Commissioning and Qualification – An Overview

Buildings and equipment used in the manufacture, processing, packaging, holding or storage of drug product are subject to the regulations set forth by the FDA in 21 CFR Part 211.  These regulations are considered the minimum current good manufacturing practices (cGMPs), for the manufacture of human and animal drug products.  Commissioning and qualification of these buildings and equipment is essential for ensuring compliance to these regulations and confirming that the drugs manufactured within them are fit for their intended use.

As described by USFDA (2011, p. 10): During the process qualification (PQ) stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture. This stage has two elements: (1) design of the facility and qualification of the equipment and utilities and (2) process performance qualification (PPQ).

To meet the goals identified by USFDA above, there are a number of accepted methods and/or practices that can be used.  This includes consensus guides such as ASTM E2500-13, Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical manufacturing systems and Equipment, industry guidance such as ISPE’s Baseline Guide Volume 5: Commissioning & Qualification, among others.  Some companies have merged elements of multiple approaches into a unique company solution.  Provided the solution meets the requirements of the cGMPs any solution should be deemed adequate.  The graphic below provides one possible solution to meet the intent of the 2011 process validation guidance. Note: Click on the graphic to enlarge.

Planning

Prior to starting commissioning activities, a plan should be developed. Depending on the organization the plan may be referred to as a Commissioning Plan, Commissioning and Qualification Master Plan (CQMP), or Validation Master Plan (VMP).  The plan should define and provide an overview of the system, facilities, and equipment to be commissioned and/or qualified.  The plan should include the scope and strategy of activities, an overview of deliverables to be completed, and the roles and responsibilities of the persons involved.  Planning is addressed in ISPE Baseline Guide Volume 5: Commissioning & Qualification, FDA Guidance for Industry: Process Validation – General Principles and Practices, and ICH Q7:  Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients.

Quality Risk Management

Quality risk management tools are utilized as a means to determine which aspects of the process will have the largest effect on product quality (USFDA, 2011).  Tools such as impact assessments are conducted on systems to evaluate their impact on product quality and to determine which system components are to be deemed critical (International Society of Pharmaceutical Engineering [ISPE}, 2007).  Other risk management tools help to identify the critical quality parameters such as Fishbone diagrams, Failure Mode Effects Analysis (FMEA), and Design of Experiments (DoE) (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH], 2005, 2009).  Utilizing quality risk management tools may also help narrow the scope of qualification to what’s most important, e.g. Critical Quality Attributes (CQAs) and Critical Process Parameters CPPs thus reducing cost (ASTM International, 2013; International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH], 2009).

Commissioning

Commissioning is a systematic approach to the start-up and turnover of facilities, systems, and equipment to end-users and ensuring that user requirements and design specifications are met (International Society of Pharmaceutical Engineering [ISPE}, 2007).  Activities within this phase may include design reviews, factory acceptance testing, installation verification, and functional testing.  Summary reports are generated at the conclusion of commissioning activities and include an overview of the results and any deviations encountered during testing. Commissioning, if well documented, may be leveraged to reduce or eliminate qualification testing.

Qualification

As defined in the FDA Process Validation Guidance, qualification refers to the activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly.  As discussed previously there are multiple approaches that demonstrate suitability for intended use.

  • Under an ISPE Baseline Guide 5 approach, systems and equipment determined to have a direct impact on product quality are typically qualified using Installation and Operational Qualifications. While systems with an indirect impact on product quality may only be commissioned.
  • Under an ASTM E2500 approach, testing typically considered as part of IQ/OQ is referred to as verification. ASTM E2500 emphasizes utilizing a science-and-risk-based approach in order to focus the verification activities on critical aspects of the system.

Commissioning activities, if performed to cGMP standards may be leveraged during the Qualification phase as they verified the system is suitable for its intended use and demonstrated proper functionality.

Acceptance

Multi-functional teams, which should include the Quality Unit for Direct Impact/Quality Critical systems, provide final approval of qualification or testing documentation and deem the system or equipment fit for its intended use.  At this stage, a declarative statement is made on the disposition of the system or equipment and the release for operational use.  Summary reports are generated at the conclusion of qualification and include an overview of the results and any deviations encountered during testing.

  • Systems that have a direct impact to product quality are accepted by the organizations quality unit among other SMEs (International Society of Pharmaceutical Engineering [ISPE}, 2007).
  • Systems with critical aspects are accepted by the organizations quality unit among other SMEs (ASTM International, 2013)

Process Performance Qualification

As described in (USFDA, 2011, p. 11): Process Performance Qualification (PPQ) combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected . PPQ is documented through an approved testing protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes .

The PPQ lots should be manufactured under normal conditions by the personnel routinely expected to perform each step of each unit operation in the process. Normal operating conditions should include the utility systems (e.g., air handling and water purification), material, personnel, environment, and manufacturing procedures.  PPQ must be successfully completed before product can be distributed commercially (USFDA, 2011, p. 13).    During PPQ, process data is collected and evaluated to ensure the manufacturing process performs as expected.

On completion of testing, a summary report is created that includes analysis of data collected, a discussion of any manufacturing nonconformance, description of corrective actions, any changes to existing procedures and controls, and a conclusion stating whether or not the process meets established acceptance criteria.

Acceptance of this report by a multi-functional team including Engineering, Area Manager, Quality Assurance, and Quality Control releases lots for distribution, provides approval of the process, and deems the process ready for Stage 3 – Continued Process Verification.  Under stage 3, the organization is responsible to establish one or more systems that will monitor the manufacturing process to detect unplanned departures from the process.  As defined by USFDA (2011, p. 14):

An ongoing program to collect and analyze product and process data that relate to product quality must be established (§ 211.180(e)). The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.

About Performance Validation

Performance Validation has assisted large and small pharmaceutical manufactures in providing turn-key or staff augmentation support for commissioning, qualification, and validation projects.  We have successfully worked with companies that have implemented an ISPE Baseline Guide methodology, an ASTM E2500 methodology, and various combinations to achieve a compliant solution.  For services offered please see the Commissioning & Qualification page of our website.  For information on projects that we have successfully completed please see the Projects Summaries page of our website.  Our goal is to provide our customers with peace of mind concerning their commissioning, qualification, and validation projects.

Please use our contact us page if you have a question on Commissioning, Qualification, and Validation or would like further information on Performance Validation’s capabilities.

References:

ASTM International. (2013). E2500-13: Standard guide for specification, design, and verification of pharmaceutical and biopharmaceutical manufacturing systems and equipment. West Conshohocken, PA: ASTM International.

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH]. (2005). Quality risk management. Retrieved from https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH]. (2009). Pharmaceutial development. Retrieved from https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf

International Society of Pharmaceutical Engineering [ISPE}. (2007). Baseline guide: Volume 5 commissioning and qualification (Vol. 5). Tampa, FL: ISPE.

USFDA. (2011). Guidance for Industry. Process Validation: General Principles and Practices.  Rockville, MD, USA: Government Printing Office.

 

 

BioPharma Facility of the Future

Today the pharma industry typically stick builds a new facility, installs permanent equipment, the financial guys max out depreciation, and when the product loses patent protection the cycle starts over.
We have already seen some trends in biopharma that buck this trend.  The use of single use systems which eliminates capital investment in stainless steel tanks, pipes, and eliminates the need for cleaning validation as this is single use.  Bags that contain relatively inexpensive single use instrumentation.  These single use systems provide for Increased flexibility space utilization allowing different configurations and the space to be used for different campaigns with minimum effort.
Industry insiders have claimed that in the near future biopharma products will exceed traditional pharma in terms of number of products and the revenue generated from these products (Aspen Report, 2017). If true we need to be aware of how biopharma is both similar and differentiated to traditional pharma manufacturing.  Please see the Rx for Change PDF which describes new design approaches that could lead to more flexible, adaptable, and sustainable BioPharma production facilities.

2017 Summer Interns

2017 Summer Interns

This summer Performance Validation, LLC engaged three interns from Rose-Hulman Institute of Technology to work with a PV project team at one of our Pharmaceutical clients in Illinois. The interns enjoyed a welcoming team environment where their contributions were appreciated and valued.

One intern commented, “The central benefit from this experience was that I felt value in my work and that every task I was given to complete was helping towards PV’s end goal with this project.” This internship experience exposed the interns to a variety of systems for example HVAC, Equipment washers and Centrifuges, and tasks such as commissioning and qualification testing. “Throughout my training, I was routinely brought out into the field to help other employees perform a multitude of commissioning tasks for several different building systems. Being exposed to the validation process from day one allowed me to feel comfortable with completing tasks by myself by the time I had finished my training” said another intern.

Technical skills were developed in conjunction with a greater understanding of the importance of effective teamwork as noted by an intern, “The opportunity to work this internship really opened my eyes as to how absolutely vital effective communication is to the success of any project involving separate groups working together.”

PV Management comments concluded, “This past summer’s internship program proved to be a very enriching experience for all parties involved. These aspiring engineers were able to gain valuable field experience, and were able to participate in a high functioning team environment. They also provided invaluable service to the project team as they worked toward completing a high-profile and high-intensity expansion project.”

If you are interested in internship opportunities with Performance Validation we welcome you to contact Human Resources, or you may submit your resume on line at our Careers Page.

2017 Georgia Temperature Mapping Summary

During 2017, Performance Validation’s Georgia team executed 24 projects that included a temperature mapping component of project work where we utilized client provided temperature mapping equipment.  Please note that Performance Validation maintains an inventory of qualified and validated temperature and humidity mapping equipment including 5 qualified and validated Kaye 2000 systems and over 100 qualified and validated Veriteq Data Loggers.  These 24 projects were completed at a large animal health facility located in the Southeastern United States. A summary of the types of equipment mapped during 2017 are identified below:

2017 Georgia Temperature Mapping Summary

mapping

Using Kaye Validator 2000 outfitted with K type wires completed the mapping of:
• A depyrogenation tunnel
• A depyrogenation oven
Using Kaye Validator 2000 completed the temperature mapping of:
• Three autoclaves.
• Six Steam-in-Place systems
Using Rotronic Data Loggers completed the temperature mapping of two warehouses.
Using Rotronic Data Loggers completed the temperature mapping of three chill rooms.
Using Rotronic Data Loggers completed the temperature mapping of:
• Four reach-in freezers
• Two walk-in freezers
Using the Kaye Validator 2000 completed the temperature mapping of two -80℃ ultra-low freezers

 

 

 
In summary, Performance Validation’s Georgia team supported a wide range of temperature mapping activities in 2017 ranging from -80℃ Sub-Freezers to +250℃ Depyrogenation Tunnels/Ovens and everything in-between.  Mapping can be completed with client provided or our own calibrated, qualified, and validated equipment.  As an additional service, Performance Validation does rent mapping equipment for client use.  Have a mapping need?  PV has the experience, expertise, and equipment to support the temperature mapping needs of the regulated life science industry.

For more information or to request a quote for your mapping needs please use our contact us form, or contact:

Neil Enlow
Principal Validation Engineer
Performance Validation, LLC
Cell: (317) 341-2819

Winter Mapping for USP Storage Areas



Winter is fast approaching in the US and soon there will be snow and ice covering the land! While nice for the holidays, those of us that are concerned about USP temperature controlled storage areas – winter brings with it the need to perform Winter Mapping. Do you have a continuous temperature monitoring system in place with a robust documented temperature mapping analysis of your storage space?  USP guidelines require extreme seasonal temperature mappings to be performed where product storage temperatures are critical.  Have you had increasing internal or external requests to demonstrate adequate temperature and/or humidity control within your facility?

Performance Validation has the resources and experience necessary to help provide a documented temperature mapping analysis of your facility, cold room, refrigerator, or freezer. Check out our project summaries for 2017 that identify the work performed by our Georgia team, or the 2016 summary that details the work executed with Performance Validation’s own mapping equipment. Our internally developed mapping/qualification protocol templates have been created based on USP guidelines and best industry practices and can be modified for your application quickly.

With offices and teams located in Indiana, Illinois, Michigan, Kansas, Georgia, and New Jersey – PV can provide a local solution to help meet your needs.  Not located nearby?  Our portable wireless data loggers can be programmed at our office, sent to your site for installation with your assistance, and returned to us for data download and analysis.

We are committed to providing our clients with up to date strategies that reflect changes in cGMPs and interpretation of regulatory guidelines.  Performance Validation has earned a strong reputation for quality, integrity, and a willingness to work with other vendors and contractors in providing solutions for our customers.  We also pride ourselves on our flexibility to meet our clients’ needs, whether we are supplementing their current staff or managing an entire project.

Have a question or looking for a quote?  Please contact Neil Enlow, PV’s Temperature Mapping Services Lead or use our contact us form.

SC Bio Event

Press Release (Indianapolis, IN September 29, 2017) Performance Validation a member of SC BIO will be attending and exhibiting at the 2017 South Carolina Bio Annual Conference.  The conference will be held on October 24-26, 2017 at The Gilliard Center in Charleston, SC.

The conference will consist of networking sessions, addresses from local and state government officials, and panel discussions from CEOs and executives from life science companies with operations in South Carolina.  These top executives are leaders in innovation and advancement from pharmaceutical research and advanced medical device manufacturing to bio-materials, diagnostics, and health IT.  The conference includes an exhibition portion which will allow attendees to learn about life science research, innovation, and services from companies and organizations.  It will also showcase South Carolina’s expanding life science industry.

Rick Van Doel and Kimberly Lee will be representing Performance Validation at this event.

 

Dr. Rick Van Doel is a Principal Validation Specialist, an Owner of PV, and the President of Performance Validation. Rick will be available to answer your questions during the networking breaks. Alternatively, you can contact Rick directly via email to schedule a meeting.

 

 

 

 

Kimberly Lee is a Validation Engineer with Performance Validation. She is a member of PV’s Georgia team and a resident of Columbia, SC.  Have a question on commissioning, qualification or validation? Kimberly will be available to answer yourquestions during the networking breaks. Alternatively, you can contact Kimberly directly via email to schedule a meeting.

Performance Validation has been providing commissioning and qualification services for the life science industry since 1988 and has local resources in Columbia SC.  Examples of the types of projects Performance Validation has supported are available on the Projects Summary page of our website.

If you are attending the South Carolina Bio Annual Conference in beautiful Charleston, please stop by our booth and speak with Rick Van Doel and Kimberly Lee to see how Performance Validation can assist with current and future projects.

 

 

 

PV Joins GABio

For Immediate Release (Augusta, GA; October 1, 2017) Performance Validation has joined Georgia Bio (GABio). GABio conducts business and economic development activities; advocates on behalf of the industry on public policy matters; educates the public about the benefits of life sciences research and product development; and provides a network for the exchange of ideas, information and opportunities.  Georgia Bio’s mission is to advance the growth of Georgia’s life sciences industry and foster strategic partnerships that can create a healthier world.

About Georgia Bio:
Georgia Bio (GABio), founded in 1989, is a non-profit, membership-based organization that promotes the interests and growth of the life sciences industry.  Members include companies, universities, research institutions, government groups and other industry associations involved in discovery and application of life sciences products and related services that improve the health and well-being of people throughout the world.

About Performance Validation:
About Performance Validation – Performance Validation has been serving the life science industries since 1988, and is a nationwide leader in providing commissioning, qualification, and validation services for pharmaceutical, biotechnology, and medical device manufacturers. We live by our Mission, which is to provide our clients with peace of mind, and we have been doing so for more than 25 years.

FDA Compounding Progress Report

January 2017, FDA released the FDA Compounding Progress Report which summarizes FDA activity in the compounding space in the 3 years following passage of the Drug Quality and Security Act.  A PDF version of the report is available here.

A few highlights as of Nov 27, 2016 FDA has (p.10):

  • Conducted more than 350 inspections of compounding facilities, 85 of which were outsourcing facilities.  Of note, 120 of the 350 inspections were “for cause”.  Meaning the inspection was triggered based on reports of serious adverse events or product quality issues.
  • Issued more than 130 warning letters advising compounders of significant violations of federal law.
  • Issued more than 30 letters referring inspectional findings to state regulatory agencies.
  • Overseen about 100 recalls involving compounded drugs. This includes sterile drugs manufactured under insanitary conditions thus calling into question the sterility of the product, and products that were sub or super potent.
  • Worked with DOJ on a number of civil and criminal enforcement actions.

On page 12, the FDA identified continued concern about the risk to patients from compounded drugs.  Many non outsourcing registered facilities were engaged in large-scale manufacturing.

 

Additionally FDA continues to identify insanitary conditions in many of the facilities inspected.  Pictures in the report identified a few of the conditions encountered during inspection.  One example provided from the report (left) identifies mold on ceiling tiles of a compounding facility.

 

 

Lastly several examples were provided of serious adverse events and product quality related issues of both sterile and non-sterile products including:

  • Super-potent Morphine Sulfate
  • Multivitamin with high amounts of Vitamin D3 recalled after FDA notified of adverse effects
  • Bacteria contaminated sterile drugs (compounded calcium gluconate) after patients developed bacterial bloodstream infections.
  • Bacteria contaminated sterile drugs (methylprednisolone acetate) distributed to 17 states resulted in adverse events including skin abscesses.

Drugs compounded under 503A and B serve a recognized and important need for patients.  However, these drugs need to meet appropriate quality standards to prevent patient harm.  FDA is committed to provide appropriate oversight to protect public health.

2016 Temp Mapping Summary

During 2016, Performance Validation executed 29 projects that included a temperature mapping component of project work where we utilized PV’s mapping equipment.  These projects were completed with multiple clients, across both Pharmaceutical and Medical Device life science industries.  These projects included mapping studies using PV’s own inventory of Vaisala Veriteq data loggers measuring temperature only, or temperature and humidity, or using the Kaye Validator 2000 for projects involving extreme cold or heat.  Performance Validation maintains its temperature mapping equipment in a calibrated and validated state for use in the regulated life science industry.  A summary of the types of equipment mapped during 2016 are identified below:

Sub-Freezers/Cryogenic Storage:
Using the Veriteq 1416 low temperature loggers, completed a -80C ultra low freezer qualification for a contract pharmaceutical packaging company.

Using the Kaye Validator 2000:

  • Completed two liquid nitrogen dewar qualifications for an animal health manufacturer cell culture lab.
  • Completed an engineering study to verify cryo vessel storage temperatures during permanent monitoring system RTD thaw for a large pharmaceutical manufacturer central cell bank facility.

USP Freezers:
Using Veriteq VL temperature loggers:

  • Completed two reach-in freezer qualifications for a large pharmaceutical manufacturer.
  • Completed mapping of two walk-in freezers for a life sciences logistics provider.
  • Completed mapping of a large clinical trials walk-in warehouse freezer for a large pharmaceutical manufacturer.

USP Cold Storage Refrigerators or Chill Rooms:
Using Veriteq VL temperature loggers:

  • Completed two reach-in refrigerator qualifications for a large pharmaceutical manufacturer.
  • Completed mapping of two walk-in coolers for a life sciences logistics provider.
  • Completed mapping of a new large clinical trials walk-in warehouse cooler for a large pharmaceutical manufacturer.
  • Completed a walk-in cooler and a packaging room refrigerator qualification for a contract pharmaceutical packaging company.
  • Completed a new reach-in refrigerator qualification for an animal health manufacturer cell culture lab.
  • Completed a cold room mapping for a generic animal health manufacturer.
  • Completed mapping of three walk-in coolers at two different sites for a specialty distribution and solutions provider.
  • Completed mapping of four reach-in coolers for a pharmacy services company.

USP Controlled Room Temperature, Water Baths, or Incubators/Stability Chambers:
Using Veriteq VL temperature and humidity data loggers:

  • Completed a warehouse and sample retention room mapping for a generic animal health manufacturer.
  • Completed a secondary packaging room temperature study for a contract pharmaceutical packaging company.
  • Completed a number of local and remote seasonal temperature mappings for multiple third party drug storage and distribution warehouses and provided recommendations for permanent monitoring locations within those facilities.
  • Completed mapping of a new large clinical trials warehouse for a large pharmaceutical manufacturer.
  • Completed a number of controlled area HVAC requalifications for a large dry products pharmaceutical manufacturer to verify temperature and humidity requirements within critical manufacturing, storage, and packaging areas.
  • Completed several reach-in stability chamber requalifications for a lab facility at a large animal health manufacturer.
  • Completed several shaker incubator qualifications for a cell culture lab at a large animal health manufacturer.  
  • Completed several incubator/stability chamber qualifications for a large pharmaceutical manufacturer and a large combination device manufacturer.  

Autoclaves, Sterilizers, Steam-in-place (SIP):
Using the Kaye Validator 2000:

  • Completed revalidation of several different steam autoclave loads for multiple steam autoclaves for a central cell bank lab and a culture lab at a large pharmaceutical manufacturer.
  • Completed initial validation of several different steam autoclave loads for two new autoclaves for a cell culture lab at a large animal health manufacturer.

In summary, Performance Validation supported a wide range of temperature mapping activities for a broad range of clients, small and large, pharma and non-pharma, in 2016.  In addition to the projects detailed above and as another available service, Performance Validation rented Veriteq data loggers and Kaye Validator 2000 equipment to several different clients for internal completion of mapping work throughout 2016.  PV has the experience, expertise, and equipment to support the temperature mapping needs of the regulated life science industry.

For additional information contact:
Neil Enlow
Principal Validation Engineer
Performance Validation, LLC
Cell: (317) 341-2819

ASTM E55 Summer Newsletter

ASTM E55 Summer Newsletter is available and is posted on the ASTM website.

The ASTM E55 committee addresses issues related to process control, design, and performance, as well as quality acceptance/assurance tests for the pharmaceutical and biopharmaceutical manufacturing industry. Topics in the ASTM E55 summer newsletter includes:

  • An introduction to ASTM’s E55 Committee.
  • E55 Subcommittee Reports.  This section includes a summary of subcommittee activities which address Process Analytical Technology (E55.01), General Pharmaceutical Standards (E55.03), and General Biopharmaceutical Standards (E55.04).
  • Planning and strategy, areas that the committee is focusing on for future standards development based on industry needs (E55.95)
  • Outreach.  How ASTM is reaching out to regulatory agencies on a global perspective (EMA, WHO), within the US with the new administration, our Fall committee meeting in Lausanne Switzerland, and increasing awareness within our membership.
  •  Lastly, the newsletter addresses membership updates and how to effectively participate as a committee member.

If you are interested in helping to develop consensus driven standards for the Pharmaceutical and Bio-pharmaceutical industry – join ASTM and be a part of the solution!