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5. 617.1 2 3 4 pH16.8 pH6.86.FDAGuidance for Industry The Use of
Mechanical Calibration of Dissolution Apparatus 1 and 2 Current
Good Manufacturing Practice (CGMP) January 2010 American Society
for Testing Materials (ASTM)E 2503-07 Standard Practice for
Qualification of Basket
ahttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlnd
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Federation (FIP) White PaperFIP Position Paper on Qualification of
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Hixson-Crowell Kormeyer-Peppas0.6 0.4 0.2 0 0 Slow Mediu Fast m 8
10 12 1 0.8246
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Shao3.1 f1 f2 2AV20128620128612
4. FDAf1 % n 1 | R t T t | f1 = 1 0 0 t= n Rtt =14.f2 % 100 f 2
= 50 log10 1 n 2 1 ( Rt Tt ) n t =1 Rtt Ttt n
201286http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html2012864.
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17 100 166 jiangxm@http://www.wenkuxiazai.com 010-6694 90031391
0834 807 010-6385 067318
2012-08 ,
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html 4570
1998 2004 FDA [2] [1] 19
[3] ;PH UVHPLC -- BE -- -- UVHPLC
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
FODT20
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nm 579.4 A271nm 167.9 A265 nm 4.0, R 2 = 0.9996CTMP = 1421.9 A277
nm 1688.4 A271nm 2637.2 A265 nm 17.2, R 2 = 0.9982 24
(,201802) FODT
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
Abstract The drug dissolution release test is a requirement for
solid dosage form pharmaceutical products. The fiber-optic in-situ
dissolution testing instrument can get real-time dissolution curves
of drugs, and making dissolution analysis a time-consuming and
labor-intensive procedure. This thesis describe the principle of
the instrument, especially how it eliminate the deviation caused by
excipients. And introduce the application of the instrument in drug
testing, use similarity factor f2 to copare two dissoution profiles
got by the fiber-optic in-situ dissolution testing instrument .
Keywords: Dissolution test; fiber-optic; dissolution profiles; f2
USP1970 12 1985 7 -(in vitro in vivo
cohttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlrrelation,
IVIVC)(Bioequivalance)(bioavailability) HPLC [1] [2-16] 1994 25
[17]2006 Fiber-Optic Dissolutiom Test SystemFODT 1 FODT 20 9
FODT 1 1 1.1 FODT FODT
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html 15s 2
FODT 26
1.2 FODT 15s 2 1.3 FODT 1.4 FODT HPLC FODT 2FODT-601 Lamber-Beer
A = ECl [ A: ECl ] A E 3 1 / CCD ,,12 27
3 http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
3.1 FODT 1 X 4 FODT ref Aref=A II III i 1~2 n 1~2 A28
A = A' Aref Aref = AAref =3.2 I II III1 2 Ai n 1FODT 5 2 a b a b
1 A1 1 A1' 1 A1" 1 A1" = A1 A1' 2 A2 ' " 2 A2 2 A2 2 '' ' ' A2 = 0
A2 = A2 A2 = A2 " A1 = A1" kA2 ' k = A2 / A1' '' ' A2 = A2I II
III29
k http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html a
bI A1 " 1 A1" 1 A2 2 bII k 4FODT 1/ / 2 / 3 4f2 4.1 3 30
6 4.2 2000 XD 200ml 0.1mol/L 1000ml1000ml 100 60 10ml 1 200ml
pH5.8 1000ml1000ml 120 10ml2
2mol/http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlL
10ml pH 7.2 180 10ml3 FODT 7 4.3 831
8~12 FODT FODT 8 4.4 32
9 FODT 8 70% - 8 70% - 10
15http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html33
30 70% 45 70% 4.5 F2 FODT F2 F2 F2 a b F2 c abc 11 F2 ab cF2
34
5[1] ,.[J]. , 2006,37(8):550~552. [2] ,,.[J].,2003,15(2): 21~23
[3] Hugo Bohets, Koen Vanhoutte, Roy De Maesschalck, et al.
Development of in situ ion selective sensors for dissolution[J].
Analytica Chimica Atca, 2007, 581:181~191. [4] Karl Peeters, Roy De
Maesschalck, Hugo Bohets, et al. In situ dissolution testing using
potentiometric sensors[J]. European Journal of Pharmaceutical
Sciences,2008,34:243~249. [5]
,,,.[J].http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
,2005,36(2):122~124 [6] Mats Josefson, Erik Johansson, Arne
Torstensson. Optical Fiber Spectrometry in Turbid Solutions by
Multivariate Calibration Applied to Tablet Dissolution
Testing[J].Anal.Chem.1988,60:2666~2671. [7] Paul K.Aldridge,
Leonard J. Kostek.In Situ Fiber Optic Dissolution
Analysis[J].Dissolution Technologies,1995,4:10~11 [8] Li Liu,ifford
Fitzgerald etc.,Technical Evaluation of Fiber-Optic Probe
Dissolution System[J]. Dissolution Technoloies,2008,2:10~20 [9]
Schatz C.,Ulmschneider M.etc.,Readers response: Hollow Shaft
Samplin with Fiber Optics,[J],Dissolution Technologies,2000,1:
Article 4. [10] Xujin Lu, Ruben Lozano, etc.,In-situ Dissolution
Testin Usin Different UV Fiber Optic Probes and
Instruments[J],Dissolution Technologies,2003,11:6~15. [11] Kun Nie,
Li Li,etc.,Monitorin Ambroxol Hydrochloride Sustained-Released
Tablets Release by Fiber-Optic Drug Dissolution In Situ Test
System[J],Dissolution
Tehttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlchnologies.
[12] Casper Schatz,Michel Ulmschneider, etc., Evaluation of the
Rainbow Dynamic Dissolution Montior Semi-automatic Fiber Optic
Tester[J],Dissolution Technologies,2000,Article [13] Kevin Bynum,
Kurt Roinestad,etc., Analytical Performance of a Fiber Optic Probe
Dissolution System[J],Dissolution Technologies,2001,1~8. [14]
Christopher J.Toher,Per E. In situ fiber optic dissolution
monitorin of a vitamin B12 solid dosae formulation[J],Dissolution
Technologies,2003,11:20~25 [15] E.DincC.Serinetc.Dissolution and
assaying of multicomponent tablets by chemometric methoods using
computer-aided spectrophometer.International Journal of
Pharmaceutics 250 (2003)339-350 [16] Paul J.GemperlineJungHwan
ChoDetermination of multicomponent dissolution profiles of
pharmaceutical products by in situ fiber-optic UV measurements.
Analytical Chimica Acta 345 1997155-159. [17] [J]. 22 6
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html35
FDA 13564-260260
chamquest@http://www.wenkuxiazai.comChamQuest121 23IND20-80 ()
100-200 () 102 -103 () NDA ChamQuest 3 ChamQuest 36
, , , , ,NDA vs. ANDAA abbreviated 312 PK Bioequibalence The
generic version must deliver the same amount of active ingredients
into a patients bloodstream in the same amount of time as the
innovator
drug.http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
Same dosage form, strength, route of administration, quality,
performance characteristics and intended use.FDA
ChamQuestChamQuest6identicalFDAidenticalDosage form Strength Route
of administration Safety Efficacy Intended use Quality Performance
characteristicsNDA ANDANDA Well-controlled clinical studies to
demonstrate effectiveness Preclinical and clinical data to show
safety Detailed descriptions of manufacturing and packaging
procedures Proposed labeling referencing all studies from which
statements contained in the package insertANDA Detained
descriptions of the components Data sufficent to assure the
bioavailability or bioequibalence of the drug to be marketed. CMC
is the same as NDA ChamQuestChamQuest7837
International Conference on Harmonization (ICH)ICH brought
together the regulatory
authorihttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlties
of Europe, Japan and the United States to discuss scientific and
technical aspects of product registration ICH developed guidelines
for the Common Technical Document for Registration of
Pharmaceuticals for Human Use (CTD) FDAChamQuest910CTD and eCTD
Informational LinksTo conform to the ICH-CTD format Encouraging all
ANDAs be submitted in the CTD format and preferably electronic CTD
to support Questionbased Review Many guidances currently exist
referencing the CTD format Refer to the CDER Guidance Document web
pageOrganization of the CTD
http://www.fda.gov/cder/guidance/4539O.PDF eCTD Submissions
http://www.fda.gov/cder/guidance/7087rev.pdf Drug Substance
http://www.fda.gov/cder/guidance/3969DFT.pdf Drug Product
http://www.fda.gov/cder/guidance/1215dft.pdf Pharmaceutical
Development http://www.fda.gov/cder/guidance/6746fnl.pdf
CTD-Efficacy http://www.fda.gov/cder/guidance/4539E.pdf
CTD-Qualhttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlityChamQuesthttp://www.fda.gov/cder/guidance/4539Q.PDFChamQuest111238
CTD and eCTD FormatModule 1: Administrative Required for ANDAs
Specific for FDA Regulatory information
and eCTD FormatModule 2: Summaries Required for ANDAs Chemistry
and Bioequivalence Information
.3 Quality Overall Summary (QOS) 2.7 Clinical
Summary-Bioequivalence Studies
and eCTD FormatModule 3: Quality (Chemistry) Required for ANDAs
Drug Substance Drug Product Product Development Regional
Information
and eCTD FormatModule 4: Nonclinical Study Reports Not Required
for ANDAs
[]
CTD and eCTD FormatModule 5: Clinical Study Reports Required for
ANDAs Bioavailability
ahttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlnd
Bioequivalence Studies Formulation BA/BE study reports
Dissolution
3-Quality
.2.S.1 General Information (Drug Substance)Nomenclature
Structure General Properties
.2.S Drug Substance
[]
3.2.S.2 Manufacture (Drug Substance)Name and full address of
facilities Helpful to provide summary table of all facilities
(contacts, addresses, phone/fax numbers, etc., CFN#, etc.) Specific
functions performed
.2.S.4 Control of Drug SubstanceTesting specifications Spectra
and chromatograms Sample statement Samples of drug substance will
be submitted upon request from FDA in accord with 21 CFR
314.50(e)(i)
or Responsibility Type II DMF number for API Note DMF for Active
Phahttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlrmaceutical
Ingredients must be stamped received by the Agency prior to
submission of an ANDA that relies upon said DMF
of Analysis (COA) API supplier Applicant
.2.P.1 Description and Composition of the Drug ProductUnit
composition of the proposed product Inactive ingredients and
amounts are appropriate per IIG
.2.P Drug Product
[]
Components and Composition of the Drug P
Use of inactive ingredients that have not been previously
approved or that are being used at a higher level than previously
approved is the most prevalent RTR (Recall Termination
Recommendation) issue. RSB (Review Support Branch) needs a complete
breakdown of all components used in the proposed formulation. This
incluhttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmldes
flavors and colors that may contain proprietary information.
Suggestion: If you know that your firm is proposing to use a
flavor/color that has not been previously approved ask your vendor
to fax a copy of the formulation to OGD at (301) 443-3847. Have the
vendor request that FDA evaluate the formulation and its use at XXX
mg. The request will be assigned a control number which your firm
may cite in its submission as proof that the ChamQuest proposed
level is acceptable. 25
and Composition of the Drug Product (Cont.)OGD will not consider
GRAS (generally recognized safe) status conclusive evidence that an
excipient may be used in a drug product at a given level.
Furthermore, use of an excipient in food products will not persuade
FDA to allow its use in drug products. Exception Excipients: minor
changes in formulation of a drug product for which an applicant may
seek approval. Parenterals:
314.94(a)http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html(9)(iii):
changes in preservative, buffer and antioxidant Ophthalmic/Otic:
314.94(a)(9)(iv): changes in preservative, buffer, substance to
adjust tonicity and thickening agent Topical Use: 314.94(a)(9)(v):
changes are not specified by the Regulations Note the use of pH
adjusters in parenterals is not an ChamQuest exception
excipient
.2.P.2 Pharmaceutical DevelopmentThe Pharmaceutical Development
section should contain information on the development studies
conducted to establish that the dosage form, the formulation,
manufacturing process, container closure system, microbiological
attributes and usage instructions are appropriate for the purpose
specified in the application. See the Guidance for Industry; Q8
Pharmaceutical Development Quality by Design (QbD)
PD QTPP (quality target product profile related to safety and
efficacy),CQA (critical quality
attrihttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlbutes)
Critical quality attributes of API, excipients, etc and type and
amount
[]
Achieving Process Understanding
by Design
Space
Q8
Space Knowledge Space30
.2.P.3 Manufacture (Drug Product)Name and full address of
facility This section includes manufacturers of drug product as
well as outside contract testing labs Please provide a summary
table of all lab addresses, contacts, and specific functions
performed
.2.P.3.2 Batch Formula (Drug Product)A batch formula should be
provided that includes a list of all components
the dosage form to be used in the manufacturing process, their
amounts on a per batch basis, including overages and a reference to
their quality standards.
://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmltion or
Responsibility Provide a detailed description of outside firms
responsibilities and functions. All firms performing any testing,
packaging, sterilization, etc. of the finished drug product and/or
active pharmaceutical ingredient must be identified so that a
request may be initiated for inspection
Certification Certification should include signature
[]
3.2.P.3.3 Description of Manufacturing Process and Process
Controls (Drug Product)A flow diagram should be presented giving
the steps of the process and showing where materials enter the
process Blank Master Production Batch Records Firms may request a
maximum production scale-up of 10X the Theoretical yield of the
exhibit batch
.2.P.3.3 Description of Manufacturing Process and Process
Controls (Cont.) (Drug Product)Reprocessing Statement Firm
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlshould
certify that it does not utilize reprocessing procedures in the
manufacture on the drug product. If the firm does wish to reprocess
the drug product they will submit a Prior Approval Supplement to
the Agency describing the process. Release of the reprocessed
product will be withheld until the PAS is approved by the
Agency
.2.P.3.4 Controls of Critical Steps and Intermediates (Drug
Product)All critical process controls and their associated numeric
ranges, limits, or acceptance criteria should be identified and
justified and a brief description of the test provided
.2.P.3.5 Process Validation and/or Evaluation (Drug
Product)Description, documentation, and results of the validation
and/or evaluation should be provided for critical steps or critical
assays used in the manufacturing process Microbiological
sterilization
validatihttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlon
Filter validation
have complete filter validation present upon submission of an
ANDA, this information may not be submitted at a later date
[]
3.2.P.4 Controls of Excipients (Inactive Ingredients)Identify
source of supplier for all inactive ingredients It is helpful if
the applicant provides a table indicating the source of all active
and inactive ingredients
.2.P.4 Controls of Excipients Inactive Ingredients
.2.P.4.1 Specifications (Inactive Ingredients)Testing
Specifications Suppliers COA Minimally OGD needs the COA,
specifications and test results from the drug substance
manufacturer and the applicants COA. We also like to have the
applicants testing specifications and data from the drug
producthttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
manufacturers 3.2.P.4.4
.2.P.4.2 Analytical Procedures (Inactive Ingredients)Analytical
procedures used for testing the excipients should be provided, when
appropriate
[]
3.2.P.4.3 Validation of Analytical Procedures (Inactive
Ingredients)Submission of validation information in the application
is normally not needed for excipients Validation information should
be submitted if there are special circumstances Characteristic of
the excipient or the excipient itself is critical to product
quality
.2.P.4.4 Justification of Specifications (Inactive
Ingredients)Applicants Certificate of Analysis Pharm/Tox studies
can be submitted in this section when appropriate to justify the
safety of an inactive ingredient Other justification of inactive
ingredients (IIG database, etc.)
://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlpar
.2.P.5 Controls of Drug Product3.2.P.5.1 Specification (s)
.2.P.5 Controls of Drug Product (Cont.)3.2.P.5.4 Batch Analysis
COA for Finished Dosage Form needed for each executed batch
.2.P.5.2 Analytical Procedures
.2.P.5.3 Validation of Analytical Procedures Sample
Statement-Sample drug product will be submitted upon request from
FDA in accord with 21 CFR 314.50(e)(i)
.2.P.5.5 Characterization of Impurities List all expected
impurities Identification of impurities
.2.P.5.6 Justification of Specifications Pharm/Tox studies can
be submitted in this section when appropriate to justify the safety
of an impurity
[]
3.2.P.7 Container Closure System1. Summary of Container/Closure
System (if new
rehttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlsin,
provide data) 2. Components Specification and Test Data 3.
Packaging Configuration and Sizes RSB is looking for engineers
drawings with exact dimensions and specifications of all components
of the Container/Closure system. This should be provided for all
dosage unit sizes.
.2.P.8.1 Stability Summary and ConclusionStability Protocol
Proposed expiration dating period Firm may propose a tentative 24
month expiration date based upon 3 months of accelerated
stability
. Container/Closure Testing 5. Source of supply and suppliers
address
.2.P.8.2 Post-approval Stability Protocol and Stability
CommitmentPost Approval Stability Protocols and Commitments Post
Approval Commitments: Firm must commit to placing first three
production lots as packaged in the largest and smallest container
on long term stability. Each year
therehttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlafter
a minimum of one lot packaged in the largest and smallest container
will be added to long term stability. Firm must report this
stability data as it becomes available (in periodic reports)
.2.P.8.3 Stability DataData from four time points should be
submitted - 0, 1, 2, and 3 months Must submit 3 months of
accelerated stability conducted under stressed conditions of 40C
and 75% relative humidity This data should be provided even if the
product fails under stressed conditions. RSB will file an ANDA with
failing accelera
stability but may not file an ANDA if only unstressed stability
is provided. If a firm is utilizing the same container closure
system for multiple package amounts/sizes then a firm may bracket
intermediate package amount/sizes and only perform stability on the
largest and smallest package amount/sizes. ChamQuest Batch number
must be the same as the exhibit batch 48
://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlpar
[]
3.2.R Drug SubstanceExecuted batch records for drug substance
(if available) Comparability Protocols (optional) (See Drug
Substance Guidance)
.2.R Regional Information
Used to demonstrate the lack of adverse effect for specified
types of post approval manufacturing changes
Validation Package 3 copies needed for paper submission
.2.R Drug ProductExecuted batch records for drug product Solid
Oral Dosage Forms: Exhibit Batch must be a minimum of 100,000 units
or 10% of the proposed production batch Must completely package the
exhibit batch in containers proposed for marketing
.2.R Drug Product (Cont.)Information on Components (See Drug
Product Guidance) Manufacturer information Function of contract
facilities COA (s)
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlParenteral
Products: Must package a minimum of 10% of the exhibit bulk in each
vial size (container) proposed for marketing Scale-up should be
based upon actual packaged amounts
Protocols (optional) Used to demonstrate the lack of adverse
effect for specified types of post approval manufacturing
changes
For all dosage forms you must provide a complete reconciliation
detailing the disposition of all dosage units Very helpful to
provide a reconciliation summary table and list in Table of
Contents
Validation Package 3 copies needed for paper submission
[]
ANDA
for ANDA CMC Sometimes assay methodology is not specified into
the monograph for older drugs or method described is not specific.
In such cases, FOI request to FDA for a copy of
phttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlertinent
regulatory assay method Carefully evaluate impurity peaks observed
in a suppliers bulk substance and compare them with those observed
in the marketed products. The extent that the peaks differ may
determine the need to obtain further information, including
toxicity. If samples of impurities, degradation products are
available from the supplier or are identified in published
literature then the assay methods should be appropriately validated
by the ANDA sponsor for their sensitivities and specifications with
respect to them. It is also recommended that the sponsor of an ANDA
set up and maitain a stability program for the bulk drug ChamQuest
substance
expiration dates: The FDA will tentatively approve a two year
expiration date for a product if satisfactory data r
at least three months storage under accelerated conditions is
submitthttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmled.
The sponsor is also expected to provide a commitment to continue to
monitor the stability of the product periodically report the
results to FDA, and to remove from market any batches failing to
meet specifications prior to products labeled expiration period.
Final approval for the expiration date is obtained when acceptable
shelflife date for two years on more than one production lot is
made available to FDA
[]
bloodstream
=
[]
/
() pKa (v. pH), Log P (v.
pH)http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html:()
Aspirin (Acetyl salicylic acid): Analgesic: A: Carboxylic acid,,
pKa 3.5 B: Phenolic ester,.: 52(pH 7.0/25oC), 40 (pH 2.5/25oC).:
estersis greater than the rate. aspirin.: Octanol/water=631A COOH B
O C O Aspirin
: Local anesthetic:
: Tertiary aliphatic amine, pKa 9.0 B: Ester, neutral C:
Aromatic amine, pKa= 2: 26 (pH 7.0/37oC): Procaine,..
3
H2N
B COOCH2CH2 N(C2H5)2 H2 N COOH HOCH2CH 2N(C 2H5 )2
O C O CH3
/ OH-
OH CH3COOH
N
CH2 N(C2H 5)2
/ OH-
[]
IbuprofenCH3 CH3CHCH2 Ibuprofen CH3 CHCOOH pKa= 4.4 CH3 CH3CHCH
2 Ionized form CH3 CHCOO
NMR, 1H, 13C MS (electrospray/ MW) IR CHN
: non-steroidal
anti-inflammahttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmltory
(NSAID): benzylic carboxylic acid
4.41 (computation),4.5-4.6 (potentiometric titation) Solubility:
50 to 300 mg/mL in water at pH> 6 0.02 mg/mL in water at pH<
4 Log P octanol/water: 3.8 (pH 1-3) to0.3 (pH
9-13).:4-isobutylacetophenone (results from oxidative
decarboxylation) 2-(4-isobutyrylphenyl)-propionic acid.
.IR HPLC.
pH (s)= 50% pHpKa, 10:1HA Ka H AKa=[H ][A-][HA]
aspirin (pKa 3.5)NaOH:
[A-] pH= pKa log[HA]Henderson-Hasselbach Equation
[]
:pKa, :, pKa pH (esters, amides)
CHOCH2CH2N(CH3)2 pKa= 9.0 Diphenhydramine Inonized Form
CHOCH2CH2NH(CH3)2
pH, pKa, pI
CH3 CHCOO
HPLC:/,,
(http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html)
HPLC
CH3CHCH2 Ibuprofen
CHCOOH pKa= 4.4
CH3CHCH2 Ionized form
(v. pH) 0.1 N HCl (pH 1.2) Acetate (pH 4.1) Phosphate (pH 6, 7,
8)
Log P= log[drug]octanol[drug]water : UVHPLC1:1octanol:water.,pH
Log P>1,
Ethanol, methanol, chloroform, acetone
(Tween, sodium lauryl sulfate) : UV, HPLC
HPLC
[]
BCS Class 1:, Class 2:, Class 3:, Class 4:,:250 mL: 1 mg/mL 100
mg 250 mg 250 mL, (100 mg dose< 250 mL)
,,,,,
?
,:,,:,,
(,,)(Decahttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlrboxylation),,(Apparent
Degradation) (recovery)
HPLC (,CE, GC, TLC)
[]
Aspirin (acetylsalicylic acid) Benzyl alcohol to aldehyde to
acidA COOHHO O HO
O C O
O
acid
COOH O C OO O
3
/ OH-
OH CH3COOH
Oxidation combined with
Ibuprofen to 4-isobutylacetophenone
acid
acid
ibuprofen 4'-Isobutylacetophenone
()
(,,, ICH,) (ANDA)
,, (ICH Q1B),
ICH (25C (15-30C) (5C) (-20C) Environment 25C/60%RH
40C/75%http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlRH
30C/65%RH Initial X X X 3 mo X X (X) 6 mo X X (X) (X) (X) 9 mo X 12
mo X 18 mo X 24 mo X 36 mo X
[]
16 14
v. CN
= 0.9753
Selectivity is too similar
10 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10
,
:
Selectivity is different (same column, same gradient, pH 2.5 and
7.5)6 3 .0 0 6 2 .5 0 6 2 .0 0 6 1 .5 0 6 1 .0 0 6 0 .5 0 6 0 .0 0
5 9 .5 0
() (HPLC, GC, TLC) :,,,, (,) () (HPLC, GC, XC-MS): ( HPLC) (GC
or LOD)/ () (XRD, melting point, IR, NIR, Raman),,,
pH 2.5 v. 7.5mV
9 .0 0 5 8 .5 0 5 8 .0 0 5 7 .5 0
50 pH 7.5 40 30 20 10 0 23 25 31.5 pH 2.5
7 .0 0 5 6 .5 0
=
0.0754http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
6 .0 0 5 5 .5 0 5 5 .0 0 5 4 .5 0 5 4 .0 0 5 3 .5 0 5 3 .0 0 5 2
.5 0 5 2 .0 0 5 1 .5 0 5 1 .0 0 4 .0 0 6 .0 0 8 .0 0 1 0 . 0 0 1 2
.0 0 1 4 .0 0 1 6 .0 0 1 8 . 0 0 2 0 . 0 0 2 2 .0 0 2 4 .0 0 M in u
t e s 2 6 .0 0 2 8 . 0 0 3 0 . 0 0 3 2 .0 0 3 4 .0 0 3 6 . 0 0 3 8
. 0 0 4 0 .0 0 4 2 .0 0
0 .0 0
9 .5 0
9 .0 0
8 .5 0
8 .0 0
7 .5 0
7 .0 0
6 .5 0 mV
6 .0 0
5 .5 0
5 .0 0
4 .5 0
4 .0 0
3 .5 0
3 .0 0
2 .5 0
2 .0 0 4 .0 0 6 .0 0 8 .0 0 1 0 .0 0 1 2. 0 0 1 4 .0 0 1 6 .0 0
1 8 .0 0 2 0. 0 0 2 2 .0 0 2 4 .0 0 2 6 .0 0 2 8 .0 0 M in u t e s
3 0 .0 0 3 2 .0 0 3 4 .0 0 3 6 .0 0 3 8 .0 0 4 0 .0 0 4 2 .0 0 4 4
.0 0 4 6 .0 0 4 8 .0 0 5 0 .0 0
[]
ICH Q3B(R2):()
Q3A
(API)://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlr
():: Q3C(R3):: Class 1: Class 2: Class 3: (
5000 ppm)
A NMT 0.5% B NMT 0.2% NMT 0.10% NMT 1.0%
API HPLC ICH Q3A (0.03-0.05%) /
:,,, HPLC HPLC HPLC CE , Karl Fischer LOD ,,
(,,,,,)
[]
(API)()(ICH Q6A)
():
()
List of Tests
(CQAs) (,) ()
ICH Q6A:(). :cGMP
5
://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlpar
[]
ICH Q6A, ppb ( 50 mg/day) e.g. ethanol, acetone
[]
. () (,)
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 6, p. 1451,
JUNE 2007
(SEM)
Effect of a few large particles
of a few large particles
[]
: : (Noyes-Whithey),
:
Where: D= diffusion coeff. A= surface area C= conc in medium Cs=
conc in diffusion layer A= diffusion layer thickness
://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlon Rate=
(D)(L) ( Cs C) L
?
(CU) API,
()
?
, MP (DSC), TGA, x-ray diffraction: API??
X-ray diffraction (XRD, PXRD)x-ray
Scanning Calorimetry (~2-3 mg). (endotherm) (exotherm) (endo)
(endo)(exo)(endo) (endo), (endo) (endo)
DSC, Differential Scanning Calorimetry TGA,,Thermogravimetric
Analysis (IR, MS)
Moisture sorption/desorption isotherms
:,,,
QC:()
[]
QC DSC x-ray IR NIR Raman
NIR
I : I, 135C,, 2 mg/mL II,110C,, III,90C,
://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlparPowder
X-Ray Diffraction
Form I Form I Form I
[]
2 : I form, 185C,, 2 mg/mL, II,50 mg/mL,
API GMP
Form IAPI API
: API: :100% Powder x-ray diffractionx-ray
,
,, GMPs, USP, ICH,, ROI
USP/Ph.Eur.,?,,
:
Form
,,
[]
API (,,)Define
Design Understand
(,,)
/, http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
,
CQAs,:, () ()
Control Monitor 61
QC
(ICH Q3B(R))
,
(GMPs) () ()
[]
(,) (
)
65
(Parabens, benzoic acid) (Butlyated hydroxy toluene) (form)
/alkalizing agents Propellants Glidants Antifoaming agents
Antimicrobials Antioxidants Buffers Chelating agents Coating agents
Colors Emulsifiers Flavors
Plasticizers Polymer membrane Solvents Sorbants Suspending
ahttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlgents
Sweetening agents Binders, diluents (solids) Disintegrant Lubricant
Wetting agents66
,
B (drug product)
[]
[] HPLC
.03.05% 0.05.1% HPLC-UV DAD, MS
0.1.2% HPLC-UV and MS match NMR, CHN Reference std
.1.0%
, calorimetry: API 1 API,,,
>0.2.0%
??70
: Define
USP: 71 2 3 4 5 6 7 USP Apparatus Rotating Basket Paddle
Reciprocating Cylinder Flow-through cell Paddle Over Disc Cylinder
Reciprocating
Holhttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlder
Application* Solid Dosage Forms Solid Dosage Forms Solid Dosage
Forms Solid Dosage Forms; Transdermal Transdermal Transdermal Solid
Dosage Forms
, ,:
Understand
, (,, HPLC)
Control Monitor
QC71
*Modified from EP
,2,5,6
[]
:Distribution Elimination (Metabolism/ (/ Excretion))
MR- IVIVC/
: W.E Brown, inPharmace
Dissolution Testing, ed. J. Dressman and J. Kramer, Taylor and
Francis, New York, (2005), p 86.
(1) (BCS) Class I Class II:>90% Surrogate in vitro models
CaCo2 Cells Isolated gut
seghttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlments
500-1000 mL (900 mL)
In vitro/in vivo (IVIVC)QC ERIRGIIVIVC ( BCS Class 2)
Sink(): 37.0 0.5 oC
III
IV
:250mL (pH 1-7.5, 37 1 oC)
0.1 N HCl (simulated gastric fluid - SGF) pH 6.8 (simulated
intestinal fluid - SIF)) See: FDA Guidance on Dissolution Testing
for Immediate Release Solid Oral Dosage Forms and USP General
Chapter
[]
(2) (IR) (,) BCS Class 1: 0.1 N HCl or pH 6.8 if acid labile
(IVIVC) BCS Class 2: As BCS Class 1, (IVIVC) BCS Class 3: As BCS
Class 2 (IVIVC) BCS Class 4: As BCS Class 3 ()
(3) (DR)2
(enterhttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlic)0.1
N HCl (pH 1.2)pH 6.8
Extended (ER) Products,( 12-24)
USP
for Delayed Release Products (General Chapter)
:Parameter (min) Setting 2(Paddle) 900 mL a) Phosphate Buffer
(pH 6.8) b) 0.01 N HCl 37.5 0.5 oC 50 rpm 0, 5, 10, 15, 30, 45 (90
and 120)
: IR
(BCS 1 and 3) (FDA Guidance) (BCS 2 and 4) (FDA Guidance)
. Klein et al.Development of Dissolution Tests on the Basis of
Gastrointestinal Physiology"InPharmaceutical Dissolution Testing J.
Dressman and J. Kramer (eds), Taylor and Francis, (2005), p.
200a
:5% to 10%2 IR: 30Q= 80%80
[]
(IR) S1 6* Q 5%
:(ER)
://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlar6
(S1 S2)Q,Q-1
%
of 24 (S1 S2 S3)Q, 2 Q-15%,Q-25% *Q 12
and FDA3 IVIVC 10%
(ER) L1 L2 6 6* 12 (L1 L2);10%10% 24(L1 L2 L3),;
24210%;24210%20%20%
[]
(CQA), ()
/
(?) ,
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
85 86
(CFR 211.137)() API
NDA/MAA
FDA
[]
,,
: 3(Q1A(R2)) (Q1A(R2)) (Q1A(R2)/Q1B) (Q1A(
)/Q1B) (Q1A(R2)/Q1B) (Q1D)
(Q1A(R2)) (Q1E)(Q1E/Q3A-C/Q6A) (Q1E/Q3A-C/Q6A)
(ICH Q1A(R2)) SelectionofBatches DrugProduct
Threeperstrengthandcontainer closuresystem(twoatpilotscale
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html0;
labscale) ManufacturingProcess Representativeofcommercialprocess
Specification Basedonmostrelevantclinicalbatches Containerclosure
Sameasproposedcommercialproduct TestingIntervals Long:0,3,6,9,12,
24monthsandthenannually Intermediate:Hold*
Accelerated:Atleastthreepointupto6months AmountofData
Twelvemonthsatlongcondition,pluseithersixmonths
atacceleratedandatleastsixmonthsatintermediate conditions
Postapproval Threefullproductionusingthesameprotocols
commitment&http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html#160;
*Significantchangeatacceleratedconditionstriggerstestingofintermediatesamples
API ThreeatPilotScale
(ICH Q1B)
Product Onebatch ExposedProduct,plus
Immediateclosure,ifnecessary,plus Finalmarketingpack,ifnecessary
ManufacturingProcess Representativeofcommercialprocess
Specification SignificantchangesasdefinedinQ1B LightSource
Option1:SourcesimilartoD65(ISO10977)
Option2:FluorescentlampsimilartoISO10977plusnearUV Exposure
1.2millionluxhourstotalandNLT200watthours/sqhttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html.mofnearUV
Postapproval None commitment SelectionofBatches Container Onebatch
Exposed
[]
(ICH Q1A(R2)
Storage Condition
StudyConditions (oC/%RH) 25/60or30/65 30/65 40/75 5/ambient
25/600/ambient
Temperature Refregirator Freezer
Term Intermediate Accelerated LongTerm Accelerated LongTerm
Submission Requirements(3 batches) 12months 6months 6months
12months 6months 12months
50C
/:-20http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html86;
25C,/:5C to 40C,
25/60% RH,
(ICH Q1A (R2)
tomeetspcification
%decreaseinpotencyfroinitialvalue
Anyspecifiedimpurityfailingtomeetingacceptancecriteria
Failuretomeetacceptancecriteriaforappearanceandph
DrugProduct properties pHexceedsitsacceptancecriteria,and
Dissolutionfailsacceptancecriteriafor12dosageunits
[]
(Q1D) :
5,http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html 10,
25 mg:5 and 25 mg strengthsStrength Batch 1 BottleCount 30 T 90 H
250 T T=Test;H=Hold
5mg 2 T H T 10mg 2 H H H H H H 1 25mg 2 T H T
T H T
: 30, 90, 250: 30 and 250 (.)
H H H
T H T
T H T
(Q1D)
(ICH Q1E) :/
,
12,,
3http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html,
95%
Regulatory Requirements,299
[]
110 105 (%) 100 95 90 Lower 95% CI Upper 95% CI
: :
?,,,,
:?
QC!! 0 3 6 9 12 18 () 24 36101 102
[]
()()
Drug Master File (DMF) API GMP(form& purity)
Summary of Basis of Approval (SBA) for the innovator drug
product NDA Tchnical literature in numerous medicinal
chemistryhttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html
and analytical chemistry journals A current analytical method used
by the API manufacturerAPI Preliminary API specifications for
release of the API Support the formulation pharmacist in developing
the dosage form for an ANDA filing.
[]
API(placebo)
Id,
API Identity Potency Purity Overall quality
1.
.
.
[]
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html 1.
2. 3. 4. 5.exclucivity
API
API API API Common compendial: water content, residue on
ignition, melting point, specific rotation, crytallinity, heavy
metas, pH, sulfide, etc. Id, assay,chromatographic purity Organic
volatiles, residual solvents ChamQuest Particle size, polymorph
Chromatographic Purity Mostly RP HPLC Method development
experience and skill critical Often more challenge than assay
method Desired sensitivity and selectivity for separating all
impurities at 0.05% level Particularly separating structural
isomer
optical isomers of actives
process testingIn-process testing objective: To control
manufacturing process
on drying or K-F water
cohttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlntent
To control moisture in dying process
solvent To control RS in blend guanules
Sometimes, semi-quantitative TLC is used.
(shared method, diff in sample prep) Blend uniformity (granules)
Content uniformity (finished dosage form) Assay
Sovents Mostly GC Headspace or direct injection Capillary GC
column
[]
Finished Product Formulation Dissolution profile Stability ID
Assay Content U Chromatographic Purity Dissolution/Disintegration
Hardness/Friability Formulation identity Dissolution screening
Product releaseAdditionally Cleaning test Absence of actives in
placeboChamQuestChamQuest1314()Specificity) (,),
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html HPLC
HPLC Normal phase Reverse phase Ion Chromatography Chiral Ion
Pairing pH Flow rate Column temp Chiral , . HPLC , .
ChamQuestChamQuest151679
HPLC Sensitivity Dynamic range Isocratic vs
gradientChromatographic Purity Sensitivity Reporting threshold Low
strength dosage CriticalWithout out a good sample prep, no matter
now good is a chromatographic procedure Solid Dosage Drug delivery
systemStability Indicating Method Specificity Forced degradation
Combo drugSample Prep Solid dosage ok Delivery system
challengingChamQuestChamQuest1718:API Solid State
Degrahttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmldation()
Solution Degradation()API : ( 20%) : 70C 3 : 70C/75%RH 3 : Suntest
XLS Xenon arc 765W/m2 at 72F 5, 24 (3xICH guideline)Finished
Product() Common Degradation Pathways:() Acid Hydrolysis () Base
Hydrolysis () Temperature () Photolysis () Oxidation () : 70C
300psi 37 Initiated : 32mg API 7 g initiator (AIBN) 70C 300psi
13ChamQuestChamQuest192080
API ) 7(For up to 7 days): Water 50C Acid 0.1N HCl in water, 50C
pH 2.0 Citrate buffer, 50C pH 4.0 Citrate buffer, 50C pH 6.0
Citrate buffer, 50C pH 8.0 Borate buffer, 50C pH 10.0 Borate
buffer, 50C Base (0.1N NaOH in water 50C) Fluorescent light (in
water RT) Oxidation 3.0%H2O2 in water, 50C Polyethylene Glycol 400
0.5% Methocel
soluthttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlion
in water 20% HPBCD in H2O(Chromatograms of Solution Stressed
Samples)Water solution, 50oC for 7 daysDAD1 A, Sig=220,20
Ref=360,100 (C:I280402-0201.D) mAU 3000 17.892 15.339
18.43225002000150010005000051011.702152020.911 21.2852529.112
304.8213540min0.1 N NaOH solution,DAD1 A, Sig=220,20 Ref=360,100
(C:I280403-0301.D) mAU 300050oC17.898for 7
days25002000150010004.880ChamQuest15.325500ChamQuest24.481 25.082
17.041 17.308 11.675 14.116 14.432 5.220 6.583 7.217 20.920 10 15
2021005222529.105 3018.4323540min(Stress Studies for Drug Product)
15% ( 90-110%) (Specificity)(stability testing) , LC-PDA (peak
purity).Solid Dosage Form Stressing Strategy(JNJ)Stressing Category
Experimental Condition Maximum
Sthttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlressing
DurationAcid / BaseExcipients and/or production steps should be
evaluated to decide if acid/base stressing is necessary. In
general, acid/base stressing of solid dosage forms is not
preferred.OxidativeNot necessary for open dish experiments. For
cases where open dish experiments are not possible, stressing under
an enriched oxygen atmosphere is suggested. In such cases, stress
the DP in a closed container having a headspace enriched with
oxygen and at an elevated temperature (see thermal stressing
experimental conditions and duration).Photostability 1 and 2 ICH
(Option 1 or 2)NA 2 weeks 70 or 80C * 8 weeks 60C 8 weeks 50C 8
weeks 40C 2 weeks 70 or 80C */ >65% 8 weeks 60C/>65% 8 weeks
50C/>65% 8 weeks
40C/>65%ThermalThermal/HumidityChamQuestChamQuest232481
/Solutions/Suspensions/CreamsSthttp://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.htmlressing
Strategy (JNJ)Stressing Category Experimental ConditionOption 1:
Formulation samples prepared at 2 pH units below the marketed pH @
50C* Acid Option 2: 0.01N 0.1 N HCl @ 50C* Add acid solution to
sample, mix well and place in oven. Add up to 10% (v/v) for
solutions and 10% (w/w) for suspensions/creams Option 1:
Formulation samples prepared at 2 pH units above the marketed pH @
50C* Base Option 2: 0.01N 0.1 N NaOH @ 50C* Add base solution to
sample, mix well and place in oven. Add up to 10% (v/v) for
solutions and 10% (w/w) for suspensions/creams Enriched Oxygen
Atmosphere** / 70 or 80C*** Oxidative Enriched Oxygen Atmosphere**/
60C Enriched Oxygen Atmosphere **/ 50C Enriched Oxygen Atmosphere
**/ 40C Photostability 1 and 2 ICH Option 1 or 2 70 or 80C ***
Thermal 60C 8 weeks 50C 8 weeks 40C Thermal/Humidity 2 weeks 8
weeks 2 weeks
http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html8 weeks
8 weeks 8 weeks NA 1 week(Orthogonality)Maximum Stressing Duration1
week1 week// / / LC-UV LC-MS CE GC1 week Reverse Phase, Normal
Phase, IC, etc Reverse Phase: C18, Phenyl-,NH2-, PDA
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too high to permit accurate measurementSpecial Case: IR tablet,
drug cannot be detected accurately in plasma Alendronate Sodium
tablets, available in strengths of 5, 10, 35, 40, 70 mg Problems
with plasma detection because of low concentrations and
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requests- single-dose fasting study on the 70 mg strength;
measurement of alendronate in urine - FDA will consider granting
bio-waivers on the lower strengths23BE Approaches:Pharmacodynamic
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otic or ophthalmic solution Must contain the same active and
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the active ingredient Example: Prednisolone sodium phosphate oral
solution To document BE, FDA requests composition data on the
generic product Generic composition can be different from RLD
composition (within certain limit) Inactive ingredients should not
have safety issuesBiowaivers Solid oral dosage forms Set forth in
21 CFR320.22(d)(2) Acceptable in vivo BE must be established for
one strength (generally the highest strength) Dissolution testing
on all strengths must be acceptable Strengths must be
proportionally similar to the bio-strength For safety reasons, OGD
may request an in vivostudy on a lower strength, and grant
biowaiver(s) on higher strength(s) Example: Terazosin Hydrochloride
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FDA
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rangeSpecial Case: ER Tablet, all strengths proportional Alprazolam
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requests Single-dose fasting and fed BE studies on the 3 mg
strength Acceptable dissolution testing in at least 3 media on all
strengths FDA will consider granting biowaivers for all lower
strengthsHighly permeableCan be established by in vivo or in vitro
methodsRapidly dissolvingAt 0.1N HCl (pH 1.2), pH 4.5, and pH 6.8
buffers; 900 mL, using paddles at 50 rpm or basket at 100 rpm
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pH http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html1.2,
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Frontage China Operations Special Case: DR Capsule, all
strengths not proportional Omeprazole DR capsules, available in 10,
20, and 40 mg strengths The 20 and 40 mg strengths are not
proportionally similar The label recommends opening capsule and
sprinkling on applesauce FDA requests the following for omeprazole
DR capsules- Single-dose fasting and fed in vivo BE studies on the
40 mg strength - A single-dose fasting BE study on the 20 mg
strength - A sprinkled fasting study on the 40 mg strength - FDA
will consider granting biowaiver for the10 mg strength16Frontage
China OperationsBio-analytical, pharmaceutical/tox, in Shanghai
Clinical Center (phase I unit 120 beds) in Zhengzhou Clinical
Center (phase I of 68 beds) in Changchun formulation, CMC, GMP
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BE for SFDA registration or US ANDA First in Human single and
multiple ascending dose Absolute and Relative BA PK/PD studies Drug
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2011http://www.wenkuxiazai.com/doc/cedce2de7f1922791688e8ca.html60;TrialVersion)
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GMP/GLP/GCPCORPORATEOVERVIEW15CORPORATEOVERVIEW166
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