Tag Archives: FDA

Oral Solid Dose – Critical Properties

Hello good people of the world! Today’s post is the first in a series covering considerations around the commissioning, qualification, and validation of facilities, systems, and equipment involved in the manufacture of oral solid dose (OSD) products. OSD is a wide-spread method of pharmaceutical delivery, including well known medicines such as aspirin, Viagra, and many antibiotics. Solid doses can take the form of powders, tablets, capsules, pills, lozenges, granules and more.

Here we’re going to cover the physical and chemical properties that should be considered in equipment design.

First, environmental factors:

  1. Temperature and Humidity: temperature and humidity should be controlled even if the product is not sensitive, as most processes are susceptible to flow issues in the extreme temperature and/or humidity ranges.
  2. Light: some OSD products are light (especially UV light) sensitive and must be protected from sunlight and even indoor light in some cases.
  3. Oxygen: some products may also be sensitive to oxygen exposure.

Second, process factors:

  1. Particle size and size distribution: powders inevitably have some variation in particle size that must be understood and controlled
  2. Particle shape: similarly to size, particles will have variation in shape
  3. Surface properties: are the particles smooth or rough? Do they stick together? Do they readily absorb moisture? Surface properties must be understood
  4. Particle strength: particles will break down under enough force. Particle strength must be understood and undue stress avoided in manufacturing processes.
  5. Density, porosity, and packing: how does a particle pack? Things like minimum bulk density, poured bulk density, and tapped bulk density should be understood.
  6. Cohesion in powders: related to surface properties, how to particles stick together? Magnetic, electrostatic, and intermolecular forces may be in play and should be understood.

What factors do you consider in your OSD manufacturing process?

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Validation Program Tenets

Hello good people of the world! What are the overarching tenets that you go to when making decisions related to your validation program? The regulations and guidance from industry only go so far and you will be regularly tasked with situations unique to your program. How do you know what is the right way to go in the grey areas? I like to keep these tenets in mind:

  1. The manufacturing process should be the most complex process on the site. Reduce complexity everywhere else. Reduce the number of deliverables. Reduce the number of process steps.
  2. Requirements feed specifications feed test protocols. Remember that you should always be able to trace a test case to a requirement through the specifications.
  3. Compliance is not binary, you are accepting degrees of regulatory risk. Make sure you understand the risk and that you accept it.
  4. Good Manufacturing Practices are not just from the CFRs. World-wide best practices need to be considered and applied where applicable.
  5. It’s all about documentation. If it’s not documented it didn’t happen. Create a logical narrative, and you’re already mostly there.
  6. Our primary purpose is to create documentation for agencies. Take any kind of writing class, and one of the first things you’ll learn is: know who your audience is and write for them. While it’s great the validation documentation can be used for commissioning, process improvement, etc. that must not come at the cost of it’s primary purpose.

What are some of your go-to tenets?  Comment below.

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Validation Project Plans

develop-project-plan-1200x480

Hello good people of the world! Today’s post is about Validation Project Plans, which is a specific type of project plan for projects in the pharmaceutical, biotechnology, and medical device regulated industries. This post covers Validation Project Plans for pharmaceutical/biotechnology industries in particular.

Often I’ve see Validation Project Plans contain a lot of fluff but little meat, making them of less value to the project team. A good project plan clearly documents the following, at a minimum:

  1. What facilities, systems, and equipment are in scope of the plan
  2. What are the expected activities and deliverables
  3. Who is responsible for what
  4. What is the validation approach and rationale for that approach
  5. What happens after the validation scope covered in the plan is completed (i.e. ongoing requirements)

Note I do not include project cost or schedule in a project plan, because these are often changing rapidly and should be maintained in a less controlled, more flexible manner, e.g. with scheduling software for a schedule.

The plan itself should be controlled (i.e. approved and revision controlled) as soon as possible in the project but early enough so that scope will not change (too much).

Additional things to think about when drafting your plan:

  1.  Commissioning versus Qualification versus Validation. If your project has multiple phases (and any decent-sized project should), be sure to clearly state responsibilities and deliverables at each stage.
  2. Include references to regulations, industry guidance, and site procedures that govern your plan. Make it clear to everyone who reads the plan what framework you are working inside.
  3. The purpose and scope of the document should be clear and up front.
  4. Get buy-in from all functional groups by having them approve the document.
  5. Like all controlled documents, the plan should have version/revision history.
  6. Use tables to clearly present information.

I put together a quick template here:

Validation Project Plan Template MWV

What do you feel is necessary in a Validation Project Plan? Comment below.

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Serialization Basics

vials
Hello good people of the world! Today’s post is high-level regarding serialization. Serialization is a process mandated by the world’s regulatory agencies to reduce counterfeit drug products in the market. Besides being costly to drug companies, counterfeit drug products are often less efficacious and less safe than the real drug they are purporting to be. Additionally, counterfeit drug products can be contaminated with other APIs and/or toxic excipients.
Continue reading Serialization Basics

Corrective Action / Preventive Action (CAPA)

CAPA Process
Hello good people of the world! Today’s post is about Corrective Action / Preventive Action, typically referred to as CAPA. CAPA is an integral part of any Quality System, and certainly one of the first things an agency will look at in any audit.

There is a ton of good information out there already on CAPA, including FDA’s own guidance from 2014.

I’ve personally used a few software packages for CAPA management, including MasterControl and Oracle’s Agile, among others, but have not seen any standouts.

The key points of the CAPA program are:

  1. Issue identification, i.e. ensuring the issue is truly understood and well documented
  2. Root cause analysis, i.e. identifying the root cause of the issue
  3. effectiveness check, i.e. verifying actions have actually resolved the issue

What tips have you learned from your CAPA program? Comment below.

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Free Offer! Get Your Org Chart Online and Organized

Portfolio10Hello good people of the world! As you probably know, one of the first things an agency is likely to ask for in an audit is your company’s organization chart. They want to know how the organization is structured, and particularly where the quality unit fits in.

If you have a SharePoint tenant, I have an offer for you. For a limited time, MWV, in conjunction with dikuw.com, is offering a free SharePoint Add-in for generating organization charts. This add-in integrates with your existing SharePoint On-Premise or Online service, and gives a secure, centralized location for your org chart. The custom interface makes it easy to navigate and update the chart in real-time.

Get all the details and download the add-in here: http://www.dikuw.com/OrgChart.html

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Environmental Control and Monitoring for Aseptic Processing

Petri dish

Hello good people of the world! Today’s post is an overview of environmental control and monitoring for aseptic processing.

Applicable references for the US are:

  • FDA Guideline for “Sterile Drug Products Produced by Aseptic Processing” September, 2004
  • FDA Guideline for the submission of “Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products”
  • 21 CFR Part 211 — Current Good Manufacturing Practices for Finished Pharmaceuticals

Purpose:

Environmental control is designed to prevent microbiological contamination of sterile products.

Environmental monitoring is designed to detect microbiological contamination in aseptic processing areas.

Scope: Environmental control and monitoring is a required part of aseptic processing, i.e. where “terminal” sterilization is not possible. Terminal sterilization means the finished drug product is sterilized at the last step of the process via heat, radiation or other. Many pharmaceuticals and most biologics do not tolerate terminal sterilization, thus the importance of aseptic processing.

Control Considerations:

  1. Air particle count: maintaining air particle counts is critical to aseptic processing, because particles themselves can be harmful, and likely carry microorganisms.
  2. Cleanroom design: for the aseptic core (where critical aseptic process steps occur, e.g. where product is open to the environment) the FDA recommends class 100. The core should surrounded by class 1,000 or class 10,000 areas.
  3. Air pressure differentials: the FDA recommends a 10-15 Pascal pressure differential between rooms of differing classification, with the higher pressure in higher-class rooms, so that air naturally flows outward to the lower class rooms.
  4. HEPA filtration: High Efficiency Particulate Air (HEPA) filters should be used in class 100 rooms to aid in particle removal
  5. Equipment: should be cleanable and non-shedding. Stainless steel is the preferred material of construction for equipment surfaces.
  6. Process design: processes should be designed with minimizing contaminate risks in mind (e.g. don’t force operators to reach over open product)
  7. Process Validation: media runs should be performed to demonstrate the process can run aseptically

Monitoring Considerations:

  1. Air quality measurements should look at viable and nonviable particulate levels
  2. Particle counting: ongoing monitoring should look at particle counts in critical areas
  3. Active sampling: devices such as impaction and membrane samplers should be used to evaluate aseptic processing areas
  4. Passive sampling: settling plates should be used to collect microbial information
  5. WFI and other excipients: should be routinely tested for microbial/particulate load
  6. Personnel: the greatest single contributor of particulates and microbes in a cleanroom. Steps (training, gowning, testing) must be taken to minimize risk

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