In 1984, the Control of Drugs and Cosmetics Regulations (CDCR 1984) was enacted in Malaysia. The implementation of this regulation had significant impact on the pharmaceutical industry in Malaysia.
One major impact was the requirement for all medicines to be registered by the Drug Control Authority before being sold in Malaysia. With that requirement, adverse reactions of registered products have to be reported to the Authority (Regulations, 1984).
The DCA, through the Malaysian Adverse Drug Reactions Advisory Committee (MADRAC) was tasked to ensure that this objective was met.
With the establishment of MADRAC in 1987, Malaysia’s national pharmacovigilance system was set up. The National Adverse Drug Monitoring Centre based at the National Pharmaceutical Regulatory Agency (NPRA), formerly known as the National Pharmaceutical Control Bureau (NPCB) served as its secretariat.
In 2002, the Malaysian Guidelines for the Reporting and Monitoring Adverse Drug Reactions was established to outline the requirements and procedures for submission and reporting of adverse drug reactions (ADRs) to the Drug Control Authority.
This guideline was subsequently updated to the Malaysian Pharmacovigilance (MPV) Guidelines, Second Edition, 2016. The MPV Guidelines Second Edition was an expanded version of the 2002 document, with processes and procedures stated in greater detail.
In addition, Part 4 and Part 5 of the MPV Guidelines Second edition were devoted to the detailed processes and requirements of Periodic Benefit-Risk Evaluation Report (PBRER) and Risk Management Plan (RMP) respectively.
RMPs which were not required for submission previously was now required with MPV Guidelines Second Edition. At the time of the release of the MPV Guidelines Second Edition, 2016, Part 6: Pharmacovigilance System Master File (PSMF) and Part 7: Pharmacovigilance Audit and Inspection were not ready and put under development.
Now, a new Malaysian Guidelines on Good Pharmacovigilance Practices (GVP) For Product Registration Holders (PRH), First Edition, August 2021 has replaced the MPV Guidelines Second Edition, 2016. This new guideline has a new part (Part 6) related to Pharmacovigilance System Master File.
Aim Of The Review
The aim of this review is to consider the challenges that may be encountered; and expectations required of Product Registration Holders (PRHs) with the updated Malaysian Guidelines on GVP for PRHs, First Edition, August 2021 from the perspective of the requirement for PSMF.
The most obvious and significant update in the Malaysian Guidelines on GVP for PRHs, 1st Edition, 2021 is the inclusion of the Part 6. Pharmacovigilance System Master File (PSMF). This PSMF is to be specific to Malaysia. With the implementation of the PSMF requirement, Malaysia is likely to move towards putting in place pharmacovigilance inspection by regulatory authority in the future.
The notable updates observed in the new Malaysian Guidelines on GVP for PRHs, 1st Edition, August 2021 are:
- The Pharmacovigilance (PV) System is stated in greater detail to include the requirements of a basic PV system, PV audit, the responsible person for PV (RPPV), engagement of third party for PV activities, training of personnel for PV and safety document retention (Part 1)
- Requirement of Quality Management System (P3.2.5)
- An Annex with Malaysian specific information is required for PBRER submission in post-registration phase (P4.5).
- A Malaysian-Specific Annex (MSA) is required for RMP submission in post-registration phase. The MSA should provide Malaysian specific information (P5.6.7 and Appendix 6).
- Malaysian specific Pharmacovigilance System Master File (P 6) is required. The RPPV has an added responsibility for the development and management of the PSMF.
One chapter which was in the 2016 guidelines, but now excluded in the new Guidelines is Part 2: Guideline for Healthcare Professionals. Instead, a new manual is now put in place: Adverse Drug Reaction (ADR)/ Adverse Events Following Immunisation (AEFI) Reporting Manual for Healthcare Providers.
Implications Of The Pharmacovigilance System Master File (Part 6) Requirement
Establishing the PSMF may be a challenge especially for PRHs that do not yet have even the basic PV system in place.
The PSMF document provides a detailed description of the PV system of the PRH, and will have to be maintained and updated as and when there are changes in the PV system.
Essentially, PRHs must already have in place standard operating procedures (SOPs) for all the different pharmacovigilance tasks and processes in order to develop the PSMF.
The content of what is to be included in the PSMF is specified in Part 6 of the new GVP guidelines.
As an initial requirement, the Pharmacovigilance System Summary (PVSS), a one-off summary of the PV system of the PRH will have to be submitted to NPRA as a commitment document that PRH will establish a PV system within the company and develop the PSMF.
Although pharmacovigilance guidelines have been in place in Malaysia since 2002, there are differing and varying levels of establishment of the PV system among companies within the pharmaceutical industry.
Subsidiaries or affiliates of multinational companies are likely to have a more mature PV system with dedicated PV personnel and function; and relevant standard operating procedures (SOPs) for PV and process optimization tools in place.
In general, establishing PSMF for these multinational subsidiaries and affiliates especially European Union based companies, may not be much of an issue as they have support from their headquarter (HQ) offices which are familiar with initiating such PSMF document.
However, the PSMF required is Malaysia-specific and necessitate local adaptation and local know-how; and understanding of the expectations of local authority.
For locally-established drug companies or small local manufacturers on the other hand, meeting this obligation may impose a steep learning curve for the stakeholders. In most cases in general, essential PV functions in these local pharmaceutical companies are shared responsibility usually with their regulatory counterpart; and capability for such new PV requirements and tasks may be lacking.
Fundamentally, all PRHs should have a system to collect, manage and process drug safety information, and a SOP to ensure compliance to this process. Personnel doing PV functions must be trained in all aspects of PV requirement.
PRH must have a responsible person for pharmacovigilance (RPPV) or a local PV contact person in place to ensure that all the required PV responsibilities and activities are carried out in compliance to the PV guidelines.
This person must be well-versed in all aspects of the PV Guidelines and ensure that PV processes within the company such as audits and quality management, PBRER management, risks management, signal detection, PV training of employees, communications with NPRA or relevant stakeholders, archival and retention of documents, are duly documented as PV Standard Operating Procedures (SOPs) for the company.
This is to ensure that all PV activities in the company are carried out in accordance to industry regulation and company’s policies, and in compliance to the Malaysian PV guidelines.
As the subject matter expert, the RPPV is likely to be the person to develop the Malaysian-specific PSMF document and be responsible for any updates and changes to it.
The task of developing the PSMF is achievable and would not pose much difficulty if the company’s PV SOPs are already in place, and the RPPV or local PV contact person is knowledgeable of the company’s PV processes.
However, for some companies where resources are limited, this requirement to develop the PSMF may increase administrative burden for the PV/regulatory function. With the need for capacity building to upskill PV personnel, additional costs to the company may have to be incurred.
Nevertheless, by having the PSMF in place, PRHs are able to show consistent and well-defined structured pharmacovigilance processes information.
This is consequential, and if sustained and managed well, would ultimately enhanced safety monitoring of the company’s medicines. The PSMF represents and is a reflection of the PV system of the company.
It will be one of the essential document that NPRA will use to verify compliance concerning all aspects of the PV system during GVP inspection.
Good Pharmacovigilance Practice Inspection
According to the Annual Report 2019 released by the NPRA, pharmacovigilance inspection is projected to be implemented in 2021 under the NPRA Strategic Plan 2021-2025.
Accordingly, the objective of the Pharmacovigilance Inspection is to ensure that PRHs monitor the safety aspects of their registered products adequately via an effective pharmacovigilance system, and complies with the Malaysian Good PV guidelines.
In this respect, PRHs have to make sure they have personnel, process systems, procedures and facilities to meet their pharmacovigilance obligations. Audits have to be carried out regularly and any failures, gaps or non-compliance to PV obligations which may jeopardize public health and safety have to be addressed.
Relevant documentation of product-specific PV issues and PV activities must be established. It is the ethical and legal responsibility of PRHs to make sure that the medicines they have been authorised to market and sell are safe and efficacious, and not cause unnecessary harm to patients.
The health authority that approves licences for public use of medicines are also responsible to safeguard the public and ensure that medicines are not only beneficial but are safe.
One practical way this is achieved, is through regular pharmacovigilance inspections. It is likely that NPRA would take on this function of PV inspection in the future. PRHs should strive to avoid critical and major findings during inspection.
Nevertheless, findings of gaps in processes, deficiencies and issues from PV inspections will provide insights to PRHs so that corrective and preventive actions may be instituted.
The implementation of the Malaysian Good Pharmacovigilance Guidelines for Product Registration Holders, First Edition, August 2021 marks a new chapter in drug safety in Malaysia. It will affect all stakeholders in the pharmaceutical industry; may increase workload of PRHs and manpower resource required.
For companies with minimum PV processes, it would be a steep learning curve for their PV/regulatory staff to learn the necessary processes and put in place the required PV operations.
A community of pharmacovigilance practitioners sharing best practices is one suggestion where members help and support one another develop and disseminate PV strategies.
Pharmacovigilance training and courses conducted by higher institutes or PV solution companies can provide structured PV learnings and courses to upskill the capabilities of PV personnel.
NPRA plays a critical role to provide a platform for continuous education in PV amongst all the stakeholders.
In the MPV Guidelines Second Edition, 2016, it is stated that PRHs and healthcare professionals are encouraged to comply with the guidelines although it is not obligatory.
This statement is no longer stated in the new Malaysian Guidelines on Good Pharmacovigilance Practices (GVP) For Product Registration Holders, First Edition, August 2021.
The legal basis of the new guideline is Regulations 28 and 29 of the Control of Drugs and Cosmetics Regulations 1984, Sale of Drugs Act 1952 (amendment in 2006).
Failure to comply with this new guideline is therefore an offence which may lead to dire consequences for the PRHs.
Although this is may be a good motivation to comply with the new guidance, ultimately abiding by the guideline is necessary for continuous patient safety and drug safety monitoring for our public.
Malaysian Guidelines for the Reporting and Monitoring Adverse Drug Reactions, 2002
Malaysian Pharmacovigilance Guidelines, 2nd edition, 2016
Malaysian Guidelines on Good Pharmacovigilance Practices (GVP) For Product Registration Holders, First Edition, August 2021
- This is the personal opinion of the writer or publication and does not necessarily represent the views of CodeBlue.