Regulatory Focus Areas

The life sciences industry operates in one of the world’s most regulated environments. Today, we are facing increasing regulatory requirements and complexity.

As a global leader in the Life Science industry, we are on top of current trends and future quality and regulatory opportunities as well as challenges. We support our customers to navigate and comply with a highly complex set of global, regional, country, and industry-specific directives and regulations.

• Pharmaceutical Industry
• Biopharma Industry
• Cell & Gene Therapies
• Food Industry
• Medical Devices/In Vitro Diagnostics

Pharmaceutical Industry (Active Pharmaceutical Ingredients & Excipients)

CFDA joint review procedure – Chinese DMF procedure for API/excipient/packaging material.

On November 30^th, 2017, the CFDA (China Food and Drug Administration) published the official regulation no. 146 for joint review procedure for API/excipient/packaging material which is effective immediately. This regulation has mainly changed the old procedure for the registration of API/excipients, which is now very similar to the US DMF procedure. This means that API/excipient manufacturers need to submit the DMF to the CFDA and get the registration No., after CDE validation. The registration No. will be published on the CDE homepage, then the drug manufacturer needs to have a Letter of Access (LoA) issued by the API/excipient manufacturer to refer to the registration No. for their drug application. For the DMF content for excipients, the former published regulation "Dossier requirements of excipients, for bundling review & approval (No.155. Nov 28, 2016. CFDA)" is still valid.

Elemental Impurities

Elemental Impurities are mostly metal residues. Metals in medicinal products may also be present as impurities. Contamination may arise from metals deliberately added as catalysts or reagents, natural source materials (e.g. in minerals or herbals), or processing equipment (like vessels, pipes or metal connections to tubes or hoses) may be further causes for metal residues. They may exert toxicological effects and therefore they should be excluded or limited.

In Europe, the ICH Q3D guideline is effective since June 2016 for new Drug Products (also new DP with existing Active substances – that means new generic products) and since Dec 2017 for existing DP.

Our Life Science business has set up a project to proactively generate data on elemental impurities to support our customers. EII (Elemental Impurity Information) Dossier is also part of our new Emprove^® "Operational Excellence Dossier".

NSF/IPEC/ANSI 363– 2014 Good Manufacturing Practices (GMP) for Pharmaceutical Excipients

The new voluntary standard, “NSF/IPEC/ANSI 363 – 2014 Good Manufacturing Practices (GMP) for Pharmaceutical Excipients” was published in December 2014 after a lengthy publication timeline. This standard is a joint publication by NSF (which develops standards and certification programs), IPEC (International Pharmaceutical Excipients Council), and ANSI (America National Standards Institute). This Standard is intended to define Good Manufacturing Practices (GMP) for excipient manufacturing and distribution for use in drug products. It sets minimum requirements for GMP applicable to all commercially available excipients.

Our manufacturing site in Darmstadt holds a joint EXCiPACT™/ NSF/IPEC/ANSI 363-2014 US National Standard certification since April 2016. This extended certification of the pharmaceutical excipients of the Emprove® brand shall specifically address the needs of the US market. NSF/ANSI Standards have a high reputation in the US and support sales into that market.

Biopharma Industry (SUS, Filter, CCM)

USP <665>: Polymeric Components and Systems Used in the Manufacturing of Pharmaceutical and Biopharmaceutical Drug Products.

USP <665> addresses the qualification of polymeric components used in the manufacture of both pharmaceutical and biopharmaceutical APIs and drug products. It is applicable to filter products, chromatography media, single-use systems and any other components that are in fluid contact in manufacturing process.

The standard is applicable to all the Bioprocess products that have plastic components in liquid contact. The level of testing required is determined by performing a risk assessment and aligning to the appropriate risk level as outlined above. Extractables testing per a protocol described in this standard has to be performed for high risk levels.

The standard is still a draft and our Life Science business actively contributes to the commenting process.

Cell & Gene Therapies

Our Life Science business is actively working in the innovative discipline of Gene Editing and Novel Modalities to address our customers’ unmet needs by developing various solutions along the therapy development and manufacturing process.

The Cell Therapy group is working on developing modular, single-use, closed and automated systems for manufacturing cell therapies. Life Science also offer kits for gene editing useful in creating gene modifications. Our Life Science site in Carlsbad, California, USA, manufactures viral vectors and is a key contract manufacturing service for the industry. There are groups within Gene Editing and Novel Modalities working on optimizing the vector production process to improve yields. Our company proactively put in place several programs to develop solutions to address this novel market.

Food Industry

The US Food Safety Modernization Act (FSMA)

The U.S. Food and Drug Administration (FDA) Food Safety Modernization Act (FSMA) shifted the focus of the FDA from responding to foodborne illness to preventing it. FSMA also includes rules to identify and mitigate risk associated with intentional adulteration of food.

FSMA Highlights

• Preventive Controls Rules for Human and Animal Food
  • Updates the Good Manufacturing Practices (GMP) for food.
  • Requiring a hazard analysis and risk-based controls similar to a HACCP (hazard analysis and critical control points) food safety management program.
• Produce Safety Rule
  • Focusing on improving produce safety.
  • Foreign Supplier Verification Program (FSVP) Rule
  • Assuring food imported into the US meets FSMA standards.
• Accredited Third-Party Certification
  • Establishing the requirements for third party auditors.
• Sanitary Transportation Rule
  • Establishing the requirements for maintaining food safety while transporting food.
• Intentional Adulteration Rule
  • Establishes Food Defense programs and requirements to prevent intentionally adulterating with the intention of causing harm.
  • Guidelines on identifying and preventing Food Fraud: the intentional adulteration of food for economic gain.
• Complying with FSMA
  • Requires that all foreign or domestic facilities that sell food in the US are registered with the FDA.
  • Establishes the requirements for the FDA to periodically inspect all domestic food facilities.
  • Provides for the risk-based inspection of foreign food facilities.
  • Give the FDA authority to hold potentially unsafe food and require food recalls as needed and pursue
  • Give the FDA authority for punitive enforcement of FSMA requirements.

EU Food Contact Materials Regulation

There are several filter products that are also marketed within the food industry in Europe. When used in the manufacturing of food and beverages, these materials must comply with the European requirements for food contact materials.

A so-called "Declaration of Compliance" (DoC) for food contact material to demonstrate compliance to the provisions of Community legislation on plastic materials and objects in contact with foodstuffs (EU 10/2011) is available for our customers.

DoCs are available for selected products out of following product families:

• Bevigard™ (Bevigard™ P, Bevigard™ L, Bevigard™ M)
• Brewpore^®
• Clarigard^®
• Durapore^®
• Lifegard™
• Milligard^®
• Polygard^®
• Polysep™
• Vitipore^® II, Vititpore^® II Plus

Medical Devices/In Vitro Diagnostics

EU Medical Devices and In Vitro Diagnostics Regulations, 2017

The EU Medical Devices and In Vitro Diagnostics Regulations from 2017 are the biggest change in European regulations related to medical devices and in vitro diagnostics (IVDs) since the introduction of the current EU CE marking directives.

This has huge implications to the medical device industry in Europe, impacting all “economic operators” (i.e., manufacturers, importing or distributing devices into Europe, authorized representatives, notified bodies and competent authorities). Critical suppliers to medical device and IVD manufacturers will also feel the impact of the new regulations. The two new regulations were published in May 2017 with a three-year transition period for the Medical Device Regulation (MDR) and a five-year transition for the In Vitro Diagnostic Regulation (IVDR). The longer transition time for the IVDR, is due to the major change in classification from the old IVDD to the new IVDR and the subsequent impact this will have on IVD manufacturers.

The regulations introduce a number of new requirements and changes. Some of the major changes include:

• Changes in the classification of IVDs which will lead to a greater number of IVDs requiring notified body conformity assessments
• New requirements for performance evaluation for IVDs including performance evaluation reports
• Introduction of a person responsible for conformity of the device before it is released
• Identification and traceability - introduction of Unique Device Identification Mandated (UDI)
• Strengthening of the position of Notified Bodies in relation to manufacturers including introduction of unannounced inspections

Our Life Science business has implemented a global project based around a core multi-functional global team providing expert project management, strategy, procedures/templates and guidance/training to local site teams and sub-teams to implement site specific project plans to meet the deadlines for the new regulations.

ISO 13485:2016

After more than ten years, the update to the global standard for medical device quality management systems (QMS) has been adopted. ISO 13485:2016 replaces previous version from 2003.

Up to March 2019, ISO 13485:2003 and ISO 13485:2016 will coexist, allowing manufacturers, accreditation/certification bodies and regulators time to transition to the new standard. The European harmonized version of the ISO 13485 standard is used to demonstrate QMS conformity for the CE marking of Medical Devices and IVDs under the current European Directives and new regulations. The new 2016 standard will also be used as the basis for the inspections under MDSAP (Medical Device Single Audit Program).

The changes between the 2003 and 2016 version include:

• Incorporation of risk-based approaches beyond product realization
• Risk is considered in the context of the safety and performance of the medical device and in meeting regulatory requirements
• Increased linkage with regulatory requirements, particularly for regulatory documentation
• Application to organizations throughout the lifecycle and supply chain for medical devices
• Harmonization of the requirements for software validation for different software applications (QMS software, process control software, software for monitoring and measurement) in different clauses of the standard
• Emphasis on appropriate infrastructure, particularly for production of sterile medical devices, and addition of requirements for validation of sterile barrier properties
• Additional requirements in design and development on consideration of usability, use of standards, verification and validation planning, design transfer and design records
• Emphasis on complaint handling and reporting to regulatory authorities in accordance with regulatory requirements, and consideration of post-market surveillance
• Planning and documenting corrective action and preventive action, and implementing corrective action without undue delay

Each of our ISO 13485:2003 certified sites are working on a gap analysis in partnership with their certification bodies to determine their individual plans for transition to the new 2016 version.