Understanding cGMPS –
What Attorneys Need to Know
The Nuts + Bolts of cGMPS
July 10, 2013
21 CFR Parts 210 and 211
cGMP case law
Andrew D. Bos
Senior Director – Legal Services
Caraco Pharmaceutical Laboratories, Ltd.
cGMPs
• Found in CFR Title 21 Parts 210
and 211
• History goes back to the 1962
amendments to the Federal Food,
Drug, and Cosmetic Act
Objectives
• Standards for methods to be used for the:
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Manufacture
Processing
Packing
Holding
• So that that the drug meets the requirements for:
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Safety
Identity
Strength
Quality
Purity
“Minimum” Standards
• The CFR regulations which make up the cGMPs
contain the “minimum” current good
manufacturing practice. - 21 CFR § 210.1(a).
Flexible
“The cGMP requirements were established to be
flexible in order to allow each manufacturer to
decide individually how to best implement the
necessary controls by using scientifically sound
design, processing methods, and testing
procedures.”
- FDA website, June 27, 2013 ,
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing
/ucm169105.htm
But yet still definite
• cGMP regulations have survived
challenges on the grounds that they are
vague, indefinite and uncertain.
– United States v. The Kendall Co., 324 F.
Supp. 628
– United States v. Bel-Mar Laboratories, Inc.,
284 F. Supp. 875
– United States v. An Article of Drug, 484 F. 2d
748
Binding Regulations
• cGMPS are binding regulations, not
merely interpretive.
– Nat’l Ass’n of Pharmaceutical Mfrs. v. Food
and Drug Admin., 487 F. Supp. 412, affirmed,
637 F.2d 877
Violations of cGMP
• Result in the drug product being adulterated. 21
CFR § 210.1(b); 21 U.S.C. § 351(a)(2)(B).
• Even if “pharmaceutically perfect in content”, a
drug is adulterated if made in violation of cGMP.
United States v. Lit Drug Co., 338 F. Supp. 990
Part 211 Subparts of cGMP
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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 Controls
Records and Reports
Returned and Salvaged Drug Products
Organization and Personnel
• The quality department is responsible for
approving or rejecting drug components,
containers, packaging, labeling and production
records.
• Adequate laboratory facilities
• Personnel qualifications
Buildings and Facilities
• Suitable size, construction and location
• Adequate space
• Operations to be performed within specifically
defined areas
Equipment
• Shall be of appropriate design, adequate size,
and suitably located
• Equipment construction
• Equipment cleaning and maintenance
• Filters
Components and Containers
• For components and drug product containers
need to have written procedures regarding:
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Receipt
Identification
Storage
Handling
Sampling
Testing
Approval or rejection
Production and Process Control
• To assure that the drugs have the identity,
strength, quality, and purity they represent to
have.
• Weighing, measuring and calculation of yield
• Equipment Identification
• Sampling and testing of in-process materials
• Time limits for production
Packaging and Labeling Control
Receipt, identification, storage,
handling, sampling, examination,
and/or testing of labeling and
packaging materials.
Holding and Distribution
• Warehousing Procedures
– Quarantine procedures
– Storage
• Temperature
• Humidity
• Light
• Distribution Procedures
– Oldest approved stock first
– Ability to facilitate a recall if necessary
Laboratory Controls
• Testing and release for distribution
• Stability testing
• Special testing requirements
• Reserve samples
Records and Reports
• Any production, control or distribution record
associated with a drug batch
– 1 year after expiration of the batch
– 3 years after distribution for OTC
– Applies to drug components, containers, closures and
labeling
• Must be “readily available” for an FDA inspection
Records and Reports, cont’d
• Complaint files
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Written and oral complaints
Determine the need for an investigation
Unexpected ADE that needs to be reported?
Written record of each complaint
Returned Product
• Storing, handling and disposition (and
possible salvaging) of returned product.
United States v. Barr
Laboratories, Inc.
• Most significant case dealing with cGMPs
• 812 F. Supp. 458 (1993)
• A court battle involving the need for manufacturing
standards, and how specific those standards would be.
• Case arose out of FDA inspectors issuing 483
observations to Barr
U.S. v. Barr, cont’d
• Key FDA criticisms of Barr
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Manufacturing process are invalid / not validated
Failure investigations are inadequate
Release of drug products that fail specifications
Cleaning validation deficiencies
Record-keeping deficiencies
Failure to validate testing methods
• FDA sought an injunction against Barr to have it
suspend, recall or revamp numerous products
United States v. Barr, cont’d
• Court recognized the regulations can
sometimes lead to “conflicting, but
plausible” interpretations.
• To the extent that there are ambiguities,
companies can turn to FDA guidance or
scientific judgment.
– Industry practice cannot be a basis to
determine compliance.
United States v. Barr, cont’d
• Court concluded Barr violated cGMP
– Did not conduct failure investigations
– Released batches on the basis of selective
data
– Refused to validate cleaning processes
• Court did acknowledge Barr made
improvements during the course of the litigation
United States v. Barr, cont’d
• No shutdown
– “In light of Barr’s recent makeover….the Court is
unwilling to order a temporary shutdown. While
Barr’s transformation from an ugly duckling to a swan
is neither natural nor complete, the Court cannot
ignore Barr’s remedial efforts.”
United States v. Barr, cont’d
• Court’s ruling
– Helped clear up uncertainty in the regulations
– Helped define parameters for drug testing
– Prompted the FDA to issue guidance to assist
companies to reach better cGMP compliance
Questions ?
Andrew D. Bos
Senior Director - Legal Services
Caraco Pharmaceutical Laboratories, Ltd.
andrew.bos@sunpharmausa.com
313-871-8400 Extension 4318