1. GMP and Pilot Manufacturing facilities
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2. cGMP and Manufacturing Process
Human Resource
Process Design and Operation
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3. Ǿ 211.25 Personnel Qualifications
(a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shell have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee’s functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with cGMP requirements applicable to them.
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4. Ǿ 211.25 Personnel Qualifications
(b) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shell have education, training, and experience, or any combination thereof, to perform the assigned functions in such manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess.
(c) There shall be adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product.
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5. Personnel Job (Types and Categories)
Research & Development
Vendors
Consultants
WHO SHOULD DO TRAINING ?
Quality Assurance
Contractors
Human Resource
Manufacturing
Packaging
Laboratory Operators
Temporary Employees
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6. Engaged in and non Engaged in the production processQA
Facilities
WCB Opt.
Storage
Directly Engaged IN
Indirectly Engaged IN
Prep. Lab. Opt
Engineering
Fermentation
NOT Engaged IN
Training
Buffer Prep.
Downstream HR
Packaging
Inform. Syst.
Security
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7. Training Requirements
Fermentation
ALL TRAINING ARE EQUALLY IMPORTANT Training requirement based on Job Task Standard Training Module is Necessary Re-training up on using new technique, New Equipment or change in SOP (if include Major change with new methods or Equipment)
Weighing
Cell Separation
Purification
Documentation
Validation
Analysis
Engineering
Filling
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8. Training and Development Cycle
Position requirement defined
Applicant Screening
Induction Training
Basic Training
Evaluation
And
Appraisal
New position
(same area or other area)
Additional Training or
Retraining
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9. Induction Training
Occurs on the first day and include: Company background, policies, procedures and some fundamentals on the importance of the employee’s role to the health and well-being of the ultimate consumer
Basic
Training
During the phase, the new employee will be closely supervised. They MUST be fully trained in all relevant techniques associated with this equipment involved and fully understand the procedures to be followed, and must be aware of the potential problems that can be created by ignoring to these procedures
Training programs MUST include appropriate evaluation steps. These will usually involve some types of evaluation at the end of each module followed by on-the-job appraisal to confirm that the lessons learned have been put into practice.
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10. IMPORTANT
Education and training records must be maintained and kept current, FDA inspectors may ask for confirmation of adequate training.
The responsibility for training of employees should reside with departmental management.
The QC Dept. should monitor or audit to ensure that the appropriate training has been given. This could include review of training module content and also of training records. Moreover, QC staff themselves are likely to be involved in providing some of the training.
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11. Ǿ 211.22 Responsibilities of Quality Control Unit
(a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products, and the authority to review production records to assure that no errors have occurred, or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.
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12. Ǿ 211.22 Responsibilities of Quality Control Unit
(b) Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in process materials, and drug products shall be available to the quality control unit.
(c) The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.
(d) The responsibilities and procedures applicable to the quality unit shall be in writing; such written procedures shall be followed.
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13. Ǿ 211.28 Personnel Responsibilities
(a) Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform. Protective apparel, such as head, face, hand, and arm coverings, shall be worn as necessary to protect drug product from contamination.
(b) Personnel shall practice good sanitation and health habits.
(c) Only personnel authorized by supervisory personnel shall enter those areas of the building and facilities designated as limited-access area.
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14. Ǿ 211.28 Personnel Responsibilities
(d) Any person shown at any time (either by medical examination or by supervisory observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components, drug product, containers, closures, in-process materials, and drug products until the condition is corrected or determined by competent medical personnel not to jeopardize the safety or quality of drug products. All personnel shall be instructed to report to supervisory personnel any health conditions that may have an adverse affect on drug products.
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15. Implementation of Personnel Responsibility
(Uniforms!)
A sufficient amount of clean uniforms is provided so that changes can be made at an adequate defined frequency or whenever they became soiled.
Washing and sanitation procedures should be checked to confirm their effectiveness.
Employee in special areas should wear only lint-free garments to prevent shedding.
Garments should be designed and use material that maximizes personnel comfort.
The range of clothing available would normally include:
Employee should be shown how and when to wear the appropriate clothing.
Work clothing should not be worn outside of the appropriate plant area, and changing rooms should be available.
Hair cover - Beard and moustache cover - Coverall - Disposable gloves
Food covers or shoes, over shoes -Masks - Safety glass - clean room suite
Control the type of cloth in different area!!!!!!!
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16. Ǿ Consultations
Consultants advising on the manufacture, processing, packing or holding of drug products shall have sufficient education, training and experience, or any combination thereof, to advise on the subject for which there are retained. Records shall be maintained stating the name, address, and qualifications of any consultants and the type of service they provide.
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17. Process Design and Product Development Flow
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18. Activities Process Design Prepare flow diagram
Prepare influence matrix
Establish Experimental Procedure
Establish Design Criteria
Prepare Study Plan and Protocols
Process Parameter Challenging
Identify Critical Variables for Unit and Overall Operation
Establish Maximum Tolerance for Process Variables
Process Characterization
Modify Study Plan and Protocols
Establish Nominal Values for Critical Variables
Establish Tolerance for Critical Variables
Process Validations
Modify Study Plan and Protocol
Determine Product Variability Under Constant Processing Condition
Prepare Process Transfer Documents
Finalize Product Specifications
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20. Important Notes for Process Design/Process Flow
1. Safety
The safety level of each step should be identified
General safety (i.e using toxic, corrosive, flammable materials)
The Biosafety level in each part of platform.
2. Equipment and Production Capacity
The following points should be considered
The time required in each step should be fully defined
(including preparation, operation and cleaning phase)
B) The capacity of each equipment
(to ensure a smooth material transfer through well balanced capacity between up-stream, down-stream, filling and packing lines)
C) Complete set of SOP for (preparation, operation and cleaning validation) for each platform component.
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21. Pilot manufacturing facilities
Things need to be considered!
Regulatory, design and operating consideration
Primary production
Secondary production
Design of facilities and equipment
Process utilities and services
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22. 1. Regulatory, design and operating consideration
Regulatory consideration
Design consideration
Operating consideration
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23. 2. Primary production Starting materials
Cell culture, fermentation and process control
Product recovery and purification
Primary production facilities
Safety issues
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24. 3. Secondary production Starting materials Final processing operations
Secondary (sterile) production facility
Safety issues
Out of specification
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25. Out of specification
'Out of specification' is defined as an examination, measurement, or test result that does not comply with such pre-established criteria.
cGMP guidelines require written procedures to be in place to determine the cause of any apparent failure, discrepancy, or out of specification result.
Out of specification results can be caused by laboratory error, non-process or operator error, or by process-related error, such as personnel or equipment failures.
If, however, the result could not be clearly attributed to sampling or laboratory error, then there should be scientifically sound procedures and criteria for the exclusion of any test data found to be invalid and, if necessary, for any additional sampling and testing.
It involved
Re-testing
Re-testing for pyrogens and endotoxins
Sterility re-testing
Reprocessing
rejection
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26. 4. Design of facilities and equipment
Facility design
Laboratory design
Equipment design
Sterilization method
Cleaning procedures and validation
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27. manufacturing and processing operations;
Facility design
When designing facilities for bio-pharmaceutical manufacture, the following activities should be considered as areas to control contamination:
the receipt, identification, storage and withholding from use of raw materials or process intermediates, pending release for use in manufacturing; as well as the quarantine storage of intermediates and final products pending release for distribution;
the holding of rejected raw materials, intermediates and final products before final disposition;
the storage of released raw materials, intermediates and final products;
manufacturing and processing operations;
packaging and labelling operations;
all laboratory operations.
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28. Equipment design Equipment capacity and location
Equipment construction and installation
Biosafety cabinets
Organism preparation
Bioreactors or fermenters
Product recovery
Isolator technology
Computer and related automated and electronic systems
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29. Sterilization method Biological indicators Sterilization by moist heat
Sterilization by dry heat
Sterilization by radiation
Sterilization with ethylene oxide
Sterilization with formaldehyde
Sterilization In Place
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30. Clean In Place
Where feasible, Clean In Place (CIP) methods should be used to clean process equipment and storage vessels.
CIP methods might include fill and soak/agitate systems, solvent refluxing, high-impact spray cleaning, spray cleaning by sheeting action, or turbulent flow systems.
CIP systems should be subjected to cleaning validation studies to ensure that they provide consistent and reproducible results, and once they are validated, appropriate documentation should be maintained to show that critical parameters, such as time, temperature, turbulence, cleaning agent concentration, rinse cycles, are achieved with each cleaning cycle.
However, the design of the equipment, particularly in facilities that employ semi-automatic or fully automatic Clean In Place (CIP) systems, can represent a significant concern.
For example, sanitary type pipework without ball valves should be used, since non-sanitary ball valves make the cleaning process more difficult.
Such difficult to clean systems should be properly identified and validated, and it is important that operators performing these cleaning operations are aware of potential problems and are specially trained in cleaning these systems and valves.
Furthermore, with systems that employ long transfer lines or pipework, clearly written procedures together with flow charts and pipework diagrams for the identification of valves should be in place.
Pipework and valves should be tagged and easily identifiable by the operator performing the cleaning function. Sometimes, inadequately identified valves, both on diagrams and physically, have led to incorrect cleaning practices.
Equipment in CIP systems should be disassembled during cleaning validation where practical to facilitate inspection and sampling of inner product surfaces for residues or contamination, even though the equipment is not normally disassembled during routine use.
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31. 5. Process utilities and services
Water systems
Medical air
HVAC systems
Decontamination techniques and waste recovery
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32. Water systems
Water of suitable quality is required depending on the culture system used, the phase of manufacture and the intended use of the product.
The water used should meet the standards for potable water as a minimum for the production of biopharmaceuticals.
The quality of water, therefore, depends on the intended use of the finished product.
Water treatment plants and distribution systems should be designed, constructed and maintained to ensure a reliable source of water of an appropriate quality.
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33. HVAC systems
Regulatory authorities require the following information to be available for pre-approval inspection:
A general description of the HVAC system(s) including the number and segregation of the air handling units, whether air is once-through or recirculated, containment features, and information on the number of air changes per hour;
Validation summary for the system with a narrative description of the validation process (or protocol), including the acceptance criteria; the certification that IQ, OQ, and certification of filters has been completed; the length of the validation period; validation data should include Performance Qualification data accumulated during actual processing; and an explanation of all excursions or failures, including deviation reports and results of investigations;
A narrative description of the routine monitoring programme including the tests performed and frequencies of testing for viable and non-viable particulate monitoring parameters; viable and non-viable particulate action and alert limits for production operations for each manufacturing area; and a summary of corrective actions taken when limits are exceeded.
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34. Decontamination techniques and waste recovery
Filtration - The primary method of decontaminating exhaust gases mixed with liquid broth is through the use of filters. Before filtration, the mixture may be passed through a condenser, a coalescing filter and a heat exchanger. Filtration is accomplished either through pairs of high efficiency particulate air (HEPA) filters, or membrane filters used in series to decontaminate vent or exhaust gases.
Incineration - Another method of decontaminating air and gaseous waste streams is thermal destruction or incineration. Incineration may be used independently, or as a supplement to filtration, and is generally used for small volume gas streams. Automatic safety devices should be used with incinerators to protect against problems resulting from power failures and overheating.
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35. Decontamination techniques and waste recovery (cont.)
Irradiation
Irradiation involves exposing the waste materials to x-rays, ultraviolet rays or other ionizing radiation to decontaminate them.
Liquid wastes
Liquid wastes can be decontaminated through chemical or heat treatment.
When liquid wastes are of limited volume, chemical treatment is often used, whilst for large volumes of liquid wastes, heat treatment is generally preferred.
Also, since proteins present in liquid wastes can deactivate the sterilant used in chemical treatment, thermal sterilization may be more appropriate for wastes involving bioengineered microorganisms.
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36. Decontamination techniques and waste recovery (cont.)
Solid wastes
Solid wastes such as microbial cultures, cell debris, glassware, and protective clothing, are generally decontaminated by autoclaving, followed by incineration if necessary.
To decontaminate laboratory devices exposed to genetically engineered products, the most common practice is the use of pressurized steam that contains an appropriate chemical.
For heat-sensitive equipment, such as electronic instruments, decontamination is generally achieved through chemical sterilization or irradiation.
Gaseous sterilants are applied by a steam ejector that sprays down from overhead.
If decontamination by steam, liquid, or gas sterilization is not possible, ionizing or ultraviolet radiation is used. However, since irradiation methods do not always inactivate all types of microbes, steam or gaseous chemical sterilization should be used for devices contaminated with genetically engineered organisms.
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