MEDICAL CANNABISHOW TO GET GMP-READY?

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GMP-Update – Part 1

Supplier Qualification

Cold WFI Manufacture

FDA/GMP trends in production & technology – Part 2

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Europe's largest Pharma Congress ahead

The Pharma Congress Production & Technology is the largest of its kind in Europe. The Congress will be held on 24 – 25 March, 2020 in Düsseldorf/Neuss.

Today it is the most important industry meeting place for staff and managers from the pharmaceutical and biopharmaceutical production as well as from tech-nical service providers. Speakers from leading pharmaceutical companies and the pharmaceutical authorities present case studies in a total of 8 conferences. Participants from over 20 countries make the Pharma Congress an international hotspot for pharmaceutical production and technology.

Parallel conferences are offered on the following topics:• Data Integrity• Aseptic Processing• Continuous Bioprocessing• Barrier Systems• Integrated Qualification, and more

If you want to learn more about what has been presented last year, please read our article on page 14. Further interesting articles about GMP trends can be found in this issue.

Enjoy reading!Oliver Schmidt

Editoral

Content

44 Cover story Medical Cannabis – How to get GMP-ready?

What does the legalisation of cannabis for medicinal purposes mean for national and inter-national legal frameworks?

7 GMP-Update – What's new in Germany and the EU? – Part 1The first part of this series on the changes in GMP regulations happening during the past year covers Nitrosamine Impurities.

9 Supplier QualificationOutsourcing is a critical process in the pharmaceutical industry. A whole series of quality assurance requirements are laid down in the corresponding GMP regulations.

12 Cold WFI Manufacture – Two Years after the Change in the PharmacopoeiaAfter almost a hundred years, the regulation for the production of water for injection (WFI) was changed in 2017.

14 FDA/GMP trends in production & technology - Part 2Second part of the Pharma Congress 2019 conference report: what has changed in the areas of data integrity, modern qualification, etc.?

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NEWS FROM OUR ASSOCIATION www.eca-foundation.org

European QP Association � The IMP Working Group leadership team planned QP Forum

IMP Sessions and discussed team's future structure. It further appointed Patryk Jegorow to the IMP Working Group leader-ship team after Philippe Van der Hofstadt had stepped down.

� A list of topics was prepared and forwarded to the EMA IWG (lists from all interested parties coordinated by EFPIA for further consolidation).

� Together with other "interested parties" the Association sent a letter to EMA to bring some priority topics to their GMP/GDP IWG. EMA agreed to a web-based meeting for two hours which was conducted in January.

� The 14th QP Forum was held in Munich. With more than 300 delegates (participants plus speakers) it set a new record. At the following Board Meeting their future activities and first ideas for the 2020 QP Forum were discussed.

� EQPA was invited by the Brazilian Association of Pharmaceuti-cal Ingredients Industry – Abiquifi to discuss recent changes in the Brazilian API regulations in Sao Paulo.

� Members were asked to provide national requirements for becoming a QP for Good Practice Guide's Annex update. Version 6.0 is now available on the website.

� 186 members provided feedback in a survey on Quality by Design sent on behalf of postgraduate at De Montfort Univer-sity in Leicester, UK. Results were summarised and published in the EPQA Newsletter.

� The website was completely revised and re-organised. www.qp-association.eu

Pharmaceutical Microbiology Group � To take into account the changes in the field of microbiology

and microbiological QC two new Board members were appointed. On the regulatory side one of the PEI representa-tives resigned. The Board is also considering an extension to give CLOs a voice.

� At the Board meeting in November the new Chapter 2 of the Group’s OOS/OOL Guideline Dealing with Deviations in Endo-toxin Testing was discussed. It is supposed to be presented at the European Microbiology Conference in May 2020.

� The new established PEI/ECA - MAT Task Force created and finalized a paper in September.

www.pharmaceutical-microbiology.org

Validation Group � The Good Practice Guide Modern Qualification was revised

and launched as second draft at Conference in October. During the conference, there were very open discussions for a further development of the public draft version 2 to a final version. Comments were possible until end of 2019. Two more planned sub-groups are supposed to concentrate on electron-ic record/digital documentation and on single-use systems.

www.validation-group.org

European GDP Association � Prabjeet Dulai was appointed as new Director of Regulatory

Affairs and Communication to the Board. � A new guidance document for interpretation and implementa-

tion of the GDP requirements for APIs is in progress together with PQG. The combined draft document is in its final review.

� As of January 2020 Dr Markus Funk will be replacing Wolfgang Schmitt as Administration Manager. We would like to thank Wolfgang Schmitt for all his hard work in support of the GDP group over the past twelve years and wish him the best of luck for his future role in ECA.

� The next GDP Board meeting will be in June 2020 in Barcelona, where we will review our future activities for the group. The GDP Forum will take place after the board meeting. We are looking forward to welcoming several expert speakers at this meeting.

� GDPA was selected as one of the expert groups from the indus-try to review and comment on the new WHO GDP guidelines. We have submitted our comments on this document to WHO, now looking forward to seeing the final version published.

� Prabjeet Dulai represented the Group at the GDP conference in Belgrade organised by the Belgrade University and the local pharmaceutical association.

� The Association's website has been revised to include new, additional information. The members' area provides access to GDPA's published guidance document free of charge.

www.good-distribution-practice-group.org

Visual Inspection Group � The updated version (3.1) of the best practice guidance on

visual inspection was published on the group's website – and handed out during the Visual Inspection event which took place in October. Further adaptations planned for the beginning of 2020 are supposed to also comprise Annex 1 draft topics.

� Further, the Position Paper on CCIT, currently available in ver-sion 1.1, will be adopted in 2020.

� The next annual meeting – the Control of Parenterals Confer-ence with CCIT & Visual Inspections Systems pre-conferences was scheduled for November 2020.

� The Group plans on conducting surveys among the ECA Visual Inspection Group members to find out more about the indus-try’s opinion regarding specific topics - like AQL limits used, criticality definitions for particles etc.

www.visual-inspection.org continued on back page

the ECA's interest and Working Groups have been working hard throughout 2019 on preparing guidance documents, responding to members' questions and organising conferences and training courses. I have summarised their achievements below:

Dr Afshin Hosseiny (Chairman ECA Foundation)

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Introduction

An increasing number of countries legalize cannabis for medicinal purposes. New Zealand1, Belgium2 and France, for example, are currently discussing to follow Germany, where cannabis for medicinal use was legalized in 2017.3

Marihuana has been legalized in 34 states of the USA for medical and / or recreational use (11 states), but not by federal law. In addi-tion to the previously legalized Marihuana (for medical and recrea-tional use), Canada proposed a new "Edibles" regulation for edible cannabis products and topicals.

France recently published a proposed framework together with a dossier for implementing a French medical cannabis pilot pro-gramme which is based on the recommendations of the French Comité scientifique spécialisé temporaire (CSST).4 The main objec-tive of this programme is to evaluate cannabis prescription and dosage and to assess its acceptance among health care profession-als and patients. In addition, safety and efficacy data for medical

cannabis will be collected. The two-year pilot programme is expected to start in the second half of 2020. Thus, medical canna-bis will not be legalized in France prior to the end of 2022.

In addition, Health Canada (HC) published a proposed regulatory approach for a new class of cannabis products referred to as Can-nabis Health Products (CHPs) which would not require practitioner oversight.5 According to HC, there is a growing interest in potential therapeutic use of cannabis for minor ailments. Moreover, canna-bis products with unauthorized health claims are emerging on the Canadian market illegally. Examples are cannabidiol (CBD) prod-ucts, i.e. products containing no more than 10 ppm tetrahydrocan-nabinol (THC). Interest in these CBD products has also increased in the Unites States since the U.S. Congress passed the Agriculture Improvement Act of 2018 (the 2018 Farm Bill) in December 20186. Among other things, this law established a new category of legal cannabis classified as "hemp" – defined as cannabis and cannabis derivatives with no more than 0.3 percent of THC (on a dry weight basis concentration). In France, it is prohibited to distribute CBD-Products if they contain any traces of THC and/or if they derived

Medical Cannabis How to get GMP-ready?

About the AuthorDr Andrea Kuehn-Hebecker is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area packaging, development and Lifecycle Management.

GMP for Cannabis – what you need to know

9/10 June 2020, Hamburg, Germanygmp-compliance.org

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from not-authorized varieties and/or parts of plants7. Manufactur-ers and distributers of CBD-Products are not allowed to claim any therapeutic use/effect.

However, the FDA approved the medicinal cannabis product Epidy-olex and the EMA followed last year and authorized Epidyolex for the treatment of rare forms of childhood epilepsy. Epidyolex contains high-purity cannabidiol (CBD) as the active ingredient. It is the first CBD product to receive a positive decision in the central-ized EU approval procedure.

Following these global developments, there will be a growing need for producers to supply chemists, physicians and patients with the newly legalized drug.

What qualifies as "medical grade Cannabis"?

Several European countries published pharmacopoeial Mono-graphs for Cannabis flowers (e.g. the German DAB Monograph8, the DK Monograph9) and extracts (the German Draft DAB Mono-graph10). In addition, other countries like, for example, New Zealand (NZ) and the U.S., have their own quality standards (NZ Product Quality Standards Monograph1; American Herbal Pharmacopoeia: Cannabis Inflorescence and Leaf (2013)). However, these standards are currently not harmonized - neither between the EU member states nor between the EU and/or Canada, the U.S., NZ, etc.

In Europe, these products must comply with the relevant require-ments laid down under Medicinal Law (including Pharmacopoe-ias, EU-GMP/GDP and GACP) and the Narcotics Law. In Germany, for example, the BfArM (the Federal Institute for Drugs and Medi-cal Devices) has taken over new responsibilities by establishing the Cannabis Agency. The goal of this agency is to contribute to ensur-ing the supply of medical-quality cannabis. Cannabis is not meant to be stored directly at BfArM during any stage of the purchasing, harvesting or distribution process. These steps will be carried out by relevant producers or other commissioned companies (i.e. suppliers, importers). Hence, the agency will only manage and monitor the cultivation, harvest, processing, quality assurance, storage, packaging and distribution of cannabis to wholesalers, chemists or manufacturers.

The EU GMP inspectorates are responsible for issuing manufactur-

ing and import licenses or EU GMP Certificates. Thus, they will perform inspections at the production sites of manufacturers who apply for these certificates and licenses. For example, the starting point for any German GMP certification is a German-based company that applies for such certificate at their local responsible authority.11

Many questions remain

Some of the questions which are currently intensely discussed in relation to medical cannabis are:

• When does GACP (Good Agricultural and Collection Practice12) end and EU GMP (Good Manufacturing Practice13) start? - Growing: What are the requirements regarding soil, light,

irrigation, facilities etc.? - Harvest: Which steps fall under "harvest" – e.g. cutting,

trimming, and washing? - Post Harvest: Is the EU/GMP certificate required only for

"drying to packaging" operations, or for the full production cycle ("growth to packaging")?

• What are the requirements relating to physical security meas-ures?

• What has to be considered in regard of EU-GDP (Good Distri-bution Practice14)?

• How to get a MA-(Manufacturing Authorization), Import License? How to get an EU-GMP Certificate?

• What are the requirements of the (German) Narcotics Law and/or the Single Narcotic Convention15?

• What are the quality requirements for Cannabis Flowers and Extracts? Are there any special requirements for extraction solvents used in the production of cannabis extracts?

• What are the differences between the various pharmacopoeial monographs and quality standards (e.g. regarding Pesticides, Heavy Metals, Microbial Contamination and Mycotoxins)?

• Equipment / Manufacturing: What has to be considered in relation to qualification and validation?

• Which type of Decontamination method could be used/is allowed? In contrast to the US situation, the use of ethylen oxide for herbal drugs is prohibited in the EU, for example.

• What are the stability requirements? Which aspects have to be considered for analytical labs?

• What are the gaps between GPP (Good Production

6

Practices1,16) and EU-GMP?• What will be checked during EU-GMP-inspections?

EU-GMP vs. GPP

Since there is currently no harmonized legislation globally and/or in the EU (e.g. regarding pharmacopoeias etc.), some of the topics listed above are very relevant for EU as well as non-EU growers/suppliers and ex -/importers.

For example, the EU-GMP guidelines include principal require-ments for

• The Pharmaceutical Quality System (PQS),• Personnel,• Premises and Equipment (including Qualification), • Documentation (including Records and Data Integrity), • Validation (including Manufacturing, Computer System, and

Analytical Validation),• Production, • Quality Control (including Stability Programme), • QP Batch Release,• Outsourced Activities (including Audits), • Complaints and Product Recall, and• Self Inspection.

In addition, the EU-GMP of Annex 7 – Manufacture of Herbal Medicinal Products provides guidance for the application of GACP.

GACP gives appropriate guidance and defines basic rules which can be adapted to specific conditions. The Principle of GACP is different to highly regulated GMP; levels and requirements for GACP need to be defined on a case-by-case basis. According to Annex 7 for pri-mary steps that take place in the field the standards of GACP is applicable. GMP is applicable to further cutting and drying steps. In Canada, for example, GPP (Good Production Practices) for culti-vation of medicinal cannabis have to be applied.16, 17 So far, the GPP

framework regulates the cultivation and processing of all cannabis products for both medicinal and recreational use. The major components of GPP concern facilities and equipment, sanitation, quality assurance, quality control, record keeping, and security requirements.18

According to reference 1, there are a number of areas where the two standards EU-GMP and GPP do not align. The EU-GMP guide-lines "are more detailed, providing principles and interpretation" on what must be included in a PQS to comply, "while the GPP standard provides less detail and is therefore more open to interpretation. This difference makes it difficult to directly compare the two standards". For example, stability testing is not required under GPP. Under EU-GMP, the stability programme designed in accordance with the ICH Q1 Guidelines is required to establish the shelf life of a product. In addition, EU-GMP requires full validation as part of the PQS, while this is currently not required under GPP1.

Since there are some substantial differences (which still have to be identified in detail) between GPP and EU-GMP, non-EU suppliers will have to implement EU-GMP standards if they want to supply medical cannabis to the EU market. However, since there is cur-rently no harmonized EU standard for medical cannabis (e.g. Ph. Eur. monograph), national legislations, guidelines and monographs will have to be followed and applied in addition to EU-GMP.

ECA Cannabis Working Group

To move forward in developing a harmonized "GMP" standard for medical cannabis, the ECA (European Compliance Academy) is cur-rently establishing a working group which will start to work on an overview of currently available Guidelines etc. from all around the world. The group will then further work on a "white paper" or some kind of framework to support the development of a harmonized standard on a global level to show and work on closing the gaps currently existing between the different regional approaches and regulations.

1 https://www.health.govt.nz/publication/medicinal-cannabis-scheme-consultation2 https://www.vbb.com/insights/corporate-commercial-regulatory/belgium-new-legislation-in-the-making-on-cannabis-for-medical-use3 https://www.bfarm.de/DE/Bundesopiumstelle/Cannabis/_node.html4 Cannabis à visée thérapeutique: Projet d’expérimentation (https://ansm.sante.fr/S-informer/Points-d-information-Points-d-information/Cannabis-a-visee-therapeutique-en-France-L-

ANSM-publie-la-proposition-du-Comite-d-experts-sur-le-cadre-de-la-phase-experimentale-de-mise-a-disposition-Point-d-Information).5 Consultation on Potential Market for Cannabis Health Products that would not Require Practitioner Oversight (https://www.canada.ca/en/health-canada/programs/consultation-

potential-market-cannabis/document.html)6 https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-new-steps-advance-agencys-continued-evaluation7 Mildeca: https://www.drogues.gouv.fr/actualites/cannabidiol-cbd-point-legislation8 DAB (Deutsches Arzneibuch, German Pharmacopoeia) Monograph “Cannabisblüten (Cannabis flos)”, BAnz AT 12.05.2017 B7 / BAnz AT 24.04.2018 B59 Monograph (Danish Pharmacopoeia), Dansk monografi „Cannabisblomst (Cannabis flos)“, Produktformer for medicinsk cannabis, Journalnummer: Sundheds- og Ældremin., Lægemid-

delstyrelsen, j.nr. 2019021125.10 Draft DAB (Deutsches Arzneibuch, German Pharmacopoeia) Monograph „Eingestellter Cannabis-Extrakt (Cannabis extractum normatum)“, BAnz AT 06.05.2019 B611 GMP certification and GMP certificate in Europe – an overview (https://www.concept-heidelberg.com/service/gmp-certification-europe.html)12 Good agricultural and collection practice for starting materials of herbal origin (https://www.ema.europa.eu/en/good-agricultural-collection-practice-starting-materials-herbal-origin)13 EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines (https://ec.europa.eu/health/documents/eudralex/vol-4_en)14 Good Distribution Practice of medicinal products & active substances for medicinal products for human use (https://ec.europa.eu/health/documents/eudralex/vol-4_en)15 United Nations Single Convention on Narcotic Drugs of 196116 Good Production Practices Guide for Cannabis – Requirements under Part 5 of the Cannabis Regulations (ISBN: 978-0-660-25850-8), 201917 https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/licensed-producers/additional-information-licensed-producers-under-access-cannabis-medical-

purposes-regulations.html#a218 https://www.cannabiscomplianceinc.com/application-of-gmp-in-the-cannabis-industry/

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Concerning the GMP regulations there hasn’t been much change in the past calendar year. But some changes can be expected for the year 2020. The long awaited annexes 1 and 21 of the EU-GMP Guidelines are expected to be published finally, for example. But more about that later. This and most of the remaining content of this series of articles were part of a live webinar presented by Dr Bernd Renger on 5 December, 20191.

Nitrosamine Impurities

Nitrosamine impurities in several medicinal products; this is one of the uppermost topics in the minds of the pharmaceutical industry, authorities, pharmacies and patients alike. Are or were the concerns always justified, however? As far as supply shortages are concerned, surely. About the background:

"Nitrosamines" is an abbreviated designation for N-nitrosamines which are formed by the reaction of secondary amines, for example N-Nitrosodimethylamin (NDMA) or Dimethylnitrosamin (DMNA):

Fig. 1: NDMA

At least in the past it had an interesting widespread technical application, for instance as additive in curing of rubber. Today nitrosamines can still be found in latex and rubber (stopper but also balloons), cosmetic products, tobacco and tobacco smoke. But many foodstuffs also contain nitrosamines. The main sources are beer, smoked meat products (bacon, salami, and ham), fresh and smoked fish, spices and cheese.2

Carcinogenity of nitrosamines was reported by scientists of the

GMP-Update – What's new in Germany and the EU? – Part 1

About the AuthorWolfgang Schmitt is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA and GMP.

8

German Cancer Research Center (DKFZ), Heidelberg, already in 1967. According to a classification by WHO’s International Agency for Research on Cancer nitrosamines belong to the so-called "co-hort of concern", a group of highly potent mutagenic carcinogens.3 For that reason they are excluded from the concept of Threshold of Toxicological Concern (TTC) in the ICH Guideline M7(R1) on assess-ment and control of DNA reactive (mutagenic) impurities in phar-maceuticals to limit potential carcinogenic risk. This means that the limit for the daily intake should be below 1.5 μg. This is the same value as for aflatoxins.

Traces of N-nitrosodimethylamine and later also N-nitrosodiethyl-amine were detected in the active pharmaceutical ingredient Vals-artan of two Chinese manufacturers in July 2018. N-nitrosodimeth-ylamine has presumably been formed during the manufacture of the tetrazole ring using sodium nitrite as a reagent. But this has only been the beginning. Very rapidly it became apparent that oth-er sartans also were affected and further contaminations with N-nitroso compounds were detected. Subsequent investigations re-vealed additional other potential sources such as carryover of nitrosamines from precursors, reagents or solvents or the use of recycled solvents. This led to a number of recalls of medicinal prod-ucts manufactured with API from the manufacturers concerned.

The European risk assessment procedure according to Article 31 Directive 2001/83/EC was completed in January 2019 and an EMA press release followed in February 20194.

Temporary limits were established on the basis of an assessment by EMA’s Safety Working Party (SWP) with different limits for the different sartans. The limits ranged between 0.3 and 3.0 ppm. The list was expanded to other N-Nitrosamines in August 2019. The

transition period for compliance with the limits is two years. After this time, a general limit of < 0.03 ppm will have to be complied with.

Unfortunately, the problems have spread even further. NDMA was identified in some batches of Pioglitazone from India in April 2019. In a press release dated 26 April, 2019 the EMA required again a review of the routes of synthesis.5 The FDA reported about NDMA impurities in Ranitidin in August 2019. This triggered investigations of Ranitidin products in the EU as well as several recalls.

On 13 September 2019 EMA’s Executive Director asked the Com-mittee for Medicinal Products for Human Use (CHMP) to provide guidance for avoiding the presence of nitrosamine impurities in human medicines containing chemically synthesised active sub-stances.6 Furthermore, there was collaboration with the EDQM to include limits and monographs in pharmacopoeias. On 26 Septem-ber 2019 an important step was carried out: The EMA published the "Information on nitrosamines for marketing authorisation hold-ers"7 requesting that marketing authorisation holders for human medicines containing chemically synthesised active substances review their medicines for the possible presence of nitrosamines. A risk assessment to be concluded at the latest within six months is supposed to be the basis for the internal measures. Products re-garded as potentially at risk also have to be tested. In parallel, the EMA issued a Q&A Paper "Information on nitrosamines for market-ing authorisation holders" which has been enhanced in the mean-time.

Two statements show that the US FDA takes a much more relaxed and maybe realistic approach to the situation concerning the limits and the ubiquitous occurrence of nitrosamines:

"Although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts expected to be found in common foods."(FDA Statement alerting patients and health care professionals of NDMA found in samples of ranitidine, 13 September 2019)8

"Through our testing so far, we have found levels of NDMA in ranitidine that are similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats."(FDA Statement on new testing results, including low levels of im-purities in ranitidine drugs, 1 November, 2019)9

This article will be continued in the next issue of the GMP Journal.

1 A recording of the webinar can be found here: https://www.gmp-navigator.com/nav_webvid_liste.html2 See also “Nitrosamine in Lebensmitteln” (Nitrosamines in food) University of Landau: https://www.uni-landau.de/umwelt/study/content/files/archiv/Soegding/SS09/Chemie_der_Ge-

brauchsartikel/Nitrosamine_Priefer.pdf3 https://www.who.int/medicines/publications/drugalerts/InformationNote_Nitrosamine-impurities/en/ 4 https://www.ema.europa.eu/en/news/sartan-medicines-companies-review-manufacturing-processes-avoid-presence-nitrosamine-impurities5 https://www.ema.europa.eu/en/documents/press-release/update-nitrosamine-impurities-ema-continues-work-prevent-impurities-medicines_en.pdf6 https://www.ema.europa.eu/en/news/ema-provide-guidance-avoiding-nitrosamines-human-medicines7 https://www.ema.europa.eu/en/news/ema-advises-companies-steps-take-avoid-nitrosamines-human-medicines8 https://www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine9 https://www.fda.gov/news-events/press-announcements/statement-new-testing-results-including-low-levels-impurities-ranitidine-drugs

Nitrosamine Impurities19 March 2020Frankfurt am Main, Germany

Learn more about Nitrosamine contamina-tion in drug substances and drug products.

Learn more about this course:

www.gmp-compliance.org

9

Outsourcing is a critical process in the pharmaceutical industry. A whole series of quality assurance requirements are laid down in the corresponding GMP regulations. EU-GMP Guidelines and national legislation refer to what has to be regulated between the contract giver and the contract acceptor or supplier to ensure the quality of the product. The qualification of suppliers, contract manufacturers and contract laboratories is an essential part of the selection and subsequent cooperation. Many aspects have to be clearly regulated in advance, e.g. in contracts. Furthermore, ques-tions arise in the operative business for which both contractual partners must find mutually acceptable answers while fulfilling the GMP requirements.

Legal basis

The pharmaceutical manufacturer is obliged to control all outsourced activities. Chapter 7 of the EU-GMP Guidelines clearly states: "Any activity covered by the GMP Guide that is outsourced should be appropriately defined, agreed and controlled [...]. There must

be a written Contract between the Contract Giver and the Contract Ac-ceptor which clearly establishes the duties of each party. The Quality Management System of the Contract Giver must clearly state the way that the Qualified Person certifying each batch of product for release exercises his full responsibility" and under point 7.4 "The pharmaceuti-cal quality system of the Contract Giver should include the control and review of any outsourced activities. The Contract Giver is ultimately responsible to ensure processes are in place to assure the control of outsourced activities."

Supply chain requirements are described in Chapter 5.29 of the EU-GMP Guidelines. API manufacturers are also and above all taken into account here and audits are clearly required: "Audits should be carried out at the manufacturers and distributors of active substances to confirm that they comply with the relevant good manu-facturing practice and good distribution practice requirements". For manufacturers of excipients it is required to carry out at least a risk assessment, which might also foster the need to perform an on-site audit.

About the AuthorWolfgang Schmitt is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA and GMP.

Supplier Qualification

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According to Annex 16 of the EU-GMP Guidelines, supplier qualifi-cation is one of the tasks of the Qualified Person, which can, how-ever, be delegated. The Qualified Person must ensure that "supplier quality management systems are in place that ensure only materials of the required quality have been supplied". (1.7.6)

The ICH Q10 Pharmaceutical Quality System Guidance also empha-sizes the responsibility of pharmaceutical manufacturers for out-sourced activities. The document states that a contract giver "should be responsible for assessing the suitability and competence of the contract acceptor to carry out the work required".

Further requirements can be found in the appendix.

Supplier qualification is more than just an audit

When it comes to supplier qualification, it is unfortunately still frequently forgotten that audits or audit reports are only one component of supplier qualification. Audit reports eventually contain a description of the GMP situation determined during the audit. In addition to the audit report, however, further information must also be consulted. For example, other available reports from authorities (e.g. FDA warning letters), non-compliance reports from the EudraGMDP database, or information from the EDQM database. The type of service or purchased goods also plays a role in the overall evaluation, as does a consideration of transport routes.

All information should be included in a risk assessment, with the help of which one can not only plan audits and audit frequency, but also evaluate and qualify suppliers accordingly. Two systematic methods of risk analysis are often mentioned in this context, FMEA (Failure Mode and Effects Analysis) and HACCP (Hazard Analysis and Critical Control Points), which can be used here.

The ICH Guideline Q9 lists a number of points that should be considered during audit planning. Those are also helpful during final and ongoing assessment and qualification:

• Existing legal requirements; • Overall compliance status and history of the company or facility; • Robustness of a company's quality risk management activities; • Complexity of the site; • Complexity of the manufacturing process; • Complexity of the product and its therapeutic significance;

• Number and significance of quality defects (e.g., recall); • Results of previous audits/inspections; • Major changes of building, equipment, processes, key personnel; • Experience with manufacturing of a product (e.g., frequency,

volume, number of batches); • Test results of official control laboratories.

A new PIC/S guideline on GMP inspections1 is being considered to help Competent Authorities prioritising their resources for GMP inspections of human or veterinary medicinal products. The docu-ment is a non-binding guide for authorities involved in the Interna-tional Coalition of Medicines Regulatory Authorities (ICMRA) and PIC/S, but the process presented can also be used by pharmaceuti-cal companies as a model for their risk-based supplier qualification and auditing activities.

A clearly structured documentation system is then required to summarise and document the risk assessment and evaluation. Forms and appropriate IT systems facilitate the procedure here. All facts and figures should be brought together. At the latest, the Qualified Person (QP) should be involved in the supplier qualifica-tion and approval process - the QP must at least have free access to all information (see also EU-GMP Guidelines Annex 16 1.7.2 and 1.7.3). A summary report with cross-references can also be presented to an authority representative during an inspection without immediately submitting complete audit reports.

Already qualified suppliers must be assessed or re-qualified regularly. This involves a comparison of the supplier's current performance with the previously defined and agreed specifications. The experiences with the supplier and the evaluation of received service or delivered goods are also taken into account here. Furthermore, changes at the supplier (e.g. personnel, manu-facturing process, etc.) must be evaluated. The pharmaceutical manufacturer should be informed of these changes immediately. Re-qualification is also supported by a documented risk assess-ment. This makes processes more transparent and comprehensible and facilitates decisions. Possible risks are identified early enough and countermeasures can be taken in due time. On the other hand, a positive risk assessment can reduce the cost of audits (less and, if possible, shorter audits). This helps to save direct and indirect costs.

Contracts

In the GMP environment, contracts are an important element to define tasks, responsibilities and specifications. Ultimately, all ele-ments of cooperation between the contract giver and the contract acceptor can be part of the contract. For a better overview, it is advisable to create different contracts:

• Supply contract: regulates individual commercial conditions for the order including delivery conditions, payment modali-ties and warranty.

• Non-disclosure/ secrecy agreement: regulates and clarifies the conditions for the exchange of information.

• Quality contracts (technical contract / quality agreement / de-limitation of responsibilities): all GMP-relevant aspects are defined here, such as - detailed description of all manufacturing and testing pro-

cesses (possibly with flow and process step diagrams) - Process parameters with specifications

Quality Oversight9-10 June 2020Copenhagen, Denmark

Master Class on the latest expectations and best practices for Quality Oversight.

Learn more about this course:

www.gmp-compliance.org

11

1 See: https://www.gmp-compliance.org/gmp-news/more-desktop-assessments-less-inspections

- Procurement, testing and storage of starting and other ma-terials

- Assignment of quality-relevant activities - Flow of information - Preparation and provision of documentation - Matrix of responsibilities

In the EU-GMP Guidelines Chapter 7 on outsourced activities, the expectations regarding quality contracts are clearly defined. In the USA, guidance on this topic was not particularly detailed until a few years ago. In 2016, the US Food and Drug Administration (FDA) finalised and published its Guidance for Industry entitled "Contract Manufacturing Arrangements for Drugs: Quality Agreements".

In order for existing contracts to fulfil their purpose, they must al-ways be up to date. As in the case of supplier qualification, this re-sults in the obligation to regularly review and evaluate contracts. This is also required in the EU Product Quality Review (PQR) (EU-GMP Guidelines Chapter 1, Section 1.10 xii).

Conclusion

Supplier qualification is intended to identify and minimise risks arising from outsourcing. The overall package of all measures is in-tended to increase the transparency of the supply chain, verify the trust placed in suppliers and service providers, aim for constant quality of the service or product and ensure a good and steady re-lationship.

Appendix: Additional Guidance

Article 8 of EU-Directive 2001/83/EC"The application [of a marketing authorization] shall be accompanied […] by […] a written confirmation that the manufacturer of the me-dicinal product has verified compliance of the manufacturer of active substance with principles and guidelines of good manufacturing prac-tice by conducting audits."

Article 46 of EU-Directive 2001/83/EC"The holder of a manufacturing and/or import authorisation shall at least be obliged […] to use only active substances, which have been

manufactured in accordance with GMP for active substances and dis-tributed in accordance with GDP for active substances and … to ensure that the excipients are suitable for use in medicinal products by ascer-taining what the appropriate GMP is."

Article 46b of EU-Directive 2001/83/EC"Active substances shall only be imported if they have been manufac-tured in accordance with standards of good manufacturing practice at least equivalent to those laid down by the European Union". This can be shown by a written confirmation or the exporting country is included in the so called white list or a waiver has been granted."

EU-GMP Guidelines Chapter 5 (Production):5.27 "The selection, qualification, approval and maintenance of suppli-ers of starting materials, together with their purchase and acceptance, should be documented as part of the pharmaceutical quality system..." 5.29 "Audits should be carried out at the manufacturers and distribu-tors of active substances to confirm that they comply with the relevant good manufacturing practice and good distribution practice require-ments. (…) Audits should be of an appropriate duration and scope to ensure that a full and clear assessment of GMP is made; (…). The [audit] report should fully reflect what was done and seen on the audit with any deficiencies clearly identified. Any required corrective and preven-tive actions should be implemented. Further audits should be under-taken at intervals defined by the quality risk management process to ensure the maintenance of standards and continued use of the ap-proved supply chain." 5.45 "The selection, qualification, approval and maintenance of suppli-ers of primary and printed packaging materials shall be accorded at-tention similar to that given to starting materials."

Chapter 7 of the EU-GMP Guidelines (Outsourced Activities) describes the responsibilities of the Contract Giver when it comes to contract manufacturing and testing. He needs to assure the con-trol of the outsourced activities, incorporating quality risk manage-ment principles and including continuous reviews of the quality of the Contract Acceptor's performance. Audits are helpful tool to assess the "legality, suitability and the competence of the Contract Ac-ceptor". Chapter 7 was designed to intensify the control of Contract Acceptors by the Contract Giver and extend those controls to sub-contractors.

Efficient Supplier Qualification PLUS Pre-course Session "What you need to know about suppliers from China and India"6-8 May 2020Vienna, Austria

During this course, you will learn all relevant aspects to implement and/ or improve a comprehensive and integrated Supplier Qualification System which fulfils regulatory GMP requirements.

Learn more about this course: https://www.gmp-compliance.org

12

In April 2017 a significant change in the European Pharmacopoeia became effective: After – incl. predecessors – almost 100 years, the regulation for the production of water for injection (WFI) was changed, the requirement "distillation" was deleted.

The new requirement of monograph 169 on WFI production isWater for injections in bulk is ... produced either by:- distillation in an apparatus of which the parts in contact with the wa-ter are of neutral glass, quartz or a suitable metal and which is fitted with an effective device to prevent the entrainment of droplets;- a purification process that is equivalent to distillation. Reverse osmo-sis, which may be single-pass or double-pass, coupled with other ap-propriate techniques such as electro-deionisation, ultrafiltration or nanofiltration, is suitable. Notice is given to the supervisory authority of the manufacturer before implementation.1

This change was preceded by years of discussions. The US and also the Japanese pharmacopoeia had already refrained from the re-quirement of distillation for a long time. Engineering technology had already considered evaporation and condensation an ineffi-

cient purification method for the manufacture of WFI since the early 1990s. In particular the advances in membrane technology (reverse osmosis, electro-deionisation, ultrafiltration) had clearly shown, for example in the electronics industry, that ultrapure wa-ter of the highest microbiological quality can be produced without the phase transition of distillation.

However, there was little interest from the regulatory authorities in Europe to allow membrane processes as an alternative to distil-lation. In 2002, this resulted in a special solution: the quality High-ly Purified Water (HPW) was introduced in the European Pharma-copoeia2. The specification of all relevant release values (conductivity, TOC, endotoxins, germs) was the same for HPW and WFI – only that distillation was still specified as the production method for WFI from 2002 to 2017. During this period, the HPW systems showed that no "steam machine" is needed to manufac-ture water that meets the specification for WFI. The use of HPW made sense for large sterile operations, which could now operate their vial / syringe / ampoule washing systems with HPW instead of WFI at considerably lower costs.

Cold WFI Manufacture – Two Years after the Change in the Pharmacopoeia

About the AuthorMarkus Multhauf is a senior engineer and has been working as a freelance engineer in the field of GMP pharmaceutical technology since 2013.

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Today, the costs for the different water qualities in pharmaceutical manufacture are as follows:

• Drinking water approx. 1 - 12 € / m³• Purified Water / Highly Purified Water approx. 10 - 25 € / m³• WFI cold with membrane process approx. (should be the same

as HPW and clearly less than WFI – reliable figures are not yet available)

• WFI hot with distillery approx. 50 - 100 € / m³• WFI in pharmacy: 1.000 – 20.000 € / m³

In this respect, HPW quality has helped pave the way for the amendment of the European Pharmacopoeia in 2017. It was ex-pected that the costs for cold WFI with membrane processes would be about the same as for HPW.

Until today the proponents of distillation technology argue as fol-lows: If the USA and Japan have not been requiring distillation for such a long time, why is it that WFI is still manufactured worldwide mainly by distillation?

There are major reasons for that, though:1) As long as distillation was mandatory in Europe, every company selling globally had to comply with the requirements in Europe.2) To manufacture WFI safely with membrane technology, one needs a very good, stable, high-quality drinking water supply. This is avail-able in 50% of Europe, but not in many areas in the rest of the world.3) In other regions of growing importance, such as China, distillation is still the only permitted production method for WFI.

In Europe, a Questions & Answers paper for European GMP inspec-tors became effective in 2017, which does not reflect the current state of the art3. This is also the opinion of the PDA, which approached the EMA in November 2016 with a letter4. For instance, the following statement can be found in the EMA Q&A paper:"The RO5 membranes are currently not designed to withstand pressur-ised steam, but those that are capable of withstanding high tempera-tures are available and should be utilised in order to allow for routine high temperature flush through the system in conjunction with routine chemical sanitisation."

The steaming (121 °C) of RO membranes does not appear to be sen-sible, since the known water germs are also killed at lower tem-peratures such as 80 °C. The phase transition steam-water would damage the only 0.2 µm thick jelly diffusion layer of the membrane due to the large volume change. It is also not possible to sanitize an RO in a meaningful chemical way. The chemicals cannot pass through the RO membrane, and RO wrap modules cannot be back-washed. No HPW plant has ever been built and operated this way.

Extremely critical, however, is another demand that can at least not easily be rejected. It is undisputed that a distillery – after the vapour-liquid phase transition – always produces WFI without viable germs according to the agar plate colony count test method. However, a break-through of such germs can occur in cold WFI manufacture using membrane technology. Therefore the EMA-Q&A-Paper demands:"Use of rapid microbiological methods should be considered as part of the control strategy to aid with rapid responses to deterioration of the system." und "Quantitative microbiological test methods – in line with Ph.Eur. 5.1.6 monograph 'Alternative Methods for control of Microbio-logical Quality'."

It is undisputed that counting germs by the plate method is not the most modern method. There are the "alternative methods" for mi-crobial count. However, it is the case that all these alternative methods find considerably higher bacterial counts. A successful validation – especially the assurance of comparability – has there-fore not been successful so far6. As of today, the batch release for medicinal products manufactured with WFI is therefore still carried out using the agar plate method.

Nevertheless, some companies have started planning and install-ing WFI generators with membrane technology. Many assume that the specifications of the EMA Q&A paper will be technically revised – and even though considering the document for that reason, de-liberately do not implement some of the required measures. How-ever, many companies do not want to take any compliance risk. For this reason, new WFI producers continue to opt for the old "steam machine technology".

With the EMA Q&A paper we have, in the author's opinion, a case of outdated regulation which hinders progress and leads to avoid-able additional costs in the manufacture of medicinal products. An important locational advantage of Central and Northern Europeans – the availability of very good feed water as an excellent prerequi-site for the use of the cold WFI manufacturing processes – is there-by eliminated. Whether and when these obstacles can be elimi-nated, and how fast the WFI manufacture with membrane processes will prevail, cannot be predicted today.

1 European Pharmacopoeia , www.edqm.eu; Monograph Water for Injections 2017-20192 Note for Guidance on Quality of water for pharmaceutical use (2002)3 www.ema.europa.eu/documents/other/questions-answers-production-water-injections-non-distillation-methods-reverse-osmosis-biofilms_en.pdf (link re-checked Jul. 2019)4 www.pda.org/docs/default-source/website-document-library/scientific-and-regulatory-affairs/regulatory-comments-resources/2016/ema-qa-production-of-wfi-by-non-distillation-

methods-submitted-4-nov-2016.pdf?sfvrsn=4 (link re-checked Dec. 2018)5 RO = Reverse Osmosis6 See presentation Pharma-Lounge 5.-7.Feb.2019 R.Roepenack, Robert Bosch Packaging Technology GmbH; Membrane based WFI manufacture according to revised monograph 0169

Ph.Eur. + K.-P.Mang, Mettler-Toledo GmbH; Experience with new technologies for determining bacterial count in pharmaceutical water in real time + R.Scheibel, PMT Partikel-Messtechnik

GmbH; Possibilities for continuous microbial process control + A.Minzenmay, BWT Pharma & Biotech GmbH; Driniking water to WFI (Ph.Eur.) with a membrane device + U.Träger, Wilhelm

Werner GmbH; Cold WFI manufacture - project introduction + T.Rücker, Letzner Wasseraufbereitung GmbH; Biofilm control strategies in pharma water treatment + P.Kreutzenbeck, Roche

Diagnostics GmbH; Trend microbiology On-line – Rapid Microbiological Method

Cold WFI Manufacture – Two Years after the Change in the Pharmacopoeia

Pharmaceutical Water - Generation, Monitoring & Compliance1/2 April 2020Berlin, GermanyLearn more about this course: https://www.gmp-compliance.org/

14

Data integrity requirements

Data integrity has been in the focus of regulatory scrutiny for some years now. Pharma Congress 2019 has therefore dedicated a two-day conference to the topic. The diverse issues made it possible to take a look at data integrity requirements from different view-points – from system and manufacturing to inspectors and suppliers.

Management responsibility – the myth of human errors

With European GMP and ICH Q10 regulations regarding data integ-rity in mind, Klaus Eichmüller reminds us of the leading manage-ment’s responsibility for the content and application of Pharma-ceutical Quality Systems (PQS). He poses the question whether "human errors" are a sufficient justification for deviations. If human errors are indeed the reason for deviations, however, training pro-grams and the increased use of data governance models should move into the centre of considerations.

Data integrity – everybody's responsibility?

As with other regulatory activities, data integrity must be part of GxP. Without the serious handling of data, GxP cannot be imple-mented. Everybody is responsible for data integrity, not just QA or production. The Qualified Person (QP) in particular is reliant upon the integrity of all GxP-relevant data when releasing batches. But not only QPs rely on data integrity. Based on a data integrity pro-gram, production and laboratory staff as well as QA must be trained regularly regarding the importance and relevance of data. Such an approach would be the only one to ensure an adequate assessment of the data integrity of systems, processes and organisations.

Supplier support for implementing data integrity

To ensure data integrity, not only procedural activities are required. Effective technical measures are also needed. In order to imple-ment an efficient e-compliance approach, such things as sensible user management, sufficient access controls, precise time stamps and Audit Trails, electronic signatures, etc. are necessary. More

FDA/GMP trends in production & technology - Part 2

About the AuthorDr Andreas Mangel is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas sterile production and computer validation.

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than 25 years after the publication of EU GMP Annex 11 (Computer-ised Systems) and more than 20 years after the publication of 21 CFR Part 11, suppliers should be able to support compliance requirements. The pharmaceutical industry needs systems to tech-nically support compliance requirements urgently. It is no longer acceptable to sell products to the regulated pharmaceutical indus-try which do not support the required GxP-compliance.

Paperless Laboratory – myth or reality?

A case study from a contract laboratory shows the benefits of a consistent data integrity and e-compliance strategy. Not only was the level of regulatory compliance increased significantly in this case, a fundamental approach to sustainability was established at the same time. To produce less or no paper and to rely on elec-tronic documentation made the consolidation and improvement of workflows and of the controls required possible without increasing the workload. The combination of effective technical controls and sensible use of the dual control principle in electronic process steps generated a significant rise in efficiency as well as reducing the required storage capacity for paper.

Inspector's expectations regarding data integrity

Based on the PIC/S draft document PI 041-1 Draft 3 and WHO TRS Annex 5, Arno Terhechte from a local German authority and Ib Alstrup from the Danish DMA showed various examples of inspec-tor expectations towards data integrity with regards to inspection subjects and practice. Both put emphasis on the importance of data definitions and data flows, including data flow disruptions. They also pointed out the necessity of implementing a sensible and reliable Audit Trail, and stressed the importance of the Audit Trail Review process.

Modern Qualification: ECA Good Practice Guide "Modern Qualification"

Based on the ECA Good Practice Guide "Modern Qualification", a conference focussed on the involvement of suppliers was estab-lished for the first time. The guide itself addresses modern coopera-tion approaches of pharmaceutical companies and their suppliers and is based on the latest GMP requirements for Quality Risk Man-agement. It is founded on a common project model and includes useful templates which may be used by pharmaceutical companies and suppliers as part of a cost-efficient project approach.

The guide was developed by a joint initiative of international phar-maceutical companies and suppliers of pharmaceutical equipment. After being reviewed by inspectors, the guide was first introduced in the presence of American and European inspectors in September 2018 in Berlin. Participants of the event focussing on suppliers had the opportunity to suggest topics for the new version which was published in October 2019.

The inspector's point of view

Klaus Eichmüller from a local German authority introduced the European requirements for qualification and validation. He empha-sised that the current European regulations of Annex 15 of the EU GMP Guidelines were built on a long European history and devel-oped together with non-European regulatory authorities, including the FDA. The inclusion of Quality Risk Management is the most significant new requirement. Annex 15 is compliant with the FDA Process Validation Guide. It does, however, contain more specific notes on qualification activities. The current Annex 15, Klaus Eichmüller stressed, intends to allow for more flexibility for the pharmaceutical manufacturer as well as the supplier involved, depending on the project. According to him, the key to avoiding unnecessary repetition of qualification activities lies in the coop-eration with the supplier.

The pharmaceutical industry's point of view

An example for the use of the ECA Modern Qualification Guide from an industry standpoint was provided by Eve-Maria Baumgartner. The project she presented allowed detailed insights into how successful cooperation with a supplier was established and how project management, quality unit and various experts were connected cost-efficiently. The case study included several useful "lessons learned" for other companies.

The suppliers' point of view

Dr Berhold Düthorn from Valicare finally presented the suppliers' viewpoint on the issue of qualification. He states that a mutual understanding of user requirements, design documents, testing activities and ultimately qualification activities is the basis for a successful and cost-efficient project. In his lecture, he discussed risks and pitfalls because of which qualification projects may fail. He gave recommendation on how a successful customer-supplier-relationship may be ensured inside and outside of Europe.

Data Integrity · Aseptic Processing · Continuous BioprocessingBarrier Systems · Integrated Qualification with Suppliers

pharma-congress.com

ISSN

1867

-797

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ATMP Group � The change at the top of the Group Leadership was complet-

ed. Sabine Hauck took over as Chair, Andrea Hauser became Vice Chair.

� The Group commented on the new PIC/S Annex 2 draft. Com-ments were collected via a survey to the members as well as in an ATMP session at the PharmaLab Congress mid of November.

� The date for the Board Meeting and the ATMP Conference 2020 was set for mid June 2020.

www.atmp-group.org

Data Integrity & IT Compliance Group � As Karl-Heinz Menges retired from the Group’s Board,

Dr Franz Schönfeld was invited to follow him. � The new Guide "DI in clinical trials" as part of the ECA DI Guide

was still in the development phase. � The Group was invited to comment on the new WHO working

document QAS/19.819. www.it-compliance-group.org

GMP Handbooks • GMP Regulations

FDA cGMP Guide y 21 CFR 210/211 cGMP Guide in English y Paperback in the handy format 11.5 x 15 cm, 40 pages

ECA Good Practice Guide - GMP Matrix (Version 21 of May 2018)"FDA cGMP, EU GMP and ISO 9001 Matrix for a pharmaceutical Quality System - A GMP Roadmap" The ECA Good Practice Guide is a comprehensive juxtaposition containing the requirements laid down in FDA's cGMP Guide, the EU GMP Guide and ISO 9001.In addition, the Good Practice Guide contains a ISO 9001/ICH10 Matrix. In total, the Guide has 683 pages.EU Guidelines to Good Manufacturing Practice Part 1, Part 2 and Part 3 incl. Annexes 1-19

y Paperback in the handy format 11.5 x 15 cm y GMP Guide in English

ICH Q7 GMP for Active Pharmaceutical Ingredients with a Side-by-Side comparison and APIC‘s How-to-do Document (Version 11, November 2018)

y Paperback in the handy format 15 x 11,5 cm y Complete text of ICH Q7 GMP for APIs and comparison of the interpretation by the Active Pharmaceutical Ingredients Committee (APIC)

To order, please visit www.gmp-compliance.org/publications/gmp-publications.Important: ECA Members receive a discount of 35% for GMP publications.

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