Beruflich Dokumente
Kultur Dokumente
Regulations
Parts 210 and 211
C o d e o f F e d e r a l R e g u la t io n s
P a rt 2 1 0
P a rt 2 1 1
Section
210.1
practice
210.2
good
practice
210.3
Definitions
Act,
Batch,
Component,
Drug,
Fiber,
filter,
Active ingredients,
Inactive ingredients,
In-Process material,
etc. are defined
Lot,
Lot number,
Strength,
Quality,
Control,
Theoretical yield,
Actual yield,
Acceptance criteria,
Representative
samples
7
Strength:
Production
Equipment
Control of Component.
Buildings
Facilities
Holding
& &Distribution
QA & QC
Laboratory Controls
Records & Reports
Returned & Salvaged Drugs
10
Subpart A
General Provisions
Subpart C
Buildings & Facilities
Subpart B
Organisation & Personnel
Subpart D
Equipment
Subpart E
Subpart F
Control of Components & Drug Product Production & Process Controls
Containers & Closures
Subpart G
Packaging & Labelling Controls
Subpart I
Laboratory Controls
General
Subpart H
Holding & Distribution
Subpart J
Records & Reports
Subpart K
Returned & Salvaged Drug Products
Production
QA QC
11
Subpart A
General Provisions
Subpart C
Buildings & Facilities
Subpart B
Organisation & Personnel
Subpart D
Equipment
Subpart E
Subpart F
Control of Components & Drug Product Production & Process Controls
Containers & Closures
Subpart G
Packaging & Labelling Controls
Subpart I
Laboratory Controls
Subpart H
Holding & Distribution
Subpart J
Records & Reports
Subpart K
Returned & Salvaged Drug Products
12
PART 211
Sub Part A GENERAL PROVISIONS
211.1
Scope:
a) Regulations in this part contain those minimum cGMPs for preparation
of drug products and biologicals for administration of humans or
animals.
b) cGMP regulations in this part pertain to drug products and in parts 600
through 680 pertain to biologicals intended for human use.
c) Requirements may not be met for OTC drug products when those and
their ingredients are marketed and consumed as human food.
211.3
Definitions:
Same definitions given under CFR 210 are applicable to
this section
too.
13
PART 211
Sub Part B ORGANISATION & PERSONNEL
211.22 Responsibilities of Quality Control Unit.
a) A Quality Control Unit shall be responsible for authorizing of various
materials in several stages along with their documents.If any errors
were observed they should be investigated fully.
b) Adequate lab facilities for testing approval or rejection of components
shall be available.
c) QC shall Approve or Reject the materials after testing as per
procedures.
d) All responsibilities and procedures applicable to QC shall be written
down and they shall be followed.
14
PART 211
Sub Part B ORGANISATION & PERSONNEL
211.25
a)
b)
c)
211.28
a)
b)
c)
d)
Personnel Qualification
There shall be adequate number of trained, experienced and qualified
people for supervising the manufacturing operations.
All personnel involved in the manufacturing and its ancillary services
shall be literate, qualified, experienced and trained.
All personnel shall protect themselves and the products integrity by
following the GMPs
Personnel Responsibilities
Personnel shall wear clean clothing appropriate for their duties who
were engaged in manufacturing operations.
Personnel shall practice good sanitation and health habits.
Authorization shall be given to Personnel along with limited access to
buildings and facilities.
Any person with illness shall be excluded from all those operations
which deal with direct product contact.
15
PART 211
Sub Part B ORGANISATION & PERSONNEL Contd.
211.34
Consultants
Consultants advising on the manufacturing operations shall be highly
qualified and experienced.
A record shall be maintained stating complete detail of the consultants.
Reject the materials after testing as per procedures.
What
does
UK
MCA
say
Organisation and personnel
about
16
PART 211
Sub Part C BUILDINGS & FACILITIES
211.42
17
PART 211
Sub Part C BUILDINGS & FACILITIES
211.42
Contd.
1) Receipt, identification, storage and withholding from use of
components, drug product containers, closures and labeling,
pending the appropriate sampling, testing, or examination by the
quality control unit before release for manufacture.
2) Holding rejected components, drug product containers, closures
and labeling before disposition.
3) Storage of released components, drug product containers, closures
and labeling.
4) Storage or In-process materials.
5) Manufacturing and processing operations.
6) Packaging and labeling operations.
7) Quarantine storage before release of drug products.
8) Storage of drug products after release.
9) Control and laboratory operations.
10) Aseptic processing, which includes as appropriate
18
PART 211
Sub Part C BUILDINGS & FACILITIES
211.42
Contd.
i.
Floors, walls and ceilings of smooth, hard surfaces that are easily
cleanable.
ii. Temperature and humidity control.
iii. Proper Air Handling Systems, HEPA filters and LAFs.
iv. System of monitoring environmental conditions.
v. Systems for cleaning and disinfecting rooms and equipment.
vi. System for maintaining any equipment used to control aseptic
conditions.
d) Any operations involving manufacture of penicillin shall be
performed in separate facilities.
211.44 Lighting
Adequate
19
PART 211
Sub Part C BUILDINGS & FACILITIES
211.46
a)
b)
c)
d)
211.48
a)
b)
20
PART 211
Sub Part C BUILDINGS & FACILITIES
211.50
211.52
211.56
a)
b)
c)
d)
PART 211
Sub Part C BUILDINGS & FACILITIES
211.58
Maintenance
Proper maintenance shall be provided to all buildings involved in
manufacturing operations
22
PART 211
Sub Part H HOLDING AND DISTRIBUTION
211.142 Warehousing procedures
There shall be written procedures for warehousing of drugs.
a) Quarantine of drug products before release by quality control unit.
b) Storage of drug products under controlled conditions shall be
followed to preserve the identity, strength, quality and purity of
the drug.
211.150 Distribution Procedures
There shall be written procedures for Distribution of drugs. They shall
include
a) Oldest approved drug product shall be distributed first.
b) Distribution records of each drug product shall help in tracking
the movement of the drug product and easy recalls when needed.
23
P r e m is e s & E q u ip m e n t
P ro d u c tio n
QA & QC
P r o d u c tio n
Q u a lity
M anagem ent
M a n u fa c tu re o f
S te r ile M e d ic in a l
P ro d u c ts
D o c u m e n ta tio n
Q u a lity C o n tr o l
C o n tr a c t M a n u fa c tu r e
& A n a ly s is
C o m p la in ts &
P r o d u c t r e c a ll
S e lf In s p e c tio n
25
PERSONNEL
People
Training
Personnel Hygiene
Premises
Equipments
26
PERSONNEL
PEOPLE.
27
PERSONNEL
PEOPLE.
TRAINING.
PERSONNEL
TRAINING
PERSONNEL HYGIENE
29
PERSONNEL
PERSONNEL HYGIENE
PREMISES
PREMISES
PREMISES
PREMISES
34
PREMISES
PREMISES
36
PREMISES
EQUIPMENTS
EQUIPMENTS
39
PART 211
Sub Part D Equipment
211.63
211.65
a)
b)
211.67
a)
40
PART 211
Sub Part D Equipment
b)
41
PART 211
Sub Part D Equipment
211.68
42
PART 211
Sub Part E Control of Components & Drugs product
Containers and Closures
211.80
a)
b)
c)
d)
General requirements
Written down procedures shall exist for Receipt, Identification,
Storage, Handling, Sampling, testing, approval and rejection of
materials.
Storage of the component containers and closure shall prevent
contamination.
Storage of bagged or boxed containers should suffice cleaning of
floor.
Distinctive code number shall be given for separate containers having
different Lot numbers, each lot shall be identified appropriately as to
its status.( Quarantined, approved or rejected).
43
PART 211
Sub Part E Control of Components & Drugs product
Containers and Closures
211.82
44
PART 211
Sub Part E Control of Components & Drugs product
Containers and Closures
c)
d)
PART 211
Sub Part E Control of Components & Drugs product
Containers and Closures
3)
e)
46
PART 211
Sub Part E Control of Components & Drugs product
Containers and Closures
211.86 Use of Approved components, drug product containers and
closures.
Oldest Approved stock shall be used first. Deviation from this
requirement shall be permitted only if it is appropriate and temporary.
211.87 Retesting of approved components, drug products, containers
and closures.
Retesting shall be done on the materials as per the appropriate
procedures for their identity, strength, quality and purity. This shall be
done after storage for long periods or after exposure to air, heat or any
other conditions which may adversely effect the drug quality.
211.89 Rejected components, drug product containers and closures.
A proper identification, control and quarantine system shall exist for
rejected materials.
47
PART 211
Sub Part E Control of Components & Drugs product
Containers and Closures
211.94
a)
b)
c)
d)
48
PART 211
Sub Part F Production and Process Controls
211.100 Written Procedures; Deviations
a) Written down procedures for production and process controls shall
exist to produce a quality product once and always. Any changes in
such procedures shall be drafted, reviewed and approved by
appropriate organizational units.
b) Written procedures shall be followed for all production process and
any deviations shall be recorded and justified.
211.101 Charge in of Components
Written procedures for production and process controls shall include
the following.
1) Batch formulation is done with an intent to provide 100 % of the
label claim of the active ingredient.
a) All components for drug product manufacturing shall be weighed,
measured or subdivided appropriately. If components are taken
from new containers they shall be identified with following
information.
49
PART 211
Sub Part F Production and Process Controls
b)
PART 211
Sub Part F Production and Process Controls
211.103 Calculation of Yield
Actual yield and percentage of theoretical yield shall be calculated
after every operation and recorded.
211.105 Equipment identification
a) All compounding and Storage containers, processing lines other
equipment used in production operation shall be identified properly.
To indicate their contents, phase of processing of batch.
b) A distinctive identification code number shall be assigned to all major
equipment. This helps in precise identification of the specific
equipment used in the manufacturing process while noted in the Batch
Production Record.
51
PART 211
Sub Part F Production and Process Controls
211.110 Sampling and testing of in-process materials and drug products.
a) To assure batch uniformity and integrity of the drug products written
procedures shall be established. Such control procedures of in-process
materials help in monitoring the output and validating the performance
of the processes. Such controls shall include but are not limited to the
following.
1) Tablet or capsule weight.
2) Disintegration time
3) Adequacy of mixing (time)
4) Dissolution time and rate,
5) Clarity, pH of solutions etc.
b) All such inprocess specifications shall be derived from previous
acceptable process average and process variability estimates.
c) In-process materials shall be tested for identity, quality, purity and
strength during the production process, after short or long breaks in
process.
52
PART 211
Sub Part F Production and Process Controls
d)
211.111
211.113
a)
53
PART 211
Sub Part F Production and Process Controls
211.115 Reprocessing
a) Written procedures shall be established for reprocessing of the batches
to ensure the established standards, specifications and characteristics.
b) Reprocessing shall be performed only with review and approval of
quality control unit.
54
PART 211
Sub Part G Packaging and labeling Controls
211.122 Materials examination and usage criteria
a) Written down procedures shall exist. Labeling and packaging
materials shall be representatively sampled, examined and tested.
b) Only approved labeling and packing materials shall be used.
Unapproved materials shall be rejected.
c) Records shall be maintained of all the received shipments indicating
receipt, examination or testing and whether accepted or rejected.
d) Different product labels shall be stored separately with suitable
identity. Access to the storage area shall be limited.
e) Obsolete and out dated labels and other packaging materials shall be
destroyed.
f) Use of gang printed labeling for different drug products, or different
strengths or net contents of same drug product, is prohibited unless
labeling from gang-printed sheets is adequately differentiated by size,
shape and colour.
55
PART 211
Sub Part G Packaging and labeling Controls
g)
56
PART 211
Sub Part G Packaging and labeling Controls
211.125 Labeling Issuance
a) Strict control shall exist on issuance of labels.
b) Careful examination for identity and conformity to labels specified in
the MFR/ BPRR shall be done.
c) Reconciliation procedures shall exist for quantities of labeling
materials used, returned etc.
d) All excess labels shall be destroyed.
e) Returned labels shall be maintained and stored to prevent mix ups and
provide proper identity.
f) Written controlled procedures for issuance of labeling material shall
exist.
211.130 Packing and labeling Operations
a) Procedures for preventing mix ups and contaminations,
b) Identification and handling of filled drug product containers that are
set aside and held.
57
PART 211
Sub Part G Packaging and labeling Controls
c)
d)
PART 211
Sub Part G Packaging and labeling Controls
211.137 Expiration Dating
a) To assure that the drug product meets applicable standards of identity,
quality, strength and purity appropriate stability testing shall be done.
b) Expiration dating shall be related to any storage conditions stated on
the label as determined by stability studies.
c) If the drug product is to be reconstituted expiration dating shall be
given to both un reconstituted drug and reconstituted solution.
d) Expiration dating shall be as per the requirements.
e) Homeopathic drug products shall be exempted from these
requirements.
f) Allergenic extracts that are labeled no U.S Standard of potency are
exempted from these requirements.
g) New drug products for investigational use shall be exempted when
they meet appropriate standards and specifications as demonstrated by
stability studies data.
What Does ORANGE GUIDE tell about Production Aspects.
59
UK MCA
4.5. PRODUCTION
4.5.1
GENERAL
Production should be performed & supervised by competent people.
Production activities from receipt of materials to packing & distribution
should be done in accordance with written procedures & recorded.
Any damage to raw material containers should be investigated, recorded &
reported.
All incoming materials should be checked to ensure that the consignment
corresponds to the order.
Incoming materials and finished product materials should be quarantined
until release or use for distribution.
Materials & products should be stored as per the manufacturers instruction.
Checks on yields & reconciliation on quantities should be carried out.
Operations on different products should not be carried out simultaneously or
consecutively in the same room, unless there is no risk of mix ups or cross
contamination.
60
UK MCA
PRODUCTION
General contd..
At every stage of processing, microbial or other contamination should be
avoided.
Power dust should be contained during processing.
Equipments shall be clearly labeled to indicate the product, strength, stage
batch number etc.
Use different colour labels to indicate status.
If deviation occurs it should be approved in writing by a competent person
with the involvement of QC.
Access to production premises should be restricted to authorised personnel.
61
UK MCA
PRODUCTION
4.5.2.
UK MCA
PRODUCTION
UK MCA
PRODUCTION
64
UK MCA
PRODUCTION
4.5.5.
PACKING MATERIALS
65
UK MCA
PRODUCTION
4.5.6.
PACKING OPERATIONS
66
UK MCA
PRODUCTION
4.5.6.
4.5.7.
FINISHED PRODUCTS
67
UK MCA
PRODUCTION
4.5.8.
End Session
68
PART 211
Sub Part I Laboratory Controls
211.160
General requirement:
a) The establishment of any specifications, standards, sampling plans,
test procedures or other laboratory control mechanisms required by
this subpart, including any change in specifications, standards,
sampling plans, test procedures or other laboratory controls shall be
drafted by the appropriate organizational unit and reviewed and
approved by the quality control unit. The requirements in this subpart
shall be followed and shall be documented at the time of performance.
Any deviation from the written specifications, standards, sampling
plans, test procedures or other laboratory control mechanisms shall be
recorded and justified.
b) Laboratory controls shall include the establishment of scientifically
sound and appropriate specifications standards, sampling plans and
test procedures designed to assure that the components of the drug
product containers, closures, in-process materials, labeling and drug
products conform to appropriate standards of identity, strength, quality
and purity. Laboratory controls shall include...
69
PART 211
Sub Part I Laboratory Controls
211.160
General requirement:
1) Determination of conformance to appropriate written specifications
for the acceptance of each lot within each shipment of components,
drug product containers, closures and labeling used in the
manufacture, processing, packing or holding of the drug products.
Samples shall be representatives and adequately identified.
2) Determination of conformance to written specifications and a
description of sampling and testing procedures and a description of
sampling and testing procedures for in-process materials. Such
samples shall be representative and properly identified.
3) The calibration of instruments, apparatus, gauges and recording
devices at suitable intervals in accordance with an established written
program containing specific directions, schedules, limits for accuracy
and precision and provisions for remedial action in the event accuracy
and precision limits are not met, instruments, apparatus, gauges and
recording devices not meeting established specifications shall not be
used.
70
PART 211
Sub Part I Laboratory Controls
211.165
Testing & Release for Distribution:
a) For each batch or drug product, there shall be appropriate laboratory
laboratory determination of satisfactory conformance to final
specification for the drug product including identity the identity and
strength of each active ingredient prior to release.
b) There shall be appropriate laboratory testing, as necessary, of each
batch of the drug product required to be free of objectionable
microorganisms.
c) Any sampling and testing plans shall be described in written
procedure that shall include the method of sampling and the number of
units per batch to be tested; such written procedure shall be followed.
d) Acceptance criteria for the sampling and testing conducted by the
quality control unit shall be adequate to assure that the batches of drug
products meet each appropriate specification and appropriate
statistical quality control criteria as a condition for their approval and
release.
e) The accuracy, sensitivity, specificity and reproducibility of test
71
methods employed by the firm shall be established and documented.
PART 211
Sub Part I Laboratory Controls
211.166
Stability testing:
a) There shall be a written testing program designed to asses the stability
characteristics of the drug products. The results of such testing shall be
used to determine the storage conditions and expiration dates. The
written program shall be followed and includes.
1. Sample size and test intervals based on statistical criteria for each
attribute examined to assure valid estimate of stability;
2. Storage conditions for samples retained for testing;
3. Reliable, meaningful and specific test methods;
4. Testing of the drug product in the same container closure system
as that in which the drug product is marketed;
5. Testing of the drug products for reconstitution at the time of
dispensing(as directed on the labeling) as well as after they are
reconstituted.
b) An adequate number of batches of each drug shall be tested to
determine an appropriate expiration date and record of such datd shall
be maintained.
72
PART 211
Sub Part I Laboratory Controls
211.166
Stability testing:
b) Accelerated stability studies along with the basic stability data on the
components and the drug products and container closure system may
be used to support tentative expiration dates provided full shelf life
studies are not available and are being conducted. Where the data
from the accelerated studies are used to project a tentative expiration
date that is beyond a date supported by actual shelf life studies, there
must be stability studies conducted, including the drug product testing
at appropriate intervals, until the tentative expiration date is verified or
the appropriate expiration date is determined.
c) For homeopathic drug products, the requirements are as follows.
1. Written assessments of stability data, of the drug product
compatibility with other ingredients shall exist. The data proving
that no degradation of the drug has occurred in normal period of
use shall also be provided.
2. Container-closure system compatibility with the drug and its
stability data shall exist.
3. Allergenic extracts that are labeled :No U.S. standard of potency
73
are exempted.
PART 211
Sub Part I Laboratory Controls
211.167
Special Testing Requirements:
a) Each batch of product purporting to be sterile or pyrogen free
shall have a specific laboratory test procedure and it shall be
documented.
b) Ophthalmic ointments shall have specific documented test
procedures showing their conformance with the foreign particles,
harsh or abrasive substances.
c) For controlled release dosages, written test procedures
determining the rate of release of the drug product shall exist.
211.170
a)
Reserve Samples:
An appropriately identified reserve sample shall be retained that
represents a specific lot. The reserve samples contain at least
twice quantity necessary for all tests required to determine
whether the active ingredient meets its established specifications,
except for sterility and pyrogen testing. The retention time is as
follows:
74
PART 211
Sub Part I Laboratory Controls
211.170
1.
Reserve Samples:
For an active ingredient in a drug product other than those
described in paragraphs (a) (2) and (3) of this section, the reserve
samples shall be retained for 1 year after the expiration date of
the last lot of the drug product containing the active ingredient.
2. For an active ingredient in a radioactive drug product, except for
nonradioactive reagent kits, the reserve samples shall be retained
for:
i.
Three months after the expiration date of the last lot of the
drug product containing the active ingredient if the expiration
dating period of the drug product is 30 days or less; or
ii. Six months after the expiration date of the last lot of the drug
product containing the active ingredient if the expiration
dating period of the drug product is more than 30 days.
iii. For an active ingredient in an OTC drug product that is
exempt from bearing an expiration date under 211.137, the
reserve sample shall be retained for 3 years after the
distribution of the last lot of the drug product containing
75
active ingredient.
PART 211
Sub Part I Laboratory Controls
211.170
Reserve Samples:
b) The reserve samples shall be stored under the conditions
consistent with product labeling. The samples shall be stored in
the same container closure system. Reserve samples shall be at
least twice the quantity to perform all the tests. Reserve samples
shall be examined visually at least once a year for evidence of
deterioration unless the visual examination would affect the
integrity of the reserve sample. Any evidence of the deterioration
of the reserve samples shall be recorded and shall be maintained
with other stability data on the drug product. Reserve samples of
compressed gases need not be maintained.
211.173
Laboratory Animals:
Animals used in testing components, inprocess material, or drug
products for compliance with the established specifications shall
be maintained and controlled in a manner that assures their
suitability for their intended use. They shall be identified adequate
records shall be maintained showing the history of their use.
76
PART 211
Sub Part I Laboratory Controls
211.176
Penicillin Contamination:
Lot/ batch
of drug products suspected for penicillin
contamination shall be vigorously tested. Penicillin levels shall be
detected as per the procedures for Detecting and Measuring the
penicillin contamination in drugs.
77
PART 211
Sub Part J Records and Reports
211.180 General Requirements:
a) Any production, control or distribution record that is required to be
maintained in compliance with this part and is specifically associated
with a batch of a drug shall be retained for at least 1 year after the
expiration date of the batch.
b) Records shall be maintained for all components, drug product
containers, closures and labeling for at least 1` year after the
expiration date.
c) All records required under this part, or copies of such records shall be
readily available for authorized inspections during the retention period
at the establishment where the activities described in such records
occurred.records that can be immediately retrieved from another
location by computer or other electronic means shall be considered as
meeting the requirements of this paragraph.
78
PART 211
Sub Part J Records and Reports
211.180 General Requirements:
d) Records under this part shall be retained as original records or as true
copies such as photo copies, microfilm etc.
e) Written records required by this part shall be maintained so that the
data can be evaluated at least annually, for determining the quality
standards of the drug product, need for changed in drug product
specifications or manufacturing or control procedures. Written
procedures shall be established and followed for such evaluations and
shall include provisions for:
1) A review of representative number of batches, whether approved
or rejected and where applicable records associated with the
batches.
2) A review of the complaints, recalls, returned or salvaged drug
products and investigations conducted under 211.192 for each
drug product.
79
PART 211
Sub Part J Records and Reports
211.180 General Requirements:
f) Procedures shall be established to assure that the responsible officials
of the firm , if they are not personally involved in or immediately
aware of such actions, are notified in writing of any investigations
conducted under 211.198, 211.204 or 211.208 of these regulations,
any recalls, reports, of inspectional observations issued by the Food
and Drug Administration, or any regulatory actions relating to good
manufacturing practices brought by the Food and Drug
Administration.
211.182 Equipment Cleaning and use log:
A written record of major equipment cleaning, maintenance and use
shall be included in individual equipment logs that show date, time, product
and a lot number of each batch processed. If the equipment is dedicated to
the manufacture of one product, then individual equipment logs are mot
required, provided that lots or batches of such product follow in numerical
order and are manufactured in numerical sequence in case where dedicated
equipment is used, the records of cleaning,maintenance and use shall be part
80
of the batch record.
PART 211
Sub Part J Records and Reports
211.184 Component, drug product container, closure and labeling records:
These records shall include the following:
a) The identity and quantity of each shipment of each lot of
components, drug product containers, closures and labeling; the
name of the supplier; the suppliers lot number if known; the
receiving cods as specified in 211.80; and the date of receipt. The
name and location of the prime manufacturer, if different from the
supplier, shall be listed if known.
b) The results of any test examination performed(including those
performed as required by 211.82(a), 211.84(d) or 211.122(a) and
the conclusions derived there from.
c) An individual inventory record of each component, drug product
container and closure and for each component, a reconciliation of
the use of each lot of such component. The inventory shall contain
sufficient detail to allow determination of any batch or lot of drug
product associated with the use of each component, drug product
container and closure.
81
PART 211
Sub Part J Records and Reports
211.184 Component, drug product container, closure and labeling records:
d) Documentation of the examination and review of labels and
labeling for conformity with established specifications in accord
with 211.122(c) and 211.130 (c ) .
e) The disposition of rejected components, drug product containers,
closure and labeling.
211.186 Master Production and control records:
a) To assure uniformity from batch to batch, master production and
control records for each drug product, including each batch size
thereof, shall be prepared dated, and signed by one person and
independently checked, dated and signed by a second person. The
preparation of master production and control records shall be
described in a written procedure and such written procedures shall
be followed.
b) Master production and control records shall include:
1) The name and strength of the product and a description of the
dosage form.
82
PART 211
Sub Part J Records and Reports
211.186 Master Production and control records:
1) The name and strength of the product and a description of the
dosage form.
2) The name and weight or measure of each active ingredient per
dosage unit or per unit weight or measure of the drug product,
and a statement of the total weight or measure of any dosage
unit.
3) A complete list of components designated by names or codes
sufficiently specific to indicate any special quality
characteristics.
4) An accurate statement of the weight or measure of each
component, using the same weight system(metric, avoirdupois
or apothecary) for each component. Reasonable variations
may be permitted, however they should be justified.
5) Statement concerning any calculated excess of component.
83
PART 211
Sub Part J Records and Reports
211.186 Master Production and control records:
6) A statement of theoretical weight or measure at appropriate
phases of processing;
7) A statement of theoretical yield, including the maximum and
minimum percentages of theoretical yield beyond which
investigation according to 211.192 is required;
8) A description of the drug product containers, closures and
packaging materials, including specimen copy of each label
and all other labeling signed and dated by the person or
persons responsible for approval of such labeling.
9) Complete manufacturing and control instructions, sampling
and testing procedures, specifications, special notations and
precautions are to be followed.
84
PART 211
Sub Part J Records and Reports
211.188 Batch production and control records:
Each batch of drug product shall have a batch production record. it shall
contain complete information relating to the production and control of the
batch. These records shall include.
a) An accurate reproduction of the appropriate master production record
or control record, checked for accuracy, dated and signed.
b) Documentation that each significant step in the manufacture,
processing, packaging or holding of the batch was accomplished,
including;
1) Dates;
2) Identity of individual major equipment and lines used;
3) Specific instrumentation of each batch of component or in-process
material used.
4) Weights and measures of components used in the course of
processing
5) Inprocess and laboratory control results
85
6) Labeling and packing areas inspection
PART 211
Sub Part J Records and Reports
211.188 Batch production and control records:
7) A statement of the actual yield and a statement of the percentage of
theoretical yield at appropriate phase of processing.
8) Complete labeling control records, including specimens or copies of
all labels used
9) Description of the drug product containers and closures used.
10) Any sampling performed
11) Identification of the persons performing and directly supervising or
checking significant steps in the operation.
12) Any investigation made according to 211.192
13) Results of the examinations made in accordance with 211.134
86
PART 211
Sub Part J Records and Reports
211.192 Production Record Review:
All drug product production and control records, including those for packing
and labeling, shall be reviewed and approved by the quality control unit to
determine compliance with all established, approved written procedures
before a batch is released or distributed. As unexplained discrepancy or the
failure of a batch or any of its components to meet any of its specifications
shall be thoroughly investigated whether or not the batch has already been
distributed.
211.194 Laboratory Records:
a) Laboratory records shall include complete data derived from all tests
to assure compliance with established specifications and standards,
including examinations and assays. As follows.
1) Description of the sample received for testing with identification
of source, quantity, lot number or other distinctive code, date on
which sample is taken etc.
2) A statement of each method used in the testing of the sample. The
suitability of all testing methods used shall be verified under
87
actual conditions of use.
PART 211
Sub Part J Records and Reports
211.194 Laboratory Records:
3) Statement of the weight or measure of sample used for each test,
where appropriate.
4) Complete record of all data secured in course of each test,
including graphs, charts and spectra, properly identified to show
the specific component, drug product container, closure, inprocess
material etc.
5) Record of all calculations of test, including units of measure,
conversion factors equivalence factors etc.
6) A statement of results, how results are compared with established
standards of identity, strength, quality and purity fot the
component.
7) The initials of the person who performed the test and date.
8) Initials and date of the second person showing that the original
record have been reviewed for accuracy, completeness and
compliance.
88
PART 211
Sub Part J Records and Reports
211.194 Laboratory Records:
a) Complete records shall be maintained of any modifications of any
modification of an established method employed in testing. Such
records shall include reason for modification.reviewed for accuracy,
completeness and compliance.
b) Records of any testing and standardization shall be maintained. Of
laboratory reference standards, reagents and standard solutions.
c) Records for periodic calibration of laboratory instruments, apparatus,
gauges and recording devices required by 211.160(b)(4)
d) Complete records shall be maintained of all stability testing performed
in accordance with 211.166
211.196 Distribution Records:
Distribution records shall contain name, strength of product and description
of dosage form, name and address of the consignee, date and quantity
shipped, lot number etc.
89
PART 211
Sub Part J Records and Reports
211.198 Complaints files:
a) Written procedures describing handling of all written and oral
complaints regarding the drug product shall be established and
followed. Such provisions shall include provisions for review by the
quality control unit. If the drug product fails to meets the
specifications an investigation shall be carried on as pre procedures.
b) A written record for each compliant shall be maintained in a file
designated for drug product complaints.the complaints record file shall
be filed up along with other manufacturing, packing records and shall
be easily retrievable. They shall be retained Atleast 1 year after
expiration date.
1) Written records shall include following information, wherte
known the name and strength of the drug product, lot number,
name of the complaint, nature of the compliant and reply to
compliant.
2) Where an investigation is conducted the finding of the same and
follow-ups shall be recorded.
3) Where an investigation was not conducted, a written record shall
include the reason that an investigation was found not to be
90
necessary and the name of the responsible person
PART 211
Sub Part K Returned and Salvaged Drug Products
211.204 Returned drug products:
Returned drug products shall be identified as such and held. If the different
conditions under which the returned products, casts doubt on the safety,
identity, strength, quality or purity of the drug product, the returned goods
shall be destroyed, unless the examination shall prove that the product meets
the quality requirements. The drug may be reprocessed if it is found to meet
appropriate standards, specifications and characteristics. Records of such
returned drug products shall be maintained.
211.208 Drug product salvaging
drug products subjected to improper storage conditions including extremes in
temperature, humidity, smoke, fumes, pressure or radiations shall not be
salvaged and returned to market place. Salvaging operations may be
conducted only if there is
Evidence from laboratory tests and assays that the drug products meet
all the applicable standards of identity, strength, quality and purity.
Evidence from the inspection of the premises that the drug products
and their associated packing materials were not subjected to improper
storage conditions.
What does ORANGE GUIDE tells about Quality Aspects
91
QUALITY MANAGEMENT
QUALITY MANAGEMENT
DOCUMENTATION
QUALITY CONTROL
Documentation
Sampling
Testing
Contract Giver
Contract Acceptor
92
QUALITY MANAGEMENT
Complaints
Recalls
SELF INSPECTION
93
QUALITY MANAGEMENT
QUALITY MANAGEMENT.
The holder of a manufacturing authorization must
manufacture medicinal products so as to ensure
that.
QUALITY MANAGEMENT
TO ACHIEVE QUALITY OBJECTIVE
95
DOCUMENTATION
96
DOCUMENTATION
97
DOCUMENTATION
DOCUMENTATION
Validation
Calibration
Training
Environmental monitoring
QUALITY CONTROL
100
QUALITY CONTROL
Documentation
Specifications
Sampling procedures
Test procedures
Analytical reports
QUALITY CONTROL
Documentation
102
QUALITY CONTROL
Sampling
103
QUALITY CONTROL
Sampling
Testing
QUALITY CONTROL
Testing
105
106
Contract Given
107
Contract Given
108
Complaints
109
Complaints
Recalls
110
Recalls
111
SELF INSPECTION
SELF INSPECTION
112
Raw Materials
Packing Materials
End Session
113