USP 797/800 Cleanroom Compliance by Terra Universal
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Understand the scope and compliance costs of the most recent CGMP standards and USP guidelines for cleanroom design and operation! Webinar topics covered by our industry-expert speakers include DQSA compliance, designing for USP 800 hazardous drug compounding, and cleanroom cost estimating. Industry experts Will summarize the revised regulations and what theymean for pharmacy cleanrooms. Registrants Will receive Terra Universal's white paper "Designing your compounding Cleanroom for USP/cGMP Compliance." Speakers Dr. Chris Munoz, PharmD and Principle Consultant at ITL Consulting and teaches pharmacy compounding at the University of Southern California (USC) School of Pharmacy, and serves on the California Pharmacists Association's Policy Committee and Board of Directors. Following Chris's earlier work in compounding pharmacies and for pharmaceutical companies, he began a consulting firm specializing in the business of, and regulatory affairs for, pharmacy compounding. Dr. Jesse Martinez, PharmD, FASCP and Vice Dean of the College of Pharmacy, Western University of Heath Sciences Dr. Jesse Martinez has 37 years Of experience in compounding, sterile and non-sterile pharmacy operations and administration, and research. He has served on local, state and national pharmacy associations and currently teaches fourth-year pharmacy students in advanced Classes that include pharmacist-in-charge training. Jesse consults for the pharmacy industry and is a recognized expert in USP 795, 797 and 300 compliance. For More Information Please visit http://www.terrauniversal.com/public/webinar-information-and-downloads.php http://www.terrauniversal.com/cleanrooms/modular-clean-rooms-x.php
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USP 797/800 Cleanroom Compliance by Terra Universal
- 1. Compounding Pharmacy Cleanroom Design for USP/FDA Compliance Chris Munoz, PharmD
- 2. Why Are We Here Today? 1
- 3. New England Compounding Center 2
- 5. The Hard Facts About the DQSA 4
- 6. 5
- 10. 9
- 12. 11
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- 24. Quick Recap Before We Move On to USP 23
- 25. State Oversight: USP <797> (Under Revision) 24
- 31. Compounding Cleanroom Design Mike Buckwalter Terra Universal, Inc.
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- 33. Allowable airborne particulates, by cubic meter*: *For ISO 1 through 6, this list refers to quantities of 0.3 micron-sized particles allowed in a controlled environment, and for ISO 7 through 9, it refers to 0.5 micron-sized particles. Source: ISO 14644-1 Particles: ISO level limits ISO Level Particle Count 1 Less than 10 2 10 3 103 4 1,020 5 10,200 6 102,000 7 352,000 8 3,520,000 9 35,200,000 FYI: A cubic meter of typical room air contains ± 52 million 0.3-0.5 micron particles. 33 Particle Counter
- 34. • Uni-directional air flow controls contaminants more effectively than uncontrolled, multi-directional air flow • Turbulence stirs-up particles • Fan/filter units force air through filters in a laminar fashion • FFUs also provide uniform air speed with proper control system • Presence of furnishings, equipment and personnel interrupts laminarity; air hits surfaces and bounces • Rapid movements create turbulence Laminar vs Turbulent Air Flow 34
- 35. Air movement promotes cleanliness. Filtered air sweeps particles toward the floor and exhaust vents. Air exchange rates shown here are IEST* recommendations but are occasionally revised downward: high ACR velocity can create unwanted turbulence. USP specifies 30 ACPH for ISO7. Air Changes Per Hour (ACPH) ISO Level Recommended ACR Ceiling FFU Coverage 1-2 360 – 600/hr 80 – 100% 3 360 – 540/hr 60 – 100% 4 300 – 640/hr 50 – 90% 5 240 – 480/hr 35 – 70% 6 150 – 240/hr 25 – 40% 7 60 – 90/hr 15 – 20% 8 5 – 48/hr 5 – 15% 9 less than 5 – 48/hr Less than 5% ISO recommendations: Range dependent upon variables like room design and access frequency. 35 FYI: Air change rates in an air-conditioned house average about one(1) per hour. *Institute of Environmental Sciences and Technology
- 36. Calculate with this formula: No. of FFUs = (Air Changes per Hour ⁄ 60) × (Cubic feet in room ⁄ 650*) *Refers to the cubic feet/minute (CFM) of a typical 2 x 4 loaded FFU at medium speed.′ ′ Example of a 10’ x 10’ x 10’ ISO 7 room: 60 – 90 ACH is required, therefore, you need 2-3 FFUs. Calculations: • (60/60) x (1000/650) = 1.54 • (90/60) x (1000/650) = 2.31 Discussion: An ISO 7 room is more forgiving than (for example) ISO 5, however the 10-foot ceiling warrants a rounding up of the calculation fractions. Air Change Rate: FFU coverage 36
- 37. • Moving (vs. stagnant) air = a cleaner environment • Too forceful = unnecessary turbulence • Consider room design: choose the higher end of the range to account for a higher ceiling (greater travel distance), for example Airflow Design Basics ISO Level Air Speed* 1-2 0.305 – 0.508 (60 – 100) 3 0.305 – 0.457 (60 – 90) 4 0.254 – 0.457 (50 – 90) 5 0.203 – 0.406 (40 – 80) 6 0.127 – 0.203 (25 – 40) 7 0.051 – 0.076 (10 – 15) 8 0.005 – 0.041 (1 – 8) 9 < 0.005 – 0.041 (1 – 8) *Expressed as meters/second (m/s). Within parentheses are feet/minute (f/m). (Source: IEST) 37
- 38. Factors that can influence air speed (velocity), air changes rates, fan/filter coverage, turbulence and air balancing: • Personnel: quantity, speed and movement patterns • Equipment: quantity, energy consumption and exhaust • Vents and Plenums: location, quantity • Ceiling height • Entryways: types, quantity • Ducting: type, size, direction • Floor plan/number of rooms • Air handling systems/HVAC Room Variables 38
- 39. • Forces air out of a room • Referred to as an “isolation” enclosure • Control systems and/or adjustable air vents control positive pressure • Protects samples, not external environment (leaks are relatively unimportant) • Softwall cleanrooms won’t maintain pressure • Air can be recirculated to extend filter life • Pressure requirement: typically 0.025 - 0.05” water column (WC) differential between rated and unrated space or between rooms of differing ISO ratings • Measure & log room pressure and differentials Pressure: Positive (USP-797) 39 ®Dwyer Instruments, Inc.
- 40. Pressure: Negative (USP-800) 40 • Exhaust system removes more air than enters room (min. 0.01” WC negative pressure) • Referred to as a “containment” enclosure • Exhaust air fed to dedicated in-house removal system; may require “scrubbing” to remove biohazards • Leaks allow particle ingress; walls must be sealed • Protects people outside the room from bio-hazards • Air enters through HEPA floor louvers or ceiling HEPA filters; recirculation generally not permitted • Requires appropriate ducting system tied to in-house exhaust system • 0.025” - 0.05” water column (WC) pressure difference between rooms of differing ISO ratings Laminar-flow cleanroom
- 45. Temperature & Humidity 45 Temperature: usually 5 - 10°F below ambient level to offset heat-generating equipment and provide comfort for garbed technicians Relative Humidity (RH): Usually 40 - 60%, but is dependent upon application/industry. Low RH invites static electricity (ESD); high RH provides environment for micro-organisms to flourish
- 47. Summary: Cost Considerations 47 Modular Cleanrooms: Reduce cost and installation schedule compared to brick-and- mortar rooms – USP 797 designs begin around $15,000. FFUs can be added for nominal cost if requirements change. Exhaust Air (503B and non-sterile-to-sterile compounding): Requires additional expense of air exhaust ducting and ceiling centrifugal exhaust fan, typically installed by a local contractor Air Conditioning: To keep control costs, use existing facility HVAC system. Supplemental A/C modules add cost and potentially fresh make-up air supply Certification: Automated control system adds up-front cost (but typically only 10- 20% of room cost) but simplifies and speeds up certification, saving in long-term expenses, as well as controlled operation expenses Energy: Upgrade to ECM fan/filter units to increase energy efficiency and comply with local energy requirements (e.g., California’s Title 24)
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- 51. • Enclosed, controlled space; may serve as the ISO 5 primary engineering control (PEC) inside an ISO 7 secondary engineering control (SEC) cleanroom • Filtered, laminar airflow • Material compatibility • Controls: Particle filtration, pressure, sterilization, temperature, static neutralization • USP designs: - Compounding Aseptic Isolator (CAI): protects sample (no containment) - Compounding Aseptic Containment Isolator (CACI): protects sample and operator (for hazardous drug compounding) Isolators (Glove Boxes) 51
- 52. • AKA “clean bench” or “laminar-flow cabinet” • Horizontal or vertical laminar flow • Positive pressure • Compatible materials: - Acrylic: economical; damaged by IPA - Static-dissipative PVC eliminates ESD* - Polypropylene: resists damage from chemicals - Powder-coated steel: strong, damage-resistant - Stainless steel: strong, resists cleaner & solvent damage • Controls: ionizing bars (neutralizes static), UV sterilization (disinfects), differential pressure gauges, air-speed gauge • Specialty designs: PCR, IV rods, explosion-proof, perforated surfaces Laminar Flow Hoods 52 *Electro-static discharge
- 53. Negative-pressure containment hoods; filtered exhaust removes pathogens (but not vapors). CDC/NSF classifications: Class I: partial containment protects personnel but not the product Class II: protects personnel and the product Biological Safety Cabinets 53 Class II Type Characteristics A1 min. air velocity of 75 fpm; low to moderate risk; 30% exhausted air into lab A2 min. air velocity of 100 fpm; low to moderate risk; exhaust into lab; some negative pressure B1 min. air velocity of 100 fpm; hard-ducted, moderate risk with some volatile chemicals or radionuclides; 70% exhausted air out of lab B2 min. air velocity of 100 fpm; low to moderate risk with some volatile chemicals or radionuclides; 100% exhausted air out of lab Class II A2 BSC Class III: Maximum containment for highest-risk pathogens; small amounts of volatile toxic chemicals or radionuclides. Filtered exhaust and make-up air. This cabinet is a glovebox, not a hood
- 54. • Purpose: exhausts fumes to ducting system • Negative pressure • Baffling system ensures no air escape (“second- pass air”) at the operator interface • Not ISO rated • Ductless designs incorporate carbon filters to allow in-door air release Fume Hood 54
- 55. • Interlocked doors prevent cross- contamination • Smooth, chemical-resistant internal surfaces (electropolished SS) • Isolated electronic interlock • Optional Air Shower minimizes particle ingress • Security features include biometric readers, logged access, wireless remote access control Transfer Options: Pass-Throughs 55
- 56. Open Q&A Session • During the webinar, please submit questions to us through the Q&A chat box within your interface • After the webinar has ended, please direct all questions to evan@TerraUniversal.com • Each participant will receive an email in the coming days containing a link to the video recording of this webinar and a PDF copy of Terra Universal’s white paper on the impact of shifting USP/FDA regulations on pharmacy cleanroom design • To contact Terra Universal directly, call 714-578-6000 56
Editor's Notes
- [Presenter introductions]
- We’re here today because the business of pharmaceutical compounding is being held to much higher standards than in years past, in regards to both the facilities and the processes of production. This push for higher standards came about due to the unfortunate events in 2012…
- Most of us have already heard the details surrounding the a fungal meningitis outbreak that was a result of contaminated injectables compounded by the New England Compounding Center. We won’t go into detail in consideration of our time. In short, over 60 people were killed, the public was outraged, and the political backlash resulted in a complete overhaul of the regulatory landscape-both federally and locally-at the state level that is.
- So today, our focus will be on these regulations that are now in play. You are all probably familiar, in a general sense, with the Drug Quality and Security Act (DQSA), cGMPs, USP 797 and 800, but you may not be as familiar with how these affect your pharmacy and its operations. We are going to examine how these new and revised regulations affect specifically your facility’s requirements, whether you’re compounding sterile medications or hazardous drugs, or both. We expect this presentation will help you to save you much wasted time and frustration in the comprehension and implementation of these regulations, because we’re going to walk you through the key highlights of each regulatory document, step-by-step, so that you can put the different pieces together in order to see the big picture. By the end of this presentation, you should be able to make better, more informed decisions when setting up or making changes to your compounding facility and operations. Rather than providing you with bullet points of information, we’re going to take you through some highlights of the actual documents where these regulations are found. You’re going to see the exact language used by the FDA and USP, in black and white (with a little bit of highlighter). Each of these documents are publicly available online, at each organization’s website. We can even provide attendees with each of the links to all of this information. But for the purpose of this presentation you will not need immediate access to them. Let’s begin with the DQSA
- Our discussion begins at the federal level, where in 2013 Congress worked across party lines to pass into law regulations that define a new category of compounding pharmacies called outsourcing facilities, and also grant the FDA the oversight of these facilities under Section 503B of the FDCA. Let’s take a quick look at a key meeting where implementation of the DQSA was discussed among the FDA and representative of state boards of pharmacy.
- Quick history lesson: These are the minutes from the 2014 Intergovernmental working meeting on pharmacy compounding, hosted by the FDA and attended by representatives from the State Boards of Pharmacy. At the bottom, they acknowledge the passage of the Drug Quality and Security Act, which you’ll notice mentions both state and FEDERAL oversight of compounded human drugs.
- In regard to oversight, they refer to section 503A, which has historically exempted pharmaceutical compounders from the regulations intended for pharmaceutical manufacturers, which are current good manufacturing practices, or cGMPs. This is nothing new, but rather an inclusion for the sake of completion given the history of pharmacy compounding. However this will be important as we move forward in our discussion.
- The new section which the DQSA added into law is section 503B, which gives the FDA the authority to regulate outsourcing facilities. In this definition, an outsourcing facility is a compounding pharmacy who either actively elects to register as such, or who does not fit the definition of the “traditional compounder” as described in section 503B. Outsourcing facilities will be expected to follow cGMP for sterile drug products while under federal oversight which means guaranteed FDA inspections according to these standards.
- So what are the current Good Manufacturing Practices that outsourcing facilities are expected to follow?
- A few months after this meeting, in July 2014, the FDA published a draft Guidance document that would generally explain their expectations of outsourcing facilities.
- In a recent draft guidance document, the FDA announced their expectations for outsourcing facilities. The key point to understand about this draft guidance is these documents are simply the EXPECTATIONS of the FDA during the interim period until they write a more definitive guidance document. This is important because, as you may know, the FDA has already started inspecting registered 503B Outsourcing Facilities according to cGMP standards and have cited the relevant sections in 21 CFR as well as specific violations pertaining to sterile and aseptic manipulations. Details on these inspection reports can be found on the FDA website under the Form 483s.
- Given that we are here to talk about the specific requirements for facilities, let’s take a look at what this guidance document specifies. The FDA’s goal for their oversight is to prevent contamination of compounded sterile medications. Throughout the document , you will see much emphasis on cleanliness and ISO classifications, which refer to the particle counts within a cleanroom. The lower the particle counts, the cleaner the air within the room. You will notice the ISO 5 rating is prominently featured in most of their recommendations. This is the minimum acceptable level of air purity where manipulations of sterile drug products must take place. This is usually achieved with a laminar air flow hood that can be certified to meet these specifications. In other cases, companies will opt to have the entire room or sections of the room certified to ISO 5 level purity. This is done by increasing the number of air changes per unit time with HEPA filters. Most modular facilities can be expanded to add room for an ISO 5 laminar air flow hood, or if an expansion is not possible, the ceiling tiles can be removed and HEPA filter units can be inserted to add greater filtration to the circulating air.
- If you are an outsourcing facility, you can undoubtedly expect the FDA to be observing your facilities and watching for any exposure of the sterile materials to anything less than ISO 5 conditions. That said, the facility will need to be carefully designed include the ISO 5 critical environment with respect to operational size and scope. We will go more into depth on design further on. Now, there are more detailed operational considerations for cGMP that can be found in older FDA documents pertaining to pharmaceutical manufacturers, but this is where the emphasis has been both on paper and during inspections with regard to facility.
- This draft guidance for outsourcing facilities we just looked at was released in 2014. As we move through this presentation chronologically, let’s take a look at more recent developments in the implementation of the DQSA.
- In March of this year, the FDA held a third intergovernmental working meeting, with the main purpose of harmonizing their enforcement efforts with those of the State Boards of Pharmacy.
- The main disconnect between the FDA and the State Boards of Pharmacy is that the FDA has moved forward very aggressively to enforce the standards indicated in cGMPs, whereas states have passed new laws for compounding, but still lack the resources and knowledge to inspect outsourcing facilities within their borders. The states have said they can not rely exclusively on the inspections of the FDA for outsourcing facilities because their standards lack the enforcement of state-specific law such as tech ratios. Because each state’s laws and resources significantly vary across the US, increased importance is placed on communication between state and federal authorities.
- Both the FDA and the State Boards recognize that there is a lack of harmony in their enforcement practices, and so essentially they’ve resolved to work together on smoothing out this regulatory overlap. As you can see at the bottom of this page, one method of accomplishing this is through cooperation on joint (or simultaneous) inspections. And who wouldn’t want a joint inspection? It’s just so much more convenient and efficient to have a whole TEAM of inspectors show up on your doorstep one day. Not surprisingly, this is something that is already being seen here in California. So far, we have primarily framed this discussion around outsourcing facilities, and you might be thinking that 503B outsourcing facilities have it rough. But the truth is there’s more to the story…
- Let’s now talk about the other half of the DQSA….the 503A, traditional compounding, also known as “everyone who is not an outsourcing facility”.
- Back in June of this year, the ASHP released a set of guidelines on pharmacy management that included a section on outsourcing facilities.
- Along with their recommendations for choosing appropriate outsourcing facilities, the ASHP gave an especially timely warning regarding 503A compounding pharmacies. They took note of the fact that if the FDA has the authority to regulate pharmacies under section 503B, then why wouldn’t they also have the power to inspect and regulate section 503A traditional pharmacies?
- Well, along came the FDA’s final guidance document aimed at section 503A compounding pharmacies, which was just published on the FDA’s website this past month.
- And right away, on page 3, the FDA makes it very clear that although they expect the State Boards of Pharmacy to take the lead on regulating any non-outsourcing facilities, they still retain the authority to enforce the provisions of the FD&C Act through inspections of 503A pharmacies. On a side note, you might be a little confused by the phrase at the top of the page which stipulates that these are “nonbinding recommendations”…
- We would argue, however, that if you look closely, these “nonbinding recommendations” are littered with references to 21 CFR and all of the various sections that are definitively written into law. Not only that, but these “recommendations” specifically outline each of the possible enforcement actions that the FDA can initiate against violators of the FD&C Act. You should also note the language used towards the bottom, where the FDA defines the possible violations using very broad, subjective terms such as “insanitary conditions” and “may have been rendered injurious to health.” This grants the FDA a huge amount of discretion in its inspections and leaves very little wiggle room for compounding pharmacy found to have any violations.
- So, for a quick recap, to frame everything properly in your mind, we now know that the FDA has the power to inspect both 503A and 503B compounding pharmacies, the question is not “if” but “when will the FDA show up?” And although the stricter standards of cGMP will only be enforced with outsourcing facilities, we know that the FDA has very flexible powers and a lot of discretion in how they define violations in 503A traditional pharmacies.
- So now we can compare the FDA’s standards with those at the state level. Since the publishing of USP 797 in 2004, the State Boards of Pharmacy have adopted the USP standards to some extent, but as we’ve seen from the intergovernmental working meetings, the FDA and state inspectors have not yet reached a common ground in terms of their enforcement practices. In an effort to “catch up” with the stricter federal regulations and create a definitive , USP is close to completing an overhaul of USP 797, which includes breaking out the section on hazardous drugs into a separate set of guidelines, called USP 800. For our purposes, we’re going to focus on the changes that affect facilities and equipment.
- This is the current draft of the updated USP 797, as posted on the USP website for public commentary. USP has completely reorganized the chapter and has also changed how they classify the risk-level for CSPs. The new classifications are Category 1 and Category 2, which as you can see, determines the Beyond-Use-Date based on whether or not it was compounded under cleanroom conditions. The key takeaway from this proposed revision is that the new Category 2 CSPs must be prepared in a cleanroom environment. Without an ISO-classified cleanroom, the Beyond-Use-Dates of all CSPs will be restricted to a maximum of 12 hours at room temperature or 24 hours in a refrigerator. You will also notice that they have removed all references in USP 797 to Hazardous Drugs and instead refer to USP 800.
- The draft version of USP 800 has been posted on the USP website in its current form since October of last year, so we’re going to assume that most of us are somewhat familiar with its provisions and we’ll just address the areas of major concern.
- From the get-go, we can already see that this draft version of USP 800 will have to undergo another revision, because they’re still using the low-, medium-, and high-risk categories rather than the new Category 1 and Category 2 classifications for CSPs. The timeline for finalizing USP 797 and 800 was already hazy, but with the both of these documents still undergoing public commentary, its very difficult to predict when these documents will become enforceable. The best approach that we can take in the meantime is to focus on the main concepts and clarifications that are unlikely to change with a revision of the language. In this case, we should take note of the elimination of a major exception for low-volume HD compounding. USP is making it clear that all hazardous drug compounding must take place in a negative pressure room, whether it is a cleanroom or a segregated compounding area.
- To further complicate matters, hazardous drugs will also need a dedicated, negative-pressure storage area (with a couple exceptions). You can see the specific storage exceptions in the first highlighted section on lines 124 and 125. The language here is very specific, so we think it’s unlikely to change significantly in any final revisions. At this point, though, we are still waiting for their response to the public comment period which just ended on May 31st. Among the experts who have actually participated in USP’s revision process, the consensus is that the final version of USP 800 will not be much different from this draft, except for the change in classifications that we noted above.
- To be safe, if you’re planning on compounding hazardous drugs, you should definitely make sure that you can install the ventilation system that will be able to achieve negative pressure in both the compounding room AND in your biological safety cabinet, as well as the negative pressure storage room. All of this negative pressure ventilation also has to be drawn through a HEPA filter before it is vented to the outside air, which can definitely pose an engineering challenge.