Concept of Cleaning Validation in Pharmaceuticals

Cleaning validation is documented evidence that an approved cleaning procedure will reproducibly remove the previous product or cleaning agents used in the equipment below the scientifically set maximum allowable carryover level.

Cleaning Validation Lifecycle

Quality Risk Management approach
  • Cleaning Validation is essential to all stages of manufacture
  • Quality Risk Management approach followed
  • To identify high-risk areas where Cleaning Validation efforts should be focused
  • This is more evident in multiproduct facilities (greater risk of cross-contamination.

preliminary risk assessment to determine the variables which may influence the effectiveness of cleaning procedure:
  • Nature of the residue
  • Equipment design (difficult to clean
  • Grouping of products and equipment & validating worst case combinations
  • Solvent or detergent (if needed) type needed to remove residue
  • CIP vs COP
  • Level of Automation as opposed to manual cleaning process
  • Processing times & total number of cycles.

Key factors to be taken into account:
  • Maximum length of a campaign and the impact it may have on cleaning effectiveness
  • The influence of the time between manufacture & cleaning (DHT)
  • The influence of the time between cleaning and use (CHT)

If cleaning procedures not capable of cleaning down to an acceptable level consider the prospect of using:
  • Dedicated equipment or facilities
  • Single use technologies.

Types of Residues
Cleaning Validation should be based on:
  • Identification & evaluation of potential residues
  • Assigning appropriate acceptable residue limits.

Typical Residues
  • API (small molecule & macromolecule)
  • Excipients
  • Degradation Products
  • Cleaning Agents
  • Microbiological agents (Bioburden & Endotoxins)

Cleaning Methods considerations
Depending on available equipment:
  • Automated vs Manual process (Automation level)
  • Equipment design allows for cleaning in place
  • Disassembly required to clean out of place

The critical cleaning parameters typically include:
  • Detergent type & concentration selection
  • Temperature & Pressure of cleaning solution
  • cleaning action
  • Detergent contact & rinse times
  • Number of cleaning cycles.

Setting acceptable limits
Typically, limits are set to support:
  • Visual cleanliness (No visible residues on surfaces)
  • Microbiological cleanliness (Absence of Bioburden & Endotoxin)
  • Chemical cleanliness (Effective removal of APIs, Excipients, Detergents)

Historically a number of methodologies have been used:
  • 10 ppm criterion
  • LD50
  • 0.001 of dose method

Health Based Exposure Limits (HBELs)
Cleaning Validation limits must be scientifically justified based on toxicological evaluation

Health Based Exposure Limits (HBELs) through Permitted Daily Exposure (PDE):
  • Represents a substance specific dose unlikely to cause an adverse effect to individuals
  • If exposed to ≤ PDE dose (every day for a lifetime )

PDE determination involves
  • several adjustment factors to account for various uncertainties
  • Weight adjustment for the individual

Once HBEL is confirmed, they should be used as part of QRM to:
  • Determine what controls need to be in place
  • A ssess if existing control measures are adequate

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Maximum Allowable Carryover (MACO)
  • PDE values are used in the determination of MACO levels
  • The acceptable transferred amount of preceding product ( α ) that can be carried over to the next product ( β )

PDEα: Permitted Daily Exposure Limit Product α
MBSβ: Minimum batch size of the next Product β
MDDβ: Maximum Daily Dose of the next Product β

Sample Acceptance Limit (SAL): The individual swab or rinse sample acceptance limit
𝑠𝑎𝑚𝑝𝑙𝑒𝑑𝑎𝑟𝑒𝑎: The area sampled trough swab or rinse sampling
𝑅𝐹: Recovery factors that relate a single sample to total amount of residue
𝑐𝑢𝑚𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑠𝑢𝑟𝑓𝑎𝑐𝑒 𝑎𝑟𝑒𝑎: Product contact surface area of the equipment train.

Would approaches other than PDE be possible?
Other approaches could be accepted if adequately justified

Example 1 (Therapeutic macromolecules)
  • Degrade & denature when exposed to pH/heat extremes → pharmacologically inactive
  • HBELs based PDE limits of (active & intact) product may not be required

Example 2 (Legacy Products)
  • Other methods e.g. 10ppm may result in a lower MACO levels than PDE based ones.

Selection of an analytical method for the detection of residues
  • Pharmacopeial or individually developed test method
  • Specific or non-specific methodology
  • Capable of detecting

Specific methods include
  • Titration

Non-specific methods include:
  • Total organic carbon (TOC)
  • pH levels
  • Conductivity

Sampling Methods
Through (post cleaning) sampling  → Estimate of the amount of residue on equipment

Equipment can be sampled through:
  • Rinse sampling
  • Swabbing

Sampling locations & sampling method must be selected, based on:
  • Equipment (type & design)
  • Residue type
  • Residue limit

  • Used to collect residues directly from surfaces
  • Preferred technique for easily accessible locations

Flushing rinsing solution over surfaces 
Residues measured in the rinse solvent

Preferred method for:
  • Large surfaces
  • Runs of piping
  • Locations inaccessible to swabbing.

  • Combination of Swab, Rinse sampling & Visual Inspection selected
  • Visual Inspection important part of the Cleaning Validation Verification
  • Supplementary to swab & rinse sampling
  • Performed under the appropriate lighting conditions
  • Borescopes & fiber optic probes used for hard to reach locations.

Recovery Studies
  • Materials of construction should be taken into account
  • Spiking coupons with known amounts of contaminants
  • Recovery factors established relating to the result of a single sample to total residue of the sampled area
  • Similar to swab rinse recovery studies, the level below which a residue is not visible should be determined.

Cleaning Verifications
Cleaning Verification refers to the practice of gathering of evidence through measurement with chemical analysis after each batch/campaign to show that the residues of the previous product or cleaning agents have been reduced below the scientifically set MACO level.

This meant to provide assurance that equipment is clean and available for further use in the following cases
  • Cleaning Validation campaign ongoing
  • To support re validations
  • In the event of cleaning failures

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