2 the regulations

Objectives

 Have an understanding of the
regulations governing GMP
 Have an understanding of application of
regulations
 Discuss interpretation of regulations

Goal

 You will have a basic understanding of
the regulation governing GMPs and be
able to apply this understanding when
presented with examples.

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

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

Part 210

 CURRENT GOOD MANUFACTURING
PRACTICE IN
MANUFACTURING, PROCESSING, PA
CKING, OR HOLDING OF DRUGS;
GENERAL

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.

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

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

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

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.

Subpart B- Organizations and
Personnel

Subpart B

 211.22 Responsibility of QC
 211.25 Personnel Qualifications
 211.28 Personnel Responsibilities
 211.34 Consultants.

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.

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

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

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.

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.

Consultants

 Consultants advising on GMP areas and
operations must be qualified by
education, training or experience.
 Maintain records of their qualification,
work and address

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

Subpart C-Buildings and Facilities

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

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

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

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

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.

Buildings and Facilities

 Separate receiving
and dispatch bays
 Materials and
products
protected
from weather
 Area to clean
incoming materials
provided

Summary

 Data must exist to show suitability or
fitness for use of major instruments.,
equipment, and systems.
 Control, cleaning and maintenance
prevents contamination

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.

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.

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

Equipment

All aspects including
 Design, installation,
operation,
performance,
specifications, logs,
maintenance, use,
cleaning,
qualification,
calibration etc…

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

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.

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

Equipment Cleaning and
Maintenance
 Equipment and utensils
 Must be cleaned
 Maintained at suitable intervals

 Written Procedures
 Assign responsibility for cleaning
 Include schedules for maintenance

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.

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

Subpart E- Control of
components and drug Product
containers and Closures

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.

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.

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

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

Summary

 Material must always be released by QC
before they are used.

 No provisional releases

 Vender CoA must be verified.

Subpart F- Production
&Process Controls

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.

Validation Requirement

 Process Validation is an Enforceable
Requirement
 Finished Dosage Form Products
 21 CFR 211.100
 21 CFR 211.110

 21 CFR 211.113

 21 CFR 211.42

 21 CFR 211.63

 21 CFR 211.165

 21 CFR 211.180

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

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.

Process Validation Lifecycle

Design Confirm

Assess Monitor

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

Qualification

 Installation Qualification (IQ)
 Operational Qualification (OQ)
 Performance Qualification (PQ)
 Maintenance Procedures (MP)

Production and process control

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

In-process testing

Rejected Product

Action Limits
Target value

Acceptable Range
Action Limits

Rejected Product

In-process testing

Rejected Product
Release Specifications
Action Limits
Target value

Acceptable Range
Action Limits
Release Specifications
Rejected Product

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.

Subpart G Packaging and Labeling
Control

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.

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

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

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

Subpart H- Holding and Distribution

Subpart H- Holding and Distribution

 § 211.142 - Warehousing procedures.

 § 211.150 - Distribution procedures.

Warehouse Procedures

 Written procedures for
 Quarantine prior to QC release
 Storage under appropriate conditions of
temperature, humidity and light

Subpart I lab controls: Instrument
Controls, Training, Standards/Reagents, Te
sting and Release, OOS

Subpart I- Laboratory Controls

 § 211.160 - General requirements.
§ 211.165 - Testing and release for
distribution.
§ 211.166 - Stability testing.
§ 211.167 - Special testing
requirements.
§ 211.170 - Reserve samples.
§ 211.173 - Laboratory animals.
§ 211.176 - Penicillin contamination.

Out of Specification (OOS)

 What does the cGMP Regulation
say about Handling OOS Results?

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

Make sure each technician
understands the calculations


 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

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

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.

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

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

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

Subpart J- Records and
Reports

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.

If it was not documented, it was not done!

83

Great Mounds of Paper?

Some may think that
GMP stands for
Great Mounds of
Paper!

There’s some truth
to that.

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

Not until
Can we ship the
this batch? paperwork
is released!

QC

Lot no.
XYZ

The GMP Paperwork is a
Product
The paperwork
produced is of equal
importance to the
products produced.

Product = Paperwork


 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.

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…

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…


 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

Subpart K- Returned and
Salvaged Drugs

Subpart K – Returned and Salvaged
Drug Products

 § 211.204 - Returned drug products.

 § 211.208 - Drug product salvaging.

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.

Returned Products- Maintained in a
separate defined area

This is for your family…

Manufacture

Raw
Materials Dispense

A word about Drug Master File…

http://wwwbdp.ncif
crf.gov/pdf1/Guidet
oRegSubsR1.pdf

2 the regulations

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