• CEP Number
• CEP Issue Date
• CEP Expiry Date
• CEP Certificate

References:

Appendix 6 : Guideline On Regulatory Control Of Active Pharmaceutical Ingredients (APIs)

The PRH should submit a copy of the most current CEP including all annexes, together with the following:

• A written assurance that no significant changes in the manufacturing methods or processing have taken place following the granting of the certificate or its last revision and
• A declaration from the API Manufacturer that the PRH and the NPCB shall be notified of any future change in the API specifications or in the manufacturing process that will likely affect the product’s quality or safety.

Note: All such written statements must state the name of the finished product (product name, dosage form and product strength) to be registered and the PRH shall responsible for finished product registration.

The Quality Overall Summary (QOS) is a summary that follows the scope and the outline of the Body of Data in Module 3. The QOS should not include information, data or justification that was not already included in Module 3 or in other parts of the CTD. The QOS should include sufficient information from each section to provide the Quality reviewer with an overview of Module 3. The QOS should also emphasize critical key parameters of the product and provide, for instance, justification in cases where guidelines were not followed. The QOS should include a discussion of key issues that integrates information from sections in the Quality Module and supporting information from other Modules (e.g. qualification of impurities via toxicological studies discussed under the CTD-S module), including cross-referencing to volume and page number in other Modules. This QOS normally should not exceed 40 pages of text, excluding tables and figures.

Reference ICH Guidelines:

• The Common Technical Document For The Registration Of Pharmaceuticals For Human Use: Quality – M4Q(R1)

To prepare the Table of Contents based on completed Print Form (Section S – Drug Substance)

To attach the Print Form (Section S – Drug Substance) once all the documents are completed prior to submission.

Open part of the DMF

• International non proprietary names / INN
• Chemical names
• Synonyms
• CAS No

1. Open part of the DMF
   
   2.1 Attachment for structure

• Structural formula (relative and absolute chemistry)
• Molecular formula
• Molecular weight
• Molecular weight (base)

Open part of the DMF

The PRH is responsible to confirm the availability of the following information:

• Physical form
• Solubility
• Melting point
• Hygroscopicity
• Polymorphism
• Particle size
• Isomerism
• Chirality
• pKa
• Partition coefficient (log P)
• pH
• Others

Open part of the DMF

• Name and address of manufacturer that produced the API
• Attach GMP certificate in S9

Manufacturers involved in each production steps, including intermediate manufacturer, milling and quality control testing sites.

State the name of synthesis route.

Open part of the DMF

- The PRH is responsible to ensure the availability of the following information:

· Discussion on studies of elucidation of structure and other characteristics.

· Discussion on particle size distribution.

· Discussion on isomerism including configuration of chiral centers, geometric isomerism cis/trans or E/Z. (if existence of isomerism is declared).

· Discussion on polymorphism including information reported in literature and polymorphism found during manufacturing of API product (if drug substance exhibiting polymorphism).   

· The information if the API has been characterized on the basis of comparison to a recognized pharmacopoeial standard or from a detailed spectral analysis.

Pharmacopoeial API:

Comparison of spectral data between pharmacopoeial reference standard & API (If comparison is not available, assess as per nonpharmacopoeial API).

Non Pharmacopoeial API:

· Elemental analysis

· Infrared Spectrophotometry (IR)

· Ultraviolet absorption spectrum (UV)

· Mass spectrometry

· Nuclear Magnetic Resonance Spectrometry (NMR)

· X-ray Diffraction

· Differential Scanning Calorimetry (DSC)

· Thermogravimetric analysis (TGA)

· Others

Information on the potential for forming polymorphs should be included. The API manufacturer is expected to have adequate knowledge about the polymorphism of the APIs produced.

• Discussion of the possible carryover of all impurities (organic impurities (actual and potential impurities), residual solvents, inorganic impurities and genotoxic impurities) that may arise during the synthesis of API, from the preparation of starting material and intermediate to the final API.
• Discussion on impurities with regard to impurities with potential genotoxicity. If, on the basis of the discussion, a genotoxic impurity is indeed liable to be present in the substance, then please demonstrate that it comply with the current genotoxic guidelines.
• Discussion on the potential impurities that may arise from the starting materials, route of synthesis and possible degradation products should be listed with name, structure, origin, LOD, LOQ and range of results in at least 3 consecutive batches as well as the proposed limits taking into account the requirements of ICH guideline.
• Any impurity greater than qualification threshold should be qualified and a rationale for establishing impurity limit/ acceptance criteria that includes safety considerations (eg. data from toxicology study, or batch analysis data of batches used in clinical trial with observed impurites content are equal or more than limit in the specification) should be provided.
• Discussion on impurities that stated in other pharmacopeia (if applicable)
• Impurities:

             - Specified, Unspecified, Total impurities, Residual solvents, Inorganic

Specification of API (with specification version no. & effective date):

• From API Manufacture (*in-house/pharmacopoeial)
• From Finished Product Manufacturer (*in-house/pharmacopoeial)

Open part of the DMF

• The PRH is responsible to ensure the availability of the following information from both API Manufacturer and Product Manufacturer:
• Calculation or equation used in the protocol.
• Standard Testing Procedure for each specification

Open part of the DMF

The PRH is responsible to ensure the availability of the following information from API Manufacturer:

• Partial validation analytical procedure and report together with chromatograms raw data (accuracy, precision, specificity, intermediate precision, LOO, LOQ, linearity, range and system suitability testing).
• Validation data on organic impurities
• The test method used other than those described in the reference shall be fully described and validated.

Open part of the DMF

*Batch Analysis-minimum three batches

- The PRH is responsible to confirm and ensure the availability of the following information from both API Manufacturer and Product Manufacture

· Provide current CoA of API from API manufacturer and FPP manufacturer (at least 2 batches each)

· Describe the use of batches of submitted and site of manufacturing for each batch analysis involved.

· Describe the date of manufacturing and batch size, batch number for each batch and batch use (e.g. validation / stability / commercial)

· Submit batch analysis with complied to current specification (applicable for API Manufacturer only).

· State testing for related substance and residual solvent in the specification of both analysis.

 (i) API Manufacturer (2 Batches)

(ii) Product Manufacturer (2 Batches)

- The PRH is responsible to ensure the availability of the following information from API Manufacturer.

· Provide justification of specification to justify the limit and each test parameter in final API specification.

Open part of the DMF

*From API manufacturer AND finished product manufacturer

· The PRH is responsible to ensure the availability of the following information from both API Manufacturer and Product Manufacture

· Official reference standard used

· State what is primary reference standard used (with batch number)

· Working standard used (with batch number)

· If the submission option choose is CEP, please provide justification & discussion on using USP reference standard instead of EP reference standard.  

Reference Standard (API Manufacturer)

Please submit:

· Working Standard qualified against official standard

· Reference standards available for impurities/related substances

· CoA of official references standard by Product Manufacturer

· IR spectra of reference standard

· Overlaid IR spectra comparing the primary and working standards

Reference Standard (Product Manufacturer)

Please provide information for API Reference Standard used by product manufacturer:

· Working Standard qualified against official standard

· Reference standards available for impurities/related substances

· CoA of official references standard by Product Manufacturer

· IR spectra of reference standard

· Overlaid IR spectra comparing the primary and working standards

• State clearly the container closure system used for storage of the API
• Identity of the material used for each component (for primary and secondary packaging)
• Specification and CoA for primary packaging material
• IR spectra of the primary packaging material
• Functional secondary packaging components.
• A discussion on suitability (eg: choice of materials, protection from moisture and light, compatibility of the materials of construction with the API, and/or safety of materials of construction).

- The PRH is responsible to ensure the availability of the following information from API Manufacturer.

· Confirm the retest period study.

· State the proposed API storage condition (eg.: Store below 25^oC, protect from light).

Stress testing data:

· Provide data for stress testing study (state batch no., stress condition and testing parameter etc.) (E.g. moisture, light, acidic, basic, oxidative and thermal stress conditions)

Long term stability data:

· Provide batch size, batch number and manufacturing date for each batches mentioned in the study.

· Clarify on packaging material used during stability study.

· Related substance is an important test parameter. Please provide clarification if the related substance test has been excluded.

· State the proposed and reason of retest period under long term

· Provide current long term stability data (at least 3 commercial batches or 3 pilot batches) to support the proposed retest period.

· Please also submit long-term stability data which conduct at Zon IVB, 30 ^oC ± 2 ^oC/75% RH ± 5% RH (if available). Otherwise, please provide written stability commitment that long-term stability will be conducted at Zon IVB, 30 ^oC ± 2 ^oC/75% RH ± 5% RH

Accelerated stability data:

· Provide batch size, batch number and manufacturing date for each batches mentioned in the study.

· Clarify on packaging material used during stability study.

· Provide current accelerated stability data (at least 3 commercial batches or 3 pilot batches) to support the proposed retest period.

· A complete and current stability data should be provided to support the proposed retest period.

· Post-approval Stability Protocol and Stability Commitment

· The type of stability study and stability protocol

· API name, API manufacturer, packaging particular

· The general methodology (e.g., duration of study, storage conditions of temperature and humidity, list of relevant testing, testing frequency, etc.)

· Proposed retest period

· The analytical test methods (e.g., assay method of quantitation, determination of degradation products, moisture etc.) with reference

· Validation of test methods

· Specification

· Result of tests

Conclusions

State the proposed retest period based on stability data provided.

State the proposed shelf life based on stability data provided.

Stress testing data:

• Provide data for stress testing study (state batch no., stress condition and testing parameter etc.) (E.g. moisture, light, acidic, basic, oxidative and thermal stress conditions)

Long term stability data:

• Provide batch size, batch number and manufacturing date for each batches mentioned in the study.
• Clarify on packaging material used during stability study.
• Provide current long term stability data (at least 3 commercial batches or 3 pilot batches) to support the proposed retest period.
• For finished product manufactured at Zon IVB, long-term stability data conducted at Zon IVB, 30 ^oC ± 2 ^oC/75% RH ± 5% RH (if available) should be provided.Otherwise, written stability commitment that long-term stability will be conducted at Zon IVB, 30 ^oC ± 2 ^oC/75% RH ± 5% RH should be provided.

Accelerated stability data:

• Provide batch size, batch number and manufacturing date for each batches mentioned in the study.
• Clarify on packaging material used during stability study.
• Provide current accelerated stability data (at least 3 commercial batches or 3 pilot batches) to support the proposed retest period.

Post-approval Stability Protocol and Stability Commitment

State the proposed API storage condition (including special label, if needed) based on study condition of stability data provided (eg: Store below 25^oC, protect from light).

· The API Manufacturer may submit the DMF via electronic copy (CD) directly to Centre of Product Registration and Lab Section of NPRA to maintain confidentiality of the contents. The information contained in the closed 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 confidential information will not be disclosed to any third party without a written authorization from the API Manufacturer.

· The PRH is responsible to ensure that the complete DMF (i.e. both the Open part and the Closed part) submitted to NPRA directly by the API Manufacturer.

· The DMF should reach NPRA at the point of screening submission. Failure to do so may result in submission rejection.

· DMF Version Number: Current version number with date

The Letter of Access from API Manufacturer/ holder of the DMF authorizes the NPRA to refer to the DMF, in support of the application for a finished product. Thus, the Letter of Access must state the following:

• The name of the finished product (product name, dosage form and product strength) to be registered;
• The PRH responsible for finished product registration; and,
• Adeclaration that both the PRH and the NPRA shall be notified of any change in the API specification or in the manufacturing process that will likely affect the product’s quality or safety.