Embracing the Computerized System Lifecycle – GAMP 5

Written by John Wasynczuk - Senior Subject Matter Expert, Ph.D at QPharma

For those of us that have participated in developing and implementing new or upgrading existing software applications, from customized distributed control systems (a.k.a. manufacturing control systems) for automated control of Bioprocessing operations, manufacture of vaccines, production of API’s, etc., Building Management Systems, PLC controlled equipment, to Laboratory Information Management or other IT Systems, we are most likely familiar and have applied the life cycle approach presented in Good Automated Manufacturing Practice (GAMP) 5 Guideline entitled “A Risk Based Approach to Compliant GxP Computerized Systems” (2008).  For those of you that are new to the game and are in the process of evaluating feasibility of a new project or have progressed to development of scope, budget, and preliminary engineering design, you need to familiarize yourself with GAMP 5 and begin developing policies, practices and procedures, consistent with its content as early as possible.  Doing so will certainly increase your chances for completing the project in an efficient, cost effective, and most importantly, regulatory compliant, manner.  This is possible because GAMP 5 incorporates ideas defined and described in FDA’s 21st Century Initiative; ICH documents Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality Systems; ISPE’s Product Quality Lifecycle Implementation (PQLI) Initiative; and ASTM E2500 Standard Guide for Specification, Design and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment.     

GAMP 5 is based on developing and integrating the following five concepts into a cohesive computerized system development, validation and maintenance program:

• Product and process understanding:  System requirements must be developed to ensure the system is fit for its intended use focusing on aspects that are critical to patient safety, product quality and data integrity, including Critical to Quality Attributes and Critical Process Parameters.
• Life Cycle Approach with a QMS (Quality Management System):  Activities and quality management systems need to be developed for each Life Cycle phase, from conception to retirement, that promote continuous process and system understanding through periodic reviews of performance and process data, root cause analysis of failures, change control, etc., assuring compliance with regulatory requirements.
• Scaleable Life Cycle Activities:  Life Cycle Activities should be scaled according to system impact on patient safety, product quality, and data integrity; system complexity and novelty; and outcome of supplier assessments. 
• Science Based Quality Risk Management:  Risk Assessments should be performed to identify critical aspects that may impact on patient safety, product quality, and data integrity; develop and implement risk mitigation reduction strategies or controls to reduce risks to acceptable levels; and monitor controls to ensure ongoing effectiveness. 
• Leveraging Supplier Involvement:  Perform Supplier Assessments and follow up audits, and if acceptable, avoid duplication of activities by leveraging their knowledge, experience and documentation by seeking their assistance in developing specifications, testing, support, and maintenance where applicable 

The following diagram, from ASTM E2500 introduces us to the Automated System Life Cycle by providing an overview of the Specification, Design and Verification process highlighting application of GEP’s, Risk Management, Design Review and Change Management throughout the life cycle.

Automated System Life Cycle

GAMP 5 goes on to classify the Computerized System Life Cycle as follows:

• Concept
• Project
• Planning
• Specification, Configuration, and Coding
• Verification
• Reporting and Release
• Operation
• Retirement

Aspects relating to the Project Phase will be covered in future discussions. Stay tuned!

The Growing GE (Genetic Engineering) Sector - Part II - A BUDDING INDUSTRY

(Note: This article is the 2nd in a 3 part series on Genetic Engineering. To read the 1st part, please click here. )

Written by Paul Melamud - Validation Manager, QPharma

Introduction

When we refer to organisms that are “transgenic”, this means that DNA from one species has been inserted into another species for expression.  Gene transfer between organisms of the same species is often called “intragenic”, and that between species that are sexually compatible is called “cisgenic”. These latter types are widely known; for example, Gregor Mendel selectively mated pea plants to study genetics in the 1800s, and for another, dog breeders continually attempt to create dogs that perfectly match the personality and stature conformation standards set forth by the Americal Kennel Club. These also comprise the basics behind the theory of evolution.

The first transgenic products were plants, made primarily to create disease-resistant and higher-nutrition foodstuffs (refer, for example, to Hope, a traditionally-produced (non-recombinant) hybrid that saved American wheat crops in the 1930s).  In the 1980s, the first true Genetically Engineered or "GE" plants (tobacco) were made with inherent insecticidal and herbicide-resistant properties.  These days, there are many bright prospects for products being dubbed “plantigens” and “plantibodies” that will contribute to public health at large, if introduced into standard crops.  What may be surprising to learn, then, is that there are not yet any FDA-approved, plant-biopharmed pharmaceutical products. 

Processes

There are two main processes that are used to genetically engineer plants for traits such as herbicide resistance.  Similar techniques would be employed to cause the plant to express phenotypes with human therapeutic use.  The first process, bacteria-mediated transformation, is accomplished with a bacterial vector, most commonly Agrobacterium tumefaciens, a plant parasite that can cause tumors by injecting DNA into host cells.  It is this unique mechanism that scientists have harnessed to deliver DNA of their choosing for expression in plants.  The second process, biolistic transformation, involves coating pellets of metal, such as tungsten or gold, with DNA and literally firing them into plant cells so that they lodge in the nuclei.  Once there, the DNA separates from the metal and becomes integrated with the host DNA for expression.

These two processes are illustrated below, one diagram from McGraw-Hill Higher Education and the other from BBC News (see links below image for references).

http://www.mhhe.com/biosci/pae/botany/botany_map/articles/article_03.html

http://news.bbc.co.uk/2/shared/spl/hi/pop_ups/03/sci_nat_how_a_plant_is_genetically_modified/html/3.stm

 There are a few other, less common methods that are used, including electroporation (electrically inducing transient holes through cell walls and membranes through which DNA can be introduced) and viral transduction (analogous to the bacterial vector transformation method). Electroporation is illustrated below.

http://www.inovio.com/images/IMG_how_ep_delivers.gif

Any of these methods can be used to attempt to transform millions or billions of cells – and that’s a good thing, because successes may occur as rarely as one in a billion.  Scientists can’t look at every cell, so they have developed techniques (as illustrated above) that can easily distinguish the successes and allow for their isolation.  The above method illustrates the use of a “selective agent” or “selectable marker,” which means that only the successfully transformed cells will survive exposure to the negative stimulus (i.e. the herbicide against which the genetic change would protect).  Another method is coupling the desired gene with a second one that will provide a “screening marker”, which can be observed by a scientist; an example would be a gene that causes a cell to fluoresce under UV light, which would indicate successful integration of the DNA that was introduced. 

Regulation

We can all appreciate how relatively new such products are, and that the process of development, testing, and eventually clinical trials and/or field studies to bring these products to the market would still be underway.  There are a few other reasons, though, that I think explains why we don’t see such products on the market yet.

 One reason behind this is that... 

FDA's De Novo/510(k) Initiative - Time to Call Your Congressman?

Written by Jeff Boatman, CQA - Sr. SME, Medical Devices and Quality Systems, QPharma

On August 5th, the Center for Devices and Radiological Health (CDRH) announced its preliminary findings on the need to update the Premarket Notification ("510(k)") process. An overview of the evaluation process can be found at http://www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHReports/ucm221069.htm, while the preliminary (read: almost certain to dramatically change) findings themselves are at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDRH/CDRHReports/UCM220784.pdf. Not linked, but available on FDA's website, is a second part of the report dealing with internal recommendations on the burden of scientific evidence that should be required by FDA's Office of Device Evaluation.

First, a recap of the current situation. In late 1976, Congress passed the Medical Device Amendments, and followed up a few years later with the Safe Medical Device Act. These laws, which for the first time brought medical devices under FDA's direct pre-market authority, designated two types of FDA authorizations: the Premarket Approval (PMA) process, and the Premarket Clearance ("510(k)"), named after the corresponding section of the original Act. PMAs are the medical device equivalent to the drug world's NDA, and correspond to the European Union's Design Dossier submission (in other words: big, complicated, and expensive), while 510(k)s are a somewhat similar idea to a generic drug's ANDA, and somewhat similar to the E.U.'s Technical File (simpler, quicker, and consisting mostly of documentation that the manufacturer would have anyway). There is also a "Product Development Protocol" route that parallels the PMA process, but it is almost never used.

In theory, a PMA is always required for a Class III device, and a Class III device is always the most serious type of medical device: complex, new and novel (i.e. unproven), can easily injure or kill someone.  And also in theory, a 510(k) is for a Class II device (and sometimes for certain Class I devices) and a Class II device is one that has a markedly lower risk to public health, especially with regards to familiarity: substantially equivalent to a device that is already on the market, the idea being that a lot is already known about that type of device.

Makes sense, right? The idea is that if you have a relatively simple device or a device whose design has already been proven through extensive experience with similar devices, you don't have to file eighteen binders of a thousand pages each. There is also a somewhat esoteric legal distinction: technically speaking, FDA only "approves" a Class III device; in the case of a Class II device, FDA merely agrees that the device is in fact Class II and that basic safety and design information is properly documented.

But unfortunately, Congress wrote a requirement into the original law that, while it may have made sense at the time, is a major burden to FDA and industry (and drives European and Japanese companies crazy): for a device to be considered Class II, and therefore be eligible for the simpler submission, it must be equivalent to a device that was already on the market when the law was written. In 1979 that may have made sense, but now more than a quarter of a century has gone by.  Look at it this way: in 1979, you could sell your medical device by showing it was equivalent to something marketed in 1975 (four years earlier), but today, you cannot sell your medical device by showing it is equivalent to something marketed in 2000 (ten years earlier).  Obviously this is a logical contradiction, but FDA cannot do anything about it directly because it is the law.

In response, companies routinely come up with crazy-quilt arguments that their device is similar to device A marketed in 2000, which is similar to device B marketed in 1990, which is kinda sorta like device C marketed in 1975. I should add that this doublespeak logic also can go in the opposite direction: I have been on projects developing devices that absolutely, clearly were Class II (injectable wrinkle remover), but due to the thread of prior "predicate" devices—marketed for much more serious indications—this Class II device became by default Class III.

It is in reference to this last situation (which happens quite often, actually) that FDA invented the "De Novo" submission process. This is an attempt by FDA to clone the Class IIa/Class IIb Notified Body review process used by the Europeans.  The idea is that some (actually, make that "many") medical devices that cannot trace back to a pre-1977 predicate device simply do not pose a serious health risk (but still are not so obvious as to sidestep risk management processes such as Design Controls, which would have classified the device as Class I like a tongue depressor). But the De Novo process is convoluted and rarely utilized, and even then, it only addresses part of the overall problem just described. CDRH's analysis linked above is FDA's latest attempt to come up with a science-based approach to intelligently classify and approve or clear medical devices, rather than ODE and firms coming up with ad hoc and frankly often silly daisy-chains of pre-1977 pedigree.

As is often the case (look at the recent debacle over electronic cigarettes!), FDA tries to do the right thing, but finds itself hamstrung by the constraints Congress wrote into a law.  For example, in a recent post on this blog I expressed dismay over FDA launching new initiatives regarding software as a medical device because I feel it is driving FDA outside of what the law allows…and opening the door for endless lawsuits and reversals.; and this latest initiative still cannot ultimately address the need to base the level of device scrutiny on the actual risk it poses, and not on some arbitrary date (although similarity to an existing device can certainly be used as a mitigating consideration, and indeed that is precisely the European regulatory model).

Again in this case, the predicate law (which FDA has no choice but to obey, even if that means finding technical loopholes and workarounds) is hopelessly out of date and needs to be revised to place the U.S. device industry on a firm footing with the rest of the world and base device review and approval on science (what is the potential risk of this device?) and not bureaucracy (did Jimmy Carter use this device?).

In the FDA Modernization Act, Congress directed FDA to harmonize regulations with those of other countries.  The result was the Quality System Regulation, universally recognized as the best GMP regulation in the world (and one that the Center for Drug Evaluation and Research is inching towards adopting in their own fashion).  Perhaps it is time that Congress do a repeat performance; this time, to allow—or order—FDA to bring the device approval process into the next millennium. 

Update on CDRH and The 510K Reform Process

Written by Nancy Tomoney - Associate Validation Manager, QPharma

In 2009, in response to fraud and device recalls associated with the 510K approval of medical devices at CDRH, FDA began a process of review of CDRH’s 510K approval process. The evaluation was completed in June 2010, and the report submitted for FDA review and government approval. The report was issued on August 4, 2010 in two parts.

The FDA’s evaluation of the medical devices process consists of two separate reports with their recommendations and is an outcome of internal discussions, public meetings and external discussion with industry. The evaluation consists of two reports:

Report #1: The CDRH Preliminary Internal Evaluations -- Volume I: 510(k) Working Group Preliminary Report and Recommendations, focuses on ways to strengthen and clarify CDRH’s review process for 510(k) approval exempt from a full premarket approval (PMA) review.

 Report #2: The CDRH Preliminary Internal Evaluations -- Volume II: Task Force Utilization of Science in Regulatory Decision Making Preliminary Report and Recommendations, details CDRH’s use of science in decision-making,  focusing on adapting new scientific information while maintaining regulatory innovation.

Based on these reports FDA has identified three major tasks for improving medical devices: fostering device innovation, enhancing regulatory predictability, and improving patient safety. Each of these major tasks has its own sub tasks.

As a means of fostering device innovation, CDRH has identified three sub areas of concentration: streamlining the premarket pathway for lower-risk novel devices; enhancing science-based professional development for CDRH staff; and establishing a network of external experts to better inform the review of cutting-edge technologies.

In an effort to enhancing regulatory predictability, CDRH has identified four sub areas of concentration: Increase the predictability of 510(k) data needs by establishing a new “Class IIb.; Create a new “Notice to Industry” tool to more rapidly communicate changes in premarket expectations; Clarify the meaning of key terms in the 510(k) “substantial equivalence” review standard to improve the consistency, transparency, and timeliness of the review process and establishing a Center Science Council as a new governance model to assure quality and consistency in CDRH’s science-based decision making.

To ensure improved patient safety, CDRH has identified three sub areas of concentration: requiring the up-front submission of more complete safety and effectiveness information to support the review of 510(k) devices; creating a searchable online public database to provide more detailed, up-to-date medical device information to industry, the health care community, and patients; and clarifying CDRH’s 510(k) rescission authority and the circumstances under which a device should not be used as a predicate.

The reports can be found on the FDA website at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm221166.htm

The tasks and identified sub tasks would certainly require a budgetary increase for CDRH to implement. The question becomes this: is the United States Congress willing to increase the already underfunded FDA budget? That question can be easily answered by the response of the United States Congress to Senate Bill S. 3690, A Bill to Provide for Additional Quality Control of Drugs, which was introduced on August 3, 2010 by Freshman Senator Michael Bennett (D-Colorado). The bill would amend and add new sections to the Food Drug and Cosmetic Act, specifically focused on quality in pharmaceuticals. The bill’s ability to come out of the Committee on Health, Education, Labor, and Pensions and be passed will speak to how seriously the current constituted government takes funding of the FDA. That bill and the list of CDRH reforms would requires serious funding and expansion of the FDA.

The Growing GE (Genetic Engineering) Sector - Part I - Of Course I've Heard of Cows!

For the next few weeks, we’re going to try something a little different. One of our Validation Managers has picked a “hot topic” that hasn’t been talked about much anywhere else, and would like to present it in the manner of an open discussion forum so that all of our blog readers, as well as our other blog writers, can learn from each other. The topic for the next couple of weeks highlights drugs that are the result of genetic engineering. We hope you find this to be a really cool and unique opportunity, and will gladly do it again with another topic if our readers enjoy this.

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 OF COURSE I’VE HEARD OF COWS…

Written by Paul Melamud - Validation Manager, QPharma

…but have you ever heard the buzzwords “pharming” or “biopharming” before? The terms refer to a growing sector of FDA-regulated industry that uses recombinant DNA technologies to genetically engineer (GE) animals (pharming) or plants (biopharming) to generate proteins and protein metabolites that they would not otherwise be capable of creating.

Such products might be delivered to a patient in a variety of ways:

• Through ingestion, perhaps as an "edible vaccine"; such was conducted as "proof of concept" by the University of Maryland's School of Medicine ('98) www.niaid.nih.gov/news/newsreleases/1998/pages/ediblevacc.aspx

• Through injection, as with the first FDA-approved transgenic animal product, which is produced in the milk of goats genetically modified to produce the anti-clotting drug Atryn (FDA-approved in 2009, approved in 2006 by EMEA) www.transgenics.com/pressreleases/pr020609.html

• Through body contact, perhaps through patches, lotions, or even clothing articles

Pharming has an innovative (and to this author, fascinating) approach to mass-production of drug products, with obvious advantages compared to more traditional processes, including cheaper facilities (e.g. farms), flexible scale-up and scale-down capabilities (e.g. breeding programs), and, to a degree, renewable/reusable bioreactors (e.g. plants or animals). 

And the potential lucrativeness of these ventures is no joke! Case in point: a fairly recent Scientific American article (see: http://www.scientificamerican.com/article.cfm?id=atryn-pharming-goats-transgenic) estimated start-up for a standard mammalian cell bioreactor facility producing 100kg/year of a drug to cost hundreds of millions of dollars, while an equivalent-volume farm could be put into service for only tens of millions of dollars, and with far cheaper operating costs – “at literally chicken feed with our chickens,” as one manufacturer put it.

While DNA was discovered as early as 1869 and its genetic ties identified in the early 1950s, and despite the fact that human drug manufacturers using transgenic recombinant DNA techniques have been around since the 1970s, regulations remain largely unspecific toward this type of process. As you can surely imagine, the relative novelty and complexity of the products and their production processes place pharmed proteins in what often seem like “uncharted waters” for development and regulatory approval.

In fact (confirmable through the below-referenced website), the U.S. government has not issued any new legislation (Acts) specific to GE products, instead relying on predicate health and safety laws to regulate them. However, regulatory agencies have issued some interesting and helpful guidelines that help manufacturers to address the special needs for these types of products. These are managed through a tripartite arrangement between government agencies, called the Coordinated Framework for Regulation of Biotechnology, which is responsible for jointly overseeing all such products. This framework was authorized in 1986 (51 FR 23302; also refer to http://usbiotechreg.nbii.gov/). It is noted that the European Union has gone a bit further than the U.S., with an official Directive (2001/18/EC) and numerous derivative regulations and guidances specific to transgenic organisms ( see http://www.biotethics.org/downloads/articles/EU%20Legislation%20GMOs.pdf for a comprehensive list, as of 2006, with hyperlinks).

Of course, where the genetic enhancement of a living organism is concerned, there is always political and humane-interest controversy. We will take a closer look at the controversy next week as we explore the current world of transgenic plants, and the week after with transgenic animals.

More on this topic next week...stay tuned!

Questions To Our Readers:

1) Have you ever heard of or been involved with (as a manufacturer or a user) any really cool products created through genetic engineering?

2) Given that the technology has been around for nearly 40 years, do you have any thoughts as to why there are few of these products yet on the market?

3) There’s been quite a bit of controversy, public opinion, and even fear out there regarding therapeutic products like these. Are there any risks and benefits about this biotechnology or the products that either scare you or thrill you? Do you think genetic engineering products, either or both from plants and/or animals, is a good idea?

Let's get a discussion started!
Please share your answers in the comment section below!