Statistical Methods for Biotechnology Products

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Statistical Methods for

Biotechnology Products

Jen-pei Liu, Ph.D., Professor

Division of Biometry, Department of Agronomy

National Taiwan University

and

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110/07/16 Copyright by Jen-pei Liu, PhD; Pr oduct Names for Illustration only and not for endorsement

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Materials

1. CGMP

Current Good Manufacturing Practice

2. USP/NF

The United States Pharmacopeia XXII and National

Formulary

3. Text book

Chow, S.C. and Liu, J.P.(1995). Statistical Design and

Analysis in Pharmaceutical Science. Marcel Dekker, Inc.,

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4. Some References

Simon et al (2003) Design and Analysis in DNA Microarray Investigations.

Springer.

Liu, J.P. and Chow, S.C.(1995). Statistics methods for quality assurance of

drug products. J. Chinese Stat. Assoc., 33, 169-186.

Ju, H.L. and Chow, S.C.(1995). On stability designs in drug shelf-life esti

mation, J. Biopharm. Stat., 5, 201-214.

Liu, J.P., Tung, S.C., and Pong, Y.M. (2005) An alternative approach to ev

aluation of poolability of stability studies, accepted by J. Biopharm. Stat.

Lesko, L. and Woodcock, J. (2004) Translation of pharmacogenomics and

pharmacogenetics: a regulatory perspective, Nature Reviews Drug Discove

Materials

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4

Shi, L., et al (2004) QA/QC: challenges and pitfalls facing the microarray co

mmunity and regulatory agencies, Expert Rev. Mol. Diagn. 4, 761-777.

Dobbin, K.K., et al. (2005) Interlaboratory comparability study of cancer gen

e expression analysis using olignonucleotide, Clinical Cancer Research, 11,

565-572.

Michiels S., Koscielny S., and Hill C. (2005) Prediction of cancer outcome w

ith microarrays: a multiple random validation strategy, Lancet, 365, 488-492

.

Ioannidis J.P.A. (2005) Microarrays and molecular research: noise discovery

, Lancet, 365, 454-455.

Materials

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

_{Members of the Toxicogenomics research Consortium (2005)}

Standardizing global gene expression analysis between labora

tories and across platforms, Nature Methods, 2, 351-356.



_{Irizarry R.A., Warren D., Spencer F., Kim I.F., Biswal S., Fra}

nk B.C. et al. (2005) Multi-laboratory comparison of microarr

ay platforms, Nature Methods, 2, 345-349.



_{Larkin J.E., Frank B.C., Gavras H., Sultana R., and Quackenb}

ush J. (2005) Independence and reproducilbility across microa

rray platforms, Nature Methods, 2, 337-343.

Materials

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Introduction

Part I: Biopharmaceutical Products

Lecture 1: Principles

Lecture 2: Review of Statistical Process Control

Lecture 3: USP tests and Specifications

Lecture 4: Regulatory Requirements for Drug Stability

Lecture 5: Accelerated Testing

Lecture 6: Statistical Designs of Stability Studies

Lecture 7: Statistical Analysis of Stability Data

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Introduction

Part II: Biochip Diagnostic Products

Lecture 8: Overview of Biochips and Microarray Techn

ology

Lecture 9: Issues of Biochip Products Based on Microa

rray Technology

Lecture 10: Evaluation of Microarray Products

Lecture 11: Examples of Regulatory Evaluation of Bioc

hip Products

Lecture 12: Tests Based on Quantitative Measurements

Lecture 13: Clinical Validation and Effectiveness

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Introduction

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Introduction



Drug development



Regulatory requirement



Current issues

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Regulatory Requirements



_{Legal basis}

- Pure Food and Drug Act (1906)

- Sherley Amendment (1912)

- Federal, Food, Drug, and Cosmetic Act (1938)

- Kefauver-Harris Amendment(1962)

- NDA Rewrite (1985)

- Treatment IND (1987)

- Parallel Track And Accelerated Approval (1992)

- U.S. FDA Modernization Act (1997)

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Regulatory Requirements



_Objectives

- Efficacy & safety

- Identity, strength, quality and purity



_{FDA regulations}

- CFR(Codes of Federal Regulations)

- cGMP (Current Good Manufacturing Practice)

- USP/NF (United States Pharmacopeia/ National Formulary)

- FDA guidances and guidelines

- ICH guidances

Continued

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Current Good Manufacturing Practice



_{Organization and Personnel}



_{Building and Facilities}



_Equipment



_{Containers and Closures}



_{Production and Process Controls}



_{Holding and Distribution}



_{Laboratory Controls}



_{Records and Report}

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Current Good Manufacturing Practice



_{Quality Control Unit}

- Statistical QC criteria

- Sampling and testing plan

- Acceptance and rejection levels



_{Representative Samples}

- Variability

- Confidence levels

- Degree of precision

- Top, middle, and bottom of the container



_Validation

- Accuracy and reliability

- Assay and process validation

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Current Good Manufacturing Practice



_{Process Controls}

- Raw material inspection

- In-process materials testing

- Release testing



_{Stability Testing}

- Expiration dating period

(or shelf-life)

- Sample size

(e.g., at least three primary batches)

- Test intervals

(e.g., 0, 3, 6, 9, 12,18,…)

- Storage conditions

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Introduction

1

2 …

i

…

N-1

N

Raw

Material

Finish

Product

Manufacturing Steps

i

Unit Process Step (i) with Associated Process Characteristics

Total Manufacturing Process =

1

(Unit Process Step i)

N i

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Process Controls

Raw Material Inspection



_{Random selection of drums}



_{Random samples from the top, middle, and}

bottom parts of each chosen drum



_{Checking the strength: uniformity – mean a}

nd varibility



_{Combination of different strengths from diff}

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Process Controls

_{Process Controls}

Example: 150-ft

3 V-blender

Objective: potency and uniformity to meet the

USP/NF specifications

Primary and final blending stage: 12 samples

from top, middle, bottom, and front and

back of the right and left sides of the

V-blender.

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Process Controls

Product Testing



_{Release Testing: Random samples from a batch}

for potency, content uniformity, dissolution,

weight variation and disintegration



_{Release target: a target set by the manufacturer so}

that (1-)% probability that the batch will meet

the USP/NF specifications.

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Current Good Manufacturing Practice



_{What if a pharmaceutical company fail to comply}

with current good manufacturing practice?

- Warning

- Issue a recall

- Legal action



_Example

New Jersey Star Ledger, July 9, 1993

A New Jersey drug company agreed to a consent decree with the

FDA for a dispute over record keeping at its two manufacturing

plants, The settlement cost the company ay least $50 million in lost

sales in the first and second quarters of 1993.

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Current Good Manufacturing Practice

Example

On May 17, 2002, Schering-Plough agrees to pay US $500 million for its vio

lation of cGMP at 4 New Jersey and Puerto Rico facilities and also had to

pay US $471,500 for inspection cost. It suspended manufacturing 198 diff

erent drugs (90%).

On April 28, 2005, GlaxoSmithKline (GSK) had signed a consent decree wit

h FDA to correct manufacturing deficiencies at its Cidra, Puerto Rico facil

ities. The Decree requires GSK to post a panel bond of US $650,000,000 c

ontingent upon GSK reconditioning drugs seized in March 2005 or destro

y them and pay costs to government. Paxil CR tablets for depression and

panic disorder, could split apart. One half may contain the whole active in

gredients and other half contains no active ingredient at all

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USP/NF Tests



_{The United States Pharmacopeia XXII and National Formulary}



_{The compendia of legally public standards}

- Safety and efficacy

- Identity, strength, quality and purity

- Packaging and labeling



_{Standard testing procedures}



_{Standard sampling plans}



_{Acceptance criteria}

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USP/NF Tests



_{Uniformity of Dosage Units}

- Sampling plan

- Acceptance criteria

- Probability of passing



_Dissolution

- Acceptance criteria

- Probability of passing



Other tests

- Potency

- Weight variation

- Disintegration

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FDA guidances and

guidelines

Guidances



_Stability

“Guideline for submitting Documentation for the Stability

if Human Drugs and Biologics” Rockville, Maryland,

1987.



cGMP

“Quality systems approach to pharmaceutical current good

manufacturing practice regulations” Rockville,

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ICH guidances

Guidances



_Stability

Q1A(R2): Stability Testing of New Drug Substances and Products.

Q5C: Stability of Biotechnology/Biological Products



cGMP

Q7A Good Manufacturing Practice for Active Pharmaceutical Ingredients



_{Specifications}

Q6A Test Procedures and Acceptance Criteria for New Drug Substances

and New Drug Products: Chemical Substances

Q6B Test Procedures and Acceptance Criteria for

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FDA draft guidances

Draft Guidances



_Genomics

-

Pharmcogenomic Data Submissions

-

Multiplex Tests for Heritable DNA Markers, Mutation, and Expression

Pattern

-Instrumentation for Clinical Mulitplex Text Systems

-Drug Metabolizing Enzyme Genotyping System

-Drug-Diagnostic Co-Developmnt – Preliminary Draft Concept Paper

-

多標的陣列平台基因診斷試劑 – 查驗登記審查指引 (2005 年 3