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- 1. A cGMP PrimerA cGMP Primer Chet French October 2011
- 2. A cGMP Primer Chet French Oct 2011 A cGMP Primer Agenda What is cGMP?What is cGMP? Basic PrinciplesBasic Principles ImplicationsImplications Drug Regulation HistoryDrug Regulation History The FDAThe FDA Inspectional MethodologyInspectional Methodology cGMP SubpartscGMP Subparts SummarySummary
- 3. A cGMP Primer Chet French Oct 2011 3 Regulations; properly applied confer benefits and protections Nuclear Power Airlines Utilities Construction Banking Minerals & Mining Pharmaceuticals Regulated Industries
- 4. A cGMP Primer Chet French Oct 2011 4 cGMP RegulationscGMP Regulations 21CFR 210 & 21121CFR 210 & 211 Proposed RegulationsProposed Regulations FDA GuidelinesFDA Guidelines Inspectional FindingsInspectional Findings Best Practices –Best Practices – feasiblefeasible andand valuablevaluable Changing Technology/TragediesChanging Technology/Tragedies Articles and Presentations by FDA personnelArticles and Presentations by FDA personnel ICH DocumentsICH Documents Drug Regulations How Do We Know the Rules?
- 5. A cGMP Primer Chet French Oct 2011 The cGMPs 21CFR Parts 210 & 211 What are the cGMPs?What are the cGMPs? A: General ProvisionsA: General Provisions B: Organization & PersonnelB: Organization & Personnel C: Buildings and FacilitiesC: Buildings and Facilities D: EquipmentD: Equipment E: Control of ComponentsE: Control of Components F: Production and Process ControlsF: Production and Process Controls G: Packaging & LabelingG: Packaging & Labeling H: Holding & DistributionH: Holding & Distribution I: Laboratory ControlsI: Laboratory Controls J: Records & ReportsJ: Records & Reports K: Returned & Salvaged Drug ProductsK: Returned & Salvaged Drug Products Federal laws Often ambiguous Establish minimum requirements
- 6. A cGMP Primer Chet French Oct 2011 Drug Regulation History Patent Medicines 19th Century
- 7. A cGMP Primer Chet French Oct 2011 Drug Regulation History Food & Drug Act 1906 ““The Jungle”The Jungle” by Upton Sinclairby Upton Sinclair The Food and Drug Act (1906)The Food and Drug Act (1906) Establishment of the FDAEstablishment of the FDA Prohibited interstate commerce in misbrandedProhibited interstate commerce in misbranded and adulterated foods, drinks, and drugsand adulterated foods, drinks, and drugs
- 8. A cGMP Primer Chet French Oct 2011 Drug Regulation History Formularies 1920’s
- 9. A cGMP Primer Chet French Oct 2011 Drug Regulation History Elixir of Sulfanilamide Tragedy 1937 Sulfa drugs were a commoditySulfa drugs were a commodity Introduction of a liquid syrup to differentiate productIntroduction of a liquid syrup to differentiate product UsedUsed diethylene glycoldiethylene glycol as solventas solvent 240 gallons produced and sold240 gallons produced and sold 107 Deaths;107 Deaths; SuicideSuicide of chemistof chemist
- 10. A cGMP Primer Chet French Oct 2011 Drug Regulation History Federal Food Drug and Cosmetics Act of 1938 Must demonstrate scientific proof that new products could beMust demonstrate scientific proof that new products could be safelysafely used before putting them on the market.used before putting them on the market. Proof of fraudProof of fraud no longer requiredno longer required to stop false claims forto stop false claims for drugs.drugs. Addition of poisonous substances to foods wasAddition of poisonous substances to foods was prohibitedprohibited except where unavoidable in production.except where unavoidable in production. Specific authority conferred forSpecific authority conferred for conducting inspections.conducting inspections. Federal court injunctions againstFederal court injunctions against violations were added to the previousviolations were added to the previous legal remedies oflegal remedies of product seizuresproduct seizures andand criminal prosecutionscriminal prosecutions..
- 11. A cGMP Primer Chet French Oct 2011 Drug Regulation History Thalidomide Tragedy 1961 Thalidomide Severe Teratogenic Properties 5,000 Pregnant women ~3,000 affected children
- 12. A cGMP Primer Chet French Oct 2011 Drug Regulation History Kefauver Hearings 1960 - 1962 Regulation AmendmentsRegulation Amendments Tightened control overTightened control over prescription drugsprescription drugs SafeSafe and effectiveand effective Adverse reaction reportingAdverse reaction reporting BenefitsBenefits and risksand risks Label changesLabel changes Ernst KefauverErnst Kefauver
- 13. Drug Regulation History Tylenol Poisoning & Recall 1982 “Raising the Bar” Tamper-proof packaging
- 14. A cGMP Primer Chet French Oct 2011 Drug Regulation History Barr Laboratories 1993 Supreme Court Decision 1993Supreme Court Decision 1993 Failure InvestigationsFailure Investigations Process ValidationProcess Validation Quality must be built into the product/process
- 15. A cGMP Primer Chet French Oct 2011 Drug Regulation History PDUFA 1997 Prescription Drug User Fee Act (1997)Prescription Drug User Fee Act (1997) Reduced the legal standard for new drug reviewsReduced the legal standard for new drug reviews Reauthorized user feesReauthorized user fees Fee for ApplicationFee for Application Fee for EstablishmentsFee for Establishments Renewal Fee for ProductsRenewal Fee for Products Promotion of drugs forPromotion of drugs for “off label” use“off label” use
- 16. A cGMP Primer Chet French Oct 2011 Mission: “Protect the Public” An enforcement agency Enforces the Federal Food Drug and Cosmetic Act of 1938 Determines the state of compliance by conducting site inspections Food Drugs Medical Devices Animal Feed Cosmetics Annual Commerce = $1,000,000,000,000+ Under Fire for Unsafe Drug Approvals* Inspections Behind Schedule Resource Constraints - High Staff Turnover *Outlook: Likely much greater safety vigilance *Source: Institute of Medicine Report 2006 $350 BL $102 BL $487 BL $39 BL The Food & Drug AdministrationThe Food & Drug Administration
- 17. A cGMP Primer Chet French Oct 2011 The Regulatory Environment Drug Safety Under Scrutiny VIOXX® (Acute Pain) Heart Attack Stroke MERIDIA® (Obesity) Heart Failure Renal Failure BEXTRA® (Arthritis) Heart Attack Stroke Stevens Johnson Syndrome AVANDIA® (Diabetes) Heart Attack TYSABRI® (MS) PML
- 18. A cGMP Primer Chet French Oct 2011 Drug Regulation Safety Data – Risks vs. Benefits Safety Data Collected ? Identified RisksIdentified Risks ClinicalClinical ApprovalApproval Do theDo the RisksRisks Outweigh theOutweigh the BenefitsBenefits?? Cumulative SafetyProfile
- 19. A cGMP Primer Chet French Oct 2011 What Clinical TrialsWhat Clinical Trials Do WellDo Well Determine with some certainty that the product isDetermine with some certainty that the product is effectiveeffective andand that thethat the common serious adverse events are identifiedcommon serious adverse events are identified LimitationsLimitations of Clinical Trialsof Clinical Trials Seldom more than 3,000 patientsSeldom more than 3,000 patients Patients with complicated medical conditions often excludedPatients with complicated medical conditions often excluded Patients receiving certain concurrent meds are often excludedPatients receiving certain concurrent meds are often excluded Pediatric and elderly populations may be excludedPediatric and elderly populations may be excluded Trials often last only weeks to months; identification of reactions dueTrials often last only weeks to months; identification of reactions due to long- term use or latent effects is difficultto long- term use or latent effects is difficult Drug Regulation Patient Safety Takes “Center Stage”
- 20. A cGMP Primer Chet French Oct 2011 Drug Development and Commercialization Stakeholders - Competing Interests AccessibleAccessible InexpensiveInexpensive ““Latest & GreatestLatest & Greatest”” Safe & EffectiveSafe & Effective Thorough ReviewsThorough Reviews Safe & EffectiveSafe & Effective Preserve Status QuoPreserve Status Quo Balance Competing InterestsBalance Competing Interests Allocate Resources JudiciouslyAllocate Resources Judiciously Quick ReviewQuick Review Quick to MarketQuick to Market First-in-ClassFirst-in-Class ProfitableProfitable
- 21. A cGMP Primer Chet French Oct 2011 FDA CBER Team Biologics ORACDER U.S. Dept of Health & Human Services Preapproval Inspections Biennial Inspections FDA Partial Organization Structure
- 22. A cGMP Primer Chet French Oct 2011 Licensure/Surveillance Inspections (Planned) Pre-Approval Inspection for Licensure (BLA) Prior Approval Supplement (PAS) GMP or Compliance Inspection (Biennial) For-Cause Inspections (Unplanned): Product Complaint Adverse Event Industry “Triggered” event Market Withdrawal Legal Authority for Inspections Sec. 704 of the Federal Food, Drug and Cosmetic Act of 1938 Sec. 351(c) of the Public Health Service Act (licensed biologics) 21 CFR 600.22 (licensed biologics) FDA Inspections Types
- 23. Goal of theGoal of the InvestigatorsInvestigators:: 1.1. Verify the integrity of informationVerify the integrity of information supporting the application (PAS)supporting the application (PAS) 2.2. Determine conformance toDetermine conformance to cGMPs at the facility used forcGMPs at the facility used for manufacturingmanufacturing,, processingprocessing,, packagingpackaging,, andand holdingholding of theof the drug product.drug product. Goal of theGoal of the InspectedInspected:: ““A favorable outcome”A favorable outcome” The Inspection Goals & Objectives
- 24. Consequences of failure areConsequences of failure are extremeextreme:: Loss of RevenueLoss of Revenue Business Viability - TimeBusiness Viability - Time JobsJobs CompanyCompany’s Reputation’s Reputation CredibilityCredibility More Rigorous Future ScrutinyMore Rigorous Future Scrutiny *Source: Tufts Center for the Study of Drug Development 2001 Drug-to-market costs: $800 million -$1.7 BBL* Facility and Product Licensure The Stakes
- 25. A cGMP Primer Chet French Oct 2011 Documents compiled for review: Deviations/OOS/CAPAs Validation/Revalidation Data/Trending Logbooks P&ID Material Review Board Minutes Critical Systems Systems Review – (examples) Cleaning Validations (Equipment and Facilities) Change Management Environmental Monitoring Stability Program HVAC/Water/Utilities Shipping/Receiving/Warehousing Raw Material In-Process Testing & Release Interested in assessing capabilities Inspection Preparation Relevant Documentation
- 26. Civil Servants - Strong belief in purposeCivil Servants - Strong belief in purpose Specialized training (Specialized training (frequentfrequent andand recurringrecurring):): Human PsychologyHuman Psychology Interview TechniquesInterview Techniques Inspection TeamInspection Team 1-5 Investigators with Lead1-5 Investigators with Lead CDER Office of ComplianceCDER Office of Compliance Office of Biotechnology ProductsOffice of Biotechnology Products CDER District OfficeCDER District Office Mix and MatchMix and Match 1- 3 weeks duration1- 3 weeks duration No vested interest in organizationsNo vested interest in organizations’ success…’ success… Application for approval must stand on own merits!! The FDA Investigators Inspectional Experts
- 27. Quality System Laboratory Control System Materials System Production System Facilities & Equipment System Packaging and Labeling System One System out of control = Noncompliance The FDA Inspection Systems-Based Approach
- 28. Credentials – Agency representedCredentials – Agency represented Visitor badge issued; seated in lobbyVisitor badge issued; seated in lobby Contact list notifiedContact list notified in orderin order Responsible Head is presented theResponsible Head is presented the NoticeNotice of Inspectionof Inspection (FDA 482 Form)(FDA 482 Form) EscortedEscorted andand SequesteredSequestered in Room(s)in Room(s) ((ControlledControlled Environment)Environment) Ms. Investigator FDA Inspections Receiving the Investigators
- 29. A cGMP Primer Chet French Oct 2011 Introductions Review FDA 482 Establish & Negotiate Agenda Inventory of Controlled Docs Prepared Overview Presentations (SMEs) CAPAs, Deviations, Failure Investigations, Prior Inspection Corrective Actions Alert: Conduct Walkthroughs of Potential Inspection Touring Areas Inspection Logistics Day One
- 30. Runners Scribe Host SMEs Front Room Manager A “well-choreographed dance” Scribe Host SME SME FDA Investigators Inspection Logistics Inside the Inspection Room
- 31. What do they do?What do they do? AskAsk lots of questionslots of questions ReviewReview lots of documentslots of documents Make copiesMake copies TalkTalk to lots of employeesto lots of employees TourTour the facility (Startthe facility (Start →→ End)End) ObserveObserve processes/equipment &processes/equipment & peoplepeople CollectCollect SamplesSamples The Inspection Day-by-Day
- 32. What do they find?What do they find? Recordkeeping ErrorsRecordkeeping Errors Documentation InconsistenciesDocumentation Inconsistencies Logsbooks, BRs, Validation ProtocolsLogsbooks, BRs, Validation Protocols Procedures not followedProcedures not followed TimelinessTimeliness ResponsibilitiesResponsibilities Electronic IssuesElectronic Issues Systems IssuesSystems Issues BATCH RECORD The Inspection Day-by-Day
- 33. A cGMP Primer Chet French Oct 2011 Daily Wrap-up Sessions Chaired by Senior Quality Host Convey trends and anticipate next areas of focus Push for spot corrections Annotated 483s FDA 483* Final DayFinal Day FDA 483 Form – List of ObservationsFDA 483 Form – List of Observations MostMost significantsignificant listed firstlisted first TypeType important; notimportant; not numbernumber Final Wrap-up SessionFinal Wrap-up Session FDA 483 Observation 1……. Observation 2 Observation 3** The Inspection Day-by-Day
- 34. A cGMP Primer Chet French Oct 2011 0 30 60 90 120 150 Media Fills Vendors Training E-Issues Cleaning Stability Specs Monitoring Adverse Events Anal. Methods Equip/Facilities RcrdKeeping Validation Failure Inv Number of FDA 483 Observations Source: BioQuality May 2010 108 (27%) 55 (14%) 68 (17%) 31 (8%) FDA 483 Observations Biologics 2010 by Category
- 35. A cGMP Primer Chet French Oct 2011 FDA 483 Form Corrective Actions Withold Approval Approval Conditional Approval Inadequate or Late Reinspection Adequate FDA Inspectional Outcomes Preapproval Inspection (PAI)
- 36. A cGMP Primer Chet French Oct 2011 FDA 483 Form Establishment Inspection Report Warning Letter Consent Decree NOIR Official Action Indicated (OAI) Continued Operation NoOfficial ActionIndicated Criminal Charges Corrective Actions FDA Inspectional Outcomes Compliance or Biennial Inspection
- 37. A cGMP Primer Chet French Oct 2011 Civil Money Penalties*Civil Money Penalties* 11 Seizures*Seizures* 66 (-44%)(-44%) Injunctions*Injunctions* 1212 ConvictionsConvictions 344344 Warning LettersWarning Letters 471471 (-39%)(-39%) Recalls*Recalls* 5,5855,585 FDA 483 ObservationsFDA 483 Observations 5,1005,100 (-1%)(-1%) Inspections*Inspections* 15,58115,581 Import RefusalsImport Refusals 49,98849,988 Fines/Restitutions*Fines/Restitutions* $1.92 BBL$1.92 BBL Source: FDA PDUFA Goals Report 2008 (*)= Voluntary Trend is to focus on more serious violations Regulatory Inspection Trends Enforcement Statistics Searchable Database at the FDA Website www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm
- 38. A cGMP Primer Chet French Oct 2011 38 QA FDA assigns quality oversight to the Quality division 211.22 The quality control unit shall have the responsibility and authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. Oversight Quality by Design A Model for cGMP Compliance Product Mfg, Processing, Holding, Testing, Packaging, Labeling
- 39. A cGMP Primer Chet French Oct 2011 39 Logbooks Labels Batch Records & Systems All cGMP records must be: • Accurate • Legible • Complete • Timely • Truthful and… reconcilable Records Match Records M atch Records and Reports - Good Documentation Subpart J Records Match
- 40. A cGMP Primer Chet French Oct 2011 40 The drug regulatory programThe drug regulatory program depends on the reliability,depends on the reliability, truthfulness, completeness andtruthfulness, completeness and accuracy of data and informationaccuracy of data and information on record.on record. “If it wasn’t documented; then it wasn’t performed” How data is entered into cGMPHow data is entered into cGMP documents is important because this isdocuments is important because this is thethe documented evidencedocumented evidence of GMPof GMP activities.activities. FDA’s View on Documentation/Recordkeeping
- 41. A cGMP Primer Chet French Oct 2011 41 … shall have the education, experience and training or any combination thereof to enable each individual to perform their assigned function. Training on cGMPs Training ongoing and current Be knowledgeable about:Be knowledgeable about: cGMP RegulationscGMP Regulations Policies, Procedures and Guidelines Stay current on:Stay current on: Regulatory inspectional activityRegulatory inspectional activity Changing technologyChanging technology Organization & Personnel Subpart B
- 42. A cGMP Primer Chet French Oct 2011 42 Process Drives Design Separation of Operations Essential Linear Facility: Parenterals and API Reduced Heating and Cooling Costs Shorter Pipe and Process Flows Gravity Feed Reduced Construction Costs Compact Facility Building and Facilities - Design Implications Subpart C
- 43. A cGMP Primer Chet French Oct 2011 Appropriate for intended purpose Adequate space & layout Ensure a state of control Components of an HVAC System: Terminal Diffusers Controlled Cleanroom Airflow Building and Facilities Subpart C HEPA Filter
- 44. A cGMP Primer Chet French Oct 2011 Equipment Subpart D Chromatography Very Large Scale HPLC - Analytical Scale Equipment adequate and appropriate for state of control* Source: FDA Guidance for Industry cGMP for Phase 1 Investigational Drugs 2008
- 45. A cGMP Primer Chet French Oct 2011 Production & Process Controls Subpart F A Typical BiopharmaceuticalA Typical Biopharmaceutical Process:Process: Raw Material Storage/HandlingRaw Material Storage/Handling Weigh/DispenseWeigh/Dispense Media/Buffer/Component Preparation & HoldMedia/Buffer/Component Preparation & Hold Inoculum PreparationInoculum Preparation Fermentation/Cell CultureFermentation/Cell Culture Recovery/HarvestRecovery/Harvest PurificationPurification Bulk FillingBulk Filling CIP/SIPCIP/SIP Biowaste DeactivationBiowaste Deactivation
- 46. A cGMP Primer Chet French Oct 2011 MMV (Parvovirus) Personnel Raw Materials Host Cells Bacteria MycoplasmaSaprolegnia Mold Production & Process Controls Subpart F Common Conduits of Contamination
- 47. A cGMP Primer Chet French Oct 2011 47 Spore Dots Production & Process Controls - Cleaning Validation Subpart F Riboflavin Surface Studies TOC Swabbing Validation: Scientifically and statistical verification of a state of control of process and equipment
- 48. A cGMP Primer Chet French Oct 2011 QA Line Clearance Critical Step 100% Reconciliation of closures containers and labels Packaging & Labeling Subpart G Labeling: #1 root cause for recalls
- 49. A cGMP Primer Chet French Oct 2011 Summary The FDA regulates the drug industryThe FDA regulates the drug industry The FDA is required by law to periodically conduct siteThe FDA is required by law to periodically conduct site inspections to assess our level of compliance with theinspections to assess our level of compliance with the regulations.regulations. GMPGMP regulationsregulations are the intent of the laware the intent of the law GMPGMP expectationsexpectations are the spirit of the laware the spirit of the law FDA focusing attention onFDA focusing attention on quality systems approachquality systems approach toto inspections to assure a sustained state of controlinspections to assure a sustained state of control Robust quality systems are the centerpiece to complianceRobust quality systems are the centerpiece to compliance with the cGMPswith the cGMPs
- 50. A cGMP Primer Chet French Oct 2011 Q & A Questions/CommentsQuestions/Comments ?
Notes de l'éditeur
- The regulation of Public utilities gives us relatively cheap and reliable energy and promotes the development of the infrastructure into even the most rural areas. Regulations associated with nuclear power ensure public safety. The airlines have an exemplary safety record when you consider the complexity of a modern jet aircraft. Lastly pharmaceuticals Regulations serve to protect commerce ensure fairness and compliance with laws And protect the safety of the public Consider industries that are poorly regulated, or where the regulations in place have been poorly enforced. What are some of the consequences of poor or inadequate regulation? Why are cGMPs so important? A consumer usually cannot detect (through smell, touch, or sight) that a drug product is safe or if it will work. While cGMPs require testing, testing alone is not adequate to ensure quality. In most instances testing is done on a small sample of a batch (for example, a drug manufacturer may test 100 tablets from a batch that contains 2 million tablets), so that most of the batch can be used for patients rather than destroyed by testing. Therefore, it is important that drugs are manufactured under conditions and practices required by the cGMP regulations to assure that quality is built into the design and manufacturing process at every step. Facilities that are in good condition, equipment that is properly maintained and calibrated, employees who are qualified and fully trained, and processes that are reliable and reproducible, are a few examples of how cGMP requirements help to assure the safety and efficacy of drug products.
- Regulations – cGMPs are minimum requirements for compliance. Were once called cGMP guidelines (not enforceable) Regulations accommodate the minimum requirements of operation and administration of methods, facilities and controls to assure that the product meets the requirements of the act as to safety and the identity, strength, quality and purity which the product purports or is represented to possess.” Preamble – FDA initial interpretation provided to industry questions. The “c” in cGMP stands for “current” therefore the interpretation of the cGMP are constantly changing. Proposed regulations – Regulations usually take a while to become law. FDA will issue proposed regulations to industry for comment. The expectation is that firms will show evidence that they will comply or state why not. FDA Guidelines – FDA’s current thinking on a topic. – Firms are not required to adhere to FDA guidelines but they must demonstrate that what they do is equal to or better than the guidelines. Inspectional Findings – Investigations may focus on a portion of the industry, such as sterile product manufacturers or within a portion of a manufacturer, such as quality laboratory. Best Practices – FDA anticipates that firms will seek and utilize best practices. In effect, they keep raising the bar as far as cGMP expectations. Best practices can be defined as those practices that are feasible and valuable. Warning letter issued to Merck and Co., in June, 1998: “We acknowledge that the cGMP regulations are not explicit about annual stability testing; however, it should be noted that the cGMP regulations are not all inclusive and that what determines a manufacturing practice to be “current” and “good” is if it can be considered feasible and valuable. In the case of annual stability testing, the agency has determined that such practice is feasible and valuable and thus, enforceable under Section 501(a)(2)(B) and the FD&C Act.” Changing Technology – The Wall Street Journal, September 03, 2003 New Prescription for Drug Makers: Update the Plants. The FDA has concluded that the pharmaceutical industry needs to adopt manufacturing innovations, partly to raise quality standards. According the FDA, industry should focus on developing continuous operations, including process analytical technology (PAT), rather than the tried and true methods (e.g. batch processing) in the past. FDA feels that the best place to start would be on new drugs, where more-efficient methods could be designed from scratch (quality by design). Industry FDA initiatives to bring industry into the 21st C include: FDA will: (1) focus oversight on the plants and processes that are most at risk for errors that could harm patients, (2) minimize the number of production changes requiring advance approval, (3) allow companies to submit interim manufacturing specifications for drugs. These could be updated when more was learned about the drug’s production line and (4) and create a team of experienced inspectors to handle only pharmaceutical plants (Pharmaceutical Inspectorate). THE BOTTOM LINE AS FAR AS CGMP EXPECTATIONS ARE THAT DRUG PRODUCTS STILL MEET THE PREDETERMINED SPECIFICATIONS AND QUALITY ATTRIBUTE AS NOTED IN THE APPLICATION TO THE FDA.
- cGMP refers to the Current Good Manufacturing Practice regulations enforced by the US Food and Drug Administration (FDA). cGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. Adherence to the cGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. This includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories. This formal system of controls at a pharmaceutical company, if adequately put into practice, helps to prevent instances of contamination, mix-ups, deviations, failures, and errors. This assures that drug products meet their quality standards. The cGMP requirements were established to be flexible in order to allow each manufacturer to decide individually how to best implement the necessary controls by using scientifically sound design, processing methods, and testing procedures. The flexibility in these regulations allows companies to use modern technologies and innovative approaches to achieve higher quality through continual improvement. Accordingly, the "c" in cGMP stands for "current," requiring companies to use technologies and systems that are up-to-date in order to comply with the regulations. Systems and equipment that may have been "top-of-the-line" to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today's standards. It is important to note that cGMPs are minimum requirements. Many pharmaceutical manufacturers are already implementing comprehensive, modern quality systems and risk management approaches that exceed these minimum standards. Regulations that provide the minimum requirements of operation and administration of methods, facilities and controls to assure that the product meets the requirements of the act as to safety and the identity, strength, quality and purity which the product purports or is represented to possess.”
- Nostrums permeated American society by the late 19th century; Products appealed to exotica, the medical knowledge of Native Americans, death, religion, patriotism, mythology (a natural for this industry!), and especially new developments in science. There was nothing to stop patent medicines makers from claiming anything and putting anything in their products, clearly seen in the famous morphine- and alcohol-laced soothing syrups for teething and colicky babies. Cancer and arthritis cures, baldness remedies, bust developers, manhood restorers--wherever a need existed, patent medicine makers stepped in. They did not have a monopoly on the market, though. The ethical pharmaceutical industry, those firms that advertised for the most part directly to health professionals, sold their share of nostrums as well. Towards the end of the period, a number of radioactive medicines, containing uranium or radium, were marketed. These apparently actually contained the ingredients promised, and there were a number of tragedies among their devotees; most notoriously, Eben McBurney Byers, a steel heir, died horribly after taking more than a thousand bottles of "radium water." What was in them? While various herbs, touted or alluded to, were often mentioned, more often they contained opium extracts, cocaine, and grain alcohol.
- The main crusader of standards for food quality at this time in history was Harvey Washington Wiley. He was the chief chemist at the U.S. Department of Agriculture, and he had a very prestigious academic and career background in the U.S. and in Germany. He was so concerned about the effects of food additives that he headed up the famous "Poison Squad," which tested the safety of preservatives by eating them. Wiley’s quest for food standards did not become a national issue, however, until the publication of a novel detailing the horrific conditions in which some food was processed. In 1906 Upton Sinclair, a muckraking journalist, published the novel The Jungle. This novel detailed the true to life filthy conditions of a Chicago meat packing plant. The publishing of this novel caused an uproar among the American public. People were appalled to learn that the food they ate was produced under such unsanitary conditions. A women’s movement was forming at this time in history, and pure food became an issue that the women took on. Women’s magazines, such as Ladies Home Journal and Colliers published articles calling for consumer protection. Congress was flooded with correspondence demanding that action be taken. The government turned to Wiley, who was clearly the expert in this field. That same year the Food and Drug Act of 1906 was passed. This, along with the Meat Inspection Act, which was passed on the same day, constituted the first federal regulation of food and drugs. The Food and Drug Act prohibited interstate commerce in misbranded and adulterated foods, drinks, and drugs. While this was a strong law for the time, it had many shortcomings. False therapeutic claims for patent medicines were basically unregulated, as the manufacturer had only to show that he personally believed that his remedy worked to avoid prosecution, and standards for food purity and content were nonexistent. The law prohibited interstate commerce in misbranded and adulterated foods, drinks, and drugs but had no provision for safety. Attempts to make changes to the law were unsuccessful until a major tragedy occurred in 1937, which we will see later. .
- Companies discovered class after class of new medicines. Antidepressants, antacids, anti-inflammatories, etc. Whenever one company broke new ground, other firms would introduce copycat versions of the original molecule. A FTC investigation revealed that the industry refused to compete with one another on PRICE, choosing instead factors such as dosage frequency, or delivery methodology. The firms intensified their advertising and their reliance on company identities. Towards the end of the period, a number of radioactive medicines, containing uranium or radium, were marketed. These apparently actually contained the ingredients promised, and there were a number of tragedies among their devotees; most notoriously, Eben McBurney Byers, a steel heir, died horribly after taking more than a thousand bottles of "radium water." What was in them? While various herbs, touted or alluded to, were often mentioned, more often they contained opium extracts, cocaine, and grain alcohol. The me-too era: Companies discovered class after class of new medicines. Antidepressants, antacids, anti-inflammatories, etc. Whenever one company broke new ground, other firms would introduce copycat versions of the original molecule. A FTC investigation revealed that the industry refused to compete with one another on PRICE, choosing instead factors such as dosage frequency, or delivery methodology. The firms intensified their advertising and their reliance on company identities. The result was a sulfa craze. For several years in the late 1930s, hundreds of manufacturers produced tens of thousands of tons of myriad forms of sulfa. This and nonexistent testing requirements led to the Elixir Sulfanilamide disaster in the fall of 1937, during which at least 100 people were poisoned with diethylene glycol. This led to the passage of the Federal Food, Drug, and Cosmetic Act in 1938. As the first and only effective antibiotic available in the years before penicillin, sulfa drugs continued to thrive through the early years of World War II. They are credited with saving the lives of tens of thousands of patients including Franklin Delano Roosevelt, Jr. (son of President Franklin Delano Roosevelt) (in 1936) and Winston Churchill. Sulfa had a central role in preventing wound infections during the war. American soldiers were issued a first-aid kit containing sulfa pills and powder and were told to sprinkle it on any open wound.
- The glaring need to revise the 1906 Food and Drug Act arose in 1937 with a tragic incident involving the drug Sulfanilamide. Sulfanilamide was a drug commonly used to treat streptococcal infections. It was produced in tablet and powder forms, but not in a liquid form that would have been easier for children to take. The S.E. Massengill company decided to develop a liquid form of Sulfanilamide. Massengill’s chief chemist and pharmacist, Harold Cole Watkins, found that diethylene glycol was a good medium for the elixir Sulfanilamide. The new substance had a nice appearance and a pleasant taste. What Watkins did not realize was that diethylene glycol, which is more commonly known as antifreeze, is a deadly poison. Unfortunately, the existing law did not require any kind of pharmacological studies proving that a drug is safe, and 240 gallons of Elixir Sulfanilamide went on the market. The people who took this drug, many of them children being treated for sore throats, suffered tremendously before they eventually died. They were ill between one and three weeks, and experienced stoppage of urine, severe abdominal pain, nausea, vomiting, stupor, and convulsions. The pain was severe and unrelenting, and eventually 107 people died. The American Medical Association began receiving complaints from physicians a few weeks after it was sold, and quickly isolated diethylene glycol as the offending ingredient. Warnings were issued not to use the drug. Once FDA was notified of the problem, it insisted on more severe letters be sent to distributors warning of the lethal nature of the product. FDA dispatched nearly its entire force of 239 investigators to the task of tracking down the remaining unused portions of the medicine. This was a very difficult task, as pharmacies often kept very poor records of who had purchased various types of medicines. But the FDA investigators were tireless in their pursuit of the dangerous medicine, and eventually tracked down 234 gallons and 1 pint of the 240 gallons. The remaining amount had been consumed. Massengill denied any responsibility for the tragic outcome of its quest for a liquid form of Sulfanilamide. Watkins, the chemist who developed it, however, committed suicide. Massengill was charged on a misbranding technicality in the incident. Unfortunately, the fact that they had produced an unsafe pharmaceutical product did not violate any existing law. Therefore, the 1906 Food and Drug Act was quickly replaced by the Federal Food, Drug, and Cosmetic Act of 1938. The legislation had been enforced by the Bureau of Chemistry until 1927, when the Food, Drug, and Insecticide Administration was created. In 1931 it was renamed the Food and Drug Administration. In 1940, FDA was transferred from the U.S. Department of Agriculture, to the Federal Security Agency, which later became the Department of Health, Education, and Welfare, and later the Department of Health and Human Services. This law, after many revisions, is still in effect today. In 1938, this law introduced the following improvements to the existing legislation: cosmetics and therapeutic devices were regulated for the first time, fraud no longer needed to be proved to prevent false claims for drugs, scientific proof of safety for new drugs was required before they could be marketed, addition of poisonous substances to food was outlawed in most cases, and tightly regulated in others, authority was created for factory inspections, food standards were required to be created, and federal court injunctions against violations were made legal. Future amendments to the 1938 law ensured that no substance could be introduced into the food supply without a prior determination that it was safe. These amendments were a result of the work of a committee sanctioned by Congress to investigate chemicals in food. They are: the Pesticide Amendment (1954), the Food Additives Amendment (1958), and the Color Additive Amendment (1960).
- When the drug thalidomide was submitted to FDA for approval, Frances Kelsey, a new FDA employee, reviewed the application very carefully, and kept it off the market until it was determined that it caused birth defects when used by pregnant women. This near catastrophe highlighted the need for more stringent drug laws. Thalidomide was a drug commonly used in Europe to treat sleep disorders and morning sickness in pregnant women. It was available starting in 1958 in West Germany, and did not even require a prescription. The William S. Merrill Company submitted an application to market thalidomide in the U.S, and Frances Kelsey, a new FDA employee, was given the job to process the approval. As it was so widely used in Europe, it was viewed as an easy task. Kelsey, however, was a first class scientist. She had helped with the collection of Elixir Sulfanilamide in 1937 and 1938, and knew the impact that her job had on millions of people. As she was reviewing the material submitted by Merrill, she noticed that it acted differently on animals than on humans. This was her first inkling that thalidomide required a closer investigation than Merrill and many others thought necessary. She returned the application and requested more information. Meanwhile, in Europe, several developments had occurred relating to the use of thalidomide. In 1960, 83 children were born with birth defects, even though there were no cases of this in the previous 5 years. These defects were attributed to several causes, but no one noticed the link to the use of thalidomide during pregnancy. In February of 1961, a letter in a British medical journal reporting a tingling nerve inflammation in the fingers of long-time thalidomide users. As this side effect was confirmed, Germany made it a prescription drug. During this time thousands of babies were born with birth defects. Kelsey started exploring the idea that the tingling could affect the fetus as well as the mother. She wanted to require that a warning be placed on all bottles telling users not to take it during pregnancy. However, she received much criticism regarding this, as it was so widely used during pregnancy. When a German scientist finally began to make the connection between thalidomide and birth defects in November of 1961, it was withdrawn in Germany, and Merrill withdrew its drug application. Some 5,000 German babies were born with birth defects resulting from use of thalidomide, and there were many more in other countries. FDA discovered that it had been distributed to over 3,000 women in the U.S. as a clinical test which also worked as a marketing promotion. This was not illegal at the time. Through the diligent efforts of Kelsey to make sure that the drug was safe and effective, thousands of birth defects were prevented in this country. This near tragedy and the need for tougher food and drug laws did not come to public attention until the Washington Post ran a story on it on July 15, 1962, stating that thalidomide could have passed the current laws in this country. This aroused concern, and Congress passed the Drug Amendments of 1962 which addressed safety requirements for testing on human subjects. It also required that patients be informed if they are taking a drug that is experimental, that drug companies must report to FDA any adverse effects of drugs found during clinical trials, that new drugs be proven effective as well as safe, that the drug label carry the common or generic name of the product as well as the brand name, and that prescription drug advertising to doctors list the side effects of a drug as well as its benefits.
- Ernst Kefauver was a Yale trained lawyer and Tennessee Senator. In the early 1960’s due largely to his support of Civil Rights and attacks on organized crime, he turned his attention to abusive corporate practices. In a series of public hearings between 1960-62 Kefauver focused attention on the drug industry’s penchant for developing copycat drugs, which in defiance of every economics textbook, rarely resulted in price competition. He was famous for putting top drug industry executives on the spot, at one point getting the retired head of R&D at Squibb to admit that over half the research was aimed at me-too drugs which promised sales, rather than new utility. The Drug Amendments of 1962, passed unanimously by the Congress, tightened control over prescription drugs, new drugs, and investigational drugs. It was recognized that no drug is truly safe unless it is also effective, and effectiveness was required to be established prior to marketing -- a milestone advance in medical history. Drug firms were required to send adverse reaction reports to FDA, and drug advertising in medical journals was required to provide complete information to the doctor -- the risks as well as the benefits. In the years since 1962 literally thousands of prescription drug items have been taken off the U.S. market because they lacked evidence of safety and/or effectiveness, or they have had their labeling changed to reflect the known medical facts
- What does this photograph bring to mind? In the early 80s, a perpetrator adulterated Tylenol capsules with cyanide. The killer laced the bottles and placed them back on the shelves for sale. The bottles were purchased and 11 people were killed. J&J acted quickly. They instituted the largest recall ever – 30 million units in 3 weeks. What was the result of the incidence? Tamper-proof packaging instituted. At this point there was no FDA regulation for tamper-proof packaging. It became an industry standard due this incident.
- In 1997, Congress reauthorized user fees as part of a "modernization"package that reduced the legal standard for new drug reviews: Instead ofrequiring two clinical trials, the FDA could accept just one. The new lawalso allowed manufacturers to promote drugs for "off label" uses the FDA hadnever approved. Other provisions greased the fast track; none enhanced thesafety of the drug-review process. It was the first time in its 91 yearsthat the Food and Drugs Act's public-health protections had been rolledback. There are however some controversies… One clinical trial instead of two Promotion of drugs for off-label usage Quid-pro-quo Funds could be spent only on new drug reviews Time-pressures reg appve drugs w/o regard to danger Safety considerations
- The FDA is one of the oldest federal agencies The FDA regulates more than $1 trillion worth of consumer goods, about 25% of consumer expenditures in the United States. This includes $466 billion in food sales, $275 billion in drugs, $60 billion in cosmetics and $18 billion in vitamin supplements. Much of the expenditures is for goods imported into the United States; the FDA is responsible for monitoring a third of all imports. The FDA's federal budget request for fiscal year (FY) 2008 (October 2007 through September 2008) totaled $2.1 billion, a $105.8 million increase from what it received for fiscal year 2007.[6] In February 2008, the FDA announced that the Bush Administration's FY 2009 budget request for the agency was just under $2.4 billion: $1.77 billion in budget authority (federal funding) and $628 million in user fees. The requested budget authority was an increase of $50.7 million more than the FY 2008 funding - about a three percent increase. In June 2008, Congress gave the agency an emergency appropriation of $150 million for FY 2008 and another $150 million for FY 2009.[5]
- But, limitations such as number of participants and subject characteristics results in uncertainties about the safety of the pharmaceutical once it is marketed and used in a wider population, over longer periods of time, in patients with co-morbidities and concomitant medications and for ‘off-label’ uses not previously evaluated. This is a weakness of the clinical trial as a safety identification process. Therefore, the true picture of product safety actually evolves over the months and even years that make up a product's lifetime in the marketplace.
- The biotechnology revolution of the late 70’s came on the heels of an explosion of knowledge about cellular interactions and set off another wave of innovations. No longer would the industry focus on developing and marketing me too drugs. However progress on delivering these new miracle cures was slow. Industry took care of the “low hanging fruit” with a handful of genetically engineered medicines that emerged in the first two decades. Companies no longer had to rely on marketing and cartel-like behavior to ensure against a decline in prices from competition. Instead they could rely on the exclusivity granted by patent law. By the 1990s drug prices, like health care in general was spiralling upward at double-digit rates. Throughout the 1990’s the FDA was approving 25-50 medicines per year. By 2002, this had dropped off to just 17. Pharmaceutical Company Lobbying $51 million campaign contributions $322 million spent lobbying efforts
- ORA – the “boots on the ground” One-third of all FDA employees are part of the ORA and are responsible for inspections and regulatory actions Although ORA accounts for about one-third of all FDA employees, it has experienced a decline in staffing over the past several years, losing approximately 800 personnel since 2003 TEAM BIOLOGICS: Elite partnership forged between CBER and ORA 1997 ~16 Investigators Ensure quality and safety of biologic products Resolve inconsistencies associated with inspections
- Section 704 of the Federal Food, Drug and Cosmetic Act (drugs and devices) – we will abbreviate as the “FFDCA” Section 351(c) of the Public Health Service Act (licensed biologics) and 361 (tissue products) 21 CFR 600.22 (licensed biologics) 21 CFR 1270 (tissue products) As a practical matter, 704 of the FFDCA is the governing law There are times when we do know in advance that we will be subject to a regulatory inspection. When we have a new product or changes to an existing product, we will undergo a pre-approval or pre-license inspection. Pre-Approval Inspection – based on submission of documentation from clinical trials. The agency will inspect our facility to determine if we can do what we say we are going to do. Are the facilities appropriately designed?, of adequate size?, do we have adequate resources? , do we have procedures in place?…. Pre-license – Before products are licensed. Post-Approval/GMP – Conducted to ensure ongoing compliance. Are we doing what we said we would do? Are we following our procedures? Did we validate our equipment/processes? Look at our Quality Systems. If we cannot product documented evidence that one or two Quality Systems (i.e. CAPA, Change Control, Documentation, Training, Validation) are operating in a fashion the verifies ongoing compliance, the agency can make the determination that our organization is not operating under a “state of control”. Unplanned inspections can come as a result of customer complaints regarding the quality of our product or an adverse reaction based on usage of our product. Example of a product related complaint – container closure system, labels, packaging, volume, reconstituted volumes, etc. Adverse Event – negative reaction by an individual to our product – rash, headache, chills, fever Overall industry concern for a certain type of product – all manufacturers of a certain product type may now have to undergo additional scrutiny based on negative consumer feedback/experiences even if the company’s own product(s) are not involved. (i.e. annual GMP inspections instead of biennial inspections for flu vaccine manufacturers based on issues with Chiron (UK) in 2004)
- These are examples of the documentation that may be reviewed during an inspection. Information is gathered in advance of a “Post/GMP Inspection”. Gather information related to previous observations, but, also gather data and/or records that reflect activity since the last inspection. Review tracking/trending data related to CRs/Deviations. Review any Level III MRBs.
- Biennial inspections are headed by the district office.
- Systems-Based Inspections Originated as a pilot program from the Office of Radiological Health and Diagnostics in 2001, later expanded to all branches as an expedient methodology. Inadequate resources at FDA to address all inspectional commitments with former program. Short, highly-focused inspections Abbreviated -- 2 Systems – Quality + 1 other Full Inspection Option -- 4 Systems – Quality + 3 others Implementation driven by resource constraints: 3 days vs. 2 weeks Quality System: Change control, reprocessing, batch release, annual record review, validation protocols and reports. Facilities & Equipment System: Physical environment, buildings and facilities, equipment qualifications, equipment calibration and preventative maintenance, cleaning and validation of cleaning processes. Utilities, HVAC, water. Materials System: water or gases, containers and closures, validation of computerized inventory systems, drug storage, distribution records. Production System: Measures and activities to control the Mfg of drugs, in-process sampling and testing, process validation. Establishing, following, and documenting performance of approved manufacturing procedures. Laboratory Control System: Includes measures and activities related to laboratory procedures, testing, analytical methodology development and validation or verification, and the stability program. Definition: Formalized business practices that define management responsibilities for organizational structure, processes, procedures, and resources needed to fulfill product/service requirements, customer satisfaction, and continual improvement.
- Provide dedicated space for FDA’s use Allow enough space for documents to be spread out and for other personnel who will be present Conference rooms are best for this purpose It’s generally OK to provide light refreshments such as coffee, tea, water, but be guided by FDA personnel and do not insist on providing lunch; allow FDA personnel to pay if they wish to do so. Limit interruptions – now is not the time for the monthly fire alarm test! Provide prompt access to personnel and records
- What does a regulatory Investigator look at when on the premises to verify ongoing compliance – review of “documented evidence” that we did/do what our procedures say in support of our Quality System requirements. Are we following our procedures/validated test methods? Are we training and qualifying employees prior to performance of GMP activities? Are we validating our systems to ensure reproducibility? Consistent results? Do we investigate deviations? Are our corrective actions effective or do we have reoccurring quality issues?
- Each MedImmune will identify the best location for the inspection process – best possible scenario – close to the main entrance Inspection Room Conf Rm 1A18 away from laboratories and manufacturing areas away from general work areas This positioning limits exposure to employee conversations, limits visibility of computer screens, limits witnessing of actual operations (without specific requests). The staging room is also used by SME’s/Management for review of all documentation requested by an inspector prior to delivery into the inspection room, itself. This preparation allows for a final review of the information/data captured and helps to prepare the SME for one on one document review with the Investigator. Adhere to reasonable security precautions, safety rules, and standards/procedures for gowning or other protective garb while in production, warehousing or lab areas Issue the FDA-483 Issue a FDA-484, Receipt for Samples, for any product or material samples collected Earlier in the presentation we identified “Scribes” as members of the Inspection Team. They play a vital role in knowing how the inspection is going, the tone, the focus, the documentation being reviewed, the questions, the answers, comments, concerns, etc. because throughout the inspection they are taking notes. A single scribe is assigned to a single Investigator. This information is valuable in daily review and may be used in the future to clarify what dialogue actually took place between an employee and an Investigator. So, knowing how critical this dialogue is….if you are speaking with an Investigator what do you need to know? Listening is key to giving an appropriate response. Sometimes in our “zest” to answer we may not have heard the question correctly or we may say too much. Answers should be direct, factual, and not too much information. Elaborating on the answer may trigger additional questions or take the Investigator in another direction. We want to keep ourselves focused. Do not speculate or guess when asked a direct question.
- If you don’t understand the question, ask for clarification rather than risk mis-stating yourself or giving unrelated information. If the question asked is not within your sphere of knowledge it is acceptable to let the Investigator know that someone else would be more suitable to provide an answer to their question. Follow through with getting the appropriate person to discuss the question. Do not leave a question unanswered or ignored. We do not want to appear as if we have something to hide or do not know the answer at all. To give the best response to a question, it may be necessary to retrieve additional documentation/records or consult with another. Request time to do so. Do not attempt to “fake it!” Do not “Guess!” Do not “Speculate”. It is also important to remember that you do not need to nor should you make any attempt to argue points of law. We have support documents, policies and procedures that reveal MedImmune’s interpretation of the laws. Our positioning will be addressed by Sr. Management. When an Investigator requests to see a specific document/training record/procedure, their expectation is that we can easily retrieve the information. This is one reason for having “Runners” in and outside the inspection room. If there is going to be a delay in retrieval, this is communicated to the Investigator. (documents must come up from Gaithersburg facility, for example) We do not want to leave the Investigator with the impression that we do not want to show them what they requested; we do not have what they requested; or there is something wrong with what they requested and we are trying to “fix it”. All requested documentation is reviewed by the appropriate personnel prior to entering the Inspection room. Documents are never handed directly to the Investigator. Any discrepancies requiring additional explanation are discussed outside the inspection room and strategies/explanations/etc. are established with all of the reviewers (SME, Compliance, Regulatory, QA, etc) reaching agreement before presentation to the Investigator. During an inspection, we may be asked to make copies for the Investigator to review, revisit later. Any documents or records that we copy, we will make duplicates. When records/documents are taken into the inspection room they are often the “original record or document”. If the Investigator needs to make notations or comments regarding the discussion we will offer to provide them with a copy of that document. We do not want additional comments or marks on our originals. When we do make a copy we will identify it as a “Copy” or “True and Exact Copy” and identify it as proprietary information with a “Confidential” stamp.
- Towards the end of every day, the Investigators will usually recap the systems/documentation that they have reviewed and the potential observations/issues with what they have seen and/or heard. They will also often elaborate on their focus for the next inspection day. This allows the management representatives in the room during the wrap-up, the opportunity to regroup overnight. To discuss strategies and a potential plan-of-action for any issues that may have been addressed in the wrap-up. Items that can be addressed quickly (overnight) will be addressed immediately by the Inspection Team Immediate corrections/improvements may possibly prevent an inspection finding write-up and the need for future corrective actions
- 2001-2005 CDER Inspectional Trends 483 Citations -1% Warning Letters -39% Seizures-44% Lack of Enforcement Political Influence Focus on more serious violations
- In order to maintain licensure, the FDA conducts an on-site inspection every two years. Since the regulators cannot be present 24/7 to ensure compliance with all of the federal regulations, the cGMPs have specifically designated the quality unit with quality oversight of the organization. Although this may appear on the surface to be a one-way relationship and inconsistent with typical business parameters and practices, this model has been intentionally designed so as to ensure compliance. An independent quality unit has a responsibility to ensure that the various operations associated with all systems are appropriately planned, approved, conducted and monitored.
- Data Entry There should never be omissions of significant data Review all documents and data prior to signing Timely Review/Approval helps to ensure awareness of errors and allows for timely corrections. Omission of significant data No written explanation when changes are made Data not recorded on a timely basis Data not direct (transposition or math errors) Inaccurate data, including improper rounding of numbers Lacks timely signature and date Fraudulent data or suspicion of fraud Date and Time Many of our GMP activities are driven by date and time so it is important that we capture this information in a manner that is consistent across the organization Preferred date format: DDMMMYY or DDMMMYYYY Use of full month names is allowed Place a zero in front of numbers less than “10”
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- Also critical to facility location is the availability of the required work force. Much of the Biopharmaceutical and pharmaceutical industry requires skilled labor in order to run production, including maintenance, engineering, QC, QA and management personnel. If the geographic location does not provide the required skilled labor, talent must be brought in increasing operational costs. Some companies prefer to construct new facilities in close proximity to existing facilities in order to leverage the knowledge base and personnel from the existing facility. This approach smoothes the start-up and transition to a new manufacturing plant in that skilled knowledgeable individuals are in critical roles. The predictable competence of existing personnel can greatly speed the operation of new facility to maximum output.
- Plant design based on process flow rather than cost is generally more spread out. Designs of this type occur where separation of operations is essential, such as when potent compound small molecule powder manufacturing and biopharmaceutical parenteral manufacturing are performed by the same company. Refer to Taiyo Pharmaceuticals Provide logical, direct, and sequential flow, minimizing the potential for confusion Minimize the moving distance; that is, the distance material has to move Provide adequate protection against contamination Provide adequate staging and access Provide the proper level of protection Many Pharmaceutical and Biopharmaceutical plants are constructed this way. This type of building structure provides certain advantages including: Reduced heating and cooling costs due to reduced exterior walls Shorter utility and electrical runs due to the compact facility layout Shorter process flow paths, whether pump driven or gravity driven due to the multi-floor design Reduced construction costs because of material consumption and roof/wall area Refer to MedImmune Design
- Example of cleanroom design for purpose. Terminal Diffusers for ensuring correct airflow patterns within clean airspaces. The air flows into the rooms via so-called registers (diffusors), which are built and installed in such a way that the air is distributed evenly. Machinery or furniture can block the passage of air from the register to the exhaust point, creating unflushed zones, where counts of particles and micro-organisms could be higher. It is therefore important to consider the CONTENT and purpose of a clean room, when planning the HVAC system. In many cases, the terminal filter panel and diffusors are incorporated into one unit. It is also important that the air diffuser supplies air evenly and does not induce the circulation of dust in the room – as illustrated by the next slide. FDA and EU dictate Proximity Cleanability Flows Minimum Requirements Quality, safety and effectiveness must be designed and built into the facility Requires Periodic Monitoring
- The risk of transmission of certain infectious pathogens cannot be completely mitigated by donor screening, vaccination of patients, a single virus inactivation step, or virus testing of cell banks and raw materials. The protein production mechanism used for Synagis is NSO cells. Because the proteins are derived from a mammal the following techniques are used to test for known and novel viruses, minute virus of mice and retroviruses. Antibody production assays for rodent viruses due to extensive passage history (MAP, RAP, HAP) Oncogenic viruses (such as -herpesviruses, polyomaviruses, papillomaviruses, adenoviruses, certain poxviruses, retroviruses) Assays for known viruses based upon species PCR (specific and generic) Infectivity (in vitro and in vivo) Western blot, ELISA, IFA As an example, CHO cell contamination viral particles are the following: Epizootic hemorrhagic disease virus (a rheovirus) Mouse minute virus (MMV) A parvovirus Vesivirus 2117 (calicivirus) Reovirus type 2 Cache Valley virus The viruses included a few known to have contaminated CHO cell-derived biologics in the past two decades, and therefore did add some new entities to the list in Table 1. Still, the list of viruses that are known to replicate in CHO cells is relatively short. Baxter (2008) had an accidental contamination with active Avian Flu Virus in vaccine that was shipped to 16 countries. Genentech (Minute Mouse Virus) contamination of unknown origin, but what is thought to have originated from raw material source. Genzyme (2009) Mass. Mfg plant shut down due to contamination with Vesivirus 2117 in one of six bioreactors; not known to cause human infection, but known to interfere with CHO cells. Speculate likely origin was a nutrient used in the manufacturing process.
- Spore Strips, dots or suspensions can all be used interchangebly: Hardware Cartridge/housing assembly Challenge with Spore Suspensions Filters Cartridge/housing assembly