Microsoft Sharepoint Online: A vaccine for US FDA’s 483s, Warning Letter plague?

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Ram Balani, CEO, FDASmart, explains how a customised, list-based Sharepoint GxP search can enhance enterprise pharma SOPs with US FDA cGMP regulatory compliance

It comes as no surprise to anyone that flawed, incomplete Standard Operation Procedures (SOPs) or SOPs in good order but not adhered to are the number one cause for US FDA 483 deficiency Inspectional Observations or worse, Warning Letters (actual US FDA sourced, compiled statistics below in this article. SOPs are written documents on step by step work performed during the manufacture, processing, packaging, storage and distribution of pharmaceutical drugs that presumably guarantees safe and reliable drugs with consistent quality. Simple enough.

Why then are SOPs still flawed ? Many ways; some obvious, some not.
SOPs can be flawed:

  • When SOPs are written by a solitary enterprise personnel without the participation of other stakeholders downstream and upstream the drug manufacturing process. (NOT written by a TEAM! Those of you who caught on to the term ‘team’ as a play on words with Sharepoint (e.g. team sites) are ahead of the game with where this article is headed, congratulations!).
  • When SOPs ignore or clearly lack written documentation of reference to infer compliance with FDA 21 CFR Part XXX predicate rules including cGMP (Parts 210 and 211), GLP (Part 58) & Quality Systems Regulations ( Part 820), etc.

This article focusses on (a) when SOPs are written NOT by a TEAM but unilaterally by a single author presumably the subject matter expert or task performer and (b) when SOPs ignore or lack references to infer US FDA GxP regulatory statutes compliance. Microsoft’s Sharepoint can assist with ample doses of remedy for both! Sharepoint is FAST emerging as the new ‘darling’ in the pharma, biotech and medical devices sector.

Deficient SOPs being a dominant source of US FDA 483 adverse inspection observations or worse Warning Letters have not gone unnoticed, i.e. many pharma companies now deploy the use of Sharepoint as its collaborative platform for development of SOPs. SOPs are written, modified, reviewed, approved, stored or archived and transmitted using the workflow collaboration features of a Sharepoint team site, for example, regardless of globally dispersed team members.

Microsoft’s Sharepoint
Online, as most of you know, is deployed on the cloud and accessible with most browsers, no installations required. Add to that various other features such as its integration with
Office 365, workflow enhancements, embedded communication or blog site out of the box without programming and much more makes it easy to see how Sharepoint can advance SOP writing to new heights. Sharepoint seems slated to replace the old school style of the solitary SOP writer(s) with a team driven, cloud-based efficiency and ease of deployment second to none.

SOPs written with a joint team approach using a downstream/upstream group of stakeholders with diverse domain specialties or subject matter qualifications adds a tremendous and critical value to the SOP writing process. It’s a game-changer.

Some pharma stakeholders involved with SOPs are listed below as an example but by no means is exclusively complete since situations may vary from one enterprise to another.

  • Formulators of drugs and manufacturing processes
  • Technical writers
  • Safety personnel
  • Environmental personnel
  • Quality assurance (QA0 or quality control (QC) personnel
  • Regulatory compliance staff or experts
  • Calibration or maintenance personnel on any equipment described in the SOP
  • Employees who will actually be using the SOPs to perform their jobs.

Using a team approach in the SOP production process just makes good plain sense. A joint team SOP development process offers many benefits. A key benefit that bears repeating with team SOP development is that SOPs are bound to be more complete and up to date since many personnel from various stakeholder departments are jointly involved in the SOP document production when certain events or milestones occur.

Some examples might include when a manufacturing or packaging process is modified or a new equipment is installed for use or a vendor replaced for API sourcing. When the manufacturing process or environment or some protocol changes, other SOPs outside of the change agent or source will likely be impacted. How and where within the enterprise the ripples effect of the change is felt on existing SOPs and its subsequent impact(s) on US FDA GxP predicate statutes needs to be dealt with to stay in compliance. They are most likely NOT. This is pharma’s Achilles’ heel! SOPs, whether defective or not adhered to today still remain the main source or leading cause of deficient 483 inspectional observations or Warning Letters from US FDA inspectors. Why?

US FDA GxP or predicate rules (e.g. cGMP- 21 CFR Part 210 & Part 211) govern safety, effectiveness and quality of drugs that meets GxPs regulatory compliance. They are tightly bound and embedded within the framework of US FDA drugs manufacturing oversight. GxP statutes and US FDA guidance publications are the ‘WHAT’ FDA expects you to be in compliance with while your enterprise written SOPs purportedly fulfills the enterprise’s performance of the ‘HOW’ to put it succinctly.

Simply put, 483s deficiencies exists because there remains a gap between the ‘WHAT’ and the ‘HOW’, the two don’t often ‘tango’. For written SOPs to be ‘un-flawed’ and sufficiently meet US FDA GxP regulatory expectations, SOPs need to be written is such a fashion that shows HOW US FDA GxP compliance are fulfilled in the context of SOP written steps and performance. SOPs with only document name, title, version, approver name, scope of the SOP, actual process or task steps therein, etc are not enough!

Apart from cGMP statutes referenced to infer FDA compliance as part of the written SOP record, SOPs must then be followed to a tee and moreover, diligently updated as things change within the enterprise. It’s the crucial step in avoiding the dreaded US FDA ‘adulterated’ drug label.

Need convincing? Read on. Note the instructions to US FDA Inspectors below straight out of the US FDA’s Drug Quality Assurance Compliance Program for Drug Manufacturing Inspections instructs inspectors to:

“Review and use the CGMP regulation of Finished Pharmaceuticals (21 CFR 210 and 211) and related guidance for industry to evaluate manufacturing process.” (Derived from Part III Inspectional below, i.e. US FDA instructions)

“Furthermore, this inspection approach will provide for fast communication and evaluation of findings. Inspectional observations noting CGMP deficiencies should be related to a requirement.”

“Guidance documents are not to be referred to as the justification for an inspectional observation. The justification comes from the statute and the CGMP regulations. Guidance documents do not establish requirements.”

See Figure Part III-Inspectional below
Translated in English, the section on Part III-Inspectional says: cGMP Parts 210 and 211 are legal statutes that can serve as the basis for issuing deficient 483 observations (or Warning Letter if not remediated), while US cGMP FDA Guidances are mere interpretations of those statutes.

(*Spoiler alert: US FDA cGMP Guidances, however, do still reference the same cGMP Parts 210 and 211 statutes for actionable legal proceedings if needed*) Simply said, the long overdue take-away for the enterprise from all these is: it’s time to get inside the US FDA
inspector’s ‘head’ long BEFORE he conducts his inspections of your premises and its operations. You can be sure your SOPs on the record in writing and their strict performance adherence (or lack thereof) coupled to cGMP statutes compliance on the manufacturing plant floors will be INVESTIGATED to justify any deficiency discoverable with your enterprise inspectional observations.

Evidencing above figures on the top page, one only needs to glance at the char(s) (Figure I, II) reproduced from the US FDA website. Source: /inspections-compliance-enforcement-and-criminal-investigations/inspection-references/fy-2017-inspectional-observation-summaries#Drug It’s appalling and frankly surprising to see the number one reason for 483 deficiency observations are due to either written procedures ( including SOPs!) not existing or being followed at 26.7 per cent occurrence and moreover these 483 deficiencies were attributed to QC as responsible! QC is where the enterprise relies on for quality assurance policing, its mission failed miserably. But why does QC fail? Drug manufacturing is inherently complex, there’s no one size fits all. Having SOPs written concisely is one stab to simplify any complex process to ensure consistent, always-on-the spot, routine but consistent performance of repetitive steps by anyone. Add to that the fact that US FDA cGMP statutes are so extraordinarily comprehensive yet so precise that no one person can possibly have a total command of most 21 CFR Part xxx, we have mission impossible or so it seems.

To explain further why enterprise compliance with US FDA cGMP is a ‘beast’, a hypothetical scenario is helpful (Figure III).

As one can see from Figure III, various enterprise stakeholders command different levels of experiences with upstream/downstream SOP process step-by-step tasks and/or the underlying implied GMP regulatory compliance statues (e.g. Parts 210 and 211). This gap amongst various enterprise stakeholders between the across-the-board SOP step-by-step processes vs. GMP statutes awareness or sophistication continues to be ‘big hole’ that muddies the SOP team writing process or their adherence.

Relying on QC alone can never be enough. This is undeniably and factually shown in the previous US FDA deficiency compilation, i.e. even QC which is held accountable to the entire enterprise as guardians of the ultimate quality assurance oversight, failed miserably with inspection observation deficiencies in 2016-2017. It is therefore mission critical for SOP development that MORE stakeholders across the enterprise need to step up to the plate to own up or assist with GxP compliance. Each stakeholder role must be preemptively more vigilant as to how changes on their respective turf’s SOPs changes impacts the entire process chain.
To paraphrase — what we have now is a classic ‘right-arm’ does not know what the ‘left-arm’ is doing scenario. Take note that your enterprise is at a disadvantage and no where close to match a US FDA inspector prowling about your premises who is ‘ambidextrous’. US FDA inspector(s) are groomed to evaluate your pharma enterprise written SOP thoroughly in the context of US FDA cGMP statute compliance they expertly know all too well to the point where, if allowed to, he can justifiably and legally declare your drugs adulterated when necessary!
So the question that goes — a-begging then is — how do you narrow or tighten the spread or gap between written SOPs on the enterprise records and their inferences towards US FDA Gxp statute compliance ? (eliminating the gap might be nice!).

Are your SOPs across-the-board processes or tasks sufficiently written and performed to completely factor in Part 211 regulatory statute compliance since that’s exactly what a US FDA inspector is gunning for to investigate when he comes visiting your enterprise premises? Can your SOPs withstand the ‘domino’ effect where a change downstream ripples into upstream operations potentially with serious consequences if unattended?

Each stakeholder needs to look with vigilance beyond his/her immediate enterprise functional ‘cubby-hole’ given one’s subject domain expertise in the context of GMP predicate rules compliance. Easier said than done!

This can better be illustrated with another hypothetical scenario, i.e. that of a manufacturing plant site, for example, where a container/ closure of an API vendor source or formulated drug stored over time has changed.

Given this scenario, how will various parts of the enterprise and their respective SOPs be impacted? What cGMP Parts 210/211 statutes needs to be incorporated anew or modified? Who is responsible for these additions or changes? When are these changes to be instilled into modified SOPs or new established tasks?

Containers and closures are made from a variety of materials including glass, plastic and metal while formulated drug being stored might be a solid, liquid, or gas or sterile? It is naturally vital to check whether there are any undesired interactions between the formulated drug and the new, replacement container.

For instance, there needs to be testing (QC laboratory needs to do spot-test and then some over an extended time period via stability study testing) carried out to see whether any of the formulation ingredients have become adsorbed on to the plastic replacement container or whether any plasticiser, lubricants, pigments or stabilisers are leaching out to the formulated preparation. Labels and their adhesives might also need to be checked out to ensure no leaking into the formulation contained, i.e. could be an actionable task for other stakeholders ( e.g. labeling or packaging department )

How does your enterprise proceed to manage this and more countless changes and modification to the manufacturing life cycle chain that may go unnoticed or unaccounted for by mistake, omission or even deliberately? One logical and prudent inclination would be to search the entire inventory of existing enterprise SOP documents on the record (which Sharepoint team sharing can enhance) or check with a local on-site or central QC for inferences on quality assurance with matters of API source or container/closure change and their ramifications.
Can you afford to merely rely on the QA group blind-sighted ? NOT! Consider QC’s record given the 483 deficiency statistics compilation from above showing laboratory control failed onerously in almost one out of every 5 times (17.9 per cent) with its flawed oversight of [components],[drug product containers] [closures] [labeling] from lacking [scientifically sound and appropriate [specifications][standards] [sampling plans] and their potential ripple effects on drug quality integrity.

Notwithstanding QC are not ‘masters of their universe’, an easy-to-use, independent (of QC) GxP search seems inevitable in order to pre-discover potential GxP deficiencies or gaps from one stakeholder to the next that could possibly arise with the necessary SOP alterations or updates . These days, we feel mostly assured that since we are in the midst of an information/data explosion where just about anything on everything is documented on some website page somewhere, we can seek answers online and in some way begin to muddle through this problem even if just to know what we do not know!

The challenge is not whether the information we need (GxP statues impacted) exist but how to find them given a very specific though hypothetical but plausible use case scenario above starting with the venerable US FDA ( website.

‘Piece of cake’ you say — try this challenge then:

(a) “What 21 CFR Part 211 GMP statues (Part 211 and Section(s) ) must anyone including QC  be investigating where ‘container’ ‘closure’ ‘contamination’ are used as search keywords ! “(**want to know what US FDA GMP Part 211 statutes are impacted when container closure are referenced with contamination?**)

The logical place to start would be here — the US FDA.GOV link (content) for 21 CFR Part 211-Current Good Manufacturing Practice for Finished Pharmaceuticals, Any luck with the single-word ‘Ctrl-F’ to find ‘container’ ‘closure’ ‘contamination’ references in 21 CFR Part 211.XX link pages above ? Not likely, ‘Ctrl-F’ is limited to single word searching!

(b) An alternative search site might be this link (search page) below provided by no less than the US FDA itself. Again-try searching for the answer to the same question above: ‘container’ ‘closure’ ‘contamination’.

Site below was created by the US FDA to ‘assist’ searching GxP so they say. And the answer is? Time to despair? All is lost. Not quite. Microsoft Sharepoint Online Search may provide a solution — though tedious to develop or set-up, it works! (See Figure IV: How a customised, repurposed Microsoft Sharepoint Online Search works) .

Microsoft’s Sharepoint search has been touted as a new generation search, we tend to agree.
To get some sense or glimpse of how a repurposed, list-based Microsoft Sharepoint GxP search from US FDA website harvested content might look like -please consult the Sharepoint GxP search scenarios screen shots captured in Figures V through VII above. See also screenshot captured as Figure VIII-A and Figure VIII-B.

The industry can expect more globally dispersed groups working together despite time zone differences, best practices and cultural challenges. SOPs are and will continue to be the lifeblood of day to day pharma manufacturing across the enterprise and with even more complex processing including biologics, one can expect evolving US FDA regulatory compliance and vigilance to go along with it.

On-demand collaboration and their challenges must evolve to new heights with more robust collaborative, integrated and feature-rich platforms like Microsoft Sharepoint Online which is paving the way with team site workflows in SOP development. Context-rich ‘search’ is the next frontier to facilitate fine-tuned, pervasive GxP compliance so it becomes not just a tribal QC village but embedded across the pharma DNA not with mere words but in action!

The recent Akorn Pharma US FDA Warning Letter (January 2019) will be addressed as a FOLLOW-UP Express Pharma ‘post-mortem’ article featuring a forensic analysis of the Akorn Warning Letter’s cGMP Part 211 violations.The analysis will, however, go beyond the Warning Letter and analyse ‘pre-emptively’ previous 483s issued to Akorn after past inspections (whether No Action or Voluntary or Official Indication type).

The Express Pharma Part II-follow up article will attempt to determine what actions or remediation steps Akorn should/could have discerned as ‘clues’ or cGMP directives to pursue remedies on its own before the US FDA issued its Warning Letter (last resort!) with a smart(er) search of US FDA cGMP Part 211 statutes or predicate rules using the actual Akorn 483 texts or inspection observation content from the FDA. We will, in this follow-up article, fish out ‘keyword(s) or combination thereof similar to what was done in the GxP search case scenarios (hypothetical) in this article. We will of course be using another version of the Gxp/Sharepoint List enhanced this time with more FDA website content including guidance on data integrity and sterile drugs processing still also repurposed as Sharepoint lists for searching. Akorn Warning Letter can be previewed here at the US FDA website – inspections-compliance-enforcement-and-criminal-investigations/ warning-letters/akorn-inc-558914-02042019 In the Warning Letter, the US FDA recommends hiring a consultant to assist Akorn with their remediation and CAPA measures to rectify the cGMP violations. No offense to pharma consultants, they serve a good purpose but by no means in our opinion should Akorn stop there. It should be a foregone conclusion that in the end, the enterprise itself (Akorn) must  on its own, long after the cGMP consultant(s) are gone, get its act together with cGMP! (and not rely on consultants hired to to fix the current deficiencies not necessarily pre-empt new ones!)

The article below, by Express Pharma’s Editor, Viveka Roychowdhury, “Beyond a Culture of Compliance’, is most instructive. In the article she states:

“Many companies, following the remedial actions prescribed by the US FDA inspection reports, have also turned to third-party consultants to get an independent impartial view of their systems and processes as well as train their teams. How effective are such GMP consultants, given that they remain ‘outsiders’ and insiders might have a better chance of identifying cGMP gaps? More so, since they will move on once the period of their consultancy is completed? How can a company internalise the advice and make more permanent changes?”

( cover-story/building-a-culture-of-compliance/) Instilling heightened cGMP awareness or even sophistication to those inside the enterprise calls for ‘insiders’ to do more ‘heavy’ lifting on their own i.e. realise that seeking out compliance with cGMP statute should be built-in within and across the enterprise into the organisation and not merely shopped into the enterprise from outside (consultants) only when forced to do so!

FDASmartRam BalaniUS FDA cGMP
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