ITFG/IPAC-RS Collaboration

CMC Leachables and Extractables Technical Team

***Leachables and Extractables Testing:***

***Points to Consider***

***A Response to the FDA draft Guidances for Industry:***

***Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products
Chemistry, Manufacturing, and Controls Documentation*; *and***

***Nasal Spray and Inhalation Solution, Suspension, and Spray Drug
Products Chemistry, Manufacturing, and Controls* *Documentation***

27 March 2001

**[Table of Contents]{.smallcaps}**

**I. OVERVIEW** 3

**II. INTRODUCTION** 4

Summary Flowchart 5

**III. CONTROL EXTRACTION STUDIES** 6

A. General Recommendations 6

B. Proposed Alternate Language 6

**IV. LEACHABLES STUDIES** ...10

A. General Recommendations 10

B. Proposed Alternate Language 11

**V. ROUTINE EXTRACTABLES TESTING** ...13

A. General Recommendations 13

B. Proposed Alternate Language 13

**VI. QUALIFICATION OF LEACHABLES** 15

A. General Recommendations 15

B. Proposed Alternate Language 16

C. Proposed Toxicological Evaluation Process 20

D. Justification of Proposed Qualification Threshold 24

**VII. SUMMARY TABLE OF RECOMMENDED LEACHABLES AND EXTRACTABLES
TESTING** 31

**VIII. CONCLUSION** 34

**IX. GLOSSARY** 35

**[I. Overview]{.smallcaps}**

-   In November 1998 and June 1999, the FDA issued for public comment
    two draft CMC Guidances for Industry: 1) Metered Dose Inhaler (MDI)
    and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing,
    and Controls (CMC) Documentation[^1]; and 2) Nasal Spray and
    Inhalation Solution, Suspension, and Spray Drug Products Chemistry,
    Manufacturing, and Controls Documentation[^2] (here referred to as
    the "draft MDI/DPI Guidance" and "draft Nasal/Nebulizer Guidance",
    respectively).

-   Following the issuance of the draft Guidances, two organizations
    with expertise in inhalation and nasal drug products ‑ the
    Inhalation Technology Focus Group of the American Association of
    Pharmaceutical Scientists (ITFG) and the International
    Pharmaceutical Aerosol Consortium on Regulation and Science
    (IPAC-RS) ‑ initiated a scientific, data-driven collaboration to
    address specific issues in the draft Guidances in order to
    contribute constructively to the Agency's development of guidance
    documents for orally inhaled and nasal drug products.

-   The CMC Leachables and Extractables Technical Team of the
    ITFG/IPAC-RS Collaboration and its Toxicology Working Group
    carefully reviewed the draft Guidances, conducted confidential
    surveys of drug product manufacturers and suppliers of
    pharmaceutical device components, and prepared recommendations on
    leachables and extractables testing.

-   This report is focused on the following topics:

(1) Control Extraction Studies

(2) Leachables Studies

(3) Routine Extractables Testing

(4) Biological Safety Qualification of Leachables (Qualification of
    Leachables)

-   For each of the four focus areas, the Team has identified sections
    of the draft Guidances that could be strengthened by rewording of
    the existing text or by addition of further clarifying statements.
    This report contains proposed alternate language drafted by the Team
    for the Agency's consideration, for inclusion in the CMC guidances
    for inhalation and nasal products.

-   A key concept that is introduced in the report is a proposal for the
    establishment of reporting and qualification thresholds for
    leachables. These thresholds are consistent with current industry
    practices and are supported by a thorough safety justification,
    provided here.

-   This report also offers certain general recommendations for
    leachables and extractables testing based on best industry
    practices.

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-   The Leachables and Extractables Technical Team and the Toxicology
    Working Group respectfully encourage the Agency to consider the
    recommendations developed by the Team and to incorporate the same in
    the next version of the draft CMC Guidance documents.

**II. INTRODUCTION**

The ITFG/IPAC-RS Leachables and Extractables Technical Team presents its
findings regarding leachables and extractables studies for orally
inhaled and nasal drug products. In this document the Team proposes new,
clarifying language recommended for adoption in the revised draft
Guidances. The proposed alternate language describes a step-wise
approach to investigating and controlling extractables and leachables in
inhalation and nasal drug products. The proposed approach was developed
based on best industry practices and science.

The approach is summarized as follows: first, the Team presents
recommendations for controlled extraction studies, performed to obtain
an extractables profile. This is followed by the Team\'s proposals for a
one-time leachables study. The Team recommends that if a correlation
between leachables and extractables is demonstrated, a specification for
leachables in drug product should not be required. The Team also
proposes a definition of a "correlation" between extractables and
leachables. Next, the Team makes general recommendations for routine
extractables testing and methodology. Finally, the Team proposes a
strategy for the biological safety qualification of leachables.

The Team believes that reasonable reporting, identification and
qualification thresholds for extractables and leachables should be
established, and that there are appropriate processes for establishing
such thresholds. Therefore, for controlled extraction studies, the Team
proposes identification thresholds for extractables. In the *Leachables
Studies* section of this paper, the Team proposes reporting and
identification thresholds for leachables. In the *Qualification of
Leachables* section, the Team proposes that only those leachables
present above the proposed reporting threshold should be considered for
potential biological safety qualification. Finally, the Team proposes a
qualification threshold. These thresholds are consistent with current
industry practices and are supported by a thorough safety justification.

A flowchart outlining the proposed process is presented in figure 1 on
page 5. A summary table of the Team's recommended strategies for
leachables and extractables testing for different dosage forms is
contained in section VII (pages 31-33).

**[Figure 1. Summary Flowchart for Leachables and Extractables
Evaluation Process\*]{.underline}**

\* For detailed description and justification of each step, see text.

**[III. Control Extraction Studies]{.smallcaps}**

**[A. General Recommendations]{.underline}**

The ITFG/IPAC-RS Leachables and Extractables Technical Team offers for
the Agency's consideration the following observations and
recommendations for control extraction studies:

1.  The Team recommends that the term *controlled* extraction study be
    used in place of the term *control* extraction in order to avoid
    confusion with tests that are conducted as part of a routine control
    strategy.

2.  Sections referring to "control extraction studies" are found
    throughout the draft Guidances (*e.g.,* lines 822-834, 869-878,
    986-1002, 1070-1080, 1165-1181 in the draft MDI/DPI Guidance and
    lines 827-831, 889-933, 939-942, in the draft Nasal/Nebulizer
    Guidance). We recommend that for clarity and ease of use, these
    sections be consolidated into one section, in each of the draft
    Guidances.

3.  Furthermore, the draft Guidances introduce several key concepts in
    the cited sections, such as "critical component" and "correlation"
    between extractables and leachables. These key concepts should be
    more clearly defined for each type of delivery system. Currently,
    the term "critical component" is only defined for DPIs (see lines
    1158-1161 of the draft MDI/DPI Guidance).

4.  The Team recommends that controlled extraction studies should be
    conducted only on those critical components of the container closure
    system which either contact the formulation or the patient's mouth
    or nasal mucosa.

5.  The current text of the draft Guidances requires the identification
    and quantitation of *each detected peak*. This requirement should be
    clarified. The Guidances should include identification criteria and
    reporting thresholds for extractables in controlled extraction
    studies.

**[B. Proposed Alternate Language for CMC Guidances for
OINDP]{.underline}**

> **A controlled extraction study is typically conducted during the
> early phases of drug development. The purpose of the study is to
> characterize the extractable compounds derived from the critical
> components of the drug delivery system which are either in contact
> with the formulation or with the patient's mouth or nasal mucosa.**
>
> **In certain cases, secondary packaging critical for the performance
> of the drug product should also be included in a controlled extraction
> study. For example, a laminate overwrap used as secondary packaging
> for inhalation solutions, particularly when the primary packaging is
> semi-permeable. For DPIs, however, controlled extraction studies on
> secondary packaging are most appropriately addressed on a case-by-case
> basis.**
>
> **In general, a controlled extraction study of a packaging component
> involves exposing a sample of the component to an appropriate solvent
> system at elevated temperature, followed by chemical analysis. The
> purpose of using elevated temperature is to increase the rate of
> extraction, so that a short experimental time may simulate a longer
> exposure time at room temperature, and/or to maximize the amount of
> extractable compounds obtained from a sample.**
>
> **The methods employed to analyze the resulting extracts vary
> depending on the purpose of the extraction study and the nature of the
> packaging component. Typically, extraction solvents with a range of
> polarity are used, which should include a solvent with a polarity
> similar to the drug product vehicle. Solvent systems with higher
> solvating power than the dosage form are also included in order to
> generate sufficient levels of extractables for structure elucidation.
> Typical solvents are listed in Table 1:**
>
> **[Table 1. Typical solvents used for controlled extraction
> studies]{.underline}**

  ----------------------------------- -----------------------------------
  ***Components for the Following     ***Typical Extraction Solvents For
  Dosage Forms***                     Controlled Extraction Studies***

  **MDIs**                            **Hexane, methylene chloride,
                                      isopropanol**

  **Inhalation solutions, nasal       **Isopropanol, water, ethanol**
  sprays, DPIs**                      

  **Mouthpieces and actuators**       **Methylene chloride, isopropanol,
                                      water**
  ----------------------------------- -----------------------------------

> **A qualitative chemical analysis of the component extracts should be
> conducted. The identification of extractables is most commonly
> achieved by techniques such as gas chromatography -- mass spectrometry
> (GCMS) and liquid chromatography-mass spectrometry (LCMS). The
> information that is typically obtained from these experiments is
> outlined in Table 2:**
>
> **[Table 2. Typical chemical identification data from analysis of
> extracts]{.underline}**

+------------------+---------------------------------------------------+
| *                | ***Typical Identification Data***                 |
| **Identification |                                                   |
| Category***      |                                                   |
+------------------+---------------------------------------------------+
| **A**            | > **Mass spectrometric fragmentation behavior**   |
+------------------+---------------------------------------------------+
| **B**            | > **Confirmation of molecular weight**            |
+------------------+---------------------------------------------------+
| **C**            | > **Confirmation of elemental composition**       |
+------------------+---------------------------------------------------+
| **D**            | > **Mass spectrum matches automated library or    |
|                  | > literature spectrum**                           |
+------------------+---------------------------------------------------+
| **E**            | > **Mass spectrum and chromatographic retention   |
|                  | > index match authentic specimen**                |
+------------------+---------------------------------------------------+

> **A combination of spectral interpretation, spectral library
> searching, and a knowledge of the materials studied are typically used
> in order to assign structures for the observed chromatographic peaks.
> The degree of certainty in the assignment of a structure is dependent
> on the identification data that has been obtained. Reasonable efforts
> should be made to assign structures as outlined in Table 3.**
>
> **[Table 3. Assignment of chemical structure related to extractable
> level]{.underline}**

+-------------------------------------+--------------------------------+
| > ***Extractable Level in           | > ***Assignment Category\****  |
| > Component***                      |                                |
+-------------------------------------+--------------------------------+
| **\> 100 μg/g**                     | **Structure Confirmed**        |
+-------------------------------------+--------------------------------+
| **20 -- 100 μg/g**                  | **Confident**                  |
+-------------------------------------+--------------------------------+
| **\< 20 μg/g**                      | **Tentative**                  |
+-------------------------------------+--------------------------------+

> ***\*Assignment category:***
>
> **[Structure confirmed]{.underline}: identification categories A, B
> (or C), and D (or E) (see Table 2) are positive.**
>
> **[Confident]{.underline}: sufficient data to preclude all but the
> most closely related structures.**
>
> **[Tentative]{.underline}: data is consistent with a class of molecule
> only.**
>
> **The levels listed in Table 3 are consistent with current industry
> practices, and with the capabilities of the analytical techniques
> mentioned above. Whenever possible, the structures of significant
> extractables (\> 100 μg/g) should be confirmed with authentic
> materials.**
>
> **A quantitative analysis of the component extracts should be
> conducted. Reasonable efforts should be made to quantify peaks down to
> the 1-20 μg/g level. The test methods should be documented in
> sufficient detail to permit duplication and verification by Agency
> laboratories. It is recognized that authentic materials for
> extractables may not be available. In such instances, it is acceptable
> to employ individual identified extractables as representative of
> compound classes as quantitation standards.**
>
> **Note that for certain elastomeric formulations, much lower detection
> limits and dedicated methods may be required for specific compounds
> with known toxicity \[*e.g.,* nitrosamines, polynuclear aromatics
> (PNAs), mercaptobenzthiazole, etc.\].**

**[IV. Leachables Studies]{.smallcaps}**

The draft MDI/DPI Guidance describes the requirements for leachables
studies in lines 715--725, and 803--840. The draft MDI/DPI Guidance
requires that

> "Appropriate acceptance criteria for the levels of leached compounds
> in the formulation should be established...Identity and concentration
> profiles of the leachables in the drug product or placebo
> formulation...should be determined through the end of the drug
> product's shelf life and correlated, if possible, with the
> extractables profiles of the container and closure components
> determined under the various control extraction study conditions. Such
> a correlation may obviate the need to evaluate leachables in the drug
> product formulation in future routine stability studies."

**[A. General Recommendations]{.underline}**

The Leachables and Extractables Team offers the following
recommendations regarding leachables studies:

> 1\. Since the draft MDI/DPI Guidance requires that a correlation
> between leachables and extractables be demonstrated in order to avoid
> the requirement for leachables testing on a routine basis, we
> recommend that the draft Guidances include a clear working definition
> of how such a correlation is established.
>
> 2\. The Guidances should also include appropriate reporting,
> identification and qualification thresholds for leachables.
> (Qualification thresholds for leachables are discussed in section IV.D
> of this document).
>
> 3\. The Team also strongly recommends that the control of leachables
> be accomplished by applying suitable controls and procedures during
> component manufacture, not after the manufacture of drug product. As
> the proper understanding of extractable profiles and toxicity issues
> is established through developmental studies, routine control of
> extractables is achieved primarily by current Good Manufacturing
> Practices (cGMPs). The cGMPs require that quality be built into all
> aspects of the manufacturing process as is necessary to ensure the
> product possesses the purported quality and purity.[^3]

The first two recommendations have been addressed in the proposed
alternate language provided below.

**[B. Proposed Alternate Language for CMC Guidances for
OINDP]{.underline}**

> **A leachables study should be conducted as a one-time study in
> support of a new drug application (NDA) or abbreviated new drug
> application (ANDA) submission, and may also be conducted on drug
> product intended for pivotal toxicological studies, and clinical
> trials. The purpose of the study is to determine the identity and
> concentration of leachables in the drug product or placebo
> formulation, through the end of the shelf life of the drug product.
> Accelerated temperature conditions may be employed to predict the
> leachables profile prior to reaching the end of product shelf life.
> The leachables study is carried out after the completion of the
> qualitative and quantitative characterization of extractables in the
> delivery system components.**
>
> **For DPI's and inhalation solutions, the leachables study should be
> conducted on the drug product packaging configuration employed for
> long term stability studies (*e.g.,* capsule with blister, low density
> polyethylene vial with overwrap).**
>
> **An in-use study should be conducted in order to determine the
> leachables derived from components which are in contact with either
> the formulation or the patient's mouth or nasal mucosa only during
> administration (such as mouthpieces and actuators).**
>
> **The analytical methods employed for the leachables studies should be
> validated for target compounds representative of those identified in
> the controlled extraction studies, following the International
> Conference on Harmonization (ICH) requirements for the validation of
> analytical methods for impurities. An assessment of the formulation
> may be done to investigate target leachables. Reasonable attempts
> should be made to evaluate method performance at or near the expected
> leachable levels.**
>
> **Method quantitation limits should be sufficient for the detection of
> predicted leachable levels (based on component extractables data).**
>
> **Table 4 presents guidance for reporting and identification
> thresholds for leachables in inhaled and nasal drug products. These
> levels are consistent with current industry practices, and with the
> capabilities of the previously mentioned analytical techniques. The
> risk assessment and justification for these levels are presented in
> section VI of this document.**

**[Table 4. Reporting and identification thresholds for
leachables]{.underline}**

+------------+-------------+-------------+-------------+------------+
|            | *           | ***Ide      | ***Ide      | ***Iden    |
|            | **Reporting | ntification | ntification | tification |
|            | threshold   | threshold   | threshold   | threshold  |
|            | for         | for         | for         | for        |
|            | le          | le          | le          | lea        |
|            | achables*** | achables*** | achables*** | chables*** |
|            |             |             |             |            |
|            |             | **          | **          | ***        |
|            |             | *(tentative | *(confident | (confirmed |
|            |             | str         | str         | stru       |
|            |             | uctures)*** | uctures)*** | ctures)*** |
+------------+-------------+-------------+-------------+------------+
| > *        | **\~0.2     | **\~0.2     | **\> 0.2    | **\~2      |
| *Leachable | μg/day**    | μg/day**    | μg/day**    | μg/day**   |
| > level    |             |             |             |            |
| > based on |             |             | **to \< 2   |            |
| > total    |             |             | μg/day**    |            |
| > daily    |             |             |             |            |
| > intake   |             |             |             |            |
| > (TDI)**  |             |             |             |            |
+------------+-------------+-------------+-------------+------------+

**[Confirmed Structures]{.underline}: identification categories A, B (or
C), and D (or E) (see Table 2) are positive.**

**[Confident Structures]{.underline}: sufficient data to preclude all
but the most closely related structures.**

**[Tentative Structures]{.underline}: data is consistent with a class of
molecule only.**

> **Note that for certain classes of potential leachable compounds with
> special toxicological concerns (*e.g.,* nitrosamines, PNA's,
> mercaptobenzthiazole, etc.), much lower reporting thresholds,
> dedicated methods, and appropriate specifications may be required.**
>
> **The identities and levels of leachables should be determined in the
> drug product (or placebo) after storage at or near expiry. The
> identities and profiles of leachables should be compared with the
> elastomeric and plastic component extractables profiles obtained from
> the controlled extraction studies.**
>
> **Provided that a correlation between leachables and extractables can
> be demonstrated, a specification for leachable compounds in the drug
> product will not be required. *A correlation is established when each
> leachable in the drug product can be assigned
> [qualitatively]{.underline}, directly or indirectly, to an
> extractable.***
>
> **The level and profile of leachables in drug product will be
> controlled by routine extractables testing of components in order to
> ensure that no new extractables are introduced and that there is no
> significant increase in the level of extractables.**

**[V. Routine Extractables Testing]{.smallcaps}**

**[A. General Recommendations]{.underline}**

Routine extractables testing is addressed in lines 898-905,
1004-1014,1081-1089, and 1182-1190 of the draft MDI/DPI Guidance, and
lines 924-942 of the draft Nasal/Nebulizer Guidance.

The Leachables and Extractables Team recommends that routine control of
extractables be dictated primarily by current Good Manufacturing
Practices (cGMPs). The cGMPs require that quality be built into all
aspects of the manufacturing process as is necessary to ensure the
product possesses the purported quality and purity.

**[B. Proposed Alternate Language for CMC Guidances for
OINDP]{.underline}**

> **The purpose of routine component extractables testing is to ensure
> that the extractables profiles of the components used for commercial
> drug product manufacture remain consistent with the profiles of the
> components evaluated as part of the development controlled extraction
> study. This testing is not a substitute for suitable elastomer and
> plastic formulation controls, which are the responsibility of the
> component supplier.**
>
> **Routine extractables testing is required on those components which
> contact either the drug product and/or the patient's mucosa. Critical
> components which do not contact the patient's mouth or nasal mucosa or
> the drug product should be controlled by tests which are relevant to
> their performance or functional attributes. Routine extractables
> testing of these components is not required.**
>
> **Routine extractables testing should be performed at the earliest
> point possible. Preferably, this testing should take place at the
> component manufacturer, and become a part of a system of manufacturing
> controls, along with in-process controls and supplier qualification.
> Routine extractables testing on plastic resins may be performed if a
> correlation can be established between the extractables profile of the
> resin and finished components.**
>
> **Based on the analytical evaluation of the extractables from the
> controlled extraction study and the toxicological evaluation of
> leachables (see section VI), the applicant should establish
> discriminatory test methods and set appropriate acceptance criteria
> for the extractable profile(s) for routine testing of the incoming
> individual components.**
>
> **The specifications should be established in order to control for
> significant changes as well as the appearance of new peaks in the
> extractables profile. The test methods employed in routine extraction
> studies should be documented and validated in accordance with ICH
> requirements for impurities. It is recognized that authentic materials
> of extractables may not be available. In such instances, it is
> acceptable to employ individual compounds as representative of
> compound classes for validation studies and as quantitation standards.
> Method performance should be assessed at or near the expected
> extractables levels.**

**[VI. Qualification of Leachables]{.smallcaps}**[^4]

**[A. General Recommendations]{.underline}**

The ITFG/IPAC-RS Toxicology Working Group has reviewed current industry
practices of evaluating the safety of extractables and leachables. The
Working Group compared these practices with the toxicological evaluation
procedures in the two draft Guidances, and concluded that there are both
areas of agreement and disagreement.

The following is a list of current industry practices that differ from
those in the draft Guidances and that we recommend be adopted in the
next version of the draft Guidances:

1.  Qualification should be performed only on leachables.

2.  Qualification should be conducted only on those leachables that
    occur above data-supported thresholds.

3.  Qualification of a product-related leachable composite mixture is
    sufficient to qualify those leachables for registration.

4.  For qualification, product samples should be qualitatively
    representative of the end-of-shelf life leachable profiles.

5.  Risk assessment of leachables may come from one or more of the
    following data sources: in-silico, structure-activity relationships
    (SAR), literature, in-vitro or in-vivo testing.

6.  For component suppliers, United States Pharmacopoeia (USP) \<87\>
    and \<88\> may have utility for extractable testing. However for a
    pulmonary drug product, USP \<87\> and \<88\> are not necessary when
    a more comprehensive in-vivo toxicological evaluation is available.

7.  Acceptance criteria for components should be based on extractable
    profiles.

In addition, the Toxicology Working Group recommends that:

8.  The draft Guidances should clarify the risk assessment modeling
    approach for carcinogenic extractables that are also leachables.

9.  Each draft Guidance should include an additional section describing
    the recommended toxicological evaluation process, along with a
    flowchart and glossary.

Below, we present detailed recommendations reflecting these
considerations:

-   the proposed alternate language (see section B below);

-   the proposed process of toxicological evaluation recommended for
    inclusion in the draft Guidances (see section C below); and

-   a justification of the proposed qualification threshold for
    leachables (see section D below).

**[B. Proposed Alternate Language for CMC Guidances for
OINDP]{.underline}**

Text highlighted in **bold** indicates proposed new language.

**For Inclusion in Draft MDI/DPI Guidance:**

+-----------+----------------------------------------------------------+
| ***Lines  | ***Proposed Alternative Language for Draft Guidance on   |
| of Draft  | Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI)  |
| Gu        | Drug Products***                                         |
| idance*** |                                                          |
+===========+==========================================================+
| **        | Toxicological evaluation, where appropriate, of the      |
| *853-4*** | **leached** materials and residues                       |
+-----------+----------------------------------------------------------+
| ***866*** | A toxicological appraisal of the **leachables** and      |
|           | residual materials should be...                          |
+-----------+----------------------------------------------------------+
| **        | For coated containers, **controlled** extraction studies |
| *883-4*** | should be performed and the profile of each extract      |
|           | should be evaluated **analytically. Only extractables    |
|           | that are found to be leachables should be evaluated      |
|           | toxicologically.**                                       |
+-----------+----------------------------------------------------------+
| **        | A toxicological appraisal of the **leachables** should   |
| *888-9*** | be provided. The results of USP Biological Reactivity    |
|           | Tests (USP \<87\> and \<88\>) should also be submitted,  |
|           | **unless other data are available as an acceptable       |
|           | substitute.**                                            |
+-----------+----------------------------------------------------------+
| **        | A toxicological appraisal of **leachable** residues from |
| *895-7*** | manufacture or canister cleaning should be provided. The |
|           | results of USP Biological Reactivity Tests (USP \<87\>   |
|           | and \<88\>) should be submitted**, unless other data are |
|           | available as an acceptable substitute.**                 |
+-----------+----------------------------------------------------------+
| ***8      | **Based on the analytical evaluation from the controlled |
| 99-902*** | extraction study, residue studies and toxicological      |
|           | evaluation of leachables and leachable residues, the     |
| (New text | applicant should establish discriminatory test methods   |
| refers to | and set appropriate acceptance criteria for the          |
| residues  | extractable profile(s) and the residues for routine      |
| and       | testing of the incoming containers.**                    |
| residue   |                                                          |
| studies,  |                                                          |
| and       |                                                          |
| excludes  |                                                          |
| re        |                                                          |
| quirement |                                                          |
| for       |                                                          |
| toxi      |                                                          |
| cological |                                                          |
| e         |                                                          |
| valuation |                                                          |
| of        |                                                          |
| extr      |                                                          |
| actables) |                                                          |
+-----------+----------------------------------------------------------+
| ***939*** | Toxicological evaluation of the **leachables**           |
+-----------+----------------------------------------------------------+
| **        | A toxicological appraisal of the **leachables**, ....    |
| *951-2*** |                                                          |
+-----------+----------------------------------------------------------+
| **        | The profile of each extract should be evaluated          |
| *990-1*** | analytically**, but only leachables require a            |
|           | toxicological evaluation.**                              |
+-----------+----------------------------------------------------------+
| **        | The toxicological evaluation should include appropriate  |
| *994-6*** | in vitro and in vivo tests. The results of USP           |
|           | Biological Reactivity Tests (USP \<87\> and \<88\>)      |
|           | should be submitted**, unless other data are available   |
|           | as an acceptable substitute.**                           |
+-----------+----------------------------------------------------------+
| ***99     | **In those cases such as when some extractable           |
| 9-1000*** | components from rubber are known genotoxicants, known    |
|           | rodent carcinogens or have compelling structural alerts  |
|           | (*e.g.,* nitrosamines, PNA\'s, mercaptobenzthiazole,     |
|           | etc.), appropriate risk assessment models may be needed  |
|           | to establish acceptance criteria if that extractable     |
|           | component is found as a leachable in drug product.**     |
+-----------+----------------------------------------------------------+
| ***       | **Based on the analytical evaluation from the controlled |
| 1005-8*** | extraction study and toxicological evaluation of         |
|           | leachables,** the applicant should establish             |
| ##        | discriminatory test methods and set appropriate          |
|           | acceptance criteria for the extractable profile(s) for   |
|           | routine testing of the incoming individual valve         |
|           | components.                                              |
+-----------+----------------------------------------------------------+
| *         | Toxicological evaluation of the **leachables**           |
| **1049*** |                                                          |
+-----------+----------------------------------------------------------+
| *         | **The profile of each extract should be evaluated        |
| **1073*** | analytically, but only leachables require a              |
|           | toxicological evaluation.**                              |
+-----------+----------------------------------------------------------+
| ***1      | Safety concerns will usually be satisfied if the         |
| 078-80*** | materials in the components meet food additive           |
|           | regulations and the actuator meets the USP Biological    |
|           | Reactivity Tests (USP \<87\> and \<88\>). **However, if  |
|           | other acceptable data are available, then USP Biological |
|           | Reactivity Tests (USP \<87\> and \<88\>) need not be     |
|           | performed.**                                             |
+-----------+----------------------------------------------------------+
| *         | **Based on the analytical evaluation from the controlled |
| **1082*** | extraction study and toxicological evaluation of         |
|           | leachables,** the applicant should establish             |
|           | discriminatory test methods and set appropriate          |
|           | acceptance criteria for the extractable profile(s) for   |
|           | routine testing of the incoming actuator component(s).   |
+-----------+----------------------------------------------------------+
| *         | Toxicological evaluation of the **leachables**           |
| **1132*** |                                                          |
+-----------+----------------------------------------------------------+
| ***       | The profile of each **extract from a critical component  |
| 1171-5*** | in contact with the formulation or the patient's mouth   |
|           | or nasal mucosa**, should be evaluated analytically**,   |
|           | but only leachables require a toxicological              |
|           | evaluation.**                                            |
+-----------+----------------------------------------------------------+
| ***       | Safety concerns will usually be satisfied if the         |
| 1175-8*** | components that contact either the patient or the        |
|           | formulation meet food additive regulations and the       |
|           | mouthpiece meets the USP Biological Reactivity Tests     |
|           | (USP \<87\> and \<88\>). **However, if other acceptable  |
|           | data are available, then USP Biological Reactivity Tests |
|           | (USP \<87\> and \<88\>) need not be performed.**         |
+-----------+----------------------------------------------------------+
| *         | **Based on the analytical evaluation from the controlled |
| **1184*** | extraction study and toxicological evaluation of         |
|           | leachables,** the applicant should establish             |
| ##        | discriminatory test methods and set appropriate          |
|           | acceptance criteria for the extractable profile(s) for   |
|           | routine testing of incoming individual critical device   |
|           | components                                               |
+-----------+----------------------------------------------------------+

# **For Inclusion in Draft Nasal/Nebulizer Guidance:**

  --------------------------------------------------------------------------
  ***Lines of     ***Proposed Alternative Language for Draft Guidance on
  Draft           Nasal Spray and Inhalation Solution, Suspension and Spray
  Guidance***     Drug Products***
  --------------- ----------------------------------------------------------
  ***860***       Toxicological evaluation of **leachables**

  ***904-5***     Extraction studies should be performed, and the profile of
                  each extract should be evaluated **analytically. Only
                  extractables that are found to be leachables will be
                  evaluated toxicologically.**

  ***908-10***    A toxicological evaluation should be made of the
                  **leachables** from the container, closure, and critical
                  pump components **(those in contact with either the
                  formulation or the patient's mouth or nasal mucosa)** and
                  the results submitted in the application.

  ***912-13***    The results of USP Biological Reactivity Tests (USP \<87\>
                  and \<88\>) should be submitted. **However, if other
                  acceptable data are available, then USP Biological
                  Reactivity Tests (USP \<87\> and \<88\>) need not be
                  performed.**

  ***919-920***   Since some extractables may be carcinogenic, appropriate
                  risk assessment models may be needed to establish
                  acceptance criteria, **if these extractable components are
                  found to be leachables in the drug product.**

  ***926-29***    **Based on the analytical evaluation from the controlled
                  extraction study and toxicological evaluation of
                  leachables,** the applicant should establish
                  discriminatory test procedures and set appropriate
                  acceptance criteria for the extractable profile(s) for
                  routine testing for each container, closure, and
                  individual pump components **(those in contact with either
                  the formulation or the patient's mouth or nasal mucosa)**.
  --------------------------------------------------------------------------

**[C. Proposed Toxicological Evaluation Process]{.underline}**

The Toxicology Working Group is proposing an approach to evaluation of
leachables that recognizes the importance of regulations and guidelines
that focus resources on substantive matters concerned with the benefits
and safety of inhaled products to patients. The approach also recognizes
a threshold below which trace leachables need not be evaluated unless
there are special concerns about the structure.

The Toxicology Working Group recommends that the following flowchart
(Figure 2), description of the toxicological evaluation process and
glossary entries be incorporated in the revised draft Guidances.

The Working Group recognizes that like all guidelines, the following
recommendations may not cover all situations and that special,
case-by-case considerations may be warranted in some instances.

A key element in the safety evaluation process is defining a threshold
below which leachables would not need to undergo qualification. A
rationale for the proposed qualification threshold for leachables is
contained in Section D*.*

**[Figure 2. Decision flowchart for evaluating toxicity and risk
evaluation (recommended for incorporation in CMC guidances for
OINDP)]{.underline}**

**\*Note that for certain classes of potential leachable compounds with
special toxicological concerns \[*i.e.,* nitrosamines, polynuclear
aromatics (PNAs), mercaptobenzthiazole, etc.\] much lower reporting
thresholds, dedicated methods, appropriate specifications, and
appropriate qualifications and risk assessments may be required.**

> **DESCRIPTION OF TOXICOLOGICAL EVALUATION PROCESS**
>
> **(Recommended for incorporation in CMC guidances for OINDP)**
>
> **[1. Collection of Toxicology Data]{.underline}**
>
> **Evaluate the potential toxicity of each leachable above the
> qualification threshold based on the intended route of administration
> (mostly through inhalation, although ingestion through swallowing is
> also likely), duration of treatment in patients, and the patient
> population (men, women of child-bearing potential, pediatrics, etc) at
> risk.**
>
> **Where sufficient toxicological information is not available in the
> literature on a specific leachable, but the class of chemical presents
> a structural alert, based upon structure activity relationship (SAR)
> analysis, additional safety testing may be warranted. The toxicology
> studies to be considered, depending on the alert, may include in vitro
> genotoxicity assays and 2-13 week general toxicity studies in the most
> appropriate species, using the drug product and the leachable (at a
> concentration, where possible, greater than or equal to that which
> will be present in the drug product at the end of the shelf life).**
>
> **[2. Qualification and Reporting Thresholds and Risk
> Assessment]{.underline}**
>
> **Based on the concentration of the leachable present in the drug
> product, calculate the total daily intake (TDI) of the leachable that
> a patient will be exposed to according to the maximum daily dose of
> the drug product. Use the assumption that the entire inhaled dose is
> delivered to the lung.**
>
> **If a leachable is present at a level below the reporting threshold
> (usually 0.2 μg TDI, see Table 4), it is considered qualified and no
> toxicological assessment is required. In general, a leachable with a
> TDI of 0.2 μg or less will have a dose so low as to present no safety
> concerns for patients using the product. However for certain classes
> of potential leachable compounds with special toxicological concerns
> \[*e.g*., nitrosamines, polynuclear aromatics (PNA\'s),
> mercaptobenzthiazole, etc.\], much lower reporting thresholds,
> dedicated methods, appropriate specifications and appropriate
> qualifications and risk assessments may be required. Such leachables
> will be considered on a case-by-case basis.**
>
> **If a leachable is present at level that will result in a TDI greater
> than 0.2 μg and less than or equal to 5 μg, SAR should be performed to
> determine if the leachable shows a structural alert. The amount of
> structural information available for SAR is dependent upon the TDI
> (see Table 4). For instance, for a leachable present at a TDI of
> approximately 0.2 μg the data available may only be sufficient to
> assign the structure to a chemical class. As the level of a leachable
> increases, up to 2 μg TDI, the degree of certainty in the assignment
> would be expected to increase until finally, for a TDI of
> approximately 2 μg or greater, the structure of the leachable can be
> confirmed.**
>
> **If a leachable shows no structural alert or no known class effect
> for carcinogenicity/genotoxicity or immediate hypersensitivity, and it
> is present at a level that will result in a TDI greater than 0.2 μg
> and less than or equal to 5 µg, it is considered qualified and no
> toxicological assessment is required.**
>
> **If a leachable shows a structural alert or a class effect for
> carcinogenicity/genotoxicity or immediate hypersensitivity, and it is
> present at a level that will result in a TDI greater than 0.2 μg and
> less than or equal to 5 μg, a toxicology risk assessment should be
> performed. Compare the TDI of the leachable to study results, or the
> toxicology data reported in the literature, to see if a sufficient
> safety margin exists.**
>
> **If any leachable is present at a level that will result in a TDI of
> greater than 5 µg, a toxicology risk assessment should be performed.
> Compare the TDI of the leachable to study results, or the toxicology
> data reported in the literature, to see if sufficient safety margin
> exists.**
>
> **Some of the leachables (*e.g*., phthalates, ethyl acetate) may be
> present in the environment at considerable concentrations where daily
> ingestion (through food or water) and inhalation (through air) occur.
> If the TDI of a leachable is estimated to be greater than 5 µg but
> lower than that reported for humans through environmental exposure,
> and the epidemiology data do not indicate adverse effects, then it may
> be possible to justify a higher level of qualification on a
> case-by-case basis.**
>
> **GLOSSARY**
>
> **[Qualification]{.underline} All data from testing (*e.g.,*
> toxicology data, literature data, SAR data, clinical safety
> experience).**
>
> **[Toxicological Studies]{.underline} Includes animal studies and
> in-vitro studies beyond those available in the literature.**
>
> **[Risk Assessment]{.underline} Evaluation of data obtained through
> qualification and toxicological studies (as defined above) to define
> potential risks relative to therapeutic use of the product.**

**[D. Justification of Proposed Qualification Threshold]{.underline}**

**[1. Introduction]{.underline}**

This section provides a scientific rationale, based on available data,
for the toxicological qualification and acceptance of leachables
(non-drug-related impurities) in inhaled drug products using a threshold
value of 5 μg per leachable for a total daily exposure irrespective of
age and disease severity.

We first provide a brief overview of the concept of inhaled drug product
leachables, and some background information on the current regulatory
approaches to controlling these leachables. We follow with a brief
summary of typical sources of leachables, then provide a rationale and
process for establishing the 5 μg threshold value. We then examine the
significance of this threshold in the context of two marketed inhaled
drug products, and also compare it to threshold data for compounds in
some approved inhaled drug products.

**[2. Background]{.underline}**

Inhalation drug products are developed for delivery of drug substance
directly to the respiratory tract to treat either a local condition
\[*e.g.*, asthma or chronic obstructive pulmonary disease (COPD)\] or a
non-respiratory disease (*e.g.*, diabetes). Inhaled drug substances are,
by far, some of the most potent chemical entities that are administered
to humans. These drugs are usually presented in delivery devices,
(*e.g.*, metered dose inhalers, dry powder inhalers or nasal spray
inhalers/pumps). These devices may contain polymers, elastomers, and
other components from which minute quantities of material may migrate
(leach) into the product and be delivered to the sensitive surfaces of
the respiratory tract along with the therapeutic agent. While every
effort is taken to reduce the levels of these leachables, complete
removal is not possible.

ICH guidelines, Q3A and Q3B cover the internationally agreed principles
for impurities in drug substances and products, respectively and the ICH
Q3C[^5] guideline covers the acceptable levels of residual solvents
allowable. These guidelines are being considered by the FDA, and have
been published in the Federal Register. According to the guidelines,
*the level of any degradation product present in a new drug product that
has been adequately tested and found safe in safety and/or clinical
studies is considered qualified.* However, identification and
qualification limits of leachable materials associated with a pulmonary
product have been held to a higher standard. This is most likely because
leachables are non-drug related impurities and may possess toxicity
characteristics unlike those associated with the drug substance or drug
product.

For instance, a metered dose inhaler (MDI) has been demonstrated to
accurately deliver low doses of drug substance to the lung. However, it
is also understood that the propellants employed in MDIs are reasonably
good solvents and will cause a certain amount of materials to leach from
the rubber-based and polymeric components in MDI delivery devices.
Because these are non-drug-related impurities, there could be an
increased concern for human risk by inhaling these leachates on a daily
basis.

Historically, acceptable levels of leachables in a pulmonary drug
product have been set by negotiation on a case-by-case basis with no
standard guidelines available.

**[3. Potential Sources of Leachables]{.underline}**

Historically, leachables in inhaled drug products tend to arise from:

-   Polymers

-   Elastomers

-   Adhesives and curing agents

-   Metal components

-   Dyes and pigments

-   Mould release agents

During product development, careful consideration is given to the choice
and rationale for selection of the components that go into the final
drug product. The selection criteria are outside the detailed scope of
this document. However, we recommend, wherever possible, that the
materials selected comply with accepted materials for food contact or
incidental food use and/or generally recognized as safe (GRAS)
materials.

### [4. Rationale for Setting a Qualification Threshold]{.underline}

Analytical techniques are increasingly sophisticated and capable of
detecting and identifying chemicals at picogram quantities. However, it
is generally accepted that there are levels of many chemicals below
which the risks to human health are so negligible as to be of no
consequence.

The premise of this document is that leachables present in inhalable
drug products when held below a qualification level are not of concern.

**[5. Establishment of a Threshold Limit (Qualification
Limit)]{.underline}**

In this section the approach to establishing a threshold limit
(qualification limit) is reviewed. The factors influencing the potential
dose of an inhalable drug product and leachables contained in the
product are reviewed. Next, representative data from the scientific
literature are used to calculate volumes of air inspired by individuals.
In the next step, the quantity of inhalable particles respired by
representative individuals exposed to levels of ambient air particles in
a typical clean United States city are calculated. These levels are well
below the standards established by the United States Environmental
Protection Agency (USEPA) as being protective of public health,
including sensitive sub-populations, with an ample margin of safety.

Finally, these levels of inhaled particulate matter are compared to a
proposed threshold limit or qualification limit of 5 μg per day. The
resulting comparison shows that the proposed qualification limit of 5 μg
per day represents a small fraction of the quantity of material
individuals are normally inhaling.

The likely patient dose of a leachable from an inhaled drug product will
be related principally to the following factors:

-   Concentration of leachable in the inhaler

-   Number of doses taken each day

-   Inspiratory volume of the patient

-   Weight of the patient

-   Disease state.

We have considered the data in the context of each of these factors.
Table 5 defines the respiratory values that have been taken into
consideration:

## **[Table 5.]{.underline} Ventilation rate (m^3^/h) of patients related to age and exercise**

+------------+-----------------+------------+------------+------------+
| Age        | Re              | Sitting    | Light      | Heavy      |
|            | sting(Sleeping) | awake      | exercise   | exercise   |
|            |                 |            |            |            |
|            | Males/Females\* | M/F        | M/F        | M/F        |
+------------+-----------------+------------+------------+------------+
| 1 year     | 0.15            | 0.22       | 0.35       | \-         |
+------------+-----------------+------------+------------+------------+
| 10 years   | 0.31            | 0.38       | 1.12       | 2.22/1.84  |
+------------+-----------------+------------+------------+------------+
| 30 years   | 0.45/0.32       | 0.54/0.39  | 1.5/1.26   | 3.0/2.7    |
+------------+-----------------+------------+------------+------------+

\*Data quoted for males and females separately where given in original
reference.[^6]

The same paper[^7] indicates the daily-inhaled volumes for different
ages and mixed daily activities and may be used for estimating likely
human exposures. These data are for "normal" healthy subjects. In
contrast, patients using inhalers, by definition, have compromised
respiratory function. The *International Asthma Guidelines*[^8] have
been used *as an approximation*, to adjust these normal volumes for
compromised patients. These guidelines define patients with mild asthma
as having a peak expiratory flow rate (PEFR) of \> 80% of normal,
moderate asthma as a PEFR as 60-80% and severe asthma as \< 60% of
normal.

Using the data from Table 5 and applying such correction factors for
disease state, estimates of the daily inhaled volumes for different
patients may be made as shown in Table 6.

[Table 6.]{.underline} Approximation of daily-inhaled volume (m^3^) for
patients of different ages and disease states.

+---------+-------------+---------------+-------------+--------------+
| Age     | Mild Asthma | Moderate      | Severe      | Normal ^\*^  |
|         |             | Asthma        | Asthma      |              |
|         | (80% of     |               |             | (for         |
|         | normal)     | (70% of       | (60% of     | comparison)  |
|         |             | normal)       | normal)     |              |
+---------+-------------+---------------+-------------+--------------+
| 1 year  | 4.11        | 3.60          | 3.08        | 5.14         |
+---------+-------------+---------------+-------------+--------------+
| 10years | 12.2        | 10.7          | 9.18        | 15.3         |
+---------+-------------+---------------+-------------+--------------+
| 30      | 14.2        | 12.5          | 10.7        | 17.8         |
| years   |             |               |             |              |
+---------+-------------+---------------+-------------+--------------+

^\*^Adapted from Roy, M., 1992

In the next step, the estimated quantities of air respired are combined
with typical concentrations of airborne particulate material that might
be inhaled by individuals. The USEPA under the authority of the *Clean
Air Act* establishes National Ambient Air Quality Standards (NAAQS) for
particulate matter. These standards are set to protect public health,
including sensitive sub-populations, with an ample margin of safety.

The current NAAQS[^9] for PM~10~ (the inhalable fraction) is set at 150
μg/m^3^ , twenty-four hour average, and 50 μg/m^3^ , annual average. The
PM~2.5~ (the fine particle fraction) is set at 65μg/m^3^ , twenty-four
hour average, and 15 μg/m^3^, annual average. The inhalable fraction,
PM~10,~ is assumed to include the range of particle sizes present in
inhalable products and, thus, the PM~10~ fraction is used for comparison
calculations.

A concentration of 18 μg/m^3^ is used for calculation of comparison
values. The 18 μg/m^3^ value was reported by Dockery, *et. al.*[^10] for
Portage, Wisconsin, the cleanest of six cities studied intensively to
establish an association between air pollution and adverse health
outcomes. This was a key study used in setting the NAAQS for particulate
matter. Portage had the best air quality and the least
cardio-respiratory disease. It was therefore used as the "control" city,
against which other cities were compared. For reference, as reported by
Daniels *et. al.,*[^11] people living in the twenty largest cities in
the United States would all be exposed to higher concentrations of
particulate matter than people in Portage.

Using the Portage air concentration for PM~10~ (18 μg/m^3^), and the
respiratory values from Table 6, the daily exposure of patients to
environmental inhalable particles is calculated (Table 7) for total
exposure (μg) and relative to body weight (μg/kg). These results have
been based, where possible, on the FDA guidelines for bodyweight (1
year, 10 kg; 10 years, 25 kg; and 30 years, 50 kg). Obviously, the
values in Table 7 would be even larger if the allowable twenty-four hour
average NAAQS for PM~10~ (150 μg/m^3^) had been used to make the
calculations.

**[Table 7.]{.underline} Estimates of the daily inhalable quantities
(μg) of environmental particulates for patients using Portage WI, USA,
inhalable particle concentrations (18 μg/m^3^)**

+-------+------+------------+--------------+------------+------------+
| Age   |      | Mild       | Moderate     | Severe     | Normal     |
|       |      | Asthma     | Asthma       | Asthma     |            |
|       |      |            |              |            | (for       |
|       |      | (80% of    | (70% of      | (60% of    | c          |
|       |      | normal)    | normal)      | normal)    | omparison) |
+-------+------+------------+--------------+------------+------------+
| 1     | (μg) | 74.0       | 64.8         | 55.4       | 92.5       |
| year  |      |            |              |            |            |
+-------+------+------------+--------------+------------+------------+
|       | (μg  | 7.40       | 6.48         | 5.54       | 9.25       |
|       | /kg) |            |              |            |            |
+-------+------+------------+--------------+------------+------------+
| 10    | (μg) | 220        | 193          | 165        | 275        |
| years |      |            |              |            |            |
+-------+------+------------+--------------+------------+------------+
|       | (μg  | 8.8        | 7.72         | 6.6        | 11.0       |
|       | /kg) |            |              |            |            |
+-------+------+------------+--------------+------------+------------+
| 30    | (μg) | 256        | 225          | 193        | 320        |
| years |      |            |              |            |            |
+-------+------+------------+--------------+------------+------------+
|       | (μg  | 10.2       | 9.0          | 7.72       | 12.8       |
|       | /kg) |            |              |            |            |
+-------+------+------------+--------------+------------+------------+

***Based on these data we propose a limit of 5μg per day of a leachable.
Below this limit no qualification should be required.*** A 5 μg per day
intake of a leachable would represent an amount of between 1 and 0.1
μg/kg/day and is between 2 and 10% of the estimated inhalable quantities
of environmental particulate matter for mild to severe asthmatics
described above.

Table 8 shows the 5 μg qualification limit as a percent of environmental
particulate matter inhaled from ambient air, for different populations.
These percentages would be even smaller if the comparison were being
made to air concentrations of PM~10~ in major cities, or to
concentrations equal to the NAAQS for PM~10~, a value considered to be
protective of public health with an ample margin of safety even for
sensitive sub-populations.

**[Table 8.]{.underline} 5 μg qualification limit expressed as a
percentage of the potential daily particulate inhaled from ambient air**

+---------+-------------+--------------+---------------+-------------+
| Age     | Mild Asthma | Moderate     | Severe Asthma | Normal      |
|         |             | Asthma       |               |             |
|         | (80% of     |              | (60% of       | (for        |
|         | normal)     | (70% of      | normal)       | comparison) |
|         |             | normal)      |               |             |
+---------+-------------+--------------+---------------+-------------+
| 1 year  | 6.8         | 7.7          | 9.0           | 5.4         |
+---------+-------------+--------------+---------------+-------------+
| 10years | 2.3         | 2.6          | 3.0           | 1.8         |
+---------+-------------+--------------+---------------+-------------+
| 30      | 1.9         | 2.2          | 2.6           | 1.6         |
| years   |             |              |               |             |
+---------+-------------+--------------+---------------+-------------+

As seen, even for the severe asthmatic patient, the 5μg qualification
limit represents a small fraction of particulate material the individual
may inhale from ambient air. The 5μg per day limit, taking into
consideration the risk/benefit to MDI patients, represents a minor
additional load on the respiratory tract compared to the daily
environmental exposure. Additionally, 5μg is considered a worst case
since, by design, it is considered a total respiratory tract burden, and
does not take into account differential lung deposition, oral deposition
and swallowing.

### [6. Threshold Applied to Typical Inhaled Drug Products]{.underline}

We examine the significance of the threshold for inhaled drug products
by applying it to ATROVENT Inhalation Aerosol and FLOVENT Inhalation
Aerosol ‑ two marketed products that represent a low and high range of
TDI for an inhaled product. When taken as recommended, ATROVENT
Inhalation Aerosol delivers 18 μg/actuation and up to 12 actuations can
be administered for a total daily dose of 216 μg/day. Following the
rationale outlined above, 5μg of a leachable would represent 2% of the
TDI. For FLOVENT Inhalation Aerosol, the highest recommended TDI is
1960 μg/day. In this case, a leachable present at 5 μg would represent
just 0.3% of the TDI.

### [7. Other Considerations]{.underline} 

The 5 μg/day (\< 1 μg/kg) threshold for a leachable in an inhaled drug
product can be put into perspective by considering other compounds in
some approved inhaled drug products.

The proposed FDA specifications for the alternative propellant HFA 134a,
include limits of 5 ppm for "total unsaturates" [^12] in the propellant.
Unsaturated compounds are highly reactive species and a patient could
easily receive 16 actuations a day (4 doses of a steroid, 4 of a long
acting β~2~-agonist and 8 actuations or more of a rescue medication).
Under these circumstances the patient could inhale 8 μg of an
unsaturated compound, which is more than the proposed leachable
threshold.

Another example can be drawn from a typical valve leachable.
2,2,4,6,6-pentamethyl-hept-3-ene (CAS 123-8-8) is a typical leachable
present in some MDI formulations. Takagi *et. al.,*[^13] quoted a
no-effect oral dose of 0.03% in the diet during chronic preclinical
studies of up to 18 months duration. This represented doses of
approximately 18 mg/kg/day. Applying the Agency's safety factors of
100[^14] an acceptable daily intake would be equivalent to NOEL/100 or
0.18 mg/kg/day some 360-1800 times greater than the proposed threshold.

**[8. Conclusions]{.underline}**

The information provided in this paper provides a scientific rationale
to establish a qualification limit of 5 μg per leachable for TDI from
individual inhalable drug products.

Based on the information provided in this technical review:

-   The current ICH guideline (Q3B) for impurities and degradants in
    drug product is considered inappropriate for leachables; and

```{=html}
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```
-   A 5 μg TDI limit for qualification of a leachable will adequately
    protect the safety of patients.

The weight of scientific evidence strongly supports the use of a 5 μg
TDI for qualification of leachables associated with inhaled
pharmaceutical products. Establishment of a 5 μg TDI threshold will
allow preclinical evaluations to focus on substantive issues related to
product safety and avoid evaluation of trace leachables unless
structural information indicates a basis for further evaluation. This
strategy provides a high level of assurance that these products are safe
for patient use.

**[VII. Summary Table of Recommended Leachables and Extractables
Testing]{.smallcaps}**

The following table summarizes the recommended strategy for leachables
and extractables testing for different product types. The Leachables and
Extractables Team recommends inclusion of this summary table in the CMC
guidances for OINDP.

+-----------+---------------+----------+---------+---------+--------+
| **Product |               | **Cont   | **Leach | **      | **R    |
| Type**    |               | rolled** | ables** | Routine | outine |
|           |               |          |         | Extract | Leach  |
|           |               | **Ex     | **      | ables** | able** |
|           |               | traction | Study** |         |        |
|           |               | Study**  |         | **Te    | **Tes  |
|           |               |          |         | sting** | ting** |
+-----------+---------------+----------+---------+---------+--------+
| **MDI**   | **Valve       | Yes      | N/A     | Yes     | N/A    |
|           | components**  |          |         |         |        |
|           |               |          |         |         |        |
|           | (polymeric    |          |         |         |        |
|           | and in        |          |         |         |        |
|           | contact with  |          |         |         |        |
|           | formulation)  |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | *             | Yes      | No      | Yes     | N/A    |
|           | *Mouthpiece** |          |         |         |        |
|           |               |          | (o      |         |        |
|           | (including    |          | ne-time |         |        |
|           | spacer, if    |          |         |         |        |
|           | attached)     |          | in-use  |         |        |
|           |               |          | study)  |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           |               |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Canister**  | Yes      | N/A     | Yes     | N/A    |
|           |               |          |         |         |        |
|           |               | (if      |         | (if     |        |
|           |               | coated)  |         | coated) |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Drug        | N/A      | Yes     | N/A     | No     |
|           | product**     |          |         |         |        |
|           |               |          |         |         | (if    |
|           |               |          |         |         | corre  |
|           |               |          |         |         | lation |
|           |               |          |         |         | with   |
|           |               |          |         |         | e      |
|           |               |          |         |         | xtract |
|           |               |          |         |         | ables) |
+-----------+---------------+----------+---------+---------+--------+

**Summary Table, continued**

+-----------+---------------+----------+---------+---------+--------+
| **Product |               | **Cont   | **Leach | **      | **R    |
| Type**    |               | rolled** | ables** | Routine | outine |
|           |               |          |         | Extract | Leach  |
|           |               | **Ex     | **      | ables** | able** |
|           |               | traction | Study** |         |        |
|           |               | Study**  |         | **Te    | **Tes  |
|           |               |          |         | sting** | ting** |
+-----------+---------------+----------+---------+---------+--------+
| **DPI**   | **Primary     | Yes      | N/A     | Yes     | N/A    |
|           | packaging**   |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Protective  | Case     | N/A     | Case-   | N/A    |
|           | secondary     | -by-case |         | by-case |        |
|           | packaging**   |          |         |         |        |
|           |               |          |         |         |        |
|           | (critical to  |          |         |         |        |
|           | the           |          |         |         |        |
|           | performance   |          |         |         |        |
|           | of the drug   |          |         |         |        |
|           | product)      |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | *             | Yes      | No      | Yes     | N/A    |
|           | *Mouthpiece** |          |         |         |        |
|           |               |          | (o      |         |        |
|           |               |          | ne-time |         |        |
|           |               |          | in-use  |         |        |
|           |               |          | study)  |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Polymeric   | Yes      | No      | Yes     | N/A    |
|           | components**  |          |         |         |        |
|           |               |          | (o      |         |        |
|           | (in direct    |          | ne-time |         |        |
|           | contact with  |          | in-use  |         |        |
|           | the           |          | study)  |         |        |
|           | formulation   |          |         |         |        |
|           | only during   |          |         |         |        |
|           | ad            |          |         |         |        |
|           | ministration) |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Drug        | N/A      | Yes     | N/A     | No     |
|           | product**     |          |         |         |        |
|           |               |          |         |         | (if    |
|           |               |          |         |         | corre  |
|           |               |          |         |         | lation |
|           |               |          |         |         | with   |
|           |               |          |         |         | e      |
|           |               |          |         |         | xtract |
|           |               |          |         |         | ables) |
+-----------+---------------+----------+---------+---------+--------+
| **Nasal** | **Pump        | Yes      | No      | Yes     | N/A    |
|           | components**  |          |         |         |        |
| **Spray** |               |          | (o      |         |        |
|           | (polymeric    |          | ne-time |         |        |
|           | and in        |          | in-use  |         |        |
|           | contact with  |          | study)  |         |        |
|           | formulation   |          |         |         |        |
|           | during        |          |         |         |        |
|           | ad            |          |         |         |        |
|           | ministration) |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Container** | Yes      | N/A     | Yes     | N/A    |
+-----------+---------------+----------+---------+---------+--------+
|           | **Actuator**  | Yes      | No      | Yes     | N/A    |
|           |               |          |         |         |        |
|           | (in contact   |          | (o      |         |        |
|           | with          |          | ne-time |         |        |
|           | formulation   |          | in-use  |         |        |
|           | during        |          | study)  |         |        |
|           | ad            |          |         |         |        |
|           | ministration) |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Drug        | N/A      | Yes     | N/A     | No     |
|           | Product**     |          |         |         |        |
|           |               |          |         |         | (if    |
|           |               |          |         |         | corre  |
|           |               |          |         |         | lation |
|           |               |          |         |         | with   |
|           |               |          |         |         | e      |
|           |               |          |         |         | xtract |
|           |               |          |         |         | ables) |
+-----------+---------------+----------+---------+---------+--------+

**Summary Table, continued**

+-----------+---------------+----------+---------+---------+--------+
| **Product |               | **Cont   | **Leach | **      | **R    |
| Type**    |               | rolled** | ables** | Routine | outine |
|           |               |          |         | Extract | Leach  |
|           |               | **Ex     | **      | ables** | able** |
|           |               | traction | Study** |         |        |
|           |               | Study**  |         | **Te    | **Tes  |
|           |               |          |         | sting** | ting** |
+-----------+---------------+----------+---------+---------+--------+
| **Inh     | **Primary     | Yes      | N/A     | Yes     | N/A    |
| alation** | Packaging**   |          |         |         |        |
|           |               |          |         |         |        |
| **Sol     | (polymeric)   |          |         |         |        |
| ution/Sus |               |          |         |         |        |
| pension** |               |          |         |         |        |
|           |               |          |         |         |        |
| (Intended |               |          |         |         |        |
| for use   |               |          |         |         |        |
| with      |               |          |         |         |        |
| generic   |               |          |         |         |        |
|           |               |          |         |         |        |
| n         |               |          |         |         |        |
| ebulizer) |               |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Protective  | Yes      | N/A     | Yes     | N/A    |
|           | Secondary     |          |         |         |        |
|           | Packaging**   |          |         |         |        |
|           |               |          |         |         |        |
|           | (critical to  |          |         |         |        |
|           | the           |          |         |         |        |
|           | performance   |          |         |         |        |
|           | of the drug   |          |         |         |        |
|           | product)      |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Drug        | N/A      | Yes     | N/A     | No     |
|           | Product**     |          |         |         |        |
|           |               |          |         |         | (if    |
|           |               |          |         |         | corre  |
|           |               |          |         |         | lation |
|           |               |          |         |         | with   |
|           |               |          |         |         | e      |
|           |               |          |         |         | xtract |
|           |               |          |         |         | ables) |
+-----------+---------------+----------+---------+---------+--------+
| **Inh     | **Primary     | Yes      | N/A     | Yes     | N/A    |
| alation** | Packaging**   |          |         |         |        |
|           |               |          |         |         |        |
| **Sol     | (polymeric)   |          |         |         |        |
| ution/Sus |               |          |         |         |        |
| pension** |               |          |         |         |        |
|           |               |          |         |         |        |
| (Intended |               |          |         |         |        |
| for use   |               |          |         |         |        |
| with      |               |          |         |         |        |
| pr        |               |          |         |         |        |
| oprietary |               |          |         |         |        |
| delivery  |               |          |         |         |        |
| system)   |               |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Protective  | Yes      | N/A     | Yes     | N/A    |
|           | Secondary     |          |         |         |        |
|           | Packaging**   |          |         |         |        |
|           |               |          |         |         |        |
|           | (critical to  |          |         |         |        |
|           | the           |          |         |         |        |
|           | performance   |          |         |         |        |
|           | of the drug   |          |         |         |        |
|           | product)      |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | *             | Yes      | No      | Yes     | N/A    |
|           | *Mouthpiece** |          |         |         |        |
|           |               |          | (o      |         |        |
|           | (including    |          | ne-time |         |        |
|           | spacer, if    |          |         |         |        |
|           | attached)     |          | in-use  |         |        |
|           |               |          | study)  |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Polymeric   | Yes      | No      | Yes     | N/A    |
|           | Components**  |          |         |         |        |
|           |               |          | (o      |         |        |
|           | (in direct    |          | ne-time |         |        |
|           | contact with  |          |         |         |        |
|           | the           |          | in-use  |         |        |
|           | formulation   |          | study)  |         |        |
|           | only during   |          |         |         |        |
|           | ad            |          |         |         |        |
|           | ministration) |          |         |         |        |
+-----------+---------------+----------+---------+---------+--------+
|           | **Drug        | N/A      | Yes     | No      | No     |
|           | product**     |          |         |         |        |
|           |               |          |         |         | (if    |
|           |               |          |         |         | corre  |
|           |               |          |         |         | lation |
|           |               |          |         |         | with   |
|           |               |          |         |         | e      |
|           |               |          |         |         | xtract |
|           |               |          |         |         | ables) |
+-----------+---------------+----------+---------+---------+--------+

**[VIII. Conclusion]{.smallcaps}**

The Leachables and Extractables Technical Team and the Toxicology
Working Group respectfully encourage the Agency to consider the
recommendations developed by the Team and to incorporate the same in the
next version of the draft CMC Guidance documents.

The Team would like to meet with the Agency in order to discuss these
proposals and, in particular, discuss and agree on recommendations
regarding reporting and toxicological qualification thresholds for
leachables. Furthermore, if the Agency considers it valuable, the
Leachables and Extractables Team, in collaboration with the Supplier
Quality Control Technical Team, will propose a control strategy
(including appropriate testing criteria) for ensuring the relevant
performance and safety characteristics of critical device components.

The ITFG/IPAC-RS Collaboration supports the Agency's efforts to develop
scientifically sound guidances for OINDP that will serve the needs of
the Agency, industry, and patients.

**[IX. Glossary]{.smallcaps}**

  ------------------ ---------------------------------------------------------
  **CAS**            Chemical Abstracts Service

  **CMC**            Chemistry, Manufacturing, and Controls

  **COPD**           Chronic Obstructive Pulmonary Disease

  **DPI**            Dry Powder Inhaler

  **Extractables**   Compounds extracted from individual components of the
                     drug delivery system, under appropriate solvent and
                     temperature conditions. Extractables studies are
                     therefore conducted during development on the components
                     that will constitute the drug product.

  **GRAS**           Generally Recognized As Safe

  **HFA**            Hydrofluoroalkane

  **ICH**            International Conference on Harmonization

  **Leachables**     Compounds that migrate from the container/closure system
                     of the drug product under normal conditions of use, or
                     during stability studies. Leachables studies are
                     therefore conducted on the final drug product.

  **MDI**            Metered Dose Inhaler

  **NAAQS**          National Ambient Air Quality Standards

  **NOEL**           No Observed Effect Level

  **OINDP**          Orally Inhaled and Nasal Drug Products

  **PEFR**           Peak Expiratory Flow Rate

  **Picogram**       10^-12^ grams

  **PM~10~**         Particulate Material 10 micrometers: refers to particles
                     collected with an aerodynamic sampling system with 50%
                     efficiency for particles with a 10 micrometer aerodynamic
                     size.

  **PM~2.5~**        Particulate Material 2.5 micrometers: refers to particles
                     collected with an aerodynamic sampling system with 50%
                     efficiency for particles with a 2.5 micrometer
                     aerodynamic size.

  **PNA**            Polynuclear Aromatic

  **Q3A**            Guideline published by the International Conference on
                     Harmonization (ICH) that addresses impurities in drug
                     substances.

  **Q3B**            Guideline published by the International Conference on
                     Harmonization (ICH) that addresses impurities in drug
                     products.

  **Q3C**            Guideline published by the International Conference on
                     Harmonization (ICH) that addresses acceptable levels of
                     residual solvents in pharmaceuticals for the safety of
                     the patient.

  **SAR**            Structure Activity Relationship

  **TDI**            Total Daily Intake

  **USEPA**          United States Environmental Protection Agency

  **USP**            United States Pharmacopeia
  ------------------ ---------------------------------------------------------

[^1]: <http://www.fda.gov/cder/guidance/2180dft.pdf>

[^2]: <http://www.fda.gov/cder/guidance/2836dft.pdf>

[^3]: The Leachables and Extractables Team is working with the
    ITFG/IPAC-RS Supplier Quality Control Team to address this
    recommendation.

[^4]: *Qualification of leachables* is understood here to mean
    *biological safety qualification of leachables.*

[^5]: <http://www.ifpma.org/ich5q.html#Impurity>; ICH Guidelines Q3A,
    Q3B, and Q3C were published in the Federal Register on 4 January
    1996, 19 May 1997 and 24 December 1997, respectively. Revised
    versions of Q3A and Q3B were published in the Federal Register on 20
    July 2000 and 19 July 2000, respectively.

[^6]: Roy, M., Age Related Aspects of Physiology in Respiratory Tract
    Modeling, in *Radiation Protection Dosimetry*, **41** (2/4), pp
    93-98, 1992; Nuclear Technology Publishing.

[^7]: *Ibid.*

[^8]: Expert Panel Report 2, *Guidelines for the Diagnosis and
    Management of Asthma*, National Asthma Education Program, National
    Institutes of Health, National Heart, Lung and Blood Institute, pp.
    1-13, 1997.

[^9]: Environmental Protection Agency, National Ambient Air Quality
    Standards for Particulate matter; *Fed. Regist.;* Volume **62**, No.
    138, 1997.

[^10]: Dockery, DW; Pope, CA III; Xu, X; An Association Between Air
    Pollution and Mortality in Six U.S. Cities; *N. Engl. J. Med.*;
    **329**, pp. 1753-9, 1993.

[^11]: Daniels, MJ; Dominici, F; Samet, JM; *et al*., Estimating
    Particulate Matter-Mortality Dose Response Curves and Threshold
    Levels: An Analysis of Daily Time-Series for the 20 Largest US
    Cities; *Am. J. Epidemiol.*, **152** (5) pp397-406, 2000

[^12]: *Guidance for Industry, Metered Dose Inhaler(MDI) and Dry Powder
    Inhaler (DPI) Drug Products; Chemistry, Manufacturing, and Controls
    Documentation*; draft Guidance; FDA, p. 13, 1998

[^13]: Takagi, *et. al.,* Acute, Subchronic and Chronic Toxicity Studies
    of a Synthetic Antioxidant, *J. Toxicol. Sci. (Japan)*, **19** (2),
    pp 77-78, 1994

[^14]: Kokoski CJ, *et. al.,* Methods Used in Safety Evaluation, in
    *Food Additives,* Chapter 15, pp 579-616, Branen AL, Davidson PM and
    Salminen S., eds.; Marcel Dekker, New York, 1990.