Tag Archives: Qualification

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

Considerations in SaaS Validation

SaaS Qualification

Hello good people of the world! Today’s post is about qualifying Software as a Service (SaaS), also known as “cloud-based” or “hosted” software. Simply, SaaS is any computer system in which any server is not hosted by the system owner. Here are some key considerations in qualifying SaaS computer systems:

Continue reading Considerations in SaaS Validation

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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Staying in Control: Alerts and Alarms

alarm

Hello good people of the world! If you work with a mix of process equipment and supervisory control or monitoring systems, you know the importance of alerts and alarms, but most companies do not take the necessary steps to ensure their alerts and alarms are well configured and meaningful. One of the enemies is so-called “nuisance-alarms,” but just as important is knowing that you have enough alerting/alarming so that critical events are not missed and appropriate actions are taken before harm is done.

And by the  way, alerts and alarms are something the FDA has historically shown to care about (e.g.  FDA had observation at Teva Irvine for lack of validation on alerts and alarms). So what considerations are at play?

What should alert/alarm? If you’ve clearly defined your Critical Process Parameters (CPPs) and know what your Critical Quality Attributes (CQAs) are, you know already what needs alerts/alarms: all CPPs.

What should the alert/alarm limits be? This part is tricky: you need limits that provide operators with sufficient information without becoming a nuisance. All too often I see the situation where alarm banners are flashing but no one is paying attention because “there’s always alarms” or whatever.

What action should occur based on alert/alarm conditions? This is another place I often see improvements needed: every alert and alarm should have a documented action associated with it, typically in the SOP, that operators are trained on. If there is no documented action required for an alert/alarm, why do you have it?

What do you find critical in configuring alerts/alarms and introducing them into a manufacturing process?

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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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EU Q&A on GDP Guidance

Drug Distribution

Hello, good people of the world! On March 28, 2014 the European Commission released a question and answer (Q&A) document related to their Good Distribution Practice (GDP) guidance. The original guidance is here. The Q&A document is here. Some highlights:

  1. Question: in Chapter 2 – Personnel, 2.5, does the statement “appropriate procedures relating to personnel hygiene, relevant to the activities being carried out, should be established and observed” refer to the health and/or cleanliness of the staff?Answer: It only refers to the cleanliness of the staff, so to avoid any alteration of the product.
  2. Question: in Chapter 3 – Premises and Equipment, 3.2.(3), is the intent of segregation to avoid “cross-contamination” as mentioned in chapter 5?Answer: The intent of this provision is to avoid handling errors and accidental swaps of products. This is why electronic segregation is allowed, except for falsified, expired, recalled and rejected products which always have to be segregated physically.
  3. Question: concerning Chapter 3 – Premises and Equipment, 3.2.1, how many probes are necessary to monitor the temperature?Answer: The number of probes and their placement depend on the risk analysis performed on the site and the placement should be in agreement with the mapping results.
  4. Question: Concerning Chapter 9 – Transportation, 9.2.(1), can we deviate from storage conditions if the manufacturer agrees to the transportation of the product within a certain temperature range (2°-25°c) for a limited time frame of 6 hours?Answer: No. Storage temperature limits as described by the manufacturer or on the outer packaging need to be respected for each stage of transport during the whole transport chain.

Any of these questions or answers leave you with more questions? Leave a comment below and please share this post with whomever you think would benefit.