Final concept papers have been published for the next two ICH quality guidelines. In both cases we can hope to see drafts in the first half of 2020. Both guidelines are intended to supplement the existing documents ICH Q8 – ICH Q12, reinforcing the principles of a risk based quality by design (QbD).
ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products
capture key technical and regulatory considerations including certain CGMP elements specific to continuous manufacturing
allow drug manufacturers to employ flexible approaches to develop, implement, or integrate continuous manufacturing for the manufacture of small molecules and therapeutic proteins for new and existing products
provide guidance to industry and regulatory agencies regarding regulatory expectations on the development, implementation, and assessment of continuous manufacturing technologies.
In the course of the preparation of this new guideline, ICH Q2 (Validation of Analytical Procedures) will also be revised. It will be adapted to the state of the art to include modern analytical methods in the future..
It’s stated that the Expert Working Group (EWG) will evaluate combining Q2 and Q14 into one document. Here’s hoping.
Warren is one of several senators eyeing White House runs who have introduced bills targeting the pharmaceutical industry. Just last week, Sens. Jeff Merkley (D-Ore.), Kamala Harris (D-Calif.) and Amy Klobuchar (D.-Minn.) introduced the CURE High Drug Prices Act, which would allow the federal government to block price increases on certain drugs. Merkley put forward separate legislation, the Low Drug Prices Act, weeks earlier. And Sen. Bernie Sanders (I-Vt.) introduced his own bill, the Prescription Drug Price Relief Act, in November.
Sonja Blignaut on More Beyond wrote a good post “All that jazz … making coherence coherent” on coherence where she states at the end “In order to remain competitive and thrive in the new world of work, we need to focus our organization design, leadership and strategic efforts on the complex contexts and create the conditions for coherence. “
Ms. Blignaut defines coherence mainly through analogy and metaphor, so I strongly recommend reading the original post.
The system creates value for the multiple stakeholders. While the ideal is to develop a design that maximizes the value for all the key stakeholders, the designer often has to compromise and balance the needs of the various stakeholders.
Congruence
The degree to which the system components are aligned and consistent with each other and the other organizational systems, culture, plans, processes, information, resource decisions, and actions.
Convenience
The system is designed to be as convenient as possible for the participants to implement (a.k.a. user friendly). System includes specific processes, procedures, and controls only when necessary.
Coordination
System components are interconnected and harmonized with the other (internal and external) components, systems, plans, processes, information, and resource decisions toward common action or effort. This is beyond congruence and is achieved when the individual components of a system operate as a fully interconnected unit.
Elegance
Complexity vs. benefit — the system includes only enough complexity as is necessary to meet the stakeholder’s needs. In other words, keep the design as simple as possible and no more while delivering the desired benefits. It often requires looking at the system in new ways.
Human
Participants in the system are able to find joy, purpose and meaning in their work.
Learning
Knowledge management, with opportunities for reflection and learning (learning loops), is designed into the system. Reflection and learning are built into the system at key points to encourage single- and double-loop learning from experience to improve future implementation and to systematically evaluate the design of the system itself.
Sustainability
The system effectively meets the near- and long-term needs of the current stakeholders without compromising the ability of future generations of stakeholders to meet their own needs.
I used the term congruence to summarize the point Ms. Blignaut is reaching with alignment and coherence. I love her putting these against the Cynefin framework, it makes a great of sense to see alignment for the obvious domain and the need for coherence driving from complexity.
So what might a drive for coherence look like? Well if we start with coherence being the long-range order (the jazz analogy) we are building systems that build order through their function – they learn and are sustainable.
One of the requirements for data integrity that has changed in detail as the various guidances (FDA, MHRA, PIC/S) have gone through draft has been review of audit trails. This will also probably be one of the more controversial in certain corners as it can be seen by some as going beyond what has traditionally been the focus of good document practices and computer system validation.
What the guidances say
Audit trail review is similar to assessing cross-outs on paper when reviewing data. Personnel responsible for record review under CGMP should review the audit trails that capture changes to data associated with the record as they review the rest of the record (e.g., §§ 211.22(a), 211.101(c) and (d), 211.103, 211.182, 211.186(a), 211.192, 211.194(a)(8), and 212.20(d)). For example, all production and control records, which includes audit trails, must be reviewed and approved by the quality unit (§ 211.192). The regulations provide flexibility to have some activities reviewed by a person directly supervising or checking information (e.g., § 211.188). FDA recommends a quality system approach to implementing oversight and review of CGMP records.
If the review frequency for the data is specified in CGMP regulations, adhere to that frequency for the audit trail review. For example, § 211.188(b) requires review after each significant step in manufacture, processing, packing, or holding, and § 211.22 requires data review before batch release. In these cases, you would apply the same review frequency for the audit trail.If the review frequency for the data is not specified in CGMP regulations, you should determine the review frequency for the audit trail using knowledge of your processes and risk assessment tools. The risk assessment should include evaluation of data criticality, control mechanisms, and impact on product quality. Your approach to audit trail review and the frequency with which you conduct it should ensure that CGMP requirements are met, appropriate controls are implemented, and the reliability of the review is proven.
Potential risk of not
meeting expectations / items to be checked
1
Consideration should be given
to data management and integrity requirements when purchasing and
implementing computerised systems. Companies should select software that includes
appropriate electronic audit trail functionality.
Companies should endeavour to
purchase and upgrade older systems to implement software that includes
electronic audit trail functionality.
It is acknowledged that some
very simple systems lack appropriate audit trails; however, alternative
arrangements to verify the veracity of data must be implemented, e.g.
administrative procedures, secondary checks and controls. Additional guidance
may be found under section 9.9 regarding Hybrid Systems.
Audit trail functionality
should be verified during validation of the system to ensure that all changes
and deletions of critical data associated with each manual activity are
recorded and meet ALCOA+ principles.
Audit trail functionalities
must be enabled and locked at all times and it must not be possible to
deactivate the functionality. If it is possible for administrative users to
deactivate the audit trail functionality, an automatic entry should be made
in the audit trail indicating that the functionality has been deactivated.
Companies should implement
procedures that outline their policy and processes for the review of audit
trails in accordance with risk management principles. Critical audit trails
related to each operation should be independently reviewed with all other
records related to the operation and prior to the review of the completion of
the operation, e.g. prior to batch release, so as to ensure that critical
data and changes to it are acceptable. This review should be performed by the
originating department, and where necessary verified by the quality unit,
e.g. during self-inspection or investigative activities.
Validation documentation
should demonstrate that audit trails are functional, and that all activities,
changes and other transactions within the systems are recorded, together with
all metadata.
Verify that audit trails are
regularly reviewed (in accordance with quality risk management principles)
and that discrepancies are investigated.
If no electronic audit trail
system exists a paper based record to demonstrate changes to data may be
acceptable until a fully audit trailed (integrated system or independent
audit software using a validated interface) system becomes available. These
hybrid systems are permitted, where they achieve equivalence to integrated
audit trail, such as described in Annex 11 of the PIC/S GMP Guide.
Failure to adequately review
audit trails may allow manipulated or erroneous data to be inadvertently
accepted by the Quality Unit and/or Authorised Person.
Clear details of which data
are critical, and which changes and deletions must be recorded (audit trail)
should be documented.
2
Where available, audit trail
functionalities for electronic-based systems should be assessed and
configured properly to capture any critical activities relating to the
acquisition, deletion, overwriting of and changes to data for audit purposes.
Audit trails should be
configured to record all manually initiated processes related to critical
data.
The system should provide a
secure, computer generated, time stamped audit trail to independently record
the date and time of entries and actions that create, modify, or delete
electronic records.
The audit trail should
include the following parameters:
– Who made the change
– What was changed, incl. old
and new values
– When the change was made,
incl. date and time
– Why the change was made
(reason)
– Name of any person
authorising the change.
The audit trail should allow
for reconstruction of the course of events relating to the creation,
modification, or deletion of an electronic record.
The system must be able to
print and provide an electronic copy of the audit trail, and whether looked
at in the system or in a copy, the audit trail should be available in a
meaningful format.
If possible, the audit trail
should retain the dynamic functionalities found in the computer system, e.g.
search functionality and export to e.g. Excel
Verify the
format of audit trails to ensure that all critical and relevant information
is captured.
The audit trail
must include all previous values and record changes must not obscure
previously recorded information.
Audit trail
entries should be recorded in true time and reflect the actual time of
activities. Systems recording the same time for a number of sequential
interactions, or which only make an entry in the audit trail, once all
interactions have been completed, may not in compliance with expectations to
data integrity, particularly where each discrete interaction or sequence is
critical, e.g. for the electronic
recording of addition of 4 raw materials to a mixing vessel. If the order of
addition is a CPP, then each addition should be recorded individually, with
time stamps. If the order of addition is not a CCP then the addition of all 4
materials could be recored as a single timestamped activity.
It has long been the requirement that computer systems have audit trails and that these be convertible to a format that can be reviewed as appropriate. What these guidances are stating is:
There are key activities captured in the audit trail. These key determined in a risk-based manner.
These key activities need to be reviewed when making decisions based on them (determine a frequency)
The audit trail needs to be able to show the reviewer the key activity
These reviews needs to be captured in the quality system (proceduralized, recorded)
This is part of the validated state of your system
So for example, my deviation system is evaluated and the key activity that needs to be reviewed in the decision to forward process. In this deviation decision quality makes the determination at several points of the workflow. The audit trail review would thus be looking at who made the decision when and did that meet criteria. The frequency might be established at the point of disposition for any deviation still in an opened state and upon closure.
What we are being asked is to evaluate all your computer systems and figure out what parts of the audit trail need to be reviewed when.
Now here’s the problem. Most audit trails are garbage. Maybe they are human readable by some vague definition of readable (or even human). But they don’t have filters, or search or templates. So companies need to be (again based on a risk based approach) evaluating their audit trails system by system to see if they are up-to-the-task. You then end up with one or more solutions:
Rebuild the audit trail to make it human readable and give filters and search criteria. For example on a deviation record there is one view for “disposition” and another for “closure”
Add reports (such as a set of crystal reports) to make it human readable and give filters and search criteria. Probably end up with a report for “disposition” and another report for “closure.”
Utilize an export function to Excel (or similar program)and use Excel’s functions to filter and search. Remember to ensure you have a data verification process in place.
The best solution is to ensure the audit trail is a step in your workflow and the review is captured as part of the audit trail. Ideally this is part of an exception reporting process driven by the system.
I find it interesting to read a different perspective. I tend to be a big fan of guidances (they always need work) as they help lay down how we can get better and improve. Being on the front line of regulatory inspections probably more than a group of lawyers, I recognize the differences in how guidances are treated differently than regulations, and how the agencies apply very long lead times on how inspections treat this material. And frankly, the 483s and Warning Letters we are seeing coming out of data integrity scare the beejeezus out of me. There is also a need for the FDA to ensure it’s thinking on matters is aligned with our European and rest-of-world counterparts, especially in this day of mutual recognition agreements.
Regulatory and administrative law is definitely continually evolving. It is important to be aware of a variety of perspectives on the subject.
Investigations of a Dog 