OOS Final Guidance: What Has Changed?

OOS Final Guidance:What Has Changed? Lynn Torbeck Lynn Torbeck, January 25, 2007, PDA WCC

Overview • Basis in CGMP’s • Barr Court case • What is out? • What is in? • Unresolved issues • Take away information Lynn Torbeck, January 25, 2007, PDA WCC

CGMP’s • 21 CFR 211.192 • “Any unexplained discrepancy of the failure of a batch or any of its contents to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed.” Lynn Torbeck, January 25, 2007, PDA WCC

CGMP’s • 21 CFR 211.192 • “The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy.” • “A written record of the investigation shall be made and shall include the conclusions and follow-up.” Lynn Torbeck, January 25, 2007, PDA WCC

Barr Court Case • Civil action by FDA, June 12, 1992. • Judge Alfred M. Wolin. • “Can the FDA expand the CGMP’s interpretation into the statistical areas of outliers, retesting, resampling, averaging and sample size and other areas of failure investigations, …” Lynn Torbeck, January 25, 2007, PDA WCC

OOS Topics in the Barr Case • Out of specification results • Product “failure” • Informal and formal investigations • Testing and retesting • Sampling and resampling • Averaging • Outliers Lynn Torbeck, January 25, 2007, PDA WCC

Other Topics in the Barr Case • Remixing • Blend testing • Retrospective validation • Concurrent validation • Prospective validation • Method validation • Cleaning validation Lynn Torbeck, January 25, 2007, PDA WCC

Draft Version • 30 September 1998 • “Guidance for Industry – Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production” • Submitted comments by 30 November 1998 • These comments can be inspected by going to the FDA offices. Lynn Torbeck, January 25, 2007, PDA WCC

Controversial Topics • Use of averaging? • Definition of reportable values? • Number of retests? • Second analyst? • Use of outlier testing? • What specification limits? • Defining testing into compliance? Lynn Torbeck, January 25, 2007, PDA WCC

PDA Involvement • A Chemical OOS Committee under the direction of the PDA Scientific Advisory Board. Lynn Torbeck, Chairman. • Seven other members of the committee. • Draft Technical Report in process. • 8 December 2006, OOS conference in Bethesda MD. 50 attendees. Lynn Torbeck, January 25, 2007, PDA WCC

Final Version • 12 October 2006 • Three general changes: • Revised the scope and background section to clarify the applicability of the document. • Reorganized the section on investigating OOS results, averaging and concluding the investigation. • Clarified or added more specific guidance. Lynn Torbeck, January 25, 2007, PDA WCC

What’s Out? • The term “failure” investigation has been removed and the terms “OOS” or “full investigation has been substituted. • “Supervisor” has been replaced with “laboratory management.” • The “laboratory quality assurance program” replaced “overall quality assurance program.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s Out? • The term “statistical errors” has been replaced by “calculation errors.” • This sentence has been removed: • “A resampling of the batch should be conducted if the investigation shows that the original sample was not representative of the batch.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s Out? • This paragraph has been removed: • “Statistical treatment of data should not be used to invalidate a discrete chemical test result. In very rare occasions and only after a full investigation has failed to reveal the cause of the OOS result, a statistical analysis may be valuable as one assessment of the probability of the OOS result as discordant, and for providing perspective on the result in the overall evaluation of the quality of the batch.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • Laboratory testing is noted to be “chemistry-based” and “of drugs regulated by CDER.” • Thus, bio-tech and micro seems to be excluded from direct application. Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • This sentence was added: “The term [OOS] also applies to all in-process laboratory tests that are outside of established specifications.” • A footnote indicates that this does not apply to adjustments to prevent process drift. Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • The regulatory references were expanded to include, “the Federal Food, Drug, and Cosmetic Act (the Act) (section 501(a)(2)(B),” as well. • Further, “The principles in this guidance also apply to in-house testing of drug product components that are purchased by a firm.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • “This guidance can also be used by contract firms performing production and/or laboratory testing responsibilities.” • A paragraph has been added noting that API’s are to be covered by this guidance as well as finished products. Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • A large paragraph has been added relative to process analytical technology, PAT. • “This guidance is not intended to address PAT approaches, as routine in-process use of these methods might include other considerations.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • A sentence has been added to expand the duties of contract laboratories. • “For contract laboratories , the laboratory should convey its data, finding, and supporting documentation to the manufacturing firms’ quality control unit (QCU), who should then initiate the full-scale OOS investigation.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • An additional step has been added to the supervisor’s assessment. • “Verify that the calculations used to convert raw data values into a final test result are scientifically sound, appropriate, and correct; also determine if unauthorized or unvalidated changes have been made to automated calculation methods.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • A full scale investigation has been expanded to include all sites. • “In cases where manufacturing occurs off-site (i.e. performed by a contract manufacturer or at multiple manufacturing sites) all sites potentially involved should be included in the investigation.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • Product or process redesign is addressed with a new paragraph. • “OOS results may indicate a flaw in product or process design. … In such cases, it is essential that redesign of the product or process be undertaken to ensure reproducible product quality.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • The recommendation for a second analyst is expanded. • “A second analyst performing a retest should be at least as experienced and qualified in the method as the original analyst.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • Retesting has an additional requirement. • “The maximum number of retests to be performed on a sample should be specified in advance in a written standard operating procedure (SOP). … Any deviation from this SOP should be rare …. In such cases, before starting additional retesting, a protocol should be prepared that describes the additional testing to be performed and specifies the scientific and/or technical handling of the data.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • Resampling has additional statements. • “The original sample from a batch should be sufficiently large to accommodate additional testing in the event an OOS result is obtained. In some situations, however, it may be appropriate to collect a new sample from the batch.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • A new definition is given. • “The term reportable result as used in this document means a final analytical result. This result is appropriately defined in the written approved test method and derived from one full execution of that method, starting from the original sample.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • This is in accord with industry literature and the USP definition. Two additional paragraphs expand on the concept. • Included is the new expectation that the variability of the replicates will have acceptance criteria and that: • “If acceptance limits for replicate variability are not met, the test results should not be used.” Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • The need to provide all reportable results to the QCU is reinforced. • “In addition, when investigation by a contract laboratory does not determine an assignable cause, all test results should be reported to the customer on the certificate of analysis.” • This may be a new procedure for some companies. Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • The section on Interpretation of Investigation Results has been expanded considerably with five new paragraphs. Interestingly, while the guidance does not give recommendations for the sample size for retesting, the example scenario given uses seven retests. • Seven was the suggestion in a footnote in the Barr Case judgment. • The sample size question is still unresolved. Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • A new section titled “Cautions” has been added. The first paragraph continues a discussion of reportable results stating that “… a firm should err on the side of caution …” • Several reviewers have felt that this paragraph is confusing, misleading and needs more interpretation. Lynn Torbeck, January 25, 2007, PDA WCC

What’s In? • The second paragraph adds a new issue to the guidance, noting that a low assay result should raise concern and that: • “One cause of the result could be that the batch was not formulated properly. Batches must be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient.” • While this is an old GMP concept, it is interesting that it is expressed here in this context. Lynn Torbeck, January 25, 2007, PDA WCC

Unresolved Issues • What specification limits? • Regulatory (External) • Accept / reject (Includes stability) • Action (Cpk=1.33 ? ) • Alert or Trend (Cpk=1.0 ?) • First paragraph of cautions seems to confuse the definition of reportable result. Lynn Torbeck, January 25, 2007, PDA WCC

Unresolved Issues • No direct guidance on retest sample size. • Outlier guidance may be difficult to meet. • The guidance is only for chemical assays but then gives a reference to the USP and microbiological assays. • No direct information for non-chemical testing and results. • Somewhat equates OOT with OOS. Lynn Torbeck, January 25, 2007, PDA WCC

Take Away Information • Companies must have an up-to-date SOP. • Write the SOP at the 8th grade level. • Use simple declarative sentences. • Use the wording directly out of the guidance where possible; copyright free! • Require the operational definition of the reportable result to be in the SOP, protocol and reports. Lynn Torbeck, January 25, 2007, PDA WCC

Take Away Information • Don’t avoid using outlier tests as part of the investigation and analysis. Just can’t reject data with it. • While the guidance is not directly intended for bioassay, it can be used as a starting point and reference. • Out of Trend is a different issue than OOS. Lynn Torbeck, January 25, 2007, PDA WCC

Thank You QUESTIONS ? Lynn Torbeck, January 25, 2007, PDA WCC

OOS Final Guidance: What Has Changed?