Control strategies in the manufacturing of sterile pharmaceutical products

The Pharmaceutical and Healthcare Sciences Society (PHSS) has prepared a whitepaper on control strategies for sterile pharmaceutical/drug product manufacture and this article uses extracts to highlight the increasing requirements for control strategies in good manufacturing practice (GMP) applications.

Control strategies are increasingly required to set out clear objectives in the manufacture of new complex sterile pharmaceutical drug products, biopharmaceuticals and substances and it is therefore important to define the approach that is taken to control certain factors, including manufacturing facilities/processes, product efficacy, product quality, regulatory compliance and importantly patient safety. However, it is all too easy to get caught up in the complex area of risk assessments and detail before setting a clear path and approach to manufacturing that provides the framework around which risk control measures are set.

There are many interactions to consider in pharmaceutical product manufacturing, including ‘open and closed’ processing systems, use of fixed- or single-use disposable systems, interfacing of automated processes and manual operations together with contamination and cross contamination control requirements. A control strategy pinpoints the approach that should be taken in the control of all interactions. Furthermore, the increasingly complex nature of pharmaceutical and therapeutic products, which may include biological delivery mechanisms such as viral vectors, make the task of defining a control strategy even more important as interactions between critical quality attributes (CQAs), processes, manufacturing environments and patients make the process of assuring compliance to the three pillars of ‘quality, efficacy and patient safety’ more challenging.

Considering the important requirement of contamination control for sterile medicines, a control strategy in this area should fall under the auspices of a Pharmaceutical Quality System (PQS) together with initiatives of Quality by Design (QbD) and Quality Risk Management (QRM). Other characteristics of the control strategy are that a change control process is implemented to account for all changes that result from increasing knowledge or process improvements; that the strategy is dynamic, iterative, holistic and proactive throughout the product life cycle and that it is based on targeted/ risk-based measures of contamination avoidance. In addition, the control strategy would use key performance indicators (KPIs) to assess the status of contamination control, and contain a defined strategy for deviation management, such as investigations and corrective and preventive action (CAPA).

Overall, the strategy should consider all aspects that contribute towards product quality, efficacy and patient safety. Among other things, scientists need to consider product type and dosage form, regulatory requirements, CQAs, manufacturing processes and facilities in manufacturing, including utilities, personnel/ interactions, practice, waste management and any energy-saving management related to control conditions of cleanrooms.

The control strategy should be supported by risk assessments that assist key decisions on how the product’s manufacturing objectives are met. The control steps can be considered as sequential; firstly by design (facilities and process), secondly by process control and thirdly by procedural control of operations within a well-designed monitoring system. In addition, the control strategy should be maintained as a ‘live’ document that can adapt to increasing knowledge of products, process and risk. Holistic considerations and a proactive response to risk escalation should be inherent.

Following the process of establishing control of a manufacturing process and related controlled environments, a system of change control will apply. That is, any change from the formal state of control should be subject to risk/ impact assessment considering risks to quality, efficacy and patient safety.  

The control strategy should be referenced in a validation master plan (refer to EU GMP Chapter 5 and Annex 15). It should be noted that the main principles of the control strategy may apply to the manufacture of other non-sterile dose forms where risks to patients need controlling or managing.

Principle components of a control strategy

The control strategy should be considered in three component parts all of which are inextricably linked:

• ‘Manufacturing control strategy’: based on product type, demand, process and risk.
• ‘Quality control strategy’: based on an understanding of risk with control of CQAs in a manufacturing process meeting regulatory requirements.
• ‘Contamination control strategy’ including cross contamination control that may include requirements for containment/ product segregation.

Manufacturing of sterile pharmaceutical products, substances and constituents requires a risk based approach, in design (Quality by Design; QbD principles) and in quality (under the auspices of a Pharmaceutical Quality System (PQS) including Quality Risk Management (QRM) following ICH Q10 integrated in EU GMP Part I Chapter 1).

Manufacturing control strategy

The ‘manufacturing control strategy’ should include considerations on the following areas together with a defined approach set out on how a specified level of control will be achieved/ implemented:

• Whether the product is to be manufactured by terminal sterilisation (preferred for risk management in patient safety) or by aseptic processing (justified for product type). For some product types that may be impacted by overkill terminal sterilisation processes it may be possible to justify suboptimal sterilisation cycles that deliver the required sterility assurance level (SAL) over aseptic processing.
• The product type, dose form, quantity required and the stage of supply; clinical batches or production batches following Marketing Authorization (MA).
• Whether the manufacturing process is by batch, campaign or continuous (with periodic shut down) and how ‘change-overs’ will be controlled.
• The specified process, equipment used and how process steps are to be integrated to form a defined process design/ flow.
• The target end points for manufacturing stages.
• The extent of automation required to meet manufacturing control requirements and how the operators will interact with the process.
• How the facility/ utilities and process equipment will combine to meet manufacturing control targets.
• The principle risks in product manufacturing that should be subjected to risk assessment.
• The country-specific regulatory requirements that apply to the given product/ process.

Quality control strategy

The ‘quality control strategy’ should be set around an understanding of the product, process and CQAs in manufacturing. The control strategy should not be used to try to mitigate or support bad design or practice.

Risks and any impact from deviating CQAs vary with the type of product and processing operations/ technologies employed. If the product requires aseptic manufacturing, but is not a high risk to process operators, different combinations of product protection, operator protection and cross contamination control are required.

The quality control strategy should take a holistic view of the life cycle of product manufacture, with control measures at every stage to meet specified objectives, requirements and end points.

It should also be recognised that there is a need for a methodical and systematic approach, using risk management based on products and processes. However, the document should be kept ‘live’. Due consideration should also be given to reassessing the initial design strategy if there is significant reliance on quality control as a form of risk management or mitigation. Product, process and risk knowledge may develop iteratively through process development and a proactive response will be required as knowledge accumulates during manufacturing implementation. The focus should always be on product quality, efficacy and patient safety.

It is essential within a Pharmaceutical Quality System (PQS) to control all changes via a change control process, through all stages of product manufacture. In addition, a strategy on how changes are managed should be included in the quality control strategy.

Contamination control strategy

Sterile pharmaceutical drug products and substances/ constituents manufactured to GMP standards need assurance of quality, sterility or bio burden control (depending on the manufacturing stage) to ensure patient safety. Such assurance that CQAs and patient safety are not compromised by contamination can only be provided with thorough product, process and risk knowledge together with risk-based control aligned with ICHQ9 principles. Control should be implemented through Quality by Design (QbD principles) and risk control measures defined by risk assessments. It is universally accepted that it is not possible to inspect or justify GMP/ cGMP compliance with monitoring data or media fill results alone, as such an approach offers little assurance of robust processes and assured quality in GMP.

A ‘contamination control strategy’ should include a strategy for environmental control of product manufacturing environments for assurance that product sterility is not compromised and patient safety is not put at risk by loss of microbial control or deviations/ excursions within the controlled environments.

Strategies in contamination control will vary depending on whether the product is aseptically processed/ manufactured, terminally sterilised, is subjected to sub-optimal heat treatment, or if a non-sterile ingredient or constituent that may require bio-burden control is used.

Relating to the important risks to patients from direct contamination and cross contamination in sterile product manufacturing, it is considered a prerequisite that a control strategy must set out the approach to control and manage such contamination risks so the approach is clear to manufacturers, auditors and GMP inspectors alike. The control strategy should take a holistic view across all elements that potentially impact contamination control including design (process and facility), process validation and manufacturing practice, in accordance with current approaches for Process Validation (PV FDA 2011, EMA draft 2012, EU GMP Annex 15 Glossary, EU GMP Annex 2 point 50).

There is a risk of cross contamination from chemical adulteration or residues between processes, product-to-product cross contamination, biological entities cross contamination and that which occurs between patients via cells or genes where manufacturing of therapeutic products is concerned.

Microbial control strategy for environmental control

The ‘microbial contamination control strategy’ should cover all aspects of establishing microbiological control in controlled and classified areas/ zones, ensuring defined regulatory limits and levels are met, with trending of data and appropriate routine analysis to verify a formal state of control. Any deviations from this state of control in key locations require investigation and correction to prevent reoccurrence. Using trend analysis data may also facilitate a proactive response to prevent a bio-contamination event, for example intervening to stop the increase of micro flora that may be developing to unacceptable numbers of counts.

It is also recommended that as part of the control strategy, key performance indicators (KPIs) are developed using a holistic review of environmental monitoring data to determine the points of contamination risk, while ensuring the KPIs do not normalise the data to such an extent that trends are not visible.

Adverse environmental monitoring trends at zone-to-zone interfaces, which may include increasing colony forming unit (CFU) counts or a change in micro-flora profile (based on qualitative and quantitative data), may provide warnings early on in the manufacturing stages that the critical manufacturing environments, processes and sterile products are at an increased risk of contamination. With an early indication of increasing risks, appropriate proactive responses can be taken to avoid contamination.

Complex root cause investigations are often used where microbiological contamination outside regulatory limits occurs. During such investigations, it can be difficult to ascertain the source or root cause of contamination, and this leads to challenges in terms of the specific effective corrective and preventative measures required. In addition, it may be difficult to assess the extent to which sterile product or batches may have been impacted by a contamination event or adverse shift in trend of microbiological control levels. Therefore, it is better to manage contamination of critical areas and/or sterile products by taking preventative measures and having a proactive early-warning system in place, than to simply react to deviation events.

Using holistic environmental monitoring data – such as zone-to-zone comparisons of pressure differentials and total particulate counts – allows for early identification that the control state is changing and may be leading to microbiological levels that are exceeding limits in critical EU Grade A/ ISO 5 manufacturing environments. Strategies of how such holistic data is collected, analysed and responded to needs to be defined in the control strategy, to enable the scientist to intervene before products are put at risk of contamination.

Summary statement

The need to have control strategies in place for sterile medicinal drug products is becoming increasingly obvious. Currently, control strategies are set as a requirement in EU GMP annex 2 for biological products, and it follows would that it would also be relevant as a requirement in GMP Annex 1 at the next revision. The PHSS White paper on control strategy for manufacture of sterile pharmaceutical/ drug products provides more detail on the composition of a control strategy and is likely to attract further discussion as requirements develop.

Acknowledgements

The author wishes to acknowledge the PHSS White paper, prepared by the PHSS Bio-contamination special interest group, from which extracts of this article were taken. The information and guidance in the PHSS White paper on Control Strategy for manufacture of Sterile Pharmaceutical products is a consensus view of the PHSS special interest group and does not necessarily represent the views of individual’s affiliations or host companies, acknowledged in the PHSS Bio-contamination monograph 20.

Biography

As head of Aseptic processing technologies and GMP Compliance at F Ziel Germany, James Drinkwater is involved in contamination control barrier technology projects, isolators, RABS and material transfer chambers.

In addition to the role at F Ziel James has a voluntary role as Chairman of Pharmaceutical and Healthcare Sciences Society.