WHO Stability testing of active pharmaceutical ingredients and finished pharmaceutical products 2009
? World Health Organization
WHO Technical Report Series, No. 953, 2009
Annex 2
Stability testing of active pharmaceutical ingredients and ? nished pharmaceutical products
1. Introduction
1.1 Objectives of these guidelines
1.2 Scope of these guidelines
principles
1.3 General
2. Guidelines
2.1 Active pharmaceutical ingredient …………………
General
2.1.1
testing
2.1.2
Stress
2.1.3 Selection of batches
2.1.4 Container closure system
Speci?cation
2.1.5
frequency
2.1.6
Testing
Storage
conditions……
2.1.7
b ility
commitment
Sta
2.1.8
Evaluation
2.1.9
2.1.10 Statements and labelling
2.1.11 Ongoing stability studies
2.2 Finished pharmaceutical product
2.2.1
General
2.2.2 Selection of batches
2.2.3 Container closure system
2.2.4
Speci?cation
frequency
Testing
2.2.5
Storage
conditions
2.2.6
commitment
b ility
Sta
2.2.7
Evaluation
2.2.8
2.2.9 Statements and labelling
sta
b ility
In-use
2.2.10
Variations
2.2.11
2.2.12 Ongoing stability studies
3. Glossary
References
Appendix 1
Long-term stability testing conditions as identi? ed by WHO Member States. Appendix 2
Examples of testing parameters…
Appendix 3
Recommended labelling statements…
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1. Introduction
1.1Objectives of these guidelines
These guidelines seek to exemplify the core stability data package required for registration of active pharmaceutical ingredients (APIs) and ? nished pharmaceutical products (FPPs), replacing the previous WHO guidelines in this area (1,2). However, alternative approaches can be used when they are scienti? cally justi? ed. Further guidance can be found in International Conference on Harmonisation (ICH) guidelines (3)and in the WHO guidelines on the active pharmaceutical ingredient master ? le procedure (4).
It is recommended that these guidelines should also be applied to products that are already being marketed, with allowance for an appropriate transition period, e.g. upon re-registration or upon re-evaluation.
1.2Scope of these guidelines
These guidelines apply to new and existing APIs and address information to be submitted in original and subsequent applications for marketing authorization of their related FPP for human use. These guidelines are not applicable to stability testing for biologicals (for details on vaccines please see WHO guidelines for stability evaluation of vaccines (5)).
1.3 General principles
The purpose of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the in? uence of a variety of environmental factors such as temperature, humidity and light. The stability programme also includes the study of product-related factors that in? uence its quality, for example, interaction of API with excipients, container closure systems and packaging materials. In ? xed-dose combination FPPs (FDCs) the interaction between two or more APIs also has to be considered.
As a result of stability testing a re-test period for the API (in exceptional cases, e.g. for unstable APIs, a shelf-life is given) or a shelf-life for the FPP can be established and storage conditions can be recommended.
Various analyses have been done to identify suitable testing conditions for WHO Member States based on climatic data and are published in the literature (6–9) on the basis of which each Member State can make its decision on long-term (real-time) stability testing conditions. Those Member States that have noti? ed WHO of the long-term stability testing conditions they require when requesting a marketing authorization are listed in Appendix 1.
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2. Guidelines
2.1Active pharmaceutical ingredient
2.1.1 General
Information on the stability of the API is an integral part of the systematic approach to stability evaluation. Potential attributes to be tested on an API during stability testing are listed in the examples of testing parameters (Appendix 2).
The re-test period or shelf-life assigned to the API by the API manufacturer should be derived from stability testing data.
2.1.2 Stress testing
Stress testing of the API can help identify the likely degradation products, which, in turn, can help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual API and the type of FPP involved.
For an API the following approaches may be used:
—when available, it is acceptable to provide the relevant data published in the scienti? c literature to support the identi? ed degradation products
and pathways;
—when no data are available, stress testing should be performed.
Stress testing may be carried out on a single batch of the API. It should include the effect of temperature (in 10 °C increments (e.g. 50 °C, 60 °C, etc.) above the temperature used for accelerated testing), humidity (e.g. 75% relative humidity (RH) or greater) and, where appropriate, oxidation and photolysis on the API. The testing should also evaluate the susceptibility of the API to hydrolysis across a justi? ed range of pH values when in solution or suspension (10).
Assessing the necessity for photostability testing should be an integral part of
a stress testing strategy. More details can be found in other guidelines (3).
Results from these studies will form an integral part of the information provided to regulatory authorities.
2.1.3 Selection of batches
Data from stability studies on at least three primary batches of the API should normally be provided. The batches should be manufactured to a minimum of pilot scale by the same synthesis route as production batches, and using a method of manufacture and procedure that simulates the ? nal process to be used for production batches. The overall quality of the batches
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of API placed on stability studies should be representative of the quality of the material to be made on a production scale.
For existing active substances that are known to be stable, data from at least two primary batches should be provided.
2.1.4C ontainer closure system
The stability studies should be conducted on the API packaged in a container closure system that is the same as, or simulates, the packaging proposed for storage and distribution.
2.1.5S peci? cation
Stability studies should include testing of those attributes of the API that are susceptible to change during storage and are likely to in? uence quality, safety and/or ef? cacy. The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes. A guide as to the potential attributes to be tested in the stability studies is provided in Appendix 2.
Validated stability-indicating analytical procedures should be applied.
Whether and to what extent replication should be performed will depend on the results from validation studies (11).
2.1.6T esting frequency
For long-term studies, frequency of testing should be suf? cient to establish the stability pro? le of the API.
For APIs with a proposed re-test period or shelf-life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every three months over the ? rst year, every six months over the second year, and annually thereafter throughout the proposed re-test period or shelf-life.
At the accelerated storage condition, a minimum of three time points, including the initial and ? nal time points (e.g. 0, 3 and 6 months), from a six-month study is recommended. Where it is expected (based on development experience) that results from accelerated studies are likely to approach signi? cant change criteria, increased testing should be conducted either by adding samples at the ? nal time point or by including a fourth time point in the study design. When testing at the intermediate storage condition is called for as a result of signi? cant change at the accelerated storage condition, a minimum of four time points, including the initial and ? nal time points (e.g.
0, 6, 9 and 12 months), from a 12-month study is recommended.
2.1.7 Storage conditions
In general an API should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its 90
sensitivity to moisture. The storage conditions and the lengths of studies chosen should be suf? cient to cover storage and shipment.
Storage condition tolerances are de?ned as the acceptable variations in temperature and relative humidity of storage facilities for stability studies. The equipment used should be capable of controlling the storage conditions within the ranges de? ned in these guidelines. The storage conditions should be monitored and recorded. Short-term environmental changes due to opening the doors of the storage facility are accepted as unavoidable. The effect of excursions due to equipment failure should be assessed, addressed and reported if judged to affect stability results. Excursions that exceed the de? ned tolerances for more than 24 hours should be described in the study report and their effects assessed.
The long-term testing should normally take place over a minimum of 12 months for the number of batches speci? ed in section 2.1.3 at the time of submission, and should be continued for a period of time suf? cient to cover the proposed re-test period or shelf-life. For existing substances that are known to be stable, data covering a minimum of six months may be submitted. Additional data accumulated during the assessment period of the registration application should be submitted to the authorities upon request. Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition can be used to evaluate the effect of short-term excursions outside the label storage conditions (such as might occur during shipping).
Long-term, accelerated and, where appropriate, intermediate storage conditions for APIs are detailed in sections 2.1.7.1–2.1.7.3. The general case applies if the API is not speci? cally covered by a subsequent section. Alternative storage conditions can be used if justi? ed.
If long-term studies are conducted at 25 °C ± 2 °C/60% RH ± 5% RH and “signi? cant change” occurs at any time during six months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against signi? cant change criteria. In this case, testing at the intermediate storage condition should include all long-term tests, unless otherwise justi? ed, and the initial application should include a minimum of six months’ data from a 12-month study at the intermediate storage condition.
“Signi?cant change” for an API is de?ned as failure to meet its speci? cation.
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2.1.9 Evaluation
The purpose of the stability study is to establish, based on testing a minimum of the number of batches speci?ed in section 2.1.3, unless otherwise justi? ed and authorized, of the API and evaluating the stability information (including, as appropriate, results of the physical, chemical, biological and microbiological tests), a re-test period applicable to all future batches of the API manufactured under similar circumstances. The degree of variability of individual batches affects the con? dence that a future production batch will remain within speci? cation throughout the assigned re-test period.
The data may show so little degradation and so little variability that it is apparent from looking at them that the requested re-test period will be granted. Under these circumstances it is normally unnecessary to go through the statistical analysis; providing a justi? cation for the omission should be suf? cient.
An approach for analysing the data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided con? dence limit for the mean curve intersects the acceptance criterion. If analysis shows that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate. This can be done by ? rst applying appropriate statistical tests (e.g. p values for level of signi? cance of rejection of more than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches. If it is inappropriate to combine data from several batches, the overall re-test period should be based on the minimum time a batch can be expected to remain within acceptance criteria.
The nature of any degradation relationship will determine whether the data should be transformed for linear regression analysis. Usually the relationship can be represented by a linear, quadratic or cubic function on an arithmetic or logarithmic scale. As far as possible, the choice of model should be justi? ed by a physical and/or chemical rationale and should also take into account the amount of available data (parsimony principle to ensure a robust prediction). Statistical methods should be employed to test the goodness of ? t of the data on all batches and combined batches (where appropriate) to the assumed degradation line or curve.
Limited extrapolation of the long-term data from the long-term storage condition beyond the observed range to extend the re-test period can be undertaken if justi? ed. This justi? cation should be based on what is known about the mechanism of degradation, the results of testing under accelerated conditions, the goodness of ? t of any mathematical model, batch size and existence of supporting stability data. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data.
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Any evaluation should cover not only the assay but also the levels of degradation products and other appropriate attributes. Where appropriate, attention should be paid to reviewing the adequacy of evaluation linked to FPP stability and degradation “behaviour” during the testing.
2.1.10 Statements and labelling
A storage statement should be established for display on the label based on
the stability evaluation of the API. Where applicable speci? c instructions should be provided, particularly for APIs that cannot tolerate freezing or excursions in temperature. Terms such as “ambient conditions” or “room temperature” should be avoided.
The recommended labelling statements for use if supported by the stability studies are provided in Appendix 3.
A re-test period should be derived from the stability information, and a re-
test date should be displayed on the container label if appropriate.
2.1.11 Ongoing stability studies
The stability of the API should be monitored according to a continuous and appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of degradation products). The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains, and can be expected to remain, within speci? cations under the storage conditions indicated on the label, within the re-test period in all future batches.
The ongoing stability programme should be described in a written protocol and the results presented in a formal report.
The protocol for an ongoing stability programme should extend to the end of the re-test period and shelf-life and should include, but not be limited to, the following parameters:
—number of batch(es) and different batch sizes, if applicable;
—relevant physical, chemical, microbiological and biological test methods;
—acceptance criteria;
—reference to test methods;
—description of the container closure system(s);
—testing frequency;
—description of the conditions of storage (standardized conditions for long-term testing as described in these guidelines, and consistent with
the API labelling, should be used); and
—other applicable parameters speci? c to the API.
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At least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring programme and tested at least annually to con? rm the stability (12). In certain situations additional batches should be included in the ongoing stability programme.
For example, an ongoing stability study should be conducted after any signi? cant change or signi? cant deviation to the synthetic route, process or container closure system which may have an impact upon the stability of the API (13).
Out-of-speci?cation results or signi?cant atypical trends should be investigated.
Any con? rmed signi? cant change, out-of-speci? cation result, or signi? cant atypical trend should be reported immediately to the relevant ? nished product manufacturer. The possible impact on batches on the market should be considered in consultation with the relevant ? nished product manufacturers and the competent authorities.
A summary of all the data generated, including any interim conclusions on
the programme, should be written and maintained. This summary should be subjected to periodic review.
2.2Finished pharmaceutical product
2.2.1 General
The design of the stability studies for the FPP should be based on knowledge of the behaviour and properties of the API, information from stability studies on the API and on experience gained from preformulation studies and investigational FPPs.
2.2.2 Selection of batches
Data from stability studies should be provided on at least three primary batches of the FPP. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing.
The manufacturing process used for primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting the same speci? cation as that intended for marketing.
In the case of conventional dosage forms with APIs that are known to be stable, data from at least two primary batches should be provided.
Two of the three batches should be at least pilot-scale batches and the third one can be smaller, if justi? ed. Where possible, batches of the FPP should be manufactured using different batches of the API(s).
Stability studies should be performed on each individual strength, dosage form and container type and size of the FPP unless bracketing or matrixing is applied.
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2.2.3 Container closure system
Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing. Any available studies carried out on the FPP outside its immediate container or in other packaging materials can form a useful part of the stress testing of the dosage form or can be considered as supporting information, respectively.
2.2.4 Speci? cation
Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to in? uence quality, safety, and/or ef? cacy. The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes, preservative content
(e.g. antioxidant or antimicrobial preservative) and functionality tests (e.g.
for a dose delivery system). Examples of testing parameters in the stability studies are listed in Appendix 2. Analytical procedures should be fully validated and stability-indicating. Whether and to what extent replication should be performed will depend on the results of validation studies.
Shelf-life acceptance criteria should be derived from consideration of all available stability information. It may be appropriate to have justi? able differences between the shelf-life and release acceptance criteria based on the stability evaluation and the changes observed on storage. Any differences between the release and shelf-life acceptance criteria for antimicrobial preservative content should be supported by a validated correlation of chemical content and preservative effectiveness demonstrated during development of the pharmaceutical product with the product in its ? nal formulation (except for preservative concentration) intended for marketing.
A single primary stability batch of the FPP should be tested for effectiveness
of the antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for veri? cation purposes, regardless of whether there is a difference between the release and shelf-life acceptance criteria for preservative content.
2.2.5 Testing frequency
For long-term studies, frequency of testing should be suf? cient to establish the stability pro? le of the FPP.
For products with a proposed shelf-life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every three months over the ? rst year, every six months over the second year and annually thereafter throughout the proposed shelf-life.
At the accelerated storage condition, a minimum of three time points, including the initial and ? nal time points (e.g. 0, 3 and 6 months), from
a six-month study is recommended. Where an expectation (based on
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development experience) exists that results from accelerated testing are likely to approach signi? cant change criteria, testing should be increased either by adding samples at the ? nal time point or by including a fourth time point in the study design.
When testing at the intermediate storage condition is called for as a result of signi? cant change at the accelerated storage condition, a minimum of four time points, including the initial and ? nal time points (e.g. 0, 6, 9 and
12 months), from a 12-month study is recommended.
Reduced designs, i.e. matrixing or bracketing, where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied if justi? ed (3).
2.2.6 Storage conditions
In general an FPP should be evaluated under storage conditions with speci?ed tolerances that test its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent loss. The storage conditions and the lengths of studies chosen should be suf?cient to cover storage, shipment and subsequent use with due regard to the climatic conditions in which the product is intended to be marketed.
Photostability testing, which is an integral part of stress testing, should be conducted on at least one primary batch of the FPP if appropriate. More details can be found in other guidelines (3).
The orientation of the product during storage, i.e. upright versus inverted, may need to be included in a protocol where contact of the product with the closure system may be expected to affect the stability of the products contained, or where there has been a change in the container closure system.
Storage condition tolerances are usually de? ned as the acceptable variations in temperature and relative humidity of storage facilities for stability studies.
The equipment used should be capable of controlling the storage conditions within the ranges de? ned in these guidelines. The storage conditions should be monitored and recorded. Short-term environmental changes due to opening of the doors of the storage facility are accepted as unavoidable. The effect of excursions due to equipment failure should be assessed, addressed and reported if judged to affect stability results. Excursions that exceed the de? ned tolerances for more than 24 hours should be described in the study report and their effects assessed.
The long-term testing should cover a minimum of six or 12 months at the time of submission and should be continued for a period of time suf? cient to cover the proposed shelf-life. For an FPP containing an API that is known to be stable and where no signi? cant change is observed in the FPP stability 98
Products meeting either of the long-term storage conditions and the accelerated conditions, as speci? ed in the table above, have demonstrated the integrity of the packaging in semi-permeable containers. A signi? cant change in water loss alone at the accelerated storage condition does not necessitate testing at the intermediate storage condition. However, data should be provided to demonstrate that the pharmaceutical product would not have signi? cant water loss throughout the proposed shelf-life if stored at 25 °C/40% RH or 30 °C/35% RH.
For long-term studies conducted at 25 °C ± 2 °C/40% RH ± 5% RH, that fail the accelerated testing with regard to water loss and any other parameters, additional testing at the “intermediate” storage condition should be performed as described under the general case to evaluate the temperature effect at 30 °C.
A 5% loss in water from its initial value is considered a signi? cant change for a product packaged in a semi-permeable container after an equivalent of three months’ storage at 40 °C not more than (NMT) 25% RH. However, for small containers (1 ml or less) or unit-dose products, a water loss of 5% or more after an equivalent of three months’ storage at 40 °C/NMT 25% RH may be appropriate, if justi? ed.
An alternative approach to studies at the low relative humidity as recommended in the table above (for either long-term or accelerated testing) is to perform the stability studies under higher relative humidity and deriving the water loss at the low relative humidity through calculation. This can be achieved by experimentally determining the permeation coef? cient for the container closure system or, as shown in the example below, using the calculated ratio of water loss rates between the two humidity conditions at the same temperature. The permeation coef? cient for a container closure system can be experimentally determined by using the worst-case scenario (e.g. the most diluted of a series of concentrations) for the proposed FPP.
Example of an approach for determining water loss
For a product in a given container closure system, container size and ? ll, an appropriate approach for deriving the rate of water loss at the low relative humidity is to multiply the rate of water loss measured at an alternative relative humidity at the same temperature, by a water loss rate ratio shown in the table below. A linear water loss rate at the alternative relative humidity over the storage period should be demonstrated.
For example, at a given temperature, e.g. 40 °C, the calculated rate of water loss during storage at NMT 25% RH is the rate of water loss measured at 75% RH multiplied by 3.0, the corresponding water loss rate ratio.
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The stability protocol used for studies on commitment batches should be the same as that for the primary batches, unless otherwise scienti? cally justi? ed.
2.2.8 Evaluation
A systematic approach should be adopted to the presentation and evaluation
of the stability information, which should include, as appropriate, results from the physical, chemical, biological and microbiological tests, including particular attributes of the dosage form (for example, dissolution rate for solid oral dosage forms).
The purpose of the stability study is to establish, based on testing a minimum number of batches of the FPP as speci?ed in section 2.2.2, a shelf-life and label storage instructions applicable to all future batches of the FPP manufactured under similar circumstances. The degree of variability of individual batches affects the con? dence that a future production batch will remain within speci? cation throughout its shelf-life.
Where the data show so little degradation and so little variability that it is apparent from looking at the data that the requested shelf-life will be granted, it is normally unnecessary to go through the statistical analysis.
However, a provisional shelf-life of 24 months may be established provided the following conditions are satis? ed:
?
The API is known to be stable (not easily degradable).
?
Stability studies, as outlined above in section 2.1.11, have been performed
and no signi? cant changes have been observed.
?
Supporting data indicate that similar formulations have been assigned a shelf-life of 24 months or more.
?
The manufacturer will continue to conduct long-term studies until the proposed shelf-life has been covered, and the results obtained will be submitted to the national medicines regulatory authority.
An approach for analysing the data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided con? dence limit for the mean curve intersects the acceptance criterion. If analysis shows that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate. This can be done by ? rst applying appropriate statistical tests (e.g. p values for level of signi? cance of rejection of more than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches. If it is inappropriate to combine data from several batches, the overall shelf-life should be based on the minimum time a batch can be expected to remain within acceptance criteria.
The nature of any degradation relationship will determine whether the data should be transformed for linear regression analysis. Usually the
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relationship can be represented by a linear, quadratic or cubic function on an arithmetic or logarithmic scale. As far as possible, the choice of model should be justi? ed by a physical and/or chemical rationale and should also take into account the amount of available data (parsimony principle to ensure a robust prediction).
Statistical methods should be employed to test the goodness of ? t of the data on all batches and combined batches (where appropriate) to the assumed degradation line or curve.
Limited extrapolation of the long-term data from the long-term storage condition beyond the observed range to extend the shelf-life can be undertaken, if justi? ed. This justi? cation should be based on what is known about the mechanism of degradation, the results of testing under accelerated conditions, the goodness of ? t of any mathematical model, batch size and the existence of supporting stability data. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data.
Any evaluation should consider not only the assay but also the degradation products and other appropriate attributes. Where appropriate, attention should be paid to reviewing the adequacy of evaluation linked to FPP stability and degradation “behaviour” during the testing.
2.2.9 Statements and labelling
A storage statement should be established for the label based on the stability
evaluation of the FPP. Where applicable, speci?c instructions should be provided, particularly for FPPs that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” must be avoided.
There should be a direct link between the storage statement on the label and the demonstrated stability of the FPP. An expiry date should be displayed on the container label.
The recommended labelling statements for use, if supported by the stability studies, are provided in Appendix 3.
In principle, FPPs should be packed in containers that ensure stability and protect the FPP from deterioration. A storage statement should not be used to compensate for inadequate or inferior packaging. Additional labelling statements could be used in cases where the results of the stability testing demonstrate limiting factors (see also Appendix 3).
2.2.10 In-use stability
The purpose of in-use stability testing is to provide information for the labelling on the preparation, storage conditions and utilization period of
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multidose products after opening, reconstitution or dilution of a solution,
e.g. an antibiotic injection supplied as a powder for reconstitution.
As far as possible the test should be designed to simulate the use of the FPP in practice, taking into consideration the ? lling volume of the container and any dilution or reconstitution before use. At intervals comparable to those which occur in practice appropriate quantities should be removed by the withdrawal methods normally used and described in the product literature.
The physical, chemical and microbial properties of the FPP susceptible to change during storage should be determined over the period of the proposed in-use shelf-life. If possible, testing should be performed at intermediate time points and at the end of the proposed in-use shelf-life on the ? nal amount of the FPP remaining in the container. Speci? c parameters, e.g. for liquids and semi-solids, preservatives, per content and effectiveness, need to be studied.
A minimum of two batches, at least pilot-scale batches, should be subjected
to the test. At least one of these batches should be chosen towards the end of its shelf-life. If such results are not available, one batch should be tested at the ? nal point of the submitted stability studies.
This testing should be performed on the reconstituted or diluted FPP throughout the proposed in-use period on primary batches as part of the stability studies at the initial and ? nal time points and, if full shelf-life, long-term data are not available before submission, at 12 months or the last time point at which data will be available.
In general this testing need not be repeated on commitment batches (see 2.2.10).
2.2.11 Variations
Once the FPP has been registered, additional stability studies are required whenever variations that may affect the stability of the API or FPP are made, such as major variations (13).
The following are examples of such changes:
—change in the manufacturing process;
—change in the composition of the FPP;
—change of the immediate packaging;
—change in the manufacturing process of an API.
In all cases of variations, the applicant should investigate whether the intended change will or will not have an impact on the quality characteristics of APIs and/or FPPs and consequently on their stability.
The scope and design of the stability studies for variations and changes are based on the knowledge and experience acquired on APIs and FPPs.
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《中国药典》2020—注射用重组人粒细胞巨噬细胞刺激因子原液相关蛋白检测国家药品标准公示稿
注射用重组人粒细胞巨噬细胞刺激因子原液相关蛋白检测 依法测定（通则 0512）。色谱柱采用四烷基硅烷键合硅胶为填充剂（如： C 4 柱，4.6mm×15cm，粒径 5μm 或其他适宜的色谱柱），柱温为室温；以 0.1% 三氟乙酸的水溶液为流动相 A ，以 0.1%三氟乙酸-90%乙腈的水溶液为流动相B ；流速为 1.2ml/min ；在波长 214nm 处检测；按下表进行梯度洗脱。 用稀释液（pH7.0 的磷酸盐缓冲液）将供试品稀释至每 1ml 中约含 0.5mg ， 作为供试品溶液；用稀释液将对照品稀释至每 1ml 中约含 0.5mg ，作为对照品溶液 A ；取对照品溶液 A 与每 1ml 中约含 0.125mg 的人或牛血清白蛋白溶液 （溶剂为稀释液），按体积比 1:4 混匀作为对照品溶液 B 。取供试品溶液与对照品溶液 A 、B 各 100μl 注入液相色谱仪。 供试品溶液与对照品溶液 A 、B 图谱中，粒细胞巨噬细胞刺激因子主峰的保留时间应一致，约为 22 分钟。对照品溶液 B 图谱中，主峰与人或牛血清白蛋白峰的分离度应不小于 2，重复进样（不少于 4 次）所得主峰峰面积的 RSD 应不大于 1.5%。 按面积归一化法只计算保留时间为 5～30 分钟的相关蛋白峰面积，单个相关蛋白峰面积应大不于总面积的 1.5%，所有相关蛋白峰面积应不大于总面积的4.0%。 备注：在该品种原液检定项下，3.1.4 纯度之后增加 3.1.5 相关蛋白项（具体内容见上文：注射用重组人粒细胞巨噬细胞刺激因子原液中相关蛋白检测）， 后续检测项目编号依次递增。 时间（分钟） A （%） B （%） 0 64 36 30 44 56 35 0 100 45 0 100 50 64 36 60 64 36
重组人粒细胞刺激因子注射液
重组人粒细胞刺激因子注射液 【药品名称】 通用名称：重组人粒细胞刺激因子注射液 英文名称：Recombinant Human Granulocyte Colonystimulating Factor Injection 【成份】 主要组成成份：重组人粒细胞刺激因子，本品系由含有高效表达人类细胞刺激因子(G-CSF)基因的大肠杆菌，经发酵、分离和高纯度化后制成。辅料名称：甘露醇;吐温-80;磷酸氢二钠;柠檬酸。 【适应症】 1.癌症化疗等原因导致中性粒细胞减少症；癌症患者使用骨髓抑制性化疗药物，特别在强烈的骨髓剥夺性化学药物治疗后，注射本品有助于预防中性粒细胞减少症的发生，减轻中性粒细胞减少的程度，缩短粒细胞缺乏症的持续时间，加速粒细胞数的恢复，从而减少合并感染发热的危险性。 2.促进骨髓移植后的中性粒细胞数升高。 3.骨髓发育不良综合征引起的中性粒细胞减少症，再生障碍性贫血引起的中性粒细胞减少症，先天性、特发性中性粒细胞减少症，骨髓增生异常综合征伴中性粒细胞减少症，周期性中性粒细胞减少症。 【用法用量】 1.肿瘤用于化疗所致的中性粒细胞减少症等，成年患者化疗后，中性粒细胞数降至1000/mm3(白细胞计数2000/mm3)以下者，在开始化疗后2～5g/kg，每日1次皮下或静脉注射给药。儿童患者化疗后中性粒细胞数降至500/mm3(白细胞计数1000/mm3)以下者，在开始化疗后2～5g/kg，每日1次皮下或静脉注射给药。当中性粒细胞数回升至5000/mm3(白细胞计数10000/mm3)以上时，停止给药。 2.急性白血病化疗所致的中性粒细胞减少症白血病患者化疗后白细胞计数不足1000/mm3，骨髓中的原粒细胞明显减少，
植物血凝素的药理作用
一、药物构成及规格： 本品又称植物血球凝集素，通过超低温萃取技术从红芸豆中提取得到的植物蛋白，主要成分为D－甘露糖、氨基葡糖醛酸衍生物所构成的低聚糖辅基与蛋白质复合物，并通过冷冻干燥技术制成。 二、理化特性 1. 本品为一种植物蛋白质； 2. 分子量大约为128KDa； 3. 本品为白色至类白色团粉末，性质稳定； 4. 本品易溶于水，溶液呈乳浊状。 三、药物特点 1. 本品通过超低温提取，并通过包被制剂技术，增强了本品抗热变性能力，同时不会被动物或昆虫胃肠的蛋白酶降解，在很大的pH范围内稳定。因而不但延长了储存周期，而且在使用时，不受胃肠道中蛋白酶的影响。 2. 本品与聚肌胞诱导干扰素有所不同。本品主要诱导产生γ-干扰素，而聚肌胞诱导机体产生α-干扰素。γ-干扰素有自己独有的受体，同时γ-干扰素可以发挥“抗原定位”作用，使免疫系统能够为特殊的病毒筛选出特殊的抗体，并且可以对那些能够吞噬和消灭病原体的免疫细胞产生活化作用。本品同样对于不同动物使用都可有效诱生干扰素，无种属限制，避免了直接使用干扰素的缺陷。 3. 本品因其独特的糖蛋白复合结构，在体内可迅速代谢掉，不会造成残留危害人类健康，符合当今用药要求。 四、效果分析： 1. 本品口服可以与小肠上皮细胞结合，从而促进幼仔畜胃肠道的发育和胃肠道功能成熟，减少肠道大分子的吸收，增加胰腺蛋白和胰岛素的含量，促进了仔畜的食欲，从而减弱了大多数仔畜都会发生的断奶后生长抑制；而注射给药PHA与肠外其他组织结合，增加了肝脏和脾脏的重量。瑞典农业大学( Swedish University of Agricultural Sciences)的研究小组在2004年国际猪兽医学会(IPVS)猪健康代表大会上报告说：现已证实植物血凝素可促进哺乳仔猪和大鼠肠道的成熟。Thomsson等研究了植物血凝素是否能促进断乳小猪肠道的发育。结果显示，使用PHA的断乳小猪在断乳后第一周生长较快（P=0.013），腹泻指数比对照组减少（P=0.10），且采食量增加（P=0.028），小肠屏障特性增加，小肠总长度长于对照组（P=0.063）。总之，断乳前饲喂植物血凝素改变了小肠的特性更有利于仔猪断乳。 2. 本品是免疫学研究中极其重要的试剂，本品在免疫学中的重要性与淋巴细胞的相互作用
中国重组人粒细胞集落刺激因子在肿瘤化疗中的临床应用专家共识(最全版)
中国重组人粒细胞集落刺激因子在肿瘤化疗中的临床应用专家共识 (最全版) 恶性肿瘤患者在化疗过程中，中性粒细胞减少是细胞毒类化疗药物主要的剂量限制性毒性，其减少程度和持续时间与患者感染风险增加相关[1,2]。发热性中性粒细胞减少症(febrile neutropenia, FN)通常被定义为中性粒细胞绝对值(absolute neutrophil count, ANC)低于0.5×109/L，或ANC低于1.0×109/L且预计在48 h内将低于0.5×109/L，同时患者单次口内温度≥38.3 ℃或≥38.0 ℃且持续1 h以上，或腋温>38.5 ℃持续1 h以上[3]。患者出现FN后可能导致化疗药物剂量降低或治疗延迟从而降低临床疗效，也可出现严重感染，甚至死亡。还可能会增加诊断和治疗的费用进而导致医疗花费增加。 重组人粒细胞集落刺激因子(recombinant human granulocyte–colony stimulating factor, rhG–CSF)是一种人工合成的促进中性粒细胞增殖、分化、激活的细胞因子，主要用于细胞毒类化疗药物治疗后出现的中性粒细胞减少症。目前临床上应用的rhG–CSF主要分为每日使用的rhG –CSF和每周期化疗仅使用一次的聚乙二醇rhG–CSF。聚乙二醇rhG–CSF 具有长效特性，由聚乙二醇分子与rhG–CSF共价结合而成，其药效学特性及防治FN相关不良事件发生方面与短效rhG–CSF基本一致[4,5,6,7,8]。 基于循证医学的荟萃分析结果表明，对已经出现发热性中性粒细胞减少症的患者，在使用广谱抗生素的基础上加用rhG–CSF可以显著缩短Ⅳ
植物血凝素的提取
植物血凝素也称为植物凝集素（PHA），可自制也可购自商品。自制的方法常用生理盐水提取法。 （A）干品制备法（1）选广东鸡子豆10g，用蒸馏水冲洗，置培养皿内用75%酒精一次性浸洗，倒掉酒精留间隙置37℃。恒温箱内24-48小时；（2）在无菌条件下研碎鸡子豆，加生理盐水30ml，摇匀后放入4℃冰箱24小时，第二天再加生理盐水70ml，再置4℃冰箱内24小时。每8-12小时摇荡一次。（也可一次性加100ml生理盐水）；（3）无菌条件下移入10-50ml离心管内，3000-4000rpm30分钟。在无菌箱内把上清液分装于10ml小瓶，置冰箱冷冻层备用；（4）效价：外周血染色体制备每100ml培养基加PHA约2ml。注：若整个过程未在无菌条件下进行，分装时用G5玻砂漏斗除菌即可。 （B）鲜品制备法：（1）选择完整无破皮鲜菜豆20g，用75%酒精浸泡10分钟；（2）在净化工作中用无菌盐水或蒸馏水漂洗二次，然后置无菌乳钵中捣成糊状，用100ml无菌盐水浸泡封口；（3）移入4℃冰箱中置24小时，中间摇动数次，次日3000rpm30分钟，在无菌情况下分装上清液于10ml小瓶内，置冰箱冷冻层备用。（4）效价：正式使用前先用一定量作效价测定，按效价使用。 青豌豆的提取：取青豌豆100克，加含0.15M氯化钠的0.01M pH7.0磷酸缓冲液200ml浸泡过夜，经膨胀后用组织捣碎机捣碎，倒入布袋中压榨出水提液，在沉渣中再力0入磷酸缓冲液100ml搅拌，浸泡1时，压榨出水提液，合并水提液，量出总体积。加0.01％叠氮钠防腐。2．蛋白质沉淀：边搅边加入固体硫酸铵达80％饱和（每升溶液加硫酸铵561克）冷藏过夜。吸取上清液，沉淀再用二层滤纸抽气过滤至干，即得粗制青豌豆素蛋白沉淀物硫酸铵糊。置冰箱保存。3．亲和层析分离(1)装柱：取直径为1.0 cm，长度为25 cm的层析柱，按（实验十五）操作，自顶部缓缓加入稀薄的Sephadex G25悬液，待凝胶上升至距顶柱约3-5 cm即可，用1M NaCl溶液平衡10分钟。（2）加样并收集：称硫酸铵糊0.3克溶于 3 ml IM氯化钠中，离心3000rPm10分钟，取上层悬液上柱，用1M NaCl洗脱收集每管 3.5 ml，在280 nrn紫外光上比色检测，直至吸光值下降到接近零为止。此洗脱峰为不与葡萄糖亲和的杂蛋白峰。改用含0.2M葡萄糖的1M NaCl进行洗脱。收集每管 3.5 ml，也在280nrn处检测、直至吸光值下降至接近零为止。此洗脱峰为青豌豆素峰，再用1M NaCl洗脱，再生柱，约需10分钟。4．青豌豆素生物活性测定。取新鲜兔血l ml于抗凝管中，离心去除血浆，血球用生理盐水洗涤离心1000rpm／5min三次，直至洗液无血色为止，加生理盐水稀释20倍制成兔红细胞悬液，置冰箱中备用。取点滴板一块在三孔中分别滴入对照生理盐水、280 nrn吸收峰的吸光值相同的杂蛋白和青豌豆蛋白各2滴（用生理盐水将二种蛋白质稀释到吸光值相同），再分别滴入兔红细胞悬液1滴。置37℃保温10分钟，取出后分别用玻棒在孔中轻轻搅动，比较三者红细胞的凝集情况。再将杂蛋白和青豌豆素溶液进一步用生理盐水稀释成1：5、l：25、l：125、1：625……再用上述方法检查比较它们对兔红细胞的凝集作用，求出它们最大生物活性的稀释倍数。兔红细胞的凝集作用也可用显微镜下进行观察、比较。注意事项：不同蛋白质凝集活性的比较需在以相同280 nrn 吸光值的蛋白质量作对比，故必需稀释
重组人粒细胞刺激因子注射液
医保乙类！ 立生素重组人粒细胞刺激因子注射液Recombinant Human Granulocyte Colony-stimulating Factor for Injection 多重机制，全面提升中性粒细胞 国际上第一个N端不含蛋氨酸的G-CSF 国家重点新产品，医保乙类 荣获北京市科技进步二等奖 荣获“北京市名牌产品”称号 与天然分子序列相同，不会导致抗体形成 工艺先进，高纯度与高活性 有效治疗放化疗所致的中性粒细胞减少 6种规格、2种包装（西林、预充），方便临床使用 北京双鹭药业股份有限公司市场部
一、立生素（重组人粒细胞刺激因子注射液）简介 G-CSF是指特异作用于造血系统中粒系祖细胞，促机其增殖、向成熟中性粒细胞分化，并维持细胞的存活及其生物功能的一种造血生长因子，是刺激骨髓细胞集落形成的集落刺激因子的一种。 规格：西林瓶包装（75ug、100ug、150ug、200ug、250ug、300ug）；预充式包装（75ug、150ug、300ug）。 二、立生素的作用机制 粒生素（G-CSF）选择性地作用于粒系造血祖细胞，促进其增殖、分化，刺激粒细胞前体细胞增殖并向成熟粒细胞分化，促进骨髓成熟中性粒细胞向外周血释放，以及增加成熟粒细胞的功能。 三、立生素对肿瘤放化疗引起的粒细胞减少症的治疗作用 化学治疗是恶性肿瘤综合治疗的主要内科手段之一。化疗中最常见的不良反应为骨髓抑制，临床主要表现为白细胞及中性粒细胞减少，患者常因此被迫减少化疗药物剂量、终止治疗以及延长化疗间歇期，使系统治疗的连续性和完整性受到影响。重度白细胞减少易并发全身感染及出血，严重者可导致死亡。 G-CSF适用于癌症化疗等原因导致的中性粒细胞减少症。癌症患者使用骨髓抑制性化疗药物，特别是在强烈的、骨髓剥夺性化学药物治疗后、注射本品有助于预防中性粒细胞减少症的发生，减轻中性粒细胞减少的程度，缩短粒细胞缺乏症的持续时间，加速粒细胞数的恢复，从而降低合并感染发热的危险。 四、立生素的临床应用 1、预防或治疗肿瘤放化疗所致的粒细胞和白细胞减少； 2、造血干细胞移植中动员外周造血干细胞，或加速造血干细胞移植后粒细胞恢复； 3、用于重症感染的辅助治疗； 4、用于非化疗药物所致的药源性的粒细胞减少症； 5、促进化疗所致的口腔粘膜溃疡的愈合； 6、动员骨髓干细胞治疗急性心肌梗死。 五、立生素的用法用量 化疗药物给药结束后24～48小时起皮下或静脉注射本品，每日一次。用量和用药时间应根据化疗强度和中性粒细胞下降的程度决定。 对化疗强度较大或粒细胞下降较明显者，以2.5μg/kg体重/日的剂量连续用药7天以上较为适宜，至中性粒细胞恢复至5000/mm3停药； 如所用化疗药物的剂量较低，估计造成的骨髓抑制不太严重者，可考虑使用较低剂量预防中性粒细胞的减少，以1.25μg/kg体重/日的剂量用药，至中性粒细胞数稳定于安全范围； 对化疗后中性粒细胞已明显降低的患者（中性粒细胞<1000/mm3），以5μg/kg体重/日的剂量用药至中性粒细胞恢复至5000/mm3以上，稳定后终止本品治疗并监视病情。
免疫学练习 2013-5
一、选择题（每道题可以有一个或多个答案） 1. 免疫细胞包括：（）A. 淋巴细胞B. 红细胞C. 抗原提呈细胞D. 粒细胞E. 巨噬细胞 2. 黏膜免疫系统包括：( )A. 扁桃体B. 阑尾C. M细胞D. 派氏集合淋巴结E. 脾索 3. 超抗原的特点是：（）A. 可以多克隆激活某些T细胞B. 必须经过抗原提呈细胞的加工和处理C.半抗原D. 有严格的MHC限制性E. 与自身免疫病无关 4. 下列哪些物质的有效成分不包括免疫球蛋白（）A. 破伤风抗毒素 B. 变应素C.胎盘球蛋白D. 植物血凝素 E. 免疫血清 5. C3b的生物学效应包括（）A. 溶解细胞B. 调理作用C. ADCC D. 免疫调节E. 趋化作用 6. 下列细胞因子的受体与IL-6受体共用β链（gp130）的有（）A. IL-10 B. IL-11 C. LIF D. G-CSF E. TNF 7. 固有免疫细胞表面模式识别受体包括（）A. TLR B. IL-6受体C. 甘露糖受体D. C3b受体E. IgG Fc受体 8. T细胞TCR识别抗原的共受体分子是（）A. CD2 B. CD3 C. CD4 D. CD8 E. CD9 9. 下列内分泌因子中下调免疫应答的有（）A．雌激素B．抗利尿激素C．皮质类固醇D．胰岛素E．甲状腺素 10. 口服免疫原最不可能建立的是（）A．胃肠黏膜局部免疫耐受B．全身免疫耐受C．中枢免疫耐受D．外周B细胞免疫耐受E．外周T细胞免疫耐受 11. 下列哪些疾病不属于自身免疫性疾病（）A．SLE B．溃疡性结肠炎C．类风湿性关节炎D．荨麻疹E．重症肌无力 12. 下列疾病属于SCID的有（）A．性联重症联合免疫缺陷病B．遗传性血管神经性水肿C．腺苷脱氨酶缺陷病D．DiGeorge综合征E．Bruton病 13. 下列抗原中属于癌-睾丸（C-T）抗原的有：（）A．MAGE-A1 B. CEA C. AFP D. NY-ESO-1 E. Her-2 14. 引起排斥反应的抗原有（）A．MHC-I类抗原B．MHC-II类抗原C．MHC-III类抗原D．癌胚抗原E．血型抗原 15. 溶血空斑试验是用于检测（）A．B细胞B．T细胞C．树突状细胞D．NK细胞E．中性粒细胞 16. CTLA-4的配体是：（）A. CD23 B. CD32 C. CD21 D. CD80/86 E. CD51/CD29 17. 有多个重复B细胞表位的抗原是：( )A. Supper antigen B. TD-Ag C. TI-Ag D. 构象决定基E. 线性决定基 18. 下列那些作用与B细胞在生发中心的分化成熟无关：（）A. 抗原受体编辑B.Ig亲和力成熟C.Ig类别转换D. B细胞表达MHC I类抗原E. 体细胞突变 19. 肿瘤相关抗原（）A. 只表达于肿瘤细胞，正常组织不表达B. 凡肿瘤细胞均有表达C. 高表达于肿瘤细胞，正常组织不表达或低表达D. 表达于胚胎细胞和肿瘤细胞 E. 只在肿瘤周围组织表达 20. 新生儿先天性胸腺缺陷，可导致（）A. 细胞免疫缺陷，抗体产生正常B. 细胞免疫正常，抗体产生下降 C. 细胞免疫缺陷，抗体产生下降D. 细胞吞噬功能障碍E. 补体系统功能紊乱 21. 可以促进B细胞产生IgE的细胞因子是（）A. IL-1 B. IL-2 C. IL-3 D. IL-4 E. IL-8 22. 抗体分子的CDR位于哪个结构域（）A. CH和CL B. VH和VL C. VH和CH D. VH和CL E. CH 23. 用以下哪种标记最适合鉴别或分离成熟的T细胞（）A. CD3 B. CD4 C. CD8 D. CD14 E. CD19
可生物降解高分子材料的分类及应用
四川工业学院学报 Journa l of S ich ua n Uni vers ity o f Sc ience and Tec hnolog y 文章编号:1000-5722(2003)增刊-0145-03 收到日期:2003-03-22 基金项目:中国石油天然气集团公司中青年创新基金项目(部(基)349):四川工业学院人才引进项目(0225964) 作者简介:王周玉(1977-),女,四川省彭州市人,西华大学生物工程系助教,硕士,主要从事高聚物的合成、改性性质及其应用的研究。 可生物降解高分子材料的分类及应用 王周玉,岳 松,蒋珍菊,芮光伟,任川宏 (西华大学生物工程系,四川成都 610039) 摘 要: 本文作者对天然高分子材料、微生物合成高分子材料、化学合成高分子材料及掺混型高分子材料四类生物降解高分子材料进行了综述,并对可生物降解高分子材料在包装、餐饮业、农业及医药领域的应用作了简要介绍。 关键词: 生物降解;高分子材料;应用 中图分类号:O631.2 文献标识码:B 0前言 塑料是应用最广泛的高分子材料,按体积计算已居世界首位,由于其难以降解,随着用量的与日俱增,废弃塑料所造成的白色污染已成为世界性的公害。意大利、德国、美国等国家已率先以法律形式,规定了必须使用降解性塑料的塑料产品范围;我国目前的塑料生产和使用已跃居世界前列,每年产生几百万吨不可降解的废旧物,严重污染着环境和危害着我们的健康。可见开发可降解高分子材料、寻找新的环境友好高分子材料来代替塑料已是当务之急。 降解高分子材料[1]是指在使用后的特定环境条件下,在一些环境因素如光、氧、风、水、微生物、昆虫以及机械力等因素作用下,使其化学结构能在较短时间内发生明显变化,从而引起物性下降,最终被环境所消纳 的高分子材料。根据降解机理[1,2] 的不同,降解高分子材料可分为光降解高分子材料、生物降解高分子材料、光-生物降解高分子材料、氧化降解高分子材料、复合降解高分子材料等,其中生物降解高分子材料是指在自然界微生物或在人体及动物体内的组织细胞、酶和体液的作用下,使其化学结构发生变化,致使分子量下降及性能发生变化的高分子材料。生物降解高分子材料的应用广泛,在包装、餐饮业、一次性日用杂品、药物缓释体系、医学临床、医疗器材等诸多领域都有广阔的应用前景,所以开发生物降解高分子材料已成为世界范围的研究热点。 1 生物降解高分子材料的分类 根据生物降解高分子材料的降解特性可分为完全 生物降解高分子材料(Biodegradable materials)和生物破坏性高分子材料(或崩坏性,Biodestruc tible ma terials);按照其来源的不同主要分为天然高分子材料、微生物合成高分子材料、化学合成高分子材料和掺混型高分子材料四类。 1.1 天然高分子材料 [3,4] 天然高分子物质如淀粉、纤维素、半纤维素、木质素、果胶、甲壳素、蛋白质等来源丰富、价格低廉,特别是天然产量居首位的纤维素和甲壳素,年生物合成量超过1010 吨。利用它们制备的生物高分子材料可完全降解、具有良好的生物相容性、安全无毒,由此形成的产品兼具天然再生资源的充分利用和环境治理的双重意义,因而受到各国的重视,特别是日本。如日本四国工业技术实验所用纤维素和从甲壳素制得的脱乙酰壳聚糖复合,采用流延工艺制成的薄膜,具有与通用薄膜同样的强度,并可在2个月后完全降解;他们还对壳聚糖)淀料复合高分子材料进行了大量的研究工作,发现调节原料的比例、热处理温度,可改变高分子材料的强度和降解时间。 天然高分子材料虽然具有价格低廉、完全降解等诸多优点,但是它的热力学性能较差,不能满足工程高分子材料加工的性能要求,因此对天然高分子进行化学修饰、天然高分子之间的共混及天然高分子与合成高分子共混以制得具有良好降解性、实用性的生物降解高分子材料是目前研究的一个主要方向。1.2 微生物合成高分子材料[3,4,5] 微生物合成高分子材料是由生物通过各种碳源发
生物降解材料
生物降解材料： 1.天然生物材料如淀粉、纤维素的改性材料制成的塑料； 2.化学合成聚脂：PLA、PCL、PBS、PPC等； 3.微生物发酵合成高分子化合物：PLA、PHA； 4.转基因植物合成高分子化合物：PHA。 生物基含量和价格 材料优缺点
1.可完全生物降解 2.可替代大部分塑料，价格可以和石油塑料 竞争 3.分子结构多样性，综合性能好 4.可单独使用或和淀粉等其他生物质共同 使用 5.可取代PCL、Ecoflex等石油基可降解材 料 6.核心技术门槛高竞争者很难模仿进入材料具体价格
生物降解塑料生产厂家 种类公司型号产能（吨/年）
PLA PLA产业链
→ → → 产业链分析： 1.PLA改性材料生产企业：其生产受到上下游的影响比较严重。 2.PLA生产企业：此类企业上游供给影响不大，来源和供应量很充足，关键在于企业的生产技术和产能。美国的natureworks处于领先地位，每年14万吨的产能，巴斯夫、日本三井和荷兰普拉克都有超万吨的产能。国内海正生物和金发科技分别拥有5000吨左右的产能，在国内PLA生产商中实力较强。 3.PLA原料（中间物）生产商：PLA生产主要有一步法和两步法两种工艺，两步法应用较多，即先由乳酸聚合并解聚得到中间体丙交酯，再由丙交酯开环聚合得到PLA，两步法中，中间体丙交酯的生产成本和纯度直接影响PLA产品的成本和性能。 4.PLA改性材料使用企业：这些企业使用PLA改性材料作为生产进一步产品的原料，成品涵盖范围包括农业、工业、门用等等领域。PLA材料经过改性和复合，其理化性质得到相应改进，可以采用传统吹塑、热塑机械生产成品，传统成品生产企业的转换成本并不高，而此类企业在国内数量巨大，并不构成对于PLA改性材料生产企业的直接瓶颈。 5.消费者终端：消费者的最终需求，决定了PLA改性和复合材料使用企业对PLA改性材料的间接需求，成为真正的、可能的需求瓶颈。因此，分析PLA改性和复合材料行业下游的关键，在于消费者终端的分析。 PLA改性材料企业
2016年上半年黑龙江全科学主治医师(高级职称)考试题
2016年上半年黑龙江全科学主治医师（高级职称）考试题 本卷共分为2大题60小题，作答时间为180分钟，总分120分，80分及格。一、单项选择题(在每个小题列出的四个选项中只有一个是符合题目要求的，请将其代码填写在题干后的括号内。错选、多选或未选均无分。本大题共30小题，每小题2分，60分。) 1、男性，66岁，高血压史30年，糖尿病史1年，未规律服用降糖药物，身高164cm，体重72kg，血清肌酐146μmol/L，空腹血糖8.5mmol/L，不应采取的治疗方案是 A．二甲双胍B．胰岛素C．瑞格列奈D．格列喹酮E．阿卡波糖+中效胰岛素2、肝肾虚所致经行发热的最佳选方是 A．蒿芩地丹四物汤B．保阴煎C．左归丸D．血府逐瘀汤E．补中益气汤 3、妊娠贫血心脾两虚证的常用方 A．六味地黄丸B．四物汤C．地黄饮子D．归脾汤E．八珍汤 4、关于强直性脊柱炎(AS)的病理表现错误的是 A．骶髂关节是AS最早累及的部位B．淀粉样变性和骨折属原发性病变C．可累及内脏或其他组织如：虹膜炎，主动脉根炎D．复发性非特异性炎症主要见于滑膜、关节囊、韧带或肌腱骨附着点E．附着点病为AS的基本病变 5、多寐的病因多责之于： A．脾虚湿盛B．心虚胆怯C．心肾不交D．肾精亏耗E．阴虚火旺 6、在牙体组织的反应中哪项反应与矫治力无关 A．矫治力过大则可发生牙髓炎B．牙髓组织可发生轻度充血，对温度的变化敏感C．牙根特发性吸收D．牙根尖进行性吸收E．牙骨质的吸收与牙槽骨相比，其吸收范围小程度轻 7、脑囊虫病出现癫痫发作主要因为 A．脑膜包囊B．小脑包囊C．脑室内包囊D．皮质包囊E．基底池内包囊 8、流感病毒分甲、乙、丙三型的依据是 A．神经氨酸酶抗原性B．病毒内部和外部的抗原结构C．植物血凝素抗原性D．临床表现E．流行病学特征 9、琼脂印膜材料的凝固原理为 A．聚合变化B．物理温度变化C．物理压力变化D．离子交换变化E．化学变化 10、盗汗又称为 A．寝汗B．黄汗C．战汗D．绝汗E．以上都不对 11、慢性血行播散型肺结核多数 A．无明显中毒症状B．X线胸片表现为哑铃型阴影C．多发生干酪样坏死D．有明显中毒症状E．结核菌素试验阳性 12、传染性非典型肺炎的病理改变主要显示 A．支气管痉挛B．弥漫性肺泡损伤和炎症细胞浸润C．肺泡水肿D．坏死组织阻塞细支气管E．炎症细胞浸润 13、女子在青春期，月经异常责之于 A．脾B．肺C．心D．肾E．肝 14、正常情况下，基底细胞分裂周期约为：
注射用重组人粒细胞巨噬细胞刺激因子
注射用重组人粒细胞巨噬细胞刺激因子 【药品名称】 通用名称：注射用重组人粒细胞巨噬细胞刺激因子 英文名称：Propranolol Hydrochloride T ablets 【成份】 本品主要组成成分： 活性成分为重组人粒细胞巨噬细胞集落刺激因子（rhGM-CSF）。 非活性成分包括甘露醇，磷酸钠，柠檬酸，聚乙二醇4000和人血白蛋白。 【适应症】 适用于治疗和预防骨髓抑制性治疗引起的白细胞减少症。可预防白细胞减少症伴发的潜在的感染的发生，使患者能更好地耐受化学药物的治疗。 【用法用量】 剂量视具体病情而定，应调节剂量使白细胞维持在正常水平。癌症化疗或放疗后24小时，按3-10μg/kg，皮下注射，每日一次，持续5-10天（注意：本药不应与抗癌药物同时使用，化疗停止24小时后方可使用）。用1毫升注射用水溶解（切勿剧烈振荡），可在腹部、大腿外侧或上臂三角肌皮肤处进行皮下注射（要求：注射后局部皮肤隆起约1cm2以便药物缓慢吸收）。 【不良反应】 大部分不良反应多属轻度中度。严重的或危及生命的反应罕见，并且一般是当剂量大于推荐剂量范围时才发生。最常见的不良反应为发热、皮疹，发热可用扑热息痛控制，胸痛、骨痛和腹泻等不良反应较少见。据国外报道，低血压和低氧综合症在首次给药时可能出现，但以后给药则无此现象，本品在临床研究中，尚未发现，但在使用本品过程中建议医生参考。另
外，据国外研究表明，对肺癌病人使用本药治疗时应特别仔细加以观察。 【禁忌】 本药禁用于对rhGM-CSF或该制剂中其它成份有过敏史的病人，同样禁用于自身免疫性血小板减少性紫癜的病人。 【注意事项】 1 本药应在专科医生指导下使用，剂量视病人情况而定，病人对rhGM-CSF的治疗反应和耐受性个体差异较大，应调节剂量使病人白细胞数量维持在所期望的水平。病人在治疗前及开始治疗后定期观察外周血白细胞或中性粒细胞、血小板数据的变化。血象恢复正常后立即停药或采用维持剂量。 2 接受本药的病人偶而会产生急性过敏反应，应立即停药，并给予适当治疗。 3 据国外文献报告：（1）rhGM-CSF很少引起胸膜炎或胸腔积液。心包炎的发生率为2%，心包积液的发 【药物相互作用】 由于rhGM-CSF可以引起血浆白蛋白降低，因此，同时使用具有高血浆白蛋白结合力的药物时应注意调整药物剂量。虽未发现rhGM-CSF不良的药物相互作用的报导，但也不能完全排除存在药物相互作用的可能性。 【药理作用】 药理作用 本品为利用基因重组技术生产的人粒细胞巨噬细胞集落刺激因子（rhGM-CSF）。rhGM－CSF作用于造血祖细胞，促进其增殖和分化，并刺激粒细胞、单核细胞和T细胞的生长，促进成熟细胞向外周血释放，另外，还能促进巨噬细胞及嗜酸性细胞的多种功能。 毒理研究
辽宁生物降解塑料项目投资建议书
辽宁生物降解塑料项目 投资建议书 规划设计/投资方案/产业运营
辽宁生物降解塑料项目投资建议书说明 《关于进一步加强塑料污染治理的意见》指出，到2020年，率先在部分地区、部分领域禁止、限制部分塑料制品的生产、销售和使用；到2022年底，一次性降解塑料制品消费量明显减少，替代品得到推广，在电商、快递、外卖等新兴领域，形成一批可复制、可推广的塑料减量和绿色物流模式；到2025年，塑料制品生产、流通、消费和回收处置等环节的管理制度基本建立，替代产品开发应用水平进一步提升，重点城市塑料垃圾填埋量大幅降低。2025年前，国内将逐渐限制、禁止使用不可降解塑料袋、一次性塑料餐具、宾馆和酒店一次性塑料制品和快递塑料袋。 该PBAT生物降解塑料项目计划总投资5851.90万元，其中：固定资产投资4682.58万元，占项目总投资的80.02%；流动资金1169.32万元，占项目总投资的19.98%。 达产年营业收入8873.00万元，总成本费用6729.64万元，税金及附加101.62万元，利润总额2143.36万元，利税总额2540.62万元，税后净利润1607.52万元，达产年纳税总额933.10万元；达产年投资利润率36.63%，投资利税率43.42%，投资回报率27.47%，全部投资回收期5.14年，提供就业职位135个。
项目建设要符合国家“综合利用”的原则。项目承办单位要充分利用国家对项目产品生产提供的各种有利条件，综合利用企业技术资源，充分发挥当地社会经济发展优势、人力资源优势，区位发展优势以及配套辅助设施等有利条件，尽量降低项目建设成本，达到节省投资、缩短工期的目的。 ...... 报告主要内容：项目总论、项目必要性分析、项目市场研究、投资方案、项目选址规划、土建方案说明、工艺先进性、项目环保分析、项目安全保护、投资风险分析、项目节能情况分析、实施进度、投资方案计划、项目盈利能力分析、综合评价结论等。 随着全球环境保护力度加大，“限塑”已在60多个国家实行。我国自2004年开始鼓励降解塑料的推广应用，2008年开始实行“限塑”。近几年法规措施不断趋严，2020年1月19日，国家发展改革委、生态环境部公布《关于进一步加强塑料污染治理的意见》，提出分阶段（2020、2022、2025年）限制、禁止使用不可降解塑料产品的行动目标与措施。在严格的限塑、禁塑令下，开发应用可降解塑料势在必行。PBAT是一种全生物可降解塑料，可广泛应用于超市购物袋、外卖餐盒、农用地膜等领域。随着“限塑令”的推出和绿色消费市场的扩大，PBAT等可生物可降解塑料呈现出良好的市场前景，成为当前国内降解塑料领域投资和关注的热点。
重组人粒细胞集落刺激因子注射液使用说明书
重组人粒细胞刺激因子注射液使用说明书 （欣粒生?使用说明书） 请仔细阅读说明书并在医生指导下使用 [药品名称] 通用名称：重组人粒细胞刺激因子注射液 商品名称：欣粒生? 英文名称 汉语拼音： [成分]重组人粒细胞刺激因子，辅料为醋酸钠、冰醋酸、甘露醇、聚梨酸酯 [性状] 无色透明液体，。 [适应症] .促进骨髓移植后中性粒细胞计数增加。 .癌症化疗引起的中性粒细胞减少。包括恶性淋巴瘤、小细胞肺癌、胚胎细胞瘤（睾丸肿瘤、卵巢肿瘤等）、神经母细胞瘤等。 .骨髓异常增生综合征伴发的中性粒细胞减少症。 .再生障碍性贫血伴发的中性粒细胞减少症。 .先天性、特发性中性粒细胞减少症。 [规格] μ支、μ支、μ支 [用法用量] .促进骨髓移植后中性粒细胞数增加。 成人及儿童的推荐剂量为μ, 通常自骨髓移植后次日至第五日给予静脉滴注，每日一次。 当中性粒细胞计数上升超过 时,停药,观察病情。 在紧急情况下，无法确定本药的停药指标中性粒细胞数时，可用白细胞的半数来估算中性粒细胞数。 .癌症化疗后引起的中性粒细胞减少症。 .恶性淋巴瘤、肺癌、卵巢癌、睾丸癌和神经母细胞瘤化疗后次日开始给药,成人及儿童推荐剂量为μ,皮下注射,每日一次。化疗后中性粒细胞数降低到(白细胞计数)以下的成人患者和化疗后中性粒细胞数减少到(白细胞计数)以下的儿童患者应给予本品。 经用药后，如果中性粒细胞计数经过最低值时期后增加到(白细胞计数)以上时，应观察病情，同时停用本品。 如皮下注射困难，应改为μ静脉滴注，成人及儿童，每日一次。 .急性白血病 通常在化疗给药结束后（次日以后），骨髓中的幼稚细胞减少到足够低的水平且外周血中无幼稚细胞时，开始给药，成人及儿童推荐剂量为μ，每日一次，皮下或静脉给药（包括静脉点滴）。 紧急情况下，无法确定本药的给药及停药时间的指标中性粒细胞数时，可用白细胞的半数来估算中性粒细胞数。 .骨髓异常增生综合征伴发的中性粒细胞减少症 中性粒细胞计数低于的患者，给予本品μ皮下或静脉滴注，每日一次。 如果中性粒细胞计数超过 ，应减少剂量或终止给药，并观察病情。 .再生障碍性贫血伴发中性粒细胞减少症 【核准日期】 【修改日期】
福建生物降解塑料项目投资分析报告
福建生物降解塑料项目投资分析报告 规划设计/投资方案/产业运营
报告说明— 生物降解塑料是指在土壤、沙土等自然条件下，可与微生物作用降解成为二氧化碳、水等小分子的塑料材料。PBAT是生物降解塑料研究中非常活跃和市场应用最好降解材料之一。PBAT是己二酸丁二醇酯（PBA）和对苯二甲酸丁二醇酯（PBT）的共聚物，兼具PBA和PBT的特性，既有良好的延展性、断裂伸长率、耐热性和抗冲击性能，又具有优良的生物降解性。PBAT成膜性能良好，通常与PLA树脂等共混改性制成终端产品，可用于塑料包装薄膜、农用地膜、一次性用具等。 该PBAT生物降解塑料项目计划总投资8033.42万元，其中：固定资产投资6236.18万元，占项目总投资的77.63%；流动资金1797.24万元，占项目总投资的22.37%。 达产年营业收入14198.00万元，总成本费用10984.45万元，税金及附加139.18万元，利润总额3213.55万元，利税总额3795.98万元，税后净利润2410.16万元，达产年纳税总额1385.82万元；达产年投资利润率40.00%，投资利税率47.25%，投资回报率30.00%，全部投资回收期4.83年，提供就业职位283个。 全球塑料产量约为3.59亿吨，其中生物塑料约占1%，2018年全球生物可降解塑料的市场金额超过11亿美元，产能合计约91.2万吨，预计2023年有望实现17亿美元与128.8万吨。欧洲是可降解塑料的主要市场，
占全球55%、亚太地区占全球25%，北美需求占19%。可降解塑料的应用范围不断扩大，包括包装、纺织纤维、汽车运输等。包装占比最大为58%。国内2019年塑料制品产量为8184万吨，其中可降解塑料优先推广的农用塑料薄膜使用量为246万吨。根据智研咨询国内可降解塑料的消费量在50万吨左右，市场潜能巨大。据统计，中国每年约消耗购物袋400万吨、农膜246万吨、外卖包装260万吨，且随着快递、外卖业务的快速发展，塑料需求持续增长。而对于这些领域，特别适用可降解塑料。假设替代10%，即可新增90万吨以上可降解塑料需求。我们认为随着技术进步、规模化生产、成本下降、环保理念提升，可降解塑料未来成长空间10倍以上。
重组人粒细胞集落刺激因子
【药品名称】重组人粒细胞集落刺激因子注射液 【英文名称】Recombinant Human Granulocyte Colony Stimulating Factor Injection 【药品别名】 商品名：惠尔血(GRAN) 结构式与分子量：根据已知来源于人类膀胱癌细胞的粒细胞集落刺激因子的基因，通过基因重组产生的含有175个氨基酸残基（C845H1339N223O243S9；分子量：18,798.88）的蛋白质。 主要组成成分：重组人粒细胞集落刺激因子 【性状】 本品为无色澄明液体。 【药理、毒理】 本品为利用基因重组技术生产的人粒细胞集落刺激因子（rhG-CSF）。与天然产品相比，生物活性在体内、外基本一致。G-CSF是调节骨髓中粒系造血的主要细胞因子之一，可选择性地作用于粒系造血祖细胞，促进其增殖、分化，并可增加粒系终末分化细胞即外周血中性粒细胞的数目与功能。 【药代动力学】 健康成年男性单次静脉或皮下注射本品1.0(g/kg，其药代动力学参数如下：静脉给药者的半衰期为 1.40小时，AUC为21.6ng(hr/ml；皮下注射者的半衰期为 2.15小时，AUC为11.7ng(hr/ml，生物利用度为0.54。连续6天静点或皮下注射本药后，开始给药日与第6日的血浆中药物浓度无显著性差异，无蓄积现象。 给健康成年男性静点本药3.0(g/kg或皮下注射1.0(g/kg后，测定24小时尿中的药物浓度，结果均在测定界限以下。 【适应症】 1．促进骨髓移植后中性粒细胞计数增加。 2．癌症化疗引起的中性粒细胞减少症。包括恶性淋巴瘤、小细胞肺癌、胚胎细胞瘤（睾丸肿瘤、卵巢肿瘤等）、神经母细胞瘤等。 3．骨髓增生异常综合征伴发的中性粒细胞减少症。 4．再生障碍性贫血伴发的中性粒细胞减少症。 5．先天性、特发性中性粒细胞减少症。 【用法与用量】 1．促进骨髓移植后中性粒细胞计数增加 成人和儿童的推荐剂量为300(g/m2，通常自骨髓移植后次日至第5日给予静脉滴注，每日一次。 当中性粒细胞数上升超过5000/mm3时，停药，观察病情。 在紧急情况下，无法确认本药的停药指标中性粒细胞数时，可用白细胞数的半数来估算中性粒细胞数。 2．癌症化疗后引起的中性粒细胞减少症。 经用药后,如果中性粒细胞计数经过最低值时期后增加到5,000/mm3（WBC：10,000/mm3）以上，应停药,观察病情。 A.恶性淋巴瘤、肺癌、卵巢癌、睾丸癌和神经母细胞瘤化疗后（次日后）开始给药。成人及儿童推荐剂量为50(g/m2,皮下注射，每日一次。化疗后中性粒细胞降到1,000/mm3（WBC：2,000/mm3）以下的成人患者应给予本品。化疗后中性粒细胞计数减少到500/mm3（WBC：1,000/mm3）以下的儿童患者,应皮下注射50(g/m2的本品,每日一次。 如皮下注射困难,应改为100(g/m2静脉滴注（成人及儿童）,每日一次。
生物降解材料
生物降解材料https://www.wendangku.net/doc/c39151775.html,work Information Technology Company.2020YEAR
生物降解材料： 1.天然生物材料如淀粉、纤维素的改性材料制成的塑料； 2.化学合成聚脂：PLA、PCL、PBS、PPC等； 3.微生物发酵合成高分子化合物：PLA、PHA； 4.转基因植物合成高分子化合物：PHA。
6.核心技术门槛高竞争者很难模仿 进入 生物降解塑料生产厂家 种类公司型号产能（吨/
PLA PLA 产业链 产业链分析： 1.PLA 改性材料生产企业：其生产受到上下游的影响比较严重。
2.PLA生产企业：此类企业上游供给影响不大，来源和供应量很充足，关键在于企业的生产技术和产能。美国的natureworks处于领先地位，每年14万吨的产能，巴斯夫、日本三井和荷兰普拉克都有超万吨的产能。国内海正生物和金发科技分别拥有5000吨左右的产能，在国内PLA生产商中实力较强。 3.PLA原料（中间物）生产商：PLA生产主要有一步法和两步法两种工艺，两步法应用较多，即先由乳酸聚合并解聚得到中间体丙交酯，再由丙交酯开环聚合得到PLA，两步法中，中间体丙交酯的生产成本和纯度直接影响PLA产品的成本和性能。 4.PLA改性材料使用企业：这些企业使用PLA改性材料作为生产进一步产品的原料，成品涵盖范围包括农业、工业、门用等等领域。PLA材料经过改性和复合，其理化性质得到相应改进，可以采用传统吹塑、热塑机械生产成品，传统成品生产企业的转换成本并不高，而此类企业在国内数量巨大，并不构成对于PLA改性材料生产企业的直接瓶颈。 5.消费者终端：消费者的最终需求，决定了PLA改性和复合材料使用企业对PLA改性材料的间接需求，成为真正的、可能的需求瓶颈。因此，分析PLA改性和复合材料行业下游的关键，在于消费者终端的分析。 PLA改性材料企业 PLA PHA 基本性能： 生物相容性，良好的力学性能，非线性光学性，气体隔离性，耐水解性能，压电性，良好的加工性能，耐热性。 性能指标： 分子量： 1000-1000000 玻璃态温度： -60℃~+60℃ 熔点： 40℃~190℃ 结晶度： 10%~60% 断裂伸长率： 5%~1000%
生物降解高分子材料
生物降解高分子材料 肖群 （东北林业大学材料科学与工程学院,黑龙江哈尔滨 150040） 摘要：高分子材料在日常生活中的使用量越来越大．然而高分子材料给人们生活带来便利、改善生活品质的同时，其使用后的大量塑料废弃物也与日俱增。给人类赖以生存的环境造成了不可忽视的负面影响。本文简要介绍生物降解高分子材料的定义、降解机理及影响因素的基础上，较为全面的阐述了当前生物降解高分子材料的应用领域。 关键词：生物降解，医用生物材料， 1 前言 聚合物工业蓬勃发展的同时也导致了环境污染的加剧，引起了人们对聚合物废料处理的关注。目前全世界每年生产塑料约1．2亿吨．用后废弃的大约占生产量的50％～60％。废塑料的处理以掩埋和焚烧为主，但这两种处理方法会产生新的有害物质。对此，一些国家实行了3R工程，即减少使用、重复使用和回收循环。但对一些回收困难、不宜回收或需要追加很大能量才能回收的领域(如食品包装、卫生用品)，实施3R工程很困难，而如果使用生物降解材料则十分有利[1]。 2生物降解高分子材料定义降解机理 2．1生物降解高分子定义 根据美国ASTM定义生物降解高分子材料是指在一定的条件下．一定的时间内能被细菌、霉菌、藻类等微生物降解的高分子材料[2，3,4]。真正的生物降解高分子在有水存在的环境下，能被酶或微生物水解降解，从而高分子主链断裂，分子量 逐渐变小，以致最终成为单体或代谢成CO 2和H 2 O[5]。 2.2生物降解高分子材料的降解机理 生物降解机理和光一生物降解机理．完全生物降解机理大致有三种途径：①生物物理作用：由于生物细胞增长而使聚合物组分水解，电离质子化而发生机械性的毁坏．分裂成低聚物碎片：②生物化学作用：微生物对聚合物作用而产生新 物质(CH 4、C0 2 和H 2 0)：③酶直接作用：被微生物侵蚀部分导致材料分裂或氧化崩 裂。而光一生物降解机理则是材料中的淀粉等生物降解剂首先被生物降解，增大表面／体积比，同时，日光、热、氧引发光敏剂等使高聚物生成含氧化物，并氧化断裂．分子量下降到能被微生物消化的水平。进一步研究发现．不同的生物降解高分子材料的生物降解性与其结构有很大关系，包括化学结构、物理结构、表面结构等。 对不同种类的生物降解材料而言．它们降解机理的不同决定了它们具有不同的性质。天然降解高分子材料．其本身来源于生物体，能保证足够的细胞及组织亲和性．降解周期一般较短．最终降解产物为多糖或氨基酸．容易被机体吸收．但是这种材料力学性能差。难于满足组织构建的速度要求，应用时需要进行改性。化学合成的生物降解材料的组成、结构和降解行为更易于控制。比如降解速度和强度可调．易构建高孔隙率三维支架．但材料本身对细胞亲和力弱．往往需要引入适量能促进细胞黏附和增值的活性基团、生长因子或黏附因子等。[6] 3生物降解高分子材料的种类及降解过程