First of a two-part article published in Pharmaceutical Technology magazine in December 2005.
Part 1 describes facility and equipment design review, validation project organization and planning, and validation master plan development.
Second of a two-part article published in Pharmaceutical Technology magazine in January 2006.
Part 2 describes protocol development and implementation (including advice and lessons learned), preparation of turnover packages, and the evaluation and management of deviations.
Installation of a High Purity Water and WFI system with no unplanned downtime.
Latest available technology including online monitoring Microbial Detection, Reduced water consumption with start / stop / sanitize cycles of water pretreatment equipment.
Both systems designed with full redundancy to provide reliability.
Second of a two-part article published in Pharmaceutical Technology magazine in January 2006.
Part 2 describes protocol development and implementation (including advice and lessons learned), preparation of turnover packages, and the evaluation and management of deviations.
Installation of a High Purity Water and WFI system with no unplanned downtime.
Latest available technology including online monitoring Microbial Detection, Reduced water consumption with start / stop / sanitize cycles of water pretreatment equipment.
Both systems designed with full redundancy to provide reliability.
the various categories of qualifications necessary for Validating an equipment or instrument before & after installation. Those are
DQ(Design Qualification)
IQ(Installation Qualification)
OQ(Operation Qualification)
PQ(Performance Qualification)
User specification requirements (urs) rashRASHMINasare
user specification requirements, factory acceptance test, & design qualification is the part of validation it is doing because the satisfaction of the customer & full filled the user requirement
Understanding DO-178: Importance and How It Affects Your CompanyAversan Inc.
Learn DO-178: Why is it important? How can it affect your company? These questions and more will be answered in this presentation, including information regarding the purpose of DO-178, Design Assurance Levels (DAL), objectives, and integral processes.
Questions? Email bd@aversan.com for more information.
the various categories of qualifications necessary for Validating an equipment or instrument before & after installation. Those are
DQ(Design Qualification)
IQ(Installation Qualification)
OQ(Operation Qualification)
PQ(Performance Qualification)
User specification requirements (urs) rashRASHMINasare
user specification requirements, factory acceptance test, & design qualification is the part of validation it is doing because the satisfaction of the customer & full filled the user requirement
Understanding DO-178: Importance and How It Affects Your CompanyAversan Inc.
Learn DO-178: Why is it important? How can it affect your company? These questions and more will be answered in this presentation, including information regarding the purpose of DO-178, Design Assurance Levels (DAL), objectives, and integral processes.
Questions? Email bd@aversan.com for more information.
Design Controls: Building Objective Evidence and Process Architecture to Mee...April Bright
This session provides detailed examples to demonstrate what objective evidence is important to generate and use during design control compliance but, more importantly, to develop and issue a beneficial design history file meeting the requirements in 21 CFR, Part 820.30 and ISO 13485:2016. Aside from the importance of design controls for compliance, Mr. Gagliardi demonstrates how this section of the QS regulation and the ISO standard can be facilitated as a leading edge business tool.
This workshop examines the approach to Continued Process Verification and demonstrating that your product and process are operating in a state of control and continue to do so over the life of the product. Without any prior coordination, the theme was elaborated by the afternoon speakers once the conference itself was underway. The concept of “step up step down” for adjusting the level of product scrutiny both for process parameters monitoring and for sampling and testing quality attributes was explored and developed.
Qualification and Validation have big Weightage in the Regulatory Compliance and GMP. Qualification and Validation only can guarantee about the Product Safety, Integrity, Strength, Purity and Quality assurance.
A leading manufacturer of golf equipment selects MetricStream to strengthen supplier quality compliance through real-time monitoring of inspections and process capability.
M.pharm (Pharmaceutics) Modern Pharmaceutics unit- Validation Part-1 introduction, scope and merits of validation, Validation and calibration of Master plan, ICH & WHO guidelines for calibration and validation of equipment.
At some stage or other, a business enterprise feels the need to implement QA processes to standardize their operations, product delivery, and empower business solutions. Maintaining a full-fledged QA standard process is vital for a product-based environment. If a given QA standard is followed in a proper way, it leads to well-defined, user-oriented, and quality products.
Similar to Essentials of Validation Project Management - Part 1 (20)
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Novas diretrizes da OMS para os cuidados perinatais de mais qualidade
Essentials of Validation Project Management - Part 1
1. The Industry’s Authoritative Source
®
Essentials of Validation
Project Management
Part I
William Garvey
T
he qualification and validation of complex pharmaceutical
manufacturing facilities requires the careful coordination
VECTOR CORPORATION
of multiple activities. Conceptual, preliminary, and detailed
designs must be reviewed to ensure compliance with cur-
rent good manufacturing practices (CGMPs); protocol and stan-
dard operating procedure (SOP) formats must be developed; and
project resources must be identified and obtained. A validation
schedule must be created and integrated with the facility construc-
tion schedule. The Quality Assurance and Calibration–Metrology
To qualify and validate a pharmaceutical
departments must be notified of impending increased workloads.
manufacturing facility, one must carefully review
And finally, the manufacturer should alert the local US Food and
the facility design for compliance with good Drug Administration district office that a new facility is planned.
manufacturing practices and manage project Considering all these activities, careful planning and cautious man-
scope definition, labor and cost estimating, and agement will increase the likelihood of a successful project out-
come, no matter how difficult or complicated the project. Success-
master-plan development. These activities,
ful project completion is never guaranteed, but by implementing
properly implemented, help deliver a validated
proven techniques and the programs described in this article, a fa-
facility on schedule, at the estimated cost, and
vorable end-result is much more likely.
with expected quality. Parts 1 and 2 of this article will examine seven critical compo-
nents of a comprehensive validation program for new and reno-
William Garvey is Validation Consultant at
vated manufacturing facilities. The programs and procedures ex-
Millipore Corporation (Billerica, MA).
plained are appropriate for all commonly manufactured dosage
Phone: (781) 533-2407.
forms (e.g., tablets and capsules, active pharmaceutical ingredients
Email: William_garvey@millipore.com
[APIs], parenterals). Given that the design, construction, and qual-
Submitted: Aug. 16, 2005. Accepted: Sept. 9, 2005.
ification and validation of a major facility are relatively infrequent
events in most corporate life cycles, some of these project compo-
nents are not well known or understood. For this reason, Part 1 of
2. DATA AND REVIEW
this article examines the following areas:
• facility- and equipment-design review to en-
sure compliance with CGMP regulations;
• project scope definition, organization, and
planning;
• project labor requirements and budget;
• validation master plan development.
Part 2 will continue with a discussion of the
following validation-related subjects:
• protocol and SOP development, scheduling,
and implementation;
• design- and construction-document collec-
tion (turnover package);
• evaluation of deviations and discrepancies.
Facility- and equipment-design review
By definition, the construction of a new or ren-
Figure 2: Fluidized bed dryer showing
ovated facility and the purchase and installation Figure 1: Valve orientation (45 above
mechanical components requiring maintenance
horizontal) and nonchloride insulation
of mechanical equipment and process systems
located outside the process space (photo
in purified water, USP system.
constitute a project. All projects have basic, com-
courtesy of Vector Corporation).
mon features: a logical start, a logical end, and
little or no possibility of recurrence (i.e., the proj-
ect will not repeat at some future time). In addition, the design understanding of GMP-compliant design often exceeds that of
process is common to all facility projects. All facilities start with a the owner and engineer combined (2). Design reviews should
design, about which engineers, owners, scientists, and other stake- be performed using a structured and systematic approach. For
holders confer to determine how the facility will appear and op- mechanical systems such as HVAC, the evaluation of drawing
erate and what equipment and systems are needed. The usual se- sets takes precedence over most other documents. Vendor sub-
quence starts with the development of a conceptual design by an mittals always should be reviewed. Although less beneficial, Di-
engineering firm, from which preliminary decisions are made about vision 15, 22, and 23 type construction specifications (3) also
facility layout and size, utilities required, and equipment capacity should be examined, even though these are often standard with
and material of construction. The process then continues into the little customization. Checklists and other reviewing aids may
preliminary and detailed engineering stages, in which costs are fi- be valuable because they prove that the designs were evaluated
nalized and designs are completed and approved. It is at this point and they may be used again for subsequent projects.
when the conceptual design transitions to preliminary engineer- Three critical steps must be taken in a design review:
ing that formal review to verify GMP compliance begins. • identify and evaluate any potential areas or items of noncom-
In general, process equipment and utility systems affecting prod- pliance;
uct quality or contacting product are the subject of design review. • ensure that designs are modified to eliminate noncompliant fea-
Typical reviewed utilities include heating, ventilation, and air-con- tures;
ditioning (HVAC), compendial waters (e.g., water-for-injection, • prepare a brief report that summarizes the design-review process
purified water, clean steam), and compressed gases such as nitro- and obtain appropriate approvals, including quality assurance.
gen and compressed air. At present, regulatory expectations for Much of the current content in both domestic and foreign GMP
other utilities such as chilled water or plant steam are minimal, regulations is limited and nonspecific. The owner is obligated to
and these may be omitted. Design review is mandatory for highly review all designs and verify conformance with industry standards
customized or unique process equipment, particularly when the and regulatory guidelines. In the absence of standard equipment
unit is custom manufactured. Equipment for critical processes specifications within the GMPs, logic dictates that process equip-
such as aseptic filling and packaging, lyophilization, and final pu- ment and utilities must be designed to be:
Nonreactive.Materials of construction must be inert and non-
rification also requires rigorous evaluation. Because the GMP reg-
ulations are interpretive and nonspecific for equipment design and additive. Type 304 and Type 316 stainless steel are commonly
construction, the design engineer and owner are responsible for used. Hastelloy C frequently is used in reactor systems and con-
assessing compliance (1). densers. Wood should be avoided, even for utensils, because it
During the design review stage, the engineer and owner can generate unwanted particulates and is porous and difficult
should evaluate all critical specifications and drawings to en- to clean. Gaskets must withstand attack by process fluids and
sure that regulatory compliance is achieved. In general, experi- be dimensionally stable under expected temperature conditions.
enced vendors understand the requirements imposed by GMP Chloride-containing insulation should not be used with stain-
regulations and design and construct their equipment and sys- less steel components (see Figure 1).
Cleanable. Equipment surfaces must be smooth and free of voids
tems accordingly. Rarely are serious design and construction
errors uncovered because a reputable vendor’s knowledge and and crevices in which material can accumulate. Welds must be
2
3. polished smooth, although mirror polishing is not always recom-
mended where glare is a concern. Short-radius corners are pre-
ferred at joined surfaces. Threaded fittings usually are not permit-
ted on sanitary systems. Diaphragm valves must be installed on
horizontal lines at 45 angles to ensure complete drainage (see
Figure 1). Labeling and packaging equipment must be designed
to permit thorough inspection. If cut labels are used, equipment
should permit stray labels to fall to the floor unimpeded. Seam-
less floor coverings should be installed where practical because
they prevent the infiltration and exfiltration of water and con-
Figure 3: Duplex steam-trap assembly at a critical air-handling unit.
taminants from and to sublayers. Valves and flanges should be
minimized in concealed-piping runs over critical process areas
where leakage or failure could be problematic. of these standards and their application to pharmaceutical man-
Maintainable. Through-the-wall designs should be used where ufacturing are readily apparent. The 3A Sanitary Standards should
serviceable mechanical components are located outside process be consulted when equipment such as holding tanks, clean-in-
spaces (see Figure 2). Such items include HVAC air-control valves place systems, valves, and pumps are undergoing GMP compli-
and instrumentation, process filters, and operator workstations. ance review. Design errors are uncommon, however, because most
Remote grease fittings should be installed on fan bearings to min- equipment vendors already fully understand and comply with these
imize air handler entry. Adequate clearance should be allowed at standards.
heat exchangers to permit coil removal and inspection. Redun- For high-value projects and facilities intended to manufacture
dancy should always be considered for mission-critical systems, sterile products, it is often required and worthwhile to contact the
including sanitary pumps, steam traps (see Figure 3), filter assem- local FDA district office. This alerts the agency that inspections
blies and regulators, and recorders on sterilizers. Ergonomics also must be scheduled, often to coincide with critical construction
should be considered. milestones and events. FDA Office of Regulatory Affairs Field Man-
Reliable and controlled. Control systems such as programmable agement Directive (FMD) 135 also encourages manufacturers to
logic controllers (PLCs) should be used to control equipment. Au- contact FDA when facility and equipment designs are being pre-
tomation allows processes to be replicated without variability, a pared (6). The following is a summary of FMD 135, which can be
fundamental principle on which GMPs are based. Mechanical- found on FDA’s Web site:
type (cam) controllers should be avoided because regulations re- Providing [FDA] review and comment is desirable because it
quire that current and modern technology be used. Manual con- may reveal [design] defects early and prevent costly construc-
trol also should be avoided where possible because replication is tion errors which could lead to defective operations and prod-
inherently difficult. Any system that may alter batch-to-batch uni- ucts. It also affords FDA the opportunity to become aware of
formity, and ultimately the product therapeutic response, must be future work load obligations and, in some cases, new technolo-
gies. Early field involvement with new or modified facilities will
very carefully considered.
increase efficiency and result in the timely processing of appli-
Correct for application. The correct design criteria must be spec-
cations (6).
ified. For example, clean compressed air must have a dewpoint
temperature of approximately –40 F to prevent condensation. Re- Companies should understand and recognize that partnering
frigerated air driers cannot meet this requirement. Oil-free com- with FDA to review proposed designs is beneficial to both parties.
pressors should be used to exclude oil contamination unless sev- Costs and delays associated with rework can be avoided if prob-
eral levels of filtration are used (4). Industry standards allow no lems are detected early. Definitive dates for facility inspections can
more than 1 ppm (1 mg/m3) of oil/hydrocarbon in compressed air. be established, which serve as endpoints that motivate project com-
Besides developing some original standards for process equip- pletion. Current agency inspectional focus also may be apparent,
ment design and construction, the pharmaceutical industry has foretold by the types of questions that are asked. Overall, early di-
borrowed standards from industries that produce similar con- alogue and FDA involvement may expedite facility completion, re-
sumer products, most notably the dairy industry. The 3-A Sani- duce engineering and construction costs, and lead to a smooth
tary Standards are voluntary guidelines followed by dairy equip- transition from start-up to operation. These results are desirable
ment vendors and dairy operators. The standards provide material for all manufacturers, regardless of company size or complexity.
specifications, design criteria, and other necessary information for
Scope definition,organization,and planning
the construction of dairy equipment to satisfy public health con-
cerns. The ultimate objective is to safeguard public health from Successfully implemented validation projects all begin with a well-
contaminated dairy products. defined scope (i.e., the set of activities and deliverables that must
To meet this objective, 3-A Sanitary Standards and 3-A occur to complete the project). Scope definition is critical if con-
Accepted Practices ensure that dairy, food, and other microbial- tracted validation resources are used because it becomes the basis
sensitive products are protected from contamination; that all prod- for cost estimates and assessing job completion.
uct contact surfaces can be cleaned in place or easily dismantled Validation project scope definition usually begins by reviewing
for manual cleaning; and that all product contact surfaces can be the following drawings and documents (7):
easily inspected to confirm cleaning effectiveness (5). The purpose • air-flow diagrams (see Figure 4);
3
4. Table I: Estimated labor hours for commissioning and qualification.
Protocol Standard operating
Commissioning Protocol preparation execution procedures
Final
System Doc. rev. Procedure Implement Doc. rev. IQ OQ IQ OQ Oper. Clean. Mainten.
Reports
Utilities
Cold glycol 2 16 20
Hot glycol 2 16 20
Steam (50 lb.) 2 16 20
Instrument air 2 16 20
Process water 2 16 24 20 16 16 16 16
Nitrogen (50 PSIG) 2 16 24 20 16 16 16 16
Chilled water 2 16 20
Tempered glycol 2 16 20
Breathing air 2 16 20
Scrubber 2 16 20
Tempered water 2 16 20
HVAC 2 24 40 32 40 20 16 16
Vacuum pump LP2 2 16 20
Vacuum pump LP4 2 8 20
Subtotal 22 168 220 6 56 88 72 72 52 48 0 48
Process equipment
T-4000 mix tank 2 16 16 24 24 16 16 16 12
Mixing vessel (T-501) 2 16 16 20 16 16 16 16 12
Mixing vessel (T-502) 2 8 8 20 16 16
T-500 reactor 2 24 24 24 24 16 16 16 16
T-504 receiver 2 16 16 20 16 16 16 16 16
T-1003 mix tank 2 8 8 20 16 16
Transfer panel system 2 16 16 24 20 12 16 16 16
Walk-in hood 2 16 20 24 24 16 16 16 16
Subtotal 16 120 124 176 156 124 96 96 88
Total 22 168 220 22 176 212 248 228 176 144 96 136
Grand total 1848
Abbreviations: Doc. rev. is document collection and review; IQ is installation qualification; OQ is operational qualification; Oper. is operation;
Clean. is cleaning; and Mainten. is maintenance.
• piping and instrumentation diagrams; qualification. Column headings and subheadings usually consist
• utility-flow diagrams; of the following:
• equipment lists. • document collection and review (to develop protocols and SOPs);
These four types of documents are common and essential to • calibration and metrology;
all validation projects, although the level of detail and content • protocol preparation (installation qualification [IQ], operational
may vary. Design-document quality is usually closely associated qualification [OQ], performance qualification [PQ], and clean-
with cost; the greater the upfront engineering costs, the more ing);
detail that can be found in drawings and lists. Because facility • protocol execution (IQ, OQ, PQ, and cleaning);
construction and protocol preparation require drawings that are • final reports;
detailed, accurate, and thoroughly checked, increased funding • turnover packages (contain construction test reports, as-built
for engineering services is usually money well spent. In general, drawings);
one can expect that the cost of facility-design services will be ap- • SOPs (operation, maintenance, cleaning).
proximately 10–12% of the facility’s total installed cost. A checkmark is placed in each cell for which a specific activity
It is useful to identify project activities on a spreadsheet when is required. This checkmark may be replaced eventually with the
establishing project scope. Systems and equipment requiring name of the individual responsible for the activity. Assigning labor
qualification and validation are first determined by reviewing the hours to each checkmark is even more useful because this provides
project documents described previously. Then, the spreadsheet an estimate of the labor required for each activity and for the en-
is created and the first column is reserved for each identified sys- tire project (see Table I).
tem and piece of equipment. Adjacent columns become a ma-
trix of activities necessary to complete system and equipment
4
5. Figure 4: Typical air-flow diagram for an API facility.
Project labor requirements and budgeting thus requiring that outside validation services be contracted. As-
By revising the spreadsheet to include labor hours, and then total- signing a dollar amount (e.g., $75) to each hour of labor provides
ing each row and column, a project labor estimate per activity and an estimate of validation project costs, which often is used to jus-
system can be derived (7). Dividing total project hours by 2080 tify requests for financial resources and to support the annual budg-
h/year provides an estimate of personnel required to complete all eting process.
activities. Total project headcount will vary depending on project Industry experience has shown that validation costs (excluding
duration, however. Anticipating the number of labor hours is im- commissioning and process validation) typically range from 2.5–5%
portant because the labor involved may exceed available resources, of the total installed cost of the facility. Aseptic-filling and biotech-
5
6. DATA AND REVIEW
nology facilities frequently have the highest validation cost, whereas portation into corresponding protocols);
API facilities tend to be the least expensive. Care must be taken not • preliminary acceptance criteria (for each system and piece of
to apply these guidelines too tightly because the percentage vali- equipment);
dation cost will vary with project size. As an example, the purchase • SOP listing;
and installation of a small steam sterilizer might have a total in- • other GMP-required activities (document control, training, en-
stalled cost of $150,000; however, the validation costs may exceed vironmental monitoring, and so forth);
$50,000 (33%), when protocol preparation and implementation, • drawings, particularly facility layouts, piping and instrumenta-
SOP development, and laboratory supplies are considered. tion diagrams, and air-flow diagrams.
On validation projects, personnel are often subdivided into If possible, special or unique features should be emphasized
teams, with one team preparing SOPs, another team preparing in the master plan, especially those that ensure product unifor-
protocols, and so forth. Alternately, one person may be assigned mity or the elimination of contamination and cross-contami-
to a specific system, taking full responsibility for protocol and SOP nation. These features might include a description of extract
preparation, implementation, and final-report development. The booths, personnel showers, and isolators used during toxic ma-
spreadsheet described previously helps with this decision. Either terials processing. Room air-change rates, personnel gowning
method is satisfactory, but the one chosen must account for per- practices, and decontamination with formaldehyde or vapor-
sonnel availability and future operational needs. Often, contrac- ized hydrogen peroxide also are worth mentioning. It is impor-
tors are employed to prepare protocols and SOPs only, while im- tant to convey quality and attention to detail in the master plan
plementation is reserved for company personnel. This approach because this document is approved by the Quality Assurance
has several benefits. First, the contractor travel expenses are min- department and often is reviewed by FDA.
imized because all document development can occur in the con- Other programs to describe in the validation master plan are
tractor’s home office. Second, protocol implementation is per- the facility revalidation program, turnover package develop-
formed by those who will ultimately operate and maintain the ment, and system or equipment commissioning. With the pub-
validated equipment and systems. This process may reduce the lication of the International Society for Pharmaceutical Engi-
transition time from start-up to manufacturing, and if properly neering’s Baseline Pharmaceutical Engineering Guide:
documented, can satisfy GMP training requirements. Commissioning and Qualification in March 2001, greater em-
phasis has been placed on system and equipment commission-
Validation master plan development ing (8). Until recently, commissioning was an activity often per-
The validation master plan complements the project scope. Al- formed without any involvement of quality assurance or
though master plans are not officially required by some regulatory validation personnel. The construction team or an agent hired
agencies, these documents may be submitted to FDA as part of the by the project manager usually performed system commission-
preoperational review program (FMD 135) discussed previously. ing. Commissioning documents were often prepared and exe-
Master plans typically describe the project scope in detail and in- cuted without any review or oversight by the Quality Assurance
clude preliminary validation acceptance criteria. They also con- department. In many instances, validation often repeated com-
tain a description of all programs that collectively make the facil- mon commissioning tests and verifications, thereby increasing
ity GMP compliant. A well-conceived and well-written master plan costs and creating inefficiencies. In addition, systems often were
reduces the likelihood that a critical activity or program will be commissioned and validated where commissioning would have
omitted and provides regulators with a sense that the company is satisfied operational requirements. It is worthwhile to identify
quality-minded and operating in a state of control. and describe the interaction between commissioning and val-
Once the project scope is determined and reduced to spread- idation in the master plan. The plan may include a description
sheet format, the spreadsheet may be imported into the draft val- of required commissioning documents and how they support
idation master plan. Master plans usually are focused on project the validation effort. In general, systems that have no product
deliverables, not costs. Therefore, estimated costs and labor hours contact are good candidates for commissioning only, although
do not need to be presented. There is no standard format for val- there are occasional exceptions to this rule.
idation master plans, although the concept has evolved so that The facility revalidation program also should be described in
many features are standard from company to company. Each mas- the master plan because the validation life cycle continues long
ter plan is an analysis and evaluation of a manufacturing facility’s after the facility is mechanically complete and handed over for op-
validation and compliance requirements. Typical master plan con- eration. Revalidation usually takes two forms: time or event based
tents include the following: (9). Time-based revalidation is the practice in which a system or
• approval page (quality-assurance approval is required); process is recertified at a specified interval. Time-based assessments
• introduction and facility description; also can include a review of historical system performance data.
• project organizational chart (optional); Event-based revalidation is implemented whenever physical or op-
• descriptions of component and material storage areas, produc- erational changes are made to the system outside the scope of the
tion areas, quality assurance areas, critical utility systems (HVAC, original validation. All such modifications are the subject of the
purified water, water-for-injection, building management sys- facility’s change control program, which also should be described
tem); in detail in the master plan.
• spreadsheet (described previously); Turnover package (TOP) development also can be described
• system and equipment descriptions (in sufficient detail for im- in the master plan. Turnover package is a system for organiz-
6