good manufacturing practice

I have short and basic question about  laboratory controls  ( We will be discussing the laboratory controls this week. Which area do you think it’d be most important to you?  Why?  And how does it compared with another industry (or area) that you are currently working with?

SUBPART I –
LABORATORY
CONTROLS
CHEM 519 – GMPs
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Equipment
Standards/Materials
ANALYTICAL
LABS
Analysts/Training
Data system
Methods/Specs
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SUBSECTION 211.160 GENERAL
REQUIREMENTS
• Establishment of or changes to required
specifications, standards, sampling plans, test
procedures or other lab control mechanisms
are drafted by the appropriate organizational
unit and approved by QA
• These are followed and documented at the
time of performance
• Deviations are recorded and justified.
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SUBSECTION 211.160 GENERAL
REQUIREMENTS
Laboratory Controls will include the establishment of
scientifically sound and appropriate specifications,
standards, sampling plans and test procedures.
It must be assured that components, drug product
containers and closures, in-process samples, labeling and
drug product, conform to standards of identity, strength,
purity and quality.
Conformance to appropriate written specification must be
determined for components, drug product containers
and closures, labels, in-process materials and drug
product.
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SUBSECTION 211.160 GENERAL
REQUIREMENTS
• Calibration of instruments, apparatus, gauges and
recording devices is done at suitable intervals
• According to a written program with specific:
• Directions
• Schedules
• Limits
• Remedial action
• Equipment and Instruments not meeting
established specifications, are not used.
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SUBSECTION 211.165 TESTING
AND RELEASE FOR DISTRIBUTION
• Each batch of drug product is tested for
conformance to final specification
• These include identity and strength tests for
each active ingredient prior to release
• Testing for microorganisms is required, if the
product is required to free of them
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SUBSECTION 211.165 TESTING
AND RELEASE FOR DISTRIBUTION
•
There are written procedures for sampling and testing
•
Acceptance criteria for sampling and testing are
adequate to assure the drug product meets specification
and statistical quality control for approval and release.
•
The accuracy, sensitivity and reproducibility of test
methods are established and documented
•
Drug product failing to meet specification or other quality
control parameters shall be rejected.
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SUBSECTION 211.166 STABILITY
TESTING
• Written program to assess the stability
characteristics of a drug product.
• Testing is done using the product in the same
container system it is to be marketed in.
• Reliable, meaningful and specific test methods are
used.
• Written assessment of stability and compatibility
to indicate no degradation of the product for the
expected period of use.
ICH Organization
Q1A(R2) harmonized US, EU & JP
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Q1A(R2) STABILITY TESTING
OF NEW DS AND DP
Establish requirements for necessary data to support an
expiration dating for a pharmaceutical products
• Storage conditions and frequency of testing
• Size and number of batches needed for registration
• Data for label storage condition and accelerated conditions
• Define forced degradation studies and stress studies
• Justification of specification
• Expectations of analytical procedures
• Requirements of labelling
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Q1A(R2) – DS STRESS
TESTING
• Stress testing is required
•
To understand the drug substance stability
•
To establish degradation pathways
•
To validate the stability indicating power of the analytical procedures used.
•
To support the severe conditions that may be encountered during
distribution.
• Use single batch of material (high temp and humidity)
•
Oxidation, photolysis (ICH Q1B)
• Study depend on the individual API and DP.
• Degradation pathways can be complex and that, under forcing conditions, and
may not be realistic on long-term testing.
• Useful in developing and validating suitable analytical methods
• Results from these studies are part of regulatory submission
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Q1A(R) DRUG SUBSTANCE
•
Testing:
• Cover attributes of the drug substance susceptible to change
during storage
• Cover, as appropriate, the physical, chemical, biological, and
microbiological attributes of the drug substance
• Validated stability-indicating test procedures should be
applied
• Acceptance criteria for the specific tests, set from preclinical
and clinical batches
• Should include individual and total upper limits for impurities
and degradation products
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SUBSECTION 211.167 SPECIAL
TESTING REQUIREMENTS
• Drug products that are to be sterile or
pyrogen-free, appropriate lab testing will be
done.
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SUBSECTION 211.170
RESERVE SAMPLES
• There are appropriately identified reserve samples
that are representative of each lot of drug substance.
• There are appropriately identified reserve samples of
each lot of drug product retained in its market
container and under labeled storage conditions.
• For drug product, the reserve sample is at least twice
the amount needed necessary to perform all required
tests except those for sterility and pyrogens
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ANALYTICAL TESTING
CHEM 519 – GMPs
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ANALYTICAL DATA
•Without Data, You Are
Just Another Person
with an Opinion
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ANALYTICAL TESTING IN
PHARMACEUTICAL LABORATORIES
• Drug Substance (API) Release/Reassay/Stability
• Drug Product Release/Reassay/Stability
• In-process Samples
• Raw Material (Excipient) Release/Reassay
• Packaging Components Release
• Equipment Cleaning Samples
• Complaint Samples
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ANALYTICAL TESTING IN
PHARMACEUTICAL LABORATORIES
• Method Transfer Samples
• Method Validation Testing
• Qualification of Standards
• Instrument Calibration
• Investigational Samples
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ANALYTICAL TESTING IN
PHARMACEUTICAL LABORATORIES
• Drug Substance Release – Tests to Consider:
• Description/Appearance
• Assay versus a qualified reference standard
• Impurity Profile
• Identification Tests
• Residual Solvents, OVIs
• Water Determination
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ANALYTICAL TESTING IN
PHARMACEUTICAL LABORATORIES
• Drug Substance Release – Tests to consider:
• Compendial tests, i.e., heavy metals, ROI, clarity
of solution, chloride, etc.
• Physical Tests, i.e., particle size, bulk and tap
density, surface area, polymorphic forms
• Microbiological tests particularly for APIs to be
used in parenteral formulations
• Chiral purity, specific rotation (as appropriate)
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ANALYTICAL TESTING IN
PHARMACEUTICAL LABORATORIES
• Drug Product Release – Tests to consider:
• Description/Appearance
• Assay versus a qualified reference standard
• Degradation Product Profile (vs API impurity
profile)
• Identification Test(s)
• Dissolution or Drug Release
• Uniformity of Dosage Units
• pH
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ANALYTICAL TESTING IN
PHARMACEUTICAL LABORATORIES
• Drug product release – Tests to Consider:
• Moisture Determination
• Clarity/Particulate Matter
• Preservative or Anti-oxidant
• Physical tests such as hardness or
disintegration
• Micro tests such as Bacterial Endotoxins or
sterility or antimicrobial preservative
effectiveness
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SPECIFICATIONS
• Specification* is defined as (ICH Q6A):
• List of tests, references to analytical procedures
• Appropriate acceptance criteria that are numerical limits, ranges
or other criteria
• Establishes the set of criteria to which a drug substance or product
should conform to be considered acceptable for use
• Critical quality standards that are proposed and justified by the
manufacturer and approved by regulatory authorities as part of the
overall approval
*Substitute monograph or Quality Standard or Specs/Methods or
Specs/Tests depending on your company nomenclature
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SPECIFICATIONS
• Specifications are part of total control strategy
designed to ensure drug substance/product quality
and consistency (also product safety)
• Characterization during development
• Adherence to GMPs
• Suitable facilities
• Validated manufacturing process
• Validated methods
• Raw material/in-house/stability testing
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TYPES OF SPECIFICATIONS
• Release vs Shelf Life vs In-house vs Alert vs ???
• Concept of release vs shelf life applies to drug product only
• Establishment of more restrictive criteria at release vs shelf life
• In US, often criteria is the same from a regulatory filing standpoint
for release and shelf life which leads to establishment of in-house
or alert criteria
• In Europe, there is an expectation that a release and a shelf life
criteria will be filed for parameters that may change such as assay
or degradation products
• Regardless of how this is done the concept is the same, a tighter
limit is applied at product release to provide increased assurance
that the product will remain within acceptance criteria throughout
its shelf life
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JUSTIFICATION OF
SPECIFICATIONS
• Development data
• Results for lots used in tox and clinical studies
(qualification of impurities)
• Results from accelerated and long-term stability
studies especially primary studies
• Reasonable analytical and manufacturing variability
• Data for scale-up/validation batches
• Exclusion of test (s)
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• USP and typical industry limits are 98.0 –
102.0% on a dried or solvent free basis
• HPLC is most common method employed as
it can be shown to be specific and stability
indicating
DRUG
SUBSTANCE
ASSAY
• Titration is also used, however it must be
augmented by a specific method for
impurities
• Analysis for assay and impurities by HPLC is
often combined in one method, however it is
not absolutely necessary and often there are
two separate methods
• The drug substance HPLC method can be
the same as the drug product method,
however it is not absolutely necessary and
quite often the methods are different
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DRUG PRODUCT ASSAY
• USP and typical industry limits are 90.0 – 110.0% of
label claim although some products have tighter limits
such as 95.0 – 105.0%
• In Europe, a release limit of 95.0 – 105.0 is an
expectation
• Many companies use in-house or alert limits set at
tighter than 90.0 – 110.0, these limits can be statistically
set based on the product degradation profile or more
arbitrarily set based on the variability in the method
and the manufacturing process
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STABILITY TESTING
• Stability testing of degradation products
• Monitoring degradation products at levels > 0.1% or >
LOQ
• Isolation and identification of newly discovered
degradation products
• Reporting of degradation products
• Individual / total
• RRT / peak name
• Specified degradation products
• Response factor
• Authentic standard
• Area %
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TESTING FOR IMPURITIES
• For new products, ICH guidelines Q3A and Q3B are in place
and include thresholds for Reporting, Identification and
Qualification of Impurities and Degradation Products
• Organic Impurities
• Identified /known impurities
• Specified impurities
• Unknown/unspecified impurities
• Total impurities
• Residual solvents
• Elemental Impurities
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DISSOLUTION TESTING
• Dissolution Testing
• USP &
• USP Apparatus are Basket (1) and Paddle (2)
• Immediate Release Product
• Typical specification is Q = 80% at 15 –
60 minutes
• Extended Release Oral Product
• Typically 3 or 4 time points with Q
ranges, e.g.
• 1 hour 20 – 40 %
• 2 hour 40 – 60%
• 4 hour 65 – 85%
• 8 hour NLT 80%
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ANALYTICAL TESTING IN
PHARMACEUTICAL LABORATORIES
• Typical Specification for:
•
•
•
•
•
Immediate Release Oral Tablet or Capsule
Extended Release Oral Tablet
Oral Liquid
Injectable solution
API
• Test
Method
Acceptance Criteria
• Assay
HPLC
90.0 – 110.0% of Label
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FOR NEXT CLASS
For Next Class
Subpart J – Records and Reports
A. Reading Assignment: Chapter 10 – Laboratory controls
B. Discussion Board Assignment – Did you check?
C. Questions for me?
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