The FDA commented in a Warning Letter to Aurolife Pharma that the manufacturer lacked data showing that the process was in “state of control” before batch release. The 483 pointed to the FDA’s guidance document Process Validation: General Principles and Practices, and found the company lacks a state of control of the process, which comes back to change control.
They also found major deficiencies in their OOS and cleaning programs.
Data integrity continued to be a focus of the FDA, though the reduced inspections definitely led to fewer 483s.
| Reference Number | Short Description | Long Description | 2020 Frequency | 2019 Frequency | 2018 Frequency |
| 21 CFR 211.194(a) | Complete test data included in records | Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards. Specifically, , *** | 15 | 38 | 33 |
| 21 CFR 211.194(a)(4) | Complete Test Data | Laboratory records are deficient in that they do not include a complete record of all data obtained during testing. Specifically, *** | 10 | 24 | 28 |
| 21 CFR 211.68(b) | Backup data not assured as exact and complete | Backup data is not assured as [exact] [complete] [secure from alteration, erasure or loss] through keeping hard copy or alternate systems. Specifically, *** | 6 | 6 | 71 |
| 21 CFR 211.194(a)(4) | Data secured in course of each test | Laboratory records do not include a complete record of all data secured in the course of each test, including all [graphs] [charts] [spectra] from laboratory instrumentation, properly identified to show the [specific component] [drug product container] [closure] [in-process material] [lot tested] [drug product tested]. Specifically, *** | 4 | 1 | 28 |
| 21 CFR 211.68(b) | Written record not kept of program and validation data | A written record of the program along with appropriate validation data has not been maintained in situations where backup data is eliminated by computerization or other automated processes. Specifically, *** | 1 | 6 | 71 |
The yearly database of 483s has been updated by the FDA. Lots will be written on themes as we end the year, so I decided to give a few of my immediate observations.
I find that over time what I focus in on changes, as my jobs evolve and change, and the interests I have shift. However, some things never change, so let us talk change.
| Reference Number | Short Description | Long Description | 2020 Frequency | 2019 Frequency | 2018 Frequency |
| 21 CFR 211.100(a) | Changes to Procedures Not Reviewed, Approved | Changes to written procedures are not [drafted, reviewed and approved by the appropriate organizational unit] [reviewed and approved by the quality control unit]. Specifically, *** | 8 | 13 | 9 |
| 21 CFR 211.160(a) | Lab controls established, including changes | The establishment of [specifications] [standards] [sampling plans] [test procedures] [laboratory control mechanisms] including any changes thereto, are not [drafted by the appropriate organizational unit] [reviewed and approved by the quality control unit]. Specifically, *** | 4 | 18 | 17 |
| 21 CFR 212.20(c) | Adverse effects of changes made | You did not demonstrate that any change does not adversely affect the [identity] [strength] [quality] [purity] of your PET drug. Specifically,*** | 1 | 1 | 1 |
I think its fair to say the decreases as a result of the pandemic and the reduced inspections.
Over on the device side of things we see:
| Reference Number | Short Description | Long Description | Frequency |
| 21 CFR 820.30(i) | Design changes – Lack of or Inadequate Procedures | Procedures for design change have not been [adequately] established. Specifically,*** | 26 |
| 21 CFR 820.40(b) | Document change records, maintained. | Records of changes to documents were not [adequately] maintained. Specifically, *** | 6 |
| 21 CFR 820.70(b) | Production and Process Change Procedures, lack of or Inad. | Procedures for changes to a [specification] [method] [process] [procedure] have not been [adequately] established. Specifically, *** | 5 |
| 21 CFR 820.75(c) | Process changes – review, evaluation and revalidation | A validated process was not [reviewed and evaluated] [revalidated] when changes or process deviations occurred. Specifically, *** | 5 |
| 21 CFR 820.40(b) | Change records, content | Records of changes did not include [a description of the change] [identification of the affected documents] [the signature of the approving official(s)] [the approval date] [when the change became effective]. Specifically, *** | 3 |
| 21 CFR 820.50(b) | Supplier notification of changes | There is no agreement with [suppliers] [contractors] [consultants] to notify you of changes in the product or service. Specifically, *** | 3 |
| 21 CFR 820.75(c) | Documentation – review in response to changes or deviations | There is no documentation of the [review and evaluation of a process] [revalidation of a process] performed in response to changes or process deviations. Specifically, *** | 1 |
I’m a firm believer that pharma should always pay attention to the medical device side for 483s. A lot of us are combination products now (or will be) and there is always good trends to be aware of.
My key takeaways:
Here’s a more detailed checklist to help you evaluate your change system.
I’ve been thinking a lot today of this article by McKinsey by Jeffrey Pfeffer and Leanne Williams “Mental health in the workplace: The coming revolution.” It is a fascinating read, not just because we are in the midst of this pandemic which has certainly caused a lot of mental health issues, including depression, in many people. I know I’ve certainly been wrestling with it myself. I’m hopeful this issue remains on the agenda as I think it will provide long term benefits to culture.
I’ve written on how we need to build processes to support our employees in issues like burnout. Mental health is definitely a wicked problem, and will require systematic efforts to address. I am glad that the senior leaders I work with are thinking about this, and I look forward to deepening the conversation.
This photo is on the embarrassing side.
If I stumbled across this on a GEMBA walk there would be coaching on proper storage techniques of documents. My only hope is some corporate communications person made it this way on purpose and the poor person in the photo was muttering under their breath the entire time.
There is an opportunity here on connecting with communications team on best ways to showcase GxP activities. I recommend writing a good policy on the subject and ensuring it is appropriately bought into.
