Guidance Document Foreign GMP Inspection Sep 2021 8th Ed Malaysia
Guidance Document Foreign GMP Inspection Sep 2021 8th Ed Malaysia
Guidance Document Foreign GMP Inspection Sep 2021 8th Ed Malaysia
Lot 36, Jalan Profesor Diraja Ungku Aziz, 46200 Petaling Jaya, Selangor.
Tel. No. : 03-78835400
Website : http://npra.gov.my
GUIDANCE DOCUMENT
FOREIGN GMP INSPECTION
8th Edition
September 2021
pg. 0
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
TABLE OF CONTENTS
pg. 1
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
1.0 INTRODUCTION
A company applying with the National Pharmaceutical Regulatory Agency (NPRA) for
registration of a medicinal product in Malaysia must provide acceptable evidence to show that
the manufacturer of the product follows an internationally accepted standard of Good
Manufacturing Practice (GMP) and recognised by the authority in Malaysia.
The Control of Drugs and Cosmetics Regulations 1984 (CDCR) requires that the standard of
manufacture and quality control of medicinal products manufactured outside Malaysia be taken
into consideration before the products are registered with the authority namely Drug Control
Authority (DCA). NPRA as the secretariat to the DCA is responsible for ensuring all
manufacturers of registered products in Malaysia are able to provide acceptable evidence that
the manufacturing premises conform to current GMP requirements. Hence, foreign
manufacturers are also subjected to GMP conformity assessments through acceptable GMP
evidence or GMP inspection.
Malaysia became the 26th member of the Pharmaceutical Inspection Co-operation Scheme
(PIC/S) since 1st January 2002. Hence, the current PIC/S Guide to GMP for Medicinal Products
and its Annexes have been adopted as the standard used by NPRA to assess the GMP
conformity of manufacturers.
2.0 DEFINITIONS/ABBREVIATIONS
RI Remote Inspection
pg. 2
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
3.0 PURPOSE
3.1 The objective of the foreign GMP inspection is to assess the conformance of foreign
manufacturers to GMP requirements and ensure quality of products that are registered or
in the process of registration/re-registration/change of manufacturing site with DCA of
Malaysia and products manufactured for clinical trial purposes (investigational medicinal
products). This activity is carried out with a view to strengthen the supervision and
administration over imported products and foreign manufacturers as well as ensuring
quality and safety of the imported products.
3.2.1 To provide information on the types of GMP evidence acceptable to the DCA of
Malaysia.
3.2.3 To provide guidance on how to apply for an on-site foreign GMP inspection, the
eligibility and application for GMP Desktop Assessment (GDA) for foreign
manufacturers previously inspected by NPRA.
4.0 SCOPE
4.1 This guidance applies to all manufacturers of medicinal products located outside
Malaysia.
pg. 3
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
5.2 For pharmaceutical product, the requirement for GMP evidence submission are laid
down in the following directives issued by the Director Pharmaceutical Services:
5.2.5 Circular Letter Ref. No. NPRA-600-1/9/12 (7) dated 11 February 2021 - Pekeliling
Berkenaan Pelaksanaan Prosedur Kerja Penilaian Desktop Bagi Aktiviti
Pemeriksaan Amalan Perkilangan Baik (APB) Ke Atas Premis Pengilang
Farmaseutikal Luar Negara.
5.3 Based on the directives listed above, starting 1st of July 2018;
pg. 4
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
5.4 Apart from the GMP Evidence’s issuing body, the documentary evidence provided must:
5.4.2 Provide the correct manufacturer’s name and address of manufacturing site,
5.4.3 Specify the dosage form class OR the facility used to manufacture the dosage
form was covered during the inspection.
5.6 Where acceptable GMP evidence of the foreign manufacturer is not available or the
documentation submitted is insufficient to demonstrate acceptable GMP standard, a
GMP inspection shall be conducted by NPRA.
5.7 Submission of acceptable GMP evidence does not guarantee that GMP inspection will
not be conducted by NPRA on the foreign manufacturer.
5.8 Beginning April 2021, for foreign manufacturers which had been inspected by NPRA with
valid acceptable GMP status (3 years after the last inspection) may be eligible for GDA.
This allows the extension of the GMP status for the foreign manufacturers to facilitate
continuous regulatory process for the new registration and renewal of medicinal products
in Malaysia only. NPRA will not issue any GMP certificate for this purpose.
6.1 The application for a foreign GMP inspection should be made by a Malaysian registered
company (PRH) acting on behalf of the foreign manufacturer.
6.2 The Malaysian registered company (PRH) shall authorise a responsible person (e.g.
Chief Executive Officer, Managing Director or Regulatory Manager) to act as the liaison
officer with NPRA for all arrangements pertaining to the proposed inspection.
pg. 5
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
6.3 The appointed liaison officer responsible for the application is required to submit the
completed application form (BPFK 501) with the processing fee of RM 5,000 and these
documents:
6.3.6 Hotel quotation [Name of hotel, hotel’s official website, distance between hotel
and manufacturing facility, accommodation during transits (if any)]
6.3.7 Declaration letter from Manufacturer stating that premise is ready to be inspected
at any time.
6.4 Any changes to the information on application form must be notified in writing within one
of week of application submission.
6.5 If the application is successful, NPRA will write to the applicant and announce the
proposed date, duration of inspection and estimated cost for inspection.
6.6 Prior to conducting the inspection, a meeting will be organized between the appointed
GMP inspectors and the applicant for a preparation of the inspection.
6.7 If the foreign manufacturer is also manufacturing registered products for other PRH, the
applicant must ensure that all the other PRH are aware and understand that the outcome
of the GMP inspection may affect the registration status of all the products manufactured
at this facility.
6.8 Applicant must undertake the responsibility to ensure that application for new product /
dosage form registration is submitted to Centre for Product and Cosmetic Evaluation
after submission of foreign GMP inspection application. Applicant must ensure that the
application has passed the screening process for new product / dosage form prior
inspection.
6.9 Failure to ensure that the product registration application has passed the screening
process may cause the cancellation of the application.
pg. 6
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
6.10 GDA is a process to extend the status of GMP for eligible foreign manufacturers, for the
purpose of registration and/or registration renewal of medicinal products in Malaysia. The
criteria for eligible application are:
• Application of BPFK-501 is submitted at least 1 year before the expiry of GMP status
(3 years after the last inspection date)
6.11 For every BPFK-501 application received, NPRA will evaluate them for GDA eligibility. If
eligible, PRH will be duly informed for further action. This is further explained in Process
Flow for GMP Foreign Inspection (Appendix 1).
6.12 Currently, there is no additional processing fees imposed for eligible application.
However, upon unsatisfactory GDA, the foreign manufacturers will be subjected to an on-
site inspection. The scheduling of the inspection will be based on the date of complete
BPFK-501 application received by NPRA.
6.13 Upon satisfactory GDA, the GMP status validity will be extended for the next two years.
For every on-site inspection, the foreign manufacturer may apply for GDA up to two times
consecutively. For example, the last inspection conducted on 01/12/2017 will expire on
30/11/2020. With satisfactory GDA (first time), the GMP status will be extended to
30/11/2022. Then, PRH may apply for another GDA which due in 2021, in which a
satisfactory GDA (second time) will be further extended to 30/11/2024. This process is
further illustrated in Appendix 2 of this document.
6.14 Starting from 1st of September 2021, Distant Assessment (DiA) which consist of Remote
Inspection (RI) will commence whereby it will replace on-site foreign GMP inspection
during the COVID-19 pandemic when border closure/travel restrictions are still in place.
6.15 On-site foreign GMP inspection will resume once COVID-19 pandemic had subsided.
6.16 This work process is only applicable to all foreign GMP inspection application (BPFK-
501) pending for on-site inspection.
6.17 Foreign manufacturers eligible for GMP Desktop Assessment (GDA) work process are
excluded from DiA as the GMP status of the manufacturer shall be confirmed following
the completion of GDA.
6.18 Remote Inspection includes documentation review followed by virtual inspection in which:
pg. 7
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
6.19 The payments involved with DiA work process includes Processing Fee and Inspection
Fee are as mentioned in para 6.23.1 & 6.23.2. Kindly note that both the fees are non-
refundable under any circumstances.
6.20 For further information regarding Remote Inspection, kindly refer to Frequently Asked
Questions (FAQs) on Foreign Good Manufacturing Practice (GMP) Inspections by NPRA
During COVID-19 Pandemic through the following link:
https://www.npra.gov.my/index.php/en/component/sppagebuilder/915-faq-gmp-foreign-
covid.html
6.21 Travelling arrangement includes both ground travel and air travel. The applicant is
expected to propose a suitable travel itinerary to NPRA (as reference) based on the
following criteria:
• Flight is normally of the shortest distance from Kuala Lumpur to the point of
destination and without transit. If transit is required due to unavailability of routes;
• Flight class is Economy Class, with fare structure allowing for change of flight date
and time without any penalty or charge;
6.22 The information on accommodation will be required in the form of an official quotation or
similar and satisfy the following criteria:
• Reasonable distance between the hotel and manufacturing facility (Please state the
estimated duration to reach the manufacturing facility from the hotel).
pg. 8
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
6.23 The payment structure for foreign GMP inspection consist of three parts, in which all shall
be borne by the applicant as follows:
• Payment of the inspection fee must be made at least one month before the
foreign inspection is conducted.
• The inspection expenses will cover all the expenses incurred to conduct the
inspection. These include flight ticket, accommodation and other associated
expenses (such as allowances, insurance, etc.)
• NPRA will calculate the inspection expenses using the information obtained
from the applicant and inform the applicant accordingly.
pg. 9
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
Account No : 21401360003459
• In the event where foreign GMP inspection was conducted, remainder of the
inspection expenses will be retained in the trust fund for future purposes as
outlined in the Arahan Amanah Penilaian, Pengiktirafan Akreditasi dan
Pemeriksaan APB.
• The inspection expenses will be refunded in the event where foreign GMP
inspection cannot be conducted.
OUTCOME OF INSPECTION
6.24 The outcome of the GMP inspection will be tabled to the Jawatankuasa Penilaian
Pemeriksaan Premis dan Kajian (JKPPPK) [Committee for the Evaluation of Premises
and Research Inspection (CEPRI)].
6.25 GMP inspection report will be issued to manufacturer through applicant e.g. PRH for on-
site inspection and DiA in which the type of inspection conducted will be clearly
mentioned. Meanwhile, for GDA, an official letter with the outcome of GDA will be issued.
6.26 For the on-site inspection and DiA, manufacturer may be required to submit a Corrective
Action and Preventative Action (CAPA) report to NPRA for the non-compliances reported
during the inspection within the time frame specified in the GMP report cover letter. The
CAPA report will be presented to the JKPPPK for further consideration.
6.27 GMP compliance status will only be concluded as acceptable when the actions outlined
in the CAPA are considered satisfactory in addressing the non-compliances and the time
frame needed to close all CAPA is not more than 6 months from the date of inspection
report issuance. If more than 6 months is required, the GMP compliance status will be
concluded as unacceptable.
6.28 After the GMP compliance status is concluded as acceptable, the applicant may apply for
a GMP certificate for the foreign manufacturer. The certificate shall be used
administratively for product registration/re-registration/change of manufacturing site
purposes with NPRA. This, however, is not applicable for GDA, whereby there will be no
GMP certificate issued upon satisfactory GDA.
6.29 GMP certificate issued shall clearly specify the type of inspection (either on-site or RI
inspection). The GMP validity for on-site inspection is 3 years and RI is 2 years.
6.30 For inspection whose GMP compliance is concluded as unacceptable, the manufacturer
is not required to submit a CAPA report as there will be no further consideration or
appeal for the GMP compliance status of the manufacturer. Applicant is required to
pg. 10
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
submit a new application for NPRA to conduct another inspection on the manufacturing
facility.
REJECTION
7.1 NPRA has the right to reject an incomplete application for example an application without
supporting documents as mentioned in para 6.3 above.
TERMINATION
7.2 The application shall be terminated if payment of inspection fee is not made at least 1
(one) month before the foreign inspection is conducted.
7.3 The estimated date of the inspection will be proposed by NPRA during the evaluation
stage, upon receipt of a completed application form (BPFK 501). The applicant and
foreign manufacturer are responsible to make sure the premise is fully prepared and not
under renovation or any other condition that may affect the GMP inspection conducted.
7.4 The applicant shall submit in writing, explaining the reason, to NPRA if there is a reason
for postponing the inspection after the date of inspection has been confirmed.
7.5 NPRA has the authority to terminate the application if the applicant is not able to comply
with the proposed date due to unavailability or unpreparedness of facility. Failure to
commit to the inspection after confirmed inspection date will result in application rejection
and the processing fee is not refundable.
7.6 An application may also be terminated if it fails to fulfil the requirement outlined in para
6.8.
7.7 Application which has been terminated or rejected will go through the submission
process once again as stated in para 6.0.
7.8 The applicant shall notify NPRA regarding withdrawal of application or any other changes
in writing.
7.10 The applicant is solely responsible to ensure all documents are complete during
submission for GDA. In the event of incomplete, missing documentation or unable to
pg. 11
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
provide requested document within specific timeline, the GDA process may be
terminated, leading to a decision to conduct on-site inspection.
8.2 The applicant shall arrange for a translator to be present during the on-site inspection, at
the company’s cost, if English or Bahasa Malaysia is not the language used in
communication and documentation by the foreign manufacturer.
8.3 The applicant shall assign an individual from the PRH to accompany the GMP inspectors
during the whole duration of the inspection.
8.4 The manufacturer must ensure that any translated version of the documentation that is
provided to the GMP Inspector during the inspection is clear, legible, accurate and in an
official manner in line with the manufacturers documentation system.
8.5 The manufacturer shall operate and run production activities as usual during the
inspection.
8.6 The number of inspectors appointed, and duration of inspection will be decided by NPRA
depending on the nature of the products, size of premise and scope of inspection. In
most circumstances, the minimum number of the inspectors are 3 and for a minimum
duration of 3 days.
8.7 Inspections are limited to one inspection per site for either sterile or non-sterile facility.
Inspections of multiple sites or to both sterile and non-sterile or to both biologics [drug
product (DP) and drug substance (DS)] facilities will require separate applications.
8.8 NPRA adopts the PIC/S Guide to GMP for Medicinal Products and its annexes for the
GMP inspection.
8.9 NPRA reserves the right to invalidate the GMP certificate issued to the manufacturer
when evidence exists (such as product complaints, serious adverse events, etc.) or have
reason to believe that the manufacturer is not complying with the GMP
guidelines/requirements.
8.10 The same GMP certificate or GDA satisfactory status may be used by the same applicant
for other product registration applications if the scope of manufacture is the same,
provided the validity date of the GMP certificate or GDA is still current.
8.11 An acceptable GMP compliance of a manufacturer does not guarantee the manufactured
product will be approved for registration in Malaysia.
8.12 Inquiries relating to foreign GMP inspection may be directed to the following contact:
pg. 12
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
Tel : (60)-378835400
9.0 FORM
BPFK 501 - Foreign GMP Inspection Application Form (downloadable via NPRA website
– http://npra.gov.my.)
pg. 13
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
APPENDIX 1
PROCESS FLOW FOR FOREIGN INSPECTION AND GMP DESKTOP ASSESSMENT (GDA)
pg. 14
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
pg. 15
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
APPENDIX 2
ILLUSTRATION OF GDA EXTENSION (3 CASES)
pg. 16
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
pg. 17
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
pg. 18
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
APPENDIX 3
Description for Pre-Assessment of GDA
2. The maximum number of • More than 7 processes The maximum total number of
different processes from manufacturing up to distribution
manufacturing to • 4 – 6 processes processes for different dosage
distribution process that are forms (number of dosage forms).
in use at the site • 1 – 3 processes Larger numbers generally give rise
to more complexity.
Campaign manufacturing
considered partial dedication. Other
than that, for a manufacturing site
consists of a totally dedicated block
for Penicillin / Cephalosporin and
another block that manufactures
steroid by campaign, it is
considered partial dedication.
4. Involvement of Real Time • Real Time Release Any Real Time Release Testing
Release Testing (RTRT) Testing (RTRT) activities (RTRT) is practiced by the
pg. 19
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
5. Complexity of products • Complex product type (low Complex products are being
manufactured concentration / high manufactured such as highly potent
potency, sustained product that may require special
release, biological) manufacturing / storage
requirement.
• Normal product
• Repacking only
6. The maximum number of • More than 6 processes The total number of each process
unit operations in a non- within the manufacturing process
sterile manufacturing • 4 – 5 processes for the intended product
process (e.g.: dispensing,
mixing, granulate, drying, • Less than 3 processes Example: Dispensing – Blending –
coating, blister, packing, Milling – Drying – Tableting –
testing, IPQC) Coating – Blistering are considered
as 7 units of operation for
manufacturing processes.
• Secondary repack
• No repack activities
• Subcontracting services:
contract lab, transport etc.
• No subcontracting
9. The maximum number of • More than 4 components For the intended product. For
components in a product, example, a pack of a tablet product
include final pack (e.g.: vial, • 2 – 3 components may have a blister strip and a
diluent, syringe, leaflet). patient information leaflet within it
• 1 component (primary which is considered 2 components.
pg. 20
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
• No specific storage
requirement
pg. 21
National Pharmaceutical Regulatory Agency
Foreign GMP Inspection Guidance Document, 8th Edition (September 2021)
REVIEW HISTORY
REVIEW
VERSION DESCRIPTION OF REVIEW
DATE
7 25/01/2021 1. Include the Review History
2. Update term ‘Centre for Compliance and Licensing’ to ‘Centre for
Compliance and Quality Control’
3. Update term ‘Centre for Product Registration’ to ‘Centre for
Product and Cosmetic Evaluation’
4. Update NPRA address to Lot 36, Jalan Profesor Diraja Ungku
Aziz
5. Update telephone number to 03-7883 5400
6. Include term ‘GDA - Good Manufacturing Practice Dekstop
Assessment’
7. Revise para 3.2.3 to add ‘…the eligibility and application for GMP
Desktop Assessment (GDA) for foreign manufacturers previously
inspected by NPRA.’
8. Include new circular under para 5.2 – Circular Letter Ref No.
NPRA-600-1/9/12 (7) dated 11 February 2021 – Pekeliling
Berkenaan Pelaksanaan Prosedur Kerja Penilaian Desktop Bagi
Aktiviti Pemeriksaan Amalan Perkilangan Baik (APB) Ke Atas
Premis Pengilang Farmaseutikal Luar Negara.
9. Additional para 5.8, 6.8, 6.10, 6.11, 6.12, 6.13, 6.17, 6.18.
10.Revise para 6.21 to add ‘…This, however, is not applicable for
GDA, whereby there will be no GMP certificate issued upon
satisfactory GDA.
8 17/08/2021 1. Removal of fax number from cover page.
2. Alignment adjustment throughout the document.
3. Update Table of Contents under item 6 with ‘Good Manufacturing
Practice Distant Assessment (DiA)’.
4. Include term ‘DiA - Good Manufacturing Practice Distant
Assessment’ and ‘RI - Remote Inspection’ under 2.0
Definitions/Abbreviations.
5. Addition of para 6.14 – 6.20.
6. Revise para 6.23.1 from ‘includes GDA’ to ‘includes on-site, GDA
& DiA’.
7. Revise para 6.23.2 from ‘only for on-site inspection’ to ‘only for
on-site inspection & DiA’.
8. Revise para 6.25 and 6.26 to add in ‘and RI’.
9. Addition of para 6.29.
pg. 22