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European Journal of Parenteral and Pharmaceutical Sciences - EJPPS
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The EJPPS Journal is highly commended peer-reviewed scientific and technical papers in the pharmaceutical and healthcare sciences. The Journal is published four times a year with a circulation of over 3,500 and is distributed to the PHSS membership as a one of the member benefits.

Journal articles are categorized into the following areas:

Editorial, Peer-Review Papers, Science and Technology Feature, Letter to the editor, Book review, Regulatory Review, Activities and Initiatives, India

The areas of interest are original papers and reviews on subjects that cover all aspects of the parenteral and pharmaceutical companies, both scientific and practical, including but not limited to the following:

Sterilisation techniques; Isolator technology; Validation; Aseptic processing; Microbial detection methods; Packaging; Lyophilisation; Cleanroom design; Biotechnology; Preservatives; LAL testing; Process filtration. Hospital Sector considerations on the above is also an important area.

 

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Latest Issue

Volume 22 Issue 1

 

Contents

Editorial: Annex 1 and memory loss

Peer-reviewed Papers

Microbial contamination risks of the surface of surgical clothing systems – an observational study
Catinka Ullmann, Bengt Ljungqvist and Berit Reinmüller

AbstractThe personnel in an operating room are usually the main source of microorganisms and the correct clothing system for staff is, therefore, of high importance for patient safety. The same surgical clothing system is often worn during a complete working day/shift, i.e. no change of clothing between operations, and the personnel may also leave the surgical department/section for different reasons.  The aim of this study was to investigate the risk of contaminating the outside of the surgical clothing during a day of use and also to evaluate if there is a higher risk of contamination if staff visit areas outside the surgical department.

 

Use of contact plates to perform environmental settle plate testing
Aleshia Samson, Andrew Sage and David Jones - Rapid Micro Biosystems, USA
AbstractAn evaluation was performed to investigate the use of contact plates in place of Petri plates to perform environmental monitoring settle plates. A Petri plate has approximately 2.5 times the surface area of a contact plate and a different agar profile for exposure to air. Petri plates also have plastic walls that extend above the agar surface and may affect air flows. To evaluate the possible use of contact plates, analysis of capture and recovery of bioburden was performed in a number of different environments, with differing numbers of exposed plates. Overall, a good correlation was shown when two contact plates were used as a substitute for one Petri plate with a 4-hour exposure time. The ability to use contact plates for a settle plate test allows the use of a single consumable, the contact plate, to be stocked for environmental monitoring testing.

Science and Technology Papers
Review on endotoxin-mediated toxic anterior segment syndrome (TASS) in ophthalmic products – outbreaks, product recall and testing limits
R. Vijayakumar, Mohammad Saleh Al- Aboody, Wael Alturaiki and Tim Sandle
Abstract: Ophthalmic products are at risk from direct or indirect contamination from Gram-negative bacteria. A by-product of Gram-negative bacteria is the lipopolysaccharide component of the cell wall (commonly known as endotoxin). Bacterial endotoxin is a potent ocular inflammatory agent and causes ‘toxic anterior segment syndrome’. This paper reviews the patient risks from endotoxin and considers the sources of endotoxin in relation to the production of ophthalmic surgical products. The paper also considers the main product contamination recalls during the past decade. The risks and requirements for testing are then considered in light of current regulatory guidances. We conclude by making recommendations for endotoxin and bioburden control for manufacturing and in setting out appropriate endotoxin test limits for the testing of finished ophthalmic products.


Regulatory review 
Malcolm Holmes
PHSS activity and initiatives report

 

 

Volume 21 Issue 4

 

Contents

Editorial: CAPA is continuous improvement NOT failure management

George Sykes Memorial Winner Announcement

 

Peer-reviewed Papers

Releasing capacity of pre-sterile cotton swabs for discharging sampled microorganisms
Ravikrishna Satyada and Tim Sandle

AbstractSurface monitoring by using swabs forms a regular part of environmental monitoring of cleanrooms.
There are different factors that affect swab recovery, from tip type to enumeration method. One factor with swabs where the microorganisms are detached from the swab tip and which are then membrane filtered is the period of vortex mixing. This paper discusses microbial surface sampling, and the factors that affect swab recovery, and presents some experimental data where vortex times are considered for a range of microorganisms. The study outcome indicates that 15 seconds of vortex mixing is sufficient to obtain microbial recoveries from the swab tip above 50%.

Science and Technology Papers
Assessing surface purity in clean process environments
Peter Knott

Abstract: The assessment of surface quality plays a significant role in the clean process. Contact and technical surfaces near a product must be monitored to ensure an optimum clean process, and a range of relevant measurement techniques and principles are available. The assessment of surface purity is a challenge.

Summary of Chapter 2 of Technical Monograph 20
Rhett Griffiths
Regulatory review
Malcolm Holmes
PHSS activity and initiatives report


 

Volume 21 Issue 3


Contents

Editorial: Compliance by Observation - A non-compliant approach?

Peer-reviewed Papers

Calculation of airborne cleanliness and air supply rate for non-unidirectional airflow cleanrooms 

W Whyte, N Lenegan and T Eaton
Abstract:Equations have been recently derived by Whyte, Lenegan and Eaton for calculating the airborne  concentration of particles and microbe-carrying particles in non-unidirectional airflow cleanrooms. These equations cover a variety of ventilation systems, and contain the variables of air supply rate, airborne dispersion rate of contamination from machinery and people, surface deposition of particles from the air, concentration of contamination in fresh make-up air, proportion of fresh air, and air filter efficiencies. The relative importance of these variables is investigated in this present research paper, with particular regard to the removal efficiency, location, and number of air filters. It was shown that air filters were important in ensuring low levels of contamination in cleanrooms but the types of filters specified in current cleanroom designs were very effective in ensuring a minimal
contribution to the cleanroom’s airborne contamination especially when a secondary filter is used in addition to a primary and terminal filter. The most important determinants of airborne contamination were the air supply rate and the dispersion rate of contamination within the cleanroom, with a lesser effect from deposition of airborne particles onto cleanroom surfaces. The information gathered confirmed the usefulness of the equation previously used by Whyte, Whyte, Eaton and Lenegan to calculate the air supply rate required for a specified concentration of airborne
contamination.

 

Assessing contamination control of pre-sterilised container tub transfers into an aseptic manufacturing filling isolator via a de-bagging/no-touch-transfer process step
Bengt Ljungqvist, Berit Reinmüller, Corinna Maier and Ann-Catherine Roth
Abstract:Experimental contamination transfer challenge studies were designed to assess whether contamination control and sterility are maintained when using a no-touch-transfer (NTT) debagging tub transfer method to ntroduce pre-sterilised containers into a FlexPro50 aseptic manufacturing isolator/restricted-access barrier system filling line system. Importantly, the sterile tubs of product containers are enclosed in double steri-bags, and remain sterile through the supply chain to point of filling. Use of NTT means that any of the current automated bio-decontamination
steps usually employed prior to material transfer into Grade A areas are rendered unnecessary; since the bag contents remain sterile and protected and can be transferred without exposing the Grade A aseptic processing zone to the outer bag. To support this rationale, two key contamination control studies were undertaken during processing of tub transfers with the NTT/de-bagging technology; 1) surface-to-surface transfer of human commensal microorganisms representing the challenge of ‘worst case’ operator handling, and 2) a structured approach evaluating the risk of airborne contamination as tubs move through the NTT process steps into the Grade A isolator environment by a particle challenge method (limitation of risks method). In these studies, the barrier–isolator
environment retained robust to adverse particle movement, without microbial contamination transfer. In addition, the sterile tub outer surfaces were confirmed as maintaining sterility during the NTT process step. These results provide proof of concept of NTT technology.

 

Revision of ISO 14644-1:1999 and ISO 14644- 2:2000 – A report on the changes, and explanation
of some of the key issues and principles

Gordon Farquharson


Brexit – Update on potential impacts on the pharmaceutical industry and its regulation
Malcolm Holmes

 

Regulatory review 

Malcolm Holmes

 

  

 

Volume 21 Issue 2


Contents
Editorial: EU and the US – vive la différence?

Peer-reviewed Papers

Equations for predicting airborne cleanliness in non-unidirectional airflow cleanrooms

W Whyte, N Lenegan and T Eaton
Abstract:Equations are derived in this paper for predicting the airborne concentration of particles and microbe-carrying particles in non-unidirectional airflow cleanrooms during manufacturing. The equations are obtained for a variety of ventilation systems with different configurations for mixing fresh and recirculated air, air filter placements, and number and efficiency of air filters. The variables in the equations are air supply rate, airborne dispersion rate of contamination from machinery and people, surface deposition of particles from air, particle concentration in fresh makeup air, proportion of make-up air, and air filter efficiencies. The equations are amenable to relatively simple modification for the study of different cleanroom ventilation systems. The use of these equations to investigate the effect of different configurations of ventilation systems and the relative importance of the equation variables on airborne concentrations will be reported in a further paper.

 

Deposition velocities of airborne microbecarrying particles
W Whyte and T Eaton
Abstract:The deposition velocity of airborne microbe-carrying particles (MCPs) falling towards surfaces was obtained experimentally in operating theatres and cleanrooms. The airborne concentrations of MCPs, and their deposition rate onto surfaces, are related by the deposition velocity, and measurements made by a microbial air sampler and settle plates allowed deposition velocities to be calculated. The deposition velocity of MCPs was found to vary with the airborne concentration, with higher deposition rates occurring at lower airborne concentrations. Knowledge of the deposition velocity allows the deposition on surfaces, such as product or settle plates, by a known airborne concentration of MCPs to be predicted, as well as the airborne concentration that should not be
exceeded for a specified product contamination rate. The relationship of airborne concentration and settle plate counts of MCPs used in Annex 1 of the EU Guidelines to Good Manufacturing Practice to specify grades of pharmaceutical cleanrooms was reassessed, and improvements suggested.

 

The use of a single growth medium for environmental monitoring of pharmacy aseptic units using tryptone soya agar with 1% glucose

John Rhodes, Jennifer Feasby, Wayne Goddard, Alison Beaney and Mike Baker

Abstract:The suitability of tryptone soya agar, Sabouraud dextrose agar and tryptone soya agar with 1% glucose plates for general environmental monitoring was compared. Plates were incubated at three different temperatures to assess an optimal temperature for growth. Results indicated that there are benefits from using tryptone soya agar with 1% glucose incubated at 25°C as an all-purpose medium for environmental monitoring.

Regulatory review 

Malcolm Holmes

 

PHSS activity and initiatives report 

 

 

 

Volume 21 Issue 1


Contents
Editorial:The relevance of quality principles – do the basics ever change?
 

Peer-reviewed Papers

Facility-based case study: A comparison of the recovery of naturally occurring species of bacteria and fungi on semi-solid media when incubated under standard and dual temperature conditions and its impact on microbial environmental monitoring approach
ID Symonds, DL Martin and MC Davies
Abstract:This study compared the recovery of naturally occurring micro-organisms on tryptone soya agar (TSA) and Sabouraud dextrose agar (SDA), when incubated under three different temperature conditions. The micro-organisms were sourced directly from a factory environment. The incubation conditions employed were 20–25°C, 30–35°C and a combination of each, termed dual temperature incubation, for a period of 5 days.
The results demonstrated that TSA was the most effective medium for the primary isolation of both bacterial and fungal/yeast micro-organisms. Bacteria were recovered best at 30–35°C with human commensals providing the largest numbers, while fungi and yeasts showed best recovery at 20–25°C. The use of dual temperature incubation at 20–25°C for 3 days followed by 2 days at 30–35°C gave reduced recovery for both types of micro-organisms.
The authors recommend that similar studies should be considered for all manufacturing facilities in order to determine the optimal incubation temperature regime for the recovery of local, naturally occurring species of bacteria and fungi which may present a threat to aseptic manufacturing areas.
This process should be undertaken as part of an overall risk assessment for the establishment and maintenance of a viable environmental monitoring programme and may also be relevant to theincubation conditions employed in process simulation studies.


 

Determination of the cleaning efficiency for glassware in the pharmaceutical microbiology laboratory
Tim Sandle and Ravikrishna Satyada
Abstract:The cleaning of glassware is an important preliminary step prior to sterilisation in the microbiology laboratory. If insufficient cleaning takes place, residues of culture media and chemicals can remain and these could potentially have an impact upon microbial growth during various microbiological qualitative and quantitative tests. This paper outlines a study where four different manual cleaning regimes were used to evaluate glassware cleaning. It was found that a 5% solution of neutral detergent, followed by two rinses was the most efficient method. The experiment is put forward as a case study for other laboratories to replicate as necessary.
 

Science and Technology Features

Summary of Chapter 1 of Technical Monograph 20

Rhett Griffiths

AbstractThis is the first in a series of five articles which will introduce, explore and summarise the key information for surface and airborne bio-contamination control and management, contained in the guidance document Biocontamination Technical Monograph 20 prepared by the PHSS Biocontamination Special Interest Group
from the pharmaceutical industry, NHS, suppliers and specialist consultants, and reviewed by the Medicines and
Healthcare products Regulatory Agency1. The monograph gives a comprehensive analysis of biocontamination risk profiling and characterisation, control, monitoring and deviation management for controlled/good manufacturing practice (GMP) classified areas (including cleanrooms employing barrier separation technology, e.g. isolators
and restricted access barrier systems (RABS))


Regulatory review 

Malcolm Holmes

 

PHSS activity and initiatives report 

PHSS and UCL Q3P Annual Conference 11 September 2015 – Impact of Changes in GMP Regulations Including Annex 1 and ISO Standards Revisions

 

Volume 20 Issue 4


Contents
Editorial: Qualified person or quivering person

 

Peer-reviewed Papers

Assessment of degree of risk from sources of microbial contamination in cleanrooms; 2: Surfaces and liquids
W Whyte and T Eaton

Abstract: The degree of risk from microbial contamination of manufactured products in healthcare cleanrooms has been assessed in a series of three articles. The first article discussed airborne sources, and this second article considers surface contact and liquid sources. A final article will consider all sources and give further information on the application of the risk method. The degree of risk to products from micro-organisms transferred from sources by surface contact, or by liquids, has been assessed by the means of fundamental equations used to calculate the
likely number of microbes deposited (NMD) onto, or into, a product. The method calculates the likely product contamination rate from each source and gives a more accurate risk assessment than those presently available. It also allows a direct comparison to be made between microbial transfer by different routes, i.e. surface, liquid and air.

 

Science and Technology Features

Microbial transfer by surface contact in cleanrooms

W Whyte and T Eaton

Abstract:Experiments were carried out to ascertain the proportion of microbes that would be transferred from  a contaminated surface to a receiving surface in a cleanroom. To simulate transfers, microbe-carrying particles (MCPs) were sampled from the skin onto donating sterile surfaces, which were latex gloves,stainless steel and clothing fabric. A contact was made between these surfaces and a sterile receiving surface of stainless steel, and the proportion of MCPs transferred ascertained. The proportion of MCPs transferred, i.e. the transfer coefficient, was 0.19 for gloves, 0.10 for stainless steel, and 0.06 for clothing fabric. These transfer coefficients would vary in different conditions and the reasons are discussed.

Risk-based environmental control and process monitoring in aseptic processing
James L Drinkwater and Marc Van Laere

Abstract: Risk-based environmental control, delivered by technical and organisational good manufacturing practice (GMP) control measures, are inherently linked to risk-based environmental monitoring (EM) and trend data analysis. Process monitoring is reported as a developing requirement in the revision of the EU Guidelines to Good Manufacturing Practice Annex 1 which combines all EM programs through classification/characterisation, media fills/process simulations, routine EM and batch/shift end surface sampling as one plan. This article considers the control measures for environmental control in different aseptically processed product types together with requirements in risk-based EM.


Regulatory review
Malcolm Holmes

 

PHSS activity and initiatives report

Volume 20 Issue 3


Contents Page

Editorial: Editorial: Annex 1 revision - guidance, rules and interpretation

 

Peer-reviewed Papers


Title: Validation of the Growth DirectTM system to perform pharmaceutical water bioburden analysis 

Author: K. Nguyen, A. Mills, A. Sage and D. Jones 

Abstract: The validation of the Growth Direct system is described for the automated incubation and counting
of microbial colonies on R2A media plates derived from a water bioburden test. The validation
strategy and sample data are given to demonstrate that the technology is accurate for enumerating
microorganisms, accurate and precise for microbial recovery and equivalent to the current
compendia test for water testing.

Title: Assessment of the disinfection of impaction air sampler heads using 70% IPA, as part of cleanroom environmental monitoring 

Author: Tim Sandle and Ravikrishna Satyada

Abstract: Active (volumetric) air-sampling is an important component of the environmental monitoring of
cleanrooms. It is important that the results of such monitoring are accurate. One aspect of ensuring
that the result is ‘valid’ is through minimising cross-contamination. The ‘at risk’ part of the sampler
is the head. There are three alternatives to control cross-contamination during active air sampling
contamination control: using multiple air samplers, autoclaving the sampler head in-between
samples, or disinfecting the sampler head intermittently. This paper summarises a study where a
disinfectant (70% isopropyl alcohol) was used to disinfect the head of an impaction air sampler
between sampling sessions (spray-and-wipe technique). The study examined two factors: disinfectant
decontamination effectiveness and the potential for the inhibition of microbial growth. With
decontamination effectiveness, successive operations of an air sampler were examined within
different cleanroom grades; with microbial growth inhibition studies, different disinfection time
points were assessed. The paper concludes that this method of contamination control is effective and
applicable to most cleanroom monitoring situations: it is unlikely to allow carry-over of microbial
contamination and it is not shown to cause inhibition of microbial growth.

Science and Technology Features


Title: Requirements and environmental monitoring in pharmaceutical production versus operating rooms in hospitals with focus on airborne particles and microorganisms

Author: Catinka Ullmann, Bengt Ljungqvist and Berit Reinmüller

Abstract: Clean areas used for aseptic manufacturing of sterile medicinal products are subject to governmental
requirements and guidelines in order to minimise risks of particulate and microbiological
contamination. High cleanliness is also a necessity in hospital environments to ensure safe conditions
for the patients. The requirements for premises within the pharmaceutical industry are compared to
those of the hospital, e.g. operating rooms including environmental monitoring with a focus on particle
and microorganism levels.

Regulatory review

Author: Malcolm Holmes

PHSS activity and initiatives report

 

Volume 20 Issue 2

Contents Page

Editorial: Cross-contamination control - new requirements

Peer-reviewed Papers

Title: Settle plate exposure under unidirectional airflow and the effect of weight loss upon microbial growth 

Author: Tim Sandle

Abstract: Settle plates play an important part in the environmental monitoring programme and for the assessment of microbial settlement at key locations within cleanrooms, particularly when situated within unidirectional airflow devices. It is important that the exposure time of the settle plate is assessed to ensure that the proportion of weight loss (through the loss of moisture) does not result in a loss of growth-promoting properties. A second important concern is with avoiding cracks in the agar which might render reading sections of the exposed plate impossible. This paper outlines a case study to assess the exposure time through microbial growth promotion.


Title: Assessment of degree of risk from sources of microbial contamination in cleanrooms: 1: Airborne

Author: W Whyte and T Eaton

Abstract: The degree of risk from microbial contamination of manufactured products by sources of
contamination in healthcare cleanrooms has been assessed in a series of three articles. This first
article considers airborne sources, and a second article will consider surface contact and liquid
sources. A final article will consider all sources and the application of the risk method to a variety of
cleanroom designs and manufacturing methods.
The assessment of the degree of risk from airborne sources of microbial contamination has been
carried out by calculating the number of microbes deposited from the air (NMDA) onto, or into, a
product from various sources. A fundamental equation was used that utilises the following variables
(risk factors): concentration of source microbes; surface area of product exposed to microbial
deposition; ease of microbial dispersion, transmission and deposition from source to product; and
time available for deposition. This approach gives an accurate risk assessment, although it is
dependent on the quality of the input data. It is a particularly useful method as it calculates the likely
rate of product microbial contamination from the various sources of airborne contamination.

Science and Technology Features

Title: Quality by design in an evolving manufacturing sector

Author: Mary Ellen Crowley and Abina M Crean

Abstract: Regulatory guidelines are changing product quality focus from a reliance on end product testing to a
quality-by-design (QbD) approach across the entire pharmaceutical product life cycle. The
introduction of QbD elements to pharmaceutical manufacturing has the ability to speed up the time to
market by facilitating scale-up during product development, enable real-time release and reduce the
risk of batch failures. Pharmaceutical manufacturing approaches to make plants more efficient and
flexible include a move towards continuous manufacturing platforms. As continuous manufacturing
processes have no defined batch size, proving rigorous process control and fault detection is crucial to
validate these processes. Continuous manufacturing, therefore, requires that a much greater burden
is placed on tight process control. To achieve this level of control, in-depth material and process
knowledge is required. QbD principles are, therefore, essential to ensure process control during
continuous production.
This article introduces and discusses the regulatory principles of the QbD approach across the
pharmaceutical product life cycle. It explores the role of QbD within an evolving pharmaceutical
manufacturing sector. The implementation of QbD is discussed together with the concepts of quality
target product profiles, material quality attributes, process parameter control, design space, process
models and process analytical technology.

Regulatory review

Author: Malcolm Holmes

PHSS activity and initiatives report

 

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