Changing USP 797 and the New Era of IT Mixing

Transcription

1 Changing USP 797 and the New Era of IT Mixing Bryan L. Martin, DO, MMAS Associate Dean, GME/DIO Associate Medical Director, UH Professor of Medicine & Pediatrics 1

2 Disclosures MEDA speaker s Bureau Member, FDA Allergenic Products Advisory Committee, Center for Biologics Evaluation and Research All opinions expressed are my own. This presentation will not include any non-fda approved or investigational uses of products or medical devices.

3 Learning Objectives Identify measures to current knowledge and procedural skills necessary for the safe preparation of effective allergen extracts Understand the key regulatory bodies which have oversight of the preparation of allergen extracts Understand current efforts to ensure that potentially onerous regulations regarding the mixing of extracts are not enacted Describe specific measures required to be compliant with USP & Allergen Immunotherapy Practice Parameter recommendations for preparing allergen extracts

4 Practice Parameters for IT Initially published in Ann Allergy 2003;90(1) Defined extracts as diagnostic Defined maintence concentrate as a vaccine Estimated effective doses Standardized labeling Second Update in JACI. 2007; 120(3) Instead of vaccines now called immunotherapy extracts Effective doses further defined Cross-reactivity patterns refined Compatibility refined Patient vials rather than off the board Standardized forms for skin testing, IT prescriptions and delivery

5 Practice Parameters for IT Third update Update published in 2011 New requirements for extract preparation USP 797 New indications for immunotherapy Further defined responses to reactions to immunotherapy Medications and immunotherapy reviewed Expanded discussion of SLIT SLIT Practice Parameters are currently being reviewed

6 years of Immunotherapy

7 Immunotherapy: the beginning In 1911 Leonard Noon first used the technique of specific immunotherapy. First two publications: Noon, L. Prophylactic inoculation against hay fever. Lancet 1911;i: Freeman J. Further Observations on the Treatment of Hay Fever by Hypodermic Inoculations of Pollen Vaccine. Lancet 1911; i:

8

9 If Dr. Noon Walked into your shot room He would be familiar with much of what being done. The issue of standardization was identified as early as 1916 Dr. R.A. Cooke established standardization by the nitrogen unit 9

10 X-ray room: 1910

11 11 In September 2012 CDC traced fungal infections to 3 lots of preservative-free methylprednisolone acetate for injection, from the Framingham, MA based New England Compounding Center Allergists compound extracts in their office and inject them into their patients. We fall under USP guidelines

12 Background: New England Compounding Center May 2012 Fungal infections Meningitis, localized spinal or paraspinal infections, infections associated with peripheral joint injections Index case Aspergillus fumigatus; others predominantly Exserohilum rostratum Sept CDC traced source 3 lots preservative-free methylprednisolone acetate for injection from Framingham, MA facility 64 deaths & >750 infected Source:

13 13

14 14

15 United States Pharmacopeial Convention (USP) Founded in the US in 1820 by a group of 11 physicians who recognized the need for a national lexicon of drug names and formulas Scientific nonprofit organization that set the standards for the identity, strength, quality and purity of medicines, food ingredients and dietary supplements manufactured, distributed and consumed worldwide. Compliance with USP regulations has always been required under federal law and under many state laws. 15

16 USP 797 General Chapter on pharmaceutical compounding Sterile Preparations This includes mixing of allergen extracts in a physician s office First published in 2004 Revised in 2007: revision effective in 2008 Special exception for allergy as part of their revision of chapter 797 of their code book Media Fill test On line examination for mixing personnel Consideration for second revision began in 2010 Initial work completed in 2015 and opened for comment 16

17 Why are we worried? The USP is concerned about the sterility of compounded materials No evidence of infection sterility. USP wants proof of sterility USP 797 as it is currently written has an exception or carve out for physician office compounding of allergen extracts. This carve out will be removed in the current language of the latest revision The USP 797 revision as written in 2015 will require A number of changes to the mixing room Positive pressure clean rooms Externally vented laminar flow hoods Proof of sterility 28 day or 42 day expiration on all compounded vials 17

18 Why doesn t the USP like Allergists? Changes don t only affect allergists Dermatologists Radiologists Hem/Onc Ophtalmologists Otolaryngologists American Academy of Otolaryngologic Allergists (AAOA) 18

19 years of Immunotherapy

20 Data 100 years of clinical experience Little high quality Prospective literature on: IT sterility Infection rates after immunotherapy USP was not satisfied with retrospective data We argued that historically this has not been an area of concern This was An answer in search of a question. 20

21 2105 The Practicing Allergist USP You aren t looking at all of the evidence. 21

22 22

23 Specific Allergen Extract section would be removed CSP= compounded sterile preparations 23

24 24 /frequently-asked-questions/pharmaceutical-compounding-sterile-preparations

25 25 /frequently-asked-questions/pharmaceutical-compounding-sterile-preparations

26 How could this affect the Practicing Allergist? Requirements for the Mixing Room and Mixing room Personnel 26

27 National Guideline Preparation Measures AIT Practice Parameter USP 797 AIT Extracts USP 797 Low Risk CSP a No Makeup/ Jewelry Y Y Y Hand Washing Y Y Y Hair/ facial covers Y Y Y Shoe covers N Y Low shed gown N Y Y Sterile Gloves N b Y Y Wear mask Y Y Y Negative Pressure Room N N Y Dedicated room/space Y c Y Air monitoring N N Y Culture space/finger N N Y Media Fill Testing Y Y Written testing Y Y a Recommendations for low risk compounded sterile products in USP 797. AIT extract preparation was considered low risk sterile compounding (single sterile transfers) prior to publication of the 2008 USP 797 revision with the allergen extract section. b Whereas use of sterile gloves is not specifically addressed by the immunotherapy practice parameter third update, use of either sterile or nonsterile gloves should be considered. c Dedicated room or space does not necessarily refer to exclusive use of that space for mixing at all times. However, dedicated use during mixing is required.

28 Editorial Columns

29 Petitions and Calls to Action

30 Whole New Mom. com

31 Sneeze.com

32 32 Gratefulfoodie.com

33 AAAAI

34 USP 797 comment period Received over 8,000 comments on chapter 797 from over 2,500 stakeholders Allergists Radiologists Hem/Onc Allergy Immunology response included a joint letter from ACAAI, AAAAI and AAOA Letter writing campaign from both physicians and patients Lobbying efforts through Congress, FDA and HHS 34

35 35 USP Wading Through Responses

36 36 USP Wading Through Responses

37 Where are we now? Our efforts have ensured that we have been heard USP is concerned with our viewpoints and listening now All comments will be reviewed They are open to physician comments ACAAI, AAAAI, and AAOA have testified and are working together Lobbying efforts have ensured our lawmakers are aware of our concerns It is expected that an updated proposed revision will be published with another comment period We are concerned, and continue to ensure two way communications with the USP 37

38 Drug & Allergen Extract Regulatory Oversight How did we get here?

39 Medication & Compounding Regulatory History 1906 Pure Food & Drug Act 1938 Food, Drug & Cosmetic Act (FDA,USP) 1962 Kefauver-Harris Amendment (safe/effective, IND) 1972 Drug Listing Act (NDC) 1996 HIPAA 2003 FDA Modernization Act (labeling) 2007 USP USP 797 revision (allergen extracts) 2012 New England Pharmacy Fungal Infections 2015 DRAFT FDA mixing guidance 2015 USP 797 revision proposal (Allergen Immunotherapy Practice Parameters)

40 Allergenic Extract Regulation Law FD&C Act (Drugs & select biologics) Section 351 of PHS Act (Biologics/biosimilarity) Drug Quality & Security Act (outsourcing) Guidelines USP 797 (Allergenic Extract Chapter) Immunotherapy Practice Parameter

41 Drug Quality and Security Act (DQSA) signed 11/27/2013 Clarifies Section 503A of the FD&C Act Removes compounding advertising uncertainty and clarifies content and FDA scope of authority (all compounding including allergen extracts in scope) Establishes new Section 503B in FD&C Act Creates optional registration as outsourcing facility permitting compounding under conditions less stringent that manufacturers via exemptions but subject to production under CGMP, reporting (SAE, production, sales), FDA site visits, and annual fees MRN take: perform all sterile compounding under stringent GMP conditions like a manufacturer, or under an exception as an outsourcing facility with specific requirements.

42 Outsourcing Facility: Qualifying for Exemption from Certain FD&C Act Sections A human drug product compounded by or under the direct supervision of a licensed pharmacist in a registered outsourcing facility can qualify for exemptions from the drug approval requirements in section 505 of the FD&C Act (21 U.S.C. 355) if the following conditions must be met. 1. Comply with registration & reporting requirements (twice yearly & AE s) 2. If bulk drug substance, must meet certain requirements. 3. If other than bulk drug substances, must meet certain requirements. 4. Not on FDA withdrawn/removed (unsafe or ineffective) list 5. Not a copy of one or more approved drugs 6. Not on FDA list of drugs that present demonstrable difficulties for compounding. 7. If under FDA risk evaluation & mitigation strategy (REMS) controls, must use them. 8. Will not be sold or transferred by another entity. 9. Outsourcing facility has paid all applicable establishment and reinspection fees. 10. Must include required elements on labels under section 503B(a)(10). 11. Must compound all drugs in accordance with section 503B.

43 DRAFT GUIDANCE: Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application Guidance for Industry (FDA, FEB 2015) C. Licensed Allergenic Extracts FDA recognizes that there are circumstances in which licensed allergenic extracts would be mixed and diluted to provide subcutaneous immunotherapy to an individual patient, even though these allergenic extract combinations are not specified in the approved BLAs for the licensed biological products. Such combinations are commonly referred to as prescription sets. For the purpose of this guidance a prescription set is defined as a vial or set of vials of premixed licensed standardized and non-standardized allergenic extracts for subcutaneous immunotherapy diluted with an appropriate diluent prepared according to instructions from a prescription or order by a licensed physician for an individual patient. BLA = Biologics License Applications

44 August 2016 CDER: Center for Drug Evaluation & Research CBER: Center for Biologics Evaluation & Research 44

45 USP! FDA! All the rest of the alphabet soup! I m just trying to take care of my patients. What s the good Doctor to do? 45

46 Immunotherapy Clinic Are our immunotherapy clinics a particular risk? Personalized Health Care Individually compounded medication Allergist devises based on his/her testing Allergist and team responsible for mixing Allergist and team responsible for delivery of medication Allergist and team responsible for monitoring Both pre and post injection USP now concerned about our sterile techniques

47 47 My advice to the practicing allergist 1. Fly the plane Regardless of what is going on, a pilot must first focus on flying the plane. 2. Continue to provide the best possible care to your individual patients 3. Follow: Most up to date Practice Parameters USP Revision Bulletin 1/08 (Effective 6/08) 4. The ACAAI and the AAAAI are working together to protect the practicing allergist and both provide regular updates on the current situation Read the updates Provide input as requested

48 Current USP 797: Pharmaceutical Compounding Sterile Preparations CSP: Compounded Sterile Preparations 48

49 USP Revision Bulletin 1/08 (Effective 6/08) JACI 2011 Allergen extracts as compounded sterile preparations are not subject to the personnel, environmental and storage requirements for all CSP Microbial Contamination Risk Levels in this chapter when of the following criteria are met: Otherwise full compliance with low risk compounding requirements including laminar flow hood use & testing with buffer area, media fill testing, ISO class V air quality, training, garb, etc., for clinics/facilities requiring compliance with USP 797 REQUIREMENTS Only simple transfer of sterile substances Include preservative Hand-cleansing to elbow for 30s Hair & facial hair cover, gown, face mask Alcohol scrub for persistent activity Powder-free sterile gloves compatible with 70% isopropyl alcohol (IPA) Disinfect gloves intermittently with IPA Wipe vials &/or ampules w/ IPA 10s Aseptic technique minimizing material contact w/ secretions, skin, glove, etc. Label w/ name, beyond use date, storage temp based on manufacturer rec. Do not store single dose allergen extracts for additional future use 49

50 50 Immunotherapy Practice Parameter: 3 rd Update (Jan 2011)

51 Immunotherapy Practice Parameter 3 rd Update Physician Responsibilities Preparer (mixer) Qualifications Aseptic Technique Effective dosing Mixing Log Labeling Storage 51

52 Physician Responsibilities Training and expertise in AIT Ensure Personnel are trained, meet requirements & use aseptic technique Maintain documentation in file Mixing log Name, extracts, date, BUD, lot numbers General oversight & supervision Policy and procedure manual or SOPs 52

53 Preparer (mixer) qualifications Training for task of mixing Written test Media fill test Identify, measure and mix ingredients Antiseptic hand & surface disinfecting Aseptic technique Designate specific site with low traffic 70% isopropanol (no dye, glycerin, etc) Hands to wrist (soap/water or 70% isopropanol) Sanitize ampule necks & stoppers Avoid contact contaminations Inspect physical integrity at completion 53

54 Mixer: Knowledge & Procedural Competency Assessment

55 Media Fill Test Recommended annually Common in pharmacies Aseptic technique focus ( 10 transfers) Sterile media (not allergen extract) Commercial or home made Commercial available on line Vendors identified at:

56 Prep- labels, form, surface, PPE 1) Using ONE 1ml syringe, transfer 0.5ml to empty/extract vial 10 times (=5ml) Media Fill Test 2) Using ONE 5 or 10ml syringe, transfer 5ml to same partially filled vial 1 time Turn in: 1) Completed form with address 2) Labeled partially empty broth vial (5ml) 3) Labeled filled extract vial (10ml)

57 Allergen Extract Written Test Initial vs annual Online access Formative & Summative Available at:

58 Best Practices: Allergen Extract Prescribing & Mixing

59 Probable Effective Dose Ranges (Practice Parameters)

60 US Standardized products (n = 19+3) D. farinae D. pteronyssinus Cat Short ragweed pollen Hymenoptera Honey bee Wasp Yellow jacket Yellow hornet White-faced hornet Mixed vespid Grass pollens Bermuda grass Red top June (Kentucky blue) Perennial rye Orchard Timothy Meadow fescue Sweet vernal Sublingual Grass (Oralair and Grastek) Ragweed (Ragwitek) 60 60/30

61 US Unitage for standardized allergens Subcutaneous Hymenoptera venoms - µg protein Mites - AU Grass pollens - BAU Short ragweed pollen - Amb a 1 U Cat BAU and Fel d 1 U Sublingual Oralair grass mix IR (Index of Reactivity) Grastek BAU Ragwitek Amb a 1-U 61/30

62 Allergen Units Currently used 62 Yonsei Medical Journal May 52(3):

63 Why is standardization so important?

64 Major Allergen Content: U.S. Unstandardized Extracts Extract Conc. Major Allergen Content g/ml olive 1:10 w/v Ole e Birch 1:10 w/v Bet v Eng plant 1:10 w/v Pla l 1 30 Brome 1;10 w/v Group Dog 1:10 w/v Can f 1 5 Dog (AP) 1:100 w/v Can f Alternaria 1:10 w/v Alt a Cockroach 1:20 gly Bla g * ALK-Abello 2004 * Jay Slater

65 CBER, FDA Allergen Extract Deletions CBER, FDA formed internal committee to review scientific and medical data and peer reviewed literature on safety and effectiveness of nonstandardized allergen extract products (Category IIIA products from 1983 review) Non-standardized licensed allergen extracts were classified into 5 categories. The list was presented to APAC (Allergenic Products Advisory Committee) for review. Currently in midst of reviewing high volume feedback

66 1,269 Allergen Extracts Classified Classification # Extracts Addressed in Literature Table Diagnosis and Treatment Table (Foods) Diagnosis addressed Table 3 73 Non-Food Diagnosis addressed Table Minimal to No Literature Relating to Diagnosis or Treatment Table 5 17 Potential Safety Issues

67 Table 4 and 5 (582 extracts) High likelihood of Table 4 and 5 extract removal: Animal Feather mx, gerbil, hamster Dairy Products-Casein, Cows milk Fish and Shellfish- flounder, crab, trout Foods- extensive list of additional foods Insects- Ants, Horse fly, Flea, Deer fly Molds- extensive list Pollen- trees, grasses, weeds

68 The Allergist s view of the perfect world Allergens would be Identified Chemically and structurally Measurable Have consistent biologic activity Allergic patients would have consistent testing and reactions Therapeutic dose would be consistent Standardized! 68

69 Current Allergy Units Weight per volume (w/v) = grams per ml (note that 1:10=1/10) Protein nitrogen units (PNU/mL) = mg protein per ml Allergy units (AU/mL) = potency of reference vials at the FDA Bioequivalent allergy units (BAU/mL) = potency that gives 50mm erythema Micrograms major allergen (mcg/ml)

70 Weight per Volume Mass/Volume percent Mass of solute in grams/amount of solution in ml Available extracts commonly come in: 1:10 1:20 1:40 This is very confusing as the ratio does not tell us anything about the overall potency of the extract. Uninformative measure: 1:20 simply means 1 gm source material in 20 ml fluid 70

71 Protein Nitrogen Unit (PNU) Early attempts at standardization were based on total protein contents of the vial Uniformative measure Non-Allergenic Diluent PNU Non-Allergenic Protein Allergenic Protein 71

72 PNU Although identified in 1916, it was still being Optimized in JACI, Feb 1979

73 73 What is the ideal way to standardize an extract?

74 74

75 Allergy Units (AU) Defined by the Unified Code for Units of Measure (UCUM) as: a biological potency unit assigned to several standardized allergenic extracts, following in-vitro comparison of the test extract to an FDA CBER reference standard. The FDA CBER reference standard may be assigned a specific AU unitage based on quantitative skin testing in allergic individuals, or based on specific allergen content. 75

76 UCUM had some issues with our units In 2008 UCUM said about the AU: The definition is not sufficient to establish this notion as a unit. This is probably the one worst possible case of an arbitrary unit which we have to deal with somehow. I don't think that all AUs are using FDA reference standards. I read they may just create idiosyncratic scales based on skin-testing separately for each product / manufacturer. 76

77 UCUM comments on AU; 2009 We can't argue against this. There is too much precedence already. Instead we will have to expand on the notion of procedure defined units. This is still a problem but no worse than with the arbitrary units which we already have. With the choice of [AU] and [BAU] we can't even be sure for the same ingredient. 77

78 Bioequivalent Allergy Units (BAU) Defined by the Unified Code for Units of Measure (UCUM) as: a biological potency unit assigned to several standardized allergenic extracts, following in-vitro comparison of the test extract to an FDA CBER reference standard. The FDA CBER reference standard is assigned a specific BAU unitage based on quantitative skin testing in allergic individuals. 78

79 UCUM had some issues with BAU too 2008 comment The definition is not sufficient to establish this notion as a unit. This being an in-vitro measurement using a reference standard makes it eligible as any other arbitrary unit such as I.U comment While applying this, it is clear that this is still not defined as a unit. But the Turkeltaub paper does provide a lot of detail for some metrologic formalization of what is going on. 79

80 80

81 UCUM Comments 2009 continued This method needs to be further investigated to determine a quantitative model which relates that would relate 1 BAU with a standardized amount of substance of the standardized allergenic protein. The situation is not unlike the titer and is not worse than for many of the arbitrary units listed already. In a future revision a stronger formalized metrologic model will be added to this specification. 81

82 The dilemma: Content vs potency measures In order to measure specific allergens, we need to know which allergens are relevant If we measure overall allergenicity, we are unable to detect the absence of specific (and potentially important) allergens 82/30 Adapted from Jay Slater FDA/CBER Update

83 Scientific advances I Cat Standardized extracts approved Overall potency: AU/mL Determined as Fel d 1 U Subsequent advances ID 50 EAL testing performed Importance of cat albumin recognized in Action: designate cat hair and cat pelt; switch to BAU/mL Turkeltaub and Matthews, J Allergy Clin Immunol 1992; 89:151 83/30 Adapted from Jay Slater FDA/CBER Update

84 Scientific advances II Mites Standardized extracts approved Overall potency: AU/mL Subsequent advances ID 50 EAL testing done Importance of Group 1/2 allergen recognized ID 50 EAL testing indicated that the AU is bioequivalent to the BAU Overall potency standards continued Original AU nomenclature was retained and dust mites are still labeled in AU.* 84/30 Adapted from Jay Slater FDA/CBER Update

85 The problem of protease

86 Protease Content of Various Extracts Pollens Cat & dog dander House dust mites (US) Alternaria alternata American cockroach Aspergillus fumigatus Penicillium notatum Trypsin Equivalent < 1 g < 1 g < 5 g 29 g 168 g 212 g 242 g Robert Esch PhD, Greer Laboratories

87 Effect of mixing on allergen extracts. Extract. Alt. Clado PCN CR Mix Mite Overall p value Timothy Bermuda Sh. ragweed Rus. Thistle 1st White oak 1st 2nd 2nd Box elder 1st 2nd D.farinae 1st 2nd Cat 1st 2nd < < < < Alt - Afternaria, Clado = Cladosporium, PCN = Penicillium, CR = cockroach, Mix = mixture of Alt, Clado, PCN and Cr. Mite = house dust mite. 1st = first of two studies with the same Combinations, 2nd = second study + - p<.05 different from sxtract alone - p>.05 different from extract alone ND = not done 87

88 Fig 1. Combinations producing low (X), moderate or risky (Ø), and favorable (+) compatibilities when allergenic extracts are mixed with protease-containing insect, fungal, and mite extracts are shown. Esch JACI 2008;122:

89 Mixing Stability Esch & Grier, Daible BJ & Rekkerth DJ, Allergy Rhinol 2015;6(1):e1-7.

90 90 Don t forget cross-reactivity

91 Patterns of Cross-Allergenicity Among Pollens There is rarely significant cross-allergenicity between families There is generally a degree of cross-allergenicity between tribes or genera of families There is generally a high degree of crossallergenicity between species of the same genus

92 VIAL Standardization Vials now should conform to a standardized color coding and labeling convention Vial standardization makes for a much more consistent work environment in the shot room

93 Suggested nomenclature for labeling dilutions from the maintenance concentrate Dilution Vol/vol label No. Color Maint. concentrate 1:1 1 Red 10-fold 1:10 2 Yellow 100-fold 1:100 3 Blue 1000-fold 1: Green 10,000-fold 1:10,000 5 Silver

94 Labels 2 forms of patient ID Contents of vial Expiration date

95 Labels Concentration Vial # 1 is MOST concentrated Dilution Color Code

96 Expiration Dates DILUTION Maintenance concentrate, vol/vol Recommended Expiration Time 6-12 Months* 1:10 6 months 1:100 6 months 1:1,000 6 weeks 1:10,000 Unknown *The expiration date of the maintenance dose should be the expiration date of the earliest expiring constituent that is added to the mixture.

97 SCIT: General Rules of Thumb Ideally use patient-specific vials Individualized to each patient with identifiers Include an effective dose of each component Avoid mixing incompatible extracts Avoid inclusion of cross-reacting antigens At least consider the effect of crossreacting antigens Esch JACI 2008;122:

98 Summary IT is safe and effective And has been for over 100 years There is still much room for improvement Standardization can help provide consistent and appropriate dosing for IT But is difficult and remains confusing Studies continue, and International standards may help USP is concerned about how we mix extracts But the sky is not falling The Magical Allergy Unit remains a myth 98

99 99 The Sky is not falling (but we ll keep an eye on it)!

100 100 Questions?