Cleanroom Management in Pharmaceuticals and Healthcare

Tim Sandle and Madhu Raju Saghee's new book is out!

Cleanroom Management in Pharmaceuticals and Healthcare

Edited by Tim Sandle and Madhu Raju Saghee.

"Everything you need to know about the operation and management of cleanrooms."

In 26 Chapters and over 600 pages this book provides a unique tool to help you achieve regulatory compliance. It first creates a foundation in history and established practice and then helps you understand how state of the art technology and engineering solutions can deliver the best practice and so provide reliable systems performance.

An essential read for practitioners in cleanroom technology: engineers, microbiologists, quality assurance, healthcare practitioners and pharmaceutical professionals.

For further details see: cleanrooms

Contents:

1. Introduction by Tim Sandle and Madhu Raju Saghee
2. History and development of cleanrooms by Tim Sandle
3. Cleanroom standards and GMP requirements by Mark Hallworth
4. Design and construction of pharmaceutical cleanrooms by Alexander Fedotov
5. Air handling systems for the protection of pharmaceutical manufacturing processes by Hans Schicht
6. Cleanrooms in hospitals by Alexander Fedotov
7. Commissioning and qualification of cleanrooms by Kevin Beauchamp and Miroslav Tonovski
8. Cleanroom certification and ongoing compliance by TimSandle and Madhu Raju Saghee
9. Fundamentals of pharmaceutical isolators by Brian Midcalf, John Neiger and Tim Sandle
10. The choice of isolators: A risk-based decision by Didier Meyer
11. Validation concepts in pharmaceutical aseptic application isolators by Rajesh Thempadiyil
12. Risk-based product and occupational exposure control in multi-product facilities by Julian Wilkins
13. Future of aseptic processing by James L Drinkwater
14. Aseptic process simulations/media fills by Marco Budini
15. Microbial risk management during aseptic manufacture by Tim Eaton
16. Airflow studies and airflow mapping by Tim Sandle,Marco Budini and T Rajesh
17. Cleanroom contamination sources and control measures by Eric Strauss
18. Particle counters and particle counting by Tony Harrison
19. Environmental monitoring in cleanrooms by Tim Sandle and Madhu Raju Saghee
20. Cleaning and disinfection practices by Tim Sandle and Madhu Raju Saghee
21. Cleanroom clothing byMatts Ramstorp
22. Quality assurance in hospital pharmacies by Richard Bateman
23. Building Management Systems for cleanroom process parameters monitoring and control by Sunil Chand Singhai and Rajesh Thempadiyil
24. Energy management and sustainable cleanrooms byNigel Lenegan and Ulla Thomsen
25. Auditing cleanroom operations by Tim Sandle and MadhuRaju Saghee
26. Developments in cleanroom technology by Tim Sandle and Madhu Raju Saghee


Published by Euromed

Posted by Tim Sandle

Guidance to Inspectors on Assessing Quality Risk Management

The Pharmaceutical Inspection Cooperation Scheme (PIC/S) has released an “Aide-Memoire” for GMP inspectors and for pharmaceutical organisations. The guide aims to provide support information for the implementation of quality risk management (QRM).

The document states that QRM aspects should be integral to the planning and content of all GMP inspections and that QRM should be integrated in all operations.

According to PIC/S:

“The Aide-Memoire has been developed by the PIC/S Expert Circle on Quality Risk Management. The purpose of the document is to assist GMP inspectors in the assessment of QRM implementation in industry during regulatory inspections. Parts of the Aide-Memoire may also be useful (with suitable modification) during other GXP inspections where similar principals of QRM also apply.”

For further details: PIC/S

Posted by Tim Sandle

To Catch a Virus (book)

Interesting new book:  To Catch a Virus

Expert storytellers weave together the science, technological advances, medical urgencies, and human stories that chronicle the development of the field of diagnostic virology.

Follows historical discoveries that defined viruses and their roles in infectious diseases over a century of developments, epidemics, and molecular advances, and continuing into the 21st century with AIDS, HIV, and a future that in no way resembles the past.

Features the great names and personalities of diagnostic virology, their contributions, their associations, and their challenges to prove findings that some considered fantasy.

Describes how scientists applied revolutionary technologies, studying viruses, first in animal models and tissue culture and progressing to molecular and genetic techniques.

Appeals to the pioneer and adventure-seeker who is interested in how a scientific field evolves.

Hardcover, 392 pages, illustrations, index.

For further details and to order, see the link below:

Posted by Tim Sandle

Antibacterial curtain study

Past research, conducted at the University of Iowa Carver College of Medicine, found that 92% of hospital privacy curtains were contaminated with potentially dangerous bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE) within one week of being laundered.

The same research group recently submitted for publication a follow-on randomised, controlled study, examining the effectiveness of PurThread privacy curtains in a clinical setting. The study is currently on press, and publication is expected later in 2012 in the American Journal for Infection Control. Both studies are funded through non-restrictive research grants from PurThread Technologies.

The latest study, titled, “Hospital Privacy Curtains are Frequently and Rapidly Contaminated with Potentially Pathogenic Bacteria,” monitored 43 privacy curtains over a three-week period in a medical ward, surgical intensive care unit (ICU) and a medical ICU.

For more details see Cleanroom Technology

Posted by Tim Sandle

Pulsed UV sterilisation tunnels

An interesting alternative to the dry heat tunnel (for sterilization, rather than depyrogenation).

SteriBeam Systems has introduced fully automated in-line pulsed UV sterilization tunnels for pilot and production lines in the biomedical, food and pharmaceutical industries.

The Kehl am Rhein, Germany based company has equipped the tunnels with intense pulsed UV flash lamps, and they feature a UV transparent conveyor with adjustable speed. They are capable of up to 6 log sterilization of the entire product surface.

The pulsed UV exposures can be set from an interactive display by installing pulse bursts with selected pulsed energy and a number of pulses for each product. It can sterilize surfaces of open products and also products wrapped in UV transparent foils at the rate of up to 1,000 products/h, sterilizing them both from the top and bottom (360° UV exposures).

SteriBeam’s basic sterilisation tunnel has two PUV lamps, a small footprint of 120 x 80cm, requires max 2kw of electrical power and can be fed from a single phase electrical line.

For more details, see the SteriBeam press release.

Tim Sandle adds:


Studies which have been undertaken in relation to the pharmaceutical sector have shown that the technology can achieve six-log microbial kill of vegetative microorganisms and microorganisms in the endospore state in vials of Water-for-Injection:

Dunn, J., Burgess, D, and Leo, F. (1997). Investigation of Pulsed Light for Terminal Sterilisation of WFI Filled Blow/Fill/Seal Polyethylene Containers, PDA J Pharm Sci Technol 51 (3):111-115

Other research, of potential relevance to the pharmaceutical industry, has been with methods to disinfect (rather than ‘sterilise’) water systems:

Demirci, A. and Krishnamurthy, K. (2006). Disinfection of water by flow-through Pulsed ultraviolet light sterilisation system. Ultrapure Water Journal. 24 (1): 35-40


Posted by Tim Sandle

Aspergillus assay

Lab21 has announced plans to collaboratively develop a new molecular diagnostic assay for the detection of Aspergillus species.

The firm has signed an agreement with a prominent but unnamed diagnostics business to create, manufacture and distribute the product, which will be based on the partner organisation's real-time polymerase chain reaction platform.

Molecular diagnostic development resources will be contributed by Lab21, in addition to intellectual property pertaining to fungal diagnostics, in order to develop the test for use as an original equipment manufacturer reagent for the partner platform.

The new product will help to combat the trend of infections caused by Aspergillus, which places an estimated ten million people at risk annually.

Graham Mullis, chief executive officer of Lab21, said: "We are pleased to enter into a new agreement to develop this assay. The MycAssay Aspergillus test provides rapid, accurate clinical information that allows health professionals to make life-saving treatment decisions quickly."

Last month, the company announced the launch of a new clinical genomics centre within the Greenville Hospital System Memorial Medical Campus in South Carolina, a move that will greatly enhance Lab21's US operations.

For more details see Analytical World

Posted by Tim Sandle

ISO 14644 Part 8 published

The cleanroom standard ISO 14644 part 8 has been updated and the new version has been published.

This part of the standard is titled ‘Cleanrooms and associated controlled environments Part 8: Classification of air cleanliness by chemical concentration (ACC)’.

The scope of the standard is:

“This part of ISO 14644 establishes the classification of air chemical cleanliness (ACC) in cleanrooms and associated controlled environments, in terms of airborne concentrations of specific chemical substances (individual, group or category) and provides a protocol to include test methods, analysis and time-weighted factors within the specification for classification.

This part of ISO 14644 currently considers only concentrations of air chemical contaminants between 100 and 10−12 g/m3 under cleanroom operational conditions.

This part of ISO 14644 is not relevant for application in those industries, processes or productions where the presence of airborne chemical substances is not considered a risk to the product or process.

It is not the intention of this part of ISO 14644 to describe the nature of air chemical contaminants.

This part of ISO 14644 does not give a classification of surface chemical contamination.”

The standard is available from national standards bodies.

Posted by Tim Sandle

Why Do Cleanrooms Fail to Meet Owners Expectations?

Raymond K. Schneider has penned a thought provoking article in a recent edition of Controlled Environments about the failure to think through and to design cleanrooms correctly. Then article it titled “Why Do Cleanrooms Fail to Meet Owners Expectations?”

The introduction to the article reads:

“Over many years of consulting with cleanroom owner/operators a number of recurring problem areas that negatively affected the performance of clean facilities, HVAC as well architecture related, were identified. Such problems, if appropriately addressed during the design phase can be avoided; if identified after construction, possibly as a result of an unfavorable certification test report, or perhaps product quality concerns, can frequently be corrected, at a cost.”

In the article, the following areas are discussed: maintainability, pressure differentials, equipment related contamination, personnel issues, humidity control, size and space, and air movement.

The article can be read here: Cleanroom Design

Posted by Tim Sandle

FDA guidance documents for 2013

Guidance Agenda: New & Revised Draft Guidances CDER is  Planning to Publish During Calendar Year 2013

FDA has released a list of more than 50 guidance documents planned for 2013. The list reflects guidance documents currently under development as of the date of the posting, Jan. 31, 2013.

CATEGORY — Advertising

•Considerations for Regulatory Submissions of  Promotional Labeling and Advertising Materials  including Submissions in Electronic Format

CATEGORY — Animal Rule

• Product Development Under the Animal Rule

CATEGORY — Biopharmaceutics

• Food-Effect Bioavailability and  Fed Bioequivalence Studies---Bioav ailability and Bioequivalence  Studies for Orally Administered Drug Products Submitted in New Drug Applications General  Consideration

CATEGORY — Biosimilarity

• Submission of Clinical Pharmacology Data as Evidence of Biosimilarity for Biologics and Protein Products

CATEGORY — Chemistry

• Allowable Excess Volume and Labeled Vial Fill Size
• Bioequivalence Studies with Pharmacokine tic Endpoints for Drug Products Submitted in  Abbreviate New Drug Applications

• CMC Postapproval Manufacturing Changes Reportable in Annual Reports for Specified Biological  Products
• Comparability Protocols for Approved Drugs: Chemistry, Manufacturing, and Controls Information
•Elemental Impurities in Drug Products Marketed in the United States
• Immunogenicity Considerations for Low Molecular Weight Heparin
• Liposome Drug Products: CMC, Human Pharmacokinetic and Bioavailability; and Labeling  Documentation

CATEGORY — Clinical/Antimicrobial

• Antibacterial Therapies for Patients with Limited or No Alternative Therapies for the Treatment of  Serious Bacterial Diseases
• Community-Acquired Bacterial Pneumonia: Developing Drugs for Treatment
• Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment
• Pulmonary Tuberculosis: Developing Drugs for Treatment

CATEGORY — Clinical/Medical

• Alzheimer’s Disease: Developing Drugs for the Treatment of Early State Disease
• Common Issues in Drug Development for Rare Diseases
• Developing Drug and Biological Products for Analgesic Indications
• Modifications and Revisions of Risk Evaluation and Mitigation Strategies (REMS)
• Pregnant Women in Clinical Trials – Scientific and Ethical Considerations

CATEGORY – CMC and CLINICAL/MEDICAL

• Immunogenicity Assessment for Therapeutic Protein Products

CATEGORY — Clinical Pharmacology

• Bioanalytical Methods Validation
• Clinical Pharmacogenomics: Study Design and Premarketing Evaluation
• Clinical Pharmacology Consideration for Therapeutics Proteins
• General Clinical Pharmacology Considerations for Pediatrics Studies for Drugs and Biological Products

CATEGORY — Clinical/Statistical

• Multiple Endpoints in Clinical Trials

CATEGORY — Current Good Manufactur ing Practices (CGMPs)/Compliance

• Quality Systems Approach to Pharmaceutical cGMP Regulation (OMPQ)
• Uniformity of In-Process Mixtures (OMPQ)
• Control of Highly Potent Compounds (OMPQ)
• Contract Manufacturing Arrangements for Drugs: Quality Agreements
• Submission of Field Alert Reports and Biological Product Deviation Reports (OMPQ)
• Pre-Launch Activities Importation Request (PLAIR)

CATEGORY — Drug Safety Information

• Best Practices in Developing Proprietary Names to Minimize Medication Errors
• Providing Postmarket Safety Reports in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report)
• Safety Considerations in Product Design to Minimize Medication Errors.
• Securing the Drug Supply Chain—Standards for Tracking and Tracing Prescription Drug Packages
• Safety Considerations for Container Label and Carton Labeling Design to Minimize Medication Errors

CATEGORY — Electronic Submissions

• Providing Regulatory Submissions in Electronic Format – General Considerations
• Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
• Providing Regulatory Submissions in Electronic Format – Postmarketing Safety Reports
• Providing Regulatory Submissions in Electronic Format – Standardized Study Data
• Providing Submissions in Electronic Format – Summary Level Clinical Site Data for CDER’s Inspection Planning
• Providing Submissions in Electronic Format – Postmarket Non-Expedited Individual Case Safety
Reports; Technical Questions and Answers

CATEGORY — IND

• Adverse Events: Collection and Reporting for Secondary Endpoints

CATEGORY — Labeling

• Drug Names and Dosage Forms

• Pediatric Information: Incorporating into  Human Prescription Drug and Biological Products  Labeling

CATEGORY – Pharmacology/Toxicology

• Endocrine Disruption Potential of Drugs: Non Clinical Evaluation

CATEGORY — Procedural

• Applying the Criteria for Requiring a Risk Evaluation and Mitigation Strategy (REMS)
• Expedited Programs for Serious Conditions, Drugs and Biologics
• Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants
• Integrated Summary of Safety
• Investigational New Drug Applications prepared and submitted by Clinical Sponsor Investigators
• Pediatric Product Development 

• Pharmacy Compounding of Human Drugs Under Section 503A of the Federal Food, Drug, and Cosmetic Act
• Public Disclosure of FDA-Sponsored Studies
• Prescription Drug Marketing  Act (PDMA) Requirements
• Reporting Drug Sample Distribution Under Section 6004 of the Affordable Care Act
• Use of a Master File for Shared System Risk Evaluation and Mitigation Strategies 

• Electronic Source Data in Clinical Investigations

Posted by Tim Sandle

Trends in Laboratory QA/QC

Lab manager Magazine has an interesting interview Michael Noble, Ph.D., professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia and chair of the Program Office for Laboratory Quality Management.

In the article, Professor Noble emphasizes that while increased awareness, education and standardization of information and protocols have helped improve laboratory quality, people still need to be reminded that the pursuit of quality is a commitment that needs constant time, effort and money. Hence, he advises lab managers to start small, stay committed and keep an eye on the “cost” of having poor quality as opposed to focusing on just the costs incurred for quality improvements.

Here is an extract:

“The reality is that, with quality, the notion is one of continual improvement. It’s not a matter of doing it right the first time. It’s picking up the error, learning from it and always going forward a step at a time. And that’s where we tend not to be particularly good in our quality implementation. We always make this assumption that we have to get it right the first time. We don’t. Quality takes a long-term commitment. But it’s worth it in the end because costs are guaranteed to go down, the amount of energy people have will go up, the amount of enthusiasm will remain, we will stop losing personnel and we will make laboratories better.”

To access the article, go to: Laboratory Manager

Posted by Tim Sandle

PIC/S - Recommended model for Risk-Based inspection planning in the GMP environment

The PIC/S (The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme) have issued a guidance document (reference PI 037-1) on a Quality Risk

Management tool that may be used by Inspectorates when planning the frequency and scope of GMP.

It is based on the following documents:

• ICH Q9 - Quality Risk Management
• Annex 20 to the PIC/S GMP Guide
• The EMA Compilations of Community Procedures Document No.
• INS/GMP/499073/2006 – A Model for risk-based planning for inspections of Pharmaceutical Manufacturers
• ICH Q10 – Pharmaceutical Quality Systems

The PIC/S document can be found at: PIC/S

PIC/S' mission is "to lead the international development, implementation and maintenance of harmonised Good Manufacturing Practice (GMP) standards and quality systems of inspectorates in the field of medicinal products."

This is to be achieved by developing and promoting harmonized GMP standards and guidance documents; training competent authorities, in particular inspectors; assessing (and reassessing) inspectorates; and facilitating the co-operation and networking for competent authorities and international organisations.

Posted by Tim Sandle

Propionibacterium acnes and clear skin

The pore-dwelling bacterial species Propionibacterium acnes has long been associated with acne. However, whilst some strains of the bacterium are associated with pimples, investigators have found another strain is associated with clear skin, according to a study published in the Journal of Investigative Dermatology.

Propionibacterium acnes is the relatively slow-growing, typically aerotolerant anaerobic, Gram-positive bacterium (rod) linked to the skin condition acne; it can also cause chronic blepharitis and endophthalmitis. This bacterium is largely commensal and part of the skin flora present on most healthy adult humans' skin. P. acnes bacteria live deep within follicles and pores, away from the surface of the skin. In these follicles, P. acnes bacteria use sebum, cellular debris and metabolic byproducts from the surrounding skin tissue as their primary sources of energy and nutrients. Elevated production of sebum by hyperactive sebaceous glands (sebaceous hyperplasia) or blockage of the follicle can cause P. acnes bacteria to grow and multiply.

P. acnes bacteria secrete many proteins, including several digestive enzymes.These enzymes are involved in the digestion of sebum and the acquisition of other nutrients. They can also destabilize the layers of cells that form the walls of the follicle. The cellular damage, metabolic byproducts and bacterial debris produced by the rapid growth of P. acnes in follicles can trigger inflammation.This inflammation can lead to the symptoms associated with some common skin disorders, such as folliculitis and acne vulgaris.

The authors of the new study used pore-cleansing strips to collect samples at clinics in California from 101 peoples’ noses, half with acne and half with clear skin. They confirmed that P. acnes was the dominant species in the pores and found that overall levels of the bacteria did not vary significantly based on whether subjects had acne or not. However, people without acne tended to harbor the strain RT6, while the acne-ridden were strongly associated with the strains RT4 and RT5.

The study could have significant implications for acne treatment.



Posted by Tim Sandle

PCR technique of genomic fragments from endogenous and adventitious viral agents

The European Medicines Agency have issued a document entitled “Detection by a highly sensitive new PCR technique of genomic fragments from endogenous and adventitious viral agents in live attenuated vaccines” (reference EMEA/H/A-5(3)/1269).

The document is concerned with the possible presence of nucleic acid sequences from endogenous and adventitious viral agents in live attenuated viral vaccines. The paper considers the potential of the analytical metagenomics approach (polymerase chain reaction (PCR) combined with pyrosequencing, for the detection of viral fragments.

In summary, the statement outlines the following position:

1. Whilst the presence of endogenous ALV and SRV DNA fragments is potentially linked to the cell lines used for the manufacture of the individual vaccines, the finding of PCV-1 DNA pointed towards the presence of non-endogenous viral DNA. The Committee is therefore asked to assess if there is any potential public health concern arising from all the findings described in the article.

2. It is understood that as more hi-tech analytical methods become available, new findings may reveal in medicinal products presence of substances at very low concentrations and/or hard to detect that were thus far not picked up because of limitations of the analytical instruments/methods declared and authorised in the marketing authorisation dossier. Specifically, the Committee is asked to indicate if the new test method described above applied to identify viral genomic nucleic acid fragments should be considered, if validated, for the development/qualification and/or routine testing of biological medicinal products, and particularly live attenuated vaccines. Recognising the limitations of this novel method, and in order to conclude on the presence or absence of specific risks, the Committee is also asked to consider whether additional tests would be needed to conclude on the presence of replication competent endogenous and adventitious viral agents.

3. The Committee should indicate if there is a need to update existing guidance related to the testing and elimination of such substances in the context of development and/or testing of live attenuated vaccines.

4. Depending on the outcome of these investigations, the Committee should consider the need for appropriate guidance for other vaccines and other biological products.

The statement can be found at: EMA

Posted by Tim Sandle

Containment Technology

Bosch Packaging Technology has issued a white paper which presents an overview of containment technology. Here is an extract:

“Containment technology has emerged as one of the major trends in the processing and manufacture of pharmaceuticals. Part of the reason for this is continuous quality improvement, which relies on new and improved containment technologies to enhance production. However, there has been a steep rise in interest in containment following medical trends leading to more volatile pharmaceuticals. Reasons for this include more targeted applications with larger molecules as well as a rise in biopharmaceuticals and anti-virals.”

For details see Bosch

Posted by Tim Sandle

Monocyte Activation Test

The EDQM is conducting a survey on the Monocyte Activation Test (MAT), as described in European Pharmacopoeia general chapter 2.6.14 to gather information from all users and to facilitate its routine application as an in vitro replacement for the Test for pyrogens (2.6.8).

The MAT works by predicting the human response to pyrogens on the basis of human fever rather than animal models. This test may be used as an alternative to the rabbit pyrogen test. The MAT can test for Gram-positive and Gram-negative organisms, other biological pyrogens (e.g., yeast) and parasitic and viral pyrogens.

Deadline for responses: 7 March. For details see EDQM.

Posted by Tim Sandle