Developments in regulatory requirements

© European Compliance Academy (ECA)
Developments in Regulatory
Requirements
Dr. Tim Sandle
European Microbiology Conference
4th
– 5th
May, Prague

Introduction
 European Pharmacopoeia
 United States Pharmacopoeia
 ISO
 PIC/S
 EMEA
 FDA
 WHO
 ICH
 NHS

Harmonisation
 USP, EP & JP: began in 1990
 Why harmonise?
• Globalisation of the pharmaceutical and associated industries
• Suppliers of raw materials operate globally for many products but need
locally adapted test methods, SOPs etc.
• Pharmaceutical manufacturers have to adapt test methods and
licensing files to local requirements
• Reduce costs

European Pharmacopoeia

 European Pharmacopoeia is revised and issued by the
European Directorate for the Quality of Medicines &
HealthCare (EDQM) (Council of Europe)
• European Pharmacopoeia was first published in 1967
 European Pharmacopoeia is published in two volumes.
• The first volume consists of general chapters (such as the
sterility test) and the second of specific monographs for
materials (such as sodium heparin).
 European Pharmacopoeia is issued at periodic intervals.
• A primary edition.
• Several supplements over a two year period.

 Supplement 6.1: January 2008
 Supplement 6.4: June 2008
 Supplement 6.5: June 2008
 Supplement 6.6: July 2008
 Supplement 6.7: September 2009
 7th
edition: January 2011

 Sterility Testing
• Supplement 6.3:
• New chapter 5.1.9 ‘Guidelines for using the test for sterility’
 Section of text deleted from 2.6.1
 To allow harmonisation with USP
 Relates to test method and method validation
• 2.6.1 is now almost fully harmonised with USP <71>
 Changes: precautions against microbial contamination, culture media and
incubation temperatures, method suitability test, main test method, minimum
number of items to be tested.
 “Residual differences” with USP: rinse fluids; volume of products tested;
number of containers of product to be tested; and acceptance criteria.
• Supplement 6.3:
• Reference added to indicate harmonization process

 Non-sterile products #1
• Supplement 6.3:
• Harmonisation with USP for:
» Microbiological examination of non-sterile products:
microbial enumeration tests (2.6.12)
» Microbial examination of non-sterile products: test for
specified micro-organisms (2.6.13)
» Microbial quality of non-sterile pharmaceutical preparations
and substances for pharmaceutical use (5.1.4)
- With 2.6.12 and 2.6.13, these chapters are now
interchangeable in the ICH regions (Q4B Annex 4A): JP & USP

 Non-sterile products #2
• Supplement 6.5:
 A negative control now required when verifying the
performance of the media AND also when testing products.
 With 2.6.13:
- E. coli has been deleted as an indicative strain for XLD agar
since it grows with difficulty on this medium
- Clostridia: the description of the test has been reworded Section
4-6-1 reads: “Divide the sample into 2 portions of at least 10
ml”. The wording has been included because a volume each of
the treated and of the untreated sample must be transferred to
a container with reinforced medium for clostridia.
- For any suspect positive Clostridia an ID test is required in
order to distinguish Clostridia from any facultative anaerobic
Bacillus species

Non-sterile products #3
 Supplement 6.5:
 2.6.13
 A maximum incubation time of 72 h has been added
(previous incubation time of exactly 48 h: too stringent)
 Recommended solutions and culture media: the
statement “Other media may be used if they have similar
growth promoting and inhibitory properties” has been
reworded because it had been considered misleading.
Revised wording:
“Other media may be used provided that their suitability
can be demonstrated”.

 Water testing
• Supplement 6.3:
• WFI 0169 and Purified Water 0008
 5-day incubation time has been replaced by a requirement of not
less than 5 days
 Addition of criteria for growth promotion of the R2A medium used for
microbiological monitoring (similar to media listed in 2.6.12 / 2.6.13)

 Bacterial Endotoxins (2.6.14)
• Supplement 6.6:
 A number of clarifications have been included.
- For the calculation of the endotoxin limit, the maximum
recommended concentration is no longer defined for a single
hour period but for a bolus dose.
 A new chapter ‘Test for bacterial endotoxins: guidelines’ (5.1.10).
- Not part of pharmacopoeial harmonisation
- Deleted from the 2.6.14 chapter and included in part 5 of the
European Pharmacopoeia.

 Pyrogens / Endotoxin
• For 7th
edition:
 General guidance
- EU Directive 86/609/EC
- Use of an in vitro method (the LAL test) as a preferred
alternative to the pyrogen test in rabbits for a number of
products (mainly blood products)
 2.6.14
- Gel-clot technique. The number 4 has been added to the
following statement:……”Determine the geometric mean end-
point concentration by calculating the mean of the logarithms of
the end-point concentrations of the 4 dilution series, take the
antilogarithm of this value, as indicated by the following
expression:………”

 New monograph: MAT
• Supplement 6.7:
• An new monograph has been published. This is 2.6.30 Monocyte-
activation test.
• The monocyte activation test (MAT) is possible replacement for the
rabbit pyrogen test and can potentially be used in conjunction with the
LAL test.

 Aspergillus brasiliensis
• Supplement 6.8:
 In relation to monographs 2.6.1 and 2.6.12
 Strain ATCC 16404, formerly Aspergillus niger has been
reclassified, following a polyphasic study, as Aspergillus brasiliensis

 2.6.21. Nucleic acid
amplification
techniques
• Supplement 6.8:
 A validation guideline for
the quantification of B19
virus DNA in plasma pools

 Biological Indicators
• For 7th
edition:
 Biological indicators (5.1.2)
 Names of organisms have been changed to be in line with current
taxonomic nomenclature
 Alignment with EN ISO 11138 (Sterilization of health care products -
Biological indicators)

 Revision of EP chapter 5.1.6. Alternative Methods for Control
of Microbiological Quality
• Describes alternative methods for the control of microbiological quality.
• Qualitative, quantitative and identification tests and guidance for using
validation criteria.
• Technology overviews including risk-benefit analysis and an annex
describing an example of a detailed protocol for the validation of an
alternative method using bioluminescence techniques.

United States Pharmacopoeia
Recent changes

USP33 2nd Supplement (October 2010)
<1072> Disinfectants and Antiseptics
 Classification of Disinfectants
 Selection of a Disinfectant for Use in a Pharmaceutical
Manufacturing Environment
 Theoretical Discussion of Disinfectant Activity
 Mechanism of Disinfectant Activity
 Microbial Resistance to Disinfectants
 Disinfectant Challenge Testing
 Disinfectants in a Cleaning and Sanitisation Program

Proposed changes

 USP <1231> ‘water’
• Under revision
• Tables of
recommendation
action limits are likely
to be deleted

 USP <1116> under
review
• Action levels for EM
likely to be replaced by
frequency tables
 E.g. Isolator, incidence
rate of <0.1%
 E.g. ISO Class 5,
incidence rate of <1%

 USP <1113> Microbial Identification (USP35-NF30)
• Title change
• Microbial Characterization, Identification, and Strain Typing
• The chapter provides general information on available microbial
identification methods, selection of appropriate methods for use, and
verification of these methods
• Emphasis on phenotypic and genotypic methods
• Trending microflora

 <85> Bacterial Endotoxins Test
• on the basis of an FDA recommendation, change the
calculation of the limit for endotoxins in products
dosed by body surface area, appearing in non
harmonized footnote 2

Possible changes

 A new monograph entitled, “Endotoxin Indicator for
Depyrogenation” was proposed in Pharmacopeial
Forum (34(6): 1444).
• Definition of the term endotoxin indicator - “carrier (challenge vial of
endotoxin or an article spiked with endotoxin) for use in depyrogenation
studies.”
• Description of the characterization (identification, purity) of an EI
 Also:
• Reference to the USP RSE
• Packaging and storage
• Expiration dating
• Recovery tests
• Disposal of endotoxin indicators.

 <1128> Nucleic Acid Based Techniques –
Microarray (new) (USP35-NF30)
• Because there is no information in USP on this subject, this
general information chapter is being proposed.
• This new chapter is a part of the series of information chapters
describing various aspects of nucleic acid-based testing:
 <1125> Nucleic Acid Based Techniques-General
 <1126> Nucleic Acid Based Techniques-Extraction, Detection and
Sequencing
 <1127> Nucleic Acid Based Techniques-Amplification
 <1129> Nucleic Acid Based Techniques-Genotyping
 <1130> Nucleic Acid Based Techniques-Approaches for detecting
Trace Nucleic Acids (Residual DNA Testing)

ISO standards

ISO
ISO14968 (under review)
Standard ISO14698 (Bio contamination control) is currently under
review by British Standards
 Part 1 General principles and methods
 Part 2 Evaluation and interpretation of biocontamiantion data
Aims:
 Classification of cleanrooms by airborne biocontamination,
including methods of measurement and the validation of
sampling methods. Similar to ISO14644
 Approaches to classify and monitor cleanroom surfaces.
 Risk management and assessment techniques.
 Establish a relationship between enumeration and the types of
isolates detected
 Consideration of some of the weaknesses of environmental
monitoring sampling methods

ISO
 ISO 14644 (under review)
• Primary change proposed is a new method for cleanroom classification
• Current standard determines the number of particle counter locations in
a cleanroom using a formula based on the square root of the surface
area of the cleanroom in cubic metres.
• The proposed change is move to classification using a table with a
formula for intermediate classes (a ‘return’ to the old FS209E).

ISO
 ISO 21501 (in place)
• Calibration of particle counters
 Size calibration
 Verification of size setting
 Counting efficiency
 Size resolution
 False count rate
 Concentration limit
 Sampling flow rate
 Sampling time
 Sampling volume
• Many older model particle counters will not meet the new standard.

PIC/S and EMA

PIC/S
 PIC/S inspection guides
• ‘Validation of Aseptic Processes’ (PI 007-5)
 That media fills should be run for a similar length of time as product fills;
 The number of containers filled should be close to the commercial
batch size;
 The frequency of re-qualifications is a minimum of six-monthly;
 There is considerable emphasis on the selection of the appropriate
culture medium, including being able to demonstrate growth promotion
(as an aside, due to concerns with TSEs in Europe some companies
have moved away from bovine based media and towards vegetable
peptones);
 The incubation conditions are established as:
- “incubate at 20-25°C for a minimum of 7 days followed
immediately, or after a first reading, by incubation at 30-35°C for a
total minimum incubation time of 14 days”

PIC/S
 PIC/S inspection guides
• PIC/S Document 007-4 ‘Recommendation on the Validation of aseptic
processes’ has been updated
• PIC/S guidance on EU GMP Annex 1
 Cleanrooms and clean air device classification; and media simulation trials.

EMA
 The EMA has published some questions and answers concerning
the use of Process Analytical Technology (PAT) on their website:
http://www.gmp-compliance.org/eca_news_1385_5940,6080,6077,6095,6

FDA

FDA
 FDA draft Process Validation Guidance
• FDA’s current thinking on process manufacture
• Reference to ICH Q8, Q9 and Q10, particularly the product lifecycle
approach.
• Main sections : process design, process qualification and continued
process verification.

FDA
 The FDA have
‘adopted’:
• three annex
documents to ICH
Q4B (4A, 4B and 4C).
• The annexes relate to
the microbiological
control of non-sterile
doses.

WHO and NHS

WHO
 New publications / updates:
• ‘WHO Expert Committee on Specifications for Pharmaceutical
Preparations’.
• WHO Good Practices for Pharmaceutical Quality Control Laboratories
 Guide to:
- Management, infrastructure, materials, working procedures, and safety
• Annex 4 “Good Manufacturing Practices for Sterile Pharmaceutical
Products”
 To come in line with ISO 14644-1

NHS
 Monitoring hospital and cleanroom gowns
• The UK NHS have a useful illustrated guide to monitoring cleanroom
gowns for hospital pharmacies (EU GMP Grade B environments). The
guide contains some useful pointers about selecting the locations for
the microbiological contact plate monitoring and frequencies of testing.

Thank You
www.pharmig.blogspot.com

Developments in regulatory requirements

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