Despite the country’s small size, Singapore boasts a highly-developed economy and serves as an Asian hub for numerous medical companies. In total, Singapore’s medical device and pharmaceutical markets are estimated at over $800 million. Leading pharmaceutical companies, such as GlaxoSmithKline, Pfizer, Eli Lilly and Bristol-Myers Squibb, have established a presence in Singapore and continue to expand their facilities. Pfizer chose Singapore for its first large-scale active pharmaceutical ingredient manufacturing facility in Asia, while GlaxoSmithKline set up its first Asia region preclinical research establishment in Singapore. In response to the growth of Singapore’s medical industry, the Health Sciences Authority has been making great efforts to boost its regulatory expertise and improve the environment of Singapore pharmaceutical regulations and medical device regulations.
The Health Sciences Authority (HSA) was established in April 2001 to ensure the quality, safety and efficacy of drugs, medical devices, cosmetics, and other health-related products in Singapore. In January 2004, the Center for Drug Administration (CDA) was established under the HSA. The CDA was formed by merging two previously-existing agencies: the Center for Pharmaceutical Administration (CPA) and the Center for Drug Evaluation (CDE), which were both responsible for the regulation and evaluation of medical products in Singapore. The CDA’s mission for Singapore pharmaceutical regulations is to further simplify and streamline the evaluation and registration processes.
The Center for Drug Administration (CDA) leads Singapore pharmaceutical regulations and separates them under the following five regulatory guidelines: Medicines Act, Poisons Act, Sale of Drugs Act, Medicines (Advertisement and Sale) Act and the Misuse of Drug Regulations. The CDA’s responsibilities include, but are not limited to, inspection and licensing of pharmaceutical manufacturers/importers/wholesalers, ensuring Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) standards, and post-marketing surveillance.
Under the Medicines Act, a medicinal product refers to a substance that is used in one of the following ways: (1) administered to humans for a medicinal purpose, or (2) used as an ingredient in the preparation of a substance to be administered to humans for a medicinal purpose. “Medicinal purposes” refer to one of the following: treating or inducing anesthesia, preventing disease, diagnosing or determining the extent or degree of a disease, contraception, or to prevent or interfere with the normal operation of a physiological state or condition.
Product License Application Process
Under Singapore pharmaceutical regulations, a pharmaceutical product may only be imported into Singapore if a product license has been granted by the HSA. In Singapore, product licenses are specific to the product name, formula, indication, use, manufacturing process, dosage form, and applicant. If any of these factors are changed, a new product license application or variation application will be required. Variation applications are acceptable for already-approved products which have a new indication, dosage recommendation, etc.
Pharmaceutical companies have the option of requesting a pre-submission consultation with the HSA. These requests should be made to the HSA in writing and a clear agenda and list of questions should be prepared by the company prior to the meeting. The information that the HSA provides is nonbinding and will not have a direct impact on the results of the application.
New and variation product license applications are evaluated via one of three possible routes, depending on the type of product change. Pharmaceutical products which have not been approved by any regulatory agency will receive a full evaluation, which according to the CDA, takes approximately nine months to complete. If a product has already been approved by another country’s regulatory authority, Singapore pharmaceutical regulations will require an abridged evaluation process, taking around six months to complete. Finally, if the product has already been approved by one of the principle regulatory agencies (US FDA, UK MHRA, Australia TGA, EU EMEA or Health Canada), only a verification evaluation will be necessary. This third evaluation process takes about six weeks to complete.
Singapore Medical Device Regulations
Currently, medical device product registration is voluntary in Singapore. (However, a few select types of devices, such as contact lenses and radiation-emitting devices, do require registration but are regulated by specific guidelines, under the Contact Lens Practitioners Act and Radiation Protection Act, respectively.) The Center for Medical Device Regulation (CMDR) regulates the voluntary registration system, which was introduced in April 2002. While the HSA has not yet implemented measures for a mandatory registration system, this voluntary scheme was established to keep up with the global trend of regulating and controlling medical devices through pre-market evaluation, manufacturing controls, and post-market surveillance.
The CMDR encourages medical device companies to voluntarily register their devices. This process allows both the industry members and government officials to become more familiar with the system and also address any potential complications or “hang-ups” prior to the implementation of the system.
An application to register a device should be submitted by a local representative in Singapore, who is a natural or legal person established in the country, and has been specifically designated to act on behalf of the medical device company.
The CMDR uses a risk-based classification system for medical devices in Singapore. Devices are divided into four categories: Class I (low risk), Class IIa and IIb (medium risk), and Class III (high risk). Generally, voluntary product registration is encouraged for Class IIa, IIb and III devices. This process involves submitting a pre-market application to the HSA, thereby guaranteeing the safety and efficacy of the device.
Medical Device Register
The HSA has also created a Medical Device Register, which is a computer database listing medical devices imported or supplied to, or exported from, Singapore. While registration with this system is currently voluntary, it is likely that the CMDR will use this database to monitor the post-marketing activities of medical device companies in the future. In the initial phase of implementation, it is expected that only Class IIa, IIb and III devices will be required to be listed.
Patent Bill Amendment
In June 2004, Singapore pharmaceutical regulations were changed through the amendment of the Patent Bill. The hope was to strengthen the country’s pharmaceutical patent system. The changes should improve the pharmaceutical sector by encouraging greater innovation and research in Singapore’s pharmaceutical industry. Specifically, the amended Bill focuses on improving three key areas in Singapore’s patent regulations, (1) the patent term, (2) parallel importation of products, and (3) improving the patent application process. These changes will not only give patent owners more security and incentive to bring new products into Singapore, but will also benefit consumers and patients as new products become available in the market.
First, the amendment to the Singapore pharmaceutical regulationprovides for flexibility in the patent term. In Singapore, after receiving a patent, the patent term begins even though the product has not been approved yet. Frequently, there are delays during the process of obtaining the market approval for a pharmaceutical in Singapore. In this case, a company could lose many weeks or months of the patent term since they are not yet able to market the product. Under the new amendment, the patent term will start once the product is approved.
Second, Singapore is trying to preserve the balance between the interests of patent owners and users of pharmaceuticals by altering the parallel importation rules for pharmaceutical products. Under this new section of the Bill, a patent owner has special rights concerning parallel (generic or similar) products. Specifically, a patent owner is able to stop a parallel importer from importing a product that is a generic equivalent or similar to the patented product, if the product has not been previously sold or distributed in Singapore. But, once the patent owner imports the product into Singapore, this right will be voided – the patent owner may be subject to competition from parallel importers.
There is one exception to the above Singapore pharmaceutical regulations. If a patented pharmaceutical product is needed for the treatment of a specific patient in Singapore, the product may be parallel imported with the HSA’s approval, regardless of whether the patent owner has brought the product into Singapore. This will ensure that Singaporeans receive adequate medical treatment and will not be denied treatment due to the lack of certain pharmaceutical products in the country.
Finally, Singapore is improving its patent approval system through the creation of a two-track system. This system will better cater to a company’s needs, rather than the current one-track system, providing little flexibility. Track one is a “fast track,” which enables a patent applicant to expedite the application process and obtain a patent as soon as possible. The second process is the “slow track,” allowing a patent applicant to spend more time working on a marketing plan and patent strategy before entering the patent term. This new system should make the patent approval process more efficient and cost-effective by catering to each applicant’s needs.
Subsidies for Cardiac Treatment and Devices
In an effort to ensure that Singaporeans receive quality healthcare at reasonable prices, Singapore’s Ministry of Health introduced the Medical Service Package (MSP) on July 2, 2004. The MSP, which took effect in all public institutions on July 5, 2004, will allow some patients to receive subsidies for medical care. The program will start by providing subsidies for a number of cardiac devices, including cardiac stents, defibrillators and pacemakers. If this program is successful, the Ministry of Health will consider expanding the program to other medical specialties.
The MSP will provide subsidies for patients in Ward/Class B2 and C (which have six or more beds per room and do not have air conditioning). Patients in Wards A1, A2 and B1 (which have four or fewer beds per room as well as air conditioning) are not eligible to receive subsidies. The MSP will cover cardiac medical devices, procedures, investigations and even some cardiac drugs. These services are grouped into three categories and are based on medical necessity. (1) The Basic service includes standard healthcare services, where the indications are not controversial. (2) The Extended service refers to newer or more advanced medical services, some of which are controversial. Extended service is only required in special circumstances for certain patients; or in a case where the indications are still evolving. (3) Excluded service consists of non-essential medical services, like cosmetic surgery or experimental treatments.
The main goal of the MSP is to ensure that patients are not “over-serviced” by healthcare providers. Therefore, the program has set up a system of peer review to make sure that patients receive the correct treatment, and are not subject to any unnecessary tests or treatment. However, the medical team in charge of treating a patient will make its treatment decision based on the patient’s needs, not the patient’s ability to pay. In the case where patients are still unable to pay their medical bills despite the subsidies, they will be referred to a medical social worker.
New Guidance on Disease Awareness Advertisements
In November 2004, the HSA released new guidelines on Disease Awareness Campaigns (DACs). For companies who produce drugs for rare diseases, DACs are a convenient way for companies to educate the public about a disease and its various treatment options through advertisements. However, a company may only provide non-biased information, with no emphasis on particular medications or treatment options. Additionally, since the intended use of DACs is to raise public awareness and knowledge about the conditions and treatments of diseases (as opposed to advertising a specific medication or treatment), it is not necessary to obtain pre-approval or advertisement licenses from the HSA.
DAC advertisements should meet the following three requirements: (1) make no mention of any brand of medication, (2) do not promote any particular medicinal product or recommend consumers to ask their health professionals for any particular product, and (3) only provide factual, up-to-date and substantiated information. In the case where there is only one treatment option, or a new treatment has recently been released, companies must make certain that they continue to focus on the general education of the disease. The HSA will continually monitor DACs and has the authority to stop a DAC if it does not follow the above guidelines.
Alternatively, companies may also indirectly advertise a particular prescription only medicine (POM), though this type of advertising cannot be done in the form of a DAC and requires approval from the HSA. The HSA released this new guideline to ensure that companies adhere to the DAC advertisement conditions as stated above, and do not attempt to indirectly advertise a POM in the form of a DAC advertisement.
Updated Good Distribution Practice (GDP) Guidelines for Pharmaceuticals
Another way in which the HSA altered Singapore pharmaceutical regulations was through the release of new guidelines on Good Distribution Practices (GDP) for pharmaceutical materials and products, effective January 1, 2005. The new guidance includes new and updated information on the GDP documentation system, electronic records, EEFO (Earliest-Expiry-First-Out) and FIFO (First-In-First-Out), and the handling of active pharmaceutical ingredients (APIs) and intermediates. The HSA issued the new guidelines in order to better ensure the reliability and quality of pharmaceutical materials and products during the distribution process.
Under the updated guidelines, some of the changes and new requirements are as follows. First, companies will be required to establish procedures for developing, controlling, and maintaining documentation related to the distribution process. The company should keep these documents up-to-date and have them readily available upon request. Second, if records are also maintained by electronic data systems, a detailed description and explanation of the system should be created. Any changes made to the data should be electronically recorded and can be used as reference information in the case of an audit. Third, companies will be required by Singapore pharmaceutical regulations to develop an EEFO/FIFO system to help avoid distributing products with approaching expiration dates. Finally, anyone who distributes, trades, or stores APIs or intermediates in Singapore will need to maintain documents for tracing these products. Documents that allow for traceability should include the name and address of the original manufacturer, purchase orders, batch numbers, transportation information and Certificates of Analysis.
New Good Distribution Practice (GDP) Certification Guidelines
The HSA recently released new guidelines on the preparation of a Site Master File (SMF) for pharmaceutical Good Distribution Practice (GDP) certification. While the application for GDP certification is voluntary in Singapore, those companies that receive a certificate should regularly update their SMF when any distribution practices are changed. A SMF should contain information describing product storage, delivery procedures, and any other distribution operations carried out by the distribution site.
According to the new Singapore pharmaceutical regulation, an SMF should include the following nine sections: (1) General Information, (2) Personnel, (3) Premises and Facilities, (4) Stock Handling and Stock Control, (5) Documentation, (6) Product Complaints and Recalls, (8) Self-Inspections, and (9) Contract Activities.
For instance, the General Information section should include practical data about the site, such as the location, contact information and number of employees. The applicant should also indicate whether the site has received approval from the home country health authority. In addition, the applicant must list all activities and operations carried out on the site, whether or not the activities are pharmaceutically-related. Under the Personnel section, job descriptions of the key employees should be included, as well as an explanation of any in-service training programs provided to the workers. When appropriate, images, drawings or layouts should be included, such as in the Premises and Facilities section. The SMF should contain approximately 25-30 pages of information in total, and may be submitted to the HSA in hardcopy or electronic format.
New Guidance on Minor Variation Applications for Pharmaceuticals
In Singapore, medical companies that plan to make a change to one of their pharmaceutical products, such as a change in labeling, packaging or manufacturing site, may submit a minor variation (MIV) application to the Center for Drug Administration under the HSA. Conversely, in many other Asian countries, these types of product changes would require complete re-registration of the product. In January 2005, the HSA released updated guidance on minor variation applications for registered pharmaceuticals. This guidance on Singapore pharmaceutical regulations divides minor variations into two categories: MIV-1 and MIV-2. Variations categorized as MIV-1 variations require regulatory approval; MIV-2 variations do not require HSA approval. The product license holder is responsible for submitting the MIV-1 or MIV-2 application and ensuring that all required documents are complete.
The following are some of the changes categorized as MIV-1 variations: (1) manufacturing site, (2) shelf-life, (3) storage conditions, (4) packager, (5) testing procedures, (6) pack size, and (7) product labeling. These changes will require that specific documents (usually 5-10 documents) be submitted to the HSA for approval, prior to the change.
MIV-2 variations require that a statement be submitted to the HSA only specifying the effective date of change, not requesting approval. This statement should be submitted at least two months prior to the implementation of the change and should be accompanied by supporting documents. MIV-2 variations include changes in the: (1) product owner, (2) manufacturer’s name or address, (3) name or address of the product license holder, (4) excipient, (5) composition of packaging material, (6) batch size, etc. Each minor variation must meet specific conditions in order to be categorized as an MIV-2 variation. If the conditions are not met, a MIV-1 application, requiring pre-approval, may be necessary.
New Safety Reporting Requirements for Pharmaceuticals
In February 2005, the CDA released new guidelines on safety reporting requirements for registered medicinal products. The new guidelines for Singapore pharmaceutical regulations apply to license holders who are responsible for bringing western medicinal products into Singapore. The guidelines define the types of safety-related reports that license holders are required to provide to the Pharmacovigilance (PV) Unit of the CDA and also define the timeline for which to do so. The new requirements cover three different types of safety reports: spontaneous suspected adverse drug reaction (ADR) reports, periodic safety update reports, and reports regarding regulatory actions or actions taken by companies due to safety issues.
Spontaneous suspected ADR refers to clinical observations of adverse reactions that originate outside of a formal study. Once a possible causal relationship is found between an ADR and the medicinal product in question, the license holder must submit a spontaneous suspected ADR report to the PV Unit of the CDA. This report must be submitted within 15 calendar days from the time any personnel of the license holder is made aware of the ADR. The report must be filed even if the license holder does not agree with the initial clinical observation.
Periodic safety update reports (PSURs) may be requested by the CDA for certain kinds of registered medicinal products under Singapore pharmaceutical regulations. License holders of selected medicinal products must submit a PSUR to the Product Evaluation & Registration Branch of the CDA every 6 months for the first two years after market approval. After two years have passed, a PSUR must then be submitted yearly for the next three years. The CDA recommends that license holders of products not requiring a PSUR still maintain a summary report on safety data. If the CDA requests this kind of report it must be submitted within 30 calendar days.
If safety concerns cause regulatory actions to be taken by other regulatory authorities, or actions to be taken by the product owner itself, the license holder must notify the PV Unit of the CDA within 7 days. Significant safety concerns that require reporting include: product withdrawal/recall, removal of approved indications by regulatory agencies, failure to obtain product license renewal, etc. Reports of this nature must describe the safety related reasons why actions were taken, review the consequences of the actions taken and also include recommendations on follow-up actions to be carried out locally.