CASE STUDY : CHALLENGES IN METHOD DEVELOPMENT FOR DRUG INTERACTION STUDIES

 

Current FDA guidance indicates that drug interactions should be "defined during drug development, as part of an adequate assessment of the drug's safety and effectiveness."(1) While in vivo drug interaction studies are typically necessary during late-stage development, in vitro drug interaction studies can sometimes serve as a cost-effective substitute to more costly in vivo drug interaction studies in earlier stages of development. Hence along with pharmacokinetic studies, studies designed to investigate drug-drug interactions represent an important step in the drug development process for new chemical entities.

Pacific BioLabs was recently approached by a client in need of quantitative HPLC test methods for 25 different pharmaceuticals as part of an in vitro drug interaction study. Each drug was to be quantified within three separate buffer formulations designed to simulate in vivo conditions. The list of pharmaceuticals included compounds displaying a broad range of chemical structures, each of which would be expected to display unique retention behavior on an HPLC system. In addition, many of the compounds were to be prepared in only trace quantities representative of bodily concentrations observed in a clinical setting.

Method development began with a chalkboard assessment of the chemical properties of each compound to estimate the most suitable HPLC conditions. A thorough literature search was conducted to examine parameters used in previously published methods. The compounds were subsequently divided into three categories corresponding to molecules with high, intermediate, and low polarity. Basic method conditions were then developed for each of the three categories: a shallow gradient (phosphate buffer/acetonitrile) with a C8 column for high polarity molecules, a moderate gradient (phosphate buffer/acetonitrile) with a C8 column for intermediate polarity molecules, and a steep gradient (H2O + formic acid/acetonitrile + formic acid) with a C18 column for low polarity molecules. These conditions served as a starting point from which more specific conditions for each compound could be adjusted and optimized as necessary.

 

Often common in method development, the occurrence of a number of stumbling blocks necessitated the application of some creative workarounds. Many of the low-polarity molecules displayed poor aqueous solubility even after repeated dilution. In these cases, addition of a small amount of DMSO to the aqueous buffers permitted successful dissolution. On the other end of the polarity scale, some compounds displayed little or no retention on C8/C18 columns.  A pentafluorophenyl (PFP) column, which has a unique bonded-phase that interacts with polar compounds, demonstrated adequate retention for an exceptionally high-polarity compound which failed to retain after repeated adjustments of mobile phase pH and gradient conditions. Adequate detection of compounds present in trace concentrations was accomplished through optimization of UV-wavelength and on-column focusing, although one compound present in extremely low concentrations required MS/MS detection.

Optimal method conditions developed at PBL were qualified to ascertain linearity, accuracy, precision, and benchtop stability. In the end, three of the compounds displayed insufficient benchtop stability and one of the compounds was dropped by the client, leaving a grand total of 21 successfully completed HPLC methods. The successful development of these methods – the majority of which were completed in roughly three months’ time – demonstrates Pacific BioLabs’ capability to respond to client needs with both scientific expertise and timeliness.

For more information about method development services and other contract research services please see our analytical services brochure or inquire by telephone at +1 510 964 9000.

1 "Draft Guidance: Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations." FDA, Feb. 2012.

 

 

 

NEW ISO 13485:2016 GUIDANCE PUBLISHED

On March 1, 2016 the International Organization for Standardization published the new edition of the ISO 13485 standard. Previously updated in 2003, the revision places more emphasis on the quality management system throughout the supply chain and product lifecycle, as well as on device usability and postmarket surveillance requirements.

ISO 13485 was written to support medical device manufacturers in designing quality management systems that establish and maintain the effectiveness of their processes. It ensures the consistent design, development, production, installation, and delivery of medical devices that are safe for their intended purpose.

While the ISO 13485 is based on the ISO 9001 process model concepts of Plan, Do, Check, Act, it is adapted for a more rigorous regulatory environment. It is more prescriptive in nature and requires a more thoroughly documented quality management system.

KEY CHANGES

  • Inclusion of risk-based approaches throughout the quality management system
  • Improved alignment with regulatory requirements, particularly for regulatory documentation.
  • Increased applicability to include all the organizations that are involved throughout the lifecycle and supply chain for the product.
  • Harmonization of the requirements for software validation for different software applications in different clauses of the standard.
  • Additional emphasis on validation of processes, particularly for production of sterile medical devices, and addition of requirements for validation of sterile barrier properties.
  • Enhanced focus on complaint handling and reporting to regulatory authorities in accordance with regulatory requirements, and consideration of post-market surveillance.
  • Better planning and documentation of the CAPA, and duly implementing the corrective action.

TRANSITION PROVISIONS

Organizations have until March 1, 2019 to transition to the new standard.  The coexistence of ISO 13485:2003 and ISO 13485:2016 over the next three years will provide the Medical device companies, certification bodies and regulators with some time to switch over to the new standard. After three years however, any existing certification issued to ISO 13485:2003 will not be valid.

 

 

Detailed Methods for Performing Extractables Testing of Materials

A recent article from the Parenteral Drug Association (PDA) Journal provides some of the best information we have found on methods to determine and characterize extractables. It is definitely suggested reading for anyone performing extractables testing, or hoping to better understand this type of materials testing.

From the Parenteral Drug Association Journal:

"Plastic and rubber materials are commonly encountered in medical devices and packaging/delivery systems for drug products. Characterizing the extractables from these materials is an important part of determining that they are suitable for use. In this study, five materials representative of plastics and rubbers used in packaging and medical devices were extracted by several means, and the extracts were analytically characterized to establish each material's profile of extracted organic compounds and trace element/metals. This information was utilized to make generalizations about the appropriateness of the test methods and the appropriate use of the test materials. "

Pacific BioLabs performs device extractables and ISO 10993-18 testing services.

Full article: Extractables Characterization for Five Materials of Construction Representative of Packaging Systems Used for Parenteral and Ophthalmic Drug Products

New FDA Expectations for Reusable Device Reprocessing Validations

In March of 2015, the FDA published a new guidance document titled, Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling.  A draft guidance on the same subject had previously been issued and has been used by device manufacturers since 2011 as the leading document concerning FDA’s expectations for validating reprocessing procedures for reusable medical devices.   In terms of cleaning, disinfection and sterilization validations, the most notable modifications to the 2015 document are:

  1. A more inclusive recommendation to incorporate multiple full simulated soiling, cleaning, disinfection or sterilization cycles to assess the accumulation of soil over time. 

  2. Guidance for using the worst case “master device” to validate other devices in a product family.

  3. Emphasis on visual inspection.  Visual inspection of both external and internal surfaces should be performed. 

  4. A statement recommending that devices that become hot, such as powered hand pieces or electrosurgical instruments, be validated while hot to replicate clinical use.

  5. A recommendation that two quantitative test methods be used to test for the amount of residual soil.  The recommendation of two different methods was not present in the draft version of the document.

  6. A recommendation that the type of soil chosen be justified and if the soil deviates from FDA-recognized standards then the deviation should be justified.

  7. A more detailed recommendation of what is expected from the positive and negative controls.  The Negative Sample Control is the blank - the extraction fluid only.  The Negative Device Controls should be unsoiled and undergo the same cleaning and extraction as the test devices.  The Positive Sample Control is the extraction fluid with a known amount of soil at or slightly above the limit of quantitation.  The Positive Device Control is a device that is soiled with a known amount of soil.  The Positive Device Control is not cleaned and the soil is then extracted.  The amount of soil extracted should be equivalent to or slightly lower than the amount of soil placed on the device.  

  8. An emphasis on disassembly during the soil extraction steps in order to remove soil from difficult to access areas.

  9. A recommendation to demonstrate that cleaning solutions are not penetrating internal compartments that are not intended to come into contact with soil or fluids.

Many of the changes above had been prescribed by AAMI documents and had become standard practice within the industry, while other modifications are welcome clarifications that had not been addressed previously.  What is not included in the new guidance document is also noteworthy.  Previous communications with the FDA indicated that six reprocessing cycles would be recommended before testing for residual soil. Surprisingly, this recommendation was not included in the most recent guidance document.  The only advice given by the FDA guidance document is that the number of reprocessing cycles must be scientifically justified.

Six Full Soiling, Cleaning, and Disinfection Cycles May be Needed

Yet there is still some question as to what the FDA specifically requires. Recently, a Pacific BioLabs client contacted us for reprocessing services because the FDA had rejected the client’s disinfection validation. This validation had been performed at another contract lab, and did not incorporate repeated soiling, cleaning and disinfection cycles.  The FDA, upon review, asked this client to conduct six repetitive soiling, cleaning, and disinfection cycles.  Thus, even though the FDA did not stipulate in the most recent guidance document that six full soiling, cleaning, and disinfection repetitive cycles be conducted, it appears that the FDA is internally subscribing to the policy that reusable devices should undergo at least six full cycles.  

Pacific BioLabs performs validations of device cleaning and disinfection protocols and other medical device reuse studies.

Why Understanding Bioburden and Sterilziation is Key to Medical Device Development

Pacific BioLabs and Nutek (a contract sterilizer specializing in e-beam irradiation) work closely together to perform the microbiology and sterilization needed for medical device sterilization validation programs. In this presentation we share some of our knowledge and advice on how to ensure a successful validation, which is a key factor in a medical device development program.

Pacific BioLabs performs medical device testing including sterilization validation services