Month: July 2024

The Importance for USP <665> for E&L

The United States Pharmacopeia (USP) General Chapter <665> focuses on the plastic components and systems used in the manufacturing of pharmaceutical drug products and biopharmaceutical drug substances and products and is one the fundamental documents for manufacturers, especially in the age of single use.

Key Changes in USP <665>

1. Effective Date Extension

The official effective date for USP <665> has been extended to May 1, 2026. This extension is intended to give stakeholders enough time to follow the new requirements and to align with the development of the ICH Q3E guideline for extractables and leachables (E&Ls).

2. Mandatory Compliance

Previously, USP <665> was informational and not mandatory for compendial compliance. The revisions will make it a mandatory chapter, meaning that compliance will be required for regulatory purposes.

3. Risk-Based Assessments

The revised chapter emphasizes risk-based assessments for the qualification of plastic components. This approach aligns with modern regulatory expectations and provides a structured methodology for evaluating the safety and compatibility of materials used in pharmaceutical manufacturing.

4. Scope and Applicability

USP <665> will cover single-use systems (SUS) and container closure systems used in the storage and processing of pharmaceutical and biopharmaceutical products. This includes guidance on the characterization and qualification of these systems to ensure they do not adversely affect product quality.

5. No Grandfathering of Existing Products

The revisions explicitly state that there will be no grandfathering of existing products. All products, including those already on the market, will need to comply with the new requirements by the effective date.

6. Alignment with USP <1665>

USP <665> is closely related to USP <1665>, which provides guidance on the characterization and qualification processes. Together, these chapters offer a comprehensive framework for managing the risks associated with plastic components in pharmaceutical manufacturing.

7. Stakeholder Engagement

The USP has planned to engage with stakeholders throughout the revision process to ensure that the new requirements are practical and achievable. This includes public notices, comment periods, and collaboration with industry experts.

Implications for Manufacturers

Preparation and Compliance

Manufacturers are advised to start preparing for the changes now to avoid potential backlogs and delays. Early compliance will help make sure a smooth transition and keep product quality.

Global Considerations

While the USP is a U.S.-based standard, its guidelines are often adopted globally. Manufacturers should consider the potential for international regulatory bodies to require equivalency to USP <665> compliance in the future.

Training Program

A reader asks what the expectations of the FDA are towards the “training program” and tips on changing the culture/attitude towards positive training behaviors.

I’ve answered the FDA part before in “Site Training Needs,” “Training Plan,” “CVs and JDs and Training Plans,” and “HR and Quality, joined at the hip” but I think it is a good idea to revisit the topic and look at some 483 observations.

Employees are not given training in the particular operations they perform as part of their function, current good manufacturing practices and written procedures required by current good manufacturing practice regulations.

Specifically, your firm does not have a written training program. There are no records to demonstrate (b)(6)(b. is qualified perform filling operations. I observed (b)(4)(b perform filling operation for Wart Control Extra Strength, 4 ml, lot USWCXx-4059 on 01/18/23. I observed (b (7)(C). perform reprocessing and packing operations. There are no records to demonstrate (b (7)C. is qualified perform these operations.

Employees are not given training in current good manufacturing practices and written procedures required by current good manufacturing practice regulations.

Specifically, your firm lacked training documentation for cGMP, SOPs, or specific job functions for all employees that perform analytical testing on finished OTC drug products. Additionally, your firm lacks a written procedure on employee training.

I could list a bunch more, but they all pretty much say the same.

  1. Have a documented training program.
  2. Conduct training on the operations an individual performs AND on general GxP principles appropriate to their job.

A documented training program should set out:

  1. Job Descriptions
  2. Organizational Charts
  3. Curriculum Vitae/Resume
  4. Identify Training
    • Individual Learning Plans (Training Assignments)
  5. Training Program Execution
    • Development and Management of Training Materials
    • Training execution
      • New Hire Orientation
      • On-the-Job Training (OJT)
      • Continuous Training
  6. Qualified Trainers
  7. Training Records of Personnel
  8. Periodic Review of Training System Performance

Conducting training starts with having a training plan to identify what appropriate training looks like.

The question is always what level of training is adequate. The honest answer is whatever works, and you aren’t training and educating your personnel enough. This is one of the things were the proof is in the pudding. Build the ways to measure effectiveness of training and you will be golden.

Ask Me a Question

The last few posts have all been questions I’ve been asked. This is one of my favorite ways to generate a blog post, as quite frankly what I am obsessing about all day at work is stuff I can’t easily turn into blog posts without running it through legal. Better to stay at a specific level of generality in these things.

So, I’m throwing open the door. Send me your questions on quality related matters or the other topics I like to write about on this blog and I will try to answer them to the best of my abilities.

Go back

Your message has been sent

Signature Logs

A colleague asks “In the era of digitalization and electronic signatures, do you believe in continuing to collect wet ink signature as part of employee training file? Can Part 11 electronic signature be used as an attestation that electronic signature is legally binding as handwritten signature?”

Great question. Collecting wet signatures is a real pain. Transitioning to digital practices can also significantly streamline our processes. It seems like a win-win. What could go wrong?

First, let’s ask “just how digital are you?”. It is essential to inventory your various practices and determine what is what. I think there are several categories here:

  1. Starts as paper, retained as paper
  2. It starts as paper and is retained as electronic. For example, you might print a form, fill it out, and route it through DocuSign or your eDMS for approval.
  3. Starts as electronic, retained as paper
  4. The entire lifecycle is electronic.

Most pharmaceutical companies are in a weird situation where we do a lot of work, starting on paper, scanning it, and then approving it. This is especially true at virtual companies, where a lot of the action happens at a CxO.

Do that inventory because you probably have more paper than you think—lots of paper. Plus, having an inventory will allow you to decide on future steps.

Before we get to the solution, let’s look at the regulatory requirements.

A is for Attributable (that’s good enough for me)

First Principle: Records should be signed and dated using a unique identifier attributable to the author. (PIC/S Data Integrity Guidance 8.6.1 Expectation 4.)

The guidance then goes on to say, “Check that there are signature and initials logs that are controlled and current and that demonstrate the use of unique examples, not just standardized printed letters.”

Second Principle: Persons using electronic signatures shall, prior to or at the time of such use, certify to the agency that the electronic signatures in their system, used on or after August 20, 1997, are intended to be the legally binding equivalent of traditional handwritten signatures. (21CFR11.100(c))

To comply with 21 CFR 11.100(c), organizations must:

  1. Prepare a Certification Letter: Draft a letter to the FDA certifying that the electronic signatures used in their system are legally binding.
  2. Submit the Certification: Send the certification letter to the FDA.
  3. Maintain Records: For future reference, keep a copy of the certification letter in the organization’s regulatory information management system (RIM) or quality management system (QMS) records.
  4. Keep Individual Records: Everyone should affirm that the electronic signature used across systems is binding.
  5. Be Prepared for Requests: Be ready to provide additional certification or testimony if the FDA requests. Like, say, an inspection.

This regulation ensures that electronic signatures are treated with the same level of trust and legal standing as traditional handwritten signatures, thereby supporting the integrity and reliability of electronic records in FDA-regulated industries.

Third Principle: The FDA lives within a constellation of other laws

Individual employees generally do not need to provide a wet signature attesting to the legally binding nature of an electronic signature. However, there are some important considerations:

  1. Legal validity: Electronic signatures are legally binding in the United States under the ESIGN Act and UETA, provided certain conditions are met.
  2. Intent and consent: Two critical elements for a legally binding electronic signature are:
  • Intent to sign
  • Consent to do business electronically
  1. Best practices for employers:
  • Implement a uniform policy on how employees sign agreements and onboarding documents.
  • Consider using two-factor verification for electronic signatures to provide additional proof of authenticity.
  • Ensure clear labeling of buttons and boxes for electronic signatures.
  • Include a consent clause for electronic transactions.
  • Provide an opt-out option for those unable to sign electronically.

While employees generally don’t need to provide a wet signature attesting to the legally binding nature of an electronic signature, employers should ensure their electronic signature process demonstrates intent and consent.

What to do

If your inventory showed everything is electronic, great. Get that attestation from the user as part of new hire orientation, and you are good to go. That attestation can be electronic. It just needs to be quickly retrievable in a way to answer an inspection.

If the inventory showed any paper, then yes, keep collecting those signature/initial logs.

Forms, forms, everywhere