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September 5, 2018

Cleaning Validation for Medical Devices: Establishing Cleaning Limits

After the potential hazardous contaminants from the manufacturing process have been identified during the review of the process flow, the acceptable levels for the contaminants is determined.   For contaminants with complete toxicological data available, follow ISO 10993-17 to set the cleaning limits for the contaminants.    When limited toxicological data is available, at a minimum the LD50 values can be used to calculate the cleaning limits.   For most contaminants the LD50 values are readily obtained from the MSDS.

The established cleaning levels are then used in the selection and evaluation of the cleaning test methods.

June 18, 2018

FDA has finalized bioanalytical validation guidance

The FDA has finalized guidance on validation of bioanalytical methods.   Differences between the draft and final guidance, which is 10 pages longer, include a re-working of the text, a new title for Section III, which was previously named “Chromatographic methods” but is now “Bioanalytical method development and validation,” and new sections on parameters of chromatographic assays (CCs) and ligand binding assays (LBAs).

“This final guidance incorporates public comments to the revised draft published in 2013 and provides recommendations for the development, validation, and in-study use of bioanalytical methods,” FDA said. “The recommendations can be modified with justification, depending on the specific type of bioanalytical method. This guidance reflects advances in science and technology related to validating bioanalytical methods.”

June 7, 2018

AET and Ophthalmic Drug Products

During the PQRI PODP Workshop at USP Headquarters on April 18-19, the PQRI toxicology sub-team announced that they could not get the FDA to agree to the analytical evaluation threshold (AET) concept for ophthalmic drug products.  FDA felt that the human eye was a unique organ that was especially susceptible to local topical effects and that ocular irritation was a key endpoint to consider.  Therefore, they rejected the use of an AET for reporting leachables.  PQRI ophthalmic drug sub-team stated in their presentation that the “unwritten FDA expectations” for ophthalmic drug packaging systems was that:

  • Leachables be reported at or above 1 ppm
  • Leachables be identified at 10 ppm
  • Leachables be qualified at 20 ppm

PQRI further stressed in this presentation that many pharmaceutical companies actually go above and beyond these FDA expectations and report, identify, and qualify all leachables > 1 ppm for ophthalmic drug products.

May 31, 2018

Update on the Status of USP <661.1> and <661.2>

USP announced last year that the newly issued <661.1> “Plastic Materials of Construction” and <661.2> “Plastic Packaging Systems for Pharmaceutical Use” were being suspended until May of 2020 so that the pharmaceutical industry could adapt to all of the significant changes made to the “old” version of <661>.  In the meantime <661> “Containers Plastic” was back in effect as the chapter of record.  However, FDA may have their own opinion on the “suspension” of <661.1> and <661.2>.  Many pharmaceutical companies submitting NDAs and ANDAs are receiving deficiencies for not having packaging systems tested according to these new chapters.  Furthermore, representatives from the USP Packaging Expert Panel announced last week at the PharmaEd Resources E&L Conference in Philadelphia that the “grandfathering” clause for currently marketed pharmaceutical drugs will be removed in edition to <661.2> that will be released in May 2020.  This means that all packaging systems will have to be tested and meet the specification of <661.1> and <661.2>.  At Pine Lake Laboratories, we recommend that our clients don’t wait until 2020 to be compliant with these new chapters.  We can design a stepwise, integrated approach to ensure that our client’s plastic packaging systems meet the FDA expectations today as well as a few years down the road.

April 28, 2018

USP <467> Residual Solvents Testing

Residual solvents are organic volatile impurities in drug substances and drug products that are byproducts of manufacturing.  Drug manufacturers need to ensure that these residual solvents are at or below acceptable levels.

The USP <467> sets the concentration limit for each solvent. Solvents are grouped according to their toxicity levels and potential adverse effects.    Class 1 solvents are known to cause unacceptable toxicities or to have environmental effects and should be avoided in the manufacturing process. Class 2 solvents are nongenotoxic animal carcinogens, and concentrations of these compounds should be limited.  Class 3 solvents are less toxic and should be used when practical.

Gas Chromatography with valve-and-loop headspace analysis is used for identification and quantification of residual solvents in drug substances and drug products.

Following USP <467>, three analytical procedures are used for identification and quantification of the residual solvents:

  • Procedure A screens for and confirms the solvents’ presence.
  • Procedure B confirms the solvents’ identity.
  • Procedure C is required to quantify the amount of residual solvents present.

At Pine Lake Laboratories, we have extensive experience in the determination of residual solvents in a wide variety of drug substances, excipients or drug products.

April 9, 2018

USP <232>

All drug products sold in the U.S. will have to comply with the limits set by USP<232>, and drug substances and excipients will have to be tested and reported for elemental impurities. January 1 of this year USP has established as the date of applicability of the Elemental Impurities Limits General Chapters.   Under GMP drug quality and regulatory requirements, elemental impurities will have to be monitored for all existing drug products, APIs, and excipients – not just for the 15 elemental impurities of USP<232>, but for the full 24 elemental impurities of Q3D.

Pine Lake Laboratories can assist you in meeting this requirement.