Category Archives: Qualification

ORAL SOLID DOSE – Unit Operations

Granulator at an OSD Plant in Vietnam

Hello good people of the world! Continuing the series on oral solid dosage forms, today we’re going to talk about unit operations typical in a oral solid dose manufacturing process.

Typical OSD processes may include some combination of weighing/dispensing, material transfer, blending, granulation, drying, milling/sieving, compression, encapsulation, and coating. Some considerations around each step may include:

  1. Weighing/Dispensing: includes sampling for quality purposes. Materials to be sampled typically include: APIs, excipients, primary and secondary packaging, cleaning agents. Sampling areas must be protected from contamination.
  2. Material Transfer: material flows should be documented and reviewed, with the intention of minimizing any contamination.
  3. Blending: materials are typically blended to ensure a uniform composition, prior to downstream process steps. Many methods exist, including: tumble blending, bin blending, and agitator mixers.
  4. Granulation: granulation is the process of combining particles into a granule. Many methods of granulation exist: wet massing/extrusion, high shear, spray, speronization, and hot melt extrusion, for example.
  5. Drying: the purpose of the drying step is to remove any excess moisture from the drug product. Drying methods include: tray , fluidized bed, and spray drying.
  6. Milling/Sieving: the purpose of this process step is to reduce granule size to conform to specification. Some methods include: impact/hammer mills, conical mills, and oscillating horizontal screens.
  7. Compression: compression is used to create tablets.
  8. Encapsulation: encapsulation is used to create capsules.
  9. Coating: coating is used to apply a coat to tablets

In the next post we’ll cover supporting equipment and quality systems. What process steps do you use in your OSD process? Comment below!

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Oral Solid Dose – Material Handling

Hello good people of the world! Continuing the series on oral solid dosage forms, today we’re going to talk about material handling. Oral solid dose manufacturing is typically a batch process, which means materials need to be transferred from step-to-step. Sometimes there is direct conveyance between steps, but often transfer is performed via Intermediate Bulk Container (IBC).

In terms of design, IBCs should be able to handle the worst-case (lowest) density material in the process. IBCs should be cleanable, especially if a single container will support many product manufacturing processes. IBCs should be designed in such a way that they drain easily. Charging/discharging must be considered.

IBCs may be transported on wheels, or by a pallet truck.

Discharging may be facilitated by applying vibrations to the IBC, either internally or externally.

For direct conveyance, gravity, pneumatic conveyance, and mechanical conveyors are options.

What considerations around material handling do you have in your OSD lines? Comment below!

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Oral Solid Dose – Equipment Cleaning

Hello good people of the world! Continuing the series on oral solid dosage forms, today we’re going to talk about equipment cleaning. OSD manufacturing equipment can be notoriously hard to clean, and manual cleaning procedures introduce high risk of contamination and carryover. It is recommended that any new or existing process equipment be cleaned with automated processes wherever possible.

The three automated cleaning processes typically used in industry are:

  • Clean-in-Place (CIP)
  • Wash-in-Place (WIP)
  • Clean-out-of-Place (COP)

CIP is done without moving the equipment, as the name implies, and uses a CIP skid to deliver cleaning and rinse solutions. CIP should not require any manual operations.

WIP is done in-place as well, but may include some manual operations, such as removing filters.

COP requires equipment to be moved to a wash station. Tanks and vessels are typically COP’d.

Some specific concerns related to cleaning OSD equipment include:

  • Dry Granulator/Roller Compactor cannot typically be CIP’d. Particularly the auger must be removed and COP’d.
  • Fluid Bed Dryers a large and complex, making cleaning difficult. Modern dryers will include CIP/WIP but typically still require manual cleaning of some parts.
  • Milling equipment typically requires the screen to be manually removed before any CIP/WIP.
  • Tablet presses can be difficult to clean, requiring many manual interventions prior to washing.
  • Capsule filling machines should be wettable to allow cleaning.
  • Tablet coaters should include WIP

Of course, cleaning processes, whether automated or not, need to be validated. Riboflavin tests may be performed to verify wash coverage, and swabbing can verify lack of residual API and cleaning solutions.

What challenges have you run into in cleaning your OSD manufacturing equipment? Comment below!

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PLC/HMI IOQ – What to Test?

PLC

Hello good people of the world! Today’s post is on initial control system Installation and Operational Qualification (IOQ) of a simple system consisting of an Human/Machine Interface (HMI), Programmable Logic Controller (PLC), and any number of end devices (valves, pumps, sensors, etc.). The question is what should be tested?

Obviously there’s a ton of guidance out there (see e.g.: GAMP) that will have a lot more detail than this post. The purpose here is to list at a high level the tests that could be expected. So let’s get started!

Installation Qualification
IQ can be its own protocol or combined with OQ in an IOQ for cases without a ton of complexity. IQ is supposed to verify the installation of hardware, software, and any peripherals. You also want to check what documentation is available/applicable here. IQ tests may include:

  • Documentation Verification (e.g. SOPs, EREC/ESIG assessment, operating/maintenance manuals, panel and electrical drawings, etc.)
  • Hardware Verification: verify the make and model of major components at a minimum
  • Software Verification: verify/record software versions. You’ve got to know what you’ll be OQ’ing!
  • Configuration Verification: verify any hardware and/or software configuration. This could be two tests, one for hardware, one for software.
  • Loop Check Verification: verify loop checks are performed.
  • Alarm Configuration Verification: ideally alarms a setup in such a way that you don’t have to functionality test them all!
  • Any other critical installation items

Operational Qualification
OQ is the meat of your control qualification. Here you want to test critical functions, that hopefully you have identified earlier (see here for one approach). OQ may test:

  • Interlock Verification including e-stops. A lot of interlocks are safety/business related, but they’re often included in OQ due to how critical they are.
  • Functional Alarm Verification – be sure to include data loss/communication alarms
  • HMI Navigation and Layout Verification
  • Restart/Recovery Verification
  • Sequence of Operations Verification

What kinds of testing are you sure to cover in your control system IOQ protocols? Comment below.

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ISPE’s Commissioning and Qualification Guide Second Edition

Hello good people of the world! Today’s post covers ISPE’s release of the second edition of their commissioning and qualification guide. This is volume 5 of the baseline guides. The first edition was first released way back in March 2001, so we should expect this to be a significant revision. Please note this guide is not available for free.

One very nice thing about this second edition is that it not only updates the first edition of the volume 5 guide, but incorporates scope from two other now-outdated guides as well: “Science and Risk-Based Approach for the Delivery of Facilities, Systems, and Equipment” and “Applied Risk Management for Commissioning and Qualification.” So if you have these in your library, you can safely archive them.

It’s always important to note that industry guides such as this one do not constitute regulations and are not required to be followed. It is often the case however that best practices documented in guides become industry standard, and then set expectations for regulators. Per the guide, it is intended to comply with EU GMP Annex 15FDA Guidance on Process Validation, and ICH Q9.

The table of contents shows the following sections:

  1. Introduction
  2. User Requirements Specification
  3. System Classification
  4. System Risk Assessment
  5. Design Review and Design Qualification
  6. C&Q Planning
  7. C&Q Testing and Documentation
  8. Acceptance and Release
  9. Periodic Review
  10. Vendor Assessment for C&Q Documentation Purposes
  11. Engineering Quality Process
  12. Change Management
  13. Good Documentation Practice for C&Q
  14. Strategies for Implementation of Science and Risk-Based C&Q Process

And the following appendices:

  1. Regulatory Basis
  2. User Requirements Specification Example
  3. System Classification Form Example
  4. Direct Impact System Examples
  5. System Risk Assessment Example
  6. Design Review/Design Qualification Examples
  7. Supporting Plans
  8. System Start-Up Examples
  9. Discrepancy Form Example
  10. Qualification Summary Report Examples
  11. Periodic Review Example
  12. Periodic Review for Controlled Temperature Chambers
  13. Vendor Assessment Tool Example
  14. Organizational Maturity Assessment Example
  15. Approach to Qualifying Legacy Systems or Systems with Inadequate Qualification
  16. References
  17. Glossary

You’ll have to purchase the guide to get all the details, but below are some highlights that stuck out to me:

  • This second edition introduces the term Critical Design Elements (CDEs). CDEs are defined as “design functions or features of an engineered system that are necessary to consistently manufacture products with the desired quality attributes.”
  • Concepts that were removed from this edition of the guide include Component Criticality Assessment, Enhanced Commissioning, Enhanced Design Review, Enhanced Document, Indirect Impact (systems are either direct impact or not direct impact now), and the V-Model.
  • A Direct Impact system is defined as a system that directly impacts product CQAs, or directly impacts the quality of the product delivered by a critical utility system. All other systems are considered to be not direct impact. An example included in section 3 demonstrates the previously categorized “indirect impact” systems would become not direct impact systems and would be commissioned only, although the commissioning for these system may be more robust than a purely “no impact” system. The guide provides an eight (8) question process for determining if a system is direct impact.
  • System boundaries should be marked on design drawings.
  • Inputs to the URS should include: CQAs, CPPs, regulatory, organization quality, business, data integrity and storage, alarm, automation, and health, safety, and environmental requirements, and engineering specifications and industry standards. The example URS template does include a classification of each requirement (e.g. business, safety, quality).
  • A system risk assessment is performed to identify CDEs and controls required to mitigate risks. Standard off-the-shelf systems typically do not require a risk assessment. Risk levels are defined as low, medium, and high and the risk assessment approach is not a typical FMECA process. Instead each CQA at each step gets one entry on how the CQA can be impacted, what are the design controls around that CQA and any alarm or procedural controls to mitigate risk. The residual risk post-controls is includes as low, medium, or high.
  • Design Qualification looks somewhat informal 0=- no DQ protocol, but a DQ report that summarizes other documents (URS, SIA) and design review meetings.
  • A C&Q plan should include clear scope, the execution strategy, documentation expected for each system (URS, FAT, SAT, IOQ, SOPs, etc.), and roles and responsibilities (e.g. approval matrix).
  • The discrepancy form has closure signatures only (no pre-implementation signatures)
  • For legacy systems without adequate C&Q documentation, focus should be on identifying product and process user requirements including Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs), and then the Critical Design Elements (CDEs) that affect them. It is necessary to confirm that accurate drawings exist, that maintenance files are up-to-date, and there is test evidence to support changes since commissioning. A risk-based approach can be used to qualify the system in the absence of typical C&Q documentation.

Do you use the ISPE guides for your C&Q approach? Comment below.

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WHO’s Draft Guidelines on Validation May 2016

Hello good people of the world! On May 15, 2016, the World Health Organization released its draft Guidelines on Validation. It is available on the WHO website for download here.

This post covers my review of the guidance. Continue reading WHO’s Draft Guidelines on Validation May 2016

Commissioning and Qualification of Process Instrumentation

Pressure Transmitter

Hello good people of the world! Today’s post is on the commissioning and qualification of instruments used in process measurement and control. Instruments may be used to measure such things as flow, temperature, pressure, level, weight, conductivity, etc. In use, many of these parameters may be quality critical, so proper commissioning and qualification is key! Continue reading Commissioning and Qualification of Process Instrumentation