Download cGMP BASIC REQUIREMENT

cGMP BASIC REQUIREMENT
cGMP Basic Requirements
Quality System
Definitions
Regulations
Requirements
Quality Management System
QMS
Management Responsibility,
Resource Management,
Product Realization,
Measurement,
Analysis and Improvement
Input
Raw Materials
Energy
Costomer Requirement
PROCESS
Output
Plan-Do-Check-Act
PLAN
-Define the systems
-- Assess current situation
- Analyze causes
ACT
- Standardize improvements
-Plan continuous
improvement
DO
-- Try out system or
improve theory
CHECK
- Study the system or
results
QMS and cGMP in Biopharmaceutical Co.
Senior Management Responsibility
- Quality
- Safety
- Efficacy
To archive the quality objectives, a well-establish and
documented system of Quality assurance (QA)
incorporating Good Manufacturing Practice (GMP) should
be followed)
Quality Assurance and Quality Control
QA
• Is defined as the sum total of organized
arrangements made with the objective of ensuring
that the products are of quality required for their
intended use.
QC
• It is the part of GMP which is concerned with
sampling, specifications, testing, documentation
and release which ensures that necessary and
relevant tests are carried out and that
materials/products are released For use/ sale only
after their quality is judged to be satisfactory.
What QA systems should includes?
1.
GMP and GLP are taken into account during designing and developing
products.
2. All production and control operations are clearly specified and
documented.
3. Key personnel responsibilities are clearly defined.
4. All arrangements for procurement and use of correct starting materials
and packaging materials are made.
5. In process checks and validations are carried out in a defined manner.
6. The final product is manufactured, packed and checked as per defined
procedures.
7. Regulatory aspects and internal requirements for the final product are
fulfilled.
8. Storage, handling and distribution procedures for the final product are
followed to ensure maintenance of quality throughout shelf life.
9. Self-inspection procedures are defined to regularly monitor the
effectiveness of the quality assurance system.
10. Corrective actions
11. Statistical process control
What QC systems should includes?
1.
Appropriate procedures, training personnel and adequate facilities for sampling,
inspection and testing of starting materials, intermediate, bulk and finished
products.
2.
Validated test methods
3.
Maintenance of records to demonstrate that all procedures have been carried
out.
4.
Certification of starting materials to be of specified quality and purity, and their
storage and adequate labeling before use in final product.
5.
Release of batch of product ONLY after certification by qualified person that it
meet required criteria or specifications.
6.
Maintain sufficient samples of starting materials and final product for future
examination, if necessary.
7.
Recording and investigation of out of specification results, changes, incidents and
deviations.
cGMP for Biohharmaceutical Industries
Is it part of QA or QC?
GMP is that part of quality assurance which ensures that
products are consistemly produced and controlled to be
quality standards appropriate to their intended use and as
required by the marketing authorization.
GMP rules are directed primarily to diminishing the risks,
inherent in any biopharmaceutical production, that cannot
be prevented completely through testing the final products.
Risk are:
1. Cross contamination (in particular by unexpected
contaminants)
2. Mix-ups (confusion) such as false labeling.
cGMP Guidelines for Biopharmaceuticals
1.
All manufacturing process are clearly defined, systematically
reviewed in the light of experience, and shown to be capable of
consistently manufacturing biopharmaceutical products of the
required quality and specifications.
2.
All steps of manufacturing processes and any significant changes
made to the process are validated.
3.
All necessary facilities are provided, including:
–
–
–
–
–
–
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Appropriate qualified and trained personnel
Adequate premises and space
Suitable equipment and services
Correct materials, containers and labels
Approved procedures and instructions
Suitable storage and transport
Adequate personnel, laboratories and equipment for in-process
control under the responsibility of the production management.
cGMP Guidelines for Biopharmaceuticals (cont)
4.
Instructions and procedures are written in clear language, specifically applicable to
the facilities provided.
5.
Operators are trained to carry out procedures correctly
6.
Records are made (Manually, with signature or recording instruments) during
manufacturing to show that all steps required by the defined procedures have been
taken and the expected quantity and quality were reached. Any significant deviations
are fully recorded and investigated.
7.
Records covering manufacturing and distribution, which enable the complete history
of a batch to be traced, are retained in a comprehensible form.
8.
Proper storage and distribution of the products minimized any risk to their quality
9.
A system is available to recall any batch or product from sale or supply
10. Complains about marketed products are examined, the causes of quality defects
investigated, and appropriate measurements taken in respect of the defective
product(s) and to prevent recurrence.
Information and material flow in pharmaceutical/ biopharmaceutical
production process
premises
personnel
storage
maintenance
In-process control
equipment
cGMP
Documentation
Calibration system
Recall procedures
Complain management
QC
Sanitation & Hygiene
Validation & Re-validation
Label control
Self inspection team
The cGMP Regulations
cGMP for finised Pharmaceuticals
21 CFR 210, 211
• First issued: June 1963
• Current = Dynamic roles (standarsd evolve over time)
www.fda.gov/cder/dmpq
Examples of cGMP codes (FDA)
Building, Facilities, Equipments
(21 CFR 211.42-72)
Equipment Identification
(21 CFR 211.105)
Equipment cleaning and use
(21 CFR 211.182)
Electronic records, electronic signature
Process validation
(21 CFR Part 11)
(General code of FDA process validation)
Rubber articles for repeated use
(21 CFR 177.2600)
Buildings and Facilities
Ǿ 211.42 Design and Construction features
a) Any building or buildings used in the manufacture,
processing, packing or holding of drug product shall
be of suitable size, construction and location to
facilities cleaning, maintenance, and proper
operation
External Environment and Internal Environment
Site preparation and Plant design
 Site arrangement and over-all layout design (green spaces parking, traffic, recreation area, tanks,
site utilities, etc..)
 Water supply and waste management area (waste contractor!!)
 Site security and access (fences, guard, cameras, etc..)
 Utilities design, layout, backup (critical utilities backup)
 Equipment-design, layout, spares, capacity
 Safety (personnel and equipment), emergency services access.
 External architecture should take in account the local environment (temperature, humidity, wind,
etc..)
 Ease of maintenance (service ducts, cat floor, etc..)
 Project management (managers, consultants, etc..)
 Validation Plans and an effective change control procedures. Provision of design and (as builds)
drawing.
 Contractor (Experienced contractor)
Ǿ 211.42 Design and Construction features
b) Any such building shall have adequate space for the
orderly placement of equipment, drug product
containers, closures, labeling, in-process materials,
or drug products, and to prevent contamination. The
flow of components, drug product containers,
closures, labeling, in-process materials, and drug
products through the buildings shall be designed to
prevent contamination.
Ǿ 211.42 Design and Construction features
c) Operations shall be performed within specifically defined areas
of adequate size. There shall be separate or defined areas or
other such control systems for the firm’s operations as are
necessary to prevent contamination or mix-ups during the
course of the following procedures:
1.
2.
3.
4.
5.
6.
7.
8.
9.
Receipt, identification, storage and with folding from use of components, drug
product containers, closures and labeling, pending the appropriate sampling,
testing, or examination by quality control unit before release for manufacturing
or packaging.
Holding rejected components, drug product containers, closures and labeling
before dispersion.
Storage of released components, drug product containers, closures and labeling
Storage of in-process materials
Manufacturing and processing operations
Packaging and labeling operations
Quarantine storage before release of drug products
Storage of drug products after release
Control and laboratory operation
Ǿ 211.42 Design and Construction features
Part (c) cont
10. Aseptic processing, which include as appropriate:
i.
ii.
iii.
iv.
v.
vi.
Floors, walls, and ceilings of smooth, hard surfaces the
easily cleanable
Temperature and humidity controls
An air supply filtered through high-efficiency particular air
filters under positive pressure, regardless of whether flow
is laminar or non-laminar
A system for monitoring environmental conditions
A system for cleaning and disinfecting the room and
equipment to produce aseptic conditions
A system for maintaining any equipment used to control
the aseptic conditions.
Construction Materials
walls
Floors
Ceilings
•Provide ordinary movement of materials and personnel
•Provide acceptable noise level during operation
•Smooth surface, cleanable, non-porous
•Flush without any projections
•Usually made of epoxy, enamel or prefabricated smooth materials
•(rounded floor to wall junction)
•Durable, cleanable, acid/base resistance, non-porous, smooth
•Usually made of epoxy materials. Subsurface finish!!
•Ceramic and vinyl tiles are not recommended
• Smooth finish surface
• All ceiling fixtures (light, fitting, air outlets and returns, etc..) should designed to ensure ease
cleaning and to minimize dust accumulation
• Cat-floor in the production area is essential for maintenance during operation.
Typical finishing materials in
Biopharmaceutical facilities
Walls
Floors
Ceiling
Warehouse
Sanitary painting
Hard, sealed
(pref. epoxy)
Clean, painted
Dispensary
Epoxy
Coved
Epoxy or in situ terrazzo
Coved
Epoxy
Coved
Manufacturing
Epoxy
Coved
Epoxy or in situ terrazzo
Coved
Epoxy
Coved
Packaging
Epoxy
Coved
Epoxy or in situ terrazzo
Coved
Epoxy
Coved
Ǿ 211.42 Design and Construction Features
d) Operations relating to the manufacture, processing
and packing of PENICILIN shall be performed in
facilities separate from those used for other drug
products for human use
Ǿ 211.44 Lighting
Adequate lighting shall be provided in all area
The amount of light reaching the working surface of each area involved in the
production chain should be defined (lux or foot-candles)
Normally, for public standard, a range of 30-50 candles is necessary to ensure
worker comfort and ability to perform efficiently and effectively
One hundred (100) foot-candles is required in some area such as inspection and
filling area
Lighting should measured periodically and the results recorded.
Routine replacement of light sources on some schedule to ensure that light levels
do not drop below the established minimum.
Ǿ 211.46 Ventilation, air filtration, air heating
and cooling
a)
Adequate ventilation should be provided.
b)
Equipment for adequate control over air pressure, micro-organisms, dust,
humidity, and temperature shall be provided when appropriate for the
manufacture, processing, packing, or holding of a drug product
c)
Air filtration system, including pre-filters and particulate matter air filters,
shall be used when appropriate on air supplies to production areas, measures
shall be taken to control recirculation of dust from production. In areas
where air contamination occurs during production, there shall be adequate
exhaust systems adequate to control contaminants.
d)
Air-handling systems for the manufacture, processing and packing of
PENICILIN shall be completely separate from those for other drug,
products for human use.
Consideration of Air-Handling System
Placement of air inlet and outlet ports. These should be sited to minimize the entry of airbone
particles or odors from the surrounding areas. Outlets should not be sited near inlet.
Where recirculation of air acceptable, adequate precautions must be taken to ensure that
particulates from a processing area are removed. This will usually require an alarm system or
an automatic cutoff in the event that a filter develops a hole. Dust extraction systems should
be provided, where appropriate, to further minimize this potential problem.
The degree of filtration and air volumes should be matched to the operations involved.
Temperature and humidity conditions should provide personnel comfort- to enhance performance
Temperature and humidity conditions should be within the optimal condition of equipment
operation
Where differential pressures are required between adjacent areas, suitable monitoring equipment
must be provided.
The siting of final air filters close to each room being serviced eliminates concerns regarding the
possibility of small leaks in the air duct system. Air usually enters rooms near the ceiling and
leaves from the opposite side near the floor.
Ǿ 211.48 Plumbing
a) Potable water shall be supplied under continuous positive
pressure in a plumbing system free of defects that could
contribute contamination to any drug product. Potable water
shall meet the standard prescribed in the Environmental
Protection Agency’s Primary Drinking Water Regulation set in
40 CFR Part 141. water not meeting such standards shall not
be permitted in the potable water systems.
b) Drains shall be of adequate size and, where connected directly
to a sewer, shall be provided with air break or other
mechanical device to prevent back-siphonage
FDA usually not inquire documents that the potable water is
meeting the standard if the manufacturer connects the
potable waterline to a public supply that meet the standard
The water can lose quality in transmission through the public
piping system and through the manufacturer’s system
If potable water is obtained from wells under the control of
manufacturer, periodic testing is mandatory.
In case of providing potable water storage system, an
automatic chlorination system should be installed, usually at
2-3ppm
Ǿ 211.50 Sewage and refuse
Sewage, trash, and other refuse in and from the building
and immediate premises shall be disposed of in a safe
and sanitary manner
Product disposal: any product requiring disposal should initially be separated from
packaging. Disposal procedures should involve agents with a proven record of dealing
with such sensitive material from plant to disposal.
Printed packaging disposal: labels, inserts and cartons poses usually no health risk.
For public. However, this may rise the public concern that product may be associated
with the packaging. Incineration of such materials is preferred.
General trash and sewage: an internal procedures should be established to ensure
that product and packaging waste does not get intermixed. Containers used wiyhin the
plant to accumulate waste materials should be clearly marked to denote their
designated use.
Facility Requirements Review
(Building)
NON-GMP area
GMP facility ( Production area)
Wall painting
PVA paints
Epoxy or enamel
Flooring
Normal floor (non-porous) Homogenous sealed floor; Epoxy finish
or welded vinyl
Windows
Windows still (openable)
Flush gluzed windows (preferably double
glass, not opened)
Floor drain
Open floor drain
Hygienic drains
Ceiling
With joints
Smooth sealed ceiling
Lighting
Exposed open light fitting
Flush light fittings
Furniture
Wooden is allowed
Must be of non-porous materials
(stainless steel or Melamine)
Ǿ 211.52 Washing and toilet facilities
Adequate washing facilities shall be provided, including hot and
cold water, soap or detergent, air driers or single-service towels, and
clean toilet facilities easily accessible to working areas.
Separates toilet facility for each sex except where individual locked toilet rooms are
available (the number is based on the number users)
Suggested additional emphasis.
Eating facility: Eating, drinking are permitted in separate area and well segregated from all
production areas. Prominent sign indicating this role at the entrance of production areas.
Enforcement procedures against violation are taken by management
In production area: Tissues and loosed disposal containers are readily available.
Lavoratories and lockers: Adequate number for personnel employed, hot shower facility,
disinfectant soaps, adequate ash and waste receptacles are provided, periodic cleaning of
area during each shift, complete daily cleaning using disinfectant, specific rest area for
female employees should provided, areas separated from all aseptic spaces by an air lock.
Ǿ 211.56 Sanitization
a) Any building used in the manufacture, processing, packing, or holding of a drug product shall
be maintained in a clean and sanitary condition. Any such building shall be free of infestation
by rodents, birds, insects, and other vermin (other than laboratory animals). Trash and
organic waste matter shall be held and disposed of in a timely and sanitary manner.
b) There shall be written procedures assigning responsibility for sanitization and describing in
sufficient detail the cleaning schedules, methods, equipment and materials to be used in
cleaning the building and facilities; such written procedures should be followed.
c) There shall be written procedure for use of suitable rodenticides, insecticides, fungicides,
fumigitation agents, and cleaning and sanitization agents. Such written, procedures shall be
designed procedures should be designed to prevent the contamination of equipment,
components, drug product containers, closures, packaging, labeling materials, or drug
product and shall be followed. Rodenticides, insecticides, fungicides shall not be used unless
registered and used in accordance with the Federal Insecticide, Fungicide, and Rodenticide
Act (7 U.S.C. 135).
d) Sanitation procedures shall apply to work performed by contractors or temporary employees
as well as work performed by full-time employees during the ordinary course of operations.
Ǿ 211.58 Maintenance
Any building used in the manufacture, processing,
packing or holding of a drug product shall be maintained
in a good state of repair
Deterioration of buildings not only presents poor image of the facility, but also can
influence product quality. Cracks in ceiling, hole in wall or floor crack is potential
source of insects, microbial contaminations.
Water leakage can cause significant damage for materials and equipment, give rise
to electrical failure and fires and result in damage to the basic structure of the
building.
Holes in the roof or near the tops of building proved ready access to birds, which
may then be encourages to nest within the building.
Equipment
Ǿ 211.62 Equipment design, size and location
Equipment used in the manufacture, processing, packing,
or holding of a drug product shall be of appropriate
design, adequate size, and suitably located to
facilitate operations for its intended use and for its
cleaning and maintenance.
Ǿ 211.65 Equipment construction
Equipment shall be constructed so that surfaces that contact
components, in-process materials, or drug products shall not be
reactive, additive, or absorptive so as to alter the safety,
identify, strength, quality, or purity of the drug product beyond
that official or other established requirements.
Any substance required for operation, such as lubricants or
coolants, shall not come into contact with components, drug
product containers, closures, in-process materials, or drug
products so as to alter the safety, identity strength, quality, or
purity of the drug product beyond the official or other
established requirements.
Ǿ 211.67 Equipment cleaning and maintenance
a) Equipment and utensils shall be cleaned, maintained and sanitized at appropriate
intervals to prevent malfunctions or contamination that would alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or other established
requirements.
b) Written procedures shall be established and followed for cleaning and maintenance of
equipment, including utensils, used in the manufacture, processing, packing, or holding
of a drug product. These Procedure shall include, but not necessarily limited to the
following:
1) Assignment of responsibility for cleaning and maintaining equipment.
2) Maintenance and cleaning schedule, including, where appropriate, sanitizing
schedule.
3) A description in sufficient detail of the methods, equipment and materials used in
cleaning and maintenance operations, and the methods of dissembling equipment as
necessary to assure proper cleaning and maintenance.
4) Removal of obliteration of previous batch identification
5) Protection of clean equipment from contamination prior to use
6) inspection of equipment for cleanliness immediately before use.
c) Records shall be kept of maintenance, cleaning, sanitizing and inspection as specified in
211.180 and 211.182
Ǿ 211.68 Automatic, mechanical, and electronic
equipment
a) Automatic, mechanical or electrical equipment or other types of
equipment, including computers, or related systems that will
perform a function satisfactorily, may be used in manufacture,
processing, packing, and holding of a drug product. If such
equipment is so used, it shall be routinely calibrated, inspected,
or checked according to a written program designed to assure
proper performance. Written records of those calibration checks
and inspections shall be maintained.
Ǿ 211.68 Automatic, mechanical, and electronic
equipment
b) Appropriate controls shall be exercised over a computer or related
systems to assure that changes in master production and control
records or other records are instituted only by authorized
personnel. Input and output from the computer or related system
of formulas or other records data shall be checked for accuracy.
The degree and frequency of input/output verification shall be
maintained except where certain data, such as calculations
performed in connection with laboratory analysis, are eliminated
by computerization or other automated processes. In such
instances a written record of the program shall be maintained
along with appropriate validation data. Hard copy or alternative
systems, such as duplicate, stapes, or microfilm, designed to
assure that backup data are exact and complete and that it is secure
from alteration, inadvertent erasures, or loss shall be maintained
Ǿ 211.70 Filters
Filters for liquid filtration used in manufacture, processing, or
packing of injectible drug products intended for human use shall
not release fibers into such products. Fiber-releasing filters may not
be used in the manufacture, processing, or packing of these
injectable drug products without the use of such filters. If use of a
fiber-releasing filter in necessary, an additional non-fiber releasing
filter of 0.22 micron maximum mean porosity (0.45 micron if the
manufacturing conditions so dictate) shall subsequently be used to
reduce the content of particles in the injectable drug product.
Use of an asbestos-containing filter, with or without subsequent use
of a specific non-fiber releasing filter, is permissible only upon
submission of proof to the appropriate bureau of the Food and Drug
Administration that use of a non-fiber-releasing filter will, or is likely
to, compromise the safety or effectiveness of the injectible drug
product
Filters in Biopharmaceuticals Factory
Air filters
- pre-filters/filter
HEPA / ULPA filters
- Microbiological Filters
(Filter defect cause contamination)
-Air filter for operation (pneumatic valves)
(Filter defect is destructive for the valve system)
- Air filter for process (aeration and transfer)
(Filter defect cause contamination)
Filters in Biopharmaceuticals Factory (cont.)
Liquid filters
A- For Cooling line
I.
Prefilter
II. Filter
(Filter defect is destructive for heat exchanger and valve on the
cooling line)
B- For Process water
I.
Water filtration before distillation
II. Medium filtration (sterilization)
III. WFI for buffer and product formulation (Pyrogen free)
(Filter defect directly affecting process and product Quality,
depending on the filter position)
C- For media preparation
I.
Microbiological filter
(Filter defect cause direct contamination)
43
Filters in Biopharmaceuticals Factory (cont.)
Steam filters
(Filtering steam from solid particles)
- Process steam:
(heating, sterilization of double jacketed vessels
(Filter defect make damage in heat exchangers and also
for steam valves)
- Sterilization steam (direct steam injection):
(for sterilization of empty vessels such as for media
transfer tanks and holding tanks), or SIP equipments
(Filter defect make damage for filter and direct
contamination of products by foreign particle!)
44
Filters in Biopharmaceuticals Factory (cont.)
Steam filters
(Filtering steam from solid particles)
-
Process steam:
(heating, sterilization of double jacketed vesels)
(Filter defect make damage in heat exchangers and steam
valves)
-
Sterilization steam (direct steam injection)
(for sterilization of empty vessels such as for media transfer
tanks and holding tanks), or SIP equipments.
(Filters defect make valve damage and direct contamination
of products by foreign particle!)
45
Filters in Biopharmaceuticals Factory (cont.)
Ultra filtration system (protein concentrator)
• Used for protein separation based on membrane
molecular weight cut-off. Different filter systems are
usually applied. The common used are
1000/10000/50000/100000 Daltons
(Filters defect cause improper protein separation and
leakage and loss of total protein production)
46
Filters in Interferons production Platform
47