AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

PDE4 inhibitor , Sumitomo Dainippon Pharma Company

 Uncategorized  Comments Off on PDE4 inhibitor , Sumitomo Dainippon Pharma Company
May 192016
 

Figure

 

2-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-5-yl]-1,3-benzoxazole Hemifumarate

Sumitomo Dainippon Pharma Company,

STR1

SCHEMBL2688684.png

CAS FREE FORM 1256966-65-0

Benzoxazole, 2-​[2-​methyl-​1-​(tetrahydro-​2H-​pyran-​4-​yl)​-​1H-​benzimidazol-​5-​yl]​-

MF C20 H19 N3 O2, MW, 333.38 FREE FORM
NMR FOR HEMIFUMARATE

1H NMR (400 MHz, DMSO-d6)

δ 13.1 (br, 1H), 8.33 (d, J = 1.5 HZ, 1H), 8.06 (dd, J = 5.1, 1.6 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.82–7.76 (m, 2H), 7.43–7.38 (m, 2H), 6.64 (s, 1H), 4.71–4.62 (m, 1H), 4.06 (dd, J = 11.4, 4.3 Hz, 2H), 3.58 (dd, J = 11.7, 11.4 Hz, 2H), 2.67 (s, 3H), 2.47–2.36 (m, 2H), 1.90–1.86 (m, 2H).

13C NMR (100 MHz, DMSO-d6)

δ 165.92, 163.26, 153.94, 150.20, 142.94, 141.75, 136.21, 133.93, 124.94, 124.67, 120.89, 119.40, 117.70, 112.44, 110.72, 66.50, 52.67, 30.70, 14.62.
Compound 1 is a PDE4 inhibitor and is expected to improve memory impairment. In addition to the mechanism of action, 1 enhances BDNF signal transduction and induces NXF, a brain specific transcription factor, in the presence of low concentrations of BDNF. NXF induction is expected to lead to nerve regeneration and neuroprotective efficacy.
US88290352014-09-09Agent for treatment or prevention of diseases associated with activity of neurotrophic factors
 STR1
Patent
WO2010/137349 A1
Example 11
5- (benzoxazol-2-yl) -2-methyl -1-(tetrahydropyran-4-yl) benzimidazole 　eggplant flask (100 mL), 2- methyl-1- (tetrahydropyran – 4-yl) reference benzimidazole-5-carboxylic acid (example 4-3) (0.64 g, 2.46 mmol ), 2- amino-phenol (0.32 g, 2.95 mmol), and polyphosphoric acid (about 18 g) put, heated to 160 ℃, and the mixture was stirred for 17 hours. After cooling, ice was added, and the mixture was about pH 9 the liquid with concentrated aqueous ammonia (28%). Extraction with chloroform (about 50 mL X 3 times), dried over anhydrous magnesium sulfate, the crude product obtained by distilling off the solvent (0.08 g) PTLC (CHCl 3 by weight deploy purified), the title compound ( 0.002 g, 0.2% yield) was obtained as a yellow-brown semi-solid. 1H-NMR (CDCl 3 ) Deruta (Ppm): 1.88-1.92 (M, 2 H), 2.58-2.68 (M, 2 H), 2.70 (S, 3 H), 3.57-3.64 (M , 2 H), 4.21-4.25 (m , 2 H), 4.43-4.49 (m, 1 H), 7.29 (d, 1H, J = 9.2 Hz), 7.33-7.35 (m, 2 H ), 7.59-7.62 (m, 1 H ), 7.76-7.78 (m, 1 H), 8.18 (dd, 1 H, J = 8.6, 1.6 Hz), 8.57 (d, 1 H, J = 1.4 Hz).

PAPER

Abstract Image

A short and practical synthetic route of a PDE4 inhibitor (1) was established by using Pd–Cu-catalyzed C–H/C–Br coupling of benzoxazole with a heteroaryl bromide. The combination of Pd(OAc)2-Cu(OTf)2-PPh3 was found to be effective for this key step. Furthermore, telescoping methods were adopted to improve the yield and manufacturing time, and a two-step synthesis of1 was accomplished in 71% overall yield.

Direct Synthesis of a PDE4 Inhibitor by Using Pd–Cu-Catalyzed C–H/C–Br Coupling of Benzoxazole with a Heteroaryl Bromide

†Process Chemistry Research and Development Laboratories, Technology Research & Development Division and‡DSP Cancer Institute, Sumitomo Dainippon Pharma Company, Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00106

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Cc1nc3cc(ccc3n1C2CCOCC2)c4nc5ccccc5o4

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ICH M7

 regulatory, Uncategorized  Comments Off on ICH M7
May 192016
 

ICH M7

 

Although relatively quiet in terms of any specific regulatory activities, the last 6 months have seen a plethora of publications that are associated with the ICH M7 guideline. Prominent within these was the Special Edition of Organic Process Research & Development in November 2015. This special edition focused on mutagenic impurities, examining the challenges and also opportunities faced when seeking to implement ICH M7.(5) This was timely as it aligned with the effective date for ICH M7 of January 2016; the guideline when finalized in June 2014 having a defined implementation phase of 18 months. ICH M7 is, in general, a well-written guideline that provides a flexible and pragmatic framework by which the risk posed by mutagenic impurities can be effectively managed. The flexibility provided by the guideline and the opportunities this presents in terms of science and risk based thinking are examined in depth through a series of articles within the special edition.
A tabulated summary of the special edition is described in Table 1.

Table 1

subject highlights authors
Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses? A survey of over 300 synthetic publications in OPR&D over a 10 year period clearly demonstrated that the synthesis of synthetic APIs was untenable without the use reactive, potentially mutagenic reagents/intermediates. That the principle of avoidance was fundamentally flawed Elder, D. P.; Teasdale, A.(6)
Strategies To Address Mutagenic Impurities Derived from Degradation in Drug Substances and Drug Products The paper outlines a strategy for the systematic assessment of the risk posed by mutagenic degradants, describing how this relates to stress testing and long-term stability studies. Within this it seeks to define appropriate thresholds for identification directly related to the extent of degradation Kleinman, M. H.; Teasdale, A.; Baertschi, S. W. et al.(7)
Assessing the Risk of Potential Genotoxic Degradation Products in a Small Molecule Kinase Inhibitor Drug Substance and Drug Product The degradation profile resulting from stress testing of galunisertib is described, focusing on formation of two N-oxides, examining the site of oxidation and the relevance of the pathway under typical storage conditions. Strege, M. A.; Osborne, L. M.; Hetrick, E. M. et al.(8)
Mutagenic Alkyl-Sulfonate Impurities in Sulfonic Acid Salts: Reviewing the Evidence and Challenging Regulatory Perceptions Provides a comprehensive review of the existing evidence relating to sulfonate esters, examining the comprehensive mechanistic and kinetic studies and safety data. It also examines the current regulatory approaches and how this appears misaligned with the data. Snodin, D.; Teasdale, A.(9)
Mutagenic Impurities: Precompetitive Collaborative and Data Sharing Initiatives Examines the nature, impact, and successes of a series of cross industry initiatives covering areas such as structural evaluation (Q)SAR, data sharing–aromatic amines, boronic acids, purging and degradation. Elder, D. P.; Williams, R.; Harvey et al.(10)
Do Carboxylic/Sulfonic Acid Halides Really Present a Mutagenic and Carcinogenic Risk As Impurities in Final Drug Products? Examines evidence that indicates that in the case of both sulfonyl and acyl chlorides that Ames positive results relate to generation of a reactive species, halodimethyl sulphides (HDMSs) through reaction with DMSO and that this is the root cause of a positive response. Confirmatory negative data from other test solvents is also provided Amberg, A.; Harvey, J.; Spirkl, H.-P. et al.(11)
Boronic Acids and Derivatives—Probing the Structure–Activity Relationships for Mutagenicity The primary purpose is to raise awareness of the potentially mutagenic nature of boronic acids and stimulate further discussion/research in the areas. It provides mutagenicity data for some 40+ examples, examining the current status of in silico predictions and postulates a potential mechanism related to oxidation of boronic acids to yield oxygen radicals Hansen, M. H.; Jolly, R. A.; Linder, R. J.(12)
A Kinetics-Based Approach for the Assignment of Reactivity Purge Factors Details an experimental approach that utilizes kinetic analysis to facilitate assignment of reactivity purge values. Betori, R. C.; Kallemeyn, J. M.; Welch, D. S.(13)
A Generic Industry Approach to Demonstrate Efficient Purification of Potential Mutagenic Impurities (PMIs) in the Synthesis of Drug Substances Based on vortioxetine and its associated PMIs predicted purge values based on the system described by Teasdale et al.(15) are compared with experimental values. The results show good correlation concluding that theoretical purge values can be used to predict purging of PMIs. Lapanja N, Zupanĉiĉ B, Toplak Ĉasar R et al(14)
Evaluation and Control of Mutagenic Impurities in a Development Compound: Purge Factor Estimates versus Measured Amounts The purging of MIs associated with the synthesis of MK-8876 were assessed using the approach described by Teasdale et al.(15)These predicted values were compared to measured values and shown to be conservative in comparison to experimental data. McLaughlin, M.; Dermenijan, R. K.; Jin, Y. et al.(16)
Several papers focused on control options, specifically ICH option 4, involving evaluation of the impact of process conditions upon the purging of mutagenic impurities. This concept was first described by Teasdale et al. in 2010(17) and augmented by a cross-industry evaluation published in 2013.(15) The practical use of such tools is examined through two papers, that of Nevenka et al.(14) and McLaughlin et al.(16) This is augmented by a further publication by Welch et al.(13)that describes work now being undertaken by an industry consortium to develop this tool still further as a robust in silico tool (Mirabilis). Welch et al. describe the work being undertaken to fully evaluate the potential fate of MIs under a range of common chemical transformations. A critical finding of these studies, examined through the reaction of benzyl bromide with triethylamine, was alignment between the rate constants and half-lives of the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol (Figure 2). This established the proof of concept that the kinetic information obtained from the stand-alone reaction can be used to predict impurity conversion in a more complex reaction.

Figure

Figure 2. Alignment between the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol.

Another area addressed in the special edition is that of sulfonate esters. This relates to the use of a sulfonic acid, used to form an API salt and the potential formation of sulfonate esters through reaction with alcoholic solvents. Snodin and Teasdale(9) have reviewed the available literature information concluding that the extensive evidence supports the view that such concerns are grossly exaggerated. In parallel to this publication there have been a series of correspondences involving the EMA quality working party, the following points were released following discussion at the CVMP committee.(18)

“The Committee endorsed the QWP response to the EDQM request for an opinion on new information on alkyl sulfonates. The QWP reviewed the article from Snodin et al. QWP acknowledges the scientific rationale in this article and that the formation of alkyl sulfonates is very low and very much depends on the reaction conditions. This makes the presence of these mutagenic impurities at toxicologically significant levels unlikely. However, as the presence and formation of these alkyl sulfonates cannot be totally excluded, QWP proposes the following approach: marketing authorization holders should justify via Risk Assessment that alkyl sulfonates are not expected to be present for their product, which may be sufficient.”

Of concern within this text is the comment that the presence and formation cannot be totally excluded; this is despite the evidence pointing clearly to fact that it can.

Similarly at the end of February EDQM issued a press release relating to the Mesilates Working party.(19) Included within this, as well as information relating to analytical methods, was the following revision of the production statement.

“In addition to the elaboration of these methods, the Ph. Eur. Commission had also decided to revise the Production section of monographs on those active substances to further assist users: “It is considered that [XXX esters] are genotoxic and are potential impurities in [name of the API]. The manufacturing process should be developed taking into consideration the principles of quality risk management, together with considerations of the quality of starting materials, process capability and validation. The general method [2.5.XX] is available to assist manufacturers.”

This also goes on to state that:

“Marketing Authorisation Applicants are not obliged to perform the testing when they can justify via risk assessment that alkyl sulfonates are not expected to be present in their product.”

Although both the QWP deliberation and the EDQM statement fall short of concluding minimal risk, they nevertheless represent for the first time at least tacit recognition that control is possible.
 
read ………….https://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Regional_Discussion_Groups/Southern_California_Pharmaceutical/SCPDG%20Impurities_Olsen%20Jan%20event.pdf

 

References

 

  1. 1.ICH Q3D Guideline for Elemental Impurities.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf(Dec 16, 2014).

  2. 2.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Training_package_Module_0-7.zip

  3. 3.Analysis of Oligonucleotides and their related substances; Okafo, G., Elder, D., and Webb, M., Eds.; Chapter 2, pp 22– 28; ChromSoc Separation Sciences Series ISBN 9781906799144.

  4. 4.http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/m5192.pdf

  5. 5.ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Step_4.pdf (June 23, 2014).

  6. 6.Elder, D. E.; Teasdale, A. Org. Process Res. Dev. 2015, 19, 1437– 1446, DOI: 10.1021/op500346q

  7. 7.Kleinman, M. H.; Teasdale, A; Baertschi, S. W. Org. Process Res. Dev. 2015, 19, 1447– 1457, DOI: 10.1021/acs.oprd.5b00091

  8. 8.Strege, M. A.; Osborne, L. M.; Hetrick, E. M. Org. Process Res. Dev. 2015, 19, 1458– 1464, DOI: 10.1021/acs.oprd.5b00112

  9. 9.Snodin, D; Teasdale, A. Org. Process Res. Dev. 2015, 19, 1465– 1485, DOI: 10.1021/op500397h

  10. 10.Elder, D. P.; Williams, R; Harvey Org. Process Res. Dev. 2015, 19, 1486– 1494, DOI: 10.1021/acs.oprd.5b00128

  11. 11.Amberg, A.; Harvey, J.; Spirkl, H.-P. Org. Process Res. Dev. 2015, 19, 1495– 1506, DOI: 10.1021/acs.oprd.5b00106

  12. 12.Hansen, M. H.; Jolly, R. A.; Linder, R. J. Org. Process Res. Dev. 2015, 19, 1507– 1516, DOI: 10.1021/acs.oprd.5b00150

  13. 13.Betori, R. C.; Kallemeyn, J. M.; Welch, D. S. Org. Process Res. Dev. 2015, 19, 1517– 1523, DOI: 10.1021/acs.oprd.5b00257

  14. 14.Lapanja, N.; Zupanĉiĉ, B.; Toplak Ĉasar, R. Org. Process Res. Dev. 2015, 19, 1524– 1530, DOI: 10.1021/acs.oprd.5b00061

  15. 15.Teasdale, A.; Elder, D.; Chang, S.-J. Org. Process Res. Dev. 2013, 17, 221– 230, DOI: 10.1021/op300268u

  16. 16.McLaughlin, M.; Dermenjian, R. K.; Jin, Y. Org. Process Res. Dev. 2015, 19, 1531– 1535, DOI: 10.1021/acs.oprd.5b00263

  17. 17.Teasdale, A.; Fenner, S.; Ray, A Org. Process Res. Dev. 2010, 14, 943– 945, DOI: 10.1021/op100071n

  18. 18.http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2015/12/WC500198748.pdf (Dec 8, 2015).

  19. 19.https://www.edqm.eu/sites/default/files/press_release_on_mutagenic_impurities_february_2016.pdf (Feb 25, 2016).

  20. 20.Pharmaceutical CGMPS for the 21st Century—A Risk-Based Approach.http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/UCM176374.pdf (Sept 2004).

  21. 21.Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Final_Concept_Paper_July_2014.pdf (July 28, 2014).

  22. 22.ICH Q9—Quality Risk Management.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf (Nov 9, 2005).

  23. 23.ICH Q10—Pharmaceutical Quality System.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf (June 4, 2008).

  24. 24.Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products,http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM448638.pdf?_sm_au_=iNH61FD2WjHZP02F (May 2015).

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EMA publishes Q&A on data required for sterilized primary packaging materials used in aseptic manufacturing processes

 Uncategorized  Comments Off on EMA publishes Q&A on data required for sterilized primary packaging materials used in aseptic manufacturing processes
May 192016
 

The European Medicines Agency, EMA, recently published questions and answers on what data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process. Read more about “What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?“.

http://www.gmp-compliance.org/enews_05330_EMA-publishes-Q-A-on-data-required-for-sterilized-primary-packaging-materials-used-in-aseptic-manufacturing-processes_15303,15493,15615,Z-PKM_n.html

The European Medicines Agency, EMA, recently published questions and answers on quality of packaging materials (H+V April 2016):

“3. What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?
Terminal sterilisation of the primary packaging, used subsequently during aseptic processing of the finished product, is a critical process and the sterility of the primary container is a critical quality attribute to ensure the sterility of the finished product. Both need to be assured for compliance with relevant Pharmacopoeial requirements for the finished product and product approval.

The site where sterilisation of the packaging materials takes place may not have undergone inspection by an EU authority and consequently may not hold an EU GMP certificate in relation to this activity1. When GMP certification is not available, certification that the sterilisation has been conducted and validated in accordance with the following ISO standards would be considered to provide an acceptable level of sterility assurance for the empty primary container:

  • I.S. EN ISO 20857:2013 Sterilization of Health Care Products – dry Heat – Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 20857:2010);
  • I.S. EN ISO 11135:2014 Sterilization of Health-care Products – Ethylene Oxide – Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11135:2014);
  • I.S. EN ISO 17665-1:2006 Sterilization of Health Care Products – Moist Heat – Part 1: Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices, and, ISO/TS 17665-2:2009 Sterilization of health care products — Moist heat — Part 2: Guidance on the application of ISO 17665-1;
  • I.S. EN ISO 11137-1:2015 Sterilization of Health Care Products – Radiation – Part 1: Requirements for Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11137-1:2006, Including 1:2013);
  • I.S. EN ISO 11137-2:2015 Sterilization of Health Care Products – Radiation – Part 2: Establishing the Sterilization Dose (ISO 11137-2:2013);
  • I.S. EN ISO 11137-3:2006 Sterilization of Health Care Products – Radiation – Part 3: Guidance on Dosimetric Aspects.

It is the responsibility of the user of the manufacturer of the medicinal product, to ensure the quality, including sterility assurance, of packaging materials. The site where QP certification of the finished product takes place, and other manufacturing sites which are responsible for outsourcing this sterilisation activity, should have access to the necessary information to demonstrate the ongoing qualification status of suppliers of this sterilisation service. This should be checked during inspections. The Competent Authorities may also decide, based on risk, to carry out their own inspections at the sites where such sterilisation activities take place.

Dossier requirements:

The following details regarding the sterilisation of the packaging components should be included in the dossier:

1. The sterilisation method and sterilisation cycle;
2. Validation of the sterilisation cycle if the sterilisation cycle does not use the reference conditions stated in the Ph. Eur.;
3. The name and address of the site of sterilisation and, where available details of GMP certification of the site. Where the component is a CE-marked Class Is sterile device (e.g. sterile syringe), confirmation from the manufacturer that the component is a Class Is sterile device, together with a copy of the declaration of conformity from the Notified Body will suffice.

In the absence of GMP certification or confirmation that the component is a CE-marked Class Is medical device, certification that the sterilisation process has been conducted and validated in accordance with the relevant ISO standards should be provided.
________________________________________
1Sites located in the EU which perform sterilisation of primary packaging components only are not required to hold a Manufacturer’s/Importer’s Authorisation (MIA). Sites located in the EU, which carry out sterilisation of medicinal products, are required to hold a MIA in relation to these activities.”

Source: European Medicines Agency – Quality of medicines Q&A: Part 2 – Packaging.

 

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FDA´s new policy regarding grouping of supplements for CMC changes

 regulatory  Comments Off on FDA´s new policy regarding grouping of supplements for CMC changes
May 192016
 

The US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) released a new document outlining how supplements can be grouped together and submitted concurrently for the same chemistry, manufacturing and controls (CMC) changes. Find out more about Policy and Procedures regarding the Review of Grouped Product Quality Supplements.

http://www.gmp-compliance.org/enews_05320_FDA%B4s-new-policy-regarding-grouping-of-supplements-for-CMC-changes_15173,Z-RAM_n.html

On April 19, 2016 the US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) released a new document outlining how supplements can be grouped together and submitted concurrently for the same chemistry, manufacturing and controls (CMC) changes to multiple approved new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biological license applications (BLAs) submitted by the same applicant.

The agency says the goal of its new policy is to make the process more efficient and consistent when reviewing grouped supplements.The term “grouped supplements” is used to describe two or more supplements reviewed and processed using the procedures set forth in the new document, though FDA makes clear that supplements cannot be grouped if submitted by a different applicant or if the supplements provide for different CMC changes. “The supporting data necessary for the review of the CMC changes should be the same for each of the grouped supplements,” FDA says. “Any supplement that provides for the same CMC changes but necessitates the review of data that is unique to that supplement (e.g., product-specific data) should not be grouped.”

Supplements can be grouped when the following criteria are met:

  • The cover letter for the supplements clearly states the purpose of the proposed CMC changes and indicates that the supplement is one of multiple submissions for the same change.
  • Each supplement includes a list of the application numbers (NDA, BLA, and ANDA, as appropriate) and identifies the drug products that will be covered by the CMC changes.
  • The supplements have the same submission date on Form FDA 356h.

“On a case-by-case basis, the Center may also group supplements that do not meet some or any of the criteria described above, if grouping the supplements is advantageous to the review process,” FDA says.

Circumstances where this may occur include cases when an applicant submits a group of supplements for the same CMC change and then, at a later date, submits additional supplements for the same change and requests FDA officials to include the second set of supplements in the group.

The Regulatory Business Project Manager (RBPM) and Branch Chief (BC) of the relevant review division will decide on a case-by-case basis whether such changes will be allowed, though FDA notes that “consideration will be given to whether the goal date for the original group of supplements could still be met if the second set of supplements is added to the review.”

Additionally, seven new procedures were outlined by FDA in the MAPP (Manual of Policies and Procedures).

Source: Regulatory Affairs Proffessional Society – See more at:  OFFICE OF PHARMACEUTICAL QUALITY Review of Grouped Product Quality Supplements

 

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