Note: This post has been updated; originally published on January 26th, 2017.
Preparing for GMP inspections, particularly pre-approval inspections, can be a challenge when resources are limited and staff may have little expertise in these important activities. This becomes especially complex for start-up companies that are virtual, or essentially virtual, and rely on contract manufacturers and contract laboratories.
Virtual firms are responsible for:
- The content of the submission
- Release of product to the clinic or for commercial distribution
- Post-approval safety reporting even though they may not manufacture an API or dosage form
Following are my top 10 suggestions for these firms to ensure a successful inspection outcome when they have limited experience in this activity and limited resources.
1. Do Your Homework In The Qualification Of Contract Laboratories And Contract Manufacturers
The selection, qualification, and oversight of contract laboratories and manufacturers enhance the likelihood for product approval and the ability to provide a consistent supply of product to the marketplace after approval.
Cost is important but should never be the primary driver.
Several Complete Response Letters (CRL) that have CMC or manufacturing components have delayed product approval. Here are some examples:
- Sanofi and Regeneron’s expected blockbuster hit with FDA CRL for manufacturing concerns
- Valeant Pharmaceuticals Receives Complete Response Letter From The FDA
- Cempra Receives Complete Response Letter From FDA For Solithromycin NDAs
BioPharmaDIVE also reports on the increase in issuance of Complete Response Letters in 2016.
Continuing that pattern, Tesaro Inc. received a CRL on January 11, 2017 in which FDA “requested additional information regarding the in vitro method utilized to demonstrate comparability of drug product produced at the two proposed commercial manufacturers for rolapitant IV that were included in the NDA” according to a press release posted on their website. And here’s the 8-K SEC filing.
According to the conference call posted on the Tesaro website, the FDA identified deficiencies at their first drug product manufacturer in mid-2016 after which Tesaro identified the second manufacturer.
Regarding the analytical method in question, concerns appear to focus on method validation and analytical results. GMP inspection issues have become more common as the reason for issuance of a CRL rather than approval or approvable letter.
‘Homework’ for supplier and contract manufacturer/laboratory qualification include:
Thorough on-site evaluations of contract manufacturers, contract laboratories, and critical raw material suppliers.
- Seek to identify potential show-stopper type of deficiencies, and not focus on one-off mistakes.
- Don’t get stuck in a conference room listening to PowerPoint presentations because you have limited time for this activity.
- Get out on the floor, talk with operators, review the laboratories and manufacturing floor.
- And, don’t forget to take a careful look at the warehouse.
A major component of contractor qualification should include a deep dive into the status of data governance and data integrity controls at the firm. It is little value if they have an elegant change control program but manage their data in such a way that it’s not trustworthy. Consider having to explain that to a regulatory authority, and how poorly that discussion might go!
Seek additional information about the compliance history of the firm. Be sure to search:
- FDA warning letters
- Import alerts
- Recall history
- Status of EU GMP certificates
Firms should gladly provide recent inspection reports after confidential information is redacted. If they won’t provide these, proceed cautiously. An amazing amount of information is publicly available, utilize all of it.
Determine who else they manufacture for and ask colleagues and friends about their experiences.
This step can take time, effort, and money. Don’t skimp. Get this right and it will go a long way to prevent expensive problems later. Get it wrong and it becomes very costly.
2. Develop And Implement A Solid Quality Agreement
Trust is nice and essential to a successful long term relationship, but clarity of responsibility is essential both to inspecting health authorities and business people.
Many organizations have published templates for Quality Agreements, here’s one from Pharmatech, for example:
Find the best of all and use them to your advantage. For example, do you want to be on-site at your contractor during inspections, and, if this isn’t possible, how frequently do you want to be updated on inspection progress and potential issues? Just like GMP documentation, if this isn’t written down it didn’t/won’t happen.
3. Plan, Plan, And Track The Plan
If you own your manufacturing site, develop a plan to prepare for the inspection. This should include specific detail of deliverables, a due date, and the actual name of someone responsible. Due dates will be revised, but keep track of which ones have been delayed and why. Letting activities accrue until the few weeks prior to inspection is a recipe for disaster.
If you use contract manufacturers, discuss with them how you will be involved in their preparations and determine which, if any, health authority questions you will be permitted to address.
[NOTE: Do you know if your CMOs are inspection-ready? Get your free CMO assessment today and make sure they’re on track.]
4. Communicate, Communicate, And Communicate
If your firm is not familiar with the inspection process, you will need to do a lot of ‘education.’ Make sure everyone understands what to expect as well as how to conduct themselves during the inspection. Regulatory affairs groups are generally in contact with the regulatory authorities regarding scheduling potential inspection dates and manufacturing plans.
5. Identify Your Shortcomings And Have A Story
Nobody is perfect. Keep a list of identified gaps and prioritize their resolution. If you cannot fix them all prior to the inspection, have a written plan and timeline you can share with the regulators. This should be documented within the Quality System, likely as a CAPA.
Determine who the staff are who will speak to these issues. Make sure you have a consistent description and presentation of what went awry, how it was investigated, and how you are remediating. Make sure everyone describes the same event and plan. To ask five different people about an event and get five different versions of what happened is disconcerting to an auditor/inspector.
6. Bring In Outside Assistance If Possible
Contract with an outside party to conduct a mock inspection if this is your manufacturing site and staff have limited experience being part of an inspection. This may well include a lot of practice and role-play. Ask the hard questions so people get comfortable in addressing them.
A deer-in-the-headlights look from a company staff member during an inspection can lead to significant problems.
7. Practice, Practice, Practice
See the second half of item 6 above. Remember, they receive training in law enforcement interview techniques. Regulators may try a variety of techniques to entice staff to think they can confide in them. Terrific for an investigator, potentially disastrous for the company.
The best description I’ve heard is to maintain ‘professional distance.’ Both the health authorities and the company have a job to do.
Respect each other. Answer questions honestly, and if you don’t understand what’s wanted, request clarification.
Don’t over communicate and don’t try to be the new found buddy for the investigator. This may not end well.
8. Implement And Follow An Inspection Management Process With Defined Responsibilities
This begins when the investigators walk into the lobby.
- Have an SOP that describes how they will be greeted
- Who will notify the appropriate staff (a telephone or email ‘tree’)
- How they will be escorted expeditiously to the conference room set aside for this purpose
First impressions count. Bungle this part of the process, let the investigators sit alone in the lobby for 30 minutes, and it’s a challenge to recover.
This is the easy stuff, get it perfect. This also includes:
- Identify escorts for each investigator. Stay with investigators all the time. Regulators should not be permitted to roam freely thru the facility both from a safety perspective and a GMP compliance perspective.
- Ensure that you understand what an investigator is requesting. You want to provide them with what they want to evaluate, nothing more and nothing less.
- Assign notetakers so you can document what each investigator requests, and in what context they make the request.
- Assign ‘back room’ staff to collect and stage requested documents. Review each page of each document. Failure to remove that ‘yellow sticky note’ with problematic comments can have an unfortunate impact or simply be embarrassing. And, yes, everyone finds these; you cannot be too careful.
- Do not delay in presenting documents to investigators without informing them of the reason for the delay. Set expectations for when documents will be provided. The FDA may deem all products made at a facility to be adulterated if the firm delays, denies, or impedes an inspection. Warning letters have been issued for this behavior.
- Assign staff to explain to selected presenters what the investigator is specifically looking for prior to walking into the room with the investigator. Communicate the context of the request to the company individual who will speak to the investigator.
9. Don’t Panic
On the day of the inspection (PAI’s are pre-scheduled) realize that if you’ve planned correctly, practiced and have confidence, you should do fine.
Yes, problems will arise, but don’t panic. It is the responsibility of the most senior Quality person to set the tone and maintain a calm and professional atmosphere.
10. The Form-483
Assume one will be issued.
This is not the time to argue or try to convince the authorities that they misunderstood something. That should have happened at close-out each day or in the response you will prepare.
The purpose of this meeting is to ensure the company understands the observations, so that they can be accurately and thoroughly addressed in the response.
FDA rarely issues a warning letter (I know of one in all the years I’ve been in the business) to a clinical development stage firm. But, an inspection identifying serious deficiencies can result in a complete response letter (CRL) that delays product approval and the resulting revenue stream. See #1 at the beginning of this list for examples.
After the first pre-approval inspection and product approval, the firm’s goal should be to be inspection-ready every day. Routine GMP inspections are unannounced in the US, although they are generally conducted every two to three years.
A serious recall or product complaint may lead to a for-cause inspection with no real time to ‘prepare’. Maintaining an inspection-ready mindset will make those next inspections go more easily and the confidence of being always ready for inspections should show through to the inspecting health authorities.
The ten steps listed above are by no means a complete list, but they provide a starting point for firms that have limited resources and are preparing for their first GMP inspection.
[NOTE: The best place to start is to familiarize yourself with the current FDA inspection trends benchmarks and to know what your peers have been hit with recently. Get your free Peer Benchmark report today.]
Learn more about how FDAzilla can help you achieve your quality and inspection preparation goals: get 483s, InspectorProfiles, Enforcement Analytics, and GMP Regulatory Intelligence. Contact us if you ever have questions at [email protected].
About the Author
Barbara W. Unger is Govzilla’s Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence. She formed Unger Consulting, Inc. in December 2014 to provide GMP Quality consulting services to the pharmaceutical and biopharmaceutical industry. At Amgen, she led the segment of the Corporate GMP Audit group at Amgen focused on API manufacturers, Quality Systems and Computers. She developed, implemented and maintained the GMP Regulatory Intelligence program for 8 years at Amgen Inc. This included surveillance, analysis and communication of GMP related legislation, regulations, guidance and industry compliance enforcement trends. This was an essential service and tool within the Corporate Audit function. Unger Consulting Inc. | www.ungerconsulting.net | 805.217.9360