By Dr. Ray Nims
In a previous posting, we described the responsibilities of the contract giver (contractee) and the contract acceptor (contractor) in outsourced pharmaceutical quality control testing. Our blog title: "Outsource it, and fuggedaboutit?" somewhat facetiously suggested that the outsourcing of quality control testing does not transfer quality control responsibility from the contract giver to the contract acceptor.
Elizabeth Meyers and I expanded upon this theme in a recent article in BioProcess International. Our conclusion in that article was more direct: “The use, by a pharma organization, of a contract testing lab to fulfill some or all of its Quality Control testing obligations does not absolve the contractee of its overall Quality responsibility of ensuring the safety, purity, identity, efficacy, and potency of its products.”
This point was illustrated nicely in a recent warning letter published on the FDA Website. The name of the firm involved is not important to this discussion. Among the other findings was the following:
“Your firm failed to properly evaluate a contract laboratory to ensure GMP compliance of operations occurring at the contract site.”
The FDA then provided the following detail: "...we are concerned about your firm’s fundamental understanding of what is required by your Quality Unit and the regulatory expectations for a firm that enters into agreements with contract testing laboratories. Although you have agreements with other firms that may delineate specific responsibilities to each party, you are ultimately responsible for the quality of your products and the reliability of test results. Regardless of who tests your products or the agreements in place, you are required to manufacture these products in accordance with section 501(a)(2)(B) of the Act to assure their identity, strength, quality, purity, and safety."
The take-home message from this is that in the outsourcing of quality control testing, responsibility for the outsourced testing is retained by the contract giver. Responsibilities of the contract giver include the following: selecting and qualifying the contract lab, ensuring the suitability of methods used (through qualification, transfer, verification, or validation); putting in place a Quality and business agreement; scheduling and submitting samples (including communicating expectations for sample results); providing in-life guidance; and monitoring of contract lab performance.
There is no denying that fulfilling these responsibilities requires a significant and ongoing effort on the part of the contract giver. In this respect, outsourcing of quality control testing is not so different from doing that testing in-house.
Showing posts with label GMP. Show all posts
Showing posts with label GMP. Show all posts
Friday, February 25, 2011
Wednesday, April 28, 2010
FDA regulation of “combination” products
by Dr. Ray Nims
The FDA’s Office of Combination Products (OCP) was established in 2002 to shepherd combination products, those comprised of a combination of drug, biological, and/or device, through the review and regulation process. An example of a combination product is the drug-releasing stent (see figure below). The OCP does not conduct the reviews, but is responsible for: assigning the product to the appropriate FDA center; coordinating reviews involving more than one center; and working with agency centers to develop guidance and regulations to make the regulation of combination products “as clear, consistent and predictable as possible”.
The complexity of combination products arises because the efficacy and safety of the individual constituent components (i.e., the drug, biologic, or device) must be considered alone, as well as within the context of the combination product. Because of this complexity, there is no single development paradigm for all combination products. The guidance recommends that combination product developers consider any prior approval/clearance of the constituent parts, as well as how their testing may be influenced by the interaction of the components. Factors that should be considered (from the guidance) include:
• Are the constituent parts already approved for an indication?
• Is the indication for a given constituent part similar to that proposed for the combination product?
• Does the combination product broaden the indication or intended target population beyond that of the approved constituent part?
• Does the combination product expose the patient to a new route of administration or a new local or systemic exposure profile for an existing indication?
• Is the drug formulation different than that used in the already approved drug?
• Does the device design need to be modified for the new use?
• Is the device constituent used in an area of the body that is different than its existing approval?
• Are the device and drug constituents chemically, physically, or otherwise combined into a single entity?
• Does the device function as a delivery system, a method to prepare a final dosage form, and/or does it provide active therapeutic benefit?
• Is there any other change in design or formulation that may affect the safety/effectiveness of any existing constituent part or the combination product as a whole?
• Is a marketed device being proposed for use with a drug constituent that is a new molecular entity?
• Is a marketed drug being proposed for use with a complex new device?
As with individual constituent drugs, biologics, and devices, the FDA will require that the combination products be manufactured according to current good manufacturing practices. In most cases, a single investigational application (IND or IDE) is submitted to enable the clinical trials planned for the combination product. The science and technology associated with the combination products should drive the selection of statistical approaches, sample sizes, study endpoints, and methods for active principle measurement and for evaluating possible interactions between components. It may be best to involve the FDA in these decisions.
Complexity for the regulation of combination products also stems from the fact that separate manufacturing processes may exist for the various constituent parts. Potential changes in any of the component manufacturing processes, subsequent to initiating clinical trials or post-market, will need to be evaluated for possible effects on the safety and efficacy of the combination product.
Combination products represent therapeutic modalities with great promise for advancing health care. We expect to see more and more pharmaceutical activity in this area going forward.
The FDA’s Office of Combination Products (OCP) was established in 2002 to shepherd combination products, those comprised of a combination of drug, biological, and/or device, through the review and regulation process. An example of a combination product is the drug-releasing stent (see figure below). The OCP does not conduct the reviews, but is responsible for: assigning the product to the appropriate FDA center; coordinating reviews involving more than one center; and working with agency centers to develop guidance and regulations to make the regulation of combination products “as clear, consistent and predictable as possible”.
An example of a drug-releasing stent.
From Wikipedia
The complexity of combination products arises because the efficacy and safety of the individual constituent components (i.e., the drug, biologic, or device) must be considered alone, as well as within the context of the combination product. Because of this complexity, there is no single development paradigm for all combination products. The guidance recommends that combination product developers consider any prior approval/clearance of the constituent parts, as well as how their testing may be influenced by the interaction of the components. Factors that should be considered (from the guidance) include:
• Are the constituent parts already approved for an indication?
• Is the indication for a given constituent part similar to that proposed for the combination product?
• Does the combination product broaden the indication or intended target population beyond that of the approved constituent part?
• Does the combination product expose the patient to a new route of administration or a new local or systemic exposure profile for an existing indication?
• Is the drug formulation different than that used in the already approved drug?
• Does the device design need to be modified for the new use?
• Is the device constituent used in an area of the body that is different than its existing approval?
• Are the device and drug constituents chemically, physically, or otherwise combined into a single entity?
• Does the device function as a delivery system, a method to prepare a final dosage form, and/or does it provide active therapeutic benefit?
• Is there any other change in design or formulation that may affect the safety/effectiveness of any existing constituent part or the combination product as a whole?
• Is a marketed device being proposed for use with a drug constituent that is a new molecular entity?
• Is a marketed drug being proposed for use with a complex new device?
As with individual constituent drugs, biologics, and devices, the FDA will require that the combination products be manufactured according to current good manufacturing practices. In most cases, a single investigational application (IND or IDE) is submitted to enable the clinical trials planned for the combination product. The science and technology associated with the combination products should drive the selection of statistical approaches, sample sizes, study endpoints, and methods for active principle measurement and for evaluating possible interactions between components. It may be best to involve the FDA in these decisions.
Complexity for the regulation of combination products also stems from the fact that separate manufacturing processes may exist for the various constituent parts. Potential changes in any of the component manufacturing processes, subsequent to initiating clinical trials or post-market, will need to be evaluated for possible effects on the safety and efficacy of the combination product.
Combination products represent therapeutic modalities with great promise for advancing health care. We expect to see more and more pharmaceutical activity in this area going forward.
Tuesday, March 23, 2010
Innovators and Perfectionists
by Dr. Ray Nims
In a previous posting, Leah Choi described her frustration over the lack of specific training, received during her undergraduate schooling, in aspects germane to the realities of employment within the biopharmaceutical industry. Employment in the highly regulated world of biopharmaceutical manufacturing, Quality, and Quality Control (biopharmaceutical operations) requires different skills and employee temperaments compared to employment within the research and development (R&D) world. The academic institutions would do well to consider this during the preparation of students for eventual life in the working world.
What do we mean by different skills and employee temperaments? Most of us are familiar with the Myers and Briggs personality typing instrument which looks at attibutes like intro/extraversion, sensing, intuition, etc. This instrument provides interesting and revealing information about how different people deal with the world. In addition to the qualities addressed by Myers & Brigg, however, there is a personality spectrum which I will refer to as Innovation ↔ Perfection.
In the R&D world, technical knowledge, mastery of the literature concerning a subject, and most importantly, innovation are the attributes which are essential for success. A researcher must long to travel untraveled paths, to uncover new ground, to learn and often develop methods where such may not have existed previously (i.e., to go where no man has gone before). Those who are well suited to this environment we refer to as innovators. The academic institutions are pretty good at fostering these attributes in students.
On the other hand, the highly regulated areas of biopharmaceutical operations require individuals who are capable of following set instructions time after time, documenting their work in a precise and strictly controlled manner. Innovation, improvisation, and experimentation with mature methodologies and standard operating procedures are not encouraged. A mind-set which is compatible with achieving perfect compliance with documented procedures is the key to success in this environment. Such individuals we refer to as perfectionists, as they are motivated by the desire (or if not desire, at least the requirement) to conduct their work exactly as proscribed. It is this particular set of attributes which many academic programs fail to address adequately. This leaves employers with the task of training their entry-level staff in such matters, and (as Leah mentioned in her posting) students with the sometimes shocking revelation that they are poorly prepared for this type of employment.
Are there individuals who can be successful both as “innovators” and as “perfectionists”? Undoubtedly so! It is more likely, however, that most people fit within a spectrum falling between the two temperaments. I, for instance, have always regarded myself more of a perfectionist than an innovator, happily conducting the same assay the 100th time and still trying to do a better job than the last time. I know of others who, as soon as they learn a method, are bored with it and anxious to move on to something new. These temperaments may be determined by our personalities and may not be subject to alteration. It would appear to be valuable for academic programs to try, therefore, to determine the temperaments of their students, and to provide training suitable and appropriate for both the innovators and the perfectionists. Both the students as well as the biomedical industry would benefit from a little temperament triage and curriculum adjustment done at the undergraduate level.
In a previous posting, Leah Choi described her frustration over the lack of specific training, received during her undergraduate schooling, in aspects germane to the realities of employment within the biopharmaceutical industry. Employment in the highly regulated world of biopharmaceutical manufacturing, Quality, and Quality Control (biopharmaceutical operations) requires different skills and employee temperaments compared to employment within the research and development (R&D) world. The academic institutions would do well to consider this during the preparation of students for eventual life in the working world.
What do we mean by different skills and employee temperaments? Most of us are familiar with the Myers and Briggs personality typing instrument which looks at attibutes like intro/extraversion, sensing, intuition, etc. This instrument provides interesting and revealing information about how different people deal with the world. In addition to the qualities addressed by Myers & Brigg, however, there is a personality spectrum which I will refer to as Innovation ↔ Perfection.
In the R&D world, technical knowledge, mastery of the literature concerning a subject, and most importantly, innovation are the attributes which are essential for success. A researcher must long to travel untraveled paths, to uncover new ground, to learn and often develop methods where such may not have existed previously (i.e., to go where no man has gone before). Those who are well suited to this environment we refer to as innovators. The academic institutions are pretty good at fostering these attributes in students.
On the other hand, the highly regulated areas of biopharmaceutical operations require individuals who are capable of following set instructions time after time, documenting their work in a precise and strictly controlled manner. Innovation, improvisation, and experimentation with mature methodologies and standard operating procedures are not encouraged. A mind-set which is compatible with achieving perfect compliance with documented procedures is the key to success in this environment. Such individuals we refer to as perfectionists, as they are motivated by the desire (or if not desire, at least the requirement) to conduct their work exactly as proscribed. It is this particular set of attributes which many academic programs fail to address adequately. This leaves employers with the task of training their entry-level staff in such matters, and (as Leah mentioned in her posting) students with the sometimes shocking revelation that they are poorly prepared for this type of employment.
Are there individuals who can be successful both as “innovators” and as “perfectionists”? Undoubtedly so! It is more likely, however, that most people fit within a spectrum falling between the two temperaments. I, for instance, have always regarded myself more of a perfectionist than an innovator, happily conducting the same assay the 100th time and still trying to do a better job than the last time. I know of others who, as soon as they learn a method, are bored with it and anxious to move on to something new. These temperaments may be determined by our personalities and may not be subject to alteration. It would appear to be valuable for academic programs to try, therefore, to determine the temperaments of their students, and to provide training suitable and appropriate for both the innovators and the perfectionists. Both the students as well as the biomedical industry would benefit from a little temperament triage and curriculum adjustment done at the undergraduate level.
Thursday, January 21, 2010
Re-educating Leah
By Leah Choi
Four grueling years of chemistry, biology, math, and physics barely prepared me for life after college. As I entered America’s workforce on November 13th, 2006, I was equipped with nothing more than a general knowledge of what was to come.
Within my first few weeks at RMC Pharmaceutical Solutions, I quickly realized my inadequacies. GMP? GLP? NDA? IND? The acronyms alone could have driven me to near insanity. Likewise, I had spent four years at the University of Colorado learning the theory behind chromatography even putting it into practice on an ancient gas chromatography system. Yet this was no match for the advanced chromatography systems used in today’s biotech industry. To complicate matters further, I did not fully understand the intricacies of working in a regulated environment. What did it mean to follow a standard operating procedure? To evaluate and qualify the design, installation, performance, and operation of an instrument? What did it mean to document deviations? To perform a corrective and preventative action? Each new client and each new project presented a fresh set of unfamiliar issues. I often questioned if I would ever be able to bridge the gap between the theories of my college education with the applications of my working world.
Am I an isolated incident or do current biotechnology educational programs lack the necessary curriculum to develop entry-level employees? According to a recent survey conducted by AAPS (American Association of Pharmaceutical Sciences) and published by the National Institute of Pharmaceutical Technology and Education (NIPTE), 35% of respondents believe that current training for entry-level pharmaceutical development scientists is inadequate, 60% believe that there is a shortage of suitable candidates and nearly 70% asserted that there is an inadequacy in the number of US colleges focusing on industrial needs. According to this survey, academic programs training the majority of pharmaceutical product development scientists have declined substantially in recent years due to the emphasis in professional pharmacy programs on patient care rather than product knowledge. Additionally, these programs lack research funding in basic physical sciences supporting development and manufacturing.
With so much on the line, what is currently being done to address these nationally recognized problems? Organizations such as NIPTE have implemented plans with hopes of providing the “highest caliber entry-level scientists/engineers for the pharmaceutical and biopharmaceutical industries”. These plans include training students in degree programs using shared curricula materials, summer training programs and industrial internships via a network of industrial and institutional collaborators. The curriculum is based on “the precepts of interdisciplinary approaches strongly advocated by the National Academy of Sciences and constructivist learning theories important in the development of modern engineering and science higher education”. Presently, only ten universities have signed onto this plan: Duquesne University, Illinois Institute of Technology, Purdue University, Rutgers University, University Puerto Rico San Juan/Mayaguez, University of Connecticut, University of Iowa, University of Kansas, University of Kentucky, University of Maryland-Baltimore, and the University of Minnesota.
Other initiatives include the National Science Foundation (NSF) which currently provides $16.3 million in support of biotechnology programs through its Advance Technological Education (ATE) program. NSF regularly brings together scientists, educators, and other stakeholders to share their opinions on official issues such as biotechnology workforce development. Panelists share their opinions about how the biotechnology industry will grow during the next five years, the skills that technicians will require to meet workforce needs, and their experiences with promising educational practices. April 2008 conference recommendations include
1. instruction in written and verbal communication and “soft skill” such as team work and time management;
2. core curriculum courses that transfer and articulate from high school to two-year and four-year degree programs;
3. a strong theoretical understanding of the entire manufacturing process encompassing upstream and downstream process;
4. the introduction of immerging technologies in basic biotechnology courses; and
5. the redesign of standard microbiology and biology curricula to include applications in industrial and environmental biotechnology.
The limitations of ordinary degree programs spurred Montgomery College in Maryland to develop curriculum specifically aimed at preparing students for life after college. By soliciting information from industry personnel, coordinators of the program have developed and continually update courses that meet the current skill sets expected from entry level employees. Students acquire real life experience through internships engineered by the program. The success of this program depends highly on the continual collaboration between working professionals and academic faculty. Without a doubt, this synergistic dynamic allows both sides to benefit: educators gain valuable input for relevant curriculum while industry gains practical, productive entry level employees. Programs like these emphasize the absolute necessity for industry involvement.
I realize the learning curve is steep but not unconquerable. To all those recent graduates or better yet, those who are still in school the best advice I can give, is to get involved. Build your own bridge, by participating in professional groups and societies. Attend local events and seminars. Organizations such as the PDA (Parental Drug Association) AAPS (American Association of Pharmaceutical Scientists) and ISPE (International Society of Professional Engineers) often provide students with special benefits and discount memberships. As a PDA Student Member, you receive access to numerous benefits which provide you with the most current scientific and technical information. You receive access to Student Programs which provide grant funding and career growth resources, subscriptions to the PDA Journal of Pharmaceutical Science and Technology, including PDA Technical Reports which offer expert guidance and opinions on a variety of important scientific and regulatory topics pertaining to pharmaceutical and biopharmaceutical production.
Begin building contacts as early as possible. Make your first professional contacts at a career fair. Collect business cards and follow up. Professional social networking sites such as LinkedIn, Xing, Plaxo, and Spoke make these connections simple and instantaneous. Seek and invite professionals to speak at your school’s student group and find other means of collaborating with industry experts. Build a bond with someone who can act as a mentor. Having a mentor can be a great way to develop your career for the long term.
Take the opportunity to educate yourself on current topics and those of interest. Earlier this year, I was afforded the opportunity to gain valuable knowledge by earning a Certificate of Good Laboratory Practices/Good Manufacturing Practices from the University of Denver. We spent 10 weeks focusing on the regulations surrounding device manufacturing and use, specifically 21CFR820 and 21CFR58. My thirst for knowledge did not end there. In the same months I earned a Yellow Belt Training Certificate from the Colorado Association of Manufacturing and Technology. For six weeks my classmates and I studied yellow belt topics, specifically in the areas of Six Sigma Root Cause Analysis, 8D Problem Solving and Statistical Process Controls. Both of these courses were free, local and most importantly, offered helpful insights into contemporary subjects.
I commend unique programs and organizations such as NIPTE, NSF and Montgomery College for offering much needed curriculum that unites academia with industry. With increasing awareness and initiatives, my hope is that future graduates will be endowed with the basic education and ability to hit the ground running within this rapidly emerging industry.
Four grueling years of chemistry, biology, math, and physics barely prepared me for life after college. As I entered America’s workforce on November 13th, 2006, I was equipped with nothing more than a general knowledge of what was to come.
Within my first few weeks at RMC Pharmaceutical Solutions, I quickly realized my inadequacies. GMP? GLP? NDA? IND? The acronyms alone could have driven me to near insanity. Likewise, I had spent four years at the University of Colorado learning the theory behind chromatography even putting it into practice on an ancient gas chromatography system. Yet this was no match for the advanced chromatography systems used in today’s biotech industry. To complicate matters further, I did not fully understand the intricacies of working in a regulated environment. What did it mean to follow a standard operating procedure? To evaluate and qualify the design, installation, performance, and operation of an instrument? What did it mean to document deviations? To perform a corrective and preventative action? Each new client and each new project presented a fresh set of unfamiliar issues. I often questioned if I would ever be able to bridge the gap between the theories of my college education with the applications of my working world.
Am I an isolated incident or do current biotechnology educational programs lack the necessary curriculum to develop entry-level employees? According to a recent survey conducted by AAPS (American Association of Pharmaceutical Sciences) and published by the National Institute of Pharmaceutical Technology and Education (NIPTE), 35% of respondents believe that current training for entry-level pharmaceutical development scientists is inadequate, 60% believe that there is a shortage of suitable candidates and nearly 70% asserted that there is an inadequacy in the number of US colleges focusing on industrial needs. According to this survey, academic programs training the majority of pharmaceutical product development scientists have declined substantially in recent years due to the emphasis in professional pharmacy programs on patient care rather than product knowledge. Additionally, these programs lack research funding in basic physical sciences supporting development and manufacturing.
With so much on the line, what is currently being done to address these nationally recognized problems? Organizations such as NIPTE have implemented plans with hopes of providing the “highest caliber entry-level scientists/engineers for the pharmaceutical and biopharmaceutical industries”. These plans include training students in degree programs using shared curricula materials, summer training programs and industrial internships via a network of industrial and institutional collaborators. The curriculum is based on “the precepts of interdisciplinary approaches strongly advocated by the National Academy of Sciences and constructivist learning theories important in the development of modern engineering and science higher education”. Presently, only ten universities have signed onto this plan: Duquesne University, Illinois Institute of Technology, Purdue University, Rutgers University, University Puerto Rico San Juan/Mayaguez, University of Connecticut, University of Iowa, University of Kansas, University of Kentucky, University of Maryland-Baltimore, and the University of Minnesota.
Other initiatives include the National Science Foundation (NSF) which currently provides $16.3 million in support of biotechnology programs through its Advance Technological Education (ATE) program. NSF regularly brings together scientists, educators, and other stakeholders to share their opinions on official issues such as biotechnology workforce development. Panelists share their opinions about how the biotechnology industry will grow during the next five years, the skills that technicians will require to meet workforce needs, and their experiences with promising educational practices. April 2008 conference recommendations include
1. instruction in written and verbal communication and “soft skill” such as team work and time management;
2. core curriculum courses that transfer and articulate from high school to two-year and four-year degree programs;
3. a strong theoretical understanding of the entire manufacturing process encompassing upstream and downstream process;
4. the introduction of immerging technologies in basic biotechnology courses; and
5. the redesign of standard microbiology and biology curricula to include applications in industrial and environmental biotechnology.
The limitations of ordinary degree programs spurred Montgomery College in Maryland to develop curriculum specifically aimed at preparing students for life after college. By soliciting information from industry personnel, coordinators of the program have developed and continually update courses that meet the current skill sets expected from entry level employees. Students acquire real life experience through internships engineered by the program. The success of this program depends highly on the continual collaboration between working professionals and academic faculty. Without a doubt, this synergistic dynamic allows both sides to benefit: educators gain valuable input for relevant curriculum while industry gains practical, productive entry level employees. Programs like these emphasize the absolute necessity for industry involvement.
I realize the learning curve is steep but not unconquerable. To all those recent graduates or better yet, those who are still in school the best advice I can give, is to get involved. Build your own bridge, by participating in professional groups and societies. Attend local events and seminars. Organizations such as the PDA (Parental Drug Association) AAPS (American Association of Pharmaceutical Scientists) and ISPE (International Society of Professional Engineers) often provide students with special benefits and discount memberships. As a PDA Student Member, you receive access to numerous benefits which provide you with the most current scientific and technical information. You receive access to Student Programs which provide grant funding and career growth resources, subscriptions to the PDA Journal of Pharmaceutical Science and Technology, including PDA Technical Reports which offer expert guidance and opinions on a variety of important scientific and regulatory topics pertaining to pharmaceutical and biopharmaceutical production.
Begin building contacts as early as possible. Make your first professional contacts at a career fair. Collect business cards and follow up. Professional social networking sites such as LinkedIn, Xing, Plaxo, and Spoke make these connections simple and instantaneous. Seek and invite professionals to speak at your school’s student group and find other means of collaborating with industry experts. Build a bond with someone who can act as a mentor. Having a mentor can be a great way to develop your career for the long term.
Take the opportunity to educate yourself on current topics and those of interest. Earlier this year, I was afforded the opportunity to gain valuable knowledge by earning a Certificate of Good Laboratory Practices/Good Manufacturing Practices from the University of Denver. We spent 10 weeks focusing on the regulations surrounding device manufacturing and use, specifically 21CFR820 and 21CFR58. My thirst for knowledge did not end there. In the same months I earned a Yellow Belt Training Certificate from the Colorado Association of Manufacturing and Technology. For six weeks my classmates and I studied yellow belt topics, specifically in the areas of Six Sigma Root Cause Analysis, 8D Problem Solving and Statistical Process Controls. Both of these courses were free, local and most importantly, offered helpful insights into contemporary subjects.
I commend unique programs and organizations such as NIPTE, NSF and Montgomery College for offering much needed curriculum that unites academia with industry. With increasing awareness and initiatives, my hope is that future graduates will be endowed with the basic education and ability to hit the ground running within this rapidly emerging industry.
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