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.

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.

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.

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!

 

 

Steam Quality Testing

The week of September 4, 2017, Clarence Raiford a Senior Validation Engineer with Performance Validation conducted training on how to perform steam quality testing per HTM 2010, and EN 285 [available for purchase from various vendors].  The effectiveness of moist heat sterilization is dependent on three key quality parameters of the clean steam provided to the sterilizer:

  • Steam Non-Condensable gas test: The amount of the steam by volume that is not steam or water, but is air or other gas that does not contribute meaningfully to sterility of the load. If the non-condensable gasses exceed 3.5%, during sterilization the non-condensable gasses can surround the items to be sterilized and inhibit head penetration to the surface of the object and thus fail to meet sterility conditions.
  • Steam Superheat test: The temperature of the steam above the temperature of saturated steam for a given moisture content. Autoclaves/ sterilizers use moist heat i.e., saturated steam.  If the steam becomes superheated (superheat > 25°K) the steam will become too dry and will not achieve the desired sterility conditions.  The autoclave may behave as a dry heat sterilizer vs moist heat requiring a longer exposure time to achieve sterility conditions.
  • Steam Dryness test: The amount of the steam by weight that is steam and not liquid water. This test is important as the effectiveness of the sterilization is dependent on the quality of the steam.  The criteria for steam dryness is ≥ .90 (steam weight compared to water weight) or >.95 w/w if metal loads are processed and throughout the operating cycle, the steam measured in the steam service pipe is within 3°C of that measured in the same location during the superheat test. Steam dryness results outside of the acceptance criteria may result in wet loads (moisture evident in the chamber or on the load post sterilization) and may indicate that sterility conditions were not achieved.

HTM 2010 recommends that these tests be completed annually and during revalidation of the sterilizer.  Performance Validation has a number of personnel who are qualified to perform these tests.  Please use our contact form if you would like additional information or a quote to perform steam quality testing in your facility.

Critical Airflow in Compounding Facilities

Based on a review of FDA Form 483’s issued to compounding facilities for inspections that occurred January to July 2017, 22 separate citations have been identified for critical airflow visualization.  Critical airflow is a key element in the protection of sterile product from contamination.  A summary of these citations include:

Critical Airflow

Summary of critical airflow observations obtained from review of FDA issued Form 483 from January to July 2017.

The design, construction, and operation of buildings and facilities are a key factor in minimizing product contamination.  Key cGMP elements include:

21 CFR 211.42(b) states, in part, that “The flow of components, drug product containers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination.”

21 CFR 211.42(c) states, in part, that “Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mixups during the course of the following procedures: * * * (10) Aseptic processing, which includes as appropriate: (i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable; (ii) Temperature and humidity controls; (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar; (iv) A system for monitoring environmental conditions; (v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions; (vi) A system for maintaining any equipment used to control the aseptic conditions.”

21 CFR 211.46(b) states that “Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.”

21 CFR 211.46(c) states, in part, that “Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas * * *.”

Equipment design, size, location, cleaning and maintenance are also a factor in minimizing product contamination.  Key cGMP elements include:

21 CFR 211.63 states that “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.”

21 CFR 211.65(a) states that “Equipment shall be constructed so that surfaces that contact components, inprocess materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”

21 CFR 211.67(a) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”

Last but not limited the production and process controls used to manage the manufacturing (or compounding) may have a significant impact to aseptic processing.  Key cGMP elements include:

21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.”

As identified in the FDA Guidance Document Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing practice (p. 6)

Proper design and control prevents turbulence and stagnant air in the critical area. Once relevant parameters are established, it is crucial that airflow patterns be evaluated for turbulence or eddy currents that can act as a channel or reservoir for air contaminants (e.g., from an adjoining lower classified area). In situ air pattern analysis should be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. The studies should be well documented with written conclusions, and include evaluation of the impact of aseptic manipulations (e.g., interventions) and equipment design. Videotape or other recording mechanisms have been found to be useful aides in assessing airflow initially as well as facilitating evaluation of subsequent equipment configuration changes. It is important to note that even successfully qualified systems can be compromised by poor operational, maintenance, or personnel practices. [bold added by author]

Critical Airflow Visualization (smoke studies) are used to demonstrate proper airflow to protect the sterility of the product during aseptic operations.  The studies should reflect actual practice i.e., what are the operations that the technicians will be performing in the ISO area.  On review of the data (including the video recording) for acceptance if the data is inconclusive, shows turbulence, the time to intervene and correct the situation is now – not during an audit.  The best systems can be invalidated through poor aseptic technique, improper gowning, poor maintenance, or failure to follow procedures.

Performance Validation has successfully performed critical airflow visualization or smoke testing in aseptic areas for many large pharmaceutical manufacturers (example summary)  We can help you in designing the study to ensure the aseptic processing and interventions are identified and included in the testing.  We can execute and document the study, and provide the documentation necessary to meet regulatory expectations.

Questions – please contact Dalton Pierson at Performance Validation.

Hurricane Harvey and Resumption of Compounding Operations

A disaster on the scale of hurricane Harvey probably has not occurred since adoption of the Drug Quality and Safety Act.  This is the first time that FDA regulated 503B Outsourcing Facilities have had to address flooding, loss of power, or other weather related issues that impact or could impact building and facilities, and/or equipment regulated by cGMPs.

Hurricane Harvey is no longer a hurricane, the flood waters are receding, and life is starting to get back to normal.  But if you are a 503A or B, with a facility that was without power and flooded with storm water, how do you insure that your facility recovers from the insanitary conditions created by the storm damage?

Without power the controlled storage conditions required by USP were not met.  Without power the clean rooms were idled for days or weeks.  Storm water entering the facility may have simply caused water damage which brings a potential for mold – or worse, storm water mixed with raw sewage, pesticides or other chemicals may have contaminated the facility.

How will you respond when the FDA inspector at your next inspection asks to see your disaster recovery plan and the actions you took to startup and resume compounding operations of your facility? This plan should follow a logical methodology:

Evaluation:  Once you regained access to the facility following the hurricane what was the status of the facility?  This includes raw materials, building and facility, and clean rooms.

Risk Assessment:  Based on your evaluation, what are the potential risks for insanitary conditions, and impact to resuming sterile compounding?

Action Plan: What actions are necessary to mitigate the risks identified in your evaluation and risk assessment?  What is required to safely resume compounding medications? What is the logical sequence of execution to properly plan out the entire scope while minimizing rework.

Execution: Execute the Action Plans.  Be aware that as you execute you may find additional damage and thus more work necessary to resume operations.  This may move you back to an earlier stage such as evaluation, risk assessment, or developing new or revising action plans.

Review and approval:  As the action plans are completed, it is time to do an after action review to ensure that all the work is completed, and post work testing (for example microbial testing) is completed in order to fully certify the facility is ready to resume operations.

Have questions contact Performance Validation.

For-Cause Facility Inspections

As identified in the Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A concept of Operations published June 6, 2017 a for-cause facility inspection may be initiated:

In response to a new registrant or a specific event or information that brings into question the compliance and/or quality of a manufacturing practice, facility, process or drug.  This type of an inspection is meant to gather additional information to determine the quality of marketed product and to determine whether enforcement actions are warranted (p. 7).

For example – report of an adverse event may trigger an FDA inspection.

Page 14 of the document provides a flow chart of the process the FDA uses to initiate, schedule, perform and follow up on the inspection.  This graphic is reproduced below:

FDA For-Cause Inspection Process

Process Flow Chart for a For-Cause Facility Inspection by FDA