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Draft guidance documents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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