Which Action Changes The Identity Of The Substance Referenced

Do the CGMP regulations permit the destruction of an internal quality assurance audit report one time the cosmetic action has been completed?
Can containers, closures, and packaging materials be sampled for receipt exam in the warehouse?
A house has multiple media make full failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through a 0.2 micron sterilizing filter. Investigation did not testify any obvious causes. What could exist the source of contagion?
How many containers of each component from each shipment must a house sample and examination to comply with the CGMP requirements for identity testing? Do the CGMPs allow the identity test on a pooled, or composite, sample of multiple containers?
What methods of analysis are suitable for testing for melamine contamination in pharmaceutical components?
Does FDA require or recommend any special precautions or controls over the manufacturing of beast-derived drug ingredients to preclude contagion?
What are FDA's chief concerns about pathogenic agent contamination of animal-derived drug ingredients?
What manufacturing contamination risks are presented past the different pathogenic agents?
What are some ways to minimize pathogenic agent contamination in incoming animate being-derived raw material?
Are at that place control measures for minimizing pathogenic agent contamination in fauna-derived drug ingredient manufacturing facilities?
What should drug manufacturers practise to prevent germination of glass lamellae (glass fragments) in injectable drugs filled in small-volume glass vials?
Are there whatever special processing or handling concerns for flexible intravenous (Iv) solution bags?
What can Iv drug manufacturers practise to help forestall the loss of sterility due to compromised Four solution bag integrity during labeling?
Must each batch of a United States Pharmacopeia (USP)-grade API be tested using the belittling procedures specified in the USP monograph?
Who is responsible for analytically testing APIs to ensure they comply with their specifications and with USP requirements, if any?

1. Exercise the CGMP regulations allow the destruction of an internal quality assurance audit report once the corrective action has been completed?

The CGMP regulations (21 CFR parts 210 and 211) for finished pharmaceutical manufacturing practice not specifically address the requirement to conduct, or to keep records of, internal quality assurance audits. If the report in question was from a routine audit to verify that the firm'south quality system is operating as intended, and so information technology would be acceptable if the firm elected to discard the report once all corrections have been verified.

However, whatsoever documentation of corrective action as a result of such an audit would take to be retained (see §§ 211.180 and 211.188). For example, if a routine internal audit finds a problem with a mixing step and the upshot is a change in mixing time, all affected procedures, including the chief production record, are to reverberate the necessary changes, and such records are subject to FDA inspection as usual. Any investigation into the impact this problem had on related batches is to be retained and as well made available for inspection past FDA (run into § 211.192).

In improver, any reports of investigations or evaluations prepared in response to, for example, a product complaint (§ 211.198), vendor qualification (§ 211.84), periodic review of records and data (§ 211.180(e)), and a failure investigation (§ 211.192) are not internal audits as discussed above. Such records are subject to FDA inspection and must be retained for at least the time specified in the CGMP regulations (encounter § 211.180).

References:

21 CFR 211.84: Testing and approval/rejection of components, drug product containers, and closures
21 CFR 211.180: General requirements
21 CFR 211.188: Batch production and command records
21 CFR 211.192: Production record review
21 CFR 211.198: Complaint files
Preamble to the Electric current Adept Manufacturing Practice in Manufacture, Processing, Packing, or Holding regulations (43 FR 45015, paragraph 4, Sept 29, 1978)
Compliance Policy Guide Sec. 130.300 FDA Access to Results of Quality Assurance Plan Audits and Inspections (CPG 7151.02)

two. Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse?

Yes. Generally, we believe that sampling in a typical drug manufacturing facility warehouse would not represent a take chances to the container or closure or touch on the integrity of the sample results. But whether the deed of collecting a sample in the warehouse violates the CGMP requirement that containers "be opened, sampled, and sealed in a manner designed to forestall contagion of their contents..." will depend on the purported quality characteristics of the material under sample and the warehouse environment. For containers or closures purporting to be sterile or depyrogenated, sampling should be under atmospheric condition equivalent to the purported quality of the material: a warehouse surround would not suffice (run into 21 CFR 211.94 and 211.113(b)). This is to preserve the fitness for utilize of the remaining containers or closures besides as to ensure sample integrity, if they are to exist examined for microbial contamination. At a minimum, any sampling should exist performed in a style to limit exposure to the environment during and later the time samples are removed (i.eastward., wiping outside surfaces, limiting time that the original packet is open, and properly resealing the original packet). Well-written and followed procedures are the critical elements.

Annotation that the CGMPs at 21 CFR 211.84 allow a manufacturer to release for use a shipment of containers or closures based on the supplier's certificate of assay and a visual identification of the containers or closures. Once a supplier's reliability has been established by validation of their examination results, a manufacturer could perform the visual examination entirely in the warehouse.

References:

21 CFR 211.84: Testing and approval or rejection of components, drug product containers, and closures
21 CFR 211.94: Drug product containers and closures
21 CFR 211.113(b): Control of microbiological contamination
21 CFR 211.122: Materials examination and usage criteria

three. A firm has multiple media fill up failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through a 0.two micron sterilizing filter. Investigation did not show any obvious causes. What could be the source of contagion?

A firm had multiple media fill failures. The media fill runs, simulating the filling process during production, were conducted within an isolator. The house used TSB (nonsterile bulk powder) from a commercial source and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter. An investigation was launched to trace the source of contamination. The investigation was not successful in isolating or recovering the contaminating organism using conventional microbiological techniques, including the use of selective (e.thousand., blood agar) and nonselective (e.chiliad., TSB and tryptic soy agar) media, and test under a microscope. The contaminant was somewhen identified to be Acholeplasma laidlawii by using 16S rRNA factor sequence. The firm afterwards conducted studies to confirm the presence of Acholeplasma laidlawii in the lot of TSB used. Therefore, it was not a contaminant from the process, but from the media source.

Acholeplasma laidlawii belongs to an order of Mycoplasma. Mycoplasma contain merely a cell membrane and have no cell wall. They are not susceptible to beta-lactams and do not take up Gram stain. Individual organisms are pleomorphic (presume various shapes from cocci to rods to filaments), varying in size from 0.ii to 0.iii microns or smaller. Information technology has been shown that Acholeplasma laidlawii is capable of penetrating a 0.2 micron filter, but is retained by a 0.1 micron filter (see Sundaram, Eisenhuth, et al. 1999). Acholeplasma laidlawii is known to be associated with animate being-derived fabric, and microbiological media is often from animate being sources. Environmental monitoring of Mycoplasma requires selective media (PPLO broth or agar).

Resolution:

For now, this firm has decided to filter prepared TSB, for utilise in media fills, through a 0.one micron filter (annotation: we practice not expect or require firms to routinely use 0.1 micron filters for media preparation). In the future, the firm will apply sterile, irradiated TSB when it becomes available from a commercial supplier. (Business firm'southward autoclave is as well pocket-size to permit processing of TSB for media fills, then this was non a viable selection.) The house will continue monitoring for Mycoplasma and has revalidated their cleaning procedure to verify its removal. In this case, a thorough investigation by the firm led to a determination of the crusade of the failure and an appropriate corrective action.

References:

21 CFR 211.113: Control of microbiological contamination
21 CFR 211.72: Filters
21 CFR 211.84(d)(half dozen): Testing and approval or rejection of components, drug product container, and closures
Sundaram, Due south, J Eisenhuth, Thou Howard, and H Brandwein, 1999, Application of Membrane Filtration for Removal of Atomic Bioburden Organisms in Pharmaceutical Products and Processes, PDA J Pharm Sci Technol, 53(4):186–201
Kong, F, One thousand James, S Gordon, A Zekynski, and GL Gilbert, 2001, Species-Specific PCR for Identification of Common Contaminant Mollicutes in Prison cell Culture, Appl Environ Microbiol, 67(vii):3195–3200
Murray, P, Due east Baron, M Pfaller, F Tenover, and R Yolken, 1995, Manual of Clinical Microbiology, sixth ed., Washington, DC: ASM Press

Appointment: v/18/2005

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4. How many containers of each component from each shipment must a firm sample and examination to comply with the CGMP requirements for identity testing? Do the CGMPs allow the identity test on a pooled, or composite, sample of multiple containers?

The CGMP regulations address component sampling and testing primarily at 21 CFR 211.84. These regulations require representative samples of each shipment of each lot of active and inactive component (or raw materials) to be tested to confirm the identity of the component as labeled prior to release for utilise in drug product manufacturing. The regulations acknowledge that more than one examination may be needed to ascertain a component'due south identity. For the purpose of this answer, a component's identity is its chemic construction and its physical course (due east.grand., polymorph, solvate, and advent) including, if appropriate, its stereochemistry or immunochemistry. (Meet also ICH guidances for industry Q6A Specifications: Exam Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances and Q6B Specifications: Examination Procedures and Credence Criteria for Biotechnological/Biological Products.)

The CGMP regulations do not specify the number of containers to be sampled from each received shipment. However, § 211.84(b) establishes the principles to be followed in designing a sampling program for components. The requirements of this department can be summarized as follows:

Samples are to be representative of the shipment received.
The number of containers sampled also as the amount of material sampled from each container is to be based on statistical criteria for component variability, confidence levels, and the degree of precision required.
The sample program takes into account the past quality history of the supplier.
The sample amount is to be sufficient for the necessary analysis and reserve samples.

The starting time three are most relevant to the question of how many containers to sample for identity testing, i.e., representative sampling, tolerance for variability and confidence required, and past history. (The corporeality needed for assay and reserve can be readily met by sampling even one container, then the number of containers is non an of import issue once the shipment'due south identity is verified.)

Unlike most component attributes, a component's identity is more often than not a detached variable, i.e., the textile in the container either is or is not what the characterization purports it to exist. The component container'south content might differ from what the container label states due to mistakes in filling and labeling by the supplier or repacker, or equally a result of the substitution of a container's contents during distribution and warehousing before receipt by the drug product manufacturer. Using a wrong component in processing could result in a serious public health hazard. For these reasons, manufacturers need to develop an approach that provides a high degree of confidence that each container in each shipment contains the textile purported by the label. (See besides 21 CFR 211.160(b), which requires all sampling to be representative and scientifically sound.) The arroyo must account for the fact that the fabric'due south identity must not vary from what is specified. The past quality history of a supplier and the scope of their operations is relevant to the chance for mistakes to occur under a supplier's command, simply does non necessarily comport on what happens to a drug once it is outside the supplier's control.

How many containers of each component from each shipment must a firm sample and test to comply with the CGMP requirements for identity testing?

The regulation at § 211.84 requires that representative samples of each shipment of each lot shall be nerveless for testing. Some manufacturers have interpreted the CGMPs to require that each container in a shipment exist sampled and tested for the aspect of identity. Testing samples from every container to make up one's mind identity may be valuable particularly for components purchased from distributors. (Analytical equipment and methods are readily bachelor that permit rapid, nondestructive identification of material direct in containers in a warehouse expanse.) The CGMPs permit each drug production manufacturer to make its own decision as to the number of containers to sample, equally long as the sampling programme is scientifically sound, leads to representative samples, and complies with the principles established at § 211.84(b). An important caveat applies with respect to § 211.84: samples are to be taken past the drug production manufacturer from containers later on receipt (i.e., pre-shipment samples or so-called piggyback samples are generally not acceptable).

Do the CGMPs permit the identity test on a pooled, or composite, sample of multiple containers?

The CGMPs address the issue of sample compositing direct but only in the context of individual container sampling. Section 211.84(c)(4) explicitly prohibits compositing samples taken from the height, middle, and bottom of a single container when such stratified sampling is considered necessary (every bit might be the case when moisture content needs to exist controlled, particularly when merely a portion of a container may be used in a drug product batch). The preamble for § 211.84(c)(4) explains farther that there "is no full general prohibition... on compositing samples [from single containers] where such compositing would not mask subdivisions of the sample that practise non meet specifications" (see 1978 preamble, paragraph 231).

Testing individual samples from multiple containers provides a high level of balls and is consistent with CGMP. Testing a blended sample for identity could satisfy the CGMP regulations (§§ 211.84 and 211.160) merely only if a manufacturer demonstrates either that the detection of a single nonconforming container is non masked past compositing or that an additional test(due south) routinely performed on the composite sample ensures that all containers sampled contain the same material. Thus, a purity assay on a blended sample prepared by mixing equal aliquots from each container may be adequate provided such a test is sufficiently sensitive to reveal the presence of a single nonconforming container.

References:

Preamble to the Electric current Skillful Manufacturing Practice in Manufacture, Processing, Packing, or Property regulations (43 FR 45014, Sept 29, 1978)
21 CFR 211.82: Receipt and storage of untested components, drug product containers, and closures
21 CFR 211.84: Testing and approval or rejection of components, drug production containers, and closures
21 CFR 211.160: General requirements (Laboratory Controls)
FDA Guidance for Industry, 2000, ICH Q6A Specifications: Examination Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances [Text or PDF]
FDA Guidance for Industry, 1999, ICH Q6B Specifications: Exam Procedures and Acceptance Criteria for Biotechnological/Biological Products [PDF]

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v. What methods of analysis are suitable for testing for melamine contagion in pharmaceutical components?

FDA recommends using a method demonstrated to be suitable for detecting melamine adulteration based on the manufacturer'south risk assessment and prevention strategy. The manufacturer'due south choice of a sampling arroyo and test method sensitivity should address the possibility that (1) melamine might not exist uniformly distributed in an at-risk component, or (2) that the source of intentional melamine contamination might be the starting material used to produce the at-risk component. The guidance for industry Pharmaceutical Components at Take chances for Melamine Contagion provides a link to assay methods capable of detecting melamine at levels as low as 2.5ppm. These methods can discover melamine and cyanuric acid in circuitous matrices (protein materials) and, therefore, may exist useful in developing test methods for other at-risk drug components. FDA likewise recognizes that a less sensitive method might also be appropriate for screening in certain cases.

References:

21 CFR part 211, subpart E: Command of Components and Drug Product Containers and Closures
FDA Guidance for Manufacture, 2009, Pharmaceutical Components at Risk for Melamine Contagion

Engagement: 12/17/2009

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6. Does FDA require or recommend any special precautions or controls over the manufacturing of animal-derived drug ingredients to forestall contamination?

Yep, FDA requires that animal-derived ingredients be controlled in a manner to ensure that contamination does non occur, beginning with initial collection and treatment of the animal-derived fabric through its processing and subsequent employ in a finished pharmaceutical. Come across, for instance, the Federal Food, Drug, and Cosmetic Act (FD&C Act) sections 501(a)(2)(A) and 501(a)(2)(B).

FDA has special concerns regarding the vulnerability of brute-derived ingredients to contamination by pathogenic agents (i.east., agents that tin cause disease or illness in humans or other animals). Every bit background, ingredients are also called components, and there are ii categories of components used in finished pharmaceutical product: inactive ingredient (often chosen excipients) and active ingredient (oft chosen active pharmaceutical ingredient (API)). For the purpose of this guidance, an fauna-derived ingredient is a substance of animal origin used to manufacture a drug production. They are primarily derived from byproducts of nutrient product and include extractions from certain animal material and milked animal fluids (eastward.m., venoms) and may even be human-derived. Products of brute cell cultures, including monoclonal antibodies and therapeutic proteins, are non considered brute-derived APIs for the purpose of this guidance. For boosted information concerning biotechnology products, refer to ICH guidance for manufacture Q5A Viral Rubber Evaluation of Biotechnology Products Derived from Cell Lines of Human being or Animate being Origin. Ingredient manufacturers are responsible for the quality and safe of the material they produce for use in finished pharmaceuticals. Ingredients are drugs and drugs are required to conform with current good manufacturing practice (FD&C Act, department 501(a)(2)(B)). Finished pharmaceutical manufacturers are also responsible for their selection, qualification, and apply of ingredients in finished pharmaceuticals (e.g., the CGMP regulations at 21 CFR part 211, subpart E). Ingredient and finished pharmaceutical manufacturers should fully empathize the potential for pathogenic amanuensis contamination offset with the livestock processing establishment (LPE) and continuing through subsequent handling and processing, and establish stringent controls to prevent contagion. Information technology is as well essential that appropriate tests or examinations are adult and practical to detect contamination as part of whatever meaningful command programme. References:

FD&C Act, sections 501(a)(ii)(A) and 501(a)(2)(B)
21 CFR part 211, subpart E: Control of Components and Drug Product Containers and Closures
FDA Guidance for Industry, 1998, ICH Q5A Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Homo or Animate being Origin

Engagement: 1/27/2011 Back to Meridian

7. What are FDA's main concerns most pathogenic agent contamination of animal-derived drug ingredients?

FDA is concerned almost contagion of animal-derived ingredients by pathogenic agents during processing at the LPE, at a subsequent consolidator of animal material or raw cloth processing plant, or during the manufacturing procedure to create the terminal ingredient. One should presume that animal-derived materials will not only harbor merely will often support growth of pathogens and appropriately should ensure appropriate control over the handling and processing of these materials. Electric current practiced manufacturing practise is to be followed in treatment such textile to ensure that contamination does not occur that would affect the textile'southward quality and purity, or that would be harmful when the product is administered to patients. Pathogenic agent contagion includes leaner, molds, viruses, protozoa, parasites, and prions. Pathogenic agents tin enter the manufacturing facility inside the animal material and contaminate excipients, h2o, processing equipment, personnel, environment, or packaging. Contaminated drug ingredients present potential wellness risks that may affect diverse patient populations, including immune-compromised patients, as well equally otherwise healthy people of all ages. An agent may be considered pathogenic if its presence represents a significant risk to patient safety. Factors affecting the pathogenic agent's ability to cause harm include the:

Nature of the agent (pathogenicity, virulence)
Amount of the pathogenic agent
Blazon of manufacturing procedure and whether it affects the pathogenic agent'south ability to survive
Ability of the pathogenic amanuensis to grow within the ingredient
Type of drug production, and its route and length of administration
Patient population for the drug product (including the most vulnerable patients who may take the drug).

Appointment: 1/27/2011

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eight. What manufacturing contamination risks are presented by the dissimilar pathogenic agents?

Manufacturing contagion risks presented by the dissimilar pathogenic agents can include the following: Vegetative Bacteria Vegetative bacteria are actively growing and reproducing bacteria. If there are no steps in the manufacturing process to kill vegetative leaner, they can proliferate and accumulate during drug ingredient processing. Toxin-Producing Microorganisms Several genera and species of microorganisms are capable of producing toxins. Microbial toxins can be divided into two general groups: exotoxins and endotoxins. An exotoxin is a soluble protein excreted by a microorganism, including leaner, fungi, algae, and protozoa. Exotoxins can include oestrus-stable toxins that remain active at temperatures as high as 100°C or heat-labile toxins that are readily inactivated by heat treatment. Exotoxins, especially oestrus-stable exotoxins, can remain in the ingredient throughout the manufacturing process and adversely affect patient wellness. An endotoxin is a component of the outer membrane of a Gram-negative bacterium. Unlike exotoxins, endotoxins are only released when the organisms are disrupted or destroyed. Endotoxins are oestrus- and chemical-resistant and, if injected, may induce reactions including delirious effect, hypotension, and shock. Spore-Forming Leaner Spore-forming bacteria can be hard to eliminate from the manufacturing environs because the spores may be extremely resistant to rut, freezing, farthermost pH, desiccation, and chemicals. Spore-forming bacteria can produce exotoxins and can remain dormant without nutrients for extended periods. Spores tin can be resistant to harsh manufacturing processes that will kill vegetative bacteria. When dormant spores are reintroduced into an acceptable germination environment they tin become agile reproductive vegetative cells. Once spores germinate and begin reproducing as vegetative cells, production of exotoxins can occur in a short period of time. Fungi/Molds Molds are a subset of fungi that reproduce by releasing spores into the air which, if they land on a moist nutrient source or creature tissue, can germinate. Some species of molds produce toxic byproducts called mycotoxins. Mycotoxins can accrue in beast tissues, rendering the affected organs/tissues unfit for employ as a source of starting material for the production of brute-derived drug ingredients. It is important to forestall molds from growing in drug ingredients and when feasible and valuable remove all molds that may contaminate such ingredients. Yeasts, some other type of fungi, tin also exist pathogenic or cause spoilage of an ingredient. Viruses Although a virus can only multiply inside its host, the inadvertent utilise of material from virus-infected animals or contact of the drug ingredient with virus-contaminated surfaces tin can transmit viral particles to patients. Virus survival rates differ based on virus blazon and variables associated with surface materials that get contaminated. On hard, nonporous surfaces, some virus species tin can survive and remain transmissible for days or weeks. The probability of an creature virus contaminating an animate being-derived ingredient will depend on the viral load of the raw material (e.g., tissue, glands, blood) and the viral clearance capability of the drug ingredient manufacturing process. Both of these factors should be considered when assessing the adventure of viral contamination of the ingredient. Internal Beast Parasites Transmission of internal parasites occurs from host to host through consumption of contaminated food or water. Parasites live and reproduce within the tissues and organs of infected hosts and are often excreted in feces. Government inspectors are trained to look for internal parasites and prevent unhealthy animals from entering the food supply. Animals deemed fit for food consumption are inspected and certified as salubrious. Prions Protection from prion contamination includes obtaining bovine meat and meat byproducts from animals not infected with bovine spongiform encephalopathy and protecting against contamination of production with high-risk tissues, particularly encephalon and spinal string tissue. Drug manufacturers importing bovine cloth into the U.s. should exist familiar with and adhere to all import eligibility requirements and government regulations pertaining to nutrient and drugs. It is important that farms, slaughterhouses, and renderers observe government regulations prohibiting the use of unhealthy animals in the nutrient supply. Animals deemed fit for nutrient consumption are normally inspected and certified as healthy in many countries.

Date: ane/27/2011

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9. What are some ways to minimize pathogenic agent contamination in incoming animal-derived raw textile?

The drug component and finished production CGMP guidances and regulations emphasize prevention of problems and avoidance of contamination rather than final testing or examination alone. In other words, control strategies that foreclose contamination are central to CGMP, while control strategies based on testing lone do not comply with CGMPs. Raw materials from animals tin can take microbial pathogen health risks based on country of origin, LPE processing, transportation, and manufacturing processing. Nether the correct circumstances, raw material from animals tin can provide a suitable (e.thousand., nutrient-rich) environment for leaner and mold to proliferate, or for viruses and other pathogenic agents to remain infective. If undetected contaminated raw material enters the manufacturing process, information technology tin can remain pathogenic in the product and a risk to the consumer. The manufacturing weather condition used in most ingredient manufacturing processes are oftentimes bereft to eliminate all pathogenic agents from the ingredient. Methods of minimizing contamination of raw fabric with pathogenic agents may include the following:

Animal source
When animal-derived material is used, it is of import that information technology be derived from healthy, disease-free animals. The occurrence of pathogens tin can vary greatly among unlike creature species. Ingredient manufacturers should understand the pathogenic risks associated with dissimilar animal species and with different organs, glands, or tissues within species. Drug ingredient manufacturers should be aware that fifty-fifty healthy animals can be reservoirs for pathogenic agents and improper handling tin spread contamination. If improperly handled, microbial contamination can transfer to uncontaminated tissues and cause contamination.

Ensuring the health of U.South. livestock is the responsibility of many Federal agencies, most of which are role of the U.S. Department of Agronomics (USDA). Animal-health and food-safety regulations are detailed in titles 9 and 21 of the Code of Federal Regulations. Fauna health regime in each State develop regulations that are consistent with the Federal agencies and are responsible for monitoring and controlling diseases in the State's domestic livestock and poultry.Land inspectors ensure compliance by companies with private State standards besides as with Federal meat and poultry inspection statutes. States assist in controlling diseases through inspections, testing, vaccinations, treatments, quarantines, and other activities.

Sensation of the weather condition of control and monitoring of source animals will assistance in determining which animals and creature parts are appropriate for drug product manufacturing.

LPE
Ingredient manufacturers should consider auditing the LPEs supplying raw materials to them and ensure their compliance with all Federal and Land government regulations. It is recommended that manufacturers develop standard operating procedures and define sanitation requirements of raw materials immediately after butchering, including, for example, the following:
- Chilling requirements, if indicated, including temperature ranges and how soon afterward butchering chilling should brainstorm
- Chemical preservation methods, if indicated, including types and concentrations of chemical preservatives used
- Storage processes, including sanitization of containers and container type/material (e.g., stainless steel vs. food grade plastics)
- Transportation criteria, including sanitization of containers, if different from storage and temperature ranges

The overall contamination of carcasses with pathogens depends on non merely the prevalence and numbers of the pathogens on the pilus, pare, and in the abdominal tract of the fauna, just is significantly affected past the degree of cross-contamination occurring from these sources during slaughter and processing (see USDA references, beneath, for additional information). FDA expects that manufacturers will establish appropriate specifications for bioburden in their in-coming raw materials. References:

USDA Animal and Plant Health Inspection Service
USDA Animal and Institute Health Inspection Service, Import and Export
USDA Nutrient Safety and Inspection Service, Parasites and Foodborne Illness Fact Sheet

Date: 1/27/2011

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10. Are there control measures for minimizing pathogenic amanuensis contamination in brute-derived drug ingredient manufacturing facilities? Yes, control measures may include the following:

Procedure control
Holding and processing times for animal-derived fabric should be minimized to reduce the likelihood of microbial proliferation. The procedure qualification studies should include microbial sampling at multiple fourth dimension points to evaluate the effects of fourth dimension, temperature, and processing weather condition on microbial growth. Routine microbial identification will provide valuable information regarding the types of organisms present in incoming cloth and throughout the manufacturing process. Processing conditions can and so be adjusted to help control the number and types of organisms present during the manufacturing process. Spores and many bacteria tin exist removed past filtration when filtration or filtration cascade systems are possible. Ordinarily filters with a pore size rating of 0.45 micron or smaller volition remove spores and many bacteria from a preparation. Viruses and many toxins are rut labile so a heat treatment should exist considered early in process development. Many purification and concentration systems may have antimicrobial effects. The timing and sequence location in the process forth with advisable property and processing times may serve to optimize the antimicrobial effects of the processes.

Development of procedure monitoring tests and acceptance criteria should be established during the procedure development stage.
Facility and equipment controls
Facilities tin also be reservoirs for pathogenic agents. Maintaining a facility inside CGMP should include but non be limited to:
- Having fairly trained staff
- Using suitable quality water during manufacturing
- Having a facility design that minimizes the risk of cross-contagion
- Providing for proper storage of the ingredient

Cleaning procedures should include cleaning of facilities and equipment that ensures the removal of all raw materials betwixt batches. Designing an constructive cleaning plan involves setting specific standards, understanding the facility'due south microbial environmental isolates, and selecting the right disinfecting agents to inactivate isolates that may be in the product or in the surround. Ingredient manufacturers should use sporicidal agents at advisable intervals in the cleaning schedule to destroy bacterial and fungal spores. References:

FDA Guidance for Industry, 2001, ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
United states of america Pharmacopeia (USP) General Information Chapter <1072> Disinfectants and Antiseptics (USP33–NF 28 Reissue, 2010)
Wiley, JM, Fifty Sherwood, and CJ Woolverton, 2008, Prescott, Harley and Klein's Microbiology, Boston: McGraw-Hill Higher Education.

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11. What should drug manufacturers do to prevent formation of glass lamellae (glass fragments) in injectable drugs filled in pocket-size-volume drinking glass vials?

Under certain atmospheric condition, glass vials can shed sparse, flexible fragments called glass lamellae (Lachman, Lieberman, et al. 1986; Iacocca, Toltl, et al. 2010). These lamellae are shed from the interior surface of the glass container directly into the drug and are difficult to detect by visual inspection. Several drugs have been recalled due to this problem: epoetin alfa, methotrexate, hyaluronidase recombinant, and fluorouracil (see Enforcement Reports on FDA'southward Web Site). No adverse events to date have been reported nor can be straight attributed to this phenomenon. Still, there is the potential for drugs administered intravenously that incorporate these fragments to cause embolic, thrombotic, and other vascular events (e.g., phlebitis); and, when administered subcutaneously, to lead to development of foreign body granuloma, local injection site reactions, and increased immunogenicity (Singh, Afonina, et al. 2010). The post-obit conditions have been associated with a higher incidence of the formation of glass lamellae:

Glass vials manufactured by a tubing process (and thus manufactured under college heat). These vials are less resistant than molded glass vials and may shed lamellae more than easily (Ennis, Pritchard, et al. 2001). The processing conditions used to manufacture drinking glass vials tin can be designed to mitigate the potential for later delamination.
Drug solutions formulated at high pH (alkaline) and with sure buffers. Mutual buffers associated with lamellae formation include citrate and tartrate (Sacha, et al. 2010).
Length of time the drug product is exposed to the inner surface of the container. The time elapsing has a direct correlation to the potential for glass lamellae germination to occur during the product shelf life (Lachman, Lieberman, et al. 1986).
Drug products with room temperature storage requirements. Drugs stored at room temperature take a greater chance of drinking glass lamellae germination than do products stored at colder temperatures (Iacocca and Allgeier 2007).
Final sterilization has a significant effect on glass stability (Iacocca, Toltl, et al. 2010).

The referenced literature, below, includes recommended actions to help forbid the germination of glass lamellae. For example, for products "at risk," the vial surface alkalinity can be minimized by proper selection of drinking glass limerick (e.k., highly resistant, nonalkaline world borosilicate glass), advisable selection and qualification of vendors, and proper quality command of the incoming vials. Accordingly, FDA advises drug manufacturers of products to reexamine their supplier quality management program with the drinking glass vial manufacturers to ensure that this phenomenon is not occurring. Farther, the Agency reminds finished drug product manufacturers that CGMP regulations require that drug containers not be reactive or additive then as to alter the safe or quality of the drug. See 21 CFR 211.94; Rx-360's Spider web site, which has commented on the issue of delamination; and deviation reporting regulations for field alert reports (21 CFR 314.81) and biological product deviation reports (21 CFR 600.14). References:

Lachman, L, H Lieberman, and J Kanig, 1986, The Theory and Practice of Industrial Pharmacy, 3rd ed., Philadelphia: Lippincott Williams & Wilkins, 645–649, 796–798
Iacocca, RG, N Toltl, et al., 2010, Factors Affecting the Chemic Durability of Glass Used in the Pharmaceutical Industry, AAPS Pharm Sci Tech, DOI:ten.1208/s12249-010-9506-9
Singh SK, N Afonina, et al., 2010, An Industry Perspective on the Monitoring of Subvisible Particles equally a Quality Aspect for Protein Therapeutics, J Pharm Sci, 99(8):3302–3321
Ennis RD, R Pritchard, et al., 2001, Glass Vials for Small Book Parenterals: Influence of Drug and Manufacturing Process on Glass Delamination, Pharm Dev and Tech, vi(3):393–405
Sacha, 1000., et al., 2010, Applied Fundamentals of Glass, Rubber, and Plastic Sterile Packaging Systems, Pharm Dev and Tech, 15(1):6–34
Iacocca, RG, and M Allgeier, 2007, Corrosive Attack of Glass by a Pharmaceutical Compound, J Mater Sci, 42:801–811
21 CFR 211.94: Drug product containers and closures
21 CFR 314.81: Other postmarketing reports
21 CFR 600.14: Reporting of biological product deviations past licensed manufacturers

Date: 3/25/2011 Back to Pinnacle

12. Are there any special processing or handling concerns for flexible intravenous (IV) solution bags?

Yep, due to their soft and flexible design, IV solution bags can be easily damaged if not handled properly during processing and labeling. A damaged IV solution pocketbook may non protect the contents from exposure to microbiological contagion as intended. Detection of a damaged 4 solution bag by leaks or past examination of the pocketbook may not be possible. In fact, a microscopic defect may non be evident until microbiological contamination becomes visible, which is too late. Prevention of this potentially serious problem is important. FDA is enlightened of product recalls where 4 products in flexible plastic bags were exposed to rough surfaces or sharp objects during labeling, creating microscopic punctures or weakening the bag surfaces. When a compromised IV solution bag is filled with liquid and expands as intended, holes may form at the weak points, leading to a loss of sterility or assurance of sterility.

Manufacturers are reminded that drug product containers and closures must exist handled and stored in a fashion to forestall contamination (meet 21 CFR 211.fourscore(b) and besides 211.94).

References:

21 CFR 211.80(b): General requirements
21 CFR 211.94: Drug product containers and closures

Date: vii/five/2011

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xiii. What can IV drug manufacturers do to help prevent the loss of sterility due to compromised IV solution bag integrity during labeling?

The risk of loss of sterility during labeling can be reduced through the use of nonimpression printing devices for labeling. If a manufacturer uses labeling equipment to employ a label on an Four solution purse and that labeling equipment makes an impression on the IV pocketbook, procedures should be in place to inspect the labeling equipment regularly, especially later on any maintenance is performed. Manufacturing equipment must non have any rough or sharp surfaces that will create punctures or areas of weakness in the Four solution bags. Prevention is important: damaged 4 numberless may elude detection by standard examinations and tests, including checks for leaks. Manufacturers are reminded that equipment maintenance and cleaning must be appropriate to preclude malfunctions or contamination that would modify the quality or purity of a drug product (see 21 CFR 211.67). Additional information: FDA Guidances

Sterile Drug Products Produced past Aseptic Processing—Current Skillful Manufacturing Exercise
Container Closure Systems for Packaging Homo Drugs and Biologics

References:

21 CFR role 211: Electric current Good Manufacturing Practice for Finished Pharmaceuticals
21 CFR 211.22: Responsibilities of quality control unit
21 CFR 211.80: Full general requirements (for the control of components and containers)
21 CFR 211.94: Drug production containers and closures
21 CFR 211.67: Equipment cleaning and maintenance
21 CFR 211.100: Written procedures; deviations

Recall announcements FDA Warning Letters Appointment: 7/v/2011

fourteen. Must each batch of a U.s.a. Pharmacopeia (USP)-form API be tested using the belittling procedures specified in the USP monograph?

No; nonetheless, in the event of a dispute, the compendial method is considered conclusive (see USP reference, below). Department 201(g) of the FD&C Act includes "articles intended for use as a component" of a finished drug product, including APIs (or drug substances), under its definition of a drug, and section 501(b) requires a drug recognized in USP to meet the standards of force, quality, and purity in the official monograph or to exist clearly labeled to designate how information technology differs from USP standards. Although each batch of a compendial article must conform to the monograph specifications/acceptance criteria, the analytical procedures used to show conformance may differ from official USP methods if the alternative methods are fully validated, suitable for use, and requite equivalent or better results than the official USP method. All APIs must likewise be manufactured in compliance with CGMP as stated in department 501(a)(2)(B) of the FD&C Human action. References:

FD&C Act Chapter V: Drugs and Devices
USP 38–National Formulary (NF) 33 (2015) General Notices, Section 6.xxx

Appointment: six/9/2015

15. Who is responsible for analytically testing APIs to ensure they comply with their specifications and with USP requirements, if any? API manufacturers perform analytical testing on APIs to ostend that they meet all applicative specifications established for release. Finished drug product manufacturers ensure that APIs used in their products encounter all of their established specifications and—for compendial APIs—meet USP requirements. Additional information is provided beneath. API Manufacturer Responsibilities Section 501(a)(2)(B) of the FD&C Human activity requires all drugs (including APIs) to exist manufactured in compliance with CGMP. FDA therefore expects API manufacturers to follow the recommendations in ICH guidance for industry Q7 Proficient Manufacturing Do Guidance for Agile Pharmaceutical Ingredients. API labeling supplied past the API manufacturer includes a certificate of analysis (COA). Section xi.4 of ICH Q7 recommends that the API manufacturer'due south COA should include, as applicable, the API's proper name, grade, batch/lot number, date of release, and a list of "each test performed in accord with compendial or client requirements, including the credence limits, and the numerical results obtained . . . ." For example, for a compendial-grade API, the COA should identify the compendial tests that were performed (besides equally customer-specified tests, if any) and the test results. If a compendial-grade API differs from a USP standard of strength, quality, or purity, that difference should be conspicuously alleged on the characterization. Finished Drug Production Manufacturer Responsibilities In the CGMP regulations for finished pharmaceuticals, 21 CFR 211.80 states that "[T]hither shall be written procedures describing in sufficient detail the . . . testing . . . of [finished drug product] components . . . ." Additionally, 21 CFR 211.84(d)(2) states that "[E]ach component shall be tested for conformity with all advisable written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a study of analysis may exist accustomed from the supplier of a component, provided that at least i specific identity examination is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier'due south exam results at appropriate intervals." Therefore, if the finished drug product manufacturer accepts the test results from an API supplier's COA rather than performing the tests itself (other than for identity, which the manufacturer is required to perform), the manufacturer must validate the API supplier'southward reliability. This validation procedure is established past the finished drug product manufacturer and should be consistent with the principles of CGMP and run a risk management. The finished drug product manufacturer should also ensure that compendial-grade APIs comply with compendial specifications, either by testing the APIs or past validating API suppliers' reliability, as described above. References:

FD&C Human action Chapter 5: Drugs and Devices
21 CFR 211.80: General requirements
21 CFR 211.84: Testing and blessing or rejection of components, drug product containers and closures
FDA Guidance for Industry, 2001, ICH Q7 Good Manufacturing Exercise Guidance for Agile Pharmaceutical Ingredients

Engagement: half-dozen/9/2015 Dorsum to Superlative

Contact for further information: CDER-OPQ-Inquiries@fda.hhs.gov