[Editor’s Note: This post has been updated; originally published on June 13, 2019.]
Preparing for GMP inspections, particularly preapproval 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
The 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 on the Qualification of Contract Laboratories and Contract Manufacturers
The selection, qualification, and oversight of contract laboratories and manufacturers enhance the likelihood of 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
CRLs continue to be issued for quality reasons, generally GMP inspection problems. These include CRLs issued to Novartis in December 2020; Braeburn Pharmaceuticals in December 2020; Alkermes in November 2020, Fennec Pharmaceuticals in August 2020; Ferring in May 2020; and finally, Intarcia Therapeutics in March 2020. These are just a few of the CRLs issued for Quality or manufacturing issues. Remote data reviews, conducted in lieu of onsite inspections in 2020, contributed to the CRLs.
“Homework” for supplier and contract manufacturer/laboratory qualification include:
Thorough onsite 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, and review the laboratories and manufacturing floor
- Do not 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 of 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
- Form 483s
- 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, potentially delaying your product approval with a Complete Response Letter.
2. Develop and Implement a Solid Quality Agreement
Trust is nice and essential to a successful long term relationship, but the clarity of responsibility is essential both to inspecting health authorities and business people. Following are guidance from the FDA on arrangements with contract manufacturers and contract laboratories and Chapter 7 from the EU GMP Guide on Outsourced Activities.
Contract Manufacturing Arrangements for Drugs: Quality Agreements Guidance for Industry
Chapter 7: EU Guidelines for Good Manufacturing Practice, Outsourced Activities
Many organizations have published templates for Quality Agreements, here’s one from Pharmatech, for example:
Pharmatech.com Quality Agreement Template
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? This provides clarity on expectations particularly with changes in personnel or during unusual times like the current COVID-19 pandemic.
[Editor’s Note: For more on Quality Agreements, read “Quality Agreements: Part I, Why They are Critical” and “Quality Agreements: Part II, How to Write Good Ones.“]
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 details 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.
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 have heard is to maintain, “professional distance.” Both the health authorities and the company have a job to do.
Respect for 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 newfound 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 through 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 note-takers so you can document what each investigator requests, and in what context they make the request.
- Assign “backroom” 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. Do Not Panic
On the day of the inspection (PAI’s are prescheduled) realize that if you’ve planned correctly, practiced, and have confidence, you should do fine.
Yes, problems will arise, but do not 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 CRL that delays product approval and the resulting revenue stream. See #1 at the beginning of this list for example.
After the first preapproval inspection and product approval, the firm’s goal should be to be inspection-ready every day. Routine GMP inspections are unannounced in the United States, 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.
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