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 6.2: January 2008 Supplement 6.3: January 2008 Supplement 6.4: June 2008 Supplement 6.5: June 2008 Supplement 6.6: July 2008 Supplement 6.7: September 2009 Supplement 6.8: January 2010 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_5940,6080,6077,6095,6062_n.html


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.


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