2 the regulations

GMP - 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.

Characteristics of GMP regulations and interpretations

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

GMP regulations are largely general and open for interpretation

GMP – Characteristics

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, PACKING, 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 ProvisionSubpart B – Organization and personnelSubpart C – Buildings and FacilitiesSubpart D – EquipmentSubpart E - Control of Components and

Drug Products Containers and ClosuresSubpart F – Production and process

controls

Part 211 cont.

Subpart G – Packaging and Labeling Control

Subpart H – Holding and distributionSubpart I – Laboratory ControlsSubpart J – Records and ReportsSubpart K – Returned and Salvaged

Drug Products

Organization and Personnel

Buildings and Facilities

Equipment

Control of components and Drug Product Containers and Closures

Production and Process Controls

Packaging and Labeling Control

Holding and Distribution

Laboratory controlsGMP

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 QC211.25 Personnel Qualifications211.28 Personnel Responsibilities211.34 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 ResponsibilityApprove or Reject all:

o Componentso Drug Product Containero Closureso in-process Materialso Packaging Materialso Labelingo 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 Construction211.44 Lighting211.46 Ventilation, HVAC211.48 Plumbing211.50 Sewage and Refuse211.52 Washing and Toilet Facilities211.56 Sanitation211.58 Maintenance

Design

First principle: Quality by Design

GMP requirements for Process Design211.42 Design of Facility211.63 Design of Equipment211.100 Design of Production and

Control Procedures211.160 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

Premises

Sanitation

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

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 proceduresTo minimize the risk of losing raw data and

analytical results Inspection/replacement of normal wear and

maintenance itemsFile back-up and recoveryData archival and retrievalSecurityLan administration

Equipment design size and location

Must be suitable for intended useEasily cleaned and maintainedMust be non reactiveLubricants coolants etc. required for

operation should not contact any component.

Equipment Design, Size, and Location

Must be suitable for intend use: Appropriate design Adequate size Suitably located

Facilitate its use, cleaning and maintenance

Equipment Construction Cannot be

Additive Absorptive Reactive

Lubricants, coolants etc. required for operations should not contact any component

Equipment Cleaning and Maintenance

Equipment and utensils Must be cleanedMaintained at suitable intervals

Written ProceduresAssign responsibility for cleaning Include schedules for maintenance

Materials

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 methodsObliteration of pervious batch

informationProtection 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 describing: Receipt Identification Storage Handling Sampling Testing Approval or Rejection

Handled and stored in a manner to prevent contamination Bagged or boxed component of containers or closure stored off

floor and suitably spaced to permit cleaning and inspection Identified with a distinctive 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 211.11021 CFR 211.11321 CFR 211.4221 CFR 211.6321 CFR 211.16521 CFR 211.180

Validation Requirement

Process Validation is an Enforceable RequirementActive 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

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: DeviationsChange ControlCharge-in of componentsCalculation of yieldEquipment IDSamplingProduction time limits

In-process testing

Rejected Product

Action Limits

Acceptable Range

Action Limits

Rejected Product

Target value

In-process testing

Rejected Product

Release Specifications

Action Limits

Acceptable Range

Action Limits

Release Specifications

Rejected Product

Target value

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 forQuarantine prior to QC release Storage under appropriate conditions of

temperature, humidity and light

Subpart I lab controls: Instrument Controls, Training, Standards/Reagents, Testing 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

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 performanceDeviations 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.

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If it was not documented, it was not done!

Great Mounds of Paper?

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

There’s some truth to that.

Records and Reports

QUALITY MANUAL

Testing Method

Note :• Blue : WI (standard, specification & procedure) • Red : record

Product Destruction Record

Return Product Handling RecordRecall Record

Product Complaint Record

Batch Production Record

Distribution Record

Master productiondocument

Master Formula

Master Prod. Procedure

Master Pack. Procedure

TYPE OF GMP DOCUMENTS

Specification/ Standard

S.O.P.

Validation Protocol Report

Work Protocol(WP)

Raw & packaging material

Bulk

Finished productTesting result record and report

Stability test record

Sampling record

Microbial and particle monitoring record

Equipment StatusMaterial Status Product Status

Identity/Label

Can we ship this batch?

QC

Not untilthe

paperwork is released!

Lot no. XYZ

The GMP Paperwork is a Product

The paperwork produced is of equal importance to the products produced.

Product = Paperwork

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.

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…

Packaging and Labeling

Holding and Distribution

General Requirements

Written Procedures describingo Receipto Identificationo Storage o Handlingo Stamping o Testingo Approval or

rejection

Handled and stored in a manner to handle contamination

Stored off the floorIdentified with a

distinctive codeEach lot identified

as to its status quarantined, approved 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 ProductsShall 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

Organization and Personnel

Buildings and Facilities

Equipment

Control of components and Drug Product Containers and Closures

Production and Process Controls

Packaging and Labeling Control

Holding and Distribution

Laboratory controlsGMP

This is for your family…

Raw Materials

Manufacture

Dispense

A word about Drug Master File…

http://wwwbdp.ncifcrf.gov/pdf1/GuidetoRegSubsR1.pdf

Questions