Friday, 30 September 2016

Preparing for ISO 13485:2016

The new ISO 13485 revision is here and, for medical device manufacturers, this is significant news.

ISO 13485:2016 provides an international standard that can be truly harmonized across multiple regions and regulatory requirements. But it also introduces notable QMS changes, particularly in the area of risk management. In this 16-page white paper, we answer your biggest questions about ISO 13485:2016, including:
  • Overview of the update to the new standard
  • Breakdown of what has changed in each section
  • Guidelines on how to prepare for the new standard
  • Deadline for recertification
  • Requirements for recertification
  • Considerations for timing the update and recertfication

With this, Emergo has issued a white paper, which introduces the standard. It can be accessed here.

Posted by Dr. Tim Sandle

Thursday, 29 September 2016

Draft PIC/S guidance on data integrity

PIC/S has issued a new draft document relating to data integrity, titled “Good practices for data management and integrity in regulated GMP/GDP environments.” (PI 041-1 (Draft 2)).

According to the document:

Good data management practices influence the integrity of all data generated and recorded by a manufacturer and these practices should ensure that data is accurate, complete and reliable. While the main focus of this document is in relation to data integrity expectations, the principles herein should also be considered in the wider context of good data management.

Data Integrity is defined as “the extent to which all data are complete, consistent and accurate, throughout the data lifecycle” and is fundamental in a pharmaceutical quality system which ensures that medicines are of the required quality. Poor data integrity practices and vulnerabilities undermine the quality of records and evidence, and may ultimately undermine the quality of medicinal products.

Data integrity applies to all elements of the Quality Management System and the principles herein apply equally to data generated by electronic and paper-based systems.

The draft can be accessed here.

Posted by Dr. Tim Sandle

Wednesday, 28 September 2016

New EMA draft guideline on sterilisation of the medicinal product

Given the importance of sterile products, in providing both a therapeutic medicine and with regards to the necessity of being free from viable microorganisms, pyrogenic substances and visible particulates, no new guidance has been issued by a regulatory authority in recent years. This has changed with a new draft guidance document from the European Medicines Agency. Issued in April 2016 for public comment, the document is titled Guideline on the Sterilisation of the Medicinal Product, Active Substance, Excipient and Primary Container.

The key points are reviewed in an article for GMP Review by Tim Sandle. The reference is:

Sandle, T. (2016) New EMA draft guideline on sterilisation of the medicinal product, GMP Review, 15 (2): 6-8

For further details, please contact Tim Sandle

Posted by Dr. Tim Sandle

Tuesday, 27 September 2016

Top Cleanroom Advances

One overriding concern with cleanrooms and cleanroom technology is maintaining product or operator protection. The drivers for developing cleanroom technology are to increase the level of protection or to decrease operational costs – but it is crucial that the latter does not impinge on the former. This article gives a rundown of his top advances in cleanrooms in recent years.

The article has been written by Tim Sandle.  The reference is:

Sandle, T. (2016) Top Cleanroom Advances, The Medicine Maker, July / August 2016 (issue 7), pp403-404

For further details see The Medicine Maker.

Posted by Dr. Tim Sandle

Monday, 26 September 2016

Disproving the five second rule

For some dropped foods, the five-second rule is about five seconds too long. Wet foods, such as watermelon, slurp up floor germs almost immediately, according to new research reported via Science News.

Robyn Miranda and Donald Schaffner of Rutgers University in New Brunswick, N.J., tested gummy candy, watermelon and buttered and unbuttered bread by dropping morsels onto various surfaces coated with Enterobacter aerogenes bacteria. Food was left on each surface — stainless steel, ceramic tile, wood and carpet — for time periods ranging from less than a second to five minutes. Afterward, the researchers measured the amount of E. aerogenes on the food, harmless bacteria that share attachment characteristics with stomach-turning Salmonella.

As expected, longer contact times generally meant more bacteria on the food. But the transfer depended on other factors, too. Carpet, for instance, was less likely to transfer germs than the other surfaces. Gummy candies, particularly those on carpet, stayed relatively clean. But juicy watermelon quickly picked up lots of bacteria from all surfaces in less than a second. These complexities, the authors write, mean that the five-second rule is probably a rule worth dropping.


R.C. Miranda and D.W. Schaffner. Longer contact times increase cross-contamination of Enterobacter aerogenes from surfaces to food. Applied and Environmental Microbiology. Published online September 2, 2016. doi: 10.1128/AEM.01838-16.

Posted by Dr. Tim Sandle

Improving bioburden testing

Tim Sandle has written an article for European Pharmaceutical Review about improving assurance in relation to microbial bioburden assessments. This relates to the use of biocontainer bags, designed to reduce the chance of false positives occurring.

Assessment of microbial levels in (and on) samples is an important part of pharmaceutical process control. Samples are drawn from intermediate product at defined stages (ideally based on risk assessment) and these allow for the microbial levels to be tracked from upstream processing to downstream processing (with an expectation that the microbial levels decrease, or at least remain unchanged provided they are below an acceptable action level). For aseptically products, European guidelines require a certain bioburden to be met at the point that a bulk product passes through a sterilising grade filter.

Due to the relatively low specification – of 10 CFU/100mL – pharmaceutical manufacturers need to ensure that false positive results are avoided (as might arise from extraneous environmental contamination). False positives can result in batch rejection. A key innovation, in recent years, is the biocontainer sampling bag. This item of irradiated plastic is in keeping with moves towards single use, sterile processing technology.

The article examines the importance of bioburden testing, particularly in relation to aseptically filled products, together with the most important criteria for sampling bags.

Sandle, T. (2016) Improving microbiological assurance for bioburden tests, European Pharmaceutical Review, 21 (3): 41-44

The article can be viewed via the European Pharmaceutical Review website.

Posted by Dr. Tim Sandle

Sunday, 25 September 2016

Mitigating Risks in Aseptic Manufacturing

The aseptic drug manufacturing sector has been under scrutiny following product recalls due to quality and manufacturing failures that threaten patient safety.

A new e-book has been issued by Pharmaceutical Technology. The book outlines the key issues of glass delamination and extractables and leachables are examined, as well as advances in blow-fill-seal technologies that can avoid manufacturing issues traditionally associated with aseptic fill processes.

For further details see: PharmaTech

Posted by Dr. Tim Sandle

Saturday, 24 September 2016

Sixteen years of Salmonella Trends reported by FSIS

FSIS reports that Salmonella is the leading cause of bacterial foodborne illness in the United States and causes an estimated 1.2 million illnesses, 19,000 hospitalizations and 380 deaths, each year. The data from 2014 estimates that 360,000 (30%) of foodborne illnesses are attributed to FSIS-regulated products, which is a 9.3% decrease compared to 2010.

FSIS conducted ednontyphoidal Salmonella serotype testing on isolates recovered from raw meat and poultry products, subject to sampling under the Pathogen Reduction Hazard Analysis and Critical Control Point (PR/HACCP) verification testing program. The results presented here provide an estimate of relative serotype distributions for each product class during the 16-year period following implementation of the PR/HACCP program (1998-2014). The top 10 Salmonella serotypes identified from the testing in 2014 are listed in Table 1a. Different types of Salmonella serotypes were found in the various types of meat and poultry.

For more details see:

Posted by Dr. Tim Sandle

Friday, 23 September 2016

EU GMP Annex 17 ‘real time testing’

The EMA has published responses to the public consultation on EU GMP Guidelines, revised Annex 17 on the Real Time Release testing.

The draft expands the concepts of ‘real time’ testing beyond just parametric release and could provide opportunities for the use of new and future technology to improve on-going process control, overall product quality and patient safety.

Such monitoring based on:

Critical Process Parameters: A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality [ICH Q8 (R2)].

Critical Quality Attributes: A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. [ICH Q8 (R2)]

These comments can be found on the EMA website.

Posted by Dr. Tim Sandle

Thursday, 22 September 2016

The mutations behind drug resistance

Antimicrobial resistance in disease-causing microbes has garnered attention in recent years, but another persistent area of drug resistance is the ability for tumors to evade chemotherapy drugs. Methotrexate is one of the oldest chemotherapy agents, and although it can be quite effective against many types of cancer and other conditions, in many cases it stops working because the patient becomes resistant to the drug's effects.

In a new study, researchers have developed a rapid, low-cost screening method to decipher the gene mutations behind drug resistance. They used baker's yeast to test the technique in the context of methotrexate resistance and identified 10 mutations that can confer resistance to the drug, offering potential new leads that could help scientists make the drug more reliable.
The research was led by postdoctoral fellow Lai Wong in the lab of Guri Giaever and Corey Nislow at the University of British Columbia, along with collaborator Pat Flaherty from the University of Massachusetts, Amherst. The method they developed is a "back-to-the-future" approach that combines a traditional screening approach for identifying sources of drug resistance with newer techniques of "massively parallel" and "deep" genetic sequencing, along with advanced statistical algorithms. The method is a significant improvement over existing techniques to understand the genetic mutations relevant to drug resistance.

The technique's success in identifying methotrexate resistance mutations demonstrates its potential uses for understanding not only the mechanisms behind resistance for this important chemotherapy agent, but potentially for many other drugs as well.

For further details see: Genetics Society of America

Posted by Dr. Tim Sandle

Wednesday, 21 September 2016

Bacterial endotoxin contamination and testing limits in ophthalmics

Endotoxin contamination in ophthalmic pharmaceuticals and medical devices presents a risk to users; moreover, endotoxins can cause acute inflammation of the eye following ocular lens replacement surgery.

A new article reviews the risks and requirements for product testing, together with current regulatory guidances. It further analyses recall data relating to ophthalmic pharmaceuticals due to endotoxin contamination. The article concludes by making recommendations for endotoxin control and sets out appropriate endotoxin test limits for finished ophthalmic products.

The article has been written by R. Vijakumar and Tim Sandle. The reference is:

Vijakumar, R. and Sandle, T. (2016) Bacterial endotoxin contamination and testing limits in ophthalmics, European Pharmaceutical Review, 21 (4): 16-18

For further details, please contact Tim Sandle

Posted by Dr. Tim Sandle

Tuesday, 20 September 2016

A Role for Endotoxin in Aggression and Depression

A link between depression and inflammation has been observed in many studies. Aberrant social behaviors, such as aggression, often present with depression and can be indicative of suicidal behavior.

A recent study addressed the association between stress-associated behaviors, such as aggression, and low-level inflammation induced by endotoxin challenge. They found that the addition of endotoxin-induced inflammation exacerbated depression in stress-induced mice but reduced signs of aggression. Specifically, endotoxin caused increases of IL-1β and 5-HT2A mRNA in the brain, increased serum corticosterone and increased TNFα in both the brain and liver. Stress alone did not cause these changes. However, the combination of stress and inflammation resulted in a reduction in the stress-induced changes in 5-HT and IL-1β. These results indicate that low-level inflammation can have significant impact on stress-induced behaviors, specifically reductions in aggression, which can lead to depression.

For further details, see the Journal of Neuroinflammation

Posted by Dr. Tim Sandle

Monday, 19 September 2016

Nuovo manuale sul cleaning e la disinfezione

E' disponibile la nuova edizione del manuale "The Cleaning and Disinfection for Cleanroom" (prima edizione 2012), completamente aggiornata ed in linea con gli standard, i regolamenti e le norme di più recenti.

Book1Il manuale è stato scritto per tutti coloro che operano nel campo farmaceutico e sanitario (nei settori di produzione, qualità, medico, ingegneria o servizi generali) ma può fornire preziose informazioni anche ai professionisti, agli studenti e al lettore comune. Il libro fornisce dettagli completi sui diversi tipi di disinfettanti e sulle loro modalità di azione; affronta i problemi legati alla distruzione microbica e al fenomeno della resistenza microbica; introduce le tecniche di pulizia e le più recenti norme di sicurezza; espone l'applicazione del cleaning in ambienti sanitari e farmaceutici, informando sugli attuali standard nazionali e internazionali.
Il libro contiene inoltre indicazioni sull'efficacia dei test sui disinfettanti confontando il punto di vista americano e quello europeo. Capitoli aggiuntivi riguardano l'utilizzo del perossido di idrogeno in forma di vapore negli isolatori, la certificazione dei fornitori di disinfettanti e la garanzia di qualità.
Redatto da esperti professionisti, il volume bilancia concetti teorici con consigli pratici, ed è destinato a diventare uno dei testi definitivi su come tenere sotto controllo la contaminazione all'interno delle aree pulite e degli ambienti controllati.

Il libro è acquistabile direttamente su Amazon (

Posted by Dr. Tim Sandle (source ASCA News)

Cleanroom Microbiology book

A feature about the Cleanroom Microbiology book, including a table of contents.

Posted by Dr. Tim Sandle

Compounded Drug Products That Are Essentially Copies

U. S. FDA has produced a draft guidance document titled “Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act.”

Section 503A, added to the FD&C Act by the Food and Drug Administration Modernization Act in 1997 and amended by the Drug Quality and Security Act in 2013, describes the conditions that must be satisfied for human drug products compounded by a licensed pharmacist in a State-licensed pharmacy or Federal facility, or by a licensed physician, to qualify for exemptions from the FD&C Act.

To qualify for exemptions under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act or the Act), a drug product must be compounded by a licensed pharmacist or physician who does not compound regularly or in inordinate amounts any drug products that are essentially copies of a commercially available drug product, among other conditions. This guidance sets forth the FDA’s policies regarding this provision of section 503A, including the terms commercially available, essentially a copy of a commercially available drug product, and regularly or in inordinate amounts.

The document can be found here: FDA

Posted by Dr. Tim Sandle

Sterility Testing Book

A feature about the comprehensive Sterility Testing book, including a table of contents
Posted by Dr. Tim Sandle

Pharmaceutical Microbiology book feature

A feature about the new Pharmaceutical Microbiology book

Posted by Dr. Tim Sandle

Risk Assessment and Management for Healthcare Manufacturing: Practical Tips and Case Studies

For further details and to order, see the PDA Bookstore.

Posted by Dr. Tim Sandle

Sunday, 18 September 2016

Characterizing the gut microbiome

Clostridium difficile infection (CDI) is a major cause of healthcare-associated infections worldwide. CDI can cause symptoms from mild diarrhea to life-threatening toxic megacolon. Antibiotics disrupt the normal intestinal microflora enabling C. difficile to proliferate in the colon and produce toxins. Currently, restoring the gut microflora through methods such as fecal microbiota transplantation is one of the most effective approaches for the treatment of CDI (read the review). Determining which components of the gut microbiota are required for protection against CDI remains unclear.

Posted by Dr. Tim Sandle

Saturday, 17 September 2016

Liquid Dose Trends

Pharmaceutical Manufacturing has issued an e-book of interest – ‘Liquid Dose Trends’.

Parenteral drugs are taking a strong position alongside the more established oral solid dose forms and are quickly coming into their own. This eBook will discuss:
  • New challenges faced by parenteral drug manufacturers
  • How equipment manufacturers are meeting the filling needs of biopharma
  • How to choose the right automated system for vaccine monitoring
  • Five questions to ask biopharma CMOs

For details see: Pharma Manufacturing

Posted by Dr. Tim Sandle

Friday, 16 September 2016

The Patient Safety Atlas

In March of 2016, in an effort to prevent healthcare associated infections (HAIs), the Centers for Disease and Prevention (CDC) issued a request for all healthcare providers and healthcare facilities to make three critical efforts to further this cause. The CDC also launched the online Patient Safety Atlas in an effort to control the rising threat of resistant bacterial infections.

The following guidelines are succinct and offer very clear advice:

1) Prevent infections related to surgery or placement of a catheter.
2) Prevent spread of bacteria from spreading between patients.
3) Improve antibiotic use.

There are six antibiotic resistant bacteria that are particularly dangerous and are considered urgent or serious threats by the CDC. They are:

  • MRSA (methicillin-resistant Staphylococcus aureus)
  • CRE (carbapenem-resistant Enterobacteriaceae)
  • ESBL-producing Enterobacteriaceae (extended-spectrum ß-lactamases)
  • VRE (vancomycin-resistant enterococci)
  • Multi-drug resistant Pseudomonas
  • Multi-drug resistant Acinetobacter

Infections caused by these organisms could lead to sepsis or even death. C. difficile infections are the most common HAI found in hospitals, and in many cases, lead to death. However, it is not antibiotic resistant like the others listed above.

Surgery and Catheters: The recommendation for preventing infections from catheters and after surgery include using catheters only when needed, following recommendations for safer surgery and catheter insertion and care, and removing catheters from patients as soon as they are no longer needed.

Patient Isolation: For preventing C.diffficile, it is recommended that healthcare providers are consistent and follow these actions for every patient without exception. When it is appropriate, patients should be isolated, and providers should know antibiotic resistance patterns in their facility and area.  In order to prevent dangerous bacteria from spreading, it is recommended that hand hygiene be improved and that gloves, gowns, and dedicated equipment be used for patients who have antibiotic resistant infections.

Antibiotic Use: Finally, to improve antibiotic use, it is recommended that cultures be obtained and antibiotics started promptly and reassessed 24 to 48 hours later, especially in cases of sepsis. Cultures should be used to reassess the need for antibiotics and to stop treatment as soon as they are no longer needed. Antibiotics should be used appropriately according to the type of infection and in the proper dosage, frequency, and duration.

The Patient Safety Atlas: A patient safety atlas (PSA) was created by the CDC and is a public portal that allows heathcare providers and the greater public to visualize and download data that is based on four years of surveillance (2011-2014) by 4,403 healthcare facilities. These include general acute care hospitals (n=3,676), long term acute care hospitals (n=506), and free-standing inpatient rehabilitation hospitals (n=221).

Source: Hardy Diagnostics

Posted by Dr. Tim Sandle

Thursday, 15 September 2016

Inflammatory diseases and the microbiome

Immune-mediated inflammatory diseases (IMID) is a term used to define a group of disorders that share common pathogenic mechanisms. IMID include inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and others. Many studies have linked IMID to dysbiosis (a disruption in the microbiome). Researchers are now investigating whether changes in the gut flora are common between IMID or if specific perturbations are associated with a single disease. A new review explores the current research on the gut microbiota in IMID.

Posted by Dr. Tim Sandle

Special offers