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FDA Guidances

FDA Guidances

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Safety Testing of Drug Metabolites Guidance for Industry

Safety Testing of Drug

Metabolites Guidance for Industry

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

November 2016 Pharmacology/Toxicology

Revision 1

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Safety Testing of Drug

Metabolites Guidance for Industry

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: This e-mail address is being protected from spambots. You need JavaScript enabled to view it 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)

November 2016 Pharmacology/Toxicology

Revision 1

I. II. III.

A. B. C.

IV.

A. B. C. D.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1

BACKGROUND ............................................................................................................... 2

GENERAL CONCEPTS IN METABOLITE SAFETY TESTING............................. 3

General Approaches for Assessing Metabolite Safety ................................................................ 4

Identification of Metabolites ......................................................................................................... 4

General Considerations for Nonclinical Study Design ............................................................... 5

RECOMMENDED STUDIES FOR ASSESSING THE SAFETY OF METABOLITES ............................................................................................................... 5

General Toxicity Studies ............................................................................................................... 6 Genotoxicity Studies ...................................................................................................................... 6 Embryo-Fetal Development Toxicity Studies..............................................................................6 Carcinogenicity Studies ................................................................................................................. 6 TIMING OF SAFETY ASSESSMENTS ........................................................................ 7

V. GLOSSARY................................................................................................................................... 8 APPENDIX A: DECISION TREE FLOW DIAGRAM ............................................................ 9 APPENDIX B: CASE EXAMPLES OF DRUG METABOLITES ........................................ 10

Contains Nonbinding Recommendations

Safety Testing of Drug Metabolites Guidance for Industry1

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This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

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I. INTRODUCTION

This guidance provides recommendations to industry on when and how to identify and characterize drug metabolites whose nonclinical toxicity needs to be evaluated. The safety of drug metabolites may need to be determined in nonclinical studies because these metabolites are either identified only in humans or are present at disproportionately higher levels in humans than in any of the animal species used during standard nonclinical toxicology testing.2

This guidance applies to small molecule nonbiologic drug products. This guidance does not apply to some cancer therapies where a risk-benefit assessment is considered.3

This guidance supersedes the guidance of the same name published in February 2008. The guidance has been revised to be in alignment with the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

1 This guidance has been prepared by the Pharmacokinetic Subcommittee of the Pharmacology and Toxicology Coordinating Committee in the Center for Drug Evaluation and Research at the Food and Drug Administration.

2 See the Glossary for the definition of disproportionate drug metabolite.

3 See the ICH guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals for the safety testing of drug metabolites in cancer therapies. We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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II. BACKGROUND

Nonclinical evaluation of drug safety usually consists of standard animal toxicology studies.4 These studies usually include assessment of drug exposure, primarily parent drug plasma concentration. Generally, drug plasma concentration and systemic exposure in the nonclinical studies are compared with systemic exposure in humans to assess the potential risks suggested by nonclinical findings and guide monitoring in clinical trials. This testing paradigm usually is sufficient when the metabolic profile in humans is similar to that in at least one of the animal species used in nonclinical studies, but metabolic profiles can vary across species both quantitatively and qualitatively, and there are cases when clinically relevant metabolites have not been identified or adequately evaluated during nonclinical safety studies. This situation can occur if the metabolite is formed only in humans and is absent in the animal test species or if the metabolite is present at disproportionately higher levels in humans than in the animal species used in the standard toxicity testing with the parent drug.

It is not standard practice for drug metabolites to be evaluated separately in a cross-species safety assessment. As a result, their specific contribution to the overall toxicity of the parent drug has often remained unknown. This lack of appreciation of the role of metabolites in drug toxicity may be partly because of the inadequate sensitivity of the analytical methods used to detect and characterize metabolites derived from the parent drug. Technological advances have greatly improved the analytical capabilities to detect, identify, and characterize metabolites and allow for a better understanding of the role metabolites play in drug safety assessment.

Drugs entering the body undergo biotransformation via Phase I and Phase II metabolic pathways. Based on the nature of the chemical reactions involved, metabolites formed from Phase I reactions are more likely to be chemically reactive or pharmacologically active and, therefore, more likely to need safety evaluation. An active metabolite may bind to the therapeutic target receptors or other receptors, interact with other targets (e.g., enzymes, proteins), and cause unintended effects. This is a particularly important problem when such a metabolite is formed in humans and not in animals, but the occurrence of a metabolite only in humans and not in any animal test species is rare. A more common situation is the formation of a metabolite at disproportionately higher levels in humans than in the animal species used in safety testing of the parent drug. This disproportionality stems from the typical qualitative and/or quantitative differences in metabolic profiles between humans and animals. If at least one animal test species forms this drug metabolite at adequate exposure levels (approximately equal to or greater than human exposure), as determined during toxicology testing of the parent drug, it can be assumed that the metabolite’s contribution to the overall toxicity assessment has been established.5

Metabolites that form chemically reactive intermediates can be difficult to detect and measure because of their short half-lives. However, they can form stable products (e.g., glutathione

4 See the ICH guidances for industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals and S7A Safety Pharmacology Studies for Human Pharmaceuticals.

5 See Appendix A: Decision Tree Flow Diagram. This diagram describes which studies may be needed to determine safety of the drug metabolite.

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Contains Nonbinding Recommendations

conjugates) that can be measured. Phase II conjugation reactions generally render a compound more water soluble and pharmacologically inactive, thereby eliminating the need for further evaluation. However, if the conjugate forms a toxic compound such as acylglucuronide, additional safety assessment may be needed.6

Demonstration that a metabolite is pharmacologically inactive at the target receptor does not guarantee that it is not toxic. Therefore, it may need to be tested in nonclinical toxicity studies.7

III. GENERAL CONCEPTS IN METABOLITE SAFETY TESTING

We encourage the identification of any differences in drug metabolism between animals used in nonclinical safety assessments and humans as early as possible during the drug development process.8,9 The discovery of disproportionate drug metabolites late in drug development can potentially cause development and marketing delays.

Generally, metabolites identified only in human plasma or metabolites present at disproportionately higher levels in humans than in any of the animal test species should be considered for safety assessment. Human metabolites that can raise a safety concern are those formed at greater than 10 percent of total drug-related exposure at steady state.10 The choice of a level of greater than 10 percent for characterization of drug metabolites reflects consistency with FDA and Environmental Protection Agency guidances.11,12

6 Faed, EM, 1984, Properties of Acyl Glucuronides. Implications for Studies of the Pharmacokinetics and Metabolism of Acidic Drugs, Drug Metab Rev, 15, 1213–1249.

7 See Appendix B: Case Examples of Drug Metabolites.

8 Baillie, TA, MN Cayen, H Fouda, RJ Gerson, JD Green et al., 2002, Drug Metabolites in Safety Testing, Toxicol Appl Pharmacol, 182, 188–196.

9 Hastings, KL, J El-Hage, A Jacobs, J Leighton, D Morse, and R Osterberg, 2003, Drug Metabolites in Safety Testing, Toxicol Appl Pharmacol, 190(1), 91–92.

10 Exposure should be at steady state unless there is some justification for a different measure of exposure. Comparison between human and animal exposure generally is based on area under the curve, but sometimes it may be more appropriate to use Cmax. See ICH M3(R2).

11 U.S. Environmental Protection Agency, 1998, Health Effects Test Guidelines, OPPTS 870.7485, Metabolism and Pharmacokinetics (http://www.epa.gov/epahome/research.htm).

12 See the Veterinary International Conference on Harmonization guidances GL46 Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-producing Animals: Metabolism Study to Determine the Quantity and Identify the Nature of Residues (MRK) and GL47 Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Animals: Comparative Metabolism Studies in Laboratory Animals available on the Veterinary International Conference on Harmonization (VICH) Guidance Documents Web page at http://www.fda.gov/RegulatoryInformation/Guidances/ucm122050.htm.

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A. General Approaches for Assessing Metabolite Safety

A metabolite identified in animals that is not present in humans can mean that a toxicity observed in that animal species, attributed to the metabolite, may not be relevant to humans. Conversely, a drug metabolite identified during clinical development that is not present in animal test species or is present at much lower levels in animals than in humans can suggest the need for further studies in animals to determine the potential toxicity of the metabolite. In such cases, two approaches can be considered to assess the drug metabolite. The first approach is to identify an animal species routinely used in toxicity studies that forms the metabolite at adequate exposure levels (equivalent to or greater than the human exposure), and then investigate the drug’s toxicity in that species. The second approach, if a relevant animal species that forms the metabolite cannot be identified, is to synthesize the drug metabolite and directly administer it to the animal for further safety evaluation. In this approach, analytical methods that are capable of identifying and measuring the metabolite in nonclinical toxicity studies should be developed.

We acknowledge the difficulties associated with synthesizing a specific metabolite as well as the inherent complexities that accompany its direct administration. Direct dosing of a metabolite to animals may lead to subsequent metabolism that may not reflect the clinical situation and thus may complicate the toxicity evaluation. Moreover, new and different toxicities may arise from administration of the metabolite that were not observed with the parent drug. However, notwithstanding these possible complications, identification and evaluation of the potential toxicity of the drug metabolite is considered important to ensure clinical safety, and the decision to conduct direct safety testing of a metabolite should be based on a comprehensive evaluation of the data on the parent drug and any information available for the metabolite. Appendix B provides three case examples when drug metabolites were formed at disproportionately higher levels in humans than in test animals used in the nonclinical studies and how the safety evaluation was approached. In Case 1, testing of the drug metabolite was not needed because the metabolite was adequately characterized in nonclinical toxicity studies with the parent drug. However, in Cases 2 and 3, the drug metabolites had to be tested in toxicity studies by direct administration to the animal. In Case 3, the drug metabolite was pharmacologically inactive at the therapeutic target receptor but showed a unique toxicity not observed with the parent molecule.

B. Identification of Metabolites

Metabolite concentrations cannot be inferred by measurement of parent drug concentrations. The metabolic profile of the drug should be identified during the drug development process. This identification can be accomplished at different stages of development using in vitro and in vivo methods. In vitro studies can use liver microsomes, liver slices, or hepatocytes from animals and humans and generally should be conducted before initiation of clinical trials.

In vivo metabolism study results in nonclinical test species generally should be available early in drug development, and their results will either confirm the results obtained from the in vitro studies or reveal quantitative and/or qualitative differences in metabolism across species. It is the latter situation that may pose a safety concern. Human in vivo metabolism studies usually have been conducted relatively later in drug development, but we strongly recommend in vivo metabolic evaluation in humans be conducted as early as feasible.

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Contains Nonbinding Recommendations

Adequacy of exposure to drug metabolites that are present at disproportionately lower levels in animals used in nonclinical studies should be considered on a case-by-case basis. Generally, systemic exposure is assessed by measuring the concentration of the parent drug at steady state, in serum or plasma. However, when measurements cannot be made in plasma of the test species for any reason, verification of adequate exposure can be made in other biological matrices such as urine, feces, or bile.13 We encourage contacting the FDA early in drug development to discuss these issues.

C. General Considerations for Nonclinical Study Design

When designing a nonclinical study for a disproportionate drug metabolite, it is important to consider the following factors:

  • Similarity of the metabolite to the parent molecule

  • Pharmacological or chemical class

  • Solubility

  • Stability in stomach pH

  • Phase I versus Phase II metabolite

  • Relative amounts detected in humans versus the amounts detected in animals

    Additional factors to consider include the proposed drug indication and patient population (e.g., nonclinical studies can be abbreviated for serious indications such as amyotrophic lateral sclerosis (ALS)). The proposed duration of use (short term, intermittent use, chronic) and levels of exposure at the therapeutic dose also should be considered when designing the nonclinical studies for the drug metabolite.

IV. RECOMMENDED STUDIES FOR ASSESSING THE SAFETY OF METABOLITES

Good laboratory practice guidelines apply to the nonclinical studies with the drug metabolite designed to evaluate safety (21 CFR part 58). The following studies may need to be conducted to assess the safety of the disproportionate drug metabolite.

13 See the ICH draft guidance for industry S3A Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies — Questions and Answers. When final, this guidance will represent the FDA’s current thinking on this topic.

Although the drug metabolite of toxicological concern usually is one circulating in plasma at greater than 10 percent of total drug-related exposure, other metabolites also can elicit safety concern. For example, a drug metabolite representing greater than 10 percent of urinary excretion relative to the bioavailable dose, or a human fecal metabolite in cases where biliary elimination is the predominant route of excretion in humans, may reflect potential localized renal or bile duct toxicity, respectively. Further characterization in these instances should be addressed on a case-by-case basis with the review division.

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A. General Toxicity Studies

The potential toxicity of a disproportionate drug metabolite should be evaluated to enable comparisons between the metabolite and its parent drug. The duration of the general toxicity study with direct dosing of the metabolite should follow the recommendations listed in ICH M3(R2). The toxicity of the drug metabolite should be investigated at multiples of the human exposure or at least at levels comparable to those measured in humans. We also recommend using the parent drug’s intended clinical route of administration. However, with justification, other routes can be used to achieve sufficient exposure to the disproportionate metabolite. If the clinical route is oral, it is important to verify the stability of the metabolite in the stomach environment. It is crucial to gather toxicokinetic data from this type of study to ensure adequate exposure.

B. Genotoxicity Studies

The potential genotoxicity of the drug metabolite should be assessed in an in vitro assay that detects point mutations and in another assay that detects chromosomal aberrations. It is important that these assays be conducted according to the recommendations in the ICH guidance for industry S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use. If one or both of the in vitro tests are equivocal and/or positive, results from a complete standard battery of genotoxicity studies may be warranted.

C. Embryo-Fetal Development Toxicity Studies

When a drug is intended for use in a population that includes women of childbearing potential, embryo-fetal development toxicity studies should be conducted with the drug metabolite. We may ask for other reproductive toxicity studies on a case-by-case basis, depending on results of the general toxicity and embryo-fetal development studies. Reproductive toxicity studies should be conducted in accordance with the ICH guidance for industry S5(R2) Detection of Toxicity to Reproduction for Medicinal Products and Toxicity to Male Fertility. Sometimes the conduct of an embryo-fetal development toxicity study in only one species that forms the drug metabolite can be justified.

D. Carcinogenicity Studies

Carcinogenicity studies should be conducted on metabolites of drugs that are administered continuously for at least 6 months, or that are used intermittently in the treatment of chronic or recurrent conditions when the carcinogenic potential of the metabolite cannot be adequately evaluated from carcinogenicity studies conducted with the parent drug. A single carcinogenicity study or an alternative bioassay should be conducted and the studies should be conducted in accordance with the ICH guidances for industry S1A The Need for Long-term Rodent Carcinogenicity Studies of Pharmaceuticals, S1B Testing for Carcinogenicity of Pharmaceuticals, and S1C(R2) Dose Selection for Carcinogenicity Studies.

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Contains Nonbinding Recommendations

V. TIMING OF SAFETY ASSESSMENTS

Early identification of disproportionate drug metabolites can provide clear justification for nonclinical testing in animals, assist in interpreting and planning clinical studies, and prevent delays in drug development. If toxicity studies of a drug metabolite are warranted, studies should be completed and study reports provided to the FDA before beginning large-scale clinical trials.

To optimize and expedite drug development for serious or life-threatening diseases other than cancer (e.g., ALS, stroke, human immunodeficiency virus), the number and type of nonclinical studies for the drug metabolites can be modified on a case-by-case basis for those drugs with major beneficial therapeutic advances, and for drugs for illnesses that lack an approved effective therapy. Sponsors should contact the appropriate review division to discuss such situations.

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Contains Nonbinding Recommendations

GLOSSARY

Disproportionate drug metabolite — A metabolite present only in humans or present at higher plasma concentrations in humans than in the animals used in nonclinical studies. In general, these metabolites are of interest if they account for plasma levels greater than 10 percent of total drug-related exposure, measured as area under the curve at steady state.

Metabolite — A compound derived from the parent drug through Phase I and/or Phase II metabolic pathways.

Pharmacologically active metabolite — A metabolite that has pharmacological activity at the target receptor. The activity may be greater than, equal to, or less than that of the parent drug.

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APPENDIX A: DECISION TREE FLOW DIAGRAM

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Disproportionate Drug Metabolite

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<10% of total drug- related exposure (area under the curve)

>10% of total drug- related exposure (area under the curve)

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Formed in any animal test species?

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No further testing needed to evaluate metabolite

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Yes How much?

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No

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Exposure in animal studies does not approach human exposure

Exposure in animal studies does approach human exposure

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Nonclinical testing with the drug metabolite

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No further testing needed to qualify metabolite

Case 1.

Contains Nonbinding Recommendations

APPENDIX B:
CASE EXAMPLES OF DRUG METABOLITES

From an initial mass balance study, a metabolite represented 1 to 2 percent of total radioactive dose in rat plasma, 5 percent in dogs, and 20 percent in humans (radioactivity of this metabolite in urine and/or feces was minimal). Based on the up-to-20 fold greater exposure in humans than in animals, nonclinical safety testing was recommended. However, the data generated in the general toxicology studies with the parent drug in the rat and dog suggested that the maximum doses tested produced metabolite exposures that represented at least the therapeutic exposure at the maximum recommended human dose. Also, the plasma concentrations of this metabolite measured in the in vivo genetic toxicity study, embryo-fetal development toxicity study, and carcinogenicity studies conducted with the parent drug provided adequate exposure and characterization of the metabolite. Therefore, no additional testing with the metabolite was needed.

Case 2.

Two primary hydroxylated metabolites, M1 and M2, were shown to undergo further oxidation to form secondary metabolites M3 and M4 using hepatic microsomes and hepatocytes from human, monkey, rat, dog, rabbit, and mouse. This metabolic profile was later confirmed by in vivo data. The results showed the following:

  • M1 and M4 were the predominant metabolites in human, monkey, and dog microsomes, whereas rat, mouse, and rabbit formed M2 and M3

  • M4 was formed in humans at 4 fold higher levels than total drug-related exposure, but M4 was formed at very low levels in rodents and only represented one-third of the total drug-related exposure in monkey (see Table 1)

    Table 1: AUC0-24hr at the Maximum Dose*

    * AUC = area under the curve; MRHD = maximum recommended human dose

  • Severe drug-related and novel target organ toxicities were observed with the parent drug in monkeys but not in rats

  • M4 was pharmacologically inactive at the drug target receptors

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Human (MRHD)*

Monkey

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Rat

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Total drug- related exposure

1,800

15,000

12,500

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M4

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7,700

5,000

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135

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The following additional studies were done with M4:

  • Subchronic toxicity study: 3 months in the rat

  • Embryo-fetal development study in the rat

  • In vitro genotoxicity testing: M4 was positive for point mutation and chromosomal aberration; the parent drug was negative

  • Because of the positive genotoxicity, a carcinogenicity study that included M4 was recommended

    Case 3.

    M2 is a Phase I oxidative metabolite that formed up to 50 percent of total drug-related exposure in humans, 10 percent of total drug-related exposure in mice, 15 percent of total drug-related exposure in dogs, and only trace amounts in rats. In vitro metabolism studies in these species supported the in vivo findings. Based on structure activity relationship analyses, there was no reason to anticipate any difference or exaggeration in toxicity of the metabolite compared to parent molecule. The parent drug showed no significant toxicity or identifiable target organ of toxicity in any of the animal species tested in safety assessment studies. Because disproportionate human exposure was identified, further safety testing was needed. When M2 was tested in a short-term tolerance study in the dog, it produced unexpected and significant cardiotoxicity at all doses and in all of the dogs. M2 was pharmacologically inactive at the therapeutic target receptor.

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Physiologically Based Pharmacokinetic Analyses — Format and Content

Physiologically Based

Pharmacokinetic

Analyses — Format and

Content Guidance for Industry

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 http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1601, 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 (CDER) Office of Clinical Pharmacology, at 301-796-5008 or This e-mail address is being protected from spambots. You need JavaScript enabled to view it .

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

December 2016 Clinical Pharmacology

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Physiologically Based

Pharmacokinetic

Analyses — Format and

Content Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
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)

December 2016 Clinical Pharmacology

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I. II. III.

A. B. C.

D.

E. F.

IV.

1. 2. 3. 4. 5.

1. 2.

1. 2. 3. 4.

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 1 FORMAT AND CONTENT ............................................................................................ 2 Executive Summary ....................................................................................................................... 2 Introduction.................................................................................................................................... 2 Materials and Methods.................................................................................................................. 2

Overview of Modeling Strategy ....................................................................................................... 2 Modeling Parameters....................................................................................................................... 3 Simulation Design............................................................................................................................3 Electronic Files and Other Documentation ..................................................................................... 3 Software...........................................................................................................................................4 Results ............................................................................................................................................. 4

Model Verification and Modification............................................................................................... 4 Model Application............................................................................................................................ 5 Discussion ....................................................................................................................................... 5

Appendices...................................................................................................................................... 5

List of Tables.................................................................................................................................... 6 List of Figures..................................................................................................................................6 Table of Acronyms and Abbreviations.............................................................................................6 References........................................................................................................................................6 REFERENCES.................................................................................................................. 6

Contains Nonbinding Recommendations

Draft – Not for Implementation

  1. 1 Physiologically Based Pharmacokinetic Analyses —

  2. 2 Format and Content 1

34 Guidance for Industry

5 6 7 8 9

10 11

12
13
14
15
I. INTRODUCTION 16

  1. 17  This guidance outlines the recommended format and content for a sponsor to submit

  2. 18  physiologically based pharmacokinetic (PBPK) analyses to the FDA to support applications

  3. 19  including investigational new drug (INDs) applications, new drug applications (NDAs),

  4. 20  biologics license applications (BLAs), or abbreviated new drug applications (ANDAs). To

  5. 21  enable efficient and consistent review, the FDA recommends including the following five

  6. 22  sections in a PBPK study report: (1) Executive Summary; (2) Materials and Methods; (3)

  7. 23  Results; (4) Discussion; and (5) Appendices. The content of each section is described in detail

  8. 24  below. This guidance does not address methodological considerations and best practices for the

  9. 25  conduct of PBPK modeling and simulation, or the appropriateness of PBPK analyses for a

  10. 26  particular drug or a drug product (i.e., both small molecules and biologics). The decision to

  11. 27  accept results from PBPK analyses in lieu of clinical pharmacokinetic (PK) data is made on a

  12. 28  case-by-case basis, taking into account the intended use for the analyses, as well as the quality,

  13. 29  relevance, and reliability of the study results.

30

  1. 31  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 32  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 33  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 34  the word should in Agency guidances means that something is suggested or recommended, but

  5. 35  not required.

36
37
38
II. BACKGROUND 39

1 This guidance has been prepared by the Office of Clinical Pharmacology, Office of Translational Sciences, in the Center for Drug Evaluation and Research at the Food and Drug Administration.

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This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

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Draft – Not for Implementation

  1. 40  A PBPK analysis uses models and simulations that combine physiology, population, and drug

  2. 41  characteristics to mechanistically describe the PK and/or pharmacodynamic (PD) behaviors of a

  3. 42  drug (Rowland, Peck, et al. 2011; Rostami-Hodjegan 2012). Throughout a drug’s life cycle,

  4. 43  PBPK model predictions can be used to support decisions on whether, when, and how to conduct

  5. 44  certain clinical pharmacology studies, and to support dosing recommendations in product

  6. 45  labeling (Zhao, Zhang, et al. 2011; Jones, Chen, et al. 2015; Shepard, Scott, et al. 2015; Wagner,

  7. 46  Zhao, et al. 2015). Because of the lack of regulatory guidance, the format and content of PBPK

  8. 47  analyses that are submitted to the FDA vary significantly across drug developers. Therefore,

  9. 48  standardizing the content and format of PBPK study reports that are submitted to the FDA can

  10. 49  facilitate FDA’s efficient assessment, consistent application, and timely decision making during

  11. 50  regulatory review and is the goal of this guidance.

51
52
53
III. FORMAT AND CONTENT 54

  1. 55  PBPK analyses may be appropriate at multiple points in the drug development process, for

  2. 56  example in IND applications, NDAs, BLAs, ANDAs, or in the postmarketing stage. The depth

  3. 57  and breadth of PBPK analyses at each stage may vary significantly because of the availability or

  4. 58  quality of clinical data. The FDA, however, suggests including the following sections in the

  5. 59  PBPK study report for all PBPK analyses.

60
61
A. Executive Summary 62

  1. 63  The executive summary should include the rationale for conducting the PBPK analyses, provide

  2. 64  a succinct overview of model development and simulation scenarios, and summarize the key

  3. 65  conclusions of the report. This section should clearly convey how the analyses address a specific

  4. 66  scientific question in a clinical setting in support of a regulatory decision.

67
68
B. Introduction 69

  1. 70  The section should provide (1) a high-level synopsis of the drug’s PK and PD properties; (2) the

  2. 71  exposure-response relationships for the efficacy and safety of the drug; and (3) a brief regulatory

  3. 72  history to provide context for the PBPK analyses.

73
74
C. Materials and Methods 75

  1. 76  This section should include sufficient information to allow the FDA reviewers to evaluate the

  2. 77  submitted modeling and simulation results and to conduct supplemental analyses when

  3. 78  necessary. Sharing this information streamlines the review process, and enables further analyses

  4. 79  (Zhao, Rowland, et al. 2012). Suggested components of the materials and methods section

  5. 80  include the following:

81
82
1. Overview of Modeling Strategy 83

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Draft – Not for Implementation

  1. 84  This section should detail the modeling procedures, including the model development, model

  2. 85  verification/modification, and model application. The procedures should be outlined in a step-

  3. 86  wise manner using a workflow, decision-tree, table, or other representation. The sponsor should

  4. 87  appropriately reference the data and studies used in each step of the modeling process.

88
89
2. Modeling Parameters 90

  1. 91  All system and drug-specific components, as well as the sources of parameter values, should be

  2. 92  clearly specified. If a parameter value has been estimated, the data source and estimation

  3. 93  method should be described. When clinical PK data are used to optimize model parameters,

  4. 94  justification for selecting a particular optimization technique should be documented. All model

  5. 95  assumptions, including the biological and/or pharmacological rationale for the assumptions,

  6. 96  should be clearly stated (Zhao, Rowland, et al. 2012).2 The sponsor should present the modeling

  7. 97  parameters using a table or other visual representation.

98
99
3. Simulation Design

100

  1. 101  The description of simulation conditions should include the following information for the model

  2. 102  development, verification, and application:

103
104
105
106
107
108
109
110
111
112
113
114
115
116

  1. 117  Submitting electronic files streamlines the review process and allows for effective

  2. 118  communication between the FDA and the sponsor or the applicant. Electronic files related to

  3. 119  modeling software and simulations should be submitted along with the study report. Supporting

  4. 120  information such as clinical pharmacokinetic or pharmacokintetic/pharmacodynamic data used in

  5. 121  PBPK analyses or a scientific publication or an orientation document for submitted simulation

  6. 122  data and model files can also be included. Cross-references to other parts of the report and other

  7. 123  parts of the application should be provided with hyperlinks. If necessary, consult the FDA

  8. 124  regarding the feasibility of submitting certain types of electronic files.

    2 International Programme on Chemical Safety,“Characterization and Application of Physiologically Based Pharmacokinetic Models in Risk Assessment” available at http://www.who.int/ipcs/methods/harmonization/areas/pbpk_models.pdf.

Route, dose, formulation of the drug product, time of administration, and fasting or fed conditions

Simulation duration
Demographics of the virtual population
Number of simulation studies for a specific scenario (simulation trials) Number of virtual subjects in each simulation trial
4. Electronic Files and Other Documentation

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125
126
5. Software 127

  1. 128  The FDA does not require the use of a particular PBPK modeling software. Because of

  2. 129  substantive differences in software models and versions, sponsors should include information on

  3. 130  the PBPK modeling software. Table 1 below highlights the information that should be included

  4. 131  regarding commercial PBPK modeling software (commercial PBPK platform) versus custom

  5. 132  modeling software (e.g., commercial software that has been modified with custom codes or

  6. 133  otherwise revised for the purpose of PBPK modeling).

134
135
Table 1. Software Information for PBPK Modeling

Suggested Software Information

PBPK Models

Custom Modeling Software

Commercial PBPK Platform

Name and version of the software

Yes

Yes

Schematic view of model structure and differential equations based on established theoretical or biological basis

Yes

Optional

Parameterization of system information and sources of parameter values

Yes

Optional

Table of drug-dependent parameters for the investigational drug of interest, including names, values, units, and sources of the parameters, prediction algorithms, and assumptions being made

Yes

Yes

Literature references and the sponsor’s prior experience/knowledge in using the software for PBPK modeling (to help the reviewer understand how PBPK models are coded using the modeling software that was tested)

Yes

Yes

Manuals on model implementation of the software (to be provided as supporting documents)

Yes

Optional

Library system models (e.g., virtual population), including justifications for any modifications made to the model’s physiological parameters by the sponsor

Not applicable

Yes

Library drug models, including justifications for any modifications to the model made by the sponsor and information on model verification

Not applicable

Yes

136
137
D. Results 138

  1. 139  The sponsor should both demonstrate that the PBPK model is relevant and appropriate for

  2. 140  subsequent analyses and describe the results of model application. Details on suggested

  3. 141  components of model verification and model application are provided below.

142
143
1. Model Verification and Modification 144

  1. 145  The sponsor should clearly present the methodological approach used to verify the model,

  2. 146  confirm model results, and conduct sensitivity analyses to allow the FDA to evaluate the

  3. 147  robustness of the model. The methods best suited for model verification are dependent upon the

  4. 148  availability of clinical data to independently either confirm or reject the proposed model.

  5. 149  Clinical PK data (e.g., steady-state plasma PK data or certain drug-drug interaction data) are

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Draft – Not for Implementation

  1. 150  generally expected to establish confidence in the appropriateness of the PBPK model in

  2. 151  addressing the study question (Vieira, Kim, et al. 2014, Wagner, Pan, et al. 2015, Wagner, Pan,

  3. 152  et al. 2016).

153

  1. 154  Sensitivity analyses are important components of model verification, especially for uncertain

  2. 155  parameters with a high potential to influence the outcome of the simulation. For example, if a

  3. 156  PBPK model is used to predict the inhibition effect of an investigational drug on the exposure of

  4. 157  a cytochrome P450 substrate, sensitivity analyses—such as simulations that test a plausible range

  5. 158  of inhibition potency (e.g., a reversible inhibition constant Ki)—would be informative. Results

  6. 159  of sensitivity analyses for uncertain parameters should be discussed in the context of the

  7. 160  simulation conditions and potential clinical consequences.

161

  1. 162  In some instances, model parameters can be refined during model verification. Such

  2. 163  modifications are important aspects of model refinement and should be described. If the

  3. 164  assumption of the model parameters cannot be confirmed during modification, further

  4. 165  verification may be needed before the model can be applied to predict untested clinical

  5. 166  situations. The ultimate goal of PBPK analyses is to obtain the most accurate model that can

  6. 167  predict unknown situations with confidence. The sponsor should clearly demonstrate that the

  7. 168  proposed PBPK model is relevant to the study population and to the modeling purpose/question

  8. 169  asked, appropriate for the drug under investigation, and robust enough to handle perturbations in

  9. 170  uncertain study parameters.

171
172
2. Model Application 173

  1. 174  The sponsor should present the results of using the verified PBPK model to address the study

  2. 175  question using tables, graphs, and text where appropriate. The best data representation is

  3. 176  dependent upon the study question, PBPK model, and other relevant parameters.

177
178
E. Discussion 179

  1. 180  In this section, the sponsor should discuss how the PBPK modeling and simulation analyses

  2. 181  adequately address the proposed scientific, regulatory, or clinical questions. The basis for any

  3. 182  requests to waive the conduct of clinical studies should be discussed and well substantiated. If

  4. 183  simulations are used to support specific dosing recommendations to be tested in future clinical

  5. 184  trials or to be included in prescription product labeling, the proposed dosing recommendations

  6. 185  should be discussed within the context of known exposure-response relationships and the level of

  7. 186  confidence in the PBPK model for the intended application (Wagner, Zhao, et al. 2015). The

  8. 187  sponsor should also note the limitations of its modeling approach and assess the potential impact

  9. 188  of these limitations on the study results and interpretation.

189
190
F. Appendices
191
192 The following information should be included in the appendices. 193

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194 1. List of Tables
195
196 Provide a list of all tables used throughout the document.
197
198
2. List of Figures
199
200 Provide a list of all figures used throughout the document.
201
202
3. Table of Acronyms and Abbreviations
203
204 Spell out all acronyms and abbreviations used in the document. 205
206
4. References
207
208 Include a list of all references.
209
210
211
IV . REFERENCES
212

  1. 213  Jones, HM, Y Chen, C Gibson, T Heimbach, N Parrott, SA Peters, J Snoeys, VV Upreti, M

  2. 214  Zheng, and SD Hall, 2015, Physiologically Based Pharmacokinetic Modeling in Drug Discovery

  3. 215  and Development: A Pharmaceutical Industry Perspective, Clin Pharmacol Ther, 97(3):247-262.

216

  1. 217  Rostami-Hodjegan, A, 2012, Physiologically Based Pharmacokinetics Joined With In Vitro-In

  2. 218  Vivo Extrapolation of ADME: A Marriage Under the Arch of Systems Pharmacology, Clin

  3. 219  Pharmacol Ther, 92(1):50-61.

220

  1. 221  Rowland, M, C Peck and G Tucker, 2011, Physiologically Based Pharmacokinetics in Drug

  2. 222  Development and Regulatory Science, Annu Rev Pharmacol Toxicol, 51:45-73.

223

  1. 224  Shepard, T, G Scott, S Cole, A Nordmark, and F Bouzom, 2015, Physiologically Based Models

  2. 225  in Regulatory Submissions: Output From the ABPI/MHRA Forum on Physiologically Based

  3. 226  Modeling and Simulation, CPT Pharmacometrics Syst Pharmacol, 4(4):221-225.

227

  1. 228  Vieira, MD, MJ Kim, S Apparaju, V Sinha, I Zineh, SM Huang, and P Zhao, 2014, PBPK Model

  2. 229  Describes the Effects of Comedication and Genetic Polymorphism on Systemic Exposure of

  3. 230  Drugs That Undergo Multiple Clearance Pathways, Clin Pharmacol Ther, 95(5):550-557.

231

  1. 232  Wagner, C, Y Pan, V Hsu, JA Grillo, L Zhang, KS Reynolds, V Sinha, and P Zhao, 2015,

  2. 233  Predicting the Effect of Cytochrome P450 Inhibitors on Substrate Drugs: Analysis of

  3. 234  Physiologically Based Pharmacokinetic Modeling Submissions to the US Food and Drug

  4. 235  Administration, Clin Pharmacokinet, 54(1):117-127.

236

  1. 237  Wagner, C, Y Pan, V Hsu, V Sinha, and P Zhao, 2016, Predicting the Effect of CYP3A Inducers

  2. 238  on the Pharmacokinetics of Substrate Drugs Using Physiologically Based Pharmacokinetic

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  1. 239  (PBPK) Modeling: An Analysis of PBPK Submissions to the US FDA, Clin Pharmacokinet,

  2. 240  55(4):475-483.

241

  1. 242  Wagner, C, P Zhao, Y Pan, V Hsu, J Grillo, SM Huang, and V Sinha, 2015, Application of

  2. 243  Physiologically Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection: Report of

  3. 244  an FDA Public Workshop on PBPK, CPT Pharmacometrics Syst Pharmacol, 4(4):226-230.

245

  1. 246  Zhao, P, M Rowland, and SM Huang, 2012, Best Practice in the Use of Physiologically Based

  2. 247  Pharmacokinetic Modeling and Simulation to Address Clinical Pharmacology Regulatory

  3. 248  Questions, Clin Pharmacol Ther, 92(1):17-20.

249

  1. 250  Zhao, P, L Zhang, JA Grillo, Q Liu, JM Bullock, YJ Moon, P Song, SS Brar, R Madabushi, TC

  2. 251  Wu, BP Booth, NA Rahman, KS Reynolds, E Gil Berglund, LJ Lesko, and SM Huang, 2011,

  3. 252  Applications of Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation

  4. 253  During Regulatory Review, Clin Pharmacol Ther, 89(2):259-267.

254

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Submission of Quality Metrics Data

Submission of Quality

Metrics Data Guidance for Industry

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 http://www.regulations.gov. Submit written 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 (CDER) Tara Gooen Bizjak at 301-796-3257 or (CBER) Office of Communication, Outreach and Development at 1-800-835-4709 or 240- 402-8010.

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2016

Pharmaceutical Quality/CMC
Current Good Manufacturing Practices (CGMPs)

Revision 1

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1063761 RevDft

Submission of Quality

Metrics Data Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research

Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993
Phone: 800-835-4709 or 240-402-8010
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2016

Pharmaceutical Quality/CMC
Current Good Manufacturing Practices (CGMPs)

Revision 1

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I. II.

A.

B. III.

A. B. C. D.

E. IV.

A. B.

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1

BACKGROUND ............................................................................................................... 2

Modernization of Regulatory Oversight of Drug Quality and Promotion of
Post-Approval Improvements....................................................................................................... 2 Quality Metrics Data – Regulatory Foundation.......................................................................... 3

REPORTING OF QUALITY DATA AND CALCULATION OF QUALITY METRICS.......................................................................................................................... 5

Who Reports and Who May Contribute to a Report ................................................................. 5 Quality Metrics that FDA Intends to Calculate .......................................................................... 7 Quality Metrics Data that May Be Reported .............................................................................. 7 How to Submit Comments Within a Quality Metric Data Report and How to

Pose Questions to FDA ................................................................................................................ 11 How to Report Quality Metrics Data to FDA............................................................................ 11

THE USE OF QUALITY METRICS AND PUBLIC REPORTING ........................ 12

How FDA Intends to Use Quality Metrics ................................................................................. 12 Quality Metric Reporters List .................................................................................................... 13

GLOSSARY................................................................................................................................. 16

APPENDIX A: APPLICABLE IDENTIFYING INFORMATION AND QUALITY METRIC DATA ELEMENTS FOR PRODUCT REPORTS AND SITE REPORTS......... 17

APPENDIX B: EXAMPLES..................................................................................................... 26

Draft – Not for Implementation Contains Nonbinding Recommendations

1 Submission of Quality Metrics Data 23 Guidance for Industry1

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This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not create any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

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4 5 6 7 8 9

10

11
12
13
14
I. INTRODUCTION 15

2

  1. 16  Quality metrics are used throughout the drugs and biologics

  2. 17  systems and processes and drive continuous improvement efforts in drug manufacturing. These

  3. 18  metrics can also be useful to FDA: to help develop compliance and inspection policies and

  4. 19  practices, such as risk-based inspection scheduling of drug manufacturers; to improve the

  5. 20  Agency’s ability to predict, and therefore, possibly mitigate, future drug shortages; and to

  6. 21  encourage the pharmaceutical industry to implement state-of-the-art, innovative quality

  7. 22  management systems for pharmaceutical manufacturing. This revised draft guidance includes an

  8. 23  explanation of how the Center for Drug Evaluation and Research (CDER) and the Center for

  9. 24  Biologics Evaluation and Research (CBER) intend to utilize submitted data and quality metrics

  10. 25  to help ensure that their policies and practices continue to support continuous improvement and

  11. 26  innovation in the pharmaceutical manufacturing industry.

27

  1. 28  In order to achieve these goals, FDA is initiating a quality metrics reporting program.

  2. 29  described in this guidance, FDA is initiating a voluntary reporting phase of the FDA quality

  3. 30  metrics reporting program.4 In the voluntary reporting phase of the program, FDA expects to

  4. 31  learn more about a limited set of quality metrics, associated analytics, and improve the FDA

  5. 32  quality metrics reporting program.

33

  1. 34  During the voluntary phase of the reporting program, FDA will accept voluntarily submissions of

  2. 35  data from owners and operators of human drug establishments. FDA expects that the large

industry to monitor quality control

3

As

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1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
2 This guidance uses the terms “drugs” to refer to both drugs and biologics.
3 FDA issued a draft guidance regarding the collection of quality metrics on July 28, 2015. In response to comments received in the public docket (FDA-2015-D-2537), FDA is replacing the draft guidance published in 2015 with this revised draft.

4 More details about the timing of the program are in the notice announcing the availability of this draft guidance in the Federal Register.

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Draft – Not for Implementation Contains Nonbinding Recommendations

  1. 36  majority of voluntary reports will be submitted by establishments engaged in the manufacture,

  2. 37  preparation, propagation, compounding, or processing of finished dosage forms (FDF) of

  3. 38  “covered drug products” or active pharmaceutical ingredients (API) used in the manufacture of

  4. 39  “covered drug products.”5

40

  1. 41  The voluntary reporting phase of the program described in this guidance is not focused on

  2. 42  reporting from certain CDER regulated manufacturers (i.e., compounders operating under

  3. 43  section 503A or registered as outsourcing facilities under section 503B of the Federal Food,

  4. 44  Drug, and Cosmetic Act (FD&C Act) or CBER regulated manufacturers of blood and blood

  5. 45  components for transfusion, vaccines, in vitro diagnostics,6 cell therapy products, gene therapy

  6. 46  products, allergenic extracts, human cells, tissues, and cellular and tissue based products).7

47

  1. 48  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 49  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 50  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 51  the word should in Agency guidances means that something is suggested or recommended, but

  5. 52  not required. Also, in this guidance, the use of the word should is used to indicate an FDA

  6. 53  preference to promote consistent reporting and counting of quality metrics data.8

54
55
56
II. BACKGROUND
57
58
A. Modernization of Regulatory Oversight of Drug Quality and Promotion of

Post-Approval Improvements

59 60

  1. 61  FDA’s approach to quality oversight has evolved in recent years. CDER and CBER are

  2. 62  committed to supporting the modernization of pharmaceutical manufacturing as part of the

  3. 63  Agency’s mission to protect and promote public health. This effort is also part of a long-term

  4. 64  strategy to mitigate drug shortages by addressing the underlying causes of shortages, as noted in

  5. 65 FDA’s Strategic Plan for Preventing and Mitigating Drug Shortages.9 In 2002, FDA launched

  6. 66  an initiative entitled “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach,” to

  7. 67  encourage the implementation of a modern, risk-based pharmaceutical quality assessment

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5 The terms “covered drug product” and “covered establishment” are defined in section III.A.
6 This guidance is not applicable to biological products that meet the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)).
7 The guidance does apply to licensed biological products that are plasma derived products, including recombinant and transgenic versions of plasma derivatives.
8 FDA intends to accept voluntary reports with quality metrics data that are inconsistent with the metrics and definitions in this guidance, as well as reports about establishments and products that are not the focus of the voluntary reporting phase of the quality metrics program as described in this guidance. However, as the data submitted in a manner inconsistent with the definitions and recommendations in this guidance may not be comparable with submissions from other reporters, we: (1) do not intend to include these reporters on the quality metrics reporters list, and (2) may not be able to integrate the submission of the report into FDA’s risk-based inspection model. Submissions will be evaluated on a case-by-case basis.
9 See FDA’s Strategic Plan for Preventing and Mitigating Drug Shortages at: http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf.

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  1. 68  system.10 The initiative was published with several goals, including ensuring that regulatory

  2. 69  review, compliance, and inspection policies support continuous improvement and innovation in

  3. 70  the pharmaceutical manufacturing industry. Since publication of the Pharmaceutical cGMPs for

  4. 71  the 21st Century, CDER has promoted a vision of “a maximally efficient, agile, flexible

  5. 72  manufacturing sector that reliably produces high-quality drug products without extensive

  6. 73  regulatory oversight.”11

74

  1. 75  FDA encourages manufacturers to routinely use additional quality metrics beyond the metrics

  2. 76  described in this guidance in performing product and establishment specific evaluations.12 The

  3. 77  selected metrics are not intended to be an all-inclusive set of the quality metrics that

  4. 78  manufacturers may find useful to assess a product and manufacturer’s state of quality.

79
80
B. Quality Metrics Data – Regulatory Foundation 81

  1. 82  FDA understands that establishments involved in the manufacture, preparation, propagation, or

  2. 83  processing of human drugs, including oversight to ensure quality,13 currently use quality metrics

  3. 84  as part of the process validation lifecycle and pharmaceutical quality system (PQS) assessment.14

  4. 85  The metrics described in this guidance could be a part of such oversight.

86

  1. 87  As described in FDA’s process validation guidance, manufacturers depend on information and

  2. 88  knowledge from product and process development as the basis for establishing an approach to

  3. 89  control of the manufacturing process (i.e., a control strategy) that results in products with the

    10 See Pharmaceutical cGMP’s for the 21st Century: A Risk-Based Approach at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodMan ufacturingPracticescGMPforDrugs/ucm137175.htm.
    11 See FDA Pharmaceutical Quality Oversight: One Quality Voice at http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM4426 66.pdf.

    12 One type of evaluation is an internal, independent audit and review of processes and procedures to determine whether established protocols and procedures have been followed. FDA’s Compliance Policy Guide Sec. 130.300, FDA Access to Results of Quality Assurance Program Audits and Inspections (June 2, 2007) describes our policy that during routine inspections and investigations, FDA will not review or copy these specific reports and records to encourage firms to conduct candid and meaningful audits and inspections. The voluntary submission of quality metrics data described in this guidance will be for specific data that are maintained on-site, routinely reviewed during inspections, and not subject to a request for the results of an internal audit. http://www.fda.gov/iceci/compliancemanuals/compliancepolicyguidancemanual/ucm073841.htm.

    13 Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) section 711 added text to section 501 of the FD&C Act clarifying that, for the purposes of paragraph 501(a)(2)(B), the term “current good manufacturing practice” includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.

    14 Refer to FDA guidance for industry Process Validation: General Principles and Practices (Rev 1). We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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Draft – Not for Implementation Contains Nonbinding Recommendations

  1. 90  desired quality attributes.15 Once a control strategy has been successfully implemented,

  2. 91  manufacturers are expected to maintain the process in a state of control over the life of the

  3. 92  process, even as materials, equipment, production environment, personnel, and manufacturing

  4. 93  procedures change.16 Current good manufacturing practice (CGMP) for human drugs require

  5. 94  manufacturers to have an ongoing program to maintain and evaluate product and process data

  6. 95  that relate to product quality.17 Best practice for this ongoing assessment is continued process

  7. 96  verification,18 which should include a Periodic Product Review (PPR), conducted at least

  8. 97  annually, in which data collected includes relevant process trends and quality of incoming

  9. 98  materials or components, in-process materials, and finished products. Some establishments may

  10. 99  call this evaluation an Annual Product Review (if conducted annually) or a Product Quality

  11. 100  Review,19 for finished drug products or APIs, respectively. We expect that most of the quality

  12. 101  metrics data described in this guidance will be collected by establishments already as part of

  13. 102  conducting the PPR.

103

  1. 104  Under Title VII section 706 of the Food and Drug Administration Safety and Innovation Act

  2. 105  (FDASIA) Public Law No. 112-144, FDA may require the submission of any records or other

  3. 106  information that FDA may inspect under section 704 of the FD&C Act, in advance or in lieu of

  4. 107  an inspection by requesting the records or information from a person that owns or operates an

  5. 108  establishment that is engaged in the manufacture, preparation, propagation, compounding, or

  6. 109  processing of a drug. The quality metrics data described in this guidance is information of the

  7. 110  type that FDA may inspect under section 704 of the FD&C Act. However, FDA does not intend

  8. 111  to require the submission of information pursuant to section 704(a)(4) of the FD&C Act in

  9. 112  implementing the voluntary phase of the quality metrics reporting program. FDA does not

  10. 113  intend to take enforcement action based on errors in a quality metrics data submission made as a

  11. 114  part of this voluntary phase of the reporting program, provided the submission is made in good

  12. 115  faith.

116

  1. 117  Section 510(h)(3) of the FD&C Act requires a risk-based inspection schedule for drug

  2. 118  establishments according to the known safety risks posed by establishments that are required to

  3. 119  register. These risks are based on certain factors described in section 510(h)(4)(A-F), including

  4. 120  the inherent risk of the drug manufactured, prepared, propagated, compounded, or processed at

  5. 121  the establishment and other factors. FDA intends to analyze the calculated quality metrics to

  6. 122  support its understanding of the safety risks of manufacturing establishments and products, and

  7. 123  as the basis for criteria it deems necessary and appropriate for allocating inspection resources.

    15 Refer to FDA guidance for industry Process Validation: General Principles and Practices (Rev 1) for a description of other sections of 21 CFR part 211 that set forth requirements related to aspects of process validation. 16 FDASIA section 711 added text to section 501 of the FD&C Act clarifying that, for the purposes of paragraph 501(a)(2)(B), the term “current good manufacturing practice” includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.
    17 See 21 CFR 211.180(e) and section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)).
    18 Refer to FDA guidance for industry Process Validation: General Principles and Practices (Rev 1).
    19 The Product Quality Review of APIs is comparable to the Annual Product Review conducted for finished drug products under 21 CFR 211.180(e). Refer to FDA guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.

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Draft – Not for Implementation Contains Nonbinding Recommendations

REPORTING OF QUALITY DATA AND CALCULATION OF QUALITY METRICS

A. Who Reports and Who May Contribute to a Report

1. Covered Establishments and Covered Drug Products

Except as noted below, owners and operators of each establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a covered drug product, or an API used in the manufacture of a covered drug product, may submit quality metrics data. For purposes of this guidance, we will refer to the types of establishments whose owners or operators directly or indirectly submit reports as “covered establishments.”

For purposes of reporting a covered drug product or an API used in the manufacture of a covered drug product, a covered drug product is:

o subject to an approved application under section 505 of the FD&C Act or under section 351 of the Public Health Service Act (PHS) Act,

o marketed pursuant to an OTC monograph, or

o a marketed unapproved finished drug product.

Covered establishments also include (but are not limited to) contract laboratories, contract sterilizers, contract packagers,20 and other establishments, as appropriate, engaged in the manufacture, preparation, propagation, compounding, or processing of a covered drug product or API used in a covered drug product.

2. Who Reports for Covered Establishments

This guidance describes two types of quality metric data reports: (1) product reports submitted by product reporting establishments,21 and (2) site reports submitted by site reporting establishments. We encourage reports from product reporting establishments and site reporting establishments. FDA prefers for all covered establishments to work with a product reporting establishment and report data for the covered drug product so that the product reporting establishment submits a single product report that includes data from all covered establishments.

20 Contract re-packagers that purchase product and repackage it into a different primary packaging configuration are included (e.g., large bottles of tablets repackaged into unit dose blister packs). Contract re-packagers that purchase product and repackage into secondary or tertiary packaging are not included.
21 A “product reporting establishment” is one establishment who will already possess or have access to all of the quality metrics data needed to submit such reports. It is further defined in section III.A.2.a.

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  1. 162  Compilation of data into a single product report will facilitate data analysis and identification of

  2. 163  product specific issues (e.g., potential loss in drug supply).

164
165 a. Submission of a product report by a product reporting establishment

166

  1. 167  The subject of a product report will generally be a covered drug product or an API used in the

  2. 168  manufacture of a covered drug product. The report may include quality metrics data from each

  3. 169  covered establishment within the manufacturing supply chain that has the data described in this

  4. 170  guidance. FDA believes that, as part of its responsibility for oversight and controls over the

  5. 171  manufacture of drugs to ensure quality, one establishment will already possess or have access to

  6. 172  all of the quality metrics data needed to submit such reports — for example, through contract or

  7. 173  because all of the covered establishments with quality metrics data related to a covered drug

  8. 174  product or API used in the manufacture of a covered drug product will be under common

  9. 175  ownership or control.22 This establishment should combine the data so that a single report is

  10. 176  submitted. For example, a single API may be the subject of a stand-alone product report, as

  11. 177  APIs are often supplied to multiple customers and finished drug product manufacturers often use

  12. 178  multiple API suppliers.

179

  1. 180  In this guidance, we refer to the covered establishments that submit product reports to FDA as

  2. 181  “product reporting establishments.” If a product reporting establishment is gathering data from

  3. 182  covered establishments in the manufacturing supply chain for a particular product for the

  4. 183  purpose of submitting a product report, but data is not available for a covered establishment,

  5. 184  FDA prefers that the product report clearly identifies the covered establishment and that specific

  6. 185  data was not received.23

186

  1. 187  FDA believes that the quality control unit (QCU)

  2. 188  drug product or API used in a covered drug product will generally be best positioned to compile

  3. 189  reports for submission to FDA, considering the QCU responsibilities and authorities for the

  4. 190  oversight of drugs as described in 21 CFR 211.22.25

191
192 b. Submission of a site report by a site reporting establishment 193

  1. 194  If the covered establishment prefers to report directly or is unsure if all products and data will be

  2. 195  reported via a product report, the covered establishment may elect to submit a site report. In this

  3. 196  guidance, we refer to the covered establishments that submit site reports to FDA as “site

  4. 197  reporting establishments.”

198

22 See, e.g., FDASIA section 711; 21 CFR 200.10(b).
23 Refer to Appendix A.1, A.2, A.3, and A.4.
24 For the purpose of this guidance, the term “quality control unit” is synonymous with “quality unit.”
25 For APIs, these responsibilities are described in FDA guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (section 2.2).

24

in each reporting establishment for a covered

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  1. 199  The subject of a site report is a single covered establishment. A complete report would list all

  2. 200  covered products with associated quality metric data specific to each product manufactured at the

  3. 201  subject establishment as described in this guidance.26

202
203
B. Quality Metrics that FDA Intends to Calculate 204

  1. 205  The following set of quality metrics that FDA intends to calculate based on industry reporting

  2. 206  was developed with stakeholder input. FDA used the following selection criteria in developing

  3. 207  the set of data that it is inviting covered establishments to submit: (1) objective data to provide

  4. 208  consistency in reporting, (2) of the type contained in records subject to inspection under section

  5. 209  704 of the FD&C Act, and (3) a valuable component in assessing the overall effectiveness of a

  6. 210  PQS, within reasonable limits, and in a reasonable manner, while avoiding an undue reporting

  7. 211  burden. FDA believes that these quality metrics data, in conjunction with other data accessible

  8. 212  to FDA, provide important information about operational reliability.

213

  1. 214  Using reported data described in the following section, FDA intends to calculate quality metrics

  2. 215  for each product and covered establishment, where applicable:

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  1. 233  Section IV.B describes the types of metrics FDA intends to calculate and the associated data that

  2. 234  may be submitted to calculate and understand each metric. FDA encourages product reporting 30

  3. 235  establishments to submit product reports, segmented by covered establishment, where possible.

    26 Refer to Appendix A.5, A.6, A.7, and A.8.
    27 This term does not refer to samples and protocols under 21 CFR 610.2.
    28 Reference this guidance’s Glossary for OOS result (e.g., lot release tests and long-term stability tests only). A single result (e.g., one value on a Certificate of Analysis) may result in only one OOS test result.
    29 The metric measures invalidated lot release OOS results and long-term stability OOS results, separately.
    30 FDA anticipates that data relevant to contract laboratories will generally be limited to the number of OOS results, the number of lot release and stability tests conducted, and the number of invalidated OOS.

Lot Acceptance Rate (LAR) as an indicator of manufacturing process performance. LAR = the number of accepted lots in a timeframe divided by the number of lots started by the same covered establishment in the current reporting timeframe.

Product Quality Complaint Rate (PQCR) as an indicator of patient or customer feedback. PQCR = the number of product quality complaints received for the product divided by the total number of dosage units distributed in the current reporting timeframe.

Invalidated Out-of-Specification (OOS) Rate (IOOSR) as an indicator of the operation of a laboratory. IOOSR = the number of OOS test results for lot release27 and long-term stability testing invalidated by the covered establishment due to an aberration of the measurement process divided by the total number of lot release and long-term stability OOS test results in the current reporting timeframe.28,29

C. Quality Metrics Data that May Be Reported

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  1. 236  The quality metrics data described in this draft guidance is developed and maintained in the

  2. 237  course of manufacturing drugs in compliance with CGMP. In general, the information that FDA

  3. 238  will receive is maintained in accordance with 21 CFR 211 subpart J and evaluated under 21 CFR

  4. 239  211.180(e). For non-finished drug products (e.g., APIs), refer to section 501(a)(2)(B) of the

  5. 240  FD&C Act and FDA guidance for industry Q7 Good Manufacturing Practice Guidance for

  6. 241 Active Pharmaceutical Ingredients. Data that is summed and reported as described in this

  7. 242  section is in a readily accessible format for analysis.

243

  1. 244  Reporting of data related to lots of drugs that are imported, intended for import into the United

  2. 245  States, or manufactured in the United States is preferred. However, FDA recognizes that it may

  3. 246  not be possible for some covered establishments to identify started lots, rejected lots, and OOS

  4. 247  results that are specific to drugs that are imported, intended for import, or manufactured in the

  5. 248  United States. Further, lots manufactured outside of the United States may be split after

  6. 249  manufacturing is completed and a portion is imported, or intended for import into the United

  7. 250  States. In these instances, if the manufacturing process uses the same process and controls data

  8. 251  for lots that are not specific to those that are imported, intended for import, or manufactured in

  9. 252  the United States, the report could include both data from lots not imported or intended for

  10. 253  import to the United States with the data from lots imported or intended for import to the United

  11. 254  States for the lot acceptance and invalidated OOS metrics. The selection of drugs that are either:

  12. 255  (1) imported, intended for import, or manufactured in the United States, or (2) all drugs using the

  13. 256  same manufacturing process and controls which are not necessarily imported, intended for

  14. 257  import, or manufactured in the United States, should remain consistent within and across

  15. 258  reporting cycles, unless otherwise specified. Product quality complaint data should be related to

  16. 259  drugs that are imported, intended for import or manufactured in the United States.

260

  1. 261  Reporting of data should include all manufacturing operations, including testing, which would be

  2. 262  included in a PPR (e.g., lots intended for commercial distribution, post-approval clinical trial lots

  3. 263  when the same manufacturing process and controls are used as for commercial lots).

264
265 (1) Lot Acceptance Rate (LAR) Data: 266
267

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The number of saleable lots started which are intended for primary packaging or distribution.

The number of saleable lots released for primary packaging or distribution.
The number of saleable lots started which are intended for primary packaging or

distribution and were rejected.
The number of lots started of in-process and packaging product lots which are intended

for distributed product.

The number of in-process and packaging product lots released which are intended for distributed product.

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281 The number of in-process and packaging product lots which were intended for distributed

product and were rejected.

282
283
284 Specific criteria for the LAR data:
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305 (2) Invalidated OOS Rate Data (IOOSR): 306
307

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320 Specific criteria for the IOOSR data:
321

Examples of saleable lots include bulk tablets, filled vials, bulk milled in-process material if manufacturing is performed at another covered establishment, bulk API, and bulk intermediate API if further manufacturing is performed at another covered establishment.

A lot may be subdivided or grouped after the first started lot is initiated. Each subsequent subdivision or grouping is considered a separate lot.

Examples of packaging product lots include multiple packaging configurations of bulk tablets (e.g., small bottles, large bottles, blisters) and labeling filled sterile vials with multiple labels (e.g., intended for different countries). The packaging operation can be stand-alone lots or included in an existing lot.

In general, FDA anticipates that the number of lots started minus the sum of lots released and lots rejected will equal the total number of lots pending disposition (e.g., work in progress, lots evaluated for batch release, lots pending disposition due to quality-related discrepancies). We recognize that there are rare instances when this construct will not be valid (e.g., lots pending disposition for an extended period) and we encourage the use of the comment text box to explain the occurrence of such an anomaly.

The number of lot release test OOS and long-term stability OOS results for the finished drug product or API where the long-term stability test supports the labeled expiration date.

The total number of lot release and long-term stability tests conducted for the finished drug product or API where the long-term stability test supports the labeled expiration date.

The number of OOS results for lot release tests and long-term stability tests for the finished drug product or API where the source of the OOS result is identified as an aberration of the measurement process and where the stability test supports the labeled expiration date.

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An investigation must be conducted whenever an OOS result is obtained.31 For the purpose of the quality metrics program, the following OOS results should be counted: (1) finished drug product and API and long-term stability test results only, and (2) all finished drug product and API and long-term stability test results that initially indicate OOS, even if the source of the OOS is investigated and determined to be an aberration of the measurement process. See FDA guidance for Industry Investigating Out-of- Specification (OOS) Test Results for Pharmaceutical Production (October 2006), section III, and FDA guidance for industry Sterile Drugs Products Produced by Aseptic Processing – Current Good Manufacturing Practice (September 2004), section XI.

The number of total tests is a measurement tool that: (1) provides context for the invalidated OOS rate, and (2) provides a secondary metric for manufacturing performance and the ability to produce product within limits (lot release and long-term stability OOS results investigated as a manufacturing aberration divided by the total number of lot release and long-term stability tests performed in the same current reporting period).

For the purpose of this program, an OOS result should be counted on the day that the test result is completed or the day that an OOS investigation is initiated.

341
342

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358
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361 (3) Product Quality Complaint Rate (PQCR):
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The number of product quality complaints received for the product.

31 See 21 CFR 211.192 and section 501(a)(2)(B) of the FD&C Act. 10

322 323
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A test includes a single analytical result for lot release or a stability timepoint with an established limit (e.g., analytical chemistry, release sterility test). For example: (1) for lot release, the final content uniformity result as reported on a Certificate of Analysis is considered one test; (2) for a stability timepoint, each test performed in the timepoint would count as an individual test.

A covered establishment that manufactures API used in a covered drug product is not expected to report stability OOS results.

For stability testing, only tests that support real-time stability of the product should be counted (i.e., accelerated stability testing is excluded).

If a lot release or long-term stability test is conducted multiple times for a lot (e.g., a retest), each test should be counted.

FDA recognizes the importance of other types of testing not discussed in this guidance (e.g., in-process testing, environmental testing, raw material and packaging component testing). However, results of these tests should not be counted in this report.

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364
365
The total number of dosage units distributed for the product. 366
367 Specific criteria for the PQCR data:
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  1. 380  Reporting establishments may submit a 300-word text comment to provide an explanation of

  2. 381  submitted data or report plans for improvement. FDA may refer to the comments if unusual data

  3. 382  or trends are identified, or in preparation for an on-site inspection. The submission of comments

  4. 383  is optional. In the future, FDA may consider establishing a set of codes to standardize the

  5. 384  comments.

385

  1. 386  Comments may describe special situations, such as natural disasters, the use of emerging

  2. 387  technology, or describe the manufacturing supply chain or a plan for improvement. For

  3. 388  example, an unexpected decrease in lot acceptance rate may be due to a situation outside the

  4. 389  control of the facility (e.g., an act of nature such as a storm or fire). For emerging technology,

  5. 390  the use of new, in-line analytical technology used for real time release testing with increased

  6. 391  sensitivity might result in better detection of in-process OOS results used for Real Time Release

  7. 392  Testing and thus, a temporary increase in total OOS results. However, improved detection that

  8. 393  allows for the diversion and rejection of poor quality product will provide improved assurance of

  9. 394  quality. In this instance, it may be appropriate to provide an explanation that new, improved

  10. 395  technology was implemented and that there is data demonstrating that more robust product was

  11. 396  released to the market as a result of this change (e.g., increased lot uniformity would be

  12. 397  appropriate).

398

  1. 399  Upon gathering this data, any questions that a covered establishment may have about their

  2. 400  specific situation can be sent to This e-mail address is being protected from spambots. You need JavaScript enabled to view it .

401
402
E. How to Report Quality Metrics Data to FDA 403

  1. 404  To facilitate the quality metrics reporters list as described in section IV.B, a defined reporting

  2. 405  period (e.g., a single calendar year) is needed to reduce discrepancies between site and product

  3. 406  reporting. Therefore, reporting establishments may submit quality metrics data reports where the

The total number of all product quality complaints is based on the definition in the glossary. This number does not include multiple counting of the same product quality complaint if the complaint receiver forwards the complaint to individual manufacturers for further investigation. This number does include all potential quality issues, such as subpotency (e.g., a patient report of lack of effect).

The total number of dosage units distributed for the product is defined in the glossary.

D. How to Submit Comments Within a Quality Metric Data Report and How to Pose Questions to FDA

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  1. 407  data is segmented on a quarterly basis throughout a single calendar year.32 FDA expects to begin

  2. 408  the data analysis when the portal is closed and then publish initial findings and the quality metric

  3. 409  reporters list on the FDA Web site.

410

  1. 411  Appendix A of the draft guidance is a quality component list with the information for submission

  2. 412  into the electronic portal as well as a description of applicable quality metrics data elements

  3. 413  relevant for different business segments/types. The associated Technical Conformance Guide

  4. 414  describes additional technical details.33

415
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IV. 418
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  1. 421  FDA intends to use data from the quality metrics reporting program to focus the use of FDA

  2. 422  resources on the areas of highest risk to public health (e.g., risk-based inspection scheduling).

  3. 423  Specifically, we intend to:

424
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  1. 427

  2. 428

  3. 429

430

  1. 431  Shortages of drugs can pose a significant public health threat; delaying, and in some cases even

  2. 432  denying, critically needed care for patients. Taking action to reduce drug shortages remains a

  3. 433  top priority for FDA. The Agency has found that the majority of drug shortages stem from

  4. 434  quality concerns—substandard manufacturing facilities or processes are discovered, or

  5. 435  significant quality defects are identified in finished drug product, necessitating remediation

  6. 436  efforts to fix the issue, which in turn, may interrupt production and cause a drug shortage. FDA

  7. 437  intends to use quality metrics, along with other measures, to identify potential shortage signals

  8. 438  and engage proactively with manufacturers to mitigate the likelihood of occurrence.

439

  1. 440  FDA may not be able to accomplish the overall goals of an FDA quality metrics reporting

  2. 441  program, as described in this draft guidance, from voluntary reporting alone. If FDA does not

  3. 442  receive a large body of data from reporting establishments, the ways in which the Agency can

  4. 443  use the information may be limited. For example, data received may not constitute a

  5. 444  representative sample of the industry. Further, a self-selection bias may increase the risk of

  6. 445  signaling an outlier where none exists. For these reasons, we expect to use the information

  7. 446  collected to specifically focus on: (1) working with establishments towards early resolution of

    32 More details about the timing of the program are in the notice announcing the availability of this draft guidance in the Federal Register.
    33 See http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM508464.pdf.

THE USE OF QUALITY METRICS AND PUBLIC REPORTING A. How FDA Intends to Use Quality Metrics

establish a signal detection program as one factor in identifying establishments and products that may pose significant risk to consumers;
identify situations in which there may be a risk for drug supply disruption; improve the effectiveness of establishment inspections; and

improve FDA’s evaluation of drug manufacturing and control operations.

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  1. 447  potential quality problems and to reduce the likelihood that the establishment’s operations will

  2. 448  be disrupted and impact the drug supply, (2) helping to prepare for and direct our inspections,

  3. 449  and (3) using the calculated metrics as an element of the post-approval manufacturing change

  4. 450  reporting program with an emphasis on encouraging lifecycle manufacturing improvement.

451

  1. 452  While FDA recognizes the value of quality metrics, we also recognize that the individual data

  2. 453  points and metrics described in this guidance, either individually or in combination, do not

  3. 454  definitively quantitate the quality of the establishment or its products. Further, FDA continues to

  4. 455  encourage the adoption of emerging technology. We request comments on implementing new

  5. 456  technology while maintaining robust quality metrics programs.

457

  1. 458  FDA intends to publish an analysis of the quality metrics data received on the FDA Web site to

  2. 459  share what the Agency has learned from the voluntary phase of the reporting program, and how

  3. 460  analyzing these data has affected the frequency of CGMP inspections and the ability of the

  4. 461  Agency to address potential drug shortage situations. We also intend to provide opportunities for

  5. 462  participating establishments to provide feedback and additional comments, as well as share

  6. 463  knowledge from ongoing, industry-driven quality metrics programs.

464
465
B. Quality Metric Reporters List 466

  1. 467  FDA intends to publish a list of the names of establishments that voluntarily report all or a subset

  2. 468  of quality data as described in this guidance (i.e., product reporting establishments and site

  3. 469  reporting establishments). We believe that there is a benefit to publicly sharing the names of

  4. 470  establishments that voluntarily choose to submit these quality data to FDA because, through their

  5. 471  participation, these establishments demonstrate a willingness to proactively engage with the

  6. 472  Agency in pursuit of the goals described in this guidance. Participation in this voluntary

  7. 473  reporting phase of the program also demonstrates a commitment to increasing transparency

  8. 474  between industry and FDA and a contribution to improving quality monitoring throughout the

  9. 475  industry.

476

  1. 477  This list may be useful to establishments within the pharmaceutical manufacturing industry when

  2. 478  selecting contract manufacturers and component suppliers as one element of robust outsourcer or

  3. 479  supplier selection (e.g., past inspection and regulatory authority history, audits of the facility and

  4. 480  associated systems, and analytical testing). This list may also be useful for healthcare purchasing

  5. 481  organizations, healthcare providers, patients, and consumers in sourcing drugs when used in

  6. 482  conjunction with other information (e.g., inspection history). The list will provide information

  7. 483  about whether an establishment voluntarily submitted quality metrics data to the Agency, and if

  8. 484  so how much data was submitted. It should be noted that inclusion on the list is not an indication

  9. 485  of FDA’s evaluation of the submitted data.

486

  1. 487  The Agency will identify participating establishments on FDA’s Web Site according to the

  2. 488  following recognition categories:

489
490
For Product Reporting Establishments (finished drug product reporter or API reporter): 491

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Product Reporter Top Tier: If complete data supporting all metrics were included for each covered establishment in the manufacturing supply chain for all covered drug products (or APIs used in the manufacture of a covered drug product) for the full year reporting period

Product Reporter Mid Tier: If all covered establishments in the manufacturing supply chain for all covered products were identified in the report, and complete quality metric data was provided from at least one of the establishments for each covered drug products (or APIs used in the manufacture of a covered drug product) for the full year reporting period

34

Product Supply Chain Reporter:
manufacturing supply chain for all covered drug products (or APIs used in the manufacture of a covered drug product) were identified in the report

35

If all covered establishments in the
For Site Reporting Establishments (finished drug product reporter or API reporter):

o o

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  1. 518  For example, if product reporting establishment Company ABC submitted a report identifying all

  2. 519  covered establishments in the manufacturing supply chain for all covered drug products (or APIs

  3. 520  used in the manufacture of a covered drug product), but did not provide quality metrics data,

Site Reporter Top Tier: If complete data supporting all metrics were included for all covered drug products (or APIs used in the manufacture of a covered drug product) for the full year reporting period

Site Reporter Mid Tier: If complete data supporting all metrics were included for at least one covered drug product (or API used in the manufacture of a covered drug product) manufactured at an establishment for the full year reporting period

  1. 521  Company ABC would have a “Product Supply Chain Reporter” designation. If product reporting

  2. 522  establishment Company ABC submitted a report identifying all establishments in the

  3. 523  manufacturing supply chain for all covered drug products (or APIs used in the manufacture of a

  4. 524  covered drug product), and metrics data was provided from the primary manufacturing

  5. 525  establishment for each product or API, but incomplete data was submitted from the other

  6. 526  establishments in the manufacturing supply chain, Company ABC would have a “Product

  7. 527  Reporter Mid Tier” designation. If product reporting establishment Company ABC submitted a

  8. 528  complete report for the data listed above for all covered drug products (or APIs used in the

  9. 529  manufacture of a covered drug product), Company ABC would have a “Product Reporter Top

  10. 530  Tier” designation.

    34 “Product Supply Chain Reporter” is defined for the purpose of FDA’s quality metric reporting program and is not associated with Title II of the Drug Quality and Security Act, the Drug Supply Chain Security Act (DSCSA).
    35 An establishment may be considered a site reporting establishment by either: (1) directly submitting data to FDA (not applicable for product reporting establishments), or (2) indirectly submitting data to FDA via a product report, submitted by a product reporting establishment.

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531

  1. 532  For site reporters, if contract manufacturer Company XYZ manufactures 30 covered drug

  2. 533  products and submitted a report with at least one covered drug product produced at the

  3. 534  establishment and data supporting all metrics, Company XYZ would have a “Site Reporter Mid

  4. 535  Tier” designation. If the report contains data for all 30 products and all metrics for each covered

  5. 536  drug product, Company XYZ would have a “Site Reporter Top Tier” designation. Alternatively,

  6. 537  if Company XYZ submitted data to reporting establishments and the data covers each product

  7. 538  manufactured at the site, and the submitted product reports reference this establishment,

  8. 539  Company XYZ would also have a “Site Reporter Top Tier” designation.

540

  1. 541  FDA does not intend to publicly disclose information submitted to the Agency as part of the

  2. 542  voluntary phase of the quality metrics program that is exempt from disclosure under the Freedom

  3. 543  of Information Act as confidential commercial information, e.g., information that would reveal

  4. 544  nonpublic commercial relationships and production volumes.

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545 GLOSSARY 546

  1. 547 Active Pharmaceutical Ingredient (API)

  2. 548  into a finished drug product and is intended to furnish pharmacological activity or other direct

  3. 549  effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the

  4. 550  structure or any function of the body. Active pharmaceutical ingredient does not include

  5. 551  intermediates used in the synthesis of the substance. The term includes those components that

  6. 552  may undergo chemical change in the manufacture of the drug product and be present in the drug

  7. 553  product in a modified form intended to furnish the specified activity or effect.

554

  1. 555 Batch – a specific quantity of a drug or other material that is intended to have uniform character

  2. 556  and quality, within specified limits, and is produced according to a single manufacturing order

  3. 557  during the same cycle of manufacture.37 A batch may be comprised of one lot or multiple lots.

558

  1. 559 Continued Process Verification – A process validation activity where ongoing assurance is

  2. 560  gained during routine production that the process remains in a state of control.38

561

  1. 562 Critical Quality Attribute (CQA) – A physical, chemical, biological, or microbiological

  2. 563  property or characteristic that should be within an appropriate limit, range, or distribution to

  3. 564  ensure the desired product quality.39

565

  1. 566 Dosage Units – the total number of individual dosage units (e.g., 100,000 tablets, 50,000 vials,

  2. 567  50 kg), distributed or shipped under the approved application or product family (for non-

  3. 568  application products) to customers, including distributors.40

569

  1. 570 Establishment – a place of business under one management at one general physical location.

  2. 571  The term includes, among others, independent laboratories that engage in control activities for a

  3. 572  registered drug establishment (e.g., consulting laboratories).41

573

  1. 574 Finished Dosage Form (FDF) – the physical manifestation of a drug product that contains the

  2. 575  active ingredient(s) and/or inactive ingredients that are intended to be delivered to the patient.

  3. 576  Examples include tablets, capsules, vials, solutions, creams, or ointments.42

577

  1. 578 Finished Drug Product – a finished dosage form (FDF) (e.g., tablet, capsule, or solution) that

  2. 579  contains at least one active pharmaceutical ingredient, generally, but not necessarily, in

  3. 580  association with other ingredients in finished package form suitable for distribution to

    36 Refer to 21 CFR 207.1 (effective November 29, 2016) and 21 CFR 210.3(b)(7).
    37 See 21 CFR 210.3(b)(2).
    38 Refer to FDA guidance for industry Process Validation: General Principles and Practices (Rev 1).
    39 Refer to FDA guidance for industry Q8(R2) Pharmaceutical Development.
    40 See 21 CFR 314.81(b)(2)(ii)(a), 211.196.
    41 See 21 CFR 207.1 (effective November 29, 2016).
    42 Refer to “dose form” as defined in ISO 11616:2012(en), Health informatics – Identification of medicinal products – Data elements and structures for the unique identification and exchange of regulated pharmaceutical product information.

36

– any substance that is intended for incorporation

page19image30016

16

Draft – Not for Implementation Contains Nonbinding Recommendations

  1. 581  pharmacies, hospitals, or other sellers or dispensers of the drug product to patients or

  2. 582  consumers.43

583

  1. 584 Long-term testing – Stability studies under the recommended storage condition for the retest

  2. 585  period or shelf life proposed (or approved) for labeling.44

586

  1. 587 Lot – a batch, or a specific identified portion of a batch, having uniform character and quality

  2. 588  within specified limits; or, in the case of a drug product produced by continuous process, it is a

  3. 589  specific identified amount produced in a unit of time or quantity in a manner that assures its

  4. 590  having uniform character and quality within specified limits.45

591

  1. 592 Accepted Lot – a started lot which has been released for distribution or for the next stage

  2. 593  of processing. If the lot is released with an unexpectedly low yield due to an assignable

  3. 594  root cause and the associated investigation supports the release of the lot, it should be

  4. 595  considered an accepted lot.46 Investigations into low yield results should be thorough and

  5. 596  managed by the quality unit. If a lot number is closed, the lot is transferred to a new lot

  6. 597  number, and subsequently released, only the original lot should be counted. An accepted

  7. 598  lot should be counted on the day of the final disposition decision. It may be possible that

  8. 599  an accepted lot is no longer considered accepted (e.g., a stability failure, a quality

  9. 600  problem identified by a contract packager, or in the marketplace). In this case, the lot

  10. 601  should no longer be counted as an accepted lot. If the change in disposition decision is

  11. 602  after submission of quality data, the reporter may submit an amendment and it would be

  12. 603  helpful if the amendment is available for discussion during a future on-site inspection.

604

  1. 605 Started Lot – a lot intended for commercial use for which the manufacturer has issued a

  2. 606  lot number, physically charged API (for finished drug manufacturers) or primary starting

  3. 607  materials (for API manufacturers), and there will be a disposition decision.47 If the

  4. 608  manufacturing spans multiple time segments (quarters), the started lot should be counted

  5. 609  when the lot number is issued or the API or primary starting material is physically

  6. 610  charged. If unique lot numbers are issued for different packaging configurations, each lot

  7. 611  number should be counted.

612

43 See 21 CFR 207.1 (effective November 29, 2016).
44 See FDA guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products.
45 See 21 CFR 210.3(b)(10).
46 For example: (1) if the power fails halfway through a tableting operation and a portion of the manufactured tablets are acceptable to release for distribution, this is considered an accepted lot, (2) if an API lot is reworked and released under the original lot number, the lot is considered an accepted lot, (3) for continuous manufacturing, if there was an unplanned shut down of the line due to quality reasons, this would be not be considered an accepted lot, (4) if the entire lot is rejected due to an OOS, the lot would not be considered an accepted lot, and (5) if the entire lot is rejected due to a potential contamination, the lot would not be an accepted lot.
47 See 21 CFR 211.101.

page20image31360

17

Draft – Not for Implementation Contains Nonbinding Recommendations

  1. 613 Lot Release Test – includes all tests of conformance to final specifications, including all real

  2. 614  time release tests, and all in-process tests that act as a surrogate for final lot release (e.g., real

  3. 615  time release testing is approved in the application).48,49

616

  1. 617 Out-of-Specification (OOS) Result – all test results that fall outside the specifications or

  2. 618  acceptance criteria established in drug applications, drug master file, official compendia, or by

  3. 619  the manufacturer.50 An investigation must be conducted whenever an OOS result is obtained.51

  4. 620  For the purpose of the quality metrics program, the following test events should be counted: (1)

  5. 621  lot release, including in-process tests that act as a surrogate for a lot release test,52 and long-term

  6. 622  stability test results only and, (2) all lot release and long-term stability test results, even if the

  7. 623  source of the OOS is later determined to be due to a measurement aberration.53

624

  1. 625 Invalidated OOS – any out-of-specification result where the investigation identifies the

  2. 626  source of the OOS result as an aberration of the measurement process. Invalidation of a

  3. 627  discrete test result may be done only upon the observation and documentation of a test

  4. 628  event that can reasonably be determined to have caused the OOS result.54 For the

  5. 629  purpose of the quality metrics program, the following test events should be included: (1)

  6. 630  lot release55 and stability test results only and, (2) all lot release and stability test results

  7. 631  that initially appear as OOS, even if invalidated by a subsequent laboratory investigation.

632

  1. 633 Periodic Product Review – an evaluation, conducted at least annually, of the quality standards

  2. 634  of a drug product to determine the need for changes in drug product specifications or

  3. 635  manufacturing or control procedures.56

636

  1. 637 Product Family – for finished drug products, any combination of National Drug Code (NDC)

  2. 638  product code segments where the API and FDF is the same (i.e., a product family could be

  3. 639  multiple strengths or only a single strength).57 For APIs, the product family is defined by the

  4. 640  NDC product code segment. A product family is defined for the purpose of grouping non-

  5. 641  application drugs for the submission of quality metric data. Grouping is likely consistent with

  6. 642  how products are grouped for the Periodic Product Review (e.g., Annual Product Review).58

    48 See 21 CFR 211.165.
    49 This term does not refer to samples and protocols under 21 CFR 610.2.
    50 See FDA guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production.
    51 See 21 CFR 211.192 and section 501(a)(2)(B) of the FD&C Act.
    52 For example, if a near infrared (NIR) spectroscopy-based method is approved for testing active content of core tablets for release as an alternative to testing active content on finished tablets by traditional high-performance liquid chromatography (HPLC) method, and the NIR result is reported on the Certificate of Analysis, this test should be counted as a single analytical result and OOS result, as appropriate, for the purpose of this guidance.
    53 Each test may also be defined as a single analytical result listed on the Certificate of Analysis.
    54 See 21 CFR 211.160(a) and FDA guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production.
    55 This term does not refer to samples and protocols under 21 CFR 610.2.
    56 See 21 CFR 211.180(e).
    57 See 21 CFR 207.35.
    58 See 21 CFR 211.180(e).

page21image32432

18

Draft – Not for Implementation Contains Nonbinding Recommendations

643

  1. 644 Product Quality Complaint – a complaint involving any possible, including actual, failure of a

  2. 645  drug to meet any of its specifications designed to ensure that any drug conforms to appropriate

  3. 646  standards of identity strength, quality, and purity.59

page22image3728

59 See, e.g., 21 CFR 211.160(b); 211.198.

19

647
648
649
650
651
652
653
654
655
656
657
658
659
660
661
662
663
664
665
666
667
668
669
670
671
672

Contains Nonbinding Recommendations

Draft — Not for Implementation

APPENDIX A: APPLICABLE IDENTIFYING INFORMATION AND QUALITY METRIC DATA ELEMENTS FOR PRODUCT REPORTS AND SITE REPORTS

This appendix provides clarity on which identifying information and quality metric data elements are applicable for submission in the voluntary phase of the quality metrics reporting program. Technical details of quality metric data submissions are provided in the Technical Conformance Guide.60 Data standards are available for certain identifying information elements (e.g., dose forms, business operations).61

Appendix A is separated into eight (8) subparts. Each subpart corresponds to a different combination of report type, establishment type, and product type, as described in this draft guidance. Specifically:

Product Report, segmented by all sites o Application Product

62

Finished Drug Product: Appendix A.1

API: Appendix A.2 o Non-Application Product

Finished Drug Product: Appendix A.3 API: Appendix A.4

Site Report, segmented by products
o Manufacturing with product quality oversight responsibilities only: Appendix A.5 o Manufacturer with testing responsibilities: Appendix A.6
o Manufacturer without testing responsibilities: Appendix A.7
o Manufacturer with testing responsibilities only: Appendix A.8

page23image16552

60 See http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM508464.pdf.
61 See http://www.fda.gov/forindustry/datastandards/structuredproductlabeling/ucm162038.htm.
62 For a product report, when information was not provided by a contract facility, the corresponding data elements should be marked as “not provided.”

page23image18632 page23image18792

17

673 674

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.1: Applicable Inputs for a Product Report Submission, Application Product, Finished Drug Product

page24image6920 page24image7808 page24image14664 page24image16000 page24image17312 page24image18624 page24image20256 page24image21128

Product Reporting Establishment [Manufacturing with oversight responsibilities only]

X

X

N/A

X

X

page24image29920

X

X

page24image31552

N/A

page24image32632 page24image32952

X

page24image34176

X

X

page24image35800

N/A

page24image36976 page24image37136

X

page24image38624

X

N/A

N/A

page24image41320

N/A

page24image42816

N/A

N/A

page24image45040

N/A

X

page24image47264

X

page24image48488

N/A

N/A

N/A

page24image55184 page24image55984 page24image56736 page24image57640 page24image67408 page24image67888 page24image69584 page24image70488 page24image71664 page24image72568 page24image73744 page24image74648 page24image76304 page24image76888 page24image77616 page24image78096

Contract Manufacturer performing release or stability testing

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page24image100360 page24image101712 page24image102192 page24image103264 page24image104592 page24image113936 page24image116112 page24image118192 page24image120272 page24image122832 page24image124144

Contract Manufacturer not performing release or stability testing (FDF, packaging, sterilizing, etc.)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page24image148752 page24image149552 page24image150304 page24image151208 page24image160976 page24image161456 page24image163152 page24image164056 page24image165232 page24image166136 page24image167312 page24image168216 page24image169872 page24image170456 page24image171184 page24image171664

Contract Laboratory performing release or stability testing only

N/A

N/A

page24image176832

N/A

N/A

page24image178720

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

page24image190752

N/A

N/A

N/A

page24image193800

N/A

N/A

page24image196120

N/A

N/A

page24image198440

N/A

X

page24image201184

X

page24image202352

X

675

X = Input is applicable to report; N/A = Input is not applicable to report

18

Product Name

Rx/OTC

OTC Monograph

Product Type

Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter

Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN

Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

676 677

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.2: Applicable Inputs for a Product Report Submission, Application Product, API

page25image6504 page25image9528 page25image14072 page25image15408 page25image19640 page25image20856

Product Reporting Establishment [Manufacturing with oversight responsibilities only]

X

N/A

N/A

X

X

page25image29488

X

X

N/A

page25image32352 page25image32776

X

page25image33832

X

X

page25image35720

N/A

page25image36904 page25image37224

X

X

page25image39512

N/A

N/A

page25image41576

N/A

page25image42800

N/A

N/A

page25image44448 page25image44768

N/A

X

page25image46576 page25image46896

X

N/A

page25image49184

N/A

N/A

page25image54368 page25image55280 page25image59008 page25image59488 page25image66192 page25image66672 page25image68368 page25image69272 page25image74880 page25image75360 page25image76768 page25image77248

Contract Manufacturer performing release or stability testing

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page25image99776 page25image100512 page25image101424 page25image102800 page25image104368 page25image105152 page25image112336 page25image114512 page25image121024 page25image122912

Contract Manufacturer not performing release or stability testing (FDF, packaging, sterilizing, etc.)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page25image147168 page25image148080 page25image151808 page25image152288 page25image158992 page25image159472 page25image161168 page25image162072 page25image167680 page25image168160 page25image169568 page25image170048

Contract Laboratory performing release or stability testing only

N/A

N/A

page25image174776

N/A

N/A

N/A

N/A

page25image179760

N/A

N/A

X

X

N/A

N/A

X

page25image187880

X

N/A

N/A

page25image190928

N/A

N/A

N/A

N/A

N/A

N/A

page25image198320

X

X

page25image200640

X

678

X = Input is applicable to report; N/A = Input is not applicable to report

19

Product Name

Rx/OTC

OTC Monograph

Product Type

Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter

Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN
Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

679 680

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.3: Applicable Inputs for a Product Report Submission, Non-application Product, Finished Drug Product

page26image6584 page26image9608 page26image14152 page26image15488 page26image19720 page26image20936

Product Reporting Establishment [Manufacturing with oversight responsibilities only]

X

X

X

X

N/A

page26image29568

N/A

N/A

X

page26image32432 page26image32856

X

page26image33912

X

X

page26image35800

X

page26image36984 page26image37304

X

X

page26image39592

N/A

N/A

page26image41656

N/A

page26image42880

N/A

N/A

page26image44528 page26image44848

N/A

X

page26image46656 page26image46976

X

N/A

page26image49264

N/A

N/A

page26image54448 page26image55360 page26image59088 page26image59568 page26image66272 page26image66752 page26image68448 page26image69352 page26image74960 page26image75440 page26image76848 page26image77328

Contract Manufacturer performing release or stability testing

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page26image99856 page26image100592 page26image101504 page26image102880 page26image104448 page26image105232 page26image112416 page26image114592 page26image121104 page26image122992

Contract Manufacturer not performing release or stability testing (FDF, packaging, sterilizing, etc.)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page26image147248 page26image148160 page26image151888 page26image152368 page26image159072 page26image159552 page26image161248 page26image162152 page26image167760 page26image168240 page26image169648 page26image170128

Contract Laboratory performing release or stability testing only

N/A

N/A

page26image174856

N/A

N/A

N/A

N/A

page26image179840

N/A

N/A

X

X

N/A

N/A

X

page26image187960

X

N/A

N/A

page26image191008

N/A

N/A

N/A

N/A

N/A

N/A

page26image198400

X

X

page26image200720

X

681

X = Input is applicable to report; N/A = Input is not applicable to report

20

Product Name

Rx/OTC

OTC Monograph

Product Type

Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter

Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN
Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

682 683

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.4: Applicable Inputs for a Product Report Submission, Non-application Product, API

page27image6504 page27image9528 page27image14072 page27image15408 page27image19640 page27image20856

Product Reporting Establishment [Manufacturing with oversight responsibilities only]

X

X

X

X

N/A

page27image29488

N/A

N/A

X

page27image32352 page27image32776

X

page27image33832

X

X

page27image35720

X

page27image36904 page27image37224

X

X

page27image39512

N/A

N/A

page27image41576

N/A

page27image42800

N/A

N/A

page27image44448 page27image44768

N/A

X

page27image46576 page27image46896

X

N/A

page27image49184

N/A

N/A

page27image54368 page27image55280 page27image59008 page27image59488 page27image66192 page27image66672 page27image68368 page27image69272 page27image74880 page27image75360 page27image76768 page27image77248

Contract Manufacturer performing release or stability testing

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page27image99776 page27image100512 page27image101424 page27image102800 page27image104368 page27image105152 page27image112336 page27image114512 page27image121024 page27image122912

Contract Manufacturer not performing release or stability testing (FDF, packaging, sterilizing, etc.)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page27image147168 page27image148080 page27image151808 page27image152288 page27image158992 page27image159472 page27image161168 page27image162072 page27image167680 page27image168160 page27image169568 page27image170048

Contract Laboratory performing release or stability testing only

N/A

N/A

page27image174776

N/A

N/A

N/A

N/A

page27image179760

N/A

N/A

X

X

N/A

N/A

X

page27image187880

X

N/A

N/A

page27image190928

N/A

N/A

N/A

N/A

N/A

N/A

page27image198320

X

X

page27image200640

X

684

X = Input is applicable to report; N/A = Input is not applicable to report

21

Product Name

Rx/OTC

OTC Monograph

Product Type

Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter

Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN
Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

685 686 687

Contains Nonbinding Recommendations

Draft — Not for Implementation

Appendix A.5: Applicable Inputs for a Site Report Submission, Manufacturer with oversight responsibilities only (e.g., application holder)

page28image10968 page28image11392 page28image11992 page28image12864 page28image14016 page28image14616 page28image15600 page28image16640 page28image18128 page28image19448 page28image19608 page28image20752

Finished Drug Product – Application

X

X

N/A

X

X

X

X

N/A

page28image33112 page28image33536

X

page28image34592

X

page28image35920

X

N/A

page28image37984

X

page28image39040

X

N/A

page28image40936

N/A

page28image42432

N/A

N/A

N/A

page28image45288

N/A

X

page28image47520 page28image47680

X

N/A

page28image49736

N/A

N/A

page28image53544 page28image53968 page28image54448 page28image54872 page28image58456 page28image59360 page28image60512 page28image61096 page28image65832 page28image66736 page28image69992 page28image70896 page28image71784 page28image72264 page28image73936 page28image74520 page28image77160 page28image78072 page28image78792 page28image79376

Finished Drug Product – Non- application

X

X

X

X

N/A

N/A

N/A

X

X

X

X

X

X

X

X

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

N/A

page28image108928 page28image109352 page28image109832 page28image110256 page28image110544 page28image111128 page28image111856 page28image112336 page28image113512 page28image114416 page28image114704 page28image115288 page28image116296 page28image116776 page28image117672 page28image118576 page28image120264 page28image120744 page28image122352 page28image122512 page28image123256 page28image123416 page28image124416 page28image125328

API – Application

X

N/A

N/A

X

X

X

X

N/A

X

X

X

N/A

X

X

X

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

N/A

page28image149416 page28image149896 page28image150664 page28image150984 page28image151464 page28image151784 page28image152960 page28image153864
688
689
690
691
692
693
694
695
696

X N/A X X N/A N/A N/A X X X X N/A X X N/A N/A N/A N/A N/A N/A X X X = Input is applicable to report; N/A = Input is not applicable to report

API – Non Application

N/A N/A N/A

page28image182800 page28image191456 page28image191616 page28image191776 page28image191936

22

Product Name Rx/OTC

OTC Monograph Product Type Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter
Dose Form
Active Ingredient Supply Chain/Process Stage

Code FEI/DUN

Started: In- process/Packaging

Started: Saleable

Rejected: In-process/ Packaging

Rejected: Saleable

Released: In- process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

697 698

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.6: Applicable Inputs for a Site Report Submission, Manufacturer that perform testing

page29image5240 page29image5664 page29image8256 page29image9576 page29image18056 page29image20088 page29image21280

Finished Drug Product – Application

X

X

N/A

X

X

X

X

N/A

page29image32328

X

page29image33504 page29image33664

X

page29image34984

X

N/A

page29image36896 page29image37216

X

page29image38440

X

X

page29image40072

X

page29image41144 page29image41568

X

page29image42792

X

X

page29image44416

X

X

page29image46752 page29image46912

X

X

page29image49400

X

X

page29image52680 page29image53104 page29image53584 page29image54008 page29image57304 page29image57784 page29image59456 page29image60040 page29image72880 page29image73464 page29image76120 page29image77024 page29image77912 page29image78392

Finished Drug Product– Non- application

X

X

X

X

N/A

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

page29image99512 page29image99936 page29image101784 page29image103352 page29image103672 page29image104136 page29image105840 page29image106288 page29image119712 page29image122952 page29image124744

API – Application

X

N/A

N/A

X

X

X

X

N/A

X

X

X

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page29image147744 page29image148224 page29image148992 page29image149312 page29image149792 page29image150112 page29image151800 page29image152280

API – Non Application

page29image173504 page29image174096

X

N/A

X

X

page29image178576

N/A

N/A

N/A

page29image181616

X

X

X

X

N/A

X

X

X

X

X

X

X

X

page29image196696

X

X

X

page29image200184

X

page29image201776

X

699
700
701
702
703
704

X = Input is applicable to report; N/A = Input is not applicable to report

23

Product Name Rx/OTC

OTC Monograph Product Type Applicant Name

Application Type Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter
Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN

Started: In-process/Packaging

Started: Saleable Rejected: In-process/Packaging Rejected: Saleable

Released: In-process/Packaging Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

705 706

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.7: Applicable Inputs for a Site Report Submission, Manufacturer that does not perform testing

page30image5320 page30image5744 page30image8456 page30image13000 page30image13424 page30image14192 page30image14904 page30image16048 page30image17872 page30image18760 page30image19184 page30image20400 page30image21168

Finished Drug Product– Application

X

X

N/A

X

X

X

page30image30552

X

N/A

page30image32192 page30image32616

X

page30image33672

X

page30image35000

X

N/A

X

X

X

X

page30image41088

X

page30image42736

X

X

page30image44384

X

X

X

N/A

page30image48736

N/A

N/A

page30image52336 page30image52760 page30image53240 page30image53664 page30image57248 page30image58152 page30image64432 page30image64856 page30image65336 page30image65760 page30image66224 page30image66704 page30image67432 page30image68016 page30image69016 page30image69920 page30image71952 page30image72752 page30image73504 page30image73928 page30image74408 page30image74832 page30image75920 page30image76720 page30image77184 page30image77664

Finished Drug Product– Non- application

X

X

X

X

N/A

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page30image98784 page30image99208 page30image103696 page30image105968 page30image107624 page30image108048 page30image108920 page30image110128 page30image110880 page30image111304 page30image112672 page30image113880 page30image115464 page30image115944 page30image117312 page30image118400 page30image118880 page30image119952 page30image120376 page30image122368 page30image122848 page30image123632

API – Application

X

N/A

N/A

X

X

X

X

N/A

X

X

X

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page30image146632 page30image147112 page30image147880 page30image148200 page30image148680 page30image149000 page30image150176 page30image151080

API – Non Application

page30image172008 page30image172600

X

N/A

X

X

N/A

page30image177808

N/A

N/A

X

X

X

X

N/A

page30image185928 page30image186520

X

page30image187520

X

X

page30image189400

X

page30image191160

X

X

X

page30image194480

X

X

page30image196368 page30image196960

X

N/A

page30image199120

N/A

page30image200280

N/A

707
708
709
710
711
712
713
714

X = Input is applicable to report; N/A = Input is not applicable to report

24

Product Name Rx/OTC

OTC Monograph Product Type Applicant Name

Application Type Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter
Dose Form

Active Ingredient
Supply Chain/Process Stage Code FEI/DUN

Started: In-process/Packaging

Started: Saleable Rejected: In-process/Packaging Rejected: Saleable

Released: In-process/Packaging Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

715 716

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.8: Applicable Inputs for a Site Report Submission, Manufacturer with Testing Only

`

page31image5696 page31image6120 page31image8832 page31image10128 page31image13472 page31image13896 page31image15272 page31image16424 page31image17192 page31image18512 page31image20544 page31image20968 page31image21736

Finished Drug Products– Application

X

X

N/A

X

X

X

X

N/A

page31image32856 page31image33280

X

page31image34336

X

page31image35664

X

N/A

X

page31image38952

X

N/A

N/A

page31image41656

N/A

N/A

N/A

page31image44936

N/A

N/A

page31image47168 page31image47592

N/A

X

X

X

page31image61224 page31image61648 page31image62128 page31image62552 page31image62840 page31image63424 page31image64152 page31image64632 page31image67176 page31image67656 page31image69352 page31image70256 page31image72368 page31image72848 page31image74456 page31image74880 page31image75360 page31image75784

Finished Drug Product – Non- application

X

X

X

X

N/A

N/A

N/A

X

X

X

X

X

X

X

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

X

page31image100872 page31image101296 page31image101760 page31image103008 page31image103328 page31image105304 page31image105784 page31image107520 page31image113160 page31image113584 page31image115472 page31image117552 page31image118496 page31image120752 page31image124312 page31image124736 page31image125680

API – Application

X

N/A

N/A

X

X

X

X

N/A

X

X

X

N/A

X

X

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

X

page31image146408 page31image146832 page31image147312 page31image147736 page31image151320 page31image152224 page31image153376 page31image153960 page31image158696 page31image159120 page31image159600 page31image160024 page31image161432 page31image161912 page31image163088 page31image163992 page31image164456 page31image164936 page31image166608 page31image167192 page31image169848 page31image170272 page31image170752 page31image171176 page31image171640 page31image172120

API – Non Application

page31image173960 page31image174552

X

N/A

X

X

N/A

page31image179760

N/A

N/A

page31image182072

X

X

X

X

N/A

page31image187880 page31image188472

X

X

page31image190632

N/A

N/A

page31image193112

N/A

page31image194112

N/A

N/A

N/A

page31image197152

N/A

N/A

X

page31image200640 page31image201232

X

page31image202232

X

717

X = Input is applicable to report; N/A = Input is not applicable to report

25

Product Name Rx/OTC

OTC Monograph Product Type Applicant Name

Application Type Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter
Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN
Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

718 APPENDIX B: EXAMPLES

719
720 (1)

721 722 723

724

725 726 727

728

729 730

731

732

733

734
735
736
737
738
739
740
741
742
743
744
745
746
747
748

749 750 751

Lot Acceptance Rate

a.

An establishment manufactures a product where six small in-process lots are combined into a single unit operation to make one saleable lot (e.g., tablet, liquid, filled vial). Two saleable lots are then combined into one packaging lot.

Assuming all lots that are started are released:

In-process and packaging lots started and released: 13 [six lots from the first saleable lot, six lots from the second saleable lot, and the single packaging lot]

Saleable lots started and released: 2
An establishment manufactures one saleable lot that is separated into five

packaged lots.
Assuming all lots that are started are released:

In-process and packaging lots started and released: 5

Saleable lots started and released: 1

For an OTC monograph product, one batch of saleable product is packaged into an unlabeled primary pack and the primary pack is subsequently labeled and placed into secondary packaging at three different packagers. In this scenario, all four of these facilities are considered covered establishments (one for the bulk manufacturing and three for primary labeling). For the manufacturer of the unlabeled primary pack OTC product, the unlabeled primary pack lots are saleable lots. The lots which are distributed by each packaging establishment are also saleable lots.

Facility A manufactures the product and Facility B packages the product. Facility B discovers a defect that leads to the rejection of the lot; the defect was due to the manufacturing at Facility A. In this situation, Facility A should not count this product lot as a released lot, despite the initial release. For Facility B, if the defect was discovered upon incoming acceptance testing and the packaging lot was not yet started, the lot should not be counted. If a packaging lot was started, it should be counted as a lot started, not as a released lot.

For a non-functional or functional film-coated tablet where the coating process consists of multiple separate coating pan loads, the count of lots depends on whether the separate pan loads are considered unique lots or if the loads are part

b.

c.

d.

e.

Contains Nonbinding Recommendations

Draft — Not for Implementation

26

752 753 754

755
756
757
758

759 (2)

760
761
762
763
764
765
766
767
768
769
770
771
772
773
774
775
776
777
778 (3)

779
780
781
782
783
784
785
786
787
788

789 790

f.

Contains Nonbinding Recommendations

Draft — Not for Implementation

of a single started lot. For either functional or non-functional coatings, samples collected and testing for finished drug product release should be representative of the lot.

Facility A initiates manufacturing of Product Z in the last quarter of the reporting cycle or ceases manufacturing of Product Y in the first quarter of the reporting cycle An explanation of the partial year can be described in the comment field. The product report or site report would be considered complete for that product.

Product Quality Complaint Rate

a. b.

c.

If a lot is distributed to five customers and all customers report the same complaint, this should be counted as five complaints.

If a lot is distributed and a single customer submits the same complaint from different departments, only a single complaint should be counted. If submitting a site report, the covered establishment may choose to include this complaint in their data if it is the least burdensome option.

A lot is distributed to three regions and a complaint is received on that lot from a region outside of the United States. In this instance, the complaint does not need to be reported as part of the quality metrics program. The covered establishment may choose to include this complaint if it could be applicable to product imported or intended for import to the United States or its territories.

a.

b. c.

Regarding analytical tests with multiple sample preparations or injections involved in the test to generate the final result, one test is represented by a single analytical result with an established limit. For example, one content uniformity test proceeding to stage two may have 30 invalidated results. Only one OOS result would be counted.

If two samples from one lot are tested with two injections each and there is one result reported on the Certificate of Analysis, this is considered one release test.

If an OOS result occurs during in-process testing for a test that is considered a real time release test, this is considered a release OOS result for the purpose of this guidance.

For a site report by a packager, if a complaint is received and potentially due to the packager’s operations (e.g., discolored tablet or powder), the complaint should be counted by the site reporting establishment.

d.
Invalidated Out of Specification (OOS) Result Rate

27

 

791 d. 792
793

794 e. 795
796
797

798 799 800

801 f. 802
803
804

805
806
807
808
809

Contains Nonbinding Recommendations

Draft — Not for Implementation

If more than one OOS result is observed during finished drug product testing (e.g., the lot fails both assay and uniformity), this is considered multiple release OOS results.

50 kg of an API is packaged into five 10 kg packages and three to five of the five containers are tested; the Certificate of Analysis reports the average. If one or more of the container results is OOS for the same attribute, the establishment should initiate an OOS investigation and count these OOS results as a single OOS result. A single API container with an OOS result should result in an investigation for the lot in its entirety. After the investigation is complete, subsequent retesting should be counted as a new release test.

Company A does not declare an OOS result until the laboratory investigation proves the result is valid.63 If invalid, and the original result is not labeled as an OOS, there will be no record of invalidating an OOS result, thus resulting in a lower Invalidated OOS Rate for Company A. For the purpose of the quality metrics program, a lot release OOS result should be counted prior to the laboratory investigation, in accordance with the term “OOS result” as defined in this guidance. Furthermore, these type of results should be evaluated as part of the PPR to determine the need for changes in drug product specifications or manufacturing or control procedures.64

page34image16480

63 It should be noted that this practice is inconsistent with the recommendations outlined in FDA guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production.
64 Refer to 21 CFR 211.180(e).

28

 

Nonprescription Sunscreen Drug Products — Safety and Effectiveness Data

Nonprescription Sunscreen Drug Products — Safety and Effectiveness Data

Guidance for Industry

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

November 2016 OTC

page1image3648 page1image3808

Nonprescription Sunscreen Drug Products — Safety and Effectiveness Data

Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

page2image5552

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

November 2016 OTC

I. II. III.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 PHARMACEUTICAL QUALITY/MANUFACTURING INFORMATION ............. 3

SAFETY DATA NEEDED TO ESTABLISH THAT AN OTC SUNSCREEN ACTIVE INGREDIENT IS GRASE............................................................................... 4

Clinical Safety Testing...................................................................................................................5

IV. V.

1. Human Dermal Safety Studies ......................................................................................................... 5

a. Human irritation and sensitization studies .................................................................................. 6

b. Human photosafety studies ......................................................................................................... 7

2.Human Absorption Studies/Maximal Usage Trial...........................................................................7

3. Pediatric Considerations ................................................................................................................. 9

B. Nonclinical Safety Testing...........................................................................................................10

1.Carcinogenicity Studies: Dermal and Systemic............................................................................ 10 2.Developmental and Reproductive Toxicity Studies........................................................................ 11 3.Toxicokinetics ................................................................................................................................ 11

C. Postmarketing Safety Data.......................................................................................................... 12 EFFECTIVENESS TESTING....................................................................................... 13 ANTICIPATED FINAL FORMULATION TESTING .............................................. 14

A.

Contains Nonbinding Recommendations

Nonprescription Sunscreen Drug Products — Safety and Effectiveness Data Guidance for Industry1

page4image3816

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

page4image16912

I. INTRODUCTION

This guidance addresses the current thinking of the Food and Drug Administration’s (FDA or Agency) about the safety and effectiveness data needed to determine whether a nonprescription (also referred to as an over-the-counter (OTC)) sunscreen active ingredient,2 or combination of active ingredients, evaluated under the Sunscreen Innovation Act (SIA) (21 U.S.C. Ch. 9, Sub. 5 Part I, enacted November 26, 2014) is generally recognized as safe and effective (GRASE) and not misbranded when used under specified conditions.

FDA is issuing this guidance in partial implementation of the SIA. Among other things, the SIA supplemented FDA’s existing regulation for adding a new active ingredient or other condition to an OTC drug monograph3 with new procedures and review time lines for determining whether or not a nonprescription sunscreen active ingredient is GRASE and not misbranded when used under the conditions specified in a final sunscreen order .4 A critical step in that process is FDA’s review of safety and effectiveness data submitted by the person requesting the GRASE

1 This guidance has been prepared by the Division of Nonprescription Drug Products in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.

2 As defined in the SIA, the term sunscreen active ingredient refers to an active ingredient that is intended for application to the skin of humans for purposes of absorbing, reflecting, or scattering ultraviolet radiation (see section 586(10) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360fff(10)).

3 FDA’s existing regulation sets out the time and extent application procedure by which a new active ingredient or other condition (e.g., dosage form, dosage strength, or route of administration) can be considered for inclusion in the OTC drug monograph system (21 CFR 330.14).
4 See section 586(4) of the FD&C Act (21 U.S.C. 360fff-1) (definition of “GRASE determination”); section 586A of the FD&C Act (21 U.S.C. 360fff-1) (submission of a new request for GRASE determination); section 586B of the FD&C Act (21 U.S.C. 360fff-2) (preliminary filing review, eligibility determination, and request for submission of safety and effectiveness data); and section 586C of the FD&C Act (21 U.S.C. 360fff-3) (GRASE determination and issuance of proposed and final sunscreen orders).

page4image36536

1

Contains Nonbinding Recommendations

determination (sponsor).5 If FDA determines that the active ingredient in question is GRASE and not misbranded for use in nonprescription sunscreens, it will issue a final sunscreen order setting out the conditions that sunscreen products containing the active ingredient must satisfy to be marketed without an approved new drug application (NDA).6 Sunscreen products that satisfy those conditions and other requirements for nonprescription drugs may be marketed immediately upon issuance of the final sunscreen order, for as long as that order remains in effect. Any future rulemaking to amend the OTC sunscreen drug monograph must include the active ingredient found GRASE in the final order.7

The SIA also directed FDA to issue guidance on the data a nonprescription sunscreen active8 ingredient would need to meet the safety and efficacy standard for a GRASE determination.
The recommendations in this guidance will help sponsors identify and obtain the safety and effectiveness data needed to show that a sunscreen active ingredient is GRASE for use in nonprescription sunscreens, as a single active ingredient and/or as part of a combination of active ingredients. Unlike the review of sunscreen
products under the new drug approval process,9 for which premarketing testing focuses on individual product formulations, the GRASE review for active ingredients takes into account that the ingredient, if found GRASE, may be included in a variety of formulations that will be marketed without product-specific review and approval.

The recommendations in this guidance are designed to ensure that FDA’s GRASE determinations for OTC sunscreen active ingredients under the SIA are consistent, up to date, and appropriately reflect current scientific knowledge and patterns of nonprescription sunscreen use by consumers. The recommendations reflect FDA’s scientific expertise, existing technical guidance, experience from reviewing safety and efficacy data submitted for GRASE review of sunscreen active ingredients under current OTC drug regulations, and input from and concurrence by outside scientific experts. This guidance also addresses FDA’s current thinking about an approach to safety-related final formulation testing that it anticipates adopting in the future.

5 See section 586C of the FD&C Act. FDA will also consider other relevant public data submitted by other parties or otherwise available.

6 See section 586C of the FD&C Act generally for detailed procedures.

7 See section 586C(e)(1)(A) of the FD&C Act (effect of final sunscreen order for sunscreen active ingredient(s) found to be GRASE) and section 586C(e)(3) of the FD&C Act (any future amendments of the OTC sunscreen monograph must include any nonprescription sunscreen active ingredient(s) that is or are subject to an effective final sunscreen order that determined it or them to be GRASE and would set forth the conditions of use).

8 See section 586D(a)(1)(B) of the FD&C Act (21 U.S.C. 360fff-4(a)(1)(B)); see also section 586D(a)(1)(A)(ii) of the FD&C Act. The SIA also requires FDA to issue three other guidances on procedural matters relating to nonprescription sunscreen active ingredients: (1) format and content of data submissions (section 586D(a)(1)(A)(i)); (2) process for withdrawing requests for a GRASE determination (section 586D(a)(1)(A)(iii)); and (3) process by which FDA will carry out section 586C(c) of the FD&C Act regarding advisory committee meetings (section 586D(a)(1)(A)(iv)).

9 This process is described in 21 CFR part 314.

page5image27168

2

Contains Nonbinding Recommendations

FDA’s specific recommendations on the data and information needed to support a positive GRASE determination under the SIA are detailed in sections II (pharmaceutical quality/manufacturing information), III (safety data), and IV (effectiveness data). Section V presents FDA’s current thinking on an approach to safety testing of final sunscreen formulations that it anticipates adopting in the future.

Although sunscreen products are typically formulated with two or more active ingredients, the recommendations in sections II through IV generally contemplate that testing will be performed using formulations including one active ingredient FDA anticipates that these data would also generally be sufficient to assess whether, and under what conditions, that active ingredient is GRASE for use as part of a combination of sunscreen active ingredients. In some situations, additional data and testing beyond what is recommended in this guidance may be needed to support a positive GRASE determination and to establish the associated conditions for a particular active ingredient. The following are examples in which additional data may be needed:

  • Data suggest that there may be a safety or efficacy concern with a particular combination of active ingredients or active and inactive ingredients

  • Information indicates that an active ingredient is unstable when exposed to sunlight and suggests that the active ingredient may need to be combined with a photostabilizer to be safe or effective

    Other situations may occur in which additional data are needed (see, e.g., section III for some additional examples). Sponsors are encouraged to discuss with FDA any questions about whether additional data may be needed for a particular active ingredient.

    In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. PHARMACEUTICAL QUALITY/MANUFACTURING INFORMATION

FDA needs information that sufficiently characterizes the identity of each sunscreen active ingredient for FDA reviewers to determine how, if at all, the safety and efficacy studies 10 submitted for review are relevant to the ingredient for which GRASE determination is sought. This information would also be needed to appropriately characterize the active ingredient in the

10 For example, if key studies were conducted using a related but different compound, or using a combination of active ingredients whose individual contributions to the observed results were not examined, those studies may have little relevance to a GRASE determination for the sunscreen active ingredient identified by the requested quality/manufacturing data.

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final sunscreen order. Sponsors should provide the compendial status of the ingredient, including reference to a United States Pharmacopeia National Formulary monograph. Sponsors should also provide any known chemical and/or manufacturing characteristics of the active ingredient that may be relevant to FDA’s GRASE evaluation and to the establishment of the conditions of any resulting final sunscreen order.11 Such information should include known interactions with other sunscreen active ingredient(s) or commonly used sunscreen vehicle component(s) and particle size information for micronized or nanoscale active ingredients. In addition, sponsors should describe any aspects of formulation that are needed to ensure stability, or other characteristics of the active ingredient that are needed to establish conditions under which it is GRASE for use in sunscreens.

III. SAFETY DATA

FDA’s OTC drug regulations identify both the general types of safety information that sponsors should submit as evidence that an OTC drug is GRASE for use as labeled (§ 330.10(a)(2) (21 CFR 330.10(a)(2))) and the standard by which such safety information is to be judged (§ 330.10(a)(4)(i)). When applying these regulations to a given active ingredient, FDA uses its scientific expertise to determine what constitutes “adequate tests by methods reasonably applicable to show the drug is safe under the prescribed, recommended, or suggested conditions of use.”12

FDA recognizes the contribution that broad spectrum sunscreens with a sun protection factor (SPF) value of 15 or higher can make to decrease the risk of skin cancer and early skin aging caused by the sun if used as directed with other sun protection measures. To protect the public health, it is also important for FDA to balance the potential benefits of these sunscreen products to consumers against their potential risks. Providing an adequate safety margin13 for OTC sunscreen active ingredients and finished sunscreen products is a key element of FDA’s risk assessment. When determining the specific testing and other data needed to adequately demonstrate that an OTC sunscreen active ingredient is safe, FDA considers both the circumstances under which OTC sunscreen products are intended to be used by consumers and current scientific knowledge and assessment technology.

11 The determination of whether a sunscreen active ingredient is GRASE and not misbranded also requires the Agency to describe the conditions under which any future product incorporating that sunscreen active ingredient will be GRASE and not misbranded (see, e.g., section 586C(e) of the FD&C Act; see also section V of this document).

12 § 330.10(a)(4)(i).

13 For drugs with a known potential for adverse effects based on animal data, the anticipated level of risk for humans may be quantified using a safety margin calculation. A safety margin calculation takes the highest animal no observed adverse effect level and estimates a maximum safe level of exposure for humans. One caveat to the safety margin calculation is that animal studies do not always predict effects in humans, and the actual threshold for an effect in humans may be different (higher or lower) than in the species tested. The human sensitivity to a drug is often unknown. To account for this, the predicted safe exposure level in humans that is reflected in the safety margin is well below where toxicities were seen in animals.

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To ensure full discussion of the kinds of data needed to address sunscreen safety, FDA held a 2- day meeting of the Nonprescription Drugs Advisory Committee on September 4-5, 2014, at which FDA presented much of the same approach that is recommended in this guidance. There was consensus among the independent scientific experts on the committee that FDA’s framework was a good starting point.14 This guidance takes into consideration the recommendations FDA received from this committee meeting.

FDA’s current approach for evaluating the clinical safety of potential nonprescription sunscreen active ingredients is based on our current scientific understanding regarding the safety evaluation of topical drug products for chronic use and thus is generally consistent with the safety data requirements that would apply to a new drug application (NDA) for a chronic-use cutaneous drug product (i.e., topical safety studies (irritation, sensitization, and photosafety), bioavailability (absorption), and evaluation of adverse events observed in clinical studies).15 In addition, an evaluation of adverse events reported during the commercial marketing of sunscreen products containing the ingredient as well as other postmarketing safety information is also relevant to FDA’ safety evaluation.

FDA’s current approach to the nonclinical safety evaluation of these active ingredients takes into account that only active ingredients that have been marketed to a material extent and for a material time in OTC sunscreen products are eligible under the SIA for a GRASE determination.16 In contrast to nonclinical data requirements for a chronic-use cutaneous drug product NDA, which include comprehensive nonclinical pharmacology and toxicology safety testing, the approach to nonclinical safety testing in this guidance is largely focused on potential long-term adverse effects or effects not otherwise readily detected from human use (i.e., carcinogenicity and reproductive toxicity). Please note, though, that testing beyond what is recommended in this guidance may be needed for active ingredients for which data suggest a concern about other long-term effects, such as hormonal disruption.

The following sections describe the specific safety data that FDA needs to determine whether an active ingredient is GRASE for use in sunscreens. However, FDA will consider alternative scientifically based approaches for addressing a particular data need. Sponsors are encouraged to discuss alternative proposals with FDA before initiating studies.

A. Clinical Safety Testing

1. Human Dermal Safety Studies

14 See the minutes of the FDA September 4-5, 2014, meeting of the Nonprescription Drugs Advisory Committee (2014 NDAC Minutes) at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCom mittee/ucm380890.htm.

15 Chronic use is defined as continuous or intermittent use of a product for at least 6 months during a lifetime. 16 See section 586B(a)(2) of the FD&C Act.

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Human dermal safety studies for topical products in which exposure to light after application is anticipated generally consist of two sets of studies—those conducted without specific exposure17 to light and those conducted to assess reactions after ultraviolet exposure (photosafety studies). These study sets usually consist of dermal irritation patch testing, dermal sensitization patch testing, dermal phototoxicity testing, and dermal photoallergenicity testing.

Because marketed sunscreen products typically contain a combination of active ingredients and because brand name product formulations frequently change, it is difficult for FDA to determine causal links between individual active ingredients and reported irritation and hypersensitivity adverse events associated with a particular product. Therefore, FDA generally expects to use data from human irritation studies, human skin sensitization studies, and human photosafety studies, in conjunction with postmarketing adverse event data, to inform GRASE determinations and labeling. Nonetheless, in some cases, depending on the rigor of available postmarketing safety information, it may be reasonable for sponsors to omit human irritation studies, human skin sensitization studies, and/or human photosafety studies. For example, if FDA concludes that there is a positive risk-benefit for a sunscreen active ingredient but that it is known to be a sensitizer, it may be possible to develop safety labeling to address this risk without data generated in the human dermal safety studies described below. Sponsors who believe there is a scientific rationale that may preclude the need for some or all of the described studies are urged to contact FDA before initiating studies.

a. Human irritation and sensitization studies

Studies of skin irritation and sensitization that use the repeat insult patch test or other relevant tests are recommended elements in FDA’s safety evaluation of topical drug products that, like sunscreens, are applied to the skin repeatedly over long periods of time. These tests, which are designed to detect the potential of topical drug products for local dermatologic events with fewer subjects than might be observed in larger clinical trials, often involve applying product more frequently and/or for longer durations than the proposed clinical dosing of those drug products. In dermal irritation studies, a test substance is applied to a small pad (patch) and affixed to the test subject’s skin, usually on the back, to determine whether the ingredient causes direct skin toxicity. Dermal sensitization studies are conducted similarly but are designed to detect immunologically mediated reactions, which require prior exposure to the allergen.

Nonprescription sunscreen active ingredients, when found to be GRASE, may be used in numerous, as yet unknown, product formulations. Therefore, FDA recommends that cumulative irritation studies evaluate (1) the proposed sunscreen active ingredient at the highest concentration for which a GRASE determination is sought, in an appropriate vehicle; (2) the vehicle alone; (3) a negative control; and (4) a positive control. The evaluation should include scoring of erythema, edema, and a papular response or skin erosion.

17 See the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidance for industry S10 Photosafety Evaluation of Pharmaceuticals. We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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Skin sensitization studies, conducted to detect immunologically mediated reactions, should be conducted in the following three phases:

(1) The induction phase (three weekly applications for 3 weeks)

(2) The rest phase (no product application for 10 to 14 days)

(3) The challenge phase (patch applications to new sites for 48 hours with a confirmatory rechallenge to exclude false positives)

Although FDA recommends separate dermal irritation and sensitization studies, irritation and sensitization studies can be combined in the same study as long as a sufficient number of subjects are included for sensitization evaluation.

b. Human photosafety studies

Topically applied dermatologic drug products should be tested for photosafety if they absorb light in the ultraviolet A, ultraviolet B, or visible spectra. FDA recommends that photosafety evaluations of sunscreen active ingredients that absorb light consist of skin photoallergenicity and skin phototoxicity testing. Photoallergy is an immunologically mediated reaction to a chemical, initiated by the formation of photoproducts (e.g., protein adducts) following a photochemical reaction. Similar to dermal sensitivity testing described above, photoallergy tests use an induction/rest/challenge/rechallenge multiphase design to assess erythema, edema, and vesiculation. Phototoxicity (or photoirritation) is an acute light-induced tissue response to a photoreactive chemical. Phototoxicity testing typically includes a test patch, a vehicle patch, and a sham patch application for 24 hours, followed by ultraviolet light exposure of the test area. A second set of patch application areas not irradiated with light serves as a control.

FDA recommends that photosafety studies of sunscreen active ingredients that absorb light be conducted using (1) the active ingredient at the highest concentration for which a GRASE determination is sought in an appropriate vehicle, (2) the vehicle alone, and (3) a negative control.

2. Human Absorption Studies/Maximal Usage Trial

Because nonprescription sunscreens are topically applied, a critical safety consideration is whether dermal application results in skin penetration and systemic exposure to the active ingredient and, if so, to what extent. This information helps identify potential safety concerns and helps determine whether an adequate safety margin exists for an active sunscreen ingredient to be included in the OTC sunscreen monograph.

The principal barrier to cutaneous drug product penetration is the multilayered, lipid-rich stratum corneum. The passage of any drug product through this layer is influenced by many factors, including the drug product’s physicochemical features, molecular weight, and vehicle/formulation properties. Vehicle/formulation properties are particularly important because the choice of vehicle can markedly affect the permeation potential of a drug product.

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Effects can range from simple hydration of the stratum corneum by occlusive vehicles/formulations to direct permeation enhancement by solvent effects on the lipids in the stratum corneum. Products absorbed through the skin have the potential to cause systemic adverse effects, affecting the safety assessment. Because sunscreens are intended to work at the skin’s surface, systemic absorption may also lower efficacy, affecting the efficacy assessment.

Since the mid-1990s, topical product NDAs have included a Maximal Usage Trial (MUsT) as part of the clinical pharmacology/bioavailability assessment. A MUsT is designed to capture the effect of maximal use on absorption into the blood with standard pharmacokinetic assessments (e.g., Cmax, Tmax, area under the curve, half-life, clearance, and volume of distribution). For a topical product NDA, the MUsT is usually conducted in subjects with the disease of interest, where disrupted skin is a feature. In situations where disrupted skin is not a feature of the disease or the topical drug product is intended for prevention of disease (e.g., sunscreens), the MUsT for a topical product NDA may be conducted in subjects with healthy, intact skin. The MUsT for a topical product NDA is conducted with the specific product formulation for which approval is sought, applied at the upper limit of surface area involvement that is studied in the phase 3 clinical trials and is proposed for labeling. That is to say, if the proposed labeling permits the product to be used on up to 30 percent of body surface area, then the coverage evaluated in the MUsT would be 30 percent of body surface area.18,19

FDA recommends that SIA sponsors of sunscreen active ingredients provide data from a MUsT to support an adequate assessment of safety.20 Because a determination that an active sunscreen product is GRASE would permit its use in a variety of finished sunscreen products, FDA recommends that the MUsT to support the GRASE determination.be conducted under maximal use conditions employing a minimum of four formulations containing the proposed sunscreen active ingredient as the only active ingredient. These formulations should be prepared using vehicle/formulation systems that are appropriate for sunscreen topical products (e.g., they are deployable or spreadable) and that are expected to produce the highest in vivo absorption. Justification for the formulations chosen, including results of in vitro testing using a human cadaver skin permeation system (e.g., static or flow-through cells),21 should be included in the study protocol. The protocol should contain sufficient detail for others to reproduce the formulations and manufacturing processes.

18 Bashaw, ED, DC Tran, CG Shukla, et al., January 2015, Maximal Usage Trial: An Overview of the Design of Systemic Bioavailability Trial for Topical Dermatological Products, Ther Innov Regul Sci, 49(1):108-115. available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663190/.

19 See the FDA draft guidance for industry Acne Vulgaris: Developing Drugs for Treatment. When final, this guidance will represent the FDA’s current thinking on this topic.

20 See the response to Discussion Question 1 in the 2014 NDAC Minutes, supra note 15, at 6 (expressing the need for human maximal use studies in all cases).

21 Bronaugh, RL and RF Stewart, January 1985, Methods for In Vitro Percutaneous Absorption Studies IV: The Flow-Through Diffusion Cell, J Pharm Sci, 74(1):64-67.

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FDA anticipates that the use of multiple formulations will help identify the overall absorption potential of the sunscreen active ingredient of interest. The MUsT for a potential monograph sunscreen active ingredient should be conducted in subjects with healthy, intact skin22 at the highest concentration of the ingredient for which a GRASE determination is sought and eligibility under the SIA has been established. Because sunscreens are recommended for use on all exposed skin, the exposed area should include at least 75 percent of the body surface area. Data from the formulation that produces the highest in vivo absorption would then be used to determine the safety margin.

The assay used in the MUsT should be properly validated according to current good laboratory practices (21 CFR part 58) and should be consistent with the FDA guidance for industry entitled Bioanalytical Method Validation. The assay’s limit of quantitation-limit of detection should be sufficiently low to allow a signal-to-noise ratio that ensures confidence in detection of a derived concentration of 0.5 nanogram (ng)/milliliter (mL).

An important consideration for designing a MUsT is that it should include testing for a duration that allows for the attainment of steady state levels to ensure that maximum penetration of the ingredient has taken place and to optimize the chances of the ingredient being detected. Thus, for sunscreen ingredients, FDA expects that single application studies would be inadequate. Because the subjects in a MUsT represent an enriched dataset in the upper range of exposures, FDA currently recommends collection of safety-related data (such as vital signs or adverse skin events) from the study’s regularly scheduled physical examinations. Sponsors are strongly encouraged to discuss their MUsT protocol with FDA before beginning the trial.

As discussed further in section V, if the sunscreen active ingredient is determined to be GRASE, the final order must set out the conditions under which any future product incorporating that sunscreen active ingredient will be GRASE and not misbranded. As such a condition, FDA is considering certain final formulation testing. FDA anticipates that the formulation that produces the highest in vivo absorption in the MUsT may be appropriate to designate as a standard control formulation for future in vitro human cadaver skin permeation system testing (e.g., static or flow-through cells) of each final sunscreen formulation that includes that active ingredient. In such a case, if in vitro permeation of the sunscreen active ingredient in the final product formulation were equal to or less than the value from in vitro testing of the standard control formulation (that was shown by the MUsT to have the highest degree of systemic absorption), FDA anticipates that the safety margin calculated would be considered adequate to support the safety of the finished formulation.

3. Pediatric Considerations

Young children have a larger ratio of skin surface to body volume compared to adults, which can increase a child’s systemic exposure to topically applied drug products. In addition, growing children have greater potential to experience deleterious developmental effects from drug exposure. If the calculated safety margin for a proposed monograph active ingredient (based on

22 As discussed infra, the MUsT should be conducted in subjects with healthy, intact skin because sunscreens are intended for prevention rather than treatment.

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nonclinical results and human MUsTs) supports a GRASE determination, but the safety margin is relatively small, FDA will exercise its scientific judgment to determine if either a sunscreen active ingredient MUsT in young children or other studies are warranted to ensure that the safety margin for marketed products containing the ingredient is within an acceptable range for this population.

B. Nonclinical Safety Testing

1. Carcinogenicity Studies: Dermal and Systemic

FDA generally recommends that carcinogenicity studies be conducted for any pharmaceutical either with an expected continuous clinical use of at least 6 months or with an expected clinical use of a minimum of 6 months in an intermittent manner.23 The animal carcinogenicity studies help characterize the potential tumor risks associated with a sunscreen active ingredient by identifying any observed tumors by type, the level of exposure at which tumors occur, and the highest level of exposure at which no adverse effects occur, referred to as the no observed adverse effect level (NOAEL). The NOAEL would be used in determining the safety margin for human exposure to sunscreens containing the active ingredient. In addition to detecting carcinogenic potential, carcinogenicity studies in animals can help identify other systemic or organ toxicities that may be associated with the proposed ingredient.

To support the safety of OTC sunscreen active ingredients, FDA recommends that sponsors conduct a dermal carcinogenicity study that involves applying the product to the skin of mice or rats for 2 years. FDA also considers it important to study the effects of systemic exposure when human bioavailability data show that dermal application of a particular formulation could result in skin penetration and systemic exposure. After the active ingredient is marketed in nonprescription sunscreens, that active ingredient is likely to be used in a wide variety of product formulations that might alter its skin penetration. Therefore, FDA also generally recommends that sponsors conduct a second carcinogenicity study by a route that produces systemic exposure.24 This study can be a 2-year study or a shorter (usually 6 months) alternative carcinogenicity model, but either study should be conducted in a species different from that used in the dermal carcinogenicity study. FDA notes that the absence of a carcinogenicity signal from

23 See the ICH guidance for industry The Need for Long-Term Rodent Carcinogenicity Studies of Pharmaceuticals.

24 FDA expects that a systemic carcinogenicity study would not be needed to support a GRASE determination for a sunscreen active ingredient if both (1) an adequately conducted human pharmacokinetic MUsT results in a steady state blood level less than 0.5 ng/mL and (2) an adequately conducted toxicology program does not reveal any other safety signals for the ingredient or for any known structurally similar compound indicating the potential for adverse effects at lower levels. The threshold value of 0.5 ng/mL is based on the principle that that level would approximate the highest plasma level below which the carcinogenic risk of any unknown compound would be less than 1 in 100,000 after a single dose. This threshold value is consistent with the Threshold of Toxicological Concern concept, which was applied to impurities in the ICH guidance for industry M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. FDA expects that the 0.5 ng/mL concentration will be sufficiently above the assay’s limit of quantitation-limit of detection to allow a signal-to-noise ratio that assures confidence in either the derived concentrations (in the case of “exaggerated” values) or lack of concentrations.

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an alternative transgenic carcinogenicity study (e.g., TgRasH2 mouse) would likely support the safety of a sunscreen active ingredient. However, if a carcinogenicity signal was observed in such a study, the study would not support the safety of a sunscreen active ingredient because there is no basis for calculating a safety margin with this study.25 All carcinogenicity studies— regardless of route—should assess a full panel of tissues.26

2. Developmental and Reproductive Toxicity Studies

FDA recommends that sponsors conduct developmental and reproductive toxicity (DART) studies to evaluate the potential effects that exposure to the sunscreen active ingredient may have on developing offspring throughout gestation and postnatally until sexual maturation, as well as on the reproductive competence of sexually mature male and female animals.27 Gestational and neonatal stages of development may be particularly sensitive to active ingredients with hormonal activity (endocrine disruption). For this reason, FDA recommends that these studies include assessments of endpoints such as vaginal patency, preputial separation, anogenital distance, and nipple retention, which can be incorporated into traditional DART study designs to assess potential hormonal effects on the developing offspring. FDA also recommends that sponsors perform behavioral assessments (e.g., assessing mating behavior) of offspring, which may detect neuroendocrine effects.28

3. Toxicokinetics29

FDA recommends that sponsors collect animal toxicokinetic data for sunscreen active ingredients because these data provide an important bridge between toxic levels seen in animal studies and any potential human adverse events associated with systemic exposure to the sunscreen’s active ingredient (see section III.A.2). Toxicokinetic measurements are usually obtained during the course of ongoing nonclinical toxicity studies, such as in carcinogenicity or DART studies, rather than through separate studies.

25 Jacobs, AC and PC Brown, July 2015, Regulatory Forum Opinion Piece: Transgenic/Alternative Carcinogenicity Assays: A Retrospective Review of Studies Submitted to CDER/FDA 1997-2014, Toxicol Pathol, 43(5):605-10.

26 FDA recommends submitting the carcinogenicity study protocol(s) for review by CDER's Executive Carcinogenicity Assessment Committee prior to initiating the studies. For further guidance regarding carcinogenicity studies, see the FDA guidance for industry Carcinogenicity Study Protocol Submissions.

27 See the ICH guidance for industry S5A Detection of Toxicity to Reproduction for Medicinal Products. FDA expects that studies to assess both fertility and prenatal or postnatal toxicity may not be needed if both (1) an adequately conducted human MUsT shows absorption that results in a steady state blood level less than 0.5 ng/mL and (2) there are no signals in an adequately conducted toxicology program indicating that the ingredient or any known structurally similar compound interacts with related pathways, such as endocrine function or signaling pathways related to growth and development. FDA would continue to recommend that effects on embryofetal development be assessed.

28 See the FDA guidance for industry Nonclinical Evaluation of Endocrine-Related Drug Toxicity.
29 See the ICH guidance for industry S3A Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies.

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C. Postmarketing Safety Data

In addition to the active ingredient safety data already described, FDA’s GRASE evaluation also takes into consideration available information about serious adverse drug experiences and known or expected adverse effects associated with commercially marketed products that contain the active ingredient(s) under consideration. FDA specifically requests that sponsors provide the following information:

  • A summary of all potentially associated serious adverse drug experiences.

  • A summary of all available potentially associated nonserious adverse drug experiences.

  • A summary of expected or frequently reported side effects, whether serious or nonserious.

  • Copies of all available reports of potentially associated serious adverse drug experiences. Each report submitted should be in the form of an individual case safety report as described in 21 CFR 314.80 and refer only to an individual consumer or to a single attached publication.

  • Any available safety information from studies of safety and effectiveness in humans.

  • Relevant medical literature describing associated adverse events. English translations should be provided for all foreign language materials.

    For products marketed outside the United States, submissions should also state whether each country’s system allows for adverse event reporting and, if so, how each country’s system identifies and collects the adverse event information.30 If adverse event information is not available from all countries where the active ingredient has been marketed in OTC sunscreen products, the sponsor should provide an explanation for the missing data. It is important to note, however, that even when countries have an adverse event reporting system that includes sunscreen products, underreporting is a significant limitation of any system that depends on spontaneous reports.

    Many factors can influence whether an adverse event is reported, including whether a possible relationship between the event and an ingredient or product is recognized by consumers or health care providers. For example, adverse events that occur many years after a causal drug exposure may not be recognized as being related to that exposure, especially if the background rate of those adverse events is high (e.g., a common cancer or a developmental problem). Thus, an absence of reports does not necessarily equate to an absence of adverse events. Despite the limitations of adverse event reporting, FDA considers postmarketing data to be relevant both to

    30 See, e.g., 21 CFR 330.14(c)(2)(v).

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the overall GRASE assessment of OTC sunscreen active ingredients and to labeling considerations because these data may reveal safety signals not otherwise observed in clinical or nonclinical testing.

IV. EFFECTIVENESS DATA

FDA’s OTC drug regulations generally identify both the types of effectiveness information that sponsors should submit as evidence that a drug product containing an active ingredient or other OTC drug condition could be GRASE for use as labeled (§ 330.10(a)(2)) and the standard by which effectiveness is to be judged, which requires controlled clinical investigations to support effectiveness (§ 330.10(a)(4)(ii)).

When applying these regulations to each potential sunscreen active ingredient, FDA requests that sponsors provide evidence from at least two adequate and well-controlled SPF studies showing that the active ingredient effectively prevents sunburn, because sunburn prevention is the minimum indication for an OTC sunscreen product. Two adequate and well-controlled SPF studies of the active ingredient at a lower concentration than the maximum requested should be conducted according to established standards.31 These SPF studies should demonstrate that the selected concentration provides an SPF value of 2 or higher.

The current standard procedure for SPF testing is described in § 201.327(i) (21 CFR 201.327(i)).32 Any new SPF tests for a particular ingredient should be performed as described in these regulations, using a test formulation containing the ingredient as the only active ingredient to identify its contribution to the overall SPF test results. These tests should also include a vehicle control arm to rule out any contribution the vehicle may have had on the SPF test results. Finally, as described in § 201.327(i), an SPF standard formulation comparator arm should be another component of the study design.

Current sunscreen testing and labeling regulations in § 201.327(j) also specify a broad spectrum testing procedure, which provides an in vitro measurement of a sunscreen product’s ability to protect against both ultraviolet A and ultraviolet B radiation. Broad spectrum protection is often the result of the combined contribution of multiple active ingredients in a final sunscreen formulation; thus, FDA does not expect that a sunscreen active ingredient would undergo broad spectrum effectiveness testing to establish its effectiveness for a GRASE determination for use in OTC sunscreen products.

Under § 201.327, the determination of whether an individual sunscreen product subject to that regulation may be labeled as broad spectrum (and therefore bear the additional claims related to

31 FDA expects that the upper bound of any concentration of the active ingredient ultimately established would be governed by the safety data, as well as by efficacy.

32 Although this SPF testing procedure is used primarily for final formulation testing of finished products marketed without approved NDAs, it is equally applicable for determining whether or not a sunscreen active ingredient is generally recognized as effective as part of the overall GRASE determination.

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that labeling) is made on a product-specific basis, applying the standard testing methods set forth in those regulations.33 If a sunscreen active ingredient evaluated under the SIA is established to be GRASE for use in nonprescription sunscreens, the final sunscreen order can address broad spectrum testing and related labeling conditions for final sunscreen formulations containing that ingredient.

V. ANTICIPATED FINAL FORMULATION TESTING

The preceding sections of this guidance have concentrated on recommendations for safety and effectiveness data needed to support FDA’s determination that a sunscreen active ingredient is GRASE for use in sunscreens. FDA’s determination that an active ingredient is GRASE will be made in the form of a final sunscreen order that will set out the conditions under which any future product incorporating that sunscreen active ingredient will be GRASE and not misbranded (see section I).34 As noted in section III.A.2, variations among individual sunscreen products— and in particular, aspects of the lotion or other vehicle in which active ingredients are delivered — can affect their absorption and thus their safety and effectiveness.

To address the variability among sunscreen formulations, FDA currently requires final formulation testing of nonprescription sunscreen products to ensure their effectiveness—namely, testing for SPF value as well as broad spectrum protection and water resistance where those attributes are claimed in product labels.35 FDA anticipates that final sunscreen orders issued for sunscreen active ingredients determined to be GRASE under the SIA will also include conditions requiring final formulation testing to ensure the safety of all sunscreen formulations permitted by the order.

The discussion that follows provides FDA’s current thinking about such final formulation safety testing, to be conducted in the future. Note that FDA has not yet determined what particular final formulation testing, if any, will be specified in future final sunscreen orders for any given sunscreen active ingredient. Such requirements will be established on an ingredient-specific basis, taking into consideration the data recommended to be supplied under other parts of this guidance to support a GRASE determination (e.g., whether any safety signals are detected in well-conducted nonclinical carcinogenicity and DART studies). Interested parties can provide relevant information and comments regarding final formulation testing for an individual sunscreen active ingredient as part of the GRASE determination process for that ingredient.

33 These standard testing methods are also described in the guidance for industry Labeling and Effectiveness Testing: Sunscreen Drug Products for Over-The-Counter Human Use—Small Entity Compliance Guide.

34 See section 586D(e) of the FD&C Act.

35 See § 201.327 for the current requirements for OTC sunscreens containing the active ingredients already evaluated under the monograph system. OTC sunscreens marketed under NDAs provide similar information in their product-specific applications to substantiate their labeling.

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FDA’s current thinking is that final formulation safety testing of nonprescription sunscreens would not generally call for an in vivo study. Instead, FDA expects that the conditions of marketing specified for sunscreen active ingredients in final sunscreen orders would require 36 manufacturers to perform in vitro permeation testing before marketing each new formulation. Consistent with the approach for final formulation efficacy testing required by § 201.327, FDA anticipates that it would not review the results of the in vitro final formulation safety testing before product marketing. Rather, FDA expects that final sunscreen orders would require manufacturers to maintain records of this testing; these records would be available to FDA.

First, as mentioned in section III.A.2, FDA anticipates establishing a standard control formulation for each sunscreen active ingredient, to be used in the final formulation testing of products containing that ingredient. The standard control formulation would be the formulation that produces the highest in vivo absorption in the MUsT. The results of in vitro human cadaver skin testing using this control formulation can then be used to bridge to a corresponding level of in vivo absorption from the MUsT used to establish the safety margin for the GRASE ingredient.

Then, FDA anticipates that final formulation testing would be conducted for each formulation intended to be marketed, using a specified human cadaver skin diffusion cell, either Franz (static) or Bronaugh (flow-through). The results of the in vitro permeation testing of the new formulation would be evaluated in light of the absorption found in the standard control formulation for the active ingredient it contains. If a final sunscreen formulation contains a combination of sunscreen active ingredients, FDA anticipates that the final formulation would be tested against the standard control formulations for each of the sunscreen active ingredients it contains. A standard control formulation might not be specified for a particular sunscreen active ingredient if FDA determines that the ingredient is unlikely to be absorbed through the skin.

If the in vitro permeation of each sunscreen active ingredient in the final formulated product is equal to or less than the value obtained from in vitro testing of the standard control formulation for that active ingredient, FDA anticipates that the product’s safety margin would be considered to fall within the parameters judged to be GRASE and thus to support marketing of the new formulation. However, if the in vitro permeation of the active ingredient from the specific final formulation is greater than the value obtained from in vitro permeation testing of the standard control formulation for that active ingredient, FDA anticipates that the formulation would not be considered GRASE. In that situation, the sponsor would have the option to either (1) reformulate the product and conduct in vitro testing to establish that the reformulated product satisfies the final formulation testing condition set forth in the order; or (2) seek NDA approval for the new formulation.

36 FDA recommends this approach as an alternative to final in vivo (MUsT) testing of final product formulations, which was recommended by the Nonprescription Drugs Advisory Committee (see the response to Discussion Question 2 in the 2014 NDAC Minutes, supra note 15, at 7).

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Safety Testing of Drug Metabolites Guidance for Industry

Safety Testing of Drug

Metabolites Guidance for Industry

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

November 2016 Pharmacology/Toxicology

Revision 1

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Safety Testing of Drug

Metabolites Guidance for Industry

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: This e-mail address is being protected from spambots. You need JavaScript enabled to view it 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)

November 2016 Pharmacology/Toxicology

Revision 1

I. II. III.

A. B. C.

IV.

A. B. C. D.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1

BACKGROUND ............................................................................................................... 2

GENERAL CONCEPTS IN METABOLITE SAFETY TESTING............................. 3

General Approaches for Assessing Metabolite Safety ................................................................ 4

Identification of Metabolites ......................................................................................................... 4

General Considerations for Nonclinical Study Design ............................................................... 5

RECOMMENDED STUDIES FOR ASSESSING THE SAFETY OF METABOLITES ............................................................................................................... 5

General Toxicity Studies ............................................................................................................... 6 Genotoxicity Studies ...................................................................................................................... 6 Embryo-Fetal Development Toxicity Studies..............................................................................6 Carcinogenicity Studies ................................................................................................................. 6 TIMING OF SAFETY ASSESSMENTS ........................................................................ 7

V. GLOSSARY................................................................................................................................... 8 APPENDIX A: DECISION TREE FLOW DIAGRAM ............................................................ 9 APPENDIX B: CASE EXAMPLES OF DRUG METABOLITES ........................................ 10

Contains Nonbinding Recommendations

Safety Testing of Drug Metabolites Guidance for Industry1

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This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

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I. INTRODUCTION

This guidance provides recommendations to industry on when and how to identify and characterize drug metabolites whose nonclinical toxicity needs to be evaluated. The safety of drug metabolites may need to be determined in nonclinical studies because these metabolites are either identified only in humans or are present at disproportionately higher levels in humans than in any of the animal species used during standard nonclinical toxicology testing.2

This guidance applies to small molecule nonbiologic drug products. This guidance does not apply to some cancer therapies where a risk-benefit assessment is considered.3

This guidance supersedes the guidance of the same name published in February 2008. The guidance has been revised to be in alignment with the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

1 This guidance has been prepared by the Pharmacokinetic Subcommittee of the Pharmacology and Toxicology Coordinating Committee in the Center for Drug Evaluation and Research at the Food and Drug Administration.

2 See the Glossary for the definition of disproportionate drug metabolite.

3 See the ICH guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals for the safety testing of drug metabolites in cancer therapies. We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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Contains Nonbinding Recommendations

II. BACKGROUND

Nonclinical evaluation of drug safety usually consists of standard animal toxicology studies.4 These studies usually include assessment of drug exposure, primarily parent drug plasma concentration. Generally, drug plasma concentration and systemic exposure in the nonclinical studies are compared with systemic exposure in humans to assess the potential risks suggested by nonclinical findings and guide monitoring in clinical trials. This testing paradigm usually is sufficient when the metabolic profile in humans is similar to that in at least one of the animal species used in nonclinical studies, but metabolic profiles can vary across species both quantitatively and qualitatively, and there are cases when clinically relevant metabolites have not been identified or adequately evaluated during nonclinical safety studies. This situation can occur if the metabolite is formed only in humans and is absent in the animal test species or if the metabolite is present at disproportionately higher levels in humans than in the animal species used in the standard toxicity testing with the parent drug.

It is not standard practice for drug metabolites to be evaluated separately in a cross-species safety assessment. As a result, their specific contribution to the overall toxicity of the parent drug has often remained unknown. This lack of appreciation of the role of metabolites in drug toxicity may be partly because of the inadequate sensitivity of the analytical methods used to detect and characterize metabolites derived from the parent drug. Technological advances have greatly improved the analytical capabilities to detect, identify, and characterize metabolites and allow for a better understanding of the role metabolites play in drug safety assessment.

Drugs entering the body undergo biotransformation via Phase I and Phase II metabolic pathways. Based on the nature of the chemical reactions involved, metabolites formed from Phase I reactions are more likely to be chemically reactive or pharmacologically active and, therefore, more likely to need safety evaluation. An active metabolite may bind to the therapeutic target receptors or other receptors, interact with other targets (e.g., enzymes, proteins), and cause unintended effects. This is a particularly important problem when such a metabolite is formed in humans and not in animals, but the occurrence of a metabolite only in humans and not in any animal test species is rare. A more common situation is the formation of a metabolite at disproportionately higher levels in humans than in the animal species used in safety testing of the parent drug. This disproportionality stems from the typical qualitative and/or quantitative differences in metabolic profiles between humans and animals. If at least one animal test species forms this drug metabolite at adequate exposure levels (approximately equal to or greater than human exposure), as determined during toxicology testing of the parent drug, it can be assumed that the metabolite’s contribution to the overall toxicity assessment has been established.5

Metabolites that form chemically reactive intermediates can be difficult to detect and measure because of their short half-lives. However, they can form stable products (e.g., glutathione

4 See the ICH guidances for industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals and S7A Safety Pharmacology Studies for Human Pharmaceuticals.

5 See Appendix A: Decision Tree Flow Diagram. This diagram describes which studies may be needed to determine safety of the drug metabolite.

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Contains Nonbinding Recommendations

conjugates) that can be measured. Phase II conjugation reactions generally render a compound more water soluble and pharmacologically inactive, thereby eliminating the need for further evaluation. However, if the conjugate forms a toxic compound such as acylglucuronide, additional safety assessment may be needed.6

Demonstration that a metabolite is pharmacologically inactive at the target receptor does not guarantee that it is not toxic. Therefore, it may need to be tested in nonclinical toxicity studies.7

III. GENERAL CONCEPTS IN METABOLITE SAFETY TESTING

We encourage the identification of any differences in drug metabolism between animals used in nonclinical safety assessments and humans as early as possible during the drug development process.8,9 The discovery of disproportionate drug metabolites late in drug development can potentially cause development and marketing delays.

Generally, metabolites identified only in human plasma or metabolites present at disproportionately higher levels in humans than in any of the animal test species should be considered for safety assessment. Human metabolites that can raise a safety concern are those formed at greater than 10 percent of total drug-related exposure at steady state.10 The choice of a level of greater than 10 percent for characterization of drug metabolites reflects consistency with FDA and Environmental Protection Agency guidances.11,12

6 Faed, EM, 1984, Properties of Acyl Glucuronides. Implications for Studies of the Pharmacokinetics and Metabolism of Acidic Drugs, Drug Metab Rev, 15, 1213–1249.

7 See Appendix B: Case Examples of Drug Metabolites.

8 Baillie, TA, MN Cayen, H Fouda, RJ Gerson, JD Green et al., 2002, Drug Metabolites in Safety Testing, Toxicol Appl Pharmacol, 182, 188–196.

9 Hastings, KL, J El-Hage, A Jacobs, J Leighton, D Morse, and R Osterberg, 2003, Drug Metabolites in Safety Testing, Toxicol Appl Pharmacol, 190(1), 91–92.

10 Exposure should be at steady state unless there is some justification for a different measure of exposure. Comparison between human and animal exposure generally is based on area under the curve, but sometimes it may be more appropriate to use Cmax. See ICH M3(R2).

11 U.S. Environmental Protection Agency, 1998, Health Effects Test Guidelines, OPPTS 870.7485, Metabolism and Pharmacokinetics (http://www.epa.gov/epahome/research.htm).

12 See the Veterinary International Conference on Harmonization guidances GL46 Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-producing Animals: Metabolism Study to Determine the Quantity and Identify the Nature of Residues (MRK) and GL47 Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Animals: Comparative Metabolism Studies in Laboratory Animals available on the Veterinary International Conference on Harmonization (VICH) Guidance Documents Web page at http://www.fda.gov/RegulatoryInformation/Guidances/ucm122050.htm.

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A. General Approaches for Assessing Metabolite Safety

A metabolite identified in animals that is not present in humans can mean that a toxicity observed in that animal species, attributed to the metabolite, may not be relevant to humans. Conversely, a drug metabolite identified during clinical development that is not present in animal test species or is present at much lower levels in animals than in humans can suggest the need for further studies in animals to determine the potential toxicity of the metabolite. In such cases, two approaches can be considered to assess the drug metabolite. The first approach is to identify an animal species routinely used in toxicity studies that forms the metabolite at adequate exposure levels (equivalent to or greater than the human exposure), and then investigate the drug’s toxicity in that species. The second approach, if a relevant animal species that forms the metabolite cannot be identified, is to synthesize the drug metabolite and directly administer it to the animal for further safety evaluation. In this approach, analytical methods that are capable of identifying and measuring the metabolite in nonclinical toxicity studies should be developed.

We acknowledge the difficulties associated with synthesizing a specific metabolite as well as the inherent complexities that accompany its direct administration. Direct dosing of a metabolite to animals may lead to subsequent metabolism that may not reflect the clinical situation and thus may complicate the toxicity evaluation. Moreover, new and different toxicities may arise from administration of the metabolite that were not observed with the parent drug. However, notwithstanding these possible complications, identification and evaluation of the potential toxicity of the drug metabolite is considered important to ensure clinical safety, and the decision to conduct direct safety testing of a metabolite should be based on a comprehensive evaluation of the data on the parent drug and any information available for the metabolite. Appendix B provides three case examples when drug metabolites were formed at disproportionately higher levels in humans than in test animals used in the nonclinical studies and how the safety evaluation was approached. In Case 1, testing of the drug metabolite was not needed because the metabolite was adequately characterized in nonclinical toxicity studies with the parent drug. However, in Cases 2 and 3, the drug metabolites had to be tested in toxicity studies by direct administration to the animal. In Case 3, the drug metabolite was pharmacologically inactive at the therapeutic target receptor but showed a unique toxicity not observed with the parent molecule.

B. Identification of Metabolites

Metabolite concentrations cannot be inferred by measurement of