INTRODUCTION
This article not only applies to the HPAPI production, but also to pharmaceutical production with HPAPIs. Therefore, the term “HPAPI manufacturing” and “HPAPI product” applies to both types of production.
It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes (i.e., carry-over risk) that take place at this stage (1).
Though most of the topics discussed apply to all pharmaceutical and biopharma industry; in HPAPI manufacturing, any CV program failure (strategy or approach) or mismanaged situation (equipment selection, protocol deviations, …) could easily result in product loss, product recall, patient injury or death; instead of just a regulatory finding or loss of production time.
The main processes or activities in the three stages of validation (development, CV, and maintenance of the CV program) are evaluated. Stage 1 requires the most consideration, preparation, and planning. Accordingly, most of the article is devoted to this stage, and discussion will focus on what should be considered in addition to what is common industry practice. Stage 2 discussion is brief because the emphasis is on accurate and detailed documentation and execution. Stage 3 discussion covers periodic monitoring, periodic review, and maintaining the CV.
When “should” is used without a reference, it is the author’s personal opinion from years of CV experience.
This article is not meant to discourage cleaning equipment instead of utilizing single use. It is simply to provide guidance and perspective on validating the cleaning on HPAPI manufacturing equipment.
STAGE 1
Risk assessments
Quality risk management (QRM) and risk assessment should follow (2) and (3) principles.
Drafting and approving risk assessments (RA) is one of the most crucial activities in CV. Therefore, it should be a cross functional effort involving individuals responsible for cleaning validation, engineering (of automated cleaning), operations, and quality, at a minimum.
RAs are the foundation of any CV program. RAs are often used to determine CV effort, uncover risks, and identify any required mitigation. That is not always the case in industry. Common practice is to utilize RAs to reduce the CV footprint and effort. RAs may reduce the CV effort for HPAPI manufacturers, but the focus should be on patient safety and mitigation.
The initial CV program RA examines each CV step/activity and determine the scope, effort, and any required remediation. The PDE/ADE value should be the main risk driver (1) (4) (5). The lower the value, the higher the risk.
Besides the initial CV program RA, a living RA of the cleaning process should be established. This type of RA reviews each cleaning process step to document current risk and any mitigation activities. For example, what is the risk (i.e., severity, probability, and detectability) if a caustic cleaning step does not execute properly (due to detergent concentration, flow, or temperature) or if the final rinse conductivity reading is incorrect (due to faulty probe). Having this type of RA in place can be very useful in a cleaning failure deviation. The living RA would be reviewed and updated periodically and due to a change to the cleaning process.
RAs require a great deal of effort, but they will illuminate issues and provide a good understanding of the cleaning process.
Lab scale trials
Studies to determine detergent selection and hardest to clean (HTC) soils should be performed by an experienced or well-trained individual. HTC studies are used to determine the worst-case (WC) soil for bracketing/grouping purposes. A misinformed or incorrect decision in choosing the wrong WC soil would not only be a regulatory finding nightmare; but can also lead to product recall or worse, serious patient injury or death. For example, often WC API or product is chosen only from solubility in water. Regulatory guidelines also discuss cleanability (6) (7). A substance can be less soluble in water than another substance but be easier to clean due to detergent chemistry interactions. Therefore, solubility or coupon studies with detergent should be performed. Additionally, for finished product manufacturing, the studies should include total product composition (i.e., excipients, tablet coatings).
It is important to note that the lab studies can only be executed in a laboratory that can handle HPAPIs.
It is also important to perform design of experiment (DoE) studies to determine the quality by design (QbD) space. This will not only provide starting cleaning cycle development parameters, but also provide cleanability knowledge and confidence.
Equipment selection
Equipment selection is not only important for manufacturing the product but also cleaning. Because the high risk of HPAPI cross contamination, cleaning of equipment should be given the appropriate consideration. Performing the lab scale studies prior to selecting equipment will help the equipment vendor determine the number and type of spray device (cascading or impinging) required. The discussion below is not an exhaustive list, but a high-level guide to some possible equipment concerns.
Equipment and parts (e.g., isolators, vessels, pumps, valves, probes/housings, agitators, connections, homogenizers, heat exchangers, and manway gaskets) need to be vetted carefully for cleanability.
Piping design is crucial. Deadlegs, pipe circuit branching (e.g., 1 in. pipe into to 3 in. pipe), pipe orientation (i.e., vertical drops), and numerous elbows can increase risk of residual active material. For example, a significant vertical drop may not only pull air into the line but would also dramatically decrease the cleanability (incomplete cleaning solution contact).
Consider how the CIP system operates and shares cleaning. If CIP skids are shared among different products/in-process material and not all CIP steps are a once-through (i.e., recirculated cleaning step), then the CIP skid system should be included in the CV scope.
It is important to make sure CIP supply and return pumps are not under or oversized. Miscalculating the supply and return pump operating relationship will create vessel draining control issues. When planning the supply pump size, it is also important not to undersize it in case higher CIP supply flow/pressure is needed to have successful cleaning. Because the high risk of not getting piping properly cleaned, flow rates for piping should be 1.5 m/s, at minimum (8).
Cleaning design
Every automated cleaning process should operate within a range of critical process parameters (CPP) such as temperature, detergent concentration, and cleaning action (i.e., flow or pressure). Best practice is to determine if there is need for performing WC trials at the low end of the CIP recipe range (i.e., low alarm values). Not only does the DoE provide the starting point for cycle development parameters but can also provide crucial information on the required level of control during cleaning. For example, flatter detergent concentration or temperature curves (soil removal vs. parameter value) may indicate that the cleaning parameter control is not crucial. In other words, if minor changes in concentration or temperature do not affect the removal of soil, then it may be possible to justify not performing WC trials for low alarm setpoints.
To support flow or pressure control, the lab scale DoE could include cleaning action.
Because of the high risk in HPAPI manufacturing, unless there is sufficient confidence, best practice is to perform additional trial(s) at lower temperature, concentration, and/or cleaning action during the cycle development phase or in CV. Determining which parameter or how many additional WC trials needed would depend on the confidence of the lab scale results and risk to patient safety.
Equipment commissioning and qualification
Equipment commissioning and qualification is always important because it affects the cleaning system capability and reproducibility. One of the greatest concerns from a cleaning perspective is spray coverage. Spray coverage testing should be faultless. Firms often fail in this commissioning step due to lack of site experience or project schedule demands. It is common to find failed coverage tests when investigating CV failures. If product contact surfaces are not wetted during the cleaning process, not only will the equipment not get cleaned but it may not be discovered because the contaminate is not collected in the CV rinse sample.
The pipe design should be vetted for bad design, overlooked automation steps, and deadlegs (8). It is not unusual to find long deadlegs or whole pipe sections being missed or mismanaged.
Cleaning validation master and validation plans
No additional considerations, but it is prudent to include all cross functional groups or departments in the planning and approval of the validation plans. What makes sense to Validation may not make sense to the site or to other departments. Early agreement of this will prevent rework and delays.
Acceptance criteria
In the pharmaceutical industry, permitted daily exposure (PDE) and acceptable daily exposure (ADE) are used to calculate health-based exposure limits (HBEL) (i.e., safety limit (SL)) (1) (9-11). The limit provides a safe dose that can be consumed every day for a lifetime with no adverse effect. (4, 5) State the SL should not be used as the cleaning limit. This is because safety limits are usually relatively high for most actives and legacy cleaning effort should not be reduced. For HPAPIs, this may not be the case. In some cases where the HBEL is very low, it may be appropriate to have the safety limit equal the cleaning limit.
Guidelines (9) and (10) are for pharmaceutical production, and (1) guidance applies to API production.
Per (1), there may be justification for including a purging factor (PF) to API production carryover calculations.
Because (4) (5) state PDE/ADE values should be reviewed periodically as toxicity could change over time as new data is compiled and the high risk in HPAPI manufacturing, there should be a site process for periodically scheduling review of PDEs and ADEs.
The identified acceptable limit might also lead to the decision that dedicated equipment should be used (12) for products with a high safety risk (e.g., biologicals or products of high potency which may be difficult to detect below an acceptable limit).
Recovery studies (swab and rinse)
Most guidelines accept low swab and rinse recoveries (50 to 70%). Because of the high toxicity of HPAPI, additional considerations should be taken. An evaluation should be performed to determine if the unrecovered percent of active is due to swabbing or rinsing technique, absorption by the Material of Construction (MOC) (i.e., elastomers), or incomplete desorption from the swab. If swabbing or rinsing technique and incomplete desorption from the swab cannot be ruled out, then (depending on risk) it may make sense to evaluate the risk to the patient because active may desorb during the manufacturing process. Below are three possible justifications:
- The surface area of the MOC having absorption issues is negligible (e.g., 2 %) in relation to total product contact surface area
- Lab studies demonstrate that production solutions/solvent under similar parameters (temperature, pressure, and time) do not desorb the active from the MOC
- The amount desorbed is a safe amount
The third bullet point could be demonstrated by artificially lowering the safety limit by subtracting out the absorb active.
For example:
Then simply subtract the WC amount absorbed from the safety maximum allowable carryover (SMAC) and calculate the safety limit from the SMAC.
Analytical method selection
Because of the high risk of the HPAPI cross contamination, the HPAPI should be analyzed using a specific analytical method. In most cases, non-specific methods would not have the needed sensitivity.
For detergent residues, it is important to identify if a specific analytical method is needed (e.g., injectable product).
Degradation studies
Forced degradation studies (i.e., stress testing) performed as part of the product assessment is usually leveraged to determine degradation in the cleaning solution. Complete justification of this would include determining if the pH and type of solution used in the product degradation study is representative of the solution used during cleaning of the equipment.
If a significant amount is degraded, a full evaluation should be performed to determine if the degradant should be included in the CV process.
SOP creation and approval
No additional considerations.
Product bracketing/grouping
Per EMA guidelines, solubility, cleanability, and concentration should be considered when bracketing products and determining a WC product; therefore, cleanability studies should include solutions used in the cleaning process (i.e., detergent).
Additionally, when bracketing products; bracketing should be conservative, and a sufficient number of runs should be performed to confirm all products can be cleaned effectively.
Bracketing non-HPAPI and HPAPI is not a good practice.
Equipment grouping
When grouping equipment, besides equipment geometry, size, and internal components, the critical process parameters (CPP) should be considered even if the equipment is identical.
Sampling locations
It is industry common practice and regulatory expectation not to sample locations on the equipment that are not easily accessible. For HPAPI manufactures, this may not be an acceptable practice. All WC locations (accessible or not easily accessible) should be sampled or have a robust RA justification in place.
For example, piping is sometimes not swab sampled because it may seem inaccessible. One way to manage this and other inaccessible areas is to sample the HTC location that is accessible. For example, piping often include sensors (pressure or temperature). These sensors can be easily removed and sampled with the rationale that a sensor would be harder to clean than smooth piping.
Cycle development
Cycle development (CD) is one of the most crucial areas in stage 1 that needs to be closely monitored. The individuals responsible for cleaning validation, engineering (of automated cleaning), operations, and quality should be involved in the pre-CD, CD, and post-CD activities.
Listed below are some evaluations to be considered.
Pre-CD
Prior to starting CD, confirm the cleaning process is ready. Prerequisites consist of successful coverage tests, no CIP alarms during automated cleaning, (preferably) qualified system (i.e., fit for intended use), lab scale studies, and cleaning design; but most importantly team agreement on the CD approach and strategy.
Do not soil equipment prior to CIP system functioning properly.
CD
During the CD, make the results and any changes visible to the CD team.
In some cases, an WC surrogate material could be used instead of the product once it is established that surrogate is more difficult to clean than the WC product. This practice could add additional cleaning trials if there are limited process trials available. At least one trial should be performed in CD with WC product.
Post-CD
Prior to releasing the cleaning of the equipment for CV, publish or communicate summary of final test results and any changes. Get team agreement on any changes and acceptance on moving forward with CV.
Part 1 Conclusions
PIC/S GMP guidance document (13) outlines that dedicated production areas should be considered when material of high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.
Therefore, if a decision is made to not dedicate equipment or demonstrate inactivation, the additional planning and effort discussed in this article should be considered.
Part 2
HPAPI Cleaning Validation Considerations Part 2 will examine stage 2 and stage 3 activities.
REFERENCES AND NOTES
- APIC Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants, Active Pharmaceutical ingredients Committee (APIC), February 2021.
- International Council for Harmonization (ICH), ICH Harmonized Tripartite Guideline, Quality Risk Management – Q9, Step 4, November 2005, www.ich.org.
- ASTM E3106-18e1 Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation, 2018, ASTM International, West Conshohocken, PA www.astm.org.
- EMA Questions and answers on implementation of risk-based prevention of cross-contamination in production and ‘Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, ‘European Medicines Agency (EMA), April 2018, www.ema.europa.eu/en/documents/other/questions-answeers-implementation-risk-based-prevention-cross-contamination-production-guideline_en.pdf.
- PIC/S Questions and Answers on Implementation of Risk-Based Prevention of Cross-Contamination in Production and ‘Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities’, PI 053-1, June 2020, Pharmaceutical Inspection Co-operation Scheme (PIC/S), www.picscheme.org.
- International Council for Harmonization (ICH), ICH Harmonized Tripartite Guideline, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients – Q7 Revision 1, 12.7 September 2016
- Eudralex Volume 4 – Guidelines for Good Manufacturing Practices for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation 10.10, March 2015, http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm.
- ASME BPE-2016 Bioprocessing Equipment, 2016, The American Society of Mechanical Engineers.
- PIC/S Guideline on Setting Health Bases Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities, PI 046-1, July 2018, Pharmaceutical Inspections Co-operation Scheme (PIC/S), www.picscheme.org.
- EMA Guideline on Setting Health Bases Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities, November 2014, European Medicines Agency (EMA), EMA/CHMP/SWP/169430/2012, www.ema.eu/docs/en_GB/document_library/Scientific_guideline/2014/11/WC500177735.pdf.
- Canada Health Products and Food Branch Inspectorate Guidance Document: Cleaning Validation Guidelines GUIDE-0028, June 2021, https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/good-manufacturing-practices/validation/cleaning-validation-guidelines-guide-0028.html.
- PIC/S, PI 006-3; Recommendations on Validation Master Plan Installation and Operational Qualification Non-Sterile Process Validation Cleaning Validation; September 2007; https://picscheme.org/docview/3447
- PIC/S PE 009-14 (Part II); Guide to Good Manufacturing Practice for Medicinal Products Part II; 1 July 2018; www.picscheme.org.
