BTP 3652 CONTEMPORARY TRENDS IN

PHARMACEUTICAL

GUIDELINE ON ACTIVE PHARMACEUTICAL INGREDIENTS

(API)

NUR HIDAYAH BINTI ABDUL RAZAK TD16004

FAHMEEDA PARVIN BINTI MOHAMED SHAJAHAN TD16009
NUR SYAHIRAH BINTI MOHD RAZI TD16021
ASHVINY A/P MURUGAN TD16005
 CONTENTS

• INTRODUCTION
• DEFINITION
• SCOPE
• PROCEDURE FOR SUBMISSION AND RELATED
INFORMATION
• DRUG MASTER FILE (DMF)
• CERTIFICATES OF SUITIBILITY (CEP)
• S-ATCD IN PRODUCT DOSSIER
• STABILITY DATA OF API
• MANUFACTURING SITE INSPECTION
• MAINTENANCE OF APPROVAL STATUS

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 INTRODUCTION

• The National Pharmaceutical Regulatory Division (NPRA) under the purview

of the Ministry of Health Malaysia has introduced mandatory control of
APIs as part of the requirements in the product registration application.

• Procedure for control of APIs established by the NPRA:

1. A general understanding of the production and quality control

2. Assessment of APIs data and information
3. Assessment of the manufacturing site or production area
4. Sampling and testing of APIs (post-marketing surveillance);
5. Handling of complaints and recalls
6. Monitoring of complaints from other agencies and countries.

• This guideline is guidance for APIs in the quality part of the product dossier
(Part II-S).
 DEFINITION

• Active Pharmaceutical Ingredients (APIs) is any substance or

mixture of substances intended to be used in the manufacture of a
pharmaceutical dosage form which is an active ingredient of that
pharmaceutical dosage form.

Classification of
API

Inorganic
Substances

Organic Substances
• Synthetic/Semi-Synthetic
• Animals/Human Origin
 SCOPE

• This Guideline for registration of new final APIs products and

current/exist in registered products (exclude traditional, veterinary and
health supplement products)

• Biological and Immunological active substances are excluded from scope

of this guideline.

• APIs used in products for export only (FEO) are exempted from the
requirement for submission of the Drug Master File (DMF) and
Certification of Suitability (CEP) in the product application.

• Assessment of an API will be performed for a new product registration

application and registered product renewal application.
 PROCEDURE FOR SUBMISSION &
RELATED INFORMATION
1. How to submit?
API(s) information can be submitted through 3 following options :
- Option 1 : Drug Master File (DMF) procedure
- Option 2 : Certificate of suitability of the European Pharmacopoeia (CEP)
- Option 3 : Full details of “Part II-S ACTD” in the Product Dossier
Note :
- The PHR should attach : i) cover letter
ii) API submission checklist

- PRH shall submit Part II-S ACTD as part of product application.

- The DMF must be submitted via electronic copy (CD) directly to the NPRA to maintain
confidential.

- The NPRA may accept a CEP issued by European Directorate for the Quality of Medicine
(EDQM) in lieu of the DMF of an API.
2. Required Information
Note :
Separate API information must be provided
for each API for:
i. Finished product contains more than one
API
ii. API from different manufacturing site
iii. API from different synthesis route

Note :
In order to gain approval for an API;
• Data should be sufficient to justify the
specifications and testing of the API
• The information should confirm the
identity and stability of the API
• The control of the API manufacturing
process as well as the ability to produce an
API with reproducible physical properties
and impurity profiles should be
demonstrated.
 DRUG MASTER FILE (DMF)

 provide confidential detailed information about facilities, processes, or articles used in

the manufacturing, processing, packaging, and storing of one or more human drugs.
 submitted to the NPRA, should contain the information as required under sections
listed in Part II-S ACTD.
 created to allow an authorized party other than the holder of the DMF to refer the
DMF without disclosing the contents of the file
 The ICH M4Q Technical Guideline and ASEAN Common Technical Requirements
(ACTR) / ACTD provide details on the information to be included in the API sections of
an application dossier
 DRUG MASTER FILE (DMF)

 Two parts of DMF , namely the Open (or PRH’s) part and the Closed (or restricted) part.
• From the PRH:
o Open part of the DMF, as part of the submitted product dossier (contains most of
the information in Part II-S (ACTD) - i.e. sections S1, S2.1 and S3 to S7) :
▪ S1 General Information : Nomenclature, Structure, General Properties
▪ S2 Manufacture
▪ S3 Characterization : impurities
▪ S4 Control of API/Drug Substance
▪ S5 Reference Standards or Materials
▪ S6 Container Closure System
▪ S7 Stability
 DRUG MASTER FILE (DMF)

• From the API Manufacturer:

o The Complete DMF (open part AND closed part); S1-S7. The closed part contains the
confidential information in section Part II-S ACTD - i.e. section S2);
▪ S2 Manufacture
o An original Letter of Access. 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. The Letter of Access must state the following:
• The name of the finished product to be registered
• The PRH responsible for finished product registration
• A declaration that both the PRH and the NPRA shall be notified of any change in the
API specification or in the manufacturing process (affect product’s quality or safety).
 DRUG MASTER FILE (DMF)

 Upon receipt of the DMF, a BPFK/NPRA DMF number will be assigned to the application
for product registration. The PRH and the API Manufacturer should make a reference to
the BPFK/NPRA DMF number for future correspondences. The NPRA will directly contact
API Manufacturer for any correspondence pertaining to API information in closed part.
The PRH is required to include a copy of the API Manufacturer’s Letter of Access in the
application.

 API Manufacturer is responsible to maintain and update the DMF. The PRH should file a
variation once they are notified with the changes to the DMF.

 The DMF should include a discussion of the potential impurities most likely to arise during
synthesis using the actual manufacturing process described in the DMF together with
evidence that these impurities are adequately controlled by the test procedures described
in the pharmacopoeia monograph.
 DRUG MASTER FILE (DMF)

 API Manufacturer Obligations:

• Any change or addition, including a change in authorization related to specific PRH, shall
be submitted to the NPRA in duplicate and adequately crossreferenced to previous
submission.

• API Manufacturer shall notify each affected PRH who has referenced the DMF of the
pertinent change.

 Common inorganic used do not required DMF and regarded as API in products (injections
and dialysis). Evidence needs to be submitted by the PRH to proof API is obtained from a
reliable source and consistently comply with the applicable pharmacopoeial
specifications.

 Any non-pharmacopoeial specifications need to be assessed by the NPRA to determine

their appropriateness and adequacy to ensure the quality of the API.
CERTIFICATES OF SUITABILITY (CEP)

• CEP stands for Certification of Suitability of European Pharmacopoeia

monographs/ Certificate of Pharmacopoeia

• Along with CEP , the PRH should submit the following information in the
product dossier:

1. General properties
2. Elucidation of structure and other characteristic
3. Specification
4. Analytical procedures and validation
5. Batch analysis
6. Reference standards or materials
7. Container closure system
8. Stability
 Part II- S ACTD

• Information on the API sections (ACTD Part II - S), including full details of
chemistry, manufacturing process, quality controls during manufacturing
and process validation for the API, should be submitted in the product
dossier.

• This ASEAN Common Technical Dossier (ACTD) is a guideline of the agreed

upon common format for the preparation of a well-structured Common Technical
Dossier (CTD) applications that will be submitted to ASEAN regulatory authorities
for the registration of pharmaceuticals for human use

• Separate dossier (Part II S – ACTD) must be provided for each API for:
i. Finished product contains more than one API
ii. API from different manufacturing site
iii. API from different synthesis route

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 STABILITY DATA OF API

• Current stability test data for an API should be provided for at

least 3 primary batches.

• Data should include :

1. The type of stability study and protocol
2. API name, API manufacturer, packaging particular
3. Batch details
4. The general test methodology
5. The analytical test methods
6. Validation of test methods
7. Specification
8. Results of tests
9. Conclusion

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 STABILITY DATA OF API

• The minimum stability data required are as follow:

1. At least 12 months of long term data and 6 months of accelerated data on

at least 3 primary batches of the API.
2. The batches should be at least pilot scale-sized and manufactured by a
method that stimulates the final commercial process.

• Different API sourced from multiples sites or from different route of

synthesis, different stability data should be provided.

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 MANUFACTURING SITE INSPECTION (MSI)

1. Depending on the outcome of the evaluation of the API dossier, risk-

based approach will be used in the planning of MSI:

 The type of APIs as well as the outcome

 Results and reports of inspections - conducted by other regulatory
authorities or competent organizations.

2. The NPRA shall plan and coordinate the performance of inspections at

the manufacturing site of the API

 to assess compliance with the relevant sections of the relevant GMP

Guidelines
 to compare the technical information

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 MANUFACTURING SITE INSPECTION (MSI)

3. Inspections shall be performed by inspectors deemed to possess

sufficient qualifications and experience.

 The inspectors have to be competent in production and quality control of

pharmaceuticals area.
 Should have appropriate experience in the area of GMP.
 Inspectors shall perform the inspections and report on its findings in
accordance with established Standard Operating Procedures (SOPs) so as to
ensure a standard harmonized approach.

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 MAINTENANCE OF APPROVAL STATUS

1. Manufacturers/suppliers of an API shall provide information on any

changes in manufacture and control that may have impact on the safety,
purity and quality of the API.
- PRH is responsible to provide the NPRA with the appropriate
documentation
- For those APIs approved by the NPRA, an evaluation of such variations shall
be performed with accordance to the Malaysian Variation Guidelines
(MVG).

2. Random samples of APIs supplied to manufacturers of finished products

may be taken for independent testing if needed.

3. The NPRA may conduct a re-evaluation of the APIs at a 5 years interval. (if
the API and manufacturing site not comply with recommended standards,
then it will be removed from approved list)
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 MAINTENANCE OF APPROVAL STATUS

4. Re-evaluation may also be done in any situation deemed necessary. For

example,
- If any omissions by the manufacturer in the initial assessment procedure or
during the follow-up activities is evident in relation to the requirements.
This includes compliance with GMP.
- If any batch(s) of supplied API is considered not to be in compliance with
the agreed specification of the API.
- If the CEP, or an API for which a CEP dossier was submitted, is cancelled or
refused based on the assessment of the dossier for any other reason.
- If in the opinion of the NPRA, changes made in the sourcing of key
intermediates, route of synthesis, facility or other production, require that
reassessment be made.

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THANK YOU