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Insight into Generic Pharmaceutical Product Development and Manufacturing


Insight g into Generic Pharmaceutical Product Development and Manufacturing
Presented by Ling g Ye Chao Ye March 7 – 8, 2009
March 7 - 8, 2009 1

Self introduction
?

? Where were you born and grew up? Where do you work now and what are your j responsibilities? p major Tell us something that you did which most likely no body here knows before and of which you were proud proud.

?

March 7 - 8, 2009

2

Learning g Objectives j

March 7 - 8, 2009

3

Course Outline
I. I II. III III. IV. V. VI VI. VII. VIII.
March 7 - 8, 2009

Self Introduction Overview API Case Study y1 Finished Product Case Study 2 Summary Evaluation
4

II. Overview
Definition of generic pharmaceuticals Trends in generic pharmaceutical industry Opportunities for China Challenges for Chinese companies Beyond generic

March 7 - 8, 2009

5

What is a generic drug?
?
– – – – – – –

Identical or bioequivalent to a brand name drug in
Dosage form S f t Safety Strength Route of administration Quality y Performance characteristics Intended use

?
– –

Less costly to produce
No costly drug discovery Reduced cost for animal and human clinical studies for safety and efficacy

?
– –

Typically sold at substantial discounts from the branded price
Save estimated $8 to $10 billion a year at retail pharmacies in the US More savings at hospitals

?

Can be sold after patents and other exclusivities expire

March 7 - 8, 2009

6

A life cycle flow chart for Generics
Product definition
Business strategy
?Growth strategy ?Market segments ?Therapeutic area ?Technical and business capabilities ?Product Product life cycle management

P t t search Patent h
?Orange Book listing ?Process and other patents ?Challenging the patents ?Licensing

M k t research Market h
?Current & potential markets ?Current & potential players ?Market segmentation ?Profit margin expected

Manufacturing

QC/QA
?Structure characterization ?Method devel. & val. ?Impurity profiling ?Stability testing

Secure API

?Process development Process scale up ?Process ?Process validation

Regulatory
?Technical package ?DMF/COS/SFDA

Marketing

API sourcing
?Vendor screening & selection

Dosage Manufacturing

Product development
?Formulation development ?Packaging & labeling ?Process development ?Quality Quality by design

QC/QA
?Method devel. & val. ?Technology transfer ?Process validation

Registration batch
?Stability testing ?Product expiry dating

Regulatory submission sub ss o

Submission package
?CTD – QOS, QbR ?Module III

PAI
?Manufacturing plants ?R&D labs ?API API man manufacturing fact ring sites

Marketing & Sales
March 7 - 8, 2009

Product launch

Post approval commitment
?Changes ?Stability testing

?

7

Global Trend in Generic Industry
– – – – – – High pressure to reduce healthcare cost Global harmonization in regulatory practices Standardi ed q Standardized quality alit req requirements irements Increasing acceptance of generic drugs Demands keep increasing Developing countries entering regulated markets Bio g generic is evolving g Stiffer competition Lowering the cost of manufacturing Faster approval for generic drugs
8

– – – –

March 7 - 8, 2009

Opportunities for China
? Low cost of manufacturing
– Large API manufacture base – Vertical integration into finished dosage – Contract C t t manufacturing f t i

?

Get into the expanding markets for generic drugs – Regulated markets (US, Europe, Australia, Japan?)
– Developing countries where affordable medicine is in great need

?

Biogeneric
– Strong biotech base and new start ups – Smaller gaps to catch up

? ?

TCM Central government support
9

March 7 - 8, 2009

Challenges for Chinese companies
? ? ? ? ? ? ? ? Meet M t the th quality lit standards t d d f for regulated l t d market k t Lack of experience in international regulatory filing Management mentality/style Lack of experience in international marketing for finished dosage Inexperienced in global business development Language barrier Recognize the value of external expertise and services and choose the right consultants Time is running out

March 7 - 8, 2009

10

Generic Drugs

Three Winning Must Haves

March 7 - 8, 2009

11

Generic Drug

Three Winning Must Haves
First to market Low cost

High quality

March 7 - 8, 2009

12

Quality issues for Chinese Companies

Can do attitude

March 7 - 8, 2009

13

Th bottom The b tt line li of f cGMP: GMP
SAY WHAT YOU DO DO WHAT YOU SAY

March 7 - 8, 2009

14

FDA CDER citations for manufacturers based in four countries in 2006 (partial)
GPhA Technical Conference, Conference Oct 2006
% of all citations Number of CDER inspections Laboratory control Quality Production Facility and equipment Material Packing and labeling China 15 35% 34% 19% 8% India 35 21% 25% 31% 15% 4% 4% Japan* 11 29% 21% 17% 8% 21% 4% Italy 12 26% 13% 22% 26% 13% Total 78 111% 93 90 57 38 8

* Japan p had the most GMP deficiencies in fiscal 2006. March 7 - 8, 2009 2007 Foreign inspections 15

Key areas for improvements
? T Top two t FDA citations it ti for f Chinese Chi companies
– Laboratories
? General laboratory controls
– Reagents R t control t l and dl labeling, b li calibration lib ti

? Documentation and record keeping
– L Lab bb book, k validation lid ti control, t l electronic l t i signature i t and d data archiving, data traceability

– Quality
March 7 - 8, 2009 16

Key areas for improvements
? T Top two t FDA citations it ti for f Chinese Chi companies
– Laboratories – Quality
? Quality assurance
– QbD, PAT, in process testing, process improvements

? Records, reports, SOPs
– Archiving, scientific reports, too much/little/inadequate SOP

? Investigations
– Complaint, OOS
March 7 - 8, 2009 17

Key areas for improvements
? There is no quick fix
– Hardware is expensive in capital – Software is expensive in time – form the right habits and frame of mind throughout the organization – Train the frontline managers well – Continuous C ti on-the-job th j b t training i i f for l lab b employees l – Independent function directly report to CEO – Have the incentive/discipline plans in place

March 7 - 8, 2009

18

Beyond generic
? How many cost saving projects can you run? ? How can you survive the price war while keeping a sustainable business? ? How to provide more value? Super generic ? Biotech to more efficient discovery for new targets ? Personalized medicine

March 7 - 8, 2009

19

Beyond generic
? Core competencies for leading companies
– Operational excellence – Customer intimacy – Product innovation

March 7 - 8, 2009

20

Ch Characteristics i i of f Th Three V Value l Di Disciplines i li
Operational Excellence Produces reliable products and services Delivers with minimal difficulty Eliminates production steps Customer Intimacy Segments and targets audience Tailors offerings to match customer needs Uses multiple modes of producing and delivering products/services Builds customer loyalty y y for the long term Has operational fl ibilit flexibility Product Leadership Offers leading-edge products and services p Commercializes quickly Looks for new product and service possibilities

p p processes Optimizes Offers competitive pricing

y Avoids bureaucracy Differentiates product portfolio tf li

March 7 - 8, 2009

21

III.

API Manufacturing and DMF Preparation

In this section we will learn: ? Product choice ? Manufacturing M f t i ? Product QC/QA ? DMF preparation and filing ? Inspection readiness
March 7 - 8, 2009 22

III.

API Manufacturing and DMF Preparation

?

Prod ct choice Product
– Align g with business strategy gy – Market research – Patent P t t expiration. i ti Orange O Book B k and d beyond (www.fda.gov/cder/ob/) – Technical capability – Leverage on outside expertise

March 7 - 8, 2009

23

III.

API Manufacturing and DMF Preparation

?

M Manufacturing f i
– QbD – Process development
? Structure, yield, purity and impurities

– Batch size and p production capacity p y – Process validation – Cleaning C and material contact
March 7 - 8, 2009 24

III.

API Manufacturing and DMF Preparation

?

Product QC/QA
– Analytical A l ti l method th d d development l t
? ? ? ? Start early, feasibility, keep improving, Linearity, accuracy, precision, stability indicating g In-process, final release, specifications Cleaning methods

March 7 - 8, 2009

25

HPLC method for in-process testing
Typical chromatographic conditions: Column: Alltech Altima, Altima 150 x 3 3.2 2 mm mm, 5 um um, or equivalent Injection volume: 10 uL Flow rate: 1 mL/min Detector: UV 252 nm Gradient: time (min) %water % acetonitrile 0 100 0 10 60 40 40 50 50 60 10 90 70 100 0

March 7 - 8, 2009

26

III.

API Manufacturing and DMF Preparation

?


Product QC/QA
Method validation protocol
? ? ? ? ? Background Objectives Method Procedure Predefined acceptance Criteria (including requirement in case of f failure) f il ) Reference of the Protocol Background Objective Materials and instruments Results and discussion Conclusion
27



Method validation report
? ? ? ? ? ?

March 7 - 8, 2009

Validation Parameters by y Type yp of Method
ID Impurity Quantitation

Impurity Limit
-* + + -* + +

Cleaning g
+ + -* + + + + + -* + + +

Assay y
+ + + + + + +

Accuracy Repeatability Intermediate precision Specificity D t ti limit Detection li it Quantitation limit Linearity Range Robustness S f Surface recovery Stability indicating Solution reagent stability Reference standard control evaluation

+ +

+ + + + -* * + + + + + + +

* May be needed in some cases March 7 - 8, 2009

28

III.
?

? ? ?

API Manufacturing and DMF Preparation

Product QC/QA
Co-validation
Development/validation/use e e op e / a da o /use labs abs are a e different d ee Well defined in protocol Adequate technical competencies


? ? ? ? ? ?

Method transfer
Lab L bt to plant l t Plant to plant Both internal and external Well e de defined ed p protocol o oco Adequate technical competencies Paper transfer


? ?

Validation and change control
Method M th d change h Protocol change


? ? ?

Validation Master Plan
Define top level scope and requirement Define responsibilities Define timelines

March 7 - 8, 2009

29

Precision
Injection sequence: sys suit std sample std 1 3 1 2

Preset acceptance criteria: intermediate precision: R Result: lt 0 60% 0.60%

NMT

0.58%

What to do?

March 7 - 8, 2009

30

III.

API Manufacturing and DMF Preparation

?


Product QC/QA
Laboratory cGMP and documentation
? ? ? ? ? ? ? ? ? Most frequent q citation for inspections p in China Clearly written SOP Strict new employee training and refresher On the job training – very important On-the-job Highly qualified first line managers and supervisors Good habits are VERY IMPORTANT and old habits die hard Regular lab walk through Management responsibility Effective plan to tie incentives to performance

March 7 - 8, 2009

31

III.

API Manufacturing and DMF Preparation

?


Product QC/QA
Impurity profiling ? Innovator product testing ? Matching profiles ? Develop the adequate test methods - being thorough rather than being sorry ? Understand your synthesis route ? Potential animal toxicity studies if not meeting ICH limits ? Impurity standard synthesis and characterization

March 7 - 8, 2009

32

ICH G Guideline ideline on Imp Impurities rities in Ne New Dr Drug gS Substance bstance (Q3A)
Maximum Daily Dose
≤ 2g / day > 2g / day

Reporting Threshold
0.05% 0.03%

Identification Threshold
0.10% or 1.0 mg per day intake (whichever is lower) 0.05%

Qualification Threshold
0.15% or 1.0 mg per day intake (whichever is lower) 0.05%

March 7 - 8, 2009

33

Deficiency
In the submission, the specification is NMT 0.1% for any other impurity. Please revise the acceptance limits for other individual impurity (unspecified) “Please in the drug substance based on the maximum daily dosage of 1200 mg/day of your drug substance and identification threshold (IT) cited in the ICH Guideline Q3A dated February 2003. 2003 The limit should be not more than 0.08% unless justified.” 1200 mg/da mg/day < 2g/da 2g/day 0.1% of 1200 mg/day = (0.001 x 1200) = 1.2 mg/day 1.0 mg/day is lower than 1.2 mg/day 1 0 mg/day / 1200 mg/day x 100% = 0 1.0 0.08 08 %

March 7 - 8, 2009

34

III.

API Manufacturing and DMF Preparation

?


Product QC/QA
Stability testing ? Stability testing schedule ? Correlation of accelerated studies ? Expiry dating Residual solvents ? Common sense: leave them out if you can ? Use the best solvents



– – –


Product P d t uniformity if it Packaging materials St Storage and d transportation t t ti
Other tests
35

March 7 - 8, 2009

Long term stability study test results for two products Impurity specification NMT 0.3%, shelf life = 5 year

Impurity

T0

6 month

1 year

3 year

5 year

P1 Batch 1 P1 Batch 2 P1 Batch 2

0 05 0.05 0.03 0 01 0.01

009 0.0.9 0.07 0 05 0.05

0 17 0.17 0.11 0 18 0.18

0 25 0.25 0.26 0 22 0.22

0 29 0.29 0.24 0 30 0.30

P2 Batch 1 P2 Batch 2 P2 Batch 3

0 12 0.12 0.04 0 25 0.25

0 08 0.08 0.15 0 10 0.10

0 21 0.21 0.14 0 18 0.18

0 32 0.32 0.03 0 30 0.30

0 20 0.20 0.09 0 24 0.24

What are your recommendations regarding the specification and expiry dating?
March 7 - 8, 2009 36

III.

API Manufacturing and DMF Preparation

?

DMF preparation and filing
– Technical package
? ? ? Help your to sell – initial assessment from potential customer Help you to prepare DMF Synthesis y and characterization, , Impurity p y profiling, method validation, stability testing

March 7 - 8, 2009

37

III.

API Manufacturing and DMF Preparation

?

DMF p preparation p and filing g
– DMF preparation
? C t t Content

– Format – The looks does count

March 7 - 8, 2009

38

III.

API Manufacturing and DMF Preparation

?

DMF preparation and filing
– Common Technical Document
?
? ?

Document Format that is used to write regulatory submission documents
Harmonized format required by US, EU and JP May be electronically filed

March 7 - 8, 2009

39

III.

API Manufacturing and DMF Preparation

?

DMF preparation and filing
– Question-Based Review (QbR) for FDA submissions
? a general framework for a science and riskbased assessment of product quality

? 2004 initiation ? 9/2006 first ANDA approval ? 1/2007 full implementation www.fda.gov/cder/ogd/ Example of the questions



DMF holders’ responsibilities
40

March 7 - 8, 2009

III.

API Manufacturing and DMF Preparation

?

DMF p preparation p and filing g
– DMF filing
? ? ? Where to Wh t file fil Who to file Updates

March 7 - 8, 2009

41

III.

API Manufacturing and DMF Preparation

?

DMF preparation and filing
– Inspection p readiness Th essence of The f cGMP: GMP XXXXXXXXXXXXXXX XXXXXXXXXXXXXXX

March 7 - 8, 2009

42

III.

API Manufacturing and DMF Preparation

?

Inspection readiness
– – – – – – – – – Quality manual Organization charts Documents (Training, SOPs, Batch Records, lab notebooks, raw data, validation packages, etc.) Employee training training, action and interaction tips Develop good habits Good looks does count Organized, efficient, adequate hospitality Respond quickly and correctly When to expect an inspection request from FDA – according to time of filing?
43

March 7 - 8, 2009

IV Case Study 1 – Which API IV. vendor to further explore
? ? ? ? ? ? Divide into six groups. groups Groups 1, 1 3, 3 5 are buyers and group 2 2, 4, 6 are corresponding vendors. Read the three proposals with the information package. y have to decide on whether the vendor is worthwhile to Buyers further explore. They can ask questions and clarifications based on the information provided from the vendor. Vendor have proactively prepare answers and plans for potential question. question There are 30 minutes of reading and preparation, 30 minutes of dialogue. Record the question, answers, decisions and the reasons for the decision, and the action plan for next step. After the dialogue, each pair of groups to report the outcome.

March 7 - 8, 2009

44

V. Finished Product
? Section Objectives
– Real examples to help understand each topic; not intended to be comprehensive – Key learning point: There are many ways to successful approvals of generic products. A smart company picks the right strategy for itself.

? Section Topics
– – – – – Generic Drug Development ANDA Submission Prior Approval Inspection (PAI) Post- Approval Commitment Case discussion and role p play y on a PAI inspection p for an ANDA submission
45

March 7 - 8, 2009

Formulation Development Packaging & Labeling Process Development Technology Transfer Submission Regulatory Affairs Post Appro Approval al Changes
March 7 - 8, 2009

Regulatory & Medical Affair

Business Marketing

Research and Development Quality y Assurance

Validation

Manufacturing PAI Preparation Appro al Approval Launch Production Validation QC Engineering
46

Generic Drug Development
? Definition
– New Drug: New Chemical Entity – Generic Drug vs. New Drug
? Must have the same: dosage, safety, strength, how it is taken, quality, performance, and intended use. Most of the labeling. g ? Difference can be: shape, release mechanisms, packaging excipients (including colors packaging, colors, flavors flavors, preservatives), expiration time

– Reference Listed Drug
March 7 - 8, 2009 47

Generic Drug Development (cont’d) (cont d)
? Strategy, strategy and strategy- first to market
– Market Research – Regulatory Strategy – earliest date of sale
? Patent
– – – – – – Granted by Patent and Trademark Office 20 years Basic patent (API, process) Formulation patent (modified release) Combination patent (decongestant+antihistamine, hypertensive+diuretic) use patent (anti-depressant for smoking cessation)

? Exclusivity (Hatch-Waxman)
– Granted by FDA – 5 years for NCE, 3 years for product improvements, 6-month for pediatric labeling

? 180-day 180 d for f first fi t ANDA sponsor –paragraph h IV

– Challenges
? Prescription to OTC Switch ? Timing and Competition ? Cost
March 7 - 8, 2009 48

G Generic i Drug D D Development l t( (cont’d) t’d)
? El Elements t of f Experimental E i t l Formulation F l ti Development
– – – – – – – – Secure API: quality and quantity Method Development and Validation Analysis of Brand Name Product Formulation and Process Development Stability and Specifications Packaging and Labeling Microbiology gy study y Documents of development history
49

March 7 - 8, 2009

G Generic i Drug D D Development l t( (cont’d) t’d)
? S Scale-up l and dT Technology h l T Transfer f – quality by design
– – – – Selection of Equipment and Batch Size Risk Assessment Scale –up trials – Experiment plans (e.g. DOE) Design g space p Output: p identification of Critical and/or Key y Process Parameters (C/KPP), Critical and/or Key Quality Attributes (C/KQA) Establishment of control limits and edge of failure Hold time, Cleaning, Shipping, compatibility, material contact St ilit A Sterility Assurance P Package k Process Development Report
50

– – – –

March 7 - 8, 2009

G Generic i Drug D D Development l t( (cont’d) t’d)
? Registration batch and stability study
– 10% of commercial batch size – Master Batch Record – Specifications-regulatory commitment – Validated method transferred to site – Stability Study Protocol – Packaging and Labeling – Stability Report
March 7 - 8, 2009 51

G Generic i Drug D D Development l t( (cont’d) t’d)
? Summary
– A good business and regulatory strategy is p to successful Generic Drug g the first step Development – Time and cost are always the pressing issues; where to spend them makes huge difference – Well thought-out and documented technical p p process is the basis for a g good development application
March 7 - 8, 2009 52

ANDA S Submission bmission
? Abbreviated New Drug Application
– What does “abbreviated” mean? – Who reviews ANDA? – Why is generic drug needed and why ANDA review i i is i important? t t?
? Safe, low cost alternative to the public

March 7 - 8, 2009

53

ANDA S Submission bmission (cont’d)
Brand Name Drug NDA Requirements 1. Chemistry 1 2. Manufacturing 3 Controls 3. 4. Labeling 5 Testing 5. 6. Animal Studies 7 Clinical Studies 7. 8. Bioavailability
Reference: From March 7 - 8, 2009 FDA website

Generic Drug ANDA Requirements 1. 1 2. 3 3. 4. 5 5. Chemistry Manufacturing Controls Labeling Testing

6 Bioequivalence 6.
54

ANDA S Submission bmission (cont’d)
? Abbreviated New Drug Application
– Common Technology Documents (CTD) – ANDA Check List
http://www.fda.gov/cder/ogd/anda_checklist.pdf

– Abbreviated New Drug Application (ANDA) Process for Generic Drugs
http://www fda gov/cder/regulatory/applications/ANDA htm http://www.fda.gov/cder/regulatory/applications/ANDA.htm

March 7 - 8, 2009

55

Generic Drug Review Process
Reference; FDA website

APPLICANT ANDA
Application Review

Refuse to Receive Letter

N
Acceptable & Complete

Y Request for Plant Inspection N
PreApproval Inspection Results OK?

Chemistry & Micro Review

Labeling Review

Bioequivalence Review N

Chem/Micro OK?

N

N

Labeling OK?

Bioequivalence OK?

Y

Y

Y

Y

Approval Withheld until Results Satisfactory

APPROVED ANDA

Not Approvable Letter

Bio Deficiency Letter

March 7 - 8, 2009

56

ANDA Submission (cont’d) ( )
? Preparation of ANDA
– Led by y Regulatory g y Affair Department p – Have a Strategy and Avoid Surprises – Key K Points P i t
? Meet all the requirements ? Many ways to write a successful package ? Consistent, Consistent coherent and concise

– Check Check Check!! – Work continues after submission!!
March 7 - 8, 2009 57

ANDA S Submission bmission
? Preparation of CMC section
– Follow CTD requirements (Question Based ) Review) – Use development reports as basis – Claims Cl i and dC Commitments it t b backed k d up b by d data t – Accurate, , concise information will help p subsequent communication and PAI – Risk analysis and contingency
March 7 - 8, 2009 58

E amples of Doc Examples Documents ments
? ? ? ? ? Citizen Petition ANDA suitability petition Sample Approvable Letter Sample p Approval pp Letter …

March 7 - 8, 2009

59

ANDA Submission (cont’d) ( )

March 7 - 8, 2009

Reference: FDA OGD Tech Meeting

60

ANDA Submission (cont’d) ( )

March 7 - 8, 2009

Reference: FDA OGD Tech Meeting

61

Prior Approval pp Inspection p ( (PAI) ) Readiness ? General Process
– What Can be Prepared
? Timing Timing, Agenda and Logistics ? People, Equipment and Facility, Documents

– What Wh t Can’t: C ’t H Human F Factors t & Randomness R d
? ? ? ? Depend on Different Inspectors Depend on Different Regulatory Agencies Depend p on Product Depend on the Firm’s Reputation and Track Record ? ………….
March 7 - 8, 2009 62

PAI Readiness (cont’d) (cont d)
? Inspection Process
– Issuance of Form 482 – Initial Meeting – Walk-through g of facilities – Review of records – Close-out Cl t meeting ti – May y issue FDA form 483 – Report wrap-up

March 7 - 8, 2009

63

PAI Readiness (cont’d) ( )
? Timing
– PAI is not always needed, but PAI preparation is – 90 days after submission

? Agenda
– Notice from Regulatory Agencies – Internal decision

? Logistics
– – – – –
March 7 - 8, 2009

Paperwork to sign Transportation “War Room” Translation IT tools
64

PAI Readiness (cont’d) (cont d)
? People
– Everyone on the site needs to be informed – Training
? Routine training for anyone who might be involved ? Special training before the PAI

– Clear Assignment of Responsibilities
? Led by y QA head ? One technical lead to answer most of questions or several technical leads for different areas ? One coordinator to address additional requests and take meeting minutes
March 7 - 8, 2009 65

PAI Readiness R di ( (cont’d) t’d)
? Equipment Eq ipment and Facility Facilit
– Appearance Counts – Supporting documents in place – Equipment and facility must operate in a predictable manner to assure consistent process performance. – Equipment and facility must be qualified/validated ? Facility: Utilities, Support systems, HVAC(Heating Ventilating and Air Conditioning), Conditioning) Building automation and control, Containment. ? Equipment: E i t shared h d vs. d dedicated, di t d IQ/OQ/PQ ? Utility: critical vs. non-critical
March 7 - 8, 2009 66

PAI Readiness R di ( (cont’d) t’d)
? Process
– Process has to be validated before PAI – What process validation is
? To show good control ? To show it meets cGMP

– What Wh t process validation lid ti i is not t
? Not a separate program from development ? Not for experimental purposes

Do not start validation until you are confident you will succeed
March 7 - 8, 2009 67

PAI Readiness ead ess (co (cont’d) t d)
? PAI Documents
– General GMP Documents – Quality System
? SOPs, , Training g Records, , Organization g Chart ? Maintenance, calibration records ? Equipment, Equipment Utility and Facility (IQ/OQ/PQ)

– Product Specific Documents
? ? ? ? ? ? Summary Quality Manual E Executed t d Batch B t h Record R d – validation lid ti l lots t Raw Data with good traceability Technical Reports Deviations and investigations
68

March 7 - 8, 2009

PAI Readiness (cont’d)
? ? ? ? Review and re re-familiarize familiarize yourself Establish working schedule with FDA Treat FDA as you wish to be treated Assure all requested records are received during audit ? Offer to copy all requested records ? Know what the FDA investigator can ask for ? Effective communications and Always speak truthfully
March 7 - 8, 2009 69

PAI Readiness (cont’d)
? PAI Process (FDA) – look from the other side
– Inspections Operations Manual
http://www fda gov/ora/inspect ref/iom/pdftoc html http://www.fda.gov/ora/inspect_ref/iom/pdftoc.html

– Guide to International Inspections and Travel
http://www.fda.gov/ora/inspect ref/giit/default.htm http://www.fda.gov/ora/inspect_ref/giit/default.htm

– Discussion points:
? ? Format, F t Expectations, E t ti Li Limitations it ti and d Goals G l System inspection
70

March 7 - 8, 2009

PAI Readiness (cont’d)
? PAI Process
– – – – Depend p on Different Inspectors p Depend on Different Regulatory Agencies D Depend d on P Product d t Depend p on the Firm’s Reputation p and Track Record – Human factor and Randomness

March 7 - 8, 2009

71

Who is the FDA In Investigator estigator
? What he/she is
– – – – – BS in biology or chemistry or equivalent Trained auditor Knowledgeable of drug development method Dedicated to protect public K Knowledgeable l d bl of f th the regulations l ti

? What he/she is not
– An expert in all medical systems – Out to get anyone – Easily fooled
March 7 - 8, 2009 72

What makes FDA suspicious s spicio s
? Att Attempts t to t delay d l inspection i ti ? Records not available ? Test results reported when capabilities nonexistent i t t ? Complaints from patients and employees ? Inconsistencies between records, lab results lt and d summary reports t ? Adverse reactions/problems p not reported p ? Any indications of record falsification
March 7 - 8, 2009 73

PAI Readiness (cont’d)
? Exit Meeting ? Written Report
– Sample 483 – Sample warning letter

? Follow Through

March 7 - 8, 2009

74

PAI Readiness (cont’d)
? Examples
– FDA Inspection
? Sample p 482, , 483 (filled) ( ) ? Sample warning letter ? Example PAI

– EU Inspection

March 7 - 8, 2009

75

Post Appro Approval al Changes
? Major Changes – Prior Approval S Supplement l t ? Moderate Changes – Changes Being Effected (CBE) ? Minor Changes – Annual Report ? SUPAC and an example of post approval change g
March 7 - 8, 2009 76

CASE PAI Inspection CASE:
? Students will be divided into two roles: plant QA/technical lead vs vs. inspectors ? Each group will be given information on a generic drug that was submitted for approval 30 45 min, min group discussion on ? Reading time 30-45 strategy 30-45 min and inspection 1 hour ? Use U what h t you l learned dt to carry out t th the i inspection ti p when y you are stuck ? Ask for help

March 7 - 8, 2009

77

Debrief
? Each group presents their exit meeting minutes i t ? What do you think about the experience? ? Summary

March 7 - 8, 2009

78

IX. Summary
?
– –

Key lessons learned:
Essence of cGMP QbD
? ? Understanding the basis science Control Tell the story Precise and to the point, sufficient evidence, accuracy System Team



QbR
? ?



Establish consistent performance p
? ?



F Form good dh habits bit and d self lf di discipline i li

March 7 - 8, 2009

79

Did we meet your learning objectives?

March 7 - 8, 2009

80

Questions?

March 7 - 8, 2009

81

Evaluations
– Quiz – Evaluation sheets

March 7 - 8, 2009

82


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2.A Generic View of Proc... 3.Process ... product measures during software development? ...insight into the quality of the software ...
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pharmaceutical | teva pharmaceutical | hisun pharmaceutical | ono pharmaceutical | cr pharmaceutical | qilu pharmaceutical | parapharmaceutical | sun pharmaceutical |