Cgmps for Pharmaceutical Manufacturing

8/3/2019 Cgmps for Pharmaceutical Manufacturing

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cGMPs for Pharmaceutical

Manufacturing


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Objectives

1. To understand where the regulations

come from, who has enforcement

authority, and why you need to comply

2. To understand the Fundamentals,

Benefits and Key Parts of cGMPs


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What are cGMPs?

Current Good Manufacturing Practices

Come from the Food Drug and CosmeticAct

Rules set up by the FDA that drugmanufacturers needs to follow in order toensure that a safe and effective product is

manufactured


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Where Did the Food Drug andCosmetic Act Come From?

1906 book by Upton Sinclair

The Jungle exposed the

dangers involved in the meatpacking industry

Helped drive public opinion to

support a new law passed byCongress

Food Drug and Cosmetic Act


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Provisions of the Law(FDC Act)

Creation of Federal Government agency

to oversee food industry

Scope expanded later to medical

industry


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Who Interprets and EnforcesThis Law?

The FDA (Food and Drug Administration) is

an agency within the Department of Healthand Human Services and consists of eight

centers/offices.


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FDA

Office of Regulatory Affairs

(ORA)

Office of the Commissioner (OC)

National Center for ToxicologicalResearch (NCTR)

Center for Veterinary Medicine(CVM)

Center for Food Safety and

Applied Nutrition (CFSAN)

Center for Drug Evaluation

and Research (CDER)

Center for Devices and

Radiological Health (CDRH)

Center for Biologics Evaluation

and Research (CBER)

The FDA consists of eight branches


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Interpretations of the Law

The Code of Federal Regulations is agovernment publication where Federal Agenciespost regulations

Contain regulations enforced by the DOT, DEA,FCC, FDA, and all other agencies

Found in Code of Federal Regulations (CFR)

Drug (cGMP): Title 21, Part 210 & 211 Device (QSR): Title 21, Part 820

Combination Product: Title 21 CFR Part 3 Subpart

A (section 3.2e)


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Interpretations of theRegulations

Guidance documents published by FDA and

International Conference on Harmonization (ICH)

Draft guidance documents

Preamble documents published by government

FDA 483 inspectional observations documents

Warning letters from FDA to various companies

www.fda.gov


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What Happens if cGMPs arenot Followed?

Adulteration: A drug is deemed to be

adulterated if the methods used in or the facilities

or controls used for its manufacture, processing,

packing, or holding do not conform to or are not

operated or administered in conformity with

cGMP to assure that such drug meets the

requirements of this act as to Safety and has theIdentity and Strength, and meets the Quality

and Purity characteristics which it purports or is

represented to possess.


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Why Comply?

Food drug and cosmetic act is the law

When charged with a violation:

Proof of criminal intent is not necessary. (Guiltyuntil proven innocent)

Actual harm from contamination does not needto be proven.

(Passing product non-adulterated product)

Consequences are numerous


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Consequences ofNon-compliance

Legal Consequences FDA 483s

FDA warning letters

Consent decree Recall of product

Product seizure

Plant Injunction

Company closure

Debarment


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Consequences ofNon-compliance

Business Consequences

Expensive to do recalls Loss of sales

Bad publicity

Potential harm to customers


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Fundamentals of cGMPs?

Based on fundamental concepts ofQuality Assurance PrinciplesControl

Quality, safety, and effectiveness must bedesigned and built into the product

Quality cannot be inspected or tested into afinished product

Each step of manufacturing must becontrolled to maximize the chances that the

Finished Good will be acceptable


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What are the Benefits of cGMPs?

They outline a Quality System that reduces orprevents errors

Ensures products are safe for use in humans

Prevent/control contamination and cross-contamination

Minimizes variations in potency of the drug

Ensures reproducible physiological activity Prevent side effects and toxicity due to

variations in drug content and potency

Prevents mislabeling and adulteration


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Key Parts of cGMPs

Subpart B: Organization and Personnel

Subpart C: Buildings and Facilities

Subpart D: Equipment

Supbart E: Control of Components and Drug

Product Containers and ClosuresSubpart F: Production and Process Controls


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Key Parts of cGMPs

Subpart G: Packaging & Labeling Control

Subpart H: Holding & Distribution

Subpart I: Laboratory Controls

Subpart J: Records & Reports

Subpart K: Returned & Salvaged DrugProduct


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Organization and Personnel

Management Responsibility

Responsible for facility, quality system,

organizational structure, ensuring adequateresources

Responsible for actions of those reporting to them

Responsible for reviewing products annually, andprocedures routinely

Responsible for providing adequate resources to

perform operations Facilities, personnel, training, equipment, etc


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Quality Unit

Responsible for approval or rejection of

all components, raw materials, containers, closures,

subassemblies, packaging, labeled finished

products, process validation reports, procedures

and product specifications

Investigative reports for non-conformances and out-

of-specifications (OOSs)


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Quality Unit

Responsible for reviewing production records

and ensuring that no errors have occurred

(may include verification activities)

Responsible for releasing product for use

Must be independent of manufacturing


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Buildings and Facilities

Buildings must be designed with adequate size and space

for operations (helps to eliminate mix-ups)

Facilities must be validated

There must be a good flow pattern for personnel,materials, products and waste materials (flow from clean to

dirty)

The facility must be easy to clean and sanitize (surfaces,equipment, exposed cords, floors, ceilings)

Environmental controls must be in place (clean rooms)

Utilities must be validated (water systems, electrical, etc)


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Buildings and Facilities

Must have engineering documents describing the layout of

the clean rooms controlled documents

Changes to the layout of the room after it has been

validated must go through change control procedures andmay require revalidation of the room

Any changes that potentially impact the ventilation in the

room must be assessed for impact on the microbial levelsin the room

Microorganisms, particulates, and hazardous materials

must be controlled


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Equipment

Equipment should be selected based on the

intended use and cleanability if it is to be in a

clean room Equipment must be placed in an appropriate

location (temperature, humidity, etc.)

Equipment must be properly qualified (Design,

Installation, Operation, Performance)


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Component/Materials Control

Suppliers must be evaluated and approved and

monitored for quality

Incoming Materials must be tested before they can be

accepted for use

Materials must be placed in stores or issued according

to FIFO (stock rotation)

Materials must be stored so that they are not mixed

up, damaged, or contaminated.


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Production/Process Control

Have & Follow Procedures: A goodprocedure is a written step-by-stepprocedure that provides a roadmap forControlled and Consistent performance.

Examples:

(Manufacturing) Work Instructions

Operating Procedures Testing Procedures

Quality Manual

Deviations must be recorded and justified


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Procedures should address

verification of critical steps by a secondperson

line clearance

monitoring of processes to make sure theyare in control

time limits and yield calculations asappropriate checks for critical processes

gowning for controlled environments

(cleanrooms)


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Packaging and Labeling Control

Label is a display of a written, printed or graphic

matter upon the immediate container of any article

Labeling is the label and any other packaging material

or container that is printed (ex. IFU, advertising

materials)

Procedures must exist that document receiving,

identity, storage, handling, sampling, and testing oflabels and ensure that integrity is maintained

throughout production and use of product


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Packaging and Labeling Control

Labeling must be separated physically in storage to

avoid mix-ups

Wording of labels cannot be changed unless the

FDA is notified

Labeling must be inspected prior to issuing to

production

All labels must be reconciled (accounted for) if not

100% inspected.

Label control begins with the design


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Holding and Distribution

Warehousing procedures should address

Quarantine of drug products

storage of products under appropriate conditions

Distribution procedures should address

FEFO (First Expiring First Out)traceability of product lots/batches


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Laboratory Controls

Written procedures must be established & followed

All actions must be documented at the time of

performance

Calculations need to be recorded

Second person must review records

Data must be directly recorded into appropriate records

Equipment, software, and methods must be validated

An Out-of-Specification (OOS) result must be investigated

and a root cause identified

Laboratory data is considered to be a quality record


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Records and Reports

Quality Records are the proof that theprocedures were followed and they showtraceability of product.

Examples:

Lot History Records

Laboratory Notebooks

Protocols Reports

Logbooks

Distribution Records

Complaint Files


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Quality Records

Records are legal documents and can be subpoenaed

in a court of law as evidence

Signatures on documentation have the same meaning

as on any kind of contract

Information must be recorded and signed for at the

time of performance on the original record


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Website References

http://www.fda.gov (Food and Drug Administration)

http://www.fda.gov/foi/warning.htm (FDA Warning Letters)

http://www.access.gpo.gov/uscode/title21/chapter9_.html(Food Drug and Cosmetic Act)

http://www.gpoaccess.gov/fr/index.html (Federal Register)

http://www.fda.gov/opacom/morechoices/industry/guidedc.htm (Guidance Documents)

http://www.ich.org (International Conference on Harmonization)

http://www.pda.org (Parenteral Drug Association)


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Q & A

Make GMP a lifestyle!!!

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