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

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

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

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

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

6 Pharmaceuticals - 40 CFR 439 n EPA’s Pharmaceutical Web-site guide/pharm/ guide/pharm/ u All FR publications u Analytical Guidance u Permit Guidance n Pharmaceutical Info on PERCS Web-site u 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 - n Research and manufacturing of pharmaceuticals, which are generally, but not exclusively, reported under SIC codes: u 2833 – medicinal chemicals and botanical products u 2934 – pharmaceutical preparations u 2836 – biological products, except diagnostic substances.

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

9 40 CFR 439 Applies to (cont.) - n 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) n 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 n 439.0(b)(4) and 439.0(c)(1) – (11) - various products that are excluded u Medical/dental/lab instruments, equipment, services u Food/Beverage/Animal feed with vitamins, antibiotics, pharmaceu- tically active, if mostly non-pharm and characteristics dif from 439 u OCPSF + Pharm CIUs where pharm portion <50% n 439.2(j) – special definition of process wastewater that excludes more flows

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

12 40 CFR 439 Applicability

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

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

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

Subpart A - Fermentation n 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 n PSES + PSNS limit cyanide, ammonia, and 22 organic compounds u Same limits as Subpart C

Subpart B - Extraction n 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 n PSES + PSNS limit 5 organic compounds u Same limits as Subpart D

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

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

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

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

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

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

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

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

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

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

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

Organic Pollutant Analysis

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

Organic Pollutant Analysis n 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 u One also approved to modify 6210D for acetone and methylene chloride u 6210D is now 6200B in Standard Methods 20 th edition n Other Alternative Method Options u 40 CFR 136 Methods 601, 602, 604, 612, 624, 625, 1624, and 1625 u Solid Waste Method 8260B u Maybe others?

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

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

Organic Pollutant Analysis n David Livingston n NC DWQ Laboratory Certification Unit n , ext. 272 n n index.htm

35 Surrogate Organic Pollutants – 40 CFR 439.1(o) n Allows monitoring for one pollutant to serve as surrogate for a group of other specific pollutants u Must receive same level of pretreatment as surrogate and be in same treatability class as surrogate – See Table 2 of Appendix A n 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) n Where more than one surrogate is available in treatability class, must use surrogate with highest concentration at that CIU n Optional but must be approved by POTW n Example – Subpart B + D Method 1666 for three acetates plus Method for acetone and methylene chloride u Acetone can be Surrogate for all three acetates, so don’t need Method 1666

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

38 Organics Sampling n Limit in IUP: Min once per year by POTW; SIU sampling-up to POTW n Pollutant neither used or generated: Annual “re-confirmation” sample by POTW or SIU (POTW’s choice) n 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 n Can collect series of grabs in 24 hour period and composite them in lab if Method allows

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

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

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

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

43 Overwhelmed?

44 Thank You! Dana Folley NC DWQ PERCS (919) ext pharm/

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