ISPE: Global regulators discuss GMP deficiencies, data integrity, real-world evidence

Regulatory NewsRegulatory News
| 27 September 2021 | By Joanne S. Eglovitch 

Regulators, panel discuss range of issues affecting pharmaceutical industry

The COVID-19 public health emergency has prompted regulators to take a different approach to uncovering data integrity violations in virtual inspections compared to onsite inspections, said an official with Australia’s Therapeutic Goods Administration (TGA). The official also provided an update on the status of the EU’s good manufacturing practice (GMP) guide Annex 1, which addresses the manufacture of sterile medicinal products, at a 24 September panel discussion sponsored by the International Society for Pharmaceutical Engineering’s biotechnology conference and workshop.
Health authorities from the US, EU and the Asia-Pacific region also shared their perspectives on the use of real-world evidence (RWE), among other issues affecting the regulated pharmaceutical industry.
Changing face of data integrity
Regulators were also asked to comment on how virtual audits have affected their enforcement focus in the data integrity area.
The panel’s moderator, David Doleski, compliance head for biologics quality operations at Sanofi, said there was a “lot of emphasis on data integrity before the pandemic” and asked the panel whether the pandemic has challenged their work in this area.
Matt Davis, an inspection team leader with Australia’s Therapeutic Goods Administration (TGA), acknowledged that data integrity violations are harder to spot in virtual inspections, compared to onsite inspections.
“Data integrity is not something that we have removed from the table but to be perfectly honest, the ability to interrogate systems from a data integrity perspective and actually follow paper trails throughout an organization will be more difficult in a remote inspection,” said Davis.
He said that during onsite inspections, auditors can physically sit down with systems administrators and look at user profiles and audit trail configurations and can see if the data has been manipulated or modified. “This is difficult to do in a remote inspection,” he said.
Rather, virtual inspections have prompted auditors to looking at data integrity “from a slightly different angle.” Inspectors are “looking at a more systems-based approach to data integrity.” While not revealing the agency’s “tricks and tips,” he said that auditors are focusing their efforts at looking at “potential vulnerabilities” in data systems to see if they can be manipulated.
Davis added that this issue is not going away anytime soon. “Data integrity is an issue and is still a high frequency item. It is still there. We are still seeing issues with data integrity. I would categorize the majority of issues that we are seeing as vulnerability issues.”
Varying viewpoints on Annex I  
Davis, a member of the Annex I working group, said there are plans to issue a revised Annex 1 “soon” but did not specify a date, when asked to provide an update and identify potential challenges in its revision.  It has been challenging to draft a chapter that that is acceptable to both large and small pharmaceutical companies, he said.
As an indication of the interest in the annex, the working group has already sifted through 6,000 comments on the first revision and 2,000 comments on the second, which was In February 2020. (RELATED: EU Begins Second Consultation to Revise Annex 1 of EU GMP Guide on Sterile Drug Manufacturing, Regulatory Focus, 6 March 2020)
The comments received, he said, reflect a “huge range of appetites for risk” as well as a range of views on the topics addressed.
To accommodate these differing viewpoints, Davis said that there is recognition among the working group that the forthcoming chapter must be flexible. It must accommodate manufacturers that have a “very mature quality system” and a high degree of process knowledge and therefore can justify the use of novel technologies. At the same time, the chapter must meet the needs of smaller manufacturers that have neither the resources nor the mature quality systems of their larger counterparts. He said that “prescriptive practices” may be useful for the “low sectors” but would not as welcome for the larger companies.
“There is a lot of debate and discussion around getting that wording right. We have spent a huge amount of time working on this. We have met every month for about 6 months going through this each chapter and poring over each word,” said Davis.
How to make real-world evidence work
Regulators were also asked to provide their views on the acceptance of RWE to accelerate the development of therapies by generating evidence of a drug’s efficacy and safety outside of clinical trials.
FDA issued a draft guidance on RWE in May 2019 outlining expectations for generating such data to support a drug’s use outside of the evidence collected in clinical trials. (RELATED:  RWE Submissions: FDA Drafts Guidance, Regulatory Focus, 8 May 2019.
Wilson Bryan, director of the FDA’s Office of Tissues and Advanced Therapies (OTAT) in FDA’s Center for Biologics Evaluation and Research, weighed in. “This is a popular topic, and a lot of folks are interested in real-world evidence to supplement or perhaps even replace clinical trials again and again to demonstrate safety and effectiveness.” He added, however, that “we are early in the process of understanding how real-world evidence can be used.”
“I have to agree, of course,” concurred Rene Thurmer, deputy head of the pharmaceutical biotechnology unit for the Federal Institute for Drugs and Medical Devices (BfArM) in Germany. RWE “is getting to be a very important topic” at the national and community-wide level at European Medicines Agency (EMA) advice meetings, added Thurmer.
Bryan said that RWE is more readily acceptable to the agency when sponsors meet with FDA early to discuss prospectively how they plan to use and gather such evidence. This works better than sponsors gathering such data after the fact, said Bryan.
“In some cases, sponsors come to us with proposals and gather evidence post hoc. The evidence is out there, and they will go out there and analyze that and those proposals generally have not looked very good to us,” noted Bryan. “What has looked good are some prospective proposals where folks come to us. We sit down and talk about the design of that real world study, and they go out and do the study and gather the real-world evidence prospectively.”
“We are optimistic that real world evidence will have an increasing role in drug development, but we encourage sponsors to come in and talk to us early if they see this is part of their drug development program,” he added.
Most common GMP findings in an inspection
Regulators were also asked to comment on the most prevalent good manufacturing practice (GMP) deficiencies in inspections.
Some of the specific problems Davis sees frequently in inspections is lack of robust investigations for out of trend results and inadequate investigation of complaints. He said that “getting that right is absolutely critical. I can’t think of single inspection I have done in the last 12 years that I have not issued a deficiency for these investigations. It is a very common trend.”
Another common failure he sees when inspecting sterile facilities is faulty validation programs.  “Validation is the backbone of everything that you do in production, and is the data that supports your processes, and sometimes the validation just doesn’t stand up,” said Davis.
ISPE biotechnology conference and workshop


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Tags: Annex, data, EMA, FDA, I, integrity, RWE, TGA

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