FOOD AND DRUG ADMINISTRATION
PROGRAM 7356.002A COMPLIANCE PROGRAM GUIDANCE MANUAL
CHAPTER 56 – DRUG QUALITY ASSURANCE
FIELD REPORTING REQUIREMENTS:
Establishment Inspection Reports (EIRs) are to be created and filed electronically using the specific module in TurboEIR or replacement system that is accessible to both ORA and CDER.
For inspections of routine commercial manufacturing classified as Official Action Indicated (OAI) due to failure to comply with 21 CFR Part 210 and 211 Current Good Manufacturing Practice (CGMP) as they apply to sterile drug process inspections, submit advisory, administrative, or judicial action recommendations via MARCS-CMS in accordance with the Regulatory Procedures Manual (RPM). Districts should immediately report significant issues according to current FACTS, Panorama and CMS procedures. This includes promptly filing and changing OAI notifications.
During an inspection, if you obtain information pertaining to inadequate adverse drug experience (ADE) reporting, unapproved drug issues, or post-approval reporting violations (application supplements, Field Alert Reports (FARs), etc.), report in accordance with directions provided in the applicable compliance programs and under separate captions in the EIR. Data system information about these inspectional activities should be reported under separate Program Assignment Codes (PACs). Expansion of coverage under these programs into a CGMP inspection should be reported under this compliance program.
The Districts are requested to use this compliance program for all sterile drug process inspections. NOTE: Districts should assure that each operation performed by direction of this program circular is entered against the correct Product Code and Program/Assignment Code (P/AC).
TABLE OF CONTENTS
PART I BACKGROUND (4)
PART II IMPLEMENTATION (5)
2.1 Objective (5)
2.2 Program Management Instructions (5)
A. Strategy (5)
B. Inspection Planning (6)
C. Profile Reporting (6)
PART III INSPECTIONAL (7)
3.1 Types of Sterilization (7)
A. Terminal sterilization (7)
B. Aseptic processing (7)
3.2 Reporting (8)
3.3 Inspection Approaches (9)
3.4 System Inspection Coverage (11)
3.5 Quality System (11)
3.6 Facilities and Equipment System (13)
A. Facilities (13)
B. Equipment (14)
3.7 Materials System (19)
3.8 Production System (21)
3.9 Packaging and Labeling System (27)
3.10 Laboratory Control System (27)
3.11 Sampling (29)
PART IV ANALYTICAL (30)
PART V REGULATORY/ADMINISTRATIVE STRATEGY (31)
PART VI REFERENCES, ATTACHMENTS AND PROGRAM CONTACTS (33)
6.1 References (33)
6.2 Attachments (34)
6.2 Contacts (34)
PART VII CENTER RESPONSIBILITIES (36)
ATTACHMENT A .................................................................................................................A
[end Cover Page]
PART I - BACKGROUND
This program covers the manufacture and testing of all sterile drug products, including drugs that are sterilized by filtration or other means and aseptically processed, and drug products that are terminally sterilized. The type of products covered by this program include sterile bulk drugs, ophthalmic drugs, otic dosage forms, small volume parenteral (SVS) products for small molecule and licensed biological therapeutic drug products, large volume parenteral (LVP) products, and any other drug products required to be sterile or labeled as sterile. Center for Biologics Evaluation and Research (CBER) regulated products and veterinary drug products are excluded from coverage under this program.
The guidance information in this program is tailored to sterile manufacturing operations and should be used in conjunction with the Compliance Program for Drug Manufacturing Inspections (CP 7356.002).
In 2004, Food and Drug Administration (FDA) published the Guidance for Industry Sterile Drug Products Produced by Aseptic Processing-- Current Good Manufacturing Practice, which is referred to throughout this Compliance Program as FDA’s “2004 Aseptic Processing Guidance.” The document represents FDA’s current thinking on Current Good Manufacturing Practices (CGMPs) for aseptically processed drugs.
The Guidance for Industry does not establish mandatory requirements and should not be referred to as the justification for an inspectional observation. Justification for inspectional observations originates from the CGMP regulations, 21 CFR Parts 210 and 211.
Manufacturers who follow the 2004 Aseptic Processing Guidance are generally considered compliant with CGMP regulations. However, alternate approaches may be used if such approaches satisfy the requirements of 21 CFR Parts 210 and 211.
For technical questions and unusual circumstances encountered during an inspection, investigators are encouraged to contact their District, ORA Office of Medical Products and Tobacco Operations/Division of Medical Products and Tobacco Program Operations and/or CDER for consultation. For questions concerning microbiological analysis, sterility and related sampling concerns, contact ORA Office of Regulatory Science/Medical Products and Tobacco Scientific Staff.
[end Part I]
PART II - IMPLEMENTATION
2.1 OBJECTIVES
The primary objective of this program is to provide guidance for conducting inspections of manufacturers of sterile bulk1 and sterile finished dosage drug products to determine compliance with the Food, Drug, and Cosmetic Act and the Current Good Manufacturing Practice Regulations (CGMPs), Title 21, CFR Parts 210 and 211.
Other objectives include:
?Obtain information on operations impacting on sterility, to identify areas for improvement and correction.
?Evaluate current good manufacturing practices in the sterile drug industry.
?Initiate appropriate action against manufacturers observed to be out of compliance.
2.2 PROGRAM MANAGEMENT INSTRUCTIONS
A. STRATEGY
(1) Inspection of Systems
Inspections of drug manufacturers should be made and reported using the system definitions and organization in this compliance program. Focusing on systems will increase inspection efficiency because the systems are often applicable to multiple profile classes. The selection of the system(s) for coverage will be made by the District Office based on the firm’s specific operation, previous coverage, compliance history, or other priorities determined by the District Office.
The inspection should normally result in a determination of acceptability or non-acceptability for all profile classes. Coverage of a system should be sufficiently detailed, i.e., select an example of each profile class, so that the conclusion about the system’s state-of-control applies to all the profiles classes. However, the determination that a system is adequately controlled for one profile class can be extended to another profile class(es) even if that other profile class(es) was not specifically reviewed. The lead Investigator must consider the uniqueness of the various manufacturing situations at the plant and use their best judgment when selecting profile classes to review.
Selecting specific areas unique functions within a system will be at the discretion of the lead Investigator.
The options for system coverage are described in CPGM 56002. Any given inspection need not cover every system. See P art III - Inspectional.
Complete inspection of one system may necessitate further follow up of some items within the activities of another system(s) to fully document the findings. Such follow up does not constitute full coverage of the other system (and cannot be reported as such in FACTS); nor does that follow up obligate the investigator to perform full coverage of the other system.
1
(2) Inspectional Scope
Inspections of sterile product drug manufacturers are performed as either Full Inspections or Abbreviated Inspections using the systems strategy outlined in Part II –Implementation, of Compliance Program 7356.002, Drug Manufacturing Inspections.
See Part III – Inspectional, of this program for a complete discussion of the coverage requested under these inspection options.
B. INSPECTION PLANNING
Implement this program when sterile drug manufacturers are inspected as part of a regular statutory inspection. CDER will identify firms for inspection based on the risk-based prioritization model on annual performance goals, as part of the initiative to ensure risk-based prioritization of inspection coverage.
Consider using a team approach for conducting inspections when appropriate. Utilize investigators familiar with sterile drug manufacturing and aseptic processing and consider the participation of a microbiologist with expertise in microbial controls. Specifically,
?All team members should be very familiar with FDA’s Guidance for Industry Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice (September
2004).
?Investigators or team members should be well qualified in sterile product manufacturing, and have completed formal training courses in parenteral drug manufacture, aseptic technique,
sterilization methods, and related procedures and equipment. Microbiologists involved should
have experience in sterility, endotoxin testing, and evaluation of microbial controls in
manufacturing.
C. PROFILE REPORTING
Update all applicable profile classes in the profile screen of the FACTS coversheet based on inspection findings. The following is a list of sterile product profile classes effective at the time this program was implemented. Use the codes corresponding to the product and process type covered.
FULL DESCRIPTION
PROFILE
CLASS
LVP Large Volume Parenterals are sterile injectable drugs packaged in containers labeled as containing more than 100 mL. Most are terminally sterilized, but some can be sterilized by
filtration and aseptically processed.
SVT Small Volume Parenterals are sterile injectable drugs packaged in containers labeled as containing less than 100 mL that are terminally sterilized.
SVS Small Volume Parenterals are sterilized by filtration and aseptically processed.
SVL Small Volume Parenteral are sterilized by filtration, aseptically filled and lyophilized.
SLQ Sterile liquid (other than suspensions and emulsions)
SON Sterile ointment
SPW Sterile powder
CSS Sterile bulk drugs that are made by chemical synthesis.
CFS Sterile crude drugs made by fermentation.
CRX API sterile or API intermediate/NEC inorganic/mineral
[end Part II]
PART III - INSPECTIONAL
3.1 TYPES OF STERILIZATION
There are two broad methods to produce a sterile drug product:
?Terminal Sterilization
?Aseptic Processing of sterilized unit components
There are basic differences between the production of sterile drug products using aseptic processing and production using terminal sterilization. Terminal sterilization should be utilized when the product and container/closure system are able to withstand the terminal sterilization process.
A. TERMINAL STERILZATION - The terminal sterilization process usually involves filling and sealing product containers under high quality environmental conditions designed to minimize microbial and particulate contamination of the product. This minimization of upstream bioburden reduces the challenge to the subsequent sterilization process. In most cases, the product, container, and closure have low bioburden, but are not sterile at the time of filling. The product is then subjected to a sterilization process in its final container.
There are various methods of terminal sterilization including:
?Moist Heat Sterilization
?Irradiation
?Ethylene Oxide (typically for assembled components/kits)
Types of sterilization cycles include:
1. Overkill method:
o Generally used for heat stable materials.
o Designed to provide a significant level of sterility assurance regardless of the number and resistance of the actual bioburden organisms in the load.
o Results in greater heat/exposure input to the product or items being sterilized.
2. Bioburden Based cycle:
o Requires studies to determine the number and resistance of the microorganisms found in the product and the bioburden load of the incoming components and containers/closures.
o Cycle development to destroy the microbial load, but not degrade the product.
o Routine bioburden monitoring of batches and ongoing knowledge of the heat/exposure resistance of organisms found in product bioburden, container/closure bioburden and
environmental monitoring samples.
Reference to terminal sterilization: PDA Technical Report No. 1 (Revised 2007) Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control.
B. ASEPTIC PROCESSING - Aseptic processing presents a higher risk of microbial contamination of the product than terminal sterilization. In an aseptic filling process, the drug product, containers and
closures are sterilized separately and then brought together under an extremely high quality environmental condition designed to reduce the possibility of a non-sterile unit. Aseptic processing involves more variables than terminal sterilization. Any manual or mechanical manipulation of the sterilized drug, containers, or closures prior to or during aseptic filling and assembly poses the risk of microbial contamination.
Some types of aseptic processing involve manual manipulations of sterile components, containers, and closures in addition to routine operator interventions in the critical area. Humans are a significant source of contamination in traditional aseptic processing, especially in production lines that require operators to routinely enter critical areas (Class 100, ISO 5, or Grade A) of the filling line. Aseptic processing systems based on more advanced control-based technologies, such as Restricted Access Barrier Systems (RABS) and Blow-Fill-Seal systems, are designed to reduce human interventions in the critical areas of the fill line while an isolator system completely separates the aseptic filling line from the external environment and minimizes employee interaction with the critical area.
Note: More information about Isolator Technology and Blow-Fill-Seal systems is found
in FDA’s 2004 Aseptic Processing Guidance.
When conducting inspections of sterile drug manufacturers, it is important to cover systems and areas within systems that present the greatest risk of product contamination and/or require strict control of processing parameters. For example, if a firm has several aseptic processing lines, cover the line(s) that require the most manual manipulations in the Class 100 (ISO 5) areas. If the firm terminally sterilizes a number of products, review one that is sensitive to heat and requires a product specific (bioburden based) sterilization cycle.
Note: For terminal sterilized products that are aseptically filled prior to terminal sterilization, less rigorous aseptic controls can be considered.
Because of the time limitations often associated with foreign inspections, careful inspection planning is particularly important. Prioritize areas for coverage based upon their potential impact on product quality.
3.2 REPORTING
Follow instructions in the current editions of the IOM (Investigations Operations Manual) and Guide to International Inspection and Travel in preparing the inspection report.
Use Turbo EIR for all reports, both domestic and international, even if a FDA-483 was not issued or was issued outside of Turbo EIR. The “Manufacturing / Design Operations” section of the report should be organized by the systems described in this program that were covered during the inspection. Briefly summarize your review of each covered system in accordance with the key elements outlined in this Compliance Program. Add more details and supporting evidence for the systems found to be deficient.
3.3 INSPECTION APPROACHES
If the sterile drug products to be inspected are radioactive drugs, then Compliance Program 7356.002C, Radioactive Drugs, should be followed as supplementary guidance. This program should not be used for the inspection of Positron Emission Tomography (PET) Drug. Compliance Program 7356.002P is specific for PET drugs.
This program (CP 7356.002A) should also be used in conjunction with Compliance Program
7356.002M, Inspection of Licensed Biological Therapeutic Drug Products for the inspection of sterile licensed biological products.
The CGMP Compliance Program 7356.002 provides general information on the system based approach to conducting inspections of drug manufacturers. It describes the six systems (Quality, Facilities and Equipment, Materials, Production, Packaging and Labeling, and Laboratory) and the two inspection options (Full Inspection and Abbreviated Inspection). It also provides guidance on when each option should be selected and discusses what “state of control” means in relation to the systems inspected. Inspections of sterile drug manufacturers are performed as either Full or Abbreviated inspections using the systems strategy outlined below.
Full Inspections include surveillance or compliance inspections and provide a comprehensive evaluation of the firm’s compliance with CGMP. A Full Inspection will normally include an inspection of at least four systems, one of which must be the Quality System. Under this program, a Full Inspection should include the Facilities & Equipment, and Production Systems due to the critical role these systems play in the sterility assurance of finished product.
Full Inspections (PAC 56002A) are conducted
?when initial inspection of the drug firm is to be conducted;
?when it is the first inspection conducted as a follow-up to a Warning Letter, regulatory action, or significant FDA 483 findings;
?when information obtained during the Abbreviated Inspection reveals significant deficiencies with the firm’s practices and procedures in one or more system areas;
?when there have been significant changes in the firm’s operations since the last inspection; or ?for surveillance purposes at the District’s discretion because the firm has a history of recurring violations, fluctuating in and out of compliance, or when other information (samples,
complaints, Field Alerts, recalls, etc.) calls into question the firm’s ability to produce quality
products.
Abbreviated Inspections (PAC 56002I) may be appropriate if the following two conditions are satisfied:
1. the firm has implemented a formal risk management program that assures effective design and
control (including maintenance). This includes a risk mitigating design of their processing lines that incorporates a modern separation and automation approach (e.g., isolators, closed RABS), and upstream bioburden controls. The responsiveness of the firm’s quality system to potential
hazards is also part of the evaluation, including whether the firm’s program provides robust
daily assurance and effective consumer protection through a formal lifecycle quality risk
management program that proactively uncovers and corrects issues in accord with ICH Q9.
2. the firm has a record of sustained acceptable compliance history and a strong risk management
program.
o the firm produces finished drug products that are terminally sterilized using robust sterilization methods. (Note: Terminal sterilization provides a much more robust process to
ensure sterility); or,
o the firm has implemented robust risk management that provides daily assurance through their overall design and control program;
o at the start of the inspection, conduct an extensive review of sterility assurance data since the last Full Inspection. The review of media fills, sterility testing data, recalls,
defect/adverse event complaints, and reports reveals no findings of sterility failure of a
distributed batch, and
o the firm has a record of satisfactory CGMP compliance (e.g., two consecutive NAI or no more than one VAI inspection), with no Class 1 recalls.
Microbial controls and sterility assurance should be the main focus of an abbreviated sterile drug inspection. The following critical elements of each system (other than the Quality System) should be covered in an Abbreviated Inspection under this program:
?Facilities and Equipment:
o cleaning and disinfection
o facility/equipment layout and air handling system for preventing viable and non-viable contamination
o material flow
o quality control of classified areas, including air pressure balance and HEPA filtration
o trending data supporting the adequacy of clean room quality
o documented investigation into discrepancy
?Materials:
o microbial and bacterial endotoxin control of incoming materials and components
o quality of water supply, maintenance, qualification
o operation of the systems that provide the requisite water and process gases
o documented investigations into OOS, deviations, and discrepancies
?Production:
o observation of adequacy of operator behavior and aseptic techniques during manufacturing o production line operations and interventions
o personnel training in aseptic techniques
o major production line repair or maintenance issues
o risk assessment on microbial and bacterial endotoxin controls, including hold times of critical steps
o validation of sterilization of equipment, container-closures and supplies
o media fills design and results
o documented investigations into, deviations, discrepancies, and OOS results
?Laboratory:
o investigations into OOS, deviations, and discrepancies
o test methods and controls, including adherence to validated methods
o training and qualifications of laboratory personnel
o trending of water system test results
o systems used for recovery, identification and trending of environmental monitoring isolates 3.4 SYSTEM INSPECTION COVERAGE
Compliance Program 7356.002, Drug Manufacturing Inspections, lists the areas that should be covered when inspecting each of the six systems. This program provides additional guidance, by system, for areas of specific concern for sterile drug products.
Attachment A is a list of questions intended to be an aid in conducting inspections and obtaining information needed to assess a firm’s operations. The answers do not have to be reported in the EIR unless they are relevant. The list of questions covers: moist heat sterilization; dry heat
sterilization/depyrogenation; aseptic filling; lyophilization; isolators; environmental monitoring; and biological indicators.
3.5 QUALITY SYSTEM
As noted in Compliance Program 7356.002, the inspection of the quality system is two-phased. The first phase is to evaluate whether the Quality Unit has fulfilled their responsibility regarding the review and approval of procedures and assured their suitability for use. The second phase is to assess the data collected by the firm to identify potential quality problems. For sterile manufacturing operations, this latter objective involves large amounts of data that link to the other inspectional systems. The comprehensive review of such data by the firm is an essential element in assuring that products are produced with a high degree of sterility assurance. It is therefore important to review the firm’s system for using the data to assess the state of control of their manufacturing operations and facility. The data summaries and trend reports maintained by the Quality Unit should be reviewed during every inspection. During a routine CGMP inspection, this review can help determine which option (Full or Abbreviated) to select.
The inspection of the Quality System should include the areas listed in CP7356.002. For this program, the inspection should include a review of all data and reports that may indicate product contamination and sterility assurance issues.
Records pertaining to quality consist of the following:
1. Periodic product evaluations, complaints, adverse events, investigations, Field Alert Reports,
product retain evaluations, complaints, rejected lots, stability, and returned goods that indicate
possible product contamination or risks to patients (for example, hazy or cloudy product,
foreign matter/particulates in injectable products, cracked, and leaky containers).
2. Discrepancy and failure investigations, such as:
o All initial positive sterility tests and endotoxin and media fill failures regardless of final disposition.
o Unexpected results or trends.
o All failures that occurred during validation or revalidation of sterilization / depyrogenation processes.
o All investigations involving media fills / process simulations.
o Environmental (microbial/viable and particle/non-viable counts) and personnel monitoring results that exceed alert or action levels.
o Process deviations or equipment malfunctions that involve critical equipment, such as sterilizers and lyophilizers.
o Out of Specification (OOS) results for assay, impurities, particulate matter, or reconstitution time, if applicable.
o Product rejects (rejects determined during manufacturing and Quality Control test)
3. Trends reports/ summaries of quality indicators:
o For aseptic processing, summary of all media fills performed since last inspection.
o Environmental monitoring trend data (microbial and particle counts).
o Personnel monitoring trend data.
o Summary of water system test results.
4. Summary of change controls for critical utilities and equipment implemented since the last
inspection, for example:
o Sterilizers, lyophilizers, depyrogenation equipment
o Aseptic processing line
o Clean steam generator, process gas system
o WFI and / or Purified Water system
o Air handling systems
o Automated building management system
Every inspection of a sterile drug manufacturer should include a review of the type of information listed above and observation of the manufacturing operations occurring in the critical areas. The information can be used to select other system(s) to be covered during the inspection.
In addition, the review of summary data and observation of operations can focus the inspection on potential problem areas and provides an overview of the effectiveness of the Quality System. The inspection of the Quality System may necessitate follow-up within another system. However, this coverage does not constitute or require complete coverage of these systems.
3.6 FACILITIES AND EQUIPMENT SYSTEM
Compliance Program 7356.002 lists the general areas to cover when inspecting the Facilities and Equipment System. The areas are applicable to sterile drug products and should be covered if this system is selected. The principle objective of an effective sterile drug manufacturing operation from a facility and equipment standpoint is to provide suitable protection of product. The inspectional evaluation of this objective is again two-part:
?Review and evaluate the firm’s rationale for, and adequacy of, the facility and equipment design (Reference: Section IV of FDA’s 2004 Aseptic Processing Guidance).
?Evaluate the data that provide information relevant to the state of control of the facility and equipment.
In addition to the review of design elements and data, investigators should look for visible deficiencies in the facility and equipment, such as cleanliness, equipment deterioration (e.g., warping, corrosion), inaccessible and/or difficult to clean surfaces, and changes to critical equipment or systems that have not been qualified which may impact product quality. Investigator should look for aberrant events due to facility deterioration, a pattern of recurring and uncorrected maintenance issues, and increase or changes in production output that exceed the capacity of the facility and equipment.
A. FACILITIES
Evaluate the design and layout of the facility (e.g., personnel/material flow, cleanroom design). Specifications for clean room areas (layout, air filtration, appropriate air classification, pressure differentials between rooms and areas, temperature, and humidity) should be appropriate, and based on the risk of product contamination with particulate matter and microorganisms. Review the certification and qualification of the clean room areas to verify the areas meet design criteria and specifications. Certification and qualification typically includes data in support of the following: air flow pattern studies, HEPA (High Efficiency Particulate Air) filter integrity testing, air velocity measurement, non- viable particle, and verification of appropriate pressure differentials, temperature and humidity setpoints. Evaluate the airflow pattern (smoke studies) conducted under dynamic conditions to verify the unidirectional airflow and air turbulence within the critical area where sterilized drug product, containers, and closures are exposed to environmental conditions.
?Reference: Section IV of FDA’s 2004 Aseptic Processing Guidance.
?Routine monitoring and maintenance to assure air handling systems continue to operate within established parameters (microbiological monitoring is discussed under the Laboratory Control System).
o Afford special attention to facilities that are performing construction in the clean areas, or at the vicinity of cleanroom. Because microbes (e.g., fungal spores) can be liberated from the
movement of walls and other construction activities, determine if the facility is returned to
acceptable environmental control through proper measures (environmental monitoring,
media fills) before production can resume.
o Verify that environmental monitoring of non-viable particle is occurring during operations including sites where there is the most risk to exposed product, container and closures.
o Check if pressure differentials, temperature, and humidity are continuously monitored during routine production.
o Determine if continuous monitoring systems are alarmed to alert operators of excursions.
o Check if excursions from acceptable ranges are investigated to determine impact on product and that needed corrective actions are taken.
o Evaluate the program for periodic testing / recertification of the HEPA filters in critical areas to maintain appropriate air flow. The tests typically include integrity testing of the
HEPA filters and air velocity checks.
?Sanitization / disinfection of clean room areas, processing lines, and non autoclavable equipment, materials, and components should be reviewed. Focus on the areas where the
sterile product is exposed up to and including sealing operations. These critical areas represent
the highest risk to the product. The suitability, efficacy, and limitations of disinfecting agents
and adequacy of procedures should be reviewed, including the data that establishes the expiry
of the disinfection solution. (Reference: Section X.A.3 of FDA’s 2004 Aseptic Processing
Guidance)
?For multi-use facilities and non-dedicated equipment, evaluate the adequacy of the changeover procedures and cleaning to prevent cross-contamination between products.
B. EQUIPMENT
Equipment used in the manufacture of sterile drug products may include the following:
?Production Equipment
?Container/closure processing equipment (e.g. stopper washer, glassware depyrogenation equipment)
?Support system/material system related equipment (e.g. WFI system and related equipment, process gas related equipment)
Specific considerations include:
(1) Production Equipment
(a) Aseptic Processing Equipment. Determine that all equipment that comes in direct contact
with product (e.g., filters, transfer lines, holding tanks, stopper bowls, filling line equipment) and sterile components (e.g., stoppers) are sterilized and protected from contamination prior to and during use. Equipment logs or other related information may provide insight into significant maintenance or other problems that may increase exposure of batches to contamination risk.
(b) Stopper washer. Inspectional considerations include the qualification of the equipment,
cycle validation and supporting data, equipment preventative maintenance (maintenance requirements and frequency), quality of water used for washing, and associated water sampling/qualification data. The appropriateness of the air supply used in any drying operations should also be verified.
(c) Capping Equipment (vials). The vial cap provides the final closure element of a sealed vial.
The capping machine folds and crimps the cap (aluminum) over the neck of the stoppered vial.
The cap on the vial protects the stopper from external damage, while firmly holding the stopper
in the fully seated, sealed position. Evaluate the established processing settings (crimp angles, pressures), and preventative maintenance schedules of the capping machine. Air supply quality to the capping units should also be evaluated.
(d) Post fill Visual Inspection/Automated Inspection Equipment. The 100% inspection of the final filled and sealed product may occur via a manual, automated, or semi-automated inspection process. Manual and semi-automated inspection processes involve specified viewing fields and calibrated light sources. Semi-automated processes may use conveyor belts and rotational units that present the filled product to an operator for visual inspection. All conveyor and rotational speed set points should be verified against established parameters. Automated inspection systems may inspect for one or all types of defects in a given filled product. Defect categories with relevant action levels should be defined. The qualification of the equipment and the challenges performed to verify equipment functionality prior to routine use should be evaluated as well as the training program for operators performing manual visual inspections.
(e) Sterilizers. The inspection should cover the Installation and Operation Qualification of equipment and the Performance Qualification of the process (IQ, OQ and PQ), and operation, calibration and preventative maintenance of representative types of equipment used to sterilize finished dosage forms, filling equipment, containers, closures, etc. Such equipment includes autoclaves, dry heat ovens, dry heat tunnels, steam-in-place (SIP) equipment and chemical sterilization systems (i.e., hydrogen peroxide, peracetic acid). Inspection of sterilizers should include physical examination of the equipment. Review the engineering specifications which may be described in the equipment’s DQ (Design Qualification). DQ is performed prior to the IQ (Installation Qualification) and OQ (Operational Qualification), and verify that the sterilizer is maintained, calibrated and drained properly and that it has appropriate measuring devices (temperature sensors, pressure gauges, etc.).
Records of unplanned maintenance, as well as preventative maintenance, should be reviewed to assure all significant changes have been evaluated and qualified as appropriate. Equipment logs should also be reviewed. For example, repeat sterilization of loads because of cycle failures can indicate a serious problem with a sterilizer. Impact of re-sterilization to product quality should be evaluated. (Performance qualification is covered under the Production System).
The equipment can be computer controlled or operated in a manual mode. For computer controlled system, programmable logic controller (PLC) or a more complex Supervisory Controlled and Data Acquisition Management System (SCADA), may require an assessment to determine if the computer control and/or monitoring system are Part 11 compliant. Reference:
o PDA Technical Report No. 1 Revised 2007 Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control;
o ISO 17665 Moist Heat Sterilization.
(f) Lyophilizer. Because partially sealed vials are used in the lyophilization process, sterile product is exposed to the environment from the time of filling until the vials are fully stoppered in the lyophilization chamber at the end of the cycle. The inspection should verify that partially
sealed vials are transported and loaded into the lyophilizers under Class 100 (ISO 5) protection.
Investigators should observe the transport of vials and loading of lyophilizers.
Other key equipment areas to cover include: validation of the sterilization of the lyophilization chamber between uses, current sterilization controls, leak testing of the chamber, integrity testing of air/gas filters, and calibration of temperature and pressure controllers.
Reference: FDA’s Guide to Inspections of Lyophilization of Parenterals.
(g) Isolators. Evaluate the design and control elements that maintain the separation or isolation
of the product. Pressure differential, glove integrity, and protection of the transfer (i.e., entry,
exit) ports are key elements for the isolators. The transfer of containers, closures and supplies
(including environmental monitoring supplies) into an isolator should be carefully controlled.
Another critical element for these systems is the effectiveness of the chamber decontamination program. Current methods (e.g., vaporized hydrogen peroxide, steam hydrogen peroxide,
peracetic acid) used to decontaminate isolator barriers are capable of surface sterilization but
lack the penetrating capabilities of steam sterilization. Investigators should be mindful of the
limitations of these surface sterilants, including their inefficiency in penetrating obstructed or
protected surfaces. Validation of the decontamination of the interior (surfaces) of an isolator
should demonstrate a 6-log reduction of the biological indicator (BI). Quantitative measuring
devices (e.g., near infrared) or chemical indicators (qualitative test) can be used to determine the worst case location for decontamination validation using BI. Factors to be considered in
decontamination validation include the location of the BI and the type of surfaces where the BIs are inoculated.
Utensils and equipment surfaces inside the isolator that have direct contact with sterile product and components should be sterilized to render them free of microorganisms. The sterilization
validation should achieve a minimum of a 6-log reduction of the BI
Reference:
o Appendix 1 of FDA’s 2004 Aseptic Processing Guidance;
o PDA Technica l Report 51 (2010) Biological Indicators for Gas and Vapor Phase Decontamination Processes: Specifications, Manufacture, Control and Use provides
general principles to be considered in decontamination by BI.
(h) Restricted Access Barrier System (RABS). In general, a RABS is a fill-finish line in a rigid
wall enclosure that provides full physical separation of the filling line from operators. It is
important to note that the inside surfaces of the RABS are disinfected with a sporicidal agent2, but this is not accomplished using the automated decontamination cycles employed for isolators.
This requires firms to carefully supervise disinfection procedures and assure ongoing
effectiveness of the disinfection program. Operators use glove ports, half suits or automation to access areas within the enclosure during filling. There are 2 types of RABS, “open” and “closed”
RABS. The doors to a “closed” RABS are never opened during an operation. While an “open”
RABS is designed to operate with doors closed at all times, on rare pre-defined circumstances
2 Robust disinfection of all non-product contact surfaces within the RABS should be performed with a suitable sporicidal
the doors of the enclosure can be opened to perform certain interventions. If doors are routinely opened during a filling operation, the system is not considered a RABS because it no longer restricts access to the critical areas. Typically, the cleanroom surrounding the RABS is controlled as a Class 10,000 (ISO 7) area and operators are fully gowned.
Reference: Restricted Access Barrier Systems (RABS) for Aseptic Processing; ISPE; August 16 2005.
When inspecting a RABS:
o Determine that the gloves and gauntlets attached to the glove ports are sterile when installed. After installation, the gloves should be disinfected or changed at appropriate
intervals to minimize the risk of contamination.
o Verify there is a well defined written procedure that describes what is done when an open- door intervention is performed. All open-door interventions should be documented and
described in batch records, and followed by disinfection.
o RABS entry is often accompanied by an appropriate line clearance, which should be clearly documented in batch records.
o Determine that all fluid pathways and product contact parts such as stopper bowl, feed and placement systems are sterilized prior to the filling of each batch.
o Observe how sterile components and supplies are transferred to the RABS. Verify that the transfer system prevents exposure of sterile surfaces to less clean environments.
o Verify that non-product contact surfaces within the RABS undergo thorough disinfection with a sporicidal agent before each batch. The effectiveness of the overall disinfection
program should be validated and routinely evaluated by the environmental monitoring
program.
(i) Blow-fill-seal (BFS) Technology. BFS is an automated aseptic filling process in which containers are formed, filled and sealed in a continuous operation. BFS systems can reduce the risk of product contamination by reducing operator interventions. The systems are typically used for filling sterile ophthalmic and respiratory care products. See Appendix 2 of FDA’s 2004 Aseptic Processing Guidance for information about BFS systems. It should be noted that the inner surfaces of the containers can be exposed to the surrounding environment during the formation and molding steps prior to filling. The sterile product can also be exposed to the environment during the filling and sealing steps of the BFS process. Therefore, the air quality should meet the microbiological level established for Class 100 (ISO 5) should be supplied to where the sterile product or its containers are exposed during the BFS process. Some of the more advanced BFS equipments that provide enhanced protection for the sterile product operation can be located in a Class 100,000 (ISO 8) area. Otherwise, a Class 10,000 (ISO 7) area is appropriate. Research has demonstrated a direct relationship between the number of contaminated units and the level of microbial contamination in the air surrounding the machine (see Reference #20). Typically, the product supply line and sterilizing product filters are steam sterilized-in-place (SIP).
When inspecting BFS:
o Verify that HEPA-filtered or sterile air is used during steps where sterile product or materials are exposed (e.g., parison formation, container molding, and filling steps).
o Evaluate the monitoring and preventative maintenance programs to determine the integrity of the utilities (cooling water, heating, etc.) associated with the BFS machine is routinely checked. Leaks in the molds or utility connections at the molds can contaminate the sterile product or containers.
o Review the SIP system used to sterilize the product line. Determine the sterilization cycle has been validated and the condensate properly drains from the line. The line should also be protected between sterilization and use.
o Verify that personnel who enter the classified environment surrounding the BFS machine are properly gowned and trained.
o If possible, observe equipment setup and any difficulties that can lead to contamination risks.
Other control procedures (media fills, environmental monitoring, disinfection of surfaces, etc.) are the same as discussed for conventional aseptic processing line.
(j) Reactor, Centrifuge, Dryer, Mill. This type of equipment can be used to aseptically manufacture sterile bulk Active Pharmaceutical Ingredients (APIs). The equipment and all transfer piping must be sterilized prior to processing. This is typically done with sterilize-in- place (SIP) systems which use clean steam or a chemical sterilant. Review the validation, cycle controls and the routine monitoring of the SIP system. The equipment and all transfer piping must remain integral (no fluid or air leaks) and sterile throughout the entire manufacturing process. Determine how the firm verifies the integrity of the equipment train throughout the process. If a piece of equipment is opened in the process (e.g. adding seed crystals), verify the area surrounding the open operation is robustly protected from contamination risks with a Class 100 (ISO 5) air system as well as implementing a carefully designed aseptic operation. Reference: FDA’s Guide to Inspections of Sterile Drug Substance Manufacturers.
(2) Container/Closure Processing Equipment
Depyrogenation equipment may include a dry heat oven and/or depyrogenation tunnel. Depyrogenation of stoppers can also be accomplished by dilution via a washing process. The final rinse of the washing process uses Water for Injection (WFI). For more information, see FDA’s Aseptic Processing Guidance, Section VI.B, Containers/Closures.
(3) Support Utilities
(a) Water System. Specifically, review WFI generation equipment and distribution loop(s), including tanks, water lines, isometric diagrams, vent filters, and preventive maintenance schedules (See also Materials System). Monitoring equipment associated with the Water System should also be evaluated.
(b)HVAC. Refer to Section IV of FDA’s 2004 Aseptic Processing Guidance on qualification and maintenance of the HVAC system.
(c) Process Gases. Gases that are in contact with the drug product or components in drug
manufacturing operations are referred to as process gases. Gases used in aseptic operations, or downstream of sterilization, must be filtered through a sterilizing grade filter to maintain asepsis.
The integrity testing of these filters (typically hydrophobic) should be evaluated. The system
used in the generation of the process gas(es) should also be evaluated including preventive
maintenance (PM) schedules, monitoring (including temperature, pressure, and humidity), and sampling. See also under Materials System.
3.7 MATERIALS SYSTEM
Compliance Program 7356.002 lists the areas to cover when inspecting the Materials System. The areas are applicable to sterile drug products and should be covered if this system is selected. In sterile operations, the quality attributes of each of the materials (ingredients, WFI, containers, closures) have a bearing on the critical attributes of the finished product. Review the firm’s procedures for receipt, handling, sampling, testing, approval and storage of manufacturing materials to verify their fitness for use. Emphasis should be placed on incoming materials that are represented to be sterile and / or pyrogen free.
Areas of special concern for sterile drug products include:
(1) Water Systems. Water for Injection (WFI) is an ingredient in many sterile drugs, including injectable products and sterile ophthalmic products. It is also used in depyrogenation (or endotoxin removal) of equipment and stoppers and in cleaning operations. The quality of the water, and its endotoxin levels and controls, used in the upstream process should also be evaluated in order to ensure the removal of bacterial endotoxin to the appropriate level downstream. Purified water can be used for some sterile non-injectable solutions.
?Observe and understand elements of the generation and distribution systems.
?Evaluate the water system “As Built” diagrams” and inspect for leaks, pipe slopes (via the isometric diagrams and verification of the degree of the slopes), so called “dead legs”, and
non-sanitary fittings in the distribution system.
?Evaluate how microbial alert and action levels are established.
?Evaluate sampling sites, procedures, frequencies and tests performed.
?Review procedures for preventative maintenance and calibration of critical instruments, including scheduling and equipment update procedures.
?Review raw data to verify that all of the above is completed per established procedure.
?Review and observe routine monitoring (in-line TOC and conductivity) of water system.
?Review trend data for chemistry, microbiological and endotoxin tests.
?Review investigation of results that are at or over alert and action levels.
Reference: FDA’s Guide to Inspections of High Purity Water Systems.
(2) Process Gas. Process gas and related equipment controls may be covered in conjunction with the Facilities and Equipment System. Specific considerations include controls over final filtration of the
processed gas and filter integrity testing. Gas used as a component in a finished product may include the Nitrogen gas overlay for Oxygen sensitive products.
(3) Pre-washed / Ready to Sterilize Closures. The CGMP regulation (21 CFR 211.94(c)) states that, where indicated, containers and closures must be processed to remove pyrogenic substances. Many manufacturers of small volume parenterals purchase stoppers that are ready-to-sterilize, (i.e., they are pyrogen-free). No washing or depyrogenation is done by the dosage form manufacturers but these firms are still responsible for assuring the stoppers are of acceptable quality for use in manufacturing. The pyrogen requirements should be included in specifications for the stoppers and, if the manufacturer does not conduct testing of each incoming lots for pyrogen/endotoxin, they should establish the reliability of the supplier’s test results by qualification of the vendor, followed by periodic testing.
(4) Microbiological and Endotoxin Testing of Component, Container and Closure. 21 CFR
211.84(d) specifies that each lot of component, container or closure that is liable to microbial contamination which is objectionable in view of its intended use shall be subjected to microbiological tests before use. Evaluate the firm’s system for determining if microbiological or endotoxin testing is required and the rationale for setting acceptance criteria. Review test data to verify that the materials meet test criteria and, if not, verify that investigations were conducted to determine the cause and corrective actions were implemented.
(5) Verification of Container and Closures. The physical and chemical characteristics of containers and closures can be critical to the sterility and stability of the finished product. Many containers and closures look alike (color and dimensions), but are made of different materials or have a different surface treatment such as silicone on stoppers and ammonium sulfate on Type I glass. Evaluate the firm’s procedures for assuring containers and closure consistently meet appropriate specifications. Determine what tests and examinations are done to verify the containers and closures are made of the correct materials with the correct dimensions (critical to ensuring continuing container-closure integrity) and are free of critical defects.
(6) Container / Closure Integrity. The integrity of the container / closure system is critical to assuring that all units of drug products remain sterile through shipment, storage and use. Leaking containers or closures lead to product contamination.
Reference: FDA’s 1994 Guidance for Industry for the Submission of Sterilization Process Validation in Applications for Human and Veterinary Drug Products.
Evaluate the tests and studies performed to demonstrate the integrity of container / closure systems for all sterile drugs, including:
?Verify that all incoming container-closure components meet specifications, including all appropriate dimensions.
?Determine studies adequately simulate the stress conditions of the sterilization process, handling and storage.
?Verify that the units tested in validation are appropriate (e.g., for terminally sterilized drug product, the units selected should be exposed to the maximum sterilization cycles using the
production process).
晋灵公不君（宣公二年） 原文： 晋灵公不君。厚敛以雕墙。从台上弹人，而观其辟丸也。宰夫胹熊蹯不熟，杀之，寘诸畚，使妇人载以过朝。赵盾、士季见其手，问其故而患之。将谏，士季曰：“谏而不入，则莫之继也。会请先，不入，则子继之。”三进及溜，而后视之，曰：“吾知所过矣，将改之。”稽首而对曰：“人谁无过？过而能改，善莫大焉。诗曰：‘靡不有初，鲜克有终。’夫如是，则能补过者鲜矣。君能有终，则社稷之固也，岂惟群臣赖之。又曰：‘衮职有阙，惟仲山甫补之。’能补过也。君能补过，衮不废矣。” 犹不改。宣子骤谏，公患之，使鉏麑贼之。晨往，寝门辟矣，盛服将朝。尚早，坐而假寐。麑退，叹而言曰：“不忘恭敬，民之主也。贼民之主，不忠；弃君之命，不信。有一于此，不如死也！”触槐而死。 秋九月，晋侯饮赵盾酒，伏甲将攻之。其右提弥明知之，趋登曰：“臣侍君宴，过三爵，非礼也。”遂扶以下。公嗾夫獒焉。明搏而杀之。盾曰：“弃人用犬，虽猛何为！”斗且出。提弥明死之。 初，宣子田于首山，舍于翳桑。见灵辄饿，问其病。曰：“不食三日矣！”食之，舍其半。问之，曰：“宦三年矣，未知母之存否。今近焉，请以遗之。”使尽之，而为之箪食与肉，寘诸橐以与之。既而与为公介，倒戟以御公徒，而免之。问何故，对曰：“翳桑之饿人也。”问其名居，不告而退。——遂自亡也。 乙丑，赵穿①攻灵公于桃园。宣子未出山而复。大史书曰：“赵盾弑其君。”以示于朝。宣子曰：“不然。”对曰：“子为正卿，亡不越竟，反不讨贼，非子而谁？”宣子曰：“呜呼!‘我之怀矣，自诒伊戚。’其我之谓矣。” 孔子曰：“董狐，古之良史也，书法不隐。赵宣子，古之良大夫也，为法受恶。惜也，越竞乃免。” 译文： 晋灵公不行君王之道。他向人民收取沉重的税赋以雕饰宫墙。他从高台上用弹弓弹人，然后观赏他们躲避弹丸的样子。他的厨子做熊掌，没有炖熟，晋灵公就把他杀了，把他的尸体装在草筐中，让宫女用车载着经过朝廷。赵盾和士季看到露出来的手臂，询问原由后感到很忧虑。他们准备向晋灵公进谏，士季说：“如果您去进谏而君王不听，那就没有人能够再接着进谏了。还请让我先来吧，不行的话，您再接着来。”士季往前走了三回，行了三回礼，一直到屋檐下，晋灵公才抬头看他。晋灵公说：“我知道我的过错了，我会改过的。”士季叩头回答道：“谁能没有过错呢？有过错而能改掉，这就是最大的善事了。《诗经》说：‘没有人向善没有一个开始的，但却很少有坚持到底的。’如果是这样，那么能弥补过失的人是很少的。您如能坚持向善，那么江山就稳固了，不只是大臣们有所依靠啊。
Biochemistry Seeks to Explain Life in Chemical Terms The molecules of which living organisms are composed conform to all the familiar laws of chemistry, but they also interact with each other in accordance with another set of principles, which we shall refer to collectively as the molecular logic of life. These principles do not involve new or yet undiscovered physical laws or forces. Instead, they are a set of relationships characterizing the nature, function, and interactions of biomolecules. If living organisms are composed of molecules that are intrinsically inanimate, how do these molecules confer the remarkable combination of characteristics we call life? How is it that a living organism appears to be more than the sum of its inanimate parts? Philosophers once answered that living organisms are endowed with a mysterious and divine life force, but this doctrine (vitalism) has been firmly rejected by modern science. The basic goal of the science of biochemistry is to determine how the collections of inanimate molecules that constitute living organisms interact with each other to maintain and perpetuate life. Although biochemistry yields important insights and practical applications in medicine, agriculture, nutrition, and industry, it is ultimately concerned with the wonder of life itself. All Macromolecules Are Constructed from a Few Simple Compounds Most of the molecular constituents of living systems are composed of carbon atoms covalently joined with other carbon atoms and with hydrogen, oxygen, or nitrogen. The special bonding properties of carbon permit the formation of a great variety of molecules. Organic compounds of molecular weight less than about 500, such as amino acids, nucleotidase, and monosaccharide, serve as monomeric subunits of proteins, nucleic acids, and polysaccharides,
6-磷酸葡萄糖脱氢酶 glucose-6-phosphate dehydrogenase Janbon综合症 Janbon's syndrome PPB浓度 parts per billion concentration pphm浓度 parts per hundred million concentration PPH浓度 parts per hundred concentration ppm浓度 parts per million concentration 安全范围 safety range 安全试验法 innocuity test method 安全系统 safety coefficient 安慰剂 placebo 螯合剂 chelating agent 靶细胞 target cell 白蛋白微球制剂 albumin microballoons 百分浓度 percentage concentration 半合成抗生素 semisynthetic antibiotics 半抗原 haptene 半数致死剂量 half lethal dose ; median lethal dose; LD50 半衰期 half-life period; half life time 包衣片 coated tablet 薄膜衣 film-coating 饱和溶液 saturated solution 贝克勒尔 Becquerel 被动免疫 passive immunity 被动转运 passive transport
崩解度 disintegration 崩解剂 disintegrants 必需氨基酸 essential aminoacid 必需脂肪酸 essential fatty acid 变态反应 allergy; allergic reaction 表面活性 surface activity 表面张力 surface tension 丙种射线 gamma rays 补体 complement 补体系统 complement system 不良反应 adverse reaction 不完全抗原 incomplete antigen 搽剂 liniments 长期毒性实验 long term toxicity test 长效制剂 prolonged action preparation 肠肝循环 enterohepatic circulation 肠溶控释片 enteric controlled release tablets 肠溶衣 enteric coating 处方 prescription;recipe 穿透促进剂 penetration enhancers 磁性控释制剂 magnetic controlled release dosage form 磁性药物制剂 magnetic medicinal preparations 大分子 macromolecule 单克隆抗体 monoclonal antibody
如何翻译古文 学习古代汉语，需要经常把古文译成现代汉语。因为古文今译的过程是加深理解和全面运用古汉语知识解决实际问题的过程，也是综合考察古代汉语水平的过程。学习古代汉语，应该重视古文翻译的训练。 古文翻译的要求一般归纳为信、达、雅三项。“信”是指译文要准确地反映原作的含义，避免曲解原文内容。“达”是指译文应该通顺、晓畅，符合现代汉语语法规范。“信”和“达”是紧密相关的。脱离了“信”而求“达”，不能称为翻译；只求“信”而不顾“达”，也不是好的译文。因此“信”和“达”是文言文翻译的基本要求。“雅”是指译文不仅准确、通顺，而且生动、优美，能再现原作的风格神韵。这是很高的要求，在目前学习阶段，我们只要能做到“信”和“达”就可以了。 做好古文翻译，重要的问题是准确地理解古文，这是翻译的基础。但翻译方法也很重要。这里主要谈谈翻译方法方面的问题。 一、直译和意译 直译和意译是古文今译的两大类型，也是两种不同的今译方法。 1．关于直译。所谓直译，是指紧扣原文，按原文的字词和句子进行对等翻译的今译方法。它要求忠实于原文，一丝不苟，确切表达原意，保持原文的本来面貌。例如： 原文：樊迟请学稼，子曰：“吾不如老农。”请学为圃。子曰：“吾不如老圃。”（《论语?子路》） 译文：樊迟请求学种庄稼。孔子道：“我不如老农民。”又请求学种菜蔬。孔子道：“我不如老菜农。”（杨伯峻《论语译注》） 原文：齐宣王问曰：“汤放桀，武王伐纣，有诸？”（《孟子?梁惠王下》） 译文：齐宣王问道：“商汤流放夏桀，武王讨伐殷纣，真有这回事吗？（杨伯峻《孟子译注》） 上面两段译文紧扣原文，字词落实，句法结构基本上与原文对等，属于直译。 但对直译又不能作简单化理解。由于古今汉语在文字、词汇、语法等方面的差异，今译时对原文作一些适当的调整，是必要的，并不破坏直译。例如： 原文：逐之，三周华不注。（《齐晋鞌之战》） 译文：〔晋军〕追赶齐军，围着华不注山绕了三圈。
Introduction to Physiology Introduction Physiology is the study of the functions of living matter. It is concerned with how an organism performs its varied activities: how it feeds, how it moves, how it adapts to changing circumstances, how it spawns new generations. The subject is vast and embraces the whole of life. The success of physiology in explaining how organisms perform their daily tasks is based on the notion that they are intricate and exquisite machines whose operation is governed by the laws of physics and chemistry. Although some processes are similar across the whole spectrum of biology—the replication of the genetic code for or example—many are specific to particular groups of organisms. For this reason it is necessary to divide the subject into various parts such as bacterial physiology, plant physiology, and animal physiology. To study how an animal works it is first necessary to know how it is built. A full appreciation of the physiology of an organism must therefore be based on a sound knowledge of its anatomy. Experiments can then be carried out to establish how particular parts perform their functions. Although there have been many important physiological investigations on human volunteers, the need for precise control over the experimental conditions has meant that much of our present physiological knowledge has been derived from studies on other animals such as frogs, rabbits, cats, and dogs. When it is clear that a specific physiological process has a common basis in a wide variety of animal species, it is reasonable to assume that the same principles will apply to humans. The knowledge gained from this approach has given us a great insight into human physiology and endowed us with a solid foundation for the effective treatment of many diseases. The building blocks of the body are the cells, which are grouped together to form tissues. The principal types of tissue are epithelial, connective, nervous, and muscular, each with its own characteristics. Many connective tissues have relatively few cells but have an extensive extracellular matrix. In contrast, smooth muscle consists of densely packed layers of muscle cells linked together via specific cell junctions. Organs such as the brain, the heart, the lungs, the intestines, and the liver are formed by the aggregation of different kinds of tissues. The organs are themselves parts of distinct physiological systems. The heart and blood vessels form the cardiovascular system; the lungs, trachea, and bronchi together with the chest wall and diaphragm form the respiratory system; the skeleton and skeletal muscles form the musculoskeletal system; the brain, spinal cord, autonomic nerves and ganglia, and peripheral somatic nerves form the nervous system, and so on. Cells differ widely in form and function but they all have certain 生理学简介 介绍 生理学是研究生物体功能的科学。它研究生物体如何进行各种活动，如何饮食，如何运动，如何适应不断改变的环境，如何繁殖后代。这门学科包罗万象，涵盖了生物体整个生命过程。生理学成功地解释了生物体如何进行日常活动，基于的观点是生物体好比是结构复杂而灵巧的机器，其操作受物理和化学规律控制。 尽管从生物学整个范畴看，生物体某些活动过程是相似的——如基因编码的复制——但许多过程还是某些生物体群组特有的。鉴于此有必要将这门学科分成不同部分研究，如细菌生理学、植物生理学和动物生理学。 要研究一种动物如何活动，首先需要了解它的构成。要充分了解一个生物体的生理学活动就必须掌握全面的解剖学知识。一个生物体的各部分起着什么作用可通过实验观察得知。尽管我们对志愿者进行了许多重要的生理调查，但是实验条件需要精确控制，所以我们当前大多生理知识还是源于对其它动物如青蛙，兔子，猫和狗等的研究。当我们明确大多数动物物种的特定生理过程存在共同之处时，相同的生理原理适用于人类也是合理的。通过这种方法，我们获得了大量的知识，从而让我们对人类生理学有了更深入的了解，为我们有效治疗许多疾病提供了一个坚实的基础。 机体的基本组成物质是细胞，细胞结合在一起形成组织。组织的基本类型有上皮组织，结缔组织，神经组织和肌组织，每类组织都有各自的特征。许多结缔组织中细胞量相对较少，但是有大量的细胞外基质。相比而言，光滑的肌组织由大量密密麻麻的肌细胞通过特定的细胞连接组成。各种器官如脑，心脏，肺，小肠和肝等由不同种类的组织聚集而成。这些器官是不同生理系统的组成部分。心脏和血管组成心血管系统；肺，器官，支气管，胸壁和膈肌组成呼吸系统；骨骼和骨骼肌组成骨骼肌系统；大脑，脊髓，自主神经和神经中枢以及
药学名词（中-英）6-磷酸葡萄糖脱氢酶glucose-6-phosphate dehydrogenase Janbon综合症Janbon's syndrome PPB浓度parts per billion concentration pphm 浓度parts per hundred million concentration PPH浓度parts per hundred concentration ppm 浓度parts per million concentration 安全范围safety range 安全试验法innocuity test method 安全系统safety coefficient 安慰剂placebo 螯合剂chelating agent 靶细胞target cell 白蛋白微球制剂albumin microballoons 百分浓度percentage concentration 半合成抗生素semisynthetic antibiotics 半抗原haptene 半数致死剂量half lethal dose ; median lethal dose; LD50 半衰期half-life period; half life time 包衣片coated tablet 薄膜衣film-coating 饱和溶液saturated solution 贝克勒尔Becquerel 被动免疫passive immunity 被动转运passive transport 崩解度disintegration 崩解剂disintegrants 必需氨基酸essential aminoacid 必需脂肪酸essential fatty acid 变态反应allergy; allergic reaction 表面活性surface activity 表面张力surface tension 丙种射线gamma rays 补体complement 补体系统complement system 不良反应adverse reaction 不完全抗原incomplete antigen 搽剂liniments 长期毒性实验long term toxicity test 长效制剂prolonged action preparation 肠肝循环enterohepatic circulation 肠溶控释片enteric controlled release tablets 肠溶衣enteric coating 处方prescription;recipe 穿透促进剂penetration enhancers 磁性控释制剂magnetic controlled release dosage form 磁性药物制剂magnetic medicinal preparations 大分子macromolecule 单克隆抗体monoclonal antibody 胆碱酯酶cholinesterase 当量equivalent weight 当量定律equivalent law 当量浓度normality 当量溶液normal solution 等张溶液isotonic solution 低聚糖oligosaccharides 低密度脂蛋白low density lipoprotein 滴定titration 滴定曲线titration curve 滴丸剂 pill 递质transmitter 电解electrolyzation 电解质electrolyte 酊剂tincture 定向药物制剂directed pharmaceutical preparations 毒理学toxicology 毒性反应toxic response; toxic reaction 短期致癌实验short term carcinogenic test 对因治疗etiological treatment 对映体antipode 对症治疗symptomatic treatment 多功能酶multifunctional enzyme 多剂量给药multiple dose administration 多糖polyose 多肽polypeptide 儿茶酚胺catecholamine 二重感染superinfection 发酵fermentation 法定处方official formula
鞌之战选自《左传》又名《鞍之战》原文：楚癸酉，师陈于鞌(1)。邴夏御侯，逢丑父为右②。晋解张御克，郑丘缓为右(3)。侯日：“余姑翦灭此而朝食(4)”。不介马而驰之⑤。克伤于矢，流血及屦2 未尽∧6)，曰：“余病矣(7)！”张侯曰：“自始合(8)，而矢贯余手及肘(9)，余折以御，左轮朱殷(10)，岂敢言病吾子忍之！”缓曰：“自始合，苟有险，余必下推车，子岂＿识之(11)然子病矣！”张侯曰：“师之耳目，在吾旗鼓，进退从之。此车一人殿之(12)，可以集事(13)，若之何其以病败君之大事也擐甲执兵(14)，固即死也(15)；病未及死，吾子勉之(16)！”左并辔(17) ，右援拐鼓(18)。马逸不能止(19)，师从之，师败绩。逐之，三周华不注(20) 韩厥梦子舆谓己曰：“旦辟左右！”故中御而从齐侯。邴夏曰：“射其御者，君子也。”公曰：“谓之君子而射之，非礼也。”射其左，越于车下；射其右，毙于车中。綦毋张丧车，从韩厥，曰：“请寓乘。”从左右，皆肘之，使立于后。韩厥俛，定其右。逢丑父与公易位。将及华泉，骖絓于木而止。丑父寝于轏中，蛇出于其下，以肱击之，伤而匿之，故不能推车而及。韩厥执絷马前，再拜稽首，奉觞加璧以进，曰：“寡君使群臣为鲁、卫请，曰：‘无令舆师陷入君地。’下臣不幸，属当戎行，无所逃隐。且惧奔辟而忝两君，臣辱戎士，敢告不敏，摄官承乏。” 丑父使公下，如华泉取饮。郑周父御佐车，宛茷为右，载齐侯以免。韩厥献丑父，郤献子将戮之。呼曰：“自今无有代其君任患者，有一于此，将为戮乎”郤子曰：“人不难以死免其君，我戮之不祥。赦之，以劝事君者。”乃免之。译文1：在癸酉这天，双方的军队在鞌这个地方摆开了阵势。齐国一方是邴夏为齐侯赶车，逢丑父当车右。晋军一方是解张为主帅郤克赶车，郑丘缓当车右。齐侯说:“我姑且消灭了这些人再吃早饭。”不给马披甲就冲向了晋军。郤克被箭射伤，血流到了鞋上，但是仍不停止擂鼓继续指挥战斗。他说:“我受重伤了。”解张说:“从一开始接战，一只箭就射穿了我的手和肘，左边的车轮都被我的血染成了黑红色，我哪敢说受伤您忍着点吧！”郑丘缓说:“从一开始接战，如果遇到道路不平的地方，我必定（冒着生命危险）下去推车，您难道了解这些吗不过，您真是受重伤了。”daier 解张说:“军队的耳朵和眼睛，都集中在我们的战旗和鼓声，前进后退都要听从它。这辆车上还有一个人镇守住它，战事就可以成功。为什么为了伤痛而败坏国君的大事呢身披盔甲，手执武器，本来就是去走向死亡，伤痛还没到死的地步，您还是尽力而为吧。”一边说，一边用左手把右手的缰绳攥在一起，用空出的右手抓过郤克手中的鼓棰就擂起鼓来。（由于一手控马，）马飞快奔跑而不能停止，晋军队伍跟着指挥车冲上去，把齐军打得打败。晋军随即追赶齐军，三次围绕着华不注山奔跑。韩厥梦见他去世的父亲对他说:“明天早晨作战时要避开战车左边和右边的位置。”因此韩厥就站在中间担任赶车的来追赶齐侯的战车。邴夏说:“射那个赶车的，他是个君子。”齐侯说: “称他为君子却又去射他，这不合于礼。”daier 于是射车左，车左中箭掉下了车。又射右边的，车右也中箭倒在了车里。（晋军的）将军綦毋张损坏了自己的战车，跟在韩厥的车后说: “请允许我搭乗你的战车。”他上车后，无论是站在车的左边，还是站在车的右边，韩厥都用肘推他，让他站在自己身后——战车的中间。韩厥又低下头安定了一下受伤倒在车中的那位自己的车右。于是逢丑父和齐侯（乘韩厥低头之机）互相调换了位置。将要到达华泉时，齐侯战车的骖马被树木绊住而不能继续逃跑而停了下来。（头天晚上）逢丑父睡在栈车里，有一条蛇从他身子底下爬出来，他用小臂去打蛇，小臂受伤，但他（为了能当车右）隐瞒了这件事。由于这样，他不能用臂推车前进，因而被韩厥追上了。韩厥拿着拴马绳走到齐侯的马前，两次下拜并行稽首礼，捧着一杯酒并加上一块玉璧给齐侯送上去，
IntroductiontoPhysiology Introduction Physiologyisthestudyofthefunctionsoflivingmatter.Itisconcernedwithhowanorganismperformsitsv ariedactivities:howitfeeds,howitmoves,howitadaptstochangingcircumstances,howitspawnsnewgenerati ons.Thesubjectisvastandembracesthewholeoflife.Thesuccessofphysiologyinexplaininghoworganismsp erformtheirdailytasksisbasedonthenotionthattheyareintricateandexquisitemachineswhoseoperationisgo vernedbythelawsofphysicsandchemistry. Althoughsomeprocessesaresimilaracrossthewholespectrumofbiology—thereplicationofthegenetic codefororexample—manyarespecifictoparticulargroupsoforganisms.Forthisreasonitisnecessarytodivid ethesubjectintovariouspartssuchasbacterialphysiology,plantphysiology,andanimalphysiology. Tostudyhowananimalworksitisfirstnecessarytoknowhowitisbuilt.Afullappreciationofthephysiolog yofanorganismmustthereforebebasedonasoundknowledgeofitsanatomy.Experimentscanthenbecarriedo uttoestablishhowparticularpartsperformtheirfunctions.Althoughtherehavebeenmanyimportantphysiolo gicalinvestigationsonhumanvolunteers,theneedforprecisecontrolovertheexperimentalconditionshasmea ntthatmuchofourpresentphysiologicalknowledgehasbeenderivedfromstudiesonotheranimalssuchasfrog s,rabbits,cats,anddogs.Whenitisclearthataspecificphysiologicalprocesshasacommonbasisinawidevariet yofanimalspecies,itisreasonabletoassumethatthesameprincipleswillapplytohumans.Theknowledgegain edfromthisapproachhasgivenusagreatinsightintohumanphysiologyandendoweduswithasolidfoundation fortheeffectivetreatmentofmanydiseases. Thebuildingblocksofthebodyarethecells,whicharegroupedtogethertoformtissues.Theprincipaltype softissueareepithelial,connective,nervous,andmuscular,eachwithitsowncharacteristics.Manyconnective tissueshaverelativelyfewcellsbuthaveanextensiveextracellularmatrix.Incontrast,smoothmuscleconsists https://www.doczj.com/doc/6f4851178.html,anssuchasthebrain,theh eart,thelungs,theintestines,andtheliverareformedbytheaggregationofdifferentkindsoftissues.Theorgans arethemselvespartsofdistinctphysiologicalsystems.Theheartandbloodvesselsformthecardiovascularsyst em;thelungs,trachea,andbronchitogetherwiththechestwallanddiaphragmformtherespiratorysystem;thes keletonandskeletalmusclesformthemusculoskeletalsystem;thebrain,spinalcord,autonomicnervesandgan glia,andperipheralsomaticnervesformthenervoussystem,andsoon. Cellsdifferwidelyinformandfunctionbuttheyallhavecertaincommoncharacteristics.Firstly,theyareb oundedbyalimitingmembrane,theplasmamembrane.Secondly,theyhavetheabilitytobreakdownlargemol eculestosmalleronestoliberateenergyfortheiractivities.Thirdly,atsomepointintheirlifehistory,theyposses sanucleuswhichcontainsgeneticinformationintheformofdeoxyribonucleicacid(DNA). Livingcellscontinuallytransformmaterials.Theybreakdownglucoseandfatstoprovideenergyforother activitiessuchasmotilityandthesynthesisofproteinsforgrowthandrepair.Thesechemicalchangesarecollect ivelycalledmetabolism.Thebreakdownoflargemoleculestosmalleronesiscalledcatabolismandthesynthes isoflargemoleculesfromsmalleronesanabolism. Inthecourseofevolution,cellsbegantodifferentiatetoservedifferentfunctions.Somedevelopedtheabil itytocontract(musclecells),otherstoconductelectricalsignals(nervecells).Afurthergroupdevelopedtheabi litytosecretedifferentsubstancessuchashormonesorenzymes.Duringembryologicaldevelopment,thispro cessofdifferentiationisre-enactedasmanydifferenttypesofcellareformedfromthefertilizedegg. Mosttissuescontainamixtureofcelltypes.Forexample,bloodconsistsofredcells,whitecells,andplatele ts.Redcellstransportoxygenaroundthebody.Thewhitecellsplayanimportantroleindefenseagainstinfection 生理学简介 介绍 生理学是研究生物体功能的科学。它研究生物体如何进行各种活动，如何饮食，如何运动，如何适应不断改变的环境，如何繁殖后代。这门学科包罗万象，涵盖了生物体整个生命过程。生理学成功地
《鞌之战》阅读答案（附翻译）原文及翻 译 鞌之战[1] 选自《左传成公二年（即公元前589年）》 【原文】 癸酉，师陈于鞌[2]。邴夏御齐侯[3]，逢丑父为右[4]。晋解张御郤克，郑丘缓为右[5]。齐侯曰：余姑翦灭此而朝食[6]。不介马而驰之[7]。郤克伤于矢，流血及屦，未绝鼓音[8]，曰：余病[9]矣！张侯[10]曰：自始合，而矢贯余手及肘[11]，余折以御，左轮朱殷[12]，岂敢言病。吾子[13]忍之！缓曰：自始合，苟有险[14]，余必下推车，子岂识之[15]？然子病矣！张侯曰：师之耳目，在吾旗鼓，进退从之[16]。此车一人殿之[17]，可以集事[18]，若之何其以病败君之大事也[19]？擐甲执兵，固即死也[20]。病未及死，吾子勉之[21]！左并辔[22]，右援枹而鼓[23]，马逸不能止[24]，师从之。齐师败绩[25]。逐之，三周华不注[26]。 【注释】 [1]鞌之战：春秋时期的著名战役之一。战争的实质是齐、晋争霸。由于齐侯骄傲轻敌，而晋军同仇敌忾、士气旺盛，战役以齐败晋胜而告终。鞌：通鞍，齐国地名，在今山东济南西北。 [2]癸酉：成公二年的六月十七日。师，指齐晋两国军队。陈，
列阵，摆开阵势。 [3]邴夏：齐国大夫。御，动词，驾车。御齐侯，给齐侯驾车。齐侯，齐国国君，指齐顷公。 [4]逢丑父：齐国大夫。右：车右。 [5]解张、郑丘缓：都是晋臣，郑丘是复姓。郤（x ）克，晋国大夫，是这次战争中晋军的主帅。又称郤献子、郤子等。 [6]姑：副词，姑且。翦灭：消灭，灭掉。朝食：早饭。这里是吃早饭的意思。这句话是成语灭此朝食的出处。 [7]不介马：不给马披甲。介：甲。这里用作动词，披甲。驰之：驱马追击敌人。之：代词，指晋军。 [8] 未绝鼓音：鼓声不断。古代车战，主帅居中，亲掌旗鼓，指挥军队。兵以鼓进，击鼓是进军的号令。 [9] 病：负伤。 [10]张侯，即解张。张是字，侯是名，人名、字连用，先字后名。 [11]合：交战。贯：穿。肘：胳膊。 [12]朱：大红色。殷：深红色、黑红色。 [13]吾子：您，尊敬。比说子更亲切。 [14]苟：连词，表示假设。险：险阻，指难走的路。 [15]识：知道。之，代词，代苟有险，余必下推车这件事，可不译。 [16]师之耳目：军队的耳、目（指注意力）。在吾旗鼓：在我们
《鞌之战》阅读答案（附翻译） 《鞌之战》阅读答案（附翻译） 鞌之战[1] 选自《左传·成公二年（即公元前589年）》 【原文】 癸酉，师陈于鞌[2]。邴夏御齐侯[3]，逢丑父为右[4]。晋解张御郤克，郑丘缓为右[5]。齐侯曰：“余姑 翦灭此而朝食[6]。”不介马而驰之[7]。郤克伤于矢， 流血及屦，未绝鼓音[8]，曰：“余病[9]矣！”张侯[10]曰：“自始合，而矢贯余手及肘[11]，余折以御，左轮 朱殷[12]，岂敢言病。吾子[13]忍之！”缓曰：“自始合，苟有险[14]，余必下推车，子岂识之[15]？——然 子病矣！”张侯曰：“师之耳目，在吾旗鼓，进退从之[16]。此车一人殿之[17]，可以集事[18]，若之何其以 病败君之大事也[19]？擐甲执兵，固即死也[20]。病未 及死，吾子勉之[21]！”左并辔[22]，右援枹而鼓[23]，马逸不能止[24]，师从之。齐师败绩[25]。逐之，三周 华不注[26]。 【注释】 [1]鞌之战：春秋时期的著名战役之一。战争的实质是齐、晋争霸。由于齐侯骄傲轻敌，而晋军同仇敌忾、 士气旺盛，战役以齐败晋胜而告终。鞌：通“鞍”，齐
国地名，在今山东济南西北。 [2]癸酉：成公二年的六月十七日。师，指齐晋两国军队。陈，列阵，摆开阵势。 [3]邴夏：齐国大夫。御，动词，驾车。御齐侯，给齐侯驾车。齐侯，齐国国君，指齐顷公。 [4]逢丑父：齐国大夫。右：车右。 [5]解张、郑丘缓：都是晋臣，“郑丘”是复姓。郤（xì）克，晋国大夫，是这次战争中晋军的主帅。又称郤献子、郤子等。 [6]姑：副词，姑且。翦灭：消灭，灭掉。朝食：早饭。这里是“吃早饭”的意思。这句话是成语“灭此朝食”的出处。 [7]不介马：不给马披甲。介：甲。这里用作动词，披甲。驰之：驱马追击敌人。之：代词，指晋军。 [8]未绝鼓音：鼓声不断。古代车战，主帅居中，亲掌旗鼓，指挥军队。“兵以鼓进”，击鼓是进军的号令。 [9]病：负伤。 [10]张侯，即解张。“张”是字，“侯”是名，人名、字连用，先字后名。 [11]合：交战。贯：穿。肘：胳膊。 [12]朱：大红色。殷：深红色、黑红色。 [13]吾子：您，尊敬。比说“子”更亲切。
药学名词（中-英） 6-磷酸葡萄糖脱氢酶glucose-6-phosphate dehydrogenase Janbon综合症Janbon's syndrome PPB浓度parts per billion concentration pphm浓度parts per hundred million concentration PPH浓度parts per hundred concentration ppm浓度parts per million concentration 安全范围safety range 安全试验法innocuity test method 安全系统safety coefficient 安慰剂placebo 螯合剂chelating agent 靶细胞target cell 白蛋白微球制剂albumin microballoons 百分浓度percentage concentration 半合成抗生素semisynthetic antibiotics 半抗原haptene 半数致死剂量half lethal dose ; median lethal dose; LD50 半衰期half-life period; half life time 包衣片coated tablet 薄膜衣film-coating 饱和溶液saturated solution 贝克勒尔Becquerel 被动免疫passive immunity 被动转运passive transport 崩解度disintegration 崩解剂disintegrants 必需氨基酸essential aminoacid