開發(fā)報批美國FDA的仿制藥與相關(guān)問題探討何平

1、開發(fā)報批美國開發(fā)報批美國fda的仿制藥的仿制藥與相關(guān)問題探討與相關(guān)問題探討藥物制劑藥物制劑目標(biāo)主流市場目標(biāo)主流市場仿制藥研發(fā)團(tuán)隊concept-1 build up a teaminformationformulationproductregulatoryanalyticalbio-pharmaceuticalprojectlegelproduct development roadmap仿制藥的仿制藥的研發(fā)過程研發(fā)過程 quality acceptably low risk of failing to achieve the desired clinical attributes pharma

2、ceutical quality= f drug substance, excipients, manufacturing. qbd product and process performance characteristicsscientifically designed to meet specific objectives, not merely empirically derived from performance of test batcheswhat is qbd (?qbdqbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？what is qbd?qbdqbd在制劑開發(fā)中怎么體現(xiàn)

3、？在制劑開發(fā)中怎么體現(xiàn)？essential elements of qbd definition of the quality target product profilehigh level quality aspects of the product: purity, drug release (dissolution/disintegration time), pharmacokinetic profile, etc. critical quality attributes (cqas) for drug product characteristics of dp which have

4、impact on desired profile conscious attempt to study and control critical process parameters (cpps) identification of material properties and process parameters which haveeffect on product cqas design space: the multidimensional combination and interaction ofinput variables and process parameters th

5、at have been demonstrated to provide assurance of quality identification of a control strategy for critical process parameterswhat is qbd?qbdqbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？raw materialsequipmentenvironmentoperatorsvariable inputs x“l(fā)ocked” process=variable qualityhow did we work in the pastwhat is qbd?qbd

6、qbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？raw materialsequipmentenvironmentoperatorsunderstood variable inputsxunderstood and controlled process=predefined qualityflexible process design spacehow can we work in the futurewhat is qbd?qbdqbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？what is qbd?qbdqbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？raw materialswet

7、 granulationfluid bed dryingblendingcompressionproductdrug substanceexcipientssourceassayimpurities lodps what is qbd?qbdqbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？raw materialswet granulationfluid bed dryingblendingcompressionwaterbindertempspray ratespeedtimep.swhat is qbd?qbdqbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？raw materialsw

8、et granulationfluid bed dryingblendingcompressionwhat is qbd?qbdqbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？raw materialswet granulationfluid bed dryingblendingcompressionair flowtemprhshock cyclep.s.what is qbd?qbdqbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？raw materialswet granulationfluid bed dryingblendingcompressionfill volumerotat

9、ion speedend point (time)blend uniformitydensitiesangle of reposewhat is qbd?qbdqbd在制劑開發(fā)中怎么體現(xiàn)？在制劑開發(fā)中怎么體現(xiàn)？raw materialswet granulationfluid bed dryingblendingcompressionfeed frametoolingpunch penetration depthcompression forcepress speedfeeder speed examples of qbd questions under qbr control of drug

10、 substance what is the drug substance specification? does it include all the critical drug substance attributes that affect the manufacturing and quality of the drug product? (2 pages) drug product what attributes should the drug product possess? (1.5 pages) how were the excipients and their grades

11、selected? how was the final formulation optimized? manufacturing process how are the manufacturing steps (unit operations) related to the drug product quality? how were the critical process parameters identified, monitored, and/or controlled? pharmaceutical development manufacture container closure

12、systemaspectstraditionalqbdpharmaceuticaldevelopmentempirical; univariateexperimentssystematic; multivariateexperimentsmanufacturingprocessfixed; validation on 3 initialfull-scale batches; focus on reproducibilityadjustable within design space; continuous verification;focus on control strategyproces

13、s controlin-process testing for go/nogo; offline analysis w/slow responsepat utilized for feedback &feed forward, real timeproductspecificationprimary means of qualitycontrol; based on batch datapart of the overall qualitycontrol strategy; based ondesired product performancecontrolstrategymainly by

14、intermediate andend product testingrisk-based; controls shiftedupstream; real-time releasereactive to problems &oos; post-approvalcontinuous improvementenabled within design spaceqbdqbd小結(jié)小結(jié)-summary-summary研發(fā)研發(fā)( (高難高難) )仿制藥的一些體仿制藥的一些體會會dissolution profile-體外溶出曲線體外溶出曲線生物等效生物等效(be)結(jié)果結(jié)果auc0-tauc0-infcma

15、xfastratio108.01%108.12%86.26%90% geometric c.i.103.49% to 112.73%103.64% to 112.79%75.28% to 98.84%fedratio111.21%112.48%85.24%90% geometric c.i.104.40% to 118.47%105.78% to 119.60%73.47% to 98.90%summary of in vivo study results of test formulation vs. rld原因調(diào)查原因調(diào)查product p data (log transformed da

16、ta, fast, n-12)ratio of geometric means x 10090% ci of log transformed datacv (%)test a vs referenceauc10690.4; 12322.0cmax10480.1; 13436.4test b vs referenceauc133114; 15522.0cmax129100; 16736.4product p data (log transformed data, fed, n-11)ratio of geometric means x 10090% ci of log transformed d

17、atacv (%)test a vs referenceauc96.175.4; 12332.7cmax10983.5; 14135.3test b vs referenceauc92.472.5; 11832.7cmax10983.7; 14135.3product p data (log transformed data)ratio of geometric means x 10090% ci of log transformed datacv (%)fastauc10293; 11133,9cmax10594.5; 11638.8fedauc98.891.6; 10726.4cmax99.689.2; 11138.4案例研究案例研究-4api is water soluble. prototype formulation was proposed based on in vitro dissolution (