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October a Busy Month for FDA Regulatory Guidances!
October of 2017 has been a busy month for the FDA and so far, they have issued several Guidance documents related to ANDA submissions/support, DMF Completeness assessments, combination product classification and eCTD submissions.
Based on a preliminary review of newly issued Guidances, content highlights and links have been provided below for Guidance documents containing references potentially impacting excipient makers and users.
Please let us know if you like this article by sending an e-mail to [email protected]. If so, we will consider adding future editions as a members only feature in the Document Depot of IPEC-Americas website.
Content hyperlinks
1) ANDA Submissions - Refuse-to-Receive Standards: : Questions and Answers Guidance for Industry .................................................................................................................................. 1
2) ANDA Submissions — Amendments to Abbreviated New Drug Applications Under GDUFA Guidance for Industry ............................................................................................................. 4
3) Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA Guidance for Industry ............................................................................................................. 4
4) Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization ........................................................................................................................ 6
5) M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use Guidance for Industry ...................................................................................... 8
6) Classification of Products as Drugs and Devices and Additional Product Classification Issues ... 12
7) Determining Whether to Submit an ANDA or a 505(b)(2) Application Guidance for Industry ... 13
1) ANDA Submissions - Refuse-to-Receive Standards: : Questions and Answers Guidance for Industry
ANDA Submissions - Refuse-to-Receive Standards: : Questions and Answers Guidance for Industry (PDF - 153KB)
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Sections and questions related to excipients and of potential interest to IPEC members are included below:
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D. Drug Master File (DMF) Review and Deficiencies
Q15: Will FDA RTR an ANDA referencing a Type II active pharmaceutical ingredient (API) DMF that has not been listed on the Available for Reference List21 as of the date the ANDA is submitted to FDA?
FDA will RTR an ANDA that relies on a Type II API DMF that has not been deemed available for reference22 at the time the filing review for such ANDA is completed. In determining whether a Type II API DMF is available for reference by an ANDA, FDA will consider those materials submitted by the relevant DMF holder as of the date that the ANDA is submitted to FDA.
Q16: Will FDA review a Type IV DMF for the formulation of flavoring agents, coloring agents, and/or imprinting inks that are referenced in an ANDA during the filing review?
FDA will review a Type IV DMF for flavoring and coloring agents and imprinting inks that are referenced in an ANDA to determine if the formulation or information on the formulation is readily available therein. Information will be considered readily available if the Right of Reference letter clearly indicates the exact location of the relevant information within the DMF, including 1) the page number and the date of submission to the DMF if such DMF is a paper or a hybrid submission or 2) the eCTD sequence number and submission date if such DMF number is fully electronic (i.e., electronically submitted in eCTD format). If any of the information identified in numbers 1 or 2 above is missing from the Right of Reference letter, FDA will contact the applicant to request submission of a revised Right of Reference letter that includes the missing information. The applicant may have the supplier or DMF holder submit the information directly to FDA. If the requested information is not provided within seven calendar days from notification, FDA will RTR the ANDA.
Q17: Will FDA review a Type IV DMF for an excipient to determine whether it contains pharmacology/toxicology (pharm/tox) data to support its use in a proposed drug product?
FDA will review a Type IV DMF for an excipient to determine whether it contains pharm/tox data to support its use in a proposed drug product, provided the pharm/tox data is readily available therein. Information will be considered readily available if the Right of Reference letter clearly indicates the exact location of the relevant information within the DMF, including 1) the page number and the date of submission to the DMF if such DMF is a paper or a hybrid submission or 2) the eCTD sequence number and submission date if such DMF number is fully electronic (i.e., electronically submitted in eCTD format). If any of the information identified in numbers 1 or 2 above is missing from the Right of Reference letter, FDA will contact the applicant to request submission of a revised Right of Reference letter that includes the missing information. Alternately, the applicant may have the supplier or DMF holder submit the information directly to FDA. If the requested information is not provided within seven calendar days from notification, FDA will RTR the ANDA.
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E. Product Quality Deficiencies
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5. Inactive Ingredients
Q25: If an application references a general listing from the Inactive Ingredient Database (IID) and does not include a justification for the grade of excipient, will FDA identify the lack of justification as a deficiency at filing?
FDA will RTR an ANDA that lacks a justification in its original ANDA submission for the grade of an inactive ingredient when referencing a nonspecific or different grade of an inactive ingredient that is available in various grades. An ANDA that references a general IID listing or an IID listing for a different grade of an inactive ingredient but fails to provide any justification for the specific grade is not a substantially complete application because FDA has no basis on which to review the safety of the specific grade of the inactive ingredient in the proposed drug product.
An applicant using a specific grade of an inactive ingredient should justify the use of that grade, and may not cite to a different grade or a nonspecific listing as support for the safety of the inactive ingredient in the proposed drug product without providing additional justification. Grades of an inactive ingredient may differ in chemical or physical properties and may affect the safety profile of a drug product. Some inactive ingredients have grades or variations that may not have undergone a full safety evaluation in a previously approved product. Some variations may rely, in part, on a finding of safety for an approved drug product that contains a similar grade of the inactive ingredient. The applicant’s justification should identify the differences between the grades of the inactive ingredient and address any implication of the change in grade on the safety of the proposed drug product using a data-driven approach. Whether the safety of a proposed grade of the inactive ingredient, in the context of the currently proposed drug product, is supported by a different grade of the inactive ingredient included in a previously approved drug product will be evaluated during the technical review of the ANDA.
An applicant may submit a controlled correspondence during product development regarding the specific grade of an inactive ingredient that the applicant proposes to use in the proposed drug product and reference the correspondence in the ANDA.
Q26: Will FDA RTR an ANDA that fails to provide an IID reference for an inactive ingredient for the particular route of administration for the proposed drug product or that provides an IID reference for the inactive ingredient for a different route of administration than the route of administration for the proposed drug product?
FDA will generally consider an applicant’s failure to provide an IID reference for an inactive ingredient for the particular route of administration for the proposed drug product or an applicant’s provision of an IID reference for an inactive ingredient for a different route of administration than the route of administration for the proposed drug product (e.g., referencing an IID listing for an inactive ingredient for an oral route of administration for a sublingual or buccal tablet) as a minor deficiency, provided FDA is able to validate the level of use. If FDA cannot validate the level of use and the applicant has not provided justification for its level of use within the original ANDA submission, then FDA will RTR the ANDA.
Generic drug products should use inactive ingredients that have previously been included in an FDA-approved product at or below the proposed maximum daily exposure, in a similar clinical context, and by the same route of administration. Applicants should consider the safety of inactive ingredients in their generic drug product. A justification may include supportive information from the IID, a controlled correspondence response from OGD, published literature, evidence of safe use in FDA-approved drug products with a similar context of use, or other relevant and science-based safety information. If a justification cites published literature, the applicant should submit a copy of the publication(s) in its ANDA.
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If an inactive ingredient is unqualified for the corresponding route of administration of the proposed drug product (unless it is a physical mixture of components that are not novel), FDA will RTR the ANDA because there is no prior evidence of safe use in an FDA-approved drug product. An inactive ingredient without prior evidence of safe use in an FDA-approved drug product is considered novel. Use of a novel excipient generally will require submission of a new drug application (NDA) under section 505(b) of the FD&C Act.
2) ANDA Submissions — Amendments to Abbreviated New Drug Applications Under GDUFA Guidance for Industry
ANDA Submissions — Amendments to Abbreviated New Drug Applications Under GDUFA Guidance for Industry (PDF - 221KB)
Guidance mostly contains information related to classification and expected timing for review of ANDA Amendments. Two sections contain some reference to DMF information; however, mostly relevant to API and not excipients.
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E. Amendments Submitted in Response to Changes in the DMF
Changes made to a DMF referenced in an ANDA that may impact the safety, efficacy, quality, or substitutability of the drug product (e.g., new facilities added by the DMF holder that need to be addressed by the applicant in an amendment to the ANDA) may be considered unsolicited amendments to the ANDA and therefore may extend existing review goals or create new review goals.
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APPENDIX A: MAJOR DEFICIENCIES
A. Pharmaceutical Quality Deficiencies
Drug Master File (DMF)
a. Inadequate selection or justification of starting materials
b. Toxicological studies are needed to qualify an unqualified impurity
c. Reference to a secondary DMF which has not been reviewed, is currently inadequate, or requires submission of a technical dossier from a third-party supplier with significant additional manufacturing information
d. Failure to provide adequate analytcal methods or method validation which would require significant new method development
e. Insufficient physical or chemical characterization data to demonstrate structure, form, or drug substance sameness (especially for complex active pharmaceutical ingredients (APIs)) in the DMF
f. Major change in drug substance manufacturing process with inadequate supporting data g. Requirement to manufacture a new API batch
3) Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA Guidance for Industry
Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA Guidance for Industry (PDF - 154KB)
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For this Guidance it is important to review the background because this appears to be a
paradigm shift in GFUFA II that encourages the FDA to meet with ANDA applicant of complex
products during development and pre-submission phases. Although probably most applicable to
APIs, this might be something to review for excipients within an existing family, but not
specifically listed on the IID.
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II. BACKGROUND
As part of GDUFA II, FDA committed to developing a program to assist ANDA applicants and prospective ANDA applicants of complex products before the submission of an ANDA to FDA. As stated in the GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022 (GDUFA II Goals or Commitment Letter),5 this pre-ANDA program is intended to:
. . . clarify regulatory expectations for prospective applicants early in product development, assist applicants to develop more complete submissions, promote a more efficient and effective ANDA review process, and reduce the number of review cycles required to obtain ANDA approval, particularly for [complex products].6
As defined in the GDUFA II Commitment Letter, complex products are:
1. Products with complex active ingredients (e.g., peptides, polymeric compounds, complex mixtures of [active pharmaceutical ingredients], naturally sourced ingredients); complex formulations (e.g., liposomes, colloids); complex routes of delivery (e.g., locally acting drugs such as dermatological products and complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions, or gels); or complex dosage forms (e.g., transdermals, metered dose inhalers, extended-release injectables);
2. Complex drug-device combination products (e.g., auto-injectors, metered dose inhalers); and
3. Other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement.
To facilitate development of complex products that may be submitted in an ANDA, FDA and industry agreed to a series of meetings between ANDA applicants or prospective ANDA applicants and FDA to discuss the proposed complex product and support submission of a high-quality, approvable ANDA.
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III. MEETING TYPES A. Product Development Meetings
Product development meetings for complex products that may be submitted in an ANDA provide for discussion of specific scientific issues or questions (e.g., a proposed study design, alternative approach, or additional study expectations), in which FDA will provide targeted advice regarding an ongoing ANDA development program.9 To engage in a substantive discussion, FDA expects that the prospective ANDA applicant has enough knowledge of the complex product to allow FDA to provide appropriate feedback that will advance product development early in the process (e.g., the prospective ANDA applicant has generated its own data to be discussed). FDA anticipates that some prospective ANDA applicants of complex products may request more than one product development meeting. FDA recommends that the prospective ANDA applicant
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submit no more than one request for a product development meeting for the specific complex product per year.
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B. Pre-Submission Meetings
Pre-submission meetings for complex products provide an opportunity for prospective ANDA applicants to discuss and explain the format and content of the ANDA to be submitted (e.g., data to support equivalence claims, types of data that will be contained in the ANDA).11 The pre- submission meeting does not include substantive review of summary data or full study reports, but FDA will identify items or information that should be clarified before submission of the ANDA. The pre-submission meeting is not an opportunity to determine whether the application is acceptable for filing.12 FDA anticipates that the pre-submission meeting will take place approximately 6 months before submission of the ANDA. FDA attendees at the pre-submission meeting will generally include staff that attended the product development meeting, if held, and additional review staff that may review the ANDA once received.
Other parts of this Guidance review details on how to request a meeting, what to prepare/submit for product development review prior to meeting, how to conduct the meeting, documentation and meeting minutes, etc.
4) Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization
Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization
This guidance provides recommendations to pharmaceutical companies interested in
participating in a program involving the submission of CMC information containing emerging
technology to FDA. The program is open to companies that intend to include the technology as
part of a regulatory submission including IND, original or supplemental NDA, ANDA or BLA, or
application-associated DMF reviewed by CDER, and where that technology meets other criteria
described in this guidance. This program does not cover products reviewed by CBER.
Summary of info potentially relevant to excipients
In this program, pharmaceutical companies can, prior to the regulatory submission, submit questions and proposals about the use of specific emerging technology to a group within FDA (Emerging Technology Team – ETT), which includes relevant representation from all FDA pharmaceutical quality functions. The ETT works in partnership with relevant pharmaceutical quality offices and assumes a leadership or co-leadership role for the cross-functional quality assessment team (including review and on-site facility evaluation or inspection) for submissions involving emerging technology. The ETT serves as the primary point of contact for companies that are interested in implementing emerging technology in the manufacture of their drug products and for the relevant quality assessment team to:
a) Answer sponsor/applicant questions about the information FDA expects to see in their submission;
b) Identify and help facilitate regulatory assessment of an emerging technology in accordance with existing legal and regulatory standards, guidance, and Agency policy related to quality assessment;
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c) Serve as the lead or co-lead on the quality assessment team (i.e., staff involved in the review of the CMC sections of the application and evaluation of the manufacturing facilities), in partnership with relevant pharmaceutical quality offices, including the Office of Compliance and Office of Regulatory Affairs, as appropriate, to conduct review, on-site evaluation, and make the final quality recommendation regarding the potential approval of submissions in the program; and
d) Identify and resolve policy issues to inform FDA approaches and recommendations regarding future submissions that involve the same technology.
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.
III. DISCUSSION
As part of this program, FDA intends to provide early engagement and additional meeting opportunities, which enable the participants and FDA to discuss: (1) product or manufacturing design and development issues, and (2) submission content related to the emerging technology. The process will include appropriate coordination with the FDA quality assessment team. Based on experience gained during the program, FDA intends to develop guidance and standards, as necessary, on emerging technologies and approaches to encourage and facilitate the innovation and modernization in pharmaceutical industry.
A. Scope
Acceptance of a request to participate in this program will depend on the applicant’s proposed plan for submission of an IND, original or supplemental ANDA, BLA, or NDA, or application associated DMF based on the criteria described below.
• The planned submission should include one or more elements which will be subject to quality assessment for which the Agency has limited review or inspection experience. Examples of such elements include an innovative or novel: (1) product technology (e.g., dosage form or container-closure system); (2) manufacturing process (e.g., design, scale-up, or lifecycle approaches); and/or (3) control strategy (e.g., testing technology or process controls).
• The proposed technology in the planned submission has the potential to improve product safety, identity, strength, quality, or purity (e.g., an innovative process design that can lead to a more robust and predictable production of quality pharmaceutical products).
In the request to the Agency, the applicant should provide sufficient justification that the proposed emerging technology in the planned submission meets the above criteria (see section III.B Process for details regarding steps to request participation in the program). Such an approach, rather than providing a prescriptive set of acceptance criteria, enables the program to be open to a wide variety of novel manufacturing technologies. As a reminder, this program only affects the quality section of the submission (CMC and facility-related information). Existing requirements related to the review and determination of adequacy or approval of a submission will not be waived, suspended, or modified for purposes of this program. Applicants must make the submission in accordance with 21 CFR parts 312, 314, 601, and other applicable standards.
B. Process
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Parties planning to submit an IND, original or supplemental BLA or NDA, or application associated DMF, and who have an interest in participating in this FDA program should submit a written request for a Type C meeting as described in the FDA guidance for industry Formal Meetings Between the FDA and Sponsors or Applicant. The request should specify the meeting request as a “Type C meeting – request to participate in the Emerging Technology Program.” Interested parties planning to submit an ANDA should submit a pre-ANDA meeting request and specify the meeting request as a “Pre-ANDA meeting – request to participate in the Emerging Technology Program.” Either type of request should be submitted at least three months prior to the planned application submission date. The meeting request and related questions should be submitted electronically to [email protected] In addition to the items outlined in the referenced guidance, the request should also include the following items and should not exceed five pages including figures and tables:
(1) A brief description of the proposed emerging technology;
(2) A brief explanation why the proposed emerging technology is substantially novel and unique and should be considered under this program;
(3) A description of how the proposed emerging technology could potentially improve product safety, identity, strength, quality, or purity;
(4) A summary of the development plan and any perceived roadblocks to implementation (e.g., technical or regulatory); and
(5) A timeline for a submission of an IND, original or supplemental ANDA, BLA, or NDA, or DMF and its associated application.
Based on the availability of Agency resources, we expect to limit acceptance into the program to technologies that are likely to advance product design or modernize pharmaceutical manufacturing, and with which the Agency has limited prior experience and knowledge. FDA expects to notify companies of its decision regarding acceptance into the program in writing within 60 days of receipt of the request. Although incomplete and/or unclear requests will generally be denied, FDA may contact the applicant to request additional information. Once accepted into the program, the participant can engage with the ETT and quality assessment team in accordance with existing meeting procedures and guidance(s)
5) M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use Guidance for Industry
M4 Organization of the Common Technical Document for the Registration of
Pharmaceuticals for Human Use Guidance for Industry
This guidance updates the Quality-related sections of the Granularity Document Annex, Module
2.3 Quality Overall Summary, and Module 3 Quality. It is intended to provide recommendations
on the organization of the CTD/eCTD and replaces the August 2001 FDA guidance for industry
‘‘M4: Organization of the CTD’’ and the October 2005 FDA guidance for industry ‘‘Granularity
Document Annex to M4: Organization of the CTD.’’
This Guidance follows the ICH CTD Guideline and the level of granularity (to be referenced in DMF Guide) is shown below:
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Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use
Module 1: Administrative Information and Prescribing Information
1.1 Table of Contents of the Submission Including Module 1
1.2 Documents Specific to Each Region (for example, application forms, prescribing information)
Module 2: Common Technical Document Summaries
2.1 Table of Contents of Modules 2-5
2.2 CTD Introduction
2.3 Quality Overall Summary
2.4 Nonclinical Overview
2.5 Clinical Overview
2.6 Nonclinical Written and Tabulated Summaries
Pharmacology
Pharmacokinetics
Toxicology
2.7 Clinical Summary
Biopharmaceutic Studies and Associated Analytical Methods
Clinical Pharmacology Studies
Clinical Efficacy
Clinical Safety
Literature References
Synopses of Individual Studies
Module 3: Quality
3.1 Table of Contents of Module
3 3.2 Body of Data
3.3 Literature References
Module 4: Nonclinical Study Reports
4.1 Table of Contents of Module 4
4.2 Study Reports
4.3 Literature References
Module 5: Clinical Study Reports
5.1 Table of Contents of Module 5
5.2 Tabular Listing of All Clinical Studies
5.3 Clinical Study Reports
5.4 Literature References
Th following level of granularity to be included in the DMF Guide
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6) Classification of Products as Drugs and Devices and Additional Product Classification Issues
This guidance document provides the Agency’s current thinking on approaches for classifying
products as drugs and devices, and on certain additional product classification issues. FDA
regularly receives questions from medical product sponsors concerning the classification of their
products. We believe that efficient, effective regulation is facilitated by providing guidance on
issues frequently raised in relation to Requests for Designation (RFDs) and other classification
activities. In addition, providing as much clarity and predictability as possible with respect to
product classifications should enable informed planning for product development.
TABLE OF CONTENTS I. Introduction
II. What Is the Process For Obtaining a Formal Classification Determination for a Product?
III. What Does FDA Consider in Determining Whether to Classify a Product as a Drug or Device?
A. Statutory Definitions
1. Drug
2. Device
B. Certain key provisions of the definition of device
1. “Similar or related article” in the definition of device
2. “Primary intended purposes” in the definition of device
3. “Chemical action” in the definition of device
4. “Within or on the body” in the definition of device
5. Illustrative Examples
C. How Is a Product Classified If It Meets the Definition for Drug (or for Both Drug and Device) and Also Meets the Definition for Biological Product?
IV. Additional Information
Frequently Asked Questions
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7) Determining Whether to Submit an ANDA or a 505(b)(2) Application Guidance for Industry
Determining Whether to Submit an ANDA or a 505(b)(2) Application Guidance for Industry (PDF - 147KB)
This guidance focuses on a describes criteria supporting the various abbreviated drug
application routes as described in bullets 2-4 below.
NDAs and ANDAs can be divided into the following four categories:
(1) A “stand-alone NDA” is an application submitted under section 505(b)(1) and
approved under section 505(c) of the FD&C Act that contains full reports of
investigations of safety and effectiveness that were conducted by or for the
applicant or for which the applicant has a right of reference or use.
(2) A 505(b)(2) application is an NDA submitted under section 505(b)(1) and
approved under section 505(c) of the FD&C Act that contains full reports of
investigations of safety and effectiveness, where at least some of the information
required for approval comes from studies not conducted by or for the applicant
and for which the applicant has not obtained a right of reference or use.
(3) An ANDA is an application for a duplicate6 of a previously approved drug product
that was submitted and approved under section 505(j) of the FD&C Act. An ANDA
relies on FDA’s finding that the previously approved drug product, i.e., the
reference listed drug (RLD), is safe and effective. An ANDA generally must
contain information to show that the proposed generic product (1) is the same as
the RLD with respect to the active ingredient(s), conditions of use, route of
administration, dosage form, strength, and labeling (with certain permissible
differences) and (2) is bioequivalent to the RLD. An ANDA may not be submitted if
studies are necessary to establish the safety and effectiveness of the proposed
product.
(4) A petitioned ANDA is a type of ANDA for a drug product that differs from the RLD
in its dosage form, route of administration, strength, or active ingredient (in a
product with more than one active ingredient) and for which FDA has determined,
in response to a petition submitted under section 505(j)(2)(C) of the FD&C Act
(suitability petition), that studies are not necessary to establish the safety and
effectiveness of the proposed drug product.
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