Tag Archives: PQ

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

Container Closure Integrity Testing

Hello good people of the world! The present post concerns itself with Container Closure Integrity (CCI) testing. CCI testing is an integral part of packaging validation, involving primary packaging such as ampoules, blisters, bottles, vials, syringes, tubes, etc. Biopharmaceuticals are typically packaged in hermetically-sealed containers to prevent the ingress of any liquid or gas that could be reactive or carry microorganisms. Packaging may also by light-resistant, if light could affect the properties of the product.

There are three regulatory/industry guidelines typically cited in the U.S. regarding CCI testing:

  1. FDA Guidance for Industry (2008), Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products
  2. PDA Technical Report No. 27 (1998), Pharmaceutical Package Integrity (not available for free)
  3. USP <1207>, Sterile Product Packaging – Integrity Evaluation

CCI testing is either physical (bubble, liquid tracer, vacuum/pressure decay, dye ingress, etc.) or microbial (microbial ingress).

Each has it’s advantages and disadvantages, as shown in the below from American Pharmaceutical Review:

When should these tests be performed? CCI testing is applicable to new container closure systems and can be performed on newly sealed containers to validate sealing performance, and then annually and at the expiration date to validate stability.

What are your preferred methods of Container Closure Integrity Testing?

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Cleanroom Isolators

RABS

Hello good people of the world! Today’s post is about cleanroom isolator technology, specifically Restricted Access Barrier Systems (RABS). RABS are typically employed at the high-risk manufacturing step of fill/finish, were finished product may be exposed to the surrounding environment (i.e. the process is “open”). In the case of parenteral (injectable) pharmaceuticals or biologics, where post-fill sterilization is not possible, environmental control at the fill step is of paramount criticality.

Heating, Ventilation, and Air Conditioning (HVAC) general concepts: HVAC is an important system in maintaining cleanroom cleanliness, but is typically categorized as an “indirect-impact” “commission-only” system, separated from the cleanroom itself via High Efficiency Air Particulate (HEPA) filters and controlled via feedback from local cleanroom differential pressure (DP), temperature, and, if required, humidity sensors.  The main components of the HVAC system include the Air Handling Unit, which may be comprised of a mixing chamber (for return and outside air), filters, heaters, coolers, and humidifiers.

Cleanroom general concepts: the cleanroom is typically classified according to ISO 14644-1, GMP EU grades, and/or US Federal Standard 209E classes, among others. A good summary is here. These classifications define the allowable number of total airborne particles and viable airborne particles. Total and viable particulates can be reduced by increasing the air exchange rate, which is the number of times (typically per hour) that the total room air volume moves through the AHU. For class B (ISO 7 in operation), 30-60 air changes are used. For class C (ISO 8 in operation), 20 air changes may be used.  Class A space (ISO 5) could require Unidirectional Air Flow (UDAF), which should be differentiated from Laminar Flow (LF), with an air velocity of 0.45 m/s ± 20%.

In cleanrooms, by far the grossest contributor to airborne particulate counts are the operators. Moving even slightly, an operator might produce more than 2.5 million particles of size 0.3 μm or greater per minute! (source). For this reason alone, barrier technology is critical in Class A cleanroom space. This is typically achieved via an active or passive Restricted Access Barrier System (RABS) or via an Isolator.

A RABS is an area that has a rigid enclosure with safety-interlocked doors, and glove ports for manual interventions. Passive RABS has no aeration equipment. Active RABS has it’s own aeration and filtration equipment.

Isolators are similar to RABS, except that they are hermetically (airtight) sealed to completely separate operators from the process area.

Both the RABS and Isolator create an UDAF over the Class A space.

Which do you use? Which do you prefer? What application would required an Isolator over a RABS?

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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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