Use a qualified weighing system to simplify compliance with Good Manufacturing Practices
Weighing ingredients properly is a critical part of manufacturing pharmaceutical products. Plant operators and customers, contract manufacturing facilities and regulatory authorities consider ingredient weighing an essential determinant of quality. Pharmaceutical industry manufacturers must follow a variety of binding regulatory requirements for quality assurance and documentation called Good Manufacturing Practices (GMPs) and Good Laboratory Practices (GLPs). Users in GMP-regulated environments must select balances of proven suitability for use in these settings, with accuracy and cleanability that meet GMP and GLP requirements and a flexible configuration to enable customization for existing workflows.
GMP guidelines for equipment
All equipment used for manufacturing and/or testing of active pharmaceutical ingredients and medicinal products must be qualified under requirements found in Annex 15 of the EU Guidelines for Good Manufacturing Practice.1 These require that manufacturers control the “…critical aspects of their particular operations through qualification and validation over the life cycle of the product and process.” Further, “Any planned changes to … equipment …, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed.”
The GMP and GLP requirements for equipping a plant or laboratory directly stipulate that the operator must demonstrate and provide documented proof of the suitability and availability of the instruments used as part of hardware qualification and software validation. These requirements cover a large number of equipment qualification stages, including user requirements specification (URS), design qualification, factory and site acceptance testing, installation qualification, operational qualification and performance qualification. Equipment must be regularly reevaluated to confirm that operators maintain a high level of control. The standards also require that manufacturing process validations use equipment that has been qualified according to the guidelines.
In addition, users must follow guidance found in the recently revised United States Pharmacopeia (USP), Chapter 41,2 which covers the minimum accuracy of weights and balances used to perform assays. USP standards and regulations are widely used by pharmaceutical companies exporting products to the U.S.
Accurate weighing and overall quality
Accurate weighing is extremely important to overall quality because any mistakes in weighing will be multiplied during any analytical tests that follow. Quality-relevant weighing processes must use equipment with balances that have been specifically developed and designed by the manufacturer for use in GMP and GLP applications.
Revised Chapter 41 rules require that users determine the balance’s operating range. This is limited above and below by the maximum capacity of the balance and begins at the point at which the balance’s repeatability is less than or equal to 0.10%. The starting point must be calculated according to a newly modified algorithm. Optimal operating range is defined from 820 d (2 * 0.41 * 1000) to the maximum weighing capacity. For an analytical balance with a readability of 0.1 mg, this means the starting point yielded is 82 mg. Depending on the particular application, further requirements may be specified for the balance in the URS.
Weighing technology to meet equipment guidelines
Figure 1 – Cubis is made for use in GMP-regulated requirements.
New weighing technology has been developed with specific design criteria and functions that ensure compliance with GMP and GLP requirements. The modular configurable Cubis (Sartorius, Bohemia, N.Y.) MSA125P-100-DI high-precision semi-micro balances (Figures 1 and 2) for use in GMP-regulated environments can be configured to the user’s requirements in adherence with GMP accuracy guidelines. Standard functions are integrated into easy-to-handle process workflows called tasks. In many cases, typical pharmaceutical Standard Operating Procedures (SOPs) can be fully transferred to these tasks and integrated into the balance. More complex or special operations can be developed and programmed, installed, documented and validated as applications, or apps. In doing so, the balance takes control and automates previously manual steps, boosting quality assurance and repeatability of weighing processes in the laboratory environment. Built-in software reduces the risk of incorrect weighing procedures. An integrated user management system and ability to generate user profiles helps avoid operating errors in regulated environments. The MSA125P-100-DI semi-micro balance is equipped with an integrated ionizer for eliminating the effects of static electricity and an automatic draft shield, ensuring highly repeatable weighing and reducing measurement uncertainty.
Figure 2 – Cubis can be configured individually to the user’s requirements.
To prevent contamination by weighed samples or objects, all relevant parts of the balance must meet GMP and GLP requirements for thorough cleaning. Surfaces must be simple to clean and resistant to cleaning agents and disinfectants. The weighing pan and draft shield should be easy remove to ensure that the area beneath the weighing pan and the bottom of the weighing chamber can be wiped clean. Cleanability of all critical points was demonstrated, including thorough removal of lipophilic and hydrophilic substances, in studies contracted out to an independent center for research services.3
In addition to designing equipment to meet GMP and GLP requirements, some equipment manufacturers offer comprehensive qualification and validation support. The Sartorius Advanced Pharma Compliance Services (ACP Services) includes software-supported selection of the right balance and configuration of accessories based on particular application. Product and user specifications are included, along with qualification and Good Automated Manufacturing Practice (GAMP) classification and validation of internal device applications and customer-specific software applications. The lifecycle monitoring process then continues with balance operation and maintenance, servicing, calibration and verification, requalification and revalidation. Documented data backup, as well as decommissioning and disposal and/or recycling of the weighing equipment, can also be provided.
- EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation; http://ec.europa.eu/health/files/gmp/2014-02_pc_draft_gmp_annex. pdf, retrieved 5/3/16.
- U.S. Pharmacopeial Convention (USP), Chapter 41, Balances;http:// www.usp.org/sites/default/files/usp_pdf/EN/41_balances.pdf, retrieved 5/3/16.
Dr. Thomas Pertsch and Steffen Gloth are with Sartorius Lab Instruments GmbH, Weender Landstrasse 94-108, 37075 Goettingen, Germany; tel.: +49 551 3080; www.sartorius.com