Karen Zink McCullough MMI Associates BET scientists have known for years that product matrices can significantly interfere with the detection of endotoxin in drug products. In fact, FDA and
Robert Westney President, Cryologics and Westney Associates On June 25, 2007, the Food and Drug Administration (FDA) published its final rule, 21 CFR 111: Current Good Manufacturing Practice
Scott Sutton, Ph.D. Microbiology Network We are familiar with the many problems surrounding “compounding” pharmacies that are functioning as de facto pharma manufacturers without any concern for GMP (Lolas, Sutton
Scott Sutton, Ph.D. Microbiology Network, Inc. There is a good deal of interest from FDA in the cosmetics industry and the Quality systems in place at manufacturing facilities. The
Submitted by moderator, Bob Westney
This year’s Fall Forum focuses on the challenges we as GMP microbiologists face in the non-sterile manufacturing industries. For many years, regulatory, compendial and industry guidance has primarily focused on aseptic manufacturing. Collectively, I believe this guidance has allowed those of us who work in the sterile manufacturing industries to understand the systems we must have in place and the regulatory compliance we must meet. However, those of us who work in the non-sterile manufacturing industries have had little, and sometimes conflicting, guidance. We’ve often had to look to aseptic manufacturing guidance to try to “cobble together” a set of “rules” that govern our environmental monitoring, contamination control and testing regimens. The advent of USP <1115>, “Bioburden Control of Non‐sterile Drug Substances and Products”, in 2014 (only three years ago!) was an instrumental first step toward offering guidance.
As we seek to further enrich our understanding of the risks associated with non-sterile manufacturing, and how to mitigate them, we look to our industry experts. This year’s Fall Forum provides this expertise. Our speakers are recognized industry experts, and you’ll leave the conference far more knowledgeable than when you arrived.
I’ve provided a list of our speakers, highlighting their experience and presentation topics.
Dr. Dilip Ashtekar will present “Technical and Regulatory Framework: Microbiological Aspects of Cleaning Validation for Non-sterile and Biotechnological Equipment”. Cleaning validation is an aspect of non-sterile manufacturing that has received little attention, so this presentation is seminal to the Forum. Dilip is a long-standing member of the USP Microbiology Expert Committee, among many other major career accomplishments.
Don Singer will present “Raw Materials Quality – You and Your Supplier Have Significant Impact”. In one regard, contamination control truly starts when the raw materials arrive at your facility. Therefore, the quality of these materials as they enter your manufacturing process is a critical consideration. Don is also a long-standing member of the USP Microbiology EC, currently serving as Vice-Chair.
Frank Settineri will present “Objectionable Microorganisms in Purified Water: Current Regulatory Expectations”. Frank will tackle the often-confused topic of “objectionable organisms”, and help us to understand its role in purified water. Frank is a well-known consultant and a member of the Microbiology Network consortium of consultants.
Amy Jo Karren will present “Training on the Right Things in the Microbiology Laboratory”. Microbiology laboratory operations is one of the pillars for meeting the challenges of non-sterile manufacturing. Amy is an accomplished expert, also serving as Chair for the USP Chemical Medicines 5 Expert Committee (our third USP EC member!).
Andrew Dick will present “Contamination Prevention in Nonsterile Manufacturing of Pharmaceutical Drugs, Cosmetics and Medical Devices”. This informative presentation will include such topics as sanitary equipment design, risk assessment, and cleaning and sanitization of equipment. Andrew has a wealth of experience in non-sterile manufacturing, and co-authored PDA Technical Report No. 67, “Exclusion of Objectionable Microorganisms from Nonsterile Pharmaceuticals, Medical Devices and Cosmetics”.
I will present “Qualifying an Environmental Monitoring Program for Non-Sterile Manufacturing: A Case Study”. I’ve audited and consulted for myriad non-sterile manufacturers, and based upon a real-life case study, I will walk you through how to qualify an EM program, and establish the path forward for monitoring, investigation of excursions and trend reporting.
We hope you are able to join us for this informative conference this October! Early bird registration ends August 1st.
Submitted by LER moderator, Karen McCullough
Before and Beyond LER is the theme of this year’s Bacterial Endotoxin Summit sponsored by the PMF. It is the ORIGINAL summit on endotoxin testing and the 11th annual summit.
In spite of the recent focus on LER, the rest of the LAL world marches on, and we are still challenged by some new concepts as well as some old ones. We are excited to expand this year’s BES offering to include discussions on some common laboratory concerns including experiences on the validation of the Monocyte Activation Test (MAT), considerations for testing of unique new cell, gene and combination products, the importance of laboratory disposables, and investigation of endotoxin OOS results, including a discussion of the rabbit Pyrogen test.
Because of the ongoing focus on LER in our industry, we will also include two talks focused on the issue. One is to help us understand what’s happening on a molecular level with LER and the other is to look at conclusions drawn from a BPOG study that used a common protocol to assess LER variability across companies.
I’ve provided a list of speakers who have committed to date and their presentation titles, and encourage you to explore the BES website for further information. I hope to see you in Dallas on February 6-7!
Jay Bolden (Lilly) will present “Results of a Harmonized Endotoxin Recovery Study Protocol Evaluation by 14 BioPhorum Operations Group (BPOG) Member Companies” This study is an important multi-laboratory study on LER using a common protocol to collect comparable data.
Allen Burgenson (LONZA) will present Challenges in testing cellular/gene therapy products and combination products which speaks to testing considerations such as calculation of endotoxin limits and test sample preparation for these unique products.
James F. Cooper, Pharm D (endotoxin consultant) will present Pyrogenic Outbreaks: 1970 to Present;OOS Investigations. This presentation will take us through OOS investigations and in the process will bring in a discussion of the rabbit Pyrogen test. Many of us have forgotten about the rabbit test, but the LER discussion has brought it back into the spotlight.
Masakazu Tsuchiya, Ph. D, (Charles River) will present “Case Studies: Invisible Interference in Bacterial Endotoxins Test “, which will help us to understand the mechanism of LER interference
Ned Mozier, PhD (Pfizer) will present “Progress and Pitfalls of the Monocyte Activation Test as Relates to Product Quality Assessment”, which speak to his experience in the validation of the Monocyte Activation Test (MAT), an alternate test to the compendial Bacterial Endotoxins Test
Veronika Wills (Associates of Cape Cod) willpresent The Importance of Using Qualified Disposables for the LAL Based Assays, which will remind us of the importance of laboratory disposables and how they can affect your BET test results.
A representative from USP will speak to the characterization and possible uses of their proposed native Control Standard Endotoxin.
Early Bird Registration ends this Thursday, December 15th. Register now to save $200! Click here to read more and register.
by Gemma Verma
A decade’s long debate has been raging about the safety of complimentary medicines versus the safety of pharmaceutical drugs. With 38% of American adults using alternative medicines in addition to their medical care, the argument has become polarized. Some doctors and members of the public refer to natural healthcare modalities as ‘quack’ medicines and want to have them restricted or banned altogether.
However, natural medicines represent the humble beginnings of pharmacology and were actually the original conventional medicine. In previous centuries, there were no chemical medicinals and the majority of the population could not afford a doctor or even an apothecary (a person who sold remedies from a retail shop – the very first chemist). The ‘middling sort’ (middle class) would treat their illnesses with herbs available to them in nature and the housewife and mother would have a herb garden in which to grow remedies for her family. For instance, mint could be grown to ease nausea and stomach pain, a popular remedy that is still in use today.
Paracelsus (1493-1541) was the first physician to formulate the idea that chemically based medicines could be made from raw plants and minerals, although much of the science of the time was incorrect and he also believed that if the plant resembled the illness, it must be the right remedy to treat it – the prevailing scientific opinion of the day that is now known to be totally false. For example, Haselwort looks like liver so doctors thought it could be used to treat liver disease.
Samuel Hahnemann, MD, a German physician, developed the principle of homeopathy in 1794 with the idea that a plant that caused symptoms of a particular disease could be used in attenuated quantities to treat that disease, an idea not dissimilar to vaccination, in which a trace of the disease is introduced to promote immunity. The practice of homeopathy had the advantage that the finished product was so diluted that it couldn’t produce the side-effects associated with herbal medicines.
While some herbal and animal remedy ideas were ridiculous by today’s standards and many were completely ineffective or made the illness worse, there were herbs and plants that really worked in easing symptoms. By the eighteenth century, Willow Bark tea began to be used to treat fever, pain and inflammation. Salicylic acid – an ingredient of Willow Bark, is the active component of aspirin – today’s widely used headache and anti-coagulant pill.
Despite having some remedies that were efficacious, no one knew how much of the herb you needed in order for it to have a medicinal effect or how much was too much so as a consequence, many people failed to find any relief and there were frequent cases of poisoning.
By the 19th century, druggist establishments similar to the modern high street pharmacy began to appear. They sold largely herbal medicines and natural substances, hence the name drug store, deriving from an old German word, droge, which meant to dry – usually herbs and spices. The name now associated with chemical pharmaceuticals referred to herbalism. Jesse Boot, the founder of Boots the Chemist in the UK, started his career wandering around fields, collecting herbs in a wheelbarrow that he could then make into remedies and sell in his father’s herbal shop.
The death of his father fueled a desire to provide cheap and safe medicines for anyone who needed them. With his enquiring scientific mind and the birth of mass advertising, he decided to concentrate more on the chemical formulations of medicine and how this could be used to help improve health and he began to stock synthetic medicines alongside the more traditional remedies.
Getting remedies from the drug store gave the customer some confidence that the amounts had been measured out correctly and the product sold was one of quality. However, there was still a long way to go. With science still in its infancy, lack of knowledge about the causes of illness led to the development of products that simply would not work for the purpose they were sold for, for instance, crushed earth worm paste to cure bruising. Others were dangerous to life, such as face creams and teething powders that contained elemental mercury commonly known as quicksilver.
Household bleach and pest control products like arsenic were freely available and sold in the drug store alongside the traditional herbs and medicines and most came in neutral packaging. This meant that it was possible for the consumer to inadvertently buy bleach instead of their usual medicine or ingest arsenic instead of the pre-cursor to aspirin. Sometimes the chemist himself would get confused and place the wrong product in the wrong bottle, with disastrous consequences. Accidental poisonings were a common occurrence and after life insurance policies began to be issued, even the occasional murder. In the 19th century, arsenic was the most frequently used murder weapon.
It was this that led to a drive to uniform medicines and bring standards and regulation to the practice of medicine. A desire for greater accountability and safety for the consumer, coupled with a desire to create medicines chemically that had the benefits of herbs without some of the disadvantages, brought about regulatory organisations for pharmacists and the first examinations.
Today, up to half of all pharmaceutical preparations are isolated directly from plants or they have chemical structures that mimic a plant. For instance, digitalis is extracted from foxglove flowers and is used to slow the heart rate in cases of tachycardia, as well as lowering blood pressure. In fact, 11% of worldwide medicines come from flowers. Morphine, the strong sedative painkiller that has made surgery painless for many, was isolated from the opium poppy.
The use of plants to formulate treatments is one of the foundations of modern medicine and is not as ‘alternative’ as it seems. Modern chemists use herbs, or synthetic preparations of herbs almost as much as the herbalist does. The distinction between the two modalities is not as far apart as the consumer imagines . The pharmaceutical industry merely helped bring the science of plant medicines into the 20th and 21st centuries by standardising formulations and developing scientific trials of products.
The question now should not be should natural medicine be banned, but what can be done to amass more evidence and make it even safer?
National Center for Complimentary and Integrative Health, accessed November 14, 2015, https://nccih.nih.gov/research/statistics/2007/camsurvey_fs1.htm
Historical Review of Medicinal Plants’ Usage, Pharmacogn Rev, accessed November 14, 2015, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358962/
Natural Products Derived from plants as a source of drugs, J Adv Pharm Technol Res, accessed November 14, 2015, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560124/
The History of Boots, accessed November 14, 2015, http://www.boots.com/en/The-history-of-Boots-making-medicines-for-over-160-years_1133893/
What Really Works for Kids: The Insider’s Guide to Natural Health for Mums and Dads, New York: Bantam Press, 2002. http://www.mattress.ge/index.php?pdfepubrx70tvy9jbm&option=com_k2&view=itemlist&task=user&id=43138
Homeopathic Remedies: Helpful, Harmful or Harmless Hype? Accessed November 14, 2015, http://www.rehabs.com/pro-talk-articles/homeopathic-remedies-helpful-harmful-or-harmless-hype/