G L P ：Good Laboratory Practice GCP：Good Clinical Practice
GPvP：Good Pharmacovigilance Practice GMP：Good Manufacturing Practice
Medicinal product life cycle management framework Figure 2-2-1
Part II - Key Administrative Results Medicinal Products Management
32
Policies and Outcomes
1. Comprehensive Regulations and Standards
A number of key addenda and revisions were made to medicinal product management laws and related standards in 2015. Revisions include the following: Pharmaceutical Affairs Act and the Rare Disease and Orphan Drug Act, Regulation of Bioavailability and Bioequivalence Studies, regulations for applying for drug hazard relief, and regulations for registration of medicinal products. Promulgated laws include the following: Regulations for Medicament Recall, standards for the registration of monoclonal antibodies for biosimilars, standards for determining the adequacy of donors of cell therapy products, and standards for the inspection, registration, and review of medicinal products. TFDA also announced the need to include the composition or name of the excipient upon the package inserts of the medicinal products and that the active pharmaceutical ingredient (API) used within the preparation must be compliant with Good Manufacturing Practice (GMP) for pharmaceuticals. Refer to Table 8 of Annex I for details on the revisions as well as promulgation of new laws.
2. Medicinal Product Registration Management
Medicinal product registration can be divided into active pharmaceutical ingredients (API) and its preparations, the latter of which can be further divided into new drugs, bioagents, generic drugs, and orphan drugs. Where local clinical trials or bioavailability (BA) and bioequivalence (BE) study results must be provided as attachments for inspection and registration applications, the corresponding project plans and reports must be reviewed and approved as well. The number of drug permit licenses approved by TFDA every year is listed in Table 9 of Annex I.
(1) Pre-market Inspection and Registration for Medicinal Products
a. In 2015, a total of 170 new drug applications have been approved (Figure 2-2-2), a historical high and a 26% increase compared to the figures of 2013. Of which, two of the applications in 2015 involved novel drugs made in Taiwan, creating a new record for global firsts in the industry.
b. Among 170 new drug applications (NDAs) in year 2015, a total of 27 NDAs were manufactured domestically while 143 NDAs were imported. 49 involved new drugs containing new chemical entities (NCE) and 44 NDAs were biopharmaceuticals. Therapeutic areas included anti-cancer drugs, anti-viral drugs, drugs for rare diseases, and vaccines required by public health services.
To encourage the provision of new treatment options, TFDA expedited the approval and market authorization of 2 anti-cancer antibody immunotherapy drugs in 2015 to benefit those afflicted by rare diseases or cancers.
0 18
2011 2012 2013 2014 2015
(cases)
Number of new drugs approved throughout the years Figure 2-2-2
33 (2) Clinical Trial Reviews
a. Reviews were conducted according to the Application Guidelines for the Clinical Trial of Medicinal Products and Ethical Review for the Clinical Trial of Medicinal Products (Central IRB) to ensure the comprehensiveness of documents submitted by the applicants and improve the efficiency of case review processes.
b. In 2015, new clinical trials and change applications in Taiwan totaled 346 and 3,130 cases respectively. These figures amounted to a near 21.5% increase in the total number of cases compared to the previous year.
c. To safeguard the rights and interests of trial subjects and maintain the quality of clinical trials, all clinical trials must be implemented in compliance with the Good Clinical Practice (GCP) Standards for Medicinal Products. A total of 52 GCP audits were completed in 2015.
(3) Reforms to Medicinal Product Review Systems
In 2015, revisions to the Priority Review System and Accelerated Approval Mechanism for New Drug Applications were promulgated to expand the applicable scope of new drugs with new chemical entity (NCE) to include other new drugs which are detined in Article 7 of the Pharmaceutical Affairs Act (namely: NCE, new therapeutic compound, and new method of administration). In order to improve the transparency of the review process, manufacturers were invited to consultation meetings in order to improve the transparency of the review process. TFDA also introduced benefit and risk evaluation systems for new drug reviews and initiated pilot for online new drug application systems in order to expedite the approval of new drugs and achieve the vision of establishing advanced technologies in Taiwan to and expanding global markets. Fifteen priority review cases were completed, with review time greatly reduced to 171 days (median value).
3. Promoting Professional Consultation for Pharmaceutical Projects
(1) To support the Taiwan Biotech Industries Take off Action Plan of the Executive Yuan, TFDA committed itself to improving pharmaceutical industry consultation and establish a Professional Consultation System for Pharmaceutical Projects for new drugs being researched and developed in Taiwan. Items were evaluated and selected according to the four selection indicators of: (1) innovativeness; (2) contribution; (3) early benefits; (4) legal compliance.
Legal inquiries and consultation were provided from the research and development (R&D) phase to ensure that drugs are released as early as possible for the patients and encourage new drug R&D in Taiwan.
(2) From 2010 to the end of 2015, TFDA provided consultation to 32 projects, and approved a novel new drug that was domestically produced in 2014. In 2015, another two novel and domestically produced new drugs were approved as well, generating a new record for world firsts in Taiwan. Approved indications for these drugs were adult hemodialysis patients with chronic kidney diseases and hyperphosphatemia (API name: Ferric Citrate) and metastatic pancreatic cancer patients that previously received chemotherapy with gemcitabine (API name: Irinotecan liposome).
Part II - Key Administrative Results Medicinal Products Management
34
Section 2. Medicinal Products Source Management
Current status
To improve manufacturing quality of medicinal products and align to international standards, Taiwan began enforcing increasingly stringent laws and international harmonization for the management of medicinal product factories. In 1982, Taiwan began implementing Good Manufacturing Practice (GMP) for pharmaceuticals and enforced the current Good Manufacturing Practice (cGMP) in 1995. In 2007, Taiwan began promoting GMP standards of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S GMP), and attained total enforcement by the end of 2014, achieving complete harmonization of Taiwan's pharmaceutical manufacturing standards with international standards. To strengthen production quality management, Taiwan promulgated GMP standards for active pharmaceutical ingredients (APIs) in 2013 and achieved complete enforcement by the end of 2015. The GMP for Modern Pharmaceutical Products (Part 3) was released in 2015 with complete enforcement scheduled by the end of 2018. The GMP implementation road map is illustrated in Figure 2-2-3.
After complete enforcement of PIC/S GMP for pharmaceutical manufacturers, the overall scope of GMP management in Taiwan was further expanded to include GMP for APIs to achieve source management in upstream industries as well as Good Distribution Practice (GDP) of downstream industries to ensure the manufacturing quality of medicinal products and achieve total quality management of the entire pharmaceutical supply chain. Complete enforcement of PIC/S GMP in modern pharmaceutical manufacturers improved quality management at the manufacturer' s end for pharmaceuticals. Measures were also taken to improve source and distribution management of pharmaceuticals to achieve safer drug use for the general public.
Roadmap for implementing GMP amongst modern pharmaceutical manufacturers
1977 1982 1988 1995 1999 2005 December
2007 December
31 2014 December 31 2015 January
2010 December
31 2018
GMP 1977 to 1988 cGMP (current GMP)1995 to 2005
Validation International GMP
Observational visit to Japan by the Department of Health and drafting of the GMP outlines Release of the Pharmaceutical GMP Complete implementation of the GMP for dosage forms Validation of sterile products Public announcement that complete validation must be performed for all medicinal products Complete establish the three-stage validation process Announcing the schedule for implementing the international PIC/S GMP standard Formal implementation of the PIC/S GMP Complete implementation of PIC/S GMP Complete implementation of GMP for API Complete implementation of GDP
Policies and Outcomes
1. Complete Compliance to the PIC/S GMP by Modern Pharmaceutical Manufacturers (1) Promotion of PIC/S GMP
a. Taiwan formally became a member of the PIC/S organization on January 1, 2013, ahead of Japan and South Korea, which proved that GMP management and auditing practices of pharmaceutical companies in Taiwan have been successfully aligned to international standards. To improve the quality of pharmaceutical manufacturing, TFDA took active measures in strengthening pharmaceutical production quality and ensure the safety of medicinal products for the public by enforcing complete compliance to PIC/S GMP in all domestic and imported western pharmaceutical manufacturers before December 31, 2014.
Figure 2-2-3
35 b. To maintain stringent management of pharmaceutical manufacturing, follow-up management
for modern pharmaceutical manufacturers include routine and non-periodic inspections.
Unannounced site inspections were also carried out for specific incidents (such as whistle-blowing incidents, nonconforming products identified during post-marketing quality surveillances, and news events). Theme-based audits were also initiated to further verify the current status of quality management in western pharmaceutical companies. On-site sampling and testing were conducted as part of the quality monitoring process to ensure that quality of medicinal products are maintained within the stated period of expiry.
c. As of the end of December 2015, a total of 120 modern pharmaceutical manufacturers in Taiwan are compliant with PIC/S GMP standards (Table 2-1-1) and 893 overseas manufacturers of imported medicinal products have been assessed as compliant. Also, by the end of December 2015, a total of 251 foreign modern pharmaceutical manufacturers have passed on-site inspections, ensuring a stable market supply of medicinal products.
d. To improve the quality of medicinal gases, consultation and promotion for GMP and PIC/S GMP have been provided since 2002. Total compliance and enforcement of PIC/S GMP was achieved by January 1st 2014. By the end of 2015, a total of 33 medicinal gases manufacturers achieved compliance to PIC/S GMP.
Note: The numbers of domestic and foreign pharmaceutical manufacturers that have passed the assessments are cumulative every year
Assessment and qualification of domestic and overseas pharmaceutical companies Year