21 CFR, Parts 210 and 211

An Overview of the Regulations

Part 210• Status of the regulations – 210.1

– Regulations set forth are “minimum” requirements!!!!

– Covers manufacturing, facilities and controls for

• Manufacturing, processing, packaging or holding of a drug product

– Failure to comply will render the drug to be adulterated

• The person who is responsible for the failure to comply shall be subject to regulatory action

Part 210

• Applicability – 210.2 – Applies to drug products for human use

Part 210

• The Definitions – 210.3

• This is a critical section – understand the definitions, learn these or you will fail!

• Here are some:– Act means the Federal Food, Drug

and Cosmetic Act

Part 210 – Definitions Cont.

• Batch– A specific quantity of drug/material intended

to have uniform character and quality produced under a single manufacturing order form during the same cycle of manufacture.

• Component– Any ingredient intended for use INCLUDING

those that may not appear in such drug product

Part 210 – Definitions Cont.

• Drug Product– Finished dosage form

• Fiber– Any particulate with a length at least 3x its

width

• Active ingredient– Any component intended to furnish

pharmacological activity

Part 210 – Definitions Cont.

• Drug is defined by the Act as any compound that has effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure or function of the body of man or animals

• In-process material– Any material fabricated, compounded,

blended or derived for use in the drug product.

Part 210 – Definitions Cont.• Manufacture, processing, packing or

holding includes– Packaging and labeling, testing and quality

control of drug products

• Quality Control– Any person or unit designated by the firm to

be responsible for duties relating to QC

• Representative Sample– Samples drawn on rational criteria intended to

accurately portray the material being sampled

Part 211

• This is the “meat” of the regulations• There are 11 subparts (identified by letters

from A through K)• Covers all sections of operations• Designed to be all encompassing

(general) – DON’T expect too many specifics

• The goal is to tell you what to do, not how to do it!

Subpart A – Part 211

• General Provisions

• 211.1 – Scope

• 211.3 – Definitions

• Scope– Minimum requirements– Applies to drugs for human use

• Definitions– Those set forth in 210.3 are applicable

211.22• Responsibilities of QC unit

• Shall be a quality control unit

• They shall have the responsibility and authority to approve or reject all components, containers, closures, in-process materials, packaging material, labeling and drug products

• Authority to review production records

• If errors have occurred, that they have been fully investigated

211.22

• The QC unit shall have adequate laboratory facilities

• They shall have the responsibility for approving/rejecting all procedures or specifications impacting the quality of the drug product

• Responsibilities shall be in writing and shall be followed

211.25

• Personnel qualifications• Everyone shall have the education,

training and experience to do their jobs• Everyone who supervises those people

shall have the education, training and experience to assign functions to provide assurance for drug quality

• There shall be an adequate number of qualified personnel

211.28

• Wear clean clothing and protective apparel

• Practice good sanitation and health habits

• Limited access areas

• If you are sick – do you belong in the area?

211.34

• Consultants

• Shall have sufficient education, training and experience to advise on the subject matter

• Records maintained stating the name, address and qualifications of consultants

Subpart C – Part 211

• 211.42 Design and construction features• 211.44 Lighting• 211.46 Ventilation, air filtration, air heating and

cooling (HVAC)• 211.48 Plumbing• 211.50 Sewage and refuse• 211.52 Washing and toilet facilities• 211.56 Sanitation• 211.58 Maintenance

211.42

• Any building shall be maintained to facilitate cleaning, maintenance and proper operations

• Adequate space

• Operations performed in defined areas– Receipt, storage, holding, etc.– All operations

• Penicillin operations in separate area

211.44 and 211.46

• 211.44 – Lighting

• Adequate lighting provided

• 211.46

• Adequate ventilation

• Adequate equipment for control of environment – micro, dust, air-pressure

• Air filtration provided

211.48 - Plumbing

• Potable water supplied under continuous positive pressure

• System free of defects

• Potable water meeting EPA requirements (40 CFR, Part 141)

• Drains of adequate size

• Air break provided or back-flow prevention

211.50 and 211.52

• 211.50 – Sewage and refuse• Dispose of trash, sewage and other refuse in a

safe and sanitary manner• 211.52 – Washing and toilet facilities• Adequate washing facilities provided• Hot and cold potable water• Soap and detergent• Air dryers or single-service towels• Easy access to working areas

211.56 Sanitation

• Facilities maintained in a clean and sanitary condition

• Free of rodents, birds, insects• Shall be written procedures on cleaning

schedules, methods, equipment and materials

• Shall be written procedures for rodentcides, insecticides, fungicides.

• Prevent contamination

211.58 Maintenance

• Facilities shall be maintained in a good state of repair

211.63 and 211.65

• 211.63 - Equipment shall be of appropriate design, adequate size and suitably located to facilitate operations, cleaning and maintenance

• 211.65 – Equipment constructed to not be reactive with product

• Lubricants/coolants shall not come into contact with product to alter their quality

211.67

• Equipment and utensils cleaned, maintained and sanitized often enough to prevent contamination and malfunctions

• Written procedures for cleaning and maintenance of equipment and utensils used within the manufacturing process arena

• Maintenance, cleaning, sanitizing and inspection records

211.68

• Automatic, mechanical and electronic equipment, computers, etc. used in the manufacturing realm shall be routinely calibrated, checked and inspected per a written program with retained records of calibrations, inspections, etc

• Change controls, input/output verification, back-ups

211.72 Filters• Shall not release fibers into drug

products– If fiber releasing filters are necessary

• Additional filtering using 0.22 micron max porosity

• 0.45 if manufacturing conditions so dictate

– Use of asbestos-containing filter is allowed only after proving to FDA safety or effectiveness is not compromised

211.80 - General

• Written procedures for receipt, sampling, approval, rejection, etc

• Handle and store to prevent contamination• Bagged or boxed items shall be stored off

of the floor and be adequately space for cleaning and inspection

• Each container of items will be ID’d with code for each lot received and status (quarantined, approved, rejected)

211.82 – Receipt/Storage of untested items

• Perform visual inspection for correctness of items, damage, contamination, etc upon receipt

• Items will be quarantined until inspected and released

211.84 – Testing and Approval/Rejection

• Each lot must be held until QC release• Sampling based upon appropriate criteria• Samples

– Cleaned where necessary– Obtained in a way to prevent contamination– Sterile equipment when necessary– No compositing of subdivided samples– Samples ID’d with lot #, container, date, etc– Containers must show samples were taken

211.84 – Testing and Approval/Rejection (con’d)

• Sample testing– Conduct at least one identity verification – Test components for conformity to specifications (C of

A is OK)– Test containers and closures for conformity to

specifications (C of T is OK)– Microscopic test of components if appropriate– Establish contamination spec if item subject to

contamination– Conduct microbiological tests on items that

microbiological contamination is objectionable

211.84 – Testing and Approval/Rejection (con’d)

• Any lot of components, drug product containers or closures that meets appropriate specifications of identity, strength, quality, purity and related tests may be approved and released for use. Any lot of such material that does not meet such specifications shall be rejected

211.86 and 211.87 and 211.89

• 211.86 - Use of approved components, etc• Use FIFO when possible (1st in - 1st out)• 211.87 – Retesting of approved

components, etc– After storing for a long time– After exposure to air, heat or other conditions

that may adversely affect quality

• 211.89 Rejected components, etc• ID and quarantine to prevent use

211.94 Drug Product Containers and Closures

• Shall not be reactive, additive or absorptive as to adversely effect product

• Provide protection from external factors that could contaminate or deteriorate drug

• Clean and suitable for use (sterilize, etc)

• Written standards, test methods to be followed (includes cleaning, sterilization and non-pyrogenation)

211.100 Written procedures; deviations

• Have written procedures for production and process controls to ensure drug products have specified identity, strength, quality and purity. Approval by QA/QC unit

• These procedures shall be followed and the execution of production and process control functions shall be recorded at time of completion. Deviations shall be recorded and justified.

211.101 Charge-in of Components

• Each batch formulation should attempt to make 100% of specified active ingredient

• When a component is transferred to a non-original container, it shall indicate– Name, item code– Receiving or control number– Weight or measurement in new container– Batch for which component was issued

including name, strength and lot number

211.101 Charge-in of Components (con’d)

• Supervision of weighing operations– QC released component– Weight or measurement is correct per batch

record– Containers are properly identified

• Each component added to a batch will have verification by a second person

211.103 Calculation of Yield

• Actual yields and percentages of theoretical yields shall be determined at the end of each appropriate phase of production. Calculations will be verified independently by a second person

211.105 Equipment Identification

• All containers, processing lines, major equipment used during production shall be identified to indicate contents of batch, and phase, if necessary

• Major equipment shall be uniquely identified and shown in the batch record to indicate the specific equipment used

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

• Procedures shall indicate in-process controls and tests in order to validate performance and monitor output, including– Tablet or capsule weight variation– Disintegration time– Adequacy of mixing to assure uniformity– Dissolution time and rate– Clarity, completeness or pH of solutions

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

• In-process specifications shall be consistent with final specifications

• In-process materials tested for ID, quality, strength and purity and be accepted or rejected by QC

• Rejected material shall be quarantined in order to prevent use in manufacturing

211.111 Time Limitations

• When appropriate, time limitations for completing each phase shall be established. Deviation from time limits is acceptable if quality is not compromised. Deviations shall be documented and justified

211.113 Control of microbiological contamination

• Appropriate written procedure for preventing microorgansims in drug products not required to be sterile

• Appropriate written procedures for preventing microorganisms in sterilized drug products. These procedures shall include any sterilization process

211.115 Reprocessing

• Written procedure describing a system for reprocessing non-conforming batches and steps taken to ensure reprocessed batches conform to standards and specs

• Reprocessing will not occur without review and approval of QC

Subpart G – Packaging and Labeling Control

• 211.122 Materials examination and usage criteria

• 211.125 Labeling issuance

• 211.130 Packaging and labeling operations

• 211.132 Tamper-resistant packaging requirements for OTC human drug products

• 211.134 Drug product inspection

• 211.137 Expiration dating

211.122 Materials examinationand usage criteria

• Written procedures for receipt, ID, storage, handling, sampling, testing, etc. There will be sampling and examining of materials

• Materials not meeting specifications will be rejected.

• Records for each shipment will be retained (receipt, examination and accept/reject)

• Labeling materials for each product will be stored separately. Access limited to authorized personnel

211.122 Materials examinationand usage criteria (con’d)

• Destroy obsolete and outdated materials• Gang printing is prohibited unless

differentiated by size, shape or color• Cut labeling

– Dedicate lines to each product and strength– Use electronic equipment to perform 100%

inspect – or –– 100% visually using 2nd person to verify

• Printing devices will be monitored

211.125 Printing Issuance

• Must use strict control when issuing

• Compare issued materials to master

• Reconcile quantities (used+returned=issued)

• All excess materials with lot number will be destroyed

• Returned materials shall be stored in a way to prevent mix-ups

• Procedures will detail control of issuance

211.130 Packaging andLabeling Operations

• Physically or spatially separate materials to prevent mix-ups or cross-contamination

• Set aside filled but unlabeled product. ID group to prevent mislabeling

• Manufacturing history of product must be available via lot or control number

• Batch record must reflect examination for correctness of labels

• Packaging and labeling facilities must be inspected before and after labeling operations and reflected in batch record

211.132 Tamper-Resistant Requirements for OTCs

• All OTCs for retail sale except for throat lozenge, dermatological, insulin and dentifrice products must be tamper-resistant else considered adulterated

• Tamper-resistant products have one or more barriers or indicators that show visible evidence of breached integrity– Two-piece hard gelatin capsules require two tamper-

resistant packaging unless capsules are sealed by a tamper-resistant means

– A minimum of one tamper-resistant feature is required even for sealed, two-piece gelatin capsules

211.132 Tamper-Resistant Requirements for OTCs

• Prominent statement indicating to consumer the tamper-resistant feature and will still be visible if the feature is breached or missing

• “Request for Exemption from Tamper-Resistant Rule” petition– Name of drug product or drug class– Reason for exemption– Alternatives or step taken for reducing tampering– Other information justifying an exemption

211.132 Tamper-Resistant Requirements for OTCs (con’d)

• OTCs subject to NDA requirements and must notify FDA of packaging changes

• This section does not affect any requirements for “special packaging” under the Poison Prevention Packaging Act of 1970

211.134 Drug Product Inspection

• Packaged and labeled product should be final inspected to assure correct labeling

• A sampling of units shall be collected and inspected for correct labeling

• Results of inspection shall be recorded in batch record

211.137 Expiration Dating

• Expiration date determined by stability testing

• Related to storage conditions on labeling determined by stability testing

• Products to be reconstituted must have an expiration date for both reconstitution and unreconstitution

• Expiration dates must be on labeling

211.137 Expiration Dating (cond’)

• Homeopathic drugs are exempt

• Allergenic extracts labeled “No U.S. Standard of Potency” are exempt

• New products for investigational use are exempt provided they meet stability specifications in their clinical investigations

• OTCs are exempt if labeling does not have dosage and are stable for three years

211.142 Warehousing

• Drug products must be quarantined prior to QC release

• Storage conditions must not affect drug products adversely (light, temperature, humidity)

211.150 Distribution

• Oldest products are distributed first. Deviation is permitted if it is temporary and appropriate

• System must be in place to readily recall distributed product if necessary

211.160• Specs, standards, sampling plans, test

procedures and any changes will be reviewed by the quality unit

• Deviations recorded and justified• Lab controls – scientifically sound

– Determine conformance to specs• Components• In-process• Sampling

– Calibration done

211.165

• Each batch shall meet final specs prior to release

• Lots free of objectionable microorganisms

• Sampling and testing described in SOPs

• Accuracy, sensitivity, specificity and reproducibility of test methods established and documented

• Lots not meeting spec are rejected

211.166

• Stability shall be done

• Results shall be used to determine storage conditions and expiry dates

• Written program includes:– Sample size, test intervals– Storage conditions– Reliable, meaningful and specific test methods

211.170

• Reserve samples shall be taken

• Representative of each lot

• Twice the quantity for full battery of tests

• Final product

• API

211.173 and 211.176

• 211.173 Lab animals maintained and controlled

• 211.176– Penicillin controlled in separate facility

211.180 General Requirements• Retain docs at least 1 year after the expiry

date or certain OTCs, 3 years after distribution

• All docs shall be readily available for review

• Docs can be copied

• Data shall be evaluated at least annually

• Procedures established to assure that management are notified of investigations, recalls and FDA issues

211.182 and 211.184• 211.182 - Records of major equipment

cleaning, maintenance (except routine) and use shall be documented

• 211.184 – Records shall be made on components, containers, closures and labeling– Name of supplier, supplier lot #, receiving

code and date received– Results of tests, individual inventory

211.186

• Master records maintained• Made by one person and checked by another

(prepared, dated, signed – full signature)• Name & strength, dosage form• Name and weight measure of API, total weight

of each dosage unit• Complete list of components• Accurate statement of weights, reasonable

variations• Theoretical reconciliation

211.188• Batch records maintained for each lot• Include

– Dates– Who did the work?– RM lot #– Weights used– Any test results– Inspections– Yields– Specimens of labeling– Sampling performed– Any investigations made

211.192

• Records reviewed by the quality unit

• Issues resolved

• Investigations performed

• “The investigation shall extend to other batches … that may have been associated with the specific failure or discrepancy”

211.194

• Lab records include complete data from all tests– Description of sample received– Statement of each method– Complete record of all data – graphs, charts– Initials of person doing test and dates– Initials of person checking and dates– Calibration data maintained– Stability records maintained

211.196 and 211.198

• 211.196 - Distribution records maintained – who, where, what, quantity

• 211.198 – Complaint files maintained– Investigations performed– Include name of product, lot number, name of

complainant, nature of complaint, reply

211.204

• Returned products identified and held

• If conditions of return or storage are in doubt, investigation is warranted

• Procedures shall be in writing

211.208

• Product subjected to improper storage conditions due to disaster or accident shall not be salvaged

• Unless,– Tests can show everything is OK– Evaluation of conditions indicates product was

not exposed to such harsh conditions

The End

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