21 CFR-FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES- UNITED STATES OF AMERICA

TRAINING PROGRAMME ON
21CFR PARTS-210 AND 211
QUALITY ASSURANCE

C - current
G - good
M - manufacturing
P - practices

“Every product must be fit for its
intended purpose”

SOURCE OF CGMP GUIDE LINES
• 21 CFR
• ICH
•WHO
• SCHEDULE - M

21 CFR
21-title NUMBER
C-CODE
of
F- FEDERAL
R-REGULATION
FOOD AND DRUG ADMINISTRATION,
DEPARTMENT OF HEALTH AND HUMAN SERVICES
- UNITED STATES OF AMERICA.

21 CFR
PART: 210
PART: 211
PART 210 : cGMP in Manufacturing, Processing,
Packing or Holding of drugs .
PART 211 : cGMP for Finished Pharmaceuticals.

21 CFR Parts 210
and 211
PART-210.1: Status of current good manufacturing practices.
PART-210.2: Applicability of current good manufacturing practices.
PART-210.3: Definitions.
PART-211 : Sub part: A - General Provisions.
PART-211 : Subpart: B - Organization and personnel
PART-211 : Subpart: C - Buildings and facilities.
PART-211 : Subpart: D - Equipment.
PART-211 : Subpart: E - control of components and drug product
containers and closures.
PART-211 : Subpart: F - Production and Process Controls.
PART-211 : Subpart: G - Packing and Labeling control.
PART-211 : Subpart: H - Holding and Distribution
PART-211 : Subpart: I - Laboratory Controls.
PART-211 : Subpart: J - Records and Reports.
PART-211 : Subpart: K - Returned and Salvaged Drug products.

21CFR Part 210
Part-210.1: Status of cGMP Regulations
The regulations set forth in this part and in parts
211 through 226 of this chapter contain the
minimum cGMP for manufacturing, processing,
packing, or holding of a drug product to assure
that such drug product meets the specification.
 Who does not complies ?
 Regulatory action under section 501(a) (2) (b) act.

210.2 Applicability of CGMP
Regulations.
01. The regulation in this part may pertain to a
biological product for human use shall be consider as
supplement.
02. If the person engages in only some operations
subject to the regulation in this part that person need
only comply with these regulations applicable to the
operations in which he or she is engaged.
[ 600 parts exist but has to verify how many applicable ]

21 CFR PART 210.3
DEFINATIONS COVER IN THIS PART.

Drug Product/ Finished Product: A finished dosage form,
for example, tablet, capsule, solution, etc., that contains an
active drug ingredient generally, but not necessarily, in
association with inactive ingredients.
Active Pharmaceutical ingredient: Any substance produced
by chemical synthesis, fermentation, recombinant DNA
processes, or recovery from natural materials that is intended
for use as a component in a drug product or a substance that is
repackaged or labeled for drug use.
DEFINITIONS

DEFINITIONS
Batch: A specific quantity of a drug or other material
that is intended to have uniform character and quality,
within specified limits, and is produced according to a
single manufacturing order during the same cycle of
manufacture.
Lot No/ Batch No: Any distinctive combination of
letters, numbers, or symbols, or any combination of
them, form which the complete history of the
manufacture, processing, packing holding, and
distribution of a batch or lot of drug product or other
material can be determined.
In-process testing: Testing performed during
production to monitor and, if necessary, adjust the
process to ensure that the drug substance or intermediate
conforms to its specifications.

DEFINITIONS
Intermediate: Any substance, whether isolated or not,
that is produced by chemical, physical, or biological action
at some stage in the production of a drug substance and that
is subsequently used at another stage of production.
Quality Control Unit: Any person or organizational
element designated by the firm to be responsible of the
duties relating to quality control.
Quarantine : The status or physical isolation of raw
materials, intermediates, packaging materials, or drug
substances to preclude their use pending a decision on their
disposition.
Recovery : The appropriate processing of materials to
make them suitable for further use.
Reprocess : Introducing previously processed material,
which did not conform to standards or specifications, back
into the process and repeating steps that are already part of
the normal manufacturing process.

DEFINITIONS
Rejected material : Any material or item that has been
determined to be unacceptable for the specified use.
Returned goods: Any material that has been rejected/
returned by the user will be called as returned goods.
Theoretical yield: The quantity that would be produced at
any appropriate phase of manufacture, processing, or
packing of a particular drug product, based upon the
quantity of components to be used, in the absence of any
loss or error in actual production.
Actual yield: The quantity that is actually produced at any
appropriate phase of manufacture, processing, or packing of
a particular drug product.
Percentage of theoretical yield: The ratio of the actual
yield to the theoretical yield, stated as a percentage.

DEFINITIONS
Cross contamination : An undesired introduction of
one or more BPC materials into another.
Expiry/ Expiration date : A date before which the
drug substance meets all specifications and after which
the drug substance can no longer be used, This date
shall be assigned based on the stability of, or
experience with, the drug substance. An expiration
date is a regulatory requirement unique to antibiotics.
Retest Period: The period of time during which the
drug substance can be considered to remain which the
specification and therefore acceptable for use in the
manufacturing of a given drug product, provided that it
has been stored under the defined conditions; after this
period, the batch should be re-tested for compliance
with specification and then used immediately.

DEFINITIONS
Shelf life/ Expiration dating period: The time interval
that a drug product is expected to remain within the
approved shelf-life specification provided that it is stored
under the conditions defined on the label in the proposed
containers and closure.
Packaging Material: Any or all materials used for the
storage or shipment of a drug substance or intermediate.
Validation : A documented program that provides a
high degree of assurance that a specific process, method,
or system will consistently produce a result meeting
predetermined acceptance criteria.
Process Suitability: The Established Capacity Of The
Manufacturing Process To Produce Effective And
Reproducible Results Consistently.

DEFINITIONS
Accelerated testing : Studies designated to increase
the rate of chemical degradation or physical change of
an active drug substance or drug product by using
exaggerated storage conditions as part of the formal,
definitive, storage program.
Long-term (real time) Testing: Stability evaluation of
the physical, chemical, biological, and microbiological
characteristics of a drug product and a drug substance,
covering the expected duration of the shelf life and retest
period, which are claimed in the submission and will
appear on the labeling.

21 CFR 211 SUB PART -A: GENERAL PROVISIONS
The Regulations Stated in This Are the
Minimum Requirements for the
Manufacture of a Drug Product Intended
for Human or Veterinary Use.
The Current Good Manufacturing
Practice Regulations in This Chapter, As
They Pertain to Drug Products, and in
Parts 600 Through 680 of This Chapter,
As They Pertain to Biological Products
for Human Use Shall Be Considered As
Supplement.

A). Responsibilities Of Quality Control Unit:
Quality Control Unit Shall Have the Responsibility and
Authority to Approve or Reject All Components, Drug
Product Containers, Closures, In-process Materials,
Packing Materials, Labeling and Drug Substance.
Adequate Laboratory Facilities Should Be Available for
Testing of All Components.
Authority to Review of Production Records.
Approval of Procedures and Specifications.
21 CFR PART 211 SUBPART: B
ORGANISATION AND PERSONNEL

B). Personal Qualifications:
Each person engaged in the manufacturing, processing,
packing, or holding of a drug substance shall have
education, training and experience.
Training shall be in the particular operations that the
employee performs.
Training on cGMP shall be conducted on continuous
basis. To assure that the employee remain familiar
with cGMP.
Adequate qualified personnel should be there to
perform and supervise the operations.

C). Personnel Responsibilities:
Personnel engaged in manufacturing, processing, packing
and holding of drug substance shall wear clean and
protective apparel.
Personnel should practice good sanitation and health
habits.
All personnel should instructed to report immediate
supervisor if any ill ness that may have adverse effect on
drug substances.

D). Consultants:
Consultants advising on the manufacturing processing
packing and holding of a drug product shall have
sufficient qualification, training and experience.
Records shall be maintained stating the name, address
and qualifications of the consultants and type of they
provide.

Suitable Size and Adequate Space.
There Shall Be Separate or Defined Areas Within Operations to
Prevent Contamination or Mix-up.
Example: Ware House - Rejected Area
- Quarantine Area
- Approved Area
Operations Shall Be Performed in Specifically Defined Areas.
Example: Production Area,
QC Area
Sewage and Refuse Areas.
Washing and Toilet Facilities.
Sanitation
Air Filtration
Plumbing
Maintenance
21 CFR PART 211 SUBPART C:
BUILDINGS AND FACILITIES

21 CFR Part 211 Subpart D: Equipment
Design
Adequate size and location.
Equipment construction.
Equipment qualification
Equipment preventive maintenance.
Equipment calibration.
Equipment cleaning.
Equipment log

PART 211 SUBPART: E
CONTROL OF COMPONENTS,
DRUG PRODUCT CONTAINERS AND CLOSURES.
There Must Be a Written Procedures Describing
the Receiving, Handling, Storage, Testing,
Disposition and Use of Components and Drug
Product Containers, Closures.

PART 211 SUBPART: E
CONTROL OF COMPONENTS,
DRUG PRODUCT CONTAINERS AND CLOSURES.
• COMPONENTS RECEIPT
• PRE INSPECTION
• QUARANTINE
• QC SAMPLING AND TESTING.
• APPROVAL
• REJECTION
• RETURN TO VENDOR
• DISPENSING

PART 211 SUBPART: F
Production and Process Controls.
Sops and specifications shall be approved by quality control
unit.
Sops shall be there each and every activity and followed.
Any deviations from written procedures shall be recorded
and justified.
Charging of material;
Material shall be approved by QC
Check the weight as per batch production record.
Check label for material code and batch number.

PART 211 SUBPART
F- Production and Process Controls.
Actual and theoretical yield shall be determined for each
and every stage of manufacturing process.
Equipment shall be identified by a distinctive identification
number and that shall be recorded in a batch card.
Written procedures shall be established for in-process
controls and tests ( i.e pH, water content, TLC, LOD etc..).
Time limit on production:
Process lead time time shall be established
to assure consistency and quality of the
product.
Any deviation form established time limits
shall be recorded and justified.

PART 211 SUBPART: G
Packaging and Labeling Control.
Records shall be maintained for each receipt.
Better separation between label to avoid mix-ups .
Labels shall be issued by authorized persons only.
Label reconciliation records shall be maintained.
Labels shall be identified to avoid mix ups.
Label should contain.:
Manufacturer name and address.
Product name
Manufacturing date and expiration date.
Batch number.
Weight ( tare, net and gross).
Storage conditions.

PART 211 SUBPART: H
Holding and Distribution
Ware housing procedures.
FIFO system is to be followed.
There shall be a system to facilitate product
recall.
Storage of drug product under appropriate
conditions.

Part 211 Subpart: I
Laboratory Controls
Established sops, specifications, standards and sampling
plans and other laboratory mechanisms.
All procedures and specifications must be scientifically
sound.
Review and approval of procedures by quality unit.
Deviations from established system shall be recorded and
justified.
Established calibration procedures and schedules for all
laboratory instruments.
Analytical methods shall be validated.
OOS shall be recorded.
Every batch has to be released after meeting the
established specification .

Part 211 Subpart: I
Laboratory Controls
Stability testing:
Stability study shall be used in determining
appropriate storage conditions and expiration
dates.
Written procedure shall be there and include
sample size and test intervals, testing methods,
storage conditions etc..
Stability samples shall be pack in simulated market
container.
1) Accelerated stability - 40°c + 2°c and 75% RH + 5%
2) Intermediate stability - 30°c + 2°c and 65% RH + 5%
3) Long term stability - 25°c + 2°c and 60% RH + 5%

RESERVE SAMPLES:
Retention samples of each lot( batch) of drug product must be kept
for 1 year past the expiration date.
The reserve sample consists of at least twice the quantity necessary
to perform all the required tests.
Reserve samples from representative sample lots or batches
selected by acceptable statistical procedures shall be examined
visually at least once a year.
For evidence of deterioration unless visual examination would
affect the integrity of the reserve sample.
Any evidence of reserve sample deterioration shall be investigated
and recorded.
PART 211 SUBPART: I
LABORATORY CONTROLS

PART 211 SUBPART: J
Records and Reports.
Records shall be maintained for receipt and issuing of
component, drug substance, packing, labeling, and
holding of a drug product.
Records and reports shall be retained one year after
expiry date of the drug substance.
All records and report shall be easily retrievable.
Equipment usage and cleaning records.
Individual inventory records for all components.
To get consistency in quality master production
records to be follow.
Master production records shall contain
Full signatures of prepared by, checked by and approved
by persons.
Standard in put weights and components
Operation instruction.
Equipment numbers and process flow lay out.
Yield summary for each and every stage.

PART 211 SUBPART:J
Batch production records:
Signatures of operator and supervisor at
each and every operation.
Equipment numbers and process.
Operation instructions for all steps in the
batch card.
In put weights and measurements
In process instructions.
Yield statement.
Complete labeling control
Sampling instructions.
Investigations for deviations.
OOS.
Parameter recording sheets.

PART 211 SUBPART: J
Production records review:
All production records shall be reviewed by the quality unit
before releasing the batch.
All deviations shall be recorded and investigated.
Investigation extrapolated to neighboring batches if require
neighboring products also.
Laboratory records:
Laboratory records shall include complete data derived from
all tests necessary to assure compliance with established
specification.
Records shall maintained for:
Raw materials,
In process controls
Final products
Laboratory reagents and chemicals
Stability tests.
Calibrations.
Changes made in standard methods
Distribution records shall be maintained.
Complete labeling control records .

Complaints files:
There shall be a SOP to define how to handle the
complaints.
A written record of each complaint shall be
maintained.
Complaints records shall be maintained until at
least year after the expiration date of the drug
product or year after the date that the complaint
received - which every is longer Complaint
PART 211 SUBPART: J

PART 211 SUBPART: K
Returned and Salvaged Drug Products.
Returned and Reprocessed drug products may be
released for use if it still meets the appropriate
standards of identity, quality, strength, and purity.
Records of returned products shall maintained.
Reason for the returned, quantity returned, date of
dispatch, and ultimate disposition of returned products
details shall maintained.
If the reason for the drug product being returned
implicates associated batches - an appropriate
investigation shall be conducted.

FDA 483 Citations
 The manufacturing process for drug substances was
not validated from a microbiological aspect.
 The powder is hand scooped, by personnel who are
not monitored for microbial contamination
 There is no environmental control of the area used for
isolation of the drug substance.
 Products requiring specific storage conditions ie., 2°c
to 8°c were stored in non air conditioned ware house
at 25°c - 30°c.
 No procedure to count incoming roll labels.
 No records of destroyed labels during packaging
operations.
 No record of number of labels issued..

 Supervision of night sift was inadequate.
 There was no written procedures for the evaluation of
training.
 Employees engaged in packaging and labeling were
inadequately trained.
 Failed to perform validation studies on cleaning
procedures for containers and closures.
 No historical file of software revisions and approvals.
 No system for the review and documentation of product
failures.
 Corrections made to batch documentation ( bprs) without
initials.
 Batch failure investigation were not extrapolated to other
batches.
 Reprocessing performed with out identification of
probable cause of the original failure.
 Batch size increased with out any validation data.
FDA 483 Citations

 Retained samples were stored in an area with no
temperature or humidity control or any record of the actual
storage condition.
 Analytical balances not checked daily with standard
weights.
 Stability study protocol for shelf life evaluation inadequate
in that it did not equate to the market conditions.
 No recording of environmental conditions in stability
cabinets.
 Investigation of product using out of specification
components into extrapolated to other batches using the
same components
 Instrument calibration frequency and methodology were not
defined. No procedure defining action to be taken when the
instruments are out side of operational tolerances.
FDA 483 Citations

MOST COMMON GMP DEFICIENCIES CITED DURING INTERNATIONAL
INSPECTIONS
Process Controls
13%
Component controls
3%
Equipment cleaning
16%
Other
11%
Water Systems
9%
Process Validations
13%
Stability Programs
4%
Records and Reports
11%
Facilities
4%
Lab Controls
16%

21 CFR-FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES - UNITED STATES OF AMERICA

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