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Options for Submitting API Data in the CTD File

Options for Submitting API Data in the CTD File : 작성자, 카테고리, 작성일, 조회수, 원문,출처, 정보 제공
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작성일 2016-05-11 조회수 2,074
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Options for Submitting API Data in the CTD File

전문가
글 Mahmoud Al
Qawasmeh
KHIDI 해외제약전문가
상임 컨설턴트
컨설팅 분야
  • 요르단 및 중동 GMP
  • 제품 등록 및 인허가
주요 약력
  • 2010-2015 JFDA(요르단식품약품관리안전처) GMP 감독
  • 2009 약국장 (Al-Hussaain 교육 병원)
  • 2008 약사 (Al-Hussaain 교육 병원- MOH)
  • 2007-2008 영업 감독(동부 지역) 하얏트 제약 (사우디아라비아)
  • 2006-2007 진팜 시니어 의학 대표 (암만-요르단수도 지역)
  • 2004∼2006 의학 산업 대표 (UAE 지역)
  • 2002-2004 의학 대표 (UAE 시장 - 약학산업)(HIKMA 그룹)
  • 1999-2000 지아드 약학 약사 대표 (자르카-요르단)

Introduction

The CTD is an internationally agreed format for the preparation of applications to be submitted to regulatory authorities in the three ICH regions of Europe, USA and Japan. It is intended to save time and resources and to facilitate regulatory review and communication.
The CTD is an effort of EMA (Europe), FDA (USA), and MHWL (Japan) and then it was maintained by ICH. The concept of CTD was proposed by Industry in 1995.In 2003, the CTD format became mandatory for the three ICH regions; EU, USA, and Japan. In 2004, other countries like Canada, Australia, and Switzerland adopted the CTD format. Later other countries started to adopt the CTD format.
*The CTD is organised into five modules:
Module1 is for administrative information and prescribing information, and should contain documents that are specific to each region; for example, application forms or the proposed label for use in the region. Module 2 contains the CTD summaries and should begin with a general introduction to the drug, including its pharmacological class, mode of action and proposed clinical use. Module 2 should also provide the overall summary of the ‘quality’ information provided, the non-clinical overview and the clinical overview, as well as the non-clinical written summaries and the tabulated summaries, and the clinical summary. As a foundation for the aforementioned material, module 3 contains information on quality topics, module 4 contains the nonclinical study reports and module 5 contains the clinical study reports.
* http://www.ich.org
So, in order for the local Korean Pharmaceutical manufacturing companies to go globally and register their product outside Korea they must start converting all the product files into CTD format.
- Today I will talk about the Quality part; Module 3 of the CTD and specifically the S (substance: Active Ingredient) part.
- The assessment of the preparation, control & stability of the API is an essential part of the FPP assessment process.
Two bodies of API information are assessed:
The preparation, control and stability of the API by the API manufacturer, and the control of the API by the FPP manufacturer (Typically it focuses on the physiochemical properties that might affect bioavailability, API specifications and test methods).
This assessment may cover more than one API manufacturer if there are multiple suppliers.

Options for submitting API data

There are three options to submit the information:

  1. Certificate of Suitability of the European Pharmacopeia (CEP)
  2. Active Pharmaceutical Ingredient Master File (APIMF)
  3. Full Details (for API) in the Product Dossier

(All options require the submission of information in CTD format).

Option 1: Certificate of Suitability: (COS) / CEP

Copy of the valid CEP, including all annexes should be submitted.
A copy of the Certificates of Suitability (including any annexes) in the annex 1.6.3 of the application form in Module 1 and in Module 3.R
CEP: Certificate of Suitability:
A Certificate issued from EDQM (European Directorate for the Quality of Medicine) to demonstrate the compliance of the substance used with the monograph of the European Pharmacopoeia. (Not issued for biological).
Substances described in the Ph. Eur. www.edqm.eu
There are two types of CEPs: Quality CEP and TSE CEP
Information found in a CEP:
  • CEP reference, CEP holder.
  • Site of manufacture of the substance
  • Monograph according to which the dossier is evaluated
  • Additional impurities and residual solvents not mentioned in the monograph, additional methods to those of the monograph are appended.
  • Re-test period with packaging system and storage condition (if applicable).
  • Date of validity of the CEP (5 years validity).
Option 1 – An EDQM CEP
Manufacturer should include Additional data to address any relevant parameter(s) not addressed in the CEP:
  • 3.2. S.1.3 General properties
    Discussions on any additional applicable physicochemical and other relevant API properties that are not controlled by the CEP and EP monograph, e.g. solubility and polymorphs…
  • 3.2. S.2
    If the sterility of the FPP is based upon the sterile manufacture of the API then data on the sterilisation process together with full validation data should be provided.
  • 3.2. S.3.1 Elucidation of Structure and other Characteristics
    Studies to identify polymorphs (exception: where the CEP specifies a polymorphic form) and particle size distribution where applicable.
  • 3.2. S.4.1 Specification
    The specifications of the FPP manufacturer including all tests and limits of the CEP and Ph.Eur. Monograph and any additional tests and acceptance criteria that are not controlled in the CEP and Ph.Eur. Monograph, such as polymorphs and/or particle size distribution.
  • 3.2. S.4.2 / 3.2.S.4.3 Analytical procedures and validation
    For any methods used by the FPP manufacturer in addition to those in the CEP and Ph.Eur. Monograph.
  • 3.2.S.4.4 Batch analysis
    - Results of batch analysis (two batches of at least pilot scale) from the API manufacturer demonstrating compliance with the Ph. Eur. monograph and including any additional tests/limits listed on the CEP (e.g. residual solvents, additional impurity tests);
    - COA(s) from API manufacturer & FPP manufacturer
  • 3.2. S.5 Reference Standards or Materials
    Information on the FPP manufacturer’s reference standards.
  • 3.2. S.6 Container Closure System
    Specifications including descriptions and identification of primary packaging components. Exception: where the CEP specifies a container closure system and the applicant declares to use the same container closure system.
  • 3.2. S.7 Stability
    Where the CEP specifies a re-test period that is of a shorter duration than that proposed, or the storage conditions have a lower temperature or humidity as proposed by the applicant.
    For option 1 CEP a Copy of the relevant monograph of the European Pharmacopoeia
    In cases where the drug product manufacturer tests the CEP certified API according to specification other than Ph.Eur (i.e. USP, JP, In-House etc.) data covering(S 4.1) to (S4.5) should be submitted by the MAH.
    It will be acceptable to refer to CEP for the following sections of The Drug Substance in Module 3.2.S:

    (S.2.2, S.2.3, S.2.4 and S.2.6)
    For Section 3.2. S.2.5: Process Validation: Process validation and / or evaluation studies for aseptic processing and sterilization should be included.

Option 2: Active Pharmaceutical Ingredient Master File (APIMF)

In situations where the MAH is not the API manufacturer or does not have access to detailed confidential documentation, the MAH is allowed to submit the Open part through the product registration application and the Closed (or confidential) part is submitted by the API manufacturer directly to authority.
The information contained in the restricted part of the DMF will be regarded as confidential and will only be evaluated in support of the applications mentioned in the Letter of Access.
The documents required for an application making a reference to an APIMF are as follows:

From the MAH:
Open part of the DMF from the MAH, as part of the submitted product dossier which contain:
  • S1 General Information
    • 1.1 Nomenclature
    • 1.2 Structure
    • 1.3 General Properties
  • S2 Manufacture
    • 2.1 Manufacture(s)/Site of Manufacture
  • S3 Characterization
    • 3.1 Elucidation of Structure and other Characteristics
    • 3.2 Impurities
  • S4 Control of API/Drug Substance
    • 4.1 Specification
    • 4.2 Analytical Procedures
    • 4.3 Validation of Analytical Procedures
    • 4.4 Batch Analysis
    • 4.5 Justification of Specification
  • S5 Reference Standards or Materials
  • S6 Container Closure System
  • S7 Stability
    • Letter of Access (or Letter of Authorization).
  • From the API Manufacturer:
    • The complete (open part and closed part) DMF from the API manufacturer. The closed part contains the confidential information (S2.2- S2.6)

Option 3: Full data for API submitted in the drug product file.

For option 2 & 3: a notarized valid copy of GMP certificate (for drug substance manufacturer/s) should be included.
GMP certificate: Issued from health authorities, the firm Follow GMP, should mention the Name of drug substance. That the company is Inspected regularly by the national health authorities.
Points to consider for API
  • 3.2. S.4 Control of the API:
    • 3.2. S.4.1 Specification:
      • - Assurance that the tests cover all the applicable physical and chemical tests
      • - If a pharmacopoeia standard is claimed then the API specifications must meet the monograph requirements, but…Compliance with a pharmacopoeia monograph may not be sufficient control, especially for impurities…
      • - Pharmaceutical monographs are considered a minimum requirement (API core information) but they do not automatically cover the particularities of an API, derived from its respective route of synthesis (E.g. Particle Size, Residual Solvents, Impurities…)
  • 3.2. S.4 Control of the API
    • 3.2. S.4.1 Specification API & FPP
      • - The FPP manufacturer should have one API specification, even if there are multiple API suppliers.
      • - The FPP manufacturer’s specification may be a compilation of all the API manufacturers’ specifications.
      • - It is important that the manufacturer provides a signed, dated and version-numbered specification.
    • 3.2. S.4.2 Analytical procedures
      • - Non-pharmacopoeia test methods should be explicitly described, and numbered.
      • - In an APIMF it is the API manufacturer’s procedures that are described.
      • - In an FPP dossier it is the FPP manufacturer’s API test methods that are described, taking into account the matrix effects of the formulation.
    • 3.2. S.4.3 Validation of Analytical Procedures
      • - The provision of validation data for pharmacopoeia methods is not usually required. (Verification).
      • - If an in-house method is used a full validation must be submitted.
  • For an FPP containing more than one API:
    • - One complete “3.2.S” section should be provided for one API, followed by other complete “3.2.S” sections for each other API.
    • - If there are several API manufacturers the FPP applicant can use a mixture of options.
For further information on GMP and Regulatory Affairs of Pharmaceutical and Medical Device in Jordan and Middle East region please contact me at :
  • - Email: mahmoud.q@khidi.or.kr
  • - Mobile : 01047637976
  • Mahmoud AlQawasmeh
    Executive Consultant
    Pharma Global Support Team
    Korea Health Industry Development Institute
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