GMP Compliance Adviser Update No. 3/2023
GMP in Practice
Chapter 3 Premises
3.K Monitoring of air handling systems of cleanrooms and clean areas
Pharma monitoring of the air handling system serves to collect, register and store data that are important for the quality of medicinal products and thus often also find their way into the batch documentation. The quality-relevant data of the air handling system must be defined based on risk analyses and described in the Contamination Control Strategy (CCS).
While pharma monitoring is used to monitor quality-critical measured parameters, it is the task of the instrumentation and controls system to register and control the technical data.
All measuring instruments used in pharma monitoring must be calibrated regularly. The computerised systems used to collect, store and process the data must be validated.
In pharma monitoring, the focus is on particulate and microbial air purity. In addition, physical measurands such as pressure (differences) and temperature can be subject to monitoring.
Microbiological data acquisition is mostly done manually and can thus become a process risk itself. The informative value of the established microbial detection methods is limited; however the results cannot be directly correlated with those of more modern measuring methods.
The monitoring data are to be subjected to a trend analysis at periodic intervals. Alert and action limits are set in order to recognise emerging problems at an early stage and to be able to counter them in a timely manner. If these limits are exceeded, alarms are triggered. The automatic recording and non-erasable registration of these is also the task of the computerised pharma monitoring systems.
The operation of an air handling system for cleanrooms and clean areas is very energy intensive. Since the conditions in the cleanroom do not change without external influences, the concept of lowered ventilation operation during idle phases represents an attractive possibility for saving energy and reducing costs. Accordingly, such a concept must already be taken into account during qualification.
(Harald Flechl)
Chapter 12 Sterile Products
12.B Contamination Control Strategy (CCS)
The CCS is a stand-alone, formal document that sets out and evaluates the site/group-wide strategy to minimise contamination.
The development of the CCS
- concerns the entire facility (equipment, personnel, processes),
- requires in-depth technical knowledge (products, processes, technology), and
- is used to evaluate and monitor the effectiveness of all aspects of contamination control.
The new Annex 1 requires the following basic orientation:
- The user's responsibility is paramount: he should know about all production processes and be actively involved in final decision-making processes.
- Quality must be considered and controlled throughout the entire production process, not just at the end of production.
- Within the framework of quality management, the management shall review the effectiveness of the CCS on a regular or event-related basis and have it updated if necessary.
- The qualified person (QP) and the management should have an appropriate understanding of the accepted residual risk as well as the consequences of the CCS.
- The measures for contamination reduction are to be advanced in the sense of the CIP; if necessary, an update is to be carried out within the pharmaceutical quality system.
- Changes to existing systems shall be reviewed for impact on the CCS before and after implementation.
The CCS contains all assessments and thus represents a holistic approach to contamination control. It is an essential strategy document for any pharmaceutical production, especially for the manufacture of sterile medicinal products.
It is to be expected that the CCS will be an important document requested in the course of inspections. Corresponding preparations should therefore begin quickly in order to be able to present an adequate concept when the new Annex1 comes into force on 25 August 2023.
(Christoph Brewi, Florian Sieder, PhD)
Chapter 16 Storage and transportation
16.A Storage
Responsibility for storage in the GMP environment lies with the Head of Production or the Responsible Person in the GDP environment. The storage conditions are determined in joint responsibility with the Head of Quality Control. Personnel working in storage must be familiar with both the storage-specific instructions and the general GMP/GDP requirements. All aspects of personnel and operational hygiene must be observed.
By controlling the handling of materials, an organised and separate storage of individual batches can be ensured. The expiry date must be controlled when handling materials (FEFO principle).
Different types of storage systems can be used to ensure released goods are stored separately from goods in quarantine. A distinction is made between spatial separation and separation controlled by a computer system. Computerised storage management systems and their functions must be validated.
(Christian Gausepohl, PhD, Jürgen Ortlepp)
16.B Storage areas
Sufficient space must be available and proper lighting in place to ensure that work processes can be carried out properly and mix-ups prevented.
The incoming goods and dispatch areas should be separate areas that are protected from the weather. Cleaning facilities should be available for incoming goods.
If sampling is carried out in the storage area, suitable measures must be taken to prevent contamination and cross-contamination.
Goods that are rejected, quarantined or returned from the market must be stored in separate quarantine storage.
Separate storage under safe and protected conditions is required for highly active or other hazardous substances as well as for printed packaging materials.
(Christian Gausepohl, PhD, Jürgen Ortlepp)
16.C Storage conditions
Materials and products should be stored in a dry, clean place under appropriate conditions of temperature and humidity.
Which conditions of temperature and humidity are suitable for storage is derived from the relevant stability testing results. Temperature and humidity must be controlled on a permanent basis. An alarm must trigger if a deviation from the target ranges occurs. All other processes and subsequent measures must be defined in advance.
Hygiene and cleanliness are important aspects of storage. This includes a cleaning plan, the avoidance of sources of contamination and open containers, as well as proper and careful handling of materials.
Pest control is necessary in addition to the general hygiene measures. UV lamps and species-specific traps for the different pests should be used. The type, number and positioning of traps should be defined by experts.
(Christian Gausepohl, PhD, Jürgen Ortlepp)
16.D Incoming goods
Several checks must be carried out on incoming goods to ensure that the delivered goods correspond to the order and meet the required standards of quality. The documentation included in the scope of delivery must be checked for completeness.
If damage or deviation is discovered, a damage report must be completed and Quality Control informed.
When containers are delivered, labels are usually attached manually. This procedure is GMP-critical and requires due care and attention.
The incoming goods documents must be stored as secondary information. The goods should only be moved in accordance with written SOPs.
In cases of deviation and complaints, it is necessary to trace and identify clearly each of the components of a finished product. This is achieved using unique material and batch numbers. The material and batch numbers can contain a large quantity of coded information.
(Christian Gausepohl, PhD, Jürgen Ortlepp)
GMP Regulations
Chapter C EU Directives and Guidelines
C.19 Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article5(3) of Regulation (EC) No726/2004 referral on nitrosamine impurities in human medicinal products
The update of 30 March 2023 amends Q&A 22 referring to the approach to control the presence of nitrosamines exceeding the AI (acceptable intake) during CAPA implementation. It is now indicated that no variation should be submitted to implement temporary above AI limits in specifications.
Chapter D USA: CFR and FDA Guidelines
D.1 Code of Federal Regulations
The Code of Federal Regulations is subject to an annual revision. As of 1 April 2023, we have reviewed the CFRs 4, 11, 210, 211, 600, 601, 606, 680, and 820. We identified one amendment to CFR 11 on electronic records and electronic signatures. All other CFRs mentioned have been re-dated to 1 April 2023 without any further changes.
D.1.3 21 CFR Part 11 Electronic Records; Electronic Signatures
§ 11.100 The general requirements were extended by paragraph (c), clarifying that:
(c) Persons using electronic signatures shall, prior to or at the time of such use, certify to the agency that the electronic signatures in their system, used on or after August 20, 1997, are intended to be the legally binding equivalent of traditional handwritten signatures.
(1) The certification shall be signed with a traditional handwritten signature and submitted in electronic or paper form. Information on where to submit the certification can be found on FDA‘s web page on Letters of Non-Repudiation Agreement.
(2) Persons using electronic signatures shall, upon agency request, provide additional certification or testimony that a specific electronic signature is the legally binding equivalent of the signer's handwritten signature.