TOC and Pharmaceutical Industry Water is a major pharmaceutical excipient and/or solvent Total Organic Carbon (TOC) is used to measure the total organic contamination of water and equipment in the US and Europe for cleaning validation applications. Pesticides, herbicides, biocides, endocrine disruptors, chlorinated organics, cleaning compounds, API’s, biological decomposition organics, water system extractables, etc TOC methodologies of on-line analyzers are different than laboratory analyzers. Different types of laboratory TOCs. USP, EP and JP: Water Limit test of 500 ppb as Carbon

How is TOC used to Measure Pharmaceutical Impurities in the US, Europe, and Japan? Laboratory TOC Analysis: Release of Purified Water (PW) and Water for Injection (WFI) Cleaning validation Online TOC Analysis Routine monitoring and system trending Real-time release of PW and WFI to manufacturing Real-time online cleaning validation Trends are towards using online TOC instrumentation for release of pharmaceutical waters and cleaning validation. The uses are consistent with the philosophies of PAT, can significantly reduce operating costs and increase production efficiencies by eliminating the delays associated with waiting for laboratory results. We’ll discuss these applications in greater detail in a subsequent presentation.

USA History of Cleaning Validation 1963 GMP Regulations: "Equipment shall be maintained in a clean and orderly manner.” 1978 cGMP Regulations: Section 211.67 added describing equipment cleaning and maintenance. 1993 FDA Guide to inspections for cleaning validation. 2000 ICH Q7 2002 FDA’s Risk Based Approach, (PAT) 2004 Pharmaceutical cGMP’s for the 21st century: A risk based approach. 2006 FDA’s API Process Inspection Guide 2007 FDA’s IOM (Inspectors Operational Manual) Well, it started in 1963 with the following statement "Equipment shall be maintained in a clean and orderly manner.“ Briefly describe the timeline of cleaning validation for the audience. With this continuing guidance, our customers should consider the following principles.

“The purpose of cleaning validation is to demonstrate that a particular cleaning process will consistently clean the equipment to a predetermined limit; the sampling and analytical test methods should be scientifically sound and provide adequate scientific rationale to support the validation”. - US FDA Cleaning Validation is a critical part of cGMP’s in the Pharma/Biotech industry and this statement from the FDA cGMP notes indicates the importance of what cleaning validation is and how to show equipment is clean. How did the FDA get to this level of guidance?

It’s this simple right? Well not exactly…. Batch & Clean Sample Analysis Direct (Swab) Here is a general process for batch to clean to sample to analysis. Indirect (Rinse) Product or Non-product Contact Verify Cleanliness per Acceptance Criteria

Cleaning Validation is a “Herculean” effort R&D, QA & QC Ops, PD, Engineering Identify Residue Worst Case ID & Designation TOC Analysis Selection Cleaning SOP Development Sampling Method Selection Cleaning Agent & Factors Selection MAC & Process Control Limits Sampling Site Selection Percent Recovery Studies Cleaning SOP Prep & Training Methods SOP Prep & Training Validation Team Adopted from Becky Brewer – Dober Group

Current Regulations Cleaning of Process Equipment: “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements”. - CFR 211.67 Lets look at CFR 211.67 and read the official statement. When a company receives a warning letter or 483, and they are deficient in cleaning validation they will be sited per this statement.

Does USA FDA have impurities acceptance limits for cleaning validation and subsequent cleaning verification? (FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.) “FDA has always been concerned with the issue of contamination and cross contamination. Such contamination may include not only carry over from a previous product or residual cleaning solvents, but also detergents and surfactants.”

FDA’s response-Cont. “When determining the acceptance limit, relevant factors generally include: (1) Evaluation of the therapeutic dose carryover; (2) toxicity of the potential contaminant; (3) concentration of the contaminant in the rinses; (4) limit of detection of the analytical test method; and, (5) visual examination. While we suggest that these factors be considered, relying only on visual examination would not be scientifically sound.” -Patricia L. Alcock , FDA CDER

FDA’s guidance on use of TOC for cleaning validation Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness? (Updated 5/18/2005) Yes. Since the publication of the inspection guide on cleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues. TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation. In order for TOC to be functionally suitable, it should first be established that a substantial amount of the contaminating material(s) is organic and contains carbon that can be oxidized under TOC test conditions. This is an important exercise because some organic compounds cannot be reliably detected using TOC. TOC use may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In either case, because TOC does not identify or distinguish among different compounds containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for comparing with the established limit. Thus, a firm should limit 'background' carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. If TOC samples are being held for long periods of time before analysis, a firm should verify the impact of sample holding time on accuracy and limit of quantitation.

A few of the companies Using TOC for CV:

New FDA Inspection Site Selection Scoreboard-Risk Based! Factor Category Description Examples Product Properties of drug Quality deficiencies Past product recalls Toxicity levels Facility Potential quality risks Lack quality systems High Risk of cross contamination Poor cGMP compliance history Process Process control deviations Multi-product process No process controls to assure quality You should understand how TOC plays a role in the following: Product = TOC for water release and Cleaning Validation Facility = TOC for water release and Cleaning Validation Process = TOC for Quality Control Reference: FDA’s IOM (Inspectors Operations Manual)

Newest FDA Focus: > More focus on process and process control > More evaluation of your process capabilities of the cleaning validation program, (and all systems) to mitigate risk The “Big” Three in Audits & Inspections Cleaning Validation Impact Non-Conformances/Deviations & Investigations CAPA’s (Corrective Action Preventative Action) Change Control

Compound Specific vs. Organic Carbon Specific Methods Compound Specific assay will allow for quantitative detection of a single ingredient Organic Carbon Specific will allow for detection of all organic components without speciation of those components Compound SPECIFIC Methods: HPLC (UV and MS) NIR IMS ELISA Used together can be effective Organic Carbon SPECIFIC Method: TOC NPOC Useful for R&D and Method Validation Useful for R&D and Manufacturing Validation

Comparison of HPLC to TOC Organic Specific Need Many methods Sensitive Detect H2O Insolubles Accepted Practice TOC Specific to all Organic C One method for all Sensitive (30 ppt) H20 Insoluble organics? Becoming well accepted Slide adopted by Andy Walsh, Hoffman La Roche

Detection of Water Insoluble Compounds? HPLC vs. TOC HPLC can detect any compound since you can use whatever solvent you want for your direct and indirect samples. So this must mean that TOC can only use water as a solvent, because TOC can only be used to detect water soluble compounds? (hydrophilic or polar compounds only?)

Recovery of Insolubles in Water? Slide adopted by Andy Walsh, Hoffman La Roche

Recovery Can be Improved by Modifying pH Adjusting the pH of the sample can improve recoveries. Slide adopted by Andy Walsh, Hoffman La Roche

Cleaning Validation TOC Analyzers Distribution in USA and Europe UV-Persulfate & NDIR: 15% UV-Persulfate & NDIR: 18% Combustion & NDIR: 10% Combustion & NDIR: 23% UV-Persulfate & MC 75% UV-Persulfate & MC 65% Europe USA