What is GMP: a short look back into the history of Good Manufacturing Practice
The GMP rules were first developed in the United States of America (USA) in the early 60ties and are consequently only about 50 years old. The reason for setting the legal framework of GMP regulations is related to the fact of recurrent scandals in manufacturing affecting the health of drug product users and patients. By the creation and implementation of GMP rules, pharmaceutical companies manufacturing drug products should be enabled to provide reliable and safe medicines to the market, overall irrespective of the education and professional experience of their employees.
GMP: what is the legal basis in Europe?
The basis for the application of GMPs in Europe is given by the following European Directives:
- Directive 2001/83/EC (community code for human medicinal products)
- Directive 2001/82/EC (community code for veterinary medicinal products)
- Directive 2001/20/EC (clinical trials, investigational medicinal products (IMPs)
According to the related Articles of these Directives (=Art. 40 of Dir. 2001/83/EC, Art. 44 of Dir. 2001/82/EC and Art. 13 of Dir. 2001/20/EC) the principles of GMP and the detailed GMP guidelines are applicable to all operations which require the authorizations referred to.
Two directives laying down principles and guidelines of good manufacturing practice (GMP) for medicinal products were adopted by the European Commission:
- Directive 2003/94/EC applies to medicinal products for human use and
- Directive 91/412/EEC for veterinary use.
Detailed guidelines in accordance with those principles are published in the “Guide to Good Manufacturing Practice”, which is used in assessing applications for manufacturing authorisations and as a basis for inspection of manufacturers of medicinal products (see below).
GMP-compliance: what is the challenge?
As already mentioned, GMP-compliance is a must for manufacturers of finished pharmaceutical products and active pharmaceutical ingredients (APIs) according to the different national legislations. The related GMP rules are typically valid for one country based upon the anchoring in the respective national laws. However, at the same time the GMP rules are more or less internationally harmonized such as e.g. the ICH Q7 Guidelines representing the “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients” being adopted by the regulatory bodies of the European Union (EU), Japan and USA (see also further GMP guidelines as referenced at the end of this article below).
So with written harmonized guidelines in place, why is GMP in-compliance nowadays still frequently observed and what is the challenge of consistent GMP compliance for manufacturers?
The challenge is related to several different potential reasons such as the following:
- Difficulty of GMP guideline interpretation: what is written? what is really meant/expected?
- Difference between national GMP guidelines and international guidelines
- Difference in cultural understanding of the GMP guideline
These reasons shall be further briefly explained including examples in the following text. However, it shall be mentioned here, that these explanations and examples can only be a quick snapshot and more detailed reference and training is needed to fully cover this quite extensive topic.
Difficulty of GMP guideline interpretation
GMP guidelines are sometimes quite general and broad in the wording, which makes it difficult for a user with limited experience to fully understand the meaning and implication of the guideline text. In such cases “How to do” documents issued by industry organizations such as APIC or “Aide memoires issued by the PIC/S provide quite helpful further explanations and guidance for the daily practice.
As an example hereunder the EU GMP part II guideline text is given together with the related “How to do” document of the APIC:
EU Good Manufacturing Practice
Medicinal Products for Human and Veterinary Use
Part II: Basic Requirements for Active Substances used as Starting Materials
APIC (ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE)
GMPs for APIs:
“How to do” Document
Interpretation of the ICH Q7a Guide
Version 6 (02/2010)
2.13 There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.
2.13. For the release of APIs there is no need for a “Qualified Person” (pharmacist) as defined by the European GMP Guideline (EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4: EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use) unless required by a specific law of the EU member state.
The responsibilities for quality duties (e.g. process and control review, validation, change control, equipment qualification, batch documentation review, batch release, regulatory compliance, auditing, deviation handling, OOS treatments and complaint investigation) should be clearly assigned to one or more person(s) or function(s). The QU should be involved in many, if not all, of these issues.
If the QA and QC department are separated units the roles and responsibilities of each unit must be clearly described and approved by the management.
2.14 The persons authorised to release intermediates and APIs should be specified.
2.14 Release of raw materials and intermediates meeting the specifications (for internal use only) by Production is acceptable, provided QU has approved specifications and test methods. Production personnel should be adequately trained for these duties, the training recorded and all equipment used qualified and calibrated at regular intervals. The QU, as part of their responsibility for batch release, has the right to review all test results and data.
APIs and intermediates (for use outside of the control of the company) have to be released by a designated person of the QU. Deputy(s) for such designated person should be nominated.
Difference between national GMP guidelines and international guidelines
National GMP guidelines may be to some extent stricter or less strict than international GMP guidelines in certain cases. As an example the structure of the EU GMP Guide and the Chinese GMP regulations is somewhat different leading sometimes to room for interpretation when comparing the requirements. However, it is important to understand, that GMP compliance is in the first instance always mandatorily related to the marketing authorizations and regulations of the importing country (=the customer country/target market). Therefore, these GMP regulations and guidelines have to be well understood and followed by exporters, and (even certified!) compliance to the own national GMP standards may not be sufficient.
Difference in cultural understanding of the GMP guideline
It goes without saying, that the cultural understanding and background plays a very important role in the interpretation of GMP guidelines. Requirement from EU GMP part II such as: “Personnel should practice good sanitation and health habits” (3.20) or “Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition” (4.70) are quite general and leave enough room for misunderstandings dependent on the differences in culture and cultural understanding of the involved people.
GMP-compliance: what is the role of inspectors from competent health authorities?
As already mentioned in the first article of this series, inspections of manufacturers by inspectors from competent health authorities are regarded as important means in Europe to maintain and support the GMP compliance level. Due to this fact and due to the underlying legal framework concerning GMP inspection, the outcome of such inspections at manufacturers’ premises is frequently the “official assessment” of GMP-noncompliance for a manufacturer of medicinal products or APIs (although manufacturers typically thought to be GMP compliant!). As a consequence, this triggers in Europe certain measures, which generally result in serious commercial consequences up to restrictions in import and sales in Europe. Further details may be derived from the respective EMA guideline “Compliance and Inspection” as referenced at the end of this text.
GMP-compliance: how to constantly improve the GMP level?
The maintenance and improvement of the GMP level within an organization must be subject to ongoing efforts supported by all levels of the company!
Regular internal audits (=self inspections) by qualified independent auditors including the implementation of meaningful corrective and preventive actions (CAPAs) related to such audits but also related to other “inputs” such as:
- Inspections from national competent health authorities (NCAs)
- External audits from e.g. third parties or customers
- Investigation results from Non-conformities and/or (major/critical) deviations
- Investigation results from customer complaints
and follow-up of the efficiency and consistence of such CAPAs by annual reviews (e.g. management reviews, product reviews, utility reviews etc.) provide suitable GMP measures and means to effectively manage such ongoing efforts. At the same time the knowledge and understanding of GMPs should be constantly further developed by suitable training measures for the employees.
This constant investment in maintaining and improving the GMP level, will be successfully grow the GMP compliance level only if it is supported by all employees i.e. from the Board members/Managing Director to the “normal” worker being responsible for conducting the work in production or quality control.
Dr. Stefan Kettelhoit, Managing Director & Shareholder of blue inspection body GmbH. The blue inspection body GmbH represents an independent, accredited 3rd party GMP audit service provider. Blue examines the Good Manufacturing Practices (GMP) of pharmaceutical companies around the globe. Blue inspection body GmbH is the first independent and accredited service provider for GMP audits in the European Union and since June 1st, 2013 cooperation partner of the China Chamber of Commerce for Import & Export of Medicines & Health Products (CCCMHPIE).
WHO GMP Guidelines: apps.who.int/medicinedocs/documents/s14136e/s14136e.pdf
- ICH Q7: Good Manufacturing Practice for Active Pharmaceutical Ingredients (APIs)
- ICH Q8: Pharmaceutical Development
- ICH Q9: Quality Risk Management
- ICH Q10: Pharmaceutical Quality System
PIC/S GMP Guide: www.picscheme.org
EU-GMP Guide(s): ec.europa.eu/health/documents/eudralex/vol-4/
Canada GMP Guide: www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php
- 21 CFR (Codes of Federal Regulations) Part 210: Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs
- 21 CFR Part 211: Current Good Manufacturing Practice for finished Pharmaceuticals
China GMP: eng.sfda.gov.cn/WS03/CL0768/65113.html
Good Manufacturing Practice for Drugs (2010 Revision) incl Annexes
APIC “How to do” Document, Interpretation of the ICH Q7a Guide Version 7 (08/2012): apic.cefic.org/publications/Howtodo_ICH_Q7_201208_V7.pdf
EMA Compilation of Community Procedures on Inspections and Exchange of Information, Compliance and Inspection, 27 June 2013, EMA/385898/2013 Rev 16: www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004706.pdf