A question raised in the packed Sept. 16 conference session spoke to everyone’s fears about overzealous investigators and how they might use FDA’s new authority to deem product adulterated whenever they believe someone is obstructing their inspection.

Recent warning letters suggest that only extreme cases will trigger FDA’s use of this powerful authority granted by section 707 of last year’s FDA Safety and Innovation Act.

The investigator “continually threatened us that we were delaying the inspection. We had to bring our VP of quality to calm her down.”

FDA’s FDASIA-mandated July 12 draft guidance, “Circumstances that Constitute Delaying, Denying, Limiting or Refusing a Drug Inspection,” gives more detail, but still leaves people uncomfortable. What about minor cases? What if a site’s seemingly reasonable explanation is deemed unreasonable?

These were some of the issues that came up, for example, in industry comments on the draft guidance Also see "Rx Companies Push For Exemptions To Breadth Of FDA Inspections" - Pink Sheet, 21 October, 2013..

The “inspection trends” session at the Parenteral Drug Association/FDA Joint Regulatory Conference in Washington provided an early opportunity for the agency to fill in some of the gray areas on how it would implement the guidance.

Brooke Higgins, pre-approval manager/investigator in FDA's Baltimore District Office, walked the group through the draft guidance, the legislative requirement for it and the way FDA has begun interpreting it, as evidenced in recent warning letters.

Zena Kaufman, senior VP of global quality at Hospira, presented an encouraging review about the conservative way FDA appears to be using the guidance document in warning letters. But not everyone was mollified.

Kaufman read the question, which someone from the audience had written on a card: During a recent combination products inspection, the FDA investigator “‘was asking for tons of documents and expected them to be given immediately. Honestly, it was almost impossible to cope with her. She continually threatened us that we were delaying the inspection. We had to bring our VP of quality to calm her down. This was abusive and an excess of power.’ And the question is, ‘Any reaction?’ So what would you advise a firm if they felt that this was going on?”

What FDASIA Section 707 Says

Under FDASIA Section 707, a drug is adulterated if it is “manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection.”

Higgins shared some practical suggestions for working with such an investigator, including using mechanisms for feedback to the agency.

Higgins and Kaufman also said it might help to provide documents as they become available rather than all at once, or provide documents more quickly by leaving out the attachments.

To help defuse such situations, Kaufman also suggested writing down the time of the request on a flip chart. “Sometimes you need to be much more transparent with the investigator to build that trust.”

Kaufman suggested a similar approach to another participant who revisited the problem of the difficult investigator.

“We’ve also had inspections that are difficult, honestly,” this participant said. “And when you have something as strong as a guidance document, with language in the Act that says the product can be [deemed] adulterated. … There are shades of gray, and we could have for example documents requested that were old and archived 100 miles off site, and one inspector may not assume that’s reasonable when almost every part of this guidance document includes that type of language. I think maybe that’s the concern.”

Given that the company would already be taking notes during the inspection, it could also compile a timeline of requests and responses, Kaufman suggested. “If you have objective evidence – these are the records you asked for, this is the time frame and it will take us a couple hours to get them to the facility – I think that would be reasonable.”

“And that happens a lot,” Higgins said, noting that investigators often must wait for manufacturers to retrieve requested documents from offsite contractors. “If you could just update us as you get updates from the services that you use, then we can understand where you are in terms of getting the documents, so that it’s just really transparent to us that you are working to get those documents for us."

Magnified impact

The FDASIA section 707 provision magnifies the potential impact of such threats. If an investigator believes that a facility is obstructing an inspection focused on one product, the provision allows the agency to deem every product at that facility to be adulterated, said Cathy Burgess, a partner with the Washington law firm Alston & Bird.

“That’s a huge, huge expansion of FDA’s authority,” Burgess told a Sept. 17 plenary session. She suggested that it could simplify things for government lawyers wanting judicial authority to seize drug products. “As a practical matter, if the government went into a U.S. district court with a complaint for a product seizure, the standard would be pretty easy.”

Worst case scenarios

Kaufman had started the inspection trends interest group session with a review of recent warning letters that show how FDA is using this new statutory authority.

In one case, she said, “an employee was observed attempting to hide manufacturing-related records in his pocket from the FDA investigator.”

In a second case, the investigator was told all raw data files were on a remote server that Quality Control staff couldn’t access, but later found that they were storing the raw data on their personal computers.

That wasn’t foreign material the investigator saw, it was just a reflection of light, they said. But the next day’s deviation report told a different story.

During this inspection, the investigator saw foreign material in a piece of equipment and requested the firm to open the equipment. But the company said that would have to wait until a knowledgeable person arrived.

When the investigator returned to look for the foreign material, the equipment appeared to have been cleaned. “The FDA was informed no material was there,” Kaufman said, “that it was just a reflection of the light.”

However, a deviation report the next day documented that there had in fact been foreign material in the equipment, and that personnel were instructed in writing to clean it.

In a third case, Kaufman said an FDA investigator saw torn, raw data records in the waste area and asked the company for a closer look. A quality assurance officer later gave the investigator 20 paper records, but they were obviously not the requested records.

“Now the investigator asked three times – and I … think that’s key, so it’s not a one-time ask, this is three times – if there were any more records, and they were told each time, ‘no.’”

The investigator then revisited the waste area and found the torn raw data, which included raw data testing worksheets, batch records and equipment calibration and stability protocol records.

How did FDA write that up? “Because you directed FDA investigators away from the requested documents, and because the FDA investigator was impeded by having to locate and reassemble torn records that FDA had requested and had the authority to inspect, you delayed the inspection.”

“So it’s not just a one-time thing,” Kaufman said. “I can tell you when I first read the guidance, I was a little bit concerned.” She realized that it’s not unusual, for example, for computer glitches to cause delays that could theoretically trigger the new FDASIA provision. “But that is not what I’m seeing in the warning letters.”

Five categories of issues

Higgins said the draft guidance contains “real-life examples that came from investigators throughout the country, [focusing on] experiences that they have had, not just domestically but also internationally.”

She went through the five categories of issues the draft guidance addresses.

Pharmaceutical manufacturers had raised concerns related to many of the categories.

First: Delay in scheduling inspections

When scheduling pre-announced inspections, the agency does “try to make reasonable accommodations for the sites that we’re going to,” such as avoiding holidays and bad weather, Higgins said. “Obviously we don’t want to show up on the day of a hurricane. We do try to make reasonable accommodations when we can.”

However, she said, sometimes a facility will not agree to a proposed inspection start date, and won’t say why. “It’s not just that they won’t agree to it, they just don’t have a reasonable explanation as to why that particular time frame doesn’t work for them.”

Or a firm may agree to a time, but then request a delay without giving a reasonable explanation.

Or a facility may simply fail to respond when FDA attempts to contact it, for example when its e-mail software inadvertently diverts FDA e-mails to the spam folder. “I would definitely recommend discussing that with your IT personnel to make sure that those e-mails don’t get thrown away accidentally,” she said.

Second: Delay during an inspection

Higgins hinted at reasonable explanations for minor delays that FDA investigators would accept.

“We do understand that there are minor delays, you have a lot of people working on the inspection, providing us documents, taking us on tours. We do understand that there may be a minor delay. But please just let us know if there’s something going on behind the scenes. As long as there’s a reasonable explanation for the delay, then we can move forward.”

She also gave two examples from the draft guidance of delays FDA would not accept:

Not allowing access to an area of the facility until some later date and time. “If the site is operational and we’re there to do the inspection, then we need to go do the inspection. If you don’t allow us, then that would be considered a delay of the inspection.”
Leaving investigators “in a conference room by ourselves for an extended period of time … If you do have to leave us for an extended period of time, please allow a telephone or some sort of way for us to get in touch with you, but just leaving us in the room by ourselves would be considered a delay of the inspection if we couldn’t move on to do the next step of the inspection."

Third: Delay producing records

It’s no problem if there’s a delay in producing records – as long as the company provides a “reasonable explanation,” Higgins said. She went on to explain what might be considered reasonable.

“We understand that your facilities may require a reasonable amount of time to produce the records that we’re requesting. You may have the records stored offsite, there may be archives, you need to find them and we understand that. If you’re having difficulty finding those records or getting in touch with whoever is archiving them for you, please let us know. But if there is a delay and there is no reasonable explanation, then that would be considered a delay producing the records."

She further clarified that “if we’re asking for documents and your printer breaks or your system goes down in some way, just let us know what’s going on so that we can understand it. If your printer breaks, whatever you’re providing to us, maybe we could look at it on disk instead. There are other ways for us to be able to look at data when we’re actually on site doing an inspection so that we can move forward as quickly as possible.”

Fourth: Denial of inspection

Denial involves “active behavior” by a facility’s owner, operator or agency “to prevent an authorized representative of the FDA from conducting an inspection or to prevent FDA from completing the inspection,” Higgins said. “This is a statement or physical action that is intended to avoid the actual inspection, so maybe they’re misleading or deceiving the investigator.”

For example:

FDA calls to schedule an inspection and the facility rejects it, saying, “No, that’s not going to work for us.”
When FDA arrives for a scheduled inspection, the facility won’t allow the investigator to proceed.
FDA arrives for an unannounced inspection and the facility says to wait because the president is not at the site.
Someone prevents an inspection by falsely telling the investigator the facility does not make drugs, or only makes them for non-U.S. markets.

Fifth: Limiting of inspections

This is when the owner, operator or agent of a drug facility “prevents an investigator from conducting an inspection to the extent allowable under the law,” Higgins said. There are four subcategories.

Limiting access to facilities

It’s fine to halt manufacturing activities for a coffee break, but not all day or all week during an inspection. There has to be a reasonable explanation, she said.

It’s not OK to limit direct observation of manufacturing to an “unreasonably short” amount of time, Higgins said. “As investigators, it’s really important for us to be able to watch manufacturing, and to watch the behaviors and practices of your operators.”

It is also not OK to make part of a facility off limits for no good reason. “You’ll be moving through a tour, and you’ll see most of the buildings, but one or two buildings you’re not allowed access to, and there’s no specific justification as to why they’re not allowing you access to that area.”

And you can’t just send the investigator away. “Halfway through the inspection, they say, ‘OK, the inspection’s over, we’re done and we’re not allowing you to come back tomorrow.’”

Limiting photography

If an investigator finds it necessary to document findings with photographs, but the facility won’t allow it, that would be considered limiting the inspection.

Higgins explained that “For us, it’s much easier to take a picture than it is to try to describe it in words,” when documenting evidence of problems such as rodent infestation, faulty equipment construction or maintenance, product storage conditions, product labeling, and visible contamination of raw materials or finished products.

Limiting access to records

Higgins went through the draft guidance’s examples of records refusal, which can include refusing to provide records or refusing to allow their review – or unreasonably redacting them.

“There are certain things that we don’t look at (such as) financial information,” she said. “But manufacturing, processing information, lab testing information, that shouldn’t be redacted for our inspection.”

Limiting collection of samples

If FDA is prevented from collecting environmental, finished product, raw material, in-process material or reserve samples, “it would be considered limiting the inspection,” Higgins said.

Refusal to permit entry

Refusing to permit entry, even if done passively, is another way of limiting an inspection that FDA would not tolerate. “This is that passive behavior I discussed earlier ... that results in a representative of the FDA not being able to enter or inspect the facility.”

This would include barring entry to areas of the facility. “For example, you get to a particular door, the door is locked, and everyone says, ‘we don’t have a key, we can’t get into that area.’ If it’s onsite, we do need to look at all those areas where manufacturing is conducted, maybe even just to look into a warehouse and say there’s nothing in there.”

Or the facility could simply fail to respond when FDA tries to contact it, including when the investigator shows up at the site. “If we arrive at a facility and the parking lot is full, and we knock on the door and nobody answers, that would be an example of this.”

Formal comments reflect concerns

Comments industry filed regarding the draft guidance document reflected the types of concerns that participants voiced in the PDA/FDA session.

PDA asked FDA for clarification about how the guidance would apply when the agency uses its new authority to request documents in lieu of an inspection. The association suggested FDA provide a secure method of receiving electronic documents like the one it uses for e-submissions.

PDA also wants clarity on whether the agency would issue Form 483 reports based on such documents and whether manufacturers would get a chance to respond to any questions FDA might have.

The Biotechnology Industry Organization worried that the draft guidance gave FDA investigators authority to declare product adulterated without giving the sponsor sufficient notice or due process. BIO said owner operators should get prior notice and an opportunity to explain delays or limitations and fix them.

BIO wanted FDA to understand that restrictions against access to aseptic processing areas should not be considered refusal of entry.

And BIO objected to the provision about photography, saying that many manufacturers have policies against photography to protect their intellectual property.

The Healthcare Distribution Management Association made a similar point, saying, “The inadvertent publication in photographs or video of highly confidential security systems, alarms and cameras could seriously compromise a warehouse’s security.”

Merck Sharp & Dohme Corp. asked for a formal appeals process to escalate disagreements with investigators over whether companies obstructed inspections.

Merck also sought clarification about what explanations for delays or limitations FDA would deem reasonable.

Novartis suggested that FDA provide better definitions of the terms “reasonable explanation” and “adequate justification” with detailed examples and explanations. “What is reasonable to one person may not be to another and this leaves it too much to the opinion of any particular FDA investigator that the inspection process is being hindered.”

How FDA Will Use Its New Authority against Denying, Limiting or Refusing Inspections – And Why Industry is Still Worried

More from Manufacturing

More from Compliance