INTRODUCTION^1,2:

Cleaning validation is documented evidence with a high degree of assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits. The objectives of good manufacturing practices (GMP) include the prevention of possible contamination and cross-contamination of pharmaceutical starting materials and products. Pharmaceutical products can be contaminated by a variety of substances such as contaminants associated with microbes, previous products (both active pharmaceutical ingredients (API) and excipient residues), residues of cleaning agents, airborne materials, such as dust and particulate matter, lubricants. Adequate cleaning procedures play an important role in preventing contamination and cross-contamination.

Validation of cleaning methods provides documented evidence that an approved cleaning procedure will provide clean equipment, suitable for its intended use.

Definition^3,4:

To attain documented evidence, which provides a high degree of assurance that the Cleaning procedure can effectively remove residues of a product and a cleaning agent from the manufacturing equipment, to a level that does not raise patient safety concerns. Cleaning validation is a documented process that proves the effectiveness and consistency in cleaning pharmaceutical production equipment. Validations of equipment cleaning procedures are mainly used in pharmaceutical industries to prevent cross contamination and adulteration of drug products hence is critically important.

Advantage of cleaning validation⁵:

· Assurance of quality and safety.

· Government regulations.

· Product integrity,

· Microbial integrity,

· Cross contamination integrity,

· Batch integrity,

· Equipment reuse,

· Reduction of quality costs.

· Making good business sense.

· Less down time, fewer batch failures and may operate/clean more efficiently.

1. U.S. Food and Drug Administration (USFDA)⁶:

FDA revised its guidance on Equipment Cleaning under Section 211.67 in 21CFR on April 1, 1993. FDA requires that: Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. FDA has mentioned clearly in the Questions and Answers on Current Good Manufacturing Practices–Equipment that the Contamination that is reasonably avoidable and removable is never considered acceptable. Hence, Cleaning Procedures must not be designed sub-optimally to remove a calculated "acceptable" level of residue but rather based on scientific understanding of the substance and its interaction with other resources within the manufacturing facility. Similarly, analytical methods should not be designed solely on the basis of the acceptable residue that needs to be achieved. FDA has come to terms with using TOC as an acceptable method for monitoring residues routinely and for cleaning validation given that the contaminating material (s) is organic and contains carbon that can be oxidized under TOC test conditions. For cleaning validation, rinse samples alone would not be acceptable; firms should also measure the residue or contaminant on the equipment surface using a direct method such as swab (if feasible). Many firms have not implemented this yet. FDA is very clear that a Continuous Verification Program needs to be in place for routing residue monitoring after Cleaning Validation. The frequency of this program will need to be determined based on risk.

2. European Medicines Agency (EMA)⁷:

EMA has certainly been a frontrunner when it comes to establishing risk-based cleaning validation guidelines for prevention of cross-contamination in shared production facilities. In guidance, effective June 01, 2015, EMA made it mandatory to establish Health-Based Exposure Limits for all the drug products. The guideline was soon followed up by a Q and A on the implementation of the above guideline. The full Q and A is a must-read however a few key items are listed here. HBELs should be established for all medicinal products. The toxicological or pharmacological data, on which the HBEL calculation relies, requires periodical reassessment throughout a product’s lifecycle. Establishing HBELs is just the start. These values work as a basis to determine the additional controls that may need to be put in place via a Quality Risk Management process. While HBELs work as Residue Acceptance Limits, the manufacturers still need to set alert limits based on the historically used Cleaning Limits (such as based on dosage) while ensuring that the Cleaning Processes are capable. This means that if your historical dosage based limit is the worst but that results in CpK < 1.33, the alert limit needs to be set based on the statistical evaluation and not based on the dosage limit. Analytical Testing at Product Changeover is now required unless the risk is quantified low. Risk quantification is done based on the Severity (Toxicity Scale), Probability (Cleaning Process Capability) and detectability (Visual Threshold).

3. World Health Organization (WHO)⁸:

WHO Cleaning Validation Guideline is very similar to that of FDA. WHO good manufacturing practices for active pharmaceutical ingredients lays out the basic requirements throughout the document but specifically under Sections 5.2 and 12.7. Here are a few things to keep in mind. WHO clearly accepts the worst product approach to select representative APIs to validate cleaning procedures. It further adds that the selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability. It is very unclear though how to incorporate stability into residue limits. WHO recommends continuous monitoring using methods such as analytical testing and visual examination. It gives a hint to the risk-based methodology but lack of any further details leaves a lot to be desired. In May 2020, WHO released a working draft for comments Points to consider on the different approaches including HBEL to establish carryover limits in cleaning validation for identification of contamination risks when manufacturing in shared facilities. This guidance is certainly inspired by the HBEL revolution that has picked up momentum across all major regulators. It also includes an indicative risk scale to measure hazard based on PDE values which is flawed as it shows risk as a discrete quantity and not as a continuous scale. But I am glad to mention that this has been removed in the Aug 2020 draft.

4. Pharmaceutical Inspection Co-operation Scheme (PIC/S)⁹:

PIC/S followed EMA quickly and released its own version of the new Cleaning Validation Guideline to the prevention of cross-contamination PI 046-1 Guideline on setting HBELs in shared facilities to be effective from July 01, 2018. This was a monumental step in moving towards a risk-based cleaning validation program since PIC/S has about 50 countries as its members. Does this mean that the regulators of over 50 countries will start expecting the cleaning program that is in-line with the EMA regulations? Only time will tell. Soon after the release of the above-mentioned PIC/S guideline, an AIDE-MEMOIRE was released which is a great resource for every pharma manufacturer as it details the things that the regulators will look for in very specific details. Not only it is an absolute must-read, not following it will lead to a lot of regulatory troubles. It’s referenced in the link below. During an inspection attention should be paid to the risk management of cross-contamination; however, the amount of time allocated will depend upon the hazard level of the molecules, the type and number of products handled, and the degree to which facilities are proven to be separated and dedicated. PIC/S came up with another AIDE-MEMOIRE called Cross Contamination in Shared Facilities. One can not recommend this document enough. Anyone looking to understand what all goes into building a holistic risk assessment plan to mitigate cross-contamination in shared facilities must read this document a few times. For those who may not be aware: PIC/S, which became operational in November 1995, is meant as an instrument to improve co-operation in the field of Good Manufacturing Practices between regulatory authorities and the pharmaceutical industry.

5. Therapeutic Goods Administration (TGA)¹⁰:

TGA pretty much adopted the PIC/S Cleaning Validation Guideline to Good Manufacturing Practices (PE009-13). This gives us the first sign that the remaining countries may soon come on board to the new ship that is the Risk and science-based Cleaning Validation SOP. The TGA is adopting version PE009-13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products (PIC/S Guide to GMP), excluding Annexes 4, 5 and 14, as the manufacturing principles for: Medicines and active pharmaceutical ingredients and Biologicals that comprise or contain live animal cells, tissues or organs.

6. Health Canada¹¹:

Health Canada, in its Cleaning Validation Guidelines (Guide-0028), has listed down quite a few unique requirements that are actually well known in the industry but surprisingly not mentioned in many other guidelines. We also slightly disagree with Principle 3.5 which specifies the worst-case risk as acceptable along with the actual risk. We feel that the guidelines should not promote the behavior of defaulting to the lazy approach of taking the worst-case risk rather than putting efforts to identify the actual risk.

7. Parenteral Drug Association (PDA)¹²:

PDA has published two separate documents related to Cleaning Validation. PDA Technical Report 29 for Actives and PDA Technical Report 49 for Biotechnology products. It has been 14 years since PDA published the original Technical Report No. 29, and cleaning validation continues to play an important role in reducing the possibility of product contamination from pharmaceutical manufacturing equipment. Cleaning validation demonstrates that the cleaning process adequately and consistently removes product residues, process residues and environmental contaminants from the manufacturing equipment/system, so that this equipment/system can be safely used for the manufacture of specified subsequent products (which may be the same or a different product). The 2012 revision of Technical Report 29 builds on the 1998 report and utilizes principles and specific wording from the 2010 PDA Technical Report No. 49, Points to Consider for Biotechnology Cleaning Validation. It presents updated information that is aligned with lifecycle approaches to validation and the International Conference on Harmonization (ICH) guidelines Q8 (R2) - Pharmaceutical Development, Q9 - Quality Risk Management and Q10 - Pharmaceutical Quality System. Also, this report aims to assist readers who want to create or benchmark a cleaning validation program for their equipment and facilities. PDA Cleaning Validation Technical Reports are the most comprehensive guides when it comes to going into the depths of the Cleaning Validations and establishing a Cleaning Validation SOP for your firm.

8. International Society for Pharmaceutical Engineering (ISPE)¹³:

ISPE also revised its Baseline Guide on Risk-MaPP (Risk-Based Manufacture of Pharmaceutical Products) and published in 2nd edition in 2020. The revisions are mostly in line with the 2015 EMA guideline on setting HBELs. This guideline has done a wonderful job in describing the high-level principles as well as practical implementation details for establishing a Cleaning Validation SOP that is based on science and risk. This ISPE Guide: Cleaning Validation Lifecycle - Applications, Methods, and Controls provides a hands-on approach to support the life science industry in the development and establishment of compliant cleaning programs that meet or exceed regulatory expectations. Topics covered include: Application of risk management, Adoption of a lifecycle approach for cleaning validation, Cleaning methodologies, Creation of cleaning validation acceptance criteria, Determination of visual inspection limits, Calculation and justification of residue limits, Validation of testing and sampling methods, Equipment issues and challenges and Change Management.

9. Active Pharmaceutical Ingredients Committee (APIC)¹⁴:

APIC Cleaning Validation Guideline is used by many organizations especially the ones that produce only raw API materials. APIC also revised its 2014 Guideline on aspects of Cleaning Validation in Active Pharmaceutical Ingredient plants in the year 2016 to incorporate the EMA guidance on using HBELs. The main changes were introduced in Chapter 4, Acceptance Criteria. Even though a popular and widely adopted guideline, and appreciated by many for the details that it provides related the uniqueness in managing small molecules, APIC is criticized frequently for its confusing terminology and inconsistencies throughout the document. Here is an example of a blatant mistake that was present in APIC 2014 and carried over to APIC 2016. In 2016, The APIC guidance was upaded to bring it in line with the EMA Guidance on setting the HBEL (health-based exposure limits). The key changes were introduced in the Chapter 4, Acceptance Criteria. In 2021, a further updated guidance has been published which address several comments received from the industry as well as align it better with the EMA Q and A on use of Health Based Exposure Limits (HBELs). We would recommend reading it if you looking to deep dive into the specifics of handling cleaning validation at an API manufacturing plant.

10. American Society for Testing and Materials (ASTM)¹⁵:

ASTM E3106 - 18e1 (Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation) is the latest document that has come out related to the Cleaning Validation Standards. A unique thing about these standards is that it incorporates many of the science-based, risk-based, and statistical concepts and principles introduced in the FDA’s guidance for Industry Process Validation. This guide supports and is consistent with, elements from ICH Q8, ICH Q9, ICH Q10, and ICH Q11. This standard is gradually becoming popular and, in our opinion, is really what the industry needs: science-based, risk-based and statistics-based approach to establishing a Cleaning Validation SOP. We also did receive an indication during a webinar conducted by Dr. Andrew Walsh that the following standard guides are underway: Standard Practice guide for the Qualification of Visual Inspection of Pharmaceutical Manufacturing Equipment and Medical Devices for Residues and Standard Practice guide for the Calculation of Cleaning Validation Limits. Our belief (and hope) is that the above upcoming guides will become a must-have practical reference for any Cleaning Validation teams across the globe.

CONCLUSION:

There is practically impossible to prove that production equipment is “clean” at the level of 100%. However, it is possible to prove that the traces of active product remaining spread through the equipment parts are within an acceptable limit and that we are capable of detecting and quantifying these trace levels. A cleaning validation program should contain the assessment of equipment and products, assessment of the impact of a process on routine process, determination of an appropriate cleaning agent and method, determination of acceptance criteria for the residues, determination of a degree of evaluation required to validate the procedure, this article contain a defined cleaning validation program.

REFERENCES:

1. FDA expects firms to have written standard operating procedures (SOP) detailing the cleaning process used for various pieces of equipment.

2. If firms have a specific cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, FDA expects the written procedures to address these different scenarios.

3. Parenteral drug association, Points to consider for cleaning validation, technical report no. 29, 1998.

4. Galatowitsch S; The importance of cleaning validation. Clean rooms; 2000

5. Babita Lodhi, Poonam Padamwar, Arif Patel; Cleaning validation for the pharmaceuticals, biopharmaceuticals, cosmetic and neutraceuticals industries, Journal of Innovations in Pharmaceuticals and Biological Sciences; 2014; 1(1); 27 – 38.

6. FDA, guide to inspections of validation of cleaning process division of investigations, office of regional operations and office regulatory affairs, 1993.

7. European Medicine Agency. Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities. London, UK: EMA; November 2014.

8. Kumar S. A review on concept of cleaning validation in pharmaceutical Industry. International Research Journal of Pharmaceutical Sciences. 2012; 3(7): 17-19.

9. Jenkins M; Cleaning validation; an overall perspective; Pharma tech, 1994; 18(4); 60-73.

10. Hyde JM; Cleaning validation strategies, ISPE CIP/SIP seminar, Atlanta-Georgia, 1994

11. Leblanc DA; Rinse sampling for cleaning validation studies; Pharma tech. 1998.

12. PDA Technical Report No. 29, Revised 2012 (TR 29) Points to Consider for Cleaning Validation (single user digital version) of Publication: Dec 2012.

13. ISPE: Volume 7 – Risk-Based Manufacture of Pharmaceutical Products (Second Edition). Published: August 2020 Pages: 236.

14. Active pharmaceutical ingredients committee (apic) guidance on aspects of cleaning validation in active pharmaceutical ingredient plants revision September 2016

15. ASTM International. "What is ASTM International?" The History of ASTM International. Retrieved 12 May 2021.

Received on 14.09.2021 Modified on 07.12.2021

Asian J. Pharm. Res. 2022; 12(2):167-170.

DOI: 10.52711/2231-5691.2022.00026