1: USP Endotoxin Limits 
322   
U.S. Pharmacopeia 
Type of Administration  Endotoxin Limits  
(USP) Reference 
USP General Chapter  Subcutaneous  5 EU/Kg/Hour 
<85>  Intrathecal   0.2 EU/Kg/Hour 
USP General Chapter 
Intraocular (e.g., intravitreal)  2.0 EU/Dose/Eye 
<771> 
323   
324  The sponsor should describe noncompendial analytical methods for the drug product, if different 
325  from the drug substance analytical methods, at the same level of detail as for the drug substance. 
326   
327  F.  Container Closure System 
328   
329  The sponsor should provide a description of the container closure system for the individualized 
330  ASO drug product, including the identity of materials of construction of each primary packaging 
331  component (e.g., USP Type 1 glass vial, bromobutyl rubber stopper, flip-off seal).  The sponsor 
332  should provide specifications for each component or the manufacturers CoA.  The sponsor 
333  should describe methods for depyrogenation and sterilization for any components that are not 
334  supplied as sterile. 
335   
336  G.  Stability 
337   
338  The sponsor should monitor the stability of the individualized ASO drug product packaged in the 
339  proposed container closure system under the proposed storage conditions.  The sponsor should 
340  provide the stability protocol for the clinical batch, including a brief description of the stability 
341  study and the test methods, with a commitment to monitor stability of the drug product 
342  throughout its use.  If initial stability data for the clinical batch are available, the sponsor should 
343  provide the data in tabular format.  If stability data for the clinical batch are not available, the 
344  sponsor should provide any available supportive stability data (e.g., data from the nonclinical 
345  batch, if different from the clinical batch; data from a laboratory batch).  
346   
347  If the individualized ASO drug product is modified before use (e.g., reconstituted or diluted for 
348  infusion), the drug product, ready for administration (e.g., in the infusion bag), should not be 
 
24 Where applicable, testing should be performed using the official compendial methods referenced in USP General 
Chapter <1> Injections and Implanted Drug Products (Parenterals)  Product Quality Tests.  
9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
349  stored at room temperature for longer than 4 hours or under refrigerated conditions for longer 
350  than 24 hours to minimize the risk for excessive growth of adventitious microbial contamination.  
351   
352  However, if extended storage conditions are necessary, the sponsor should conduct 
353  microbiological studies supporting the postconstitution/postdilution storage time (as stated in the 
354  proposed product labeling) as recommended in the ICH guidances for industry Q8(R2) 
355  Pharmaceutical Development (November 2009)25 and Q1A(R2) Stability Testing of New Drug 
356  Substances and Products (November 2003).26  The submission should include a description of 
357  the test methods and results of studies that are designed using a minimum countable inoculum 
358  (less than or equal to 100 colony forming units (CFU)/ milliliter (mL)) to simulate potential 
359  microbial contamination that may occur during drug product constitution or dilution.  
360  Additionally, the sponsor should justify the selected test conditions and/or diluents as necessary.  
361  Challenge organisms can include strains described in USP General Chapter <51> in addition to 
362  typical skin flora, species associated with nosocomial infection, or psychrophilic organisms.  The 
363  sponsor should provide a positive control that demonstrates the viability of the organisms over 
364  the duration of the test period. 
365   
366   
367  V.  IMMEDIATE PACKAGING LABELING 
368   
369  The sponsor must submit in the IND a copy of the proposed immediate packaging label.27  The 
370  immediate packaging label must include the statement Caution: New Drug  Limited by 
371  Federal (or United States) law to investigational use.28  
372   
373   
374  VI.  ENVIRONMENTAL EXCLUSION 
375   
376  The IND sponsors should either include a claim for categorical exclusion of environmental 
377  analysis requirements under 21 CFR 25.30 or 25.31 or provide an environmental assessment 
378  under 21 CFR 25.40.29  For an individualized ASO drug product under an IND, we recommend 
379  that the sponsor provide a claim for categorical exclusion under 21 CFR 25.31(e).  
 
25 See section II., E. of the guidance. 
 
26 See 2.2.7 (section II., B., 7.) of the guidance. 
 
27 21 CFR 312.23(a)(7)(iv)(d). 
 
28 21 CFR 312.6(a). 
 
29 See 21 CFR 312.23(a)(7)(iv)(e). 
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