Forms 483 Addressing Sterility Assurance and Cross-Contamination 

Along with data integrity, deficiencies in sterility assurance and the potential for product or API contamination identified during FDA inspections often lead to warning letters. Also, many product recalls are based on lack of sterility assurance or less frequently on potential cross contamination. Here we take a look at six forms 483 that include observations associated with sterility assurance and potential cross contamination.

These are certainly not meant to provide an all-inclusive view of the topic, but rather represent recent inspection observations in these areas to demonstrate the broad scope of the topic. FDA’s flurry of inspections and enforcement actions against compounding pharmacies and outsourcing facilities focuses heavily of requirements associated with expectations regarding aseptic manufacture of sterile drug products. These sites are often also cited for the potential for cross contamination. Lack of sterility assurance and the potential for cross contamination, particularly by high potency compounds or sensitizing agents both have potentially serious consequences for patient safety. Many compounding pharmacies and outsourcing facilities have recalled large numbers of products due to concerns about sterility assurance. We include one example of this type of facility in the collection presented below.

Failure to complete adequate cleaning validation for multiproduct equipment is often another source of potential cross contamination even when products do not include high potency compounds or sensitizing agents. We include forms 483 issued to four sites in the US, one in the UK and one in India. One of the sites where FDA cited observations in the area of potential cross contamination manufactures solid oral dosage forms, four manufacture sterile parenteral products and one manufactures APIs. One of the sites is a compounding pharmacy, a facility type to which FDA has issued more than 50% of their drug warning letters in the past three years. The forms 483 below are provided in chronological order.

Bayer Health Care LLC of Shawnee, Kansas received a 10-page form 483 at the end of an inspection on June 17, 2009. Thomas Arista was one of the investigators. The EIR from this inspection is also available at the FDAzilla store. FDA focused on deficiencies in media simulations, cleaning, environmental monitoring and airflow patterns. These include but are not limited to:

  • The firm failed to follow exiting procedures regarding: time and temperature of incubation of media fill vials; discrepancies in the batch record when three media filled vials could not be accounted for.
  • The design of the personnel entry into the facility does not protect against microbial contamination because: the locker rooms do not adequately segregate the areas of street clothes and facility uniforms and shoes; shelving is made of wood and is not cleaned or sanitized and further a buildup of dirt and dust was present on the shelves; sanitization / cleaning of factory shoes is not conducted and recorded on a routine schedule.
  • Gram positive Bacillus species were identified in the facility EM program but no investigation was conducted nor was root cause for this recurrence identified. Gowning rooms are not included in the EM program. EM alert actions are based on historical data though action limits are not based on historical data. The non-viable particle monitoring probe is positioned above the work area without justification for this positioning.
  • “Smoke studies” do not adequately demonstrate unidirectional airflow. Further “…the Microbiology Supervisor confirmed that they have not performed an assessment of the smoke studies, which are used to demonstrate unidirectional airflow within the Class 100 and Class 10,000 aseptic fill areas.”
  • EM sampling sites are not scientifically justified.
  • Aseptic processing areas are not adequately cleaned or disinfected. For example, the top areas of the curtain in Class 100 filling areas are not sprayed or wiped, and a scientific justification for this practice was not available.
  • Sterile filling room cleaning was left at rest in excess of the duration identified in the company SOP.
  • Records do not include the disposition of rejected components.

Ranbaxy Laboratories, Ltd site in Mohali, Punjab, India received an 8-page form 483 at the close of inspection on September 26, 2012. The site was placed on import alert in September, 2013. The observations focus on the manufacture of solid oral dosage forms. Most of the observations address events outside the scope of the topic of this article. But regarding the potential for cross contamination the following observations are relevant:

  • The written procedures of cleaning of non-dedicated equipment are not written in adequate detail to ensure ‘consistent / reproducible cleaning results.’ Visible residue was visible in the air inlet and exhaust areas of cleaned and inspected process equipment.
  • In the tablet bottling operations, the air filter equipment, Air Displacement Unit did not include HEPA filters ‘…to prevent the release and recirculation of dust created during the bottling operation, whereby the potential for cross-contamination may exist.”

Hospira, Inc (now Pfizer), in Rocky Mount, NC received a 22-page form 483 at the close of an inspection on March 1, 2013. A total of 20, often multi-part, observations were identified. Thomas Arista, Penny McCarver, and Jason Chancey were among the five investigators. The EIR from this inspection is available from FDAzilla also. The firm received a warning letter for an inspection at this site conducted later in the year, ending November 15, 2013. We provide only a selected number of items; it is not meant to be full summary of the form 483 content. The form 483 focuses on observations in the area of aseptic processing, including but not limited to:

  • Anaerobic media fills are not performed under anaerobic conditions to mimic the drug product fills that are overlaid with [what I assume is] nitrogen.
  • Media fills do not require that repeat manual interventions are performed the same number of times and for the same duration of time during media fills as they would be expected to be performed during routine manufacture.
  • Not all manual interventions are included in media fill operations.
  • Routine autoclave load configurations are not documented to ensure they do not exceed the validated load configuration.
  • There are no records to document the life cycle (number of laundry cycles) of gowning attire (scrubs, cleanroom gowning / coverall etc.) to ensure they are fit for use.
  • Smoke studies to demonstrate unidirectional airflow are inadequate, seven examples are provided.
  • The Quality Unit failed to ensure that all procedures and test methods comply with CGMPs.
  • Environmental monitoring conditions were deficient, five detailed examples provided.
  • Visual and audio alarms in the manufacturing area are not addressed appropriately.
  • Humidity controls in the aseptic processing areas are deficient.
  • Not all critical surfaces are adequately evaluated in the aseptic processing areas. Further, no justification exists for the selection of surfaces included.
  • Staff who perform visual inspection of in process and finished drug products are not qualified to detect defects under the conditions normally used during routine operation. FDA provided a laundry list of examples in support of this observation.
  • Equipment require “ad hoc’ modifications that include adhesive tape to secure items.

Americare Compounding LLC of Garden City South, NY compounds sterile drug products and received a 5-page form 483 at the close of inspection on June 19, 2013. This form 483 includes observations regarding aseptic manufacture and the potential for cross contamination of products with penicillin. Observations include but are not limited to:

  • The firm does not have written procedures governing operations conducted at the facility.
  • The firm failed to test drug product for assay or identification, only one of the parenteral products is tested for sterility, and no endotoxin testing data is available for any lot of sterile product manufactured.
  • The ‘beyond use date’ given to the products is not supported by stability studies conducted by the firm. They rely on the scientific literature or vendor information to establish these dates that do not exceed 30 days.
  • Sterilization processes have not been validated.
  • Penicillin products are not processed under a separate air handling system, or in a separate facility from other sterile products. Included in this lack of separation are beta-lactam non-penicillin drugs such as ceftazidime.
  • The firm does not have adequate environmental monitoring data to demonstrate the ability to maintain the necessary ISO room classifications.
  • Gowning is inadequate: gowning in the ISO 7 areas can be reused during the week; exposed skin was visible on staff working in the ISO 5 work station areas.
  • The firm does not use sporicidal cleaning agents inside the ISO 5 hoods.
  • Environmental monitoring is not performed on a frequent basis under dynamic conditions. Further, environmental monitoring of personnel is not performed each day of production, there is no sampling of operator’s gloves.

The firm also received a form 483 at the close of inspections in June, 2015 and a warning letter in April 2014.

Luitpold Pharmaceuticals, Inc. in Shirley, NY received a form 483 at the close of inspection on October 29, 2014. This form 483 addresses the always challenging issue of mold identified in aseptic processing areas. Observations include but are not limited to:

  • Mold was repeatedly recovered in both the aseptic processing areas and support areas. Several roof leaks in 2013 and 2014 were not considered in the investigation. The firm could not determine how long the roof damage existed prior to the leaks documented in 2013 and 2014.
  • The firm conducted ‘surveillance sampling’ of a variety of facility areas, including interstitial facility spaces to identify possible entry points of mold spores. The FDA identifies four specific deficiencies in the process and methods used in this analysis.
  • Investigations associated with mold recovery were open for extended periods of time without resolution.
  • The firm does not have procedures to evaluate potential for adsorption of compounds from contact filling components such as silicone tubing used in peristaltic pumps.
  • The firm does not have documentation to ensure that they reviewed the disinfectant effectiveness studies performed by a contractor.

And finally, SmithKline Beecham Limited in West Sussex UK received a 9-page form 483 at the end of inspection on July 10, 2015. The firm manufactures APIs, and the inspection focused on potential for cross contamination with penicillin. This inspection resulted in a warning letter issued on June 30, 2016. Observations include but are not limited to:

  • Penicillin was found on the surface of non-penicillin processing areas 187 times between 2012 and the time of conduct of this inspection. The corrective actions did not include a comprehensive cleaning and decontamination of the associated areas and equipment.
  • The cleaning methods used to remove penicillin on surfaces have not been adequately validated.
  • Methods used to test for the presence of penicillin are not adequate.
  • A variety of possible causes for the presence of penicillin in non-penicillin areas were identified but the corrective actions did not fully correct the findings.
  • Investigations into microbial alert and action level findings in the water system did not establish a root cause. FDA identified 18 examples.  Conclusions regarding ‘sampling errors’ were not supported by data

In conclusion, FDA observations regarding problems in aseptic processing and sterility assurance include facility design and operations issues, training of operating staff, and deficiencies in media fill exercises. We also show that potential cross contamination can result from deficient cleaning and failure to conform to requirements that penicillin and other similar sensitizing agents should be handled in a ‘separated’ facility. Failures in both areas, sterility assurance and potential cross contamination, can have serious impact on patient safety and FDA takes these shortcomings seriously.

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

In-depth analysis of the findings

Lessons learned

How companies can avoid similar shortcomings.

Download the Special Report

Download your copy of THE FDA INSPECTION LANDSCAPE IN MID-2020 AND A LOOK AT VIRTUAL INSPECTION

In this summary we identify:

  • Trend analysis of FDA inspections through mid-2020
  • Strategies for preparing and hosting virtual inspections
  • New technologies to support remote inspections
Redica Systems Enforcement Analytics

Monitor compliance at your Clinical Investigator sites.

Enter your email address and someone will contact you shortly to get you started.

Redica Systems Enforcement Analytics

Prepare for inspections of Clinical Investigator sites.

Enter your email address and someone will contact you shortly to provide more Clinical Investigator data about your sites.

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore enforcement trends. 

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore observations and trends. 

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to run your custom report.

Redica Systems Enforcement Analytics

Get help choosing the right CRO.

Enter your email address and someone will contact you shortly to customize your insights.

Redica Systems Enforcement Analytics

Compare two companies of your choice.

Enter your email address and someone will contact you shortly to customize your report.

Download the Special Report

CDMO Comparison opt-in

In this summary we identify:

FY2018-FY2020 GMP data for Lonza & Catalent

Top GMP primary citations

Top FDA 483 observations

Redica Systems Enforcement Analytics

Compare the inspection history of your CDMO sites.

Enter your email address and someone will contact you shortly to customize your report.

Panel Discussion – Remote Audits

Panel Discussion opt in image

Featuring Panelists:
—Barbara W. Unger, Unger Consulting, Inc.
—Jerry Chapman, Redica Systems
—Stephanie Gaulding, Pharmatech Associates

Who Will Benefit?
This session will be valuable to GMP quality, regulatory, compliance, and management personnel in FDA-regulated industries who want to have a conversation on remote audits and get to know what is going on in the industry.

Turning Failure into Success

Presented on Tuesday, April 27, 2021 by Steve Greer, Executive Coach, Genesis Assist, and former Quality Leader, Procter and Gamble

What you will learn:

  • How to use the Leadership SOS Model to transform quality culture
  • How to strengthen quality systems to eliminate human error
  • How to generate ideas on how to set your organization up for success for shareholders, FDA, and staff
Redica Systems Enforcement Analytics

Get Full Access to Redica Enforcement Analytics

Enter your email address and someone will contact you shortly to answer all of your questions and get you started.

Quality Management Systems for Small Pharma and Biotech Firms

Webinar: QMS for Small Pharma and Biotech Firms

Presented by Fenton Fong, Founder, Managing Director, & Principal at xCellarate

Get instant access to the webinar video and slides.

What you will learn:

  • Common challenges small pharma firms face when developing a QMS
    Recent enforcement trends involving the Quality Unit
    Impact of the COVID-19 pandemic

Download the Special Report

APAC ad

In this summary we identify:

GMP data from FY2017 to FY2020 for the Asia-Pacific region

Top 3 GMP primary and secondary citations

Top 3 483 observations

Download the Special Report

An Analysis Of MHRA’s Latest Annual GMP Inspection Deficiencies Report

In this summary we identify:

  • Data from 2019 UK MHRA Inspections
  • Trends from 2015, 2016, 2018, and 2019 inspections
  • Conclusions drawn from an analysis of drug inspection data

Experience the Power of Redica Systems

Redica_Vert_Periwinkle_RGB_Large

SEARCH Find the inspection records you want by inspector’s name, company name, site, city, country, etc.

WARNING LETTERS Easily search the largest database of FDA Warning Letters by date, company, FDA office, or subject

SITES Quickly assess inspection records including dates and inspectors across all of your sites

INSPECTIONS Complete list of FDA inspections by date, company, category, and country

Get Complete Access to the Redica Systems Platform

Please submit your email address and one of our team members will contact you shortly to answer all of your questions and get you started with the new Enforcement Analytics platform.

Redica Systems Enforcement Analytics

Compare the enforcement history of your CDMOs.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Evaluate Your CDMOs

Enter your email address and someone will contact you shortly to customize your report.

Experience the Power of Redica Systems

Redica Systems Expert Jerry Chapman to Present at SQA Annual Meeting

Index Information Redica consolidates regulatory data in real-time on the single largest database for quality, safety, and compliance intelligence.

Strengthen Datasets Redica machine intelligence algorithms identify and triage risk signals to derive meaning from vast amounts of private and public data.

Analyze & Interpret Patterns Redica instantly models the customer-specific regulatory risks, trends, and opportunities that stand to fundamentally change compliance operations.

Redica Systems Enforcement Analytics

Save your team valuable time when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Download the 510(k) Sample

What You Will Learn from This Sample:

See how a 510(k) submission is structured

Find out what information to include

Review correspondence between sponsor and FDA

Redica Systems Enforcement Analytics

Unlimited Access to Reports and Data

Enter your email address and someone will contact you shortly.

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

The first countrywide import alert issued by FDA

An inadequate deviation investigation

An inadequate product specifications and a product recall

Process validation issues at a CMO

A different perspective on process validation and the culpability of the quality unit

 

A.I. for Quality and Compliance Teams

August 3 webinar

Presented by Redica Systems Senior GMP Quality Expert Jerry Chapman

What you will learn:

  • A basic understanding of data sources, machine learning, NLP, and A.I. tools
  • Building and applying Expert Models
  • Two case studies, one on sterile manufacturing/503B and one on data integrity

Get the scoop on recent data integrity 483 observations!

  • FY 2020 Data Integrity 483 Observations
  • Data Integrity Observations for Human Drugs
  • Observations Falling Under GMP
  •  

Human Factors – Compliance and Applications

June webinar

Presented by Alison Sathe, Founder, Regulatory Mark & Valerie Fenster, Director of Insights and  Human Factors, Kaleidoscope Innovation 

What you will learn:

  • Human factors strategies from simple drug products to complex surgical devices
  • Primary and secondary labeling development and evaluation for usability
  • Human factors activities from product development to post-market
  • International strategies: expectations for human factors in regulatory submissions in international markets

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Let us know who you are and we’ll be in touch to answer all of your questions and get you started.

Redica Systems Enforcement Analytics

Keep up with the latest Regulatory Developments on Clinical Trials

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Save time and Resources when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Experience the Power of Redica Systems

Complete the form and one of our experts will reach out to you to schedule a demo and answer questions about our subscription options.

INDEX INFORMATION  Redica consolidates regulatory data in real-time on the single largest database for quality, safety, and compliance intelligence.

STRENGTHEN DATASETS Redica machine intelligence algorithms identify and triage risk signals to derive meaning from vast amounts of private and public data.

ANALYZE & INTERPRET PATTERNS Redica instantly models the customer-specific regulatory risks, trends, and opportunities that stand to fundamentally change compliance operations.

Redica Systems Enforcement Analytics

Get immediate access to the news that matters to your sites.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

See how we can help you eliminate yet another spreadsheet.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Stay ahead of changing regulations.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your CDMO monitoring strategy.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your CDMO management strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Sign up for your FREE account today and get instant access to Enforcement Analytics.

Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need to prepare for your next inspection.

Discover the power of the most comprehensive database of 483s in existence.

Our database of over 20,000 483s is retyped and tagged, making it easy to create an Observation Report in seconds.

Eliminate days of work and get your FREE personalized 483 Observation Report.