The Future of Quality Control

While most of the advanced technologies already exist today, few pharmaceutical companies have yet to see any significant benefits. On one side, quality leaders struggle to define a clear business case for the technological changes, and thus fail to bring to management attention to the significant impact potential associated with lab digitization or automation. On the other side, companies often neglect the development of a clear long-term lab evolution strategy and blueprint, which can lead to some costly investments with unclear benefits.
— Read on https://www.pharmamanufacturing.com/articles/2018/the-future-of-quality-control/

Good overview of some current trends in QC labs.

PDF fillable forms

On my.ASQ.org the following question was asked “The Device History Record is a form in fillable PDF format. Worker opens the PDF from a secure source within the local network. The only thing they can change is checkmark Pass/Fail, Yes/No and enter serial numbers in the allowed fields. Then after the assembly process is done for each procedure, the worker prints the DHR, signs and dates it by hand, to verify the accuracy of data entered. No re-printing or saving PDF’s is allowed.”

This comes up a lot. This is really a simple version of a hybrid situation, where both electronic and paper versions of the record exists.

Turning to the PIC/S draft guidance we find on page 44 of 52 “Each element of the hybrid system should be qualified and controlled in accordance with the guidance relating to manual and computerised systems”

Here would be my recommendation (and its one tried and tested).

The pdf form needs to be under the same document management system and controls as any other form. Ideally the exact same system. This provides version control and change management to the form. It also allows users to know they have the current version at all times.

Once it is printed, the paper version is the record. It has a wet-signature and it under all the same predicate record requirements. This record gets archived appropriately.

Where I have seen companies get messed up here is when the pdf exists in a separate, usually poorly controlled system from the rest of your document management. Situations like this should really be evaluated from the document management perspective and not the computer systems life-cycle perspective. But its all data integrity.

Q13 and Q14 path forward

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

Final concept paper and business plan. This new quality guideline will:

  • 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.

ICH Q2/Q14: Analytical Procedure Development

Concept paper and business plan. Q14 will bring the QbD principles to analytical development.

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.

Review of Audit Trails

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.

US FDA. “Who should review audit trails?”  Data Integrity and Compliance With Drug CGMP Questions and Answers Guidance for Industry. Section 7, page 8

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.


US FDA. “How often should audit trails be reviewed?”  Data Integrity and Compliance With Drug CGMP Questions and Answers Guidance for Industry. Section 8, page 8
  Expectations 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.

PIC/S. PI 041-1 “Good Practices for Data Management and Data Integrity in regulated GMP/GDP Environments“ (3rd draft) section 9.4 “Audit trail for computerised systems” page 36

Thoughts

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.

What risk based questions should drive this?

  • Overall risk of the system
  • Capabilities of audit trail
  • Can the data be modified after entry? Can it be modified prior to approval?
  • Is the result qualitative or quantitative 
  • Are changes to data visible on the record itself?

Data Integrity and the Role of Guidances

Interesting piece over at FDALawBlog on the new data integrity guidance “New Data Integrity Guidance Imposes Significant Burdens, Yet FDA Claims It Does Not Regulate by Guidance.”

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.