Pharmaceutical companies typically require considerable resources, in terms of time, money, and specialized personnel, to validate a current Good Manufacturing Practice (cGMP) facility. This can be overwhelming to a small company or plant with limited resources. This paper identifies some of the key areas in a facility upgrade project that have been found to result in inefficiencies, project, and facility start-up delays. It seeks to demonstrate that the integration and streamlining of the design, construction, commissioning, and validation phases can accelerate the start-up effort, reduce the validation effort and costs, produce superior documentation, and ensure that product is produced in a cGMP-compliant facility. It will also prove that even though the original focus of validation was to satisfy regulatory expectations, facility validation has in fact become good business and engineering practice that enhances reliability, cost, and quality of the products.
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Monday, August 18, 2008
Facility Validation: A Case Study for Integrating and Streamlining the Validation Approach to Reduce
Modular Construction: Innovation, Flexibility, and Adaptibility by Design
Identifying issues in the factory that traditionally arise in the field minimized onsite equipment rework and subsequent qualification work.Risk is part of biopharmaceutical development. Planning for commercialization typically starts after completion of phase 1 trials. If you wait until the end of phase 3 to build a manufacturing facility, years of profitable sales will be lost. If you build a factory too early, you risk the possibility that the factory will be idle while waiting for product approval. After all, in today's regulatory and economic climate, the odds of successfully bringing a product from discovery through clinical development to commercial success are less than 1 in 100. Companies cannot be blamed for questioning when, or even if, they should build a new facility to manufacture a product for commercial launch. However, modular design can reduce this risk by reducing construction time and increasing flexibility.
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Validation of Sterile Filtration of Liquid Nitrogen
Liquid nitrogen (LN2) is widely used in the pharmaceutical,biopharmaceutical, and life sciences industries for lyophilization and quick-freezing of pharmaceutical preparations and storage of cells and microbial cultures.
As a refrigerant, LN2 can act as a vehicle for transmitting contaminant
microorganisms.Whether as the original source of contamination or as a conduit, LN2 has been reported as a potential biohazard (1). Fungal and bacterial contaminants have been found in both the freezers that use LN2 and the cultures stored in them (2). An outbreak of hepatitis B in patients undergoing
cytotoxic treatment has been traced to LN2, suggesting that contaminants can move both in and out of cryostorage containers (3). In other instances, storage tanks that use LN2 were reported to be contaminated by Bacillus (4), and storage tanks holding cryopreserved stem cells also were found to be contaminated (5).
Monitoring Blend Uniformity with Effusively
The authors describe the measurement of the effusivity of blended and unblended commercial pharmaceutical formulations to effectively differentiate between materials and then to determine if the effusivity changed with blending time. Eight components of a commercially available formulation were tested to determine if their effusivity values were unique enough to permit them to be distinguished.Two aliquots were tested, and the variance between the two was 1.6%.The effusivity values indicated that the blend of the eight components was sensitive to uniformity. The eight components then were blended and samples were extracted at times ranging from 2 to 60 min.The results, when compared with assay results from the drug manufacturer, showed excellent agreement in terms of uniformity determination.
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Validation Training: How Do You Do It?
Pharmaceutical organizations have a training need for validation skills that cover the areas of protocol execution, protocol development, validation project management, and documentation control. This need can best be met through knowledge and skills training that is customized for individual organizations. Customized training is intended to enhance the transfer of knowledge and skills from the learning environment to the working environment. Critical to getting the greatest benefit out of customized-training dollars is selecting the best candidates for training, and providing immediate opportunities after training to use newly acquired knowledge and skills.
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Immunological Responses of Mice following Administration of Natural Rubber Latex
Although the prevalence of IgE-mediated latex allergy has increased over the past decade, the circumstances which culminate in sensitization remain uncertain. The objective of these studies was to evaluate the role which sensitization route plays in the development of latex allergy using murine models representative of potential exposure routes by which health care workers (topical and respiratory) and spina bifida patients (subcutaneous) may be sensitized. BALB/c mice administered latex proteins by the subcutaneous, topical, intranasal, or intratracheal routes exhibited dose-responsive elevations in total IgE. In vitro splenocyte stimulation initially demonstrated specificity of the murine immune response to latex proteins. Subsequently, immunoblot analysis was used to compare latex-specific IgE production amongst sensitization routes. Immunoblots of IgE from subcutaneously sensitized mice demonstrated recognition of latex proteins with molecular weights near 14 kDa and 27 kDa. These protein sizes are consistent with the molecular weights of major latex allergens (Hev b 1 and Hev b 3), to which high percentages of spina bifida patients develop antibodies.
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Process Validation of Existing Processes and Systems Using Statistically .Part3
Andrew W. Jones, Technical Manager, KMI/PAREXEL LLC
ISPE, September 2001 Determine the Confidence Interval as compared to +/- 3S.D. With the +/- 3 S.D. ranges determined, it can be considered important to evaluate what confidence there is that the next data point will fall within this range. The rationale for determining this level is to justify that the +/- 3 S.D. range provides a confidence that 99% of the data is within that range. Similar to the +/- 3 S.D. range, the confidence interval is a range between which the next measurement would fall. This level is typically 99% or greater. Thus a 99% confidence interval means, "there is 99% insurance that the next value would be in the range."
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Prerequisites for Successful Validation
Validation was hinted in the 1960s, almost four decades ago. What has changed over the last 30 o 40 years? Has the overall understanding of the term improved? Have all responsible firms truly embraced validation? Are they doing everything within their power to make validations a success? Unfortunately not. While validation is a very necessary element of any firm that falls under the scrutiny of the governing regulatory agencies – both United States and foreign – it has not received the recognition it deserves.
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The End of Process Validation As We Know It?
In 1987, when the US Food and Drug Administration issued its Guideline on General Principles of Process Validation, a young FDA reviewer asked her supervisors, "What does this term validation really mean?"
"We don't know," they responded.
Much has changed in the past 18 years. So much has changed, in fact, that the current concept of process validation, once a fresh idea in quality control, and which later became accepted dogma, may now be ready for the trash bin. With companies achieving new levels of process understanding, what does it mean to validate a manufacturing process? Industry leaders and FDA are now examining that question and looking at new models to follow.
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Essentials of Validation Project Management
All pharmaceutical validation projects are labor and capital intensive, and each must be planned and managed carefully. Numerous tasks and activities must be identified early and then scheduled to support the project completion date. Stakeholders such as the Quality Assurance (QA) and Calibration–Metrology departments must be alerted to impending increased workloads under compressed time frames. Standard operating procedures (SOPs) and protocol formats must be developed, test equipment must be purchased or rented, and contractors must be evaluated and hired. Managers must decide whether the US Food and Drug Administration will participate in the design review process, and if so, what will be the agency's exact involvement and participation. Considering the set of activities and programs that require timely completion, pharmaceutical validation projects must be carefully organized, managed, and monitored.
Part I of this article covered the following four critical components common to all successful validation projects: design review to ensure GMP compliance, project scope definition, project labor and cost estimating, and validation master plan development (1). Part II of this article introduces three additional programs, thereby providing validation project managers and participants the knowledge to plan and execute a project properly, no matter how difficult or complex. This final article also examines activities that are initiated well after project inception and often continue to project completion and operations:
protocol and SOP development, scheduling, and implementation;
turnover package preparation;
deviation and discrepancy management.
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Characterization, Qualification, and Validation of a Disposable Final Filling Process for Parenteral
Many articles describe the growing need for and benefits of the replacement of traditional, reusable technologies with disposable, single-use components in the pharmaceutical and biotechnology industries (1–6). Replacing reusable materials (e.g., stainless steel) with disposable products is cost effective and increases operator and product safety (3–6).
For disposable technologies to be accepted by an industry, vendors must show that disposable systems can have equal or better performance than traditional systems. As vendors begin supplying complete sterile, disposable solutions to the pharmaceutical and biotechnology industries, suppliers will be required to have complete validation packages and an in-depth understanding of their products.
The first decision that must be made when designing and manufacturing a disposable assembly is the choice of materials to be used. The materials typically chosen are polymeric materials that must be sterilized using common sterilization methods. Typically, prepackaged, presterilized disposable assemblies are gamma irradiated at >25 kGy. Therefore, the materials of these assemblies must be nontoxic and resist changes to their physical properties after being irradiated.
Once the materials are chosen, bioburden (i.e., the level of contamination) must be minimized during the assembly process. Low levels of bioburden are required throughout the product fluid path to ensure endotoxin levels are well below accepted levels. Overall bioburden levels for inner and outer material surfaces also must be monitored carefully and maintained during the manufacture of the disposable modules to ensure the validity of the subsequent sterilization process.
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Method Validation Guidelines
So, is your assay fit for the job ?
Validated analytical test methods are required by good manufacturing practice (GMP) regulations for products that have been authorized for sale and almost certainly for late-stage trial clinical material.3 Also, some methods used during the pre-clinical phase of drug development under good laboratory practice (GLP) regulations may also require validation.4
However, during the development of biopharmaceuticals, methods may be employed that may not need full validation — for example, those used only for process validation or comparability studies. The various terms applied to the "not-quite-validation" of such methods include "test characterization," "qualified method," and "validated for Phase I." Considerable confusion has arisen over this topic, which has been the subject of several articles and numerous presentations at conferences. This article also seeks to explain and clarify the situation.
In basic terms, a suitable method must be based on firm scientific principles; capable of providing the necessary sensitivity, accuracy, precision, etc.; and capable of generating reliable results. During test development, we learn more about the ability of a test to meet these requirements, and we decide whether the test is going to meet suitability standards. The key questions to be answered are:
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Author(s):
Alex D. Kanarek, Ph.D.
Journal:
BioPharm International, September 2005.
Validation of Spectrometry Software: Critique of the GAMP Good Practice Guide for Validation of Labo
In this column over the past few years, I have not mentioned in any great detail guidance documents on computer validation but started the discussion on a specific topic from the regulations themselves. This is due to the fact that most guidance has concentrated to a large extent on manufacturing and corporate computerized systems rather than laboratory systems including spectrometers.
This has changed with the publication of the Good Automated Manufacturing Practice (GAMP) Forum's Good Practice Guide (GPG) on Validation of Laboratory Computerized Systems (1). However, this publication needs to be compared and contrasted with the AAPS publication on Qualification of Analytical Instruments (AIQ) (2). Both publications have been written by a combination of representatives from the pharmaceutical industry, regulators, equipment vendors, and consultants.
Overview of the Guide
Published in 2005, the stated aim of the GPG is to develop a rational approach for computerized system validation in the laboratory and provide guidance for strategic and tactical issues in the area. Section 5 of the GPG also notes that: ". . . the focus should be on the risk to data integrity and the risk to business continuity. The Guide assumes that these two factors are of equal importance" (1).
However, the GPG notes that companies must establish their own policies and procedures based upon their risk own management approaches. Of interest, the inside page of the GPG states that if companies manage their laboratory systems with the principles in the guide there is no guarantee that they will pass an inspection, and therefore: caveat emptor!
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Packaging Process Validation
Packaging process validation is often supplemented by 100% inspection online. Many firms take the approach that a 100% online inspection is the way to go. Even today, many companies have inspectors set up offline to sort out or rework unacceptably packaged product. Often, process variables are not adequately studied or the process is not observed to “nail it” through process validation. The following approach used by a large pharmaceutical company to validate the blister packaging process may shed some insights on how Design of Experiments (DOE)—prior to packaging validation—can help.
This case study is about an OTC product. The product launch date was set in stone; the marketing managers were even talking about pre-launching the product to select large-scale retailers. The operations team was under tremendous pressure to finish the process validation and pre-launch activities of this OTC product. The product was a coated tablets, the packaging put-up was a carton with three blister cards, each card with eight tablets per card, making it a pack of 24 tablets.
The team consisted of a Packaging Engineer, an Operations Engineer, a Production Manager, a Quality Engineer and a Project Manager. Traditionally, the company validated the packaging process by optimizing the packaging process variables and making three runs. A statistically valid sampling plan would be implemented and sample packages would be tested per the finished product specifications. In most cases, this approach worked. But this was not one of those usual projects.
Let us look into the specifics. The package design required the patient to peel the foil by holding on to a center tab. See Figure 1, which shows an example of the four-way notch at the center tab. Since the product was geared towards the elderly, the package design presented some unique challenges. A trial run was performed and some samples were shown to marketing. While the overall package quality in terms of appearance and integrity was fine, Marketing thought that the package was simply too hard to open.
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Validation of Spectrometry Software: Risk Analysis Methodologies for Commercial Spectrometer Softwa
In the last "Focus on Quality" column (1), I noted that the risk analysis methodology used in the GAMP Good Practices Guide for Validation of Laboratory Computerized Systems (GPG) (2), which was based upon failure mode effect analysis (FMEA), was too complicated. The rationale was that we purchase mostly commercial software in regulated laboratories that already has been tested by the respective vendor. Therefore, why do we need to potentially repeat work that has already been performed?
Before we begin this discussion, it is worth mentioning that I have written a paper on risk assessment at the system level, and determination of how much validation is required has been published recently by Advanstar Communications (3). This publication looked at the nature of the software used in the system and the impact of the records produced by the system to determine how much validation was required. The outcome if validation was required was one of two options: Full validation based upon a system implementation life cycle when the detailed steps to be undertaken are defined in a validation plan for the system. Lower-risk systems could be validated using a single integrated validation document that defined the intended use, security and access control, compliance issues, and preservation of the records produced by the system.
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A Compliance Perspective on Dissolution Method Validation for Immediate-Release Solid Oral Dosage Fo
As the pace of product development accelerates, the approach to dissolution-method development must advance beyond a manual method and an assay. A natural progression of the method-development process must include the transfer of the manual method onto automated instrumentation.
Aseptic Process Validation
What are the regulatory pressures facing aseptic process validation today and what will they be like over the next few years? An inquiry into existing literature and with current industry personnel reveals a corner of the pharmaceuticals industry driven by a lattice of suggested improvements, a constant hum of activity and improvements that fight to keep pace with general industry trends and emerging technology. Those working in aseptic processing validation must consistently look five years ahead and five years behind, at rules and informative processes and market realities, all of which play off one another like so many strings on a musical instrument. With an important FDA guidance revision just now beginning its long fade into routine and a brand new one described as imminent, aseptic processing and its regulatory outlook is at the forefront of pharma and biopharma business plans.
Validation & Compliance: Using Risk Analysis in Process Validation
Process validation is used to confirm that the resulting product from a specified process consistently conforms to product requirements. A risk-based approach to process validation provides a rational framework for developing an appropriate scope for validation activities, focusing on processes that have the greatest potential risk to product quality. This article presents a case study in which a risk-based approach was used to evaluate a typical mammalian cell culture and purification process. This risk assessment used a Failure Modes and Effects Analysis (FMEA) to evaluate the impact of potential failures and the likelihood of their occurrence for each unit operation. Unit operations included in the process validation required a risk priority number greater than or equal to a specified threshold value. Unit operations that fell below the threshold were evaluated for secondary criteria such as regulatory expectations or historical commitments.
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K. Dashora, D. Singh, Swarnlata Saraf and S. Saraf *. Institute of Pharmacy, Pt.RavishankarShuklaUniversity, Raipur 492 010. *Author for ...
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Validation of the Autoclave is classified into the following 1.0 OQ – Operational Qualification 2.0 PQ – Performance Qualification The valid... -
Cold storage is a relatively simple cold room that is commonly used to store material between 2[degrees] to 8[degrees]C. Such cold rooms a...
