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Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry DRAFT GUIDANCE - PharmaFacts
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Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry DRAFT GUIDANCE

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Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact (CDER) Sau L. Lee 240-506-9136.

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

December 2015 Pharmaceutical Quality/CMC

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Advancement of Emerging

Technology Applications to

Modernize the Pharmaceutical

Manufacturing Base

Guidance for Industry

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

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

Floor

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

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

December 2015 Pharmaceutical Quality/CMC

I. II. III.

A. B.

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 DISCUSSION .................................................................................................................... 3 Scope ............................................................................................................................................... 3 Process............................................................................................................................................. 4

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 1 Advancement of Emerging Technology Applications to Modernize

  2. 2 the Pharmaceutical Manufacturing Base

34 Guidance for Industry1

5 6 7 8 9

10 11

12
13
14
15
I. INTRODUCTION 16

  1. 17  This guidance provides recommendations to pharmaceutical companies interested in participating

  2. 18  in a program involving the submission of chemistry, manufacturing, and controls (CMC)

  3. 19  information containing emerging manufacturing2 technology to FDA. The program is open to

  4. 20  companies that intend the technology to be included as part of an investigational new drug

  5. 21  application (IND) or original or supplemental new drug application (NDA), abbreviated new

  6. 22  drug application (ANDA), or biologic license application (BLA) reviewed by the Center for

  7. 23  Drug Evaluation and Research (CDER), and where that technology meets other criteria described

  8. 24  in this guidance.

25

  1. 26  Issues in pharmaceutical manufacturing have the potential to significantly impact patient care in

  2. 27  that failures in quality may result in product recalls and harm to patients. Additionally, failures

  3. 28  in product or facility quality are a major factor leading to disruptions in manufacturing.

  4. 29  Modernizing manufacturing technology may lead to a more robust manufacturing process with

  5. 30  fewer interruptions in production, fewer product failures (before or after distribution), and

  6. 31  greater assurance that the drug products manufactured in any given period of time will provide

  7. 32  the expected clinical performance. For example, contemporary aseptic manufacturing facilities

  8. 33  that are highly automated and use isolators and other modern separation technologies have the

  9. 34  potential to decrease the risk of contamination from the processing line. Encouraging the

  10. 35  development of emerging manufacturing technology may lead to improved manufacturing, and

  11. 36  therefore improved product quality and availability throughout a product’s lifecycle.

37

  1. 38  In this program, pharmaceutical companies can submit pre-submission questions and proposals

  2. 39  about the use of specific emerging technology to a group within CDER (Emerging Technology

  3. 40  Team – ETT). The ETT will work in partnership with relevant pharmaceutical quality offices

  4. 41  and assume a leadership or co-leadership role for the cross-functional quality assessment team

    1 This guidance has been prepared by representatives from the Office of Pharmaceutical Quality and the Office of Compliance in the Center for Drug Evaluation and Research at the Food and Drug Administration.
    2 For the purpose of this guidance, the definition of manufacturing also includes testing, packaging and labeling operations, and quality control.

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

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Contains Nonbinding Recommendations

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  1. 42  (including review and on-site Agency evaluation) for submissions involving emerging

  2. 43  technology. The ETT will serve as the primary point of contact for companies that are interested

  3. 44  in implementing emerging manufacturing technology in the manufacture of their drug products

  4. 45  and for the relevant quality assessment team to:

46
47 (a) 48
49
50 (b) 51
52
53
54 (c) 55
56
57
58 (d) 59
60

  1. 61  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 62  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 63  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 64  the word should in Agency guidances means that something is suggested or recommended, but

  5. 65  not required.

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67
68
II. BACKGROUND 69

  1. 70  CDER is committed to supporting and enabling the modernization of pharmaceutical

  2. 71  manufacturing as part of the Agency’s mission to protect and promote the public health. These

  3. 72  efforts also may be one long-term solution to avoid drug shortages, as noted in FDA’s drug

  4. 73  shortage strategic plan.3 As part of its commitment to modernizing pharmaceutical

  5. 74  manufacturing, in 2002, FDA launched an initiative entitled “Pharmaceutical cGMPs for the 21st

  6. 75  Century: A Risk-Based Approach,” to encourage the implementation of a modern, risk-based

  7. 76  pharmaceutical quality assessment system.4 The initiative was published with several goals,

  8. 77  including encouraging the early adoption of new technological advances by the pharmaceutical

  9. 78  industry and ensuring that regulatory review, compliance, and inspection policies are based on

  10. 79  state-of-the-art pharmaceutical science. In 2004, this was further described in an FDA guidance

  11. 80  for industry entitled PAT—A Framework for Innovative Pharmaceutical Development,

  12. 81 Manufacturing, and Quality Assurance.5 This guidance describes the concept that quality cannot

    3 See http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf.
    4 See http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodMan ufacturingPracticescGMPforDrugs/ucm137175.htm#_Toc84065754.

    5 See http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070305.pdf. We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA

Answer sponsor/applicant questions about the information FDA expects to see in their submission;

Identify and help facilitate regulatory review of a new manufacturing technology in accordance with existing legal and regulatory standards, guidance, and Agency policy related to quality assessment;

Serve as the lead or co-lead on the quality assessment team, in partnership with relevant CDER pharmaceutical quality offices, to review and make the final quality recommendation regarding the potential approval of submissions in the program; and

Identify and capture resolution to policy issues that may inform FDA approaches and recommendations regarding future submissions that involve the same technology.

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  1. 82  be tested into products; in other words, it should be built-in or should be present by design.

  2. 83  Quality is built into pharmaceutical products through a comprehensive understanding of the

  3. 84  intended use of the product, the characteristics of the product, and the design of the product and

  4. 85  manufacturing process using principles of engineering, material science, and quality assurance to

  5. 86  ensure acceptable and reproducible product quality and performance throughout a product’s

  6. 87  lifecycle.

88

  1. 89  While the implementation of emerging technology is critical to modernizing pharmaceutical

  2. 90  manufacturing and improving quality, FDA also recognizes that innovative approaches to

  3. 91  manufacturing may represent challenges to industry and the Agency. By the very nature of an

  4. 92  approach being innovative, a limited knowledge and experiential base about the technology may

  5. 93  exist. Pharmaceutical companies may have concerns that using such technologies could result in

  6. 94  delays while FDA reviewers familiarize themselves with the new technologies and determine

  7. 95  how they fit within existing regulatory approaches. Through the ETT, FDA intends to encourage

  8. 96  the adoption of innovative approaches to pharmaceutical manufacturing by leveraging existing

  9. 97  resources within the Agency to facilitate the regulatory review of submissions to the Agency

  10. 98  involving manufacturing technologies likely to improve product safety, identity, strength,

  11. 99  quality, and purity.

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101
102
III. DISCUSSION 103

  1. 104  As part of this program, FDA intends to provide for early engagement and additional meeting

  2. 105  opportunities for the participants and FDA to discuss manufacturing design and development

  3. 106  issues as well as recommendations for submission content related to the emerging technology.

  4. 107  FDA intends to work with each participant on an individual basis, and expects that the process

  5. 108  will include appropriate coordination with the quality assessment team (FDA staff involved in

  6. 109  the review of the CMC sections of the application and evaluation of the manufacturing facilities).

  7. 110  Based on experience gained during the program, FDA intends to develop guidance and

  8. 111  standards, as necessary, on emerging technologies and approaches to enable the modernization of

  9. 112  the pharmaceutical manufacturing base.

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A. Scope 115

  1. 116  Acceptance of a request to participate in this CDER program will depend on the applicant’s

  2. 117  proposed plan for submission of an IND or original or supplemental ANDA, BLA, or NDA,

  3. 118  based on the criteria described below. The planned submission should include one or more

  4. 119  elements subject to quality assessment for which the Agency has limited review or inspection

  5. 120  experience, where the technology has the potential to modernize the pharmaceutical

  6. 121  manufacturing body of knowledge to support more robust, predictable, or cost-effective

  7. 122  processes. Examples of such elements include an innovative or novel: (1) product manufacturing

  8. 123  technology, such as the dosage form; (2) manufacturing process (e.g., design, scale-up, and/or

  9. 124  commercial scale); and/or (3) testing technology. Every effort will be made to ensure that many

  10. 125  companies have the opportunity to participate and that a wide variety of novel manufacturing

    Drugs guidance Web page at

    http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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  1. 126  technologies are included in this program. This program only affects the quality section of the

  2. 127  submission (CMC and facility-related information). Existing requirements related to the review

  3. 128  and approval of a submission will not be waived, suspended, or modified for purposes of this

  4. 129  program. Applicants must make the submission in accordance with 21 CFR parts 312, 314, 601,

  5. 130  and other applicable standards.

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132
B. Process 133

  1. 134  Interested parties planning to submit an IND or original or supplemental BLA or NDA as part of

  2. 135  this CDER program should submit a written request for a Type C meeting as described in the

  3. 136  guidance on Formal Meetings Between the FDA and Sponsors or Applicant.6 The request

  4. 137  should specify the meeting request as a “Type C meeting – request to participate in the ETT

  5. 138  program.” Interested parties planning to submit an ANDA should submit a pre-ANDA meeting

  6. 139  request and specify the meeting request as a “Pre-ANDA meeting – request to participate in the

  7. 140  ETT program.” Either type of request should be submitted at least three months prior to the

  8. 141  planned application (IND, ANDA, BLA, NDA) submission date. The meeting request and

  9. 142  related questions should be submitted electronically to This e-mail address is being protected from spambots. You need JavaScript enabled to view it . In addition to

  10. 143  the items outlined in the referenced guidance, the request should also include the following

  11. 144  items:

145
146 (1) 147
148 (2) 149
150
151 (3) 152
153
154

  1. 155  (4) A summary of the development plan and any perceived roadblocks to implementation

  2. 156  (e.g., technical or regulatory); and

157
158 (5) A timeline for a submission (IND, ANDA, BLA, NDA, original or supplemental). 159

  1. 160  The request document should generally not exceed five pages of narrative, including up to five

  2. 161  figures or tables. Based on the availability of Agency resources, we expect to limit acceptance

  3. 162  into the program to technologies that are likely to modernize pharmaceutical manufacturing in

  4. 163  order to improve product safety, identity, strength, quality, or purity, and with which the Agency

  5. 164  has limited prior experience and knowledge. FDA expects to notify companies of its decision

  6. 165  regarding acceptance into the program in writing within 60 days of receipt of the request.

  7. 166  Although incomplete and/or unclear requests will generally be denied, FDA may contact the

  8. 167  applicant to request additional information. Once accepted into the program, the participant can

    6 See http://www.fda.gov/downloads/Drugs/Guidances/ucm153222.pdf. 4

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A brief description of the proposed testing, process, and/or proposed technology;

A brief explanation why the proposed testing, process, and/or technology are substantially novel and unique and should be considered under this program;

A description of how the proposed testing and/or technology could modernize pharmaceutical manufacturing and thus improve product safety, identity, strength, quality, or purity;

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Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 168  engage with the ETT and CMC review team in accordance with existing meeting procedures and

  2. 169  guidance(s)7 based on the availability of Agency resources.

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7 See the guidances on Formal Meetings Between the FDA and Sponsors or Applicants (see information on “Type C” meetings) and Controlled Correspondence Related to Generic Drug Development.

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