Overview of Pharmaceutical Regulations that Apply to Microbiologists

1
Overview of Pharmaceutical Regulations that Apply
to Microbiologists

• Scott Sutton

2
Scope of Topics

• Will Cover
• Process Validations
• (including BIs)
• In-process Controls
• Sterility
• Microbial Limits
• Antimicrobial Preservative Effectiveness Test

• Will Not Cover
• Antibiotics
• Bacterial Endotoxins

3
Scope of Regulations

• Will Cover
• Pharmacopeia
• CPMP
• Some ISO, ICH

• Will Not Cover
• Voluntary Standards (ASTM, ANSI)
• Industry groups
• Most ISO, ICH

4
USP Routing Process
Input from the Field
USP Headquarters
Relevant Subcommittee Members
Revised/New Chapter in PF
5
Input from the Field
Regulatory
Industry
Academia
USP
6
Pharmacopeial Forum

• Pharmacopeial Forum is published to provide an
  opportunity for public review of and comment on
  revision activities affecting the United States
  Pharmacopeia and the National Formulary. It also
  provides a forum for the exchange of ideas and
  information relating to the development and
  revision of standards and analytical methods.

7
Revision Process
Requests/comments Submitted Subcommittee Reviews
Requests/comments Publish in PF as Pharmacopeial
Preview or In-process Revision Subcommittee
Approves Executive Committee of Revision
Approves Board of Trustees Approves Publication
in USP-NF
8
Major USP Conferences

• Open Conference on Microbiological Compendial
  Issues in Sanibel Harbour, FL (1/96)
• Interpharm Convention of the USP, JP, and EP for
  International Harmonization of the Sterility Test
  and Antimicrobial Effectiveness Test in
  Barcelona, Spain (2/96)
• North American Conference on Setting
  Specifications for Drug Substances and Drug
  Products" A joint conference of the FDA, USP,
  PDA, AAPS, and FIP on the ICH Q6A document held
  in Washington, DC (9/96)
• USP Workshop on Microbiology and Pharmaceutical
  Water held in San Juan, Puerto Rico (4/97)
• Open Conference on Microbiological Compendial
  Issues held in New Orleans, LA (5/98)

9
Methods to Contact USP

• Conferences
• Letters
• Roger Dabbah, PhD
• USPC, Inc.
• 12601 Twinbrook Parkway
• Rockville, MD 20852 USA
• Email
• rd_at_usp.org

10
Email Lists of Interest

• PDA Pharmaceutical Sci-Tech Discussion Group
• http//www.pharmweb.net/pwmirror/pwq/pharmwebq2.ht
  ml
• Web Site http//www.pda.org
• Pharmaceutical Microbiology Forum
• http//microbiol.org/PMFList_info.htm
• List of Lists
• http//microbiol.org/mailist.htm

11

• Process Validations

12
lt55gt Biological Indicators - Resistance
Performance Tests

• Primary goal of this revision was to present the
  calculations for D-value determination in an
  improved, systematic series of equations that
  include the summation expressions previously
  explained in the text.
• In-Process Revision Published in Sept/Oct 1996
  Pharm. Forum
• Final version in 5th Supplement, effective Nov
  15, 1997
• Final version in 6th Supplement, effective May
  15, 1997

13
lt1035gt Biological Indicators for Sterilization

• The chapter was rewritten for clarity.
• Separate sections on performance evaluations for
  manufacturers and for users.
• Section on in-house preparation
• Spore Crop Preparation
• Instrumentation for the Evaluation of Resistance
  Performance Characteristics
• The use of Biological Indicators for In-process
  Validation
• In Process Revision in July/Aug 1997 Pharm Forum

14
ISO Guidance on Sterilization

• ISO 11137 - Terminal Sterilization of Health Care
  Products by Irradiation
• ISO 11134 - Terminal Sterilization of Health Care
  Products by Moist Heat
• ISO 14160 - Terminal Sterilization of Health Care
  Products by Chemical Sterilants
• ISO 11135 - Terminal Sterilization of Health Care
  Products by Ethylene Oxide

15
EMEA Position

• Terminal Sterilization is preferred.
• EMEA/QWP/54/98 Decision Trees for the Selection
  of Sterilization Methods - Annex to Note for
  Guidance on Development Pharmaceutics

16
Japanese Perspective

• Chapter 6 of General Information - Disinfection
  and Sterilization Methods in Supplement I of JP
  XIII (1/1/98)
• Chapter 8 of General Information - Terminal
  Sterilization and Sterilization Indicators in
  Supplement I of JP XIII (1/1/98)

17
In-process Controls

• Water
• Raw Material Bioburden
• Environmental Monitoring
• Pre-sterilized Bulk Bioburden

18
Water Controls

• USP lt1231gt Water for Pharmaceutical Purposes
• EP
• ICH - Q6A Document

19
lt1231gt Water for Pharmaceutical Purposes

• Extensive revision includes flowcharts on
• Water System Validation Life Cycle
• Water for Pharmaceutical Purposes
• Selection of Water for Pharmaceutical Purposes
• Large section on Microbial Monitoring of Water
• Methods, Identification, Alert and Action Limits
• Final version in 4th Supplement, effective May
  15, 1996
• Final version in 5th Supplement, effective Nov
  15, 1996
• In-Process Revision in May/June 1997 Pharm Forum
• 18th Interim Revision Announcement in July/Aug
  1997 Pharm Forum
• Final version in 7th Supplement, effective Nov
  15, 1997

20
Raw Material Bioburden

• ICH - Q6A Document CPMP/ICH/367/96 Note for
  Guidance Specifications Test Procedures and
  Acceptance Criteria for New Drug Substances and
  New Drug Products Chemical Substances
• Guidance provided in Decision Tree 6

21
Environmental Monitoring

• lt1116gt Microbiological Evaluation of Cleanrooms
• Major change is an emphasis on microbial
  monitoring of clean rooms with the understanding
  that different test methods will yield different
  viable count measurements.
• In-Process Revision Published in Jan/Feb 1997
  Pharm. Forum
• In-Process Revision Published in Nov/Dec 1997
  Pharm. Forum
• Final version in 8th supplement, effective May
  15, 1998
• In-Process Revision Published in May/June 1999
  Pharm. Forum

22
Environmental Monitoring

• ISO 13408-1 Aseptic Processing of Health Care
  Products - Part 1 General Requirements
• Specific instructions on Environmental Monitoring
  Programs
• Media Fills
• Discussion of Alert and Action Levels
• Requirements for Investigations and Reports
• See Korczynski, M.S. 1996. The ISO
  International Standard - Aseptic Processing of
  Health Care Products PDA J. Pharm. Sci. Tech.
  50(3)189-195

23
Pre-sterilized Bulk Bioburden

• CPMP/QWP/486/95 Note for Guidance on Manufacture
  of the Finished Dosage Form
• Terminal Sterilization is preferred
• Sterilization by Filtration requires strict
  control of pre-sterilized bulk bioburden - 10
  CFU/100 mL target.
• See also
• EMEA/QWP/54/98 Decision Trees for the Selection
  of Sterilization Methods - Annex to Note for
  Guidance on Development Pharmaceutics and
• CPMP/QWP/155/96 Note for Guidance on
  Development Pharmaceutics

24
Parametric Release

• USP lt1222gt Terminally Sterilized Pharmaceutical
  Products - Parametric Release
• Cycle must be validated to SAL of 10-6
• Physical Microbiological Parameters of Process
  Validated
• Use of BI or PI
• Requires a Change Control System
• May be possible for different modes of
  sterilization
• Pharmacopoeial Preview in Nov/Dec 1997 Pharm.
  Forum
• CPMP/QWP/2431/98 - Concept Paper on the
  Development of a Committee for Proprietary
  Medicinal Products (CPMP) Note for Guidance on
  Parametric Release.

25
Sterility Tests

• USP
• JP
• European Pharmacopoeia
• Harmonized
• Australias Contribution to the Discussion

26
USP Sterility Tests

• Several changes to try to meet the needs of
  industry, FDA, and International Harmonization
• In-Process Revision Published in Sept/Oct 1996
  Pharm. Forum
• In-Process Revision Published in Nov/Dec 1997
  Pharm. Forum
• Final version in 8th Supplement, effective May
  15, 1998
• In-Process Revision Published in Sept/Oct 1998
  Pharm. Forum
• Final version in 10th Supplement, effective May
  15, 1999

27
lt1208gt Sterility Testing - Validation of Isolator
Systems

• Isolator Design and Construction
• Validation of the Isolator System
• Package Integrity Verification
• Sterility Maintenance of the Isolator Environment
• Interpretation of Sterility Test Results
• Training and Safety
• Pharmacopoeial Preview Published in Nov/Dec 1997
  Pharm. Forum
• In-Process Revision Published in Jan/Feb 1999
  Pharm. Forum

28
Pharm. Eur. Sterility Test

• 2.6.1 Sterility
• Several significant differences from USP
• Different organisms and incubation times for B/F
• Different product categories
• Different amounts of product per unit and number
  of units to be tested
• Incubation conditions for turbid samples
• European Pharmacopoeia - Supplement 20000 pp.
  45-49

29
Sterility Test Precautions Against Microbial
Contamination

• Proposal for expansion of the section
  precautions against microbial contamination
  from chapter 2.6.1 Sterility -
• Discussion of the environment of the Sterility
  Test, and the protective function of laminar flow
  hoods and isolators.
• Pharmeuropa 11(4)645 December 1999

30
JP Sterility Test

• Issued in Supplement II of JP XIII (1/1/00)
• Identical to that currently in EP

31
Participants in the Issue
Industry Groups
ICH Working Parties
PDG USP, JP, EP
EMEA
FDA
32
Harmonized Sterility Test

• Product of the PDG - agreement has been reached
  on
• Number of units to be tested
• Validation of media and rinses
• Incubation times and conditions
• Categories of products

33
Australian Perspective

• 12/98 - Standard for Sterile Therapeutic Goods
  was revoked and BP 98 Sterility Test adopted.
• 1998 - TGA Guidelines on Sterility Testing of
  Therapeutic Goods published.
• 1999 - Recommendations for inclusion of three
  points in the application
• State that the method used is the harmonized
  Sterility Test as in EP
• Explicit statement of in-house interpretation of
  how invalidation conditions (a) through (d) would
  be met.
• Statement of methods used to justify (d) -
  particularly identification of identical
  isolates.
• Sterility Testing - A Matter of
  Interpretation TGA News Sept. 1999 p.6

34
Container Closure Systems

• USP lt1207gt Sterile Product Packaging -
  Integrity Evaluation
• Pharmacopoeial Preview Published in Nov/Dec 1997
  Pharm. Forum
• FDA
• Container and Closure Integrity Testing in lieu
  of Sterility Testing as a Component of the
  Stability Protocol for Sterile Products. Jan.
  1998
• Container Closure Systems for Packaging Human
  Drugs and Biologics May 1999

35
Microbial Limits
36
USP Microbial Limits

• The Mar/Apr 1999 Pharmacopeial Forum contained a
  proposal to split the old chapter lt61gt Microbial
  Limit Tests into two chapters
• lt61gt Microbial Enumeration Tests
• lt62gt Microbiological Procedures for Absence of
  Objectionable Organisms
• This proposal appeared in the Pharmacopeial
  Preview section (Pharmacopeial Forum 25(2)7761 -
  7785).
• A second proposal for a Microbial Attributes
  chapter also appeared in this issue.

37
lt61gt Microbial Enumeration Tests

• Buffers and Media
• Sampling
• Preparatory Testing
• Test Procedure
• TAMC
• Total Combined Yeasts and Molds
• Coliform Count
• Enterobacterial Count
• Pharmacopeial Preview Published in Mar/Apr 1999
  Pharm. Forum

38
lt62gt Microbiological Procedures for Absence of
Objectionable Microorganisms

• Buffers and Media
• Preparatory Testing
• Sampling and Sample Preparation
• Test Procedures
• Tests for Absence of S. aureus, P. aeruginosa,
  Burkholderia cepacia, Salmonella, and E. coli
• Test for Absence of C. albicans
• Test for Absence of Clostridium spp.
• Pharmacopeial Preview Published in Mar/Apr 1999
  Pharm. Forum

39
USP lt1111gt Microbiological Attributes of
Pharmacopeial Articles

• Intent is to provide guidance on microbial
  requirements for GMPs
• Raw material bioburden specifications
• Final product guidance specifications proposed
• Inhalations Vaginal
• Nasal/Otic/Topical Rectal
• Liquid Oral Solid Oral
• Pharmacopeial Preview Published in Nov/Dec 1996
  Pharm. Forum
• Pharmacopeial Preview Published in Mar/Apr 1999
  Pharm. Forum

40
Pharm Eur Microbial Limits

• 2.6.12. Microbiological Examination of
  Non-Sterile Products (Total Viable Aerobic
  Count)
• Sample Preparation
• Sample Examination
• Membrane Filtration
• Plating
• MPN
• Validation
• Interpretation
• Interesting discussion of the meaning of limits -
  NMT 100 CFU is interpreted as a plate count of
  NMT 500 CFU
• European Pharmacopoeia - Supplement 20000 pp.
  52-55

41
Pharm Eur Microbial Limits

• 2.6.13. Microbiological Examination of
  Non-sterile Products (Test for Specified
  Micro-Organisms)
• Enterobacteria
• E. coli
• Pseudomonas aeruginosa
• Staphylococcus aureus
• Validation
• Clostridia
• Media
• European Pharmacopoeia - Supplement 20000
  pp. 56-60

42
Pharm Eur Microbial Limits

• 5.1.4. Microbiological Quality of Pharmaceutical
  Preparations
• Category 1 - Sterile
• Category 2 - Topicals
• TAMC NMT 100 CFU/gm Specific requirements for
  enterobacteria and P. aeruginosa, S. aureus
• Category 3 - Oral Rectal
• TAMC NMT 1000 CFU/gm Specific requirements for
  enterobacteria Salmonella, E. coli, S. aureus
• Category 4 - Herbals
• TAMC dependent on type - /- boiling water
• European Pharmacopoeia - Supplement 20000 pp.
  260-261

43
USP vs EP Microbial Limits

• lt61gt Microbial Enumeration Tests
• lt62gt Microbial Procedures for Absence of
  Objectionable Organisms
• lt1111gt Microbiological Attributes of
  Pharmacopeial Articles

• 2.6.12. Microbiological Examination of
  Non-Sterile Products (Total Viable Aerobic Count)
• 2.6.13. Microbiological Examination of
  Non-sterile Products (Test for Specified
  Micro-Organisms)
• 5.1.4. Microbiological Quality of Pharmaceutical
  Preparations

44
USP Chapters on Nutraceuticals

• lt2021gt Microbial Enumeration Tests - Nutritional
  and Dietary Articles
• lt2022gt Microbiological Procedures for Absence of
  Objectionable Microorganisms in Nutritional and
  Dietary Articles
• lt2023gt Microbiological Attributes of Nonsterile
  Nutritional and Dietary Articles
• Pharmacopeial Previews in Sept-Oct 1999 Pharm
  Forum

45
Australian Perspective

• TGAL Guidelines issued in 1994, updated in 1995
• Topicals - NMT 100 CFU/mL
• Antiseptics corticosteroids - NMT 10 per mL
• Orals (NMT 1,000, 10,000, 100,000 CFU/mL no E.
  coli or salmonellae
• Topicals and Antiseptics/Corticosteroids - No
  pseudomonads or S. aureus
• - Tang, S. 1998. Microbial Limits Reviewed
  the Basis for Unique Australian Regulatory
  Requirements for Microbial Quality of Non-Sterile
  Pharmaceuticals. PDA J Pharm. Sci. Tech.
  52(3)100-9.
• - Microbial Limits for Non-Sterile
  Pharmaceuticals. TGA News. April 1998. p. 8

46
Preservative Efficacy Tests
47
lt51gt Antimicrobial Efficacy Test

• Major Changes
• Preparation of inoculum clearly defined
• Addition of categories for different product
  types
• 7 day criterion added for category 1A products
• Removal of environmental isolates as test
  organisms
• In-Process Revision Published in July/Aug 1995
  Pharm. Forum
• In-Process Revision Published in Nov/Dec 1996
  Pharm. Forum
• In-Process Revision Published in Mar/Apr 1997
  Pharm. Forum
• Final version Published in Supplement 8
  (effective May 15, 1998)
• In-Process Revision Published in Jan/Feb 1999
  Pharm. Forum

48
lt52gt Antimicrobial Effectiveness Testing for
Vaccines

• Requested by Pharm Eur to write a chapter for
  harmonized AET test for vaccines.
• Criteria
• In-process Revision in May/Jun 1998 Pharm Forum

49
Consensus Antimicrobial Effectiveness Test

• Effort of the European Pharmacopeia, Japanese
  Pharmacopeia, and United States Pharmacopeia to
  come to a harmonized assay.

50
Antimicrobial Efficacy Test

• Contentious Harmonization Effort
• USP - generally viewed as less stringent
  requirements, fewer time points
• EP - more difficult criteria, more time points
• No fundamental difference in procedure or
  materials (with the exception of E. coli).

51
Criteria for Passage
52
Major Issue with Harmonization

• FDA must detail a mechanism for handling
  grandfathered products.
• In the absence of protection, USP cannot agree to
  regulate safe and effective products off the
  market
• In the presence of protection, USP is inclined to
  accept EP criteria

53
Australian Perspective

• Australia prefers the EP standards for compendial
  preservation test, although has accepted USP in
  the past.
• TGA is unconvinced that compendial AET is
  sufficient to demonstrate open bottle dating.
• Open Bottle AET should be demonstrated over the
  entire stability program and include either
• Repeated microbial challenge test
• ML tests on products used by patients over the
  full shelf-life of the product.
• Preservative Efficacy in Multidose
  Pharmaceutical Preparations TGA News May 1999
  pp.11-12

54
In-Use Stability Testing

• European Pharmacopoeia (2000) 5.1.3 Efficacy of
  Antimicrobial Preservation
• CPMP/QWP/159/96 Note for Guidance on Maximum
  Shelf-life for Sterile Products for Human Use
  After First Opening or Following Reconstitution
• EMEA/CVMP/127/95 Note for Guidance In-use
  Stability Testing of Veterinary Medicinal
  Products
• CPMP/QWP/155/96 "Note for Guidance on Development
  Pharmaceutics
• ISO/TC 172/SC7 (Document ISO/DIS 14730) Optics
  and Optical Instruments Contact Lens Care
  Products Multidose Preserved Contact Lens Care
  Products Antimicrobial Preservative Efficacy
  Testing and Guidance on Determining Discard
  Dating
• CPMP/CVMP/QWP/115/95 Note for guidance on
  inclusion of antioxidants and antimicrobial
  preservatives in medicinal products

55
In-Use Stability Testing

• CPMP/QWP/2934/99 Not for Guidance on In-use
  Stability Testing of Human Medicinal Products.
  Annex to
• Note for guidance on Stability Testing of
  Existing Active Substances and Related Finished
  Products and
• Note for guidance on Stability Testing of New
  Drug Substances and Products
• EMEA/CVMP/198/99 Note for Guidance Maximum
  Shelf-Life for Sterile Medicinal Products After
  First Opening or Following Reconstitution
• EMEA/CVMP/127/95 FINAL Note for Guidance
  In-Use Stability Testing of Veterinary Medicinal
  Products.

56
In-use Stability Testing

• When it Should be Performed
• If the product does not have sufficient intrinsic
  antimicrobial activity
• If the preservative system is subject to
  oxidative degradation
• If the product is packaged in oxygen impermeable
  container
• If the product will be used for extended periods
  of time.
• In-use Shelf-Life Testing What Data are
  Required and When? 1998. S. Sutton, B.
  Matthews and D. Dunn. Reg. Affairs J.
  9728-733.

57
Review of USP Changes
58
Review of USP Changes
59
Review of USP Changes