Entering a new market like Singapore can indeed be a strategic move for Chinese pharmaceutical companies expanding into Southeast Asia. Today TRC would like to highlight 6 key areas from a regulatory perspective:

1. Quality of the CMC documents- Drug Substance

a)     GMP Compliance: Starting from October 2024, compliance with Good Manufacturing Practice (GMP) regulations will be necessary for drug substance manufacturers in Singapore. This requires either a valid GMP certificate issued by the Pharmaceutical Inspection Co-operation Scheme (PIC/S) authority or a Certificate of Suitability and valid Active Pharmaceutical Ingredient (API) registration certificate covering the drug substance of interest listed on the European Union Drug Regulatory Authorities (EURDRA) GMP. Without these documents, product registration in Singapore will not be possible.

b)    Specifications: Specifications and limits  for the drug substance must be established in accordance to validated analytical methodology and based on understanding of the manufacturing process and data collected from the course of stability studies, stress testing and process validation . Reference to ICHQ2 and Q6A will be appropriate. The drug product manufacturer should have final control over the quality of the drug substance incorporated into the final formulation. Therefore, the drug product manufacturer should maintain  a final controlled version of the drug substance specifications.

c)     Process Validation: Process validation data should be submitted in accordance with the requirements outlined in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M4Q guidelines.

d)    Stability Studies: Stability data from at least three primary batches, two pilot batches, or one small-scale batch should be submitted from the drug substance manufacturer based on ICH Q1 requirements. If the drug substance is sourced from multiple sites, stability data from each site should be provided. Additionally, stress testing data should be submitted to assess the stability of the drug substance under various conditions.

 2. Quality of the CMC documents- Drug Product

a)  Certificate of Pharmaceutical Product (CPP) –Proof of approval should be in World Health Organization (WHO) format and issued from the country of origin or the country where the product owner/manufacturer is based. If the CPP indicates that the product is not marketed, it will not be accepted.

b)    GMP Compliance- The drug product (DP) manufacturing site should have valid proof of Good Manufacturing Practice (GMP) compliance at the time of submission. Singapore follows the standards of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) guidelines. The manufacturing site should evaluate compliance with PIC/S standards. For more information, you may check out this article: https://theregconsultants.com/registering-an-overseas-manufacturing-site-in-singapore-for-pharmaceutical-products/

c)    Specifications of the Drug Product – Specifications and limits for the drug product should be established and conducted based on validated analytical procedures in accordance with ICH Q2 and ICH Q6A guidelines. These specifications govern the release and stability of the drug product which impacts on the safety and quality of the drug product.

d)    Process Validation – Process validation data requirements depend on the type of dosage form, including solid oral drug products, aseptically processed drug products, and terminally sterilized drug products. Submission should include data from three consecutive manufactured batches according to the proposed manufacturing process and batch size.

e)     Stability-  Stability studies should cover data specified for Zone IVb (30°C/75%RH) and include data from three primary batches of 12 months for critical dosage form such as injectables  and two primary batches of  6 months for conventional dosage form such as tablets and capsules . Studies should be conducted according to the proposed batch size, strength, and container closure system intended for marketing in Singapore.

3. Clinical efficacy

a) Acceptance of Foreign Clinical Trial Data –Most ASEAN countries, including Singapore, accept foreign clinical trial data. This means that data generated from clinical trials conducted outside of Singapore can be used to support product registration in these countries as long as they are conducted in accordance to GCP guidelines and relevant ICH guidelines.

b)Phase III Confirmatory Trials –To support each requested indication and dosing regimen for the product being registered,  data from Phase III trials, which are confirmatory, randomized, controlled pivotal trials, compliance with Good Clinical Practice (GCP) guidelines is required.

c) Bridging Studies/Comparative Studies –In the case of biosimilars and generics, bridging studies or comparative studies may be required. These studies aim to demonstrate that the biosimilar or generic product is comparable to the reference product in terms of pharmacokinetic (PK) and pharmacodynamic (PD) parameters. The goal is to show that there are no significant differences between the test product and the reference product in terms of safety and efficacy.

    5.Language Barrier-  Dossier written in  simplified Mandarin should be translated and verified in a way that the content reflects what is written in the original language and official documentation such as Proof of GMP, approval letters should be authenticated by the foreign embassy or consulate of the country of origin. 

    6. Marketing Authorization RequirementsIn Singapore, only a local registered entity can hold the marketing authorization for pharmaceutical products. This means that companies seeking to market their products in Singapore must either establish their own legal entity in Singapore or engage a consultant who operates locally.

    The MAH is responsible for ensuring compliance with regulatory requirements throughout the lifecycle of the product. This includes responsibilities such as product registration, pharmacovigilance, labeling and advertising compliance, and maintaining a quality management system.

    To learn more about the responsibilities of a MAH, please visit: https://theregconsultants.com/responsibilities-of-a-marketing-authorization-holder-mah/

    With that we have concluded key areas to evaluate prior to entering the Singapore market, if you need help and support to evaluate your dossier for registration in Singapore, please feel free to get in touch: https://theregconsultants.com/contact-us/

     

     

    All overseas manufacturing sites are subjected to GMP conformity assessment by the local authority. GMP conformity assessment is in support a therapeutic product registration. Only local registered entity in Singapore can support the GMP conformity assessment application. The cost and timeline is dependent on the pathway in accordance to the pathway.

     

    What is GMP conformity assessment?
    GMP conformity assessment or Overseas Audit Program Assessment refers to evaluation of a new overseas manufacturing site in compliance to established GMP guidelines. Singapore being part of PIC/S scheme member countries adopt the PIC/s standard for Good Manufacturing Practices for Medicinal Products.

     

    1st pathway : GMP Documentary Evidence Verification (DEVA)
    This pathway is only feasible for proof of GMP compliance that are issued by PIC/S member authority. Acceptable proof of GMP compliance includes manufacturing license, GMP certificate and CPP issued in WHO format.
    Applicant would need to ensure that the submission of the proof of GMP compliance is in English language, original scanned colour copy and indicates the basic information of the manufacturing site including name and address, dosage form, authorized activity and GMP standards of which the manufacturer complies with.
    The fee is SGD$630 per manufacturing site per dosage form. There is no specific timeline involved as this is evaluated in conjunction with the submission of a product registration. Once the site is registered, there will not be a need to go through a similar conformity assessment for a similar dosage form.

     

    2nd pathway Overseas On-site Audit 
    Manufacturers would be subjected to this pathway due to the following conditions such as unavailability of acceptable GMP evidence, inadequate GMP evidence to demonstrate compliance, regulatory concern regarding GMP compliance of manufacture or product alert related to product defect or recall associated with the site concerned.
    For this pathway, application would need to prepare a Quality System Dossier in accordance to Preparation of a Quality System Dossier (GUIDE-MQA-019) with a list of supporting documents to the authority for evaluation. Once the application is accepted for evaluation, an overseas inspection will take place based on the schedule of inspectors and availability of the manufacturing site that is to be audited.

     

    The fees are presented below:
    QSD evaluation- $4,770
    On site audit located in ASEAN country- $18,400
    On site audit located in ASEAN- $20,400
    On-site audit located outside of Asia- $24,400

     

    Post inspection, the authority will issue a letter to summarize the inspection including any potential observations or deficiencies that are required to be addressed. Applicant will be given about a month time to provide CAPA.
    Upon successful close out of the post inspection findings, the applicant will be informed of the outcome.

     

    We hope the above information is supportive for your product registration in Singapore If you need help to evaluate your GMP documents , please get in touch or if not feel free to share with your peers.

     

    Useful references:
    1. https://www.hsa.gov.sg/therapeutic-products/register/gmp-conformity-assessment
    2. PIC/S Guide to GMP for Medicinal Products.

    Flags of ASEAN countries.

    The ASEAN Joint Assessment Procedure is a procedure in which the same marketing authorization application is simultaneously submitted to all participating ASEAN National Medicines Regulatory Authorities (NRAs).

    ASEAN National Medicines Regulatory Authorities (NRAs) includes:

    • Health Sciences Authority (HSA)- Singapore
    • National Pharmaceutical Regulatory Agency (NPRA)- Malaysia
    • Thai Food and Drug Administration (Thai FDA)
    • Food and Drug Administration (Philippines FDA)
    • Badan Pengawas Obat dan Makanan (BPOM),Indonesia
    • Drug Administration of Vietnam (DAV)
    • Ministry of Health, Brunei (MoH, Brunei)
    • Department of Drugs and Food (DDF), Cambodia
    • Food and Drug Administration Myanmar
    • Food and Drug Department (FFD) , Laos

    The join assessment procedure is initiated with minimum of 3 NRAs.

    At the moment , it covers only :

    1. a) medicines for treatment of priority diseases in ASEAN region such as but not limited to: treatment for specific cancers such as breast , lung, Hepatitis C, treatment of AIDS/HIV, Tuberculosis, Treatment-Resistant Depression.
    2. b) products already approved by a reference National Regulatory Authority(NRA) ,prequalified by WHO-PQP, or assessed through special regulatory pathways such as EU Article 58 or US-FDA tentative approval;
    3. c) products manufactured in a PIC/S-GMP compliant site

    Process in brief

    1. Participating National Regulatory Authority(NRA) publish on their website in the form of a Notice : Notices of Invitation to Express Interest.
    2. Applicant can submit their interest by filling up the appropriate application form to the authority.
    3. Lead NRA seeks concurrence of participating NRAs for accepting Expression of Interest
    4. Lead NRA requests applicant to submit required documentation to participating NRAs.
    5. Assessment work is then carried out together by all participating NRAs and a joint assessment report is prepared
    6. At the end of the process, the final decision on the application is then taken, within established time lines, by each individual NRA through their normal decision-making process based on the joint report and, where applicable, nationally-relevant considerations.

    Applications must comply to the following:

    1. the technical application dossier must include the same technical information as that submitted to reference NRA or WHO-PQP;
    2. b) the technical part of the dossier in ACTD or ICH-CTD format shall be provided in electronic form to be uploaded to a dedicated, secure web site set up by WHO; only participating NRAs will be able to access and download the dossiers;
    3. c) administrative part of dossier specific to each participating NRA requirements will be submitted directly to each participating authority;
    4. d) fees as required by each participating NRA will be paid according to normal national procedures.

    Processing timeline: 180  working days for assessment procedure

    If you have a product that may fall into the therapeutic area mentioned  and need support for submission, please feel free to get in touch with TRC.

    Useful references:

    1. List of Priority Products
    2. Processing timelines
    3. ASEAN-JA-Procedure-for-Pharmaceutical-Products-Information-for-Applicants

     

    As a country facing an ageing population and a growing incidence of chronic diseases, it is unsurprising that various pharmaceutical businesses seek to make their products available in Singapore to meet the increasing demand for advanced medical treatments.

    However, the selling of new pharmaceutical products is heavily regulated in Singapore and is only permitted after a valid product license has been obtained through registration with the Health Sciences Authority (HSA). Such stringent regulations are in place to ensure the product is safe for consumption by the public.

    For pharmaceutical companies planning to introduce their products into Singapore’s market, navigating the regulatory landscape seamlessly and ensuring compliance with the HSA’s requirements are paramount. Fortunately, the entire process need not be complicated. Let us share six essential tips to ensure a smooth and successful pharma registration in Singapore.

    Tip #1: Familiarise yourself with the regulatory requirements in Singapore

    A man facing a laptop

    When you fail to plan, you plan to fail. Without adequate knowledge of the registration process and an intimate understanding of the HSA’s regulatory requirements, you are only setting yourself up for failure.

    So, thoroughly study the HSA’s guidelines pertaining to pharmaceutical product registration beforehand, encompassing everything from product safety to manufacturing processes. Familiarising yourself with the regulations provides a robust foundation, allowing you to tailor your submission to meet all requirements, thus ensuring a successful registration.

    Tip #2: Compile a comprehensive registration dossier

    Your registration dossier serves as the foundation of your application to the HSA. Every information contained within the dossier will be scrutinised to ensure your product complies with existing regulations. Any omission of relevant data could compromise your entire pharma registration effort. So, ensure your submission is complete with all relevant information about your product, including its composition, efficacy data, manufacturing processes, and safety profiles.

    Tip #3: Engage the help of a local regulatory consultant

    Image of 2 women discussing

    Navigating the medical regulatory landscape can be complex even for a pharmaceutical company based in Singapore, let alone foreign businesses from a different market. If you are unsure where to begin, leveraging the expertise of a consultant with experience in the local regulatory scene can prove invaluable.

    A reliable pharmaceutical regulatory consulting firm can provide helpful insights and guide you through the various intricacies of the administrative process, ensuring your application aligns seamlessly with the HSA’s guidelines, thus boosting your chances of success.

    Tip #4: Understand your product classification

    Pharmaceutical products in Singapore are classified into several categories based on their intended use, risk level, and mode of action. The HSA’s classification system is as below:

    • Complimentary Health Product (CPM) “Health supplements”
    • Therapeutic Products covering chemical drugs, biotechnology products, blood products, biosimilars
    • Medical devices (Risk Class A, B,C and D)
    • Chinese Proprietary Medicine (CPM)
    • Cell Gene Therapy Product (Class 1 or Class 2)

     

    Each class is governed by distinct regulatory requirements. So, understanding this classification system and which category your pharmaceutical product belongs to is paramount. Accurate classification ensures you follow the appropriate guidelines, streamlining the pharma registration process and preventing your application from being dismissed on a technicality.

    Learn More: Misconception of regulatory classification of medical products

    Tip #5: Clinical trials

    Conduct clinical trials

    HSA often requires robust clinical evidence to support registration applications. Overseas clinical trial data are accepted for registration which saves the hassle of conducting local trials. Also, engaging the help of a local regulatory consultancy firm to analyse the clinical documentation could cement your compliance to the local requirements pertaining to the safety and efficacy of your pharmaceutical product. This ensures compliance with HSA guidelines.

    Tip #6: Ensure compliance and good practice

    HSA governs more than the safety and manufacturing process of a pharmaceutical product. Its labelling and packaging must also comply with the HSA’s good manufacturing practice (GMP) standards and quality control.

    So, prepare detailed documentation and evidence, such as inspection reports, certificates, and quality control processes, showcasing adherence to the GMP standards. This diligence can help expedite the pharma registration process and establish a foundation for long-term compliance.

    Ultimately, a thorough and well-executed registration strategy requires meticulous planning, strict adherence to regulatory guidelines, and a keen understanding of the local regulatory landscape. With these elements in place, you can set the stage for a successful market entry and ensure sustained success in Singapore.

    If you require assistance with your product registration, look no further than The Reg Consultants for your pharmaceutical regulatory consulting needs. With a wealth of experience in assisting pharmaceutical and medical companies, both local and overseas, we can aid your business in streamlining the product registration process and securing the necessary approvals for marketing and distribution within the ASEAN region. Contact us today to learn how we can help.