01252014 Cvc c gmp presentation

cGMP
Current Good Manufacturing
Practices
FDA Requirements
Annual cGMP and New Employee
Training Session
25 JAN 2014
CiVentiChem Proprietary and Confidential Information

Overview
I.

Background
A.

Laws, Regulations, Guidelines

II. The GMP Regulations
A.

Part 210 Current Good Manufacturing Practice in Manufacturing,
Processing, Packing or Holding of Drugs: General

B.

Part 211 Current Good Manufacturing Practice For Finished
Pharmaceuticals


Background
A. Laws, Regulations, Guidelines
•
•
•
•
•

Cover the product development process during its entire life and
continue after its eventual marketing approval.
Pre-clinical conditions to start clinical trials
Regulations during the development period
Documentation for marketing application
The review and approval process

FDA regulations = nine volumes of 21CFR


Overview of the GMP Regulations
Part 210 & 211-226 - Current Good Manufacturing Practice in
Manufacturing, Processing, Packing or Holding of Drugs:
General Status of cGMP regulations
(A)

The regulations set forth in this parts 210 and 211226 contain the minimum current good
manufacturing practice to assure the drug product
meets the safety, identity, strength, quality and
purity characteristics that it purports or is
represented to possess.


Part 210 & 211 - 226

(B)

The failure to comply with any regulation set forth
in this part and parts 211...in the manufacture,
processing, packing, or holding of a drug shall
render such drug to be adulterated and such drug,
as well as the person responsible for the failure to
comply, shall be subject to regulatory action.


Part 211
Subpart B - Organization and Personnel
Responsibilities of Quality Assurance Unit
• authority to approve or reject all components, drug
product containers, closures, intermediates, packaging
material, labeling, and drug products
• review production records, assure no errors have
occurred or that errors have been fully investigated.
• responsibility for approving or rejecting all procedures or
specifications impacting on the identity, strength,
quality, and purity of the drug product.


Part 211
–

Personnel Qualifications
•
Each person engaged in the manufacture, processing,
packing, or holding of a drug product shall have
education, training, and experience, to perform the
assigned functions.
•
There shall be an adequate number of qualified
personnel to perform and supervise the manufacture,
processing, packing, or holding of each drug product.

•

Personnel Responsibilities
•

•
•

Wear clean clothing appropriate for duties to protect
drug products from contamination.
Personnel shall practice good sanitation habits.
Limited-access areas.


Part 211
•

Aseptic processing, which includes as appropriate:
– Floors, walls, and ceilings of smooth, hard surfaces
that are easily cleanable;
– Temperature and humidity controls
– An air supply filtered through high-efficiency
particulate air filters under positive pressure;
– A system for monitoring environmental conditions;
– A system for cleaning and disinfecting the room and
equipment to produce aseptic conditions;
– A system for maintaining any equipment used to
control the aseptic conditions.


Part 211
–

Sanitation
•

•

•

Any building used in the manufacture, processing, packing or
holding of a drug product maintained in a clean and sanitary
condition.
SOPs assigning responsibility for sanitation and describing in
sufficient detail the cleaning schedules, methods, equipment,
and materials to be used in cleaning the buildings and facilities
established and followed.
SOPs for use of suitable cleaning and sanitizing agents. SOPs
prevent the contamination of equipment, components, drug
product containers, closures, packaging, labeling materials, or
drug products established and followed.


Part 211
•

Subpart D - Equipment
•
–
•
•

–
•

•

Appropriate design, adequate size and suitability.
Equipment Construction
contact surfaces not reactive, additive, or absorptive
lubricants or coolants do not come into contact with
components, drug product.
Equipment cleaning and maintenance.
Equipment and utensils shall be cleaned, maintained, and
sanitized at appropriate intervals to prevent malfunctions or
contamination.
Records of maintenance, cleaning, sanitizing, inspection.


Part 211
–

Automatic, mechanical, and electronic equipment.
•

•
•

Automatic, mechanical, or electronic equipment or other types
of equipment, including computers, or related systems
routinely calibrated, inspected, or checked. Appropriate
controls shall be exercised over computers.
Input to and output from the computer or data shall be
checked for accuracy, degree and frequency.
Backup file of data entered into the computer or related system
maintained.


Part 211
•

Subpart E -Control of Components and Drug Product Containers
and Closures
–

General Requirements
•

•
•

SOPs for the receipt, identification, storage, handling, sampling,
testing, approval, rejection of components, containers,
closures.
Handled and stored to prevent contamination.
Each lot of components, drug products, closures identified with
distinctive code.


Part 211
–

Receipt and storage of untested components, drug product
containers, and closures.
•
•

–

Upon receipt and before acceptance, visually examine for
damage, broken seals, contamination.
Stored under quarantine until tested and released.

Testing and approval or rejection of components, drug
product containers, and closures.
•
•

Not used until lot sampled, and released by QA.
Representative samples of each shipment of each lot shall be
collected for testing, based upon statistical criteria.


Part 211
–
–

Samples shall be examined and tested with at least 1 identity test.
Any lot of components, containers or closures that meet specs for
id, strength, quality, purity may be approved for use.

•

Use of approved components, drug product containers, and
closures.

•

Rejected components, drug product containers, and closures
identified and controlled under quarantine.
Components, containers, and closures approved for use shall be
rotated so that oldest approved stock is used first (FIFO).

•


Part 211
•

Subpart F - Production and Process Controls
–
Written procedures: deviations
•

•

SOPs for all requirements in this subpart; drafted, reviewed,
approved by all applicable functional units
•
Written production and process control procedures followed,
documented at the time of performance of production and process
control functions. Any deviation from SOPs recorded and justified.
Charge-in of components
•
Components shall be weighed; new containers properly identified
if component removed from original container.
•
Weighing shall be adequately supervised; Each container of
components dispensed to manufacturing steps shall be examined
by a second person.
•
Each component shall be added by one person and verified by a
second person.


Part 211
•

Equipment Identification.
–

–

•

All major equipment used during the production of a batch shall be
properly identified at all times to indicate their contents, and phase
of processing of the batch.
Major equipment shall be identified by a distinctive number and
recorded in the batch record.

Sampling and testing of in-process materials and drug
products
–

SOPs established and followed describing in-process controls, tests,
examinations to be done on samples of each batch.


Part 211
–

–
–

Valid in-process specs consistent with final specs, derived from
previous process; Testing of samples assure that material conforms
to specs.
Intermediates tested for ID, strength, quality, purity,
approved/rejected by QU.
Rejected in-process phases materials shall be identified and
controlled under quarantine.

Time limitations on production.
–
Completion of each phase established to assure quality; deviations
acceptable if quality not effected, shall be justified and
documented.


Part 211
•

Control of microbiological contamination.
–

SOPs designed to prevent objectionable microorganisms
products established and followed.

–

Reprocessing.
• SOPs established, followed for reprocessing;
• Reprocessing not performed without review, approval of
QU.

•

Subpart G-Packaging and Labeling Control
• Materials examination and usage criteria.
• SOPs sufficient detail for receipt, identification, storage,
handling


Part 211

–

Labeling/packaging materials meeting written specs approved,
released for use; not meet specs, rejected before use.

–

Record for each shipment received indicating receipt, examination
or testing, and acceptance/rejection maintained.

–

Labels for each different product, strength, dosage form, quantity
stored separately with suitable identification; limited access to
storage area.


Part 211

•

Labeling Issuance
–
–
–
–

•

Strict control over issuance.
Materials examined for identity and conformity to label in the
master or batch production records.
Procedures to reconcile issuance, used, returned, evaluation of
discrepancies, investigation.
SOPs describing control for label issuance written and followed.

Packaging and Labeling Operations
–
–
–

Physical separation of operations.
Identification, handling of filled drug product containers.
Identification of drug product with a lot or control number for
determination of history of manufacture and control.


Part 211
•

Drug Product Inspection.
–
–
–

•

Packaged and labeled products examined to assure correct label.
Representative sample examined visually for correct labeling.
Results recorded.

Expiration Dating.
–
–
–

Determined by appropriate stability testing.
Related to storage conditions on the labeling.
Expiration dates appear on the labeling.


Part 211
• Subpart H - Holding and Distribution
•

Warehousing procedures.
–
–

•

SOPs established, followed including quarantining before
release by QA;
Storage of drug products under appropriate conditions of
temperature, humidity, light.

Distribution procedures.
–
–

SOPs established, followed including oldest approved stock
distributed first.
System by which each lot can be recalled.


Part 211
•

Subpart I - Laboratory Controls
• General Requirements
–
–

•

QA review of any specifications, standards, sampling plans,
test procedures
Include scientifically sound plan to assure conformance to
specifications for components, in-process materials, drug
products identified;

Testing and release for distribution.
–

For each batch of drug product, appropriate laboratory
determination of conformance to final specs, including
identity and strength of each active ingredient prior to
release.


Part 211
–

–
–

•

Appropriate testing of each batch for drug products to be free of
objectionable microorganisms.
Sampling, testing plans described in SOPs
Drug products failing to meet specs shall be rejected.
Reprocessing may be performed, must meet standards, specs.

Reserve Samples.
– Representative of each lot in each shipment of each active
ingredient shall be retained, at least 2x quantity necessary for all
tests, retained for 1 year after expiration.
– Representative of each lot, stored under conditions consistent
with product labeling, in the same container/closure system.


Part 211
–

–

Annual visual examination for evidence of deterioration unless
integrity effected; sample deterioration investigated, recorded.
Retained for 1 year after expiry date.

Subpart J - Records and Reports
• General Requirements.
–

Any production, control, distribution record required for a batch
retained at least 1 year after expiry date.

–

Records for components, labeling retained 1 year after expiry.


Part 211
–

All records or copies readily available for authorized inspection at
the location where the activities occurred, subject to copying.

–

Records retained either as original or as true copies.

–

Per SOP, annually evaluate quality standards.

–

Establish procedures so that responsible persons at firm notified
in writing of any investigations, any recalls, FDA inspectional
observations or regulatory actions related to GMPs.


Part 211
•

Equipment cleaning and use log.
–

•

Written record of major equipment cleaning, maintenance, and
use

Component, drug product container, closure, and labeling
records.
–

–
–

Identity and quantity of each shipment of each lot of
components, containers, closures, labeling; name of supplier,
supplier’s lot number, receiving code, date of receipt, name,
location of manufacturer.
Results of any test or examination and the conclusions.
Individual inventory record of each component, reconciliation of
use of each lot so can determine associated batch.


Part 211
–

–

•

Documentation of label examination and review for conformity
to established specifications.
Disposition of rejected components, product, containers,
closures, labeling.

Master production and control records.
–
–

To assure uniformity from batch to batch records for each drug
product
Preparation of master batch records described in SOP includes
name, strength of product, name, weight, measure of each active
ingredient etc.


Part 211
•

Batch production and control records.
⁻

•

Accurate reproduction of the master record, checked for
accuracy, dated and signed documenting each significant step in
manufacture, processing, packing, or holding was accomplished

Production record review.
⁻

All production and control records, including packaging, labeling
shall be reviewed and approved by QA. Any unexplained
discrepancy or failure of a batch or components to meet specs
thoroughly investigated;


Part 211
•

Laboratory records.
–

•

Distribution records.
–

•

Include complete data derived from all tests necessary to assure
compliance with established specs and standards.
Name, strength of product, description of dosage form, name,
address of consignee, date and quantity shipped, lot/control #.

Complaint files.
–

SOPs handling written, oral complaints established, followed;
review by QU of any complaint involving possible failure to meet
specs, and determination of need to investigate; review for
determination of serious and unexpected adverse event.


Part 211
Subpart K-Returned and Salvaged Drug Products
•
Returned Drug Products.
⁻

•

Shall be identified as such and held. If condition under which
held, stored, or shipped before or during return or condition of
product as a result of shipping casts doubt, then returned drug
product destroyed, unless testing reveals meets specs. May be
reprocessed, must meet specs.

Drug Products Salvaging
⁻

Improper storage conditions due to natural disasters, fires,
accidents, or equipment failures shall not be salvaged, returned
to marketplace unless they meet all applicable standards.


DOCUMENT #:
FX-005

REVISION NO:
1

EFFECTIVE
DATE:

TITLE:
GXP Required Documentation Review Training
Matrix Form for New/Transferred Employees
Doc
Number

Document Title

QA-003

Quality Assurance
Document Control

REV
#

Read &
Understood

1

□Y
□N
□Y

1

□N
□Y

GXP Training

QA-006

Laboratory Notebooks
1

□N
□Y

QA-008

GXP Corrective
Action/Preventative Action
(CAPA)

1

QA-009

GXP Deviation Reporting
(DR) Procedure

□N
□Y

Data Handling and
Reporting results

1

□N
□Y

1

□N
□Y

0

□N
□Y

0

□N
□Y

QA-010
QA-011
QA-025
QA-027

Handling of Logbooks
Vendor & Supplier Approval
Agency Inspections


PAGE:
1 of 1

DOCUMENT CATEGORY:
FX

1

QA-004

SUPERSEDE
DATE:

□N

Employee Signature/Date

DOCUMENT #:
FX-005

REVISION NO:
1

EFFECTIVE
DATE:

TITLE:
GXP Required Documentation Review Training
Matrix Form for New/Transferred Employees
Doc
Number

Document Title

QA-030

Numbering/Tracking
System

REV
#

Read &
Understood
□Y

0

□N
□Y

1

□N
□Y

1

□N
□Y

Chemical Handling,
Storage, and Disposal

1

□N
□Y
□N
□Y

LA-006

Receiving Shipments
from External Vendors

1
1

□N
□Y

LA-007

Use and Testing of
Showers and Eyewash
Station

0

LA-016

Receiving and escorting
visitors

□N
□Y

□N
□Y

LA-017

Receipt and Quarantine
of raw materials

0
0

□N
□Y

LA-021

Employee Gowning for
the cGMP Synthesis
Area

Facility Emergency

LA-001

Safety Incident,
Accidental Prevention,
and Reporting

LA-003

Equipment ID Numbers

LA-004


PAGE:
1 of 1

DOCUMENT CATEGORY:
FX

0

QA-033

SUPERSEDE
DATE:

□N

Employee
Signature/Date

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