Transcript Analytical Chem

Applications of Analytical Chemistry
in Pharmaceuticals
Corey M. Chong
10Mar10
Topics of Discussion
- What to test: the drug product
- Why to test: the Code of Federal Regulations
(CFRs)
- How to test: compendial and non-compendial
methods presented in regulatory documents
(IND/NDA)
About the Speaker
- Started as environmental analytical chemist.
- Transitioned to pharmaceuticals as a Quality
Control analyst.
- Worked for “Big Pharma” in Analytical R&D.
- Now specializes in Regulatory CMC (Chemistry,
Manufacturing, and Control).
The Big Picture
(Drug Product for Sale to the Public)
- Product Label (the box/carton and the individual
container label)
-
-
List of ingredients including strength of the API
Expiration date
Recommended storage condition
- Package Insert
-
Chemical formula and description of the API
Drug product composition (description of formulation)
Directions for use
Container Example
Expiration date printed
on container label
Label Information Example
Usual Dosage: Read accompanying prescribing literature
NDC 59011-100-10
OxyContin® (oxycodone hydrochloride controlled-release) tablets
100 Tablets Rx Only
Swallow tablets whole. Do not crush or chew.
Dispense in a tight, light-resistant container.
Store at 25°C (77°F); excursions permitted between 15°–30°C
(59°–86°F).
10 mg
Purdue Pharma L.P.
Stamford, CT 06901-3431
Lot 0137BA 0314540B
Package Insert Example
See OxyContin® Package Insert PDF
- Page 2: API description and drug product
formulation
- Page 25: packaging and drug product description
- Page 27: storage conditions
- Page 1 and 28: directions for use
21 CFR Part 211
cGMPs for Finished Pharmaceuticals
- Subpart B Organization and Personnel
-
Sec 211.22 Responsibilities of quality control unit.
“Adequate lab facilities for testing and approval…”
21 CFR Part 211 cont’d
- Subpart E Control of Components and Drug
Product Containers and Closures
-
Sec 211.84 Testing and approval or rejection of
components and drug product containers and closures.
(d)(1) “At least one test shall be conducted to verify
identity…”
(d)(2) “Each component shall be tested for conformity
with all appropriate written specifications for purity,
strength, and quality.”
21 CFR Part 211 cont’d
- Subpart F Production and Process Controls
-
Sec 211.110 Sampling and testing of in-process
materials and drug product.
(c) “In-process materials shall be tested for identity,
strength, quality, and purity…”
21 CFR Part 211 cont’d
- Subpart G Packaging and Labeling Control
-
Sec 211.137 Expiration dating.
(a) “To assure that a drug product meets applicable
standards for identity, strength, quality, and purity at
the time of use, it shall bear an expiration date
determined by appropriate stability testing described
in Sec 211.166.”
21 CFR Part 211 (cont’)
- Subpart I Laboratory Controls
-
-
Sec 211.165 Testing and release for distribution.
(a) “For each batch of drug product, there shall be
appropriate laboratory determination of satisfactory
conformance to final specification for the drug
product, including identity and strength of each
active ingredient prior to use.”
Sec 211.166 Stability testing
(a) “There shall be a written testing program…”
Regulatory Information
(IND/NDA using eCTD format)
- Module 3 Quality
-
-
3.2.S Drug Substance (Active Pharmaceutical
Ingredient)
3.2.P Drug Product
3.2.S Drug Substance
-
3.2.S.1 General Information
3.2.S.2 Manufacture
3.2.S.3 Characterization
3.2.S.4 Control of Drug Substance
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure
3.2.S.7 Stability
3.2.S.1 General Information
- S.1.2 Structure
-
As determined in S.3.1
- S.1.3 General properties
-
Appearance
Solubility, aqueous and non-aqueous
Melting range
Polymorphism
3.2.S.2 Manufacture
- S.2.2 Description of Manufacturing Process and
Process Controls
-
Flow diagram indicating when in-process testing occurs
- S.2.4 Controls of Critical Steps and Intermediates
-
Moisture (USP<921>)
Residual solvents (USP<467>)
Heavy metals (USP<231>)
Content Uniformity (USP<905>)
3.2.S.3 Characterization
- S.3.1 Elucidation of Structure
-
UV-Vis Spectroscopy (USP<857>)
XRD (X-ray Diffraction) (USP<941>)
MS (Mass Spectroscopy)
IR Spectroscopy (Infrared) (USP<857> or <1119>)
NMR (Nuclear Magnetic Resonance) (USP<761>)
DSC (Differential Scanning Calorimetry)
TGA (Thermogravimetric Analyses)
Melting Range (USP<741>)
Elemental analysis
3.2.S.4 Control of Drug Substance
- S.4.1 Specification
-
Purity (HPLC)
Impurities (HPLC), limits should conform to ICH Q3
Residual solvents (GC, USP<467>)
Moisture (USP<921>)
Appearance (Visual)
Heavy Metals (USP<231>)
X-ray Diffraction (USP<941>)
Particle Size (USP <786>)
Bacterial Endotoxin (USP<85>)
Microbial Limits (USP<61>)
3.2.S.4 Control of Drug Substance
(cont’)
- S.4.2 Analytical Procedures
-
Actual method details e.g., chromatography column
conditions, gradients, and mobile phases; instrument
settings and detector wavelengths.
- S.4.3 Validation of Analytical Procedures
-
-
Accuracy, Precision, Specificity, Linearity, Range,
Ruggedness, LOD, LOQ.
See ICH Q2
3.2.S.7 Stability
- S.7.1 Stability Summary and Conclusions
-
Typically the same methods listed on the specification
with all the stress conditions that support the
recommended storage condition. Stress conditions
designed following ICH Q1.
- S.7.2 Post-Approval Stability Protocol and
Stability Commitment
-
Typically the same methods listed on the specification
with all the stress conditions that support the
recommended storage condition.
- S.7.3 Stability Data
3.2.P Drug Product
- 3.2.P.1 Description and Composition of the Drug
Product
- 3.2.P.2 Pharmaceutical Development
- 3.2.P.3 Manufacture
- 3.2.P.4 Control of Excipients
- 3.2.P.5 Control of Drug Product
- 3.2.P.6 Reference Standards or Materials
- 3.2.P.7 Container Closure
- 3.2.P.8 Stability
3.2.P.1 Description and Composition
of the Drug Product
- Description of drug product including formulation
and packaging options. A manufacturing formula
for each formulation is presented per unit e.g., the
amount of excipient and API per pill or vial.
3.2.P.3 Manufacture: Example for
Tablets
- P.3.3 Description of Manufacturing Process and
Process Controls
-
e.g., tablets via dry or wet granulation
- P.3.4 Controls of Critical Steps and Intermediates
-
Loss on Drying (USP<731>)
Weight Variability
Bulk/Tap Density (dry, USP<616>)
Hardness (compression force)
Blend uniformity
Particle Size (USP<786>)
3.2.P.3 Manufacture: Example for
Solution for Injection
- P.3.3 Description of Manufacturing Process and
Process Controls
-
e.g., asceptic fill
- P.3.4 Controls of Critical Steps and Intermediates
-
pH (USP<791>)
Osmolality (USP<785>)
Bioburden (USP<60>)
Assay
Endotoxin (USP<85>)
3.2.P.4 Control of Excipients
- Same format as Control of Drug Product but
specific for individual excipients used in the
formulation.
3.2.P.5 Control of Drug Product:
Example for Tablets
- P.5.1 Specification(s)
-
-
Label Claim (HPLC)
Dissolution (HPLC, USP<711>)
Friability (USP<1216>)
Moisture (Karl Fischer, USP<921>)
Bisect (HPLC)
Appearance (Visual, Munsell color)
Degradents (HPLC)
Disintegration (USP<701>)
Hardness (USP<1217>)
Content Uniformity (USP<905>)
Residual solvents (USP<467>)
3.2.P.5 Control of Drug Product: Example
for Solution for Injection
- P.5.1 Specification(s)
- Assay (HPLC)
- Appearance (Visual)
- Degradents (HPLC)
- Determination of Volume of Inj in Containers (USP<1>)
- Particulate Matter (USP<788>)
- pH (USP<791>)
- Osmolality (USP<785>)
- Endotoxin (USP<85>)
- Sterility (USP<71>)
3.2.P.5 Control of Drug Product
(cont’)
- P.5.2 Analytical Procedures
-
Actual method details e.g., chromatography column
conditions, gradients, and mobile phases; instrument
settings and detector wavelengths.
- P.5.3 Validation of Analytical Procedures
-
-
Accuracy, Precision, Specificity, Linearity, Range,
Ruggedness, LOD, LOQ.
See ICH Q2
- P.5.5 Characterization of Impurities
-
See ICH Q3
3.2.P.8 Stability
- P.8.1 Stability Summary and Conclusions
-
Typically the same methods listed on the specification
with all the stress conditions that support the
recommended storage condition. Stress conditions
designed following ICH Q1.
- P.8.2 Post-Approval Stability Protocol and
Stability Commitment
-
Typically the same methods listed on the specification
with all the stress conditions that support the
recommended storage condition.
- P.8.3 Stability Data
References
- 21CFR Part 211
- United States Pharmacopeia (USP)
- International Conference on Harmonisation (ICH)
Quality Guidelines
-
Q1 Stability
Q2 Analytical Validation
Q3 Impurities
- FDA Guidance Documents
-
Changes to an Approved NDA or ANDA
INDs for Phase 2 and Phase 3 Studies CMC Infomation
Closing
“It is not enough to do your best; you must know
what to do, and THEN do your best.”
W. Edwards Deming