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Timestamp: 2017-09-20 09:09:26
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Matched Legal Cases: ['art 58', 'art 58', 'art 820', 'art 820', 'art 820', 'art 58', 'art 58']

Make GLP Great Again?
Posted on January 28, 2017 by PRCSQA
Article written by: Hector Gamboa, RQAP-GLP
The regulations for Good Laboratory Practices (GLP) for nonclinical laboratory studies in America came into effect in June 1979. Since then, the GLP regulations (including its revision in 1987) have been recognized nationally and internationally as a robust and sound quality system to ensure the quality and integrity of safety data. It has inspired other nations, for instance, to come up with the OECD Principles of GLP which in turn has been compared with and deemed compatible (and complementary) with international quality standards such as ISO 17025. Throughout the years that the GLPs have been implemented changes in technology and business practices have given rise to new needs in nonclinical testing facilities. The Society of Quality Assurance (SQA), a premiere organization for Quality Professionals in the Regulated Research industry, government and academia, has been in the forefront of calling for tweaking the GLPs and modernizing it to meet the current needs of the changing nonclinical testing facilities. As a response to many years of pleas from industry and quality professionals, on August 24, 2016 the US FDA has released its proposed rule (NPRM) in revising the current GLP regulations. Did the NPRM address the needs of the GLP community? Did it, to borrow President Donald Trump’s words, make GLP great again? The SQA has evaluated the FDA’s NPRM and this article shows the key areas of concern by the SQA as well as a couple of added objections.
The following shows the key areas of concern of the SQA regarding the NPRM.
The NPRM has a comment regarding whether the regulations have “…sufficient flexibility to allow the regulated parties to meet these requirements in a manner that best suits their organizational needs.” The current regulations have adequate flexibility to perform any type of safety study and maintain clear responsibilities of the study director, sponsor, testing facility management, QAU, and study personnel, whether the study is performed by the sponsor, performed by a contract research organization, or performed as a multi-site study. The current regulations can also be applied to the extent practical in support of FDA Animal Rule studies.
The proposed rule lacks clear accountability for who is responsible for various aspects of a study (e.g., it is unclear how a contributing scientist differs from a principal investigator). The proposed regulations attempt to provide a rigid structure dictating how studies are conducted rather than providing a framework that allows testing facility management and the study director to perform the study.
Animal Rule/Animal Care – Welfare
SQA recommends creation of a separate regulation to address animal rule studies, since they have a significant impact on public health, and should therefore be clearly defined and regulated. The reiteration of animal care and use requirements is not necessary and blurs the lines of responsibility between study director, testing facility management, attending veterinarian, and Institutional Animal Care and Use Committee.
Conflict with OECD
The remit of the OECD GLP Principles is environmental chemicals, rather than pharmaceuticals and medical devices. The latter have been included as common practice because the same monitoring agencies tend to monitor both chemicals and pharmaceuticals. The OECD GLP Principles, and specifically Consensus Document 13, are driven by environmental chemical testing at field sites. FDA should consider if this is the appropriate model to follow in the United States for FDA GLP regulated articles.
Multi-site studies have been performed in the United States prior to the promulgation of the current GLPs, and the preamble to the 1976 proposed rule addresses studies or portions of studies run by contractors. The roles and responsibilities are clear in the current GLPs, and individual accountability is maintained for studies run by a sponsor, studies run entirely by a contract research organization, or studies run at multiple facilities. Additional requirements regarding multi-site studies will not add value, will add complexity, and may negatively impact study conduct.
The proposed definition weakens one of the fundamental precepts of GLPs, i.e., the study director serves as the single point of study control. The landmark cases that led to the development of FDA GLPs were replete with examples of multiple points of study control, the absence of study control, or unqualified individuals in positions of study control. Diminishing the role of the study director, as this proposal does, by placing other individuals in equivalent or superior positions of study control will lead to the same problems that existed before the current GLP regulations were issued. Study director responsibilities were addressed in the 1978 Final Rule preamble, comment #59, “The study director is charged with the technical direction of a study including interpretation, analysis, documentation, and reporting of results.”
Responsibility for the availability of procedures, resources, and facilities should reside with the testing facility management of an organization, rather than a scientist that is responsible for the technical conduct of a study. The difference between management responsibility for administrative activities and technical conduct of a study was thoroughly addressed in the 1978 Final Rule preamble, comment #58, “Duties which are more administrative than scientific are the responsibility of management; however, management may delegate appropriate administrative duties to the study director.” Management with executive responsibility should not apply to management of a “test site” unless the intention is to have every test site have a complete quality management system. A consulting cardiologist or ophthalmologist could satisfy the definition of a test site, thereby requiring such individuals to have a complete quality management system; this is improbable and would not be feasible.
SQA questions the need to define a “fully implemented GLP Quality System.” FDA GLPs have defined a robust quality management system for nonclinical laboratory studies for over 30 years. It has been recognized nationally and internationally as a sound and effective quality system regulation and has also served as the basis of commercial quality system standards, e.g., ISO 17025. The assertion that it is not a fully implemented quality system is incongruous with its development and over 30 years of successful implementation.
The ability to view QA audit findings does not take into account how QA was designed to be FDA’s ‘left hand’ on site, with total ability to voice compliance concerns without repercussion (as evidenced by their reporting relationship to be separate of and independent from study activity). If this proposal is accepted, management may request QA not to report significant findings. Personnel may focus on the number of findings/observations rather than the importance of the findings/observations and content of the audits. If this requirement is kept, SQA anticipates a reduction in the number of QA audits performed to meet a minimal standard. If implemented as proposed, the amended GLPs may adulterate the mechanism for QA audits to be used by management to improve quality and compliance. We concur and support the FDA Commissioner’s position as stated in the 1978 Preamble, comment #91, “The Commissioner shares the concerns of the comments that general FDA access to QAU inspection reports would tend to weaken the inspection system. He believes that FDA’s review of quality assurance programs is important, and he recognizes the need to maintain a degree of confidentially if QAU inspections are to be complete and candid.” In the event that FDA determines a specific and significant need to review QA audit reports (i.e., in order to determine if systematic failures exist), there currently exists a formal mechanism by which to do so.
Notification to FDA When Archived Materials are Relocated
Almost every study performed at a contract research organization will have a data transfer from its archive to another archive after the study is finalized. SQA is unaware of any situations where study data could not be found to support an FDA investigator’s review. This requirement would add additional record keeping and reporting requirements to almost all contracted studies without enhancing the expedient retrieval of raw data. The processes used by testing facilities has been successful and a new requirement for reporting data transfer to FDA is not necessary.
Facility-based Inspections
Differentiating quality assurance inspections into “facility-based, process-based, and study-based” adds unnecessary complexity. The requirement to “inspect every study at frequencies adequate to assure the integrity of the study” has effectively provided QA with the authority to perform inspections and audits whether study-based, process-based, or facility-based.
Tracking Draft Reports
This requirement will be unenforceable. SQA concurs that it is important to have effective collaboration between sponsors and contract research organizations to complete studies in a timely manner. However, at what point is a final draft of a study report the final draft? Until concurrence is reached by the sponsor and study director, there may be multiple iterations of a draft report. Defining, tracking, and archiving all drafts will be cumbersome and time consuming when the study director should only have responsibility for the signed final report. The significance of signing the final report must be maintained.
Revising the meaning of testing facility to separate it from exposure of the test system to the test article has numerous ramifications to the structure and operation of the quality system and to the integrity of nonclinical laboratory studies. This revision will permit sponsors to declare themselves to be the testing facility when in reality they have little to no direct involvement in the conduct of the study. Contract testing facilities (under the current regulations) will need to align their respective quality systems with multiple sponsors and will no longer be able to operate their organizations in a consistent and reliable manner. The end result may be compromised data integrity and study compliance. Redefining testing facility also has ramifications for how quality assurance will be performed. Should the sponsor declare itself the testing facility and testing facility management with executive authority, they are likely to designate their quality assurance organization as the lead quality assurance organization. Such a construct would put the sponsor in control of when, what, and how frequently quality assurance inspections are performed, thereby further diminishing contract testing facility (under the current regulations) operational control and result in inconsistent and unreliable quality assurance oversight of testing facility operations.
For a more detailed look at the SQA comments, please refer to the official SQA response or login to the SQA website to access the document.
If one were to review the NPRM in detail what seems to stand out is the apparent attempt to assimilate the GLPs with the Quality System Regulations (QSR), which is the current Good Manufacturing Practice requirements for medical devices intended for human use, instead of the modernization being pushed by quality and industry professionals in the GLP world. In fact, a few of the new terms and items in the NPRM came from the QSRs. Adopting these to the GLPs is somewhat like trying to shoehorn a large elephant’s foot inside a person’s size 7 shoe. In a lot of cases the rules applicable to manufacturing are not applicable for early development and are often unnecessary. Take for instance the proposed requirement for a “Management Representative” (MR). Under the QSRs the MR is defined as:
“…a member of management who, irrespective of other responsibilities, shall have established authority over and responsibility for:
(ii) Reporting on the performance of the quality system to management with executive responsibility for review.”
The definition of MR in the NPRM was worded very similar to the QSRs. The problem with this is that this requirement is akin to the addition of an extra layer of fat – it just isn’t necessary under the GLP setting. In GLP, one of the responsibilities of the Quality Assurance Unit (QAU) is to “assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations”. What is the value of the addition of a MR if the MR’s mandate is already under the ambit of the QAU’s role already? If the FDA is merely concerned about proper hierarchy in the organization – that someone senior should report to the top management as oppose to a mere quality assurance staff member then facilities often have Quality Assurance Managers or Directors who can relay the report to top management. In fact this is what happens in a lot of cases, particularly in larger companies. In addition, this requirement for another layer of management level (i.e. the MR) seems to ignore the fact that there are small organizations that would incur increased cost and undue burden with this proposed requirement.
Next, the proposed addition of a GLP Quality System definition in the NPRM seems to imply that the existing GLP regulations do not have a quality system in itself (or a mechanism for its management). In addition, the proposed definition seems to overemphasize harmonization with definitions in the QSR but lacks important components of the GLPs such as planning, performing, monitoring, recording, archiving, and reporting. The OECD Principles of GLP, on the other hand, offers the following definition:
“Good Laboratory Practice (GLP) is a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.”
The OECD’s definition offers a better description of the GLPs as a quality system as this is more reflective of how regulated industry professionals experienced in the conduct of nonclinical studies understand and implement the GLPs.
While there are some points where the NPRM offers appealing and sensible proposals (e.g. a grace period of for archival after the completion of studies and allowing for process-based inspections for procedures that are repetitive in nature wherein study-based inspections are impractical to undertake), in general the NPRM has shown to be quite disappointing. Instead of tweaking the current GLPs as needed and instead of the modernization that regulated industry professionals have hoped the FDA would deliver, the FDA seems to be merely taking the opportunity to radically revise the GLPs just to meet the GMPs (and ISO). Different worlds, different purposes. By making the GLPs fit the requirements of the cGMPs and ISO, there will be a one size fits all type of standard instead of separate specific rules for specific needs. It won’t be too far-fetched to expect more GMP inspectors inspecting GLP facilities expecting its operations to be conducted like the cGMPs. This definitely would not make GLP great again.
Posted in GLPTagged cGMP, GLP, GMP, ISO, ISO 17025, NPRM, OECD, SQALeave a comment
When “Creeps” Pose a Threat to Your Compliance Audit Readiness
Posted on November 20, 2015 November 20, 2015 by PRCSQA
Article written by Hector Gamboa, RQAP-GLP
You are in-charge of the Quality Assurance of your company’s nonclinical (GLP) testing facility. As part of your job, you monitor the state of your facility’s compliance status to 21 CFR Part 58 to assure your management that the facility, the equipment, all the personnel, the methods, practices, records and controls are in conformance with the regulations. Then one day an FDA inspector shows up and gives you a Form 482 informing your facility that your facility is being inspected for GLP compliance. You say to yourself: “No sweat! I’m running a tight ship here. We are prepared for a GLP inspection. This should be a breeze!” Then all of a sudden you get asked for your facility’s Quality Manual. The confidence you have suddenly turns to bewilderment. You now have a feeling that you will be dealing with a regulatory scope creep. How would you deal with it without antagonizing the inspector?
Regulatory scope creep seems to be very common in inspections nowadays. This happens when, for instance, an inspector who is more used to performing GMP or GCP inspections, get assigned to do a GLP inspection of a nonclinical testing facility. But what exactly is the reason why this happens even with experienced quality compliance professionals? I think Lord Digby Jones, the UK’s former CBI Director-General, may have covered the idea best. According to him:
“Regulatory creep arises when the rules are unclear – when there is confusion about the standards, guidance and regulation.”
So to deal with regulatory creep, it is best for quality assurance professionals to not only be armed with knowledge of the correct standards, guidance, and regulations but to also be aware of other regulations where the inspector may be coming from. This way, there is a better chance of striking common ground with the inspector by speaking his (or at least being familiar with his) language.
Inspector asks for your Quality Manual
In a purely GLP world, Quality Manuals do not exist. There is no mention of Quality Manuals or even a Quality Policy in 21 CFR Part 58. However, in the GMPs (in Medical Device in particular), these are very much existent. According to the Quality System Inspection Technique (QSIT), which is essentially the FDA’s playbook on inspections of quality systems, a Quality Manual is one of the first things an inspector would ask for. The QSIT document states:
“When contacting the firm for the preannounced QSIT Inspection, the investigator should ask for a copy of the firm’s Quality Policy and high level Quality System Procedures (including Management Review Procedures), Quality Manual, Quality Plan or equivalent documents to preview prior to the inspection. The firm is not required to supply these documents. The investigator should tell the firm that the preview of these procedural documents would facilitate the inspection.”
The GLP quality professional has to realize that the inspector may be coming from a 21 CFR Part 820 (I am using GMPs for medical devices in this article as I am currently working in the medical device industry) mindset and the objective of looking at the Quality Manual is to try to see if the management of the facility has ensured that the requirements of the regulations have been established and maintained. In the world of medical device GMPs, 21 CFR Part 820.20 states:
(a) Quality policy.
Management with executive responsibility shall establish its policy and objectives for, and commitment to, quality. Management with executive responsibility shall ensure that the quality policy is understood, implemented, and maintained at all levels of the organization.
(e) Quality system procedures.
Each manufacturer shall establish quality system procedures and instructions. An outline of the structure of the documentation used in the quality system shall be established where appropriate.
In the world of GLP, the testing facility management has the responsibility to assure that personnel, resources, facilities, equipment, materials, and methodologies are available. So in looking for a common language, we can equate the inspector’s Part 820 mindset with what the FDA’s BIMO guidance document for GLP inspections say. The BIMO guidance document states that the inspector has to determine if the facility has established and follows written SOPs necessary to carry out study operations in a manner designed to ensure the quality and integrity of the data. A good approach for the GLP quality professional to take is to redirect the inspector to the testing facility’s index list of SOPs and perhaps even show a representative sample of an SOP to show that written procedures exist to cover what the regulations expect of a GLP facility to cover. A representative SOP showing approval by the testing facility management would help the inspector realize that the nonclinical testing facility’s management has established appropriate procedures and instructions at the GLP testing facility.
Inspector wants Sponsor approval of protocol deviations, protocol amendments, and CRFs
Again , in a purely GLP world, approval function of protocol deviations and amendments rests with the Study Director. Although the study protocol is approved by the Sponsor, anything else between the initiation of the study (which is when the Study Director signs and dates the protocol) and it’s archival is under the responsibility of the Study Director. With regards to Case Report Files (CRFs), these are not even mentioned in 21 CFR Part 58. There are no provisions in the GLPs with regards to approval of CRFs or any study specific supplements such as data collection forms. The GLP quality professional has to realize that the inspector may be coming from a GCP mindset. According to the ICH GCP Guidelines (E6 Good Clinical Practice: Consolidated Guidance) with regards to Sponsor approval of protocol deviations and amendments:
4.5.2 The investigator should not implement any deviation from, or changes of, the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), change of telephone number(s)).
Moreover, it also states:
The contents of a trial protocol should generally include the following topics.
On the CRF front, the GCP ICH guidelines state:
The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design should include:
6.4.9 The identification of any data to be recorded directly on the CRFs (i.e., no prior written or electronic record of data), and to be considered to be source data.
So in case the inspector may be using a different regulation or standard in his or her assessment, such as using the GCPs to assess a GLP facility, it is important to acknowledge where the inspector may be coming from but it is also important to redirect the inspector to the appropriate standard and regulation. If needed, the GLP quality professional may even try to persuade the inspector by referring to the 1978 GLP Preamble which explains why the FDA insists on the study director having only a single point of control or responsibility for the overall technical conduct of the GLP study. In the 1978 GLP Preamble, the Commissioner stated that:
“The potential for conflicting instructions and confusion in study implementation is too great to diffuse the responsibility by, for example, study direction by a committee.” – 43 FR 59995
Moreover, 21 CFR Part 58 clearly states that the Study Director is responsible for approving any changes to the protocol. It states that:
Sec. 58.33 Study director.
(a) The protocol, including any change, is approved as provided by 58.120 and is followed.
The 1978 GLP Preamble helps clear up any possible confusion behind the interpretation of what the GLP regulation says about the matter. The Preamble states:
“The Commissioner advises that 58.120(a)(15) requires that the sponsor approve the protocol, and 58.120(c) requires that the study director approve any changes or revisions to the protocol. The language in 58.33(a) has been revised to reference 58.120.” – 43 FR 59995
The regulations, guidance and advisory documents, Preambles, Q&A documents, and many other resources are available for the GLP quality professional to use. It is important to take advantage of these powerful resources, as basis, in defending one’s facility as oppose to merely applying philosophical and intellectual acrobatics in interpreting the regulations when engaged with an inspector, especially one bringing a regulatory scope creep. Regulation scope creep can skew the intended focus of an inspection and it is up to us quality professionals to help in redirecting the scope of the inspection using substantive basis and a calm, respectful, and measured demeanor.
Disclaimer: Reference to “GLP” or “GLPs” in this article pertain to US FDA GLPs and not the GLPs under OECD, EPA, MHLW, and other jurisdictions.
(Photo taken from gleekingsongalbums.tumblr.com)
Posted in GLPTagged FDA GLP inspection, GCP creep, GLP, GMP creep, Regulatory Scope Creep2 Comments
Welcome to the PRCSQA Blog!
Posted on November 16, 2015 November 16, 2015 by PRCSQA
The Pacific Regional Chapter of the Society of Quality Assurance serves as the focal point for Research Quality Assurance interests in the region of California, Washington, Oregon, Idaho, Nevada, Hawaii, Alaska, British Columbia, and the Yukon Territory. We also have members in Taiwan, Japan, South Korea, and China. We encourage interactions among Quality Assurance professionals in government, industry and academia; and also sponsor educational programs in Quality Assurance.
This blog offers insights on Quality Assurance matters, especially in the Research Quality Assurance field. We hope you will find postings here helpful in meeting your organization’s quality assurance needs, especially in areas of Good Laboratory Practices, Good Clinical Practices, and Good Manufacturing Practices.
Please feel free to share your comments, inputs, and questions about the topics discussed in this blog. Thank you very much and we look forward to engaging our fellow QA professionals in lively and insightful discussions.
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