Tuesday, December 28, 2010

FINDING THE BEST INTERNATIONAL HEATH COVERAGE

When you decide to move abroad, one of the most important choices you’ll make Is selecting the heath insurance coverage that best suits your needs. At first glance, many of the international private plans seem identical. However, if you investigate the benefits and service standards of the providers, many differences emerge. The devil is indeed in the details! Here are some important factors to consider.

In-patient treatment claims 

Does the provider offer direct settlement for in-patient treatment? If not, you will have to meet these expenses out-of-pocket. Make sure the provider you choose offers a 24-hour, multi-lingual helpline so you can get emergency assistance and approval for treatment when you need it. 

Out-patient claims

If claims are settled through reimbursement, find out how quickly the provider pays. Also, are there deductions for bank charges or will you be fully reimbursed?

Emergency evacuation and repatriation
 
This is one of the most important benefits and the “acid test” of any international health plan. Beware the small print!

Some providers pay for you to be evacuated but will not pay your return airfare back to the country of residence after treatment. Others, however, cover the cost of a return flight as well as accommodation for someone to accompany you. The most comprehensive emergency evacuation benefit covers your evacuation, medical treatment and repatriation back to your country of residence and, in addition, covers the travel and accommodation costs of your dependants. Make sure the plan covers evacuation where and when adequate medical treatment is not available locally; not all plans cover this.

Other medical benefits

Are you just looking for emergency and in-patient coverage? Or do you want out-patient treatment, visits to your general practitioner, physiotherapy, complementary therapies, dental treatment or wellness (prevention) tests to be covered? If you are planning a family, be sure to look at plans with maternity coverage.


Chronic conditions 

Some plans exclude chronic conditions completely; some pay for treatment for stabilization of acute episodes of the condition. Others also pay for maintenance of the condition so will cover things like routine check-ups and prescription drugs.


Non-medical benefits
 
Some plans cover legal expenses if you suffer an injury as the result of a third party. Some plans cover a visit to a critically ill relative; some providers only pay for a visit back to your home country, while others will pay for a visit anywhere in the world. Note that some providers offer travel and personal accident insurance as add-on plans. Again, be sure to read the fine print.
Do you want coverage in your home country? Not all plans offer this. Also, look at whether the plan covers emergency treatment outside of the geographic area of coverage.
If you are based in an area of instability, you will also want to be covered for treatment required as a result of war or terrorism, provided you are not active participants. Some plans exclude this.
How much coverage do you want or need in the U.S.? A number of different options are available to U.S. citizens living abroad, all of which need to be given serious thought in find the best plan for your needs.
Depending on where you live outside of the U.S., you could choose to have a plan which covers you on an accident- and emergency-only basis for short trips back home. Or, you could choose one which gives you full coverage for a set amount of time per year, generally six months. You might also choose one which will cover you for returning to the U.S. for “elective treatment” (i.e. you need medical treatment and choose to have it in the U.S.) or a plan that will give full worldwide coverage, including in the U.S. regardless where you are in the world.
In the international insurance marketplace, there now exist plans that you can keep when you return to the U.S. on a permanent basis in the future. Please note that, although these plans offer full coverage on return to the U.S., your exact coverage will depend on the state where you will be living. Insurance laws and regulation vary state to state. An independent broker will be able to advise on this for you.
An important point to consider is that although many international medical plans offer different degrees of coverage in the U.S., very few meet the state laws allowing them to be kept on if you return to the U.S. permanently. In most instances, you would then need a new insurance policy.

Ways to reduce your premium
 
Some providers offer a no-claims discount, special rates for families or the option to select a voluntary higher excess/deductible. .

Above all, the most important thing is to make sure you understand the plan and, if in doubt, speak to an independent broker such as http://www.medibroker.com/ who can analyze your needs and advise you on the best coverage for you.

Premium Comparisons
 
Comprehensive Coverage (inpatient, day patient, outpatient, local doctors/specialists, medical evacuation).

Worldwide incl Full U.S. Coverage

HTH Worldwide Global Citizen ($500 Deductible)
$4188.00
$7392.00
$8484.00
$19548.00
37 y/o Female
50 y/o Female
59 y/o Male
66 y/o Male
IHI danmark IHHP ($400 Deductible)
$6975.00
$8996.00
$8996.00
$14572.50
37 y/o Female
50 y/o Female
59 y/o Male
66 y/o Male
GoodHealth Mobile Health ($250 Deductible) US Cover Limited to 6 months per year
$1834.00
$2935.00
$3713.00
N/A
37 y/o Female
50 y/o Female
59 y/o Male
66 y/o Male
InterGlobal Comprehensive ($42.50 Excess) US Cover Limited to 180 days per trip)
$4462.00
$7628.00
$9379.00
$14143.00
37 y/o Female
50 y/o Female
59 y/o Male
66 y/o Male
Premiums Quoted are for one year of coverage and may be dependent on the country of residence at the time of purchase. Where "n/a" is shown, the plan is not available for new business at that age (it will be available for renewals for people who took out cover at an earlier age).
Worldwide incl Limited U.S. Coverage (Accident & Emergency Only - No elective treatment)

Validation - The Essential Quality Assurance Tool For Pharma Industries

Quality is always an imperative prerequisite when we consider any product. It becomes prime when it relates to life saving products like pharmaceuticals. Although it is mandatory from the government and regulatory bodies but it is also a fact that quality of a pharmaceutical product can not be adequately controlled solely by pharmacopoeial analysis of the final product. Today quality has to be built in to the product right from its inception and rigorous international environmental, safety and regulatory standards need to be followed. Validation had proven to be an important tool for quality management of pharmaceuticals. According to ISO 9000:2000
Validation is defined as "Confirmation, through the provision of objective evidence, that the requirements for a specific intended use or application have been fulfilled". In contrast with Verification, Validation rather focuses on the question whether a system can perform its desired functions. This review is an attempt to prove the it as essential tool for quality management in pharmaceutical industry.

INTRODUCTION TO VALIDATION

Validation is a concept that has been evolving continuously since its first formal appearance in United States in 1978. The concept of validation has expanded through the years to encompass a wide range of activities from analytical methods used for the quality control of drug substances and products to computerized system for clinical trial, labeling or process control.1
Validation is the overall expression for a sequence of activities in order to demonstrate and document that a specific product can be reliably manufactured by the designed processes, usually, depending on the complexity of today’s pharmaceutical products, the manufacturer must ensure; "that products will be consistently of a quality appropriate to their intended use”. 2
To achieve this with confidence, only in process control and finished product testing alone are not sufficient to assure product quality; but all factors including the services which could affect product quality must be correctly designed, demonstrated to work effectively. Consistently and their performance is also regularly conformed so that consistent quality product is obtained. For example, no sampling plan for applying sterility tests to a specified proportion of discrete units selected from a sterilization load is capable of demonstrating with complete assurance that all of the untested units are infect sterile .
In recent year many manufacture houses have attempted to define their philosophy and strategy for self inspecting their plants for manufacturing ,processing and packing ,including holding of drugs .As much these manufacturers are interpreting the GMP guidelines as evaluated by Food and drug Authority and the schedule M after due modification in 1988.3
A philosophy of performing systematic inspection has worked and may be termed “Drug in- process inspection and validation”. The compliance to their working rules defines a validated manufacturing process as “one has been proven to do what it purport or it represented to do. The proof of validation is obtained through the collection and evaluation of data, preferably beginning from the process development phase and continuing through in to the product phase. Validation necessarily includes process qualification such as materials, equipment, system, building and personnel, but it also includes the control of the entire process for repeated batches or runs.
The word “validation” simply means assessment of validity or action of proving effectiveness. According to European community for medicinal products, validation is action of proving in accordance with the principals of good manufacturing practices, that any procedure, process, equipment, material, activity or system actually leads to expected results.
Validation is a proof that a process works and this must be done using scientific and statically principles. This is done to establish process capability and to confirm product acceptability.4 Validation determined process variables and the acceptable limits for these variables and accordingly sets up appropriate in process controls, which specifies alert and action levels.5

REGULATORY REQUIRMENTS FOR VALIDATION
Conducting process validation is not only a regulatory requirement, but also makes a great deal of sense from engineering as well as a business point of view .It is evident that pharmaceutical companies that are well versed in conducting process validation have a competitive advantage over those who are not6. Process validation is required, in both general and specific terms, by the Current Good Manufacturing Practices regulations for finished pharmaceuticals, 21 CFR parts 210 and 2117,8 . A requirement for process validation is set forth in general terms in sections 211.100 written procedures; deviations–which states, in parts; “there shall be written procedures for production and process control designed to assure that the drug products have the identity , strength, quality, and purity they purport or are represented to posses”. Several sections of cGMP regulations states, validation requirement in more specific terms. Excerpts from some of the sections are:-section 211,100, sampling and testing of in –process materials and drug products.
a ) “------------- Control procedures shall be established to monitor the output and validate the performance of those manufacturing process that may be responsible for causing variability in the characteristics of in process material and drug products.”
Section 211, 113, control of microbiological contamination
b) “------------- Appropriate written procedures, design to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.”
The requirement of process validation is implicit in the language of schedule M, Good manufacturing practices regulation which states “To achieve the objective, each licensee shall evolve methodology and procedure which should be documented and kept for reference and inspection”.
Process validation is required by the medical device GMP regulation,21 CFR part 820.Section 820.5 requires every finished device manufacturer to states: “……………….. Prepared and implement a quality assurance program that is appropriate to the specific device manufactured……………….”
Section 820.3 states: “………………….All activities necessary to verify confidence in the quality of the process used to manufacture a finished device…………”
A generally stated requirement for process validation is contained in section 820.100, states:
“Written manufacturing specification and processing procedure shall be established, implemented, and controlled to assure that device conforms to its original design or any approved changes in that design”. Validation is an essential element in the establishment and implementation of a process procedure, as well as in determining what process controls are required in order to assure conformance to specification.
Section 820.100(a) (1), states: “Control measures shall be established to assure that the designed basis for device, components and packaging is correctly translated in to approved specification” 9.
{mospagebreak title=Importance and Scope Of Validation}

IMPORTANCE OF VALIDATION

The most compelling reasons to optimize and validate pharmaceutical productions and supporting processes are quality assurance and cost reduction .the basic principles of quality assurance has as their goal and the production of articles that are fit for there intended use.10 These principles are Quality, safety, and effectiveness must be designed and built in to the product, quality cannot be inspected or tested in the finished products and each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specification. The relationship of quality assurance and process validation goes well beyond the responsibility of any quality assurance functions, nevertheless it is fair to say that process validation is a quality assurance tool because it is establishes a quality standard for the specific process.
Quality control is the part of GMP, it is concerned with the sampling specification, testing and with organization documentation and release procedures.11,12 Where as assurance of quality is derived from careful attention to a number of factors including selection of quality materials, equipments, adequate product, process design ,selection of approved vendors, proper GMP inspections , employee training ,technical audit, critical evaluation of market complaints, in-process control of processes, and end product testing.13-20
Process validation should result in fewer product recalls and trouble shooting .process consistently under control requires less process support, will have less down time, fewer batch failures , and may operate more efficiently with greater output .In addition timely and appropriate validation improves quality assurance ,reduces cost by process optimization ,enables more effective and rapid trouble shooting ,shortens lead time leading to low inventories ,empowers all employees to control their processes and to improve them ,enables better system control ,maintains, and improves a high degree of assurance that specific process will consistently produce a product meetings its predetermined specifications and quality characteristics 21,22.

SCOPE OF VALIDATION

Following are the area were validation can be implied : Analytical test methods, Instrument calibration, Process utility services, Raw materials, Packaging materials, Facilities, Manufacturing, Product design, Cleaning and Operators. 23-26

PHASES OF VALDATION

The activities relating to validation studies are classified into three phases.
Phase 1:
Pre-validation phase or the qualification phase ,which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage form, equipment qualification ,installation qualification, master production documents, operational qualification, process capability.
Phase 2:
Process validation phase (process qualification phase) designed to verify that all established of the critical process parameters are valid and that satisfactory products can be produced even under the worst case conditions.
Phase 3:
Validation maintenance phase requiring frequent review of all process related documents ,including validation audit report to assure that there have been no changes ,deviations, failures modification to production process, and that all SOP’s have been followed including change control procedures. At this stage the validation team also assures that there have been no changes /deviations that should have resulted in requalification and revalidation.

PROCESS VALIDATION

It would normally be expected that process validation be completed prior to the distribution of a finished product that is intended for sale (prospective validation). Where this is not possible, it may be necessary to validate processes during routine production (concurrent validation). Processes which have been in use for some time without any significant changes may also b validated according to an approved protocol (retrospective validation) 27,28.

Prospective validation:

In prospective validation, the validation protocol is executed before the process is put in to commercial use. During the product development phase the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical consideration to determine the critical parameters that may affect the quality of finished product. A series of experiment should be design to determine criticality of these factors. Each experiment should be planned and documented fully in an authorized protocol.
All equipment, production environment and the analytical testing methods to be used should have been fully validated. Master batch documents can be prepared only after the critical parameters of the process have been identified and machine settings, component specification and environment conditions have been determined. By using this defined process a series of batches should be produced. In theory, the number of the process runs carried out and observations made should be sufficient to allow the normal extent variation and trends to be established to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs with in the final agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate these data.
Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipments and facilities dedicated of commercial production, operating range of critical process, and a thorough analysis of the process data in case of requalification and revalidation 29,30.
During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages, and should be documented comprehensively. Detail testing should also be done on the final product in its package.
Upon completion of the review, recommendation should be made on the extent of monitoring and the in-process control necessary for routine production. These should be incorporated into the batch manufacturing record and packaging record or appropriate standard operating procedures. Limits, frequencies and action to be taken in the even to the limits being exceeded should be specified.

Concurrent validation:

In using this approach there is the always the risk of having to modify process parameters or specifications over a period of time .this situation often leads to question regarding disposition of the batches that had already been released for the sale, subsequently known to have undesired quality characteristics.
Concurrent validation may be the practical approach under some circumstance. Example:
· When a previously validated process is being transferred to a third party contract manufacturer or to another manufacturing unit.
· Where the product is different strength of a previously validated product with the same ratio of active/inactive ingredients.
· When the number of lots evaluated under the retrospective validation were not sufficient to obtain a high degree assurance demonstrating that the process is fully under control.
· When the number of batches produced are limited.
It is important in these cases however, that the system and equipment to be used have been fully validated previously. The justification for conducting concurrent validation must be documented and the protocol must be approved by validation team. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. It is generally considerable acceptable that a minimum of three consecutive batches within the finally agreed parameters giving the product the desired quality would constitute a proper validation of the process.

Retrospective validation:

In many establishments, processes that are stable and in routine use have not under gone a formally documented validation process. Historical data may be utilized to provide necessary documentary evidence that the processes are validated.
The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation.
Retrospective validation is only acceptable for well established detailed process and will be inappropriate where there have been recent changes in the formation of the product, operating procedures, equipments and facility.
The source of data for retrospective validation should include amongst others, batch documents, process control charts ,maintenance log book, process capability studies, finished product test results, including trend analysis, and stability results.
For the purpose of retrospective validation studies, it is considered acceptable that data for a minimum ten consecutive batches produced be utilized. When the less than ten batches are available, it is considered that the data are not sufficient to demonstrate retrospective that the process is fully in control .In such cases the study should be supplemented with concurrent or prospective validation.
Some of the essential elements for retrospective validation are:
  • Batches manufactured for a defined period (minimum of last ten consecutive batches)
  • Number of lots released per year.
  • Batch size /strength /manufacturer /year /period.
  • Master manufacturing/packaging documents.
  • Current specification for active materials/finished products.
  • List of process deviation, corrective actions and changes to manufacturing documents.
  • Data for stability testing for several batches.
  • Trend analysis including those for quality related complaints.

Process Revalidation

Revalidation provides the evidence that change in a process and /or the process environments that are introduced do not adversely affect the process characteristics and product quality. Documentation requirement will be the same as for the initial validation of the process.
Revalidation becomes necessary in certain situations .Some of the changes that require revalidation are as follows.
  • Changes in raw materials properties such as density, viscosity, particle size distribution, moisture, etc. that may affect the process of product.
  • Changes in the sources of active raw material manufacturer.
  • Changes in packing material (primary container/closure system).
  • Changes in the process (such as mixing time, drying temperature, and batch size).
  • Changes in the equipment (e.g. addition of automatic detection system).Changes of equipment which involves the replacement of equipment on a “like for like ’’basis would not requires are validation except that this new equipment must be qualified.
  • Changes in the plant /facility.

CHANGE CONTROL:

All changes must be formally requested documented and accepted by the validation team .The likely impact/risk of the change on the product must assess and the need for the extent of revalidation should be determined .
Commitment of the company to control all change to premises, supporting utilities, system, materials, equipment and process used in the fabrication/packaging of pharmaceutical dosage forms essential to ensure a continued validation status of the system concerned.
The change control system should ensure that all notified or requested changes are satisfactory investigated, documented and authorized. Products made by process subjected to changes should not be released for sale without full awareness and consideration of the changes by the validation team. The team should decide if a. revalidation must be conducted prior to implementation of the proposed change.

FDA VALIDATION DOCUMENTATION

The FDA’s guideline defines validation as:
“Establishing documented evidence, which provide a high degree of assurance that a specific process will consistently produce a product meeting with its pre-determined specifications and quality characteristics”.
The development of validation documentation is an essential part of any successful validation programmed or study. The documentation should be concise, unambiguous, detailed, and thorough31,32.
Table 1: Components of a good validation document.
Good validation documentation

A written historical perspective of what was manufactured, filled, cleaned, packaged, how it was done, and which controls were in place.
A way to minimize mistakes and variables.
Provide evidence that “something happened” how, when, and by whom.
Everything you wanted to know but were afraid to ask, written history of product, its components, equipment, and its process before product introduction to market.
Compliance to GMP requirement and ensure reproducibility
Validation takes place within following areas: New : Formula/product, process, procedures, manufacturing, packaging, Changes in : Processing procedures, manufacturing, packaging, cleaning, equipment, computer system and infrastructure and Failures : Revalidation.Within these area, the validation documentation requirements will depend on complexity of the process, project scope, GMP risk (it increases with the complexity of the system), and GAP analysis (define the strategies for achieving goals, identify the weakness).

Key Validation Documents

· Validation master plan (VMP).
·Validation protocols: Installation qualification (IQ), Operational qualification (OQ), Performance qualification (PQ), Computer systems, Facility/utility/equipment qualification protocols, process, packaging, and cleaning.
· Standard operating procedures.
·Optimization batch guidelines.
· Validation reports.
· Change control system 31,33,34.
Importance of the VMP:
The VMP describes clearly and concisely the company’s philosophy, expectations and approach to be followed. It identifies the systems and controls to be validated and the level of testing required. It covers all aspects of the project as equipment qualification, training, maintenance, and change control. It should be developed in the early stages of a project and allow a logical progression from plan to validation schedule. The VMP can also assist in monitoring and tracking the progress of the project by performing periodic audit reviews v/s the approved version of the VMP 31.
Contents of typical VMP:
Following are the contents of VMP : Introduction, Purpose, Scope, Overview /Description of system to be validated, Responsibilities, Validation methodology, Acceptance criteria, Validation report, Change control, Validation project milestone, Deliverables.
Benefits of VMP:
A VMP is created when the project is complex, include high risk ,and when more extensive and thoroughly verification and system review are required. If study is simple involving only one validation study /variables, a validation protocols may be used instead. The benefits of VMP includes, i) It provides the total pictures of the project. ii) It is a management tool for tracking progress. iii) Assignment of responsibility, which promote team work. iv) It identifies acceptance criteria before the start of validation.
The Validation protocol for process, packaging, and cleaning:
The Validation protocol for process, packaging, and cleaning studies is a written plan stating how validation will be conducted including purpose, scope overview/description of system to be validated, responsibilities, validation methodology, acceptance criteria, validation report, change control, required SOPs and decision points on what constitutes acceptable test results.
Format for validation protocol:
·Cover page (approvals)
·Scope of project (which process being validated)
·Objectives /backgrounds
·Description
· Installation qualification (IQ), Operational qualification (OQ), Performance qualification (PQ)
· Role and responsibilities.
· SOP’s requirement.
· Process monitoring.
· Sampling and testing.
· Process monitoring.
· Acceptance criteria /test methods.
· Deliverables.
· Documentation requirement
· Additional information-
§ A flow chart of the process
§ Sampling methods to be used
§ In process samples to be collected and details of collection
§ Testing to be conducted on samples collected
§ Sample size ,type of container, and swab techniques
§ Tools and precautions 31,33.

Equipment /Facility /Utility qualification protocols:

The qualification protocols are a very important document of the protocol process. The complexity of the equipment, facility, utility systems, involved and their relationship to the quality of the product dictate the scope ,details, and contents of the qualification protocol. The major component of the qualification protocols are 1,35.
  • Installation qualification (IQ):

Document that the equipment is properly installed according to the manufacturer and purchaser’s specifications. It covers equipment /system descriptions, which includes principle of operation, design requirements, equipment specifications piping, instruments diagrams, facility functional specifications, equipment utility requirements, and equipment safety features.
  • Operational qualification (OQ):

Document that the equipment operates within established limits and tolerances. It covers equipment operation procedures established and challenged equipment control functions, calibration requirements and schedules established, and maintenance requirements.
  • Performance qualification (PQ):

Document, which the equipment can operate reliably as intended for the process under routine, minimum, and maximum operating ranges.
  • Facility /Utility qualification: 31

It involves installation, operation and performance qualification of the building and the equipment. It covers -
  • Plant layout /construction. it includes material flow ,air locks, structure and finishing ,fire safety /alarm system ,manufacturing rooms ,and ware house.
  • Utilities and services. . it includes potable water, cooling water, drainage, plant system, purified water system, compressed air , heating ventilation air conditioning (HVAC) systems.

TYPICAL FORMAT FOR AN EQUIPMENT / FACILITY /UTILITY QUALIFICATION PROTOCOL:

· Purpose.
· Scope.
· Equipment description includes master list of equipment requiring installation qualification/operational qualification.
· Role and responsibilities.
· Definitions.
· Qualification criteria for IQ methodology/execution, OQ methodology/execution, PQ methodology.
· Deviation reports.
· Acceptance criteria.
· SOP requirements.
· Executive summary report.
· Change control.
· Deliverables.
· Attachments: Raw data sheets, test results, preventive maintenance schedules, test incidence reports, and equipment calibration certifications.

Validation reports:

It summarizes the results, disposition, conclusions, and recommendations of the validation study relative to the protocol / VMP. The main components of the report are as follows 31:
· Cover page.
· Over view.
· Product name.
· Description of the process being validated.
· Location.
· Number of batches being validated.
· Validation study plan.
· Scope.
· Results.
· Discussion.
· Recommendations.
· Conclusion.
· Change control.

CONCLUSION

The quality assurance of pharmaceutical product involves a number of factors. The complexity of modern day medical products requires more than the routine end product testing, as the end product testing is not sufficient to assure quality of finished product.
The review highlights various aspects on process elements, regulatory requirements, and validation documentation that are considered by regulatory agencies. The particular requirement of process validation will vary according to the nature of the pharmaceutical product and type of process. The broad concepts stated in this review have general applicability and provide an acceptable framework for building a comprehensive approach for the validation.

Sunday, December 26, 2010

Improving Process Quality for Pharmaceutical Liquids

Since its introduction into the North American pharmaceutical market more than 40 years ago, blow/fill/seal (B/F/S) aseptic processing has established itself as a highly efficient and safe system for the filling and packaging of sterile pharmaceutical liquids and other healthcare products, such as creams and ointments. B/F/S product usage has been widely established in the ophthalmic and respiratory therapy markets for some time, and B/F/S technology has lately been gaining worldwide acceptance in the parenteral drug marketplace, replacing traditional glass vial processing in a growing number of applications.


B/F/S enables a container to be molded from plastic, aseptically filled and then hermetically sealed in one continuous, integrated and automatic operation, without human manipulation. The process provides flexibility in container design and system changeovers, high volume product output, low operational costs and a high assurance of product sterility. The inherent safety of the process — packaging sterile products under aseptic conditions without human intervention — has led the FDA and the United States Pharmacopoeia to characterize B/F/S technology as an "advanced aseptic process," indicating its use as a preferred technology.

New advances in drug delivery, the desire to improve convenience in handling pharmaceutical products, growing emphasis on combination products, the increasing focus on protein-based drugs and other biologics, and tighter regulatory criteria on product safety, have focused more attention on B/F/S technology over traditional aseptic methods as a better solution for the sterile, aseptic processing of pharmaceutical liquids.

Traditional Aseptic Processing and Sterility of Pharmaceutical Liquids



Microbial contamination is a serious issue for companies manufacturing liquid pharmaceutical formulations. Such liquids are ideal growth areas for bacteria like Salmonella, E. coli and Staphylococcus, microbes that have been found in various liquid drug products. A supposedly sterile product that becomes contaminated may result in deterioration of the drug and loss of potency, pyrogenic reactions after administration to a patient (particularly in parenterals), infection of the patient and colonization of microorganisms in the patient with the risk of a secondary infection. Any microorganism, pathogen or nonpathogenic, found in a supposedly sterile pharmaceutical product is dangerous.

Drug manufacturers have pursued various methods of sterilizing packaging components, product ingredients and equipment in order to achieve a sterile product in its final form. One system used is traditional processing, followed by terminal sterilization, which involves initially filling and sealing product containers within a cleanroom environment. The environment is set up to minimize the microbial content of the product while it is being manufactured. Each component of the process — the product, container and closure — has a low bioburden, but may or may not be sterile. The product, in the final container, is subjected to a “terminal” sterilization process, such as heat or radiation.The most common method uses autoclaving with saturated steam under pressure.

Traditional aseptic processing allows a final sterile drug product to be achieved by individually sterilizing the containers, material and equipment in-process, resulting in a unified sterilized product. In traditional aseptic processing, the containers are either supplied cleaned and sterilized to the filling line, or they are cleaned and sterilized within the aseptic filling line. Plastic containers are usually washed, dried, sterilized and cooled before filling. Glassware containers, which have been the dominant packaging material for terminally sterilized and traditionally sterilized pharmaceutical liquids, are usually sterilized in-line, exposed to hot air at 350° C while being passed through a Class 100 tunnel. A glass container temperature of 180 to 200° C is adequate for achieving sterility.

Methods of sterilization used in aseptic processing include filtering the solution by dissolving it in a solvent, such as Water For Injection (WFI), where the solution is passed through a sterilizing filter or membrane. Filter sterilization is used where the component is soluble and likely to be adversely affected by heat. A variation of this method includes subjecting the filtered solution to aseptic crystallization and precipitation (lyophilization) of the component as a sterile powder.Dry heat sterilization is another effective method for sterilizing components that are heat stable and insoluble. Irradiation can also be used to sterilize some components.

Aseptic processing handles components, materials and equipment in such a manner that foreign microbial and endotoxin contaminents that exceed pre-determined acceptable levels are not introduced to the product stream. To this end, it is critical that all storage, conveying, filling and container-sealing stages be carefully controlled at each step of the process to maintain sterility of the product. Traditional aseptic processing, involving filling open glass bottles or vials, requires that the manufacturer maintain aseptic conditions in critical processing areas at all times. Unfortunately, the majority of liquid drug product contamination during the past several decades has come about from products produced in traditional aseptic processing facilities.

Personnel Intervention in Traditional Aseptic Critical Areas



Traditional aseptic sterilization involves handling and manipulation of the material, containers, and sterilization filling processes with human intervention, and therefore has a higher potential for contamination during processing. The FDA’s 2004 Guidance for Industry Sterile Drug Products Produced by Aseptic Processing states that the design of equipment used in aseptic processing should limit the number and the complexity of aseptic interventions by personnel. Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures or the surrounding environment.

The act of walking by a person emits roughly 10,000 skin particles per minute. Such particles can and do hold microbial contamination. A rip in a worker’s uniform, a momentary exposed wrist, a mask placed too low on the nose or physical contact with an open fill port will increase microbial contamination within a critical area.

According to the FDA’s guide, airborne contamination is directly related to the number of people working in a cleanroom and the level of congregation by personnel in areas where critical aseptic manipulations are performed. Isolation of personnel from these critical areas would eliminate the major source of contamination in traditional aseptic processing.

In traditional aseptic processing, changing or adjusting filling nozzles and heads necessitates the shutdown of the filling operation and requires re-sterilization of the entire equipment. This increases manual intervention in this critical area. Cleaning and sterilization, which is carried out by personnel, opens the door to breaching of established procedures for microbial decontamination and potential introduction of other particulates like dirt, oil and chemicals.

Mold is common flora found on floors, walls and ceilings of buildings. Contamination occurs due to the retention of water in cracks, edges and joints that are susceptible because of inadequate sealing. Brooms, mops and anything used for cleaning can become contaminated and increase atmospheric contamination because of raised dust or splashing water. In traditional aseptic processing, significant manual intervention is required in critical areas to maintain compliance with established sterile mandates.

Advanced blow/fill/seal Aseptic Technology



In advanced aseptic B/F/S processing, containers are formed from a thermoplastic granulate, filled with a liquid pharmaceutical product and then sealed within a continuous, integrated and automatic operation without human intervention. Bulk solution prepared under low bioburden or sterile conditions is delivered to the machine through a product delivery system that has been previously sterilized using an automated steam-in-place process.

Modern B/F/S machines are fully automated, designed to require minimum human access and operate in a classified environment using the following steps:
  1. granules of a polymer resin, conforming to a predetermined set of specifications, such as polyethylene, poly-propylene, co-polymers or other blow-moldable resins, are pneumatically conveyed from a non-classified area into the hopper of the B/F/S machine, from which the plastic is fed into a multi-zone rotating screw extruder which produces a sterile homogenous polymer melt (160–250° C);
  2. then to a parison head which produces hollow tubular forms of the hot resin (called parisons). The parisons are prevented from collapsing by a stream of sterile filtered support air. Some high-speed B/F/S machines have as many as 16 parisons being formed simultaneously;
  3. container mold(s) close around the parisons, and the bottom of the parison is pinched closed, while the top is held open in a molten state;
  4. the container is formed in the mold by blowing sterile air or creating a vacuum;
  5. filling needles deposit the stipulated volume of product into the container;
  6. the filling needles are withdrawn, and the upper part of the mold closes to form and seal the upper part of the B/F/S container;
  7. the mold is opened and the completed, filled containers are conveyed out of the B/F/S machine to a remote station where excess plastic is removed and the finished product is then conveyed to final packaging.

Various in-process control parameters, such as container weight, fill weight, wall thickness and visual defects provide information that is monitored and facilitates ongoing process control.

The forming, filling and sealing steps are achieved in one unit operation; the cycle is completed within seconds. Automation of B/F/S process steps eliminates manual intervention and reduces risk to the product. No production personnel are present in the filling room during normal operation.

Microbial and Particulate Integrity in the Aseptic blow/fill/seal System



Sterility of B/F/S polymeric containers, materials and processes is validated by verifying that time and temperature conditions of the extrusion, filling and sealing processes are effective against endotoxins and spores.

Challenge studies have been conducted on the sterility levels of advanced B/F/S technology, which demonstrate a uniform capability of achieving contamination rates not exceeding 0.001% throughout the entire process. Even higher sterility assurance levels, approaching 0.000001%, have been achieved using high levels of airborne microbiological challenge particles.

Endotoxins are a potential pyrogenic contaminant, essentially dead bacterial cellular matter. They can lead to serious reactions in patients, particularly with those receiving injections, ranging from fever to death. A critical aspect of B/F/S technology is its pyrogen-free molding of containers and ampoules. Extensive experiments confirming the efficacy of the B/F/S extrusion process have been performed using high levels of spores and endotoxin-contaminated polymer granules. The typical B/F/S extruders have demonstrated spore contamination rates of 0.000001%, and 0.00001% for endotoxins.

Control of air quality is critical for sterile drug product manufacture. B/F/S equipment design typically employs the use of specialized measures to reduce microbial contamination and particle levels that can contaminate the exposed product. The B/F/S process inherently produces a very low level of particulate matter and much of potential B/F/S microbial contamination (viable) in the air is mitigated by the absence of manual intervention in its critical areas. Non-viable particles generated during the plastic extrusion, cutting, and sealing processes are controlled. Provisions for carefully controlled airflow protect the product by forcing created particles outward while preventing any inflow from the adjacent environment. These “zones of protection” can also incorporate designs that separate them from the surrounding environment, providing additional product protection.

The B/F/S critical processing zone is continually supplied with HEPA-filtered air by an air shower device (shroud). The B/F/S critical zone is the area where the containers are exposed during filling. Air in the critical zone meets Class 100 (ISO 5) microbiological standards during operations. The critical zone is continuously monitored to ensure a positive differential pressure is maintained between the shroud and the adjacent cleanroom.

Plastic vs. Glass Containers



Injectables, ophthalmics, biologicals and vaccines are produced in a number of different types of containers, including bottles, vials and ampoules that are made from glass and plastic. Protecting the contents of these aseptic liquid drugs through filling, packaging and transportation, and allowing for safe and easy administration are critical objectives in the aseptic process. The industry is infused with a strong emphasis on quality control. Raw materials, and in-process and finished products are continually checked for approval and rejection.

The packaging needs for pharmaceutical liquids are quite demanding. It is not unusual for degradation of the product to occur during processing or while in transit. The physical properties of liquids can be altered with inadequate packaging components. For aseptic filling, the package must be produced, stored, filled and sealed under conditions that preserve sterility. Likewise, the appearance of particulates in sterile solutions is equally undesirable.

Glass, although a standard in the aseptic pharmaceutical liquids industry, is not without its limitations. There is the safety issue; glass vials are subject to breakage, both in transit and while being administered. Handling glass containers always involves a certain amount of risk of lacerations and glass splinters. Glass ampoules, for example, generate a fine array of small glass particles during opening.

Manufacturers using glass containers are also subjected to design limitations when the designs become somewhat complex. With glass containers, as design complexity increases so does the cost. Once glass containers are produced, they need to be transported to the aseptic facility. Glass is typically transported in cardboard boxes, which can contain mold spores such as Penicillin sp. and Aspergillus sp., as well as bacteria like Bacillus sp. Paper, also used in the shipping of glass, can contain mold spores, too. The rubber closures used on the glass containers may have mold contamination.

Domestic drug companies have been slow to change to plastic, primarily due to the existing installed base of glass production of small-volume parenteral drugs in the U.S. However, the same is not the case with new drugs that are coming onto the market. These are more frequently being looked at, and submitted for FDA approval, in plastic containers produced by advanced B/F/S aseptic processing. Supporting this move is that the B/F/S processing resins, polyethylene and polypropylene, are generally considered inert by the FDA. Many of the blow molding resins used in B/F/S processing have received international acceptance as suitable for food and drug applications, and many of the drug products produced outside of the U.S. can be found packaged with these resins.

With the continued refinement of B/F/S technology, its acknowledgment by the FDA as a preferred technology for aseptic processing, and its growing acceptance by drug companies, the migration from glass to plastic containers used for aseptic pharmaceutical liquids is growing rapidly. It has become more cost effective to use plastic containers for aseptic liquids, which effectively costs manufacturers one-third of the cost of glass. Plastic is less expensive to ship because the containers are lighter. For small-volume parenterals, the use of plastic is inevitable, and increasingly being considered for these reasons.

Although many B/F/S systems make available only a limited number of container choices within each container category, some B/F/S machines do allow for broad versatility in container design. Advanced B/F/S machines can design virtually any container mold through the use of sophisticated CAD/CAM technology and 3-D modeling. These design systems, when interfaced with the latest in CNC and EDM machinery, ensure fabrication of key components to precise tolerances.

B/F/S machine designs also allow for mounting of separate sterile items (inserts) within the B/F/S container, and in-mold coding and engraving, which provide further opportunities for innovative design over that of glass products.

Changeover Flexibility for Shorter Runs, Increased Uptime, Maximized Throughput



Modern B/F/S system design is focused on simplicity and flexibility. Many B/F/S machines are configured to produce more than one bottle shape or format. This makes it easy to change over from one container size to another. A B/F/S machine might produce a family of 2, 3 and 5ml, then switch to a family of 5, 10 and 15ml, or to one of 10, 15 and 20ml, moving from one to the other with relative ease of machine set-up. This is ideal for manufacturers performing contract packaging of aseptic liquid pharmaceutical solutions, because of their need for changeover flexibility.

The growing usage of biologics demands different formats of packaging. They usually require smaller process runs and are typically heat sensitive. Many of these new biotechnological drugs do not withstand steam sterilization or irradiation and so are best treated aseptically. More advanced B/F/S machines have been designed so they can handle these heat sensitive products.

Machine models are available that can produce containers ranging in size from 0.1mL to 1000mL at production rates of 15,000 units per hour, depending on container configuration. B/F/S machine efficiency is very high. More advanced B/F/S machines can approach 99% uptime efficiency, significantly higher than traditional aseptic processing, which is plagued with slow-downs due in part to manual interventions. To further minimize potential system downtime, some manufacturers are now segmenting their high-volume process lines into more short-run lines, so that if one of the lines goes down for maintenance or repair, it will not stop the entire production throughput.

When aseptic throughput is interrupted, or not running because of downtime, the entire process line is affected, which represents a significant production loss to the manufacturer.

An Aseptic Technology Destined to Prevail



More rapid container closure processing, elimination of aseptic critical-area personnel interventions, increased system uptime over traditional processing, pyrogen-free molding of containers and ampoules, more flexibility with container design, and an increased capability to capitalize on short runs: these are some of the benefits for manufacturers inherent in advanced blow/fill/seal aseptic technology. And for the consumer, increased safety and confidence in their drug products are strong additional benefits.

These are advances that are significant, if not fully realized yet within the aseptic liquid pharmaceutical marketplace. But it is apparent that advanced B/F/S aseptic technology is destined to become a major player in this arena.

Good Manufacturing Practice for Pharmaceutical Products

Chapter 1: General Provisions
Article 1: This Regulation is enacted in accordance with the "Drug Administration Law of The People's Republic of China".
Article 2: This Regulation is promulgated as the basic guideline for manufacturing and quality control of pharmaceutical products. This Regulation shall be applicable to all the manufacturing processes of drug preparations and to the key manufacturing processes of raw materials which may cause variation in the quality of finished products.
Chapter 2: Organization and Personnel
Article 3: A pharmaceutical enterprise shall establish production and quality control departments. The responsibilities of departments at all levels and personnel shall be clarified, and each department shall be staffed by an appropriate number of management and technical personnel with expert knowledge, manufacturing experience and organization ability.
Article 4: The enterprise personnel responsible for supervision of manufacture and quality control shall, at a minimum, have a bachelor's degree in medicine, pharmaceuticals, or related sciences, and have appropriate experience in drug manufacturing and quality control. They shall be responsible for the implementation of the GMP regulations and the quality of products.
Article 5: The responsible person of the manufacture and quality control departments shall, at a minimum, have a college degree of medicine, pharmaceuticals or related sciences, have actual management experience in production and quality control, and have the ability to correctly decide and handle practical problems in production and quality control.
The managers of production and quality control departments shall be independent of each other.
Article 6: All personnel engaged in drug manufacture and quality control shall have been professionally and technically trained so as to acquire the basic theory and practical technical skills.
Personnel engaged in the production and quality control of products with high organic activity, high toxicity, strong contamination, high sensitivity and other substances with special requirements shall have received corresponding professional technical training.
Article 7: Personnel at all levels who are engaged in drug manufacturing shall be trained and pass examinations in accordance with the requirements of this Regulation.
Chapter 3: Building and Facilities
Article 8: A pharmaceutical enterprise shall be located in a clean environment. The surface of the ground and roads and transportation of the plant area shall not be a source of contamination of drug products. The general lay-out of the production, administration, living and ancillary areas shall be appropriately arranged and not interfere with each other.
Article 9: Buildings shall be appropriately located in accordance with the technological process and requisite cleanness levels. The manufacturing operations undertaken in the same and nearby areas shall not interfere with each other.
Article 10: Buildings shall have the facilities to protect against the entrance of vermin and other animals.
Article 11: The ease and convenience to conduct cleaning shall be considered in the design and construction of buildings. The interior surfaces of the clean room (area) shall be smooth, without cracks, with airtight junction points. The interior surfaces shall not shed any particulate granules and shall withstand washing and disinfecting. The joints between walls and floors are preferably constructed with round corners or by other means so as to reduce the collection of dust and for ease of cleaning.
Article 12: In production and storage areas, there shall be adequate floor and air space for the orderly placement of equipment and materials so as to facilitate production, operations, storage of materials, in-process products, finished products and those under quarantine, and to the greatest degree possible minimize errors and cross-contamination.
Article 13: The various pipes, light fixtures, ventilation points and other public facilities in the clean room (area) shall be designed and installed so as to avoid areas being difficult to clean.
Article 14: The clean room (area) shall be provided with sufficient lighting according to the production requirements. Illumination for main production rooms shall be 300 Lux. For production areas with special requirements, appropriate lighting shall be installed. Emergency lighting shall be provided in the facilities.
Article 15: Air supplied into the clean room (area) must be purified and the clean level of the area shall be classified in accordance with the requirements of the production process. The number of microorganisms and particulates in the air of the clean room (area) shall be tested periodically and the results shall be filed.
Article 16: The windows, ceilings, entering pipes, ventilation, light fixtures and joints between walls and ceilings in clean room (area) shall be airtight. The static pressure difference between areas of different cleanliness class shall be maintained more than 5 Pa, the static pressure difference between clean rooms (area) and the atmosphere outside shall be maintained at more than 10 Pa and devices for indicating pressure difference shall be installed.
Article 17: The temperature and relative humidity in the clean rooms (areas) shall comply with the requirements of the production process. When there are no special requirements, the temperature and relative humidity may be controlled at 18-26¡æ and 45-65%, respectively.
Article 18: Sinks and drains in clean rooms (areas) shall be installed so that drugs will not be contaminated.
Article 19: Measures shall be taken to protect against cross contamination of personnel and materials entering or leaving clean rooms (areas) of different cleanliness class.
Article 20: Separates buildings and facilities must be used in the production of highly sensitive drugs, such as penicillin. In filling rooms of these drugs a negative pressure shall be maintained relative to other rooms. Before being discharged outside the room, the used steam (or air) shall be cleaned so as to comply with the requirements. The opening for the discharge of used steam shall be far away from the air intake or other air cleaning systems. Drugs with the structure of B-lactam must have specialized equipment and a separate air cleaning system and the production area must be strictly separated from other production areas.
Article 21: Buildings for production of contraceptives shall be separated from those of other drugs. An independent dedicated air cleaning system shall be installed. Chemical drugs such as hormones and anti-tumor pharmaceuticals shall not use the same equipment or air-cleaning system with other drugs; however, if such use cannot be avoided, effective precautions must be taken and necessary validations obtained.
Dedicated and safe equipment shall be used in the processing, packaging and storage of radioactive drugs. Air discharged from the production area shall not be circulated for use. Discharged air shall not contain radio active particles and the requirements and regulations regarding radiation protection shall be complied with.
Article 22: The processing or filling of: bacterial and viral strains used for production or non-production, cells used for production or non-production, wild and attenuated strains, dead and live strains, pre-detoxified and post-detoxified products, live or inactivated vaccines, human blood products and preventive products; shall not be conducted in the same building, and their storage shall be strictly separated from each other. Treatment and filling of different types of live vaccines shall be separated from each other. The production area for wild microorganisms and spore-forming microorganisms preparations shall be under negative pressure relative to neighboring areas and shall have an independent air cleaning system.
Article 23: The pretreatment, extraction, concentration (evaporation) of TCM and the washing and treatment areas of animal organs and tissues shall be strictly separated from the production areas of other preparations.
The steaming, stir-frying, roasting and baking processes for preparing Chinese crude drugs shall be carried out in areas equipped with ventilation, de-fuming, dust extraction, and cooling facilities. The process of selection, slicing, and mashing shall be carried out in areas equipped with effective dust-catching and ventilation facilities.
Article 24: The buildings shall be provided with dust protection devices and dust-catching devices if necessary.
Article 25: Air directly in contact with products which has been dried, compressed or made inert shall be cleaned and shall comply with the requirements of production.
Article 26: Storage areas shall be kept clean and dry. The facilities of lighting, ventilation, etc. as well as temperature control and humidity shall comply with the storage requirements and shall be periodically tested.
Storage areas may be equipped with sampling room(s) for raw materials provided the air cleanliness class is the same as that of production requirements. If sampling is not conducted in a sampling room, measures to prevent contamination and cross-contamination shall be adopted.
Article 27: In accordance with requirements of the production process, the air cleanliness class of the weighing room and material preparation (to get material ready for production) room in the clean room (area) shall be the same as the production requirements and shall be provided with facilities to catch dust and to protect against cross contamination.
Article 28: Rooms for testing, Chinese crude drug specimens, sample retention and other similar laboratories as determined by the quality control department shall be separated from the production area. Areas for biological, micro-biological, or radioactive isotope tests shall be separated from each other.
Article 29: Instruments and meters with special requirements shall be placed in a dedicated instrument room and facilities to protect against static electricity, vibration, humidity or other external factors shall be provided.
Article 30: Any animal experiment house shall be strictly separated from other areas and its design and construction shall comply with relevant national regulations.
Chapter 4: Equipment
Article 31: The design, selection and installation of equipment shall comply with the production requirements and the equipment shall be easy to clean, disinfect or sterilize, convenient to operate and maintain and be able to prevent errors and minimize contamination.
Article 32: The surface of equipment which comes into direct contact with drugs shall be smooth and even, easy to clean and disinfect and be corrosion resistant. The lubricants or coolant of the equipment shall not contaminate the products or their containers.
Article 33: The main fixed pipelines connected to equipment shall be marked with the name of material inside the pipe and flow direction.
Article 34: The preparation, storage and distribution of purified water and water for injection shall be protected from microorganism breeding and contamination. Storage tanks and delivery pipelines shall be made from non-toxic and corrosion-resistant materials. Inaccessible places and dead spots shall be avoided in design and installation of pipelines. Storage tanks and pipelines shall be cleaned periodically. Vents of tanks of water for injection shall be protected by a non-fiber-releasing hydrophobic microbial air filter. Water for injection shall be stored at 80¡æ minimum, or at 4¡æ maximum or maintained in constant circulation at 65¡æ minimum.
Article 35: Each instrument, meter, weighing and measuring device used for production and testing shall have a range of operation and precision meeting production and testing requirements and shall be clearly labeled as certified and be calibrated periodically.
Article 36: Equipment for production shall have its condition clearly marked and shall be periodically maintained and validated. It's installation, maintenance and repair shall not affect product quality. Non-conforming equipment shall be moved from the production area, if possible, and shall be clearly marked before moving.
Article 37: The equipment for production and testing shall have records of use, maintenance and repair and these records shall be kept by a designated person.
Chapter 5: Materials
Article 38: Written procedures for purchase, storage, dispatching, use, etc. of materials for production shall be established.
Article 39: Materials for drug production shall comply with drug specifications, package material specifications, biological product processes or other relevant standards, and shall not have any adverse influence on drug quality. An imported bulk chemical shall have a certificate issued by the coastal institute for drug control.
Article 40: All Chinese crude drugs for drug production shall be purchased in accordance with quality standards and the production site shall be kept stable.
Article 41: All materials used for drug production shall be purchased from units complying with the national regulations and, in entering the factory, shall be placed in storage according to the regulations.
Article 42: Materials whether quarantined, qualified or unqualified shall be strictly controlled. The unqualified materials shall be stored in special areas clearly marked which are easy to recognize and be duly handled according to regulations.
Article 43: Materials, semi-finished or finished products which have special in temperature, humidity or other requirements, shall be stored in accordance with regulations. Solid and liquid materials shall be separately stored. Volatile materials shall be stored so as to avoid contaminating other materials. Prepared, selected, and pretreated Chinese crude drugs shall be packed in clean containers or packages and strictly separated from unprocessed and processed Chinese crude drugs.
Article 44: The acceptance, storage and keeping of narcotics, psychotropics, toxic drugs (including crude drugs), radioactive drugs, flammable and explosive materials and other dangerous substances shall strictly comply with relevant national regulations. The acceptance, storage, keeping, usage and destroying of bacterial and viral strains shall comply with the national regulations on storage and keeping of medical microorganism strains.
Article 45: Materials shall be stored within the period of validity. For those without a regulated expiration date, the storage period generally shall not be more than 3 years and upon expiration shall be retested. In special cases, the retest shall be conducted immediately during storage.
Article 46: Drug labels and insert sheets (direction for use) shall be consistent with those approved by drug regulatory authorities in content, style and written language. Labels and insert sheets cannot be printed, dispatched and used until they are checked by the quality control department of the enterprise.
Article 47: Drug labels and insert sheets shall be kept and drawn by designated persons, and shall meet the following requirements:
1. Labels and insert sheets shall be placed in a dedicated cabinet or dedicated storehouse according to varieties and specifications. They are to be distributed in accordance with batch package instruction and drawn in according to the practical need;
2. The labels shall be counted as distributed, and the designated person shall check and sign. The sum of the distributed, damaged and remaining labels shall be reconciled. The damaged and remaining labels with batch number shall be counted and destroyed by the designated person(s);
3. The dispatching, usage and destruction of labels shall be recorded.
Chapter 6: Hygiene and Sanitation
Article 48: Drug manufacturing enterprises shall adopt hygiene and sanitation measures to prevent contamination and establish hygiene and sanitation system for which a designated person shall be responsible.
Article 49: Cleaning procedures of building, equipment, containers, etc. shall be established for the production plant, work rules and job classifications in accordance with production requirements and cleanliness classes. The content includes cleaning methods, cleaning process, cleaning interval, detergents or disinfectants used, cleaning method for cleaning tools and place for their storage.
Article 50: Non-production articles and materials and personal items shall not be placed in production area. Production discharges shall be duly handled.
Article 51: The dressing rooms, bath rooms and toilets shall not have any adverse influence on the clean rooms (areas).
Article 52: The material, style and way of wearing of protective garments shall be appropriate to the requirements of operation and cleanliness class and shall not be otherwise used.
The garments used in clean areas shall be smooth, free from static electricity, and not shed fibers and particulates. The aseptic garments shall be able to cover completely hair, beard and feet and prevent body materials from being left.
The garments used for production of different cleanliness classes shall be cleaned and arranged separately and disinfected or sterilized if necessary. Granules shall not be added into garments when being washed and sterilized. The cleaning frequency of garments shall be fixed.
Article 53: The entrance to clean rooms (areas) shall be limited only to the operators working in the area and other authorized personnel.
Article 54: Personnel entering into clean rooms (areas) are not allowed to put on any cosmetics, wear any ornaments and touch drug products with bare hands.
Article 55: Clean rooms (areas) shall be periodically disinfected. The disinfectants used shall not cause any contamination on equipment, material and finished products. The different varieties of disinfectants shall be used alternatively so as to prevent the development of resistant strains of microorganisms.
Article 56: Health files shall be established and kept for personnel engaged in production. As to those who have direct contact with drug products, a physical examination shall be conducted at least once a year. No person with an infectious disease, skin disease or wound on an exposed surface of the body shall be engaged in the production which comes into direct contact with the drug.
Chapter 7: Validation
Article 57: The validation of drug production refers to: installation qualification of building and facilities (IQ), operational qualification (OQ), performance qualification (PQ) and product validation (PV).
Article 58: The validation of production process and key facilities and equipment shall be conducted according to a protocol. Re-validation shall be conducted at defined intervals or after any significant modifications that may affect the product quality, e.g. manufacturing process, quality control method, important raw material and excipient, or equipment, etc.
Article 59: The items to be validated, validation protocol and its implementation shall be made on the basis of the validation objectives. A validation report shall be written after validation is finished, which shall be reviewed and approved by the responsible person.
Article 60: The data and content of analysis obtained in the validation process shall be recorded and filed. The files should include validation protocol, validation report, evaluation and suggestions, approval person, etc.
Chapter 8 Documentation
Article 61: Drug manufacturing enterprises shall have the following management documents and records for production and quality control:
1. written procedures and records for use, maintenance and repair of buildings, facilities and equipment;
2. written procedures and records for material checking and acceptance, production operation, testing, material dispatching, releasing, finished product distribution and consumer complaints, etc;
3. written procedures and records for control of unqualified materials and products, return of goods to the warehouse, disposal reports, and handling of emergencies, etc.
4. written procedures and records for hygiene and sanitation of the environment, building, equipment and personnel, etc, and
5. written procedures and records for GMP and professional technical training.
Article 62: Production control documents mainly include:
1. Master formula, job position instructions or standard operating procedures. Master formula includes: drug name, dosage form, formula, the operational requirements of process, quality standards of materials, in-process product and finished product, technical parameter as well as storage precautions, reconciliation of materials, requirements of packaging materials and container for finished products.
Job position instructions include: production operation methods and key points, checking and review of critical operations, specification and its control of in-process products, safety and labor protection, maintenance and cleaning of equipment, treatment and report of abnormal situation, process and environmental sanitation, etc.
Standard operating procedure includes: title, numbering code, writer, date of establishing, reviewer and reviewing date, approval person and approving date, issuing department, date of effect, receiving and distributing departments, heading and text.
2. Batch production records
Batch production records include: product name, batch number, production date, signature of operator and checker, a description of related operations and equipment, quantity in relevant production stages, reconciliation of material, process control records as well as records of special problems.
Article 63: The product quality control documents mainly include:
1. all application and approval documents of the drug;
2. specification of materials, in-process products and the finished product and their test procedures;
3. stability testing records of the product; and,
4. batch test records.
Article 64: Written procedures for drafting, revising, reviewing, approving, withdrawing, distributing and retaining of documents shall be established in drug manufacturing enterprises. Only the approved current documents may be distributed and used. Withdrawn and out-of-dates documents shall not be present at work site, except those maintained in archives for reference purposes.
Article 65: The requirements for establishing production and quality control documents are as follows:
1. the title shall clearly describe the nature of the document;
2. the documents shall have a numbering code system as well as date to identify their version and category ;
3. the language used in documents shall be exact and understandable;
4. the documents shall have a sufficient space to fill in the data;
5. the responsibility for drafting, reviewing and approving documents shall be clearly defined, and there shall be the signature of the responsible person on documents.
Chapter 9: Production Management
Article 66: Master formula, post instruction or standard operating procedures shall not be changed arbitrarily. If there is a necessity to revise, the amendment to such documents shall be reviewed and approved in accordance with the same procedures as in the preparation of the original documents.
Article 67: Checks on yields and reconciliation of quantities should be carried out for each batch. If there is a significant difference, the cause shall be identified and products shall not be treated as normal products unless the cause is rationally explained and no potential quality risk is confirmed.
Article 68: The batch production record shall be completed in a timely manner, written clearly, truthful in content and complete in data and shall be signed by both the operator and checker. The records shall be kept clean and tidy, and shall not be destroyed and changed arbitrarily. When there is a revision, the reading of the original information shall be permitted and the person making the revision shall sign his name at the place of the revision.
Batch production records shall be filed with batch number and kept one year after the expiration date of the product. The production records of the drugs without expiration date shall be kept at least for three years.
Article 69: A defined quantity of drug product with identical properties and quality within a specified limit, produced continuously in a same production cycle is called a batch. A batch number shall be assigned to each batch of product.
Article 70: The production operations shall adopt the following measures to prevent drugs from contamination and mix-ups:
1. confirm before production that there are no residues from the previous batch;
2. prevent the generation and spreading of particulates;
3. products of different varieties and specifications shall not be produced in the same room at the same time. When several package lines are in operation at the same time, segregation or other measures shall be adopted to prevent contamination or mix-up;
4. during production, the cross-contamination caused by gas, vapor, spraying substances or biological bodies generated from materials and products shall be prevented;
5. each production room, equipment and container shall be labeled with the name of product or material, batch number and quantity, etc.
6. circulating water is required for the washing of selected crude drugs, recovered water is not allowed to be used for washing of other crude drugs. Crude drugs of different properties may not be washed together. Outdoor drying is not appropriate for washed, sliced, and processed crude drugs.
The sterilization of crude drugs and in-process products shall not change their effect and quality. A micro-biological test shall be conducted before directly injecting drugs with crude drug powder and preparation materials.
Article 71: Processing water shall be selected in accordance with the master formula which shall comply with quality specifications, be tested and recorded periodically. The test interval shall be defined in accordance with validation results.
Article 72: A batch package record shall be provided for each batch of products. The record shall include:
1. the name, batch number and specification of the bulk product;
2. label with batch number, insert sheet as well as product quality certificate;
3. the received quantities of bulk product and package materials, signatures of the dispatcher, the receiver and the checker;
4. the quantities of packaged product;
5. line-clean record of previous packaging batch (duplicate original) and the record of this batch (original);
6. the post completion inspection and checking results of this packaged batch and signature of the checker;
7. the signature of the person responsible for the production operation.
Article 73: Line-clean must be conducted and recorded by operators after completion of each production stage. The record shall include section (stage), name of the product, production batch, line-clean date, items of examination and their results, signatures of the person performing the line-clean and the checker. The line-clean records shall be included in the batch record.
Chapter 10: Quality Management
Article 74: The quality control department of drug manufacturing enterprises shall be responsible for the quality management and testing of the whole process of drug production and shall be directly led by the enterprise leaders. Quality control department shall be staffed by an adequate number of quality management and testing personnel and shall be provided with the space, facilities, instruments and equipment adapted to the requirements of production scale of the drug, product variety and tests.
Article 75: The main responsibilities of quality control department are as follows:
1. to establish and revise in house specification and analytical operational procedure of materials, in-process and finished products, and to establish sampling and sample retention procedures;
2. to establish the procedures for controlling testing equipment, instrument, reagent, testing solution, standard substance (or reference substance), titration solution, culture medium, experiment animals, etc;
3. to decide the use of material and in-process products;
4. to review the batch production record before releasing a finished product and to decide the release of a finished product;
5. to review the treatment procedure of rejected products;
6. to sample, test, retain samples and issue analytical reports for materials, in-process and finished products;
7. to monitor the number of particulates and microorganisms in the clean room (area);
8. to evaluate the stability of raw material, in-process and finished product and to provide data for determining the storage period of materials and expiration date of a drug; and,
9. to establish the responsibilities of the people engaged in quality management and quality test.
Article 76: The quality control department together with other related departments shall audit the quality system of suppliers of main materials.
Chapter 11: Product Distribution and Recall
Article 77: Distribution records shall be available for every batch of finished product. The marketing of each batch of drugs shall be traced according to the distribution record and, if necessary, the batch shall be duly recalled. The distribution record shall include: drug name; dosage form, batch number, specifications; quantity, unit receiving goods and its address and dates of distribution.
Article 78: Distribution records shall be kept for one year after expiration date of the product. The records of the drugs with no expiration date shall be kept for five years.
Article 79: A drug manufacturing enterprise shall establish the written procedures and records of drug return and recall. Drug return and recall record shall include: drug name, batch number, specifications, quantity, units from whom the product is returned or recalled and their address, the reason and date of return and recall and suggestions of treatment.
If drug preparations are returned or recalled for quality problems, then, under the supervision of quality control department, the drugs shall be destroyed. If other batches are affected, they should also be handled at the same time.
Chapter 12: Complaints and Adverse Reactions Report
Article 80: A drug manufacturing enterprise shall establish a reporting system for supervising drug adverse reactions. The designated technical organization or personnel shall be responsible for the management of the system.
Article 81: Any complaints on drug quality from the consumer and drug adverse reactions shall be recorded in detail and treated based on thorough investigation. Drug adverse reactions shall be duly reported to the local drug administration authorities.
Article 82: A report shall be provided to local drug regulatory authorities whenever any serious problems in drug production occur.
Chapter 13: Self-Inspection
Article 83: Self inspection shall be periodically conducted by drug manufacturing enterprises. Self inspection shall be the periodical inspection of personnel, buildings, equipment, documents, production, quality control, drug distribution, consumer's complaint and the treatment of product recall in accordance with the predetermined procedure so as to confirm consistency with GMP.
Article 84: Self inspection reports shall be kept. The report shall be written after the completion of self-inspection, and it shall include the results of self-inspection, conclusions of evaluation as well as improvement measures and suggestions.
Chapter 14: Miscellaneous
Article 85: The terms used in this Regulation are defined as follows:
1. Materials: raw materials, excipient, packaging materials, etc;
2. Batch number: A distinctive combination of numbers and/or letters by which one is able to trace and review the manufacturing history of the batch of the drugs;
3. Quarantine: The status of material, in-process and finished products being held and waiting for evaluation result.
4. Batch production record: All documents associated with the manufacture of a batch of bulk product or finished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the final product.
5. Reconciliation : A comparison, making due allowance for normal variation, between the amount of product or materials theoretically produced or used and the amount actually produced or used.
6. Standard Operation Procedure (SOP): An authorized documented procedure giving instructions for performing operations of a general nature or describing management methods.
7. Master Formula: A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls.
8. Water for processing: Water used in the production process of drugs, including drinking water, purified water, water for injection;
9. Purified water: Water for pharmaceutical use obtained by methods of distillation, ion exchange, reverse osmosis, or other proper methods, without any additional agents;
10. Clean Room (Area): An room (area) with defined environmental control of particulates and microbilogical contamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area.
11. Validation: The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.
Article 86: The special requirements on production quality management for various categories of drugs are included in the Appendix of this Regulation.
Article 87: The State Drug Administration of P.R.China is responsible for interpretation of this Regulation.