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Pharmaceutical Regulations

Delve into the detailed history and revisions of the Federal Categorical Regulation 40 CFR 439 governing pharmaceutical waste management. Explore its applicability, exclusions, and key subparts for different manufacturing methods and active ingredients.

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Pharmaceutical Regulations

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  1. Pharmaceutical Regulations • Dana Rees Folley • DWQ Pretreatment, Emergency Response, and Collection Systems Unit (PERCS) • NC Pretreatment Consortium Annual Pretreatment Workshop • September 19, 2006

  2. Pharmaceuticals - 40 CFR 439 • second most common categorical IU in NC – 29 in 17 cities • grouped togethertown with 3 SIUs – all 439town with 80+ SIUs - 2 439s • 5 subcategories - 4 ways to make drugs, plus research

  3. Pharmaceuticals - 40 CFR 439 • Federal Categorical Regulation • 10/27/1983 - EPA published original Rule in Federal Register • Only regulated cyanide • IU could certify cyanide not used or generated – then not considered “categorical”

  4. Pharmaceuticals - 40 CFR 439 • 5/2/95 - EPA published Proposed New Rule – added ammonia and many organics parameters • 9/21/98 - EPA published Final Rule in Federal Register • BUT…

  5. Pharmaceuticals - 40 CFR 439 • Revised Six Times! • Most typos and reorganization • But • 3/4/99 – preamble wording changes; limits changes due to “rounding errors” and typos • 3/13/03 - delete methyl cellulose altogether • 3/16/99, 9/2/99, 6/11/03, 5/6/04

  6. Pharmaceuticals - 40 CFR 439 • EPA’s Pharmaceutical Web-sitehttp://www.epa.gov/waterscience/guide/pharm/ • All FR publications • Analytical Guidance • Permit Guidance • Pharmaceutical Info on PERCS Web-sitehttp://h2o.enr.state.nc.us/percs/ • Pharmaceutical Sections on Pretreatment Permit Writing and Headworks Analysis Pages – 40 CFR 439 7/1/05 version + lots more

  7. 40 CFR 439 Applies to - • Research and manufacturing of pharmaceuticals, which are generally, but not exclusively, reported under SIC codes: • 2833 – medicinal chemicals and botanical products • 2934 – pharmaceutical preparations • 2836 – biological products, except diagnostic substances.

  8. 40 CFR 439 Applies to (cont.) - • Other products manufactured by 4 subcategory methods - fermentation, extraction, chemical synthesis, mixing, compounding and formulation - And… • considered “pharmaceutical active ingredient” by FDA • Or • Multiple end-use products intended for use primarily in pharmaceutical application

  9. 40 CFR 439 Applies to (cont.) - • pharm products + intermediates not subject to other categorical regs, provided manufacturing generates process wastewaters similar to those derived from manufacture of pharmaceuticals (ex., citric acid) • Cosmetic preparations SIC 2844 containing pharmaceutical active ingredients, or active ingredients intended for treatment of a skin condition

  10. 40 CFR 439 Does Not Apply to • 439.0(b)(4) and 439.0(c)(1) – (11) - various products that are excluded • Medical/dental/lab instruments, equipment, services • Food/Beverage/Animal feed with vitamins, antibiotics, pharmaceu-tically active, if mostly non-pharm and characteristics dif from 439 • OCPSF + Pharm CIUs where pharm portion <50% • 439.2(j) – special definition of process wastewater that excludes more flows

  11. 40 CFR 439 Does Not Apply to • EPA’s January 2006 Pharmaceutical Permit Guidance-More exclusions + clarifications • Page 3-3, 8-15+16: 439 could be used as BPJ for bioengineering operations if products and wastewater characteristics are similar to 439 • 8-16: Incidental Passivating + Electropolishing during cleaning of Process Tanks - Not 433 • Guidance on developing permit limits, monitoring requirements, case studies

  12. 40 CFR 439 Applicability

  13. 40 CFR 439 Applicability • Ask lots of questions! • Read regulation with SIU and have them explain terms in “regular” words and words used in the industry… • …and have them explain what they do and why they think they are or are not covered by which parts • Confirm with PERCS • Document in IUP Synopsis • Including why not covered

  14. Each Subpart-5 Sets of Limits • BPT, BCT, BAT, NSPS – For “direct” dischargers, i.e., pharmaceutical has their own NPDES permit • PSES - Pretreatment Standards for Existing Sources • PSNS - Pretreatment Standards for New Sources • Don’t confuse with NSPS – New Source Performance Standards

  15. Each Subpart-5 Sets of Limits • PSES + PSNS 439 Limits Identical • Only Issue: When must comply • New Source Date 5/2/95 • “begin construction” or “significant change” after this date = New Source. See 403.3(m) for details. • Existing Sources must comply by 9/21/2001 • New Sources must comply immediately upon start-up

  16. 439 Subpart A - Fermentation • Process operations that utilize a chemical change induced by a living organism or enzyme, specifically bacteria, or the microorganisms occurring in uni-cellular plants such as yeasts, molds, or fungi to produce a specific product • PSES + PSNS limit cyanide, ammonia, and 22 organic compounds • Same limits as Subpart C

  17. 439 Subpart B - Extraction • Process operations that derive pharmaceutically active ingredients from natural sources such as plant roots and leaves, animal glands, and parasitic fungi by chemical and physical extraction • PSES + PSNS limit 5 organic compounds • Same limits as Subpart D

  18. 439 Subpart C - Chemical Synthesis • Process operations that utilize a chemical reaction or series of chemical reactions in the manufacturing process of a specified product • PSES + PSNS limit cyanide, ammonia, and 22 organic compounds • Same limits as Subpart A

  19. 439 Subpart D – Mixing, Compounding + Formulation • Mixing, compounding, and formulating operations means processes that put (previously manufactured) pharmaceutical products into dosage forms • Includes ampules, tablets, capsules, vials, ointments, medicinal powders, solutions, and suspensions • both human and veterinary use • PSES + PSNS limit 5 organic compounds • Same limits as Subpart B

  20. 40 CFR 439 Subpart E - Research • process wastewaters, products, or services resulting from research and product development activities • no PSES or PSNS – yeah!!

  21. Categorical versus Local Limits • Categorical-Technology Based • 439 pollutants and untreated concentrations • Pre-treatment technologies available, and “expected effluent” • Cost of installing + operating close down too many CIUs? • If no, and CIU technology has higher removal rate than typical POTW, assign “expected effluent” as pretreatment categorical limit • Compare costs to environmental benefits, but not deciding factor

  22. Categorical versus Local Limits • Local Limits –Technically Based • How much and still protect stream, WWTP bugs, sludge, people • Ammonia,Cyanide: Regular HWA/AT

  23. Pharmaceutical Organics Headworks Analysis (POHWA) • Spreadsheet and Directions on PERCS HWA web-page • Download • Fill in blue outlined fields (ask PERCS for stream flows) • Complete Allocation Table, including other IUPS with Organics limits (ex. OCPSF) • Reduce IUP limits below categorical to resolve over allocation • Submit with IUP

  24. Proposed New NC Benzene Water Quality Standard • NC Water Quality Standard for Class C Waters proposed as part of Triennial Review • Reduce from 71.4 ug/l to 51 ug/l • Benzene Class WS Waters - No change • DWQ Planning Section, Classification + Standards Unit, Jeff Manning ext. 579 • http://www.ncwaterquality.org/csu/TriRCurrent.html#TRIENNIALReview • Triennial Review - changes for other (non-pharmaceutical) parameters, too.

  25. 40 CFR 439 Ammonia Limits • Subpart A: Fermentation: 439.16, .17 • Subpart C: Chemical Synthesis: .36, .37 • PSES and PSNS Ammonia limits not applicable to CIU if POTW nitrifies as defined in 439.1(I) • Discuss in IUP Synopsis • Still may need IUP Ammonia Limit to protect WWTP (CIU average discharge >5% MAHL) • If have Limit, Composite; POTW min. 1/6 months; SIU – up to POTW

  26. 40 CFR 439 Cyanide Limits • Subpart A: Fermentation: .16, .17 • Subpart C: Chemical Synthesis: .36, .37 • PSES and PSNS Cyanide limits not applicable if CIU certifies to POTW that manufacturing processes neither use or generate cyanide • Discuss in IUP Synopsis • If have Limit, Grab; POTW min-1/6 months; SIU – up to POTW • Can composite preserved grabs over 24 hours • 1983 cyanide limits for Subpart B and D are withdrawn

  27. 439 Organic Pollutant Analysis • 9/21/98 Federal Register also modified 40 CFR 136 • 40 CFR 136.3(a)Table IF –Approved Methods for each parameter: • New EPA Methods 1666, 1667, 1671 • 40 CFR 141 Drinking Water Methods 502.2 and 524.2 • ASTM Methods D3371, D3695, D4763 • 40 CFR 136.3(b)(40) – Lists Method Sources

  28. 439 Organic Pollutant Analysis • Subparts A and C: 2 or 3 Approved Methods to cover all POCs • Subparts B and D: 524.2 for acetone and methylene chloride, 1666 for three acetates • Only one lab does 1666 (main method) • 1666 expensive, plus more $ to do multiple methods • NC DWQ Lab Certification not available for most Table IF Methods

  29. 439 Organic Pollutant Analysis

  30. 439 Organic Pollutant Analysis • 136.3(d)–(f) allows Alternative Methods • EPA August 1999 Guidance allows transfer of analytes to another method (Table IF or Alternative) • Must show that will adapt Alternative Method and/or Analyte Transfer to meet QA/QC of applicable Table IF Method • POTW’s choice to allow Alternative Method or Analyte Transfer to be explored • Lab must submit documentation to NC DWQ Lab Certification Unit for approval

  31. 439 Organic Pollutant Analysis • Example: A few NC labs approved by NC DWQ Lab Cert to use 6210D from Standard Methods for the 3 Subpart B+D acetates, with conditions • One also approved to modify 6210D for acetone and methylene chloride • 6210D is now 6200B in Standard Methods 20th edition • Other Alternative Method Options • 40 CFR 136 Methods 601, 602, 604, 612, 624, 625, 1624, and 1625 • Solid Waste Method 8260B • Maybe others?

  32. 439 Organic Pollutant Analysis • Analytical Methods for Determination of Pollutants in Pharmaceutical Manufacturing Industry, EPA July 1998 • Methods 1666, 1667, and 1671 • Analytical Method Guidance for the Pharmaceutical Manufacturing Point Source Category, EPA August 1999 • Alterative methods and analyte transfer procedures • Solutions to matrix problems • Choosing the best method • Questions and answers

  33. 439 Organic Pollutant Analysis • NC DWQ Lab Certification not available for most Table IF Methods • Available for some but not all Alterative Methods • Pretreatment Permits typically require Certified Lab (Part II, 4) • POTWs must include special test method language in IUP • Updated Example IUP Language on Permit Writing Page

  34. 439 Organic Pollutant Analysis • David Livingston • NC DWQ Laboratory Certification Unit • 919-733-3908, ext. 272 • david.livingston@ncmail.net • http://h2o.enr.state.nc.us/lab/index.htm

  35. Surrogate Organic Pollutants – 40 CFR 439.1(o) • Allows monitoring for one pollutant to serve as surrogate for a group of other specific pollutants • Must receive same level of pretreatment as surrogate and be in same treatability class as surrogate – See Table 2 of Appendix A • Violation of limit for surrogate means are considered to violate limits for all pollutants represented by that surrogate

  36. Surrogate Organic Pollutants – 40 CFR 439.1(o) • Where more than one surrogate is available in treatability class, must use surrogate with highest concentration at that CIU • Optional but must be approved by POTW • Example – Subpart B + D Method 1666 for three acetates plus Method 524.2 for acetone and methylene chloride • Acetone can be Surrogate for all three acetates, so don’t need Method 1666

  37. Organic Pollutants Not Usedor Generated – 40 CFR 439.4 • Determination based on: • Review of all raw materials in use • Assessment of process chemistry, products and by-products resulting from each manufacturing process • Submit to POTW for approval • Annual “reconfirmation” sample still required - by POTW or SIU • Updated Example IUP Language on Permit Writing Page

  38. Organics Sampling • Limit in IUP: Min once per year by POTW; SIU sampling-up to POTW • Pollutant neither used or generated:Annual “re-confirmation” sample by POTW or SIU (POTW’s choice) • Grab or Composite - POTW’s choice, must be representative of CIU’s discharge without jeopardizing the integrity of the volatile organic compounds found in the sample • Can collect series of grabs in 24 hour period and composite them in lab if Method allows

  39. Costs of Organics Sampling • Organic sampling may cost $1,000 or more • POTW Cost Recovery • Permitting Fees • Sample Collection Fees • Sample Analysis Fees • Administration Fees

  40. Organics Sampling in LTMP/STMP • May be required if SIU discharges a “significant amount” • Case by Case Basis

  41. 439 IUP Limits • Concentration based 439 limits apply directly if sample location contains NO dilution wastestreams – see 403.6(e) • Otherwise, Combined Wastestream Formula (CWF) uses process to total flow ratio to adjust 439 limit down • if CWF limit below detection, cannot apply CWF. Instead, SIU must provide “process only” sample location • Can convert to Equivalent Mass Limits per 40 CFR 403.6(c)(5)

  42. Potential Impact to Other Industrial Users • Directly-None • Indirectly-YES! • New HWA and New MAHL’s may bring new things to light • Identify New Pollutants of Concern (POCs) • May need data from other industrial users • Collection system data

  43. Overwhelmed?

  44. Thank You! Dana Folley NC DWQ PERCS (919) 733-5083 ext. 523 dana.folley@ncmail.net http://h2o.enr.state.nc.us/percs/ http://www.epa.gov/ost/guide/ http://www.epa.gov/waterscience/guide/pharm/

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