2. Objectives
Have an understanding of the
regulations governing GMP
Have an understanding of application of
regulations
Discuss interpretation of regulations
3. Goal
You will have a basic understanding of
the regulation governing GMPs and be
able to apply this understanding when
presented with examples.
4. GMP – Characteristics
Characteristics of GMP regulations
and interpretations
GMP regulations are largely general and open for interpretation
Benefit:
Manufacturers and researchers are able to
interpret and apply the regulations in ways that
may work best for their unique situations
Risk:
The flexibility may lead to confusion during the
interpretation of the regulation and misapplied
control mechanisms
5. The Regulations
21 CFR Parts 210 and 211 (Drug
Industry)
21 CFR Part 820 (Medical Device
Industry)
21 CFR Part 110 (Food Industry)
21 CFR Part 606 (Blood Industry
6. Part 210
CURRENT GOOD MANUFACTURING
PRACTICE IN
MANUFACTURING, PROCESSING, PA
CKING, OR HOLDING OF DRUGS;
GENERAL
7. Remember “current”
In the US, the phrase "current good
manufacturing practice" appears in 501(B) of
the 1938 Food, Drug, and Cosmetic Act
(21USC351). US courts may theoretically hold
that a drug product is adulterated even if there
is no specific regulatory requirement that was
violated as long as the process was not
performed according to industry standards.
8. Part 211
Subpart A – General Provision
Subpart B – Organization and personnel
Subpart C – Buildings and Facilities
Subpart D – Equipment
Subpart E - Control of Components and
Drug Products Containers and Closures
Subpart F – Production and process
controls
9. Part 211 cont.
Subpart G – Packaging and Labeling
Control
Subpart H – Holding and distribution
Subpart I – Laboratory Controls
Subpart J – Records and Reports
Subpart K – Returned and Salvaged
Drug Products
10. Packaging
and Labeling
Production Control
and Holding and
Process Distribution
Controls
Control of
Laboratory
components and
Drug Product GMP controls
Containers and
Closures
Organization
and Personnel
Equipment
Buildings
and
Facilities
11. Subpart A – General Provisions
Scope - The regulations in this part
contain the minimum current good
manufacturing practice for preparation of
drug products for administration to
humans or animals.
13. Subpart B
211.22 Responsibility of QC
211.25 Personnel Qualifications
211.28 Personnel Responsibilities
211.34 Consultants.
14. Quality Control Unit
The quality control unit shall have the
responsibility for approving or rejecting
all procedures or specifications
impacting on the
identity, strength, quality, and purity of
the drug product.
15. 211.22 Responsibility of Quality
Control Unit
Authorities and Responsibility
Approve or Reject all:
o Components
o Drug Product Container
o Closures
o in-process Materials
o Packaging Materials
o Labeling
o Drug Products
Review Production records to assure no erros have
occurred
If errors have occurred the responsibility to assure
that they have been fully investigated
16. Subpart B – Organization and
Personnel
Personnel qualifications. Each person engaged in the
manufacture, processing, packing, or holding of a drug product
shall have education, training, and experience, or any
combination thereof, to enable that person to perform the
assigned functions.
Personnel responsibilities- Personnel engaged in the
manufacture, processing, packing, or holding of a drug product
shall wear clean clothing appropriate for the duties they perform.
Consultants advising on the manufacture, processing, packing, or
holding of drug products shall have sufficient
education, training, and experience, or any combination
thereof, to advise on the subject for which they are retained
17. Quality Assurance Manual
Should indicate that have a well-
documented Quality Assurance (QA)
program in place.
The QA program should provide a
systematic approach for evaluation,
inspection, testing, calibration or
whatever is needed to monitor and
assure the quality of your product.
18. Qualifications of Personnel (training)
All personnel in manufacturing or management must
have education training and experience or a
combination thereof to perform assigned duties
Training in the GMPs and operations performed by the
employees
Training conducted on a continuing basis by qualified
individuals
Adequate number of personnel to perform functions.
Clean clothing and protective apparel worn as
necessary to protect drug products from contamination
Good sanitation and health habits should be followed.
19. Consultants
Consultants advising on GMP areas and
operations must be qualified by
education, training or experience.
Maintain records of their qualification,
work and address
20. Summary
The quality unit must have the authority
to make independent quality related
decisions.
Personnel must have documented
adequate training & experience.
Training for staff and contractors
22. Subpart C
211.42 Design and Construction
211.44 Lighting
211.46 Ventilation, HVAC
211.48 Plumbing
211.50 Sewage and Refuse
211.52 Washing and Toilet Facilities
211.56 Sanitation
211.58 Maintenance
23. Design
First principle: Quality by Design
GMP requirements for Process Design
211.42 Design of Facility
211.63 Design of Equipment
211.100 Design of Production and
Control Procedures
211.160 Design of Laboratory Controls
24. Buildings and Facilities
The temperature and
relative humidity
should be
controlled, monitored
in accordance with an
SOP, and the results
recorded. The limits
should be appropriate
according to the
materials stored and
product processed
27. Sanitation
Building maintained in a clean and
sanitary condition
Written procedures assigning
responsibility for sanitation methods.
Written procedures for use of suitable
elimination of pests and environmental
contaminants
All agents used must be in accordance
with EPA standards
28. Sanitation
Buildings maintained in a clean and sanitary condition
Written procedures assigning responsibility for
sanitation methods, equipment, materials & schedules
Written procedures for the use of suitable:
Insecticides
Rodenticides
Fungicides
Fumigating agents
Cleaning and sanitizing agents
All pest control products must be registered and used
in accordance with EPA standards.
29. Buildings and Facilities
Separate receiving
and dispatch bays
Materials and
products
protected
from weather
Area to clean
incoming materials
provided
30. Summary
Data must exist to show suitability or
fitness for use of major instruments.,
equipment, and systems.
Control, cleaning and maintenance
prevents contamination
32. Subpart D – Equipment
§ 211.63 Equipment design, size, and
location.
§ 211.65 - Equipment construction.
§ 211.67 - Equipment cleaning and
maintenance.
§ 211.68 - Automatic, mechanical, and
electronic equipment.
§ 211.72 - Filters.
33. Equipment
Adequate space to facilitate cleaning and
maintenance of equipment
To prevent contamination there should
be separate or defined areas or other
control systems for the receipt
identification, storage and withholding of
all materials.
Orderly placement of equipment.
34. Equipment
Design of areas for
weighing of materials
Proper air supply
Dust control measures
(including extraction of
dust and air)
Easily cleanable
surfaces
No areas for dust
accumulation
Protection of
material, product and
operator
35. Equipment
All aspects including
Design, installation,
operation,
performance,
specifications, logs,
maintenance, use,
cleaning,
qualification,
calibration etc…
36. Maintenance Procedures (MP)
Periodic procedures
To minimize the risk of losing raw data and
analytical results
Inspection/replacement of normal wear and
maintenance items
File back-up and recovery
Data archival and retrieval
Security
Lan administration
37. Equipment design size and location
Must be suitable for intended use
Easily cleaned and maintained
Must be non reactive
Lubricants coolants etc. required for
operation should not contact any
component.
38. Equipment Design, Size, and
Location
Must be suitable for Equipment
intend use: Construction
Appropriate design Cannot be
Adequate size Additive
Suitably located Absorptive
Reactive
Facilitate its
Lubricants, coolants
use, cleaning and
maintenance etc. required for
operations should
not contact any
component
39. Equipment Cleaning and
Maintenance
Equipment and utensils
Must be cleaned
Maintained at suitable intervals
Written Procedures
Assign responsibility for cleaning
Include schedules for maintenance
41. Equipment Cleaning and
Maintenance
Equipment and utensils must be cleaned and
maintained at suitable intervals
Written procedures assign responsibility for
cleaning and schedules for maintenance.
State methods, materials and equipment for
cleaning
State disassembly reassembly procedures
Obliteration of previous batch information
Inspection of equipment before use.
42. Written Procedures
State methods, materials and equipment
for cleaning
State disassembly/reassembly methods
Obliteration of pervious batch information
Protection of equipment prior to use
Inspection of equipment immediately
before use
43. Subpart E- Control of
components and drug Product
containers and Closures
44. Subpart E- Control of Components
General requirements.
§ 211.82 - Receipt and storage of untested
components, drug product containers, and closures.
§ 211.84 - Testing and approval or rejection of
components, drug product containers, and closures.
§ 211.86 - Use of approved components, drug
product containers, and closures.
§ 211.87 - Retesting of approved components, drug
product containers, and closures.
§ 211.89 - Rejected components, drug product
containers, and closures.
§ 211.94 - Drug product containers and closures.
45. General Requirements
Written Procedures Handled and stored in a
describing: manner to prevent
Receipt contamination
Identification Bagged or boxed component
Storage
of containers or closure
stored off floor and suitably
Handling
spaced to permit cleaning
Sampling and inspection
Testing Identified with a distinctive
Approval or Rejection code for each lot in each
shipment received
Each lot identified as to its
status: quarantined,
approved, rejected.
46. Component Tests
At least one test must be conducted to verify the
identity of each component of a drug product
Specific identity tests, if they exist, should be used
Each component must be tested for conformity with all
appropriate written specification for
purity, strength, and quality. A certificate of analysis
may be accepted from the supplier provided that:
At least one specific identity test is conducted
The manufacturer has established the reliability of the
supplier’s analyses through appropriate validation of the
supplier's test results at appropriate intervals
47. Containers and Closures
Should not be reactive, additive, or adsorptive
Provide adequate protection against
foreseeable external factors in storage and
use
Clean, and if appropriate, sterilized and
processed to remove pyrogenic properties
Written procedures for: standards or
specifications, methods of testing, and where
indicated, methods of cleaning, sterilizing, and
processing to remove pyrogenic properties
48. Summary
Material must always be released by QC
before they are used.
No provisional releases
Vender CoA must be verified.
50. Subpart F- Production and Process
Controls
Written procedures; deviations.
§ 211.101 - Charge-in of components.
§ 211.103 - Calculation of yield.
§ 211.105 - Equipment identification.
§ 211.110 - Sampling and testing of in-
process materials and drug products.
§ 211.111 - Time limitations on production.
§ 211.113 - Control of microbiological
contamination.
§ 211.115 - Reprocessing.
52. Validation Requirement
Process Validation is an Enforceable
Requirement
Active Pharmaceutical Ingredients
Statutory CGMP provisions of 501(a)(2)(b) of the
Food Drug and Cosmetic Act
No regulations
GMP guidance available - ICH Q7A
53. Goal of Process Validation
Drug product meeting the needs of the
patient, i.e., safe and effective; and has
the identity, strength, purity, and quality
characteristics it is represented to
possess.
Achieved through proper product development
and proper process validation.
55. Validation
Principle
Documented evidence: Process is capable of reliably
and repeatedly rendering a product of the required
quality
Planning, organizing and performing process
validation
Process validation protocols
Data collected and reviewed against predetermined
acceptance criteria – recorded in validation report
58. Pertains to processing steps-
Dispensing to Bulk dose
Written Procedures: Deviations
Change Control
Charge-in of components
Calculation of yield
Equipment ID
Sampling
Production time limits
59. In-process testing
Rejected Product
Action Limits
Target value
Acceptable Range
Action Limits
Rejected Product
60. In-process testing
Rejected Product
Release Specifications
Action Limits
Target value
Acceptable Range
Action Limits
Release Specifications
Rejected Product
61. Summary
Use only valid processes and systems.
Keep adequate records to allow
deviations to be recorded and
investigated.
Make drug products right, first
time, every time.
63. Subpart G – Packaging and
Labeling Control
Materials examination and usage criteria.
§ 211.125 - Labeling issuance.
§ 211.130 - Packaging and labeling
operations.
§ 211.132 - Tamper-evident packaging
requirements for over-the-counter (OTC)
human drug products.
§ 211.134 - Drug product inspection.
§ 211.137 - Expiration dating.
64. Labeling Issuance
Labeling issued for each batch shall be
examined for identity and conformity with
labeling in master or batch records
Reconciliation between labeling issued,
used and returned and product produced
Discrepancies outside of narrow preset
limits, based on historical data, require
an investigation
65. Packaging and Labeling Operations
Written procedures
Procedures should incorporate the following
features:
• Prevention of mix-ups and cross-contamination
• Identification and handling of filled drug containers
• Examination of labels for correctness
• Line inspection before packaging to assure that
lines have been cleared
• Documentation of all activities in the batch record
66. Drug Product Inspection
Examine packaged and labeled products
during finishing operations to assure the
correct label has been used
Collect a representative sample of units
at the completion of finishing and
examined for correct labeling
Record results of the examination of the
batch record
68. Subpart H- Holding and Distribution
§ 211.142 - Warehousing procedures.
§ 211.150 - Distribution procedures.
69. Warehouse Procedures
Written procedures for
Quarantine prior to QC release
Storage under appropriate conditions of
temperature, humidity and light
70. Subpart I lab controls: Instrument
Controls, Training, Standards/Reagents, Te
sting and Release, OOS
72. Out of Specification (OOS)
What does the cGMP Regulation
say about Handling OOS Results?
73. Averaging
Assay results should never be averaged
because averaging hides individual variability:
e.g. 89, 89, 92 (x=90)
Individual content uniformity tests should not be
averaged to obtain passing value
Microbiology averaging is acceptable due to
biological variability
75. General Requirements
Scientifically sound specifications,
standards, sampling plans, test
procedures and other laboratory controls
procedures and any changes should be
drafted by the appropriate organization
and approved by QC
Documented at the time of performance
Deviations recorded and justified
76. Testing and Release
Appropriate laboratory determination of
each lot for conformance to final
specifications
Appropriate laboratory testing of each lot
of drug required to be free of
objectionable microorganisms
77. Stability Defined
Definition (ICH/FDA)
The capacity of a drug substance or drug
product to remain within specifications
established to ensure its
identity, strength, quality and purity
throughout a retest or expirations dating
period.
78. Stability Testing
Written testing program designed to assess
stability of drug and determine expiration dates
Sample size & test interval based on statistical
criteria for each attribute examined.
Storage conditions
Reliable, meaningful and specific test methods.
Utilization of same container/closure system as
marketed drug
Test products for reconstitution at time of
dispensing and after reconstitution
79. Stability Testing
An adequate number of batches need to
be tested to determine the expiration
date.
Accelerated studies, combined with data
from long-term stability studies support
tentative expiration dates.
Expiration dates assigned from
accelerated study data much be verified
by ongoing shelf-life studies
80. Reserve Samples
2X quantity for tests (except sterility
&pyrogen)
Representative samples, selected
statistically, examined visually at least
annually for deterioration
Any evidence of deterioration shall be
investigated and results maintained with
other stability data
82. Subpart J- Records and Reports
§ 211.180 - General requirements.
§ 211.182 - Equipment cleaning and use log.
§ 211.184 - Component, drug product
container, closure, and labeling records.
§ 211.186 - Master production and control
records.
§ 211.188 - Batch production and control
records.
§ 211.192 - Production record review.
§ 211.194 - Laboratory records.
§ 211.196 - Distribution records.
§ 211.198 - Complaint files.
86. TYPE OF GMP DOCUMENTS
QUALITY MANUAL
S.O.P.
Equipment Status
Master production Specification/ Testing Work Protocol Identity/ Material Status
document Standard Method (WP) Label Product Status
Master Formula Raw & packaging material
Master Prod. Procedure Bulk Validation Protocol Report
Master Pack. Procedure Finished product Sampling record
Testing result record and report
Microbial and particle monitoring record
Batch Production Record Stability test record
Return Product Handling Record
Recall Record
Product Destruction Record Note :
Product Complaint Record •Blue : WI (standard, specification & procedure)
Distribution Record •Red : record
87. Not until
Can we ship the
this batch? paperwork
is released!
QC
Lot no.
XYZ
88. The GMP Paperwork is a
Product
The paperwork
produced is of equal
importance to the
products produced.
Product = Paperwork
89. General Requirements
Retain all records at least 1 year after
expiration date of the batch
OTC drugs lacking expiration dates
retain all records for at least 3 years after
distribution of the batch
Records for components, containers,
closures, and labeling follow the same
rules.
90. cGMP Part 211.192
The failure of a batch or any of its components
to meet any of its specifications shall be
thoroughly investigated…
The investigation shall extend to other batches
of the same drug product and other drug
products that may have been associated with
the specific failure of discrepancy…
91. cGMP Part 211.194
A written record of the investigation shall
include the conclusions and follow-up…
A complete record of all data secured in the
course of each test…
Complete records shall be maintained of all
stability testing performed…
94. General Requirements
Written Procedures Handled and stored
describing in a manner to
handle
o Receipt
contamination
o Identification
Stored off the floor
o Storage
Identified with a
o Handling distinctive code
o Stamping Each lot identified as
o Testing to its status
o Approval or quarantined, approv
rejection ed or rejected
96. Subpart K – Returned and Salvaged
Drug Products
§ 211.204 - Returned drug products.
§ 211.208 - Drug product salvaging.
97. Returned and Salvaged Drugs
Returned Drug Products
Shall be identified and held
If the condition of the drug, packaging or
labeling casts doubt on its safety, identity,
strength, quality or purity, it must be
destroyed unless examination, testing, or
investigation proves the drug meets its
specifications.
99. Packaging
and Labeling
Production Control
and Holding and
Process Distribution
Controls
Control of
Laboratory
components and
Drug Product GMP controls
Containers and
Closures
Organization
and Personnel
Equipment
Buildings
and
Facilities
100. This is for your family…
Manufacture
Raw
Materials Dispense
101. A word about Drug Master File…
http://wwwbdp.ncif
crf.gov/pdf1/Guidet
oRegSubsR1.pdf