Transcript 3. gmp for Process Development Facilitiesx

GMP for Process Development
Facilities
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 Laboratory, Upstream and Downstream
Equipments
Formulation and Filling Equipments
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Ǿ 211.63 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
Effectiveness of Equipment = Product Quality
Equipment value = Part in your assess
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1.
Operating criteria are adequate for the process (size, speed,
effectiveness)
2.
Availability of spare and servicing (GLOCAL!!)
3.
Maintenance: ease of maintenance, frequency, ease of disassembly
and reassembly
4.
Environmental issue: dust/noise production, utility consumption
(electricity, water, steam, air)
5.
Construction material and Design (Ǿ211.65)
6.
Availability of process control for main parameters and connectability
to SCADA system for the main supervisory computer system and ability
to work in cascade to other equipments
7.
Cost: base price and other direct and indirect costs, points (2, 3) other
cost for validation files
8.
Availability of design and detailed maintenance manuals. Guidelines
and manuals for qualifications, maintenance and validation program.
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Ǿ 211.65 Equipment construction
a) 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, identity, strength, quality, or purity
of the drug beyond that official or other established
requirements.
1. The manufacturer should determine which materials are to be processed in the
equipment and where contact between materials and machinery occurs.
2. Grade of glass or stainless steel used in each part of the equipment (eg: distilled
water is very corrosive. The stainless steel used usually 316L passivated with 1530% nitric acid.
3. Any reaction between materials and equipment is undesirable and will reflect on the
chemical and physical characteristics of the final product
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Ǿ 211.65 Equipment construction
b) Any substances 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 establish requirements.
1. This have direct relation with the design, construction, and placement of manufacturing
equipment.
2. Motors, drive belts, gears and other potential sources of lubricants contamination should
be located away from any part in contact with the products (eg: vessel, dispensers, etc)
3. Lubricants should be usually monitored and MUST be of FOOD GRADE (GRAS code)
4. Gaskets and O-rings should be monitored to ensure not break down which cause both
external contamination as well as internal contamination. (gaskets and O-ring particles
contaminating the materials). BOTH gaskets and O-ring MUST be of FOOD GRADE
(GRASS code)
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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.
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Ǿ 211.67 Equipment cleaning and maintenance
(cont)
b)
Written procedures shall be established and followed, including utensils,
used in the manufacture, processing, packing or holding of a drug
products. 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
material used in cleaning and maintenance operations, and the
methods of disassembling and reassembling 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
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The regulation require written procedures for
cleaning, maintenance and sanitation plan.
Engineering department approve the maintenance
plan, where QC approve cleaning and
sanitation
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Availability of approved validation protocol
Approved validation reports
Equipment design and cleanability
Define, appropriate cleaning SOP to address difficult
cleaning areas
Time scales between use and cleaning and between
cleaning and re-use
Operator training
Specificity and sensitivity of analytical methods
Sampling methods (swab test, solvent rinse, placebo
flush as lactose flush for solid mixing machines, visual
examination)
Acceptable residue limit (some guidelines accept
from 1/100 to 1/1000 of the minimum therapeutic
dose)
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Ǿ 211.68
Automatic, mechanical and electrical
equipment
a) Automatic, mechanical, or electrical equipment or other
types of equipment, including computers, or related
systems that will perform a function satisfactory, may be
used in the 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.
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Ǿ 211.68
Automatic, mechanical and electrical equipment (cont)
b) Appropriate controls shall be exercised over 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 systems of formulas or other
records or data shall be checked for accuracy
…………………………………………………………….
the degree and frequency of input/output verification shall
be based on the complexity and reliability of the computer
or related system
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Ǿ 211.68
Automatic, mechanical and electrical equipment (cont)
b) A backup file or data entered into the computer or related
system shall be maintained except where certain data
such as calculations performed in connection with
laboratory analysis, are eliminated by computerization or
other automated process. In such instances a written
record of the program shall be maintained along with
appropriate validation data.
Hard copy or alternative system, such as duplicates tapes,
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.
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Validated equipments (IQ, OQ), working under
cGMP (standard version is preferred unless
special design is required)
Cleanable (no dead point), easy to clean with
CIP system
Sterilizable (all components and connections
can stand steam for sterilization)
Flexible for upgradability, multipurpose design,
easy to maintain
Able to connect with SCADA system
Easy to operate as ease as posible
Easy to maintain either by local engineers
(maintenance and calibration contract)
Environment friendly with minimal power
consumption (ECO version)
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Utilities Equipments
Laboratory Equipments (QC, QA, etc)
Production Equipment
Preparation Lab
Cell breaking
Purification
Fermentation
Cell separation
I B Separation
Vial filling
Labeling
Refolding
Lyophilization
Packing
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Utilities Equipments
Water station (tap water quality)
Steam generator
Distilled water Unit
Oxygen station
Chiller
Water tanks
Air compressor
Deionized water unit
Nitrogen station
WFI unit
Carbon dioxide station
Killing tank (liquid waste decontamination system)
Crushing autoclave (solid waste decontamination system)
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• Full material certification
• FDA / USP class VI approved
material certification
• Surface finish certification
• Welding procedures and
qualifications
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• IQ and OQ documentation (cGMP
version)
• Biological safety class
• construction material of bench place
• Validated cleaning procedure
• Type of HEPA filter and validation
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• utility consumption
• construction materials
• Welding quality
• piping and valve quality
• SIP and CIP
• Cooling / heating efficiency
• computer control system
(Validated)
• Safety
• mechanical seal and ports
design
• mixing efficiency
• MANY MORE!!
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Freezer
LAF
incubator
fermentor
Vial filling
refolding
Cell separator
Lyophilization
purification
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IB separation
Cell breaking
Labeling
Packing
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• Double body construction, single chamber for steam and
water, covered externally by outer shell.
• Lid made of thick stainless steel, pressure up to 22 PSI
factory set at 15 PSI.
• Complete unit with automatic air purging, Digital Temperature
control & Indication with 0.1°c Accuracy/ Resolution, with
electronic Digital timer range 0 to 99 min.
• Autoclaving time cycle automatically starts when set pressure
is achieved.
• Automatic steam release once autoclaving cycle complete.
• Complete with pressure gauge, safety valve, steam release
valve, extra safety valve.
• Incorporated with an Automatic Pressure Control Switch as an
additional safety device.
• Low Water level cut-off : Low water level cut-off assembly
connected to heater which automatically cuts off power to
heater if water level is not sufficient thus eliminating heater burn
outs.
• Foot lifting arrangement included for Capacity 125 Ltr. and
above. Not included/required for lower sizes.
• Provided with S.S. L-304 grade perforated basket.
• Unit works on 230 V Ac, 50 Hz.
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STANDARD MODEL :
001 B
GMP MODEL :
HIPL-
Inner body made of heavy
gauge Stainless Steel LM-304
grade with argon welded joints,
outer body made of S.S. LM304 grade mirror finished.
HIPL-001 C
Inner body made of heavy
gauge Stainless Steel LM-316
grade with argon-welded joints,
outer body made of SS LM-304
grade mirror finished
Provided with Validation
Documents.
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Sampling of pharmaceutical products and
related materials
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Purpose of sampling
 Sampling may be required for different purposes, such
as pre-qualification; acceptance of consignments;
batch release testing; in-process control; special
controls; inspection for customs clearance,
deterioration or adulteration; or for obtaining a
retention sample.
 The tests to be applied to the sample may include:
— verifying the identity;
— performing complete pharmacopoeial or analogous
testing; and
— performing special or specific tests.
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Classes and types of pharmaceutical
products and related materials
 The materials to be sampled may belong to the following
classes:
— starting materials for use in the manufacture of finished
pharmaceutical products;
— intermediates in the manufacturing process (e.g. bulk
granule);
— pharmaceutical products (in-process as well as before
and after packaging);
— primary and secondary packaging materials; and
— cleaning and sanitizing agents, compressed gases and
other processing agents.
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Sampling facilities
 Sampling facilities should be designed to:
— prevent contamination of the opened container, the materials and
the operator;
— prevent cross-contamination by other materials, products and the
environment; and
— protect the individual who samples (sampler) during the sampling
procedure.
 Sampling from large containers of starting material or bulk products
can present difficulties. Whenever possible, this work should be
carried out in a separate, closed cubicle within the warehouse, to
reduce the risk of contamination (e.g. by dust) of either the sample or
the materials remaining in the container, or of cross-contamination.
 Some materials should be sampled in special or dedicated
environments (e.g. when sampling articles for which contamination
with dirt or particles from the environment should be avoided, such as
aerosol valves, hormones and penicillins).
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Sampling plans for starting
materials, packaging materials
and finished products
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Starting materials
 The n plan
 The p plan
 The r plan
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The n plan
 The “n plan” should be used with great caution and only when the material to be
sampled is considered uniform and is supplied from a recognized source.
 Samples can be withdrawn from any part of the container (usually from the top
layer).
 The n plan is based on the formula n = 1 + √N, where N is the number of
sampling units in the consignment. The value of n is obtained by simple
rounding. A minimum number of containers needs to be sampled, e.g. if N is
less than or equal to 4, then every container is sampled.
 According to this plan, original samples are taken from n sampling units
selected at random and these are subsequently placed in separate sample
containers. The control laboratory inspects the appearance of the material and
tests the identity of each original sample according to the relevant
specification. If the results are concordant, the original samples are combined
into a final, composite sample from which an analytical sample is prepared, the
remainder being kept as a retention sample.
 Note: The n plan is not recommended for use by control laboratories of
manufacturers who are required to analyse and release or reject each received
consignment of the starting materials used to produce a drug product.
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The p plan
 The “p plan” may be used when the material is uniform, is
received from a recognized source and the main purpose is
to test for identity.
 The p plan is based on the formula p = 0.4√N, where N is
the number of sampling units. The figures for p are obtained
by rounding up to the next highest integer.
 According to this plan, samples are taken from each of the
N sampling units of the consignment and placed in separate
sample containers. These original samples are transferred
to the control laboratory, visually inspected and tested for
identity (a simplified method may be used). If the results
are concordant, p final samples are formed by appropriate
pooling of the original samples.
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The r plan
 The “r plan” may be used when the material is suspected to
be nonuniform and/or is received from a source that is not
well known. The r plan may also be used for herbal
medicinal products used as starting materials.
 This plan is based on the formula r = 1.5√N, where N is the
number of sampling units. The figures for r are obtained by
rounding up to the next highest integer.
 Samples are taken from each of the N sampling units of the
consignment and placed in separate sample containers.
These original samples are transferred to the control
laboratory and tested for identity. If the results are
concordant, r samples are randomly selected and
individually subjected to testing. If these results are
concordant, the r samples are combined for the retention
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Examples of use of sampling plans
n, p and r
 Consider a consignment of 40 containers of a starting
material.
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n Plan
 Assuming a uniform material from a recognized
source where there is a high degree of confidence
in the source
 Using the n plan, samples would be taken from seven
containers selected at random. The appearance and
identity of each of these seven samples is checked.
 If the results are concordant, the seven samples are
combined to produce a single, composite sample from
which an analytical sample is prepared for full testing.
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p Plan
 Assuming a uniform material from a recognized
source with the main purpose of checking the
identity
 Using the p plan, samples would be taken from each
container. The appearance and identity of each of
these samples is checked.
 If the results are concordant, the samples are
appropriately combined to form three final,
composite samples to be used for retention (or full
testing if required).
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r Plan
 Assuming the material is non-uniform and/or
from a source that is not well-known
 Using the r plan, samples would be taken from each
container. The appearance and identity of each of
these samples is checked.
 If the results are concordant, 10 samples are selected
at random and individually subjected to full testing.
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Packaging materials
 Sampling plans for packaging materials should be
based on defined sampling standards, for example,
British Standard BS 6001-1, ISO 2859 or ANSI/
ASQCZ1.4-1993.
 The objective is to ensure that there is a low
probability of accepting material that does not comply
with the predefined acceptance level.
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Finished products
 As for packaging materials, sampling plans for finished
products should be based on defined sampling standards
such as BS 6001-1, ISO 2859 or ANSI/ASQCZ 1.4-1993.
 In some cases it may be sufficient to limit examination of
finished goods to visual inspection only. If physical and
chemical testing is required, however, the sampling units
should consist of whole packs. Individual packs should not
be broken open for the purposes of sampling.
 An example of the steps to be considered when sampling
finished products is given in Appendix 3, based on the
sampling plans given in ISO 2859-1.
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