01252014 cvc c gmp presentation

cGMP Current Good Manufacturing

PracticesFDA 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 211-226 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.


(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 210 & 211 - 226


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

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.– Include complete data derived from all tests necessary to assure

compliance with established specs and standards.• Distribution records.

– 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.


Doc Number Document Title

REV #

Read & Understood Employee Signature/Date

QA-003Quality Assurance Document Control

1 □ Y

□ N

QA-004 GXP Training1 □ Y

□ N

QA-006 Laboratory Notebooks1 □ Y

□ N

QA-008GXP Corrective

Action/Preventative Action (CAPA)

1 □ Y

□ N

QA-009GXP Deviation Reporting

(DR) Procedure

1 □ Y

□ N

QA-010Data Handling and Reporting results

1 □ Y

□ N

QA-011 Handling of Logbooks1 □ Y

□ N

QA-025 Vendor & Supplier Approval0 □ Y

□ N

QA-027 Agency Inspections0 □ Y

□ N

DOCUMENT #:FX-005

REVISION NO:1

EFFECTIVE DATE:

SUPERSEDE DATE:

PAGE:1 of 1

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

DOCUMENT CATEGORY:FX


Doc Number Document Title

REV #

Read & Understood Employee

Signature/Date

QA-030Numbering/Tracking

System

0 □ Y

□ N

QA-033 Facility Emergency0 □ Y

□ N

LA-001Safety Incident,

Accidental Prevention, and Reporting

1 □ Y

□ N

LA-003 Equipment ID Numbers1 □ Y

□ N

LA-004Chemical Handling,

Storage, and Disposal

1 □ Y

□ N

LA-006Receiving Shipments from External Vendors

1 □ Y

□ N

LA-007Use and Testing of

Showers and Eyewash Station

1 □ Y

□ N

LA-016Receiving and escorting

visitors

0 □ Y

□ N

LA-017Receipt and Quarantine

of raw materials

0 □ Y

□ N

LA-021Employee Gowning for the cGMP Synthesis

Area

0 □ Y

□ N

DOCUMENT #:FX-005

REVISION NO:1

EFFECTIVE DATE:

SUPERSEDE DATE:

PAGE:1 of 1

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

DOCUMENT CATEGORY:FX

01252014 cvc c gmp presentation

Business

confidential information

drug products

equipment cleaning

drug product containers

contamination of equipment

electronic equipment

cfrciventichem proprietary

types of equipment