Transcript 4. GMP and Pilot Manufacturing facilitiesx

GMP and Pilot Manufacturing
facilities
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cGMP and Manufacturing Process
 Human Resource
 Process Design and Operation
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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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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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Personnel Job (Types and Categories)
Research &
Development
Quality Assurance
Vendors
WHO
SHOULD DO
TRAINING ?
Consultants
Contractors
Human Resource
Manufacturing
Packaging
Laboratory Operators
Temporary Employees
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Engaged in and non Engaged in the production process
QA
Facilities
WCB Opt.
Storage
Prep. Lab. Opt
Fermentation
Directly
Engaged
IN
Indirectly
Engaged
IN
Buffer Prep.
NOT
Engaged
IN
Downstream
HR
Packaging
Engineering
Training
Inform. Syst.
Security
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Training Requirements
Fermentation
ALL TRAINING ARE EQUALLY IMPORTANT
Weighing
Training requirement based on Job Task
Cell Separation
Standard Training Module is Necessary
Purification
Re-training up on using new technique,
New Equipment or change in SOP (if
include Major change with new
methods or Equipment)
Documentation
Validation
Analysis
Engineering
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Filling
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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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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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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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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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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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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 limitedaccess area.
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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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Implementation of Personnel Responsibility
(Uniforms!)
1. A sufficient amount of clean uniforms is provided so that changes can be
made at an adequate defined frequency or whenever they became soiled.
2. Washing and sanitation procedures should be checked to confirm their
effectiveness.
3. Employee in special areas should wear only lint-free garments to prevent
shedding.
4. Garments should be designed and use material that maximizes personnel
comfort.
5. The range of clothing available would normally include:
-Hair cover - Beard and moustache cover - Coverall - Disposable gloves
-Food covers or shoes, over shoes -Masks - Safety glass - clean room suite
6. Employee should be shown how and when to wear the appropriate clothing.
7. Work clothing should not be worn outside of the appropriate plant area, and
changing rooms should be available.
Control the type of cloth in different area!!!!!!!
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Ǿ 211.34 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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Process Design and Product
Development Flow
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Activities
Process Design
Process Parameter
Challenging
-Prepare flow diagram
- Prepare influence matrix
- Establish Experimental Procedure
- Establish Design Criteria
- Prepare Study Plan and Protocols
-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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Important Notes for Process Design/Process Flow
1. Safety
The safety level of each step should be identified
1. General safety (i.e using toxic, corrosive, flammable materials)
2. 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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Pilot manufacturing facilities
Things need to be considered!
1.
2.
3.
4.
5.
Regulatory, design and operating consideration
Primary production
Secondary production
Design of facilities and equipment
Process utilities and services
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1. Regulatory, design and operating
consideration
• Regulatory consideration
• Design consideration
• Operating consideration
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2. Primary production
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Starting materials
Cell culture, fermentation and process control
Product recovery and purification
Primary production facilities
Safety issues
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3. Secondary production
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Starting materials
Final processing operations
Secondary (sterile) production facility
Safety issues
Out of specification
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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
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Re-testing
Re-testing for pyrogens and endotoxins
Sterility re-testing
Reprocessing
rejection
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4. Design of facilities and equipment
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Facility design
Laboratory design
Equipment design
Sterilization method
Cleaning procedures and validation
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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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• 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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• 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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Clean In Place
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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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5. Process utilities and services
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Water systems
Medical air
HVAC systems
Decontamination techniques and waste
recovery
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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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HVAC systems
Regulatory authorities require the following information to be available for preapproval 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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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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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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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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