DRAFT 5
APPENDIX 13: 
DRUG MASTER FILES AND CERTIFICATES OF SUITABILITY
1. GENERAL OVERVIEW
1.1.Who should submit the document?
•The applicant of the product registration shall submit the DMF or the Certificate  
of Suitability (CEP) with the product registration dossier.
•The DMF holder may submit the DMF via electronic copy (CD) and hardcopy  
(optional) directly to NPCB to maintain confidentiality of the contents. 
1.2.Classification of Active Pharmaceutical Ingredient (API)
•Any substance or combination of substances used in a finished product, intended  
to  furnish  pharmacological  activity  or  to  otherwise  have  direct  effect  in  the  
diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct  
effect  in  restoring,  correcting  or  modifying  physiological  functions  in  human  
beings. (Ref: WHO)
•API can be classified into:      
oNew API, used for the first time in a medicinal product either for human  
or veterinary use
oExisting API not described in the European Pharmacopoeia (Ph.Eur.)  
or the pharmacopoeia of an EU Member State
oExisting API described in the Ph.Eur. or in the pharmacopoeia of an  
EU Member State
•API can further be divided into:
oInorganic substances
oOrganic substances (isolated from material of animal or human  
origin)
oOrganic substances (synthetic or semi-synthetic or isolated from  
herbal sources or micro-organisms)
1.3.Scope
•API  for  new  application  for  product  registration.  It  is  applicable  to  all  
pharmaceutical products (excluding traditional products) locally manufactured or  
imported. API used in product for export only (FEO) is exempted from submitting  
the DMF and CEP in product application.
•Separate registration of the API is not a requirement for the purpose of product  
registration. However, the required technical documentation pertaining to each  
API should be submitted with the product application.
1•An API is assessed once an application using the related API is submitted for  
registration of a product by a Marketing Authorisation Holder (MAH).
1.4.Required Information
•Drug Master File
oA Drug Master File (DMF) is a submission to the National Pharmaceutical  
Control Bureau (NPCB) that may be used to provide confidential detailed  
information  about  facilities,  processes,  or  articles  used  in  the  
manufacturing, processing, packaging, and storing of one or more human  
drugs. 
oTechnical contents of a DMF are reviewed only in connection with the  
review of a new application for product registration.
oDMF’s are generally created to allow a party other than the holder of the  
DMF to reference material without disclosing to that party the contents of  
the file. 
oSee section 2 for details (page 3).
•Certificates of Suitability (CEP)
oCEP stands for  Certification  of suitability of  European Pharmacopoeia  
monographs. COS (“Certificate of Suitability”) means the same and, even  
if often used, is not the official acronym.
oThe role of the CEP is to demonstrate that the purity of a given substance  
produced by a given manufacturer is suitably controlled by the relevant  
monograph(s) of the European Pharmacopoeia. By demonstrating that  
they  have  been  granted  a  CEP  for  their  substance,  suppliers  of  raw  
materials can prove this suitability to their pharmac eutical industry clients 
                               and/or  the  NPCB.
oNote that technical information (such as functionality tests, stability data  
when  a retest  period  is not  mentioned on  the Certificate) is  optional.  
However when it is not covered by the CEP and it may be required by  
NPCB and Marketing Authorisation Holder (MAH), it should be part of the  
application for product registration .
oWhere a CEP for an API is available or the API is listed on the list of APIs  
prequalified by WHO, Drug Master File (DMF) of such API may not be  
required  by  NPCB.  However,  the  NPCB  may  request  any  additional  
information about the API if it is deemed appropriate.  
oSee section 3 for details  (page 5).
22. DRUG MASTER FILE (DMF)
2.1.The ICH M4Q technical guideline and ASEAN Common Technical Requirements  
(ACTR) provide details on the information to be included in the API sections of an  
application dossier. 
2.2.If drug product contains more than one API, the information within Module 3.2.S  
(ICH CTD) or part 2.S (ACTD) must be provided in its entirety for each API. 
2.3.If an API is manufactured by a manufacturer different from the product owner, data  
on its manufacture, quality control and stability shall be submitted via a DMF.
2.4.Where the API and drug product are manufactured by the same manufacturer, data  
on its manufacture, quality control and stability shall be submitted via a DMF. 
2.5.The DMF is divided into two parts: an open (or applicant’s) part and a closed (or  
restricted) part. 
2.6.The documentary requirements for an application making a reference to a DMF are  
as follows:
•From Applicant: 
oThe open part of the DMF from the applicant , as part of the submitted dossier  
(the open part contains most of the information in Module 3.2S (ICH CTD) or  
Part 2.S (ACTD) - i.e. S1, S2.1 and S3 to S7 sections);
S1 General Information
−1.1 Nomenclature
−1.2Structure
−1.3 General Properties
S2 Manufacture
−2.1 Manufacturer (s)
S3 Characterisation
−3.1 Elucidation of Structure and other Characteristics
−3.2 Impurities
S4 Control of 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
3•From DMF Holder: 
oThe complete (open and closed parts) DMF  from the API manufacturer  – i.e. 
the  DMF  holder  (the  closed  part  contains  the  confidential  information  in  
section 3.2.S.2.) and,
S2 Manufacture
−2.1 Manufacturer (s)
−2.2 Description of Manufacturing Process and Process Controls
−2.3 Control of Materials
−2.4 Controls of Critical Steps and intermediates
−2.5 Process Validation and/or Evaluation
−2.6 Manufacturing Process Development
oAn original Letter of Authorisation (see below).
2.7.The Letter of Authorisation authorises NPCB to refer to the DMF in support of the  
application for  a drug product. Thus,  the Letter of  Authorisation must  state the  
following: 
•The name of the drug product (product name, dosage form and product strength) to  
be registered; 
•The local applicant responsible for product registration; and, 
•A declaration that the local applicant and NPCB will be notified of any change in the  
API specification or in the manufacturing process that will likely affect the product’s  
quality or safety.
2.8.If a Letter of Authorisation does not fulfill these requirements, NPCB reserves the  
right to return the DMF to the DMF holder.
2.9.The  DMF  holder  may  submit  the  DMF  via  electronic  copy  (CD)  or  hardcopy  
(optional)  directly  to  NPCB  to  maintain  confidentiality  of  the  contents.  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 authorisation. The confidential information will not be disclosed to any third  
party without a written authorisation from the DMF Holder.
2.10.Upon receipt of the DMF or CEP or any certification recognized by the NPCB, a  
DMF number or reference number will be assigned. For future correspondence, the  
applicant  and  the  DMF  holder  should  make  a  reference  to  the  assigned  DMF  
number or reference number. Should there be deficiencies within the restricted part  
of the DMF, NPCB will raise queries directly with the DMF holder. The applicant  
referencing a DMF  is  required to  include  a  copy of  the DMF holder’s letter  of  
authorisation in the application.
42.11.Applicants are responsible to maintain and update the DMF. Applicants should file a  
variation if there are changes to the DMF. Please refer Annex A for Type I & Type II  
variations for DMF.
2.12.DMF Holder Obligations:
•Any  change  or  addition,  including  a  change  in  authorisation  related  to  specific  
applicants, should be submitted in duplicate and adequately cross referenced to  
previous  submission(s).  The  reference  should  include  the  date(s),  volume(s),  
section(s), and/or page number(s) affected.
•A DMF holder must notify each affected applicant who has referenced its DMF of  
any pertinent change in the DMF. Notice should be provided well before making the  
change  in  order  to  permit  the  applicant  to  supplement  or  amend  any  affected  
application(s) as needed.
2.13.A DMF is not required for common inorganic salts (for example, sodium chloride,  
and other common electrolytes)  used and regarded as API drug substances in  
products such as injections and dialysis solutions, and simple organic compounds  
available commercially in high purity (for example, natural occurring organic acids  
and their salts, including ascorbic acid and sodium citrate, and simple mono- and  
disaccharides such as glucose and sucrose). Although a DMF is not required for  
these active ingredients, evidence needs to be submitted by the finished product  
manufacturer that the substance is obtained from a reliable source and consistently  
comply with the applicable phamacopoeial specifications. Any non-pharmacopoeial  
specifications need to be assessed by the NPCB to determine their appropriateness  
and adequacy to ensure the quality of the substance.
2.14.Where a DMF is submitted for an API controlled according to a pharmacopoeial  
monograph, 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 pharmacopoeial monograph. Where particular  
impurities found in the substance are not listed in the monograph, but are proposed  
to  be  allowed  at  certain  level,  a  justification  (including  toxicological  data,  if  
appropriate) should be provided.
3. CERTIFICATES OF SUITABILITY (CEP) 
3.1.If reference is made to a CEP, the applicant should submit a copy of the valid   CEP, 
including all annexes, in lieu of a DMF or Section S of the CTD. However, the  
following documents must accompany the CEP (and inserted into its corresponding  
CTD S section): 
•Results  of  batch  analysis  (S4.4)  from  the  API  manufacturer*  demonstrating  
compliance with the Ph. Eur. monograph and including any additional tests/limits  
listed on the CEP; and, 
5•Additional data to address any relevant parameter(s) not addressed in the CEP,  
such as stability data (S7), if a re-test period is not stated on the CEP and  
physico-chemical  characteristics  (e.g.  particle  size,  polymorphism,  etc),  if  
applicable.
3.2.NPCB reserves the right to request for any additional information about the API if it  
deemed appropriate.
3.3.If there is a CEP for animal-derived material used in the drug product, the applicant  
may submit the CEP in lieu of the documents stipulated in DRGD. 
3.4.It is the applicant’s responsibility to submit the latest CEP updates, with annexes, as  
soon as it is available from the European Directorate for the Quality of Medicines  
and Healthcare (EDQM). 
3.5.NPCB will recognize the evaluation of relevant APIs by the regulatory authorities of  
the reference countries (Australia, Japan, France, Switzerland, United Kingdom,  
Canada,  Sweden,  United  State  of  America),  WHO  (prequalified  list  of  
pharmaceutical)  and  the  European  Directorate  for  the  Quality  of  Medicines  &  
Healthcare (EDQM).
* If the API manufacturer is CEP certified and drug product manufacturer claims otherwise  
(USP, JP, In-House etc), data covering S4.1 to S4.5 from the drug product manufacturer  
should be submitted instead.
4. STABILITY DATA OF API (3.2.S.7) 
4.1Stability test data should be provided for at least 3 production batches and should
include:
•batch details (batch number, date of manufacture);
•the general test methodology (duration of study, storage conditions of temperature and  
humidity, time points when samples were removed for analysis etc.);
•the analytical test methods (assay method of quantitation, determination of degradation  
products, moisture etc);
•validation of test methods;
•results of tests;
•conclusions.
4.2In circumstances where complete real time stability data is not available at the time of  
submission, the minimum stability data required are as follows: 
•At least 12 months of real time data  and 6 months of accelerated data on at least  
three primary batches of the API; 
•The batches should be at least pilot scale-sized and manufactured by a method that  
simulates the final commercial process.
6In view of this, the shelf life may be extended beyond the end of real time studies  
which can be extrapolated not more than 12 months covered by the real time data. 
4.3If the API is sourced from multiple sites, stability data from each site should be provided.  
4.4NPCB may request for additional stability data if deemed necessary for the evaluation of  
the application. 
5. SITE INSPECTION 
5.1.Dependent  on  the  outcome  of  the  evaluation  of  the  API  dossier,  a  risk-based  
approach will be used in planning of inspections, taking into account the type of APIs  
and the outcome, results and reports of inspections conducted by other regulatory  
authorities or competent organizations. 
5.2.NPCB will plan and coordinate the performance of inspections at the manufacturing  
site(s) of APIs and that of the key intermediate (if relevant) to assess compliance with  
the relevant sections of relevent GMP Guidelines, and will compare the technical  
information on the manufacturing process given in the API dossier submitted with the  
manufacturing process actually carried out on the site. 
5.3.The inspections will be performed by auditors who have the relevant qualifications  
and  experience  to  perform  such  inspections,  be  competent  in  areas  such  as  
production and quality control of pharmaceuticals, and have appropriate experience  
in GMP. Auditors will perform the inspections and report on its findings in accordance  
with established SOPs so as to ensure a standard harmonized approach. 
6. MAINTENANCE OF APPROVAL STATUS 
6.1.Manufacturers  of  finished  products  should  establish  a  mechanism  by  which  
manufacturers/suppliers of API will provide information on any changes (variations) in  
manufacture and control that may have impact on the safety, efficacy and quality of  
the API. It is the applicant's responsibility to provide NPCB with the appropriate  
documentation (referring to relevant parts of the dossier) to prove that any intended  
or implemented variation will not have an impact on the quality of the API that has  
been previously approved. For those APIs approved by NPCB, an evaluation of  
variations according to the established guidelines will need to be done.
  
6.2.Random  samples  of  APIs  supplied  to  manufacturers  of  finished  pharmaceutical  
products may be taken for independent testing if there is a need. Certificates of  
Analysis released by the manufacturer and specifications for test methods should be  
provided by the manufacturer or applicant to NPCB for review upon request. In the  
event of failure to meet the established criteria for testing, NPCB will investigate the  
problem and communicate this to the manufacturer concerned. 
76.3.NPCB may conduct a re-evaluation of the APIs at a 5 year interval. If, as a result of  
this re-evaluation, it is found that a API and/or specified manufacturing site no longer  
complies with the recommended standards, such APIs and manufacturing sites will  
be removed from the approved list. 
6.4.Re-evaluation, including re-inspections, may also be performed:  
•if any fraud or omissions by the applicant or manufacturer(s) of APIs in the initial  
assessment procedure or during the follow-up activities, becomes evident; and 
•if NPCB or other parties as user of the procedure consider(s) that a batch or  
batches  of  supplied  prequalified  APIs  are  not  in  compliance  with  the  
specifications which were found to be applicable upon prequalification.
8ANNEX A – TYPE I & TYPE II VARIATION ON DMF
Type  I:  Minor  variation  with  a 14  days  validation  period.  The  applicant  may proceed  to  
implement  the  change  after  a  14  days  validation  period  upon  the  date  of  receiving  the  
documents by variation unit.
Dossier requirements for Type 1 variation:
1.Renaming (e.g. street name, postal code) of Manufacturing Site of Drug Substance  
-Condition:  The manufacturing site of the drug substance remains at the same  
physical location.
-Supporting Documents:
i.Updated information of the manufacturer of the drug substance
ii. A declaration from the applicant that manufacturing site remains the same and  
that the remaining does not involve changes of the manufacturing process and/or  
quality of the product.
2.Withdrawal/Deletion  of  Manufacturer  (Drug  Substance,  Drug  Product,  Packager  or   
Batch Releaser)
-Supporting Documents:
i.Reason for withdrawal/deletion
3.Minor Change of Manufacturing Process of Drug Substance  
-Conditions:
The synthetic route remains the same;
Specification of the drug substance remains the same;
No change in the physical properties;
No new impurities or change in level of impurities which would require further  
qualifications in safety studies.
-Supporting Documents:
i.Relevant CTD section S;
ii.Tabulation of the current and proposed process with changes highlighted;
iii.Batch analysis data (in a comparative table) of at least two batches (pilot scale or  
production scale) manufactured according to the currently approved and proposed  
process;
iv.A declaration from the applicant that no new impurities have been introduced at or  
above the accepted threshold for qualification of impurities or that there is no  
increase in the level of impurities, which require further safety studies;
v.A declaration from the applicant that the specification of the drug substance has not  
changed or if there is any change to the specification (i.e. tightening), the texts of  
the current and proposed specifications should be provided (in a comparative table  
where possible).
9vi.A  declaration  from  the  applicant  that  the  relevant  stability  studies  of  the  drug  
substance in accordance with the relevant guidelines have been started and that  
the relevant stability studies will be finalized; data should be provided only if outside  
specification (with proposed action). 
4.Change of batch size of drug substance  
-Condition: 
The change does not affect the reproducibility of the process.
-Supporting documents:
i.Amended relevant CTD Section S;
ii.Batch analysis data (in a comparative table) on a minimum of one production batch  
manufactured to both the currently approved and the proposed batch sizes. Batch  
data  on  the  next  2  full  production  batches  should  be  available  on  request  or  
reported if outside specification (with proposed action);
iii.Specification of the drug substance.
5.Change to comply with accepted pharmacopoeia(s) for drug substance  
Pharmacopoeia accepted by NPCB are EP, USP, BP and JP.
-Conditions:
Change is made exclusively to comply with an update of relevant monograph of  
the pharmacopoeia;
Exclude change from one accepted pharmacopoeia to another.
-Supporting documents:
i.Tabulation of the current and revised specifications with changes highlighted;
ii.Revised specification of the drug substance;
iii.Batch analysis of the drug substance for all tests in the new specification
6.Change of test procedure of drug substance  
-Condition
Results of method validation show new test procedure to be at least equivalent to  
the former procedure.
-Supporting documents
i.Description  of  the  analytical  methodology,  a  summary  of  validation  data,  and  
comparative  analytical  result  between  the current test and the propose one, if  
appropriate;
ii.Specification of the drug substance;
iii.A declaration from the applicant that the specification of the drug substance has not  
changed.
7.Tightening of specification or addition of new test parameter(s) and limit(s) of drug   
substance
10-Condition
-New test method does not concerned a novel non-standard technique or a  
standard technique used in a novel way
-Supporting documents
i.Tabulating of the current and revised specification of drug substance with changes  
highlighted;
ii.Revised specification of drug substance;
iii.Batch analysis of the drug substance for all tests in the new specification
iv.Description of any new analytical method and summary of the validation data, if  
applicable.
8.Extension of shelf life or retest period of drug substance  
-Condition
The studies must show compliance with specification
-Supporting documents
i.Stability data of the drug substance should be presented on at least two pilot or  
production scale batches of the requested shelf life or retest period;
ii.Specification of the drug substance.
9.Change  of  imprints,  bossing  or  other  markings  on  tablet  or  printing  on  capsules   
including addition or change of inks used for product marking
-Conditions
New markings do not cause confusion with other tablets or capsules;
The inks have not been rejected for pharmaceutical use;
Release and shelf life specifications of the drug product have not changed (except for  
appearance).
-Supporting documents
i.Details of the proposed new inks (where applicable);
ii.Detailed drawing or written description of the current and proposed imprint/ bossing/  
marking/ ink;
iii.Official letter of commitment to inform users of the relevant changes, and that the  
current products stocks will be exhausted before the product labeled with the new  
name is marketed;
iv.A declaration from the applicant that the release and shelf life specifications of the  
product have not changed (except for appearance).
11Type  II:  Major  variation  is  considered  a  major  change  and  approval  is  required  prior  to  
implementation. The applicant is responsible for ensuring that all the necessary validation has  
been conducted to demonstrate that the change does not reduce the quality, safety or efficacy  
of the product.
Dossier requirements for Type 2 variation:
1.Change or inclusion of Manufacturing site(s) of drug substance  
Supporting documents:
i.CTD section S, CEP for the drug substance or both the open and closed portions of  
the DMF;
ii.Tabulation of the differences compared with the registered manufacture information  
(if applicable);
iii.Batch  analysis  data  (in  a  comparative  tabular  format)  for  at  least  2  batches  
(minimum  pilot  scale)  of  the  drug  substance  from  the  current  and  proposed  
manufacturers/sites;
iv.A letter of commitment to conduct the appropriate stability study for the drug product  
manufactured with the drug substance from the proposed manufacturer.
2.Major change of manufacturing process of drug substance  
Supporting documents:
i.Relevant CTD section S;
ii.Tabulation of the current and proposed process with changes highlighted;
iii.Batch  analysis  data  (in  a  comparative  tabular  format)  for  at  least  2  batches  
(minimum  pilot  scale)  manufactured  according  to  the  currently  approved  and  
proposed process;
iv.A declaration from the applicant that no new impurities have been introduced at or  
above  the  accepted  threshold  for  qualification  of  impurities  or  that  there  is  no  
increase in the level of impurities, which require further safety studies;
v.If any potential new impurities are detectable at an acceptable limit of detection,  
appropriate evidence must be provide;
vi.A declaration from the applicant that the specification of the drug substance has not  
changed or if there is any change to the specification (i.e. tightening), the texts of the  
current and proposed specifications should be provided (in a comparative tabulation  
form where possible’
vii.Relevant stability studies of the drug substance in accordance with the relevant  
guidelines should be provided;
viii.A letter of commitment to conduct the appropriate stability study for the drug product  
manufactured with the drug substance from the new manufacturing process, and  
report if any results fall outside shelf life specification (with proposed action).
3.Change of specification of drug substance  
Supporting documents
i.Scientific and/or historical data used to support the change;
12ii.Currently registered version of the release and/or shelf life specifications with the  
proposed change(s) clearly highlighted, underscored, or otherwise indicated (in a  
comparative tabulation form).
13