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Micro Molding and Micro Assembly of Medical and Drug Delivery Devices

12/1/17     Micro Engineering Solutions is a product development CMO specializing in the development of micro devices through Phase 1 Clinical trials.

This article is an excellent resource explaining the FDA ruling on rules and efficiencies of developing drug delivery devices in non-aseptic and non- cGMP facilities through Phase 1.  MES is well suited and equipped to execute testing and retain design history for this crucial and expedited phase of development activity.

Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms

www.drug-dev.com

 

  1.  Introduction

As a product transitions from pre-clinical development to a clinical development phase, the manufacturing process takes on a much greater role in the overall success of the project. This transition is particularly difficult for emerging pharmaceutical companies whose expertise typically lies in the biology and chemistry of how their drug interacts with targets in the body, and less on the engineering, regulatory and quality aspects of manufacturing the drug product. This critical milestone is made even more challenging when the drug product is intended to be a sterile, injectable dosage form as the manufacturing and quality requirements can be overwhelming for a small company. Most small pharma companies turn to Contract Development and Manufacturing Organizations (CDMOs) to outsource this activity, as the cost to establish the capability internally often does not merit the investment for an early-stage product.

Many CDMOs do not provide manufacturing services for injectable products, and those that do often have facilities suitable for large scale production. Since early-stage products are almost always manufactured in small batches, there is a market need for CDMOs with the flexibility to provide manufacturing services for Phase I sterile dosage forms. For example, in some cases, it may be advantageous for a CDMO to establish a GMP area within a “laboratory setting” for the manufacture of drug product in early development. The rationale for this approach is to avoid the significant investment in setting up a dedicated facility and to create simpler, more flexible systems that meet GMP requirements, but are tailored for the specific activity envisioned. As long as the appropriate GMP controls are maintained, especially as related to operator safety, cleaning, and prevention of cross-contamination, there is  no compliance barrier to using “lab-type” facilities for the  manufacture of early phase clinical batches. This article describes the considerations for establishing this capability, and focuses on dosage forms that are sterile and dispersible.

 

  1. Regulatory Landscape for Phase 1 Dosage Forms

On September 15, 2008 the FDA made effective an amended rule that applies to small-molecule drugs and biologics, including vaccines and gene therapy products. The note in the Federal Register of 15 July 2008 (Volume 73, No. 136) announced an adaptation of 21 CFR 210 and 211: investigational medicinal products solely intended for use in Phase 1 are to be exempted from complying with the “final rule” under FD&C Act 505(i) (21 U.S.C 355(i)). The text stresses that the cGMP requirements of 21 CFR 211 are applicable only to Phase 2 and Phase 3 drugs (note, however, the exemption does not apply once the investigational drug has been made available for use by or for the sponsor in a Phase 2, a Phase 3 trial, or if the drug has been lawfully marketed).

“FDA’s position is that the United States’ [GMP] regulations were written primarily to address commercial manufacturing and do not consider the differences between early clinical supply manufacture and commercial manufacture,” the agency says.

For example, the requirements for a fully validated manufacturing process, rotation of stock for drug product containers, repackaging and relabeling of drugs and separate packaging and production areas need not apply  to investigational drug products made for use in Phase 1  trials, the agency says. This makes for solid rationale, as  the typical batch size needed for Phase 1 clinical trials is  typically much smaller in comparison to Phase 3 and  commercial scale batches, and hence the critical controls needed for Phase I should focus on safety of manufacture rather than qualification of processes at this point of drug development (note, however, the FDA did emphasize the importance of meeting the “statutory GMP requirements” of the Food and Drug Act ” 501 (a)2(B) which direct 21 CFR Parts 210 and 211).

In connection with the final rule on Phase I drug GMPs, the FDA issued a guidance recommending approaches to satisfy statutory GMP requirements for such drugs:

“During product development, the quality and safety of Phase I investigational drugs are maintained, in part, by  having appropriate [quality control (QC)] procedures in  effect,” the guidance states. “Using established or  standardized QC procedures and following appropriate cGMP will also facilitate the manufacture of equivalent or comparable IND product for future clinical trials as needed.”

While the basic requirements to reduce or eliminate  contamination that would cause adulteration in  non-sterile drug products are demanding, the standards for aseptic manufacturing of medicinal drug products are even more stringent. The pharmaceutical product must be non-pyrogenic, in addition to a strict sterility requirement.  Medicinal drug products that do not meet the sterility and non-pyrogenicity requirements can otherwise cause severe harm or a life-threatening health risk to the patient. Hence, these attributes are of utmost importance and concern during Phase 1 manufacture. Since the injectable dosage form must be sterile, the drug product can be terminally sterilized in its packaging, or manufactured aseptically.

Aseptic Manufacturing Regulations In Europe, aseptic manufacturing of sterile products is still seen as a last resort which is only acceptable if all methods of terminal sterilization in the final sealed container have  be excluded. Such being not feasible or applicable, for  example when the drug substance is thermally labile, the EU guidelines require the sterilization in the final container closure system whenever possible. Only the stability of the drug substance is considered, but not the container closure system. The European Pharmacopoeia (EP) prioritizes the terminal sterilization of the final container in manufacturing sterile drug products. The “EU Guidelines to GMP for  Medicinal Products for Human and Veterinary Use, Annex 1, Rev. 2008, Manufacture of Sterile Products” compiles the recommended procedures for sterile products and includes the aspects of aseptic manufacturing.

In the USA, the FDA’s 2004 publication “Guidance for  Industry Sterile Drug Products Produced by Aseptic  Processing” describes the expectations of the FDA for the validation of aseptic processing in a more detailed manner. This guidance updates the 1987 guidance primarily with  respect to personnel qualification, cleanroom design and  isolators, air supply system, integrity of container closure systems, process design, quality control, environmental  monitoring, and review of production records. The use of isolators for aseptic processing is also discussed. According to the  latest guidance, acceptance criteria for the  evaluation of media fill states that each contaminated unit should be examined independent of the number of filled units. The microbial environmental monitoring (more  frequency in testing) is accorded more importance to get greater quality assurance. Table 1 lists an overview of  regulatory guidelines for aseptic processing.

 

  1. Sterile, Dispersable Dosage Forms

Suspensions Some drugs are insoluble in all acceptable media and  must, therefore, for parenteral use, be administered as a suspension. One advantage is that drugs in suspension are often chemically more stable than in solution; however, their primary disadvantage is physical stability; i.e., that they tend to settle over time leading to a lack of uniformity of dose.  Issues with settling can be minimized by careful formulation and by shaking the suspension before each dose is  delivered. Physical stability in suspensions is controlled by  (1) the addition of flocculating agents to enhance particle  “dispersability” and (2) the addition of viscosity enhancers to reduce the sedimentation rate in the flocculated  suspension. Flocculating agents are electrolytes which carry an electrical charge opposite that of the net zeta potential of the suspended particles. The addition of the flocculating agent, at some critical concentration, negates the surface charge on the suspended particles and allows the formation of floccules, or clusters of particles, that are held loosely together by weak van der Waals forces. Since the particles are linked together only loosely, they will not cake and may be easily re-dispersed by shaking the suspension. Floccules have approximately the same size particles; therefore a  clear boundary is seen when the particles settle. Viscosity enhancers are typically hydrocolloids (natural, semisynthetic, or synthetic) or clays use in a concentration range from 0.5% to 5%, but the target viscosity will depend on the suspended particle’s tendency to settle.

A couple methods are used to prepare parenteral  suspensions. First, aseptically combining sterile powder  and vehicle involves aseptically dispersing the sterile, milled  active ingredient(s) into a sterile vehicle system (solvent plus necessary excipients); aseptically milling the resulting  suspension as required, and aseptically filling the milled  suspension into suitable containers. For example, this  process is used for preparation of parenteral procaine  penicillin G suspension. Or, second, in-situ crystal formation by combining sterile solutions. In this method active  ingredient(s) are solubilized in a suitable solvent system,  a sterile vehicle system or counter solvent is added that causes the active ingredient to crystallize, the organic  solvent is aseptically removed, the resulting suspension is aseptically milled as necessary, and then filled into suitable containers. For example, this process is used for testosterone and insulin parenteral suspensions.

Nano-Particles A drug’s low solubility often presents a serious challenge to developing bioavailable dosage forms. This challenge can be exacerbated for drugs with chemical stability issues when solubility-enhancing approaches utilize excipients that  are incompatible with the drug substance. To overcome these challenges many technologies have been developed including particle size reduction to nanometer-size drug crystals with greater surface area for dissolution, production of amorphous solid dispersions for reducing the energy  required for dissolution, and lipid-based drug delivery  systems for dissolving a hydrophilic drug in either a lipid  or oil phase.

Nano-Emulsions Oil-in-water emulsions, which are comprised of oil  droplets dispersed in an aqueous continuous phase, can provide unique solutions for overcoming drug solubility and stability problems; for example, Diprivan® (propofol), an  injectable anesthetic, is an nano-emulsion.

Emulsions can be characterized as macro, micro or nano. Macro-emulsions are typically opaque in appearance, since the average particle size of the hydrophobic droplet in a macro-emulsion is typically > 500 nm and thus scatters light.  Micro-emulsions and nano-emulsions are obtained when the size of the droplet is typically in the range of 50-500 nm. In addition, emulsions in this size range can appear translucent or optically clear if the average oil droplet size is < 100 nm, as droplets in that size range no longer scatter light.

The distinction between micro- and nano-emulsions  relates to their thermodynamic stability. Micro-emulsions  are thermodynamically stable due to the use of sufficient  co-solvents and co-surfactants to prevent Ostwald ripening – essentially the coalescence of the droplets into larger  particles. Ostwald ripening is the most frequent physical instability mechanism, although gravitational separation can also occur with larger particles. Nano-emulsions contain much less of the stabilizing co-solvents and co-surfactants, and as such are meta-stable and more susceptible to  Ostwald ripening. In addition, nano-emulsions require  greater kinetic formation energy, and are usually prepared using high-pressure homogenization or ultrasonic  generators. Because of the undesirable side-effects  caused by many solvents and surfactants, micro-emulsions are disadvantageous compared to nano-emulsions. In  order to achieve physically stable nano-emulsions, long chain triglyceride oils are sometimes employed, but  typically require the use of organic co-solvents or toxic co-surfactants (e.g., Cremaphor). The addition of co-solvents and co-surfactants significantly reduces the safety and  tolerability profile of the pharmaceutical formulation. These excipients may not be suitable for pediatric administration, may cause injection site pain and irritation, and are  becoming less acceptable in general for use in  pharmaceutical formulations.

 

  1. Facility Size & Manufacturing Space Considerations

Matching the product to an appropriate facility size is  important. Facility infrastructure typically increases along with facility size, and facility size increases with the scale  of the pharmaceutical project. The development phase of the drug will dictate the capacity requirements of the  formulation and fill. For larger, later stage production  activities the maximum capacity of the facility is critical to ensure success, but this is not a critical factor for early-stage development projects. It is important to evaluate the  product’s requirements and determine the best fit.

The ideal CDMO is one that can grow with a product’s  success, but this is difficult — if not impossible — to find.  Pure CMOs that manufacture high volume commercial  products typically lack the equipment and personnel to manage a developing product that requires low volume, and flexibility in scheduling. Companies that specialize in small volume early stage products have staff experienced in rapid small-scale manufacturing campaigns. A smaller support staff generally has greater flexibility with regard to changes and timing. The lead time for changes at a smaller CDMO should be less than for a CMO that is use to filling lots greater then 100,000 units per day. Although larger CMOs have much greater capacity, they tend to be more rigid and generally have defined systems in place that are not easily changed.  Scheduling is done well in advance (the lead time for scheduling or bringing a product in can be six months  to a year) so the lead time for changes can be a factor.  Evaluating the structure that you require for your stage  of production is an important aspect in choosing the  CDMO that will meet your current and potential  future requirements.

 

  1. Equipment – Both Process and Cleanroom

Cleanrooms are used in practically every industry where small particles can adversely affect the manufacturing  process. A cleanroom is any given contained space where provisions are made to reduce particulate contamination  and control other environmental parameters such as  temperature, humidity and pressure. The key component is the High Efficiency Particulate Air (HEPA) filter that is used to trap particles that are 0.3 micron and larger in size. All  of the air delivered to a cleanroom passes through HEPA filters, and in some cases where stringent cleanliness  performance is necessary, Ultra Low Particulate Air (ULPA) filters are used.

Cleanrooms are classified by how clean the air is. In Federal Standard 209 (A to D) of the USA, the number of particles equal to and greater than 0.5mm is measured in one cubic foot of air, and this count is used to classify the cleanroom. This metric nomenclature is also accepted in the most recent 209E version of the USA Standard. The newer standard  is TC 209 from the International Standards Organization  (ISO 14644-1). Large numbers like “class 100” or “class 1000” refer to the 209E Standard; the standard also allows  interpolation, so it is possible to describe e.g. “class 2000.”

Cleanrooms classified using single digit numbers refer to  ISO 14644-1 standards, which specify the decimal logarithm of the number of particles 0.1 µm or larger permitted per cubic meter of air. So, for example, an ISO class 5 cleanroom has at most 105 = 100,000 particles per m3. Both FS 209E and ISO 14644-1 assume log-log relationships between  particle size and particle concentration. For that reason, there is no such thing as zero particle concentration.  Ordinary room air is approximately class 1,000,000 or ISO 9.

Personnel selected to work in cleanrooms undergo extensive training in contamination control theory. They enter and  exit the cleanroom through airlocks, air showers and/or gowning rooms, and they must wear special clothing  designed to trap contaminants that are naturally generated by skin and the body. Since Phase 1 batches usually are  small scale, one popular alternative of CDMOs is to utilize compounding isolators for sterile manufacture.  Isolators consist of a decontaminated unit, supplied with class 100 or higher air quality that provides uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding clean room and personnel).

An isolator is defined as an ISO 5 enclosure if it meets the following criteria: •  uses rapid transfer ports or another type of  decontaminated, high-integrity interface to transfer compounding materials into the isolator; •  uses an automatic sporicidal  decontamination system; •  constantly maintains a significant overpressure  relative to the surrounding environment; and •  the manufacturer provides documentation verifying that the isolator can maintain ISO 5 at all times.

Any Compounding Aseptic Isolator (CAI) that does not meet all of the isolator criteria would be classified as a restricted access barrier system (RABS). A RABS is an ISO 5 enclosure that provides a physical separation from the compounding area through the use of glove ports, but the openings for transferring materials would not provide the same level of protection as an isolator. In addition, the RABS is cleaned and decontaminated manually.

Aseptic Manufacturing Considerations Aseptic manufacturing consists of a lot of single working steps. But the whole process is only as good as the worst single step. To achieve the aim of a sterile product, several aspects have to be considered and have to be separately validated. In the end, process simulation with media fill is the key validation measure and allows the final evaluation of the appropriateness of the whole process. It is state-of-the-art  to produce medicinal products under aseptic controlled  conditions. This control requires monitoring of the  environment. The design of the monitoring (frequency,  number of sampling sites, method of sampling, procedure  in regard of deviations etc.) is not specifically mandated;  however, the common aim is to recognize any deviation  of the validated state.

The necessity of monitoring the environment as a  key element of a quality assurance program is widely  accepted. Air, surfaces and personnel are all identified as contamination risk sources for the environment. To come to reasonable limits, the rooms of the production areas have firstly to be classified depending on the production step. Limits of air, surfaces and personnel are proposed under consideration of the official recommendations. There are separate requirements for non-viable air particles, and for viable organisms, and the time when the measurements are performed (either at rest, or in operation). The differences determine the nomenclature for clean rooms. Both  personnel and material flow should be optimized to prevent  unnecessary activities that could increase the potential for introducing contaminants to exposed product, container  closures or the surrounding environment. Air (including  purified air) is a main source for contamination. Per EU GMP, viable airborne particles have to be identified and regarded in batch release.  Surfaces which have immediate contact with the product are highly critical. Indirect transfer of  particles from surfaces via air must also be taken into  account. The design of the facility (smooth surfaces without unevenness and tears) is important to avoid contamination and support the success of sanitization procedures.

 

  1. Quality Control, Approach & Audits

Although quality is the responsibility of all personnel  involved in manufacturing, it is highly recommended that individual(s) who are assigned to perform QC functions are independent of manufacturing responsibilities, especially for the cumulative review and release of phase 1 investigational drug batches.

The CDMO engaged in the manufacture of phase 1  investigational drugs should follow written manufacturing and process control procedures that provide for the  following records:

  • A record of manufacturing data that details the materials, equipment, procedures used, and any problems encountered during manufacturing.  Production records should be sufficient to replicate the manufacturing process. Similarly, if the  manufacture of a phase 1 investigational drug batch is initiated but not completed, the record must  include an explanation of why manufacturing  was terminated; •  A record of changes in procedures and processes used for subsequent batches along with the  rationale for any changes; and •  A record of the laboratory (quality control and  microbiological) that have been implemented  (including written procedures) for the production  of sterile-processed phase 1 investigational drugs.

In the early stages of drug development, processing  parameters will be adjusted to meet efficiency targets  better and/or overcome processing hurdles. The CDMO  making these adjustments should have a formal change  control system that allows the client to present this  documentation to the FDA (or other agency) during  later stage filings.

Proper QC documentation also includes a Quality  Agreement. The quality agreement should define  expectations between the CDMO and the sponsor  to review and approve documents, and how they will  communicate with each other, both verbally and in writing.  It also should describe how changes may be made to  standard operating procedures, manufacturing records, specifications, laboratory records, validation documentation, investigation records, annual reports, and other documents related to products or services provided by the contract  facility. The quality agreement should also define owners’ and contract facilities’ roles in making and maintaining  original documents or true copies in accordance with cGMP.

It should explain how those records will be made readily available for inspection. The quality agreement also should indicate that electronic records will be stored in accordance with cGMP and will be immediately retrievable during the  required record-keeping time frames established in  applicable regulations.

Laboratory Controls Laboratory tests used in manufacturing (e.g., testing of  materials, in-process material, packaging, drug product) should be scientifically sound (e.g., specific, sensitive, and accurate), suitable and reliable for the specified purpose.  Tests must be performed under controlled conditions  and follow written procedures describing the testing  methodology. Records of all test results, procedures,  and changes in procedures, must be maintained. The main  purpose of laboratory testing of a Phase 1 investigational drug is to evaluate quality attributes including those that define its identity, strength, potency, and purity, as  appropriate. Specified attributes should be monitored,  and acceptance criteria applied appropriately. For known safety-related concerns, specifications should be established and met. For some Phase 1 investigational drug attributes, all relevant acceptance criteria may not be known at this stage of development as this information will be reviewed in the IND submission.

To ensure reliability of test results, calibration and  maintenance of laboratory equipment at appropriate  intervals according to established written procedures is  required. Personnel verify that the equipment is in good working condition when samples are analyzed (e.g., system suitability). A representative sample from each batch of Phase 1 investigational drug should be retained. Retention  of both the API and Phase 1 investigational drug in  containers used in the clinical trials is essential. The sample should consist of a quantity adequate to perform additional testing or investigation if required at a later date (e.g., twice the quantity necessary to conduct release testing, excluding testing for pyrogenicity and sterility). Storage and  retention the samples for at least two years following clinical trial termination, or withdrawal of the IND application is recommended.

Finally, initiation of a stability study using representative samples of the phase 1 investigational drug to monitor the stability and quality of the phase 1 investigational drug during the clinical trial (i.e., date of manufacture through date of last administration) should be performed under ICH temperature, humidity and light storage conditions.

Audits A drug sponsor should always visit the CDMO’s site during the evaluation process. This visit gives the drug developer a good overview of how the CDMO works. Touring the facility shows if it is a clean and functioning facility. Evaluate  whether the staff grasps the scope of your project, and determine whether the scientists have familiarity with the product type. Drawing on a CDMO’s experience can save time and potentially deliver a better outcome. For instance, a sponsor may believe that filling their product in a multi-dose vial is the best administration method for a clinical setting.  However, this practice could lead to errors in dosing, loss of extremely scarce product, and potentially determining the path forward for container stability. In the early stages  of drug development, processing parameters will be  adjusted to meet efficiency targets better and/or overcome  processing hurdles. The CDMO making these adjustments should have a formal change control system that allows the client to present this documentation to the FDA (or other agency) during later stage filings. After a successful site  visit, the next step is to conduct an in-depth audit.

During the audit you will review documentation systems  and discuss the project in more depth. All information and discussions should be viewed from a quality standpoint. First, learn about the company’s history, size, services,  financial stability, future plans for growth and technological innovations. Then determine the training of personnel and the expertise level of the staff. Find out about the Quality Assurance and Quality Control systems, manuals, reviews and methodology; also determine certifications, document management, procedures and problem solution systems, and equipment maintenance and calibrations. Also, look  at measurements/metrics for monitoring and controls,  deviations (the number and significance of them), technical transfer controls, capabilities, test methods and validations, material controls and inspections, supplier and material qualifications, purchasing controls, and laboratory controls.  Determine the GMP compliance history, and SOP (Standard Operating Procedures) records. From this review a drug  developer will be able to determine if a CDMO has the  technological knowledge, compliance record, and experience to provide solutions to problems and be able to complete documentation in a timely fashion. 7.  Personnel & Training

Double gloves are often used in industrial practice, as a  result of the dressing technique (the second pair of gloves is worn after finalizing the dressing). Some aspects for aseptic technique and behavior in the clean room are mentioned  in the FDA Guidance 2004. Very important for aseptic  manufacturing process are the detailed SOPs of the CDMO such as aseptic operation, gowning room cleaning as well as personnel and room environmental monitoring procedures.

Depending on the room classification or function,  personnel gowning may be as limited as lab coats and  hairnets, or as extensive as fully enveloped in multiple  layered bunny suits with self-contained breathing  apparatus. Cleanroom clothing is used to prevent  substances from being released off the wearer’s body  and contaminating the environment. The cleanroom  clothing itself must not release particles or fibers to prevent contamination of the environment by personnel. Cleanroom garments include boots, shoes, aprons, beard covers,  bouffant caps, coveralls, face masks, frocks/lab coats, gowns, glove and finger cots, hairnets, hoods, sleeves  and shoe covers. The type of cleanroom garments used should reflect the cleanroom and product specifications.

Low-level cleanrooms may only require special shoes having  completely smooth soles that do not track in dust or dirt. However, shoe bottoms must not create slipping hazards since safety always takes precedence. A cleanroom suit is usually required for entering a cleanroom. Class 10,000 cleanrooms may use simple smocks, head covers, and  booties. For Class 10 cleanrooms, careful gown wearing  procedures with a zipped cover all, boots, gloves and  complete respirator enclosure are required. 8.  Process Simulation Validation

All manufacturing procedures in a pharmaceutical  manufacturing operation must be validated – according  to European Pharmacopoeia and FDA guidelines. This  is especially important for aseptic manufacturing of  parenteral dosage forms, where contamination poses a significant patient risk. Process validation includes checks on the process by means of process simulation tests using microbial growth media (i.e., media fill tests). Since, in   pharmaceutical production, validated methods have been  already used for sterilizing equipment, processing air and  water and filtration techniques, media fill validation is very much focused on the aseptic technique of the human  operator. Intensive training and education of personnel is required in order to ensure that media fill validation is  recognized as a means of checking sterility level of aseptic processing. According to all guidelines, process simulation with media fill is state-of-the-art for validation of an  aseptic manufacturing process. Media fill means that a  microbiological nutrient media will be filled into a container closure system (ampules, vials, etc.) instead of the  actual product. The filled container closure systems are incubated under defined parameters and finally checked for microbiological contamination. This is to demonstrate that rooms, equipment and personnel are able to manufacture a product with very low contamination rate.

The EU GMP Guide provides more details on this issue: “Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill) …  The process simulation test should imitate as closely as  possible the routine manufacturing process and include  all the critical subsequent manufacturing steps”.

The validation covers filling of media, environmental  monitoring, and incubation and evaluation of the filled  vials. Additionally the growth promotion properties of the  nutrient must be demonstrated. Microbiological examination of positive vials, bio-burden examination of the materials used and identification of contaminants are as well issues that need to be considered. The simulation should consider such conditions which simulate the highest risk (worst case) of maximum expected and permitted loads. Examples for worst case conditions are defined in ISO 13408. For example, for vial dimension and filling speed, the worst condition is the largest vial with the longest filling time. All interventions and measures of the usual process should be simulated in media fill. For example manual control of the filling volume, change in personnel, and performance of environmental monitoring. Even technical interruptions should be  considered (lack of air system, stopping of the filling  process, etc).

Liquid nutrient growth medium, capable of  supporting a wide range of microorganisms, is prepared, sterilized, and filled in simulation of a normal manufacturing process that includes compounding, sterile filtration,  in-process controls, sterilization of manufacturing process, materials (garments, primary containers, filling equipment), cleaning and sterilization process (e.g., cleaning in place – CIP / sterilization in place – SIP) and filling. The sealed  containers of medium thus produced are then incubated  under prescribed conditions and subsequently examined  for evidence of microbial growth. If the media fill reflects  the standard procedure of product filling, the contamination rate or contamination probability may be used as indicator for the safety of the production process. Comprehensive control of production environment, personnel, and installations, influencing the overall hygienic state of  manufacturing processes will be performed. Since, in  pharmaceutical production, validated methods have been already used for sterilizing equipment, processing air and water and filtration techniques, media fill validation is very much focused on the aseptic technique of the human  operator. Intensive training and education of personnel is required in order to ensure that media fill validation is  recognized as a means of checking sterility level of  aseptic processing.

Preparation of Media Fill Liquid nutrient growth medium, capable of supporting a wide range of microorganisms, is prepared, sterilized, and then filled to simulate a normal manufacturing process that includes compounding, sterile filtration, in-process controls, sterilization of manufacturing process, materials (garments, primary containers, filling equipment), and filling. The sealed containers of medium thus produced are then incubated under prescribed conditions and subsequently examined for evidence of microbial growth. If the media fill reflects the standard procedure of product filling, the contamination rate or contamination probability may be used as indicator for   the safety of the production process.

Environmental monitoring, comprising airborne counts,  particle counts, and hygiene status of personnel and  materials – e.g., balances and compounding vessels –  is conducted during the weighing and compounding of  materials. Prior to filtration, the pH-value of the nutrient broth is checked and in-process controls (IPC) on  identity, clarity, and bioburden are conducted. Samples   are controlled for analytical and microbiological controls  like that of any other product. Holding and process times  are documented and may be prolonged for validation  purposes. The bulk solution is sterile-filtered using the same filter material as in normal aseptic processing. Filter integrity is checked prior to and after use. Environmental monitoring is conducted at this processing step. Prior to filling, primary containers are sterilized and depyrogenized, the filling line is cleaned and sterilized (CIP/SIP) or transfer lines and dosage pumps are sterilized separately.

Number of Fill Units and Filling  Process Duration According to FDA Guidance the minimum number of filled units of media fill is 3,000 units (to reach a confidence level of 95% for demonstration of a contamination rate of less than 0.1%). For batch sizes smaller than 3,000 units,  smaller numbers are acceptable (requirements are given in ISO 13408 and EU GMP Guide Annex 1). For small batch sizes (for example products used for clinical trials) at least the actual batch size should be simulated during media fill.  For very large batches, it is recommended to simulate media fill with 1% of the actual daily batch size. The vials with the smallest and the biggest size should be regarded in media fill. Table 1 gives the minimum units require required for a media fill both for initial qualification and re-qualification  as well as the acceptable warning/action limits.

 

 

Table 1. First Qualification and Re-Qualification: Warning and Action Limits in Media Fill According to ISO 13408-1

 

Analytical Method Validation The extent of analytical procedures and methods validation necessary will vary with the phase of the IND. Hence the CDMO may elect to take a fundamental approach to  validation or qualification when appropriate. The main  goal of performing “staged’ validation in the early drug development is to provide test procedures that are reliable, able to support clinical studies, and evaluate the safety  of the product. The methods should use appropriate  parameters and sound scientific judgment, sufficient  information is defined as to ensure proper identification, quality, purity, strength, and/or potency. The validation data should be retained to link analytical procedures used in early phase/pivotal clinical  studies and a formal validation report with change  control may not be required. A brief summary of the validation studies is recommended to be submitted  in the original IND.

The suitability of an analytical procedure (e.g., USP/NF, the Official Methods of Analysis of AOAC International, or other recognized standard references) should be verified under  actual conditions of use. Information to demonstrate that USP/NF analytical procedures are suitable for the drug  product or drug substance should be included in the  submission and generated under a verification protocol.  The verification protocol should include, but is not limited  to: (1) compendial methodology to be verified with  predetermined acceptance criteria, and (2) details of the methodology (e.g., suitability of reagent(s), equipment,  component(s), chromatographic conditions, column,  detector type(s), sensitivity of detector signal response, system suitability, sample preparation and stability). The procedure and extent of verification should dictate which validation characteristic tests should be included in the protocol (e.g., specificity, LOD, LOQ, precision, accuracy).  Considerations that may influence what characteristic tests should be in the protocol may depend on situations such as whether specification limits are set tighter than compendial acceptance criteria.

Once an analytical procedure (including compendial  methods) is successfully validated (or verified) and  implemented, the procedure should be followed during  the life cycle of the product to continually assure that it  remains fit for its intended purpose. Trend analysis on  method performance should be performed at regular  intervals to evaluate the need to optimize the analytical  procedure or to revalidate all or a part of the analytical  procedure. If an analytical procedure can only meet the  established system suitability requirements with repeated adjustments to the operating conditions stated in the  analytical procedure, the analytical procedure should be  reevaluated, revalidated, or amended, as appropriate.  Over the life cycle of a product, new information and  risk assessments (e.g., a better understanding of product CQAs or awareness of a new impurity) may warrant the  development and validation of a new or alternative  analytical method. New technologies may allow for  greater understanding and/or confidence when ensuring product quality. Applicants should periodically evaluate  the appropriateness of a product’s analytical methods  and consider new or alternative methods. 9.  Conclusion

A small CDMO may choose to establish a GMP area  within a “laboratory setting” for the manufacture of drug product in early development. Also, the use of isolators and  modular cleanrooms provides flexibility for adjusting the manufacturing process to the product. Also, injectable,  sterile, dispersable products can be manufactured aseptically to avoid a terminal sterilization requirement. The FDA has provided an amended rule that stresses that the cGMP  requirements of 21 CFR 211 are applicable only to Phase 2 and Phase 3 drugs and has provided guidance on the  requirements for small-scale Phase I cGMP manufacture.

Some of the regulatory burden is lifted for the manufacture of Phase I materials as long as basic tenets of quality control and validation are met.

A True Platform Single Dose, Disposable Dry Powder Inhaler

10/26/17     DoseOne is a patient friendly single dose inhaler. It is compact, simple and easy to use. It is actuated with a simple compressive snap and gives visual cues for ‘dose ready’ and ‘dose completed’. Just three easy steps, including inhalation!

Just as attractive as its simplicity of use is its competitive performance at a competitive cost. Its simple three-part assembly composed of all injection molded plastic parts makes it highly manufacturable. The assembled unit costs less than $0.10USD at 100MM quantities. It has a capsule based drug storage making filling lines, loading and drug handling efficient and flexible. The simple design also allows for a huge range of material selections based on manufacturing needs. Along with the ease of manufacturability, the emitted dose and respirable fractions are competitive with, if not better than, most current marketed devices. The capsule based technology allows for a wide range of dose volumes and weights of less than 5mg up to 100mg without major design changes. In addition, it is evaluated and optimized for both lactose carrier blends and low density spray dried formulations.

Its simple elegance means faster time-to-market and inherent opportunities. The inherent regulatory advantages include:

• The simplicity and reduced part count reduces complexity, development time and product development risk
• The single dose disposable eliminates complex dose counting requirements
• The capsule based storage is well understood and low risk
• A unique device for each dose eliminates powder holdup and reduces dose consistency concerns
• The simple three component assembly allows for use of almost any USP class VI materials tailored for cost or API compatibility

The simple nature of this device and lack of complex mechanism allows for a huge assortment of industrial designs and branding opportunities for the product design and shape.

The markets and opportunities are endless. DoseOne is a perfect platform for delivery of vaccines, biologics, and single dose rescue or prevention therapies. The simple operation means minimal to no training is needed, which makes it ideal for third world countries or fast acting rescue. Its high efficiency and large dose load capability allow for delivery of large doses such as antibiotics or hormone therapy. In fact the simple assembly and capsule based nature of this device make it the ideal device for use as a clinical development platform for all dry powder inhaler programs for pivotal clinicals or powder development.

The DoseOne is a combination of prior art and new intellectual property fully covered by the following patents: 7,832,399 – 8,360,399 – 8,464,712. The multiple filing and grant patents cover the basic technology in addition to multiple engine configurations, blister packing options, multi dose configurations and dual drug delivery options.

DoseOne is considering all business opportunities including license arrangements or a sale of the intellectual property as a whole. DoseOne is wholly owned by the inventors with no additional ownership interests or silent partners. Previous licensing opportunities have resulted in successful freedom to operate evaluations and pre-phase I device analysis. DoseOne currently has single cavity tools and is Phase I clinical ready. Donna Bibber is the Director of Global Relations for DoseOne and is ready to speak with you about your project. Please email her at DBibber@Dose-One.com.

•Compact, simple, easy to use
•Actuated with a simple compressive snap
•Visual user cues for dose ready and dose completed
•No complex mechanism or user manipulation required
•Three easy steps including inhalation

Dry Powder Inhaler Makes Patient Use Easy

10/6/17     Pulmonary drug delivery has the potential to produce maximum therapeutic benefit to patients by directly targeting drugs to the lungs. The dry powder inhaler (DPI) is the preferred device for the treatment of an increasingly diverse range of diseases. Do to the fact that drug delivery from a DPI involves a complex interaction between the device and the patient, the engineering development of this medical technology is key.

DPI systems target the delivery of fine drug particles to the deeper airways in the lungs using a combination of improved drug formulations and enhanced delivery device technologies. These factors contribute to the overall performance of the aerosol system. There are a large range of devices that are currently available, or under development, for clinical use, but a major concern is that the daily patient use of this device may result in under-dosing. That is one of the factors that makes the DoseOne™ DPI is different from the others.

The DoseOne™ is equipped with a simple dose readiness indicator and a dose delivery indicator, and its size and ease of use (relying on patient inhalation rather than propellant technologies) make it well suited to environments where local health services are sub-optimal. As a single dose device it minimizes the dose-to-dose consistency risk and also negates the requirement for priming needed by many devices.

In addition, as DoseOne™ is a single use disposable device, a new device is used for each dose, eliminating the frequent problem of powder caking and flaking which can affect dose volumes in multi-dose devices. Also, as a single use device, the issue of, and problems associated with, dose counting — which preoccupies the FDA and other health organizations around the world — is made redundant. In its current state, DoseOne™ contains a simple dose readiness indicator as well as a dose delivery indicator in the form of a viewing window, therefore promoting patient compliance by confirming the dose is ready and has been completely administered.
To learn more about DoseOne™ and how to partner up with us, please visit the website: www.Dose-one.com and contact Donna Bibber at 774-230-3459 with any questions you may have.

Tiny Medical Device Validation – Designing or Success

9/20/17     This is a blog from isomicro.com:

VALIDATION

Picture this – your medical device is designed and you’re ready to validate the tiniest component – the technology piece that enables your intellectual property. You dive in head first, knowing your part has +/- 5 micron tolerances on a plastic part. You start like any engineer would start – with a solid stack-up tolerance plan and <20% gage R&R – you should be fine, right?

Consider this general micro molding rule of thumb – BEFORE you even design the injection mold. If you work backwards with the numbers, you’ll have ~0.0004” total tolerance

Total   10 microns = (0.000397”)

Tooling = 20% of 10 microns = 0.00008” (wow, really? This is difficult to do but SO critical to hitting the final Cpk.

Cpk of 1.33 or better on this tolerance means you need ~20% of the tolerance left (and be tightly controlled) to hit your CPK.  The error breakdown generally speaking is:

Tooling 20%
Gage R&R 20%
Molding process 20%
Material lot to lot variation 10% – melt flow, venting
In the bank- 10% for some unforeseen couple of microns

Starting with the tooling (it’s almost always about the tooling), anything we can do to reduce the 20% of steel tolerance in a critical tolerance will increase the numerical dance of success as explained above. Achieving steel tolerances of +/- 0.0002” is fairly straight forward in the precision mold-making industry, however achieving 20% of this is not straight-forward and requires some good research to make sure you have one that can. Selecting the right tooling supplier is the #1 absolute critical contributor to overall micro molding product success.

It’s equally important to understand the gage R&R error in the still measurement as well as the end plastic component. Creating the steel may require EDM, milling, wire EDM, or grinding. Validating steel or pieces of steel that make up a critical feature requires that the metrology equipment is capable of one more resolution higher than the tolerance. For example 20% of 0.000397” = < 0.00008” which requires 0.00001” or better in measurement capability in both steel and plastic. If the tooling supplier doesn’t have this capability, there’s no way to quantify the very start of the process to creating a micro molded part. If the tooling supplier has this capability, you are off to a great start in achieving the final goal of CPK 1.33 or better – a necessary requirement for many medical and drug delivery devices.

Micro Expert to speak at upcoming conference

9/8/17     Medtech notable Donna Bibber, Vice President of Sales and Marketing for Isometric Micro Molding Inc. and President at Micro Engineering Solutions Inc., will be the keynote speaker at the medical extrusion conference. A University of Massachusetts-Lowell graduate with 25 years of experience in micro manufacturing, Bibber has published technical papers on micro and ultra-precision manufacturing topics worldwide. She was named one of 100 notable people in the medical device industry by sister brand MD+DI in 2008. Bibber was president of Micro Engineering Solutions at the time.

The conference, scheduled for Nov. 7, 2017, in St. Louis Park, MN, will address a range of technical issues related to medical extrusion, including:
• Manufacturing micro-medical devices using precision over-molded tubing;
• the role of pellet size in process stability of PA-12 micro-extrusion;
• medical tubing die and process optimization;
• jacketing of discrete guidewire lengths and automation of secondary processes;
• vacuum sizing small-bore tubing; and
• processing semi-crystalline materials

Speakers include Anthony Walder, Global Technology Manager at Lubrizol Corp.; John Perdikoulias, PhD, President of Compuplast Canada Inc.; Jonathan Jurgaitis, Senior Extrusion Engineer at Apollo Medical Extrusion; and Dave Czarnick, a tooling expert with 25 years of experience who holds five extrusion-related patents.
This conference is designed for individuals interested in extruding medical tubing and performing secondary operations such as braiding, over molding, surface treatment and laser drilling for catheters and delivery systems.

The Fall Spotlight Medical Extrusion & Secondary Operations Conference is hosted by Graham Engineering brand American Kuhne.
For more information and to register to attend, click here.

Micro Motor Drug Delivery

8/31/17     Researchers at the University of California San Diego have created micromotors to treat bacterial infections in the stomach. These micro sized vehicles (half the width of a human hair) swim rapidly through the stomach to release antibiotics at a desired pH. This micromotor-enabled delivery approach is a promising new method for treating stomach and gastrointestinal tract diseases with acid-sensitive drugs.

When people take orally administered drugs such as antibiotics and protein-based pharmaceuticals, gastric acid in the stomach can wreck havoc with them. Because of this, drugs used to treat bacterial infections, ulcers and other diseases in the stomach are normally taken with additional substances, called proton pump inhibitors, to suppress gastric acid production. The problem arises when taken over longer periods or in high doses, proton pump inhibitors can cause adverse side effects including headaches, diarrhea and fatigue. In more serious cases, they can cause anxiety or depression. To conquer this, the micromotors have a built-in mechanism to neutralize gastric acid and effectively deliver their drug payloads in the stomach, without the use of proton pump inhibitors.

Each micromotor consists of a spherical magnesium core coated with a protective layer of titanium dioxide, followed by a layer of the antibiotic clarithromycin, and an outer layer of a positively-charged polymer called chitosan that enables the motors to stick to the stomach wall. This binding is enhanced by the propulsion of the micromotors, which is fueled by the stomach’s own acid. The magnesium cores react with gastric acid, generating a stream of hydrogen microbubbles that propel the motors around inside the stomach. This reaction temporarily reduces the amount of acid in the stomach, increasing the pH level enough to allow the micromotors to release the drug and perform treatment. The normal stomach pH is restored within 24 hours.

Clinical trials on mice with Helicobacter pylori infections were done. The micromotors, loaded with clarithromycin, were administered orally once a day for five consecutive days. Afterwards, researchers evaluated the bacterial count in each mouse stomach and found that treatment with the micromotors was slightly more effective than when the same dose of antibiotic was given in combination with proton pump inhibitors.

So what happens to these micromotors after they deliver their drug? Since they are made of mostly biodegradable materials, the magnesium cores and polymer layers are dissolved by gastric acid without producing harmful residues.

Our Dry Powder Inhaler is ready for your application

8/16/17     DoseOne, LLC holds multiple patents and prepared to partner the most innovative DPIs available today, the DoseOne™ Single Dose Powder Inhaler.

Below is an article in FiercePharma about the dry powder inhaler we have blogged about in the past.

Development of the DoseOne™ single dose powder inhaler (US Patents #7,832,399 B2 and #8,360,057 B2) required a multi-disciplinary team approach, as any such drug delivery device needs to combine not just design skills, but also software and mechanical engineering capabilities, and expertise in analytical science and industrialization. From concept to creation, the DoseOne™ device was designed to be sympathetic to the requirements for mass manufacture and regulatory compliance.

The two patents associated with the DoseOne™ single dose powder inhaler cover the unique dosing mechanism of the device, and the ability to use the technology for dual-drug delivery. The DoseOne™ inhaler contains multiple, segregated air pathways, which keeps powder hold-up to a minimum, and makes device optimization for powder properties considerably easier. Using this technology which drives the DoseOne™ inhaler, designs have been developed and patented for dual drug delivery, the device allowing for simultaneous release of two different and separately contained drugs.

From a manufacturability point of view, the key advantage of the DoseOne™ is its simplicity and intuitive use (one motion and complete). Through the expeditious use of design and micro manufacturing expertise, DoseOne™ is an easy to manufacture and assemble 3-component device. The simplicity is of great importance as an inexpensive drug delivery option, costing $0.16 per device at full volume. The ultra-precise nature of the design and components also ensures that the device is small, which makes it easy to carry and package for mass drug distribution.

The inherent characteristics, size, and nature of the drug delivery technology make the DoseOne™ inhaler hugely advantageous for numerous end use applications. One obvious area of interest is in third world treatments of pandemics and epidemics, where there is an enormous emphasis on safety of drug delivery, simplicity of drug delivery, and ways to show compliance with dose administered. The DoseOne™ is equipped with a simple dose readiness indicator and a dose delivery indicator, and its size and ease of use (relying on patient inhalation rather than propellant technologies) make it well suited to environments where local health services are sub-optimal. In addition, for mass drug administration the low unit cost of the device is obviously hugely significant.

The DoseOne™ is extremely easy to validate, and is ideal for drop-shipping with all this implies in reduction of total inventory management and shipping costs, which can reduce the end use cost of the device.

The simplicity of the design also makes it easy to revise to accommodate specific formulations. Of especial importance, however, is the ability using the DoseOne™ inhaler to simultaneously pierce capsules containing different drugs, meaning that the drugs mix within the body, so there is no necessity to address drug interaction issues as would be the case if the drugs were mixed in one capsule.

DoseOne™ is a perfect example of what can be achieved if an innate understanding of micro manufacturing design and manufacturing is combined with an understanding of the regulatory environment that exists around drug delivery devices these days, and a realization of the potential for innovative solutions that cater for mass “self” administration of drugs in a cost-effective and safe way.

The Market for DPIs.
Powder inhalers deliver drugs in the form of dry powder directly to the lungs, and are typically used in the treatment of respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD), asthma, and emphysema. However, due to many of their innate characteristics and advantages as a drug delivery mechanism, there is burgeoning interest around the use of dry powder inhalers (DPIs) in the pharmaceutical and medical device sectors.
In many ways, DPIs have become more prevalent as they have been tailored for markets previously catered for by Metered Dose Inhalers (MDIs), which many patients find difficult to use, which rely on propellants that have come under more and more legislative scrutiny, and — from the device manufacturers and pharmaceutical company’s perspective — are often expensive to make. It is generally agreed that DPIs are easier to use as they simply rely on patient inspiration to deliver the drug, and are less likely to lead to side-effects such as irritation of the airways.

As with all families of drug delivery devices, the balance for drug companies is between affordability and functionality. Unit cost per device is obviously critical, as is the ability for the drug to be delivered in the correct dose, and for there to be minimum drug wastage.

The DoseOne™ Solution
DoseOne™ is a single-use disposable DPI, and as such overcomes many of the problems associated with multi-use DPIs and MDIs. As a single dose device, for example, it minimizes dose-to-dose consistency risk, and also negates the requirement for priming needed by many devices, with all this implies in respect of drug wastage.

In addition, as DoseOne™ is a single use disposable device — and therefore a new device is used for each dose — it eliminates the frequent problem of powder caking and flaking which can affect dose volumes in multi-dose devices.

Also, as a single use device, the issue of, and problems associated with, dose counting — which preoccupies the FDA and other health organizations around the world — is made redundant. In its current state, DoseOne™ contains a simple dose readiness indicator as well as a dose delivery indicator in the form of a viewing window, therefore promoting patient compliance by confirming the dose is ready and has been completely administered.

As such, DoseOne™ satisfies the regulatory demands previously only achieved by complicated and expensive designs. So for any pharma or device manufacturer looking to locate a novel, cost-effective, and efficient drug delivery option please call or email Donna Bibber at dbibber@doseone.com to discuss potential partnerships.

The Merging of Medical Device and Pharmaceutical Industries

7/27/17     As product technology advances and the general demand for healthcare expands, the industry line between medical device manufacturers and pharmaceutical companies are being blurred as innovative products continue to emerge. Manufacturers are exploring new technologies that adhere to better patient compliance, improve product safety and utilize unique drug delivery methods.

These new technologies include:
–  Small adhesive patches that are encapsulated and swallowed. Once in the body they dissolve and stick to the wall of the intestine to deliver time released    medication
– Implantable devices that automatically run tests and dose medications
– Transdermal patches that are embedded with micro sized needles that deliver medication over a period of time

As technology advances and healthcare treatments become more complex, the pharmaceutical and medical device industries will continue to merge their technologies and expertise to deliver patient solutions that combine both pharmaceuticals and medical devices into one simple and convenient product. Currently about half of all manufacturers in both industries have turned to contract services to meet demand as products become more intertwined.

As this newly meshed relationship forms there are many concerns and factors that both industries need to keep in mind, with the top two being:
1. Regulations: Government regulation requires manufacturers to adapt their processes to meet changing production demands of speed, flexibility, and safety while continuing to comply with regulations. Complying with these regulations usually requires a large investment in machinery and software systems, with two out of three companies reporting that they will be spending more on capital equipment in the next two years. Smaller manufacturers are having a hard time with this large expenditure burden, so they are turning to OEMs to help with regulation compliance strategies by adapting their machines to meet data acquisition and storage requirements for marking and tracking products which includes coding and vision inspection systems.
2. High Demand: In addition to complying with numerous regulations, pharmaceutical and medical device manufacturers also face the challenge of increasing consumer demand. This demand is fueled by increased insurance coverage rates and improved healthcare availability. To meet this demand, manufacturers have to produce products at a faster rate, while adhering to stringent regulations. As a result, many manufacturers have turned to smaller batch runs with greater product diversity and more frequent changeovers, requiring machines that are both fast and versatile. OEMs can be a valuable partner in adjusting to process changes by providing manufacturers with innovative, flexible machine builds that are designed to integrate seamlessly into production lines and software systems.

Manufacturers Need a Partner – As pharmaceutical and medical device companies strive to keep up with market demand, they will search for trusted partners to help them comply with the maze of complex regulations. Manufacturers will also need help with the process of implementing new technology, especially automation and data management solutions, which will play a crucial role in a manufacturer’s ability to operate efficiently in a growing market. OEMs and technology suppliers are perfectly situated to offer their experience and expertise to manufacturers as an invaluable tool in resolving future challenges; expertise in automation, integration services, and regulation compliance are key. OEMs and technology suppliers can form stronger relationships by working collaboratively to address a manufacturer’s unique needs on an individual level, in order to achieve a mutually beneficial partnership.

Removing the “patient factor” from glaucoma treatment

7/20/17     Over 3 million Americans suffer with glaucoma and 75% of them administer their own drug treatment incorrectly. These “patient factors” include not being able to see clearly enough to pick up the right medication to use, the inability to successfully put droplets into the eye, and simple forgetfulness.
Sustained delivery devices that take glaucoma therapy out of patients’ hands may be the answer to the many issues related to adherence, with significant benefits for patients and physicians. These technologies are broken into 3 general categories: injectable sustained-release formulations, drug-eluting rings and contact lenses, and punctal plug reservoirs.

glaucoma ring
Drug-eluting rings are currently in clinical trial right now. They are made of a silicone polymer and can house most any drug combination. The ring is put under the eye lid and slowly excretes drug delivery for up to 6 months. This alleviates the patient having to remember to take their medicine. An issue researchers are trying to overcome with rings is they can fall out without the patient being aware of it happening, making it virtually unknown how much of the drug the patient actually received. Once this hurdle is overcome the next obstacle is to figure out the timing of introducing this treatment to a patient. Timing can be a critical factor in the successful treatment of glaucoma. Once the clinical trials are completed and the logistics figured out, drug-eluting rings will most likely play a significant role in glaucoma treatment.

Micro Molder vs. Conventional Molder

7 reasons you need a Micro Molder vs. Conventional Molder

  1. Shot size is less than 30% of barrel capacity
  2. Your tooling source thinks it’s doable but “hasn’t made a mold quite that small before”
  3. Optimized runner systems in comparison to longer runner systems
  4. Your molding source doesn’t have metrology equipment with high resolution
  5. Highly complex detail is achievable with a micro molder
  6. Low tolerance tooling and molding processes
  7. Minimal material waste = money savings