INSPECTION DIVISION Starting materials inspection division Date: 30/03/2016 Version: 1 public Status: Final SITUATION REPORT ON THE ACTIVE SUBSTANCE AMOXICILLIN I. INTRODUCTION .................................................................................................................................. 2 II. BACKGROUND .................................................................................................................................. 3 III. APPLICABLE REGULATIONS/GUIDELINES IN FORCE ................................................................ 3 IV. AMOXICILLIN SUPPLY .................................................................................................................... 3 IV.1. Process for obtaining amoxicillin ................................................................................................ 3 IV.2. Sources of supply of medicinal product manufacturing sites in France ..................................... 5 V. EVALUATION OF AMOXICILLIN MANUFACTURERS BY PHARMACEUTICAL SITE .................. 8 VI. REVIEW OF RECENT INSPECTIONS .............................................................................................. 8 VI.1. Collaboration between competent authorities ............................................................................ 8 VI.2. Monitoring of amoxicillin (sodium or trihydrate) manufacturing sites by international authorities since 2010 ........................................................................................................................................... 9 VII. CONCLUSION ................................................................................................................................ 12 VIII. LIST OF REFERENCES ................................................................................................................ 13 IX. ACRONYMS .................................................................................................................................... 15 X. APPENDICES ................................................................................................................................... 16 X.1. Appendix 1: List of pharmaceutical sites and proprietary medicinal products ........................... 16 Distribution ANSM website I. INTRODUCTION Amoxicillin is an antibiotic of the beta-lactam family, which includes five structural classes: - penicillins (e.g., Ampicillin/Amoxicillin/Oxacillin); - cephalosporins (e.g., Cephalexin/Cefaclor); - carbapenems (e.g., Imipenem/Meropenem); - carbacephems (e.g., Loracarbef); - monobactams (e.g., Aztreonam). The structure of penicillins derives from the penam core, which comprises an azetidine-2-one ring. 6- aminopenicillanic acid (6-APA) is the basic structure of penicillins. Substitution of the amino function by acylation results in derivatives that differ in their pharmacokinetics, stability, antibiotic spectrum, and resistance to β-lactamases. R1 S R3 R2 Penam core N R4 O R6 R5 R1 R3 Azetidine-2-one (β lactam) R2 R4 N O R5 H N H 2 S Me 6-aminopenicillanic acid (6-APA) N Me O COOH H N H S Me Penicillin G (PEN G) O N Me O COOH NH 2 H N H S Me O Amoxicillin HO N Me O COOH Amoxicillin belongs to the group of extended-spectrum penicillins, also called group “A” penicillins (ampicillin and similar). The spectrum of these semi-synthetic penicillins corresponds to that of benzyl- penicillin (PEN G), extended to certain Gram-negative bacilli. The bactericidal effect of penicillins occurs through inhibition of transpeptidation, a necessary step in the development of peptidoglycan, a major polymer of the bacterial wall. This antibiotic, commonly used since the early 1980s in the treatment of bronchopulmonary, pleural, and ENT infections [amoxicillin: Clamoxyl®; amoxicillin and clavulanic acid (inhibitor of β-lactamases): Augmentin®] is registered in France in several medicinal products (proprietary and many generics). It appears on the WHO List of Essential Medicines. Depending on the type of proprietary medicinal product, amoxicillin comes in two forms: - sterile sodium amoxicillin for injectable medicinal products (IM/IV); - amoxicillin trihydrate for oral medicinal products. Its dosage may be greater than 2 g/day. The injectable form is indispensable in the management of patients who are unable to take oral forms. Situation report on the active substance Amoxicillin 2 / 18 ANSM-DI-INSMP The study published in November 2014 by ANSM and devoted to the evolution of consumption of antibiotics in France between 2000 and 20131 stresses that in hospitals or pharmacies, penicillins are the most used class of antibiotics, and their use even increased in pharmacies during the study period. While amoxicillin remains the reference molecule, it is mostly used in association with clavulanic acid. Note that this association is on the list of antibiotics that particularly generate bacterial resistance2. Amoxicillin (alone or in combination) was the fifth-highest selling active substance sold in pharmacies in 2013, and the top generic with 39 million boxes of amoxicillin and 18 million boxes of amoxicillin/clavulanic acid3. Its availability is therefore a major challenge for the treatment of patients in pathologies of bacterial infections due to germs with antibiotic sensitivity. The full list of medicinal products marketed in 2015 throughout the national territory appears in Appendix 1. The purpose of this summary is to provide a situation report on the quality and supply of amoxicillin (sodium and trihydrate) used in medical products placed on the domestic market, on the basis of information collected during an investigation conducted with ordering pharmaceutical companies and the results of inspections of manufacturing sites. II. BACKGROUND In May 2013, quality issues (non-compliant annual aseptic process simulation test) encountered by a manufacturer of the active substance sterile sodium amoxicillin used in Panpharma’s medicinal products led to an inventory shortage for Panpharma amoxicillin 1g, powder for injectable solution, and Panpharma amoxicillin 2g, powder for injectable solution. The massive switch too Clamoxyl®, GSK’s powder for injectable solution, led to a further inventory shortage4. Furthermore, the inspection of the “Zhuhai United Laboratories Co, Ltd” site conducted from 30 March 2015 to 2 April 2015 by the EDQM and the Romanian authorities led to the recording of a notice of non- compliance in the EudraGMDP database (no. NCF/011/RO) and the decision to suspend CEP 2013- 125 concerning the manufacture of sterile sodium amoxicillin5. In France, this decision directly impacted Panpharma amoxicillin 1g, powder for injectable solution, and Panpharma amoxicillin 2g, powder for injectable solution. After reviewing all the evidence gathered during the investigation and the provisional measures put in place, and given the essential nature of this active substance in France, Romania, and the UK, a restricted GMP certificate (no. 016/2015/RO)5 was issued to authorise the use of this AS in the three countries until the qualification of a new supplier by each MA holder. These incidents highlight the critical nature of the supply of the active ingredient amoxicillin (sodium or trihydrate) on the availability of medicinal products present on the domestic market. III. APPLICABLE REGULATIONS/GUIDELINES IN FORCE The standards of good practice, enforceable or not enforceable, applicable to amoxicillin are listed below: - Part II of the Good Manufacturing Practices for active substances used as starting materials in medicines; - Guideline 1 of the European Guidelines for Good Manufacturing Practices: Manufacture of sterile medicinal products; - European pharmacopoeia monograph no. 0577: sodium amoxicillin (semi-synthetic product derived from a fermentation product); - European pharmacopoeia monograph no. 0260: amoxicillin trihydrate (semi-synthetic product derived from a fermentation product); - A draft revision of EP monographs no. 0260 and 0577, presented in volume 26.2 of Pharmeuropa of July 2014, is currently under review. IV. AMOXICILLIN SUPPLY IV.1. Process for obtaining amoxicillin In terms of the industrial production described in the literature, the processes for obtaining amoxicillin trihydrate from the key intermediate 6-APA are chemical or enzymatic6. The 6-APA is obtained from penicillin G (PEN G/benzyl-penicillin) after breaking the amide bond [-CONH-] through the use of enzymatic or chemical methods. Situation report on the active substance Amoxicillin 3 / 18 ANSM-DI-INSMP Examples of processes for obtaining amoxicillin: H N H S Me O N Me O COOH PEN G 1) Chemical hydrolysis [4 steps] or 2) Enzymatic hydrolysis with Penicillin G acylase (PGA) [1 step] H N H 2 S Me N Me O COOH 6-APA Enzymatic way Chemical way [Penicillin G acylase (PGA)] (Dane salt) + + O NH2 OMe H OMe O HO Me NH O R p-hydroxyphenylglycine methyl ester HO O O + mixed anhydride 1) (CH ) SiCl PGA 3 3 N(C2H5)3 2) Acid hydrolysis Acidification/purification 3) Purification NH 2 H N H S Me O HO N Me O COOH Amoxicillin The conventional methods for chemically obtaining (using Dane salt) amoxicillin typically involve more than 10 steps, require low-reaction temperatures (-30°C), and use toxic solvents like methylene chloride and silylation reagents. It is reported that the production of one kilogram of amoxicillin generates up to about 70 kg of non-recyclable waste7. In contrast, enzymatic methods require far fewer steps, use milder reaction conditions, and generate less waste. The latter approach is