SCIENTIFIC DISCUSSION
1. Introduction
Human papillomavirus (HPV) infection is currently the most common sexually transmitted disease worldwide. By 5 years after sexual debut, ~50% of young women will have been infected with at least one of the 40 HPV types that preferentially infect the genitals. Thirteen of these HPV types are highly carcinogenic. Although a consistent picture of the epidemiology and pathogenesis of genital infections in women has developed during the past two decades, less is known about these infections in men. However, studies suggest a similar infection pattern in men, who are the most important vectors for transmission of HPV disease to women. The peak incidence of HPV infection occurs in young adults between the ages 16 and 23 years.
Human papillomaviruses are double-stranded DNA viruses that infect epithelial cells and are significantly associated with low-grade cervical intraepithelial neoplasia (CIN), genital condyloma and cervical cancer. HPVs are judged to be the primary cause of cervical cancer, which is the second most common type of cancer causing deaths in women worldwide. Other HPV-related cancers in young women include vulvar and vaginal cancers, which are preceded by dysplastic lesions (vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN). In men anal cancer is the most common HPV-related cancer. The virus is also related to penile and certain oropharyngeal cancers. Other benign HPV-associated conditions include condyloma acuminata (genital warts) located in the genital or perianal region and juvenile recurrent respiratory papillomatosis (JRRP) primarily located in the larynx. JRRP is thought to occur by transmission of the virus from an infected mother to her child.
HPV types are classified into different categories based on their association with cancer in humans. Epidemiological studies on the prevalence of HPV types in cervical cancer show some geographical differences. However, all over the world the majority of cervical cancers are related to two types, HPV 16 (~55%) and HPV 18 (~15%). The contributions of HPV 16 and HPV 18 to high-grade CIN and to HPV-related vulvar, vaginal and anal cancers are similar to those found in cervical cancer. HPV 6, 11, 16 and 18 together cause ~35% of CIN 1 cases. HPV 6 and HPV 11 cause approximately 90% of genital warts and RRP and 10% and 20% of CIN 1 lesions, respectively, but are not associated with cervical or anal carcinoma. These data provide the basis for the selection of the four HPV types 6, 11, 16 and 18 in the current HPV vaccine.
Mechanism of action
There are no animal models for human papillomavirus infection. In animal models vaccination with LI Virus-like Particles (VLPs) derived from species-specific papillomaviruses protected against acquisition of infection and disease. Successful passive transfer experiments have also been performed suggesting that type-specific antibody responses are virus-neutralizing. The quadrivalent HPV vaccine was developed based on these animal data that suggest that a systemic neutralizing anti-HPV response by vaccination with type-specific HPV L1 VLPs result in protective immunity against type-specific HPV infection and disease.
The vaccine also elicits cell-mediated responses as detected by in vitro stimulation of PBMCs, Th1 and Th2 cytokines and immunoglobulin subclasses. The LI responses are not expressed in the cellular department and therefore it is not expected CTLs will assist in vaccine-induced protective immunity. The induced T-cell responses may play an important role in establishing long-lived B-cell immune memory.
The exact role of various immune mechanisms in the protective efficacy of the HPV L1 VLP vaccine remains to be determined. It is believed that the vaccine provides protection by inducing type-specific antibodies that interfere with transmission by binding to and neutralizing contaminating HPV prior to entry into basal cells.
Sanofi Pasteur MSD SNC submitted a Marketing Authorization Application for Gardasil in accordance with Article 8.3(i) of Directive 2001/83/EC as a complete application.
The approved indications are as follows: “Gardasil is a vaccine for the prevention of high-grade cervical dysplasia (CIN 2/3), cervical carcinoma, high-grade vulvar dysplastic lesions (VIN 2/3), and external genital warts (condyloma acuminata) causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18. The indication is based on the demonstration of efficacy of Gardasil in adult females 16 to 26 years of age and on the demonstration of immunogenicity of Gardasil in 9- to 15-year old children and adolescent. Protective efficacy has not been evaluated in males”.
2. Quality aspects
Introduction
Gardasil contains virus-like particles (VLPs) of the recombinant major capsid (L1) protein of HPV types 6, 11, 16, and 18 as active substance. The recombinant proteins forming the VLPs are produced by separate fermentation in recombinant Saccharomyces cerevisiae. VLPs of each type are adsorbed on amorphous aluminium hydroxyphosphate sulfate adjuvant, and the formulation also includes sodium chloride, L-histidine, polysorbate 80, sodium borate, and water for injection. The final product is presented as a sterile suspension either in a single-dose vial or in a prefilled syringe for intramuscular injection.
Active Substance
The drug substance consists of the four Monovalent Bulk Adsorbed Products (MBAPs), one for each of the four human papillomavirus (HPV) types included in the final product. The active components in each MBAP are virus-like particles (VLPs) made up of the recombinant major capsid (L1) protein for that HPV type, produced in recombinant S. cerevisiae. L1 is the major structural protein of the human papillomavirus viral capsid.
Native papillomavirus virions have an icosahedral symmetry consisting of 72 pentamers of L1 protein, and are nearly spherical with an approximate diameter of 60 nm. The pentamers are stabilized by intra- and inter-L1 disulfide bonds, and there is also evidence of interpentamer disulfide bonds stabilizing the capsid. The HPV VLPs mimic the structure of the virion capsid.
? Manufacture
Genetic Development
The pGAL110 yeast expression vector was used for expression of all four HPVL1 proteins. Differences in the cell substrates among the HPV types were introduced when cloning the particular HPVL1 open reading frame (ORF), when inserting the ORF into the pGAL110 vector, and when transforming the yeast host strain with the resulting vector. Plasmid or phage libraries were constructed from DNA obtained from human clinical specimens or cell lines positive for HPV types 6, 11, 16, or 18. The L1 genes were derived by a direct cloning protocol. However, the coding sequence for HPV11L1 was synthetically rebuilt based on HPV6L1 nucleotide sequences that supported good VLP expression in yeast and that were appropriately changed to encode the HPV11L1 polypeptide. Following sub-cloning of either the whole HPV genomes or parts thereof into standard cloning vectors, polymerase chain reaction (PCR) was used to subclone the L1 genes into the yeast expression vector pGAL110, which contains the divergent yeast GAL1-GAL10 promoter and the yeast ADH1 terminator (ADH1t) for transcription termination and polyadenylation.
The pGAL110-related yeast expression vectors for each of the four HPV types were used to transform spheroplasts of the recombinant S. cerevisiae. Transformations were conducted independently for each of the HPV types by a published method.
Based on analyses of HPV VLP expression productivity, one high-producing isolate of each type was selected as the source seed for preparation of a premaster seed.
Cell Banking
Master Cell bank (MCB)
Four cell substrates were derived from Saccharomyces cerevisiae, which were transformed by pGAL110 based yeast expression vectors, each containing the gene of interest coding for HPVL1 types 6, 11, 16, or 18 respectively. A clone for each type was selected to establish the four MCBs.
All cGMP master seed stocks were prepared using a two-stage expansion. Optical density, pH, and residual dextrose were monitored to assure consistency of growth among all cGMP seed stocks.
A series of characterization tests have been performed on the MC
B to verify culture purity, species identity, host strain identity, viable count, plasmid identity and integrity by restriction mapping, DNA sequencing of the L1-encoding genes and junctions, and specific productivity.
Working Cell bank (WCB)
Master seed vials are used to inoculate the HPV Shakeflask Medium. Future working seeds will be manufactured using the same process steps and similar equipment used for the original working seed. Following freezing, seed supplies are stored at ≤-60 °C.
End of Production Cells (EOP)
The genetic stability has been analysed for one full-scale fermentation for each type of end of production cells (culture purity, species identity, host strain identity, restriction endonuclease mapping, plasmid retention and DNA sequencing).
Fermentation
The manufacturing process of the drug substance consists of two main steps: 1) fermentation and harvest of the recombinant yeast cell slurry, and 2) purification of the VLPs and adsorption of the purified VLPs onto aluminium-containing adjuvant to form the MBAP.
The fermentation process consists of a seed fermentation and a production fermentation.
During the seed fermentation process all HPV types use the same Seed Fermentation Medium. Culture growth and dextrose utilization are monitored. Upon completion of this stage, the seed culture is transferred to the production fermentor, which contains the HPV Production Fermentation Medium. Following fermentation, the cells are then harvested by microfiltration to produce the cell slurry, which is dispensed and frozen for storage.
Purification
The downstream processing is initiated by thawing the frozen cell slurry and releasing the VLPs from yeast cells by homogenization/microfiltration run. The cell lysates are then incubated. The VLPs are purified by cross-flow membrane filtration, chromatography and ultrafiltration. The final steps in the purification process for all four types are buffer exchange and sterile filtration to produce the final aqueous product (FAP). The FAP for each type is then adsorbed onto amorphous aluminium hydroxyphosphate sulfate to produce the MBAP. The MBAP for each type is then filled into bulk storage containers and stored at 2-8°C.
The amorphous aluminium hydroxyphosphate sulfate adjuvant used in the manufacture of the MBAP is manufactured Merck & Co. at the same site as the drug substance. The adjuvant is manufactured by adding sodium hydroxide to a solution of aluminium potassium sulfate and collecting the precipitate.
Process control and validation
The validation studies were executed according to prospectively approved protocols.
Selection of Critical process parameter (CPP) and Critical quality attribute (CQA) and their respective ranges were established based on data at lab, pilot, and full scale, including data from laboratory experiments specifically designed to test process parameter ranges. Some of the CPPs and CQAs were later defined as “critical controls”.
Separate validation studies for filters and column sanitization and reuse are presented. Validation of the aseptic processing is described. Bulk media challenges have been performed by simulating all steps in the manufacturing of the MBAP, including holding times, after the sterile filtration. After the initial qualification consisting of three consecutive media challenges, the aseptic process is re-qualified by one yearly media challenge.
Manufacturing process development
Initial clinical trials focused on monovalent Type 11 or 16 VLP vaccines, because Type 11 had the only known assay for neutralising antibody and type 16 is the HPV type predominantly associated with cervical cancer. Type 6 and 18 VLPs were added later.
Process development proceeded in parallel with clinical development, culminating in the Final Manufacturing Processes (FMPs), which were validated. Most clinical trials of the quadrivalent vaccine (trials No. 011, 012, 015, 016, and 018) used the final manufacturing process for both fermentation and purification.
Elucidation of structure and other characteristics
Testing was carried out on the Final Aqueous Product (FAP), Monovalent Bulk Adsorbed Product (MBAP), and in some cases, intermediate. The characterization testing was performed on a minimum of three full-scale lots per HPV type for each assay.
Monomers were analyzed by peptide map (LysC + AspN) followed by MALDI-MS, Reduced SDS-PAGE (intact monomer), Isoquant (deamidation), free thiol groups, circular dichroism, and FT-IR spectroscopy. Size exclusion chromatography was used to analyse oligomers of L1 proteins. No evidence has been found of N-linked glycosylation.
Virus-like particles were analyzed by CD and FT-IR spectroscopies, Transmission Electron Microscopy (TEM), Cryo-electron microscopy (cryoEM), Dynamic Light Scattering (DLS), epitope mapping, inhibitory concentration at 50% response (IC50) by competitive ELISA and affinity of monoclonal Antibody (mAb) to the different epitopes.
Epitope mapping was performed on the different HPV types prior assembly and after reassembly (FAP) using a surface plasmon resonance (SPR) technique with a panel of monoclonal antibodies (mAbs) that recognizes conformational or linear epitopes.
Adsorbed VLPs (MBAP) were analyzed by differential scanning calorimetry (DSC), mouse potency, and In-Vitro Relative Potency (IVRP). It has been concluded that adsorption to the aluminium adjuvant does not result in significant changes in VLPs structure.
The mouse potency assay was performed on BALB/c mice in which anti-HPV antibodies were measured using an ELISA based assay four weeks post-immunisation. This in vivo potency assay was used to establish the immunogenicity of MBAP in mice and the assay was used to release early clinical lots and to characterise the stability of MBAP.
The IVRP assay is the proposed potency assay for release. It is a sandwich-type ELISA used to measure the antigenicity of drug substance and was shown to be specific for the four types. Impurities
Non-L1 protein impurities originated from yeast host cells were analyzed by SDS-PAGE, Western blot, and protease activity. These assays are typically performed on FAP. Purity results show successive clearance of protein impurities through the process.
? Specification
The tests applied for release of the cell slurry are as follows: culture purity and host strain ID.
The release specifications for drug substance (MBAP) include tests for protein concentration, percent purity (SDS-PAGE), percent intact monomer (SDS-PAGE), in vitro relative potency (ELISA), identity, sterility, endotoxin, aluminium and pH. Satisfactory validation of the analytical procedures has been performed in accordance with current ICH guidelines.
The drug substance batch analysis was provided for at least 4 batches of each type produced with the final manufacturing process. The tests parameters applied are the ones retained in the drug substance specification, completed with the analysis of polysorbate 80 for FAP, and completeness of adsorption, freezing point, mouse potency and calculated protein concentration for MBAP.
The proposed IVRP limits are based on the variability of the manufacturing process and the variability of the analytical method, and they represent the lower bounds on IVRP values expected to be observed at release under routine manufacturing and testing conditions.
The reference standard used for the routine IVRP testing is a batch of drug product (quadrivalent final container product: QFCP) stored at 2-8 °C. In addition to this working standard, four FAPs, one per type, have been implemented as primary standards and stored at -60°C.
? Stability
Stability studies were performed on cell slurry (one batch per type) and three full-scale lots of MBAP per type under long-term storage conditions (2-8 °C) and on MBAP under accelerated conditions at 23-27 °C. An additional study was initiated using one lot of MBAP per type manufactured by the full manufacturing process. Results of stability studies performed on cell slurry support the proposed holding time for cell slurry when stored frozen.
For the MBAP, results are provided on three lots per HPV type stored at 2?8 °C. No change in physical appearance, pH, or completeness of adsorption is observed. A certain degree of variability is observed by IVRP, mouse potency and percent intact monomer, but no clear and consistent degradation trend was observed for all types.
All tests in the release specification for drug substance were included in the stability studies, except for protein concentration, percent purity, identity, and aluminium. In addition, the following tests were included: physical appearance, completeness of adsorption, and mouse potency.
Finished Product
The vaccine is a sterile liquid suspension prepared from the Type 6, Type 11, Type 16, and Type 18 Monovalent Bulk Adsorbed Products (MBAPs) combined with a histidine buffer and a suspension of the aluminium-containing adjuvant. It is filled into single-dose vials or syringes with a minimum recoverable volume of 0.5 mL.
? Pharmaceutical Development
Formulation development
The early clinical studies were made with monovalent vaccines, however, the majority of the studies on quadrivalent vaccine (011, 012, 015, 016, 018) were all made with the final formulation described in this application.
The choice of adjuvant was based on preclinical studies showing that vaccine formulations containing this adjuvant induce substantially higher anti-HPV responses than vaccine formulations without adjuvant. The other excipients and their respective concentrations were selected based on stability considerations.
Manufacturing process development
The most significant changes to the manufacturing process were changes to the filling process from a manual to an automated process (Type 6 study, Protocol 004) and introducing the quadrivalent formulation (Quadrivalent study, Protocol 007). Only minor modifications were made upon transfer from the research pilot facilities to full manufacturing scale.
There are no overages. An overfill is provided to ensure that a minimum recoverable volume of 0.5 mL/dose is achieved.
? Manufacture of the Product
The manufacturing process consists of two main steps: formulation and aseptic filling.
The Quadrivalent Bulk Adsorbed Product (QBAP) formulation is prepared from six sterile ingredients: histidine buffer, adjuvant diluent, and the four MBAPs (Types 6, 11, 16, and 18). The
QBAP is then mixed to ensure homogeneity, aseptically sampled to test sterility and aluminium concentration. The portable formulation tank is maintained under positive pressure before it is transferred to the appropriate fill line for subsequent filling.
Aseptic filling and stoppering of QFCP in vials or syringes occurs in a barrier isolator system. Before filling, homogeneity is ensured by mixing the QBAP by agitation and recirculation. The QBAP is aseptically filled into vials or syringes such that each vial or syringe contains a minimum recoverable volume of 0.5 ml. After each vial or syringe is filled, it exits the isolator and is inspected for defects. Quality control samples for in vitro relative potency (IVRP), identity, sterility, pH, endotoxin, aluminium, package identity, and recoverable volume are taken during the fill. After inspection, the vials are placed into trays and stored at 2-8°C until they are labeled and packaged.
Process Controls and validation
For the purpose of process validation, six formulation lots were manufactured to prepare three lots of QFCP in vials and three lots of QFCP in syringes. All validation lots satisfied the validation criteria and met all release tests for both QBAP and QFCP.
Control of Excipients
The vaccine contains the following excipients: amorphous aluminium hydroxyphosphate sulfate adjuvant, sodium chloride, L-histidine, polysorbate 80, sodium borate and water for injection.
The adjuvant amorphous aluminium hydroxyphosphate sulfate is a non-compendial insoluble aluminium based precipitate to which the VLPs are adsorbed. This adjuvant has been used in HPV VLP vaccine clinical lots and in four other licensed vaccines manufactured by Merck & Co., Inc.
All other excipients comply with the Ph.Eur. None of the excipients are of animal origin, and no animal-derived materials are used in the manufacture of any excipient.
? Product Specification
The specifications for drug product include tests for in vitro relative potency (IVRP, same assay as for drug substance), identity, sterility, endotoxin, aluminium, pH, package identity, recoverable volume and syringeability (syringes only).
The acceptance criteria for IVRP at release and end-expiry for the drug product take into account process capability, as well as assay variability and stability data. The results from a clinical substudy of Protocol 016 (designed to place in context these limits with respect to immunogenicity) support the proposed limits, all of which are the lowest dose evaluated in clinical trials.
An upper IVRP specification for individual type is not proposed; a limit has been established for the Total IVRP and is a safety limit derived from the highest dose used in clinical studies (Clinical Protocol 007).
Batch analysis data for both the Quadrivalent Bulk Adsorbed Product (QBAP) and the Quadrivalent Final Container Product (QFCP) in vials and in syringes are provided and analyzed according to the drug product specification.
The reference standard used for routine testing is a quadrivalent final container product (QFCP) lot, which is referred to as the working standard. The same standard is used for both IVRP and completeness of adsorption. The same reference standard is used to test the drug substance lots.
? Stability of the Product
The proposed shelf-life for both container type is considered acceptable. No difference in the product stability profile has been observed among the different final contained images, including both vials and syringes. No change in physical appearance, sterility, endotoxin, pH, or completeness of adsorption is anticipated during the proposed shelf-life.
A photostability study was performed to assess the stability of the drug product to cool, white light and UV radiation.
? Adventitious Agents
Nonviral Adventitious Agents (TSE aspects)
D-galactose, which is used in the fermentation culture medium, is the only raw material identified as being of ruminant origin using in the manufacturing process. D-galactose is obtained from bovine milk sourced from healthy animals in the same manner as milk for human consumption, and no other ruminant material are used in its production. It is thus compliant with the EMEA Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01 rev 2, July 2004). Other materials used in the purification process, and four amino acids, used in the HPV fermentation culture media, are products of microbial fermentation where the fermentation media contained material of animal origin.
Viral Adventitious Agents
There are no live viruses and no cell lines of human or animal origin used in the manufacture of Quadrivalent HPV VLP Vaccine.
2. Non-clinical aspects
Introduction
There is no animal model for human papillomavirus infection, however there are other species-specific papillomaviruses that have been studied in animal models. Cottontail rabbit papillomavirus (CRPV) induce tumours, which are cutaneous rather than mucosal. Canine oral papillomavirus (COPV) infects and induces lesions at a mucosal site (oral mucosa). These studies with species-specific papillomaviruses have demonstrated the possibility to vaccinate against infection and development of tumour lesions using virus-like particles formed by recombinant viral capsid proteins (Breitburd et al 1995, Jansen et al 1995, Suzich et al 1995) and have been used as models for vaccine development. African green monkeys were immunised with HPV-11 VLPs. Sera from immunised monkeys neutralised HPV-11 in an ex vivo model for HPV infection (human foreskin tissue was infected with HPV and then implanted into athymic mice). Significant levels of HPV-11-neutralising antibodies were observed in cervicovaginal secretions (Lowe et al 1997).
GLP
Pharmacology studies were not performed under GLP conditions. All 5 toxicology studies were carried out under GLP conditions.
Pharmacology
? Primary pharmacodynamics
A series of studies which were performed to determine the immunogenicity of the monovalent HPV 6, 11, 16 and 18 L1 VLP vaccines and/or the quadrivalent HPV 6, 11, 16 and 18 L1 VLP vaccine (Gardasil) in non-human primates were submitted. The monovalent L1 VLP and quadrivalent Gardasil vaccine formulations tested in these studies were made by the same manufacturing process as the GMP lots and are, therefore, similar to lots that were used in the clinic. Monovalent HPV VLP vaccines or Gardasil were administered by intramuscular injection on 3 or 4 occasions during the course of 52 weeks followed by an immunogenicity assessment of antibody titres raised against the relevant HPV types. Studies were conducted in rhesus macaques, chimpanzees,and African Green monkeys.
In each of the 3 non-human primate species tested, the intramuscular administration of Gardasil, or it’s monovalent components, was found to elicit immune responses resulting in production of antibodies against the HPV VLP types present in the vaccine. These studies showed that Merck’s aluminium adjuvant is necessary to induce an increased immune response against the vaccine antigens. Serum
antibodies to all 4 HPV types were shown to neutralize pseudovirus infection of a cervical carcinoma cell line (C33A) indicating the potential of HPV VLP vaccines to protect against HPV infection. High titres of total IgG are induced in addition to noteworthy IgA levels and measurable IgM, IgG1, and IgG4. The isotype of the antibodies were indicative of a TH2 response.
? Safety pharmacology programme
Safety pharmacology studies were not performed. However in the toxicological studies safety daily monitoring for physical signs did not reveal any notable respiratory problems. This approach is in accordance with Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95).
? Pharmacodynamic drug interactions
Such studies are not required according Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95).
Pharmacokinetics
Experimental studies to demonstrate absorption, distribution, metabolism, and excretion of the active ingredients in Gardasil have not been performed for any of the component viruses. This is in line with Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95).
The Merck Aluminium Adjuvant (aluminium hydroxyphosphate sulphate adjuvant) is used in other vaccines, which are approved in Europe, and it is agreed that no further studies on the adjuvant are required according Guideline on adjuvants in vaccines for human use (CHMP/VEG/134716/2004). Toxicology
? Single dose toxicity
Single-dose toxicity of Gardasil was assessed in 2 GLP studies in mice and rats. The dose administered intramuscular represents approximately 1200-fold excess in mice and 300-fold excess in rats of the human dose. The vaccine was well tolerated and there were no treatment-related effects on mortality, physical signs, or body weight over a 14-day observation period.
? Repeat dose toxicity (with toxicokinetics)
A 10-week repeat-dose toxicity study was performed in BALB/c mice. Vaccine-treated mice received
1 or 3 doses of Gardasil at a concentration of 160/160/80/160 μg/ml of the HPV types 6/11/16/18 L1 VLPs. Control mice received 1 or 3 doses of Merck’s aluminium adjuvant placebo control. For each dose, approximately 50 μl of the vaccine or placebo control was administered. On a body weight basis, the dose of the vaccine administered to mice was approximately 1450-fold the projected human dose. All animals were dosed with either vaccine or placebo on Day 1. Necropsy was performed at day 8, 29, 57 and 60.
There were no treatment-related changes in physical signs, body weight gain, food consumption, haematology, or serum biochemistry. There was a treatment-related enlargement of the iliac lymph nodes. Treatment-related microscopic changes were noted in lymph nodes (hyperplasia) and in the muscle at the injection sites (inflammation). Despite the slightly increased severity of the cellular infiltration in the muscle in some vaccine-injected animals, the overall damage at the injection sites was not more severe in these animals as compared to controls.
? Genotoxicity
No genotoxicity studies were conducted, and this is in line with CPMP/SWP/465/95.
? Carcinogenicity
No carcinogenicity studies were conducted, and this is in line with CPMP/SWP/465/95.
? Reproduction Toxicity
The reproductive and developmental toxicity was assessed in a study in female Sprague-Dawley rats addressing all phases of reproduction and foetal development.
An immune response to the vaccine was observed, and antibodies were shown to be transferred to the offspring during gestation and also lactation. There were no adverse findings in the study.
? Local tolerance
Local tolerance was assessed by intramuscular administration of the vaccine in rabbits. Intramuscular administration of Gardasil caused minimal irritation at injection site and the changes observed were similar in severity to those produced by the injection of the Merck aluminium adjuvant as placebo control.
? Other toxicity studies
Two non-GLP exploratory immunogenicity studies were performed in rats. The purpose of these studies was to confirm that Gardasil induced an immune response in the animal model used for reproductive and developmental toxicology testing.
There were no deaths or treatment-related physical signs during the study. All animals mounted specific antibody responses to all 4 HPV VLPs. The immune response was consistent with a typical prime-boost effect. The highest HPV type-specific antibody titres were observed with a regimen which included 3 initial administrations of the vaccine, 3 weeks apart, followed by a fourth administration 10 weeks after the third dose.
A second exploratory immunogenicity study was carried out in order to confirm the immune response in rats. In both exploratory studies, it was demonstrated that the vaccine was immunogenic in rats and that an anti-HPV antibody response was seen for each HPV type present in the vaccine. These results show that the rat is an appropriate animal model for investigating the potential toxic effects related to administration of Gardasil.
Ecotoxicity/environmental risk assessment
It is anticipated that the environmental impact of the Gardasil vaccine would be minimal to none for the following reasons:
The vaccine is comprised of Virus-like Particles (VLPs) and therefore does not contain any live or attenuated virus. The VLPs are simply protein sub-units found in the virus capsid.
The VLP vaccine is not capable of replicating. Therefore, there is no risk of transmission from an immunised host to a susceptible host.
The VLP vaccine is specific for humans and will not impact the organisms of a sewage treatment plant or the effluent receiving stream.
The environmental risk assessment has shown that there is no environmental risk associated with the use of Gardasil.
4. Clinical aspects
Introduction
The clinical development programme to support licensure of the quadrivalent HPV vaccine consisted of 12 clinical studies. Approximately 21,514 subjects (11,813 HPV vaccine/9,701 placebo) were included and vaccinated.
Initial phase I/IIa studies evaluated the immunogenicity and safety of monovalent vaccine precursors in 3,160 study subjects. Monovalent HPV 11 LI VPL vaccine was evaluated in one study (Protocol
001), HPV 16 L1 VPL vaccine in four studies (Protocols 002, 004, 005 and 012) and HPV 18 L1 VPL vaccine in one study (Protocol 006). Anti-HPV responses were followed up for 1.5 to 3.5 years.
The quadrivalent HPV vaccine programme was divided into 2 sets of studies based on the age range of enrolled subjects: 1) efficacy studies were performed in female subjects 16 to 26 years of age and 2) studies to bridge efficacy, immunogenicity and safety in 16- to 23-year old female subjects to younger age cohorts. Seven phase II/III studies evaluated the quadrivalent HPV L1 VLP vaccine (Protocols 007, 011, 012, 013, 015, 016 and 018). Protocols 011 and 012 were sub-studies of Protocol 013.
Immunogenicity of the quadrivalent HPV vaccine was evaluated in Protocols 007 (dose selection study), 011 (concomitant hepatitis B vaccine), 012 (monovalent HPV 16 bridging), 015V1 (consistency lots), 016V1 (adolescent bridging), 016V2 (end-expiry dose) and 018 (preadolescent /adolescent) and involved a total of 12,345 subjects.
Efficacy was assessed in 4 randomised placebo-controlled clinical studies including a total number of 20,541 subjects. There were two phase II studies, 005 (n=2,391) that evaluated the HPV 16 component and 007 (n=551) that evaluated the quadrivalent HPV (types 6, 11, 16,
18) LI VPL vaccine. The two pivotal phase III studies, termed FUTURE (Female United To
Unilaterally Reduce Endo/Ectocervical Disease) I (Protocol 013; n=5,442) and FUTURE II (Protocol 015; n=12,157) evaluated the quadrivalent HPV vaccine in the prevention of HPV 6/11/16/18-related CIN/external genital lesions (EGLs) and HPV 16- or HPV 18-related CIN 2/3 or AIS (Cervical Adenocarcinoma In situ), respectively. The efficacy trials recruited 16- to 26-year-old adolescent and young adult women, who were mostly HPV na?ve, but were at risk for HPV infection. The Phase II and Phase III studies did not have screening phases; women were enrolled regardless of their baseline HPV status and Pap test (Papanicolau’s test) result.
Safety of the different HPV vaccine formulations has been evaluated in a total of 16,041 subjects. Of these 11,813 received quadrivalent HPV vaccine and the remaining monovalent vaccine formulations. All studies were placebo controlled and the total population that received placebo included 9,701 subjects(the placebo was aluminium adjuvant in all studies except study 018 (pre-/adolescent safety study) which used a non-aluminium-containing placebo).
GCP
The Clinical trials were performed in accordance with GCP as claimed by the applicant.
The applicant has provided a statement to the effect that clinical trials conducted outside the community were carried out in accordance with the ethical standards of Directive 2001/20/EC.
Pharmacokinetics
Pharmacokinetic studies were not performed in accordance with the Note for guidance on clinical evaluation of new vaccines (CPMP/EWP/463/97).
Pharmacodynamics
The pharmacodynamics of the vaccine relate to its interaction with the immune system. Therefore, this section will discuss the data on the systemic immune response to vaccination.
Initial phase I/IIa studies evaluated the immunogenicity of monovalent HPV vaccine precursors. Overview phase I and phase II immunogenicity studies (monovalent HPV vaccines)
Study Protocol No. of study
centres/
locations/dat
e Study vaccine
No/study arm
No subjects and
age group
Primary Endpoint Durati
on
follow
-up
P001
Phase I
Dose escalating study US (n=2 sites)
1997-2002
HPV 11 VPL vaccine
(10/20/50/100 mcg)/ Placebo
N=112 / 28
3 doses 0, 2, 6 months + subset
N=140
18- to 25- year old
women (HPV 11/6-
na?ve)
- Percentage of subjects achieving
anti-HPV 11 serum RIA* levels
>200mMU/ml** and neutralizing
antibody (xenograft anti-HPV 11
NT-assay) at month 7
3 years
dose 4 at month 12 - Safety and tolerability
P002
Phase I
Dose escalating study US (n=1 site)
1998-2001
HPV 16 VLP vaccine
(10/40/80mcg) /Placebo
N=82 / 27
3 doses 0, 2, 6 months
N=109
18- to 25- year old
women (HPV-na?ve)
- Percentage of subjects achieving
anti-HPV 16 serum RIA levels
>20mMU/ml at month 7
-Persistence of anti-HPV 11
- Safety and tolerability
3 years
P006
Phase I
US (n=3 sites)
2000-2001 HPV 18 VPL vaccine (80mcg) /
Placebo
N=27 /13
3 doses 0, 2, 6 months
N=40
16- to 23- year old
women
- Percentage of subjects achieving
anti-HPV 18 serum RIA levels
>200mMU/ml at month 7
- Safety and tolerability
7
months
P004
Phase IIa Dose escalating study US (n=15 sites)
1998-2001
HPV 16 VLP vaccine
(10/20/40/80mcg)/
Placebo
N=428 /52
3 doses 0,2,6 months
N=480
18- to 25- year old
women
- Percentage of subjects achieving
anti-HPV 16 serum cRIA levels
>20mMU/ml and neutralizing
antibody at month 7
- Safety and tolerability
2 years
P005
Phase IIb
US (n=16 sites)
1998-2004 HPV 16 VLP vaccine (40mcg)
/Placebo
N=1204 / 1205
3 doses 0,2,6 months
N=2409
16- to 23- year old
women
Primary: Efficacy: Prevention of
persistent HPV16 infection cf
placebo- Safety and tolerability
-Immunogenicity: Anti-HPV 16
levels (RIA) and correlate of
protection. -Long-term persistence
of anti- HPV 16 antibodies
3.5
years
* RIA: Radioimmunoassay
** mMU/ml: milli Merck Units per milliliter
Immunogenicity of the quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine was evaluated in a Phase II dose selection (study Protocol 007, see below), and six phase III studies 011, 012, 013, 015, 016 and 018, a total of 12,344 subjects 9 to 26 years of age were enrolled. The studies were conducted in 33 countries and 5 continents with 3,453 subjects recruited from Europe. All studies were randomised, double-blind, and placebo-controlled (except P016).
Overview of phase II/III immunogenicity studies (quadrivalent HPV vaccine)
Study Protocol No. of study
centres /
locations/dat
e Study vaccine
No/study arm
No subjects and
age group
Primary Endpoint Duration
P007 Phase IIb
Part A: Dose- escalation
Part B: Dose-ranging US, Brazil,
Scandinavia
(n=23 sites)
2000-2004
Quadrivalent HPV (Types
6,11, 16,18) L1 VLP vaccine
(20/40/40/20mcg
40/40/40/40mcg
80/80/40/80mcg) /Placebo
Part A n=52
Part B n=1106
N=1158
16- to 23- year old
females
Part A: General
tolerability
Part B: Identify a
formulation with
acceptable type specific
anti-HPV responses
(cRIA) for phase 3
Investigate anti cLIA
levels:
- Ab kinetics/
seroconversion
- General tolerability
Secondary: Efficacy
endpoints.
HPV 6/11/16/18–related
persistent infection,
EGL, CIN, AIS and or
cervical cancer
Mean:
2.4 yrs
Median 3.0
yrs
P011
Phase III Substudy to
P013 Concomitant Hep B vaccine US, Europe,
Peru, Brazil
(n=21)
2001-2004
Quadrivalent HPV (Types
6,11, 16, 18) L1VLP vaccine
(20/40/ 40/20mcg) /
Hepatitis B vaccine/ Placebo
3 doses 0, 2, 6 months
N=1877
16- to 23- year old
females
-Evaluation of
concomitant
administration of HPV
vaccine and hepatitis B
vaccine regarding
immune interferences as
measured by GMTs
*(HPV) and serocon-
version rates at Week 4
postdose 3
-Safety and tolerability
of co-administration
7 months
(FU within
P013)
P012
Phase III Substudy to
P013 Bridging study to P005 US, Canada,
Europe, Latin
Am,
Australia,
New Zealand,
Asia, Russia,
(n=48 sites)
2002-2004
Quadrivalent HPV (Types
6,11, 16, 18) L1 VLP
vaccine (20/40/ 40/20mcg) /
HPV16 L1 VLP vaccine/
Placebo
N=1784/ 304/ 1794
N=3882
16- to 23- year old
females
-Non-inferiority of the
monovalent HPV 16 L1
vaccine to quadrivalent
HPV vaccine with
respect to anti-HPV 16
response (GMTs) at 4
weeks post-dose 3
7 months
(FU within
P013)
P013 Phase III efficacy study Quadrivalent HPV (Types
6,11, 16, 18 ) L1 VLP
(20/40/40/20 mcg) / placebo
N=2732 / 2717
N=5455
16- to 23-year old
females
Persistence of immune
response
1.5 years
(FU 48
months)
P015 Phase III Substudy: Lot-to-lot consistency North
America,
Europe, Latin
Am,
Singapore
(n=80 sites)
-Feb to May
2003
Quadrivalent HPV (Types
6,11, 16,18) L1 VLP vaccine
(20/40/ 40/20mcg)
3 vaccine lots
N=500 / 510 / 504
N=1514
16- to 23- year old
females
Substudy: -
Demonstration that 3
vaccine lots induce a
consistent anti-HPV
6,11,16,18 response 4
weeks post-dose 3
- Long-term persistence
of antibody response
1.5 years
(FU 48
months)
P016
Phase III Substudies: A) Adolescent Bridging study
B) End Expiry US, Canada,
Europe, Latin
America, Asia
(n=61 sites)
2002-2004
A) Quadrivalent HPV (Types
6,11, 16,18) L1 VLP vaccine
(20/40/ 40/20mcg)
B) 20%/ 40%/ 60%/ 100%
formulations
N=503/ 513/ 508/ 1017
Total: 3,055
A) N=1525
10-15 -year old
males (n=508)
10-15 -year old
females (n=506)
16-23-year old
females (n=511)
B) N=2545
10-15 -year old
females
16-23-year old
females
A) Adolescent substudy:-
Non-inferiority of the
younger age group cf
16-23 year- old females
with respect to GMTs at
Week 4 post-dose 3
- Safety and tolerability
B) Expiry dose substudy:
-Identify the minimum
partial dose formulation
that is similar to full
dose (GMTs at Week 4
postdose 3)
7 months
P018 Phase III Europe, North
America,
Latin
America, Asia
(n=47 sites)
2003-2005
Quadrivalent HPV (Types
6,11, 16,18) L1 VLP vaccine
(20/40/ 40/20mcg)/
Placebo (non-Alum)
1184 / 597
N=1781
9-15 year-old
females (n=939)
9-15 year-old
males (n=842)
Primary: Safety and
tolerability
-Non-inferiority of boys
to girls with respect to
GMTs at Week 4 post-
dose 3.
-Persistence of anti-
HPV response
7 month
(18 months)
*GMTs: Geometric Mean Titres
The immunogenicity of the HPV vaccines was measured using three methods:
? A competitive radio-immunoassay (cRIA)
? A competitive Luminex-based immunoassay (cLIA) and
? A xenograft based HPV 11 neutralization (NT) assay.
During the development programme, the early cRIA assay was transitioned to cLIA assay, which was subsequently used during the phase III trials. The immune response to each vaccine HPV type was measured separately.
Primary study population was the per-protocol immunogenicity (PPI) population defined as:
? Subjects who were seronegative and PCR negative to the relevant HPV type(s) at Day 1, remained HPV PCR negative through 1 month post dose 3 (month 7), received all 3
vaccinations within pre-specified time intervals, and no deviation from the study protocol.
The following immunogenicity objectives were focused on:
? To evaluate vaccine-induced serum anti-HPV responses during the vaccination regimen, 4 weeks following the completion of a the 3-dose regimen as well as persistence of antibody
response for up to 3.5 years
? To define impact of base-line covariates (e.g. age, gender, ethnicity) and deviations from vaccination regimen at 4 weeks post-dose 3
? To bridge the efficacy data obtained in female subjects aged 16 to 26 years of age at enrolment to subjects 10 to 15 years of age at enrolment by demonstrating that the post dose 3 anti-HPV
responses in the younger age group are non-inferior to those observed in the older group
? For HPV 11 to demonstrate that immune responses are virus neutralizing
? To establish that vaccine-induced responses are comparable or superior to immune responses to natural infection
? To establish that the HPV vaccine can generate memory responses in subjects seropositive for one or more HPV types at baseline
? To investigate potential immune correlates of vaccine efficacy
? The phase III trials also compared immune responses between treatment groups to address questions of concomitant administration of recombinant hepatitis B vaccine (P011), consistency of manufacturing process (P015) and evaluation of partial-dose formulations (P016)
Primary immunological endpoints were:
? Geometric mean titres (GMTs) of anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18, 4 weeks after the third dose (Month 7)
? Proportion of subjects who seroconverted to each of the four antigens 4 weeks after the third dose.
Since the minimum anti-HPV levels associated with protection from acquisition of HPV is not known, the cut-off value of validated assays was used as a surrogate for seropositive level. The cLIA cutoffs for seropositivity were as follows: >20 mMU/ml for HPV 6 and 16, >16 mMU/ml for HPV 11 and >24 mMU/ml for HPV 18.
? Monovalent HPV vaccines (n=3,160 subjects)
Initial phase I/IIa studies evaluated the immunogenicity of monovalent vaccine precursors in 3,160 16- to 26-year-old female subjects (1,842 vaccine/1,318 placebo). All studies were randomised, double blind and placebo-controlled and all vaccine candidates were given in a 3-dose schedule (0, 2, 6 months). Monovalent HPV 11 LI VPL vaccine was evaluated in one study (P001).
The HPV 11 L1 VLP vaccine was chosen as the first vaccine for evaluation in humans, since it was possible to use the nude mouse xenograft model for HPV 11 infection to determine if the vaccine could induce neutralizing antibodies. A correlation was demonstrated between functional (neutralizing) antibodies and cRIA/cLIA antibodies. The vaccine proved immunogenic with 90-100% of subjects reaching the pre-specified cRIA level of >200 mMU/ml 4 weeks postdose 3. Anti-HPV levels were shown to decline after Month 7, but were still detectable at Month 36 at levels above those induced by natural infection. A fourth dose at Month 12 was shown to induce higher anti-HPV levels than postdose 3, but the differences dissipated after one year and therefore it was decided to use the 3-dose regimen in subsequent trials. Anti-HPV levels in cervicovaginal mucosa was measured in lavage, but proved difficult to standardise due to intrinsic problems encountered in accurate sampling of the mucosal surface. Therefore, it was determined not to include this assay in subsequent studies.
The other phase I/IIa studies (P002, P004 and P006) confirmed the immunogenicity results obtained in P001. It is to be noted that the pre-specified cRIA cut-off levels varied by study. The kinetics of vaccine-induced anti-HPV responses were evaluated, demonstrating a priming effect of 2 doses with peak titres achieved at Month 7, after which titres declined rapidly by around 1 log to reach a plateau at Month 24, which remained stable to Month 36. Based on dose-ranging data from P002 and P004, the 40mcg-dose for the HPV 16 vaccine was selected for the first efficacy trial (P005).
Mode of action
A substudy in an early monovalent HPV 11 L1 VLP vaccine clinical trial was conducted to measure HPV 11 L1-VLP vaccine priming of humoral and cellular immune responses in seronegative, HPV DNA-negative, college-age women. The results of this study were consistent with those observed in the non-human primate study; Th1 or Th2 cytokines (IFN-γ or IL-5) were detected in response to HPV 11 L1 VLP in vitro re-stimulation for all vaccine recipients and none of the placebo recipients tested. The predominant T-cell population with detectable IFN-γ and IL-5 production was the T-cell subpopulation depleted of CD8+ T-cells. The overall HPV-specific T-cell activity was observed as a discrete proliferative response consistent with homeostasis in memory T-cell responses. In addition the
immunoglobulin isotype and subclass profiles elicited by vaccination demonstrated the generation of both Th1 and Th2 responses (IgG1 and IgG2).
In a separate sub study several cohorts, including a cohort of 10- to 15-year-old virgin females who participated in one of the quadrivalent HPV vaccine trials were evaluated for Th1 T-cell immunity. The results demonstrated no response prior to vaccination, however post-vaccination strong HPV 16 L1 peptide-specific T-cell responses were observed in all subjects. Vaccination of young females with the quadrivalent HPV L1 VLP vaccine resulted in induction of a strong L1 peptide-specific IFNγ-associated T-cell response and a concomitant B-cell response producing L1 VLP-specific antibodies.
? Quadrivalent HPV vaccines (n=12,344 subjects)
Study 012
This substudy to study P013, aimed at bridging anti-HPV 16 responses between the monovalent HPV 16 vaccine used in the first efficacy trial 005 (Pilot Manufacturing Material, PMM) and the quadrivalent HPV vaccine (Final Manufacturing Process, FMP) used in the pivotal efficacy trials. Non-inferiority of the anti-HPV 16 GMTs and seroconversion responses at Month 7 in the FMP quadrivalent HPV vaccine group relative to the PMM HPV 16 vaccine was demonstrated. This allowed including the P005 trial in the pooling of efficacy data from all efficacy trials.
Study 015V1
Study P015V1, a substudy to study 015, was a lot consistency study. The primary objective was to demonstrate that 3 separate lots of the quadrivalent vaccine induced similar GMTs to HPV types 6, 11, 16 and 18 at Week 4 postdose 3. Based on the non-inferiority criteria defined, consistency of the anti-HPV responses in the 3 vaccine lot groups was demonstrated.
Study 016
This study consisted of two immunogenicity studies, the adolescent substudy and the end-expiry substudy that partly used the same study participants.
The adolescent study 016V1 was designed to bridge the efficacy findings in the older age groups to virginal aged 15 years and younger by demonstrating that 10- to 15-year-old subjects had immune responses to a 3-dose regimen that were non-inferior to those observed in the 16- to 23-year olds. In the absence of an immune correlate of efficacy, immune responses in the demographic groups were compared using GMTs and the proportion of subjects who were na?ve to HPV vaccine types and who became seropositive to the relevant HPV types at Month 7.
Summary of vaccine immune response by demographic group
Quadrivalent HPV vaccine
10- to 15 year-old females
N=506 10- to 15-year-old males
N=506
16- to 23-year-old females
N=506
Assay Time
point n GMT Sero.conv n GMT Sero.conv n GMT Sero.conv
Anti-HPV 6 Day 1
Month 3
Month 7
426
417
426
<8
635.2
989.9
100
100
431
430
431
<8
673.5
1118.6
100
100
320
315
320
<8
437.7
603.0
100
100
Anti-HPV 11 Day 1
Month 3
Month 7
426
418
426
<8
781.1
1270.6
100
100
431
430
431
<8
794.7
1399.6
100
100
320
315
320
<8
549.7
739.2
100
100
Anti-HPV 16 Day 1
Month 3
Month 7
427
419
427
<12
2842.3
4873.0
99.8
100
431
429
430
<12
2993.1
5962.1
100
100
306
302
306
<12
1.705.6
2,753.0
100
100
Anti-HPV 18 Day 1
Month 3
Month 7
429
421
429
<8
369.1
957.7
98.8
100
432
431
432
<8
413.1
1241.6
98.6
99.8
340
334
340
<8
216.6
470.5
97.6
99.1
For each of the 4 HPV types the vaccine induced numerically higher GMTs 4 weeks postdose 2 and 3 in adolescents than in adult females. Postdose 2 anti-HPV 6/11/16/18 levels among adolescents were comparable to those observed postdose 3 among 16- to 23-old females. Numerically higher GMTs were also observed in the male adolescent group compared with the female adolescent group consistently across the HPV vaccine types. The results of the statistical analyses demonstrated that the quadrivalent HPV vaccine induced non-inferior immune responses in the 10- to 15-year-old females and 10- to 15-year-old males compared with 16- to 23-year-old females.
The primary objective of the end-expiry study 016V2 was to identify the minimum partial-dose formulation of quadrivalent HPV vaccine among the 20, 40, 60% partial-dose formulations, given in a 3-dose regimen, that induced immune responses non-inferior to administration of 100% full-dose formulation. The key assumption in this study was that testing partial doses of the vaccine could approximate the impact of manufacturing process loss in addition to vaccine potency loss over time on the immunogenicity of the vaccine. The primary immunogenicity hypothesis compared GMTs within 3 pairs of vaccination groups 20% formulation vs. 100% formulation, 40% vs. 100% and 60% vs. 100%. The criteria for declaring success required success on at least 1 of the 3 comparisons. A nested testing procedure was performed in 3 stages using an alpha level of 0.025 (1-sided) at each stage. In the first stage the 20% partial-dose formulation of the HPV vaccine was compared with the full-dose formulation. Since this comparison fulfilled the criteria for non-inferiority, testing stopped at this stage and all partial-dose formulations were declared non-inferior to the 100% formulation. All lower confidence bounds exceeded 0.5 and correspondingly, all p-values were <0.025.
Study 018
This study was conducted to further define the safety and immunogenicity of the quadrivalent HPV vaccine in 9- to 15-year-old subjects. Study P018 also provided a comparison to non-aluminium-containing placebo. Enrolment was stratified by gender and age (1:1 male/female; 2:1 9-12 year-old/13-15 year-old). The study population contained almost 700 subjects aged 9 to 12 years.
Primary objective was to assess safety, but the study also included secondary immunogenicity objectives to demonstrate that the 4-week postdose 3 anti-HPV 6/11/16/18 immune responses (GMTs and percentage of subjects who seroconvert) in pre-/adolescent boys were non-inferior to the responses observed in pre-/adolescent girls All subjects demonstrated a strong antibody response to the HPV vaccine. GMTs at Month 7 were higher among boys than girls. The Month 7 GMTs for all vaccine types were higher among 9- to 12-year-old subjects than among 13- to 15-year-old subjects. The statistical criteria for non-inferiority with respect to both GMTs and seroconversion rates were met.
Dose response study
Study 007
Study 007 was designed as a dose-ranging study evaluating immunogenicity (cRIA) of 3 vaccine formulations. The dose ranging concerned HPV 6 and HPV 18, whereas HPV 11 was tested only at a higher dose (80mcg) in one formulation. The dose of HPV 16 (40mcg) was fixed, based on results from previous phase I/II trials. The primary objective of P007 was to select a dose for the phase III trials, which was performed in a pre-planned interim analysis after 50% of the subjects had received Dose 3. Antibody kinetics was also evaluated and demonstrated a priming effect of the first 2 doses. All 3 doses were demonstrated to induce high anti-HPV levels without any clear dose response pattern, which favoured the lowest dose 20/40/40/20mcg. Moreover, a modest increase in injection-adverse events was observed with the higher dose formulations.
Preliminary data on an extension of study P007 up to 5 years were provided. Subjects in the quadrivalent HPV vaccine 20/40/40/20-mcg dose formulation group and placebo subjects who were enrolled in Europe and Brazil (n=241) were followed through Month 60. The plateau of anti-HPV GMTs reached at Month 24 was shown to remain stable through the follow-up period up to Month 60. Administration of a pre-planned fourth dose (booster dose) at Month 60 was evaluated in 78-87 subjects. A strong anamnestic response was observed for all 4 HPV types included in the vaccine, suggesting that the quadrivalent HPV vaccine induces an immune memory. The booster dose appeared well tolerated.
Co-administration
Study 011
This substudy of study 013 was designed to evaluate the immunogenicity and safety of the HPV vaccine when administered alone or concomitantly with the recombinant hepatitis B vaccine. The primary objective was to demonstrate that concomitant administration of the two vaccines did not interfere with the immune response to either vaccine. Non-inferiority of the anti-HPV responses (GMTs and seroconversion rates) after the third dose in the concomitant group relative to the HPV vaccine only group was demonstrated. Also with regard to the anti-HBV seroprotection rates in the concomitant group relative to hepatitis B vaccine alone, non-inferiority criteria were met. However, with respect to the anti-HBs GMTs, lower titres were observed in the concomitant group (535 vs 792 mIU/ml). Thus, the HPV vaccine appears to have a negative impact on the hepatitis B GMTs, although the clinical significance of these lower titres is not known. Overall, the anti-HBs responses seemed lower than would be expected in this group of young healthy females, which might be associated with the low immunogenicity of the hepatitis B component. Additional analyses of the data were provided, which did not add further concern.
A statement, regarding the reduced anti-HBs titres following the concomitant vaccination with Gardasil is included in the SPC section 4.5. The applicant was strongly recommended to perform a non-inferiority study with the new upgraded hepatitis
B vaccine and also include an additional arm with the other recombinant hepatitis B vaccine available on the EU market.
Clinical efficacy
Efficacy was assessed in 4 randomised double-blind placebo-controlled phase II and phase III clinical studies:
Study Protocol No. of study
centres /
locations/dates Study vaccine
No/study arm
No subjects
and age
group
Primary Endpoint Duration
Post-7
mo FU
P005
Phase IIb
USA (n=16 sites)
Oct 1998 - Sep
2001 HPV 16 L1 VLP
vaccine (40mcg)/
Placebo
(1193 / 1198)
N=2,409
16- to 23-
year-old
women
Mean 21.5
yrs
1. Safety and tolerability of
vaccine, 3 doses
2. Efficacy in prevention of
persistent HPV 16 infection cf
placebo
Mean:
3.1 years
Median:
4.0 years
P007 Phase IIb Dose-ranging study USA, Europe
Latin America
(n=23 sites)
May 2000 - May
2004
Quadrivalent HPV
VLP vaccine
(20/40/40/20mcg
40/40/40/40mcg
80/80/40/80mcg)
or Placebo
Part A n=52
Part B n=1106
N=1,158
16- to 23-
year-old
women
Mean 20.0
yrs
1. Identify formulations with
acceptable type specific anti-
HPV responses
2. Efficacy in prevention of
persistent HPV 6,11, 16, 18
infection and clinical disease cf
placebo
3. General tolerability
Mean:
2.4 years
Median
3.0 years
P013 Phase III FUTURE I North Am, Latin
America, Europe,
Asia-Pacific
(n=62 sites)
Dec 2001 - July
2005
Quadrivalent HPV
VLP vaccine
20/40/40/20mcg
/ Placebo
(2717 / 2725)
N=5,455
16- to 23-
year-old
women
Mean
20.3yrs
Co-primary endpoint:
i) External genital lesion:
efficacy in reducing HPV
6,11,16,18-related genital warts,
VIN, VaIN, vulvar or vaginal
cancer cf placebo
ii) Cervical endpoint: efficacy in
reducing the incidence of HPV
6,11, 16,18-related CIN (any
grade), AIS or cervical cancer cf
placebo
- Safety and tolerability
Mean:
1.7 years
Median:
2.4 years
P015 Phase III FUTURE II North Am, Latin
America, Europe,
Asia-Pacific
(n=90 sites)
June 2002 - June
2005
Quadrivalent HPV
VLP vaccine
20/40/40/20mcg
/ Placebo
(6082 / 6075)
N=12,167
16- to 23
(26) - year-
old women
Mean 19.9
yrs
Primary Cervical endpoint:
Efficacy in reducing the
incidence of HPV 6,11,16,18-
related CIN 2/3, AIS or invasive
cervical cancer in HPV na?ve
subjects
- Safety and tolerability
Mean :
1,4 years
Median:
2.0 years
(Sentinel
planned
10 years
follow-
up)
A total of 20,887 subjects were enrolled in studies 005, 007, 013, and 015. This includes 304 subjects who received monovalent HPV 16 L1 VLP vaccine in study 012, a sub-study of study 013. The subjects were enrolled from 5 continents and 22 countries, with Europe well represented.
Study 005 was the proof-of-concept study, evaluating efficacy of a monovalent HPV 16 L1 VLP 40 mcg vaccine in preventing persistent HPV 16 infection.
Study 007 was the dose-ranging study of the quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine, and involved 551 female subjects evaluated for efficacy of the phase III formulation (20/40/40/20 mcg) in preventing persistent HPV 6/11/16/18-related persistent infection or disease.
Studies 013 and 015 are the pivotal studies of the efficacy of the quadrivalent vaccine against vaccine HPV-related EGL and CIN and enrolled 5,746 and 12,157 female subjects, respectively. All studies were double-blind, randomised and placebo-controlled. The study subjects were healthy 16- to 23 (26)-year-old women.
M ETHODS
Study Participants
The study subjects were healthy 16- to 23 (26)-year-old women. The studies did not include a screening phase. Thus, both na?ve individuals and individuals who had been exposed to HPV prior to enrolment were included. All subjects had at inclusion:
Serum anti-HPV testing
Pap test
Cervicovaginal sampling for HPV typing
Colposcopy if Pap test showed some abnormalities
Irrespectively of results of these examinations, subjects were randomised to either HPV vaccine or placebo. Five populations were considered for HPV-specific efficacy analysis:
Per-protocol efficacy (all studies):
Received all 3 doses of study vaccine
Were seronegative to relevant vaccine HPV type(s) at Day 1
Were PCR negative to relevant vaccine HPV type(s) Day 1 to Month 7
Did not have general protocol violations
Cases counted starting 30 days postdose 3 (Month 7).
Since subjects were not pre-screened for HPV and were included regardless of HPV status and Pap test at baseline, only 64% to 84% (depending on HPV type) of all study subjects were included in the primary per-protocol efficacy (PPE) cohort.
The Per-Protocol Efficacy (PPE) population was used as the primary efficacy population.
MITT-populations (modified Intend to Treat Populations):
MITT-1 population included protocol violators, but was otherwise similar to the PPE
MITT-2 included HPV-vaccine-type na?ve subjects who received at least 1 dose
MITT-4 included HPV-vaccine-type na?ve subjects who received at least 2 doses (only P013) MITT-3 population (all studies)
Received at least 1 injection
Pap test: normal or abnormal at Day 1
Regardless of HPV serology /PCR status at Day 1
The MITT-3 population represents the general (female) population in this age group.
For the analyses that were not HPV-vaccine-type specific (population benefit analyses) the following populations were defined:
Restricted MITT-2 population (P013, P015)
Received at least 1 injection
Were seronegative to all 4 vaccine HPV types at Day 1
Were PCR negative to all 4 vaccine HPV types at Day 1
Pap test: normal at Day 1 (used as a surrogate for non-vaccine HPV types)
This population represents virginal HPV-na?ve adolescents.
Restricted MITT-3 population (P013, P015, combined analysis)
Received at least 1 injection
Pap test: normal at Day 1
Regardless of HPV serology/PCR status at Day 1
For potential therapeutic benefit of the vaccine (P013, P015) the following subpopulations were evaluated:
Subjects who were seronegative and PCR positive at Day 1 to the relevant vaccine HPV type Subjects who were seropositive and PCR negative at Day 1 to the relevant vaccine HPV type Subjects who were seropositive and PCR positive at Day 1 to the relevant vaccine HPV type
Treatments
All subjects received either quadrivalent HPV VLP vaccines (HPV LI VLP vaccine 40 mcg in study 005) or placebo at day 0, month 2 and month 6.
All subjects underwent Pap testing and cervicovaginal sampling for HPV testing every 6 months (studies 005, 007, and 013) or every 12 months (study 015). Referral to colposcopy was based on Pap
test diagnosis. All colposcopies were to be performed at study site by an experienced colposcopist. Referral to definitive therapy during the trial (surgical ablation and histological assessment) was based on Pap test (repeated CIN 1, high-grade squamous intraepithelial lesions (HSIL)) +/-abnormal colposcopy.
Objectives
The study objectives of the clinical program for the HPV vaccine were to demonstrate that administration of the HPV vaccine would reduce the incidence of:
? HPV 16/18-related high-grade cervical intraepithelial neoplasia (CIN 2/3) or cervical adeno-carcinoma in situ (AIS) as surrogate for cervical cancer
? HPV 6/11/16/18-related CIN of any grade
? HPV 6/11/16/18-related external genital lesions (EGLs) - condyloma acuminata (genital warts) vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN)
? HPV 16/18-related VIN 2/3 or VaIN 2/3 as surrogates for vaginal cancer and vulvar cancer And that administration of the HPV vaccine will reduce the overall incidence of HPV-related cervical and genital disease.
Outcomes/endpoints
The Applicant defined two types of endpoints:
Persistent HPV infection: used in study 005 (primary endpoint) and study 007, defined as:
? Persistent vaccine-type HPV infections without confirmed CIN: detection of vaccine-type HPV DNA by PCR on at least 2 consecutive visits spaced for at least 4 months
? Detection of vaccine-type HPV DNA by PCR on the last visit without confirmation of persistence
? Vaccine-type HPV infection with confirmed CIN: histologically confirmed CIN 1, 2, 3, AIS, or cervical carcinoma due to vaccine-type HPV
Disease endpoints: were included in all efficacy studies
? The incidence of HPV 16-related CIN 1, CIN 2, CIN 3 or worse (study 005)
? The combined incidence of CIN 1, CIN 2, CIN 3 or worse and combined incidence of external genital lesions related to HPV 6, 11, 16 and 18 (study 007)
? The combined incidence of CIN 1, CIN 2, CIN 3 or worse related to HPV 6, 11, 16 and 18 and combined incidence of condyloma acuminata VIN 1, VIN 2/3, VaIN 1, VaIN 2/3 or worse related to HPV 6, 11, 16 and 18 (two co-primary endpoints: external genital lesion endpoint and cervical lesion endpoint) (study 013)
? The incidence of AIS, CIN 2/3 or worse related to HPV 16 or HPV 18 (study 015).
Study 005 used a primary virological endpoint, whereas histological endpoints were used in study 007 and the two phase III trials (P013 and P015).
Disease endpoint definitions differed among the studies due to differences in the vaccines tested, i.e. 005 evaluating the HPV 16 vaccine, 007 evaluating different quadrivalent HPV vaccine doses and 013/015 evaluating the quadrivalent HPV vaccine. Endpoint definitions also differed among studies 005, 007, 013, and 015 due to the evolution of the method used to assess the causal HPV type within a lesion.
All HPV endpoints were histologically classified. The primary CIN and EGL endpoints of the studies were based on biopsies and required HPV DNA to be detected in the same tissue specimen by thin-section PCR. An independent blinded Pathology Panel was used for adjudication of all study endpoints. A comprehensive testing program was used for HPV-related disease. The results of the ThinPrep Pap test were used to identify subjects with cervical HPV disease and thorough genital
inspection to identify subjects with EGLs. The protocol-specified genital examinations and mandatory guidelines for triage of abnormal Pap test to colposcopy ensured consistency and standardised ascertainment of HPV-related lesions among study sites.
Sample size / Statistical methods
Neither study 013 nor study 015 was individually powered to provide substantial evidence to demonstrate that the HPV vaccines reduce the incidence of HPV 16/18-related CIN 2/3 or AIS, efficacy data were to be combined from all 4 studies in a pre-specified analysis.
Studies 013 and 015 were designed as fixed-case studies. The vaccine efficacy (VE) evaluations were to be performed when a pre-specified number of endpoint cases had been observed. Final efficacy analyses were to be performed at the end of studies. The requisite numbers of endpoint cases for both studies were obtained in August 2005, when the majority of subjects had been followed for at total of 2 years (1.5 years after completion of the 3-dose regimen). Data available at this time point were unblinded and analysed and form the basis of this application. Study 013 and study 015 are currently ongoing and vaccine efficacy is to be re-estimated at the end of the 4-year follow-up.
R ESULTS
Overall 19,321 subjects (93% of subjects who received at least 1 one vaccine dose) continued in the study from the time of enrolment through the date at which the database was closed (Aug 2005). Except for the study 005, where 84.6% of patients received the 3 injections (in the vaccine group), in other studies 93 to 98% of patients received 3 injections.
There were regional differences between studies. Study 005 was recruiting subjects only in the US; study 013 had the largest recruitment in Latin America (41%) and study 015 in Europe (65%). Overall 13% of the combined population had a test compatible with CIN at Day 1 and 27% of the combined population was either seropositive or PCR positive to a vaccine HPV type at baseline.
The median durations of follow-up were 4.0, 3.0, 2.0 and 2.0 years for P005, P007, P013 and P015, respectively.
Baseline data
The demographic characteristics were generally comparable between vaccine and placebo groups regarding the age, race, geographic region, smoking status, alcohol consumption, and history of sexually transmitted diseases at enrolment.
Sexual demographics differed by geographic region. Age at sexual debut occurred at a mean age of 16.7 years. Hormonal contraception was the most common form of contraception (59%) and highest in Europe (68%).
The demographic profile of subjects in the PPE population was general comparable to the overall population.
Outcomes and estimation
Primary efficacy results of individual studies
Study 005: The primary efficacy endpoint of study 005 was the incidence of new persistent HPV 16 infection. Two efficacy analyses were performed, a fixed-case analysis and a final analysis at the end of the 4-year study follow-up. In the first analysis in the PPE population, all 41 cases of persistent HPV 16 infection were in the placebo group. At end-of-study, 7 cases in the vaccine group had HPV 16 detected at the last study visit (without confirmed persistence). There were no cases of HPV-related CIN in the vaccine group in the fixed-case or end-of-study analyses versus 9 and 24, respectively in the placebo group. The MITT-2 results supported those of the PPE analyses.
Primary efficacy endpoint: persistent HPV 16 infection (P005)
欧盟化学品分类、标签及包装法案 欧盟通过一项关于化学物质和混合剂分类、标签及包装的法规议案。新法规修订第67／548／EEC号指令、第1999／45／EEC号指令及第1907/2006号法规。新法规对化学物质的分类及标签的准则或责任做出规定，填补了REACH法规具体化学物质分类及标签内容的缺失，并与其相辅相成，共同构筑欧盟抵御危险化学品的绿色壁垒。20l0年12月1日依照本法规对物质进行分类；于2015年6月1日对混合物进行分类，现行的相关法规、法案、指令拟从相应的过渡期结束后予以废止。 新法规重点对化学品分类的方法、要求及时间限定等进行了解读。标签方面，须提供供应商的名称、地址和电话，可以识别物质或混合剂的资料、危害标志、危害声明、提防声明，以及有关危害的补充资料。 该提案与联合国全球化学品统一分类和标签制度(GHS制度)和我国现有化学品 分类和标签体系存在较大差异，将对我国化学品行业造成影响。该法规与GHS 及我国于2008年1月1日正式实施的以联合国GHS制度为基础的《化学品分类、警示标签和警示性说明安全规范》系列标准(GB 20576－2006～GB 20602－2006)具有明显差异。由于分类体系的不同，该法规的实施将会涉及REACH相关要求的修订，增加REACH的实施难度，势必进一步对我国化学品贸易产生巨大冲击。 10.1 CLP法规与欧盟现有化学品分类和标签制度的区别 欧盟是当前世界上对化学品控制和管理体系最为完善的区域，欧盟通过立法体系、管理体制、主要制度等对化学品实施了有效的监管。 欧盟现行的化学品分类和标签制度 第67／548／EEC号指令：危险物质分类、标签和包装要求； 第1999／45／EC号指令：危险配制品分类、标签和包装要求； 第91／l55／EEC号指令：安全数据表要求，该指令则确保了物质和配制品的供应商向职业消费者提供化学品的危险信息及安全使用指南。 欧盟REACH法规第11篇规定了化学品分类和标记目录的有关要求，将上述三项指令纳入其中，要求注册者以上述三项指令为依据，按要求向化学品管理局通报相关信息，并根据化学品的危险类别对其采取不同的管理措施。 新法规与现有法规相比，最大的差异主要表现为：危害类别、判定阈值及标签要素不同；涉及的物质条目大幅增加，与原法规相比新增条目896种；增加了更多混合物分类的要求。 10.2CLP法规与GHS制度之间的差异
欧盟技术性贸易壁垒的状况及我国的对策 随着关税壁垒逐渐降低，非关税贸易壁垒在国际贸易中的重要性日益上升，这已成为一个世界性趋势，技术壁垒则是非关税贸易壁垒中最重要的一个。欧盟国家是最先意识并研究国际贸易中技术性贸易壁垒的国家，同时其成员国也是设置技术性贸易壁垒最严重的国家，尤其在有关汽车、电机、机械和制药产业更为明显。概括起来，欧盟实施的技术性贸易壁垒体系有以下四个方面： 1．技术标准和法规。欧盟各国由于经济、技术实力普遍较高，因而各国的技术标准水平较高，法规较严，尤其是对产品的环境标准要求，让一般发展中国家的产品望尘莫及。在欧济一体化过程中，迫切需要协调各国的技术标准。欧盟不仅有统一的技术标准、法规，而且各国也有各自的严格标准，它们对进口商品可以随时选择对自己有利的标准，从总体来看，要进入欧盟市场的产品必须至少达到三个条件之一，即：(1)符合欧洲标准EN，取得欧洲标准化委员会CEN认证标志；(2)与人身安全有关的产品，要取得欧共体安全认证标志cE；(3)进入欧共体市场的产品厂商，要取得Is09000合格证书。同时，欧共体还明确要求进入欧共体市场的产品凡涉及欧共体指令的，必须符合指令的要求并通过一定的认证，才允许在欧洲统一市场流通。 2．产品质量认证制度和合格评定。欧洲以外的国家的产品要进入欧洲市场，必须符合欧盟指令和标准(CE)，才能在欧洲流通。欧盟12个新指令把市场上流通的产品都做了规定这12个新指令覆盖的产品都必须有CE标志，在国家之间互相承认检验(认证)结果之前，外国产品要进入欧洲市场，就必须取得一个欧洲国家的认证。这12个指令覆盖的产品生产厂，要想把产品卖到欧洲，生产厂要有较好的质保体系，在取得cE标志之前是否应取得体系认证，这要看具体情况。欧盟部长理事会通过一项决议，要求对输入盟的产品加强安全检查，不管从哪个成员国的口岸进来，均需根据统一标准接受安全和卫生检查，任何一个海关，只要在检查时发现进口的产品不符合欧盟的标准，可能会危及消费者的健康和安全，不仅有权中止报关手续，还应该立即通知其他海关口岸。欧盟主要加强对进口玩具、食品和药品的卫生和安全检查。 3．标签、包装壁垒。欧盟一直通过产品包装、标签的立法来设置外国产品的进口障碍。如对易燃、易爆、腐蚀品、有毒品，法律规定其包装和标签都要符合一系列特殊标志要求。 欧盟对纺织品等的进口产品还要求加贴生态标签。目前在欧盟最为流行的生态标签为0KOTexStandard 100(生态纺织品标准100)，是纺织品进入欧洲纺织品市场的通行证，对服装和纺织品中的某些物质的含量要求高达PPb级。这无疑给发展中国家的纺织品出口贸易造成很大的困难，一方面由于技术有限，很难控制到PPb级，另一方面由于经济、实验条件有限，而无法检测出PPb级的物质。如果让发达国家的检测机构检测，其费用相当昂贵，这势必加大了出口商的成本支出。 4．绿色技术壁垒。这是欧盟最为严厉的一种技术性贸易壁垒，主要有下述几种：(1)绿色生产。要求进口商品的生产企业严格执行他们制定的清洁生产标准，控制生产过程中化学物料尤其是有害物料、清水和有 机溶剂的用量，采用他们的清洁生产技术和设备。(2)绿色技术标准。欧盟制定了许多发展中国家难以达到的环境标准，限制国外产品进口。1995年4月，由发达国家控制的国际标准化组织开始实施《国际环境监查标准制度》，要求产品达到Is09000系列标准体系。欧盟也启动一项名为Isol4000的环境管理系统，要求进入欧盟国家的产品从生产前到制造、销售、使用以及最后的处理阶段都要达到规定的技术标准。(3)绿色环境标志。它是一种在产品或其包装上的图形，表明该产品不但质量符合标准，而且在生产、使用、处理过程中符合环保要求，对生态环境和人类健康均无损害。发展中国家产品为了进入欧盟市场，必须提出申请，经批准才能得到绿色通行证，即绿色环境标志。1992年5月欧共体正式实施所谓生态标签制
危险化学品安全管理制度 1.目的 为了加强公司危险化学品的安全管理，预防危险化学品在储存、使用、废弃过程中由于防护不当或违规而导致的各类事故，以保障员工生命健康安全及公司财产安全。根据《中华人民共和国安全生产法》、《危险化学品安全管理条例》等法律法规，特制定本制度。 2.范围 本制度适用于本公司内一切危险化学品相关活动及作业。 3.责任 3.1 安环主任负责本制度的监督执行。 3.2 危险化学品采购、储存、使用、废弃等部门配合履行本制度。 4.内容 4.1 定义 爆炸品第2类 压缩气体和液化气体、第3类，易燃液体、第4类，易燃固体、自燃物品和遇湿易燃物品、第5类， 氧化剂和有机过氧化物、第6类，有毒品、第7类，放射性物品、第8类，腐蚀品。
5.内容 5.1 危险化学品的采购 5.1.1 凡因生产需要所购买的危险化学物品，生产厂家必须持有国家安监部 门颁发的安全生产许可证书，经营销售商须有危险化学品经营许可证，所有入厂的危险化学品均须有合格的安全技术说明书及安全标签； 5.1.2 采购应向经营销售单位索取化学品安全技术说明书(MSDS),MSDS 安全数 据需包括经测定的产品燃点、自燃点、闪点、爆炸极限、毒性、预防等详细中文资料,并具有符合国标的标志和包装。 5.2 危险化学品的运输及装卸 5.2.1 危险化学品运送的供货商及运送车辆、押运人员须符合相关法规的规定。运输需有资质，押运人员经培训合格有上岗证。 5.2.2 化学性质相抵制或灭火方法不同的危险化学品禁止在同一辆车 上混合运输。
危险化学品装卸时，仓库管理人员对装卸区进行标识，确保厂区其它员工不进入装卸区，并检查装卸人员的上岗资格证书，监督其佩戴必要的防护用品及按正确的方式轻装轻卸，严禁拖、拉、抛、滚。 5.3危险化学品的储存 5.3.1 仓库保管的易燃易爆品，必须在专库储存。 5.3.2 仓库配备足够的与危险化学品性质相适应的消防器材，并由专人维护和保养。 5.3.3 危险化学品按性质及不兼容性分隔离、隔开、分离在种形式储存（见附件1），同库房要满足“5距”要求。 5.3.3.1 顶距：须为50cm以上，人字形屋顶，堆货顶面以不超过横梁为准。 5.3.3.2 灯距：货物距离灯的距离，灯距不应小于50cm； 5.3.3.3 墙距：外墙距在30cm以上，内墙距在30cm以上。以便通风散潮和防火，一旦发生火灾，可供消防人员出入。
中国提出一带一路倡议4年来，全球100多个国家和国际组织积极支持和参与一带一路建设。一带一路沿线包括65个国家和地区，东亚的蒙古和东盟10国、西亚18国、南亚8国、中亚5国、独联体7国和中东欧16国。在这些国家中，化学品贸易占据了贸易总额的近10%，而他们的监管法规如何？ 早在2002年，世界永续发展高峰会议提出联合国国际化学品管理策略方针SAICM执行计划书，其目标是2020年前将化学品重大负面效益降到最低。随后，世界各地纷纷出台各自的化学品法规管理，如大家所熟知的欧盟REACH法规、美国的TSCA法规、日本化审法、中国新化学物质申报、韩国REACH、台湾TCSCA&OSHA法规等等。其中，包括不少一带一路的国家。 作为专业技术服务机构，瑞旭公司专注研究和分析了中国、中东欧国家、欧亚经济联盟（俄罗斯）、西亚的土耳其、东南亚的菲律宾、马来西亚、新加坡、越南、老挝、印度尼西亚、泰国、印度等主要国家的化学品法规管理情况。 一、中国化学品法规管理 中国新化学物质申报：在中国，不在《中国现有化学物质名录》（IECSC）里的物质，称为新化学物质，需要履行《中国新化学物质环境管理办法》（环境保护部7号令）。7号令要求，新化学物质在生产或进口活动之前，需要完成中国新化学物质申报。申报后，需履行市场后监督义务，如提交年度报告、采取风险控制措施、传递合规的SDS和标签、危险废物进行合规处置等。2017年8月31日，环境保护部发布了《关于调整《新化学物质申报登记指南》数据要求的公告》（2017年，第42号），公告称为提高新化学物质申报数据要求的科学性和规范性，对《新化学物质申报登记指南》（以下简称《指南》）规定的常规申报毒理学、生态毒理学最低数据要求，理化特性、毒理学和生态毒理学数据的豁免条件进行了调整。该公告自2017年10月15日起施行。此次的调整，充分
浅谈欧盟贸易壁垒新动态(一) 论文关键词：欧盟；绿色贸易壁垒(GBT)；REACH法规；国际标准；“绿色护照”论文摘要：欧盟(EU)是极具吸引力的发达经济市场，是我国最大贸易伙伴和出口地。EU近年来出于产业市场保护等多方面的考虑，发布了“绿色”系列指令，构筑起“合法”的“绿色屏障”，即绿色贸易壁垒(GBT，GreenBarrierstoTrade)以限制进口。我国出口因之损失巨大，对EU的出口在成本、技术方面，遭遇到严峻的挑战与考验。要保持我国对EU的出口优势，需要多方联合行动、多方面入手，积极应对。 随着经济全球化、贸易自由化已成为国际趋势，WTO下的多边贸易谈判，使关税的贸易保护作用变得极其有限，传统的非关税政策也仅能在特定条件下使用。于是，因技术体制、经济技术水平差异等产生的技术性措施以其“合法性”、隐蔽和灵活性演变成贸易壁垒，这种技术性贸易壁垒(TBT，TechnicalBarrierstoTrade)将成为贸易自由化背景下国际贸易壁垒的主体，而“保护我们共同的地球，维持可持续发展”这一全球共同目标使得以环保标准支撑的GBT 成为了TBT的核心。 近年来，欧盟发布了一系列与环保相关的“绿色指令”，包括：PPW指令，《包装及包装废弃物指令》(DirectiveonPackagingandPackagingWaste)；WEEE指令，《关于报废电子电气设备指令》(DirectiveonWasteElectricalandElectronicEquipment)；RoHS指令，《关于在电子电气设备中限制使用某些有害物质指令》(DirectiveontheRestrictionoftheUseofCertainHazardousSubstancesinElectricalandElectronicEquip ment)；ELV指令，《关于报废汽车的技术指令》(End-ofLifeVehicle)；REACH法规，《化学品登记，评估及授权法规》(RegulationCoveringtheRegistration，evaluationandAuthorizationofChemicals)；EuP指令，《用能产品生态设计框架指令》(DirectiveonEnergy-usingProductDesign)，这些指令构成了EU整合性产品政策的基础，对外形成了GBT。 一、欧盟发布系列绿色指令的动机 1、利用WTO协议绿色规则缺口构筑贸易壁垒 WTO有关环境问题的内容主要体现在其一系列的相关协定中，虽然这些协定规定“不得妨碍正常国际贸易”，但另一方面却肯定各国的“环保例外权”，而在行使此种权力时，WTO有关环境贸易规范一般都比较概括和抽象，含混其词、模棱两可，缺乏有效和明确的约束性，导致了GBT在世界范围内盛行。 EU正是利用这点，制定出一系列严格、繁多、苛刻的绿色环保标准，构筑起“绿色贸易壁垒”，名正言顺地达到既有利于EU商品出口，又有利于限制别国商品进口的目的。 2、出于产业保护，培养竞争力的考虑 EU现有25个成员国，人口超过4.5亿，是极具吸引力而有价值的市场。EU担心中国这样的新兴市场力量出口迅速增长，连年对其巨额贸易顺差，2006年高达916.6亿美元，会挤占了其市场并对当地经济产生冲击。而EU东扩后，新进成员竞争力还很弱，加之近年EU经济增长乏力，为保护对国民经济、国际贸易、就业综合影响大的相关产业，培养和提升竞争力，需要制定更加“合理”有效的TBT。如REACH法规的立论之一就是为了提高EU化学工业的竞争力，化学工业是eU的三大产业之一，直接雇工超170万人，年产值约5000亿欧元(高全德，2003)，显然EU要极力保护这个重点产业和市场，保持自己在该行业的优势地位。3、人们环境保护意识的增强 环境问题已是当今人们关注的热点，EU等发达国家的环保组织、消费者尤其关注同日常生活密切相关，与人身安全、环境保护、动植物健康等相关的产品质量与性能。 二、欧盟最新系列绿色指令解析及影响 1．EU最新绿色系列指令内容概要
危险化学品安全管理法律法规 化学品种类繁多、性质复杂，在生产、运输、使用过程中稍有疏漏，就会对人体健康和生态环境造成巨大危害。因而，从20世纪60年代开始，世界各工业国家和一些国际组织纷纷制定有关法规、标准和公约，旨在强化化学品的安全管理，有效预防和控制化学品的危害和事故。 我国是世界上化学品生产和进口的大国。我国政府十分关注和重视化学品的安全生产、安全流通和安全使用，相继颁布了一系列法律、法规、规章和标准，对化学品实行从“摇篮’’到“坟墓’’的全生命周期管理。 一、化学品安全法规与规章 随着我国化学品工业的发展，我国在化学品安全管理方面制定了一系列法规。 (1)经全国人大批准发布的、涉及危险化学品的法律 20xx年6月29日，全国人大九届二十八次会议审议通过了《安全生产法》。《安全生产法》的颁布实施，是我国安全生产领域影响深远的一件大事，是我国安全生产法制建设的里程碑。在《安全生产法》中，有不少条款明确了危险化学品的安全管理要求，如第20条、第32条、第34条等。《安全生产法》是安全生产领域的基本法，危险化学品的安全管理也必须遵从该法。 2001年10月27日，全国人大九届二十四次会议通过了《职业病防治法》。《职业病防治法》的施行，标志着我国预防、控制和消除职业危害因素，防治职业病，保护劳动者的健康和权益工作将走上规范化、法制化的轨道。根据《国家安全生产监督管理总局主要职责内设机构和人员编制规定的通知》(国办发E20xx3 11号)，安全生产监督管理部门负有作业场所职业卫生监督检查的职责。危险化学品，尤其是有毒有害危险化学品，是职业卫生监督检查必不可少的内容之一。 1 994年10月27日，全国人大八届十次会议批准了《作业场所安全使用化学品公约》(170号公约)。《作业场所安全使用化学品公约》就化学品的危险性鉴别与
欧盟REACH（《关于化学品注册、评估、许可和限制制度》）简介 什么是REACH “Registration，Evaluation，Authorization and Restriction of Chemicals，化学品注册、评估、许可和限制”，是欧盟对进入其市场的所有化学品进行预防性管理的法规。将于2007年6月1日正式实施。 REACH的目的 保护人类健康和环境；保持和提高欧盟化学工业的竞争力；增加化学品信息的透明度；减少脊椎动物试验；与欧盟在WTO框架下的国际义务相一致。 从实质意义上讲，REACH法规将促进化学工业的革新，使其生产更安全的产品，刺激竞争和增长。与现行复杂的法规体系不同，REACH将在欧盟范围内创建一个统一的化学品管理体系，使企业能够遵循同一原则生产新的化学品及其产品。 REACH的主要内容 注册（Registration）年产量或进口量超过1吨的所有化学物质需要注册，年产量或进口量10吨以上的化学物质还应提交化学安全报告。 评估（Evaluation）包括档案评估和物质评估。档案评估是核查企业提交注册卷宗的完整性和一致性。物质评估是指确认化学物质危害人体健康与环境的风险性。 许可（Authorization）对具有一定危险特性并引起人们高度重视的化学物质的生产和进口进行授权，包括CMR，PBT ，vPvB等。
限制（Restriction）如果认为某种物质或其配置品、制品的制造、投放市场或使用导致对人类健康和环境的风险不能被充分控制，将限制其在欧盟境内生产或进口。 注：PBT 持久性、生物富积和毒性化学物质 vPvB 高持久性、高度生物富积化学物质 CMR 致癌性、诱变性和生物毒性物质 REACH制度影响对中国出口贸易的影响 一、影响产业范围广：除了对化工企业有直接影响外，REACH将对包括纺织、机电、玩具、家具等所有的生产化工下游产品的企业产生影响，所涉及的产品有100多万种。 二、企业出口成本大大增加：据欧盟估算，每一种化学物质的基本检测费用约需8.5万欧元，每一种新物质的检测费用约需57万欧元。 三、要求的数据量大：REACH要求提供化学品安全数据表、安全评估报告、风险评估等一系列的注册档案技术文件，涉及的数据量复杂庞大。 REACH注册流程图 注册Registration 要求年产量超过1吨的所有现有化学品和新化学品及应用于各种产品中的化学物质注册其基本信息。只有通过注册的物质才能在欧盟内生产或进口。 每一个物质的生产商和进口商须向化学管理署提交该物质的注册档案，并缴纳相应的费用。但是要求联合提交同一个物质的注册信息，即遵循“一个物质，一次注册”原则。作为联合注册的成员，可以与其他成员共同分摊注册的费用。 为了易于管理、接受大量注册档案的提交，提交给化学署的注册档案需电子化处理。化学管理署会给每一个收到的注册档案一个注册编号和注册日期，并立刻把这些信息传递给注册人。
第一章总则? 第一条根据《中华人民共和国监控化学品管理条例》（以下简称《条例》），并结合现 （含 监控化学品的生产技术是指生产监控化学品的各种技术手段。? 监控化学品的专用设备是指采用各种技术手段，生产监控化学品过程中所需要的产品
合成、分离、提纯、热传导和自控仪表等设备，以及凡与监控化学品接触到的设备和含高镍合金或其它特种耐腐蚀材料所制成的设备。第二章监控化学品生产的特别许可办法? 第五条国家对第二类、第三类监控化学品和第四类监控化学品中含磷、硫、氟的特 可手续。? 第八条申请生产特别许可的单位和个人应具备以下条件：?
一、必须有完整的企业基本情况资料（按附件要求填报）；? 二、必须持有工商行政管理部门核发的营业执照；? 七、生产、储存、销售有标准、完整的台帐；? 八、国家其他管理部门颁发生产许可证所规定的批准文件和证书，以及生产该品种所必需的其它有关证件；?
九、必须具有熟悉监控化学品数据统计的专职或兼职管理人员以及相应的管理制度；? 十、必须具备国家履行《禁止化学武器公约》事务主管部门要求的标准设施位置图、 ? 二、各省级《禁止化学武器公约》事务主管部门在对有关材料认真审核后，以正式文件报国家履行《禁止化学武器公约》事务主管部门审批（已取得国家其他部门颁发生产许可证的产品，不再进行产品质量考核，只对监控化学品管理要求部分进行考核）；?
三、国家履行《禁止化学武器公约》事务主管部门在接到省级《禁止化学武器公约》事务主管部门的报告后，及时组织审核；? 四、经审核，凡符合生产监控化学品各项条件的，由国务院化学工业主管部门颁发生 ＸＸＸ代表发证产品序号?
欧盟技术性贸易壁垒对中国产品出口的影响及对策摘要：随着中国对欧盟贸易顺差的不断扩大，尤其是2009年欧债危机后，欧盟贸易保护主义呈现抬头趋势，对华贸易政策也日趋强硬。近年来欧盟颁布了大量的技术标准和法规，并制定了相应的合格评定程序，对中国产品出口造成很大不利影响。欧盟对华技术性贸易壁垒已成为中国产品出口难以逾越的障碍。我国政府、行业协会、企业应积极采取对策，攻破欧盟对我国产品出口的技术性贸易壁垒。 关键词：欧盟技术性贸易壁垒影响对策 1.技术性贸易壁垒的内涵 1.1技术性贸易壁垒的概念 技术性贸易壁垒（Technical Barriers to Trade，简称TBT）是贸易壁垒中非关税壁垒的一种，主要是指货物进口国所制定的那些强制性和非强制性的技术法规、标准以及检验商品的合格评定程序所形成的贸易障碍，即一国通过颁布法律、法令、条例、规定，建立技术标准、认证制度、检验检疫制度等方式，对外国进口商品制定苛刻繁琐的技术、卫生检疫、商品包装和标签等标准，从而提高进口产品要求，增加进口难度，最终达到限制进口的目的。 WTO关于技术性贸易壁垒的檔有两个，分别是“技术技术性贸易壁垒性贸易壁垒协议”（TBT协议）和“实施卫生与动植物卫生措施协定”（SPS协定），于1995年1月1日WTO正式成立起开始执行。它是目前各国，尤其是发达国家人为设置贸易壁垒，推行贸易保护主义的最有效手段。 涉及到贸易的各个领域和环节：农产品、食品、机电产品、纺织服装、信息产业、家电、化工医药，包括它们的初级产品、中间产品和制成品，涉及到加工、包装、运输和储存等环节。 1.2技术性贸易壁垒产生的背景及原因 （1）维护该国的利益是一切国际关系的根本目的。虽然为了推进经济全球化和贸易自由化的发展，各国在乌拉圭回合谈判中承诺进一步降低关税和在保持现状下逐步消除各种非关税壁垒。但现在国际竞争日益激烈，各国为了维护该国的贸易利益，在逐步取消明显有违WTO精神的一些传统的非关税壁垒的同时又不断推出更为隐蔽的技术性贸易壁垒，而且名目繁多，要求越来越苛刻。在发达国
SVHC测试服务——高度关注物质测试应对REACH实质性措施 从10月28日起，REACH法规下的新义务随着第一份高关注物质候选清单的正式发布开始生效。 对于进入候选清单中高关注度物质的相关义务如下所示：公司必须为归入授权候选清单中的物质承担相应义务。这些义务针对的不仅仅是物质本身，同时还针对存在于配制品中，以及物品中的物质。 物品 1. 从物质被归入候选清单开始： 如果物品含有候选清单中的物质，且质量百分浓度大于0.1%，则欧盟范围内此类物品的供应商必须向顾客提供其可获取的充足信息;或者，应消费者要求，在收到要求的45天内向其提供可获取的充足信息。这类信息应保证物品的安全使用，且至少包括物质的名称。 2. 从2011年开始： 如果物品含有候选清单中的物质，且该物质质量百分浓度大于0.1%，并且在物品中的总含量超过1吨/年/公司，则欧盟范围内此类物品的制造商或进口商必须向ECHA进行通报。 3. 在2010年12月1日前归入候选清单中的物质，必须在2011年6月1日前完成通报; 4. 在2010年12月1日或在之后归入候选清单中的物质，必须在归入后的六个月内完成通报。 物质 从物质被归入候选清单开始： 如果物质被归入候选清单之中，则欧盟范围内该物质的供应商必须向他们的客户提供一份安全数据表(SDS)。 配制品 从物质被归入候选清单开始： 如果根据1999/45/EC指令，配制品本身不被分类为危险品，但配制品中至少含有一种候选清单中的物质，且单个物质的质量百分浓度在非气体配制品中不低于0.1%，在气体配制品中不低于0.2%，则欧盟范围内该配制品的供应商在收到配制品的接收者的请求时，须向其提供一份安全数据表(SDS)。 SVHC清单如下
技术标准与国际贸易壁垒案例 1.江苏省紫菜协会对日反贸易壁垒案例 时间：2003 年 2 月 15 日 地点：南通和连云港两地 事件缘由： 江苏省是中国条斑紫菜的主要生产地区，目前栽培面积10 万多亩，达到 年产紫菜标准制品 17 亿枚、产值 7 亿元的产业规模；产品 90% 以上出口，已初步形成配套完整的产业体系。但由于紫菜交易分散经营，缺乏统一的质量标准；紫菜加工技术和销售价格基本上被日本控制，中国紫菜的国际价格非常低；紫菜消费大国日本采取配额分配和进口许可证制度，导致中国紫菜迟迟不能直 接进入日本市场，对日出口多年来一直保持零的记录。这些问题严重侵害了中 国紫菜厂商的利益，并阻碍了江苏紫菜产业的进一步发展。 详细过程： 2003 年 2 月 15 日，南通和连云港两地的紫菜加工、生产单位和个人自 愿联合起来，组建了一个非盈利的社团组织，即江苏省紫菜协会，并经过民主 协商制定了协会章程。目前，协会已发展单位会员和个人会员共 110 个，约占 全省紫菜生产加工企业的 62%。江苏省紫菜协会成立后，组织考察团赴日本考察，采集到了日本官方对干紫菜进口配额情况的第一手资料，认定日本对中国 产紫菜出口存在歧视性贸易壁垒。2004 年 2 月 25 日，江苏省紫菜协会代表其 下属 110 个会员，向国家商务部申请反贸易壁垒调查，商务部公平贸易局正式 受理了上述申请后，与日方政府有关部门共举行了 3 次磋商。 最后处理结果： 2005 年2 月 21 日，日本经济产业省在日本《经济产业公报》和《通商 弘报》上登载了经济产业省第 19 号“进口通告”，公布了日本2005年紫菜进 口配额方案。进口通告取消了对进口干紫菜和调味紫菜原产国的限定，并载明2005年日本干紫菜和调味紫菜进口配额总量为 4 亿张，值此日本对中国紫菜进口关闭了 2 0 年的大门终于开启。最新的进展是，今年中国已经从日本紫菜协 会获得 8 0 0 0 万张配额。 事件影响：日本取消了对中国紫菜进口的贸易壁垒。江苏省紫菜协会作为仲裁者，从管理层面上对紫菜配额进行分配，这种分配过程实施上是南通和连云港 的紫菜生产企业进行谈判的过程。 资料来源：知网。江静.江苏省紫菜协会对日反贸易壁垒案例[J].中国改 革,2005(11):47.
化学品采购规章制度 化学品采购管理制度 1、目的 为了加强对本公司的化学品进行有效管理，防止在采购、贮存、使用、废弃等过程中对环境保护、人员安全造成不良影响。 2、适用范围 适用于本公司化学品的管理。 3、引用标准 《危险化学品安全管理条例》 《常用化学危险品贮存通则》GB15603-1995 《工作场所安全使用化学品规定》 4、定义 4.1化学品:是指天然和人造的各种元素(也称化学元素)、由元素组成的化合物和混合物。 4.2一般化学品:指除危险化学品、剧毒化学品、易制毒化学品以外的所有化学品。 4.4危险化学品:爆炸性品;压宿气体、液化气体;易燃液体;易燃固体、自燃物品、遇湿易燃物品;氧化剂、有机过氧化物;有毒品、感 染性物品;放射性物品;腐蚀品等几大类。 5、职责 5.1各部门经理负责本部门有关化学品采购、贮存、使用和废弃的管理，并监督承包商对所使用的化学品参照公司制度进行管理。 5.2各部门采购人员负责化学品的采购及物质安全技术说明书(MSDS)的收集。
5.3可持续发展部职业健康与安全小组负责对各部门化学品的管理进行监督。 5.,各部门经理负责组织本部门化学品保管人员和使用人员进行化学品安全知识培训工作。 6、管理规定 6.1化学品的请购、采购 6.1.1使用部门根据生产使用实际情况以及安全库存量(满足生产使用,月的量)，并按公司采购程序填写“请购(定购)单”，注明化学品的名称、规格、数量等。 6.1.2各部门采购人员根据“请购(定购)单”对化学品的供应商进行选择，确定供应商具有有效的经营资质，若购买的是危险化学品、剧毒品、易制毒品等则要求供应商具有有效的“危险化学品经营许可证”，然后按《财务及信息管理手册》的“采购”程序进行。同时编制本部门的“化学品清单”，汇总新使用化学品的类别、特性等内容，并按清单向供方收集有关化学品的物质安全技术说明书(MSDS)，然后将MSDS反馈至公司可持续发展部职业健康与安全小组。 6.1.3若危险化学品采购后由供方负责运输及装卸，采购人员要求其应具有“危险品运输许可证”;若由本公司人员负责运输及装卸则须经过化学品安全知识专门培训，取得上岗资质的人员进行;若是大批量的运输和装卸，可由采购的部门选择合格的承包方进行，并要求其按国家防范措施，严防化学品的泄漏及出现意外。 6.2、储存 6.2.1各部门须设置化学品储存的专用仓库和化学品保管人员。化学品采购人员对送至公司的化学品进行确认，对其数量、包装情况、标识、有效期等进行检查，验收合格后由部门化学品保管人员将化学品全部放至于各自的化学品仓库，并
【达人吧：布鲁塞尔——不只是欧盟】欧盟布鲁塞尔条例 “狂欢通宵达旦。”拜伦在《恰尔德·哈罗德游记》中这样写道，他描述的正是里奇蒙公爵夫人在滑铁卢战役前夜举办的宴会，宴会的地点就在布鲁塞尔。布鲁塞尔确实不比巴黎，可要说它是欧洲最无聊的首都，未免有失公平。首先，全世界最壮观的巴洛克式广场就坐落在布鲁塞尔。大广场的历史可以追溯到十四世纪，1695年毁于法国人之手，经过了四年的重建才得以恢复它的美丽与庄严。马克思和恩格斯在广场一侧的天鹅咖啡馆相识，两个人也是在那里开始撰写《共产主义宣言》。大广场永远游人如织，如果你喜欢清静，可以去萨布隆广场看看，从大广场出发走路10分钟就能到达。漫步在鹅卵石铺就的小路上，穿梭在各式古董店和咖啡馆间，可以品味真正的布鲁塞尔味道。 顺着坡路往上走，不一会儿就能看到比利时皇宫。在皇宫前俯瞰整座城市，欧洲最美的都市之景尽收眼底。向右看，100多米高的司法宫威严矗立，隔着几英里都能感受到这座金顶大楼的气派。向左看，几英里之外就是拜占庭风格的圣玛丽大教堂。布鲁塞尔绝对是政治迷的天堂：绕着欧盟区走一圈，你就能看到Berlaymont大厦（欧盟委员会所在地），JustusLipsius大厦（欧盟部长理事会所在地）以及欧盟议会大楼。 ★最佳观景地 司法宫 参观完100米高的司法宫，走下台阶再往左拐就到了Poelaert广场。在这里，俯瞰布鲁塞尔市区绵延的建筑，你会感慨这座城市的沧桑与壮丽。司法宫地势很高，乘观景梯能直达位于司法宫脚下的Marolles区。Marolles区有些老旧衰败，文艺复兴时期的著名画家老彼得·布吕赫尔的故居就位于Haute大街132号。 星期一至星期五；免费开放 ★最佳免费旅游项目 Ixelles池塘 Ixelles池塘位于布鲁赛尔最时尚、艺术气息最浓的地区，参观完池塘，还
中国危险化学品监管面临的GHS新法规和企业的应对 1992年联合国环境与发展大会通过的《21世纪进程》文件，其中第19章关于有毒化学品环境无害化管理中确定了将“统一全球化学品分类和标签制度”列为需要完成的六项化学品国际安全行动计划之一。 2002年12月11-13日全球化学品统一分类和标签（GHS）文件建议稿通过审议核准，并在全球推广使用。 我国国务院2002年颁布的《危险化学品安全管理条列》规定，对危险化学品进行监督管理，此条列中化学品的危险性分类，主要依据《联合国关于危险货物运输建议书规章范文》中危险货物的分类确定的，其中危险化学品的分类只是包含：爆炸品，压缩气体和液化气体，易燃液体，易燃固体，自燃物品和遇湿易燃物品，氧化剂和有机过氧化物，有毒品和腐蚀品8类危险物质。 我国政府有关部门自2002年GHS标准颁布和实施以来，一直高度关注，并且多次派专家参加联合国有关机构召开的GHS标准修订国际议会。2007年起国家安全生产监督管理总局，环保部，卫生部，质检总局等主管部门开始着手修改2002版《危险化学品安全管理条列》，主要修改内容包括以下几点： (1) 危险化学品的定义：由原来根据联合国危险货物的定义修改为依据GHS标准定义。 (2) 危险化学品名录：根据2002版《危险化学品安全管理条列》的规定，国家安监总局等有关主管部门，依据《联合国关于危险货物运输建议书规章范文》的危险货物一览表发布了2002年版本的《危险化学品名录》，收录3700多种危险化学品并按照危险货物分类标准对每种化学品的主要危险性和次要危险性类别进行分类。 (3)按照GHS标准制定推出中国GHS国标： 分类国标——GB 13690-2009：化学品分类和危险公示通则； 标签国标——GB 15258-2009：化学品安全标签编写规定 SDS国标——GB/T 16483-2008：化学品安全技术说明书内容和项目顺序 包装国标——GB 190-2009：危险 26项针对中国GHS下每个分类类别的详细国标GB 20576- 20599，GB 20601-2006，GB 20602-2006 2011年3月11日，国务院总理温家宝于3月2日签署第591号国务院令，公布了新修订的《危险化学品安全管理条例》。新条例自2011年12月1日起施行。新条例的实施启动了中
危险化学品管理制度 1 目的 为使安全部在生产、生活中的油料、油漆、化学品、易燃及易爆品得到有效控制，保护人民生命和财产安全。 2 范围 适用于公司使用的易燃、易爆品、所有油料、油漆及化学品的控制和管理。 3 职责 3.1 安全部制定并组织实施本制度，负责油料、油漆及化学品的收发，建立收发台账。 3.2 综合部负责对机关办公区、生活区的易燃易爆品的控制。 3.3 安全部负责对施工现场的易燃易爆品的控制；负责对易燃、易爆品防火控制的监督检查。 4 工作程序 4.1 加强对人员的管理 4.1.1 做好全员的学习宣传教育工作。 4.1.2 严格执行防火安全制度。 4.1.3 落实防火安全责任制。 4.1.4 做好防火、灭火准备。 4.1.5 经常性的检查消防安全工作的落实情况。 4.2 加强对易燃、易爆品的管理 4.2.1 易燃、易爆品的储存 a）易燃、易爆品必须储存在专用仓库、专用场地，并设专人管理。 b）仓库内应当配备消防力量和灭火设施，严禁在仓库内吸烟和使用明火。 c）仓库要符合有关安全、防火规定，物品之间通道要保证安全距离。 d）遇火、遇潮容易燃烧、爆炸的物品，不得在露天、潮湿、漏雨和低洼容易积水的地点存
放。 e）受阳光照射容易燃烧、爆炸物品应当在阴凉通风地点存放。 f）化学性质或防护、灭火方法相抵触的易燃、易爆品，不得在同一仓库内存放。 4.2.2 易燃、易爆品的运输装卸 a）在装卸过程中应轻拿轻放，防止撞击、拖拉和倾倒。 b）对碰撞、互相接触易引起燃烧、爆炸和化学性质或防护、灭火方法互相抵触的易燃、易爆品不得违反配装限制和混合装运。 c）遇热、遇潮容易引起燃烧、爆炸的易燃、易爆物品，装运时应当采取隔热措施。 4.2.3 易燃、易爆品的使用管理 a）使用易燃、易爆品的单位要填写《易燃、易爆、油料及化学品收发台账》，对物品的名称、数量及入库日期进行登记，并及时进行清点。 b）易燃、易爆品的使用及灭火方法应按照有关操作规程或产品使用说明严格执行。 c）各种气瓶在使用时，距离明火10 m以上，氧气瓶的减压器上应有安全阀，严防沾染油脂，不得曝晒、倒置、平时与乙炔瓶工作间距不小于5m。 d）加强对火源、电源和生产中贮存、使用易燃、易爆品的场所监控。 4.3 油料、油漆及化学品管理 4.3.1 油料、油漆及化学品大部分是油液、胶质的易燃物或可燃物，既易干燥、挥发，又易受外界影响变质。因此，油料、油漆及化学品的储存及运输，必须特别注意防火、防爆、防毒、防变质。 4.3.2 明火管理及消防 贮存油料、油漆及化学品的库房必须加强消防及明火管理，必须在明显地点标明“严禁吸烟”、“严禁火种”等醒目字样或标志。库房区必须备有充足的并与各类油料、油漆及化学品相适应的消防器材。 4.3.3 库房温度和湿度 储存油料、油漆及化学品的库房必须干燥、阴凉、通风，库房尽可能保持适当的温度和湿度，库房最好面向北，防止烈日曝晒。 油料、油漆及化学品过冷过热易变质，库房温度过高，会加速油料、油漆及化学品挥发而引起容器变形，甚至爆裂渗漏，也会引起油料、油漆及化学品胶凝或粘度增浓，库房温度过低会使水溶性漆、乳胶漆结冰，影响物理化学性能，给环境带来污染。
欧盟ECHA(化学品管理署)发布公告：首批SVHC通报截止 2011-06-08 08:40 来源：中国质量新闻网进入论坛点此收藏 2011年6月1日，欧盟ECHA(化学品管理署)发布公告——首批SVHC通报截止。 公告里称，符合条件的物品生产商和进口商必须向ECHA对授权候选清单物质(SVHC)进行通报。对于2010年12月1日之后归入授权候选清单的物质，通报须在归入开始6个月内提交;而2010年12月1日之前列入的物质通报则须在2011年6月1日之前提交。ECHA 提醒企业，尽管前三批38项SVHC已经截止通报，另有8种物质截止期在2011年6月15日，相关企业应引起重视。 今年6月1日起，凡包含欧盟《化学品的注册、评估、授权和限制制度》(REACH法规)列为38种高度关注物质(SVHC)达到一定浓度、总量的产品，必须按规定程序进行申请通报，否则将无法进入欧盟市场。
欧盟2007年6月1日实施的REACH法规要求对进入其市场的所有化学品进行预防性管理，化学品必须经过注册、评估等程序才可准入。 该法规实施后，先后多次更新SVHC名单，累计已经有4批、46种物质被欧盟化学品管理局列入授权候选清单，其中前38种在物品中质量百分比浓度超过0.1%，且每年总量大于1吨的SVHC必须于今年6月1日前完成向欧盟化学品管理局通报的义务;总量不超过1吨的，如果消费者有要求，制造商或者进口商必须在45天内免费传递相关信息。此外，还有8种SVHC必须在今年6月15日前完成通报。 据欧盟估算，每种化学物质的基本检测费用为8.5万欧元，每种新物质的检测费用为57万欧元。欧盟REACH法规出台后，我国化学、化工产品出口成本平均增加了5%，超过100万种化工产业下游产品受到影响。 检验检疫部门提醒输欧企业，应主动了解自己原料所涉及的化学物质是否属于SVHC;输欧货物原料中，若包含欧盟REACH法规列为38种SVHC达到一定浓度、总量的产品，必须按照规定程序进行申请通报，以免造成经济损失。 检验检疫部门同时提醒输欧企业，不断关注该项法规的SVHC名单及候选名单的更新情况，以便提前应对。由于单一的企业根本无法承担高昂的检测费用，因此可根据REACH 法规“一种物质，一次注册”的原则，通过行业协会等方式进行联合注册，实现费用分摊，以降低对成本的影响。 据中国REACH解决中心——瑞旭技术SVHC项目负责人李兰芳介绍，在SVHC通报功能开放一个多月以来，全球已有数百家企业完成了SVHC通报，通报物质包括硼酸、硅酸铝耐火陶瓷纤维、氧化锆硅酸铝耐火陶瓷纤维、邻苯二甲酸盐等，我国许多玩具企业、塑料制品企业等均已完成或者在积极应对通报。从瑞旭技术统计数据来看，除了我国相关企业外，欧盟境内的进口商与生产商，日本、韩国、土耳其、美国等国的相关企业也在积极应对。 从SVHC通报物质与企业来看，SVHC通报存在行业的集中性，像硼酸就常在纤维素聚合物、陶瓷纤维等材料中添加;硅酸铝耐火陶瓷纤维、氧化锆硅酸铝耐火陶瓷纤维是常用的耐火材料的主体成分;而邻苯二甲酸盐(DEHP、BBP、DBP、DIBP)则是软塑料的常用增塑剂，在玩具等物品中经常检出。一般来说，大件复杂物品需要通报的可能性比较小，材料较为均一的小件物品通报的可能性相对较大，尤其是材料均一、容易添加SVHC的产品。
论网络侵犯人格权案件的国际管辖权论文 摘要：互联网由于其即时性、无边界性、读者群体的无限制性等特点，突破了传统 的传播手段在时间和空间上的局限。这些特点使得传统适用于一般媒体侵犯人格权的规则，难以有效地适用于互联网侵犯人格权的情形。由此，欧洲联盟法院 2021 年的判决就网络侵犯人格权的国际管辖权问题，突破了传统的规则，允许根据利益 中心地标准行使管辖权。联系我国的立法和司法实践，为有效评估受害人的损害，尽可能 给予受害人以充分保护，建议我国应借鉴前述欧盟法院的立场，除传统的“侵权行为地” 之外，也采纳受害人利益中心地作为确立网络侵犯人格权的国际管辖权的依据。 关键词：网络侵权;侵权行为地侵权结果发生地;最密切联系;私生活。 论文正文： 论网络侵犯人格权案件的国际管辖权 网络是当今社会十分重要的信息交流和共享的手段，网络的即时性和无国界性克服了 传统的交流手段在时间和空间上的局限。然而，毋庸置疑，网络同样也对作为主体的人带 来了挑战。人格权作为主体的存在和发展所不可或缺的权利，其诸多要素在网络的威胁下 显得尤为脆弱;网络的即时性、无国界性、登录访问的无限制性等，意味着损害的难以阻 止和范围的难以限定。而人格权在网络上遭受侵害后，互联网的全球通达性意味着损害的 范围遍及全球。在此情况下，对于此种损害的管辖就存在着多个连接点，传统的理论一般 认为有管辖权的法院是被告住所地或侵权行为地的法院。欧洲联盟法院在 2021 年的一项判决，却基于网络侵犯人格权的特殊性，对于传统的侵权之债的管 辖权实现了重要突破，值得关注。 一、“侵权行为地”标准及其例外。 人格权作为绝对权之一，对其侵害引发侵权责任的承担。而在侵权事件具有涉外性的 情况下，受害人与加害人可能拥有不同的国籍和住所，而侵权事件的发生地和结果地可能 分处于不同的国家，这就带来管辖权和准据法方面的冲突。就侵权之债的管辖权冲突而言，根据传统理论，一般由侵权行为地的法院管辖。以侵权行为地作为管辖地，是法院对侵权 案件进行管辖的主要依据，其原因在于：侵权行为地管辖是属地管辖原则的要求，而属地 管辖是国家领土主权在国际民商事案件诉讼管辖权问题上的体现[1];而以侵权行为地法院 作为管辖法院，在判定侵权要件是否成立、确定侵权后果等方面，具有很大的便利性。 不难理解的是，侵权案件由侵权行为地法院管辖的原则，已为大多数国家所接受。以 欧盟 2000 年“布鲁塞尔条例”欧盟理事会 2000 年 12 月 22 日第 4/2001/EC 号条例———《关于民商事案件的管辖权和判决的承认和执行的条例》①为例，该条例第 5 条第三款规定：“居住在某一成员国的人，得在另一成员国的法院被诉……涉及侵 权案件，包括侵权与准侵权，得到侵权事件发生地或可能发生地的法院起诉”。“侵权事 件发生地”的措辞，表明《布鲁塞尔条例》采取的是同样是“侵权行为地”的标准。