Marketing, Manufacturing, Packaging & Labeling, Advertising
Everything you need to know about the marketing, manufacturing, packaging, labeling and advertising of pharmaceuticals in Singapore. Prepared in association with Drew & Napier LLC, this is an extract from The Pharma Legal Handbook: Singapore, available to purchase here for USD 99.
1. What is the authorization process for the marketing of new drugs, biologics, medical devices, over-the-counter medications, and other medicinal products?
For therapeutic products, marketing approval may be obtained by making an application to the Health Sciences Authority (HSA) for product registration.
The applicant (or product registrant) must be a locally registered entity in Singapore, which is responsible for the quality, safety and efficacy of the product.
The production registration process involves, broadly, the following steps:
- pre-submission preparation, which involves:
- considering the type of application (new drug application (NDA) or a generic drug application (GDA));
- considering which one of the four evaluation routes is appropriate (full, abridged, verification or verification-CECA route); and
- arranging for a pre-submission consultation with the HSA for advice (if required);
- application submission through the HSA’s online portal, PRISM;
- application screening by the HSA to ensure the correctness of the application type and of the dossier submitted, following which the application may be accepted if there are no deficiencies, or when all deficiencies have been adequately addressed and the HSA is satisfied that the dossier is complete for evaluation;
- application evaluation by the HSA; and
- regulatory decision by the HSA. The HSA may register a product subject to post-approval commitments.
There are four types of evaluation routes for registering a new therapeutic product:
- full route: for a new therapeutic product that has not been approved by any drug regulatory agency at the time of submission of the application to the HSA;
- abridged route: for a therapeutic product that has been evaluated and approved by at least one foreign drug regulatory agency, and which meet certain other criteria;
- verification route: for a therapeutic product with similar indication(s), dosing regimen(s), patient group(s), and/or direction(s) for use, that has been approved by at least one (for GDAs) or two (for NDAs) of the HSA’s reference drug regulatory agencies and which meet certain other criteria; and
- verification-CECA route: for a generic product manufactured in India which has been evaluated and approved by HSA’s reference drug regulatory agencies via certain specified routes.
For medical devices, similarly, marketing approval may be obtained by making an application to the HSA for product registration.
The appropriate product registration route and evaluation route depends on the risk classification of the medical device, whether the medical device has received reference agency approvals (if any) and the prior safe marketing history of the medical device (if applicable).
The HSA adopts the following risk classification for medical devices:
- Class A, for low risk devices, such as wheelchairs and tongue depressors;
- Class B, for low to moderate risk devices, such as hypodermic needles and suction equipment;
- Class C, for moderate to high risk devices, such as lung ventilators and bone fixation plates; and
- Class D, for high risk devices, such as heart valves and implantable defibrillators.
There are certain statutory exemptions where product registration is not required. For instance, all Class A medical devices, except those that are supplied in a sterile state, are exempted from the registration requirements.
All applications for medical device registration must be submitted via the HSA’s online portal, MEDICS.
Generally, the registration of a medical device which has not obtained prior approval from any of the HSA’s reference agencies at the point of application will need to be done via the full evaluation route, which generally involves a longer and more complex registration process. Medical devices which have obtained the approval from the HSA’s reference regulatory agencies may qualify for the abridged, expedited or immediate evaluation routes where they meet the criteria specified by the HSA for such evaluation routes.
For applications under the full or abridged routes, after submission of the application, the application will be verified for eligibility and completeness before it is accepted for evaluation. Following the HSA’s evaluation of the submitted dossier, it will make a regulatory decision. Applications which satisfy the registration requirements will be registered and listed on the Singapore Medical Device Register. For applications under the immediate route, the medical device will be registered immediately and will generally be listed on the Singapore Medical Device Register within the hour.
2. What is the authorization process for the marketing of generic versions of these products?
The overall authorisation process for marketing of generic drugs is generally similar to that for non-generic drugs (see Question 1 above). A generic drug application (GDA) may be submitted for a therapeutic product that is essentially the same as a product currently registered in Singapore (known as the Singapore reference product) in terms of its qualitative and quantitative composition of active ingredients, pharmaceutical dosage form and clinical indication. It should be noted that biosimilar products are not eligible for a GDA and product registrations for biosimilars must be submitted via an NDA.
3. What are the typical fees for marketing approval?
The relevant application fee payable for product registration depends on the application type, and the level of screening and evaluation required.
More information on the applicable fees can be found on the HSA’s website, http://www.hsa.gov.sg/content/hsa/en.html.
4. What is the period of authorization and the renewal process?
Generally, once a therapeutic product or a medical device has been registered, the registration will remain in force for so long as the product registrant pays to the HSA the relevant annual retention fee within the prescribed time.
The HSA may cancel the registration if it has reasonable grounds to believe that:
- the registration has been obtained by fraud or misrepresentation;
- the registrant of the product has contravened or is contravening any applicable statutory requirements, and/or condition(s) attached to the registration;
- the formulation, composition, design specification, quality, safety or presentation of the product has changed such as to render it unsuitable to continue to be registered;
- the product no longer complies with a prescribed requirement; or
- it is in the public interest to do so.
5. What are the requirements, if any, for post-approval pharmacovigilance?
For therapeutic products, the product registrant is required to comply with the obligations set out in Part VIII of the Health Products Act and Part 6 of the Health Products (Therapeutic Products) Regulations 2016, which include:
- maintaining records of every receipt and supply of the product to another person, and records of defects in and adverse effects arising from the use of the product, and producing these records for inspection by the HSA if required;
- reporting defects and adverse effects of the product to the HSA within specified timeframes;
- notifying the HSA at least 24 hours before recalling the product;
- obtaining prior approval from the HSA before making any change to the particulars of the registered product or any change which may affect the quality, safety or efficacy of the product;
- informing the HSA within 15 days of receiving information that adversely affects the validity of any data relating to the quality, safety or efficacy of the product; and
- submitting periodic benefit-risk evaluation reports or implementing a risk management plan as and when required by the HSA.
For medical devices, the product registrant is required to comply with the obligations set out in Part VIII of the Health Products Act and Part VIII of the Health Products (Medical Devices) Regulations 2010, which include:
- ensuring and maintaining objective evidence to establish that the medical device complies with the safety and performance requirements for the medical device as set out on the HSA’s website;
- maintaining records of every complaint received by it pertaining to the medical device, and producing such records for inspection by the HSA if required;
- informing the HSA of defects or adverse effects arising from the use of the medical device within the prescribed time limits;
- informing the HSA within 15 days of receiving information that adversely affects the validity of any data relating to the quality, safety or efficacy of the medical device; and
- notifying the HSA at least 24 hours before recalling the medical device;
- notifying the HSA of any intended field safety corrective action it intends to take in relation to a medical device, before carrying out such field safety corrective action; and
- obtaining prior approval from the HSA before making any change to the particulars of the registered medical device or any change which may affect the quality, safety or efficacy of the medical device.
6. Are foreign marketing authorizations recognized?
Depending on the scope and type of the marketing authorisation granted by the foreign regulator, and which and how many regulatory agencies have given their approval, a therapeutic product or medical device may be subject to a lower level of screening and evaluation by the HSA (e.g. may qualify for the abridged evaluation route, or verification evaluation route).
7. Are parallel imports of medicines or devices allowed?
Generally, parallel imports of therapeutic products and medical devices are allowed, provided that the importers of therapeutic products or medical devices hold the requisite product registrations and licences (e.g. import licence) for the products imported (where applicable).
Under Regulation 23 of the Health Products (Therapeutic Products) Regulations 2016, when the HSA is determining whether to approve a therapeutic product registration application, it will consider:
- whether a patent under the Patents Act (Chapter 221) is in force in respect of the product;
- whether the applicant is the patent proprietor or has obtained the consent of the patent proprietor.
- whether the patent is invalid or will not be infringed by doing the act for which the licence is sought.
The patent proprietor (if it is not the applicant) can oppose the licence application, by applying for an order or a declaration by a court or the Registrar of Patents.
8. What are the restrictions on marketing practices such as gifts, sponsorships, consultancy agreements, travel and entertainment, or other incentives for healthcare organizations and individual medical practitioners?
The Health Products Act and its subsidiary legislation set out restrictions governing the advertising, marketing and sale of products. Statutory offences under the Health Products Act and its subsidiary legislation include the advertisement of therapeutic products which encourage, or are likely to encourage, inappropriate or excessive use of the therapeutic product, or which offer a prize as an inducement to purchase the therapeutic product.
Additionally, healthcare professionals are required to comply with statutorily imposed obligations under various legislation such as the Medical Registration Act (Chapter 174) and also the ethical codes and guidelines applicable to their profession (e.g. the Singapore Medical Council Ethical Code and Ethical Guidelines).
Members of the Singapore Association of Pharmaceutical Industries (SAPI) and the Singapore Manufacturing Federation Medical Technology Industry Group (SMF MTIG) respectively must also comply with the SAPI Code of Marketing Practices and the SMF MTIG Revised Code of Ethical Conduct for Interactions with Healthcare Professionals.
The industry codes contain set out principles and guidelines regarding the relationship between individual doctors and the pharmaceutical/medical device industry, including in relation to:
- acceptance of gifts, promotional items and educational materials by doctors; and
- invitations from pharmaceutical/medical device companies for doctors to travel overseas to attend medical conferences and associated sponsorships or grants.
More generally, it is also an offence under the Prevention of Corruption Act (Chapter 241) for a person to corruptly solicit or receive, or agree to receive for himself or for another person (or corruptly give, promise or offer to a person, for the benefit of that person or another person), any gratification as an inducement to or reward for a person doing or not to do anything in respect of any matter or transaction, actual or proposed. This also applies to acts of Singapore citizens outside Singapore.
9. How is the manufacturing of medicines and devices regulated and by which agencies?
The manufacturing of therapeutic products and medical devices are regulated under the Health Products Act and its subsidiary legislation, including the Health Products (Therapeutic Products) Regulations 2016 and the Health Products (Medical Devices) Regulations 2010. The HSA has regulatory oversight over these regulations.
Generally, manufacturers of therapeutic products and medical devices will need to obtain a manufacturer’s licence from the HSA. The manufacture of the products/devices will need to be carried out in accordance with the conditions of the licence, statutory requirements and other regulatory requirements as may be imposed by the HSA. The manufacture of the product/device can only be carried out at the premises or facility which has been authorised by the HSA for the manufacture of the product/device.
10. Are local manufacturing requirements compatible with Good Manufacturing Practices (GMPs) as defined by the US Food & Drug Administration (US FDA) and/or the European Medicines Agency (EMA)?
Yes, the HSA adopts the standards set out in the Pharmaceutical Inspection Convention/Co-operation Scheme (PIC/S) Guide to Good Manufacturing Practice (GMP) for Medicinal Products. The U.S. Food and Drug Administration is a member of the PIC/S and has adopted the PIC/S GMP standard. Generally, the HSA would only grant a Manufacturer’s Licence when the manufacturing facilities has been assessed, audited and found to comply with the PIC/S GMP for Medical Products.
11. What is the inspection regime for manufacturing facilities?
Local manufacturers will be subject to the following audit process when applying for a manufacturer’s licence:
- pre-audit, which involves preparation and submission of a Site Master File, which is description of the manufacturing site or plant, and its level of GMP compliance, to the HSA;
- site audit, where the HSA’s audit team will identify any non-conformities; and
- post-audit, which involves the HSA sending a report to the manufacturer to obtain his response to any non-conformities observed during the audit and the time frames required to correct the non-conformities.
The frequency of GMP audits for holders of a manufacturer’s licence is determined by the HSA based on a risk-assessment approach, which includes risk classification of the manufacturer, degree of compliance to the GMP and other quality and regulatory concerns (if any).
Overseas manufacturers who intend to register their therapeutic products in Singapore will be subject to a GMP conformity assessment by the HSA. This involves an on-site audit by the HSA’s GMP auditors to assess whether the manufacturing site, facilities, and the quality system of the operations comply to the PIC/S GMP standard. If an overseas manufacturer has previously been audited and found to conform to the GMP standards by a PIC/S member authority or any of the HSA’s benchmark GMP inspection authorities, and have submitted appropriate GMP evidence to the HSA (e.g. a valid GMP Certificate), such manufacturer may not need to be audited by the HSA.
12. Are manufacturing facilities open for inspection by foreign inspectors or third-party inspectors as authorized by the FDA/EMA?
On-site inspections of local manufacturing facilities by foreign authorities or regulators are not specifically regulated under the Health Products Act.
13. What are the requirements for storage, packaging, and handling of medicines and devices and their constituent components?
The requirements with regard to the storage, packaging and handling of therapeutic products and medical devices are generally set out in the PIC/S GMP standard and the HSA’s Guidance Notices on Good Distribution Practice (GDP). Dealers such as manufacturers, importers and wholesalers are required to hold the appropriate dealers’ licence(s) in order to engage in the local manufacture, import and wholesale supply of therapeutic products and medical devices in Singapore. As part of the licensing regime, manufacturers are required to conform to the PIC/S GMP standard whereas importers and wholesalers are required to conform to the HSA’s GDP standard.
14. What information must be included in medicine and device labeling?
In general, the following information must be included on the label of every therapeutic product:
- the proprietary name and the appropriate non-proprietary name of the therapeutic product;
- the appropriate quantitative particulars of any active ingredient of the therapeutic product;
- an appropriate control number, such as a serial number, batch number or lot number;
- the expiry date of the therapeutic product;
- where the therapeutic product is registered, the registration number assigned to the registered therapeutic product by the HSA; and
- where the therapeutic product contains any of those substances specified in the Fourth or Fifth Schedules to the Health Products Act, an appropriate statement or cautionary warning that the therapeutic product contains such substance.
Additional requirements may apply depending on the type of packaging used for the therapeutic product, e.g. on the outer carton box and on the blister strips. For instance, the outer carton box may need to contain information such as the manufacturing date, expiry date, dosage form, route of administration, storage condition, name and address (or logo) of the product owner or product registrant, name and address of the manufacturer, and pack size (unit or volume).
For medical devices, generally, the following information must accompany the medical device when it is supplied:
- the trade or brand name of the medical device;
- where the medical device is supplied for use in any investigational testing, the statement “For Clinical Trial Use” or any other statement in English that conveys the same meaning;
- where the medical device is contained in a package and the contents of the package are not readily apparent, an indication of what the package contains, expressed in terms appropriate to the medical device, such as the size, net weight, length, volume or number of units;
- the expiry date of the medical device, if the medical device has one, as determined by the product owner of the medical device on the basis of the component of the medical device that has the shortest projected useful life;
- the product owner’s name or trading name, address, telephone number and electronic mail address; and
- an appropriate control number, such as a batch code, lot number or serial number.
Additionally, specific labelling requirements may apply to certain types of medical devices, e.g. medical devices that are supplied in a sterile state, medical devices that are intended for single-use only, refurbished medical devices, and medical devices incorporating or administering medicinal or biological substances.
15. What additional information may be included in labeling and packaging?
For both therapeutic products and medical devices, the product label must be in English. If non-English text is included in the labelling, the non-English text must be complete, accurate and unbiased and it must also be consistent with the English text.
16. What items may not be included in labeling and packaging?
The following may not be included in the labelling or on the packaging of therapeutic products and medical devices:
- trade descriptions which are false or misleading;
- trade descriptions which explicitly or implicitly suggest that the supply or use of the therapeutic product or medical device (as the case may be) is promoted or endorsed by the HSA, the Ministry of Health or the Health Promotion Board.
17. What are the restrictions and requirements for the marketing and advertising of medicines and devices?
In general, therapeutic products and medical devices must not be advertised in a false or misleading way. Registered therapeutic products or registered medical devices must not be advertised in such a way as to represent the registered product or device as being usable for any purpose other than that for which it has been registered.
Advertisements of therapeutic products must comply with the applicable legislative requirements including those under the Health Products (Advertisement of Therapeutic Products) Regulations 2016. Amongst others, these regulations restrict the advertisement of prescription-only medicines and prohibit certain specified types of sales promotions to the public, for instance:
- the offer of a prize as an inducement to purchase the therapeutic product;
- the offer of any other health product or medicinal product with a therapeutic product; and
- the offer of any sample of a therapeutic product.
Advertisements of medical devices must comply with the applicable legislative requirements including those under the Health Products (Medical Devices) Regulations 2010 and the HSA’s Guidance on Medical Devices Advertisements and Sales Promotion of Medical Devices. Amongst others, the regulations restrict the advertisement of certain “professional use only” medical devices to only qualified practitioners.
18. Where can medicines and devices be sold or delivered? Can medicines and devices be sold or delivered via post?
In Singapore, therapeutic products are classified as prescription-only medicines, pharmacy-only medicines, and general sales list (GSL) medicines. Prescription-only medicines can generally only be supplied by a qualified doctor or dentist, from licensed retail pharmacies or at or from licensed healthcare institutions to their own patients. Pharmacy-only medicines can be supplied by or under the supervision of a pharmacist without a prescription, from licensed retail pharmacies or at or from licensed healthcare institutions to their own patients. GSL medicines can be purchased from any retailer, over-the-counter or by means of an automatic vending machine, provided that the relevant statutory requirements are met.
Medical devices may only be supplied in accordance with the prescribed requirements, which may depend on the risk classification of the medical device and the licence conditions applicable to it. For instance, “professional use only” medical devices may only be supplied by way of administration or application by a qualified doctor or dentist or by a person who is acting under the supervision of a qualified doctor or dentist.
19. What are the restrictions and requirements for electronic marketing and advertising via email, by Internet, social media, and other channels?
The advertising and marketing restrictions under the Health Products Act and its subsidiary legislation apply to all forms of advertisements relating to therapeutic products and medical devices, including the following:
- publication in a newspaper, magazine, journal or other periodical;
- display of posters or notices;
- circulars, handbills, brochures, pamphlets, books or other documents;
- letters addressed to individuals or bodies corporate or unincorporate;
- photographs or cinematograph films;
- sound broadcasting, television, the Internet or other media;
- public demonstration of the use of the product or device;
- offer of trials of the product or device to members of the public; and
- sales promotions or campaigns, exhibitions, competitions or any activities meant to introduce, publicise or raise the profile or public awareness or visibility of any product or device for the purpose of promoting the sale or use of the product or device.
All advertisements in Singapore will generally also need to comply with the Singapore Code of Advertising Practice (SCAP). The Advertising Standards Authority of Singapore, a self-regulatory body which enforces the SCAP, acknowledges that it may be difficult to ensure compliance with the SCAP for advertisements received through the Internet and mail-order brochures from overseas. The Appendices of the SCAP contain further guidance in this area, in particular Appendix D on interactive advertisements concerning commercial communications over the Internet and Appendix E on direct marketing of goods sold directly to consumers outside of retail establishments.
20. May medicines and devices be advertised or sold directly to consumers?
Prescription-only medicines can generally only be supplied by a qualified doctor or dentist, from licensed retail pharmacies or at or from licensed healthcare institutions to their own patients. Advertisements of prescription-only medicines to the general public are generally prohibited. Pharmacy-only medicines can be supplied by or under the supervision of a pharmacist without a prescription, from licensed retail pharmacies or at or from licensed healthcare institutions to their own patients. GSL medicines can be purchased from any retailer, over-the-counter or by means of an automatic vending machine provided that the relevant statutory requirements are met. Advertisements of pharmacy-only and GSL medicines to the general public are permitted, provided that the relevant regulatory requirements are met. For instance, advertisements of pharmacy-only medicines will generally need to contain or be accompanied by the appropriate advisory or warning statement required by the HSA.
Medical devices may only be supplied and advertised in accordance with the prescribed requirements, which may depend on the risk classification of the medical device and the licence conditions applicable to it. For instance, “professional use only” medical devices may only be supplied by way of administration or application by a qualified doctor or dentist or by a person who is acting under the supervision of a qualified doctor or dentist. Advertisements of such “professional use only” medical devices can be distributed only to, or contained only in a publication intended for circulation mainly among, qualified practitioners.
21. How is compliance monitored?
The HSA’s Vigilance and Compliance Branch actively monitors advertisements of therapeutic products and medical devices, amongst others, as part of its routine compliance review and investigations. In this regard, the HSA is empowered to require any advertiser or a manufacturer, importer, supplier or registrant of a medical device to furnish it with copies of any advertisements which have been advertised or are about to be advertised within a specified timeframe.
Where any advertisement is found to be in contravention of the applicable regulatory requirements, the HSA may order corrective measures to be taken, such as requiring the advertiser to:
- stop the advertisement with immediate effect;
- take reasonable measures to remove the offending advertisements that have been published or distributed; and/or
- publish a corrective advertisement in such manner and containing such information as may be specified by the HSA.
22. What are the potential penalties for noncompliance?
In relation to non-compliant advertisements, the HSA may order that corrective measures be taken by the person who has advertised or caused the non-compliant advertisement to be advertised. The failure to comply with such order by the HSA may constitute an offence, for which the person may be liable on conviction to a fine of up to S$20,000, imprisonment for a term of up to 12 months, or both.